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Sample records for hematopoietic orbital tumors

  1. Anxiety, fatigue, and attentional bias toward threat in patients with hematopoietic tumors.

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    Kohei Koizumi

    Full Text Available Cancer patients with hematopoietic tumors exhibit particularly high rates of anxiety disorders and depression, and often develop negative affect. In addition, psychological problems experienced by cancer patients impair their quality of life. When cancer patients feel anxious, they tend to direct their attention toward stimuli associated with threat in the surrounding environment. If attentional bias occurs in patients with hematopoietic tumors, who are at particular risk of developing negative affect, resolution of the bias could be useful in alleviating their anxiety. The current study examined the association between attentional bias and negative affect in patients with hematopoietic tumors and tested the hypothesis that negative affect would be more severe in those who exhibited greater attentional bias. Twenty-seven patients with hematopoietic tumors participated in the study. Reaction time (RT was measured as the time between the presentation of the threatening and neutral images, and the subject's button press to indicate choice (neutral expressions. Eight combinations of "threatening" expressions with high emotional valence and "neutral" expressions with low emotional valence were presented. The images used to measure attentional bias were taken from the Japanese Female Facial Expression Database and had been rated as expressive of anger, sadness, or neutrality, with predetermined emotional valence. Psychological testing was performed with the Profile of Mood States (POMS. To examine the association between attentional bias and negative affect, we calculated Spearman's rank correlation coefficients for RTs and POMS. Subjects' mean RT was 882.9 (SD = 100.9 ms, and 19 of the 27 subjects exhibited slower RTs relative to healthy individuals. RT was significantly positively correlated with Tension-Anxiety (r = .679, p < .01 and Fatigue (r = .585, p < .01 subscale scores. The results of the study suggested that attentional bias toward

  2. Contrast enhancement and morphological findings of hematopoietic regions of bone marrow on MR imaging. Comparative study with spondylitis and vertebral tumors

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    Amano, Yasuo; Hayashi, Hiromitsu; Matsuura, Maki; Watari, Jun; Kumazaki, Tatsuo [Nippon Medical School, Tokyo (Japan)

    1995-06-01

    The enhanced MR findings of hematopoietic regions in aplastic anemia were compared with those of spondylitis, metastatic vertebral tumors and hematologic neoplasms. The enhanced MR images showed hematopoietic regions to homogeneously enhance and occupy the margin of vertebral bodies, while spondylitis and metastatic tumors appeared as round, inhomogeneously enhancing lesions. MR images of leukemia and myelodysplastic syndrome showed homogeneous enhancement at the margins of vertebrae that was difficult to differentiate from hematopoietic regions. Enhanced MR images were useful in detecting the hematopoietic areas in marrow and differentiating them from spondylitis and metastatic tumors, although further experience is needed to distinguish between tumorous hyperplastic regions and benign hematopoietic regions in marrow. (author).

  3. Risk Factors for Subsequent Central Nervous System Tumors in Pediatric Allogeneic Hematopoietic Cell Transplant

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    Gabriel, Melissa; Shaw, Bronwen E; Brazauskas, Ruta

    2017-01-01

    Survivors of hematopoietic cell transplantation (HCT) are at risk of subsequent solid tumors, including central nervous system (CNS) tumors. The risk of CNS tumors after HCT in pediatric HCT recipients is not known. We evaluated the incidence and risk factors for CNS tumors in pediatric recipients...

  4. Orbital Chondroma: A rare mesenchymal tumor of orbit

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    Ruchi S Kabra

    2015-01-01

    Full Text Available While relatively common in the skeletal system, cartilaginous tumors are rarely seen originating from the orbit. Here, we report a rare case of an orbital chondroma. A 27-year-old male patient presented with a painless hard mass in the superonasal quadrant (SNQ of left orbit since 3 months. On examination, best-corrected visual acuity of both eyes was 20/20, with normal anterior and posterior segment with full movements of eyeballs and normal intraocular pressure. Computerized tomography scan revealed well defined soft tissue density lesion in SNQ of left orbit. Patient was operated for anteromedial orbitotomy under general anesthesia. Mass was excised intact and sent for histopathological examination (HPE. HPE report showed lobular aggregates of benign cartilaginous cells with mild atypia suggesting of benign cartilaginous tumor - chondroma. Very few cases of orbital chondroma have been reported in literature so far.

  5. Computed tomography of the orbital tumors

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    Choi, Jai Korl; Lee, Hwang Bok; Kang, Eun Young; Seol, Hae Young; Suh, Won Hyuck; Ahn, Byeong Yeob

    1987-01-01

    The development of computed tomography (CT) provided a noninvasive safe technique for imaging the orbit in any plane exquisitely demonstrating its normal anatomy as well as its pathologic process. The orbit is an ideal structure to be examined by CT because of large difference of absorption values between the intraorbital fat, muscle, optic nerve and vessels. In this study, the authors reviewed CT findings of 66 pathologically proven orbital tumors and tumorous conditions among the total of 98 cases who had taken orbital CT scan because if exophthalmos, ocular pain, diplopia and other ophthalmologic symptoms suggesting orbital masses during the period of 3 years. For the analysis of characteristic CT findings of the orbital lesions, all lesions are divided into 4 groups according to the site of origin, i.e., tumors arising in the eyeball (group 1); from intraconal space (group 2); from extraconal space (group 3); and from extraorbital regions (group 4). The results are as follows; 1.Extra tumor detection and localization was possible in 63 cases. Thus the detection rate was 95% with CT scan. 2.Among 36 males and 30 females, their age ranged from 10 months to 72 years. 3.Intraocular tumors (group 1) were 10 cases. Retinoblastoma occurred wholly in the young children under 5 years and combined with calcification in 57%. Choroidal melanoma occurred wholly in adults. 4.Intraconal tumors (group 2) were 9 cases. Vascular tumors (7 cases) were the most frequent and well enhancing mass. 5.The tumors arising in the extraconal region (group 3) were pseudotumor (12 cases), lymphoma (3 cases), dermoid cyst (4 cases), metastasis (2 cases), adenoid cystic carcinoma (1 case) and teratoma (1 case). A case of lymphoma demonstrating retrobulbar ill defined mass with scleral l thickening could not be differentiated from the pseudotumor which showing similar finding. 6.The lesions arising from extraorbital region (group 4) were PNS cancer (9 cases), mucocele (3 cases), lid cancer (4

  6. Computed tomography of the orbital tumors

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    Choi, Jai Korl; Lee, Hwang Bok; Kang, Eun Young; Seol, Hae Young; Suh, Won Hyuck [College of Medicine, Korea University, Seoul (Korea, Republic of); Ahn, Byeong Yeob [Han Mi Hospital, Seoul (Korea, Republic of)

    1987-04-15

    The development of computed tomography (CT) provided a noninvasive safe technique for imaging the orbit in any plane exquisitely demonstrating its normal anatomy as well as its pathologic process. The orbit is an ideal structure to be examined by CT because of large difference of absorption values between the intraorbital fat, muscle, optic nerve and vessels. In this study, the authors reviewed CT findings of 66 pathologically proven orbital tumors and tumorous conditions among the total of 98 cases who had taken orbital CT scan because if exophthalmos, ocular pain, diplopia and other ophthalmologic symptoms suggesting orbital masses during the period of 3 years. For the analysis of characteristic CT findings of the orbital lesions, all lesions are divided into 4 groups according to the site of origin, i.e., tumors arising in the eyeball (group 1); from intraconal space (group 2); from extraconal space (group 3); and from extraorbital regions (group 4). The results are as follows; 1.Extra tumor detection and localization was possible in 63 cases. Thus the detection rate was 95% with CT scan. 2.Among 36 males and 30 females, their age ranged from 10 months to 72 years. 3.Intraocular tumors (group 1) were 10 cases. Retinoblastoma occurred wholly in the young children under 5 years and combined with calcification in 57%. Choroidal melanoma occurred wholly in adults. 4.Intraconal tumors (group 2) were 9 cases. Vascular tumors (7 cases) were the most frequent and well enhancing mass. 5.The tumors arising in the extraconal region (group 3) were pseudotumor (12 cases), lymphoma (3 cases), dermoid cyst (4 cases), metastasis (2 cases), adenoid cystic carcinoma (1 case) and teratoma (1 case). A case of lymphoma demonstrating retrobulbar ill defined mass with scleral l thickening could not be differentiated from the pseudotumor which showing similar finding. 6.The lesions arising from extraorbital region (group 4) were PNS cancer (9 cases), mucocele (3 cases), lid cancer (4

  7. HLA-mismatched hematopoietic stem cell tranplantation for pediatric solid tumors

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    Andrea Pession

    2011-06-01

    Full Text Available Even if the overall survival of children with cancer is significantly improved over these decades, the cure rate of high-risk pediatric solid tumors such as neuroblastoma, Ewing’s sarcoma family tumors or rhabdomiosarcoma remain challenging. Autologous hematopoietic stem cell transplantation (HSCT allows chemotherapy dose intensification beyond marrow tolerance and has become a fundamental tool in the multimodal therapeutical approach of these patients. Anyway this procedure does not allow to these children an eventfree survival approaching more than 50% at 5 years. New concepts of allogeneic HSCT and in particular HLA-mismatched HSCT for high risk solid tumors do not rely on escalation of chemo therapy intensity and tumor load reduction but rather on a graft-versus-tumor effect. We here report an experimental study design of HLA-mismatched HSCT for the treatment of pediatric solid tumors and the inherent preliminary results.

  8. Tumors of protective system of eye, eyeball and orbit

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    Vajnshtejn, E.S.; Brovkina, A.F.; Burdyanskaya, E.I.; Zarubej, G.D.

    1985-01-01

    Peculiarities of eyelid tissues, eyeball and orbit reaction on ionizing radiation are considered. Methods of radiotherapy in ophthalmology - X-ray therapy, gamma therapy, beta therapy - used for treatment of eyelid tumors, tumors of tear secretion tracts, epibulbar tumors, intraocular tumors, and orbit tumors, are described

  9. Multiple brown tumors of the orbital walls: case report Tumor marrom múltiplo das paredes orbitárias: relato de caso

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    Mário Luiz Ribeiro Monteiro

    2009-02-01

    Full Text Available We report the case of a 40-year-old woman with chronic renal failure and secondary hyperparathyroidism that presented with slowly progressive proptosis of the right eye and mass sensation in the temporal and frontal orbital margins. Computerized tomography scan revealed two separate hyperdense and well-circumscribed lesions in the right orbital walls. A biopsy followed by histopathologic study revealed a dense lesion, with fibrous proliferation associated with osseous metaplasia and osteoclastic activity in the tumor, compatible with the diagnosis of brown tumor. The patient was submitted to surgical removal of the parathyroid glands that resulted in marked improvement in her condition and regression of the orbital tumors. Although the occurrence of more than one separate bone lesion in the orbit usually suggests metastasis, our case shows that brown tumors should also be included in the differential diagnosis of such lesions, particularly in patients with hyperparathyroidism.Este trabalho relata o caso de uma paciente de 40 anos, com insuficiência renal crônica e hiperparatireoidismo secundário que se apresentou com proptose progressiva e tumoração nas regiões lateral da órbita e superior da órbita. Tomografia computadorizada revelou duas lesões ósseas separadas, bem delimitadas e hiperdensas nas paredes orbitárias. Uma biópsia seguida de estudo histopatológico revelou um tumor denso, com proliferação fibrosa associada a metaplasia óssea e atividade osteoclástica no tumor, características compatíveis com tumor marrom. A paciente foi submetida a remoção das glândulas paratiróides que resultou em melhora dramática do seu estado geral e regressão dos tumores orbitais. Embora a presença de mais de uma lesão óssea separada na órbita geralmente sugira o diagnóstico de lesões metastáticas, nosso caso evidencia que tumores marrons devem também ser incluídos no diagnóstico diferencial, particularmente em pacientes com

  10. A GIANT CONGENITAL ORBITAL TUMOR - AN UNUSUAL PRESENTATION OF RETINOBLASTOMA

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    ZWAAN, CM; DEWAAL, FC; KOOLE, FD; MENKO, FH; VANDERVALK, P; SLATER, RM; SCHEFFER, H; VANWAVEREN, G; MOLL, AC; SCHOUTENVANMEETEREN, AYN; TAN, KEWP

    1994-01-01

    We report a case of an unusual giant congential tumor presenting in a newborn infant as a large exophytic mass emerging from the left orbit. After enucleation orbital recurrence developed within 14 days. No anti-tumor treatment was given and the child died at the age of 4 weeks. The

  11. Orbital Tumors Excision without Bony Marginotomy under Local and General Anesthesia

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    Robert A. Goldberg

    2014-01-01

    Full Text Available To present our experience of removing middle to deep orbital tumors using a combination of minimally invasive soft tissue approaches, sometimes under local anesthesia. Methods. In this retrospective case series, 30 patients (13 males and 17 females underwent tumor removal through eyelid crease (17 eyes, conjunctival (nine eyes, lateral canthal (two eyes, and transcaruncular (two eyes approaches. All tumors were located in the posterior half of the orbit. Six cases were removed under monitored anesthesia care with local block, and 24 were under general anesthesia. Results. The median (range age and follow-up duration were 48.5 (31–87 years old and 24.5 (4–375 weeks, respectively. Visual acuity and ocular motility showed improvement or no significant change in all but one patient at the latest followup. Confirmed pathologies revealed cavernous hemangioma (15 cases, pleomorphic adenoma (5 cases, solitary fibrous tumor (4 cases, neurofibroma (2 cases, schwannoma (2 cases, and orbital varix (1 case. None of the patients experienced recurrence. Conclusions. Creating a bony marginotomy increases intraoperative exposure of the deep orbit but adds substantial time and morbidity. Benign orbital tumors can often be removed safely through small soft-tissue incisions, without bone removal and under local anesthesia.

  12. Clinical and Treatment Features of Orbital Neurogenic Tumors

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    Pınar Bingöl Kızıltunç

    2013-10-01

    Full Text Available Purpose: To evaluate the clinical and treatment features of orbital neurogenic tumors. Material and Method: The records of 35 patients with orbital neurogenic tumors who were diagnosed and treated at Ankara University Faculty of Medicine, Department of Ophthalmology, between 1998 and 2011 were evaluated retrospectively. Results: Orbitotomy via a cutaneous approach was performed in 21 (60% cases and orbitotomy via a transconjunctival approach was performed in 7 (20% cases. Three (8% cases had been operated at different centers. Four (12% cases were diagnosed clinically. Total excisional biopsy was performed in 11 (31.4% cases, subtotal excisional biopsy was performed in 7 (20%, and incisional biopsy was performed in 10 (28.6% cases. 14 (40% 35 cases were diagnosed as meningioma, 12 (34% as peripheral nerve sheath tumor, and 9 (26% cases were diagnosed as optic nerve glioma. Six (43% meningioma cases were optic nerve sheath meningioma, 5 (36% were sphenoid wing meningioma, 2 (14% were ectopic meningioma, and 1 (7% was perisellar meningioma. Six (50% of peripheral nerve sheath tumors were schwannoma, 2 (16% were solitary neurofibroma, 4 (34% were plexiform neurofibroma. External beam radiotherapy was performed in 15 (42.8% cases, cyberknife radiosurgery in 1 (2.8% , chemotherapy in 1 (2.8%, and enucleation ( because of neovascular glaucoma and vitreous hemorrhage was performed in 1 (2.8% case. Discussion: The most common orbital neurogenic tumors are meningioma, peripheral nerve sheath tumor, and optic nerve glioma. For meningioma and glioma, external beam radiotherapy is required; for schwannoma and solitary neurofibroma, total excisional biopsy is the preferred treatment. The success of visual and anatomic results are high after treatment. (Turk J Ophthalmol 2013; 43: 335-9

  13. CT and MRI evaluation of orbital tumors: our experience

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    Cabrini, Marcelo; Docampo, Jorge; Martinez, Manuel; Bruno, Claudio; Morales, Carlos

    2007-01-01

    Purpose: To show our experience in the evaluation of orbital masses on computed tomography (CT) and magnetic resonance imaging (MRI). To describe their most important findings and epidemiological features found on literature review, related to their differential diagnosis. Materials and methods: During a 48-months period of time, 26 patients (13 male, 13 female; age range, 3 to 75 years) with orbital tumors were evaluated. Seventeen patients underwent MR scans, 8 underwent CT scans, and one underwent both imaging methods. It was employed 0,5 and 1 Tesla MR scanners, and axial-helical CT scanners. Results: Benign lesions were found on 7 patients (cavernous hemangioma [n=2], meningioma [n=1], epidermoid cyst [n=1], dermoid cyst [n=1], lipoma [n=1], orbital vein deformity [n=1]). It was found lesions with undetermined behavior (optical nerve glioma [n=2]), and malignant ones were found on 17 patients (metastatic lesions [n=5], non- Hodgkin's lymphoma [n=3], hemangiopericytoma [n=2], retinoblastoma [n=2], rhabdomyosarcoma [n=2], melanoma [n=1], and lacrimal adenocarcinoma [n=1]). Conclusion: In our experience, 65.4% was malignant tumors (orbital metastasis was the most common; 19.2%). More than one-quarter was benign tumor, where cavernous hemangioma was the most frequent. (author) [es

  14. A SOLITARY FIBROUS ORBITAL TUMOR IN A PATIENT WITH NEUROFIBROMATOSIS AND AN UTERINE CARCINOMA

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    E. E. Grishina

    2016-01-01

    Full Text Available We present a rare combination of a solitary fibrous orbital tumor and uterine cancer in a  female patient with type I  neurofibromatosis. This 77-year old patient developed a  left painless exophthalmos within 2 years and decreased visual acuity of the left eye. At the age of 20  she was diagnosed with type I neurofibromatosis. Half a year ago she underwent hysteron-oophorectomy due to uterine adenocarcinoma. The visual acuity of her left eye was decreased to 0.3, with an increase of intraocular pressure to 30 mm Hg. She had a 13-mm left-sided exophthalmos with misplacement of the eye downwards and laterally at 40°. Reposition of the left eye was severely impaired, with limitation of the eye movements to all directions. Ophthalmoscopy showed optic disc discoloration and blunting of its inner border. The patient underwent trans-conjunctival orbitotomy, with removal of three encapsulated tumor nodules. Histological and immunochemical studies of the removed tissue identified solitary fibrous tumor of the left orbit with an undetermined malignant potential. In the post-operative period, visual acuity of the left eye was 0.2, with no exophthalmos and right position of the eye. There was a non-significant limitation of the left eye movement to the left and to the right. X-ray computed tomography confirmed radical tumor excision. Conclusion: Solitary fibrous tumor is a  rare orbital neoplasm. Nevertheless, it should be included into the differential diagnosis list of spin-cell orbital tumors. It is necessary to aim at tumor removal through the least traumatic orbital access. Relapsing course of the tumor is the rationale for a  long-term follow-up of patients after removal of solitary fibrous orbital tumor.

  15. Contribution of endothelial progenitors and proangiogenic hematopoietic cells to vascularization of tumor and ischemic tissue

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    Kopp, Hans-Georg; Ramos, Carlos A.; Rafii, Shahin

    2010-01-01

    Purpose of review During the last several years, a substantial amount of evidence from animal as well as human studies has advanced our knowledge of how bone marrow derived cells contribute to neoangiogenesis. In the light of recent findings, we may have to redefine our thinking of endothelial cells as well as of perivascular mural cells. Recent findings Inflammatory hematopoietic cells, such as macrophages, have been shown to promote neoangiogenesis during tumor growth and wound healing. Dendritic cells, B lymphocytes, monocytes, and other immune cells have also been found to be recruited to neoangiogenic niches and to support neovessel formation. These findings have led to the concept that subsets of hematopoietic cells comprise proangiogenic cells that drive adult revascularization processes. While evidence of the importance of endothelial progenitor cells in adult vasculogenesis increased further, the role of these comobilized hematopoietic cells has been intensely studied in the last few years. Summary Angiogenic factors promote mobilization of vascular endothelial growth factor receptor 1-positive hematopoietic cells through matrix metalloproteinase-9 mediated release of soluble kit-ligand and recruit these proangiogenic cells to areas of hypoxia, where perivascular mural cells present stromal-derived factor 1 (CXCL-12) as an important retention signal. The same factors are possibly involved in mobilization of vascular endothelial growth factor receptor 2-positive endothelial precursors that may participate in neovessel formation. The complete characterization of mechanisms, mediators and signaling pathways involved in these processes will provide novel targets for both anti and proangiogenic therapeutic strategies. PMID:16567962

  16. The Role of Toll Like Receptors in Hematopoietic Malignancies

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    Darlene Monlish

    2016-09-01

    Full Text Available Toll-like receptors (TLRs are a family of pattern recognition receptors (PRRs that shape the innate immune system by identifying pathogen-associated molecular patterns (PAMPS and host-derived damage associated molecular patterns (DAMPS. TLRs are widely expressed on both immune cells and non-immune cells, including hematopoietic stem and progenitor cells, effector immune cell populations, and endothelial cells. In addition to their well-known role in the innate immune response to acute infection or injury, accumulating evidence supports a role for TLRs in the development of hematopoietic and other malignancies. Several hematopoietic disorders, including lymphoproliferative disorders and myelodysplastic syndromes, which possess a high risk of transformation to leukemia, have been linked to aberrant TLR signaling. Furthermore, activation of TLRs leads to the induction of a number of pro-inflammatory cytokines and chemokines, which can promote tumorigenesis by driving cell proliferation and migration and providing a favorable microenvironment for tumor cells. Beyond hematopoietic malignancies, the upregulation of a number of TLRs has been linked to promoting tumor cell survival, proliferation, and metastasis in a variety of cancers, including those of the colon, breast, and lung. This review focuses on the contribution of TLRs to hematopoietic malignancies, highlighting the known direct and indirect effects of TLR signaling on tumor cells and their microenvironment. In addition, the utility of TLR agonists and antagonists as potential therapeutics in the treatment of hematopoietic malignancies is discussed.

  17. Haploidentical hematopoietic SCT increases graft-versus-tumor effect against renal cell carcinoma.

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    Budak-Alpdogan, T; Sauter, C T; Bailey, C P; Biswas, C S; Panis, M M; Civriz, S; Flomenberg, N; Alpdogan, O

    2013-08-01

    Allogeneic hematopoietic SCT (HSCT) has been shown to be an effective treatment option for advanced renal cell cancer (RCC). However, tumor resistance/relapse remains as the main post transplant issue. Therefore, enhancing graft-versus-tumor (GVT) activity without increasing GVHD is critical for improving the outcome of HSCT. We explored the GVT effect of haploidentical-SCT (haplo-SCT) against RCC in murine models. Lethally irradiated CB6F1 (H2K(b/d)) recipients were transplanted with T-cell-depleted BM cells from B6CBAF1 (H2K(b/k)) mice. Haplo-SCT combined with a low-dose haploidentical (HI) T-cell infusion (1 × 10(5)) successfully provided GVT activity without incurring GVHD. This effect elicited murine RCC growth control and consequently displayed a comparative survival advantage of haplo-SCT recipients when compared with MHC-matched (B6D2F1CB6F1) and parent-F1 (B6CB6F1) transplant recipients. Recipients of haplo-SCT had an increase in donor-derived splenic T-cell numbers, T-cell proliferation and IFN-γ-secreting donor-derived T-cells, a critical aspect for anti-tumor activity. The splenocytes from B6CBAF1 mice had a higher cytotoxicity against RENCA cells than the splenocytes from B6 and B6D2F1 donors after tumor challenge. These findings suggest that haplo-SCT might be an innovative immunotherapeutic platform for solid tumors, particularly for renal cell carcinoma.

  18. The role of tumor suppressor p15Ink4b in the regulation of hematopoietic progenitor cell fate

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    Humeniuk, R; Rosu-Myles, M; Fares, J; Koller, R; Bies, J; Wolff, L

    2013-01-01

    Epigenetic silencing of the tumor suppressor gene p15Ink4b (CDKN2B) is a frequent event in blood disorders like acute myeloid leukemia and myelodysplastic syndromes. The molecular function of p15Ink4b in hematopoietic differentiation still remains to be elucidated. Our previous study demonstrated that loss of p15Ink4b in mice results in skewing of the differentiation pattern of the common myeloid progenitor towards the myeloid lineage. Here, we investigated a function of p15Ink4b tumor suppressor gene in driving erythroid lineage commitment in hematopoietic progenitors. It was found that p15Ink4b is expressed more highly in committed megakaryocyte–erythroid progenitors than granulocyte–macrophage progenitors. More importantly, mice lacking p15Ink4b have lower numbers of primitive red cell progenitors and a severely impaired response to 5-fluorouracil- and phenylhydrazine-induced hematopoietic stress. Introduction of p15Ink4b into multipotential progenitors produced changes at the molecular level, including activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) signaling, increase GATA-1, erythropoietin receptor (EpoR) and decrease Pu1, GATA-2 expression. These changes rendered cells more permissive to erythroid commitment and less permissive to myeloid commitment, as demonstrated by an increase in early burst-forming unit-erythroid formation with concomitant decrease in myeloid colonies. Our results indicate that p15Ink4b functions in hematopoiesis, by maintaining proper lineage commitment of progenitors and assisting in rapid red blood cells replenishment following stress

  19. A Multidisciplinary Orbit-Sparing Treatment Approach That Includes Proton Therapy for Epithelial Tumors of the Orbit and Ocular Adnexa

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    Holliday, Emma B. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Esmaeli, Bita [Orbital Oncology and Ophthalmic Plastic Surgery Program, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Pinckard, Jamie [School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (United States); Garden, Adam S.; Rosenthal, David I.; Morrison, William H. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Kies, Merrill S. [Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Gunn, G. Brandon; Fuller, C. David; Phan, Jack; Beadle, Beth M. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Zhu, Xiarong Ronald; Zhang, Xiaodong [Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Frank, Steven J., E-mail: sjfrank@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2016-05-01

    Purpose: Postoperative radiation is often indicated in the treatment of malignant epithelial tumors of the orbit and ocular adnexa. We present details of radiation technique and toxicity data after orbit-sparing surgery followed by adjuvant proton radiation therapy. Methods and Materials: Twenty patients underwent orbit-sparing surgery followed by proton therapy for newly diagnosed malignant epithelial tumors of the lacrimal gland (n=7), lacrimal sac/nasolacrimal duct (n=10), or eyelid (n=3). Tumor characteristics, treatment details, and visual outcomes were obtained from medical records. Acute and chronic toxicity were prospectively scored using Common Terminology Criteria for Adverse Events version 4.0. Results: The median radiation dose was 60 Gy(RBE) (relative biological effectiveness; [range 50-70 Gy]); 11 patients received concurrent chemotherapy. Dose to ipsilateral anterior optic structures was reduced in 13 patients by having them gaze away from the target during treatment. At a median follow-up time of 27.1 months (range 2.6-77.2 months), no patient had experienced local recurrence; 1 had regional and 1 had distant recurrence. Three patients developed chronic grade 3 epiphora, and 3 developed grade 3 exposure keratopathy. Four patients experienced a decrease in visual acuity from baseline but maintained vision sufficient to perform all activities of daily living without difficulty. Patients with grade ≥3 chronic ocular toxicity had higher maximum dose to the ipsilateral cornea (median 46.3 Gy[RBE], range 36.6-52.7 Gy[RBE] vs median 37.4 Gy[RBE], range 9.0-47.3 Gy(RBE); P=.017). Conclusions: Orbit-sparing surgery for epithelial tumors of the orbit and ocular adnexa followed by proton therapy successfully achieved disease control and was well tolerated. No patient required orbital exenteration or enucleation. Chronic grade 3 toxicity was associated with high maximum dose to the cornea. An eye-deviation technique can be used to limit the maximum

  20. Metastatic neuroendocrine tumor with initial presentation of orbital apex syndrome

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    Yen-Yu Huang

    2017-03-01

    Full Text Available The possible etiologies of orbital apex syndrome range from inflammatory, infectious, neoplastic, iatrogenic/traumatic, to vascular processes. In patients without obvious infection or systemic cancer history, judicious use of corticosteroids is a reasonable strategy. We describe a 64-year-old man who presented with orbital apex syndrome and had progressed to total visual loss in three days after admission. Radiological imaging and pathological studies were consistent with a neuroendocrine tumor with multiple metastases. We recommend that a biopsy-proven specimen is warranted in patient with orbital apex syndrome even without a cancer history.

  1. Two- versus four-handed techniques for endonasal resection of orbital apex tumors.

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    Craig, John R; Lee, John Y K; Petrov, Dmitriy; Mehta, Sonul; Palmer, James N; Adappa, Nithin D

    2015-01-01

    Open versus endonasal resection of orbital apex (OA) tumors is generally based on tumor size, location, and pathology. For endonasal resection, two- and four-handed techniques have been reported, but whether one technique is more optimal based on these tumor features has not been evaluated. To determine whether two- versus four-handed techniques result in better outcomes after endoscopic resection of OA tumors, and whether either technique is better suited for intra- versus extraconal location and for benign versus malignant pathology. A retrospective review of all expanded endonasal approaches for OA tumors was performed at a single institution from 2009 to 2013. A PubMed database search was also performed to review series published on endonasal OA tumor resection. Across all the cases reviewed, the following data were recorded: two- versus four-handed techniques, intra- versus extraconal tumor location, and benign versus malignant pathology. The relationship between these variables and resection extent was analyzed by the Fisher exact test. Postoperative visual status and complications were also reviewed. Ten cases from the institution and 94 cases from 17 publications were reviewed. Both two- and four-handed techniques were used to resect extra- and intraconal OA tumors, for both benign and malignant pathology. Four-handed techniques included a purely endonasal approach and a combined endonasal-orbital approach. On univariate analysis, the strongest predictor of complete resection was benign pathology (p = 0.005). No significant difference was found between the extent of resection and a two- versus a four-handed technique. Visual status was improved or unchanged in 94% of cases, and other complications were rare. Benign tumors that involve the medial extraconal and posterior inferomedial intraconal OA can be treated by either two- or four-handed endonasal techniques. Selecting two- versus four-handed techniques and endonasal versus endonasal-orbital four

  2. Ultrasonography and computed tomography in the study of orbital tumors and pseudo-tumoral lesions

    International Nuclear Information System (INIS)

    Marins, J.L.C.; Pereira, R.M.; Prando, A.; Selos Moreira, A.R. de

    1987-01-01

    The computerized tomography and the ultrasonography in the ocular and orbital patologies were considered as complementary each other. the ultrasonography method as choice for the detection of the eye lesions in the adult, particularly of vascular origin and in the follow-up of inflammatory and pseudo-tumoral lesions was chosen. (L.M.J.) [pt

  3. Orbital melanocytoma: When a tumor becomes a relieving surprise

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    Haytham E. Nasr

    2018-06-01

    Full Text Available Purpose: Melanocytomas are rare pigmented tumors that arise form melanocytes and have been reported in the central nervous system. Orbital melanocytomas “also known as blue nevus” are rarely reported. The occurrence of choroidal melanoma and orbital melanocytomas has never been described. Observations: This is a case of orbital melanocytoma in a 34 year old female who presented with left proptosis and ecchymosis. She has the right eye enucleated to treat a large choroidal melanoma, 6 years earlier. Orbital metastasis was suspected. After orbital imaging and systemic evaluation, incisional biopsy was planned yet the mass could be totally excised and it turned out to be melanocytoma. The condition was not associated with nevus of Ota and the patient is not known to have any predisposing condition for melanocytic lesions. Conclusion and importance: Melanocytoma and malignant melanoma share the same cell of origin. The benign course, the well differentiated cells, absence of anaplasia and the positive reaction to Human Melanoma Black-45 (HMB-45 and S-100 proteins established the diagnosis of the former. Such diagnosis was a relief for this one eyed patient.(HMB-45:human melanoma black-45. Keywords: Orbit, Melanocytoma, Choroidal melanoma, HMB-45, S-100

  4. [Bilateral anophthalmia and left-sided orbital tumor : case of an eight-month-old infant].

    Science.gov (United States)

    Hundertmark, P; Dierks, P; Gottschalk, J; Kreusch, T; Wiegand, W

    2011-08-01

    An 8-month-old infant from Russia with bilateral anophthalmia presented with an expanding orbital tumor. The tumor was extirpated and the histological examination revealed a non-malignant pseudocystic process with residual neuro-ectodermal structures.

  5. Complicações oftálmicas em pacientes com tumores malignos extra-orbitários Ophthalmic complications in patients with extraorbital malignant tumors

    Directory of Open Access Journals (Sweden)

    Ana Célia Baptista

    2003-10-01

    Full Text Available OBJETIVO: Correlacionar as complicações oftálmicas, presentes em pacientes portadores de tumores malignos extra-orbitários, com o sítio de origem e diagnóstico histopatológico destas neoplasias, por meio de tomografia computadorizada. MÉTODOS: Foram estudados retrospectivamente, por tomografia computadorizada, 29 pacientes com neoplasias malignas extra-orbitárias, sem qualquer tratamento prévio do tumor, e evidência clínico-radiológica de comprometimento orbitário associado. RESULTADOS: Houve predomínio do carcinoma epidermóide (28%, seguido pelo carcinoma basocelular (14%. As complicações oftálmicas mais comumente observadas foram proptose (38%, epífora (24% e dor ocular (24%. Redução da acuidade visual foi referida em 14 % dos casos. Os sítios de origem mais comuns das neoplasias foram o seio maxilar (28%, o seio etmoidal (17% e a pele e subcutâneo da face (17%. Proptose ocular foi causada predominantemente por tumores não carcinomatosos e tumores originados no seio etmoidal, ao passo que epífora ocorreu preferencialmente nos casos de tumores carcinomatosos e de neoplasias do seio maxilar. Redução da motilidade ocular, irritação ocular e secreção no olho foram as complicações oftálmicas mais freqüentes em pacientes com tumores dos anexos oculares, ao passo que dor ocular foi a complicação oftálmica dominante nos pacientes com neoplasias originadas na pele e subcutâneo da face. CONCLUSÕES: Os autores sugerem que, diante de paciente com epífora e massa maxilo-nasal, carcinoma do seio maxilar deve ser considerado primariamente no diagnóstico diferencial da lesão. Da mesma forma, tumores não carcinomatosos, como sarcomas e linfomas, devem ser considerados, sobretudo no diagnóstico de pacientes com proptose e massa naso-etmoidal.OBJECTIVE: To correlate the ophthalmic complications in patients with extra-orbital malignant tumors with the site of origin and histopathologic diagnosis of the tumors by

  6. Role of TPS in 125I brachytherapy for orbital tumors

    International Nuclear Information System (INIS)

    Ren Ling; Dai Haojie; Li Quan

    2012-01-01

    Objective: To investigate the role of TPS in 125 I brachytherapy for orbital tumors. Methods: Sixty-six patients with orbital tumor treated with 125 I seeds from 2005 to 2009 were retrospectively analyzed. Forty-three patients were treated using TPS guided brachytherapy and the prescribed dose was 140 Gy. Other 23 patients were treated without TPS but simply implanted with 125 I seeds at 1 cm intervals in parallel with each other intraoperatively. CT and TPS quality verification were performed postoperatively in all patients. Also, CT and (or) MRI examination were performed at 3, 6, 12 and 24 months after brachytherapy for follow-up. χ 2 test and Kaplan-Meier survival analysis with log-rank significance test were used with SPSS 17.0. Results: A total of 1070 125 I seeds were implanted in 66 cases, on average, (16.2 ± 7.3) seeds for each patient. The satisfaction rates of postoperative quality verification in patients with and without TPS pre-plans were 79.07% (34/43) and 43.48% (10/23) respectively (χ 2 =8.542, P=0.003). Ten patients were lost in follow-up. Local recurrence rates in patients with favorable postoperative quality verification were 0 (0/37) in 3 months, 6.25% (2/32) in 6 months, 13.64% (3/22) in 12 months and 3/9 in 24 months respectively, which were significantly different from those (5.26% (1/19), 16.67% (3/18), 30.77% (4/13), 6/6) in the patients with inferior postoperative quality verification (χ 2 =9.017, P=0.0003). Conclusions: TPS plays an important role in 125 I brachytherapy for orbital tumors. Also, postoperative quality verification by TPS may help predict the local recurrence after brachytherapy. (authors)

  7. CT-criteria of orbital hemangiomas and their importance in differential diagnosis of intraconal tumors

    Energy Technology Data Exchange (ETDEWEB)

    Unsoeld, R; Hoyt, W F [California Univ., San Francisco (USA). Dept. of Neurosurgery; California Univ., San Francisco (USA). Dept. of Neurology and Opthalmology; California Univ., San Francisco (USA). Dept. of Neuroradiology)

    1979-12-01

    CT-Scans of 29 histologically proven cavernous hemangiomas were evaluated with respect to their location, shape, delineation from surrounding tissue, contrast-enhancement, and secondary changes of the bony orbit. Whenever a round or oval tumor, located in the outer upper muscle cone, sharply delineated from surrounding tissue, unattached to optic nerve and ocular muscles, spares a small triangular space in the orbital apex, it is in all probability a cavernous hemangioma. Evaluation of the tumors shape and its separation from surrounding tissues requires imaging in multiple sections in two planes oriented, if possible, at right angles. Changes in position of the optic nerve and eye muscles in different directions of gaze demonstrated by CT rule out significant tumor-attachments. The portion of the intraconal space least affected by optic nerve shifts and muscle contractions during eye movements, as demonstrated by CT, is the upper outer quadrant, the site preferred by the mobile tumor. Tumors which cannot be differentiated from cavernous hemangiomas by CT-criteria are rare usually benign. Reports of rare examples of well delineated or encapsulated malignant intraconal lesions indicate the possibility - however remote - of mistaking a malignant tumor for a cavernous hemangioma by CT.

  8. Multilineage hematopoietic recovery with concomitant antitumor effects using low dose Interleukin-12 in myelosuppressed tumor-bearing mice

    Directory of Open Access Journals (Sweden)

    Miller Joseph D

    2008-05-01

    Full Text Available Abstract Background Interleukin-12 (IL-12 is a cytokine well known for its role in immunity. A lesser known function of IL-12 is its role in hematopoiesis. The promising data obtained in the preclinical models of antitumor immunotherapy raised hope that IL-12 could be a powerful therapeutic agent against cancer. However, excessive clinical toxicity, largely due to repeat dose regimens, and modest clinical response observed in the clinical trials have pointed to the necessity to design protocols that minimize toxicity without affecting the anti-tumor effect of IL-12. We have focused on the lesser known role of IL-12 in hematopoiesis and hypothesized that an important clinical role for IL-12 in cancer may be as an adjuvant hematological cancer therapy. In this putative clinical function, IL-12 is utilized for the prevention of cancer therapy-related cytopenias, while providing concomitant anti-tumor responses over and above responses observed with the primary therapy alone. This putative clinical function of IL-12 focuses on the dual role of IL-12 in hematopoiesis and immunity. Methods We assessed the ability of IL-12 to facilitate hematopoietic recovery from radiation (625 rad and chemotherapy (cyclophosphamide in two tumor-bearing murine models, namely the EL4 lymphoma and the Lewis lung cancer models. Antitumor effects and changes in bone marrow cellularity were also assessed. Results We show herein that carefully designed protocols, in mice, utilizing IL-12 as an adjuvant to radiation or chemotherapy yield facile and consistent, multilineage hematopoietic recovery from cancer therapy-induced cytopenias, as compared to vehicle and the clinically-utilized cytokine granulocyte colony-stimulating factor (G-CSF (positive control, while still providing concomitant antitumor responses over and above the effects of the primary therapy alone. Moreover, our protocol design utilizes single, low doses of IL-12 that did not yield any apparent toxicity

  9. Solitary fibrous tumor of the orbit presenting in pregnancy

    Directory of Open Access Journals (Sweden)

    Das Jayanta

    2009-01-01

    Full Text Available A 32-year-old woman, three months pregnant, reported with the complaint of protrusion of the right eye for six months. She gave history of rapid protrusion of eyeball for the last two months along with the history of double vision for the last one month. Computer tomography (CT scan revealed a well-defined mass lesion in the intraconal space of the right orbit which was excised through a lateral orbitotomy approach. Histological examination and immunohistochemistry revealed a solitary fibrous tumor, which showed a rapid progression in pregnancy.

  10. Malignant perivascular epithelioid cell tumor of the orbit: Report of a case and review of literature

    Directory of Open Access Journals (Sweden)

    Md Shahid Alam

    2017-01-01

    Full Text Available Perivascular epithelioid cell tumor (PEComa is a rare neoplasm considered to arise from myomelanocytic cell lineage. The uterus is reportedly the most common site to be involved. Orbital PEComa is extremely rare with only two cases reported till date. A 5-year-old male presented with a right medial orbital mass for the last 6 months. The patient was diagnosed with alveolar soft part sarcoma elsewhere. Magnetic resonance imaging features were suggestive of lymphangioma with bleeding. The excision biopsy revealed multiple tumor cells comprising epithelioid cells with clear cytoplasm, along with nuclear atypia and mitosis. Immunohistochemistry was positive for HMB-45, smooth muscle actin, vimentin, and CD-34. It was negative for cytokeratin, S-100, and synaptophysin, which clinched the diagnosis of malignant orbital PEComa. Neoadjuvant chemotherapy was administered. There was no recurrence at 24 months of follow-up. At present, there is no consensus on management protocol for malignant PEComa. Complete surgical excision with chemotherapy appears to offer the best prognosis.

  11. Endoscopic trans-nasal approach for biopsy of orbital tumors using image-guided neuro-navigation system

    International Nuclear Information System (INIS)

    Sieskiewicz, A.; Mariak, Z.; Rogowski, M.; Lyson, T.

    2008-01-01

    Histopathological diagnosis of intraorbital tumors is of crucial value for planning further therapy. The aim of the study was to explore clinical utility of image-guided endoscopy for biopsy of orbital tumors. Trans-nasal endoscopic biopsy of intraorbital mass lesions was performed in 6 patients using a neuro-navigation system (Medtronic Stealth Station Treon plus). The CT and MRI 1 mm slice images were fused by the system in order to visualise both bony and soft tissue structures. The anatomic fiducial registration protocol was used during the procedure. All lesions were precisely localised and the biopsies could be taken from the representative part of the pathological mass. None of the patients developed aggravation of ocular symptoms after the procedure. The operative corridor as well as the size of orbital wall fenestration could be limited to a minimum. The accuracy of neuro-navigation remained high and stable during the entire procedure. The image-guided neuro-navigation system facilitated endoscopic localisation and biopsy of intraorbital tumors and contributed to the reduction of surgical trauma during the procedure. The technique was particularly useful in small, medially located, retrobulbar tumors and in unclear situations when the structure of the lesion resembled surrounding intraorbital tissue. (author)

  12. Short Stat5-interacting peptide derived from phospholipase C-β3 inhibits hematopoietic cell proliferation and myeloid differentiation.

    Directory of Open Access Journals (Sweden)

    Hiroki Yasudo

    Full Text Available Constitutive activation of the transcription factor Stat5 in hematopoietic stem/progenitor cells leads to various hematopoietic malignancies including myeloproliferative neoplasm (MPN. Our recent study found that phospholipase C (PLC-β3 is a novel tumor suppressor involved in MPN, lymphoma and other tumors. Stat5 activity is negatively regulated by the SH2 domain-containing protein phosphatase SHP-1 in a PLC-β3-dependent manner. PLC-β3 can form the multimolecular SPS complex together with SHP-1 and Stat5. The close physical proximity of SHP-1 and Stat5 brought about by interacting with the C-terminal segment of PLC-β3 (PLC-β3-CT accelerates SHP-1-mediated dephosphorylation of Stat5. Here we identify the minimal sequences within PLC-β3-CT required for its tumor suppressor function. Two of the three Stat5-binding noncontiguous regions, one of which also binds SHP-1, substantially inhibited in vitro proliferation of Ba/F3 cells. Surprisingly, an 11-residue Stat5-binding peptide (residues 988-998 suppressed Stat5 activity in Ba/F3 cells and in vivo proliferation and myeloid differentiation of hematopoietic stem/progenitor cells. Therefore, this study further defines PLC-β3-CT as the Stat5- and SHP-1-binding domain by identifying minimal functional sequences of PLC-β3 for its tumor suppressor function and implies their potential utility in the control of hematopoietic malignancies.

  13. In vivo engineering of bone tissues with hematopoietic functions and mixed chimerism.

    Science.gov (United States)

    Shih, Yu-Ru; Kang, Heemin; Rao, Vikram; Chiu, Yu-Jui; Kwon, Seong Keun; Varghese, Shyni

    2017-05-23

    Synthetic biomimetic matrices with osteoconductivity and osteoinductivity have been developed to regenerate bone tissues. However, whether such systems harbor donor marrow in vivo and support mixed chimerism remains unknown. We devised a strategy to engineer bone tissues with a functional bone marrow (BM) compartment in vivo by using a synthetic biomaterial with spatially differing cues. Specifically, we have developed a synthetic matrix recapitulating the dual-compartment structures by modular assembly of mineralized and nonmineralized macroporous structures. Our results show that these matrices incorporated with BM cells or BM flush transplanted into recipient mice matured into functional bone displaying the cardinal features of both skeletal and hematopoietic compartments similar to native bone tissue. The hematopoietic function of bone tissues was demonstrated by its support for a higher percentage of mixed chimerism compared with i.v. injection and donor hematopoietic cell mobilization in the circulation of nonirradiated recipients. Furthermore, hematopoietic cells sorted from the engineered bone tissues reconstituted the hematopoietic system when transplanted into lethally irradiated secondary recipients. Such engineered bone tissues could potentially be used as ectopic BM surrogates for treatment of nonmalignant BM diseases and as a tool to study hematopoiesis, donor-host cell dynamics, tumor tropism, and hematopoietic cell transplantation.

  14. Eye tracking and gating system for proton therapy of orbital tumors

    International Nuclear Information System (INIS)

    Shin, Dongho; Yoo, Seung Hoon; Moon, Sung Ho; Yoon, Myonggeun; Lee, Se Byeong; Park, Sung Yong

    2012-01-01

    Purpose: A new motion-based gated proton therapy for the treatment of orbital tumors using real-time eye-tracking system was designed and evaluated. Methods: We developed our system by image-pattern matching, using a normalized cross-correlation technique with LabVIEW 8.6 and Vision Assistant 8.6 (National Instruments, Austin, TX). To measure the pixel spacing of an image consistently, four different calibration modes such as the point-detection, the edge-detection, the line-measurement, and the manual measurement mode were suggested and used. After these methods were applied to proton therapy, gating was performed, and radiation dose distributions were evaluated. Results: Moving phantom verification measurements resulted in errors of less than 0.1 mm for given ranges of translation. Dosimetric evaluation of the beam-gating system versus nongated treatment delivery with a moving phantom shows that while there was only 0.83 mm growth in lateral penumbra for gated radiotherapy, there was 4.95 mm growth in lateral penumbra in case of nongated exposure. The analysis from clinical results suggests that the average of eye movements depends distinctively on each patient by showing 0.44 mm, 0.45 mm, and 0.86 mm for three patients, respectively. Conclusions: The developed automatic eye-tracking based beam-gating system enabled us to perform high-precision proton radiotherapy of orbital tumors.

  15. Inflammatory myofibroblastic tumor of the orbit: A clinico-pathological study of 25 cases

    Directory of Open Access Journals (Sweden)

    Diego Strianese

    2018-01-01

    Full Text Available Background: Inflammatory myofibroblastic tumor (IMT is a rare entity characterized by the presence of myofibroblasts and inflammatory cells within a fibrous stroma, which typically occurs in children or young adults. The IMT is considered generally a benign lesion, although about 20% of cases may experience recurrence, and most rarely develop metastasis. Herein, we present the largest series of primary orbital IMT ever reported. Patients and methods: The clinical records of 25 patients, collected between the 1995 and 2015, with biopsy-proven diagnosis of orbital IMT were retrospectively reviewed to determine demographic, clinical, radiologic and pathological features, management, and outcome. Results: The study included 13 females and 12 male patients, age ranged from 5 to 76 years. Disease onset was in all cases unilateral (25/25, with posterior location (10/25 or extending anterior to posterior (7/25. The most common signs and symptoms were: proptosis (19/25, ptosis (18/25, diplopia (10/25, periocular swelling (9/25, pain (8/25, redness (7/25. All patients underwent to incisional biopsy which included total or subtotal tumor resection avoiding arming of the adjacent structure, followed by systemic steroid therapy (22/25 or radiotherapy (3/25. The disease recurred in 6 (24% patients who responded to the subsequent therapy. No one developed metastasis or died because of the disease. Conclusion: IMT is a distinct entity which may occur in the orbit primarily. It should be considered in differential diagnosis in all orbital masses, particularly with onset of acute or subcronic inflammation. Surgical biopsy associated to a partial debulcking of the tumor, avoiding to damage adjacent vital structure may contribute to improve the outcome. Steroid therapy, seems to be the suitable as first line medical therapy, although, as reported in literature, not all cases respond to this treatment regimen. Radiotherapy, may be considered as an alternative

  16. Hematopoietic Stem and Progenitor Cell Migration After Hypofractionated Radiation Therapy in a Murine Model

    Energy Technology Data Exchange (ETDEWEB)

    Kane, Jonathan [Department of Biological Sciences, Oakland University, Rochester, Michigan (United States); Radiation Oncology, William Beaumont Health System, Royal Oak, Michigan (United States); Krueger, Sarah A.; Dilworth, Joshua T.; Torma, John T.; Wilson, George D.; Marples, Brian [Radiation Oncology, William Beaumont Health System, Royal Oak, Michigan (United States); Madlambayan, Gerard J., E-mail: madlamba@oakland.edu [Department of Biological Sciences, Oakland University, Rochester, Michigan (United States)

    2013-12-01

    Purpose: To characterize the recruitment of bone marrow (BM)-derived hematopoietic stem and progenitor cells (HSPCs) within tumor microenvironment after radiation therapy (RT) in a murine, heterotopic tumor model. Methods and Materials: Lewis lung carcinoma tumors were established in C57BL/6 mice and irradiated with 30 Gy given as 2 fractions over 2 days. Tumors were imaged with positron emission tomography/computed tomography (PET/CT) and measured daily with digital calipers. The HSPC and myelomonocytic cell content was assessed via immunofluorescent staining and flow cytometry. Functionality of tumor-associated HSPCs was verified in vitro using colony-forming cell assays and in vivo by rescuing lethally irradiated C57BL/6 recipients. Results: Irradiation significantly reduced tumor volumes and tumor regrowth rates compared with nonirradiated controls. The number of CD133{sup +} HSPCs present in irradiated tumors was higher than in nonirradiated tumors during all stages of regrowth. CD11b{sup +} counts were similar. PET/CT imaging and growth rate analysis based on standardized uptake value indicated that HSPC recruitment directly correlated to the extent of regrowth and intratumor cell activity after irradiation. The BM-derived tumor-associated HSPCs successfully formed hematopoietic colonies and engrafted irradiated mice. Finally, targeted treatment with a small animal radiation research platform demonstrated localized HSPC recruitment to defined tumor subsites exposed to radiation. Conclusions: Hypofractionated irradiation resulted in a pronounced and targeted recruitment of BM-derived HSPCs, possibly as a mechanism to promote tumor regrowth. These data indicate for the first time that radiation therapy regulates HSPC content within regrowing tumors.

  17. Hematopoietic Stem and Progenitor Cell Migration After Hypofractionated Radiation Therapy in a Murine Model

    International Nuclear Information System (INIS)

    Kane, Jonathan; Krueger, Sarah A.; Dilworth, Joshua T.; Torma, John T.; Wilson, George D.; Marples, Brian; Madlambayan, Gerard J.

    2013-01-01

    Purpose: To characterize the recruitment of bone marrow (BM)-derived hematopoietic stem and progenitor cells (HSPCs) within tumor microenvironment after radiation therapy (RT) in a murine, heterotopic tumor model. Methods and Materials: Lewis lung carcinoma tumors were established in C57BL/6 mice and irradiated with 30 Gy given as 2 fractions over 2 days. Tumors were imaged with positron emission tomography/computed tomography (PET/CT) and measured daily with digital calipers. The HSPC and myelomonocytic cell content was assessed via immunofluorescent staining and flow cytometry. Functionality of tumor-associated HSPCs was verified in vitro using colony-forming cell assays and in vivo by rescuing lethally irradiated C57BL/6 recipients. Results: Irradiation significantly reduced tumor volumes and tumor regrowth rates compared with nonirradiated controls. The number of CD133 + HSPCs present in irradiated tumors was higher than in nonirradiated tumors during all stages of regrowth. CD11b + counts were similar. PET/CT imaging and growth rate analysis based on standardized uptake value indicated that HSPC recruitment directly correlated to the extent of regrowth and intratumor cell activity after irradiation. The BM-derived tumor-associated HSPCs successfully formed hematopoietic colonies and engrafted irradiated mice. Finally, targeted treatment with a small animal radiation research platform demonstrated localized HSPC recruitment to defined tumor subsites exposed to radiation. Conclusions: Hypofractionated irradiation resulted in a pronounced and targeted recruitment of BM-derived HSPCs, possibly as a mechanism to promote tumor regrowth. These data indicate for the first time that radiation therapy regulates HSPC content within regrowing tumors

  18. Central nervous system tumors: Radiologic pathologic correlation and diagnostic approach

    Directory of Open Access Journals (Sweden)

    Ishita Pant

    2015-01-01

    Full Text Available Objective: This study was conducted to formulate location-wise radiologic diagnostic algorithms and assess their concordance with the final histopathological diagnosis so as to evaluate their utility in a rural setting where only basic facilities are available. Materials and Methods: A retrospective analysis to assess the concordance of radiology (primarily MRI with final histopathology report was done. Based on the most common incidence of tumor location and basic radiology findings, diagnostic algorithms were prepared. Results: For supratentorial intraaxial parenchymal location concordance was seen in all high-grade astrocytomas, low- and high-grade oligodendrogliomas, metastatic tumors, primitive neuroectodermal tumors, high-grade ependymomas, neuronal and mixed neuro-glial tumors and tumors of hematopoietic system. Lowest concordance was seen in low-grade astrocytomas. In the supratentorial intraaxial ventricular location, agreement was observed in choroid plexus tumors, ependymomas, low-grade astrocytomas and meningiomas; in the supratentorial extraaxial location, except for the lack of concordance in the only case of metastatic tumor, concordance was observed in meningeal tumors, tumors of the sellar region, tumors of cranial and paraspinal nerves; the infratentorial intraaxial parenchymal location showed agreement in low- as well as high-grade astrocytomas, metastatic tumors, high-grade ependymoma, embryonal tumors and hematopoietic tumors; in the infratentorial intraaxial ventricular location, except for the lack of concordance in one case of low-grade astrocytoma and two cases of medulloblastomas, agreement was observed in low- and high-grade ependymoma; infratentorial extraaxial tumors showed complete agreement in all tumors of cranial and paraspinal nerves, meningiomas, and hematopoietic tumors. Conclusion: A location-based approach to central nervous system (CNS tumors is helpful in establishing an appropriate differential diagnosis.

  19. Development of tumor-reactive T cells after nonmyeloablative allogeneic hematopoietic stem cell transplant for chronic lymphocytic leukemia.

    Science.gov (United States)

    Nishida, Tetsuya; Hudecek, Michael; Kostic, Ana; Bleakley, Marie; Warren, Edus H; Maloney, David; Storb, Rainer; Riddell, Stanley R

    2009-07-15

    Allogeneic nonmyeloablative hematopoietic stem cell transplant (NM-HSCT) can result in durable remission of chronic lymphocytic leukemia (CLL). It is thought that the efficacy of NM-HSCT is mediated by recognition of tumor cells by T cells in the donor stem cell graft. We evaluated the development of CTLs specific for CLL after NM-HSCT to determine if their presence correlated with antitumor efficacy. Peripheral blood mononuclear cells obtained from 12 transplant recipients at intervals after NM-HSCT were stimulated in vitro with CLL cells. Polyclonal T-cell lines and CD8(+) T-cell clones were derived from these cultures and evaluated for lysis of donor and recipient target cells including CLL. The presence and specificity of responses was correlated with clinical outcomes. Eight of the 12 patients achieved remission or a major antitumor response and all 8 developed CD8(+) and CD4(+) T cells specific for antigens expressed by CLL. A clonal analysis of the CD8(+) T-cell response identified T cells specific for multiple minor histocompatibility (H) antigens expressed on CLL in six of the responding patients. A significant fraction of the CD8(+) T-cell response in some patients was also directed against nonshared tumor-specific antigens. By contrast, CLL-reactive T cells were not detected in the four patients who had persistent CLL after NM-HSCT, despite the development of graft-versus-host disease. The development of a diverse T-cell response specific for minor H and tumor-associated antigens expressed by CLL predicts an effective graft-versus-leukemia response after NM-HSCT.

  20. Uncommon primary tumors of the orbit diagnosed by computed tomography-guided core needle biopsy: report of two cases

    Energy Technology Data Exchange (ETDEWEB)

    Tyng, Chiang Jeng; Matushita Junior, Joao Paulo Kawaoka; Bitencourt, Almir Galvao Vieira; Amoedo, Mauricio Kauark; Barbosa, Paula Nicole Vieira; Chojniak, Rubens, E-mail: almirgvb@yahoo.com.br [A.C.Camargo Cancer Center, Sao Paulo, SP (Brazil). Dept. de Imagem; Neves, Flavia Branco Cerqueira Serra [Hospital do Servidor Publico Estadual, Sao Paulo, SP (Brazil). Div. de Oftalmologia

    2014-11-15

    Computed tomography-guided percutaneous biopsy is a safe and effective alternative method for evaluating selected intra-orbital lesions where the preoperative diagnosis is important for the therapeutic planning. The authors describe two cases of patients with uncommon primary orbital tumors whose diagnosis was obtained by means of computed tomography-guided core needle biopsy, with emphasis on the technical aspects of the procedure. (author)

  1. Sodium Caseinate (CasNa) Induces Mobilization of Hematopoietic Stem Cells in a BALB/c Mouse Model.

    Science.gov (United States)

    Santiago-Osorio, Edelmiro; Ledesma-Martínez, Edgar; Aguiñiga-Sánchez, Itzen; Poblano-Pérez, Ignacio; Weiss-Steider, Benny; Montesinos-Montesinos, Juan José; Mora-García, María de Lourdes

    2015-09-25

    BACKGROUND Hematopoietic stem cells transplantation has high clinical potential against a wide variety of hematologic, metabolic, and autoimmune diseases and solid tumors. Clinically, hematopoietic stem cells derived from peripheral blood are currently used more than those obtained from sources such as bone marrow. However, mobilizing agents used in the clinic tend to fail in high rates, making the number of mobilized cells insufficient for transplantation. We investigated whether sodium caseinate induces functional mobilization of hematopoietic stem cells into peripheral blood of Balb/c mice. MATERIAL AND METHODS Using a mouse model, we administrated sodium caseinate or Plerixafor, a commercial mobilizing agent, and analyzed counts of hematopoietic stem cells in peripheral blood, and then cells were transplanted into lethally irradiated mice to restore hematopoiesis. All assays were performed at least twice. RESULTS We found that sodium caseinate increases the number of mononuclear cells in peripheral blood with the immunophenotype of hematopoietic stem cells (0.2 to 0.5% LSK cells), allowing them to form colonies of various cell lineages in semisolid medium (psodium caseinate as a mobilizer of hematopoietic stem cells and its potential clinical application in transplantation settings.

  2. CONGENITAL ORBITAL TERATOMA

    African Journals Online (AJOL)

    was done without contrast and 3mm/5mm/10mm slices were obtained to cover the orbit, skull base and brain. The findings included a soft tissue mass arising from the orbit. The left eye ball was extra orbital. There was no defect .... love's Short Practice of Surgery. 7 Edition,. Levis London, 1997; 45-64. 2. Orbital tumor Part 1, ...

  3. [A Case of an Orbital Angioleiomyoma].

    Science.gov (United States)

    Sato, Kohei; Ogawa, Yukari; Kinoshita, Keita; Takai, Hiroki; Hirai, Satoshi; Ishihara, Manabu; Hara, Keijiro; Toi, Hiroyuki; Matsubara, Shunji; Uno, Masaaki

    2017-12-01

    A 70-year-old woman presented with a 4-year history of painless conjunctival congestion and proptosis of the right eye. Computed tomography and magnetic resonance imaging revealed a 48-mm lesion in the right medial orbit. As the symptoms progressed, the tumor was resected by performing fronto-orbital craniotomy. Histopathological examination revealed a vascular tumor surrounded by smooth muscle fibers and immunohistochemistry demonstrated tumor positivity for smooth muscle actin and desmin. The tumor was diagnosed as an angioleiomyoma, and no recurrence has been observed as of 5 years postoperatively. Angioleiomyomas in the orbit are extremely rare;thus, we have reported this case with reference to the literature.

  4. Value of MR imaging in the differentiation of benign and malignant orbital tumors in adults

    International Nuclear Information System (INIS)

    Xian, Junfang; Zhang, Zhengyu; Wang, Zhenchang; Li, Jing; Yang, Bentao; Man, Fengyuan; Chang, Qinglin; Zhang, Yunting

    2010-01-01

    To prospectively evaluate magnetic resonance (MR) imaging including dynamic contrast-enhanced MR imaging in the differentiation of benign from malignant orbital masses and to evaluate which MR imaging features are most predictive of malignant tumors. The study was approved by the institutional review board and signed informed consent was obtained. Nonenhanced, static, and dynamic contrast-enhanced MR imaging was performed in 102 adult patients with an orbital mass. Diagnosis was based on histologic findings. MR imaging features of benign and malignant orbital lesions were evaluated correlated with histological findings. Multivariate logistic regression analysis was employed to identify the best combination of MR imaging features that might be predictive of malignancy. Nonenhanced, static, and dynamic enhancement MR imaging was significantly superior to two other models in prediction of malignancy (p < 0.05). Multivariate logistic regression analysis identified that the most discriminating MR imaging features were isointense mass on T2-weighted imaging and a washout-type time-intensity curve for both observers. Nonenhanced, static, and dynamic enhancement MR imaging improved differentiation between benign and malignant orbital masses in adult patients. (orig.)

  5. Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation

    DEFF Research Database (Denmark)

    Storb, Rainer; Gyurkocza, Boglarka; Storer, Barry E

    2013-01-01

    We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the pures...

  6. Unusual intraconal localization of orbital giant cell angiofibroma.

    Science.gov (United States)

    Ekin, Meryem Altin; Ugurlu, Seyda Karadeniz; Cakalagaoglu, Fulya

    2018-01-01

    Giant cell angiofibroma (GCA) is a recently reported rare soft-tissue tumor that can develop in various sites including orbit. Orbital GCAs were mainly located in the eyelid or extraconal regions such as lacrimal gland and conjunctiva. We report an atypical case of a GCA arising in the intraconal area of the orbit in a 65-year-old male patient. The tumor was excised in total by lateral orbitotomy. Histological and immunohistochemical features were consistent with the diagnosis of GCA. No recurrence was observed during the follow-up of over 2 years. GCA is a rare tumor that should be considered in the differential diagnosis of intraconal orbital tumors. Complete surgical removal is the current optimal treatment option.

  7. Postenucleation orbits in retinoblastoma: treatment with 125I brachytherapy

    International Nuclear Information System (INIS)

    Stannard, Clare; Sealy, Ross; Hering, Egbert; Hough, Jan; Knowles, Ruth; Lecuona, Karin; Reddi, V. Bala

    2002-01-01

    Purpose: Children with retinoblastoma that extends into or through the choroid, sclera, or optic nerve are at risk of developing orbital disease, as well as metastases. Previously, these enucleated orbits were treated with external beam radiotherapy in addition to chemotherapy. 125 I brachytherapy for tumors in and around the eye was pioneered by Sealy in Cape Town, South Africa, in 1974. In 1983, he developed a technique to irradiate the contents of the orbit while limiting the dose to the bony orbit and eyelids. Methods and Materials: Six nylon tubes containing 125 I seeds were implanted through the eyelids around the periphery of the orbit. Each contained a metal gutter that screens the outer part of the seeds from the bony orbit. A seventh unscreened tube was placed in the center, and a metal disc with 125 I seeds on its posterior surface was secured beneath the eyelids. Between 1983 and 2000, 57 orbits were treated in 56 children with retinoblastoma. Thirty-six were treated prophylactically and 21, with tumor at the resection line of the nerve, extrascleral tumor, or metastases, were treated therapeutically. They received a median dose of 34 Gy in 70 h; 30 also received chemotherapy. Children with tumor at the resection line of the nerve also received treatment to the craniospinal axis. Results: The median follow-up of the 35 patients treated prophylactically was 35 months (range 0-187). Seven patients died, 6 of metastases, at a median of 10 months (range 4-29) after the implant. Eight of the 13 patients with microscopic extraocular tumor survived a median of 29 months (range 5-156). None of the 8 patients presenting with orbital tumor or metastases survived. No orbital recurrences developed in any of the patients. Cosmesis was considerably improved compared with previous forms of irradiation. Conclusion: Orbital brachytherapy is an effective method of irradiating the orbit to prevent recurrent tumor, the treatment time is short, and the cosmesis is much more

  8. MR imaging of orbital disease

    Energy Technology Data Exchange (ETDEWEB)

    Yamashita, Yasuyuki; Sato, Ryuiti; Sakamoto, Yuji; Kojima, Ryutaro; Takahashi, Mutsumasa; Maruoka, Syouko; Okamura, Ryoichi; Oguni, Tatsuro.

    1989-05-01

    Sixty five cases with orbital and ocular lesions were evaluated by MRI in comparison with high resolution CT. MRI was performed with spin echo techniques (short TR/TE and long TR/TE) using a 0.22 tesla resistive unit (Toshiba MRT-22A) or a 1.5 tesla superconductive unit (Siemens Magnetom). MRI was superior to CT in (1) detecting ocular lesions and vitreous changes, (2) differentiating a tumor from the adjacent extraocular muscles and optic nerves, (3) identifying the lesion in the orbital apex and demonstrating the posterior extent of the tumor and (4) detecting the abnormal flow in the orbital vascular structures. Although some tumors had specific signal intensities including hemangioma, menigioma, and pseudotumor, majority of tumors revealed non-sepcific signal intensities. CT was superior to MRI in detection for small and calcified lesions as well as visualization of bone details. (author).

  9. Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions.

    Science.gov (United States)

    Guitart, Amelie V; Panagopoulou, Theano I; Villacreces, Arnaud; Vukovic, Milica; Sepulveda, Catarina; Allen, Lewis; Carter, Roderick N; van de Lagemaat, Louie N; Morgan, Marcos; Giles, Peter; Sas, Zuzanna; Gonzalez, Marta Vila; Lawson, Hannah; Paris, Jasmin; Edwards-Hicks, Joy; Schaak, Katrin; Subramani, Chithra; Gezer, Deniz; Armesilla-Diaz, Alejandro; Wills, Jimi; Easterbrook, Aaron; Coman, David; So, Chi Wai Eric; O'Carroll, Donal; Vernimmen, Douglas; Rodrigues, Neil P; Pollard, Patrick J; Morton, Nicholas M; Finch, Andrew; Kranc, Kamil R

    2017-03-06

    Strict regulation of stem cell metabolism is essential for tissue functions and tumor suppression. In this study, we investigated the role of fumarate hydratase (Fh1), a key component of the mitochondrial tricarboxylic acid (TCA) cycle and cytosolic fumarate metabolism, in normal and leukemic hematopoiesis. Hematopoiesis-specific Fh1 deletion (resulting in endogenous fumarate accumulation and a genetic TCA cycle block reflected by decreased maximal mitochondrial respiration) caused lethal fetal liver hematopoietic defects and hematopoietic stem cell (HSC) failure. Reexpression of extramitochondrial Fh1 (which normalized fumarate levels but not maximal mitochondrial respiration) rescued these phenotypes, indicating the causal role of cellular fumarate accumulation. However, HSCs lacking mitochondrial Fh1 (which had normal fumarate levels but defective maximal mitochondrial respiration) failed to self-renew and displayed lymphoid differentiation defects. In contrast, leukemia-initiating cells lacking mitochondrial Fh1 efficiently propagated Meis1 / Hoxa9 -driven leukemia. Thus, we identify novel roles for fumarate metabolism in HSC maintenance and hematopoietic differentiation and reveal a differential requirement for mitochondrial Fh1 in normal hematopoiesis and leukemia propagation. © 2017 Guitart et al.

  10. Hhex Regulates Hematopoietic Stem Cell Self-Renewal and Stress Hematopoiesis via Repression of Cdkn2a.

    Science.gov (United States)

    Jackson, Jacob T; Shields, Benjamin J; Shi, Wei; Di Rago, Ladina; Metcalf, Donald; Nicola, Nicos A; McCormack, Matthew P

    2017-08-01

    The hematopoietically expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of common lymphoid progenitors (CLPs) to lymphoid lineages. Here, we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation, due to a failure of progenitor expansion. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature progenitors. Transcriptome analysis of Hhex-null Lin - Sca + Kit + cells showed that Hhex deletion leads to derepression of polycomb repressive complex 2 (PRC2) and PRC1 target genes, including the Cdkn2a locus encoding the tumor suppressors p16 Ink 4 a and p19 Arf . Indeed, loss of Cdkn2a restored the capacity of Hhex-null blast colonies to generate myeloid progenitors in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to promote PRC2-mediated Cdkn2a repression to enable continued self-renewal and response to hematopoietic stress. Stem Cells 2017;35:1948-1957. © 2017 AlphaMed Press.

  11. Unusual intraconal localization of orbital giant cell angiofibroma

    Directory of Open Access Journals (Sweden)

    Meryem Altin Ekin

    2018-01-01

    Full Text Available Giant cell angiofibroma (GCA is a recently reported rare soft-tissue tumor that can develop in various sites including orbit. Orbital GCAs were mainly located in the eyelid or extraconal regions such as lacrimal gland and conjunctiva. We report an atypical case of a GCA arising in the intraconal area of the orbit in a 65-year-old male patient. The tumor was excised in total by lateral orbitotomy. Histological and immunohistochemical features were consistent with the diagnosis of GCA. No recurrence was observed during the follow-up of over 2 years. GCA is a rare tumor that should be considered in the differential diagnosis of intraconal orbital tumors. Complete surgical removal is the current optimal treatment option.

  12. Parameningeal rhabdomyosarcoma (including the orbit): results of orbital irradiation

    International Nuclear Information System (INIS)

    Jereb, B.; Haik, B.G.; Ong, R.; Ghavimi, F.

    1985-01-01

    Twenty-three patients with parameningeal (including orbital rhabdomyosarcoma (RMS)) were treated at Memorial Sloan-Kettering Cancer Center (MSKCC) between July 1971 and January 1983. Twenty were children with a mean age of 6 and 3 were adults. In 6 patients, the primary tumor was from the orbit, whereas the remaining 17 had other parameningeal primary sites. The tumors were in a very progressive local stage, with extensive destruction of the facial bones in 19 patients. Eight patients were treated with T2 chemotherapy protocol and 15 received T6. Seven patients received 5,000 to 7,200 rad delivered to the primary tumor in 11-16 weeks, 15 patients received between 4,500 to 5,000 rad in 4-7 weeks, and 1 patient received 3,000 rad in 3 weeks for residual microscopic disease following surgery. Two patients were treated with radiation to the whole brain; no patients received radiation of the whole central nervous axis (CNA). Fifteen of the 23 patients (65%) are alive and well with a medical follow-up time of 5 years. Two patients died of therapeutic complications and six died of tumor spread. In five patients, involvement of the central nervous system (CNS) was the cause of death. The prognosis of orbital RMS with parameningeal involvement is no better than in other tumors of parameningeal sites. In those patients who had impaired vision because of optic nerve damage prior to treatment, the vision did not improve following treatment. There was no impaired vision seen due to radiation damage of eye structures except in the lens

  13. Eye and orbital cavity

    International Nuclear Information System (INIS)

    Panfilova, G.V.; Koval', G.Yu.

    1984-01-01

    Radioanatomy of eyes and orbit is described. Diseases of the orbit (developmental anomalies, inflammatory diseases, lacrimal apparatus deseases, toxoplasmosis, tumors and cysts et al.), methods of foreign body localization in the eye are considered. Roentgenograms of the orbit and calculation table for foreign body localization in spherical eyes of dissimilar diameter are presented

  14. Telomeres and Telomerase in Hematopoietic Dysfunction: Prognostic Implications and Pharmacological Interventions

    Directory of Open Access Journals (Sweden)

    Theresa Vasko

    2017-10-01

    Full Text Available Leukocyte telomere length (TL has been suggested as a marker of biological age in healthy individuals, but can also reflect inherited and acquired hematopoietic dysfunctions or indicate an increased turnover of the hematopoietic stem and progenitor cell compartment. In addition, TL is able to predict the response rate of tyrosine kinase inhibitor therapy in chronic myeloid leukemia (CML, indicates clinical outcomes in chronic lymphocytic leukemia (CLL, and can be used as screening tool for genetic sequencing of selected genes in patients with inherited bone marrow failure syndromes (BMFS. In tumor cells and clonal hematopoietic disorders, telomeres are continuously stabilized by reactivation of telomerase, which can selectively be targeted by telomerase-specific therapy. The use of the telomerase inhibitor Imetelstat in patients with essential thrombocythmia or myelofibrosis as well as the use of dendritic cell-based telomerase vaccination in AML patients with complete remissions are promising examples for anti-telomerase targeted strategies in hematologic malignancies. In contrast, the elevation in telomerase levels through treatment with androgens has become an exciting clinical intervention for patients with BMFS. Here, we review recent developments, which highlight the impact of telomeres and telomerase targeted therapies in hematologic dysfunctions.

  15. Radioresistant canine hematopoietic cells

    International Nuclear Information System (INIS)

    Kawakami, T.G.; Shimizu, J.; Rosenblatt, L.S.; Goldman, M.

    1987-01-01

    Survival of dogs that are continuously exposed to a moderate dose-rate of gamma radiation (10 cGy/day) is dependent on the age of the dog at the time of exposure. Most dogs exposed postpartum to gamma radiation suffered from suppressed hematopoiesis and died of aplasia. On the other hand, none of the in utero-exposed dogs suffered from suppressed hematopoiesis and most became long-term survivors, tolerating 10-fold greater total dose, but dying of myeloproliferative disease (MPD). Using acute gamma irradiation of hematopoietic cells and colony forming unit cell assay (CFU), they observed that a canine hematopoietic cell line established from a myeloid leukemic dog that was a long-term survivor of continuous irradiation was approximately 4-fold more radioresistant than a hematopoietic cell line established from a dog with nonradiation-induced myeloid leukemia or hematopoietic cells from normal canine bone marrow. In utero dogs that are long-term survivors of continuous irradiation have radioresistant hematopoietic cells, and radioresistance that is a constitutive property of the cells

  16. Primary Orbital Chondromyxoid Fibroma: A Rare Case.

    Science.gov (United States)

    Mullen, Martin G; Somogyi, Marie; Maxwell, Sean P; Prabhu, Vikram; Yoo, David K

    A 56-year-old male with history of chronic sinusitis was found to have a 3 cm left orbital lesion on CT. Subsequent MRI demonstrated a multilobulated enhancing soft tissue lesion at the superotemporal region of the left orbit. Initial biopsy was reported as a low-grade sarcoma. On further evaluation, a consensus was made that the lesion was likely a benign mixed mesenchymal type tumor but should nonetheless be surgically removed. Left lateral orbitotomy was performed which revealed a tumor originating in the lateral orbital bone with segments eroding through the wall of the orbit. Intraoperative frozen sections revealed myoepitheliod tissue with locally aggressive features and the tumor was completely removed. The final histopathologic analysis of the tissue was consistent with a chondromyxoid fibroma. Chondomyxoid fibroma is a rare entity in the orbital bones and is more commonly seen in long bones.

  17. Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice.

    Science.gov (United States)

    Zhang, Qing-Shuo; Tang, Weiliang; Deater, Matthew; Phan, Ngoc; Marcogliese, Andrea N; Li, Hui; Al-Dhalimy, Muhsen; Major, Angela; Olson, Susan; Monnat, Raymond J; Grompe, Markus

    2016-12-15

    Fanconi anemia (FA) is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently the only curative therapy for the hematopoietic complications of this disorder. However, long-term morbidity and mortality remain very high, and new therapeutics are badly needed. Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2 -/- mice. Metformin is the first compound reported to improve both of these FA phenotypes. Importantly, the beneficial effects are specific to FA mice and are not seen in the wild-type controls. In this preclinical model of FA, metformin outperformed the current standard of care, oxymetholone, by improving peripheral blood counts in Fancd2 -/- mice significantly faster. Metformin increased the size of the hematopoietic stem cell compartment and enhanced quiescence in hematopoietic stem and progenitor cells. In tumor-prone Fancd2 -/- Trp53 +/- mice, metformin delayed the onset of tumors and significantly extended the tumor-free survival time. In addition, we found that metformin and the structurally related compound aminoguanidine reduced DNA damage and ameliorated spontaneous chromosome breakage and radials in human FA patient-derived cells. Our results also indicate that aldehyde detoxification might be one of the mechanisms by which metformin reduces DNA damage in FA cells. © 2016 by The American Society of Hematology.

  18. The effect of carbon beam on the survival of hematopoietic stem cells in irradiated mice

    International Nuclear Information System (INIS)

    Tsuboi, Atsushi; Kojima, Eiichi; Tanaka, Kaoru

    1993-01-01

    The new cyclotron for heavy ion radiotherapy will be completed in the very near future at NIRS. High LET radiations having different qualities are known to produce differences in biological effectiveness. It is necessary to determine the biological effectiveness of this new radiation source in both normal and tumor tissues. In this paper, the effects of 200 kVp x-rays and a 135 MeV/u carbon 12 beam on hematopoietic stem cells (CFU-S and GM-CFC) are described. The rationale for this experimental approach is that the sensitivity of hematopoietic stem cells and the committed stem cells to radiation is often the treatment limiting-factor for radiotherapy. (author)

  19. Donor-Cell Origin High-Risk Myelodysplastic Syndrome Synchronous with an Intracranial Meningioma-Like Tumor, 8 Years after Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    G. Brás

    2017-01-01

    Full Text Available Secondary neoplasias are well known consequences of radiotherapy or chemotherapy for a primary cancer. In this report, we describe two rare secondary neoplasias occurring in the same patient: a meningioma-like intracranial tumor and high-risk myelodysplastic syndrome (MDS of donor-cells origin, both diagnosed simultaneously, 8 years after an allogeneic hematopoietic stem cell transplantation (allo-HSCT for chronic lymphocytic leukemia (CLL. Due to an engraftment failure during the first allo-HSCT of a matched related donor for CLL treatment, the salvage treatment was a second allo-HSCT. At the moment of meningioma-like tumor diagnosis, the patient was pancytopenic due to high-risk MDS, so it was decided to postpone a surgical intervention until hematological improvement. For the high-risk MDS of donor-cells origin the chosen treatment was induction with intensive chemotherapy. Due to refractory disease, the patient was treated with 5-azacitidine and donor-lymphocytes infusion with no response and, finally, a third allo-HSCT of a matched unrelated donor was performed. The patient died 6 months after the third allo-HSCT, in cytogenetic remission but without hematological recovery, due to an intracranial hemorrhage with origin in the meningioma-like tumor.

  20. Pre-Transplantation Blockade of TNF-α-Mediated Oxygen Species Accumulation Protects Hematopoietic Stem Cells.

    Science.gov (United States)

    Ishida, Takashi; Suzuki, Sachie; Lai, Chen-Yi; Yamazaki, Satoshi; Kakuta, Shigeru; Iwakura, Yoichiro; Nojima, Masanori; Takeuchi, Yasuo; Higashihara, Masaaki; Nakauchi, Hiromitsu; Otsu, Makoto

    2017-04-01

    Hematopoietic stem cell (HSC) transplantation (HSCT) for malignancy requires toxic pre-conditioning to maximize anti-tumor effects and donor-HSC engraftment. While this induces bone marrow (BM)-localized inflammation, how this BM environmental change affects transplanted HSCs in vivo remains largely unknown. We here report that, depending on interval between irradiation and HSCT, residence within lethally irradiated recipient BM compromises donor-HSC reconstitution ability. Both in vivo and in vitro we demonstrate that, among inflammatory cytokines, TNF-α plays a role in HSC damage: TNF-α stimulation leads to accumulation of reactive oxygen species (ROS) in highly purified hematopoietic stem/progenitor cells (HSCs/HSPCs). Transplantation of flow-cytometry-sorted murine HSCs reveals damaging effects of accumulated ROS on HSCs. Short-term incubation either with an specific inhibitor of tumor necrosis factor receptor 1 signaling or an antioxidant N-acetyl-L-cysteine (NAC) prevents TNF-α-mediated ROS accumulation in HSCs. Importantly, pre-transplantation exposure to NAC successfully demonstrats protective effects in inflammatory BM on graft-HSCs, exhibiting better reconstitution capability than that of nonprotected control grafts. We thus suggest that in vivo protection of graft-HSCs from BM inflammation is a feasible and attractive approach, which may lead to improved hematopoietic reconstitution kinetics in transplantation with myeloablative conditioning that inevitably causes inflammation in recipient BM. Stem Cells 2017;35:989-1002. © 2016 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  1. Technetium tc 99m-labeled red blood cells in the preoperative diagnosis of cavernous hemangioma and other vascular orbital tumors.

    Science.gov (United States)

    Polito, Ennio; Burroni, Luca; Pichierri, Patrizia; Loffredo, Antonio; Vattimo, Angelo G

    2005-12-01

    To evaluate technetium Tc 99m (99mTc) red blood cell scintigraphy as a diagnostic tool for orbital cavernous hemangioma and to differentiate between orbital masses on the basis of their vascularization. We performed 99mTc red blood cell scintigraphy on 23 patients (8 female and 15 male; mean age, 47 years) affected by an orbital mass previously revealed with computed tomography (CT) and magnetic resonance imaging (MRI) and suggesting cavernous hemangioma. In our diagnosis, we considered the orbital increase delayed uptake with the typical scintigraphic pattern known as perfusion blood pool mismatch. The patients underwent biopsy or surgical treatment with transconjunctival cryosurgical extraction when possible. Single-photon emission tomography (SPET) showed intense focal uptake in the orbit corresponding to radiologic findings in 11 patients who underwent surgical treatment and pathologic evaluation (9 cavernous hemangiomas, 1 hemangiopericytoma, and 1 lymphangioma). Clinical or histologic examination of the remaining 22 patients revealed the presence of 5 lymphoid pseudotumors, 2 lymphomas, 2 pleomorphic adenomas of the lacrimal gland, 1 astrocytoma, 1 ophthalmic vein thrombosis, and 1 orbital varix. The confirmation of the preoperative diagnosis by 99mTc red blood cell scintigraphy shows that this technique is a reliable tool for differentiating cavernous hemangiomas from other orbital masses (sensitivity, 100%; specificity, 86%) when ultrasound, CT, and MRI are not diagnostic. Unfortunately, 99mTc red blood cell scintigraphy results were positive in 1 patient with hemangiopericytoma and 1 patient with lymphangioma, which showed increased uptake in the lesion on SPET images because of the vascular nature of these tumors. Therefore, in these cases, the SPET images have to be integrated with data regarding clinical preoperative evaluation and CT scans or MRI studies. On the basis of our study, a complete diagnostic picture, CT scans or MRI studies, and

  2. Regulation of Hematopoietic Cell Development and Function Through Phosphoinositides

    Directory of Open Access Journals (Sweden)

    Mila Elich

    2018-05-01

    Full Text Available One of the most paramount receptor-induced signal transduction mechanisms in hematopoietic cells is production of the lipid second messenger phosphatidylinositol(3,4,5trisphosphate (PIP3 by class I phosphoinositide 3 kinases (PI3K. Defective PIP3 signaling impairs almost every aspect of hematopoiesis, including T cell development and function. Limiting PIP3 signaling is particularly important, because excessive PIP3 function in lymphocytes can transform them and cause blood cancers. Here, we review the key functions of PIP3 and related phosphoinositides in hematopoietic cells, with a special focus on those mechanisms dampening PIP3 production, turnover, or function. Recent studies have shown that beyond “canonical” turnover by the PIP3 phosphatases and tumor suppressors phosphatase and tensin homolog (PTEN and SH2 domain-containing inositol-5-phosphatase-1 (SHIP-1/2, PIP3 function in hematopoietic cells can also be dampened through antagonism with the soluble PIP3 analogs inositol(1,3,4,5tetrakisphosphate (IP4 and inositol-heptakisphosphate (IP7. Other evidence suggests that IP4 can promote PIP3 function in thymocytes. Moreover, IP4 or the kinases producing it limit store-operated Ca2+ entry through Orai channels in B cells, T cells, and neutrophils to control cell survival and function. We discuss current models for how soluble inositol phosphates can have such diverse functions and can govern as distinct processes as hematopoietic stem cell homeostasis, neutrophil macrophage and NK cell function, and development and function of B cells and T cells. Finally, we will review the pathological consequences of dysregulated IP4 activity in immune cells and highlight contributions of impaired inositol phosphate functions in disorders such as Kawasaki disease, common variable immunodeficiency, or blood cancer.

  3. [Orbital inflammation].

    Science.gov (United States)

    Mouriaux, F; Coffin-Pichonnet, S; Robert, P-Y; Abad, S; Martin-Silva, N

    2014-12-01

    Orbital inflammation is a generic term encompassing inflammatory pathologies affecting all structures within the orbit : anterior (involvement up to the posterior aspect of the globe), diffuse (involvement of intra- and/or extraconal fat), apical (involvement of the posterior orbit), myositis (involvement of only the extraocular muscles), dacryoadenitis (involvement of the lacrimal gland). We distinguish between specific inflammation and non-specific inflammation, commonly referred to as idiopathic inflammation. Specific orbital inflammation corresponds to a secondary localization of a "generalized" disease (systemic or auto-immune). Idiopathic orbital inflammation corresponds to uniquely orbital inflammation without generalized disease, and thus an unknown etiology. At the top of the differential diagnosis for specific or idiopathic orbital inflammation are malignant tumors, represented most commonly in the adult by lympho-proliferative syndromes and metastases. Treatment of specific orbital inflammation begins with treatment of the underlying disease. For idiopathic orbital inflammation, treatment (most often corticosteroids) is indicated above all in cases of visual loss due to optic neuropathy, in the presence of pain or oculomotor palsy. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  4. A case series of clinically undiagnosed hematopoietic neoplasms discovered at autopsy.

    Science.gov (United States)

    Podduturi, Varsha; Guileyardo, Joseph M; Soto, Luis R; Krause, John R

    2015-06-01

    In the United States, autopsy rates have diminished to less than 5% during the last half of the 20th century and the beginning of the 21st century for a multitude of reasons. Many believe this results in unrecognized malignancies that could have explained a patient's death. We describe six deaths in which hematopoietic neoplasms were identified at autopsy but were not diagnosed clinically. The six undiagnosed hematopoietic malignancy cases discovered at autopsy include four men and two women ranging from 50 to 78 years of age. One patient was African American and five patients were white, all with multiple comorbidities. The tumors included diffuse large B-cell lymphoma, activated B-cell type, intravascular large B-cell lymphoma, ALK-negative anaplastic large cell lymphoma arising in a setting of human immunodeficiency virus, and a myeloid sarcoma. These cases illustrate the importance of the traditional postmortem examination in not only confirming clinical diagnoses but also identifying previously unknown diagnoses. Hematologic malignancies may present with nonspecific clinical manifestations, and this series of cases also emphasizes the necessity for widening the differential diagnosis in patients with unexplained lactic acidosis and hepatic failure to include hematopoietic malignancies since prompt treatment may be lifesaving. Copyright© by the American Society for Clinical Pathology.

  5. Primary primitive neuroectodermal tumor of the orbit

    Directory of Open Access Journals (Sweden)

    Das Dipankar

    2009-01-01

    Full Text Available Primitive neuroectodermal tumor (PNET is a small round cell malignant tumor of neuroectodermal origin. Most of the PNETs occur in the central nervous system (CNS. PNETs recognized outside of CNS are diagnosed as peripheral PNET (pPNET. This tumor which expresses MIC-2 gene (CD99 seems to be least aggressive after complete tumor resection. We describe a rare case of PNET in a young girl.

  6. Loss of Folliculin Disrupts Hematopoietic Stem Cell Quiescence and Homeostasis Resulting in Bone Marrow Failure.

    Science.gov (United States)

    Baba, Masaya; Toyama, Hirofumi; Sun, Lei; Takubo, Keiyo; Suh, Hyung-Chan; Hasumi, Hisashi; Nakamura-Ishizu, Ayako; Hasumi, Yukiko; Klarmann, Kimberly D; Nakagata, Naomi; Schmidt, Laura S; Linehan, W Marston; Suda, Toshio; Keller, Jonathan R

    2016-04-01

    Folliculin (FLCN) is an autosomal dominant tumor suppressor gene that modulates diverse signaling pathways required for growth, proliferation, metabolism, survival, motility, and adhesion. FLCN is an essential protein required for murine embryonic development, embryonic stem cell (ESC) commitment, and Drosophila germline stem cell maintenance, suggesting that Flcn may be required for adult stem cell homeostasis. Conditional inactivation of Flcn in adult hematopoietic stem/progenitor cells (HSPCs) drives hematopoietic stem cells (HSC) into proliferative exhaustion resulting in the rapid depletion of HSPC, loss of all hematopoietic cell lineages, acute bone marrow (BM) failure, and mortality after 40 days. HSC that lack Flcn fail to reconstitute the hematopoietic compartment in recipient mice, demonstrating a cell-autonomous requirement for Flcn in HSC maintenance. BM cells showed increased phosphorylation of Akt and mTorc1, and extramedullary hematopoiesis was significantly reduced by treating mice with rapamycin in vivo, suggesting that the mTorc1 pathway was activated by loss of Flcn expression in hematopoietic cells in vivo. Tfe3 was activated and preferentially localized to the nucleus of Flcn knockout (KO) HSPCs. Tfe3 overexpression in HSPCs impaired long-term hematopoietic reconstitution in vivo, recapitulating the Flcn KO phenotype, and supporting the notion that abnormal activation of Tfe3 contributes to the Flcn KO phenotype. Flcn KO mice develop an acute histiocytic hyperplasia in multiple organs, suggesting a novel function for Flcn in macrophage development. Thus, Flcn is intrinsically required to maintain adult HSC quiescence and homeostasis, and Flcn loss leads to BM failure and mortality in mice. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  7. Degree of Predicted Minor Histocompatibility Antigen Mismatch Correlates with Poorer Clinical Outcomes of Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation

    DEFF Research Database (Denmark)

    Larsen, Malene Erup; Kornblit, B; Larsen, Mette Voldby

    2010-01-01

    In fully HLA-matched allogeneic hematopoietic cell transplantations (HCT), the main mechanism of the beneficial graft-versus-tumor (GVT) effect and of the detrimental graft-versus-host disease (GVHD) is believed to be caused by donor cytotoxic T cells directed against disparate recipient minor hi...

  8. CD30 ligand is frequently expressed in human hematopoietic malignancies of myeloid and lymphoid origin.

    Science.gov (United States)

    Gattei, V; Degan, M; Gloghini, A; De Iuliis, A; Improta, S; Rossi, F M; Aldinucci, D; Perin, V; Serraino, D; Babare, R; Zagonel, V; Gruss, H J; Carbone, A; Pinto, A

    1997-03-15

    CD30 ligand (CD30L) is a type-II membrane glycoprotein capable of transducing signals leading to either cell death or proliferation through its specific counterstructure CD30. Although several lines of evidence indicate that CD30L plays a key role as a paracrine- or autocrine-acting surface molecule in the deregulated cytokine cascade of Hodgkin's disease, little is known regarding its distribution and biologic significance in other human hematopoietic malignancies. By analyzing tumor cells from 181 patients with RNA studies and immunostaining by the anti-CD30L monoclonal antibody M80, we were able to show that human hematopoietic malignancies of different lineage and maturation stage display a frequent and broad expression of the ligand. CD30L mRNA and surface protein were detected in 60% of acute myeloid leukemias (AMLs), 54% of B-lineage acute lymphoblastic leukemias (ALLs), and in a consistent fraction (68%) of B-cell lymphoproliferative disorders. In this latter group, hairy cell leukemia and high-grade B-cell non-Hodgkin's lymphoma (B-NHL) expressed a higher surface density of CD30L as compared with B-cell chronic lymphocytic leukemia and low-grade B-NHL. Purified plasmacells from a fraction of multiple myeloma patients also displayed CD30L mRNA and protein. A more restricted expression of CD30L was found in T-cell tumors that was mainly confined to neoplasms with an activated peripheral T-cell phenotype, such as T-cell prolymphocytic leukemia, peripheral T-NHL, and adult T-cell leukemia/lymphoma. In contrast, none of the T-lineage ALLs analyzed expressed the ligand. In AML, a high cellular density of CD30L was detected in French-American-British M3, M4, and M5 phenotypes, which are directly associated with the presence on tumor cells of certain surface structures, including the p55 interleukin-2 receptor alpha-chain, the alpha(M) (CD11b) chain of beta2 integrins, and the intercellular adhesion molecule-1 (CD54). Analysis of normal hematopoietic cells

  9. The orbital and sinonasal hemangiopericytoma, 2 case reports:

    Directory of Open Access Journals (Sweden)

    Maryam Maghbol

    2016-03-01

    Full Text Available Background & objective: Hemangiopericytoma is an uncommon vascular tumor derived from the pericytes of Zimmermann. . The most common location of the tumor is pelvic retroperitoneum and musculoskeletal system of the lower extremities. It is rarely seen in the head and neck area. In addition, only 0.8% to 3% of all orbital tumors and less than 5 % of primary sinonasal tumors are primary hemangiopericytoma, which demonstrates that the orbital and sinonasal cavities are rare locations for this tumor. Case: 2 cases of primary orbital and sinonasal hemangiopericytoma that were successfully treated through surgery were reported. Conclusion: Hemangiopericytoma is an uncommon vascular tumor which has a potentially malignant behavior. Histopathologic features alone do not predict the biologic behavior of the tumor but the increased cellularity, necrosis, hemorrhage and more than 4 mitotic figures per 10 high power field, may elicit a diagnosis of malignant hemangiopericytoma . The local recurrence and the distant metastasis might also occur with an incomplete excision.  The lung, bone and liver are the most common sites of distant metastasis. Thus, the long-term follow-up is recommended after the surgical removal of the tumor.

  10. Imaging of complications from hematopoietic stem cell transplant

    International Nuclear Information System (INIS)

    Pandey, Tarun; Maximin, Suresh; Bhargava, Puneet

    2014-01-01

    Stem cell transplant has been the focus of clinical research for a long time given its potential to treat several incurable diseases like hematological malignancies, diabetes mellitus, and neuro-degenerative disorders like Parkinson disease. Hematopoietic stem cell transplantation (HSCT) is the oldest and most widely used technique of stem cell transplant. HSCT has not only been used to treat hematological disorders including hematological malignancies, but has also been found useful in treamtent of genetic, immunological, and solid tumors like neuroblastoma, lymphoma, and germ cell tumors. In spite of the rapid advances in stem cell technology, success rate with this technique has not been universal and many complications have also been seen with this form of therapy. The key to a successful HSCT therapy lies in early diagnosis and effective management of complications associated with this treatment. Our article aims to review the role of imaging in diagnosis and management of stem cell transplant complications associated with HSCT

  11. Extramedullary hematopoiesis in a case of benign mixed mammary tumor in a female dog: cytological and histopathological assessment

    Directory of Open Access Journals (Sweden)

    Leão João

    2010-09-01

    Full Text Available Abstract Backgroud Extramedullary hematopoiesis (EMH is defined as the presence of hematopoietic stem cells such as erythroid and myeloid lineage plus megakaryocytes in extramedullary sites like liver, spleen and lymph nodes and is usually associated with either bone marrow or hematological disorders. Mammary EMH is a rare condition either in human and veterinary medicine and can be associated with benign mixed mammary tumors, similarly to that described in this case. Case presentation Hematopoietic stem cells were found in a benign mixed mammary tumor of a 7-year-old female mongrel dog that presents a nodule in the left inguinal mammary gland. The patient did not have any hematological abnormalities. Cytological evaluation demonstrated two distinct cell populations, composed of either epithelial or mesenchymal cells, sometimes associated with a fibrillar acidophilic matrix, apart from megakaryocytes, osteoclasts, metarubricytes, prorubricytes, rubricytes, rubriblasts, promyelocytes, myeloblasts. Histological examination confirmed the presence of an active hematopoietic bone marrow within the bone tissue of a benign mammary mixed tumor. Conclusions EMH is a rare condition described in veterinary medicine that can be associated with mammary mixed tumors. It's detection can be associated with several neoplastic and non-neoplastic mammary lesions, i.e. osteosarcomas, mixed tumors and bone metaplasia.

  12. Towards effective and safe immunotherapy after allogeneic stem cell transplantation: identification of hematopoietic-specific minor histocompatibility antigen UTA2-1

    NARCIS (Netherlands)

    Oostvogels, R.; Minnema, M. C.; van Elk, M.; Spaapen, R. M.; te Raa, G. D.; Giovannone, B.; Buijs, A.; van Baarle, D.; Kater, A. P.; Griffioen, M.; Spierings, E.; Lokhorst, H. M.; Mutis, T.

    2013-01-01

    Donor T cells directed at hematopoietic system-specific minor histoconnpatibility antigens (mHags) are considered important cellular tools to induce therapeutic graft-versus-tumor (GvT) effects with low risk of graft-versus-host disease after allogeneic stem cell transplantation. To enable the

  13. Successful Large-volume Leukapheresis for Hematopoietic Stem Cell Collection in a Very-low-weight Brain Tumor Infant with Coagulopathy

    Directory of Open Access Journals (Sweden)

    Yu-Mei Liao

    2013-06-01

    Full Text Available Peripheral apheresis has become a safe procedure to collect hematopoietic stem cells, even in pediatric patients and donors. However, the apheresis procedure for small and sick children is more complicated due to difficult venous access, relatively large extracorporeal volume, toxicity of citrate, and unstable hemostasis. We report a small and sick child with refractory medulloblastoma, impaired liver function, and coagulopathy after several major cycles of cisplatin-based chemotherapy. She successfully received large-volume leukapheresis for hematopoietic stem cell collection, although the patient experienced severe coagulopathy during the procedures. Health care providers should be alert to this potential risk.

  14. Hematopoietic Stem Cell Transplantation—50 Years of Evolution and Future Perspectives

    Directory of Open Access Journals (Sweden)

    Israel Henig

    2014-10-01

    Full Text Available Hematopoietic stem cell transplantation is a highly specialized and unique medical procedure. Autologous transplantation allows the administration of high-dose chemotherapy without prolonged bone marrow aplasia. In allogeneic transplantation, donor-derived stem cells provide alloimmunity that enables a graft-versus-tumor effect to eradicate residual disease and prevent relapse. The first allogeneic transplantation was performed by E. Donnall Thomas in 1957. Since then the field has evolved and expanded worldwide. New indications beside acute leukemia and aplastic anemia have been constantly explored and now include congenital disorders of the hematopoietic system, metabolic disorders, and autoimmune disease. The use of matched unrelated donors, umbilical cord blood units, and partially matched related donors has dramatically extended the availability of allogeneic transplantation. Transplant-related mortality has decreased due to improved supportive care, including better strategies to prevent severe infections and with the incorporation of reduced-intensity conditioning protocols that lowered the toxicity and allowed for transplantation in older patients. However, disease relapse and graft-versus-host disease remain the two major causes of mortality with unsatisfactory progress. Intense research aiming to improve adoptive immunotherapy and increase graft-versus-leukemia response while decreasing graft-versus-host response might bring the next breakthrough in allogeneic transplantation. Strategies of graft manipulation, tumor-associated antigen vaccinations, monoclonal antibodies, and adoptive cellular immunotherapy have already proved clinically efficient. In the following years, allogeneic transplantation is likely to become more complex, more individualized, and more efficient.

  15. Pathology of orbital bones. The XXXII Edward Jackson Memorial Lecture.

    Science.gov (United States)

    Blodi, F C

    1976-01-01

    The orbital bones may show nearly all the pathologic changes observed in the skull and in the face. The congenital anomalies in this area are numerous and involve various forms of craniostenoses. Among the benign osseous tumors the osteoma is most frequently encountered in the orbit. Fibrous dysplasia is a tumefaction of indeterminate behavior that often involves the orbit. Osteosarcoma or other malignant neoplasms are rarely seen in this area. Eosinophilic granuloma and Hand-Schüller-Christian disease are tumor-like lesions that may involve the orbit.

  16. Exogenous endothelial cells as accelerators of hematopoietic reconstitution

    Directory of Open Access Journals (Sweden)

    Mizer J

    2012-11-01

    Full Text Available Abstract Despite the successes of recombinant hematopoietic-stimulatory factors at accelerating bone marrow reconstitution and shortening the neutropenic period post-transplantation, significant challenges remain such as cost, inability to reconstitute thrombocytic lineages, and lack of efficacy in conditions such as aplastic anemia. A possible means of accelerating hematopoietic reconstitution would be administration of cells capable of secreting hematopoietic growth factors. Advantages of this approach would include: a ability to regulate secretion of cytokines based on biological need; b long term, localized production of growth factors, alleviating need for systemic administration of factors that possess unintended adverse effects; and c potential to actively repair the hematopoietic stem cell niche. Here we overview the field of hematopoietic growth factors, discuss previous experiences with mesenchymal stem cells (MSC in accelerating hematopoiesis, and conclude by putting forth the rationale of utilizing exogenous endothelial cells as a novel cellular therapy for acceleration of hematopoietic recovery.

  17. [Immunological mechanisms of graft versus tumor effect].

    Science.gov (United States)

    Ine, Shoji; Yamada, Minami; Miyamura, Koichi; Sasaki, Takeshi

    2003-09-01

    Lesson from hematopoietic stem cell transplantation demonstrated that donor immuno-surveillance system can eradicate tumor cells. This is so-call graft versus tumor(GVT) effect. Antigen presenting cells show peptide from minor antigen rather leukemic specific antigen in the context of major histocompatibility complex. The effector cells composed of CD8 T lymphocyte, CD4 T lymphocyte, natural killer cell and natural killer T cell. Death signal was transmitted from effector cells via granzyme/perforin system and FasL/Fas system, and recently TRAIL system seems most important for GVT effect.

  18. Clinical practice of radiotherapy

    International Nuclear Information System (INIS)

    Horiuchi, Junichi; Masaki, Norie; Onoyama, Yasuto

    1987-01-01

    This chapter presents in greater detail radiotherapy used in each clinical setting. The descriptions are given under the following sections: the tongue and oral cavity; the maxilla, larynx, and pharynx; brain tumors; the eyes and orbit; pediatric tumors; lung cancer; the esophagus; breast cancer; the abdominal digestive system; the urogenital system; the uterine cervix; the ovaries and vulva; bone and soft tissues; the skin; hematopoietic tumors; lymph node metastases; and radiotherapy as palliative treatment. (Namekawa, K.)

  19. Outcomes following autologous hematopoietic stem cell transplant for patients with relapsed Wilms’ Tumor: A CIBMTR retrospective analysis

    Science.gov (United States)

    Malogolowkin, Marcio H.; Hemmer, Michael T.; Le-Rademacher, Jennifer; Hale, Gregory A; Metha, Parinda A.; Smith, Angela R.; Kitko, Carrie; Abraham, Allistair; Abdel-Azim, Hisham; Dandoy, Christopher; Diaz, Miguel Angel; Gale, Robert Peter; Guilcher, Greg; Hayashi, Robert; Jodele, Sonata; Kasow, Kimberly A.; MacMillian, Margaret L.; Thakar, Monica; Wirk, Baldeep M.; Woolfrey, Ann; Thiel, E L

    2017-01-01

    Despite the dramatic improvement in the overall survival for patients diagnosed with Wilms’ tumor (WT), the outcomes for those that experience relapse have remained disappointing. We describe the outcomes of 253 patients with relapsed WT who received high-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplant (HCT) between 1990 and 2013, and reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR). The 5-year estimates for event free survival (EFS) and overall survival (OS) were 36% (95% CI; 29 – 43%) and 45% (95% CI; 38 – 51%) respectively. Relapse of primary disease was the cause of death in 81% of the population. EFS, OS, relapse and transplant-related mortality (TRM) showed no significant differences when broken down by disease status at transplant, time from diagnosis to transplant, year of transplant or conditioning regimen. Our data suggest that HDT followed by autologous HCT for relapsed WT is well tolerated and outcomes are similar to those reported in the literature. Since attempts to conduct a randomized trial comparing maintenance chemotherapy with consolidation versus high-dose chemotherapy followed by stem cell transplant have failed, one should balance the potential benefits with the yet unknown long-term risks. Since disease recurrence continues to be the most common cause of death, future research should focus on the development of consolidation therapies for those patients achieving complete response to therapy. PMID:28869618

  20. Diagnostic Approaches to Metastatic Hepatocellular Carcinoma of the Orbit.

    Science.gov (United States)

    Geske, Michael J; Bloomer, Michele M; Kersten, Robert C; Vagefi, M Reza

    Orbital metastasis of hepatocellular carcinoma is exceedingly rare and caries a grave prognosis. Three cases of metastatic orbital hepatocellular carcinoma in which the primary tumor was initially unknown and the diagnostic challenges encountered are presented. With hepatocellular carcinoma, open biopsy and palliative tumor debulking has an increased bleeding risk due to the highly vascular nature of the tumor and coagulopathy associated with chronic liver disease. As an alternative, fine needle aspiration biopsy should be considered for hepatocellular carcinoma with a readily accessible mass and the availability of an experienced cytopathologist.

  1. Tumor-altered dendritic cell function: implications for anti-tumor immunity

    Directory of Open Access Journals (Sweden)

    Kristian Michael Hargadon

    2013-07-01

    Full Text Available Dendritic cells are key regulators of both innate and adaptive immunity, and the array of immunoregulatory functions exhibited by these cells is dictated by their differentiation, maturation, and activation status. Although a major role for these cells in the induction of immunity to pathogens has long been appreciated, data accumulated over the last several years has demonstrated that DC are also critical regulators of anti-tumor immune responses. However, despite the potential for stimulation of robust anti-tumor immunity by DC, tumor-altered DC function has been observed in many cancer patients and tumor-bearing animals and is often associated with tumor immune escape. Such dysfunction has significant implications for both the induction of natural anti-tumor immune responses as well as the efficacy of immunotherapeutic strategies that target endogenous DC in situ or that employ exogenous DC as part of anti-cancer immunization maneuvers. In this review, the major types of tumor-altered DC function will be described, with emphasis on recent insights into the mechanistic bases for the inhibition of DC differentiation from hematopoietic precursors, the altered programming of DC precursors to differentiate into myeloid-derived suppressor cells or tumor-associated macrophages, the suppression of DC maturation and activation, and the induction of immunoregulatory DC by tumors, tumor-derived factors, and tumor-associated cells within the milieu of the tumor microenvironment. The impact of these tumor-altered cells on the quality of the overall anti-tumor immune response will also be discussed. Finally, this review will also highlight questions concerning tumor-altered DC function that remain unanswered, and it will address factors that have limited advances in the study of this phenomenon in order to focus future research efforts in the field on identifying strategies for interfering with tumor-associated DC dysfunction and improving DC-mediated anti-tumor

  2. Diffusion weighted imaging for differentiating benign from malignant orbital tumors: Diagnostic performance of the apparent diffusion coefficient based on region of interest selection method

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Xiao Quan; Hu, Hao Hu; Su, Guo Yi; Liu, Hu; Shi, Hai Bin; Wu, Fei Yun [First Affiliated Hospital of Nanjing Medical University, Nanjing (China)

    2016-09-15

    To evaluate the differences in the apparent diffusion coefficient (ADC) measurements based on three different region of interest (ROI) selection methods, and compare their diagnostic performance in differentiating benign from malignant orbital tumors. Diffusion-weighted imaging data of sixty-four patients with orbital tumors (33 benign and 31 malignant) were retrospectively analyzed. Two readers independently measured the ADC values using three different ROIs selection methods including whole-tumor (WT), single-slice (SS), and reader-defined small sample (RDSS). The differences of ADC values (ADC-ROI{sub WT}, ADC-ROI{sub SS}, and ADC-ROI{sub RDSS}) between benign and malignant group were compared using unpaired t test. Receiver operating characteristic curve was used to determine and compare their diagnostic ability. The ADC measurement time was compared using ANOVA analysis and the measurement reproducibility was assessed using Bland-Altman method and intra-class correlation coefficient (ICC). Malignant group showed significantly lower ADC-ROI{sub WT}, ADC-ROI{sub SS}, and ADC-ROI{sub RDSS} than benign group (all p < 0.05). The areas under the curve showed no significant difference when using ADC-ROI{sub WT}, ADC-ROI{sub SS}, and ADC-ROI{sub RDSS} as differentiating index, respectively (all p > 0.05). The ROI{sub SS} and ROI{sub RDSS} required comparable measurement time (p > 0.05), while significantly shorter than ROI{sub WT} (p < 0.05). The ROI{sub SS} showed the best reproducibility (mean difference ± limits of agreement between two readers were 0.022 [-0.080–0.123] × 10{sup -3} mm{sup 2}/s; ICC, 0.997) among three ROI method. Apparent diffusion coefficient values based on the three different ROI selection methods can help to differentiate benign from malignant orbital tumors. The results of measurement time, reproducibility and diagnostic ability suggest that the ROI{sub SS} method are potentially useful for clinical practice.

  3. Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia

    Science.gov (United States)

    Wang, Wenwen; Stiehl, Thomas; Raffel, Simon; Hoang, Van T.; Hoffmann, Isabel; Poisa-Beiro, Laura; Saeed, Borhan R.; Blume, Rachel; Manta, Linda; Eckstein, Volker; Bochtler, Tilmann; Wuchter, Patrick; Essers, Marieke; Jauch, Anna; Trumpp, Andreas; Marciniak-Czochra, Anna; Ho, Anthony D.; Lutz, Christoph

    2017-01-01

    In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse. PMID:28550184

  4. Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia.

    Science.gov (United States)

    Wang, Wenwen; Stiehl, Thomas; Raffel, Simon; Hoang, Van T; Hoffmann, Isabel; Poisa-Beiro, Laura; Saeed, Borhan R; Blume, Rachel; Manta, Linda; Eckstein, Volker; Bochtler, Tilmann; Wuchter, Patrick; Essers, Marieke; Jauch, Anna; Trumpp, Andreas; Marciniak-Czochra, Anna; Ho, Anthony D; Lutz, Christoph

    2017-09-01

    In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse. Copyright© 2017 Ferrata Storti Foundation.

  5. Hematopoietic stem cell expansion : challenges and opportunities

    NARCIS (Netherlands)

    Walasek, Marta A.; van Os, Ronald; de Haan, Gerald; Kanz, L; Fibbe, WE; Lengerke, C; Dick, JE

    2012-01-01

    Attempts to improve hematopoietic reconstitution and engraftment potential of ex vivo-expanded hematopoietic stem and progenitor cells (HSPCs) have been largely unsuccessful due to the inability to generate sufficient stem cell numbers and to excessive differentiation of the starting cell

  6. Biology and flow cytometry of proangiogenic hematopoietic progenitors cells.

    Science.gov (United States)

    Rose, Jonathan A; Erzurum, Serpil; Asosingh, Kewal

    2015-01-01

    During development, hematopoiesis and neovascularization are closely linked to each other via a common bipotent stem cell called the hemangioblast that gives rise to both hematopoietic cells and endothelial cells. In postnatal life, this functional connection between the vasculature and hematopoiesis is maintained by a subset of hematopoietic progenitor cells endowed with the capacity to differentiate into potent proangiogenic cells. These proangiogenic hematopoietic progenitors comprise a specific subset of bone marrow (BM)-derived cells that homes to sites of neovascularization and possess potent paracrine angiogenic activity. There is emerging evidence that this subpopulation of hematopoietic progenitors plays a critical role in vascular health and disease. Their angiogenic activity is distinct from putative "endothelial progenitor cells" that become structural cells of the endothelium by differentiation into endothelial cells. Proangiogenic hematopoietic progenitor cell research requires multidisciplinary expertise in flow cytometry, hematology, and vascular biology. This review provides a comprehensive overview of proangiogenic hematopoietic progenitor cell biology and flow cytometric methods to detect these cells in the peripheral blood circulation and BM. © 2014 International Society for Advancement of Cytometry.

  7. The biochemistry of hematopoietic stem cell development

    NARCIS (Netherlands)

    P. Kaimakis (Polynikis); M. Crisan (Mihaela); E.A. Dzierzak (Elaine)

    2013-01-01

    textabstractBackground: The cornerstone of the adult hematopoietic system and clinical treatments for blood-related disease is the cohort of hematopoietic stem cells (HSC) that is harbored in the adult bone marrow microenvironment. Interestingly, this cohort of HSCs is generated only during a short

  8. Tritium contamination of hematopoietic stem cells alters long-term hematopoietic reconstitution

    International Nuclear Information System (INIS)

    Di Giacomo, F.; Barroca, V.; Laurent, D.; Lewandowski, D.; Saintigny, Y.; Romeo, P.H.; Granotier, Ch.; Boussin, F.D.

    2011-01-01

    Purpose: In vivo effects of tritium contamination are poorly documented. Here, we study the effects of tritiated Thymidine ([ 3 H] Thymidine) or tritiated water (HTO) contamination on the biological properties of hematopoietic stem cells (HSC). Materials and methods: Mouse HSC were contaminated with concentrations of [ 3 H] Thymidine ranging from 0.37-37.03 kBq/ml or of HTO ranging from 5-50 kBq/ml. The biological properties of contaminated HSC were studied in vitro after HTO contamination and in vitro and in vivo after [ 3 H] Thymidine contamination. Results: Proliferation, viability and double-strand breaks were dependent on [ 3 H] Thymidine or HTO concentrations used for contamination but in vitro myeloid differentiation of HSC was not affected by [ 3 H] Thymidine contamination. [ 3 H] Thymidine contaminated HSC showed a compromised long-term capacity of hematopoietic reconstitution and competition experiments showed an up to two-fold decreased capacity of contaminated HSC to reconstitute hematopoiesis. These defects were not due to impaired homing in bone marrow but to an initial decreased proliferation rate of HSC. Conclusion: These results indicate that contaminations of HSC with doses of tritium that do not result in cell death, induce short-term effects on proliferation and cell cycle and long-term effects on hematopoietic reconstitution capacity of contaminated HSC. (authors)

  9. Ophthalmic Artery Embolization as Pretreatment of Orbital Exenteration for Conjunctival Squamous Cell Carcinoma

    International Nuclear Information System (INIS)

    Matsuo, Toshihiko; Ohara, Nobuya; Namba, Yuzaburo; Koshima, Isao; Ida, Kentaro; Kanazawa, Susumu

    2009-01-01

    The aim of this study is to describe the effect of transarterial embolization from the ophthalmic artery as a pretreatment for orbital exenteration. A 75-year-old Chinese man with a 7-year history of gradual increase of the left eye swelling showed a massive conjunctival tumor growing outwardly from the interpalpebral fissure and had no light perception in the left eye. Magnetic resonance imaging showed orbital invasion of the tumor around the left eyeglobe. The initial surgery for the planned orbital exenteration was discontinued after skin incision around the orbital margin due to massive hemorrhage. The patient underwent transarterial embolization with gelatin sponge (Spongel) of the feeding arteries from the left ophthalmic artery and, the next day, had orbital exenteration with well-controllable bleeding and reconstruction with free vascularized anterolateral thigh cutaneous flap transfer. Pathologically, well-differentiated squamous cell carcinoma proliferated in exophytic, papillary, and nested fashions, arising from the bulbar conjunctiva. Tumor cells were also found in the conjunctival stroma around the vessels. The sclera at the equator had a perforated site with tumor cell invasion, but no intraocular invasion was found. Hematoxylin-positive gelatin sponges were found inside the orbital vessels and large choroidal vessels. In conclusion, transarterial embolization of feeding arteries arising from the ophthalmic artery is a useful pretreatment to control bleeding at orbital exenteration for malignancy.

  10. Orbital manifestations in patients with acquired immunodeficiency syndrome.

    Science.gov (United States)

    Sodhi, Punita Kumari

    2014-01-01

    The orbital manifestations of acquired immunodeficiency syndrome(AIDS) are uncommon. To provide a review of orbital manifestations of AIDS, the predisposing factors, investigations, treatment and outcome. Meticulous and systematic literature search of Pubmed to identify manuscripts describing orbital manifestations of AIDS was done and the articles were reviewed.The keywords used in the search were “orbit and AIDS”, “HIV positive and orbit”,“orbit manifestations in AIDS”, “orbital disease and AIDS” and “orbital infections and AIDS”. The orbital involvement in AIDS may present with opportunistic infections from organisms like fungi, viruses, bacteria and protozoa or with malignancies like Kaposi’s sarcoma, squamous cell carcinoma, smooth muscle cell tumors and lymphoma.The predisposing factors for orbital involvement in AIDS are low CD4+ cell count and the immunosuppressive states like diabetes, diabetic ketoacidosis, intravenous drug abuse and neutropenia. A patient may present with fever, headache, nausea, vomiting,decreased vision, ocular pain, and, in cases of mass formation, there is periorbital swelling, axial proptosis, globe displacement and swollen optic disc. Radiologically,mass formation, orbital bony destruction, and spread of disease to contiguous structures including the central nervous system may be seen. The medical management includes therapy for infection and HIV-1 protease inhibitors (highly active antiretroviral therapy)to suppress HIV-1 replication. For tumors, radical surgery including debulking followed by postoperative radiotherapy is generally needed. Orbital involvements with AIDS in any form, infective or malignancy, causes significant morbidity and mortality and should be diagnosed and managed as early as possible.

  11. Imaging of childhood inflammatory myofibroblastic tumor

    Energy Technology Data Exchange (ETDEWEB)

    Oguz, Berna; Ozcan, Hatice Nursun; Omay, Burak; Ozgen, Burce; Haliloglu, Mithat [Division of Pediatric Radiology, Hacettepe University Faculty of Medicine, Department of Radiology, Altindag / Sihhiye, Ankara (Turkey)

    2015-10-15

    Inflammatory myofibroblastic tumor is a rare benign neoplasm and most commonly involves the lung but occurs in extrapulmonary locations. To present imaging findings in inflammatory myofibroblastic tumors in children based on a single-centre experience. We retrospectively reviewed CT and MRI findings of children diagnosed with inflammatory myofibroblastic tumor in a single institution. We identified 15 children (range: 1-17 years) with inflammatory myofibroblastic tumor. The tumor was localized to the lung (n = 5), mediastinum (n = 3), trachea (n = 1), bronchus (n = 1), abdomen (n = 2) and orbit (n = 3). All the extraorbital tumors were solid masses with homogeneous or heterogeneous enhancement. Four lung tumors and one posterior mediastinal tumor contained calcification. Local recurrence following surgical removal occurred in two children with invasion of the esophagus and of the left atrium in one. Localized masses were seen in all children with orbital tumour. Two of these had episcleritis and perineuritis; one had episcleritis, tendonitis, perineuritis, myositis and dacryoadenitis. The locations and imaging features of inflammatory myofibroblastic tumors are variable. (orig.)

  12. Exosome function: from tumor immunology to pathogen biology.

    Science.gov (United States)

    Schorey, Jeffrey S; Bhatnagar, Sanchita

    2008-06-01

    Exosomes are the newest family member of 'bioactive vesicles' that function to promote intercellular communication. Exosomes are derived from the fusion of multivesicular bodies with the plasma membrane and extracellular release of the intraluminal vesicles. Recent studies have focused on the biogenesis and composition of exosomes as well as regulation of exosome release. Exosomes have been shown to be released by cells of hematopoietic and non-hematopoietic origin, yet their function remains enigmatic. Much of the prior work has focused on exosomes as a source of tumor antigens and in presentation of tumor antigens to T cells. However, new studies have shown that exosomes might also promote cell-to-cell spread of infectious agents. Moreover, exosomes isolated from cells infected with various intracellular pathogens, including Mycobacterium tuberculosis and Toxoplasma gondii, have been shown to contain microbial components and can promote antigen presentation and macrophage activation, suggesting that exosomes may function in immune surveillance. In this review, we summarize our understanding of exosome biogenesis but focus primarily on new insights into exosome function. We also discuss their possible use as disease biomarkers and vaccine candidates.

  13. Intraosseous hemangioma of the orbit.

    Science.gov (United States)

    Choi, June Seok; Bae, Yong Chan; Kang, Gyu Bin; Choi, Kyung-Un

    2018-03-01

    Intraosseous hemangioma is an extremely rare tumor that accounts for 1% or fewer of all osseous tumors. The most common sites of its occurrence are the vertebral column and calvaria. Occurrence in a facial bone is very rare. The authors aim to report a case of the surgical treatment of intraosseous hemangioma occurring in the periorbital region, which is a very rare site of occurrence and to introduce our own experiences with the diagnosis and treatment of this condition along with a literature review. A 73-year-old male patient visited our hospital with the chief complaint of a mass touching the left orbital rim. A biopsy was performed by applying a direct incision after local anesthesia. Eventually, intraosseous hemangioma was diagnosed histologically. To fully resect the mass, the orbital floor and zygoma were exposed through a subciliary incision under general anesthesia, and then the tumor was completely eliminated. Bony defect was reconstructed by performing a seventh rib bone graft. Follow-up observation has so far been conducted for 10 months after surgery without recurrence or symptoms.

  14. Two Hemocyte Lineages Exist in Silkworm Larval Hematopoietic Organ

    OpenAIRE

    Nakahara, Yuichi; Kanamori, Yasushi; Kiuchi, Makoto; Kamimura, Manabu

    2010-01-01

    BACKGROUND: Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. METHODOLOGY/PRINCIPAL FINDINGS: To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO) into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocyto...

  15. Differentiation of embryonic stem cells towards hematopoietic cells: progress and pitfalls.

    Science.gov (United States)

    Tian, Xinghui; Kaufman, Dan S

    2008-07-01

    Hematopoietic development from embryonic stem cells has been one of the most productive areas of stem cell biology. Recent studies have progressed from work with mouse to human embryonic stem cells. Strategies to produce defined blood cell populations can be used to better understand normal and abnormal hematopoiesis, as well as potentially improve the generation of hematopoietic cells with therapeutic potential. Molecular profiling, phenotypic and functional analyses have all been utilized to demonstrate that hematopoietic cells derived from embryonic stem cells most closely represent a stage of hematopoiesis that occurs at embryonic/fetal developmental stages. Generation of hematopoietic stem/progenitor cells comparable to hematopoietic stem cells found in the adult sources, such as bone marrow and cord blood, still remains challenging. However, genetic manipulation of intrinsic factors during hematopoietic differentiation has proven a suitable approach to induce adult definitive hematopoiesis from embryonic stem cells. Concrete evidence has shown that embryonic stem cells provide a powerful approach to study the early stage of hematopoiesis. Multiple hematopoietic lineages can be generated from embryonic stem cells, although most of the evidence suggests that hematopoietic development from embryonic stem cells mimics an embryonic/fetal stage of hematopoiesis.

  16. Computed tomography of the eye and orbit

    International Nuclear Information System (INIS)

    Hammerschlag, S.B.; Hesselink, J.R.; Weber, A.L.

    1982-01-01

    This book is the product of the evolution of computed tomography (CT) into subspecialization and the need for one source of information for the busy radiologist. The authors have succeeded in providing a readable overview of orbital CT as well as a reference book. The book is divided into seven major catagories of pathology (Neurofibromatosis, Primary Orbital Neoplasms, Secondary and Metastic Tumors of the Orbit, Vascular Disorders, Inflammatory Disease, Occular Lesions, and Trauma) after separate discussions of anatomy and technique

  17. Gene transfer to pre-hematopoietic and committed hematopoietic precursors in the early mouse Yolk Sac: a comparative study between in situ electroporation and retroviral transduction

    Directory of Open Access Journals (Sweden)

    Lécluse Yann

    2007-07-01

    Full Text Available Abstract Background Hematopoietic development in vertebrate embryos results from the sequential contribution of two pools of precursors independently generated. While intra-embryonic precursors harbour the features of hematopoietic stem cells (HSC, precursors formed earlier in the yolk sac (YS display limited differentiation and self-renewal potentials. The mechanisms leading to the generation of the precursors in both sites are still largely unknown, as are the molecular basis underlying their different potential. A possible approach to assess the role of candidate genes is to transfer or modulate their expression/activity in both sites. We thus designed and compared transduction protocols to target either native extra-embryonic precursors, or hematopoietic precursors. Results One transduction protocol involves transient modification of gene expression through in situ electroporation of the prospective blood islands, which allows the evolution of transfected mesodermal cells in their "normal" environment, upon organ culture. Following in situ electroporation of a GFP reporter construct into the YS cavity of embryos at post-streak (mesodermal/pre-hematopoietic precursors or early somite (hematopoietic precursors stages, high GFP expression levels as well as a good preservation of cell viability is observed in YS explants. Moreover, the erythro-myeloid progeny typical of the YS arises from GFP+ mesodermal cells or hematopoietic precursors, even if the number of targeted precursors is low. The second approach, based on retroviral transduction allows a very efficient transduction of large precursor numbers, but may only be used to target 8 dpc YS hematopoietic precursors. Again, transduced cells generate a progeny quantitatively and qualitatively similar to that of control YS. Conclusion We thus provide two protocols whose combination may allow a thorough study of both early and late events of hematopoietic development in the murine YS. In situ

  18. PARASITIC INFECTIONS IN HEMATOPOIETIC STEM CELL TRANSPLANTATION

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    Isidro Jarque

    2016-07-01

    Full Text Available Parasitic infections are rarely documented in hematopoietic stem cell transplant recipients. However, they may be responsible for fatal complications that are only diagnosed at autopsy. Increased awareness of the possibility of parasitic diseases both in autologous and allogeneic stem cell transplant patients is relevant not only for implementing preventive measures but also for performing an early diagnosis and starting appropriate therapy for these unrecognized but fatal infectious complications in hematopoietic transplant recipients. In this review, we will focus on parasitic diseases occurring in this population especially those with major clinical relevance including toxoplasmosis, American trypanosomiasis, leishmaniasis, malaria, and strongyloidiasis, among others, highlighting the diagnosis and management in hematopoietic transplant recipients.

  19. Differential Requirements for c-Myc in Chronic Hematopoietic Hyperplasia and Acute Hematopoietic Malignancies in Pten-null Mice

    Science.gov (United States)

    Zhang, Jun; Xiao, Yechen; Guo, Yinshi; Breslin, Peter; Zhang, Shubin; Wei, Wei; Zhang, Zhou; Zhang, Jiwang

    2011-01-01

    Myeloproliferative disorders (MPDs), lymphoproliferative disorders (LPDs), acute T-lymphocytic or myeloid leukemia and T-lymphocytic lymphoma were developed in inducible Pten-knockout (Pten−/−) mice. The appearance of these multiple diseases in one animal model provides an opportunity to study the pathogenesis of multiple diseases simultaneously. To study whether Myc function is required for the development of these hematopoietic disorders in Pten−/− mice, we generated inducible Pten/Myc double-knockout mice (Pten−/−/Myc−/−). By comparing the hematopoietic phenotypes of these double-knockout mice with those of Pten−/− mice, we found that both sets of animals developed MPDs and LPDs. However, none of the compound-mutant mice developed acute leukemia or lymphoma. Interestingly, in contrast to the MPDs which developed in Pten−/− mice which are dominated by granulocytes, megakaryocytes predominate in the MPDs of Pten−/−/Myc−/− mice. Our study suggests that the deregulation of PI3K/Akt signaling in Pten−/− hematopoietic cells protects these cells from apoptotic cell death, resulting in chronic proliferative disorders. But due to the differential requirement for Myc in granulocyte as compared to megakaryocyte proliferation, Myc deletion converts Pten−/− MPDs from granulocyte-dominated to megakaryocyte-dominated conditions. Myc is absolutely required for the development of acute hematopoietic malignancies. PMID:21926961

  20. Hematopoietic tissue repair under chronic low daily dose irradiation

    International Nuclear Information System (INIS)

    Seed, T.M.

    1994-01-01

    The capacity of the hematopoietic system to repair constantly accruing cellular damage under chronic, low daily dose gamma irradiation is essential for the maintenance of a functional hematopoietic system, and, in turn, long term survival. In certain individuals, however, such continuous cycles of damage and repair provide an essential inductive environment for selected types of hematopathologies, e.g., myeloid leukemia (ML). We have been studying temporal and causal relationships between hematopoietic capacity, associated repair functions, and propensities for hematologic disease in canines under variable levels of chronic radiation stress (0.3-26.3 cGy d -1 ). Results indicate that the maximum exposure rate tolerated by the hematopoietic system is highly individual-specific and is based largely on the degree to which repair capacity, and, in turn, hematopoietic restoration, is augmented under chronic exposure. In low-tolerance individuals (prone to aplastic anemia, subgroup (1), the failure to augment basic m-pair functions seemingly results in a progressive accumulation of genetic and cellular damage within vital progenitorial marrow compartments particularly marked within erythroid compartments. that results in loss of reproductive capacity and ultimately in collapse of the hematopoietic system. The high-tolerance individuals (radioaccomodated and either prone- or not prone to ML, subgroup 2 ampersand 3 appear to minimize the accumulating damage effect of daily exposures by extending repair functions, which preserves reproductive integrity and fosters regenerative hematopoietic responses. As the strength of the regenerative response manifests the extent of repair augmentation, the relatively strong response of high- tolerance individuals progressing to patent ML suggests an insufficiency of repair quality rather than repair quantity

  1. Hematopoietic (stem) cell development — how divergent are the roads taken?

    NARCIS (Netherlands)

    M.-L. Kauts (Mari-Liis); C.S. Vink (Chris); E.A. Dzierzak (Elaine)

    2016-01-01

    textabstractThe development of the hematopoietic system during early embryonic stages occurs in spatially and temporally distinct waves. Hematopoietic stem cells (HSC), the most potent and self-renewing cells of this system, are produced in the final ‘definitive’ wave of hematopoietic cell

  2. Hematopoietic defects in response to reduced Arhgap21

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    Juliana Xavier-Ferrucio

    2018-01-01

    Full Text Available Arhgap21 is a member of the Rho GTPase activating protein (RhoGAP family, which function as negative regulators of Rho GTPases. Arhgap21 has been implicated in adhesion and migration of cancer cells. However, the role of Arhgap21 has never been investigated in hematopoietic cells. Herein, we evaluated functional aspects of hematopoietic stem and progenitor cells (HSPC using a haploinsufficient (Arhgap21+/− mouse. Our results show that Arhgap21+/− mice have an increased frequency of phenotypic HSC, impaired ability to form progenitor colonies in vitro and decreased hematopoietic engraftment in vivo, along with a decrease in LSK cell frequency during serial bone marrow transplantation. Arhgap21+/− hematopoietic progenitor cells have impaired adhesion and enhanced mobilization of immature LSK and myeloid progenitors. Arhgap21+/− mice also exhibit reduced erythroid commitment and differentiation, which was recapitulated in human primary cells, in which knockdown of ARHGAP21 in CMP and MEP resulted in decreased erythroid commitment. Finally, we observed enhanced RhoC activity in the bone marrow cells of Arhgap21+/− mice, indicating that Arhgap21 functions in hematopoiesis may be at least partially mediated by RhoC inactivation. Keywords: Arhgap21, Hematopoiesis, Erythroid cells, Hematopoietic stem and progenitor cells, Fate decision

  3. Fetal liver stromal cells promote hematopoietic cell expansion

    International Nuclear Information System (INIS)

    Zhou, Kun; Hu, Caihong; Zhou, Zhigang; Huang, Lifang; Liu, Wenli; Sun, Hanying

    2009-01-01

    Future application of hematopoietic stem and progenitor cells (HSPCs) in clinical therapies largely depends on their successful expansion in vitro. Fetal liver (FL) is a unique hematopoietic organ in which hematopoietic cells markedly expand in number, but the mechanisms involved remain unclear. Stromal cells (StroCs) have been suggested to provide a suitable cellular environment for in vitro expansion of HSPCs. In this study, murine StroCs derived from FL at E14.5, with a high level of Sonic hedgehog (Shh) and Wnt expression, were found to have an increased ability to support the proliferation of HSPCs. This effect was inhibited by blocking Shh signaling. Supplementation with soluble Shh-N promoted the proliferation of hematopoietic cells by activating Wnt signaling. Our findings suggest that FL-derived StroCs support proliferation of HSPCs via Shh inducing an autocrine Wnt signaling loop. The use of FL-derived StroCs and regulation of the Shh pathway might further enhance HPSC expansion.

  4. Epigenetic Loss of MLH1 Expression in Normal Human Hematopoietic Stem Cell Clones is Defined by the Promoter CpG Methylation Pattern Observed by High-Throughput Methylation Specific Sequencing.

    Science.gov (United States)

    Kenyon, Jonathan; Nickel-Meester, Gabrielle; Qing, Yulan; Santos-Guasch, Gabriela; Drake, Ellen; PingfuFu; Sun, Shuying; Bai, Xiaodong; Wald, David; Arts, Eric; Gerson, Stanton L

    Normal human hematopoietic stem and progenitor cells (HPC) lose expression of MLH1 , an important mismatch repair (MMR) pathway gene, with age. Loss of MMR leads to replication dependent mutational events and microsatellite instability observed in secondary acute myelogenous leukemia and other hematologic malignancies. Epigenetic CpG methylation upstream of the MLH1 promoter is a contributing factor to acquired loss of MLH1 expression in tumors of the epithelia and proximal mucosa. Using single molecule high-throughput bisulfite sequencing we have characterized the CpG methylation landscape from -938 to -337 bp upstream of the MLH1 transcriptional start site (position +0), from 30 hematopoietic colony forming cell clones (CFC) either expressing or not expressing MLH1 . We identify a correlation between MLH1 promoter methylation and loss of MLH1 expression. Additionally, using the CpG site methylation frequencies obtained in this study we were able to generate a classification algorithm capable of sorting the expressing and non-expressing CFC. Thus, as has been previously described for many tumor cell types, we report for the first time a correlation between the loss of MLH1 expression and increased MLH1 promoter methylation in CFC derived from CD34 + selected hematopoietic stem and progenitor cells.

  5. Importance of killer immunoglobulin-like receptors in allogeneic hematopoietic stem cell transplantation

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    Danilo Santana Alessio Franceschi

    2011-01-01

    Full Text Available Hematopoietic stem cell transplantation is the treatment of choice for many hematologic diseases, such as multiple myeloma, bone marrow aplasia and leukemia. Human leukocyte antigen (HLA compatibility is an important tool to prevent post-transplant complications such as graft rejection and graft-versus-host disease, but the high rates of relapse limit the survival of transplant patients. Natural Killer cells, a type of lymphocyte that is a key element in the defense against tumor cells, cells infected with viruses and intracellular microbes, have different receptors on their surfaces that regulate their cytotoxicity. Killer immunoglobulin-like receptors are the most important, interacting consistently with human leukocyte antigen class I molecules present in other cells and thus controlling the activation of natural killer cells. Several studies have shown that certain combinations of killer immunoglobulin-like receptors and human leukocyte antigens (in both donors and recipients can affect the chances of survival of transplant patients, particularly in relation to the graft-versusleukemia effect, which may be associated to decreased relapse rates in certain groups. This review aims to shed light on the mechanisms and effects of killer immunoglobulin-like receptors - human leukocyte antigen associations and their implications following hematopoietic stem cell transplantation, and to critically analyze the results obtained by the studies presented herein.

  6. Prevention of radiochemotherapy-induced toxicity with amifostine in patients with malignant orbital tumors involving the lacrimal gland: a pilot study

    International Nuclear Information System (INIS)

    Goldblum, David; Ghadjar, Pirus; Curschmann, Juergen; Greiner, Richard; Aebersold, Daniel

    2008-01-01

    To use amifostine concurrently with radiochemotherapy (CT-RT) or radiotherapy (RT) alone in order to prevent dry eye syndrome in patients with malignancies located in the fronto-orbital region. Five patients (2 males, 3 females) with diagnosed malignancies (Non-Hodgkin B-cell Lymphoma, neuroendocrine carcinoma) involving the lacrimal gland, in which either combined CT-RT or local RT were indicated, were prophylactically treated with amifostine (500 mg sc). Single RT fraction dose, total dose and treatment duration were individually adjusted to the patient's need. Acute and late adverse effects were recorded using the RTOG score. Subjective and objective dry eye assessment was performed for the post-treatment control of lacrimal gland function. All patients have completed CT-RT or RT as indicated. The median total duration of RT was 29 days (range, 23 – 39 days) and the median total RT dose was 40 Gy (range, 36 – 60 Gy). Median lacrimal gland exposure was 35.9 Gy (range, 16.8 – 42.6 Gy). Very good partial or complete tumor remission was achieved in all patients. The treatment was well tolerated without major toxic reactions. Post-treatment control did not reveal in any patient either subjective or objective signs of a dry eye syndrome. The addition of amifostine to RT/CT-RT of patients with tumors localized in orbital region was found to be associated with absence of dry eye syndrome

  7. Mitigation of radiation induced hematopoietic injury via regulation of Nrf-2 and increasing hematopoietic stem cells

    International Nuclear Information System (INIS)

    Patwardhan, R.S.; Sharma, Deepak; Checker, Rahul; Santosh Kumar, S.

    2014-01-01

    Therapeutic doses of ionizing radiation (IR) that can be delivered to tumors are restricted due to radiation induced damage to surrounding normal tissues thereby limiting the effectiveness of radiotherapy. Strategies to develop agents that selectively protect normal cells yielded limited success in the past. There is pressing need to develop safe, syndrome specific and effective radiation countermeasures to prevent or mitigate the harmful consequences of radiation exposure. Survival of bone marrow stem cells (HSCs) play a key role in protecting against IR induced hematopoietic injury. Many studies have shown manipulation of HSC frequency and/or survival as principal mechanism of radioprotection. It is known that, Nrf-2 plays crucial role in HSC survival and maintenance under oxidative stress conditions. In the present study, we have investigated the radioprotective ability of a flavonoid baicalein (5,6,7-trihydroxyflavone), extracted from the root of Scutellaria baicalensis Georgi, a medicinal plant traditionally used in Oriental medicine. There are numerous reports showing anti-inflammatory, anti-apoptotic, anti-oxidant, anti-cancer, anti-microbial, anti-mutagenic and neuroprotective properties of baicalein. Based on these reports, we have investigated the ability of baicalein to protect against radiation induced hematopoietic injury. Baicalein administration to mice protected against WBI induced mortality. Interestingly, the stem cell frequency increased in bone marrow cells obtained from baicalein administered mice as compared to vehicle treated mice. Baicalein treatment led to increased phospho-Nrf-2 levels in lineage negative BM-MNC. Administration of mice with Nrf-2 inhibitor prior to baicalein treatment led to significant abrogation of radioprotective ability of baicalein. This result suggests that, Nrf-2 may be playing a key role in baicalein mediated radioprotection. Here, we have shown that baicalein administration augments stem cell frequency, induces

  8. PET/CT and beta-2-microglobulin in staging and therapeutic control after hematopoietic stem cell transplantation

    International Nuclear Information System (INIS)

    Vassileva, D.; Garcheva, M.; Kostadinova, I.

    2013-01-01

    Full text: Introduction: The transplantation of hematopoietic stem cells is used in lymphomas refractory to standard treatment. An exact re-staging is critical and the use of hybrid imaging methods has increased. The determined serum levels of beta-2 - microglobulin levels are also related to the progress of the disease and may be involved in determining the therapeutic effect. Materials and Methods: PET / CT studies were performed before and after transplantation of hematopoietic stem cells in patients with Hodgkin's disease and non-Hodgkin's lymphomas according to a the standard protocol, 60 minutes after injection of 18F-FDG using the apparatus Discovery 600. At the same time, the serum levels of beta-2 - microglobulin were determined. Results: Prior to transplantation nodal and extra nodal tumor infiltrates were visualized in the lungs and bones. In some of the patients a residual tumor was observed after the stem cell transplantation, which shows a partial response to the therapy. The serum levels of beta-2 - microglobulin were increased in the active phase of the disease and were normalized at remission. In the patients with partial response the values of the beta -2- microglobulin remain elevated. Conclusion: The use of PET / CT allows an accurate staging in patients with refractory lymphomas directed for transplantation and allows to register the effect of the therapy. The scintigraphic data show a good correlation with the beta-2 – microglobulin values in the serum

  9. Development of hematopoietic stem and progenitor cells from human pluripotent stem cells.

    Science.gov (United States)

    Chen, Tong; Wang, Fen; Wu, Mengyao; Wang, Zack Z

    2015-07-01

    Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), provide a new cell source for regenerative medicine, disease modeling, drug discovery, and preclinical toxicity screening. Understanding of the onset and the sequential process of hematopoietic cells from differentiated hPSCs will enable the achievement of personalized medicine and provide an in vitro platform for studying of human hematopoietic development and disease. During embryogenesis, hemogenic endothelial cells, a specified subset of endothelial cells in embryonic endothelium, are the primary source of multipotent hematopoietic stem cells. In this review, we discuss current status in the generation of multipotent hematopoietic stem and progenitor cells from hPSCs via hemogenic endothelial cells. We also review the achievements in direct reprogramming from non-hematopoietic cells to hematopoietic stem and progenitor cells. Further characterization of hematopoietic differentiation in hPSCs will improve our understanding of blood development and expedite the development of hPSC-derived blood products for therapeutic purpose. © 2015 Wiley Periodicals, Inc.

  10. Hematopoiesis and hematopoietic organs in arthropods.

    Science.gov (United States)

    Grigorian, Melina; Hartenstein, Volker

    2013-03-01

    Hemocytes (blood cells) are motile cells that move throughout the extracellular space and that exist in all clades of the animal kingdom. Hemocytes play an important role in shaping the extracellular environment and in the immune response. Developmentally, hemocytes are closely related to the epithelial cells lining the vascular system (endothelia) and the body cavity (mesothelia). In vertebrates and insects, common progenitors, called hemangioblasts, give rise to the endothelia and blood cells. In the adult animal, many differentiated hemocytes seem to retain the ability to proliferate; however, in most cases investigated closely, the bulk of hemocyte proliferation takes place in specialized hematopoietic organs. Hematopoietic organs provide an environment where undifferentiated blood stem cells are able to self-renew, and at the same time generate offspring that differentiate into different blood cell types. Hematopoiesis in vertebrates, taking place in the bone marrow, has been subject to intensive research by immunologists and stem cell biologists. Much less is known about blood cell formation in invertebrate animals. In this review, we will survey structural and functional properties of invertebrate hematopoietic organs, with a main focus on insects and other arthropod taxa. We will then discuss similarities, at the molecular and structural level, that are apparent when comparing the development of blood cells in hematopoietic organs of vertebrates and arthropods. Our comparative review is intended to elucidate aspects of the biology of blood stem cells that are more easily missed when focusing on one or a few model species.

  11. Mobilization of hematopoietic stem and progenitor cells in mice

    NARCIS (Netherlands)

    Robinson, Simon N; van Os, Ronald P; Bunting, Kevin

    2008-01-01

    Animal models have added significantly to our understanding of the mechanism(s) of hematopoietic stem and progenitor cell (HSPC) mobilization. Such models suggest that changes in the interaction between the HSPC and the hematopoietic microenvironmental 'niche' (cellular and extracellular components)

  12. Cytokine-Regulated GADD45G Induces Differentiation and Lineage Selection in Hematopoietic Stem Cells

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    Frederic B. Thalheimer

    2014-07-01

    Full Text Available The balance of self-renewal and differentiation in long-term repopulating hematopoietic stem cells (LT-HSC must be strictly controlled to maintain blood homeostasis and to prevent leukemogenesis. Hematopoietic cytokines can induce differentiation in LT-HSCs; however, the molecular mechanism orchestrating this delicate balance requires further elucidation. We identified the tumor suppressor GADD45G as an instructor of LT-HSC differentiation under the control of differentiation-promoting cytokine receptor signaling. GADD45G immediately induces and accelerates differentiation in LT-HSCs and overrides the self-renewal program by specifically activating MAP3K4-mediated MAPK p38. Conversely, the absence of GADD45G enhances the self-renewal potential of LT-HSCs. Videomicroscopy-based tracking of single LT-HSCs revealed that, once GADD45G is expressed, the development of LT-HSCs into lineage-committed progeny occurred within 36 hr and uncovered a selective lineage choice with a severe reduction in megakaryocytic-erythroid cells. Here, we report an unrecognized role of GADD45G as a central molecular linker of extrinsic cytokine differentiation and lineage choice control in hematopoiesis.

  13. Kimura's Disease of the Orbit Successfully Treated with Radiotherapy Alone: A Case Report

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    Yoshio Monzen

    2014-03-01

    Full Text Available We performed radiotherapy in a 28-year-old patient with Kimura's disease of the orbit. Irradiation with 21.6 Gy was administered to the tumor bed with a single dose of 1.8 Gy in 5 weekly fractions delivered via a high-energy linear accelerator (6-MV X-ray. Complete remission of the tumor and improvements in the neurological findings were achieved. Neither tumor regrowth nor late complications were detected up to 84 months after radiotherapy. Radiotherapy is an effective treatment for Kimura's disease of the orbit.

  14. Low-Cost 3D Printing Orbital Implant Templates in Secondary Orbital Reconstructions.

    Science.gov (United States)

    Callahan, Alison B; Campbell, Ashley A; Petris, Carisa; Kazim, Michael

    Despite its increasing use in craniofacial reconstructions, three-dimensional (3D) printing of customized orbital implants has not been widely adopted. Limitations include the cost of 3D printers able to print in a biocompatible material suitable for implantation in the orbit and the breadth of available implant materials. The authors report the technique of low-cost 3D printing of orbital implant templates used in complex, often secondary, orbital reconstructions. A retrospective case series of 5 orbital reconstructions utilizing a technique of 3D printed orbital implant templates is presented. Each patient's Digital Imaging and Communications in Medicine data were uploaded and processed to create 3D renderings upon which a customized implant was designed and sent electronically to printers open for student use at our affiliated institutions. The mock implants were sterilized and used intraoperatively as a stencil and mold. The final implant material was chosen by the surgeons based on the requirements of the case. Five orbital reconstructions were performed with this technique: 3 tumor reconstructions and 2 orbital fractures. Four of the 5 cases were secondary reconstructions. Molded Medpor Titan (Stryker, Kalamazoo, MI) implants were used in 4 cases and titanium mesh in 1 case. The stenciled and molded implants were adjusted no more than 2 times before anchored in place (mean 1). No case underwent further revision. The technique and cases presented demonstrate 1) the feasibility and accessibility of low-cost, independent use of 3D printing technology to fashion patient-specific implants in orbital reconstructions, 2) the ability to apply this technology to the surgeon's preference of any routinely implantable material, and 3) the utility of this technique in complex, secondary reconstructions.

  15. Limited transplantation of antigen-expressing hematopoietic stem cells induces long-lasting cytotoxic T cell responses.

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    Warren L Denning

    2011-02-01

    Full Text Available Harnessing the ability of cytotoxic T lymphocytes (CTLs to recognize and eradicate tumor or pathogen-infected cells is a critical goal of modern immune-based therapies. Although multiple immunization strategies efficiently induce high levels of antigen-specific CTLs, the initial increase is typically followed by a rapid contraction phase resulting in a sharp decline in the frequency of functional CTLs. We describe a novel approach to immunotherapy based on a transplantation of low numbers of antigen-expressing hematopoietic stem cells (HSCs following nonmyeloablative or partially myeloablative conditioning. Continuous antigen presentation by a limited number of differentiated transgenic hematopoietic cells results in an induction and prolonged maintenance of fully functional effector T cell responses in a mouse model. Recipient animals display high levels of antigen-specific CTLs four months following transplantation in contrast to dendritic cell-immunized animals in which the response typically declines at 4-6 weeks post-immunization. Majority of HSC-induced antigen-specific CD8+ T cells display central memory phenotype, efficiently kill target cells in vivo, and protect recipients against tumor growth in a preventive setting. Furthermore, we confirm previously published observation that high level engraftment of antigen-expressing HSCs following myeloablative conditioning results in tolerance and an absence of specific cytotoxic activity in vivo. In conclusion, the data presented here supports potential application of immunization by limited transplantation of antigen-expressing HSCs for the prevention and treatment of cancer and therapeutic immunization of chronic infectious diseases such as HIV-1/AIDS.

  16. Novel anti-c-Mpl monoclonal antibodies identified multiple differentially glycosylated human c-Mpl proteins in megakaryocytic cells but not in human solid tumors.

    Science.gov (United States)

    Zhan, Jinghui; Felder, Barbara; Ellison, Aaron R; Winters, Aaron; Salimi-Moosavi, Hossein; Scully, Sheila; Turk, James R; Wei, Ping

    2013-06-01

    Thrombopoietin and its cognate receptor, c-Mpl, are the primary molecular regulators of megakaryocytopoiesis and platelet production. To date the pattern of c-Mpl expression in human solid tumors and the distribution and biochemical properties of c-Mpl proteins in hematopoietic tissues are largely unknown. We have recently developed highly specific mouse monoclonal antibodies (MAb) against human c-Mpl. In this study we used these antibodies to demonstrate the presence of full-length and truncated human c-Mpl proteins in various megakaryocytic cell types, and their absence in over 100 solid tumor cell lines and in the 12 most common primary human tumor types. Quantitative assays showed a cell context-dependent distribution of full-length and truncated c-Mpl proteins. All forms of human c-Mpl protein were found to be modified with extensive N-linked glycosylation but different degrees of sialylation and O-linked glycosylation. Of note, different variants of full-length c-Mpl protein exhibiting differential glycosylation were expressed in erythromegakaryocytic leukemic cell lines and in platelets from healthy human donors. This work provides a comprehensive analysis of human c-Mpl mRNA and protein expression on normal and malignant hematopoietic and non-hematopoietic cells and demonstrates the multiple applications of several novel anti-c-Mpl antibodies.

  17. Direct observation of hematopoietic progenitor chimerism in fetal freemartin cattle

    Directory of Open Access Journals (Sweden)

    Taponen Juhani

    2007-11-01

    Full Text Available Abstract Background Cattle twins are well known as blood chimeras. However, chimerism in the actual hematopoietic progenitor compartment has not been directly investigated. Here, we analyzed fetal liver of chimeric freemartin cattle by combining a new anti-bovine CD34 antibody and Y-chromosome specific in situ hybridization. Results Bull-derived CD34+ cells were detected in the liver of the female sibling (freemartin at 60 days gestation. The level of bull-derived CD34+ cells was lower in the freemartin than in its male siblings. Bull (Y+ and cow hematopoietic cells often occurred in separate clusters. Around clusters of Y+CD34+ cells, Y+CD34- cells were typically observed. The thymi were also strongly chimeric at 60 days of gestation. Conclusion The fetal freemartin liver contains clusters of bull-derived hematopoietic progenitors, suggesting clonal expansion and differentiation. Even the roots of the hematopoietic system in cattle twins are thus strongly chimeric from the early stages of fetal development. However, the hematopoietic seeding of fetal liver apparently started already before the onset of functional vascular anastomosis.

  18. Plerixafor (a CXCR4 antagonist following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery

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    Michael M. B. Green

    2016-08-01

    Full Text Available Abstract Background The binding of CXCR4 with its ligand (stromal-derived factor-1 maintains hematopoietic stem/progenitor cells (HSPCs in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT promotes hematopoiesis by inducing HSC proliferation. Methods We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis. Results Thirty patients received plerixafor following peripheral blood stem cell (n = 28 (PBSC or bone marrow (n = 2 transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04 and platelet recovery >20 K (p = 0.04 compared to the controls. Conclusions Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted. Trial registration ClinicalTrials.gov NCT01280955

  19. The biochemistry of hematopoietic stem cell development.

    Science.gov (United States)

    Kaimakis, P; Crisan, M; Dzierzak, E

    2013-02-01

    The cornerstone of the adult hematopoietic system and clinical treatments for blood-related disease is the cohort of hematopoietic stem cells (HSC) that is harbored in the adult bone marrow microenvironment. Interestingly, this cohort of HSCs is generated only during a short window of developmental time. In mammalian embryos, hematopoietic progenitor and HSC generation occurs within several extra- and intraembryonic microenvironments, most notably from 'hemogenic' endothelial cells lining the major vasculature. HSCs are made through a remarkable transdifferentiation of endothelial cells to a hematopoietic fate that is long-lived and self-renewable. Recent studies are beginning to provide an understanding of the biochemical signaling pathways and transcription factors/complexes that promote their generation. The focus of this review is on the biochemistry behind the generation of these potent long-lived self-renewing stem cells of the blood system. Both the intrinsic (master transcription factors) and extrinsic regulators (morphogens and growth factors) that affect the generation, maintenance and expansion of HSCs in the embryo will be discussed. The generation of HSCs is a stepwise process involving many developmental signaling pathways, morphogens and cytokines. Pivotal hematopoietic transcription factors are required for their generation. Interestingly, whereas these factors are necessary for HSC generation, their expression in adult bone marrow HSCs is oftentimes not required. Thus, the biochemistry and molecular regulation of HSC development in the embryo are overlapping, but differ significantly from the regulation of HSCs in the adult. HSC numbers for clinical use are limiting, and despite much research into the molecular basis of HSC regulation in the adult bone marrow, no panel of growth factors, interleukins and/or morphogens has been found to sufficiently increase the number of these important stem cells. An understanding of the biochemistry of HSC

  20. Neural Crossroads in the Hematopoietic Stem Cell Niche.

    Science.gov (United States)

    Agarwala, Sobhika; Tamplin, Owen J

    2018-05-29

    The hematopoietic stem cell (HSC) niche supports steady-state hematopoiesis and responds to changing needs during stress and disease. The nervous system is an important regulator of the niche, and its influence is established early in development when stem cells are specified. Most research has focused on direct innervation of the niche, however recent findings show there are different modes of neural control, including globally by the central nervous system (CNS) and hormone release, locally by neural crest-derived mesenchymal stem cells, and intrinsically by hematopoietic cells that express neural receptors and neurotransmitters. Dysregulation between neural and hematopoietic systems can contribute to disease, however new therapeutic opportunities may be found among neuroregulator drugs repurposed to support hematopoiesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

  1. Orbital exenteration: Institutional review of evolving trends in indications and rehabilitation techniques.

    Science.gov (United States)

    Kiratli, Hayyam; Koç, İrem

    2018-06-01

    To determine the changes in indications for orbital exenteration over 20 years and to assess its impact on patient survival. Evolving techniques of rehabilitation of the orbit in our institution were also evaluated. This was a retrospective review of hospital records of patients who underwent orbital exenteration from 1995 to 2015 in a tertiary care center. Data extracted included primary location of the tumor, preoperative treatments, interval between initial diagnosis and exenteration, status of surgical margins, presence of metastatic disease, and postoperative survival. The types of prosthesis utilized over the years were also reviewed. Cox regression analysis was performed for categorical variables. Kaplan-Meier analysis was used to estimate post-exenteration survival. Over a 20-year period, orbital exenteration was performed on 100 orbits of 100 patients. The mean age was 39.4 years (range: 2 months to 90 years). The most common indications among 98 malignant causes were retinoblastoma, squamous cell carcinoma, basal cell carcinoma, extraocular extension of uveal melanoma, and conjunctival melanoma. Postoperative survival was significantly related to age and tumor location but independent from gender, surgical margin, histopathological diagnosis, previous treatment modality, and preoperative interval. In the whole cohort, 1-year and 5-year survival rates were 97% and 84%, respectively. Exenteration appears to be life-saving in children with orbital extension of retinoblastoma. While patients exenterated for malignant eyelid tumors have the best chance of survival, those with orbital extension of uveal melanoma and adenoid cystic carcinoma of the lacrimal gland have the worst prognosis.

  2. Instruction of hematopoietic lineage choice by cytokine signaling

    Energy Technology Data Exchange (ETDEWEB)

    Endele, Max; Etzrodt, Martin; Schroeder, Timm, E-mail: timm.schroeder@bsse.ethz.ch

    2014-12-10

    Hematopoiesis is the cumulative consequence of finely tuned signaling pathways activated through extrinsic factors, such as local niche signals and systemic hematopoietic cytokines. Whether extrinsic factors actively instruct the lineage choice of hematopoietic stem and progenitor cells or are only selectively allowing survival and proliferation of already intrinsically lineage-committed cells has been debated over decades. Recent results demonstrated that cytokines can instruct lineage choice. However, the precise function of individual cytokine-triggered signaling molecules in inducing cellular events like proliferation, lineage choice, and differentiation remains largely elusive. Signal transduction pathways activated by different cytokine receptors are highly overlapping, but support the production of distinct hematopoietic lineages. Cellular context, signaling dynamics, and the crosstalk of different signaling pathways determine the cellular response of a given extrinsic signal. New tools to manipulate and continuously quantify signaling events at the single cell level are therefore required to thoroughly interrogate how dynamic signaling networks yield a specific cellular response. - Highlights: • Recent studies provided definite proof for lineage-instructive action of cytokines. • Signaling pathways involved in hematopoietic lineage instruction remain elusive. • New tools are emerging to quantitatively study dynamic signaling networks over time.

  3. Tfe3 expression is closely associated to macrophage terminal differentiation of human hematopoietic myeloid precursors

    International Nuclear Information System (INIS)

    Zanocco-Marani, Tommaso; Vignudelli, Tatiana; Gemelli, Claudia; Pirondi, Sara; Testa, Anna; Montanari, Monica; Parenti, Sandra; Tenedini, Elena; Grande, Alexis; Ferrari, Sergio

    2006-01-01

    The MItf-Tfe family of basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors encodes four family members: MItf, Tfe3, TfeB and TfeC. In vitro, each protein of the family binds DNA in a homo- or heterodimeric form with other family members. Tfe3 is involved in chromosomal translocations recurrent in different tumors and it has been demonstrated, by in vivo studies, that it plays, redundantly with MItf, an important role in the process of osteoclast formation, in particular during the transition from mono-nucleated to multi-nucleated osteoclasts. Since mono-nucleated osteoclasts derive from macrophages we investigated whether Tfe3 might play a role upstream during hematopoietic differentiation. Here we show that Tfe3 is able to induce mono-macrophagic differentiation of U937 cells, in association with a decrease of cell proliferation and an increase of apoptosis. We also show that Tfe3 does not act physiologically during commitment of CD34+ hematopoietic stem cells (HSCs), since it is not able to direct HSCs toward a specific lineage as observed by clonogenic assay, but is a strong actor of terminal differentiation since it allows human primary myeloblasts' maturation toward the macrophage lineage

  4. Prostaglandin E2 regulates hematopoietic stem cell

    International Nuclear Information System (INIS)

    Wang Yingying; Zhou Daohong; Meng Aimin

    2013-01-01

    Prostaglandin E2 (PGE2) is a bioactive lipid molecule produced by cyclooxygenase (COX), which plays an important role on hematopoiesis. While it can block differentiation of myeloid progenitors but enhance proliferation of erythroid progenitors. Recent research found that PGE2 have the effects on hematopoietic stem cell (HSC) function and these effects were independent from effects on progenitor cells. Exposure of HSC cells to PGE2 in vitro can increase homing efficiency of HSC to the murine bone marrow compartment and decrease HSC apoptosis, meanwhile increase long-term stem cell engraftment. In-vivo treatment with PGE2 expands short-term HSC and engraftment in murine bone marrow but not long-term HSC.In addition, PGE2 increases HSC survival after radiation injury and enhance hematopoietic recovery, resulting maintains hematopoietic homeostasis. PGE2 regulates HSC homeostasis by reactive oxygen species and Wnt pathway. Clinical beneficial of 16, 16-dimethyl-prostaglandin E2 treatment to enhance engraftment of umbilical cord blood suggest important improvements to therapeutic strategies. (authors)

  5. Computed tomographic features of orbital lesions

    International Nuclear Information System (INIS)

    Azevedo, C.M. de; Hoch, H.; Azevedo, M. de L.

    1990-01-01

    The purpose of this m anuscript is to present the use of CT in the evaluation of 42 cases of orbital lesions studied at the National Institute of Cancer in an one year and half period. Correlation with clinical and pathological data was performed and the results compared with those of the literature. Four cases of rare lesions are shown: alveolar soft tissue sarcoma, giant cell tumor and hematogenic metastatic deposits of a clear cell sarcoma and epidermoid carcinoma. The value of CT in the evaluation of all orbital masses is emphasized. (author) [pt

  6. Cholesterol granuloma of the orbit: An atypical presentation

    Directory of Open Access Journals (Sweden)

    Syed A R Rizvi

    2014-01-01

    Full Text Available Cholesterol granuloma is a rare, well-defined lesion of the orbit. In the orbit, diploe of the frontal bone is involved almost exclusively. We report an atypical case of cholesterol granuloma involving superomedial quadrant of orbit. A 42-year-old male presented with progressive, painless, proptosis with infero-temporal displacement of left eye. A large mass was felt beneath the bony orbital margin in the superomedial quadrant of the left orbit. Computerized tomography (CT scan revealed an extraconal superomedial, heterogeneous enhancing mass which was isodense with brain and pushing the globe inferolaterally and anteriorly. Excision biopsy of the tumor revealed the typical features of a cholesterol granuloma without any epithelial elements. Cholesterol granuloma of the orbit is a rare entity, but it can be diagnosed and differentiated from other lesions of the superior orbit by its characteristic clinical, radiological and histopathological features. An appropriate intervention in time carries a good prognosis with almost no recurrence.

  7. Hematopoietic differentiation: a coordinated dynamical process towards attractor stable states

    Directory of Open Access Journals (Sweden)

    Rossi Simona

    2010-06-01

    Full Text Available Abstract Background The differentiation process, proceeding from stem cells towards the different committed cell types, can be considered as a trajectory towards an attractor of a dynamical process. This view, taking into consideration the transcriptome and miRNome dynamics considered as a whole, instead of looking at few 'master genes' driving the system, offers a novel perspective on this phenomenon. We investigated the 'differentiation trajectories' of the hematopoietic system considering a genome-wide scenario. Results We developed serum-free liquid suspension unilineage cultures of cord blood (CB CD34+ hematopoietic progenitor cells through erythroid (E, megakaryocytic (MK, granulocytic (G and monocytic (Mo pathways. These cultures recapitulate physiological hematopoiesis, allowing the analysis of almost pure unilineage precursors starting from initial differentiation of HPCs until terminal maturation. By analyzing the expression profile of protein coding genes and microRNAs in unilineage CB E, MK, G and Mo cultures, at sequential stages of differentiation and maturation, we observed a coordinated, fully interconnected and scalable character of cell population behaviour in both transcriptome and miRNome spaces reminiscent of an attractor-like dynamics. MiRNome and transcriptome space differed for a still not terminally committed behaviour of microRNAs. Conclusions Consistent with their roles, the transcriptome system can be considered as the state space of a cell population, while the continuously evolving miRNA space corresponds to the tuning system necessary to reach the attractor. The behaviour of miRNA machinery could be of great relevance not only for the promise of reversing the differentiated state but even for tumor biology.

  8. Radioprotection by murine and human tumor-necrosis factor; Dose-dependent effects on hematopoiesis in the mouse

    Energy Technology Data Exchange (ETDEWEB)

    Sloerdal, L; Muench, M O; Warren, D J; Moore, M A.S. [James Ewing Laboratory of Developmental Hematopoiesis, Memorial Sloan-Kettering Cancer Center, New York (USA)

    1989-01-01

    Tumor-necrosis factor (TNF) has been shown to confer significant radioprotection in murine models. Herein, we demonstrate a dose-dependent enhancement of hematological recovery when single doses of either murine or human recombinant TNF are administered prior to irradiation. In addition to its action upon leukocytes and erythocytes, TNF also alleviates radiation-induced thrombocytopenia in the mouse. These effects on circulating blood constituents are further reflected in increased numbers of both primitive (CFU-S) and more differentiated (CFU-GM, CFU-Mega) hematopoietic progenitors in TNF-treated animals. This suggests that TNF exerts it radioprotective effects on a pool of primitive multi-potential hematopoietic cells. (author).

  9. Insulin-Like Growth Factor 1 Mitigates Hematopoietic Toxicity After Lethal Total Body Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Dunhua; Deoliveira, Divino; Kang, Yubin; Choi, Seung S. [Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States); Li, Zhiguo [Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina (United States); Chao, Nelson J. [Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States); Department of Pathology, Duke University Medical Center, Durham, North Carolina (United States); Department of Immunology, Duke University Medical Center, Durham, North Carolina (United States); Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina (United States); Chen, Benny J., E-mail: chen0032@mc.duke.edu [Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina (United States); Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States)

    2013-03-15

    Purpose: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. Results: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) in the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. Conclusions: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells.

  10. Insulin-Like Growth Factor 1 Mitigates Hematopoietic Toxicity After Lethal Total Body Irradiation

    International Nuclear Information System (INIS)

    Zhou, Dunhua; Deoliveira, Divino; Kang, Yubin; Choi, Seung S.; Li, Zhiguo; Chao, Nelson J.; Chen, Benny J.

    2013-01-01

    Purpose: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. Results: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) in the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. Conclusions: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells

  11. The fps/fes proto-oncogene regulates hematopoietic lineage output.

    Science.gov (United States)

    Sangrar, Waheed; Gao, Yan; Zirngibl, Ralph A; Scott, Michelle L; Greer, Peter A

    2003-12-01

    The fps/fes proto-oncogene is abundantly expressed in myeloid cells, and the Fps/Fes cytoplasmic protein-tyrosine kinase is implicated in signaling downstream from hematopoietic cytokines, including interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin (EPO). Studies using leukemic cell lines have previously suggested that Fps/Fes contributes to granulomonocytic differentiation, and that it might play a more selective role in promoting survival and differentiation along the monocytic pathway. In this study we have used a genetic approach to explore the role of Fps/Fes in hematopoiesis. We used transgenic mice that tissue-specifically express a mutant human fps/fes transgene (fps(MF)) that was engineered to encode Fps/Fes kinase that is activated through N-terminal myristoylation (MFps). Hematopoietic function was assessed using lineage analysis, hematopoietic progenitor cell colony-forming assays, and biochemical approaches. fps(MF) transgenic mice displayed a skewed hematopoietic output reflected by increased numbers of circulating granulocytic and monocytic cells and a corresponding decrease in lymphoid cells. Bone marrow colony assays of progenitor cells revealed a significant increase in the number of both granulomonocytic and multi-lineage progenitors. A molecular analysis of signaling in mature monocytic cells showed that MFps promoted GM-CSF-induced STAT3, STAT5, and ERK1/2 activation. These observations support a role for Fps/Fes in signaling pathways that contribute to lineage determination at the level of multi-lineage hematopoietic progenitors as well as the more committed granulomonocytic progenitors.

  12. Bone marrow adipocytes as negative regulators of the hematopoietic microenvironment

    Science.gov (United States)

    Naveiras, Olaia; Nardi, Valentina; Wenzel, Pamela L.; Fahey, Frederic; Daley, George Q.

    2009-01-01

    Osteoblasts and endothelium constitute functional niches that support hematopoietic stem cells (HSC) in mammalian bone marrow (BM) 1,2,3 . Adult BM also contains adipocytes, whose numbers correlate inversely with the hematopoietic activity of the marrow. Fatty infiltration of hematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia 4. To explore whether adipocytes influence hematopoiesis or simply fill marrow space, we compared the hematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. By flow cytometry, colony forming activity, and competitive repopulation assay, HSCs and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 “fatless” mice, which are genetically incapable of forming adipocytes8, and in mice treated with the PPARγ inhibitor Bisphenol-A-DiGlycidyl-Ether (BADGE), which inhibits adipogenesis9, post-irradiation marrow engraftment is accelerated relative to wild type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone marrow microenvironment, and suggest that antagonizingmarrow adipogenesis may enhance hematopoietic recovery in clinical bone marrow transplantation. PMID:19516257

  13. Hematopoietic cell phosphatase is recruited to CD22 following B cell antigen receptor ligation

    NARCIS (Netherlands)

    Lankester, A. C.; van Schijndel, G. M.; van Lier, R. A.

    1995-01-01

    Hematopoietic cell phosphatase is a nonreceptor protein tyrosine phosphatase that is preferentially expressed in hematopoietic cell lineages. Motheaten mice, which are devoid of (functional) hematopoietic cell phosphatase, have severe disturbances in the regulation of B cell activation and

  14. TET2 deficiency inhibits mesoderm and hematopoietic differentiation in human embryonic stem cells

    DEFF Research Database (Denmark)

    Langlois, Thierry; da Costa Reis Monte Mor, Barbara; Lenglet, Gaëlle

    2014-01-01

    . Here, we show that TET2 expression is low in human embryonic stem (ES) cell lines and increases during hematopoietic differentiation. ShRNA-mediated TET2 knockdown had no effect on the pluripotency of various ES cells. However, it skewed their differentiation into neuroectoderm at the expense...... profile, including abnormal expression of neuronal genes. Intriguingly, when TET2 was knockdown in hematopoietic cells, it increased hematopoietic development. In conclusion, our work suggests that TET2 is involved in different stages of human embryonic development, including induction of the mesoderm...... and hematopoietic differentiation. Stem Cells 2014....

  15. Curative radiotherapy for primary orbital lymphoma

    International Nuclear Information System (INIS)

    Bhatia, Sudershan; Paulino, Arnold C.; Buatti, John M.; Mayr, Nina A.; Wen, B.-C.

    2002-01-01

    Purpose: To review our institutional experience with primary orbital lymphoma and determine the prognostic factors for survival, local control, and distant metastases. In addition, we also analyzed the risk factors for complications in the radiotherapeutic management of this tumor. Methods and Materials: Between 1973 and 1998, 47 patients (29 women [62%] and 18 men [38%], median age 69 years, range 32-89) with Stage IAE orbital lymphoma were treated with curative intent at one department. Five had bilateral orbital involvement. The tumor was located in the eyelid and extraocular muscles in 23 (44%), conjunctiva in 17 (33%), and lacrimal apparatus in 12 (23%). The histologic features according to the World Heath Organization classification of lymphoid neoplasms was follicular lymphoma in 25, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type in 8, diffuse large B-cell lymphoma in 12, mantle cell lymphoma in 6, and peripheral T-cell lymphoma in 1. For the purposes of comparison with the existing literature on orbital lymphomas, the grading system according to the Working Formulation was also recorded. The histologic grade was low in 33 (63%), intermediate in 18 (35%), and high in 1 (2%). All patients were treated with primary radiotherapy alone. The median dose for low-grade tumors was 3000 cGy (range 2000-4020); the median dose for intermediate and high-grade tumors was 4000 cGy (range 3000-5100). A lens-sparing approach was used in 19 patients (37%). Late complications for the lens and cornea were scored according to the subjective, objective, management, and analytic (SOMA) scale of the Late Effects of Normal Tissue (LENT) scoring system. The median follow-up was 55 months (range 6-232). Results: The local control rate was 100% in the 52 orbits treated. The 5-year overall survival and relapse-free survival rate was 73.6% and 65.5%, respectively. Tumor grade and location did not predict for overall survival or relapse-free survival

  16. Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part I. Biology of relapse after transplantation.

    Science.gov (United States)

    Gress, Ronald E; Miller, Jeffrey S; Battiwalla, Minoo; Bishop, Michael R; Giralt, Sergio A; Hardy, Nancy M; Kröger, Nicolaus; Wayne, Alan S; Landau, Dan A; Wu, Catherine J

    2013-11-01

    In the National Cancer Institute's Second Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on the Biology of Relapse discussed recent advances in understanding some of the host-, disease-, and transplantation-related contributions to relapse, emphasizing concepts with potential therapeutic implications. Relapse after hematopoietic stem cell transplantation (HSCT) represents tumor escape, from the cytotoxic effects of the conditioning regimen and from immunologic control mediated by reconstituted lymphocyte populations. Factors influencing the biology of the therapeutic graft-versus-malignancy (GVM) effect-and relapse-include conditioning regimen effects on lymphocyte populations and homeostasis, immunologic niches, and the tumor microenvironment; reconstitution of lymphocyte populations and establishment of functional immune competence; and genetic heterogeneity within the malignancy defining potential for clonal escape. Recent developments in T cell and natural killer cell homeostasis and reconstitution are reviewed, with implications for prevention and treatment of relapse, as is the application of modern genome sequencing to defining the biologic basis of GVM, clonal escape, and relapse after HSCT. Published by Elsevier Inc.

  17. Investigation of CT and MRI findings of cranio-orbital communicating lesions

    International Nuclear Information System (INIS)

    Wang Zhenchang; Jiang Dingyao; Xian Junfang; An Yuzhi; Zhang Tianming; Li Bin; Liang Xihong; Yang Bentao

    2001-01-01

    Objective: To investigate CT and MRI findings of cranio-orbital communicating lesions so as to find out communicating passages and their imaging features. Methods: Fifty-one cases of cranio-orbital communicating lesions confirmed by pathology and follow-up results were studied. CT was performed in all cases and MRI in 45 cases. Post-contrast CT and MRI was completed in 44 cases. Results: There were 31 cases (60.8%) with lesions communicating between the orbital cavity and the cranial cavity through optic canal or superior orbital fissure showing communicating soft tissue mass and enlargement of optic canal or superior orbital fissure. Four cases of optic gliomas involving optic nerve and optic chiasm, three cases with meningiomas of optic nerve sheath, and 2 cases with retinoblastoma involving optic nerve and optic chiasm showed cranio-orbital communicating masses through the optic canal. Cranio-orbital communicating mass with enlargement of superior orbital fissure was found in 22 patients including 5 meningiomas, 4 neurogenic tumors, 1 dermoid cyst, 3 inflammatory pseudotumors, 2 Tolosa-Hunt syndromes and 7 metastases from nasopharyngeal carcinoma. In addition, 20 of 51 cases (39.2%) communicated through perforating blood vessels or bony defect resulted from tumor destruction. Of these lesions, there were 10 metastases showing bone destruction in orbital walls, 5 cases with en plaque meningiomas of sphenoid bone with marked hyperostosis and widespread dural involvement, 1 chondrosarcoma involving frontal lobe and orbit, 3 adenoid cystic carcinomas involving frontal lobe, and 1 malignant meningioma with bone destruction of the superior orbital wall. Conclusion: CT and MRI could definitely demonstrate communicating passages of cranio-orbital communicating lesions and their imaging changes, which could contribute to diagnosis and differential diagnosis and provide valuable information for determining treatment measures and surgical approach

  18. Orbital MALT Lymphoma: A Case Report

    Directory of Open Access Journals (Sweden)

    Shobha G Pai

    2004-08-01

    Full Text Available A case of orbital MALT (mucous associated lymphoid tissue lymphoma is reported for its rarity. It presented as a large tumor obscuring the whole eye with loss of vision, without any signs of dissemination and remained free of recurrence or metastasis 12 months after undergoing simple surgical excision.

  19. MRI of orbital hydroxyapatite implants

    International Nuclear Information System (INIS)

    Flanders, A.E.; De Potter P.; Rao, V.M.; Tom, B.M.; Shields, C.L.; Shields, J.A.

    1996-01-01

    Our aim was to use MRI for the postsurgical assessment of a new form of integrated orbital implant composed of a porous calcium phosphate hydroxyapatite substrate. We studied ten patients 24-74 years of age who underwent enucleation and implantation of a hydroxyapatite ball; 5-13 months after surgery, each patient was examined by spin-echo MRI, with fat suppression and gadolinium enhancement. Fibrovascular ingrowth was demonstrated in all ten patients as areas of enhancement at the periphery of the hydroxyapatite sphere that extended to the center to a variable degree. The radiologist should aware of the MRI appearances of the coralline hydroxyapatite orbital implant since it is now widely used following enucleation. MRI is a useful means to determine successful incorporation of the substrate into the orbital tissues. The normal pattern of contrast enhancement should not be mistaken for recurrent tumor or infection. (orig.)

  20. Symptoms after hospital discharge following hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Gamze Oguz

    2014-01-01

    Full Text Available Aims: The purposes of this study were to assess the symptoms of hematopoietic stem cell transplant patients after hospital discharge, and to determine the needs of transplant patients for symptom management. Materials and Methods: The study adopted a descriptive design. The study sample comprised of 66 hematopoietic stem cell transplant patients. The study was conducted in Istanbul. Data were collected using Patient Information Form and Memorial Symptom Assessment Scale (MSAS. Results: The frequency of psychological symptoms in hematopoietic stem cell transplant patients after discharge period (PSYCH subscale score 2.11 (standard deviation (SD = 0.69, range: 0.93-3.80 was higher in hematopoietic stem cell transplant patients than frequency of physical symptoms (PHYS subscale score: 1.59 (SD = 0.49, range: 1.00-3.38. Symptom distress caused by psychological and physical symptoms were at moderate level (Mean = 1.91, SD = 0.60, range: 0.95-3.63 and most distressing symptoms were problems with sexual interest or activity, difficulty sleeping, and diarrhea. Patients who did not have an additional chronic disease obtained higher MSAS scores. University graduates obtained higher Global Distress Index (GDI subscale and total MSAS scores with comparison to primary school graduates. Total MSAS, MSAS-PHYS subscale, and MSAS-PSYCH subscale scores were higher in patients with low level of income (P < 0.05. The patients (98.5% reported to receive education about symptom management after hospital discharge. Conclusions: Hematopoietic stem cell transplant patients continue to experience many distressing physical or psychological symptoms after discharge and need to be supported and educated for the symptom management.

  1. Management of periorbital basal cell carcinoma with orbital invasion.

    Science.gov (United States)

    Sun, Michelle T; Wu, Albert; Figueira, Edwin; Huilgol, Shyamala; Selva, Dinesh

    2015-11-01

    Basal cell carcinoma (BCC) is the most common eyelid malignancy; however, orbital invasion by periocular BCC is rare, and management remains challenging. Established risk factors for orbital invasion by BCC include male gender, advanced age, medial canthal location, previous recurrences, large tumor size, aggressive histologic subtype and perineural invasion. Management requires a multidisciplinary approach with orbital exenteration remaining the treatment of choice. Globe-sparing treatment may be appropriate in selected patients and radiotherapy and chemotherapy are often used as adjuvant therapies for advanced or inoperable cases, although the evidence remains limited. We aim to summarize the presentation and treatment of BCC with orbital invasion to better guide the management of this complex condition.

  2. Reconstruction of Midface and Orbital Wall Defects After Maxillectomy and Orbital Content Preservation With Titanium Mesh and Fascia Lata: 3-Year Follow-Up.

    Science.gov (United States)

    Motiee-Langroudi, Maziar; Harirchi, Iraj; Amali, Amin; Jafari, Mehrdad

    2015-12-01

    To describe the authors' experience in the reconstruction of patients after total maxillectomy with preservation of orbital contents for maxillary tumors using titanium mesh and autogenous fascia lata, where no setting for free flap reconstruction is available. Twelve consecutive patients with paranasal sinus tumors underwent total maxillectomy without orbital exenterations and primary reconstruction. The defects were reconstructed by titanium mesh in combination with autogenous fascia lata in the orbital floor performed by 1 surgical team. Titanium mesh (0.2 mm thick) was contoured and fixed to reconstruct the orbital floor and obtain midface projection. Fascia lata was used to cover the titanium mesh along the orbital floor to prevent fat entrapment in the mesh holes. The most common pathology was squamous cell carcinoma (50%). Patients' mean age was 45.66 years (33 to 74 yr). The mean follow-up period was 35.2 months (30 to 49 months). During follow-up, no infection or foreign body reaction was encountered. Extrusion of titanium mesh occurred in 4 patients who underwent postoperative radiotherapy. Two cases of mild diplopia at extreme gaze occurred early during the postoperative period that resolved after a few months. Placing fascia lata between the titanium mesh surface of the orbital implant and the orbital contents was successful in preventing long-term diplopia or dystopia. Nevertheless, exposure of the titanium implant through the skin surface represented a complication of this technique in 25% of patients. Further studies are required with head-to-head comparisons of artificial materials and free flaps for reconstruction of maxillectomy defects. Copyright © 2015 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  3. Vav promotes differentiation of human tumoral myeloid precursors

    International Nuclear Information System (INIS)

    Bertagnolo, Valeria; Brugnoli, Federica; Mischiati, Carlo; Sereni, Alessia; Bavelloni, Alberto; Carini, Cinzia; Capitani, Silvano

    2005-01-01

    Vav is one of the genetic markers that correlate with the differentiation of hematopoietic cells. In T and B cells, it appears crucial for both development and functions, while, in non-lymphoid hematopoietic cells, Vav seems not involved in cell maturation, but rather in the response of mature cells to agonist-dependent proliferation and phagocytosis. We have previously demonstrated that the amount and the tyrosine phosphorylation of Vav are up-regulated in both whole cells and nuclei of tumoral promyelocytes induced to granulocytic maturation by ATRA and that tyrosine-phosphorylated Vav does not display any ATRA-induced GEF activity but contributes to the regulation of PI 3-K activity. In this study, we report that Vav accumulates in nuclei of ATRA-treated APL-derived cells and that the down-modulation of Vav prevents differentiation of tumoral promyelocytes, indicating that it is a key molecule in ATRA-dependent myeloid maturation. On the other hand, the overexpression of Vav induces an increased expression of surface markers of granulocytic differentiation without affecting the maturation-related changes of the nuclear morphology. Consistent with an effect of Vav on the transcriptional machinery, array profiling shows that the inhibition of the Syk-dependent tyrosine phosphorylation of Vav reduces the number of ATRA-induced genes. Our data support the unprecedented notion that Vav plays crucial functions in the maturation process of myeloid cells, and suggest that Vav can be regarded as a potential target for the therapeutic treatment of myeloproliferative disorders

  4. Epigenetic changes in solid and hematopoietic tumors.

    Science.gov (United States)

    Toyota, Minoru; Issa, Jean-Pierre J

    2005-10-01

    There are three connected molecular mechanisms of epigenetic cellular memory in mammalian cells: DNA methylation, histone modifications, and RNA interference. The first two have now been firmly linked to neoplastic transformation. Hypermethylation of CpG-rich promoters triggers local histone code modifications resulting in a cellular camouflage mechanism that sequesters gene promoters away from transcription factors and results in stable silencing. This normally restricted mechanism is ubiquitously used in cancer to silence hundreds of genes, among which some critically contribute to the neoplastic phenotype. Virtually every pathway important to cancer formation is affected by this process. Methylation profiling of human cancers reveals tissue-specific epigenetic signatures, as well as tumor-specific signatures, reflecting in particular the presence of epigenetic instability in a subset of cancers affected by the CpG island methylator phenotype. Generally, methylation patterns can be traced to a tissue-specific, proliferation-dependent accumulation of aberrant promoter methylation in aging tissues, a process that can be accelerated by chronic inflammation and less well-defined mechanisms including, possibly, diet and genetic predisposition. The epigenetic machinery can also be altered in cancer by specific lesions in epigenetic effector genes, or by aberrant recruitment of these genes by mutant transcription factors and coactivators. Epigenetic patterns are proving clinically useful in human oncology via risk assessment, early detection, and prognostic classification. Pharmacologic manipulation of these patterns-epigenetic therapy-is also poised to change the way we treat cancer in the clinic.

  5. Iodine-125 orbital brachytherapy with a prosthetic implant in situ

    Energy Technology Data Exchange (ETDEWEB)

    Stannard, Clare [Groote Schuur Hospital and Cape Town Univ. (South Africa). Dept. of Radiation Oncology; Maree, Gert; Munro, Roger [Groote Schuur Hospital and Cape Town Univ. (South Africa). Dept. of Medical Physics; Lecuona, Karin [Groote Schuur Hospital and Cape Town Univ. (South Africa). Dept. of Ophthalmology; Sauerwein, Wolfgang [Universitaetsklinikum Essen (Germany). Strahlenklinik, NCTeam

    2011-05-15

    Purpose: Brachytherapy is one method of irradiating the orbit after enucleation of an eye with a malignant tumor that has a potential to recur. It consists of 6 trains of I-125 seeds placed around the periphery of the orbit, a shorter central train, and a metal disc, loaded with seeds, placed beneath the eyelids. The presence of a prosthetic orbital implant requires omission of the central train and adjustment of the activity of the seeds in the anterior orbit around the prosthesis. Patients and Methods: This is a retrospective review of the technical modifications and outcome of 12 patients treated in this manner: 6 with retinoblastoma, 5 with malignant melanoma, and 1 with an intraocular rhabdomyosarcoma. The median dose was 35.5 Gy in 73 hours for retinoblastoma and 56 Gy in 141 hours for malignant melanoma. Patients with retinoblastoma and rhabdomyosarcoma also received chemotherapy. Results: The tubes can be placed satisfactorily around the prosthesis. The increased activity in the anterior half of the tubes produced comparable dose distributions. There have been no orbital recurrences, no extrusion of the prosthesis, and cosmesis is good. Conclusion: Insertion of a prosthetic implant at the time of enucleation greatly enhances the subsequent cosmetic appearance. This should be encouraged unless there is frank tumor in the orbit. Orbital brachytherapy without the central train continues to give excellent local control. The short treatment time and good cosmesis are added advantages. The patient is spared the expense and inconvenience of removing and replacing the prosthetic implant. (orig.)

  6. The transcriptional landscape of hematopoietic stem cell ontogeny

    Science.gov (United States)

    McKinney-Freeman, Shannon; Cahan, Patrick; Li, Hu; Lacadie, Scott A.; Huang, Hsuan-Ting; Curran, Matthew; Loewer, Sabine; Naveiras, Olaia; Kathrein, Katie L.; Konantz, Martina; Langdon, Erin M.; Lengerke, Claudia; Zon, Leonard I.; Collins, James J.; Daley, George Q.

    2012-01-01

    Transcriptome analysis of adult hematopoietic stem cells (HSC) and their progeny has revealed mechanisms of blood differentiation and leukemogenesis, but a similar analysis of HSC development is lacking. Here, we acquired the transcriptomes of developing HSC purified from >2500 murine embryos and adult mice. We found that embryonic hematopoietic elements clustered into three distinct transcriptional states characteristic of the definitive yolk sac, HSCs undergoing specification, and definitive HSCs. We applied a network biology-based analysis to reconstruct the gene regulatory networks of sequential stages of HSC development and functionally validated candidate transcriptional regulators of HSC ontogeny by morpholino-mediated knock-down in zebrafish embryos. Moreover, we found that HSCs from in vitro differentiated embryonic stem cells closely resemble definitive HSC, yet lack a Notch-signaling signature, likely accounting for their defective lymphopoiesis. Our analysis and web resource (http://hsc.hms.harvard.edu) will enhance efforts to identify regulators of HSC ontogeny and facilitate the engineering of hematopoietic specification. PMID:23122293

  7. Aging of hematopoietic stem cells : Intrinsic changes or micro-environmental effects?

    NARCIS (Netherlands)

    Woolthuis, Carolien M.; de Haan, Gerald; Huls, Gerwin

    During development hematopoietic stem cells (HSCs) expand in number and persist throughout life by undergoing self-renewing divisions. Nevertheless, the hematopoietic system does not escape the negative effects of aging, suggesting that self-renewal is not complete. A fundamental issue in stem cell

  8. An in vitro model of hemogenic endothelium commitment and hematopoietic production

    NARCIS (Netherlands)

    Yvernogeau, Laurent; Gautier, Rodolphe; Khoury, Hanane; Menegatti, Sara; Schmidt, Melanie; Gilles, Jean Francois; Jaffredo, Thierry

    2016-01-01

    Adult-type hematopoietic stem and progenitor cells are formed during ontogeny from a specialized subset of endothelium, termed the hemogenic endothelium, via an endothelial-to-hematopoietic transition (EHT) that occurs in the embryonic aorta and the associated arteries. Despite efforts to generate

  9. Tumors of the optic nerve

    DEFF Research Database (Denmark)

    Lindegaard, Jens; Heegaard, Steffen

    2009-01-01

    A variety of lesions may involve the optic nerve. Mainly, these lesions are inflammatory or vascular lesions that rarely necessitate surgery but may induce significant visual morbidity. Orbital tumors may induce proptosis, visual loss, relative afferent pupillary defect, disc edema and optic...... atrophy, but less than one-tenth of these tumors are confined to the optic nerve or its sheaths. No signs or symptoms are pathognomonic for tumors of the optic nerve. The tumors of the optic nerve may originate from the optic nerve itself (primary tumors) as a proliferation of cells normally present...... in the nerve (e.g., astrocytes and meningothelial cells). The optic nerve may also be invaded from tumors originating elsewhere (secondary tumors), invading the nerve from adjacent structures (e.g., choroidal melanoma and retinoblastoma) or from distant sites (e.g., lymphocytic infiltration and distant...

  10. Effect of cotransplantation of hematopoietic stem cells and embryonic AGM stromal cells on hematopoietic reconstitution in mice after bone marrow transplantation

    International Nuclear Information System (INIS)

    Tao Si; Sun Hanying; Liu Wenli

    2007-01-01

    Objective: To explore the effects of cotransplantation of hematopoietic stem cells and stromal cells derived from aorta-gonad-mesonephros (AGM) region on hematopoietic reconstitution in mice after bone marrow transplantation (BMT). Methods: The typical mice model of syngeneic BMT was established and the mice were randomly divided into 4 groups: the control group, the BMT group, the group of cotransplantation of HSC with AGM stromal cells (the cotransplantation group) and the ligustrazine group (the LT group). On days 3, 7, 10, 14, 21 and 28 after BMT, the peripheral blood cells and bone marrow mononuclear cells (BMMNC) were counted, and histology changes of bone marrow were detected. Results: The levels of peripheral WBC, RBC, platelet, and BMMNC in the contransplantation group were significantly higher than those in the single BMT group and the LT group (P<0.05). Conclusions: Cotransplantation with AGM stromal cells could significantly promote hematopoietic reconstruction in mice after BMT. (authors)

  11. Radioimmunotherapy of small cell lung cancer xenograft mice with a 90Y anti-ROBO1 monoclonal antibody: Pathological study of effects on tumor and normal organs

    International Nuclear Information System (INIS)

    Fujiwara, K.; Koyama, K.; Kitada, T.; Takahashi, M.; Momose, T.; Suga, K.

    2015-01-01

    Full text of publication follows. ROBO1 is a membrane protein that is concerned about axon guidance. It is reported that ROBO1 contributes to tumor metastasis and angio genesis. ROBO1 is specifically expressed at high levels in small cell lung cancer (SCLC). In this study, we performed radioimmunotherapy (RIT) to SCLC models, and analyzed pathological alteration of tumor and organs. Methods: For the biodistribution study, 111 In-DOTA anti-ROBO1 IgG (about 370 kBq, 111 In anti-ROBO1) was injected into NCI-H69 xenograft mice via tail vein. To evaluate antitumor effect, RIT study was performed. 90 Y-DOTA anti-ROBO1 IgG (about 7.4 MBq, 90 Y anti-ROBO1) was injected. The experiments measured tumor volume, mouse weights and blood cell counts periodically. The tumors and organs (liver, kidney, intestine, spleen, femoral and sternum) of mice were obtained, and histopathologic analysis were carried out. Results: as a result of biodistribution study, the specific accumulation in the tumor of 111 In anti-ROBO1 was observed. Liver, kidney, spleen and lung showed comparatively high accumulation of 111 In anti-ROBO1. In the RIT study, 90 Y anti-ROBO1 significantly reduced tumor volume compared with original volume and increased median survival time to 58 days (p<0.01, versus saline, 28 days), while 90 Y anti-ROBO1 induced transient pancytopenia. Histopathologic analysis of tumors and organs further validated the therapeutic efficacy and the systemic toxicity of 90 Y anti-ROBO1. In day 7 when tumor volume reduced to 60% compared with original volume, irreversible nuclear denaturation and fibrosis were observed. The percentage of TUNEL-positive cells increased to 11.4%±5.1 in the day 7 (p<0.01, versus control, 4.14%±1.4), which showed increase of DNA fragmentation and apoptosis in the tumor tissues. Normal organs excluding spleen and sternum showed no significant injury. In day 7 post injection, spleen showed transient reduction of hematopoietic cells. Hematopoietic cells in

  12. Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Patients in the Black Sea Region of Turkey

    Directory of Open Access Journals (Sweden)

    Alişan Yıldıran

    2017-12-01

    Full Text Available Hematopoietic stem cell transplantation is a promising curative therapy for many combined primary immunodeficiencies and phagocytic disorders. We retrospectively reviewed pediatric cases of patients diagnosed with primary immunodeficiencies and scheduled for hematopoietic stem cell transplantation. We identified 22 patients (median age, 6 months; age range, 1 month to 10 years with various diagnoses who received hematopoietic stem cell transplantation. The patient diagnoses included severe combined immunodeficiency (n=11, Chediak-Higashi syndrome (n=2, leukocyte adhesion deficiency (n=2, MHC class 2 deficiency (n=2, chronic granulomatous syndrome (n=2, hemophagocytic lymphohistiocytosis (n=1, Wiskott-Aldrich syndrome (n=1, and Omenn syndrome (n=1. Of the 22 patients, 7 received human leukocyte antigen-matched related hematopoietic stem cell transplantation, 12 received haploidentical hematopoietic stem cell transplantation, and 2 received matched unrelated hematopoietic stem cell transplantation. The results showed that 5 patients had graft failure. Fourteen patients survived, yielding an overall survival rate of 67%. Screening newborn infants for primary immunodeficiency diseases may result in timely administration of hematopoietic stem cell transplantation.

  13. Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Patients in the Black Sea Region of Turkey.

    Science.gov (United States)

    Yıldıran, Alişan; Çeliksoy, Mehmet Halil; Borte, Stephan; Güner, Şükrü Nail; Elli, Murat; Fışgın, Tunç; Özyürek, Emel; Sancak, Recep; Oğur, Gönül

    2017-12-01

    Hematopoietic stem cell transplantation is a promising curative therapy for many combined primary immunodeficiencies and phagocytic disorders. We retrospectively reviewed pediatric cases of patients diagnosed with primary immunodeficiencies and scheduled for hematopoietic stem cell transplantation. We identified 22 patients (median age, 6 months; age range, 1 month to 10 years) with various diagnoses who received hematopoietic stem cell transplantation. The patient diagnoses included severe combined immunodeficiency (n=11), Chediak-Higashi syndrome (n=2), leukocyte adhesion deficiency (n=2), MHC class 2 deficiency (n=2), chronic granulomatous syndrome (n=2), hemophagocytic lymphohistiocytosis (n=1), Wiskott-Aldrich syndrome (n=1), and Omenn syndrome (n=1). Of the 22 patients, 7 received human leukocyte antigen-matched related hematopoietic stem cell transplantation, 12 received haploidentical hematopoietic stem cell transplantation, and 2 received matched unrelated hematopoietic stem cell transplantation. The results showed that 5 patients had graft failure. Fourteen patients survived, yielding an overall survival rate of 67%. Screening newborn infants for primary immunodeficiency diseases may result in timely administration of hematopoietic stem cell transplantation.

  14. Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells.

    Science.gov (United States)

    Ruud, Johan; Wilhelms, Daniel Björk; Nilsson, Anna; Eskilsson, Anna; Tang, Yan-Juan; Ströhle, Peter; Caesar, Robert; Schwaninger, Markus; Wunderlich, Thomas; Bäckhed, Fredrik; Engblom, David; Blomqvist, Anders

    2013-05-01

    Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

  15. SIMPL enhancement of tumor necrosis factor-α dependent p65-MED1 complex formation is required for mammalian hematopoietic stem and progenitor cell function.

    Directory of Open Access Journals (Sweden)

    Weina Zhao

    Full Text Available Significant insight into the signaling pathways leading to activation of the Rel transcription factor family, collectively termed NF-κB, has been gained. Less well understood is how subsets of NF-κB-dependent genes are regulated in a signal specific manner. The SIMPL protein (signaling molecule that interacts with mouse pelle-like kinase is required for full Tumor Necrosis Factor-α (TNFα induced NF-κB activity. We show that SIMPL is required for steady-state hematopoiesis and the expression of a subset of TNFα induced genes whose products regulate hematopoietic cell activity. To gain insight into the mechanism through which SIMPL modulates gene expression we focused on the Tnf gene, an immune response regulator required for steady-state hematopoiesis. In response to TNFα SIMPL localizes to the Tnf gene promoter where it modulates the initiation of Tnf gene transcription. SIMPL binding partners identified by mass spectrometry include proteins involved in transcription and the interaction between SIMPL and MED1 was characterized in more detail. In response to TNFα, SIMPL is found in p65-MED1 complexes where SIMPL enhances p65/MED1/SIMPL complex formation. Together our results indicate that SIMPL functions as a TNFα-dependent p65 co-activator by facilitating the recruitment of MED1 to p65 containing transcriptional complexes to control the expression of a subset of TNFα-induced genes.

  16. Cord blood hematopoietic cells from preterm infants display altered DNA methylation patterns.

    Science.gov (United States)

    de Goede, Olivia M; Lavoie, Pascal M; Robinson, Wendy P

    2017-01-01

    Premature infants are highly vulnerable to infection. This is partly attributable to the preterm immune system, which differs from that of the term neonate in cell composition and function. Multiple studies have found differential DNA methylation (DNAm) between preterm and term infants' cord blood; however, interpretation of these studies is limited by the confounding factor of blood cell composition. This study evaluates the epigenetic impact of preterm birth in isolated hematopoietic cell populations, reducing the concern of cell composition differences. Genome-wide DNAm was measured using the Illumina 450K array in T cells, monocytes, granulocytes, and nucleated red blood cells (nRBCs) isolated from cord blood of 5 term and 5 preterm (blood cells (nRBCs) showed the most extensive changes in DNAm, with 9258 differentially methylated (DM) sites (FDR  0.10) discovered between preterm and term infants compared to the blood cell populations. The direction of DNAm change with gestational age at these prematurity-DM sites followed known patterns of hematopoietic differentiation, suggesting that term hematopoietic cell populations are more epigenetically mature than their preterm counterparts. Consistent shifts in DNAm between preterm and term cells were observed at 25 CpG sites, with many of these sites located in genes involved in growth and proliferation, hematopoietic lineage commitment, and the cytoskeleton. DNAm in preterm and term hematopoietic cells conformed to previously identified DNAm signatures of fetal liver and bone marrow, respectively. This study presents the first genome-wide mapping of epigenetic differences in hematopoietic cells across the late gestational period. DNAm differences in hematopoietic cells between term and <31 weeks were consistent with the hematopoietic origin of these cells during ontogeny, reflecting an important role of DNAm in their regulation. Due to the limited sample size and the high coincidence of prematurity and

  17. Two hemocyte lineages exist in silkworm larval hematopoietic organ.

    Science.gov (United States)

    Nakahara, Yuichi; Kanamori, Yasushi; Kiuchi, Makoto; Kamimura, Manabu

    2010-07-28

    Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO) into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocytoids, and spherulocytes. Five days after implantation of enzymatically-dispersed HPO cells from a GFP-expressing transgenic line into the hemocoel of normal larvae, differentiation into plasmatocytes, granulocytes and oenocytoids, but not spherulocytes, was observed. When the HPO cells were cultured in vitro, plasmatocytes appeared rapidly, and oenocytoids possessing prophenol oxidase activity appeared several days later. HPO cells were also able to differentiate into a small number of granulocytes, but not into spherulocytes. When functionally mature plasmatocytes were cultured in vitro, oenocytoids were observed 10 days later. These results suggest that the hemocyte precursors in HPO first differentiate into plasmatocytes, which further change into oenocytoids. From these results, we propose that B. mori hemocytes can be divided into two major lineages, a granulocyte lineage and a plasmatocyte-oenocytoid lineage. The origins of the spherulocytes could not be determined in this study. We construct a model for the hematopoietic lineages at the larval stage of B. mori.

  18. In Utero Hematopoietic Cell Transplantation for Hemoglobinopathies

    Directory of Open Access Journals (Sweden)

    Tippi C. Mackenzie

    2015-01-01

    Full Text Available In utero hematopoietic cell transplantation (IUHCTx is a promising strategy to circumvent the challenges of postnatal hematopoietic stem cell (HSC transplantation. The goal of IUHCTx is to introduce donor cells into a naïve host prior to immune maturation, thereby inducing donor–specific tolerance. Thus, this technique has the potential of avoiding host myeloablative conditioning with cytotoxic agents. Over the past two decades, several attempts at IUHCTx have been made to cure numerous underlying congenital anomalies with limited success. In this review, we will briefly review the history of IUHCTx and give a perspective on alpha thalassemia major, one target disease for its clinical application.

  19. Persistent Fatigue in Hematopoietic Stem Cell Transplantation Survivors.

    Science.gov (United States)

    Hacker, Eileen Danaher; Fink, Anne M; Peters, Tara; Park, Chang; Fantuzzi, Giamila; Rondelli, Damiano

    Fatigue is highly prevalent after hematopoietic stem cell transplantation (HCT). It has been described as intense and may last for years following treatment. The aim of this study is to compare fatigue, physical activity, sleep, emotional distress, cognitive function, and biological measures in HCT survivors with persistent fatigue (n = 25) with age- and gender-matched healthy controls with occasional tiredness (n = 25). Data were collected using (a) objective, real-time assessments of physical activity and sleep over 7 days; (b) patient-reported fatigue assessments; (c) computerized objective testing of cognitive functioning; and (d) biological measures. Differences between groups were examined using multivariate analysis of variance. Survivors of HCT reported increased physical (P < .001), mental (P < .001), and overall (P < .001) fatigue as well as increased anxiety (P < .05) and depression (P < .01) compared with healthy controls. Red blood cell (RBC) levels were significantly lower in HCT survivors (P < .001). Levels of RBC for both groups, however, were in the normal range. Tumor necrosis factor-α (P < .001) and interleukin-6 (P < .05) levels were significantly higher in HCT survivors. Persistent fatigue in HCT survivors compared with healthy controls with occasional tiredness is accompanied by increased anxiety and depression along with decreased RBC counts. Elevated tumor necrosis factor-α and interleukin-6 levels may be important biomarkers. This study provides preliminary support for the conceptualization of fatigue as existing on a continuum, with tiredness anchoring one end and exhaustion the other. Persistent fatigue experienced by HCT survivors is more severe than the occasional tiredness of everyday life.

  20. Effects of hematopoietic growth factors on purified bone marrow progenitor cells

    NARCIS (Netherlands)

    F.J. Bot (Freek)

    1992-01-01

    textabstractWe have used highly enriched hematopoietic progenitor cells and in-vitro culture to examine the following questions: 1. The effects of recombinant lL-3 and GM-CSF on proliferation and differentiation of enriched hematopoietic progenitor cells have not been clearly defined: - how do IL~3

  1. Hematopoietic Gene Therapies for Metabolic and Neurologic Diseases.

    Science.gov (United States)

    Biffi, Alessandra

    2017-10-01

    Increasingly, patients affected by metabolic diseases affecting the central nervous system and neuroinflammatory disorders receive hematopoietic cell transplantation (HCT) in the attempt to slow the course of their disease, delay or attenuate symptoms, and improve pathologic findings. The possible replacement of brain-resident myeloid cells by the transplanted cell progeny contributes to clinical benefit. Genetic engineering of the cells to be transplanted (hematopoietic stem cell) may endow the brain myeloid progeny of these cells with enhanced or novel functions, contributing to therapeutic effects. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Induction of various immune modulatory molecules in CD34(+) hematopoietic cells

    DEFF Research Database (Denmark)

    Umland, Oliver; Heine, Holger; Miehe, Michaela

    2004-01-01

    revealed that T cell proliferation can be induced by TNF-alpha-stimulated KG-1a cells, which is preventable by blocking anti-ICAM-1 monoclonal antibodies. Our results demonstrate that CD34(+) HCs have the potential to express a variety of immune-regulatory mediators upon stimulation by inflammatory......Lipopolysaccharide (LPS) has been shown to induce proliferation of human T-lymphocytes only in the presence of monocytes and CD34(+) hematopoietic cells (HCs) from peripheral blood. This finding provided evidence of an active role of CD34(+) HCs during inflammation and immunological events....... To investigate mechanisms by which CD34(+) HCs become activated and exert their immune-modulatory function, we used the human CD34(+) acute myeloid leukemia cell line KG-1a and CD34(+) bone marrow cells (BMCs). We showed that culture supernatants of LPS-stimulated mononuclear cells (SUP(LPS)) as well as tumor...

  3. Activated H-Ras regulates hematopoietic cell survival by modulating Survivin

    International Nuclear Information System (INIS)

    Fukuda, Seiji; Pelus, Louis M.

    2004-01-01

    Survivin expression and Ras activation are regulated by hematopoietic growth factors. We investigated whether activated Ras could circumvent growth factor-regulated Survivin expression and if a Ras/Survivin axis mediates growth factor independent survival and proliferation in hematopoietic cells. Survivin expression is up-regulated by IL-3 in Ba/F3 and CD34 + cells and inhibited by the Ras inhibitor, farnesylthiosalicylic acid. Over-expression of constitutively activated H-Ras (CA-Ras) in Ba/F3 cells blocked down-modulation of Survivin expression, G 0 /G 1 arrest, and apoptosis induced by IL-3 withdrawal, while dominant-negative (DN) H-Ras down-regulated Survivin. Survivin disruption by DN T34A Survivin blocked CA-Ras-induced IL-3-independent cell survival and proliferation; however, it did not affect CA-Ras-mediated enhancement of S-phase, indicating that the anti-apoptotic activity of CA-Ras is Survivin dependent while its S-phase enhancing effect is not. These results indicate that CA-Ras modulates Survivin expression independent of hematopoietic growth factors and that a CA-Ras/Survivin axis regulates survival and proliferation of transformed hematopoietic cells

  4. SBR-Blood: systems biology repository for hematopoietic cells.

    Science.gov (United States)

    Lichtenberg, Jens; Heuston, Elisabeth F; Mishra, Tejaswini; Keller, Cheryl A; Hardison, Ross C; Bodine, David M

    2016-01-04

    Extensive research into hematopoiesis (the development of blood cells) over several decades has generated large sets of expression and epigenetic profiles in multiple human and mouse blood cell types. However, there is no single location to analyze how gene regulatory processes lead to different mature blood cells. We have developed a new database framework called hematopoietic Systems Biology Repository (SBR-Blood), available online at http://sbrblood.nhgri.nih.gov, which allows user-initiated analyses for cell type correlations or gene-specific behavior during differentiation using publicly available datasets for array- and sequencing-based platforms from mouse hematopoietic cells. SBR-Blood organizes information by both cell identity and by hematopoietic lineage. The validity and usability of SBR-Blood has been established through the reproduction of workflows relevant to expression data, DNA methylation, histone modifications and transcription factor occupancy profiles. Published by Oxford University Press on behalf of Nucleic Acids Research 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  5. Aging impairs long-term hematopoietic regeneration after autologous stem cell transplantation

    NARCIS (Netherlands)

    Woolthuis, Carolien M; Mariani, Niccoló; Verkaik-Schakel, Rikst Nynke; Brouwers-Vos, Annet Z.; Schuringa, Jan Jacob; Vellenga, Edo; de Wolf, Joost T M; Huls, Gerwin

    Most of our knowledge of the effects of aging on the hematopoietic system comes from studies in animal models. In this study, to explore potential effects of aging on human hematopoietic stem and progenitor cells (HSPCs), we evaluated CD34(+) cells derived from young (<35 years) and old (>60 years)

  6. Inverted papilloma of lacrimal sac invading into the orbit: Case report and review of literature

    Directory of Open Access Journals (Sweden)

    Alistair W Hardy

    2015-01-01

    Full Text Available Inverted papilloma (IP is a sinonasal tumor of benign etiology with local invasion and malignant potential. IP arising in lacrimal sac invading the orbit is extremely rare with only one case reported so far. The presented case appears to be the second such case reported in the literature. A 60-year-old Caucasian male presented with a medial canthal mass and epiphora. Incisional biopsy confirmed a transitional neoplasm. The lesion was completely excised enbloc with clear margins by using a Weber-Ferguson incision; orbital clearance and nasolacrimalfossa clearance was achieved via a medial maxillectomy. Enbloc resection of orbital and nasolacrimal parts of the tumor with clear margins is recommended.

  7. Autologous Hematopoietic Stem Cell Transplantation to Prevent Antibody Mediated Rejection After Vascularized Composite Allotransplantation

    Science.gov (United States)

    2017-10-01

    Award Number: W81XWH-16-1-0664 TITLE: Autologous Hematopoietic Stem Cell Transplantation to Prevent Antibody-Mediated Rejection after...Annual 3. DATES COVERED 15 Sep 2016 – 14 Sep 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Autologous Hematopoietic Stem Cell Transplantation to...sensitization, autologous hematopoietic stem cell transplantation, antibody mediated rejection, donor specific antibodies 16. SECURITY CLASSIFICATION OF

  8. VE-cadherin expression allows identification of a new class of hematopoietic stem cells within human embryonic liver.

    Science.gov (United States)

    Oberlin, Estelle; Fleury, Maud; Clay, Denis; Petit-Cocault, Laurence; Candelier, Jean-Jacques; Mennesson, Benoît; Jaffredo, Thierry; Souyri, Michèle

    2010-11-25

    Edification of the human hematopoietic system during development is characterized by the production of waves of hematopoietic cells separated in time, formed in distinct embryonic sites (ie, yolk sac, truncal arteries including the aorta, and placenta). The embryonic liver is a major hematopoietic organ wherein hematopoietic stem cells (HSCs) expand, and the future, adult-type, hematopoietic cell hierarchy becomes established. We report herein the identification of a new, transient, and rare cell population in the human embryonic liver, which coexpresses VE-cadherin, an endothelial marker, CD45, a pan-hematopoietic marker, and CD34, a common endothelial and hematopoietic marker. This population displays an outstanding self-renewal, proliferation, and differentiation potential, as detected by in vitro and in vivo hematopoietic assays compared with its VE-cadherin negative counterpart. Based on VE-cadherin expression, our data demonstrate the existence of 2 phenotypically and functionally separable populations of multipotent HSCs in the human embryo, the VE-cadherin(+) one being more primitive than the VE-cadherin(-) one, and shed a new light on the hierarchical organization of the embryonic liver HSC compartment.

  9. STAT5-mediated self-renewal of normal hematopoietic and leukemic stem cells

    NARCIS (Netherlands)

    Schepers, Hein; Wierenga, Albertus T. J.; Vellenga, Edo; Schuringa, Jan Jacob

    2012-01-01

    The level of transcription factor activity critically regulates cell fate decisions such as hematopoietic stem cell self-renewal and differentiation. The balance between hematopoietic stem cell self-renewal and differentiation needs to be tightly controlled, as a shift toward differentiation might

  10. Cross-platform array comparative genomic hybridization meta-analysis separates hematopoietic and mesenchymal from epithelial tumors

    NARCIS (Netherlands)

    Jong, C.; Marchiori, E.; van der Vaart, A.W.; Chin, S.F.; Carvalho, B; Tijssen, M.; Eijk, P.P.; van den IJssel, P.; Grabsch, H.; Quirke, P.; Oudejans, J.J.; Meijer, G.J.; Caldas, C.; Ylstra, B.

    2007-01-01

    A series of studies have been published that evaluate the chromosomal copy number changes of different tumor classes using array comparative genomic hybridization (array CGH); however, the chromosomal aberrations that distinguish the different tumor classes have not been fully characterized.

  11. Two hemocyte lineages exist in silkworm larval hematopoietic organ.

    Directory of Open Access Journals (Sweden)

    Yuichi Nakahara

    Full Text Available BACKGROUND: Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. METHODOLOGY/PRINCIPAL FINDINGS: To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocytoids, and spherulocytes. Five days after implantation of enzymatically-dispersed HPO cells from a GFP-expressing transgenic line into the hemocoel of normal larvae, differentiation into plasmatocytes, granulocytes and oenocytoids, but not spherulocytes, was observed. When the HPO cells were cultured in vitro, plasmatocytes appeared rapidly, and oenocytoids possessing prophenol oxidase activity appeared several days later. HPO cells were also able to differentiate into a small number of granulocytes, but not into spherulocytes. When functionally mature plasmatocytes were cultured in vitro, oenocytoids were observed 10 days later. These results suggest that the hemocyte precursors in HPO first differentiate into plasmatocytes, which further change into oenocytoids. CONCLUSIONS/SIGNIFICANCE: From these results, we propose that B. mori hemocytes can be divided into two major lineages, a granulocyte lineage and a plasmatocyte-oenocytoid lineage. The origins of the spherulocytes could not be determined in this study. We construct a model for the hematopoietic lineages at the larval stage of B. mori.

  12. Orbital lymphoma masquerading as thyroid ophthalmopathy.

    Science.gov (United States)

    Boyce, P J

    1998-10-01

    Lymphoid tumors are known to originate within the lacrimal gland and orbital fat. Ocular findings commonly seen are a palpable mass with proptosis and downward displacement of the globe. Graves' ophthalmopathy is the most common orbital pathology occurring in the general population. Signs and symptoms of Graves' ophthalmopathy, such as unilateral or bilateral proptosis, double vision, limitation of movement of the extraocular muscles, are not specific for this condition. A 57-year-old man came to us with a chief symptom of "eye swelling" for the last 3 years. He had been diagnosed with hyperthyroidism and had received three surgical procedures for orbital decompression. Clinical findings included limitation of upward and downward gaze, exophthalmometry readings of 30 1/2 mm O.D. and 31 mm O.S. (with a base of 112), and profound proptosis with fatty tissue prolapse. Subsequent thyroid testing revealed euthyroid status and computed tomography scan revealed orbital lymphoma. Orbital involvement from a malignant nodular histiocytic lymphoma resulted in a proptosis similar to that observed in Graves' ophthalmopathy. This very unusual presentation of orbital lymphoma mimicked Graves' disease so closely that the true cause was overlooked. This case emphasizes the need to include space-occupying lesions in the differential diagnosis of proptosis and gaze restrictions. The disease process and controversial management strategies are discussed.

  13. Therapeutic approaches of hematopoietic syndrome after serious accidental global irradiation. Ex vivo expansion interest of hematopoietic cells

    International Nuclear Information System (INIS)

    Thierry, D.

    1994-01-01

    Aplasia is one of the main syndrome, appearing after one global accidental irradiation by one ionizing radiation source. The hematopoietic syndrome is characterized by a peripheric blood cell number fall; the cell marrow is reduced too

  14. Are neural crest stem cells the missing link between hematopoietic and neurogenic niches?

    Directory of Open Access Journals (Sweden)

    Cécile eCoste

    2015-06-01

    Full Text Available Hematopoietic niches are defined as cellular and molecular microenvironments that regulate hematopoietic stem cell (HSC function together with stem cell autonomous mechanisms. Many different cell types have been characterized as contributors to the formation of HSC niches, such as osteoblasts, endothelial cells, Schwann cells, and mesenchymal progenitors. These mesenchymal progenitors have themselves been classified as CXC chemokine ligand (CXCL12-abundant reticular (CAR cells, stem cell factor expressing cells, or nestin-positive mesenchymal stem cells (MSCs, which have been recently identified as neural crest-derived cells (NCSCs. Together, these cells are spatially associated with HSCs and believed to provide appropriate microenvironments for HSC self-renewal, differentiation, mobilization and hibernation both by cell-to-cell contact and soluble factors. Interestingly, it appears that regulatory pathways governing the hematopoietic niche homeostasis are operating in the neurogenic niche as well. Therefore, this review paper aims to compare both the regulation of hematopoietic and neurogenic niches, in order to highlight the role of NCSCs and nervous system components in the development and the regulation of the hematopoietic system.

  15. Are neural crest stem cells the missing link between hematopoietic and neurogenic niches?

    Science.gov (United States)

    Coste, Cécile; Neirinckx, Virginie; Gothot, André; Wislet, Sabine; Rogister, Bernard

    2015-01-01

    Hematopoietic niches are defined as cellular and molecular microenvironments that regulate hematopoietic stem cell (HSC) function together with stem cell autonomous mechanisms. Many different cell types have been characterized as contributors to the formation of HSC niches, such as osteoblasts, endothelial cells, Schwann cells, and mesenchymal progenitors. These mesenchymal progenitors have themselves been classified as CXC chemokine ligand (CXCL) 12-abundant reticular (CAR) cells, stem cell factor expressing cells, or nestin-positive mesenchymal stem cells (MSCs), which have been recently identified as neural crest-derived cells (NCSCs). Together, these cells are spatially associated with HSCs and believed to provide appropriate microenvironments for HSC self-renewal, differentiation, mobilization and hibernation both by cell-cell contact and soluble factors. Interestingly, it appears that regulatory pathways governing the hematopoietic niche homeostasis are operating in the neurogenic niche as well. Therefore, this review paper aims to compare both the regulation of hematopoietic and neurogenic niches, in order to highlight the role of NCSCs and nervous system components in the development and the regulation of the hematopoietic system.

  16. Tumor orbitário como primeira manifestação clínica de mieloma múltiplo: relato de caso Orbital tumor as the first clinical manifestation of multiple myeloma: case report

    Directory of Open Access Journals (Sweden)

    Aline Ruilowa de Pinho

    2009-02-01

    Full Text Available O acometimento da órbita pelo mieloma múltiplo é raro. Neste estudo, os autores descrevem um caso infrequente de proptose como primeiro sinal clínico do mieloma múltiplo. A presença de lesão orbitária expansiva associada a destruição do rebordo superior da órbita, notáveis à tomografia computadorizada, fez com que a diagnóstico de mieloma múltiplo fosse considerado. Aspectos diagnósticos e terapêuticos são discutidos.Orbital involvement by multiple myeloma is rare. In this study, the authors report an unusual case of proptosis as the first clinical sign of multiple myeloma. The presence of an orbital lesion expanding and destroying the superior orbital rim, disclosed by computed tomography, lead us to consider multiple myeloma. Diagnostic and therapeutic aspects are discussed.

  17. HMB-45 negative angiomyolipoma of the orbit: a case report and review of the literature.

    Science.gov (United States)

    Lin, Che-Yu; Tsai, Chieh-Chih; Kau, Hui-Chuan; Yu, Wei-Kuang; Kao, Shu-Ching; Liu, Catherine Jui-Ling

    2016-01-11

    Angiomyolipoma is a benign mesenchymal tumor composed of variable amounts of smooth muscle, adipose tissue and thick-walled blood vessels, and usually named PEComas (perivascular epithelioid cell tumors). PEComas share overlapping histopathological features with epithelioid cells along a perivascular distribution and characteristic immunohistochemistry with coexpression of myoid and melanocytic markers (HMB-45 /or Melan-A). We report the first case of primary orbital angiomyolipoma with negative melanocytic marker. An 80-year-old Asian woman had a 2-year history of progressive swelling in the left upper eyelid. External examination revealed 3 cm of relative proptosis of the left eye and a palpable mass in the left superonasal orbit. Computed tomographic scan demonstrated a circumscribed, heterogeneous orbital mass. Excision biopsy was done and the histological finding demonstrated the orbital mass was composed of mature adipocytes, intermingled with spindle or oval-shaped cells, and accompanied by thick-walled blood vessels. Immunohistochemically, tumor cells were positive for CD34 and HHF-35, but negative for cytokeratin, HMB-45 and Melan-A. The diagnosis of angiomyolipoma was made. No recurrence was noted at 2-year follow-up. In our case, the HMB-45 negativity may be explained by the rarity of the epithelioid cells, and the HMB-45 positivity is often weaker or absent in spindle cells. Angiomyolipoma, although rare, should be added to the differential diagnosis of space-occupying orbital lesion.

  18. Radiation therapy for primary orbital lymphoma

    International Nuclear Information System (INIS)

    Chao, Cliff K.S.; Lin Hsiusan; Rao Devineni, V.; Smith, Morton

    1995-01-01

    Purpose: The influence of tumor size, grade, thoroughness of staging workup, and radiation dose on disease control, radiation-related complications, and incidence of systemic progression of primary orbital lymphoma is analyzed. Methods and Materials: Twenty patients with Stage I primary orbital lymphoma were treated from August 1976 through August 1991 at Mallinckrodt Institute of Radiology. Staging workups included physical examination, chest x-ray, complete blood count (CBC), liver function test, and computerized tomography (CT) scan of the orbit, abdomen, and pelvis. Nineteen patients had bone marrow biopsy. The histological types based on the National Cancer Institute working formulation were 9 low-grade and 11 intermediate-grade, including five lymphocytic lymphomas of intermediate differentiation. The extension of disease and the volume of tumor were evaluated by CT scan of the orbit. The most commonly used radiation therapy technique was single anterior direct field with 4 MV or 6 MV photons. Lens was shielded or not treated in eight patients. Dose ranged from 20 to 43.2 Gy. Thirteen of 20 patients received 30 Gy. Minimum follow-up was 24 months (median, 4 years). Results: Local control was achieved in all 20 patients. One patient with lymphocytic lymphoma with intermediate differentiation developed disseminated disease. Actuarial disease-free survival (DFS) was 100% and 90% at 2 and 5 years, respectively. No retinopathy was observed. Cataracts were noted in seven patients at 1 to 10 years following irradiation (median, 2 years). Three patients developed lacrimal function disorder, however, no corneal ulceration occurred. Conclusions: Thirty Gy in 15 fractions appears to be a sufficient dose for local control with acceptable morbidity, especially for low-grade, as well as certain types of intermediate-grade lymphomas, such as diffuse small cleaved cell and lymphocytic lymphoma of intermediate differentiation. Systemic dissemination is minimal, provided local

  19. Radiation therapy for primary orbital lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Chao, Cliff K.S.; Hsiusan, Lin; Rao Devineni, V; Smith, Morton

    1995-02-15

    Purpose: The influence of tumor size, grade, thoroughness of staging workup, and radiation dose on disease control, radiation-related complications, and incidence of systemic progression of primary orbital lymphoma is analyzed. Methods and Materials: Twenty patients with Stage I primary orbital lymphoma were treated from August 1976 through August 1991 at Mallinckrodt Institute of Radiology. Staging workups included physical examination, chest x-ray, complete blood count (CBC), liver function test, and computerized tomography (CT) scan of the orbit, abdomen, and pelvis. Nineteen patients had bone marrow biopsy. The histological types based on the National Cancer Institute working formulation were 9 low-grade and 11 intermediate-grade, including five lymphocytic lymphomas of intermediate differentiation. The extension of disease and the volume of tumor were evaluated by CT scan of the orbit. The most commonly used radiation therapy technique was single anterior direct field with 4 MV or 6 MV photons. Lens was shielded or not treated in eight patients. Dose ranged from 20 to 43.2 Gy. Thirteen of 20 patients received 30 Gy. Minimum follow-up was 24 months (median, 4 years). Results: Local control was achieved in all 20 patients. One patient with lymphocytic lymphoma with intermediate differentiation developed disseminated disease. Actuarial disease-free survival (DFS) was 100% and 90% at 2 and 5 years, respectively. No retinopathy was observed. Cataracts were noted in seven patients at 1 to 10 years following irradiation (median, 2 years). Three patients developed lacrimal function disorder, however, no corneal ulceration occurred. Conclusions: Thirty Gy in 15 fractions appears to be a sufficient dose for local control with acceptable morbidity, especially for low-grade, as well as certain types of intermediate-grade lymphomas, such as diffuse small cleaved cell and lymphocytic lymphoma of intermediate differentiation. Systemic dissemination is minimal, provided local

  20. IP3 3-kinase B controls hematopoietic stem cell homeostasis and prevents lethal hematopoietic failure in mice

    Science.gov (United States)

    Siegemund, Sabine; Rigaud, Stephanie; Conche, Claire; Broaten, Blake; Schaffer, Lana; Westernberg, Luise; Head, Steven Robert

    2015-01-01

    Tight regulation of hematopoietic stem cell (HSC) homeostasis ensures lifelong hematopoiesis and prevents blood cancers. The mechanisms balancing HSC quiescence with expansion and differentiation into hematopoietic progenitors are incompletely understood. Here, we identify Inositol-trisphosphate 3-kinase B (Itpkb) as an essential regulator of HSC homeostasis. Young Itpkb−/− mice accumulated phenotypic HSC, which were less quiescent and proliferated more than wild-type (WT) controls. Itpkb−/− HSC downregulated quiescence and stemness associated, but upregulated activation, oxidative metabolism, protein synthesis, and lineage associated messenger RNAs. Although they had normal-to-elevated viability and no significant homing defects, Itpkb−/− HSC had a severely reduced competitive long-term repopulating potential. Aging Itpkb−/− mice lost hematopoietic stem and progenitor cells and died with severe anemia. WT HSC normally repopulated Itpkb−/− hosts, indicating an HSC-intrinsic Itpkb requirement. Itpkb−/− HSC showed reduced colony-forming activity and increased stem-cell-factor activation of the phosphoinositide-3-kinase (PI3K) effectors Akt/mammalian/mechanistic target of rapamycin (mTOR). This was reversed by treatment with the Itpkb product and PI3K/Akt antagonist IP4. Transcriptome changes and biochemistry support mTOR hyperactivity in Itpkb−/− HSC. Treatment with the mTOR-inhibitor rapamycin reversed the excessive mTOR signaling and hyperproliferation of Itpkb−/− HSC without rescuing colony forming activity. Thus, we propose that Itpkb ensures HSC quiescence and function through limiting cytokine-induced PI3K/mTOR signaling and other mechanisms. PMID:25788703

  1. Human CD8 T cells generated in vitro from hematopoietic stem cells are functionally mature

    Directory of Open Access Journals (Sweden)

    Zúñiga-Pflücker Juan

    2011-03-01

    Full Text Available Abstract Background T cell development occurs within the highly specialized thymus. Cytotoxic CD8 T cells are critical in adaptive immunity by targeting virally infected or tumor cells. In this study, we addressed whether functional CD8 T cells can be generated fully in vitro using human umbilical cord blood (UCB hematopoietic stem cells (HSCs in coculture with OP9-DL1 cells. Results HSC/OP9-DL1 cocultures supported the differentiation of CD8 T cells, which were TCR/CD3hi CD27hi CD1aneg and thus phenotypically resembled mature functional CD8 single positive thymocytes. These in vitro-generated T cells also appeared to be conventional CD8 cells, as they expressed high levels of Eomes and low levels of Plzf, albeit not identical to ex vivo UCB CD8 T cells. Consistent with the phenotypic and molecular characterization, upon TCR-stimulation, in vitro-generated CD8 T cells proliferated, expressed activation markers (MHC-II, CD25, CD38, secreted IFN-γ and expressed Granzyme B, a cytotoxic T-cell effector molecule. Conclusion Taken together, the ability to direct human hematopoietic stem cell or T-progenitor cells towards a mature functional phenotype raises the possibility of establishing cell-based treatments for T-immunodeficiencies by rapidly restoring CD8 effector function, thereby mitigating the risks associated with opportunistic infections.

  2. Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1

    Science.gov (United States)

    Zhou, Bo O; Ding, Lei; Morrison, Sean J

    2015-01-01

    Hematopoietic stem cells (HSCs) are maintained by a perivascular niche in bone marrow but it is unclear whether the niche is reciprocally regulated by HSCs. Here, we systematically assessed the expression and function of Angiopoietin-1 (Angpt1) in bone marrow. Angpt1 was not expressed by osteoblasts. Angpt1 was most highly expressed by HSCs, and at lower levels by c-kit+ hematopoietic progenitors, megakaryocytes, and Leptin Receptor+ (LepR+) stromal cells. Global conditional deletion of Angpt1, or deletion from osteoblasts, LepR+ cells, Nes-cre-expressing cells, megakaryocytes, endothelial cells or hematopoietic cells in normal mice did not affect hematopoiesis, HSC maintenance, or HSC quiescence. Deletion of Angpt1 from hematopoietic cells and LepR+ cells had little effect on vasculature or HSC frequency under steady-state conditions but accelerated vascular and hematopoietic recovery after irradiation while increasing vascular leakiness. Hematopoietic stem/progenitor cells and LepR+ stromal cells regulate niche regeneration by secreting Angpt1, reducing vascular leakiness but slowing niche recovery. DOI: http://dx.doi.org/10.7554/eLife.05521.001 PMID:25821987

  3. Myeloid leukemias and virally induced lymphomas in miniature inbred swine; development of a large animal tumor model

    Directory of Open Access Journals (Sweden)

    RAIMON eDURAN-STRUUCK

    2015-11-01

    Full Text Available The lack of a large animal transplantable tumor model has limited the study of novel therapeutic strategies for the treatment of liquid cancers. Swine as a species provide a natural option based on their similarities with humans and their already extensive use in biomedical research. Specifically, the MGH miniature swine herd retains unique genetic characteristics that facilitate the study of hematopoietic cell and solid organ transplantation. Spontaneously arising liquid cancers in these swine, specifically myeloid leukemias and B cell lymphomas, closely resemble human malignancies. The ability to establish aggressive tumor cell lines in vitro from these naturally occurring malignancies makes a transplantable tumor model a close reality. Here, we discuss our experience with myeloid and lymphoid tumors in MHC characterized miniature swine and future approaches regarding the development of a large animal transplantable tumor model.

  4. Effects of low dose radiation combined with cyclophosphamide on tumor cell apoptosis, cell cycle and proliferation of bone marrow in tumor-bearing mice

    International Nuclear Information System (INIS)

    Yu Hongsheng; Fei Conghe; Shen Fangzhen; Liang Jun

    2004-01-01

    Objective: To study the effect of low dose radiation (LDR) combined with cyclophosphamide on tumor cell apoptosis, cell cycle, and proliferation of bone marrow in mice tumor-bearing mice. Methods: Kunming strain male mice were implanted with S180 sarcoma cells in the left hind leg subcutaneously as an experimental animal model. Five and 8 days after implantation, the mice were given 75 mGy whole-body γ-ray radiation and CTX(300 mg/kg) by intraperitoneal injection 36 hour after LDR. All mice were sacrificed to measure the tumor volume, tumor cell apoptosis, and cell cycle; the proliferation of bone marrow was analyzed by flow cytometry. Results: Tumor growth was significantly slowed down in the treated groups. The apoptosis of tumor cells increased significantly after LDR. The tumor cells were arrested in G 1 phase in CTX and CTX+LDR groups, more significantly in the latter group than in the former group. Concentration of bone marrow cells and proliferation index in CTX + LDR group were higher than those in CTX group, although concentration of bone marrow cells in CTX and CTX+LDR groups were much lower than that in normal mice. Conclusion: Low dose radiation combined with cyclophosphamide causes more significant G 1 -phase arrest than cyclophosphamide alone and enhances anti-tumor effect markedly. At the same time LDR significantly protects hematopoietic function of bone marrow, which is of practical significance as an adjuvant chemotherapy

  5. Expression of human adenosine deaminase in mice reconstituted with retrovirus-transduced hematopoietic stem cells

    International Nuclear Information System (INIS)

    Wilson, J.M.; Danos, O.; Grossman, M.; Raulet, D.H.; Mulligan, R.C.

    1990-01-01

    Recombinant retroviruses encoding human adenosine deaminase have been used to infect murine hematopoietic stem cells. In bone marrow transplant recipients reconstituted with the genetically modified cells, human ADA was detected in peripheral blood mononuclear cells of the recipients for at least 6 months after transplantation. In animals analyzed in detail 4 months after transplantation, human ADA and proviral sequences were detected in all hematopoietic lineages; in several cases, human ADA activity exceeded the endogenous activity. These studies demonstrate the feasibility of introducing a functional human ADA gene into hematopoietic stem cells and obtaining expression in multiple hematopoietic lineages long after transplantation. This approach should be helpful in designing effective gene therapies for severe combined immunodeficiency syndromes in humans

  6. Primitive neuroectodermal tumor of the orbit in a 5-year-old girl with microphthalmia

    DEFF Research Database (Denmark)

    Alyahya, Ghassan Ayish Jabur; Heegaard, Steffen; Fledelius, Hans C.

    2000-01-01

    ophthalmology, primitive neuroectodermal tumor (PNET), Ewing's sarcoma, small round-cell tumors, retinoblastoma, medulloepithelioma, microphthalmia, orbitotomy......ophthalmology, primitive neuroectodermal tumor (PNET), Ewing's sarcoma, small round-cell tumors, retinoblastoma, medulloepithelioma, microphthalmia, orbitotomy...

  7. Next-generation sequencing and FISH studies reveal the appearance of gene mutations and chromosomal abnormalities in hematopoietic progenitors in chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Miguel Quijada-Álamo

    2017-04-01

    genetic alterations in CLL was derived, suggesting that most of the genetic events appear on the hematopoietic progenitors, although these mutations could induce the beginning of tumoral cell expansion at different stage of B cell differentiation. Conclusions Our study showed the presence of both gene mutations and chromosomal abnormalities in early hematopoietic progenitor cells from CLL patients.

  8. The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals

    Directory of Open Access Journals (Sweden)

    A. Alicia Koblansky

    2016-03-01

    Full Text Available NOD-like receptor (NLR proteins are intracellular innate immune sensors/receptors that regulate immunity. This work shows that NLRX1 serves as a tumor suppressor in colitis-associated cancer (CAC and sporadic colon cancer by keeping key tumor promoting pathways in check. Nlrx1−/− mice were highly susceptible to CAC, showing increases in key cancer-promoting pathways including nuclear factor κB (NF-κB, mitogen-activated protein kinase (MAPK, signal transducer and activator of transcription 3 (STAT3, and interleukin 6 (IL-6. The tumor-suppressive function of NLRX1 originated primarily from the non-hematopoietic compartment. This prompted an analysis of NLRX1 function in the Apcmin/+ genetic model of sporadic gastrointestinal cancer. NLRX1 attenuated Apcmin/+ colon tumorigenesis, cellular proliferation, NF-κB, MAPK, STAT3 activation, and IL-6 levels. Application of anti-interleukin 6 receptor (IL6R antibody therapy reduced tumor burden, increased survival, and reduced STAT3 activation in Nlrx1−/−Apcmin/+ mice. As an important clinical correlate, human colon cancer samples expressed lower levels of NLRX1 than healthy controls in multiple patient cohorts. These data implicate anti-IL6R as a potential personalized therapy for colon cancers with reduced NLRX1.

  9. Insight into the tumor suppressor function of CBP through the viral oncoprotein tax.

    Science.gov (United States)

    Van Orden, K; Nyborg, J K

    2000-01-01

    CREB binding protein (CBP) is a cellular coactivator protein that regulates essentially all known pathways of gene expression. The transcriptional coactivator properties of CBP are utilized by at least 25 different transcription factors representing nearly all known classes of DNA binding proteins. Once bound to their target genes, these transcription factors are believed to tether CBP to the promoter, leading to activated transcription. CBP functions to stimulate transcription through direct recruitment of the general transcription machinery as well as acetylation of both histone and transcription factor substrates. Recent observations indicate that a critical dosage of CBP is required for normal development and tumor suppression, and that perturbations in CBP concentrations may disrupt cellular homeostasis. Furthermore, there is accumulating evidence that CBP deregulation plays a direct role in hematopoietic malignancies. However, the molecular events linking CBP deregulation and malignant transformation are unclear. Further insight into the function of CBP, and its role as a tumor suppressor, can be gained through recent studies of the human T-cell leukemia virus, type I (HTLV-I) Tax oncoprotein. Tax is known to utilize CBP to stimulate transcription from the viral promoter. However, recent data suggest that as a consequence of the Tax-CBP interaction, many cellular transcription factor pathways may be deregulated. Tax disruption of CBP function may play a key role in transformation of the HTLV-I-infected cell. Thus, Tax derailment of CBP may lend important information about the tumor suppressor properties of CBP and serve as a model for the role of CBP in hematopoietic malignancies.

  10. HUMAN NK CELLS: FROM SURFACE RECEPTORS TO THE THERAPY OF LEUKEMIAS AND SOLID TUMORS

    Directory of Open Access Journals (Sweden)

    LORENZO eMORETTA

    2014-03-01

    Full Text Available Natural Killer (NK cells are major effector cells of the innate immunity. The discovery, over two decades ago, of MHC-class I specific NK receptors and subsequently of activating receptors, recognizing ligands expressed by tumor or virus-infected cells, paved the way to our understanding of the mechanisms of selective recognition and killing of tumor cells. Although NK cells can efficiently kill tumor cells of different histotypes in vitro, their activity may be limited in vivo by their inefficient trafficking to tumor lesions and by the inhibition of their function induced by tumor cells themselves and by the tumor microenvironment. On the other hand, the important role of NK cells has been clearly demonstrated in the therapy of high risk leukemias in the haploidentical hematopoietic cell (HSC transplantation setting. NK cells derived from donor HSC kill leukemic cells residual after the conditioning regimen, thus preventing leukemia relapses. In addition, they also kill residual dendritic cells and T lymphocytes, thus preventing both GvHD and graft rejection.

  11. Granular cell tumor with orbital involvement in a child

    Energy Technology Data Exchange (ETDEWEB)

    Reis, Fabiano [Universidade Estadual de Campinas (FCM/UNICAMP), SP (Brazil). Fac. de Ciencias Medicas. Dept. de Radiologia; Iyeyasu, Josie Naomi; Carvalho, Keila Monteiro de [Universidade Estadual de Campinas (FCM/UNICAMP), SP (Brazil). Fac. de Ciencias Medicas. Dept. de Oftalmo-Otorrinolaringologia; Altemani, Albina Messias [Universidade Estadual de Campinas (FCM/UNICAMP), SP (Brazil). Fac. de Ciencias Medicas. Dept. de Anatomia Patologica

    2011-09-15

    The authors report a rare case of granular cell tumor in the left medial rectus muscle of a seven-year-old boy. Clinical, pathologic and radiologic findings of the present case are described and a brief literature review is undertaken. (author)

  12. Granular cell tumor with orbital involvement in a child

    International Nuclear Information System (INIS)

    Reis, Fabiano; Iyeyasu, Josie Naomi; Carvalho, Keila Monteiro de; Altemani, Albina Messias

    2011-01-01

    The authors report a rare case of granular cell tumor in the left medial rectus muscle of a seven-year-old boy. Clinical, pathologic and radiologic findings of the present case are described and a brief literature review is undertaken. (author)

  13. Regulatory Systems in Bone Marrow for Hematopoietic Stem/Progenitor Cells Mobilization and Homing

    Directory of Open Access Journals (Sweden)

    P. Alvarez

    2013-01-01

    Full Text Available Regulation of hematopoietic stem cell release, migration, and homing from the bone marrow (BM and of the mobilization pathway involves a complex interaction among adhesion molecules, cytokines, proteolytic enzymes, stromal cells, and hematopoietic cells. The identification of new mechanisms that regulate the trafficking of hematopoietic stem/progenitor cells (HSPCs cells has important implications, not only for hematopoietic transplantation but also for cell therapies in regenerative medicine for patients with acute myocardial infarction, spinal cord injury, and stroke, among others. This paper reviews the regulation mechanisms underlying the homing and mobilization of BM hematopoietic stem/progenitor cells, investigating the following issues: (a the role of different factors, such as stromal cell derived factor-1 (SDF-1, granulocyte colony-stimulating factor (G-CSF, and vascular cell adhesion molecule-1 (VCAM-1, among other ligands; (b the stem cell count in peripheral blood and BM and influential factors; (c the therapeutic utilization of this phenomenon in lesions in different tissues, examining the agents involved in HSPCs mobilization, such as the different forms of G-CSF, plerixafor, and natalizumab; and (d the effects of this mobilization on BM-derived stem/progenitor cells in clinical trials of patients with different diseases.

  14. CT findings of orbital inflammatory diseases

    International Nuclear Information System (INIS)

    Kim, Jang Min; Shin, Hyun Joon; Kim, Jung Hyuk; Suh, Won Hyuck

    1991-01-01

    Twenty-nine patients with orbital inflammatory disease (OIDs) were retrospectively reviewed in order to analyze detailed CT findings which might aid in differentiating OIDs. This study comprised 18 pseudotumors, 5 thyroid ophthalmopathies, and 6 cases of orbital cellulitis. CT scans of the pseudotumors showed various findings such as exophthalmos, scleritis, myositis of the extraocular muscle (MOM), and bone lesion. Bone lesions of the pseudo tumors, which have been rarely reported, were present in 7 cases in our series. Bilateral exophthalmos, myositis, and retrobulbar fat deposition were readily detected by CT in thyroid ophthalmopathy, and, in addition, we found bone erosions involving the orbital apices in 2 cases. In orbital cellulitis, extraorbital soft tissue swelling and lateral displacement of the medial rectus muscle in cases with ethmoiditis were the most conspicuous features. In summary, because of the overlapping CT findings in OIDs, careful examination of CT findings regarding the mode of EOM involvement and the presence or absence of scleritis or sinusitis might help narrow down the differential diagnosis. A pseudotumor with bone lesions could be mistaken as a malignant lesion, and therefore it is necessary to correlate clinical features with CT findings for an accurate diagnosis

  15. Chimeric antigen receptor T cell (CAR-T) immunotherapy for solid tumors: lessons learned and strategies for moving forward.

    Science.gov (United States)

    Li, Jian; Li, Wenwen; Huang, Kejia; Zhang, Yang; Kupfer, Gary; Zhao, Qi

    2018-02-13

    Recently, the US Food and Drug Administration (FDA) approved the first chimeric antigen receptor T cell (CAR-T) therapy for the treatment CD19-positive B cell acute lymphoblastic leukemia. While CAR-T has achieved remarkable success in the treatment of hematopoietic malignancies, whether it can benefit solid tumor patients to the same extent is still uncertain. Even though hundreds of clinical trials are undergoing exploring a variety of tumor-associated antigens (TAA), no such antigen with comparable properties like CD19 has yet been identified regarding solid tumors CAR-T immunotherapy. Inefficient T cell trafficking, immunosuppressive tumor microenvironment, suboptimal antigen recognition specificity, and lack of safety control are currently considered as the main obstacles in solid tumor CAR-T therapy. Here, we reviewed the solid tumor CAR-T clinical trials, emphasizing the studies with published results. We further discussed the challenges that CAR-T is facing for solid tumor treatment and proposed potential strategies to improve the efficacy of CAR-T as promising immunotherapy.

  16. Hematopoietic cell transplantation in Fanconi anemia: current evidence, challenges and recommendations.

    Science.gov (United States)

    Ebens, Christen L; MacMillan, Margaret L; Wagner, John E

    2017-01-01

    Hematopoietic cell transplantation for Fanconi Anemia (FA) has improved dramatically over the past 40 years. With an enhanced understanding of the intrinsic DNA-repair defect and pathophysiology of hematopoietic failure and leukemogenesis, sequential changes to conditioning and graft engineering have significantly improved the expectation of survival after allogeneic hematopoietic cell transplantation (alloHCT) with incidence of graft failure decreased from 35% to 40% to <10%. Today, five-year overall survival exceeds 90% in younger FA patients with bone marrow failure but remains about 50% in those with hematologic malignancy. Areas covered: We review the evolution of alloHCT contributing to decreased rates of transplant related complications; highlight current challenges including poorer outcomes in cases of clonal hematologic disorders, alloHCT impact on endocrine function and intrinsic FA risk of epithelial malignancies; and describe investigational therapies for prevention and treatment of the hematologic manifestations of FA. Expert commentary: Current methods allow for excellent survival following alloHCT for FA associated BMF irrespective of donor hematopoietic cell source. Alternative curative approaches, such as gene therapy, are being explored to eliminate the risks of GVHD and minimize therapy-related adverse effects.

  17. Studies on hematopoietic cell apoptosis and the relative gene expression in irradiated mouse bone marrow

    International Nuclear Information System (INIS)

    Peng Ruiyun; Wang Dewen; Xiong Chengqi; Gao Yabing; Yang Hong; Cui Yufang; Wang Baozhen

    2001-01-01

    Objective: To study apoptosis and expressions bcl-2 and p53 in irradiated mouse bone marrow. Methods: LACA mice were irradiated with 60 Co γ-rays. By means of in situ terminal labelling, in situ hybridization and image analysis, the authors studied radiation-induced apoptosis of hematopoietic cells and the expressions of bcl-2 and p53. Results: The characteristics of apoptosis appeared in hematopoietic cells at 6 hrs after irradiation. The expression of bcl-2 was obviously decreased when apoptosis of hematopoietic cells occurred, whereas it increased in the early recovery phase; p53 protein increased during both apoptosis of hematopoietic cells and the recovery phase, and mutant type p53 DNA was positive only in the recovery phase. Conclusion: Radiation may induced apoptosis of hematopoietic cells in a dose-dependent manner; Both bcl-2 and p53 genes play an important role in apoptosis and recovery phase

  18. Selection of genetically modified hematopoietic cells in vitro and in vivo using alkylating agent lysomustine.

    Science.gov (United States)

    Rozov, F N; Grinenko, T S; Levit, G L; Krasnov, V P; Belyavsky, A V

    2010-09-15

    Efficient gene transfer into hematopoietic stem cells is vital for the success of gene therapy of hematopoietic and immune system disorders. An in vivo selection system based on a mutant form of the O(6)-methylguanine-DNA-methyltransferase gene (MGMTm) is considered one of the more promising strategies for expansion of hematopoietic cells transduced with viral vectors. Here we demonstrate that MGMTm-expressing cells can be efficiently selected using lysomustine, a nitrosourea derivative of lysine. K562 and murine bone marrow cells expressing MGMTm are protected from the cytotoxic action of lysomustine in vitro. We also show in a murine model that MGMTm-transduced hematopoietic cells can be expanded in vivo on transplantation into sublethally irradiated recipients followed by lysomustine treatment. These results indicate that lysomustine can be used as a potent novel chemoselection drug applicable for gene therapy of hematopoietic and immune system disorders. 2010 Elsevier Inc. All rights reserved.

  19. Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche.

    Science.gov (United States)

    Mitroulis, Ioannis; Chen, Lan-Sun; Singh, Rashim Pal; Kourtzelis, Ioannis; Economopoulou, Matina; Kajikawa, Tetsuhiro; Troullinaki, Maria; Ziogas, Athanasios; Ruppova, Klara; Hosur, Kavita; Maekawa, Tomoki; Wang, Baomei; Subramanian, Pallavi; Tonn, Torsten; Verginis, Panayotis; von Bonin, Malte; Wobus, Manja; Bornhäuser, Martin; Grinenko, Tatyana; Di Scala, Marianna; Hidalgo, Andres; Wielockx, Ben; Hajishengallis, George; Chavakis, Triantafyllos

    2017-10-02

    Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF- or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by β3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis.

  20. A unique method of retaining orbital prosthesis with attachment systems - a clinical report.

    Science.gov (United States)

    Guttal, Satyabodh S; Akash, N R; Prithviraj, D R; Lekha, K

    2014-06-01

    Diminution of the orbital contents post-surgical removal of a malignant tumor can have a severe psychological impact on the patient in terms of function and esthetics. Therefore, esthetic remedy should be planned subsequently, since tumor obliteration precedes cosmetic concern. A convenient option for successful rehabilitation in such patients is a simple, user-friendly, removable orbital prosthesis. Retention of the prosthesis is one of the key factors for the successful rehabilitation. Spectacle frame, conformers, adhesives, osseointegrated implants, magnets or buttons have been used to impart retention to the prosthesis. The use of semi precision attachments in maxillofacial prostheses is limited to the osseointegrated prostheses. This case report describes a conventional spectacle frame technique, to retain the silicone orbital prosthesis using two different types of stud attachments viz., dalla bona and O-ring attachment systems. Copyright © 2013 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

  1. Proton MR spectroscopy of hyperplastic hematopoietic marrow in aplastic anemia

    Energy Technology Data Exchange (ETDEWEB)

    Amano, Yasuo; Kumazaki, Tatsuo [Nippon Medical School, Tokyo (Japan); Arai, Nobuyuki

    1997-04-01

    The purpose of this study was to compare the findings of magnetic resonance (MR) spectroscopy of hyperplastic hematopoietic marrow with those of normal bone marrow. Twenty-four samples of normal marrow from eight control subjects and 19 samples of hyperplastic marrow in aplastic anemia were examined with a 1.5 T MR unit. The former showed low intensity on opposed-phase T1-weighted images, while the latter showed high intensity on both fast STIR and opposed-phase T1-weighted images. MR spectroscopy quantitatively confirmed that the water; fat ratio was increased and the transverse relaxation time of water was changed in hyperplastic bone marrow, compared with normal bone marrow. In summary, MR imaging is able to detect hematopoietic regions among a wide range of bone marrow of aplastic anemia, while MR spectroscopy allowed us to quantitatively analyze the cell population of hyperplastic hematopoietic marrow in aplastic anemia. (author)

  2. Proton MR spectroscopy of hyperplastic hematopoietic marrow in aplastic anemia

    International Nuclear Information System (INIS)

    Amano, Yasuo; Kumazaki, Tatsuo; Arai, Nobuyuki.

    1997-01-01

    The purpose of this study was to compare the findings of magnetic resonance (MR) spectroscopy of hyperplastic hematopoietic marrow with those of normal bone marrow. Twenty-four samples of normal marrow from eight control subjects and 19 samples of hyperplastic marrow in aplastic anemia were examined with a 1.5 T MR unit. The former showed low intensity on opposed-phase T1-weighted images, while the latter showed high intensity on both fast STIR and opposed-phase T1-weighted images. MR spectroscopy quantitatively confirmed that the water; fat ratio was increased and the transverse relaxation time of water was changed in hyperplastic bone marrow, compared with normal bone marrow. In summary, MR imaging is able to detect hematopoietic regions among a wide range of bone marrow of aplastic anemia, while MR spectroscopy allowed us to quantitatively analyze the cell population of hyperplastic hematopoietic marrow in aplastic anemia. (author)

  3. Hematopoietic stem cell origin of connective tissues.

    Science.gov (United States)

    Ogawa, Makio; Larue, Amanda C; Watson, Patricia M; Watson, Dennis K

    2010-07-01

    Connective tissue consists of "connective tissue proper," which is further divided into loose and dense (fibrous) connective tissues and "specialized connective tissues." Specialized connective tissues consist of blood, adipose tissue, cartilage, and bone. In both loose and dense connective tissues, the principal cellular element is fibroblasts. It has been generally believed that all cellular elements of connective tissue, including fibroblasts, adipocytes, chondrocytes, and bone cells, are generated solely by mesenchymal stem cells. Recently, a number of studies, including those from our laboratory based on transplantation of single hematopoietic stem cells, strongly suggested a hematopoietic stem cell origin of these adult mesenchymal tissues. This review summarizes the experimental evidence for this new paradigm and discusses its translational implications. Copyright 2010 ISEH - Society for Hematology and Stem Cells. All rights reserved.

  4. Proteomic cornerstones of hematopoietic stem cell differentiation

    DEFF Research Database (Denmark)

    Klimmeck, Daniel; Hansson, Jenny; Raffel, Simon

    2012-01-01

    Regenerative tissues such as the skin epidermis, the intestinal mucosa or the hematopoietic system are organized in a hierarchical manner with stem cells building the top of this hierarchy. Somatic stem cells harbor the highest self-renewal activity and generate a series of multipotent progenitors...... which differentiate into lineage committed progenitors and subsequently mature cells. In this report, we applied an in-depth quantitative proteomic approach to analyze and compare the full proteomes of ex vivo isolated and FACS-sorted populations highly enriched for either multipotent hematopoietic stem....../progenitor cells (HSPCs, Lin(neg)Sca-1(+)c-Kit(+)) or myeloid committed precursors (Lin(neg)Sca-1(-)c-Kit(+)). By employing stable isotope dimethyl labeling and high-resolution mass spectrometry, more than 5,000 proteins were quantified. From biological triplicate experiments subjected to rigorous statistical...

  5. SINONASAL AND ORBITAL MALIGNANT NEOPLASMS IN PEDIATRIC POPULATION: A STUDY FROM A TERTIARY CARE CENTRE IN INDIA

    Directory of Open Access Journals (Sweden)

    Koyela Mondal

    2015-01-01

    Full Text Available NTRODUCTION : Paranasal and extra - ocular orbital malignant tumors are comparatively rare in pediatric patients and difficult to diagnose early. Malignant lesions in this region tend to be locally aggressive, often presenting at an advanced stage. Non osseous, extra ocular orbital tumors represent a different histologic spectrum in children than in adults. AIMS: To study the spectrum of malignant lesions of paranasal sinuses and orbital area in patients under 18 years of age. MATERIALS AND METHODS: A retrospective and prospective study was done from July 2004 to June 2014. Malignant paranasal and orbital neoplasms were recorded including clinico - radiological and cytological data. Review of histopathological slides along with immunohistochemistry (IHC of selected cases were done. RESULTS: Total 69 cases were recorded over the ten year period as per our inclusion criteria. Out of these, 46 (67% patients presented with malignant paranasal neoplasm and 23 (33% with orbital mass. Most cases were found in the age group of 7 - 12 years, where females were preponderant. Rhabdomyosarcoma (RMS was the commonest tumor arising in paranasal as well as in orbital area (33%. IHC aided the confirmation of our diagnoses. CONCLUSION: Paranasal malignancy in the pediatric population often presents with non - specific symptoms, and high index of suspicion along with better diagnostic tools like computed tomography (CT scan is necessary for a timely diagnosis . IHC should be done in all malignant neoplasms of pediatric population to arrive at a proper diagnosis, to facilitate proper management to these patients

  6. Analysis and manipulation of hematopoietic progenitor and stem cells from murine embryonic tissues

    NARCIS (Netherlands)

    A. Medvinsky (Alexander); S. Taoudi (Samir); S.C. Mendes (Sandra); E.A. Dzierzak (Elaine)

    2008-01-01

    textabstractHematopoietic development begins in several locations in the mammalian embryo: yolk sac, aorta-gonad-mesonephros region (AGM), and the chorio-allantoic placenta. Generation of the most potent cells, adult definitive hematopoietic stem cells (HSCs), occurs within the body of the mouse

  7. A novel serum-free monolayer culture for orderly hematopoietic differentiation of human pluripotent cells via mesodermal progenitors.

    Directory of Open Access Journals (Sweden)

    Akira Niwa

    Full Text Available Elucidating the in vitro differentiation of human embryonic stem (ES and induced pluripotent stem (iPS cells is important for understanding both normal and pathological hematopoietic development in vivo. For this purpose, a robust and simple hematopoietic differentiation system that can faithfully trace in vivo hematopoiesis is necessary. In this study, we established a novel serum-free monolayer culture that can trace the in vivo hematopoietic pathway from ES/iPS cells to functional definitive blood cells via mesodermal progenitors. Stepwise tuning of exogenous cytokine cocktails induced the hematopoietic mesodermal progenitors via primitive streak cells. These progenitors were then differentiated into various cell lineages depending on the hematopoietic cytokines present. Moreover, single cell deposition assay revealed that common bipotential hemoangiogenic progenitors were induced in our culture. Our system provides a new, robust, and simple method for investigating the mechanisms of mesodermal and hematopoietic differentiation.

  8. Engineering Hematopoietic Cells for Cancer Immunotherapy: Strategies to Address Safety and Toxicity Concerns.

    Science.gov (United States)

    Resetca, Diana; Neschadim, Anton; Medin, Jeffrey A

    2016-09-01

    Advances in cancer immunotherapies utilizing engineered hematopoietic cells have recently generated significant clinical successes. Of great promise are immunotherapies based on chimeric antigen receptor-engineered T (CAR-T) cells that are targeted toward malignant cells expressing defined tumor-associated antigens. CAR-T cells harness the effector function of the adaptive arm of the immune system and redirect it against cancer cells, overcoming the major challenges of immunotherapy, such as breaking tolerance to self-antigens and beating cancer immune system-evasion mechanisms. In early clinical trials, CAR-T cell-based therapies achieved complete and durable responses in a significant proportion of patients. Despite clinical successes and given the side effect profiles of immunotherapies based on engineered cells, potential concerns with the safety and toxicity of various therapeutic modalities remain. We discuss the concerns associated with the safety and stability of the gene delivery vehicles for cell engineering and with toxicities due to off-target and on-target, off-tumor effector functions of the engineered cells. We then overview the various strategies aimed at improving the safety of and resolving toxicities associated with cell-based immunotherapies. Integrating failsafe switches based on different suicide gene therapy systems into engineered cells engenders promising strategies toward ensuring the safety of cancer immunotherapies in the clinic.

  9. OP9-Lhx2 stromal cells facilitate derivation of hematopoietic progenitors both in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Xiaoli Chen

    2015-09-01

    Full Text Available Generating engraftable hematopoietic stem cells (HSCs from pluripotent stem cells (PSCs is an ideal approach for obtaining induced HSCs for cell therapy. However, the path from PSCs to robustly induced HSCs (iHSCs in vitro remains elusive. We hypothesize that the modification of hematopoietic niche cells by transcription factors facilitates the derivation of induced HSCs from PSCs. The Lhx2 transcription factor is expressed in fetal liver stromal cells but not in fetal blood cells. Knocking out Lhx2 leads to a fetal hematopoietic defect in a cell non-autonomous role. In this study, we demonstrate that the ectopic expression of Lhx2 in OP9 cells (OP9-Lhx2 accelerates the hematopoietic differentiation of PSCs. OP9-Lhx2 significantly increased the yields of hematopoietic progenitor cells via co-culture with PSCs in vitro. Interestingly, the co-injection of OP9-Lhx2 and PSCs into immune deficient mice also increased the proportion of hematopoietic progenitors via the formation of teratomas. The transplantation of phenotypic HSCs from OP9-Lhx2 teratomas but not from the OP9 control supported a transient repopulating capability. The upregulation of Apln gene by Lhx2 is correlated to the hematopoietic commitment property of OP9-Lhx2. Furthermore, the enforced expression of Apln in OP9 cells significantly increased the hematopoietic differentiation of PSCs. These results indicate that OP9-Lhx2 is a good cell line for regeneration of hematopoietic progenitors both in vitro and in vivo.

  10. Metastatic breast cancer in the eye and orbit, use three-dimensional conformal radiotherapy. Our first experience

    International Nuclear Information System (INIS)

    Correa Pablos, Tamara; Caceres Toledo, Maria

    2009-01-01

    The eye and orbit metastases are a significant clinical problem, both by the inability and the deterioration in the quality of life that occur. The most common malignant tumors in the eye and orbit is metastasis. Cancer breast cancer is the most common tumor metastatic to the eye and orbit in a 40% and 50% of cases according to different series. With the introduction of Three-Dimensional Conformal Radiotherapy (3D-CRT) in our hospital from In 2007 we were able to treat patients with cancer different regions with the technique (2D) was impossible because caused irreparable damage to surrounding healthy tissue in this way thanks to potential of 3D technology to shape the planning volume will ensure greater protection for critical organs. (Author)

  11. An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia.

    Science.gov (United States)

    Zhou, Yuan; He, Yongzheng; Xing, Wen; Zhang, Peng; Shi, Hui; Chen, Shi; Shi, Jun; Bai, Jie; Rhodes, Steven D; Zhang, Fengqui; Yuan, Jin; Yang, Xianlin; Zhu, Xiaofan; Li, Yan; Hanenberg, Helmut; Xu, Mingjiang; Robertson, Kent A; Yuan, Weiping; Nalepa, Grzegorz; Cheng, Tao; Clapp, D Wade; Yang, Feng-Chun

    2017-06-01

    Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation. Copyright© Ferrata Storti Foundation.

  12. Flotillins are involved in the polarization of primitive and mature hematopoietic cells.

    Directory of Open Access Journals (Sweden)

    Lawrence Rajendran

    Full Text Available BACKGROUND: Migration of mature and immature leukocytes in response to chemokines is not only essential during inflammation and host defense, but also during development of the hematopoietic system. Many molecules implicated in migratory polarity show uniform cellular distribution under non-activated conditions, but acquire a polarized localization upon exposure to migratory cues. METHODOLOGY/PRINCIPAL FINDINGS: Here, we present evidence that raft-associated endocytic proteins (flotillins are pre-assembled in lymphoid, myeloid and primitive hematopoietic cells and accumulate in the uropod during migration. Furthermore, flotillins display a polarized distribution during immunological synapse formation. Employing the membrane lipid-order sensitive probe Laurdan, we show that flotillin accumulation in the immunological synapse is concomittant with membrane ordering in these regions. CONCLUSIONS: Together with the observation that flotillin polarization does not occur in other polarized cell types such as polarized epithelial cells, our results suggest a specific role for flotillins in hematopoietic cell polarization. Based on our results, we propose that in hematopoietic cells, flotillins provide intrinsic cues that govern segregation of certain microdomain-associated molecules during immune cell polarization.

  13. Explanation of application standards of hematopoietic stimulating factors in the treatment of acute radiation sickness

    International Nuclear Information System (INIS)

    Xing Zhiwei; Jiang Enhai; Wang Guilin; Luo Qingliang

    2012-01-01

    Occupational standard of the Ministry of health-Application Standards of Hematopoietic Stimulating Factors in the Treatment of Acute Radiation Sickness has been completed as a draft standard. Based on the wide study and analysis of related animal experimental literature about hematopoietic stimulating factor in the treatment of acute radiation sickness and domestic and foreign clinical reports about application of hematopoietic stimulating factor in radiation accidents in the past decade, the standard was enacted according to the suggestions of International Atomic Energy Agency and the United States Strategic National Stockpile Radiation Working Group and European countries about the application of hematopoietic stimulating factor. It is mainly used for nuclear accident emergency and the treatment of the bone marrow form of acute radiation sickness caused by radiation accidents. It also applies to other hematopoietic failure diseases. In order to implement this standard correctly, the relevant contents of the standard were interpreted in this article. (authors)

  14. The many faces of hematopoietic stem cell heterogeneity

    Science.gov (United States)

    2016-01-01

    Not all hematopoietic stem cells (HSCs) are alike. They differ in their physical characteristics such as cell cycle status and cell surface marker phenotype, they respond to different extrinsic signals, and they have different lineage outputs following transplantation. The growing body of evidence that supports heterogeneity within HSCs, which constitute the most robust cell fraction at the foundation of the adult hematopoietic system, is currently of great interest and raises questions as to why HSC subtypes exist, how they are generated and whether HSC heterogeneity affects leukemogenesis or treatment options. This Review provides a developmental overview of HSC subtypes during embryonic, fetal and adult stages of hematopoiesis and discusses the possible origins and consequences of HSC heterogeneity. PMID:27965438

  15. Radionuclide and thermographic diagnosis of head and neck tumors

    Energy Technology Data Exchange (ETDEWEB)

    Bogdasarov, Yu.B.; Lenskaya, O.P.; Polyakov, B.I.; Belkina, B.M. (Akademiya Meditsinskikh Nauk SSSR, Moscow. Onkologicheskij Nauchnyj Tsentr)

    1983-10-01

    Radionuclide and thermographic studies using /sup 67/Ga-citrate and /sup 111/In-bleomycin were performed in 129 patients with laryngeal cancer, chemodectoma of the neck, retinoblastoma, rhabdomyosarcoma of the orbital and facial soft tissues and cancer of the tongue. Elevated amounts of the radiopharmaceuticals were found in patients with tumors. In thermographic studies higher temperature activity corresponding to the tumor was noted. Radio-nuclide thermographic studies extend diagnostic opportunities for head and neck tumors.

  16. Radionuclide and thermographic diagnosis of head and neck tumors

    International Nuclear Information System (INIS)

    Bogdasarov, Yu.B.; Lenskaya, O.P.; Polyakov, B.I.; Belkina, B.M.

    1983-01-01

    Radionuclide and thermographic studies using 67 Ga-citrate and 111 In-bleomycin were performed in 129 patients with laryngeal cancer, chemodectoma of the neck, retinoblastoma, rhabdomyosarcoma of the orbital and facial soft tissues and cancer of the tongue. Elevated amounts of the radiopharmaceuticals were found in patients with tumors. In thermographic studies higher temperature activity corresponding to the tumor was noted. Radio-nuclide thermographic studies extend diagnostic opportunities for head and neck tumors

  17. AF10 plays a key role in the survival of uncommitted hematopoietic cells.

    Directory of Open Access Journals (Sweden)

    Raquel Chamorro-Garcia

    Full Text Available Hematopoiesis is a complex process regulated by both cell intrinsic and cell extrinsic factors. Alterations in the expression of critical genes during hematopoiesis can modify the balance between stem cell differentiation and proliferation, and may ultimately give rise to leukemia and other diseases. AF10 is a transcription factor that has been implicated in the development of leukemia following chromosomal rearrangements between the AF10 gene and one of at least two other genes, MLL and CALM. The link between AF10 and leukemia, together with the known interactions between AF10 and hematopoietic regulators, suggests that AF10 may be important in hematopoiesis and in leukemic transformation. Here we show that AF10 is important for proper hematopoietic differentiation. The induction of hematopoietic differentiation in both human hematopoietic cell lines and murine total bone marrow cells triggers a decrease of AF10 mRNA and protein levels, particularly in stem cells and multipotent progenitors. Gain- and loss-of-function studies demonstrate that over- or under-expression of AF10 leads to apoptotic cell death in stem cells and multipotent progenitors. We conclude that AF10 plays a key role in the maintenance of multipotent hematopoietic cells.

  18. Transcriptome Analysis of Individual Stromal Cell Populations Identifies Stroma-Tumor Crosstalk in Mouse Lung Cancer Model

    Directory of Open Access Journals (Sweden)

    Hyejin Choi

    2015-02-01

    Full Text Available Emerging studies have begun to demonstrate that reprogrammed stromal cells play pivotal roles in tumor growth, metastasis, and resistance to therapy. However, the contribution of stromal cells to non-small-cell lung cancer (NSCLC has remained underexplored. We used an orthotopic model of Kras-driven NSCLC to systematically dissect the contribution of specific hematopoietic stromal cells in lung cancer. RNA deep-sequencing analysis of individually sorted myeloid lineage and tumor epithelial cells revealed cell-type-specific differentially regulated genes, indicative of activated stroma. We developed a computational model for crosstalk signaling discovery based on ligand-receptor interactions and downstream signaling networks and identified known and novel tumor-stroma paracrine and tumor autocrine crosstalk-signaling pathways in NSCLC. We provide cellular and molecular insights into components of the lung cancer microenvironment that contribute to carcinogenesis. This study has the potential for development of therapeutic strategies that target tumor-stroma interactions and may complement conventional anti-cancer treatments.

  19. Investigation of the imaging diagnosis on the ophthalmic orbital diseases

    International Nuclear Information System (INIS)

    Yoshizawa, Toshikazu

    1991-01-01

    Ultrasonographic examination, X-ray computerized tomography (CT) and magnetic resonance imaging (MRI) were performed on orbital diseases. Ultrasonographic examination was a simple, rapid and harmless noninvasive precedure as a diagnostic tool for evaluation of soft tissues. Echography was not more precise than X-ray CT and MRI scan in orbital diagnosis of the localization, size and well-defined outline of the lesion, relating to the peri- and retroorbital organs, however, was useful for screening study of an orbital lesion. B-mode of orbital tumors was effective for the ultrasonic diagnosis and classification according to four types; solid, cystic, angiomatous and infiltrative patterns. B-scan study of intraorbital inflammatory pseudo tumor could provide a differential diagnosis between inflammatory edema and an inflammatory mass lesion. Echographic pictures of dural arterio-venous fistula disclosed the vascular dilatation of superior ophthalmic vein and those of Basedow's disease with thickening of extraocular muscles. X-ray CT revealed intraorbital and intraocular disease, the globes and its immediate surrounding tissue (optic nerve, extraocular muscle, etc.) and bony orbital walls as the same slice of film. X-ray CT pictures of a coronal section, the contrast enhancement, calcification and destruction of the bone were helpful for diagnosis. However, the displays of disorders near the bone were ill-defined because of an artifact induced by high X-ray absorptive power of the bone. MRI was an equipment for superior contrast resolution, with provided a tomography of any section, without artifacts of the bone, and was the superior technique for displaying a vascular lesion. MRI of orbital disease was effective for reconstructing the spatial correlations between the lesion and its surounding tissues. MRI, however, provided no information of the skeleton, being not available for subjects with a magnetic substance. (author)

  20. Diffusion-weighted MR imaging in benign and malignant orbital masses

    International Nuclear Information System (INIS)

    Guo Jian; Wang Zhenchang; Xian Junfang; Niu Yantao; Zhao Bo; Yan Fei; Liu Zhonglin; Yang Bentao

    2007-01-01

    Objective: To analyse the characteristics of orbital benign and malignant masses on diffusion weighted imaging in combination with conventional MR imaging and evaluate the diagnostic value of apparent diffusion coefficient in distinguishing benign and malignant orbital lesions. Methods: Seventy- seven cases with orbital masses, including fifty-five benign lesions and twenty-two malignant tumors, who underwent conventional MRI and diffusion imaging scanning were studied with use of a 1.5 T magnetic resonance system. Quantitative ADC measurements of masses (ADCM) and of the white matter of contralateral temporal lobe (ADC w ) were made with two different b-values of 0 and 1000 s/mm 2 . The ADC ratio (ADCR) of the lesion to the control was calculated. The receiver operating characteristic curves(ROC) were constructed using various cut points of ADCM and ADCR for different parameters to differentiate between benign and malignant masses. The area under the ROC curve for each parameter was also calculated. Results: All cases were proved by histopathology. The mean ADCM and ADCR of benign orbital masses were (1.56 ± 0.75) x 10 -3 mm 2 /s and 1.85 ± 0.91, respectively. The mean ADCM and ADCR of malignant orbital masses were (1.09 ± 0.42) x 10 -3 mm 2 /s and 1.28 ± 0.53, respectively. There were significant difference both between ADCM and ADCR of benign and malignant masses (t=2.803, 2.735, P -3 mm 2 /s for ADC M of the tumor, the sensitivity, specificity and accuracy were 59.1%, 78.2% and 72.7%, respectively. And by using cut point of 1.24 for ADCR, the sensitivity, specificity and accuracy were 59.1%, 76.4%, 71.4%, respectively. Conclusion: Diffusion MR imaging and ADC value could provide additional information for conventional magnetic resonance imaging in distinguishing benign and malignant orbital masses. (authors)

  1. The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice

    Directory of Open Access Journals (Sweden)

    Xiaoying Zhou

    2015-07-01

    Full Text Available Prior efforts to identify regulators of hematopoietic stem cell physiology have relied mainly on candidate gene approaches with genetically modified mice. Here we used a genome-wide association study (GWAS strategy with the hybrid mouse diversity panel to identify the genetic determinants of hematopoietic stem/progenitor cell (HSPC frequency. Among 108 strains, we observed ∼120- to 300-fold variation in three HSPC populations. A GWAS analysis identified several loci that were significantly associated with HSPC frequency, including a locus on chromosome 5 harboring the homeodomain-only protein gene (Hopx. Hopx previously had been implicated in cardiac development but was not known to influence HSPC biology. Analysis of the HSPC pool in Hopx−/− mice demonstrated significantly reduced cell frequencies and impaired engraftment in competitive repopulation assays, thus providing functional validation of this positional candidate gene. These results demonstrate the power of GWAS in mice to identify genetic determinants of the hematopoietic system.

  2. Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice

    Directory of Open Access Journals (Sweden)

    Yi Liu

    2017-04-01

    Full Text Available Summary: Natural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC function. Latexin (Lxn is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner. Gene profiling of Lxn-null HSCs showed altered expression of genes enriched in cell-matrix and cell-cell interactions. Thrombospondin 1 (Thbs1 was a potential downstream target with a dramatic downregulation in Lxn-null HSCs. Enforced expression of Thbs1 restored the Lxn inactivation-mediated HSC phenotypes. This study reveals that Lxn plays an important role in the maintenance of homeostatic hematopoiesis, and it may lead to development of safe and effective approaches to manipulate HSCs for clinical benefit. : In this article, Liang and colleagues show that loss of latexin in vivo expands the HSC population and increases their survival and engraftment. Latexin regulates HSC function and hematopoiesis via the Thbs1 signaling pathway. Keywords: latexin, hematopoietic stem cell, repopulating advantage, expansion, survival, thrombospondin 1

  3. Recent advances in hematopoietic stem cell biology

    DEFF Research Database (Denmark)

    Bonde, Jesper; Hess, David A; Nolta, Jan A

    2004-01-01

    PURPOSE OF REVIEW: Exciting advances have been made in the field of hematopoietic stem cell biology during the past year. This review summarizes recent progress in the identification, culture, and in vivo tracking of hematopoietic stem cells. RECENT FINDINGS: The roles of Wnt and Notch proteins...... in regulating stem cell renewal in the microenvironment, and how these molecules can be exploited in ex vivo stem cell culture, are reviewed. The importance of identification of stem cells using functional as well as phenotypic markers is discussed. The novel field of nanotechnology is then discussed...... in the context of stem cell tracking in vivo. This review concludes with a section on the unexpected potential of bone marrow-derived stem cells to contribute to the repair of damaged tissues. The contribution of cell fusion to explain the latter phenomenon is discussed. SUMMARY: Because of exciting discoveries...

  4. Low antigenicity of hematopoietic progenitor cells derived from human ES cells

    Directory of Open Access Journals (Sweden)

    Eun-Mi Kim

    2010-02-01

    Full Text Available Eun-Mi Kim1, Nicholas Zavazava1,21Department of Internal Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa, USA; 2Immunology Graduate Program, University of Iowa, Iowa City, Iowa, USAAbstract: Human embryonic stem (hES cells are essential for improved understanding of diseases and our ability to probe new therapies for use in humans. Currently, bone marrow cells and cord blood cells are used for transplantation into patients with hematopoietic malignancies, immunodeficiencies and in some cases for the treatment of autoimmune diseases. However, due to the high immunogenicity of these hematopoietic cells, toxic regimens of drugs are required for preconditioning and prevention of rejection. Here, we investigated the efficiency of deriving hematopoietic progenitor cells (HPCs from the hES cell line H13, after co-culturing with the murine stromal cell line OP9. We show that HPCs derived from the H13 ES cells poorly express major histocompatibility complex (MHC class I and no detectable class II antigens (HLA-DR. These characteristics make hES cell-derived hematopoietic cells (HPCs ideal candidates for transplantation across MHC barriers under minimal immunosuppression.Keywords: human embryonic stem cells, H13, hematopoiesis, OP9 stromal cells, immunogenicity

  5. Hematopoietic stem cell development requires transient Wnt/β-catenin activity

    DEFF Research Database (Denmark)

    Ruiz-Herguido, Cristina; Guiu, Jordi; D'Altri, Teresa

    2012-01-01

    in the aorta-gonad-mesonephros (AGM) region. We show here that β-catenin is nuclear and active in few endothelial nonhematopoietic cells closely associated with the emerging hematopoietic clusters of the embryonic aorta during mouse development. Importantly, Wnt/β-catenin activity is transiently required...... of mutant cells toward the hematopoietic lineage; however, these mutant cells still contribute to the adult endothelium. Together, those findings indicate that Wnt/β-catenin activity is needed for the emergence but not the maintenance of HSCs in mouse embryos....

  6. Mismatch repair deficient hematopoietic stem cells are preleukemic stem cells.

    Directory of Open Access Journals (Sweden)

    Yulan Qing

    Full Text Available Whereas transformation events in hematopoietic malignancies may occur at different developmental stages, the initial mutation originates in hematopoietic stem cells (HSCs, creating a preleukemic stem cell (PLSC. Subsequent mutations at either stem cell or progenitor cell levels transform the PLSC into lymphoma/leukemia initiating cells (LIC. Thymic lymphomas have been thought to develop from developing thymocytes. T cell progenitors are generated from HSCs in the bone marrow (BM, but maturation and proliferation of T cells as well as T-lymphomagenesis depends on both regulatory mechanisms and microenvironment within the thymus. We studied PLSC linked to thymic lymphomas. In this study, we use MSH2-/- mice as a model to investigate the existence of PLSC and the evolution of PLSC to LIC. Following BM transplantation, we found that MSH2-/- BM cells from young mice are able to fully reconstitute multiple hematopoietic lineages of lethally irradiated wild-type recipients. However, all recipients developed thymic lymphomas within three and four months post transplantation. Transplantation of different fractions of BM cells or thymocytes from young health MSH2-/- mice showed that an HSC enriched fraction always reconstituted hematopoiesis followed by lymphoma development. In addition, lymphomas did not occur in thymectomized recipients of MSH2-/- BM. These results suggest that HSCs with DNA repair defects such as MSH2-/- are PLSCs because they retain hematopoietic function, but also carry an obligate lymphomagenic potential within their T-cell progeny that is dependent on the thymic microenvironment.

  7. Angiotensin-converting enzyme (CD143) marks hematopoietic stem cells in human embryonic, fetal, and adult hematopoietic tissues

    NARCIS (Netherlands)

    Jokubaitis, Vanta J.; Sinka, Lidia; Driessen, Rebecca; Whitty, Genevieve; Haylock, David N.; Bertoncello, Ivan; Smith, Ian; Peault, Bruno; Tavian, Manuela; Simmons, Paul J.

    2008-01-01

    Previous studies revealed that mAb BB9 reacts with a subset of CD34(+) human BM cells with hematopoietic stem cell (HSC) characteristics. Here we map B89 expression throughout hernatopoietic development and show that the earliest definitive HSCs that arise at the ventral wall of the aorta and

  8. The biology of NK cells and their receptors affects clinical outcomes after hematopoietic cell transplantation (HCT).

    Science.gov (United States)

    Foley, Bree; Felices, Martin; Cichocki, Frank; Cooley, Sarah; Verneris, Michael R; Miller, Jeffrey S

    2014-03-01

    Natural killer (NK) cells were first identified for their capacity to reject bone marrow allografts in lethally irradiated mice without prior sensitization. Subsequently, human NK cells were detected and defined by their non-major histocompatibility complex (MHC)-restricted cytotoxicity toward transformed or virally infected target cells. Karre et al. later proposed 'the missing self hypothesis' to explain the mechanism by which self-tolerant cells could kill targets that had lost self MHC class I. Subsequently, the receptors that recognize MHC class I to mediate tolerance in the host were identified on NK cells. These class I-recognizing receptors contribute to the acquisition of function by a dynamic process known as NK cell education or licensing. In the past, NK cells were assumed to be short lived, but more recently NK cells have been shown to mediate immunologic memory to secondary exposures to cytomegalovirus infection. Because of their ability to lyse tumors with aberrant MHC class I expression and to produce cytokines and chemokines upon activation, NK cells may be primed by many stimuli, including viruses and inflammation, to contribute to a graft-versus-tumor effect. In addition, interactions with other immune cells support the therapeutic potential of NK cells to eradicate tumor and to enhance outcomes after hematopoietic cell transplantation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Risk of Hematopoietic and Lymphoproliferative Malignancies among U. S. Radiologic Technologists

    International Nuclear Information System (INIS)

    Linet, M. S.; Fredman, D. M.; Mohan, A.; Morin Doody, M.; Ron, E.; Mabuchi, K.; Alexander, B. B.; Sigurdson, A.; Matanoski, G.; Hauptmann, M.

    2004-01-01

    To evaluate risks of hematopoietic and lymphoproliferative malignancies among medical workers exposed to protracted low-to-moderate-dose radiation exposures, a follow-up investigation was conducted in a nation wide cohort of U. S. radiologic technologists. eligible for this study were 71.894 technologists (78% female) certified for at least 2 years during 1926-82, who had responded to a baseline mail questionnaire during 1983-89, were cancer-free except for non-melanoma skin cancer at completion of the questionnaire, and completed a second questionnaire during 1994-98 or died through August 1998. There were 241 technologists with hematopoietic or lymphoproliferative malignancies, including 41 with leukemia subtypes associated with radiation exposures (specifically acute myeloid, acute lymphoid and chronic myeloid leukemias, hereafter designated radiogenic leukemias), 23 with chronic lymphocytic leukemia, 28 with multiple myeloma, 118 with non-Hodgkin lymphoma, and 31 with Hodgkin lymphoma. Of the 241 hematopoietic or lymphoproliferative malignancies identified among radiologic technologists, 85 percent were confirmed by medical records or death certificates, including 98 percent of radiogenic leukemia. Risks of the hematopoietic or lymphoproliferative malignancies were evaluated in relation to questionnaire-derived information on employment as a radiologic technologist, including procedures, work practices, and protective measures. cox proportional hazards regression analysis was used to compute relative risks and 95% confidence intervals, using age at diagnosis as the response, stratifying at baseline for birth cohort in 5-year intervals, and adjusting for potential confounding. Risks were not increased for any of the hematopoietic or lymphoproliferative neoplasms according to year first worked or total duration of years worked as radiologic technologist. For the combined radiogenic leukemias, risks rose significantly with an increasing number of years worked

  10. Protracted radiation-induced alterations in hematopoietic repair and recovery

    International Nuclear Information System (INIS)

    Seed, T.M.; Fritz, T.E.

    1997-01-01

    Pathologic predisposition of beagle dogs under chronic, low daily dose (7.5 cGy day -1 ) whole-body gamma irradiation has been studied relative to molecular repair and hematopoietic competency. Molecular repair, assessed by a microscopy-based unscheduled DNA synthesis (UDS) response, was measured within proliferative and nonproliferative marrow myeloid elements of dogs with markedly different hematopoietic capacities (low capacity, aplasia-prone [AA + ] versus high capacity, myeloproliferative disease-prone [MPD + ]) under protracted radiation stress. Results indicated that protracted exposure elicited a net increase in UDS-repair capacity that was largely independent of exposure duration. This enhanced capacity resulted from the increased strength of the UDS signal together with an expanded number of positively responding cells. The combined response was strong in primitive blasts and weak in more differentiated myelocytic cells. The UDS repair response of the MPD + dogs was significantly greater than that of the AA + animals and was clearly modified relative to the controls. These results suggest that both resiliency and pathologic potential of the hematopoietic system under protracted radiation stress is, in part, associated with an augmentable DNA repair within the more primitive myeloid marrow elements. (author)

  11. Cell cycle regulation of hematopoietic stem or progenitor cells.

    Science.gov (United States)

    Hao, Sha; Chen, Chen; Cheng, Tao

    2016-05-01

    The highly regulated process of blood production is achieved through the hierarchical organization of hematopoietic stem cell (HSC) subsets and their progenies, which differ in self-renewal and differentiation potential. Genetic studies in mice have demonstrated that cell cycle is tightly controlled by the complex interplay between extrinsic cues and intrinsic regulatory pathways involved in HSC self-renewal and differentiation. Deregulation of these cellular programs may transform HSCs or hematopoietic progenitor cells (HPCs) into disease-initiating stem cells, and can result in hematopoietic malignancies such as leukemia. While previous studies have shown roles for some cell cycle regulators and related signaling pathways in HSCs and HPCs, a more complete picture regarding the molecular mechanisms underlying cell cycle regulation in HSCs or HPCs is lacking. Based on accumulated studies in this field, the present review introduces the basic components of the cell cycle machinery and discusses their major cellular networks that regulate the dormancy and cell cycle progression of HSCs. Knowledge on this topic would help researchers and clinicians to better understand the pathogenesis of relevant blood disorders and to develop new strategies for therapeutic manipulation of HSCs.

  12. Herpes zoster-associated voiding dysfunction in hematopoietic malignancy patients.

    Science.gov (United States)

    Imafuku, Shinichi; Takahara, Masakazu; Uenotsuchi, Takeshi; Iwato, Koji; Furue, Masutaka

    2008-01-01

    Voiding dysfunction is a rare but important complication of lumbo-sacral herpes zoster. Although the symptoms are transient, the clinical impact on immunocompromised patients cannot be overlooked. To clarify the time course of voiding dysfunction in herpes zoster, 13 herpes zoster patients with voiding dysfunction were retrospectively analyzed. Of 13 patients, 12 had background disease, and six of these were hematopoietic malignancies; four of these patients were hematopoietic stem cell transplant (HSCT) recipients. Ten patients had sacral lesions, two had lumbar, and one had thoracic lesions. Interestingly, patients with severe rash, or with hematopoietic malignancy had later onset of urinary retention than did patients with mild skin symptoms (Mann-Whitney U analysis, P = 0.053) or with other background disease (P = 0.0082). Patients with severe skin rash also had longer durations (P = 0.035). In one case, acute urinary retention occurred as late as 19 days after the onset of skin rash. In immune compromised subjects, attention should be paid to patients with herpes zoster in the lumbo-sacral area for late onset of acute urinary retention even after the resolution of skin symptoms.

  13. Orbital metastasis: A rare manifestation of scapular bone osteosarcoma

    Directory of Open Access Journals (Sweden)

    Mohammad Taher Rajabi

    2014-01-01

    Full Text Available Purpose: To report a case of orbital metastasis from scapular bone osteosarcoma. Case Report: A 55-year-old man who was a known case of scapular bone osteosarcoma, was referred to our clinic with ocular symptoms including acute painful decreased vision, proptosis, conjunctival injection, and chemosis. He had undergone surgical excision of the original tumor and received systemic chemotherapy 4 months before. Imaging studies and incisional biopsy were performed for the orbital lesion, the histopathological examination confirmed the diagnosis of metastatic osteosarcoma. The patient was referred to the oncologist for palliative chemotherapy and further intervention; however, he deceased 2 months later due to sepsis in the context of immunosuppression. Conclusion: Metastatic involvement of the orbit due to osteosarcoma is a rare condition manifesting with orbital mass, pain, diplopia and ocular motility disturbance. Although there is no effective treatment, the combination of modalities such as chemotherapy, radiotherapy, and surgery may delay progression of the disease.

  14. Supra-orbital keyhole removal of anterior fossa and parasellar meningiomas Minicraniotomia supra-orbitária superciliar no tratamento de meningiomas na fossa craniana anterior e para-selares

    Directory of Open Access Journals (Sweden)

    Manoel Antonio de Paiva-Neto

    2010-06-01

    Full Text Available The improvement of surgical techniques as well as the introduction of new surgical instruments promoted the use of keyhole craniotomies in neurosurgery. We evaluated the technical aspects of the supra-orbital keyhole approach considering the indications, limitations, and complications of this approach to treat anterior cranial fossa and parasellar meningiomas. Twenty-four patients (21 females; mean age, 53±8.6 years operated on between 2002 and 2006 through a supra-orbital eyebrow approach were studied. Maximal tumor diameter ranged from 1.6 to 6 cm. Gross total resection was done in 20 (83.3%. All tumors were histologically benign. Two patients (8% experienced CSF rinorhea and another two patients suffered transitory diabetes insipidus (8%. One patient experienced transitory hemiparesis. There was one case of meningitis and one mortality. Follow-up ranged between 6 to 66 months (mean 31.5±20.1 months, with no recurrence. The supra-orbital keyhole craniotomy is a useful minimally invasive approach to treat selected anterior fossa and parasellar meningiomas.A evolução técnica e a introdução de instrumentais cirúrgicos mais delicados proporcionaram o uso de craniotomias menores no tratamento de patologias intracranianas. Avaliamos os aspectos técnicos da minicraniotomia supra-orbitária superciliar, considerando as indicações, limitações e complicações no tratamento de meningiomas na fossa craniana anterior e para-selares. Vinte e quarto pacientes (21 mulheres; idade média, 53±8,6 anos operados entre 2002 e 2006 foram estudados. O diâmetro tumoral máximo variou de 1,6 a 6 cm. Ressecção total foi obtida em 20 (83,3%. Todos os tumores eram histologicamente benignos. Dois pacientes (8% apresentaram fistula liquórica pós-operatória e outros dois diabetes insipido transitórioa (8%. Um paciente evoluiu com hemiparesia transitória. Houve um caso de meningite e um de evolução fatal. O seguimento variou de 6 a 66 meses (m

  15. MALT LYMPHOMA OF PALATE AND ORBIT

    Directory of Open Access Journals (Sweden)

    VIVIANA ANDREA CIFUENTES NAVAS

    2018-05-01

    Full Text Available TITLE: Malt palate and orbit lymphoma  Authors: CIFUENTES NAVAS-Viviana Andrea; MARTÍN PASCUAL- María Consolación; FERNÁNDEZ RODRÍGUEZ- Ana; ALONSO MESONERO- Marta; CHAVIANO GRAHJERA-Juan; MORAIS PÉREZ-Darío. INTRODUCTIONMALT-type lymphomas are lymphoid proliferations originated in the glandular epithelium of organs like the stomach, the salivary and lacrimal glands, and even, we can find lymphoid neoformations of non-epithelial localization, like in the orbital soft tissue. The lymphomas of the mucosal-associated lymphatic tissue (MALT represent only 0.2-0.3% and constitute a well-defined group of non-Hodgkin lymphomas of B origin. In the field of oral pathology, the salivary glands, tonsils and palate are mainly affected, it is more rare to find it in jugal mucosa.We present a rare case of MALT lymphoma with involvement of the palate and orbit. MATERIAL AND METHODS84-year-old patient with multiple pathologies. Derived from his primary care physician due to pharyngeal complaints of 4 to 5 days of evolution, associated with a painful palate lesion.He presented in right hemipaladar a tumoration of elastic consistency in submucosa, ulcerated in the center, with normal neck. Also left orbital tumor that limits the visual field. RESULTSCT and MRI of the neck report mass of 4x4 x2.5 cm in right hemipaladar, noninfiltrating concordant with possible lymphoma. The orbital MRI describes an intra and extra nasal left nasal lesion of 2.3x1.2x2 cm with characteristics consistent with lymphoma. CT of the neck: It demostrates a great mass of right hemipaladar, with lobulated contours and homogeneous enhancement of 40x32x25 mm, in intimate contact with medial pterygoid muscle, although there were no signs of infiltration, the rest of the edges being well delimited. Images characteristics look like a lymphoma, without being able to rule out other etiologies. MRI of the neck: It demostrates a diffuse thickening of right side of the soft palate that

  16. Anterior eye protection with orbital neoplasia

    International Nuclear Information System (INIS)

    Hancock, S.L.

    1986-01-01

    The administration of adequate doses of radiation to tumors involving the orbit and surrounding facial structures and sinuses is often complicated by the need to protect the sensitive ocular components, the lens and cornea. A technique has been devised that uses four photon beam fields and an optional electron field to treat the contents of both orbits and adjacent sinuses with effective, reproducible protection of cornea and lens. Essential features include: alignment of the corneal surfaces with the central plane of rotation of the treatment machine, use of a narrow eye block across the entire beam to shield a strip equal to the width of the cornea, positioned symmetrically across the central plane of rotation, fine alignment of the eye block with both corneal surfaces by altering pedestal angle, treatment with paired, wedged, anterior oblique fields to encompass desired orbital and sinus volumes with additional blocking placed as needed, and complementary, lateral strip fields using collimators set to eye block thickness to equalize dose in the posterior orbit shielded by the strip eye block. A similar anterior electron beam strip field may be added to boost the medial orbit and ethmoid regions covered by the eye block. Bite block head immobilization and easy, direct daily visualization of block position assures eye protection for each treatment and provides substantial reduction in dose to the cornea, lens and iris. Additional blocking may be incorporated to provide partial lacrimal and parotid sparing

  17. Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization

    NARCIS (Netherlands)

    van Pel, M; van Os, R; Velders, GA; Hagoort, H; Heegaard, PMH; Lindley, IJD; Willemze, R; Fibbe, WE

    2006-01-01

    Here, we report that cytokine-induced (granulocyte colony-stimulating factor and IL-8) hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is completely inhibited after low-dose (0.5 Gy) total-body irradiation (TBI). Because neutrophil granular proteases are regulatory

  18. Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization

    DEFF Research Database (Denmark)

    van Pel, M.; van Os, R.; Velders, G.A.

    2006-01-01

    Here, we report that cytokine-induced (granulocyte colony-stimulating factor and IL-8) hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is completely inhibited after low-dose (0.5 Gy) total-body irradiation (TBI). Because neutrophil granular proteases are regulat...

  19. Cellular memory and, hematopoietic stem cell aging

    NARCIS (Netherlands)

    Kamminga, Leonie M.; de Haan, Gerald

    Hematopoietic stem cells (HSCs) balance self-renewal and differentiation in order to sustain lifelong blood production and simultaneously maintain the HSC pool. However, there is clear evidence that HSCs are subject to quantitative and qualitative exhaustion. In this review, we briefly discuss

  20. Hematopoietic stem cell transplantation in multiple sclerosis

    DEFF Research Database (Denmark)

    Rogojan, C; Frederiksen, J L

    2009-01-01

    Intensive immunosuppresion followed by hematopoietic stem cell transplantation (HSCT) has been suggested as potential treatment in severe forms of multiple sclerosis (MS). Since 1995 ca. 400 patients have been treated with HSCT. Stabilization or improvement occurred in almost 70% of cases at least...

  1. Human hematopoietic cell culture, transduction, and analyses

    DEFF Research Database (Denmark)

    Bonde, Jesper; Wirthlin, Louisa; Kohn, Donald B

    2008-01-01

    This unit provides methods for introducing genes into human hematopoietic progenitor cells. The Basic Protocol describes isolation of CD34(+) cells, transduction of these cells with a retroviral vector on fibronectin-coated plates, assaying the efficiency of transduction, and establishing long-te...

  2. Functional analysis of human hematopoietic stem cell gene expression using zebrafish.

    Directory of Open Access Journals (Sweden)

    2005-08-01

    Full Text Available Although several reports have characterized the hematopoietic stem cell (HSC transcriptome, the roles of HSC-specific genes in hematopoiesis remain elusive. To identify candidate regulators of HSC fate decisions, we compared the transcriptome of human umbilical cord blood and bone marrow (CD34+(CD33-(CD38-Rho(lo(c-kit+ cells, enriched for hematopoietic stem/progenitor cells with (CD34+(CD33-(CD38-Rho(hi cells, enriched in committed progenitors. We identified 277 differentially expressed transcripts conserved in these ontogenically distinct cell sources. We next performed a morpholino antisense oligonucleotide (MO-based functional screen in zebrafish to determine the hematopoietic function of 61 genes that had no previously known function in HSC biology and for which a likely zebrafish ortholog could be identified. MO knock down of 14/61 (23% of the differentially expressed transcripts resulted in hematopoietic defects in developing zebrafish embryos, as demonstrated by altered levels of circulating blood cells at 30 and 48 h postfertilization and subsequently confirmed by quantitative RT-PCR for erythroid-specific hbae1 and myeloid-specific lcp1 transcripts. Recapitulating the knockdown phenotype using a second MO of independent sequence, absence of the phenotype using a mismatched MO sequence, and rescue of the phenotype by cDNA-based overexpression of the targeted transcript for zebrafish spry4 confirmed the specificity of MO targeting in this system. Further characterization of the spry4-deficient zebrafish embryos demonstrated that hematopoietic defects were not due to more widespread defects in the mesodermal development, and therefore represented primary defects in HSC specification, proliferation, and/or differentiation. Overall, this high-throughput screen for the functional validation of differentially expressed genes using a zebrafish model of hematopoiesis represents a major step toward obtaining meaningful information from global

  3. Proliferative capacity of murine hematopoietic stem cells

    International Nuclear Information System (INIS)

    Hellman, S.; Botnick, L.E.; Hannon, E.C.; Vigneulle, R.M.

    1978-01-01

    The present study demonstrates a decrease in self-renewal capacity with serial transfer of murine hematopoietic stem cells. Production of differentiated cell progeny is maintained longer than stem cell self-renewal. In normal animals the capacity for self-renewal is not decreased with increasing donor age. The stem cell compartment in normal animals, both young and old, appears to be proliferatively quiescent. After apparent recovery from the alkylating agent busulfan, the probability of stem cell self-renewal is decreased, there is a permanent defect in the capacity of the bone marrow for serial transplantation, and the stem cells are proliferatively active. These findings support a model of the hematopoietic stem cell compartment as a continuum of cells with decreasing capacities for self-renewal, increasing likelihood for differentiation, and increasing proliferative activity. Cells progress in the continuum in one direction and such progression is not reversible

  4. Fine-tuning Hematopoiesis: Microenvironmental factors regulating self-renewal and differentiation of hematopoietic stem cells

    NARCIS (Netherlands)

    T.C. Luis (Tiago)

    2010-01-01

    markdownabstract__Abstract__ Hematopoietic stem cells (HSCs) have the ability to self renew and generate all lineages of blood cells. Although it is currently well established that hematopoietic stem cells (HSCs) regenerate the blood compartment, it was only in the 1960s that was introduced the

  5. Investigation of radioprotective effect of indraline of hematopoietic system in different species of animal

    International Nuclear Information System (INIS)

    Vasin, M.V.; Antipov, V.V.; Chernov, G.A.

    1996-01-01

    The experiments were made on mice, guinea pigs and dogs. Radioprotector indraline increased radioresistant state of hematopoietic stem cells in vivo and in vitro, decreased the amount of post-radiation chromosome aberrations in marrow, induced more early and intensive post-radiation proliferative repair of marrow and spleen, faster regeneration of the initial amount of leukocytes thrombocytes and erytrocytes in blood of mice, guinea pigs and dogs. Antiradiation efficiency of indraline in hematopoietic system is equal to 1.5-2 by FMD. Radioprotective mechanism of indraline effect on hematopoietic system is discussed. 22 refs.; 8 figs.; 4 tabs

  6. Magnetic resonance imaging of intraorbital tumors

    International Nuclear Information System (INIS)

    Inoue, Tooru; Fukui, Masashi; Matsushima, Toshio; Fujii, Kiyotaka; Hasuo, Kanehiro

    1991-01-01

    Ten cases of histologically confirmed intraorbital tumors were studied with magnetic resonance imaging (MRI). Two meningiomas were nearly isointense on the T 1 -weighted image (T 1 WI) and the T 2 -weighted image (T 2 WI) relative on the cerebral cortex. The hemangiopericytoma, lacrimal gland tumor, optic glioma, and encephalocele were hypointense on the T 1 WI. The pseudotumor was hypoisointense on both the T 1 WI and the T 2 WI. The metastatic tumor (prostatic carcinoma) was hyperintense on both the T 1 WI and the T 2 WI. Gd-DTPA MRI was performed in five cases. The anatomical relationships between the tumor and the orbital tissue could be discriminated well by means of the coronal and sagittal views. MRI is thus found to be useful for the preoperative diagnosis of the intraorbital tumor and the selection of the surgical approach. (author)

  7. Hematopoietic chimerism and transplantation tolerance: a role for regulatory T cells

    Directory of Open Access Journals (Sweden)

    Lise ePasquet

    2011-12-01

    Full Text Available The major obstacle in transplantation medicine is rejection of donor tissues by the host’s immune system. Immunosuppressive drugs can delay but not prevent loss of transplants, and their efficiency is strongly impacted by inter-individual pharmacokinetic differences. Moreover, due to the global immunosuppression induced and to the broad distribution of their targets amongst human tissues, these drugs have severe side effects. Induction of donor-specific non-responsiveness (i.e. immunological tolerance to transplants would solve these problems and would substantially ameliorate patients’ quality of life. It is widely believed that bone marrow or hematopoietic stem cell transplantation, and resulting (mixed hematopoietic chimerism, invariably leads to immunological tolerance to organs of the same donor. A careful analysis of the literature, reviewed here, indeed shows that chimerism consistently prolongs allograft survival. However, in absence of additional conditioning leading to the development of active regulatory mechanisms, it does not prevent chronic rejection. A central role for active tolerance in transplantation-tolerance is also supported by recent data showing that genuine immunological tolerance to organ allografts can be achieved by combining induction of hematopoietic chimerism with infusion of regulatory T lymphocytes. Therefore, conditioning regimens that lead to the establishment of hematopoietic chimerism plus active regulatory mechanisms appear required for induction of genuine tolerance to allogeneic grafts.

  8. Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression.

    Science.gov (United States)

    Guo, Peipei; Poulos, Michael G; Palikuqi, Brisa; Badwe, Chaitanya R; Lis, Raphael; Kunar, Balvir; Ding, Bi-Sen; Rabbany, Sina Y; Shido, Koji; Butler, Jason M; Rafii, Shahin

    2017-12-01

    Angiocrine factors, such as Notch ligands, supplied by the specialized endothelial cells (ECs) within the bone marrow and splenic vascular niche play an essential role in modulating the physiology of adult hematopoietic stem and progenitor cells (HSPCs). However, the relative contribution of various Notch ligands, specifically jagged-2, to the homeostasis of HSPCs is unknown. Here, we show that under steady state, jagged-2 is differentially expressed in tissue-specific vascular beds, but its expression is induced in hematopoietic vascular niches after myelosuppressive injury. We used mice with EC-specific deletion of the gene encoding jagged-2 (Jag2) to demonstrate that while EC-derived jagged-2 was dispensable for maintaining the capacity of HSPCs to repopulate under steady-state conditions, by activating Notch2 it did contribute to the recovery of HSPCs in response to myelosuppressive conditions. Engraftment and/or expansion of HSPCs was dependent on the expression of endothelial-derived jagged-2 following myeloablation. Additionally, jagged-2 expressed in bone marrow ECs regulated HSPC cell cycle and quiescence during regeneration. Endothelial-deployed jagged-2 triggered Notch2/Hey1, while tempering Notch2/Hes1 signaling in HSPCs. Collectively, these data demonstrate that EC-derived jagged-2 activates Notch2 signaling in HSPCs to promote hematopoietic recovery and has potential as a therapeutic target to accelerate balanced hematopoietic reconstitution after myelosuppression.

  9. DNA Damage: A Sensible Mediator of the Differentiation Decision in Hematopoietic Stem Cells and in Leukemia

    Directory of Open Access Journals (Sweden)

    Cary N. Weiss

    2015-03-01

    Full Text Available In the adult, the source of functionally diverse, mature blood cells are hematopoietic stem cells, a rare population of quiescent cells that reside in the bone marrow niche. Like stem cells in other tissues, hematopoietic stem cells are defined by their ability to self-renew, in order to maintain the stem cell population for the lifetime of the organism, and to differentiate, in order to give rise to the multiple lineages of the hematopoietic system. In recent years, increasing evidence has suggested a role for the accumulation of reactive oxygen species and DNA damage in the decision for hematopoietic stem cells to exit quiescence and to differentiate. In this review, we will examine recent work supporting the idea that detection of cell stressors, such as oxidative and genetic damage, is an important mediator of cell fate decisions in hematopoietic stem cells. We will explore the benefits of such a system in avoiding the development and progression of malignancies, and in avoiding tissue exhaustion and failure. Additionally, we will discuss new work that examines the accumulation of DNA damage and replication stress in aging hematopoietic stem cells and causes us to rethink ideas of genoprotection in the bone marrow niche.

  10. Molecular regulation of human hematopoietic stem cells

    NARCIS (Netherlands)

    van Galen, P.L.J.

    2014-01-01

    Peter van Galen focuses on understanding the determinants that maintain the stem cell state. Using human hematopoietic stem cells (HSCs) as a model, processes that govern self-renewal and tissue regeneration were investigated. Specifically, a role for microRNAs in balancing the human HSC

  11. Aging, Clonality and Rejuvenation of Hematopoietic Stem Cells

    Science.gov (United States)

    Akunuru, Shailaja; Geiger, Hartmut

    2016-01-01

    Aging is associated with reduced organ function and increased disease incidence. Hematopoietic stem cell (HSC) aging driven by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration, aging-associated immune remodeling, and increased leukemia incidence. Compromised DNA damage responses and increased production of reactive oxygen species have been previously causatively attributed to HSC aging. However, recent paradigm-shifting concepts such as global epigenetic and cytoskeletal polarity shifts, cellular senescence, as well as clonal selection of HSCs upon aging provide new insights into HSC aging mechanisms. Rejuvenating agents that can reprogram the epigenetic status of aged HSCs or senolytic drugs that selectively deplete senescent cells provide promising translational avenues for attenuating hematopoietic aging and potentially, alleviating aging-associated immune remodeling and myeloid malignancies. PMID:27380967

  12. Differentiation of orbital lymphoma and idiopathic orbital inflammatory pseudotumor: combined diagnostic value of conventional MRI and histogram analysis of ADC maps.

    Science.gov (United States)

    Ren, Jiliang; Yuan, Ying; Wu, Yingwei; Tao, Xiaofeng

    2018-05-02

    The overlap of morphological feature and mean ADC value restricted clinical application of MRI in the differential diagnosis of orbital lymphoma and idiopathic orbital inflammatory pseudotumor (IOIP). In this paper, we aimed to retrospectively evaluate the combined diagnostic value of conventional magnetic resonance imaging (MRI) and whole-tumor histogram analysis of apparent diffusion coefficient (ADC) maps in the differentiation of the two lesions. In total, 18 patients with orbital lymphoma and 22 patients with IOIP were included, who underwent both conventional MRI and diffusion weighted imaging before treatment. Conventional MRI features and histogram parameters derived from ADC maps, including mean ADC (ADC mean ), median ADC (ADC median ), skewness, kurtosis, 10th, 25th, 75th and 90th percentiles of ADC (ADC 10 , ADC 25 , ADC 75 , ADC 90 ) were evaluated and compared between orbital lymphoma and IOIP. Multivariate logistic regression analysis was used to identify the most valuable variables for discriminating. Differential model was built upon the selected variables and receiver operating characteristic (ROC) analysis was also performed to determine the differential ability of the model. Multivariate logistic regression showed ADC 10 (P = 0.023) and involvement of orbit preseptal space (P = 0.029) were the most promising indexes in the discrimination of orbital lymphoma and IOIP. The logistic model defined by ADC 10 and involvement of orbit preseptal space was built, which achieved an AUC of 0.939, with sensitivity of 77.30% and specificity of 94.40%. Conventional MRI feature of involvement of orbit preseptal space and ADC histogram parameter of ADC 10 are valuable in differential diagnosis of orbital lymphoma and IOIP.

  13. Genetic modification of hematopoietic stem cells with nonviral systems: past progress and future prospects.

    Science.gov (United States)

    Papapetrou, E P; Zoumbos, N C; Athanassiadou, A

    2005-10-01

    Serious unwanted complications provoked by retroviral gene transfer into hematopoietic stem cells (HSCs) have recently raised the need for the development and assessment of alternative gene transfer vectors. Within this context, nonviral gene transfer systems are attracting increasing interest. Their main advantages include low cost, ease of handling and large-scale production, large packaging capacity and, most importantly, biosafety. While nonviral gene transfer into HSCs has been restricted in the past by poor transfection efficiency and transient maintenance, in recent years, biotechnological developments are converting nonviral transfer into a realistic approach for genetic modification of cells of hematopoietic origin. Herein we provide an overview of past accomplishments in the field of nonviral gene transfer into hematopoietic progenitor/stem cells and we point at future challenges. We argue that episomally maintained self-replicating vectors combined with physical methods of delivery show the greatest promise among nonviral gene transfer strategies for the treatment of disorders of the hematopoietic system.

  14. Daunorubicin, Cytarabine, and Cladribine Regimen Plus Radiotherapy and Donor Lymphocyte Infusion for Extramedullary Relapse of Acute Myeloid Leukemia after Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Marco Sanna

    2013-01-01

    Full Text Available Myeloid sarcoma is a rare tumor consisting of myeloid blasts that involve anatomic sites outside the bone marrow. Fatal prognosis is inevitable in patients with extramedullary relapse after hematopoietic stem cell transplantation (HSCT, and no standard treatments are available yet. We report the first case of extramedullary relapse after HSCT treated with a combination of daunorubicin, cytarabine, and cladribine (DAC regimen plus radiotherapy and donor lymphocyte infusion (DLI. This treatment induced a new and durable remission in our patient. The favorable toxicity profile and the reduced cost make this combination worthy of further investigations.

  15. Transformation of human mesenchymal cells and skin fibroblasts into hematopoietic cells.

    Directory of Open Access Journals (Sweden)

    David M Harris

    Full Text Available Patients with prolonged myelosuppression require frequent platelet and occasional granulocyte transfusions. Multi-donor transfusions induce alloimmunization, thereby increasing morbidity and mortality. Therefore, an autologous or HLA-matched allogeneic source of platelets and granulocytes is needed. To determine whether nonhematopoietic cells can be reprogrammed into hematopoietic cells, human mesenchymal stromal cells (MSCs and skin fibroblasts were incubated with the demethylating agent 5-azacytidine (Aza and the growth factors (GF granulocyte-macrophage colony-stimulating factor and stem cell factor. This treatment transformed MSCs to round, non-adherent cells expressing T-, B-, myeloid-, or stem/progenitor-cell markers. The transformed cells engrafted as hematopoietic cells in bone marrow of immunodeficient mice. DNA methylation and mRNA array analysis suggested that Aza and GF treatment demethylated and activated HOXB genes. Indeed, transfection of MSCs or skin fibroblasts with HOXB4, HOXB5, and HOXB2 genes transformed them into hematopoietic cells. Further studies are needed to determine whether transformed MSCs or skin fibroblasts are suitable for therapy.

  16. Rhizomucor and Scedosporium Infection Post Hematopoietic Stem-Cell Transplant

    Directory of Open Access Journals (Sweden)

    Dânia Sofia Marques

    2011-01-01

    Full Text Available Hematopoietic stem-cell transplant recipients are at increased risk of developing invasive fungal infections. This is a major cause of morbidity and mortality. We report a case of a 17-year-old male patient diagnosed with severe idiopathic acquired aplastic anemia who developed fungal pneumonitis due to Rhizomucor sp. and rhinoencephalitis due to Scedosporium apiospermum 6 and 8 months after undergoing allogeneic hematopoietic stem-cell transplant from an HLA-matched unrelated donor. Discussion highlights risk factors for invasive fungal infections (i.e., mucormycosis and scedosporiosis, its clinical features, and the factors that must be taken into account to successfully treat them (early diagnosis, correction of predisposing factors, aggressive surgical debridement, and antifungal and adjunctive therapies.

  17. Comparison of chemotherapy and hematopoietic stem cell ...

    African Journals Online (AJOL)

    2013-02-19

    Feb 19, 2013 ... scores before and after hematopoietic stem cell transplantation (HSCT) and chemotherapy. Materials and Methods: Thirty-six patients undergoing HSCT were included in the study. A pre-HSCT dental treatment protocol was implemented that consisted of restoration of all active carious lesions, treatment of ...

  18. Hematopoietic stem cell aging and self-renewal

    NARCIS (Netherlands)

    Dykstra, Brad; de Haan, Gerald

    A functional decline of the immune system occurs during organismal aging that is attributable, in large part, to changes in the hematopoietic stem cell (HSC) compartment. In the mouse, several hallmark age-dependent changes in the HSC compartment have been identified, including an increase in HSC

  19. Evaluation of hematopoietic potential generated by transplantation of muscle-derived stem cells in mice.

    Science.gov (United States)

    Farace, Francoise; Prestoz, Laetitita; Badaoui, Sabrina; Guillier, Martine; Haond, Celine; Opolon, Paule; Thomas, Jean-Leon; Zalc, Bernard; Vainchenker, William; Turhan, Ali G

    2004-02-01

    Muscle tissue of adult mice has been shown to contain stem cells with hematopoietic repopulation ability in vivo. To determine the functional characteristics of stem cells giving rise to this hematopoietic activity, we have performed hematopoietic reconstitution experiments by the use of muscle versus marrow transplantation in lethally irradiated mice and followed the fate of transplanted cells by Y-chimerism using PCR and fluorescence in situ hybridization (FISH) analysis. We report here that transplantation of murine muscle generate a major hematopoietic chimerism at the level of CFU-C, CFU-S, and terminally-differentiated cells in three generations of lethally irradiated mice followed up to 1 year after transplantation. This potential is totally abolished when muscle grafts were performed by the use of muscle from previously irradiated mice. As compared to marrow transplantation, muscle transplants were able to generate similar potencies to give rise to myeloid, T, B, and natural killer (NK) cells. Interestingly, marrow stem cells that have been generated in primary and then in secondary recipients were able to contribute efficiently to myofibers in the muscle tissue of tertiary recipients. Altogether, our data demonstrate that muscle-derived stem cells present a major hematopoietic repopulating ability with evidence of self-replication in vivo. They are radiation-sensitive and similar to marrow-derived stem cells in terms of their ability to generate multilineage hematopoiesis. Finally, our data demonstrate that muscle-derived hematopoietic stem cells do not lose their ability to contribute to myofiber generation after at least two rounds of serial transplantation, suggesting a potential that is probably equivalent to that generated by marrow transplantation.

  20. Magnetic resonance imaging of intraorbital tumors

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Tooru; Fukui, Masashi; Matsushima, Toshio; Fujii, Kiyotaka; Hasuo, Kanehiro (Kyushu Univ., Fukuoka (Japan). Faculty of Medicine)

    1991-12-01

    Ten cases of histologically confirmed intraorbital tumors were studied with magnetic resonance imaging (MRI). Two meningiomas were nearly isointense on the T[sub 1]-weighted image (T[sub 1]WI) and the T[sub 2]-weighted image (T[sub 2]WI) relative on the cerebral cortex. The hemangiopericytoma, lacrimal gland tumor, optic glioma, and encephalocele were hypointense on the T[sub 1]WI. The pseudotumor was hypoisointense on both the T[sub 1]WI and the T[sub 2]WI. The metastatic tumor (prostatic carcinoma) was hyperintense on both the T[sub 1]WI and the T[sub 2]WI. Gd-DTPA MRI was performed in five cases. The anatomical relationships between the tumor and the orbital tissue could be discriminated well by means of the coronal and sagittal views. MRI is thus found to be useful for the preoperative diagnosis of the intraorbital tumor and the selection of the surgical approach. (author).

  1. Quantitative and qualitative assessment of reactive hematopoietic bone marrow in aplastic anemia using MR spectroscopy with variable echo times

    Energy Technology Data Exchange (ETDEWEB)

    Amano, Yasuo; Kumazaki, Tatsuo [Department of Radiology, Nippon Medical School, Tokyo (Japan)

    2002-01-01

    Objective: To assess quantitative and qualitative differences in water components between normal bone marrow and reactive hematopoietic marrow in aplastic anemia using magnetic resonance (MR) spectroscopy with variable echo times (TEs). Design: Water content, T2 value of the water component, and signal change in water related to TE were assessed in normal bone marrow and reactive hematopoietic bone marrow by a stimulated echo acquisition mode with TEs of 30, 45, 60, and 90 ms. Patients: Six patients with aplastic anemia (13-84 years) and seven normal volunteers (25-38 years) were examined. Results and conclusion: Reactive hematopoietic marrow showed significantly higher water content than normal bone marrow. The T2 value of water components tended to be longer in reactive hematopoietic marrow. Water signal ratio related to TE was significantly higher in reactive hematopoietic marrow. These results suggest a quantitative and qualitative difference in water components between normal and reactive hematopoietic bone marrow. (orig.)

  2. Orbital involvement by non-Hodgkin lymphoma NK T cells.

    Science.gov (United States)

    Hervás-Ontiveros, A; España-Gregori, E; Hernández-Martínez, P; Vera-Sempere, F J; Díaz-Llopis, M

    2014-11-01

    The case is presented of 37 year-old male with a history of nasal obstruction with right rhinorrhea, headache, hearing loss and right exophthalmos of 4 months progression. The MRI revealed that the ethmoidal and maxillary sinuses contained inflammatory tissue extending into the orbital region. The biopsy confirmed a non-Hodgkin lymphoma of natural killer (NK) T cells. Non-Hodgkin's T NK lymphoma is a rare tumor in the orbital area that requires an early detection and multi-disciplinary care to ensure appropriate monitoring and treatment. Copyright © 2012 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

  3. Reconstruction of hematopoietic inductive microenvironment after transplantation of VCAM-1-modified human umbilical cord blood stromal cells.

    Directory of Open Access Journals (Sweden)

    Yao Liu

    Full Text Available The hematopoietic inductive microenvironment (HIM is where hematopoietic stem/progenitor cells grow and develop. Hematopoietic stromal cells were the key components of the HIM. In our previous study, we had successfully cultured and isolated human cord blood-derived stromal cells (HUCBSCs and demonstrated that they could secret hemopoietic growth factors such as GM-CSF, TPO, and SCF. However, it is still controversial whether HUCBSCs can be used for reconstruction of HIM. In this study, we first established a co-culture system of HUCBSCs and cord blood CD34(+ cells and then determined that using HUCBSCs as the adherent layer had significantly more newly formed colonies of each hematopoietic lineage than the control group, indicating that HUCBSCs had the ability to promote the proliferation of hematopoietic stem cells/progenitor cells. Furthermore, the number of colonies was significantly higher in vascular cell adhesion molecule-1 (VCAM-1-modified HUCBSCs, suggesting that the ability of HUCBSCs in promoting the proliferation of hematopoietic stem cells/progenitor cells was further enhanced after having been modified with VCAM-1. Next, HUCBSCs were infused into a radiation-damaged animal model, in which the recovery of hematopoiesis was observed. The results demonstrate that the transplanted HUCBSCs were "homed in" to bone marrow and played roles in promoting the recovery of irradiation-induced hematopoietic damage and repairing HIM. Compared with the control group, the HUCBSC group had significantly superior effectiveness in terms of the recovery time for hemogram and myelogram, CFU-F, CFU-GM, BFU-E, and CFU-Meg. Such differences were even more significant in VCAM-1-modified HUCBSCs group. We suggest that HUCBSCs are able to restore the functions of HIM and promote the recovery of radiation-induced hematopoietic damage. VCAM-1 plays an important role in supporting the repair of HIM damage.

  4. Age-related mutations associated with clonal hematopoietic expansion and malignancies.

    Science.gov (United States)

    Xie, Mingchao; Lu, Charles; Wang, Jiayin; McLellan, Michael D; Johnson, Kimberly J; Wendl, Michael C; McMichael, Joshua F; Schmidt, Heather K; Yellapantula, Venkata; Miller, Christopher A; Ozenberger, Bradley A; Welch, John S; Link, Daniel C; Walter, Matthew J; Mardis, Elaine R; Dipersio, John F; Chen, Feng; Wilson, Richard K; Ley, Timothy J; Ding, Li

    2014-12-01

    Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5-6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion.

  5. Efficacy of Vismodegib (Erivedge) for Basal Cell Carcinoma Involving the Orbit and Periocular Area.

    Science.gov (United States)

    Demirci, Hakan; Worden, Francis; Nelson, Christine C; Elner, Victor M; Kahana, Alon

    2015-01-01

    Evaluate the effectiveness of vismodegib in the management of basal cell carcinoma with orbital extension and/or extensive periocular involvement. Retrospective chart review of 6 consecutive patients with biopsy-proven orbital basal cell carcinoma and 2 additional patients with extensive periocular basal cell carcinoma who were treated with oral vismodegib (150 mg/day) was performed. Basal cell carcinoma extended in the orbit in 6 of 8 patients (involving orbital bones in 1 patient), and 2 of 8 patients had extensive periocular involvement (1 with basal cell nevus syndrome). Vismodegib therapy was the only treatment in 6 patients, off-label neoadjuvant in 1 patient, and adjuvant treatment in 1 patient. Orbital tumors in all 4 patients who received vismodegib as sole treatment showed partial response with a mean 83% shrinkage in tumor size after a median of 7 months of therapy. In the 2 patients receiving vismodegib as neoadjuvant or adjuvant therapies, there was complete response after a median of 7 months of therapy and no evidence of clinical recurrence after discontinuing therapy for a median of 15 months. The 2 patients with extensive periocular involvement experienced complete clinical response after a median 14 months of treatment. During treatment, the most common side effects were muscle spasm (75%) followed by alopecia (50%), dysgeusia (25%), dysosmia, and episodes of diarrhea and constipation (13%). Basal cell carcinoma with orbital extension and extensive periocular involvement responds to vismodegib therapy. The long-term prognosis remains unknown, and additional prospective studies are indicated.

  6. Case of false positive scanning observed after radiation therapy for orbital tumor

    Energy Technology Data Exchange (ETDEWEB)

    Ohara, H [Gifu Prefectural Tajimi Hospital (Japan); Nakamura, K; Maeda, S; Watanabe, R; Miyajima, T

    1978-12-01

    A report was made of 56-year-old female patient of abducensparesis. In the early stage the cause remained undetermined with nothing abnormal noted in scintigraphy. Diplopia disappeared once, but right, exophalmus relapsed. In gammaencepharography, a hot spot was noted in the orbita, sinus ethmoidalis and sirus sphenoidalis. In an operation, squamous cell carcinoma was removed and radiation therapy was performed (total dose of 3520 r) and, three months later a scintigraphy disclosed a high spot of /sup 203/Hg uptake ratio in the right orbita and its lower portions. The biopsy of these portions disclosed a necrotic tissue instead of a tumor. In scintigraphy after radiation therapy against the tumor, it was reported that a positive scintigraphy was present because of the vascular trouble of said portions, although the tumor had disappeared. Attention should be given as well as an opinion of high density together with the examination by CT, especially as to enhancement.

  7. Generating autologous hematopoietic cells from human-induced pluripotent stem cells through ectopic expression of transcription factors.

    Science.gov (United States)

    Hwang, Yongsung; Broxmeyer, Hal E; Lee, Man Ryul

    2017-07-01

    Hematopoietic cell transplantation (HCT) is a successful treatment modality for patients with malignant and nonmalignant disorders, usually when no other treatment option is available. The cells supporting long-term reconstitution after HCT are the hematopoietic stem cells (HSCs), which can be limited in numbers. Moreover, finding an appropriate human leukocyte antigen-matched donor can be problematic. If HSCs can be stably produced in large numbers from autologous or allogeneic cell sources, it would benefit HCT. Induced pluripotent stem cells (iPSCs) established from patients' own somatic cells can be differentiated into hematopoietic cells in vitro. This review will highlight recent methods for regulating human (h) iPSC production of HSCs and more mature blood cells. Advancements in transcription factor-mediated regulation of the developmental stages of in-vivo hematopoietic lineage commitment have begun to provide an understanding of the molecular mechanism of hematopoiesis. Such studies involve not only directed differentiation in which transcription factors, specifically expressed in hematopoietic lineage-specific cells, are overexpressed in iPSCs, but also direct conversion in which transcription factors are introduced into patient-derived somatic cells which are dedifferentiated to hematopoietic cells. As iPSCs derived from patients suffering from genetically mutated diseases would express the same mutated genetic information, CRISPR-Cas9 gene editing has been utilized to differentiate genetically corrected iPSCs into normal hematopoietic cells. IPSCs provide a model for molecular understanding of disease, and also may function as a cell population for therapy. Efficient differentiation of patient-specific iPSCs into HSCs and progenitor cells is a potential means to overcome limitations of such cells for HCT, as well as for providing in-vitro drug screening templates as tissue-on-a-chip models.

  8. Intrathoracic extramedullary hematopoiesis presenting as tumor-simulating lesions of the mediastinum in α-thalassemia: A case report.

    Science.gov (United States)

    An, Jun; Weng, Yimin; He, Jinyuan; Li, Yun; Huang, Shaohong; Cai, Songwang; Zhang, Junhang

    2015-10-01

    Extramedullary hematopoiesis (EMH) is a rare disease, where hematological disorder drives extramedullary hematopoietic tumor formation in multiple regions of the body. The present study reports a case of EMH presenting as multiple tumor-like lesions of mediastinum in a 61-year-old male with α-thalassemia, which was subjected to a video-assisted thoracoscopic surgery tissue biopsy to differentiate it from other mediastinal tumors. To date, only three cases of EMH in patients with α-thalassemia have been described in the literature. Patients with EMH typically exhibit no hematological disorder preoperatively and therefore EMH is frequently misdiagnosed. In the present study, along with a literature review of the clinicopathological features of EMH, the diagnosis and treatment of this rare case was discussed, in order to differentiate diagnosis, and particularly to distinguish EHM from extramedullary myeloid sarcoma.

  9. [Orbital alveolar rhabdomyosarcoma masked by ethmoid sinusitis in a 25-year-old].

    Science.gov (United States)

    Sanz-Marco, E; España, E; Alamar, A; Pérez-Rojas, J; López-Prats, M J; Díaz-Llopis, M

    2014-05-01

    A 25-year-old woman with right subacute sinusitis, complained about discomfort in her right eye. Clinical manifestations and computed tomography were suggestive of sub-periosteal orbital ethmoid wall abscess, for which the patient underwent urgent drainage. A solid tumor was found, with a positive biopsy for alveolar rhabdomyosarcoma. Complete remission and resolution of orbital symptoms were achieved with chemotherapy and radiation therapy. Alveolar orbital rhabdomyosarcoma in adults is uncommon. Rhabdomyosarcoma has a high risk of spreading. It can simulate a sinusitis, as in our patient, early diagnosis and early treatment being especially important in these patients. Copyright © 2010 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

  10. The human and murine hematopoietic stem cell niches: are they comparable?

    Science.gov (United States)

    van Pel, Melissa; Fibbe, Willem E; Schepers, Koen

    2016-04-01

    Hematopoietic stem cells (HSCs) reside in specific niches that provide various instructive cues that regulate HSC self-renewal and their development into all mature cells of the peripheral blood. Progress in this research field has largely been guided by mouse studies. However, parallel studies with human subjects, tissues, and cells, in combination with xenotransplantation experiments in immunodeficient mice, have contributed to our increased understanding of the human HSC niche. Here, we summarize our current knowledge of the various specialized subsets of both stromal and hematopoietic cells that support HSCs through cell-cell interactions and secreted factors, and the many parallels between the murine and human HSC niches. Furthermore, we discuss recent technological advances that are likely to improve our understanding of the human HSC niche, a better understanding of which may allow further identification of unique molecular and cellular pathways in the HSC niche. This information may help to further improve the outcome of HSC transplantation and refine the treatment of hematopoietic diseases. © 2015 New York Academy of Sciences.

  11. Radiation therapy of a metastatic tumour of the orbit caused by prostatic carcinoma

    International Nuclear Information System (INIS)

    Daniel, F.; Langmann, G.; Faulborn, J.; Poschauko, J.

    1994-01-01

    We report a case of metastatic carcinoma to the apex of the orbit in a 66-year old patient. Orbital metastasis occurred while the patient suffered from another metastatic activity especially in his bony structures. The orbital tumour caused rapid visual impairment because of compression of the optic nerve. The metastasis was treated by radiation therapy. With CT-scan, electrophysiological examination, visual field examination, and visual function we demonstrate the regression of the tumour. One year after therapy the tumor was no longer detectable. Visual function had recovered and visual fields were normally. Radiation therapy prolonged high quality life for our patient due to preservation of visual function. (authors)

  12. Aging of hematopoietic stem cells: DNA damage and mutations?

    Science.gov (United States)

    Moehrle, Bettina M; Geiger, Hartmut

    2016-10-01

    Aging in the hematopoietic system and the stem cell niche contributes to aging-associated phenotypes of hematopoietic stem cells (HSCs), including leukemia and aging-associated immune remodeling. Among others, the DNA damage theory of aging of HSCs is well established, based on the detection of a significantly larger amount of γH2AX foci and a higher tail moment in the comet assay, both initially thought to be associated with DNA damage in aged HSCs compared with young cells, and bone marrow failure in animals devoid of DNA repair factors. Novel data on the increase in and nature of DNA mutations in the hematopoietic system with age, the quality of the DNA damage response in aged HSCs, and the nature of γH2AX foci question a direct link between DNA damage and the DNA damage response and aging of HSCs, and rather favor changes in epigenetics, splicing-factors or three-dimensional architecture of the cell as major cell intrinsic factors of HSCs aging. Aging of HSCs is also driven by a strong contribution of aging of the niche. This review discusses the DNA damage theory of HSC aging in the light of these novel mechanisms of aging of HSCs. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  13. Placenta as a source of hematopoietic stem cells

    NARCIS (Netherlands)

    E.A. Dzierzak (Elaine); C. Robin (Catherine)

    2010-01-01

    textabstractThe placenta is a large, highly vascularised hematopoietic tissue that functions during the embryonic and foetal development of eutherian mammals. Although recognised as the interface tissue important in the exchange of oxygen, nutrients and waste products between the foetus and mother,

  14. The Microtubule Plus-End Tracking Protein CLASP2 Is Required for Hematopoiesis and Hematopoietic Stem Cell Maintenance

    Directory of Open Access Journals (Sweden)

    Ksenija Drabek

    2012-10-01

    Full Text Available Mammalian CLASPs are microtubule plus-end tracking proteins whose essential function as regulators of microtubule behavior has been studied mainly in cultured cells. We show here that absence of murine CLASP2 in vivo results in thrombocytopenia, progressive anemia, and pancytopenia, due to defects in megakaryopoiesis, in erythropoiesis, and in the maintenance of hematopoietic stem cell activity. Furthermore, microtubule stability and organization are affected upon attachment of Clasp2 knockout hematopoietic stem-cell-enriched populations, and these cells do not home efficiently toward their bone marrow niche. Strikingly, CLASP2-deficient hematopoietic stem cells contain severely reduced mRNA levels of c-Mpl, which encodes the thrombopoietin receptor, an essential factor for megakaryopoiesis and hematopoietic stem cell maintenance. Our data suggest that thrombopoietin signaling is impaired in Clasp2 knockout mice. We propose that the CLASP2-mediated stabilization of microtubules is required for proper attachment, homing, and maintenance of hematopoietic stem cells and that this is necessary to sustain c-Mpl transcription.

  15. Current status of secondary leukemia following cancer chemotherapy and/or radiotherapy

    International Nuclear Information System (INIS)

    Kawashima, Kohei; Nagura, Ei-ichi.

    1990-01-01

    As part of a study on hematopoietic effects of A-bombing, a nationwide questionnaire survey was made in 1,487 facilities to analyze secondary leukemia. A total of 232 patients, who were reported to have developed secondary hematopoietic or solid tumor, were eligible for this study. For 62 each evaluable male and female patients, the most common primary solid cancer was gastric cancer (27/62) for men; and breast cancer (25/62) and urinary cancer (27/62) for women. Of a total of 124 patients, 73 (59%) developed acute leukemia as secondary hematopoietic tumor, 53 of whom had underwent chemotherapy and/or radiotherapy for primary cancer. For primary hematopoietic tumor seen in 90 patients, non-Hodgkin's disease was the most common (38%, 34/90), followed by multiple myeloma (20%, 18/90). Of a total of 155 patients developing secondary hematopoietic tumor, 111 had received chemotherapy and/or radiotherapy. Chemotherapy or radiotherapy for primary cancer may have the potential risk for developing secondary cancer. (N.K.)

  16. Melanotic neuroectodermal primitive tumor of infancy. Report of a case

    International Nuclear Information System (INIS)

    Suarez Mattos, Amaranto; Restrepo, Ligia; Penagos, Pedro; Rubio, Alba

    2002-01-01

    The melanotic neuroectodermal tumor of infancy is a rare neoplasia originated from the neural crest, it is frequently located in orofacial bones, although other localizations have been reported; occurs predominantly in infants. The behavior is benign and the treatment consists mainly in complete surgical resection. A four-month old male with an orbital tumor and intracranial extension, managed surgically with favorable outcome, is described

  17. Conversion of adipose-derived stem cells into natural killer-like cells with anti-tumor activities in nude mice.

    Directory of Open Access Journals (Sweden)

    Hongxiu Ning

    Full Text Available Efforts to develop peripheral blood-derived nature killer (NK cells into therapeutic products have been hampered by these cells' low abundance and histoincompatibility. On the other hand, derivation of NK-like cells from more abundant cell sources such as embryonic stem cells (ESCs and umbilical cord blood (UCB requires the selection of rare CD34+ cells. Thus, we sought to convert adipose-derived stem cells (ADSCs, which are abundant and natively CD34+, into NK-like cells. When grown in hematopoietic induction medium, ADSCs formed sphere clusters and expressed hematopoietic markers CD34, CD45, and KDR. Further induction in NK cell-specific medium resulted in a population of cells that expressed NK cell marker CD56, and thus termed ADSC-NK. Alternatively, the hematopoietically induced ADSCs were transduced with NK cell-specific transcription factor E4BP4 prior to induction in NK cell-specific medium. This latter population of cells, termed ADSC-NKE, expressed CD56 and additional NK cell markers such as CD16, CD94, CD158, CD314, FasL, and NKp46. ADSC-NKE was as potent as NK leukemia cell NKL in killing breast cancer cell MCF7 and prostate cancer cells DU145, PC3, LnCap, DuPro, C4-2 and CWR22, but exhibited no killing activity toward normal endothelial and smooth muscle cells. In nude mice test ADSC-NKE was able to significantly delay the progression of tumors formed by MCF7 and PC3. When injected into immunocompetent rats, ADSC-NKE was detectable in bone marrow and spleen for at least 5 weeks. Together, these results suggest that ADSCs can be converted into NK-like cells with anti-tumor activities.

  18. TLR-mediated albuminuria needs TNFα-mediated cooperativity between TLRs present in hematopoietic tissues and CD80 present on non-hematopoietic tissues in mice

    Directory of Open Access Journals (Sweden)

    Nidhi Jain

    2016-06-01

    Full Text Available Transient albuminuria induced by pathogen-associated molecular patterns (PAMPs in mice through engagement of Toll-like receptors (TLRs is widely studied as a partial model for some forms of human nephrotic syndrome (NS. In addition to TLRs, CD80 has been shown to be essential for PAMP-mediated albuminuria. However, the mechanistic relationships between TLRs, CD80 and albuminuria remain unclear. Here, we show that albuminuria and CD80-uria induced in mice by many TLR ligands are dependent on the expression of TLRs and their downstream signalling intermediate MyD88 exclusively in hematopoietic cells and, conversely, on CD80 expression exclusively in non-hematopoietic cells. TNFα is crucial for TLR-mediated albuminuria and CD80-uria, and induces CD80 expression in cultured renal podocytes. IL-10 from hematopoietic cells ameliorates TNFα production, albuminuria and CD80-uria but does not prevent TNFα-mediated induction of podocyte CD80 expression. Chitohexaose, a small molecule originally of parasite origin, mediates TLR4-dependent anti-inflammatory responses, and blocks TLR-mediated albuminuria and CD80-uria through IL-10. Thus, TNFα is a prominent mediator of renal CD80 induction and resultant albuminuria in this model, and small molecules modulating TLR-mediated inflammatory activation might have contributory or adjunct therapeutic potential in some contexts of NS development.

  19. In vitro effects of recombinant human stem cell factor on hematopoietic cells from patients with acute radiation sickness

    International Nuclear Information System (INIS)

    Li Chuansheng; Cheng Tao; Xu Yanqun

    1994-01-01

    The effects of rhSCF, rhPIXY 321, rhGM-CSF and rhIL-3 on clonal proliferation of hematopoietic cells from five cases of acute radiation sickness were studied. The results showed that rhSCF could stimulate clonal proliferation of normal hematopoietic cells and the best results were obtained when the concentration of rhSCF was 5 x 10 4 ng/L. Clonal proliferation of hematopoietic cells from four cases of acute radiation sickness was stimulated while that from one case was inhibited. Moreover, the responsiveness of cells to rhSCF was correlated with the doses of radiation. Analysis of cell surface antigen, cell morphology and histochemistry revealed that rhSCF promoted predominantly the proliferation of granulocyte-macrophage lineage. rhSCF in combination with other three factors could further enhance the clonal proliferation of hematopoietic cells. The effects of rhPIXY 321, a fusion protein of GM-CSF and IL-3, were also analysed and found it to be a novel valuable hematopoietic growth factor

  20. Accelerated postirradiation recovery of hematopoietic marrow following priming with low doses of vincristine

    International Nuclear Information System (INIS)

    Johnke, R.M.; Abernathy, R.S.

    1990-01-01

    The present investigation is a continuation of efforts to characterize the radioprotective potential of priming with vincristine (VcR). In this study, the postirradiation recovery kinetics of the marrow's hematopoietic stem cell, progenitor cell, and stromal cell compartments were monitored following exposure to a range of sublethal radiation doses to determine (a) the optimal VcR/radiation intertreatment interval for achieving maximal hematopoietic protection, (b) whether this optimal interval is influenced by the dose of radiation administered, and (c) whether the radioprotection observed involves the hematopoietic stroma. The results demonstrate that the degree of radioprotection observed was significantly influenced by the scheduling of the VcR priming dose with respect to the radiation exposure. An intertreatment interval of 24 h provided maximal radioprotective benefit irrespective of the radiation dose administered. Additionally, the radioprotection following VcR priming appeared to be more the result of an accelerated recovery in the hematopoietic stem cell and progenitor cell compartments than a change in their intrinsic radiosensitivity. The data also suggest that this accelerated recovery was not a consequence of greater radioprotection of marrow stroma. Finally, the radioprotection observed following VcR priming did not appear to involve a selective lineage response by either the erythroid or the granulomonocytic progenitor compartments

  1. Longitudinal Analysis of DNA Methylation in CD34+ Hematopoietic Progenitors in Myelodysplastic Syndrome

    DEFF Research Database (Denmark)

    Wong, Yan Fung; Micklem, Chris N; Taguchi, Masataka

    2014-01-01

    Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells (HSCs) that is often treated with DNA methyltransferase 1 (DNMT1) inhibitors (5-azacytidine [AZA], 5-aza-2'-deoxycytidine), suggesting a role for DNA methylation in disease progression. How DNMT inhibition retards disease...... regulators not expressed within the hematopoietic compartment and was distinct from that observed between healthy hematopoietic cell types. After AZA treatment, we observed only limited DNA demethylation at sites that varied between patients. This suggests that a subset of the stem cell population...... is resistant to AZA and provides a basis for disease relapse. Using gene expression data from patient samples and an in vitro AZA treatment study, we identified differentially methylated genes that can be activated following treatment and that remain silent in the CD34+ stem cell compartment of high-risk MDS...

  2. Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency

    DEFF Research Database (Denmark)

    Qasim, Waseem; Cavazzana-Calvo, Marina; Davies, E Graham

    2009-01-01

    OBJECTIVES: Leukocyte adhesion deficiency is a rare primary immune disorder caused by defects of the CD18 beta-integrin molecule on immune cells. The condition usually presents in early infancy and is characterized by deep tissue infections, leukocytosis with impaired formation of pus, and delayed...... of leukocyte adhesion deficiency who underwent hematopoietic stem-cell transplantation between 1993 and 2007 was retrospectively analyzed. Data were collected by the registries of the European Society for Immunodeficiencies/European Group for Blood and Marrow Transplantation, and the Center for International......, with full donor engraftment in 17 cases, mixed multilineage chimerism in 7 patients, and mononuclear cell-restricted chimerism in an additional 3 cases. CONCLUSIONS: Hematopoietic stem-cell transplantation offers long-term benefit in leukocyte adhesion deficiency and should be considered as an early...

  3. Depression and anxiety following hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Kuba, K; Esser, P; Mehnert, A

    2017-01-01

    In this prospective multicenter study, we investigated the course of depression and anxiety during hematopoietic stem cell transplantation (HSCT) until 5 years after transplantation adjusting for medical information. Patients were consulted before HSCT (n=239), at 3 months (n=150), 12 months (n=102...

  4. Pharmacoeconomics of Hematopoietic Stem Cell Mobilization : An Overview of Current Evidence and Gaps in the Literature

    NARCIS (Netherlands)

    Shaughnessy, Paul; Chao, Nelson; Shapiro, Jamie; Walters, Kent; McCarty, John; Abhyankar, Sunil; Shayani, Sepideh; Helmons, Pieter; Leather, Helen; Pazzalia, Amy; Pickard, Simon

    Adequate hematopoietic stem cell (HSC) mobilization and collection is required prior to proceeding with high dose chemotherapy and autologous hematopoietic stem cell transplant. Cytokines such as G-CSF, GM-CSF, and peg-filgrastim, alone or in combination with plerixafor, and after chemotherapy have

  5. Alveolar soft-part sarcoma of the orbit: a clinicopathologic analysis of seventeen cases and a review of the literature.

    Science.gov (United States)

    Font, R L; Jurco, S; Zimmerman, L E

    1982-06-01

    This is a clinicopathologic study of 17 cases of alveolar soft-part sarcoma of the orbit. The mean age of patients was 23 and the median was 18 (range, 11 months to 69 years); 13 patients (76.5 per cent) were women and four were men (ratio, 3.25:1). The right and left orbits were equally involved (eight patients each), and in one the laterality was not specified. Histologically, the tumors had a distinctive organoid pattern outlined by thin-walled capillaries and were composed of nests of large polyhedral cells with abundant, finely granular, acidophilic cytoplasm. Approximately two thirds of the tumors had diagnostic PAS-positive diastase-resistant crystalline structures. Histologically, the differential diagnosis included nonchromaffin paraganglioma, granular cell tumor, metastatic renal cell carcinoma, vascular tumor, alveolar rhabdomyosarcoma, and amelanotic malignant melanoma. Electron microscopic studies of one tumor disclosed mitochondria with abnormal cristae, increased amounts of glycogen, and cytoplasmic crystalline structures with a periodicity of 8 to 10 nm. Smaller membrane-bound electron-dense granules appeared to be precursors of the crystals. Follow-up studies showed that eight patients were alive and well (median follow-up period, 11.4 years). Six of the eight patients at the time of diagnosis were 20 years of age or younger. A ninth patient was alive and well 13 years after excision of the orbital mass and four years after bilateral thoracotomy with resection of nine pulmonary nodules. Two patients died as a result of metastatic disease, one 14 years and the other 21 years after initial orbital surgery. Two patients died of other causes, one of whom had pulmonary metastases at autopsy. The follow-up period on two recent cases was less than three years, and two patients were lost to follow-up. The disease pursued an indolent clinical course. Surgery offers the best chance to control the disease.

  6. T lymphocytes derived from human cord blood provide effective antitumor immunotherapy against a human tumor

    Directory of Open Access Journals (Sweden)

    Kim Tae-Sik

    2011-06-01

    Full Text Available Abstract Background Although the graft-versus-tumor (GVT effect of donor-derived T cells after allogeneic hematopoietic stem cell transplantation has been used as an effective adoptive immunotherapy, the antitumor effects of cord blood (CB transplantation have not been well studied. Methods We established the animal model by transplantation of CB mononuclear cells and/or tumor cells into NOD/SCID mice. The presence of CB derived T cells in NOD/SCID mice or tumor tissues were determined by flow cytometric and immunohistochemical analysis. The anti-tumor effects of CB derived T cells against tumor was determined by tumor size and weight, and by the cytotoxicity assay and ELISPOT assay of T cells. Results We found dramatic tumor remission following transfer of CB mononuclear cells into NOD/SCID mice with human cervical tumors with a high infiltration of CD3+ T cells in tumors. NOD/SCID mice that receive neonatal CB transplants have reconstituted T cells with significant antitumor effects against human cervical and lung tumors, with a high infiltration of CD3+ T cells showing dramatic induction of apoptotic cell death. We also confirmed that T cells showed tumor specific antigen cytotoxicity in vitro. In adoptive transfer of CD3+ T cells into mice with pre-established tumors, we observed much higher antitumor effects of HPV-specific T cells by ELISPOT assays. Conclusions Our results show that CB derived T lymphocytes will be useful for novel immunotherapeutic candidate cells for therapy of several tumors in clinic.

  7. Ionizing radiation induces apoptosis in hematopoietic stem and progenitor cells

    International Nuclear Information System (INIS)

    Meng, A.; Zhou, D.; Geiger, H.; Zant, G.V.

    2003-01-01

    The aims of this study was to determine if ionizing radiation (IR) induces apoptosis in hematopoietic stem (HSC) and progenitor cells. Lin-cells were isolated from mouse bone marrow (BM) and pretreated with vehicle or 100 μM z-VAD 1 h prior to exposure to 4 Gy IR. The apoptotic and/or necrotic responses of these cells to IR were analyzed by measuring the annexin V and/or 7-AAD staining in HSC and progenitor populations using flow cytometry, and hematopoietic function of these cells was determined by CAFC assay. Exposure of Lin-cells to IR selectively decreased the numbers of HSC and progenitors in association with an increase in apoptosis in a time-dependent manner. Pretreatment of Lin- cells with z-VAD significantly inhibited IR-induced apoptosis and the decrease in the numbers of HSC and progenitors. However, IR alone or in combination with z-VAD did not lead to a significant increase in necrotic cell death in either HSC or progenitors. In addition, pretreatment of BM cells with z-VAD significantly attenuated IR-induced reduction in the frequencies of day-7, -28 and -35 CAFC. Exposure of HSC and progenitors to IR induces apoptosis. The induction of HSC and progenitor apoptosis contributes to IR-induced suppression of their hematopoietic function

  8. Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO3

    Science.gov (United States)

    Rimmelé, Pauline; Liang, Raymond; Bigarella, Carolina L; Kocabas, Fatih; Xie, Jingjing; Serasinghe, Madhavika N; Chipuk, Jerry; Sadek, Hesham; Zhang, Cheng Cheng; Ghaffari, Saghi

    2015-01-01

    Hematopoietic stem cells (HSC) are primarily dormant but have the potential to become highly active on demand to reconstitute blood. This requires a swift metabolic switch from glycolysis to mitochondrial oxidative phosphorylation. Maintenance of low levels of reactive oxygen species (ROS), a by-product of mitochondrial metabolism, is also necessary for sustaining HSC dormancy. Little is known about mechanisms that integrate energy metabolism with hematopoietic stem cell homeostasis. Here, we identify the transcription factor FOXO3 as a new regulator of metabolic adaptation of HSC. ROS are elevated in Foxo3−/− HSC that are defective in their activity. We show that Foxo3−/− HSC are impaired in mitochondrial metabolism independent of ROS levels. These defects are associated with altered expression of mitochondrial/metabolic genes in Foxo3−/− hematopoietic stem and progenitor cells (HSPC). We further show that defects of Foxo3−/− HSC long-term repopulation activity are independent of ROS or mTOR signaling. Our results point to FOXO3 as a potential node that couples mitochondrial metabolism with HSC homeostasis. These findings have critical implications for mechanisms that promote malignant transformation and aging of blood stem and progenitor cells. PMID:26209246

  9. Quantitative analysis by next generation sequencing of hematopoietic stem and progenitor cells (LSK and of splenic B cells transcriptomes from wild-type and Usp3-knockout mice

    Directory of Open Access Journals (Sweden)

    Cesare Lancini

    2016-03-01

    Full Text Available The data described here provide genome-wide expression profiles of murine primitive hematopoietic stem and progenitor cells (LSK and of B cell populations, obtained by high throughput sequencing. Cells are derived from wild-type mice and from mice deficient for the ubiquitin-specific protease 3 (USP3; Usp3Δ/Δ. Modification of histone proteins by ubiquitin plays a crucial role in the cellular response to DNA damage (DDR (Jackson and Durocher, 2013 [1]. USP3 is a histone H2A deubiquitinating enzyme (DUB that regulates ubiquitin-dependent DDR in response to DNA double-strand breaks (Nicassio et al., 2007; Doil et al., 2008 [2,3]. Deletion of USP3 in mice increases the incidence of spontaneous tumors and affects hematopoiesis [4]. In particular, Usp3-knockout mice show progressive loss of B and T cells and decreased functional potential of hematopoietic stem cells (HSCs during aging. USP3-deficient cells, including HSCs, display enhanced histone ubiquitination, accumulate spontaneous DNA damage and are hypersensitive to ionizing radiation (Lancini et al., 2014 [4]. To address whether USP3 loss leads to deregulation of specific molecular pathways relevant to HSC homeostasis and/or B cell development, we have employed the RNA-sequencing technology and investigated transcriptional differences between wild-type and Usp3Δ/Δ LSK, naïve B cells or in vitro activated B cells. The data relate to the research article “Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells” (Lancini et al., 2014 [4]. The RNA-sequencing and analysis data sets have been deposited in NCBI׳s Gene Expression Omnibus (Edgar et al., 2002 [5] and are accessible through GEO Series accession number GSE58495 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE58495. With this article, we present validation of the RNA-seq data set through quantitative real-time PCR and comparative analysis. Keywords: B

  10. Fanconi anemia genes are highly expressed in primitive CD34+ hematopoietic cells

    Directory of Open Access Journals (Sweden)

    Brodeur Isabelle

    2003-06-01

    Full Text Available Abstract Background Fanconi anemia (FA is a complex recessive genetic disease characterized by progressive bone marrow failure (BM and a predisposition to cancer. We have previously shown using the Fancc mouse model that the progressive BM failure results from a hematopoietic stem cell defect suggesting that function of the FA genes may reside in primitive hematopoietic stem cells. Methods Since genes involved in stem cell differentiation and/or maintenance are usually regulated at the transcription level, we used a semiquantitative RT-PCR method to evaluate FA gene transcript levels in purified hematopoietic stem cells. Results We show that most FA genes are highly expressed in primitive CD34-positive and negative cells compared to lower levels in more differentiated cells. However, in CD34- stem cells the Fancc gene was found to be expressed at low levels while Fancg was undetectable in this population. Furthermore, Fancg expression is significantly decreased in Fancc -/- stem cells as compared to wild-type cells while the cancer susceptibility genes Brca1 and Fancd1/Brac2 are upregulated in Fancc-/- hematopoietic cells. Conclusions These results suggest that FA genes are regulated at the mRNA level, that increased Fancc expression in LTS-CD34+ cells correlates with a role at the CD34+ differentiation stage and that lack of Fancc affects the expression of other FA gene, more specifically Fancg and Fancd1/Brca2, through an unknown mechanism.

  11. Haemopedia: An Expression Atlas of Murine Hematopoietic Cells

    Directory of Open Access Journals (Sweden)

    Carolyn A. de Graaf

    2016-09-01

    Full Text Available Hematopoiesis is a multistage process involving the differentiation of stem and progenitor cells into distinct mature cell lineages. Here we present Haemopedia, an atlas of murine gene-expression data containing 54 hematopoietic cell types, covering all the mature lineages in hematopoiesis. We include rare cell populations such as eosinophils, mast cells, basophils, and megakaryocytes, and a broad collection of progenitor and stem cells. We show that lineage branching and maturation during hematopoiesis can be reconstructed using the expression patterns of small sets of genes. We also have identified genes with enriched expression in each of the mature blood cell lineages, many of which show conserved lineage-enriched expression in human hematopoiesis. We have created an online web portal called Haemosphere to make analyses of Haemopedia and other blood cell transcriptional datasets easier. This resource provides simple tools to interrogate gene-expression-based relationships between hematopoietic cell types and genes of interest.

  12. Use of magnetic resonance imaging to detect neoplastic meningitis: Limited use in leukemia and lymphoma but convincing results in solid tumors

    International Nuclear Information System (INIS)

    Pauls, Sandra; Fischer, Ann-Cathrin; Brambs, Hans-Jürgen; Fetscher, Sebastian; Höche, Wolfram; Bommer, Martin

    2012-01-01

    Background: An early diagnosis of meningitis is important to improve patients’ survival. Data about a direct comparison of cerebrospinal fluid cytology (CSF-cytology) and MRI are very limited. Therefore, the aim of this study was to compare these two diagnostic modalities in diagnosing meningitis in patients with hematopoietic and solid malignancies. Methods: In 68 patients suspicious for neoplastic meningitis, cytology and MRI (1.5 T) was performed. The meningeal, pial or intraparenchymal hyperintense signal or contrast enhancement was correlated to the final CNS diagnosis and to cytology. Results: 44 patients (64.7%) had neoplastic meningitis, 21 patients (30.9%) had non-neoplastic meningitis. The sensitivity to diagnose meningeal disease was 49.2% for MRI and 95.4% for cytology (p < 0.001). In patients with neoplastic meningitis, sensitivity was 45.5% for MRI and 93.2% for cytology (p < 0.001). In patients with infectious meningitis, sensitivity was 57.1% for MRI and 100% for cytology (p = 0.0013). In patients with solid tumors, the sensitivity was 84.6% for both diagnostic methods. The sensitivity for MRI was low in patients with leukemia (20.0%) and lymphoma (37.5%). The positive predictive value (PPV) for MRI to differentiate infectious from neoplastic meningitis was high in patients with infectious meningitis (75.0%), in patients with lymphoma (83.3%), and in patients with solid tumors (72.7%). Ppv was low in patients with leukemia (33.3%). Conclusion: Diagnostic value of MRI for diagnosing meningitis is especially limited in patients with hematopoietic malignancies. MRI better detected leptomeningeal involvement caused by solid tumors than by leukemia or lymphoma. The ppv to specify neoplastic meningitis depends on tumor subtype.

  13. Orbital lymphoma associated with Graves’ disease: A case report

    Directory of Open Access Journals (Sweden)

    Hajduković Zoran

    2014-01-01

    Full Text Available Introduction. The presence of bilateral exophthalmos and palpebral, periorbital edema associated with hyperthyroidism is most often considered as an initial sign of Graves’ ophthalmopathy. However, in up to 20% of cases, Graves’ ophthalmopathy might precede the occurrence of hyperthyroidism, which is very important to be considered in the differential diagnosis, especially if it is stated as unilateral. Among other less common causes of non-thyroid-related orbitopathy, orbital lymphoma represents rare conditions. We presented of a patient with Graves’ disease, initially manifested as bilateral orbitopathy and progressive unilateral exophthalmos caused by the marginal zone B-cell non-Hodgkin lymphoma of the orbit. Case report. A 64-yearold man with the 3-year history of bilateral Graves’ orbitopathy and hyperthyroidism underwent the left orbital decompression surgery due to the predominantly left, unilateral worsening of exophthalmos resistant to the previously applied glucocorticoid therapy. A year after the surgical treatment, a substantial exophthalmos of the left eye was again observed, signifying that other non-thyroid pathology could be involved. Orbital ultrasound was suggestive of primary orbital lymphoma, what was confirmed by orbital CT scan and the biopsy of the tumor tissue. Detailed examinations indicated that the marginal zone B-cell non-Hodgkin lymphoma extended to IV - B-b CS, IPI 3 (bone marrow infiltration: m+ orbit+. Upon the completion of the polychemiotherapy and the radiation treatment, a complete remission of the disease was achieved. Conclusion. Even when elements clearly indicate the presence of thyroid-related ophthalmopathy, disease deteriorating should raise a suspicion and always lead to imaging procedures to exclude malignancy.

  14. Bcl11a Deficiency Leads to Hematopoietic Stem Cell Defects with an Aging-like Phenotype

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    Sidinh Luc

    2016-09-01

    Full Text Available B cell CLL/lymphoma 11A (BCL11A is a transcription factor and regulator of hemoglobin switching that has emerged as a promising therapeutic target for sickle cell disease and thalassemia. In the hematopoietic system, BCL11A is required for B lymphopoiesis, yet its role in other hematopoietic cells, especially hematopoietic stem cells (HSCs remains elusive. The extensive expression of BCL11A in hematopoiesis implicates context-dependent roles, highlighting the importance of fully characterizing its function as part of ongoing efforts for stem cell therapy and regenerative medicine. Here, we demonstrate that BCL11A is indispensable for normal HSC function. Bcl11a deficiency results in HSC defects, typically observed in the aging hematopoietic system. We find that downregulation of cyclin-dependent kinase 6 (Cdk6, and the ensuing cell-cycle delay, correlate with HSC dysfunction. Our studies define a mechanism for BCL11A in regulation of HSC function and have important implications for the design of therapeutic approaches to targeting BCL11A.

  15. bantam miRNA is important for Drosophila blood cell homeostasis and a regulator of proliferation in the hematopoietic progenitor niche

    Energy Technology Data Exchange (ETDEWEB)

    Lam, Victoria; Tokusumi, Tsuyoshi; Tokusumi, Yumiko; Schulz, Robert A., E-mail: rschulz@nd.edu

    2014-10-24

    Highlights: • bantam miRNA is endogenously expressed in the hematopoietic progenitor niche. • bantam is necessary and sufficient to induce cellular proliferation in the PSC. • bantam is upstream of the Insulin Receptor signaling pathway. • A model for positive regulation of hematopoietic niche growth is proposed. - Abstract: The Drosophila hematopoietic system is utilized in this study to gain novel insights into the process of growth control of the hematopoietic progenitor niche in blood development. The niche microenvironment is an essential component controlling the balance between progenitor populations and differentiated, mature blood cells and has been shown to lead to hematopoietic malignancies in humans when misregulated. MicroRNAs are one class of regulators associated with blood malignancies; however, there remains a relative paucity of information about the role of miRNAs in the niche. Here we demonstrate that bantam miRNA is endogenously active in the Drosophila hematopoietic progenitor niche, the posterior signaling center (PSC), and functions in the primary hematopoietic organ, the lymph gland, as a positive regulator of growth. Loss of bantam leads to a significant reduction in the PSC and overall lymph gland size, as well as a loss of the progenitor population and correlative premature differentiation of mature hemocytes. Interestingly, in addition to being essential for proper lymph gland development, we have determined bantam to be a novel upstream component of the insulin signaling cascade in the PSC and have unveiled dMyc as one factor central to bantam activity. These important findings identify bantam as a new hematopoietic regulator, place it in an evolutionarily conserved signaling pathway, present one way in which it is regulated, and provide a mechanism through which it facilitates cellular proliferation in the hematopoietic niche.

  16. bantam miRNA is important for Drosophila blood cell homeostasis and a regulator of proliferation in the hematopoietic progenitor niche

    International Nuclear Information System (INIS)

    Lam, Victoria; Tokusumi, Tsuyoshi; Tokusumi, Yumiko; Schulz, Robert A.

    2014-01-01

    Highlights: • bantam miRNA is endogenously expressed in the hematopoietic progenitor niche. • bantam is necessary and sufficient to induce cellular proliferation in the PSC. • bantam is upstream of the Insulin Receptor signaling pathway. • A model for positive regulation of hematopoietic niche growth is proposed. - Abstract: The Drosophila hematopoietic system is utilized in this study to gain novel insights into the process of growth control of the hematopoietic progenitor niche in blood development. The niche microenvironment is an essential component controlling the balance between progenitor populations and differentiated, mature blood cells and has been shown to lead to hematopoietic malignancies in humans when misregulated. MicroRNAs are one class of regulators associated with blood malignancies; however, there remains a relative paucity of information about the role of miRNAs in the niche. Here we demonstrate that bantam miRNA is endogenously active in the Drosophila hematopoietic progenitor niche, the posterior signaling center (PSC), and functions in the primary hematopoietic organ, the lymph gland, as a positive regulator of growth. Loss of bantam leads to a significant reduction in the PSC and overall lymph gland size, as well as a loss of the progenitor population and correlative premature differentiation of mature hemocytes. Interestingly, in addition to being essential for proper lymph gland development, we have determined bantam to be a novel upstream component of the insulin signaling cascade in the PSC and have unveiled dMyc as one factor central to bantam activity. These important findings identify bantam as a new hematopoietic regulator, place it in an evolutionarily conserved signaling pathway, present one way in which it is regulated, and provide a mechanism through which it facilitates cellular proliferation in the hematopoietic niche

  17. Non-invasive bioluminescence imaging to monitor the immunological control of a plasmablastic lymphoma-like B cell neoplasia after hematopoietic cell transplantation.

    Directory of Open Access Journals (Sweden)

    Martin Chopra

    Full Text Available To promote cancer research and to develop innovative therapies, refined pre-clinical mouse tumor models that mimic the actual disease in humans are of dire need. A number of neoplasms along the B cell lineage are commonly initiated by a translocation recombining c-myc with the immunoglobulin heavy-chain gene locus. The translocation is modeled in the C.129S1-Igha(tm1(MycJanz/J mouse which has been previously engineered to express c-myc under the control of the endogenous IgH promoter. This transgenic mouse exhibits B cell hyperplasia and develops diverse B cell tumors. We have isolated tumor cells from the spleen of a C.129S1-Igha(tm1(MycJanz/J mouse that spontaneously developed a plasmablastic lymphoma-like disease. These cells were cultured, transduced to express eGFP and firefly luciferase, and gave rise to a highly aggressive, transplantable B cell lymphoma cell line, termed IM380. This model bears several advantages over other models as it is genetically induced and mimics the translocation that is detectable in a number of human B cell lymphomas. The growth of the tumor cells, their dissemination, and response to treatment within immunocompetent hosts can be imaged non-invasively in vivo due to their expression of firefly luciferase. IM380 cells are radioresistant in vivo and mice with established tumors can be allogeneically transplanted to analyze graft-versus-tumor effects of transplanted T cells. Allogeneic hematopoietic stem cell transplantation of tumor-bearing mice results in prolonged survival. These traits make the IM380 model very valuable for the study of B cell lymphoma pathophysiology and for the development of innovative cancer therapies.

  18. Interleukin-21 promotes thymopoiesis recovery following hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Aurélie Tormo

    2017-06-01

    Full Text Available Abstract Background Impaired T cell reconstitution remains a major deterrent in the field of bone marrow (BM transplantation (BMT due to pre-conditioning-induced damages inflicted to the thymi of recipient hosts. Given the previously reported thymo-stimulatory property of interleukin (IL-21, we reasoned that its use post-BMT could have a profound effect on de novo T cell development. Methods To evaluate the effect of IL-21 on de novo T cell development in vivo, BM derived from RAG2p-GFP mice was transplanted into LP/J mice. Lymphocyte reconstitution was first assessed using a hematological analyzer and a flow cytometer on collected blood samples. Detailed flow cytometry analysis was then performed on the BM, thymus, and spleen of transplanted animals. Finally, the effect of human IL-21 on thymopoiesis was validated in humanized mice. Results Using a major histocompatibility complex (MHC-matched allogeneic BMT model, we found that IL-21 administration improves immune reconstitution by triggering the proliferation of BM Lin−Sca1+c-kit+ (LSK subsets. The pharmacological effect of IL-21 also culminates in the recovery of both hematopoietic (thymocytes and non-hematopoietic (stromal cells within the thymi of IL-21-treated recipient animals. Although T cells derived from all transplanted groups proliferate, secrete various cytokines, and express granzyme B similarly in response to T cell receptor (TCR stimulation, full regeneration of peripheral naïve CD4+ and CD8+ T cells and normal TCRvβ distribution could only be detected in IL-21-treated recipient mice. Astonishingly, none of the recipient mice who underwent IL-21 treatment developed graft-versus-host disease (GVHD in the MHC-matched allogeneic setting while the graft-versus-tumor (GVT effect was strongly retained. Inhibition of GVHD onset could also be attributed to the enhanced generation of regulatory B cells (B10 observed in the IL-21, but not PBS, recipient mice. We also tested the

  19. Intensive chemotherapy as salvage treatment for solid tumors: focus on germ cell cancer

    International Nuclear Information System (INIS)

    Selle, F.; Gligorov, J.; Richard, S.; Khalil, A.; Alexandre, I.; Avenin, D.; Provent, S.; Soares, D.G.; Lotz, J.P.

    2014-01-01

    Germ cell tumors present contrasting biological and molecular features compared to many solid tumors, which may partially explain their unusual sensitivity to chemotherapy. Reduced DNA repair capacity and enhanced induction of apoptosis appear to be key factors in the sensitivity of germ cell tumors to cisplatin. Despite substantial cure rates, some patients relapse and subsequently die of their disease. Intensive doses of chemotherapy are used to counter mechanisms of drug resistance. So far, high-dose chemotherapy with hematopoietic stem cell support for solid tumors is used only in the setting of testicular germ cell tumors. In that indication, high-dose chemotherapy is given as the first or late salvage treatment for patients with either relapsed or progressive tumors after initial conventional salvage chemotherapy. High-dose chemotherapy is usually given as two or three sequential cycles using carboplatin and etoposide with or without ifosfamide. The administration of intensive therapy carries significant side effects and can only be efficiently and safely conducted in specialized referral centers to assure optimum patient care outcomes. In breast and ovarian cancer, most studies have demonstrated improvement in progression-free survival (PFS), but overall survival remained unchanged. Therefore, most of these approaches have been dropped. In germ cell tumors, clinical trials are currently investigating novel therapeutic combinations and active treatments. In particular, the integration of targeted therapies constitutes an important area of research for patients with a poor prognosis

  20. Intensive chemotherapy as salvage treatment for solid tumors: focus on germ cell cancer

    Energy Technology Data Exchange (ETDEWEB)

    Selle, F.; Gligorov, J. [Medical Oncology and Cellular Therapy Department, Hospital Tenon, Public Assistance Hospitals of Paris, Alliance for Cancer Research (APREC), Paris (France); Pierre & Marie Curie University (UPMC Paris VI), Paris (France); Richard, S.; Khalil, A. [Medical Oncology and Cellular Therapy Department, Hospital Tenon, Public Assistance Hospitals of Paris, Alliance for Cancer Research (APREC), Paris (France); Alexandre, I. [Medical Oncology Department, Hospital Centre of Bligny, Briis-sous-Forges (France); Avenin, D.; Provent, S.; Soares, D.G. [Medical Oncology and Cellular Therapy Department, Hospital Tenon, Public Assistance Hospitals of Paris, Alliance for Cancer Research (APREC), Paris (France); Lotz, J.P. [Medical Oncology and Cellular Therapy Department, Hospital Tenon, Public Assistance Hospitals of Paris, Alliance for Cancer Research (APREC), Paris (France); Pierre & Marie Curie University (UPMC Paris VI), Paris (France)

    2014-11-04

    Germ cell tumors present contrasting biological and molecular features compared to many solid tumors, which may partially explain their unusual sensitivity to chemotherapy. Reduced DNA repair capacity and enhanced induction of apoptosis appear to be key factors in the sensitivity of germ cell tumors to cisplatin. Despite substantial cure rates, some patients relapse and subsequently die of their disease. Intensive doses of chemotherapy are used to counter mechanisms of drug resistance. So far, high-dose chemotherapy with hematopoietic stem cell support for solid tumors is used only in the setting of testicular germ cell tumors. In that indication, high-dose chemotherapy is given as the first or late salvage treatment for patients with either relapsed or progressive tumors after initial conventional salvage chemotherapy. High-dose chemotherapy is usually given as two or three sequential cycles using carboplatin and etoposide with or without ifosfamide. The administration of intensive therapy carries significant side effects and can only be efficiently and safely conducted in specialized referral centers to assure optimum patient care outcomes. In breast and ovarian cancer, most studies have demonstrated improvement in progression-free survival (PFS), but overall survival remained unchanged. Therefore, most of these approaches have been dropped. In germ cell tumors, clinical trials are currently investigating novel therapeutic combinations and active treatments. In particular, the integration of targeted therapies constitutes an important area of research for patients with a poor prognosis.

  1. Skeletal Muscle-derived Hematopoietic Stem Cells: Muscular Dystrophy Therapy by Bone Marrow Transplantation

    OpenAIRE

    Asakura, Atsushi

    2012-01-01

    For postnatal growth and regeneration of skeletal muscle, satellite cells, a self-renewing pool of muscle stem cells, give rise to daughter myogenic precursor cells that contribute to the formation of new muscle fibers. In addition to this key myogenic cell class, adult skeletal muscle also contains hematopoietic stem cell and progenitor cell populations which can be purified as a side population (SP) fraction or as a hematopoietic marker CD45-positive cell population. These muscle-derived he...

  2. Identification of a population of cells with hematopoietic stem cell properties in mouse aorta-gonad-mesonephros cultures

    International Nuclear Information System (INIS)

    Nobuhisa, Ikuo; Ohtsu, Naoki; Okada, Seiji; Nakagata, Naomi; Taga, Tetsuya

    2007-01-01

    The aorta-gonad-mesonephros (AGM) region is a primary source of definitive hematopoietic cells in the midgestation mouse embryo. In cultures of dispersed AGM regions, adherent cells containing endothelial cells are observed first, and then non-adherent hematopoietic cells are produced. Here we report on the characterization of hematopoietic cells that emerge in the AGM culture. Based on the expression profiles of CD45 and c-Kit, we defined three cell populations: CD45 low c-Kit + cells that had the ability to form hematopoietic cell colonies in methylcellulose media and in co-cultures with stromal cells; CD45 low c-Kit - cells that showed a granulocyte morphology; CD45 high c-Kit low/- that exhibited a macrophage morphology. In co-cultures of OP9 stromal cells and freshly prepared AGM cultures, CD45 low c-Kit + cells from the AGM culture had the abilities to reproduce CD45 low c-Kit + cells and differentiate into CD45 low c-Kit - and CD45 high c-Kit low/- cells, whereas CD45 low c-Kit - and CD45 high c-Kit low/- did not produce CD45 low c-Kit + cells. Furthermore, CD45 low c-Kit + cells displayed a long-term repopulating activity in adult hematopoietic tissue when transplanted into the liver of irradiated newborn mice. These results indicate that CD45 low c-Kit + cells from the AGM culture have the potential to reconstitute multi-lineage hematopoietic cells

  3. Teratoma cístico da órbita: estudo clínico patológico: relato de caso Cystic orbital teratoma: clinicopathologic study: case report

    Directory of Open Access Journals (Sweden)

    Iluska Fagundes Andrade

    2008-06-01

    Full Text Available Apresentamos um caso de tumor orbitário congênito de grande tamanho, ocorrendo em criança recém-nascida. A paciente foi submetida a exenteração da órbita e o diagnóstico anatomopatológico foi de teratoma cístico. Os aspectos clínico-patológicos desta rara doença são comentados.We report on a case of an congenital orbital tumor of impressive size, occurring in a newborn. The patient underwent orbital exenteration with a histopathologic diagnosis of cystic teratoma. The clinicopathological aspects of such a rare disease are commented.

  4. Brown tumor mimicking maxillary sinus mucocele as the first manifestation of primary hyperparathyroidism

    DEFF Research Database (Denmark)

    Guldfred, Liviu-Adelin; Daugaard, Søren; von Buchwald, Christian

    2012-01-01

    We describe the first case of brown tumor mimicking a maxillary sinus mucocele as the first manifestation of the patient's primary hyperparathyroidism. A 34-year old woman presented with a 14 days history of elevation of the right orbit, retrobulbar pain and cheek anesthesia. The CT and MR evalua...... either giant cell granuloma or brown tumor. The finding of hyperparathyroidism confirmed the diagnosis of brown tumor. To our knowledge, this is the first report of cystic brown tumor mimicking a mucocele of the maxillary sinus....

  5. Low-dose radiation (LDR) induces hematopoietic hormesis: LDR-induced mobilization of hematopoietic progenitor cells into peripheral blood circulation.

    Science.gov (United States)

    Li, Wei; Wang, Guanjun; Cui, Jiuwei; Xue, Lu; Cai, Lu

    2004-11-01

    The aim of this study was to investigate the stimulating effect of low-dose radiation (LDR) on bone marrow hematopoietic progenitor cell (HPC) proliferation and peripheral blood mobilization. Mice were exposed to 25- to 100-mGy x-rays. Bone marrow and peripheral blood HPCs (BFU-E, CFU-GM, and c-kit+ cells) were measured, and GM-CSF, G-CSF, and IL-3 protein and mRNA expression were detected using ELISA, slot blot hybridization, and Northern blot methods. To functionally evaluate LDR-stimulated and -mobilized HPCs, repopulation of peripheral blood cells in lethally irradiated recipients after transplantation of LDR-treated donor HPCs was examined by WBC counts, animal survival, and colony-forming units in the recipient spleens (CFUs-S). 75-mGy x-rays induced a maximal stimulation for bone marrow HPC proliferation (CFU-GM and BFU-E formation) 48 hours postirradiation, along with a significant increase in HPC mobilization into peripheral blood 48 to 72 hours postradiation, as shown by increases in CFU-GM formation and proportion of c-kit+ cells in the peripheral mononuclear cells. 75-mGy x-rays also maximally induced increases in G-CSF and GM-CSF mRNA expression in splenocytes and levels of serum GM-CSF. To define the critical role of these hematopoietic-stimulating factors in HPC peripheral mobilization, direct administration of G-CSF at a dose of 300 microg/kg/day or 150 microg/kg/day was applied and found to significantly stimulate GM-CFU formation and increase c-kit+ cells in the peripheral mononuclear cells. More importantly, 75-mGy x-rays plus 150 microg/kg/day G-CSF (LDR/150-G-CSF) produced a similar effect to that of 300 microg/kg/day G-CSF alone. Furthermore, the capability of LDR-mobilized donor HPCs to repopulate blood cells was confirmed in lethally irradiated recipient mice by counting peripheral WBC and CFUs-S. These results suggest that LDR induces hematopoietic hormesis, as demonstrated by HPC proliferation and peripheral mobilization, providing a

  6. The role of apoptosis in the development of AGM hematopoietic stem cells revealed by Bcl-2 overexpression

    NARCIS (Netherlands)

    C. Orelio; K.N. Harvey; C. Miles; R.A. Oostendorp (Robert); K. van der Horn; E.A. Dzierzak (Elaine)

    2004-01-01

    textabstractApoptosis is an essential process in embryonic tissue remodeling and adult tissue homeostasis. Within the adult hematopoietic system, it allows for tight regulation of hematopoietic cell subsets. Previously, it was shown that B-cell leukemia 2 (Bcl-2) overexpression in

  7. Reexamination of the role of hematopoietic organs on the ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-08-04

    Aug 4, 2009 ... Sciences, 300 Fenglin Rd. Shanghai 200032, P.R. China. ... Key words: Hematopoietic organ, wing disc, hemocytes, surgical operation, silkworm, ... They were reared on artificial diet at 25°C under a 16 h ..... The image was.

  8. MR imaging of hematopoietic regions in bone marrow of aplastic anemia. Diagnostic usefulness of opposed phase T1-weighted images

    Energy Technology Data Exchange (ETDEWEB)

    Amano, Yasuo; Tanabe, Yoshihiro; Amano, Maki; Kumazaki, Tatsuo [Nippon Medical School, Tokyo (Japan)

    1996-01-01

    The signal intensity of hematopoietic regions in the marrow of aplastic anemia were investigated on opposed phase T1-weighted images (op-T1WI) with a 0.5-Tesla MR unit. Hematopoietic regions were classified into two groups: low intensity hematopoietic areas (LH) isointense to normal marrow and high intensity hematopoietic regions (HH) with higher intensity than normal marrow on op-T1WI. The signal intensity of LH was significantly lower than that of HH on STIR. LH converted into HH with improvement of laboratory data after therapy, whereas HH decreased with impairment of data. HH were hyperintense to cerebrospinal fluid on op-T1WI. These results indicated that the signal intensity of hematopoietic regions on op-T1WI reflected the cellularity in these regions and that aplastic anemia included hypercellular regions relative to normal marrow. (author).

  9. Identifying States along the Hematopoietic Stem Cell Differentiation Hierarchy with Single Cell Specificity via Raman Spectroscopy.

    Science.gov (United States)

    Ilin, Yelena; Choi, Ji Sun; Harley, Brendan A C; Kraft, Mary L

    2015-11-17

    A major challenge for expanding specific types of hematopoietic cells ex vivo for the treatment of blood cell pathologies is identifying the combinations of cellular and matrix cues that direct hematopoietic stem cells (HSC) to self-renew or differentiate into cell populations ex vivo. Microscale screening platforms enable minimizing the number of rare HSCs required to screen the effects of numerous cues on HSC fate decisions. These platforms create a strong demand for label-free methods that accurately identify the fate decisions of individual hematopoietic cells at specific locations on the platform. We demonstrate the capacity to identify discrete cells along the HSC differentiation hierarchy via multivariate analysis of Raman spectra. Notably, cell state identification is accurate for individual cells and independent of the biophysical properties of the functionalized polyacrylamide gels upon which these cells are cultured. We report partial least-squares discriminant analysis (PLS-DA) models of single cell Raman spectra enable identifying four dissimilar hematopoietic cell populations across the HSC lineage specification. Successful discrimination was obtained for a population enriched for long-term repopulating HSCs (LT-HSCs) versus their more differentiated progeny, including closely related short-term repopulating HSCs (ST-HSCs) and fully differentiated lymphoid (B cells) and myeloid (granulocytes) cells. The lineage-specific differentiation states of cells from these four subpopulations were accurately identified independent of the stiffness of the underlying biomaterial substrate, indicating subtle spectral variations that discriminated these populations were not masked by features from the culture substrate. This approach enables identifying the lineage-specific differentiation stages of hematopoietic cells on biomaterial substrates of differing composition and may facilitate correlating hematopoietic cell fate decisions with the extrinsic cues that

  10. Intestinal tumor suppression in ApcMin/+ mice by prostaglandin D2 receptor PTGDR

    International Nuclear Information System (INIS)

    Tippin, Brigette L; Kwong, Alan M; Inadomi, Michael J; Lee, Oliver J; Park, Jae Man; Materi, Alicia M; Buslon, Virgilio S; Lin, Amy M; Kudo, Lili C; Karsten, Stanislav L; French, Samuel W; Narumiya, Shuh; Urade, Yoshihiro; Salido, Eduardo; Lin, Henry J

    2014-01-01

    Our earlier work showed that knockout of hematopoietic prostaglandin D synthase (HPGDS, an enzyme that produces prostaglandin D 2 ) caused more adenomas in Apc Min/+ mice. Conversely, highly expressed transgenic HPGDS allowed fewer tumors. Prostaglandin D 2 (PGD 2 ) binds to the prostaglandin D 2 receptor known as PTGDR (or DP1). PGD 2 metabolites bind to peroxisome proliferator-activated receptor γ (PPARG). We hypothesized that Ptgdr or Pparg knockouts may raise numbers of tumors, if these receptors take part in tumor suppression by PGD 2 . To assess, we produced Apc Min/+ mice with and without Ptgdr knockouts (147 mice). In separate experiments, we produced Apc Min/+ mice expressing transgenic lipocalin-type prostaglandin D synthase (PTGDS), with and without heterozygous Pparg knockouts (104 mice). Homozygous Ptgdr knockouts raised total numbers of tumors by 30–40% at 6 and 14 weeks. Colon tumors were not affected. Heterozygous Pparg knockouts alone did not affect tumor numbers in Apc Min/+ mice. As mentioned above, our Pparg knockout assessment also included mice with highly expressed PTGDS transgenes. Apc Min/+ mice with transgenic PTGDS had fewer large adenomas (63% of control) and lower levels of v-myc avian myelocytomatosis viral oncogene homolog (MYC) mRNA in the colon. Heterozygous Pparg knockouts appeared to blunt the tumor-suppressing effect of transgenic PTGDS. However, tumor suppression by PGD 2 was more clearly mediated by receptor PTGDR in our experiments. The suppression mechanism did not appear to involve changes in microvessel density or slower proliferation of tumor cells. The data support a role for PGD 2 signals acting through PTGDR in suppression of intestinal tumors

  11. [Exenteration of the Orbit for Basal Cell Carcinoma].

    Science.gov (United States)

    Furdová, A; Horkovičová, K; Krčová, I; Krásnik, V

    2015-08-01

    Primary treatment of basal cell carcinoma of the lower eyelid and the inner corner is essentially surgical, but advanced lesions require extensive surgical interventions. In some cases it is necessary to continue with the mutilating surgery--exenteration of the orbit. In this work we evaluate the indications of radical solutions in patients with basal cell carcinoma invading the orbit and the subsequent possibility for individually made prosthesis to cover the defect of the cavity. Indications to exenteration of the orbit in patients with basal cell carcinoma findings in 2008-2013. Case report of 2 patients. In period 2008-20013 at the Dept. of Ophthalmology, Comenius University in Bratislava totally 221 patients with histologically confirmed basal cell carcinoma of the eyelids and the inner corner were treated. In 5 cases (2.7 %) with infiltration of the orbit the radical surgical procedure, exenteration was necessary. In 3 patients exenteration was indicated as the first surgical procedure in the treatment of basal cell carcinoma, since they had never visited ophthalmologist before only at in the stage of infiltration of the orbit (stage T4). In one case was indicated exenteration after previous surgical interventions and relapses. After healing the cavity patients got individually prepared epithesis. Surgical treatment of basal cell carcinoma involves the radical removal of the neoplasm entire eyelid and stage T1 or T2 can effectively cure virtually all tumors with satisfactory cosmetic and functional results. In advanced stages (T4 stage) by infiltrating the orbit by basal cell carcinoma exenteration of the orbit is necessary. This surgery is a serious situation for the patient and also for his relatives. Individually made prosthesis helps the patient to be enrolled to the social environment.

  12. Long-term culture and differentiation of porcine red bone marrow hematopoietic cells co-cultured with immortalized mesenchymal cells.

    Science.gov (United States)

    Garba, Abubakar; Acar, Delphine D; Roukaerts, Inge D M; Desmarets, Lowiese M B; Devriendt, Bert; Nauwynck, Hans J

    2017-09-01

    Mesenchymal cells are multipotent stromal cells with self-renewal, differentiation and immunomodulatory capabilities. We aimed to develop a co-culture model for differentiating hematopoietic cells on top of immortalized mesenchymal cells for studying interactions between hematopoietic and mesenchymal cells, useful for adequately exploring the therapeutic potential of mesenchymal cells. In this study, we investigated the survival, proliferation and differentiation of porcine red bone marrow hematopoietic cells co-cultured with immortalized porcine bone marrow mesenchymal cells for a period of five weeks. Directly after collection, primary porcine bone marrow mesenchymal cells adhered firmly to the bottom of the culture plates and showed a fibroblast-like appearance, one week after isolation. Upon immortalization, porcine bone marrow mesenchymal cells were continuously proliferating. They were positive for simian virus 40 (SV40) large T antigen and the mesenchymal cell markers CD44 and CD55. Isolated red bone marrow cells were added to these immortalized mesenchymal cells. Five weeks post-seeding, 92±6% of the red bone marrow hematopoietic cells were still alive and their number increased 3-fold during five weekly subpassages on top of the immortalized mesenchymal cells. The red bone marrow hematopoietic cells were originally small and round; later, the cells increased in size. Some of them became elongated, while others remained round. Tiny dendrites appeared attaching hematopoietic cells to the underlying immortalized mesenchymal cells. Furthermore, weekly differential-quick staining of the cells indicated the presence of monoblasts, monocytes, macrophages and lymphocytes in the co-cultures. At three weeks of co-culture, flow cytometry analysis showed an increased surface expression of CD172a, CD14, CD163, CD169, CD4 and CD8 up to 37±0.8%, 40±8%, 41±4%, 23±3% and 19±5% of the hematopoietic cells, respectively. In conclusion, continuous mesenchymal cell

  13. Gene editing in hematopoietic stem cells: a potential therapeutic approach for Fanconi anemia

    International Nuclear Information System (INIS)

    Diez Cabezas, B.

    2015-01-01

    Gene therapy nowadays constitutes a safe and efficient treatment for a number of monogenic diseases affecting the hematopoietic system. Risks of insertional mutagenesis derived from the use of integrative vectors cannot, however, be completely excluded. Therefore, gene targeting has been proposed as a safer alternative, since the insertion of the herapeutic gene is driven to a specific locus in the genome. Gene targeting approaches are based on the use of specific nucleases which generate double strand breaks (DSBs) in a specific site of the genome,markedly enhancing the efficacy of homologous recombination (HR) with donor constructs harboring the gene of interest flanked by the corresponding homology arms. In this study we have optimized the conditions to target human lymphoblastic cell lines (LCLs) and also hematopoietic stem cells (HSCs) from healthy donors, with the final aim of correcting by gene editing the hematopoietic progenitor cells from Fanconi anemia subtype A (FA-A) patients. In particular, we have established a robust method to target both LCLs and HSCs in a safe harbor site in the genome, the AAVS1 locus. Our approach is based on the transduction of these cells with integrase-defective lentiviral vectors carrying a donor with the gene of interest, followed by the nucleofection of these cells with zinc finger nucleases used as mRNA. Using a control donor vector carrying the GFP reporter gene we have obtained, on average, 9.43% gene targeting efficiency in cord blood CD34+ cells from healthy donors. Moreover, we confirmed that gene targeting was also efficient in HSCs with long term and multipotent repopulation capacity, as demonstrated by transplants into immunodeficient mice. To improve the gene targeting efficiency, we investigated the feasibility of using gold nanoparticles, which were shown to improve the transduction efficiency of integrase-defective and competent lentiviral vectors in HSCs. This increment, however, did not lead to a higher gene

  14. Gene editing in hematopoietic stem cells: a potential therapeutic approach for Fanconi anemia

    Energy Technology Data Exchange (ETDEWEB)

    Diez Cabezas, B.

    2015-07-01

    Gene therapy nowadays constitutes a safe and efficient treatment for a number of monogenic diseases affecting the hematopoietic system. Risks of insertional mutagenesis derived from the use of integrative vectors cannot, however, be completely excluded. Therefore, gene targeting has been proposed as a safer alternative, since the insertion of the herapeutic gene is driven to a specific locus in the genome. Gene targeting approaches are based on the use of specific nucleases which generate double strand breaks (DSBs) in a specific site of the genome,markedly enhancing the efficacy of homologous recombination (HR) with donor constructs harboring the gene of interest flanked by the corresponding homology arms. In this study we have optimized the conditions to target human lymphoblastic cell lines (LCLs) and also hematopoietic stem cells (HSCs) from healthy donors, with the final aim of correcting by gene editing the hematopoietic progenitor cells from Fanconi anemia subtype A (FA-A) patients. In particular, we have established a robust method to target both LCLs and HSCs in a safe harbor site in the genome, the AAVS1 locus. Our approach is based on the transduction of these cells with integrase-defective lentiviral vectors carrying a donor with the gene of interest, followed by the nucleofection of these cells with zinc finger nucleases used as mRNA. Using a control donor vector carrying the GFP reporter gene we have obtained, on average, 9.43% gene targeting efficiency in cord blood CD34+ cells from healthy donors. Moreover, we confirmed that gene targeting was also efficient in HSCs with long term and multipotent repopulation capacity, as demonstrated by transplants into immunodeficient mice. To improve the gene targeting efficiency, we investigated the feasibility of using gold nanoparticles, which were shown to improve the transduction efficiency of integrase-defective and competent lentiviral vectors in HSCs. This increment, however, did not lead to a higher gene

  15. Hematopoietic stem cell fate through metabolic control.

    Science.gov (United States)

    Ito, Kyoko; Ito, Keisuke

    2018-05-25

    Hematopoietic stem cells (HSCs) maintain a quiescent state in the bone marrow to preserve their self-renewal capacity, but also undergo cell divisions as required. Organelles such as the mitochondria sustain cumulative damage during these cell divisions, and this damage may eventually compromise the cells' self-renewal capacity. HSC divisions result in either self-renewal or differentiation, with the balance between the two directly impacting hematopoietic homeostasis; but the heterogeneity of available HSC-enriched fractions, together with the technical challenges of observing HSC behavior, has long hindered the analysis of individual HSCs, and prevented the elucidation of this process. However, recent advances in genetic models, metabolomics analyses and single-cell approaches have revealed the contributions made to HSC self-renewal by metabolic cues, mitochondrial biogenesis, and autophagy/mitophagy, which have highlighted mitochondrial quality as a key control factor in the equilibrium of HSCs. A deeper understanding of precisely how specific modes of metabolism control HSC fate at the single cell level is therefore not only of great biological interest, but will have clear clinical implications for the development of therapies for hematological disease. Copyright © 2018. Published by Elsevier Inc.

  16. Effect of radiation dose-rate on hematopoietic cell engraftment in adult zebrafish.

    Directory of Open Access Journals (Sweden)

    Tiffany J Glass

    Full Text Available Although exceptionally high radiation dose-rates are currently attaining clinical feasibility, there have been relatively few studies reporting the biological consequences of these dose-rates in hematopoietic cell transplant (HCT. In zebrafish models of HCT, preconditioning before transplant is typically achieved through radiation alone. We report the comparison of outcomes in adult zebrafish irradiated with 20 Gy at either 25 or 800 cGy/min in the context of experimental HCT. In non-transplanted irradiated fish we observed no substantial differences between dose-rate groups as assessed by fish mortality, cell death in the kidney, endogenous hematopoietic reconstitution, or gene expression levels of p53 and ddb2 (damage-specific DNA binding protein 2 in the kidney. However, following HCT, recipients conditioned with the higher dose rate showed significantly improved donor-derived engraftment at 9 days post transplant (p ≤ 0.0001, and improved engraftment persisted at 31 days post transplant. Analysis for sdf-1a expression, as well as transplant of hematopoietic cells from cxcr4b -/- zebrafish, (odysseus, cumulatively suggest that the sdf-1a/cxcr4b axis is not required of donor-derived cells for the observed dose-rate effect on engraftment. Overall, the adult zebrafish model of HCT indicates that exceptionally high radiation dose-rates can impact HCT outcome, and offers a new system for radiobiological and mechanistic interrogation of this phenomenon. Key words: Radiation dose rate, Total Marrow Irradiation (TMI, Total body irradiation (TBI, SDF-1, Zebrafish, hematopoietic cell transplant.

  17. Improvement in the quality of hematopoietic prostaglandin D synthase crystals in a microgravity environment

    International Nuclear Information System (INIS)

    Tanaka, Hiroaki; Tsurumura, Toshiharu; Aritake, Kosuke; Furubayashi, Naoki; Takahashi, Sachiko; Yamanaka, Mari; Hirota, Erika; Sano, Satoshi; Sato, Masaru; Kobayashi, Tomoyuki; Tanaka, Tetsuo; Inaka, Koji; Urade, Yoshihiro

    2011-01-01

    Crystals of hematopoietic prostaglandin D synthase grown in microgravity show improved quality. Human hematopoietic prostaglandin synthase, one of the better therapeutic target enzymes for allergy and inflammation, was crystallized with 22 inhibitors and in three inhibitor-free conditions in microgravity. Most of the space-grown crystals showed better X-ray diffraction patterns than the terrestrially grown ones, indicating the advantage of a microgravity environment on protein crystallization, especially in the case of this protein

  18. Hematopoietic Acute Radiation Syndrome (Bone marrow syndrome, Aplastic Anemia): Molecular Mechanisms of Radiation Toxicity.

    Science.gov (United States)

    Popov, Dmitri

    Key Words: Aplastic Anemia (AA), Pluripotential Stem Cells (PSC) Introduction: Aplastic Anemia (AA) is a disorder of the pluripotential stem cells involve a decrease in the number of cells of myeloid, erythroid and megakaryotic lineage [Segel et al. 2000 ]. The etiology of AA include idiopathic cases and secondary aplastic anemia after exposure to drugs, toxins, chemicals, viral infections, lympho-proliferative diseases, radiation, genetic causes, myelodisplastic syndromes and hypoplastic anemias, thymomas, lymphomas. [Brodskyet al. 2005.,Modan et al. 1975., Szklo et al. 1975]. Hematopoietic Acute Radiation Syndrome (or Bone marrow syndrome, or Radiation-Acquired Aplastic Anemia) is the acute toxic syndrome which usually occurs with a dose of irradiation between 0.7 and 10 Gy (70- 1000 rads), depending on the species irradiated. [Waselenko et al., 2004]. The etiology of bone morrow damage from high-level radiation exposure results depends on the radiosensitivity of certain bone marrow cell lines. [Waselenko et al. 2004] Aplastic anemia after radiation exposure is a clinical syndrome that results from a marked disorder of bone marrow blood cell production. [Waselenko et al. 2004] Radiation hematotoxicity is mediated via genotoxic and other specific toxic mechanisms, leading to aplasia, cell apoptosis or necrosis, initiation via genetic mechanisms of clonal disorders, in cases such as the acute radiation-acquired form of AA. AA results from radiation injury to pluripotential and multipotential stem cells in the bone marrow. The clinical signs displayed in reticulocytopenia, anemia, granulocytopenia, monocytopenia, and thrombocytopenia. The number of marrow CD34+ cells (multipotential hematopoietic progenitors) and their derivative colony-forming unit{granulocyte-macrophage (CFU-GM) and burst forming unit {erythroid (BFU{E) are reduced markedly in patients with AA. [Guinan 2011, Brodski et al. 2005, Beutler et al.,2000] Cells expressing CD34 (CD34+ cell) are normally

  19. Neurological Findings in Myeloproliferative Neoplasms

    Directory of Open Access Journals (Sweden)

    Semra Paydas

    2013-04-01

    Full Text Available Myeloproliferative neoplasms (MPN arise from genetic deficiencies at the level of pluripotent stem cells. Each of these neoplasms is a clonal stem cell disorder with specific phenotypic, genetic and clinical properties. Age is one of the most important factors in the development of symptoms and complications associated with MPNs.High white blood cell counts in chronic myelocytic leukemia also known as leukocytosis may lead to central nervous system findings. Tumors developing outside the bone marrow named as extramedullary myeloid tumors (EMMT could be detected at the initial diagnosis or during the prognosis of the disease, which may cause neurological symptoms due to pressure of leukemic cell mass on various tissues along with spinal cord. Central nervous system involvement and thrombocytopenic hemorrhage may lead to diverse neurological symptoms and findings.Transient ischemic attack and thrombotic stroke are the most common symptoms in polycythemia vera. Besides thrombosis and hemorrage, transformation to acute leukemia can cause neurological symptoms and findings. Transient ischemic attack, thrombotic stroke and specifically hemorrage can give rise to neurological symptoms similar to MPN in essential thrombocytosis.Extramedullary hematopoiesis refers to hematopoietic centers arise in organ/tissues other than bone marrow in myelofibrosis. Extramedullar hematopoietic centers may cause intracranial involvement, spinal cord compression, seizures and hydrocephalia. Though rare, extramedullary hematopoiesis can be detected in cranial/spinal meninges, paraspinal tissue and intracerebral regions. Extramedullary hematopoiesis has been reported in peripheral neurons, choroid plexus, pituitary, orbits, orbital and lacrimal fossa and in sphenoidal sinuses. [Cukurova Med J 2013; 38(2.000: 157-169

  20. Umbilical cord bloods hematopoietic stem cells ex vivo expansion (the literature review

    Directory of Open Access Journals (Sweden)

    T. V. Shamanskaya

    2012-01-01

    Full Text Available Umbilical cord blood (CB is now an attractive source of hematopoietic stem cells (HSCs for transplantation in pediatric and adult patients with various malignant and non-malignant diseases. However, its clinical application is limited by low cells numbers in graft, which correlates with delayed engraftment, an extension of time to platelets and neutrophils recovery and increasing risk of infectious complications. Several strategies have been suggested to overcome this limitation, one of which is obtaining a sufficient number of hematopoietic progenitor cells by ex vivo expansion. Literature review about CB HSCs expansion in given article is presented.

  1. Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells

    International Nuclear Information System (INIS)

    Goto, Aya; Mouri, Akihiro; Nagai, Tomoko; Yoshimi, Akira; Ukigai, Mako; Tsubai, Tomomi; Hida, Hirotake; Ozaki, Norio; Noda, Yukihiro

    2016-01-01

    Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100 μM) and doxorubicin (0.2 µM) decreased the cell survival rate, but olanzapine (1–100 µM) did not. Under granulocytic differentiation for 5 days, clozapine, even at a concentration of 25 μM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H 4 receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H 4 receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H 4 receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H 4 receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation. - Highlights: • HL-60

  2. Strategies to Genetically Modulate Dendritic Cells to Potentiate Anti-Tumor Responses in Hematologic Malignancies

    Directory of Open Access Journals (Sweden)

    Annelisa M. Cornel

    2018-05-01

    Full Text Available Dendritic cell (DC vaccination has been investigated as a potential strategy to target hematologic malignancies, while generating sustained immunological responses to control potential future relapse. Nonetheless, few clinical trials have shown robust long-term efficacy. It has been suggested that a combination of surmountable shortcomings, such as selection of utilized DC subsets, DC loading and maturation strategies, as well as tumor-induced immunosuppression may be targeted to maximize anti-tumor responses of DC vaccines. Generation of DC from CD34+ hematopoietic stem and progenitor cells (HSPCs may provide potential in patients undergoing allogeneic HSPC transplantations for hematologic malignancies. CD34+ HSPC from the graft can be genetically modified to optimize antigen presentation and to provide sufficient T cell stimulatory signals. We here describe beneficial (gene-modifications that can be implemented in various processes in T cell activation by DC, among which major histocompatibility complex (MHC class I and MHC class II presentation, DC maturation and migration, cross-presentation, co-stimulation, and immunosuppression to improve anti-tumor responses.

  3. Oxidative stress in normal hematopoietic stem cells and leukemia.

    Science.gov (United States)

    Samimi, Azin; Kalantari, Heybatullah; Lorestani, Marzieh Zeinvand; Shirzad, Reza; Saki, Najmaldin

    2018-04-01

    Leukemia is developed following the abnormal proliferation of immature hematopoietic cells in the blood when hematopoietic stem cells lose the ability to turn into mature cells at different stages of maturation and differentiation. Leukemia initiating cells are specifically dependent upon the suppression of oxidative stress in the hypoglycemic bone marrow (BM) environment to be able to start their activities. Relevant literature was identified by a PubMed search (2000-2017) of English-language literature using the terms 'oxidative stress,' 'reactive oxygen species,' 'hematopoietic stem cell,' and 'leukemia.' The generation and degradation of free radicals is a main component of the metabolism in aerobic organisms. A certain level of ROS is required for proper cellular function, but values outside this range will result in oxidative stress (OS). Long-term overactivity of reactive oxygen species (ROS) has harmful effects on the function of cells and their vital macromolecules, including the transformation of proteins into autoantigens and increased degradation of protein/DNA, which eventually leads to the change in pathways involved in the development of cancer and several other disorders. According to the metabolic disorders of cancer, the relationship between OS changes, the viability of cancer cells, and their response to chemotherapeutic agents affecting this pathway are undeniable. Recently, studies have been conducted to determine the effect of herbal agents and cancer chemotherapy drugs on oxidative stress pathways. By emphasizing the role of oxidative stress on stem cells in the incidence of leukemia, this paper attempts to state and summarize this subject. © 2018 APMIS. Published by John Wiley & Sons Ltd.

  4. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block

    DEFF Research Database (Denmark)

    Kirstetter, Peggy; Anderson, Kristina; Porse, Bo T

    2006-01-01

    Wnt signaling increases hematopoietic stem cell self-renewal and is activated in both myeloid and lymphoid malignancies, indicating involvement in both normal and malignant hematopoiesis. We report here activated canonical Wnt signaling in the hematopoietic system through conditional expression...... of hematopoietic stem cell function was associated with decreased expression of Cdkn1a (encoding the cell cycle inhibitor p21(cdk)), Sfpi1, Hoxb4 and Bmi1 (encoding the transcription factors PU.1, HoxB4 and Bmi-1, respectively) and altered integrin expression in Lin(-)Sca-1(+)c-Kit(+) cells, whereas PU.1...... of a stable form of beta-catenin. This enforced expression led to hematopoietic failure associated with loss of myeloid lineage commitment at the granulocyte-macrophage progenitor stage; blocked erythrocyte differentiation; disruption of lymphoid development; and loss of repopulating stem cell activity. Loss...

  5. Application of Mesenchymal Stem Cells for Therapeutic Agent Delivery in Anti-tumor Treatment

    Directory of Open Access Journals (Sweden)

    Daria S. Chulpanova

    2018-03-01

    Full Text Available Mesenchymal stem cells (MSCs are non-hematopoietic progenitor cells, which can be isolated from different types of tissues including bone marrow, adipose tissue, tooth pulp, and placenta/umbilical cord blood. There isolation from adult tissues circumvents the ethical concerns of working with embryonic or fetal stem cells, whilst still providing cells capable of differentiating into various cell lineages, such as adipocytes, osteocytes and chondrocytes. An important feature of MSCs is the low immunogenicity due to the lack of co-stimulatory molecules expression, meaning there is no need for immunosuppression during allogenic transplantation. The tropism of MSCs to damaged tissues and tumor sites makes them a promising vector for therapeutic agent delivery to tumors and metastatic niches. MSCs can be genetically modified by virus vectors to encode tumor suppressor genes, immunomodulating cytokines and their combinations, other therapeutic approaches include MSCs priming/loading with chemotherapeutic drugs or nanoparticles. MSCs derived membrane microvesicles (MVs, which play an important role in intercellular communication, are also considered as a new therapeutic agent and drug delivery vector. Recruited by the tumor, MSCs can exhibit both pro- and anti-oncogenic properties. In this regard, for the development of new methods for cancer therapy using MSCs, a deeper understanding of the molecular and cellular interactions between MSCs and the tumor microenvironment is necessary. In this review, we discuss MSC and tumor interaction mechanisms and review the new therapeutic strategies using MSCs and MSCs derived MVs for cancer treatment.

  6. Longitudinal Assessment of Hematopoietic Stem Cell Transplantation and Hyposalivation

    DEFF Research Database (Denmark)

    Laaksonen, Matti; Ramseier, Adrian; Rovó, Alicia

    2011-01-01

    Hyposalivation is a common adverse effect of anti-neoplastic therapy of head and neck cancer, causing impaired quality of life and predisposition to oral infections. However, data on the effects of hematopoietic stem cell transplantation (HSCT) on salivary secretion are scarce. The present study...

  7. The 2017 World Health Organization classification of tumors of the pituitary gland: a summary.

    Science.gov (United States)

    Lopes, M Beatriz S

    2017-10-01

    The 4th edition of the World Health Organization (WHO) classification of endocrine tumors has been recently released. In this new edition, major changes are recommended in several areas of the classification of tumors of the anterior pituitary gland (adenophypophysis). The scope of the present manuscript is to summarize these recommended changes, emphasizing a few significant topics. These changes include the following: (1) a novel approach for classifying pituitary neuroendocrine tumors according to pituitary adenohypophyseal cell lineages; (2) changes to the histological grading of pituitary neuroendocrine tumors with the elimination of the term "atypical adenoma;" and (3) introduction of new entities like the pituitary blastoma and re-definition of old entities like the null-cell adenoma. This new classification is very practical and mostly based on immunohistochemistry for pituitary hormones, pituitary-specific transcription factors, and other immunohistochemical markers commonly used in pathology practice, not requiring routine ultrastructural analysis of the tumors. Evaluation of tumor proliferation potential, by mitotic count and Ki-67 labeling index, and tumor invasion is strongly recommended on individual case basis to identify clinically aggressive adenomas. In addition, the classification offers the treating clinical team information on tumor prognosis by identifying specific variants of adenomas associated with an elevated risk for recurrence. Changes in the classification of non-neuroendocrine tumors are also proposed, in particular those tumors arising in the posterior pituitary including pituicytoma, granular cell tumor of the posterior pituitary, and spindle cell oncocytoma. These changes endorse those previously published in the 2016 WHO classification of CNS tumors. Other tumors arising in the sellar region are also reviewed in detail including craniopharyngiomas, mesenchymal and stromal tumors, germ cell tumors, and hematopoietic tumors. It is

  8. Orbital irradiation for Graves' ophthalmopathy - Is it safe? A long-term follow-up study

    NARCIS (Netherlands)

    Wakelkamp, Iris M. M. J.; Tan, Hendra; Saeed, Peerooz; Schlingemann, Reinier O.; Verbraak, Frank D.; Blank, Leo E. C. M.; Prummel, Mark F.; Wiersinga, Wilmar M.

    2004-01-01

    Purpose: We evaluated the frequency of long-term complications of orbital irradiation (radiation-induced tumors, cataract, and retinopathy) in comparison with glucocorticoids. Design: We conducted a follow-up study in a cohort of 245 Graves' ophthalmopathy patients who had been treated with

  9. Regulation of the hematopoietic stem cell lifecycle by the endothelial niche.

    Science.gov (United States)

    Ramalingam, Pradeep; Poulos, Michael G; Butler, Jason M

    2017-07-01

    Hematopoietic stem cells (HSCs) predominantly reside either in direct contact or in close proximity to the vascular endothelium throughout their lifespan. From the moment of HSC embryonic specification from hemogenic endothelium, endothelial cells (ECs) act as a critical cellular-hub that regulates a vast repertoire of biological processes crucial for HSC maintenance throughout its lifespan. In this review, we will discuss recent findings in endothelial niche-mediated regulation of HSC function during development, aging and regenerative conditions. Studies employing genetic vascular models have unequivocally confirmed that ECs provide the essential instructive cues for HSC emergence during embryonic development as well as adult HSC maintenance during homeostasis and regeneration. Aging of ECs may impair their ability to maintain HSC function contributing to the development of aging-associated hematopoietic deficiencies. These findings have opened up new avenues to explore the therapeutic application of ECs. ECs can be adapted to serve as an instructive platform to expand bona fide HSCs and also utilized as a cellular therapy to promote regeneration of the hematopoietic system following myelosuppressive and myeloablative injuries. ECs provide a fertile niche for maintenance of functional HSCs throughout their lifecycle. An improved understanding of the EC-HSC cross-talk will pave the way for development of EC-directed strategies for improving HSC function during aging.

  10. Protective effect study of polysaccharides from tremella fuciformis on hematopoietic function in radiation-injured mice

    International Nuclear Information System (INIS)

    Xu Wenqing; Chinese Academy of Medical Sciences, Tianjin; Gao Wenyuan; Shen Xiu; Wang Yueying; Liu Peixun

    2006-01-01

    Objective: To study the protective effects of polysaccharides of Tremella fuciformis on hematopoietic function in radiation-injured mice. Methods; Colony-forming unit of spleen (CFU-S), number of nucleated cells in bone marrow (BMNC) and spleen index were used to investigated the effect of polysacharides from tremella fuciformis at 6 mg/kg, 12 mg/kg, 24 mg/kg on hematopoietic function of mice irradiated with 7.5 Gy 137 Cs γ-rays. Results: On the 9 the day after irradiation compared with the negative control group number of nucleated cells in bone marrow, colony-forming unit of spleen and spleen index of mice have treated with polysaccharides from Tremella fuciformis intraperitoneally for three days prior to irradiation increased markedly. Conclusion: Polysaccharides of tremella fuciformis have protective effect on hematopoietic function of radiation-injured mice. (authors)

  11. H-Ras and K-Ras Oncoproteins Induce Different Tumor Spectra When Driven by the Same Regulatory Sequences.

    Science.gov (United States)

    Drosten, Matthias; Simón-Carrasco, Lucía; Hernández-Porras, Isabel; Lechuga, Carmen G; Blasco, María T; Jacob, Harrys K C; Fabbiano, Salvatore; Potenza, Nicoletta; Bustelo, Xosé R; Guerra, Carmen; Barbacid, Mariano

    2017-02-01

    Genetic studies in mice have provided evidence that H-Ras and K-Ras proteins are bioequivalent. However, human tumors display marked differences in the association of RAS oncogenes with tumor type. Thus, to further assess the bioequivalence of oncogenic H-Ras and K-Ras, we replaced the coding region of the murine K-Ras locus with H-Ras G12V oncogene sequences. Germline expression of H-Ras G12V or K-Ras G12V from the K-Ras locus resulted in embryonic lethality. However, expression of these genes in adult mice led to different tumor phenotypes. Whereas H-Ras G12V elicited papillomas and hematopoietic tumors, K-Ras G12V induced lung tumors and gastric lesions. Pulmonary expression of H-Ras G12V created a senescence-like state caused by excessive MAPK signaling. Likewise, H-Ras G12V but not K-Ras G12V induced senescence in mouse embryonic fibroblasts. Label-free quantitative analysis revealed that minor differences in H-Ras G12V expression levels led to drastically different biological outputs, suggesting that subtle differences in MAPK signaling confer nonequivalent functions that influence tumor spectra induced by RAS oncoproteins. Cancer Res; 77(3); 707-18. ©2016 AACR. ©2016 American Association for Cancer Research.

  12. Blood on the tracks: hematopoietic stem cell-endothelial cell interactions in homing and engraftment.

    Science.gov (United States)

    Perlin, Julie R; Sporrij, Audrey; Zon, Leonard I

    2017-08-01

    Cells of the hematopoietic system undergo rapid turnover. Each day, humans require the production of about one hundred billion new blood cells for proper function. Hematopoietic stem cells (HSCs) are rare cells that reside in specialized niches and are required throughout life to produce specific progenitor cells that will replenish all blood lineages. There is, however, an incomplete understanding of the molecular and physical properties that regulate HSC migration, homing, engraftment, and maintenance in the niche. Endothelial cells (ECs) are intimately associated with HSCs throughout the life of the stem cell, from the specialized endothelial cells that give rise to HSCs, to the perivascular niche endothelial cells that regulate HSC homeostasis. Recent studies have dissected the unique molecular and physical properties of the endothelial cells in the HSC vascular niche and their role in HSC biology, which may be manipulated to enhance hematopoietic stem cell transplantation therapies.

  13. Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually.

    Science.gov (United States)

    Passweg, J R; Baldomero, H; Bader, P; Bonini, C; Cesaro, S; Dreger, P; Duarte, R F; Dufour, C; Kuball, J; Farge-Bancel, D; Gennery, A; Kröger, N; Lanza, F; Nagler, A; Sureda, A; Mohty, M

    2016-06-01

    A record number of 40 829 hematopoietic stem cell transplantation (HSCT) in 36 469 patients (15 765 allogeneic (43%), 20 704 autologous (57%)) were reported by 656 centers in 47 countries to the 2014 survey. Trends include: continued growth in transplant activity, more so in Eastern European countries than in the west; a continued increase in the use of haploidentical family donors (by 25%) and slower growth for unrelated donor HSCT. The use of cord blood as a stem cell source has decreased again in 2014. Main indications for HSCT were leukemias: 11 853 (33%; 96% allogeneic); lymphoid neoplasias; 20 802 (57%; 11% allogeneic); solid tumors; 1458 (4%; 3% allogeneic) and non-malignant disorders; 2203 (6%; 88% allogeneic). Changes in transplant activity include more allogeneic HSCT for AML in CR1, myeloproliferative neoplasm (MPN) and aplastic anemia and decreasing use in CLL; and more autologous HSCT for plasma cell disorders and in particular for amyloidosis. In addition, data on numbers of teams doing alternative donor transplants, allogeneic after autologous HSCT, autologous cord blood transplants are presented.

  14. Beneficial Effect of the Nutritional Support in Children Who Underwent Hematopoietic Stem Cell Transplant.

    Science.gov (United States)

    Koç, Nevra; Gündüz, Mehmet; Tavil, Betül; Azik, M Fatih; Coşkun, Zeynep; Yardımcı, Hülya; Uçkan, Duygu; Tunç, Bahattin

    2017-08-01

    The aim of this study was to evaluate nutritional status in children who underwent hematopoietic stem cell transplant compared with a healthy control group. A secondary aim was to utilize mid-upper arm circumference as a measure of nutritional status in these groups of children. Our study group included 40 children (18 girls, 22 boys) with mean age of 9.2 ± 4.6 years (range, 2-17 y) who underwent hematopoietic stem cell transplant. Our control group consisted of 20 healthy children (9 girls, 11 boys). The children were evaluated at admission to the hospital and followed regularly 3, 6, 9, and 12 months after discharge from the hospital. In the study group, 27 of 40 patients (67.5%) received nutritional support during hematopoietic stem cell transplant, with 15 patients (56%) receiving enteral nutrition, 6 (22%) receiving total parenteral nutrition, and 6 (22%) receiving enteral and total parenteral nutrition. Chronic malnutrition rate in the study group was 47.5% on admission to the hospital, with the control group having a rate of 20%. One year after transplant, the rate decreased to 20% in the study group and 5% in the control group. The mid-upper arm circumference was lower in children in the study group versus the control group at the beginning of the study (P groups at follow-up examinations (P > .05). During follow-up, all anthropometric measurements increased significantly in both groups. Monitoring nutritional status and initiating appropriate nutritional support improved the success of hematopoietic stem cell transplant and provided a more comfortable process during the transplant period. Furthermore, mid-upper arm circumference is a more sensitive, useful, and safer parameter that can be used to measure nutritional status of children who undergo hematopoietic stem cell transplant.

  15. Fat suppression applied to MR imaging of the pathologic orbit

    International Nuclear Information System (INIS)

    Simon, J.H.; Kido, D.K.; Ekholm, S.E.; Totterman, S.; Szumowski, J.; Manzione, J.V. Jr.; Joy, S.E.

    1987-01-01

    Previous MR studies of the normal orbit have shown that fat suppression sequences applied at the proper T1-T2 weighting will decrease artifacts from chemical shift, and can be used to enhance contrast in selected anatomic regions. The purpose of this study was to evaluate the clinical application of fat suppression to studies of the pathologic orbit. The studies included conventional imaging sequences and comparative fat suppression sequences through a range of T1-T2 weighting (repetition time [TR] 400 msec, echo time [TE]20 msec, to TR 2,000 msec, TE 90 msec), using the chopper fat suppression technique developed by J. Szumowski and D. Plewes, which requires no postprocessing and no increased scan time to achieve relatively linear fat suppression. Fat suppression was advantageous in determining tumor margins (extension through sclera); increasing diagnostic specificity (fat vs. water content); detailing anatomic relationships along bony margins (particularly in the orbital apex); and for demonstrating true thickness of optic nerve separate from adjacent cerebrospinal fluid and fibrous sheath. Disadvantages included susceptibility to motion artifact and a perception of lower quality due to lower overall orbital signal

  16. Quantitative assessment of hematopoietic chimerism by quantitative real-time polymerase chain reaction of sequence polymorphism systems after hematopoietic stem cell transplantation.

    Science.gov (United States)

    Qin, Xiao-ying; Li, Guo-xuan; Qin, Ya-zhen; Wang, Yu; Wang, Feng-rong; Liu, Dai-hong; Xu, Lan-ping; Chen, Huan; Han, Wei; Wang, Jing-zhi; Zhang, Xiao-hui; Li, Jin-lan; Li, Ling-di; Liu, Kai-yan; Huang, Xiao-jun

    2011-08-01

    Analysis of changes in recipient and donor hematopoietic cell origin is extremely useful to monitor the effect of hematopoietic stem cell transplantation (HSCT) and sequential adoptive immunotherapy by donor lymphocyte infusions. We developed a sensitive, reliable and rapid real-time PCR method based on sequence polymorphism systems to quantitatively assess the hematopoietic chimerism after HSCT. A panel of 29 selected sequence polymorphism (SP) markers was screened by real-time PCR in 101 HSCT patients with leukemia and other hematological diseases. The chimerism kinetics of bone marrow samples of 8 HSCT patients in remission and relapse situations were followed longitudinally. Recipient genotype discrimination was possible in 97.0% (98 of 101) with a mean number of 2.5 (1-7) informative markers per recipient/donor pair. Using serial dilutions of plasmids containing specific SP markers, the linear correlation (r) of 0.99, the slope between -3.2 and -3.7 and the sensitivity of 0.1% were proved reproducible. By this method, it was possible to very accurately detect autologous signals in the range from 0.1% to 30%. The accuracy of the method in the very important range of autologous signals below 5% was extraordinarily high (standard deviation real-time PCR method over short tandem repeat PCR chimerism assays is the absence of PCR competition and plateau biases, with demonstrated greater sensitivity and linearity. Finally, we prospectively analyzed bone marrow samples of 8 patients who received allografts and presented the chimerism kinetics of remission and relapse situations that illustrated the sensitivity level and the promising clinical application of this method. This SP-based real-time PCR assay provides a rapid, sensitive, and accurate quantitative assessment of mixed chimerism that can be useful in predicting graft rejection and early relapse.

  17. Unilateral Eyelid Edema as Initial Sign of Orbital Sarcoidosis

    Directory of Open Access Journals (Sweden)

    Sílvia Miguéis Picado Petrarolha

    2016-01-01

    Full Text Available Introduction. Sarcoidosis is a rare multisystemic granulomatous inflammatory disease of unknown etiology affecting the respiratory system, skin, and eyes. Sarcoidosis outside the lacrimal gland is rare. The case study concerns a patient with a final diagnosis of orbital sarcoidosis. Case Report. A 37-year-old male patient went to the ophthalmic emergency room complaining of pain in the left eye, diplopia, and decreased visual acuity. An external eye examination showed hard and cold edema of the lower eyelid, ocular motility with limitation of adduction, and discreet ipsilateral proptosis. Magnetic resonance of the orbit showed left eye proptosis and thickening and increase of soft tissues associated with heterogeneous impregnation of contrast in the infralateral region of the left eyelid. A biopsy of the lesion showed a chronic inflammatory process, with numerous compact nonnecrotizing granulomas surrounded by lamellar hyaline collagen, providing histological confirmation of sarcoidosis. Discussion. A biopsy of the orbital tumor is essential for the diagnosis of sarcoidosis, in addition to the search for systemic findings such as hilar adenopathy or parenchymal lung disease found in 90% of patients.

  18. Nicaraven attenuates radiation-induced injury in hematopoietic stem/progenitor cells in mice.

    Directory of Open Access Journals (Sweden)

    Miho Kawakatsu

    Full Text Available Nicaraven, a chemically synthesized hydroxyl radical-specific scavenger, has been demonstrated to protect against ischemia-reperfusion injury in various organs. We investigated whether nicaraven can attenuate radiation-induced injury in hematopoietic stem/progenitor cells, which is the conmen complication of radiotherapy and one of the major causes of death in sub-acute phase after accidental exposure to high dose radiation. C57BL/6 mice were exposed to 1 Gy γ-ray radiation daily for 5 days in succession (a total of 5 Gy, and given nicaraven or a placebo after each exposure. The mice were sacrificed 2 days after the last radiation treatment, and the protective effects and relevant mechanisms of nicaraven in hematopoietic stem/progenitor cells with radiation-induced damage were investigated by ex vivo examination. We found that post-radiation administration of nicaraven significantly increased the number, improved the colony-forming capacity, and decreased the DNA damage of hematopoietic stem/progenitor cells. The urinary levels of 8-oxo-2'-deoxyguanosine, a marker of DNA oxidation, were significantly lower in mice that were given nicaraven compared with those that received a placebo treatment, although the levels of intracellular and mitochondrial reactive oxygen species in the bone marrow cells did not differ significantly between the two groups. Interestingly, compared with the placebo treatment, the administration of nicaraven significantly decreased the levels of the inflammatory cytokines IL-6 and TNF-α in the plasma of mice. Our data suggest that nicaraven effectively diminished the effects of radiation-induced injury in hematopoietic stem/progenitor cells, which is likely associated with the anti-oxidative and anti-inflammatory properties of this compound.

  19. A clinical trial comparing the responses of animal tumors receiving heat sensitizing drugs prior to whole body hyperthermia

    International Nuclear Information System (INIS)

    Klein, M.K.; Forsyth, K.; Dewhirst, M.W.; Fuller, D.J.M.

    1984-01-01

    Whole body hyperthermia (WBH) has rarely been found effective in inducing complete tumor responses. Recent in vitro studies showing that heat sensitizion is possible have renewed interest in this field. In this protocol, WBH is induced via a commercially available inductive device and maintained at 42 0 C for thirty minutes. The heat sensitizing drugs, difluoromethylornithine (DFMO) methylglyoxal bis (guanylhydrazone) (MGBG) are administered 48 hours before, in accordance with in vitro studies. Goals of the study include evaluation of normal tissue toxicity and tumor response. Two normal dogs were treated to study acute toxicities before inception of the clinical trial. The gastrointestinal and hematopoietic systems were used to monitor toxicities using systems review and serial bloodwork. These studies and preliminary clinical results of observed tumor regression in dogs with lymphomas are discussed. Consistent changes in all patients included elevations in liver enzymes, creatine phosphokinase (CPK), and white blood cell counts, as well as, decreases in platelet counts. All changes were transient and clinical signs were not associated with them. Tumor volume reductions from 25% to 74% have been documented

  20. [Pott's puffy tumor: a rare complication of frontal sinusitis].

    Science.gov (United States)

    Aínsa Laguna, D; Pons Morales, S; Muñoz Tormo-Figueres, A; Vega Senra, M I; Otero Reigada, M C

    2014-05-01

    Pott's puffy tumor is a rare complication of frontal sinusitis characterized by swelling and edema in the brow due to a subperiosteal abscess associated with frontal osteomyelitis. Added complications are cellulitis by extension to the orbit and intracranial infection by posterior extension, with high risk of meningitis, intracranial abscess, and venous sinus thrombosis. Early diagnosis and aggressive medical or surgical treatment are essential for optimal recovery of affected patients. In the antibiotic age it is extremely rare, with very few cases described in the recent literature. A case is presented of a Pott inflammatory tumor in a 7 year-old boy, as a complication of acute pansinusitis who presented with front preseptal swelling and intracranial involvement with thrombosis of ophthalmic and superior orbital veins and frontal epidural abscess extending to the subarachnoid space. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

  1. 27-Hydroxycholesterol induces hematopoietic stem cell mobilization and extramedullary hematopoiesis during pregnancy.

    Science.gov (United States)

    Oguro, Hideyuki; McDonald, Jeffrey G; Zhao, Zhiyu; Umetani, Michihisa; Shaul, Philip W; Morrison, Sean J

    2017-09-01

    Extramedullary hematopoiesis (EMH) is induced during pregnancy to support rapid expansion of maternal blood volume. EMH activation requires hematopoietic stem cell (HSC) proliferation and mobilization, processes that depend upon estrogen receptor α (ERα) in HSCs. Here we show that treating mice with estradiol to model estradiol increases during pregnancy induced HSC proliferation in the bone marrow but not HSC mobilization. Treatment with the alternative ERα ligand 27-hydroxycholesterol (27HC) induced ERα-dependent HSC mobilization and EMH but not HSC division in the bone marrow. During pregnancy, 27HC levels increased in hematopoietic stem/progenitor cells as a result of CYP27A1, a cholesterol hydroxylase. Cyp27a1-deficient mice had significantly reduced 27HC levels, HSC mobilization, and EMH during pregnancy but normal bone marrow hematopoiesis and EMH in response to bleeding or G-CSF treatment. Distinct hematopoietic stresses thus induce EMH through different mechanisms. Two different ERα ligands, estradiol and 27HC, work together to promote EMH during pregnancy, revealing a collaboration of hormonal and metabolic mechanisms as well as a physiological function for 27HC in normal mice.

  2. Proceedings of the 3. Muenster symposium on late effects after tumor therapy in childhood and adolescence. Abstracts

    International Nuclear Information System (INIS)

    Willich, Normann; Boelling, Tobias

    2009-01-01

    The volume on the 3rd Muenster Symposion on late effects after tumor therapy in childhood and adolescence contains 7 contributions: Evaluation of side effects after radiotherapy in childhood and adolescence; from retrospective case reports to a perspective, multicentric and transnational approach; late effects surveillance system after childhood cancer in Germany, Austria and parts of Switzerland - update 2009; second malignant neoplasm after childhood cancer in Germany - results from the long-term follow-up of the German childhood cancer registry; secondary neoplasm after Wilm's tumor in Germany; second cancer after total-body irradiation (TBI) in childhood; late toxicity in children undergoing hematopoietic stem cell transplantation with TBI-containing conditioning regimens for hematological malignancies; radiation toxicity following busulfan/melphalan high-dose chemotherapy in the EURO-EWING-99-trials: review of GPOH data

  3. Proceedings of the 3. Muenster symposium on late effects after tumor therapy in childhood and adolescence. Abstracts

    Energy Technology Data Exchange (ETDEWEB)

    Willich, Normann; Boelling, Tobias (eds.) [Univ. Hospital Muenster (Germany). Dept. of Radiotherapy

    2009-08-15

    The volume on the 3rd Muenster Symposion on late effects after tumor therapy in childhood and adolescence contains 7 contributions: Evaluation of side effects after radiotherapy in childhood and adolescence; from retrospective case reports to a perspective, multicentric and transnational approach; late effects surveillance system after childhood cancer in Germany, Austria and parts of Switzerland - update 2009; second malignant neoplasm after childhood cancer in Germany - results from the long-term follow-up of the German childhood cancer registry; secondary neoplasm after Wilm's tumor in Germany; second cancer after total-body irradiation (TBI) in childhood; late toxicity in children undergoing hematopoietic stem cell transplantation with TBI-containing conditioning regimens for hematological malignancies; radiation toxicity following busulfan/melphalan high-dose chemotherapy in the EURO-EWING-99-trials: review of GPOH data.

  4. Noonan syndrome, PTPN11 mutations, and brain tumors. A clinical report and review of the literature.

    Science.gov (United States)

    Siegfried, Aurore; Cances, Claude; Denuelle, Marie; Loukh, Najat; Tauber, Maïté; Cavé, Hélène; Delisle, Marie-Bernadette

    2017-04-01

    Noonan syndrome (NS), an autosomal dominant disorder, is characterized by short stature, congenital heart defects, developmental delay, and facial dysmorphism. PTPN11 mutations are the most common cause of NS. PTPN11 encodes a non-receptor protein tyrosine phosphatase, SHP2. Hematopoietic malignancies and solid tumors are associated with NS. Among solid tumors, brain tumors have been described in children and young adults but remain rather rare. We report a 16-year-old boy with PTPN11-related NS who, at the age of 12, was incidentally found to have a left temporal lobe brain tumor and a cystic lesion in the right thalamus. He developed epilepsy 2 years later. The temporal tumor was surgically resected because of increasing crises and worsening radiological signs. Microscopy showed nodules with specific glioneuronal elements or glial nodules, leading to the diagnosis of dysembryoplastic neuroepithelial tumor (DNT). Immunohistochemistry revealed positive nuclear staining with Olig2 and pERK in small cells. SHP2 plays a key role in RAS/MAPK pathway signaling which controls several developmental cell processes and oncogenesis. An amino-acid substitution in the N-terminal SHP2 domain disrupts the self-locking conformation and leads to ERK activation. Glioneuronal tumors including DNTs and pilocytic astrocytomas have been described in NS. This report provides further support for the relation of DNTs with RASopathies and for the implication of RAS/MAPK pathways in sporadic low-grade glial tumors including DNTs. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  5. An evidence-based analysis of epidemiologic associations between lymphatic and hematopoietic cancers and occupational exposure to gasoline.

    Science.gov (United States)

    Keenan, J J; Gaffney, S; Gross, S A; Ronk, C J; Paustenbach, D J; Galbraith, D; Kerger, B D

    2013-10-01

    The presence of benzene in motor gasoline has been a health concern for potential increased risk of acute myelogenous leukemia and perhaps other lymphatic/hematopoietic cancers for approximately 40 years. Because of the widespread and increasing use of gasoline by consumers and the high exposure potential of occupational cohorts, a thorough understanding of this issue is important. The current study utilizes an evidence-based approach to examine whether or not the available epidemiologic studies demonstrate a strong and consistent association between occupational exposure to gasoline and lymphatic/hematopoietic cancers. Among 67 epidemiologic studies initially identified, 54 were ranked according to specific criteria relating to the relevance and robustness of each study for answering the research question. The 30 highest-ranked studies were sorted into three tiers of evidence and were analyzed for strength, specificity, consistency, temporality, dose-response trends and coherence. Meta statistics were also calculated for each general and specific lymphatic/hematopoietic cancer category with adequate data. The evidence-based analysis did not confirm any strong and consistent association between occupational exposure to gasoline and lymphatic/hematopoietic cancers based on the epidemiologic studies available to date. These epidemiologic findings, combined with the evidence showing relatively low occupational benzene vapor exposures associated with gasoline formulations during the last three decades, suggest that current motor gasoline formulations are not associated with increased lymphatic/hematopoietic cancer risks related to benzene.

  6. Role of reactive oxygen species in the radiation response of human hematopoietic stem/progenitor cells.

    Directory of Open Access Journals (Sweden)

    Masaru Yamaguchi

    Full Text Available Hematopoietic stem/progenitor cells (HSPCs, which are present in small numbers in hematopoietic tissues, can differentiate into all hematopoietic lineages and self-renew to maintain their undifferentiated phenotype. HSPCs are extremely sensitive to oxidative stressors such as anti-cancer agents, radiation, and the extensive accumulation of reactive oxygen species (ROS. The quiescence and stemness of HSPCs are maintained by the regulation of mitochondrial biogenesis, ROS, and energy homeostasis in a special microenvironment called the stem cell niche. The present study evaluated the relationship between the production of intracellular ROS and mitochondrial function during the proliferation and differentiation of X-irradiated CD34(+ cells prepared from human placental/umbilical cord blood HSPCs. Highly purified CD34(+ HSPCs exposed to X-rays were cultured in liquid and semi-solid medium supplemented with hematopoietic cytokines. X-irradiated CD34(+ HSPCs treated with hematopoietic cytokines, which promote their proliferation and differentiation, exhibited dramatically suppressed cell growth and clonogenic potential. The amount of intracellular ROS in X-irradiated CD34(+ HSPCs was significantly higher than that in non-irradiated cells during the culture period. However, neither the intracellular mitochondrial content nor the mitochondrial superoxide production was elevated in X-irradiated CD34(+ HSPCs compared with non-irradiated cells. Radiation-induced gamma-H2AX expression was observed immediately following exposure to 4 Gy of X-rays and gradually decreased during the culture period. This study reveals that X-irradiation can increase persistent intracellular ROS in human CD34(+ HSPCs, which may not result from mitochondrial ROS due to mitochondrial dysfunction, and indicates that substantial DNA double-strand breakage can critically reduce the stem cell function.

  7. CD45lowc-Kithigh cells have hematopoietic properties in the mouse aorta-gonad-mesonephros region

    International Nuclear Information System (INIS)

    Nobuhisa, Ikuo; Yamasaki, Shoutarou; Ramadan, Ahmed; Taga, Tetsuya

    2012-01-01

    Long-term reconstituting hematopoietic stem cells first arise from the aorta of the aorta-gonad-mesonephros (AGM) region in a mouse embryo. We have previously reported that in cultures of the dispersed AGM region, CD45 low c-Kit + cells possess the ability to reconstitute multilineage hematopoietic cells, but investigations are needed to show that this is not a cultured artifact and to clarify when and how this population is present. Based on the expression profile of CD45 and c-Kit in freshly dissociated AGM cells from embryonic day 9.5 (E9.5) to E12.5 and aorta cells in the AGM from E13.5 to E15.5, we defined six cell populations (CD45 − c-Kit − , CD45 − c-Kit low , CD45 − c-Kit high , CD45 low c-Kit high , CD45 high c-Kit high , and CD45 high c-Kit very low ). Among these six populations, CD45 low c-Kit high cells were most able to form hematopoietic cell colonies, but their ability decreased after E11.5 and was undetectable at E13.5 and later. The CD45 low c-Kit high cells showed multipotency in vitro. We demonstrated further enrichment of hematopoietic activity in the Hoechst dye-effluxing side population among the CD45 low c-Kit high cells. Here, we determined that CD45 low c-Kit high cells arise from the lateral plate mesoderm using embryonic stem cell-derived differentiation system. In conclusion, CD45 low c-Kit high cells are the major hematopoietic cells of mouse AGM.

  8. A distinct hematopoietic stem cell population for rapid multilineage engraftment in nonhuman primates.

    Science.gov (United States)

    Radtke, Stefan; Adair, Jennifer E; Giese, Morgan A; Chan, Yan-Yi; Norgaard, Zachary K; Enstrom, Mark; Haworth, Kevin G; Schefter, Lauren E; Kiem, Hans-Peter

    2017-11-01

    Hematopoietic reconstitution after bone marrow transplantation is thought to be driven by committed multipotent progenitor cells followed by long-term engrafting hematopoietic stem cells (HSCs). We observed a population of early-engrafting cells displaying HSC-like behavior, which persisted long-term in vivo in an autologous myeloablative transplant model in nonhuman primates. To identify this population, we characterized the phenotype and function of defined nonhuman primate hematopoietic stem and progenitor cell (HSPC) subsets and compared these to human HSPCs. We demonstrated that the CD34 + CD45RA - CD90 + cell phenotype is highly enriched for HSCs. This population fully supported rapid short-term recovery and robust multilineage hematopoiesis in the nonhuman primate transplant model and quantitatively predicted transplant success and time to neutrophil and platelet recovery. Application of this cell population has potential in the setting of HSC transplantation and gene therapy/editing approaches. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  9. Involvement of the histamine H{sub 4} receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells

    Energy Technology Data Exchange (ETDEWEB)

    Goto, Aya; Mouri, Akihiro; Nagai, Tomoko; Yoshimi, Akira; Ukigai, Mako; Tsubai, Tomomi; Hida, Hirotake [Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503 (Japan); Ozaki, Norio [Department of Psychiatry, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Noda, Yukihiro, E-mail: ynoda@meijo-u.ac.jp [Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503 (Japan)

    2016-09-01

    Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100 μM) and doxorubicin (0.2 µM) decreased the cell survival rate, but olanzapine (1–100 µM) did not. Under granulocytic differentiation for 5 days, clozapine, even at a concentration of 25 μM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H{sub 4} receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H{sub 4} receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H{sub 4} receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H{sub 4} receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation

  10. Protein Kinase C Enzymes in the Hematopoietic and Immune Systems.

    Science.gov (United States)

    Altman, Amnon; Kong, Kok-Fai

    2016-05-20

    The protein kinase C (PKC) family, discovered in the late 1970s, is composed of at least 10 serine/threonine kinases, divided into three groups based on their molecular architecture and cofactor requirements. PKC enzymes have been conserved throughout evolution and are expressed in virtually all cell types; they represent critical signal transducers regulating cell activation, differentiation, proliferation, death, and effector functions. PKC family members play important roles in a diverse array of hematopoietic and immune responses. This review covers the discovery and history of this enzyme family, discusses the roles of PKC enzymes in the development and effector functions of major hematopoietic and immune cell types, and points out gaps in our knowledge, which should ignite interest and further exploration, ultimately leading to better understanding of this enzyme family and, above all, its role in the many facets of the immune system.

  11. Definitive hematopoietic stem/progenitor cells manifest distinct differentiation output in the zebrafish VDA and PBI.

    Science.gov (United States)

    Jin, Hao; Sood, Raman; Xu, Jin; Zhen, Fenghua; English, Milton A; Liu, P Paul; Wen, Zilong

    2009-02-01

    One unique feature of vertebrate definitive hematopoiesis is the ontogenic switching of hematopoietic stem cells from one anatomical compartment or niche to another. In mice, hematopoietic stem cells are believed to originate in the aorta-gonad-mesonephros (AGM), subsequently migrate to the fetal liver (FL) and finally colonize the bone marrow (BM). Yet, the differentiation potential of hematopoietic stem cells within early niches such as the AGM and FL remains incompletely defined. Here, we present in vivo analysis to delineate the differentiation potential of definitive hematopoietic stem/progenitor cells (HSPCs) in the zebrafish AGM and FL analogies, namely the ventral wall of dorsal aorta (VDA) and the posterior blood island (PBI), respectively. Cell fate mapping and analysis of zebrafish runx1(w84x) and vlad tepes (vlt(m651)) mutants revealed that HSPCs in the PBI gave rise to both erythroid and myeloid lineages. However, we surprisingly found that HSPCs in the VDA were not quiescent but were uniquely adapted to generate myeloid but not erythroid lineage cells. We further showed that such distinct differentiation output of HSPCs was, at least in part, ascribed to the different micro-environments present in these two niches. Our results highlight the importance of niche in shaping the differentiation output of developing HSPCs.

  12. The kinetic alteration of hematopoietic stem cells irradiated by ionizing radiation

    International Nuclear Information System (INIS)

    Ishikawa, Junya; Ojima, Mitsuaki; Kai, Michiaki

    2014-01-01

    Ionizing radiation (IR) brings oxidative stress, and can cause damages not only on DNA but also proteins and lipids in mammalian cells, and increases the mitochondria-dependent generation of reactive oxygen species (ROS), with the subsequent induction of cell death, cell cycle arrest, and stress related responses. It is well known that IR induces acute myeloid leukemia that originates in hematopoietic cells. However, the mechanisms of leukemogenesis following IR remain unclear. To clarify these mechanisms, it is necessary to quantify the several biological events induced by IR in hematopoietic stem/progenitor cells. In this review, we focus and summarize several recent findings, especially survival/clonogenic potential, cell cycle distribution, generation of ROS, DNA damage/repair, chromosomal abbreviation, and senescence. (author)

  13. Hormone Use for Therapeutic Amenorrhea and Contraception During Hematopoietic Cell Transplantation

    Science.gov (United States)

    Chang, Katherine; Merideth, Melissa A.; Stratton, Pamela

    2015-01-01

    There is a growing population of women who have or will undergo hematopoietic stem cell transplant for a variety of malignant and benign conditions. Gynecologists play an important role in addressing the gynecologic and reproductive health concerns for these women throughout the transplant process. As women undergo cell transplantation, they should avoid becoming pregnant and are at risk of uterine bleeding. Thus, counseling about and implementing hormonal treatments such as gonadotropin-releasing hormone agonists, combined hormonal contraceptives, and progestin-only methods help to achieve therapeutic amenorrhea and can serve as contraception during the peritransplant period. In this commentary, we summarize the timing, risks and benefits of the hormonal options just prior, during and for the year after hematopoietic stem cell transplantation. PMID:26348182

  14. Epigenetic regulation of hematopoietic stem cell aging

    International Nuclear Information System (INIS)

    Beerman, Isabel; Rossi, Derrick J.

    2014-01-01

    Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and play a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging

  15. Epigenetic regulation of hematopoietic stem cell aging

    Energy Technology Data Exchange (ETDEWEB)

    Beerman, Isabel, E-mail: isabel.beerman@childrens.harvard.edu [Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138 (United States); Department of Pediatrics, Harvard Medical School, Boston, MA 02115 (United States); Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children' s Hospital, MA 02116 (United States); Rossi, Derrick J. [Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138 (United States); Department of Pediatrics, Harvard Medical School, Boston, MA 02115 (United States); Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children' s Hospital, MA 02116 (United States)

    2014-12-10

    Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and play a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging.

  16. Nutraceutical augmentation of circulating endothelial progenitor cells and hematopoietic stem cells in human subjects.

    Science.gov (United States)

    Mikirova, Nina A; Jackson, James A; Hunninghake, Ron; Kenyon, Julian; Chan, Kyle W H; Swindlehurst, Cathy A; Minev, Boris; Patel, Amit N; Murphy, Michael P; Smith, Leonard; Ramos, Famela; Ichim, Thomas E; Riordan, Neil H

    2010-04-08

    The medical significance of circulating endothelial or hematopoietic progenitors is becoming increasing recognized. While therapeutic augmentation of circulating progenitor cells using G-CSF has resulted in promising preclinical and early clinical data for several degenerative conditions, this approach is limited by cost and inability to perform chronic administration. Stem-Kine is a food supplement that was previously reported to augment circulating EPC in a pilot study. Here we report a trial in 18 healthy volunteers administered Stem-Kine twice daily for a 2 week period. Significant increases in circulating CD133 and CD34 cells were observed at days 1, 2, 7, and 14 subsequent to initiation of administration, which correlated with increased hematopoietic progenitors as detected by the HALO assay. Augmentation of EPC numbers in circulation was detected by KDR-1/CD34 staining and colony forming assays. These data suggest Stem-Kine supplementation may be useful as a stimulator of reparative processes associated with mobilization of hematopoietic and endothelial progenitors.

  17. Experimental study on relationship between expression of SDF-1 and homing of hematopoietic cells

    International Nuclear Information System (INIS)

    Sun Suping; Cai Jianming; Xiang Yingsong; Zhao Fang; Huang Dingde; Gao Jianguo; Yang Rujun

    2002-01-01

    Objective: To investigate the role of chemo-attractant SDF-1 in of homing hematopoietic cells. Methods: A mouse allogeneic bone marrow transplantation model and double staining of immunohistochemistry were used in this study. Relationship between expression of chemo-attractant SDF-1 and of homing hematopoietic cells was observed. Results: In bone marrow, SDF-1 was mainly expressed at sites near endosteum, in microvessel endothelium, osteocytes and around donor cells. Contrast to non-irradiation group, SDF-1 was significantly expressed by osteocytes, and at sites near endosteum in the irradiation group, suggesting that pretreatment with irradiation might enhance secretion of SDF-1 by bone marrow stromal cells and SDF-1 could have a close relation with homing cells. Conclusion: Pretreatment with irradiation might be one of the stimulating factors significantly increasing the level of SDF-1 produced by bone marrow stromal cells and the chemo-attractant SDF-1 could play an important role in homing of hematopoietic cells

  18. Nutraceutical augmentation of circulating endothelial progenitor cells and hematopoietic stem cells in human subjects

    Directory of Open Access Journals (Sweden)

    Minev Boris

    2010-04-01

    Full Text Available Abstract The medical significance of circulating endothelial or hematopoietic progenitors is becoming increasing recognized. While therapeutic augmentation of circulating progenitor cells using G-CSF has resulted in promising preclinical and early clinical data for several degenerative conditions, this approach is limited by cost and inability to perform chronic administration. Stem-Kine is a food supplement that was previously reported to augment circulating EPC in a pilot study. Here we report a trial in 18 healthy volunteers administered Stem-Kine twice daily for a 2 week period. Significant increases in circulating CD133 and CD34 cells were observed at days 1, 2, 7, and 14 subsequent to initiation of administration, which correlated with increased hematopoietic progenitors as detected by the HALO assay. Augmentation of EPC numbers in circulation was detected by KDR-1/CD34 staining and colony forming assays. These data suggest Stem-Kine supplementation may be useful as a stimulator of reparative processes associated with mobilization of hematopoietic and endothelial progenitors.

  19. The Hematopoietic Stem Cell Therapy for Exploration of Space

    Science.gov (United States)

    Roach, Allana Nicole; Brezo, Jelena

    2002-01-01

    Astronauts experience severe/invasive disorders caused by space environments. These include hematological/cardiac abnormalities, bone and muscle losses, immunodeficiency, neurological disorders and cancer. While the cause of these symptoms are not yet fully delineated, one possible explanation could be the inhibition of hematopoietic stem cell (HSC) growth and hematopoiesis in space. HSCs differentiate into all types of blood cells, and growing evidence indicates that the HSCs also have the ability to transdifferentiate to various tissues, including muscle, skin, liver, neuronal cells and possibly bone. Therefore, a hypothesis was advanced in this laboratory that the hematopoietic stem cell-based therapy, herein called the hematopoietic stem cell therapy (HSCT), could mitigate some of the disorders described above. Due to the magnitude of this project our laboratory has subdivided it into 3 sections: a) HSCT for space anemia; b) HSCT for muscle and bone losses; and c) HSCT for immunodeficiency. Toward developing the HSCT protocol for space anemia, the HSC transplantation procedure was established using a mouse model of beta thalassemia. In addition, the NASA Rotating Wall Vessel (RWV) culture system was used to grow HSCs in space condition. To investigate the HSCT for muscle loss and bone loss, donor HSCs were genetically marked either by transfecting the beta-galactosidase-containing plasmid, pCMV.SPORT-beta-gal or by preparing from b-galactosidase transgenic mice. The transdifferentiation of HSCs to muscle is traced by the reporter gene expression in the hindlimb suspended mice with some positive outcome, as studied by the X-gal staining procedure. The possible structural contribution of HSCs against muscle loss is being investigated histochemically.

  20. Peripheral blood CD34+ cell count as a predictor of adequacy of hematopoietic stem cell collection for autologous transplantation

    Directory of Open Access Journals (Sweden)

    Combariza, Juan F.

    2016-10-01

    Full Text Available Introduction: In order to carry out an autologous transplantation, hematopoietic stem cells should be mobilized to peripheral blood and later collected by apheresis. The CD34+ cell count is a tool to establish the optimal time to begin the apheresis procedure. Objective: To evaluate the association between peripheral blood CD34+ cell count and the successful collection of hematopoietic stem cells. Materials and methods: A predictive test evaluation study was carried out to establish the usefulness of peripheral blood CD34+ cell count as a predictor of successful stem cell collection in patients that will receive an autologous transplantation. Results: 77 patients were included (median age: 49 years; range: 5-66. The predominant baseline diagnosis was lymphoma (53.2 %. The percentage of patients with successful harvest of hematopoietic stem cells was proportional to the number of CD34+cells in peripheral blood at the end of the mobilization procedure. We propose that more than 15 CD34+cells/μL must be present in order to achieve an adequate collection of hematopoietic stem cells. Conclusion: Peripheral blood CD34+ cell count is a useful tool to predict the successful collection of hematopoietic stem cells.

  1. Skull base tumors: a comprehensive review of transfacial swing osteotomy approaches.

    Science.gov (United States)

    Moreira-Gonzalez, Andrea; Pieper, Daniel R; Cambra, Jorge Balaguer; Simman, Richard; Jackson, Ian T

    2005-03-01

    Numerous techniques have been proposed for the resection of skull base tumors, each one unique with regard to the region exposed and degree of technical complexity. This study describes the use of transfacial swing osteotomies in accessing lesions located at various levels of the cranial base. Eight patients who underwent transfacial swings for exposure and resection of cranial base lesions between 1996 and 2002 were studied. The mandible was the choice when wide exposure of nasopharyngeal and midline skull base tumors was necessary, especially when they involved the infratemporal fossa. The midfacial swing osteotomy was an option when access to the entire clivus was necessary. An orbital swing approach was used to access large orbital tumors lying inferior to the optic nerve and posterior to the globe, a region that is often difficult to visualize. Gross total tumor excision was possible in all patients. Six patients achieved disease control and two had recurrences. The complications of cerebrospinal fluid leak, infection, hematoma, or cranial nerve damage did not occur. After surgery, some patients experienced temporary symptoms caused by local swelling. The aesthetic result was considered good. Transfacial swing osteotomies provide a wide exposure to tumors that occur in the central skull base area. Excellent knowledge of the detailed anatomy of this region is paramount to the success of this surgery. The team concept is essential; it is built around the craniofacial surgeon and an experienced skull base neurosurgeon.

  2. Radiotherapy in the management of orbital lymphoma

    International Nuclear Information System (INIS)

    Bolek, Timothy W.; Moyses, H. Michael; Marcus, Robert B.; Gorden, Lemuel; Maiese, Russell L.; Almasri, Nidal M.; Mendenhall, Nancy Price

    1999-01-01

    Purpose: This retrospective study reviews the treatment technique, disease outcome, and complications of radiotherapy used in the management of lymphoma involving the orbits. Patients and Methods: Thirty-eight patients were treated between May 1969 and January 1995, with a median follow-up of 8.3 years. All patients had biopsy-proven orbital lymphoma. Twenty patients who had limited disease were treated with curative intent, and 18 patients who had known systemic disease were treated with palliative intent. Of the 20 patients treated with curative intent, 14 had low-grade and 6 had intermediate- or high-grade disease. None received chemotherapy. Most patients received treatment with 250 kVP or 60 Co radiation, using either an en face anterior field or wedged anterior and lateral fields. Median treatment dose was 25 Gy. Lens shielding was performed if possible. For patients treated for cure, cause-specific survival and freedom from distant relapse were calculated using the Kaplan-Meier method. Results: Control of disease in the orbit was achieved in all but 1 patient, who developed an out-of-field recurrence after irradiation of a lacrimal tumor and was salvaged with further radiotherapy. In the patients treated curatively, the 5-year rate of actuarial freedom from distant relapse was 61% for those with low-grade and 33% for those with intermediate/high-grade disease (p = 0.08). Cause-specific survival at 5 years was 89% for patients with low-grade and 33% for those with intermediate/high-grade disease (p = 0.005). Two patients with low-grade disease had contralateral orbital failures; both were salvaged with further irradiation. Acute toxicity was minimal. Cataracts developed in 7 of 21 patients treated without lens shielding and 0 of 17 patients treated with lens shielding. No patient developed significant late lacrimal toxicity. Conclusion: Radiotherapy is a safe and effective local treatment in the management of orbital lymphoma

  3. Sexual function 1-year after allogeneic hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Noerskov, K. H.; Schjødt, I.; Syrjala, K. L.

    2016-01-01

    Treatment with allogeneic hematopoietic stem cell transplantation (HSCT) is associated with short and long-term toxicities that can result in alterations in sexual functioning. The aims of this prospective evaluation were to determine: (1) associations between HSCT and increased sexual dysfunction...

  4. Fetal and adult hematopoietic stem cells require beta1 integrin function for colonizing fetal liver, spleen, and bone marrow

    DEFF Research Database (Denmark)

    Potocnik, A J; Brakebusch, C; Fässler, R

    2000-01-01

    hematolymphoid differentiation potential in vitro and in fetal organ cultures but were unable to seed fetal and adult hematopoietic tissues. Adult beta1 integrin null HSCs isolated from mice carrying loxP-tagged beta1 integrin alleles and ablated for beta1 integrin expression by retroviral cre transduction......Homing of hematopoietic stem cells (HSCs) into hematopoietic organs is a prerequisite for the establishment of hematopoiesis during embryogenesis and after bone marrow transplantation. We show that beta1 integrin-deficient HSCs from the para-aortic splanchnopleura and the fetal blood had...

  5. Knockdown of Fanconi anemia genes in human embryonic stem cells reveals early developmental defects in the hematopoietic lineage.

    Science.gov (United States)

    Tulpule, Asmin; Lensch, M William; Miller, Justine D; Austin, Karyn; D'Andrea, Alan; Schlaeger, Thorsten M; Shimamura, Akiko; Daley, George Q

    2010-04-29

    Fanconi anemia (FA) is a genetically heterogeneous, autosomal recessive disorder characterized by pediatric bone marrow failure and congenital anomalies. The effect of FA gene deficiency on hematopoietic development in utero remains poorly described as mouse models of FA do not develop hematopoietic failure and such studies cannot be performed on patients. We have created a human-specific in vitro system to study early hematopoietic development in FA using a lentiviral RNA interference (RNAi) strategy in human embryonic stem cells (hESCs). We show that knockdown of FANCA and FANCD2 in hESCs leads to a reduction in hematopoietic fates and progenitor numbers that can be rescued by FA gene complementation. Our data indicate that hematopoiesis is impaired in FA from the earliest stages of development, suggesting that deficiencies in embryonic hematopoiesis may underlie the progression to bone marrow failure in FA. This work illustrates how hESCs can provide unique insights into human development and further our understanding of genetic disease.

  6. Assessment of benzene-induced hematotoxicity using a human-like hematopoietic lineage in NOD/Shi-scid/IL-2Rγnull mice.

    Directory of Open Access Journals (Sweden)

    Masayuki Takahashi

    Full Text Available Despite recent advancements, it is still difficult to evaluate in vivo responses to toxicants in humans. Development of a system that can mimic the in vivo responses of human cells will enable more accurate health risk assessments. A surrogate human hematopoietic lineage can be established in NOD/Shi-scid/IL-2Rγ(null (NOG mice by transplanting human hematopoietic stem/progenitor cells (Hu-NOG mice. Here, we first evaluated the toxic response of human-like hematopoietic lineage in NOG mice to a representative toxic agent, benzene. Flow cytometric analysis showed that benzene caused a significant decrease in the number of human hematopoietic stem/progenitor cells in the bone marrow and the number of human leukocytes in the peripheral blood and hematopoietic organs. Next, we established chimeric mice by transplanting C57BL/6 mouse-derived bone marrow cells into NOG mice (Mo-NOG mice. A comparison of the degree of benzene-induced hematotoxicity in donor-derived hematopoietic lineage cells within Mo-NOG mice indicated that the toxic response of Hu-NOG mice reflected interspecies differences in susceptibilities to benzene. Responses to the toxic effects of benzene were greater in lymphoid cells than in myeloid cells in Mo-NOG and Hu-NOG mice. These findings suggested that Hu-NOG mice may be a powerful in vivo tool for assessing hematotoxicity in humans, while accounting for interspecies differences.

  7. HIF1α is a regulator of hematopoietic progenitor and stem cell development in hypoxic sites of the mouse embryo

    Directory of Open Access Journals (Sweden)

    Parisa Imanirad

    2014-01-01

    Full Text Available Hypoxia affects many physiologic processes during early stages of mammalian ontogeny, particularly placental and vascular development. In the adult, the hypoxic bone marrow microenvironment plays a role in regulating hematopoietic stem cell (HSC function. HSCs are generated from the major vasculature of the embryo, but whether the hypoxic response affects the generation of these HSCs is as yet unknown. Here we examined whether Hypoxia Inducible Factor1-alpha (HIF1α, a key modulator of the response to hypoxia, is essential for HSC development. We found hypoxic cells in embryonic tissues that generate and expand hematopoietic cells (aorta, placenta and fetal liver, and specifically aortic endothelial and hematopoietic cluster cells. A Cre/loxP conditional knockout (cKO approach was taken to delete HIF1α in Vascular Endothelial-Cadherin expressing endothelial cells, the precursors to definitive hematopoietic cells. Functional assays show that HSC and hematopoietic progenitor cells (HPCs are significantly reduced in cKO aorta and placenta. Moreover, decreases in phenotypic aortic hematopoietic cluster cells in cKO embryos indicate that HIF1α is necessary for generation and/or expansion of HPCs and HSCs. cKO adult BM HSCs are also affected under transplantation conditions. Thus, HIF1α is a regulator of HSC generation and function beginning at the earliest embryonic stages.

  8. Mean Orbital Elements for Geosynchronous Orbit - II - Orbital inclination, longitude of ascending node, mean longitude

    Directory of Open Access Journals (Sweden)

    Kyu-Hong Choi

    1990-06-01

    Full Text Available The osculating orbital elements include the mean, secular, long period, and short period terms. The iterative algorithm used for conversion of osculating orbital elements to mean orbital elements is described. The mean orbital elements of Wc, Ws, and L are obtained.

  9. Malignant tumors of the nasal cavity: computed tomography and magnetic resonance imaging

    International Nuclear Information System (INIS)

    Souza, Ricardo Pires de; Paes Junior, Ademar Jose de Oliveira; Gonzalez, Fabio Mota; Cordeiro, Flamarion de Barros; Yamashiro, Ilka; Lenh, Carlos Neutzling; Rapoport, Abrao

    2004-01-01

    The aim of this study is to evaluate the role of computed tomography and magnetic resonance imaging in the characterization of deep tissue extension of malignant tumors of the nasal cavity. Twelve patients diagnosed with malignant tumors of the nasal cavity were retrospectively evaluated at the Departments of Diagnostic Imaging and Head and Neck Surgery of the 'Complexo Hospitalar Heliopolis', Sao Paulo, Brazil, between 1990 and 2000. All cases were confirmed by histopathologic examination. The results were: extension to the maxillary and ethmoid sinuses was identified in six patients, extension to contralateral nasal cavity, orbit and lamina cribosa in five patients, extension to nasal pharynx and masticator space in two patients, extension to cavernous sinus, anterior/middle cranial fossa, pterygomaxillary fossa, inferior/superior orbital fissure, frontal sinus, contralateral ethmoid sinus, contralateral lamina cribosa, hard palate and pterygopalatine fossa in one patient. Conclusion: It is important to precisely assess the local extension and spread of tumor by computed tomography and magnetic resonance imaging in order to plan the approach to treatment, which will influence the prognosis. (author)

  10. A review of nasal, paranasal, and skull base tumors invading the orbit

    DEFF Research Database (Denmark)

    Jørgensen, Morten; Heegaard, Steffen

    2018-01-01

    of ophthalmological and otorhinolaryngological symptoms, including proptosis, pain, decreased visual acuity, restrictions in motility of the eye, epistaxis, and nasal obstruction. Sarcomas and benign bone and cartilage tumors arise from surrounding structures, whereas carcinomas usually arise from the paranasal...

  11. Validation of a Pediatric Early Warning Score in Hospitalized Pediatric Oncology and Hematopoietic Stem Cell Transplant Patients.

    Science.gov (United States)

    Agulnik, Asya; Forbes, Peter W; Stenquist, Nicole; Rodriguez-Galindo, Carlos; Kleinman, Monica

    2016-04-01

    To evaluate the correlation of a Pediatric Early Warning Score with unplanned transfer to the PICU in hospitalized oncology and hematopoietic stem cell transplant patients. We performed a retrospective matched case-control study, comparing the highest documented Pediatric Early Warning Score within 24 hours prior to unplanned PICU transfers in hospitalized pediatric oncology and hematopoietic stem cell transplant patients between September 2011 and December 2013. Controls were patients who remained on the inpatient unit and were matched 2:1 using age, condition (oncology vs hematopoietic stem cell transplant), and length of hospital stay. Pediatric Early Warning Scores were documented by nursing staff at least every 4 hours as part of routine care. Need for transfer was determined by a PICU physician called to evaluate the patient. A large tertiary/quaternary free-standing academic children's hospital. One hundred ten hospitalized pediatric oncology patients (42 oncology, 68 hematopoietic stem cell transplant) requiring unplanned PICU transfer and 220 matched controls. None. Using the highest score in the 24 hours prior to transfer for cases and a matched time period for controls, the Pediatric Early Warning Score was highly correlated with the need for PICU transfer overall (area under the receiver operating characteristic = 0.96), and in the oncology and hematopoietic stem cell transplant groups individually (area under the receiver operating characteristic = 0.95 and 0.96, respectively). The difference in Pediatric Early Warning Score results between the cases and controls was noted as early as 24 hours prior to PICU admission. Seventeen patients died (15.4%). Patients with higher Pediatric Early Warning Scores prior to transfer had increased PICU mortality (p = 0.028) and length of stay (p = 0.004). We demonstrate that our institution's Pediatric Early Warning Score is highly correlated with the need for unplanned PICU transfer in hospitalized oncology and

  12. Mechanism of hematopoietic stem cell homing

    International Nuclear Information System (INIS)

    Jiang Fuquan

    2000-01-01

    The clinical transplantation of hematopoietic stem cell (HSC) originating from many sources such as bone marrow, peripheral blood and cord blood has been widely applied in recent years. At the same time, the development of the study on the mechanism of HSC homing which involves multi-procedures has been achieved. And a lot of molecular and cytokines on the surface or in the microenvironment of HSC are functioning in homing. The purpose of is to review those molecular and cytokines on which more studies have been focused in the past

  13. Circulating hematopoietic progenitors and CD34+ cells predicted successful hematopoietic stem cell harvest in myeloma and lymphoma patients: experiences from a single institution

    Directory of Open Access Journals (Sweden)

    Yu JT

    2016-02-01

    Full Text Available Jui-Ting Yu,1,2,* Shao-Bin Cheng,3,* Youngsen Yang,1 Kuang-Hsi Chang,4 Wen-Li Hwang,1 Chieh-Lin Jerry Teng,1,5,6 1Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, 2Division of Hematology/Medical Oncology, Tungs' Taichung MetroHarbor Hospital, 3Division of General Surgery, Department of Surgery, 4Department of Medical Research and Education, Taichung Veterans General Hospital, 5Department of Life Science, Tunghai University, 6School of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China *These authors contributed equally to this work Background: Previous studies have shown that the numbers of both circulating hematopoietic progenitor cell (HPC and CD34+ cell are positively correlated with CD34+ cell harvest yield. However, the minimal numbers of both circulating HPCs and CD34+ cells required for performing an efficient hematopoietic stem cell (HSC harvest in lymphoma and myeloma patients have not been defined in our institution. Patients and methods: Medical records of 50 lymphoma and myeloma patients undergoing peripheral blood HSC harvest in our institution were retrospectively reviewed. The minimal and optimal HSC harvest yield required for the treatment was considered to be ≥2×106 CD34+ cells/kg and ≥5×106 CD34+ cells/kg, respectively. Results: The minimally required or optimal HSC yield obtained was not influenced by age (≥60 years, sex, underlying malignancies, disease status, multiple rounds of chemotherapy, or history of radiotherapy. The numbers of both circulating HPC and CD34+ cell were higher in patients with minimally required HSC yields (P=0.000 for HPC and P=0.000 for CD34+ cell and also in patients with optimal HSC yields (P=0.011 for HPC and P=0.006 for CD34+ cell. The cell count cutoff for obtaining minimally required HSC harvest was determined to be 20/mm3 for HPCs and 10/mm3 for CD34+ cells. Furthermore, the cell count cutoff for obtaining

  14. Magnetic resonance tomography of the orbit: First experiences with the paramagnetic contrast medium gadolinium-DTPA

    International Nuclear Information System (INIS)

    Markl, A.; Vogl, T.; Scheidhauer, K.; Riedel, K.G.; Oeckler, R.

    1986-01-01

    In 21 patients with orbital mass lesions MRI was performed before and after administration of paramagnetic contrast medium, gadolinium-DPTA. In comparison to the plain scan the differentiation of the tumorous tissue against the surrounding structures was improved after application of contrast medium despite a partially moderate increase in signal intensity. Especially highly vascular tumors and vessel diseases show a significant contrast enhancement. With increasing experience in larger number of patients a tissue differentiation seems to be possible. (orig.) [de

  15. Long-term propagation of distinct hematopoietic differentiation programs in vivo

    NARCIS (Netherlands)

    Dykstra, Brad; Kent, David; Bowie, Michelle; McCaffrey, Lindsay; Hamilton, Melisa; Lyons, Kristin; Lee, Shang-Jung; Brinkman, Ryan; Eaves, Connie

    Heterogeneity in the differentiation behavior of hematopoietic stem cells is well documented but poorly understood. To investigate this question at a clonal level, we isolated a subpopulation of adult mouse bone marrow that is highly enriched for multilineage in vivo repopulating cells and

  16. Lifelong dietary intervention does not affect hematopoietic stem cell function

    NARCIS (Netherlands)

    Lazare, Seka; Ausema, Albertina; Reijne, Aaffien C; van Dijk, Gertjan; van Os, Ronald; de Haan, Gerald

    Hematopoietic stem cells (HSCs) undergo a profound functional decline during normal aging. Because caloric or dietary restriction has been shown to delay multiple aspects of the aging process in many species, we explored the consequences of lifelong caloric restriction, or conversely, lifelong

  17. Interferon-gamma impairs proliferation of hematopoietic stem cells in mice

    NARCIS (Netherlands)

    de Bruin, Alexander M.; Demirel, Özlem; Hooibrink, Berend; Brandts, Christian H.; Nolte, Martijn A.

    2013-01-01

    Balancing the processes of hematopoietic stem cell (HSC) differentiation and self-renewal is critical for maintaining a lifelong supply of blood cells. The bone marrow (BM) produces a stable output of newly generated cells, but immunologic stress conditions inducing leukopenia increase the demand

  18. Indications of hematopoietic stem cell transplantations and therapeutic strategies of accidental irradiations

    International Nuclear Information System (INIS)

    2003-01-01

    Produced by a group of experts, this document first discusses the issue of accidental irradiations in terms of medical management. They notably outline the peculiar characteristics of these irradiations with respect to therapeutic irradiations. They agreed on general principles regarding casualty sorting criteria and process, and their medical treatment (systematic hematopoiesis stimulation, allogeneic transplantation of hematopoietic stem cells). They discuss some practical aspects of these issues: casualty sorting within a therapeutic perspective (actions to be performed within 48 hours), therapeutic strategies (support therapy, use of cytokines, and therapy by hematopoietic stem cell transplant). They state a set of recommendations regarding the taking into care and diagnosis, therapeutic strategies, research perspectives, and teaching

  19. Bone Marrow Suppression by c-Kit Blockade Enhances Tumor Growth of Colorectal Metastases through the Action of Stromal Cell-Derived Factor-1

    Directory of Open Access Journals (Sweden)

    Kathrin Rupertus

    2012-01-01

    Full Text Available Background. Mobilization of c-Kit+ hematopoietic cells (HCs contributes to tumor vascularization. Whereas survival and proliferation of HCs are regulated by binding of the stem cell factor to its receptor c-Kit, migration of HCs is directed by stromal cell-derived factor (SDF-1. Therefore, targeting migration of HCs provides a promising new strategy of anti-tumor therapy. Methods. BALB/c mice (=16 were pretreated with an anti-c-Kit antibody followed by implantation of CT26.WT-GFP colorectal cancer cells into dorsal skinfold chambers. Animals (=8 additionally received a neutralizing anti-SDF-1 antibody. Animals (=8 treated with a control antibody served as controls. Investigations were performed using intravital fluorescence microscopy, immunohistochemistry, flow cytometry and western blot analysis. Results. Blockade of c-Kit significantly enhanced tumor cell engraftment compared to controls due to stimulation of tumor cell proliferation and invasion without markedly affecting tumor vascularization. C-Kit blockade significantly increased VEGF and CXCR4 expression within the growing tumors. Neutralization of SDF-1 completely antagonized this anti-c-Kit-associated tumor growth by suppression of tumor neovascularization, inhibition of tumor cell proliferation and reduction of muscular infiltration. Conclusion. Our study indicates that bone marrow suppression via anti-c-Kit pretreatment enhances tumor cell engraftment of colorectal metastases due to interaction with the SDF-1/CXCR4 pathway which is involved in HC-mediated tumor angiogenesis.

  20. PyORBIT: A Python Shell For ORBIT

    Energy Technology Data Exchange (ETDEWEB)

    Jean-Francois Ostiguy; Jeffrey Holmes

    2003-07-01

    ORBIT is code developed at SNS to simulate beam dynamics in accumulation rings and synchrotrons. The code is structured as a collection of external C++ modules for SuperCode, a high level interpreter shell developed at LLNL in the early 1990s. SuperCode is no longer actively supported and there has for some time been interest in replacing it by a modern scripting language, while preserving the feel of the original ORBIT program. In this paper, we describe a new version of ORBIT where the role of SuperCode is assumed by Python, a free, well-documented and widely supported object-oriented scripting language. We also compare PyORBIT to ORBIT from the standpoint of features, performance and future expandability.

  1. PyORBIT: A Python Shell For ORBIT

    International Nuclear Information System (INIS)

    Jean-Francois Ostiguy; Jeffrey Holmes

    2003-01-01

    ORBIT is code developed at SNS to simulate beam dynamics in accumulation rings and synchrotrons. The code is structured as a collection of external C++ modules for SuperCode, a high level interpreter shell developed at LLNL in the early 1990s. SuperCode is no longer actively supported and there has for some time been interest in replacing it by a modern scripting language, while preserving the feel of the original ORBIT program. In this paper, we describe a new version of ORBIT where the role of SuperCode is assumed by Python, a free, well-documented and widely supported object-oriented scripting language. We also compare PyORBIT to ORBIT from the standpoint of features, performance and future expandability

  2. FIFTY YEARS OF MELPHALAN USE IN HEMATOPOIETIC STEM CELL TRANSPLANTATION

    Science.gov (United States)

    Bayraktar, Ulas D.; Bashir, Qaiser; Qazilbash, Muzaffar; Champlin, Richard E.; Ciurea, Stefan O.

    2015-01-01

    Melphalan remains the most widely used agent in preparative regimens for hematopoietic stem-cell transplantation. From its initial discovery more than 50 years ago, it has been gradually incorporated in the conditioning regimens for both autologous and allogeneic transplantation due to its myeloablative properties and broad antitumor effects as a DNA alkylating agent. Melphalan remains the mainstay conditioning for multiple myeloma and lymphomas; and has been used successfully in preparative regimens of a variety of other hematological and non-hematological malignancies. The addition of newer agents to conditioning like bortezomib or lenalidomide for myeloma, or clofarabine for myeloid malignancies, may improve antitumor effects for transplantation, while in combination with alemtuzumab may represent a backbone for future cellular therapy due to reliable engraftment and low toxicity profile. This review summarizes the development and the current use of this remarkable drug in hematopoietic stem-cell transplantation. PMID:22922522

  3. Therapeutic gene editing in CD34+ hematopoietic progenitors from Fanconi anemia patients.

    Science.gov (United States)

    Diez, Begoña; Genovese, Pietro; Roman-Rodriguez, Francisco J; Alvarez, Lara; Schiroli, Giulia; Ugalde, Laura; Rodriguez-Perales, Sandra; Sevilla, Julian; Diaz de Heredia, Cristina; Holmes, Michael C; Lombardo, Angelo; Naldini, Luigi; Bueren, Juan Antonio; Rio, Paula

    2017-11-01

    Gene targeting constitutes a new step in the development of gene therapy for inherited diseases. Although previous studies have shown the feasibility of editing fibroblasts from Fanconi anemia (FA) patients, here we aimed at conducting therapeutic gene editing in clinically relevant cells, such as hematopoietic stem cells (HSCs). In our first experiments, we showed that zinc finger nuclease (ZFN)-mediated insertion of a non-therapeutic EGFP-reporter donor in the AAVS1 "safe harbor" locus of FA-A lymphoblastic cell lines (LCLs), indicating that FANCA is not essential for the editing of human cells. When the same approach was conducted with therapeutic FANCA donors, an efficient phenotypic correction of FA-A LCLs was obtained. Using primary cord blood CD34 + cells from healthy donors, gene targeting was confirmed not only in in vitro cultured cells, but also in hematopoietic precursors responsible for the repopulation of primary and secondary immunodeficient mice. Moreover, when similar experiments were conducted with mobilized peripheral blood CD34 + cells from FA-A patients, we could demonstrate for the first time that gene targeting in primary hematopoietic precursors from FA patients is feasible and compatible with the phenotypic correction of these clinically relevant cells. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

  4. Long-term hematopoietic stem cell damage after external irradiation with X rays

    International Nuclear Information System (INIS)

    Grande, M.T.; Varas, F.; Bueren, J.A.

    1997-01-01

    We have investigated the functionality of the lympho-hematopoietic stem cells long-term (9 months) after the irradiation (X rays) of mice at different stages of development, by means of a competitive bone marrow repopulation assay. Our data revealed that a dose of 1 Gy was only capable of inducing significant long-term failures in the functionality of the primitive repopulating cells in mice irradiated at the young-adult stage (12 week-old), but not in mice irradiated at the late stages of foetus development (17 day-old fetuses) nor at the early development of the embryo (4 day-old embryos). The differential generation of long-term stem cell defects as a function of the age was confirmed in mice irradiated with 3 Gy. While no significant effects in the long-term repopulating cells were observed in 4 day-old embryos, significant repopulation deficiencies were observed in this population when mice were irradiated at the 17 day of foetus development, and more markedly at the adult stage of growth. These data offer new evidence about the influence of the developmental stage of the animal on the generation of residual hematopoietic dysfunctions by external irradiation, with particular relevance to the very primitive lympho-hematopoietic stem cells. (author)

  5. Improved hematopoietic differentiation efficiency of gene-corrected beta-thalassemia induced pluripotent stem cells by CRISPR/Cas9 system.

    Science.gov (United States)

    Song, Bing; Fan, Yong; He, Wenyin; Zhu, Detu; Niu, Xiaohua; Wang, Ding; Ou, Zhanhui; Luo, Min; Sun, Xiaofang

    2015-05-01

    The generation of beta-thalassemia (β-Thal) patient-specific induced pluripotent stem cells (iPSCs), subsequent homologous recombination-based gene correction of disease-causing mutations/deletions in the β-globin gene (HBB), and their derived hematopoietic stem cell (HSC) transplantation offers an ideal therapeutic solution for treating this disease. However, the hematopoietic differentiation efficiency of gene-corrected β-Thal iPSCs has not been well evaluated in the previous studies. In this study, we used the latest gene-editing tool, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9), to correct β-Thal iPSCs; gene-corrected cells exhibit normal karyotypes and full pluripotency as human embryonic stem cells (hESCs) showed no off-targeting effects. Then, we evaluated the differentiation efficiency of the gene-corrected β-Thal iPSCs. We found that during hematopoietic differentiation, gene-corrected β-Thal iPSCs showed an increased embryoid body ratio and various hematopoietic progenitor cell percentages. More importantly, the gene-corrected β-Thal iPSC lines restored HBB expression and reduced reactive oxygen species production compared with the uncorrected group. Our study suggested that hematopoietic differentiation efficiency of β-Thal iPSCs was greatly improved once corrected by the CRISPR/Cas9 system, and the information gained from our study would greatly promote the clinical application of β-Thal iPSC-derived HSCs in transplantation.

  6. Orbital floor reconstruction using a tensor fascia lata sling after total maxillectomy.

    Science.gov (United States)

    Jung, Bok Ki; Yun, In Sik; Lee, Won Jai; Lew, Dae Hyun; Choi, Eun Chang; Lee, Dong Won

    2016-05-01

    Reconstruction after total maxillectomy with extensive orbital floor defects poses a significant challenge for the reconstruction. The aim of this study is to present the outcomes of orbital floor reconstruction using tensor fascia lata slings after total maxillectomy and to compare these results to orbital floor reconstruction using alloplastic implants. This was a retrospective analysis of 19 consecutive patients who underwent tumor resection with orbital floor removal for malignancies. Reconstructions were performed using either tensor fascia lata slings (Group A) or alloplastic implants (Group B). The early and late postoperative outcomes such as wound infection, plate exposure, ectropion, diplopia, and enophthalmos, were analyzed and compared between the two groups. Patients in group A had significantly less wound complication than in group B (p < 0.05). In group A, there were no early or late wound complications after the operation. However, in group B, five patients had infection, the plate was exposed in eight of fourteen patients, and three patients had enophthalmos. Eight patients in group B underwent reoperation to correct their complications. Reconstruction of the orbital floor with a tensor fascia lata sling offers reliable support to the globe and prevents the ophthalmic complications associated with loss of orbital support. Copyright © 2016 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

  7. Wnt3a protein reduces growth factor-driven expansion of human hematopoietic stem and progenitor cells in serum-free cultures

    NARCIS (Netherlands)

    L.E. Duinhouwer (Lucia); N. Tüysüz (Nesrin); E.J. Rombouts (Elwin); M.N.D. Ter Borg (Mariëtte N. D.); E. Mastrobattista; J. Spanholtz (Jan); J.J. Cornelissen (Jan); D. ten Berge (Derk); E. Braakman (Eric)

    2015-01-01

    textabstractAbstract Ex vivo expansion of hematopoietic stem and progenitor cells (HSPC) is a promising approach to improve insufficient engraftment after umbilical cord blood stem cell transplantation (UCB-SCT). Although culturing HSPC with hematopoietic cytokines results in

  8. Hepatocellular Carcinoma Metastasis to the Orbit in a Coinfected HIV+ HBV+ Patient Previously Treated with Orthotopic Liver Transplantation: A Case Report

    Directory of Open Access Journals (Sweden)

    S. Guerriero

    2011-01-01

    Full Text Available Hepatocellular carcinoma rarely metastasizes to the orbit. We report a 45-year-old male, HBV+, HIV+, with a past history of a liver transplant for ELSD (end-stage liver disease with hepatocellular carcinoma and recurrent HCC, who presented with proptosis and diplopia of the left eye. CT scans of the head revealed a large, irregular mass in the left orbit causing superior and lateral destruction of the orbital bone. Biopsy specimens of the orbital tumor showed features of metastatic foci of hepatocellular carcinoma. Only 16 other cases of HCC metastasis to the orbit have been described in literature, and this is the first case in a previously transplanted HIV+, HBV+ patient.

  9. Polycomb group proteins in hematopoietic stem cell aging and malignancies

    NARCIS (Netherlands)

    Klauke, Karin; de Haan, Gerald

    Protection of the transcriptional "stemness" network is important to maintain a healthy hematopoietic stem cells (HSCs) compartment during the lifetime of the organism. Recent evidence shows that fundamental changes in the epigenetic status of HSCs might be one of the driving forces behind many

  10. FAM20: an evolutionarily conserved family of secreted proteins expressed in hematopoietic cells

    Directory of Open Access Journals (Sweden)

    Cobos Everardo

    2005-01-01

    Full Text Available Abstract Background Hematopoiesis is a complex developmental process controlled by a large number of factors that regulate stem cell renewal, lineage commitment and differentiation. Secreted proteins, including the hematopoietic growth factors, play critical roles in these processes and have important biological and clinical significance. We have employed representational difference analysis to identify genes that are differentially expressed during experimentally induced myeloid differentiation in the murine EML hematopoietic stem cell line. Results One identified clone encoded a previously unidentified protein of 541 amino acids that contains an amino terminal signal sequence but no other characterized domains. This protein is a member of family of related proteins that has been named family with sequence similarity 20 (FAM20 with three members (FAM20A, FAM20B and FAM20C in mammals. Evolutionary comparisons revealed the existence of a single FAM20 gene in the simple vertebrate Ciona intestinalis and the invertebrate worm Caenorhabditis elegans and two genes in two insect species, Drosophila melanogaster and Anopheles gambiae. Six FAM20 family members were identified in the genome of the pufferfish, Fugu rubripes and five members in the zebrafish, Danio rerio. The mouse Fam20a protein was ectopically expressed in a mammalian cell line and found to be a bona fide secreted protein and efficient secretion was dependent on the integrity of the signal sequence. Expression analysis revealed that the Fam20a gene was indeed differentially expressed during hematopoietic differentiation and that the other two family members (Fam20b and Fam20c were also expressed during hematcpoiesis but that their mRNA levels did not vary significantly. Likewise FAM20A was expressed in more limited set of human tissues than the other two family members. Conclusions The FAM20 family represents a new family of secreted proteins with potential functions in regulating

  11. Orbital lymphoma: radiotherapy outcome and complications

    International Nuclear Information System (INIS)

    Stafford, Scott L.; Kozelsky, Timothy F.; Garrity, James A.; Kurtin, Paul J.; Leavitt, Jacqueline A.; Martenson, James A.; Habermann, Thomas M.

    2001-01-01

    Background and purpose: Orbital non-Hodgkin's lymphomas (NHL) have traditionally been treated with radiation. Forty-eight patients presenting with orbital NHL were treated with radiation and were evaluated for local control, overall survival, cause-specific survival, and complications. Materials and methods: Forty-five patients had low-grade and 3 patients had intermediate-grade histologic findings. Orbit-only disease occurred in 22 patients, the conjunctiva in 16, both in five, and lacrimal gland only in five. Patient age ranged from 35 to 94 years (median, 68). Ann Arbor stages were cIEA (34), cIIEA (six), cIIIEA (two), and cIVEA (six). Radiation doses ranged between 15 and 53.8 Gy (median, 27.5 Gy). Results: Follow-up ranged from 0.14 to 18.23 years (median, 5.35). Median overall survival and cause-specific survival were 6.5 and 15.5 years, respectively. Patients with clinical stage I or II disease had significantly better overall and cause-specific survival than patients with stage III or IV disease. Ten-year relapse-free survival in 41 patients with stage I or II disease was 66%. However, there was continued downward pressure on relapse-free survival out to 18 years. One local failure occurred. Twenty-five patients sustained acute complications. There were 17 minor and four major late complications. All major late complications occurred with doses more than 35 Gy. Conclusions: Excellent local control with radiation doses ranging from 15 to 30 Gy is achieved. Patients with stage I or II disease have better overall and cause-specific survival than patients with stage III or IV disease. Late relapse occurs in sites other than the treated orbit, even in patients with early-stage disease. Doses 35 Gy or higher result in significant late complications and are therefore not indicated for patients with low-grade tumors

  12. [Surgical treatment of diffuse adult orbital lymphangioma: two case studies].

    Science.gov (United States)

    Berthout, A; Jacomet, P V; Putterman, M; Galatoire, O; Morax, S

    2008-12-01

    Orbital lymphangioma is a rare vascular malformation; it is a benign but severe anomaly because of its infiltrative, diffuse, and hemorrhagic nature, and its high morbidity rate. Surgical resection is a real challenge on account of the intricate architecture of the lesion. The authors report their surgical experience concerning two cases of diffuse orbital lymphangioma whose diagnosis was established in adulthood and whose surgical treatment was successful. Two patients presented with adult orbital lymphangioma. Progression was slow during the first decade and then was quickly followed by complications: major exorbitism, compressive optic neuropathy, and corneal exposure. Neuroimaging showed a diffuse and cystic orbital malformation. Surgical resection was performed as completely as possible, in one case with a Krönlein orbitotomy and in the other case only via a conjunctive route. An aspirate drain was put in the orbit for 48 h so as to prevent dead spaces forming after resection, an essential risk factor of hemorrhagic or cystic recurrence. Systemic corticotherapy was administered for the 5 days following surgery. The resection was total in one case and subtotal in the other. The surgical follow-up was uneventful with an excellent aesthetic result and an improvement in visual acuity. After 12 months, no tumoral or hemorrhagic recurrence was noted. The surgical treatment of orbital lymphangiomas is challenging because of their infiltrative nature. In diffuse forms, a complete resection is rarely possible because of the risk of sacrificing visual function. In the two cases reported herein, the resection of the extraconal portion was complete, but the intraconal portion was completely removed only in one case. Using the aspirate drain, negative pressure was maintained in the orbital cavity, preventing the formation of chocolate cysts induced by surgery. Although the clinical result was very satisfying, long-term follow-up is necessary to evaluate recurrence

  13. Autologous hematopoietic stem cell transplantation in classical Hodgkin's lymphoma

    Directory of Open Access Journals (Sweden)

    Afonso José Pereira Cortez

    2011-02-01

    Full Text Available BACKGROUND: Hodgkin's lymphoma has high rates of cure, but in 15% to 20% of general patients and between 35% and 40% of those in advanced stages, the disease will progress or will relapse after initial treatment. For this group, hematopoietic stem cell transplantation is considered one option of salvage therapy. OBJECTIVES: To evaluate a group of 106 patients with Hodgkin's lymphoma, who suffered relapse or who were refractory to treatment, submitted to autologous hematopoietic stem cell transplantation in a single transplant center. METHODS: A retrospective study was performed with data collected from patient charts. The analysis involved 106 classical Hodgkin's lymphoma patients who were consecutively submitted to high-dose chemotherapy followed by autologous transplants in a single institution from April 1993 to December 2006. RESULTS: The overall survival rates of this population at five and ten years were 86% and 70%, respectively. The disease-free survival was approximately 60% at five years. Four patients died of procedure-related causes but relapse of classical Hodgkin's lymphoma after transplant was the most frequent cause of death. Univariate analysis shows that sensitivity to pre-transplant treatment and hemoglobin < 10 g/dL at diagnosis had an impact on patient survival. Unlike other studies, B-type symptoms did not seem to affect overall survival. Lactic dehydrogenase and serum albumin concentrations analyzed at diagnosis did not influence patient survival either. CONCLUSION: Autologous hematopoietic stem cell transplantation is an effective treatment strategy for early and late relapse in classical Hodgkin's lymphoma for cases that were responsive to pre-transplant chemotherapy. Refractory to treatment is a sign of worse prognosis. Additionally, a hemoglobin concentration below 10 g/dL at diagnosis of Hodgkin's lymphoma has a negative impact on the survival of patients after transplant. As far as we know this relationship has not

  14. CAR T Cells Releasing IL-18 Convert to T-Bethigh FoxO1low Effectors that Exhibit Augmented Activity against Advanced Solid Tumors

    Directory of Open Access Journals (Sweden)

    Markus Chmielewski

    2017-12-01

    Full Text Available Adoptive therapy with chimeric antigen receptor (CAR-redirected T cells has achieved remarkable efficacy in the treatment of hematopoietic malignancies. However, eradicating large solid tumors in advanced stages of the disease remains challenging. We explored augmentation of the anti-tumor immune reaction by establishing an acute inflammatory reaction. Systematic screening indicates that IL-18 polarizes CAR T cells toward T-bethigh FoxO1low effectors with an acute inflammatory response. CAR T cells engineered with inducible IL-18 release exhibited superior activity against large pancreatic and lung tumors that were refractory to CAR T cells without cytokines. IL-18 CAR T cell treatment was accompanied by an overall change in the immune cell landscape associated with the tumor. More specifically, CD206− M1 macrophages and NKG2D+ NK cells increased in number, whereas Tregs, suppressive CD103+ DCs, and M2 macrophages decreased, suggesting that “iIL18 TRUCKs” can be used to sensitize large solid tumor lesions for successful immune destruction.

  15. Childhood Hematopoietic Cell Transplantation (PDQ®)—Health Professional Version

    Science.gov (United States)

    Hematopoietic cell transplantation involves the infusion of blood stem cells (peripheral/umbilical cord blood, bone marrow) into a patient to reconstitute the blood system. Get detailed information about autologous and allogeneic transplant, including cell selection, HLA matching, and preparative regimens, and the acute complications and late effects of treatment in this summary for clinicians.

  16. Orbit Propagation and Determination of Low Earth Orbit Satellites

    Directory of Open Access Journals (Sweden)

    Ho-Nien Shou

    2014-01-01

    Full Text Available This paper represents orbit propagation and determination of low Earth orbit (LEO satellites. Satellite global positioning system (GPS configured receiver provides position and velocity measures by navigating filter to get the coordinates of the orbit propagation (OP. The main contradictions in real-time orbit which is determined by the problem are orbit positioning accuracy and the amount of calculating two indicators. This paper is dedicated to solving the problem of tradeoffs. To plan to use a nonlinear filtering method for immediate orbit tasks requires more precise satellite orbit state parameters in a short time. Although the traditional extended Kalman filter (EKF method is widely used, its linear approximation of the drawbacks in dealing with nonlinear problems was especially evident, without compromising Kalman filter (unscented Kalman Filter, UKF. As a new nonlinear estimation method, it is measured at the estimated measurements on more and more applications. This paper will be the first study on UKF microsatellites in LEO orbit in real time, trying to explore the real-time precision orbit determination techniques. Through the preliminary simulation results, they show that, based on orbit mission requirements and conditions using UKF, they can satisfy the positioning accuracy and compute two indicators.

  17. Age-related cancer mutations associated with clonal hematopoietic expansion

    Science.gov (United States)

    Xie, Mingchao; Lu, Charles; Wang, Jiayin; McLellan, Michael D.; Johnson, Kimberly J.; Wendl, Michael C.; McMichael, Joshua F.; Schmidt, Heather K.; Yellapantula, Venkata; Miller, Christopher A.; Ozenberger, Bradley A.; Welch, John S.; Link, Daniel C.; Walter, Matthew J.; Mardis, Elaine R.; Dipersio, John F.; Chen, Feng; Wilson, Richard K.; Ley, Timothy J.; Ding, Li

    2015-01-01

    Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. We analyzed blood-derived sequence data from 2,728 individuals within The Cancer Genome Atlas, and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia/lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5–6% of people older than 70 years) contain mutations that may represent premalignant, initiating events that cause clonal hematopoietic expansion. PMID:25326804

  18. Rehabilitation of orbital cavity after orbital exenteration using polymethyl methacrylate orbital prosthesis

    Directory of Open Access Journals (Sweden)

    Sumeet Jain

    2016-01-01

    Full Text Available Squamous cell carcinoma of the eyelid is the second most common malignant neoplasm of the eye with the incidence of 0.09 and 2.42 cases/100 000 people. Orbital invasion is a rare complication but, if recognized early, can be treated effectively with exenteration. Although with advancements in technology such as computer-aided design and computer-aided manufacturing, material science, and retentive methods like implants, orbital prosthesis with stock ocular prosthesis made of methyl methacrylate retained by anatomic undercuts is quiet effective and should not be overlooked and forgotten. This clinical report describes prosthetic rehabilitation of two male patients with polymethyl methacrylate resin orbital prosthesis after orbital exenteration, for squamous cell carcinoma of the upper eyelid. The orbital prosthesis was sufficiently retained by hard and soft tissue undercuts without any complications. The patients using the prosthesis are quite satisfied with the cosmetic results and felt comfortable attending the social events.

  19. Non-odontogenic tumors of the facial bones in children and adolescents: role of multiparametric imaging

    International Nuclear Information System (INIS)

    Becker, Minerva; Stefanelli, Salvatore; Poletti, Pierre Alexandre; Merlini, Laura; Rougemont, Anne-Laure

    2017-01-01

    Tumors of the pediatric facial skeleton represent a major challenge in clinical practice because they can lead to functional impairment, facial deformation, and long-term disfigurement. Their treatment often requires a multidisciplinary approach, and radiologists play a pivotal role in the diagnosis and management of these lesions. Although rare, pediatric tumors arising in the facial bones comprise a wide spectrum of benign and malignant lesions of osteogenic, fibrogenic, hematopoietic, neurogenic, or epithelial origin. The more common lesions include Langerhans cell histiocytosis and osteoma, while rare lesions include inflammatory myofibroblastic and desmoid tumors; juvenile ossifying fibroma; primary intraosseous lymphoma; Ewing sarcoma; and metastases to the facial bones from neuroblastoma, Ewing sarcoma, or retinoblastoma. This article provides a comprehensive approach for the evaluation of children with non-odontogenic tumors of the facial skeleton. Typical findings are discussed with emphasis on the added value of multimodality multiparametric imaging with computed tomography (CT), magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI), positron emission tomography CT (PET CT), and PET MRI. Key imaging findings and characteristic histologic features of benign and malignant lesions are reviewed and the respective role of each modality for pretherapeutic assessment and post-treatment follow-up. Pitfalls of image interpretation are addressed and how to avoid them. (orig.)

  20. Non-odontogenic tumors of the facial bones in children and adolescents: role of multiparametric imaging

    Energy Technology Data Exchange (ETDEWEB)

    Becker, Minerva; Stefanelli, Salvatore; Poletti, Pierre Alexandre; Merlini, Laura [University of Geneva, Division of Radiology, Department of Imaging and Medical Informatics, Geneva University Hospital, Geneva (Switzerland); Rougemont, Anne-Laure [University of Geneva, Division of Clinical Pathology, Department of Genetic and Laboratory Medicine, Geneva University Hospital, Geneva (Switzerland)

    2017-04-15

    Tumors of the pediatric facial skeleton represent a major challenge in clinical practice because they can lead to functional impairment, facial deformation, and long-term disfigurement. Their treatment often requires a multidisciplinary approach, and radiologists play a pivotal role in the diagnosis and management of these lesions. Although rare, pediatric tumors arising in the facial bones comprise a wide spectrum of benign and malignant lesions of osteogenic, fibrogenic, hematopoietic, neurogenic, or epithelial origin. The more common lesions include Langerhans cell histiocytosis and osteoma, while rare lesions include inflammatory myofibroblastic and desmoid tumors; juvenile ossifying fibroma; primary intraosseous lymphoma; Ewing sarcoma; and metastases to the facial bones from neuroblastoma, Ewing sarcoma, or retinoblastoma. This article provides a comprehensive approach for the evaluation of children with non-odontogenic tumors of the facial skeleton. Typical findings are discussed with emphasis on the added value of multimodality multiparametric imaging with computed tomography (CT), magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI), positron emission tomography CT (PET CT), and PET MRI. Key imaging findings and characteristic histologic features of benign and malignant lesions are reviewed and the respective role of each modality for pretherapeutic assessment and post-treatment follow-up. Pitfalls of image interpretation are addressed and how to avoid them. (orig.)

  1. The histone demethylase Jarid1b is required for hematopoietic stem cell self-renewal

    DEFF Research Database (Denmark)

    Stewart, Morag H; Albert, Mareike; Sroczynska, Patrycja

    2015-01-01

    Jarid1b/KDM5b is a histone demethylase that regulates self-renewal and differentiation in stem cells and cancer, however its function in hematopoiesis is unclear. Here, we find that Jarid1b is highly expressed in primitive hematopoietic compartments and is overexpressed in acute myeloid leukemias...... compromises hematopoietic stem cell (HSC) self-renewal capacity and suggest that Jarid1b is a positive regulator of HSC potential.......Jarid1b/KDM5b is a histone demethylase that regulates self-renewal and differentiation in stem cells and cancer, however its function in hematopoiesis is unclear. Here, we find that Jarid1b is highly expressed in primitive hematopoietic compartments and is overexpressed in acute myeloid leukemias....... Constitutive genetic deletion of Jarid1b did not impact steady-state hematopoiesis. In contrast, acute deletion of Jarid1b from bone marrow increased peripheral blood T cells and, following secondary transplantation, resulted in loss of bone marrow reconstitution. Our results reveal that deletion of Jarid1b...

  2. CT and MR imaging of primary tumors of the masticator space

    International Nuclear Information System (INIS)

    Aspestrand, F.; Boysen, M.

    1992-01-01

    A retrospective study of CT and MR examinations in 14 patients with benign and malignant tumors originating in the masticator space is presented. At presentation, 12 patients revealed tumor extension to adjacent regions and spaces. Perineutral tumor spread along trigeminal nerve branches to the cavernous sinus and orbits was combined with facial pain, and/or numbness, ophthalmoplegia, and exophthalmus. Detailed analysis of tumor growth and spread, enhancement and signal features at CT and MR imaging indicated that tumor histology was, with a few exceptions, nonspecific. More extensive growth and bone destruction was noted only among malignant tumors. MR imaging was found superior to CT in delineating tumor extension due to better soft tissue contrast resolution and multiplanar imaging. Posttreatment examinations were available in 11 patients and showed long-standing regional edema of the adjacent temporal lobe and masticator muscles in 4 out of 5 patients without clinical evidence of tumor. In 6 patients, CT and MR features were found almost unchanged with only small size differences after various forms of treatment. (orig.)

  3. Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies

    DEFF Research Database (Denmark)

    Sorror, Mohamed L; Sandmaier, Brenda M; Storer, Barry E

    2011-01-01

    A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbid conditions.......A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbid conditions....

  4. Whole-transcriptome analysis of endothelial to hematopoietic stem cell transition reveals a requirement for Gpr56 in HSC generation.

    Science.gov (United States)

    Solaimani Kartalaei, Parham; Yamada-Inagawa, Tomoko; Vink, Chris S; de Pater, Emma; van der Linden, Reinier; Marks-Bluth, Jonathon; van der Sloot, Anthon; van den Hout, Mirjam; Yokomizo, Tomomasa; van Schaick-Solernó, M Lucila; Delwel, Ruud; Pimanda, John E; van IJcken, Wilfred F J; Dzierzak, Elaine

    2015-01-12

    Hematopoietic stem cells (HSCs) are generated via a natural transdifferentiation process known as endothelial to hematopoietic cell transition (EHT). Because of small numbers of embryonal arterial cells undergoing EHT and the paucity of markers to enrich for hemogenic endothelial cells (ECs [HECs]), the genetic program driving HSC emergence is largely unknown. Here, we use a highly sensitive RNAseq method to examine the whole transcriptome of small numbers of enriched aortic HSCs, HECs, and ECs. Gpr56, a G-coupled protein receptor, is one of the most highly up-regulated of the 530 differentially expressed genes. Also, highly up-regulated are hematopoietic transcription factors, including the "heptad" complex of factors. We show that Gpr56 (mouse and human) is a target of the heptad complex and is required for hematopoietic cluster formation during EHT. Our results identify the processes and regulators involved in EHT and reveal the surprising requirement for Gpr56 in generating the first HSCs. © 2015 Solaimani Kartalaei et al.

  5. Engineering antigen-specific T cells from genetically modified human hematopoietic stem cells in immunodeficient mice.

    Directory of Open Access Journals (Sweden)

    Scott G Kitchen

    Full Text Available There is a desperate need for effective therapies to fight chronic viral infections. The immune response is normally fastidious at controlling the majority of viral infections and a therapeutic strategy aimed at reestablishing immune control represents a potentially powerful approach towards treating persistent viral infections. We examined the potential of genetically programming human hematopoietic stem cells to generate mature CD8+ cytotoxic T lymphocytes that express a molecularly cloned, "transgenic" human anti-HIV T cell receptor (TCR. Anti-HIV TCR transduction of human hematopoietic stem cells directed the maturation of a large population of polyfunctional, HIV-specific CD8+ cells capable of recognizing and killing viral antigen-presenting cells. Thus, through this proof-of-concept we propose that genetic engineering of human hematopoietic stem cells will allow the tailoring of effector T cell responses to fight HIV infection or other diseases that are characterized by the loss of immune control.

  6. ORBITAL INJURIES

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    Andrej Kansky

    2002-12-01

    Full Text Available Background. Orbit is involved in 40% of all facial fractures. There is considerable variety in severity, ranging from simple nondisplaced to complex comminuted fractures. Complex comminuted fractures (up to 20% are responsible for the majority of complications and unfavorable results. Orbital fractures are classified as internal orbital fractures, zygomatico-orbital fractures, naso-orbito-ethmoidal fractures and combined fractures. The ophtalmic sequelae of midfacial fractures are usually edema and ecchymosis of the soft tissues, subconjuctival hemorrhage, diplopia, iritis, retinal edema, ptosis, enophthalmos, ocular muscle paresis, mechanical restriction of ocular movement and nasolacrimal disturbances. More severe injuries such as optic nerve trauma and retinal detachments have also been reported. Within the wide range of orbital fractures small group of complex fractures causes most of the sequelae. Therefore identification of severe injuries and adequate treatment is of major importance. The introduction of craniofacial techniques made possible a wide exposure even of large orbital wall defects and their reconstruction by bone grafts. In spite of significant progress, repair of complex orbital wall defects remains a problem even for the experienced surgeons.Results. In 1999 121 facial injuries were treated at our department (Clinical Centre Ljubljana Dept. Of Maxillofacial and Oral Surgery. Orbit was involved in 65% of cases. Isolated inner orbital fractures presented 4% of all fractures. 17 (14% complex cases were treated, 5 of them being NOE, 5 orbital (frame and inner walls, 3 zygomatico-orbital, 2 FNO and 2 maxillo-orbital fractures.Conclusions. Final result of the surgical treatment depends on severity of maxillofacial trauma. Complex comminuted fractures are responsable for most of the unfavorable results and ocular function is often permanently damaged (up to 75% in these fractures.

  7. Bone marrow transplantations to study gene function in hematopoietic cells

    NARCIS (Netherlands)

    de Winther, Menno P. J.; Heeringa, Peter

    2011-01-01

    Immune cells are derived from hematopoietic stem cells in the bone marrow. Experimental replacement of bone marrow offers the unique possibility to replace immune cells, to study gene function in mouse models of disease. Over the past decades, this technique has been used extensively to study, for

  8. Wnt3a protein reduces growth factor-driven expansion of human hematopoietic stem and progenitor cells in serum-free cultures

    NARCIS (Netherlands)

    Duinhouwer, Lucia E.; Tüysüz, Nesrin; Rombouts, Elwin W J C; Ter Borg, Mariette N D; Mastrobattista, Enrico; Spanholtz, Jan; Cornelissen, Jan J.; Berge, Derk Ten; Braakman, Eric

    2015-01-01

    Ex vivo expansion of hematopoietic stem and progenitor cells (HSPC) is a promising approach to improve insufficient engraftment after umbilical cord blood stem cell transplantation (UCB-SCT). Although culturing HSPC with hematopoietic cytokines results in robust proliferation, it is accompanied with

  9. Orbital

    OpenAIRE

    Yourshaw, Matthew Stephen

    2017-01-01

    Orbital is a virtual reality gaming experience designed to explore the use of traditional narrative structure to enhance immersion in virtual reality. The story structure of Orbital was developed based on the developmental steps of 'The Hero's Journey,' a narrative pattern identified by Joseph Campbell. Using this standard narrative pattern, Orbital is capable of immersing the player quickly and completely for the entirety of play time. MFA

  10. Transplantation Dose Alters the Differentiation Program of Hematopoietic Stem Cells.

    Science.gov (United States)

    Brewer, Casey; Chu, Elizabeth; Chin, Mike; Lu, Rong

    2016-05-24

    Hematopoietic stem cell (HSC) transplantation is the most prevalent stem cell therapy, but it remains a risky procedure. To improve this treatment, it is important to understand how transplanted stem cells rebuild the blood and immune systems and how this process is impacted by transplantation variables such as the HSC dose. Here, we find that, in the long term following transplantation, 70%-80% of donor-HSC-derived clones do not produce all measured blood cell types. High HSC doses lead to more clones that exhibit balanced lymphocyte production, whereas low doses produce more T-cell-specialized clones. High HSC doses also produce significantly higher proportions of early-differentiating clones compared to low doses. These complex differentiation behaviors uncover the clonal-level regeneration dynamics of hematopoietic regeneration and suggest that transplantation dose can be exploited to improve stem cell therapy. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  11. Effect of combined 5-fluorouracil and radiation on murine hematopoietic tissue

    International Nuclear Information System (INIS)

    Nielsen, O.S.; Overgaard, J.; Von der Maase, H.

    1988-01-01

    The interaction of 5-fluorouracil (5-FU) and radiation in hematopoietic tissue was assessed as the survival of hematopoietic stem cells (CFUs) by means of the spleen colony assay. 5-FU was given intraperitoneally in the dose range 50-500 mg/kg body weight. In this dose range, stem cell survival decreased exponentially as a function of 5-FU dose. After 150 mg/kg of 5-FU alone, the stem cell survival rapidly decreased, reaching a minimum after 1-2 days. A similar regeneration was observed after 0.75 Gy radiation alone 5-FU given 15 min before whole-body irradiation resulted in a pronounced reduction in stem cell survival due to an increase in the slope of the radiation survival curve by a factor of 2.1. After combined 5-FU and radiation, the survival rapidly decreased to a minimum at day 1, and it showed only a slight increase within the next 7 days. After this delay, the stem cells regenerated with a doubling time of about 30 h, reaching pretreatment values on day 15. The delayed stem cell regeneration was not seen following 3.5 Gy radiation alone or 225 mg/kg 5-FU alone, which resulted in the same nadir of CFUs survival as found after the combined treatment. Thus, 5-FU greatly enhances the hematopoietic damage after radiation by reducing the number of surviving stem cells and delaying the stem cell regeneration. 24 refs.; 6 figs.; 1 table

  12. ULTRASOUND AND COMPUTED TOMOGRAPHIC DIAGNOSIS OF OPTIC NERVE TUMORS

    Directory of Open Access Journals (Sweden)

    S. V. Saakyan

    2012-01-01

    Full Text Available A comprehensive examination was made in 93 patients, including 18 children, with tumors of the optic nerve (ON. Duplex ultrasound scanning was performed in 39 patients, of them there were 11 patients with ON gliomas and 28 with ON meningiomas. The specific computed tomographic and echographic signs of ON glioma and meningiomas were detected. The studies have shown that duplex ultrasound scanning and structural computed tomography of orbital sockets are highly informative complementary imaging procedures for ON tumors, which permits one to make their correct diagnosis, to specify surgical volume, and to plan adequate treatment.

  13. Orbit Functions

    Directory of Open Access Journals (Sweden)

    Anatoliy Klimyk

    2006-01-01

    Full Text Available In the paper, properties of orbit functions are reviewed and further developed. Orbit functions on the Euclidean space E_n are symmetrized exponential functions. The symmetrization is fulfilled by a Weyl group corresponding to a Coxeter-Dynkin diagram. Properties of such functions will be described. An orbit function is the contribution to an irreducible character of a compact semisimple Lie group G of rank n from one of its Weyl group orbits. It is shown that values of orbit functions are repeated on copies of the fundamental domain F of the affine Weyl group (determined by the initial Weyl group in the entire Euclidean space E_n. Orbit functions are solutions of the corresponding Laplace equation in E_n, satisfying the Neumann condition on the boundary of F. Orbit functions determine a symmetrized Fourier transform and a transform on a finite set of points.

  14. Umbilical Cord-Derived Mesenchymal Stem Cells for Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Yu-Hua Chao

    2012-01-01

    Full Text Available Hematopoietic stem cell transplantation (HSCT is becoming an effective therapeutic modality for a variety of diseases. Mesenchymal stem cells (MSCs can be used to enhance hematopoietic engraftment, accelerate lymphocyte recovery, reduce the risk of graft failure, prevent and treat graft-versus-host disease, and repair tissue damage in patients receiving HSCT. Till now, most MSCs for human clinical application have been derived from bone marrow. However, acquiring bone-marrow-derived MSCs involves an invasive procedure. Umbilical cord is rich with MSCs. Compared to bone-marrow-derived MSCs, umbilical cord-derived MSCs (UCMSCs are easier to obtain without harm to the donor and can proliferate faster. No severe adverse effects were noted in our previous clinical application of UCMSCs in HSCT. Accordingly, application of UCMSCs in humans appears to be feasible and safe. Further studies are warranted.

  15. Turnover of circulating hematopoietic stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Dorie, M J; Maloney, M A; Patt, H M

    1979-10-01

    Short-term parabiosis of male and female CBA/CaJ mice was used to investigate the turnover of circulating hematopoietic stem cells. The change and subsequent disappearance of donor stem cells were monitored by spleen colony assay and chromosome analysis of individual colonies. The results revealed an exponential disappearance of pluripotent stem cells from blood with a characteristic half time of 1.7 h. Blood-borne stem cells were shown to be equilibrated with a subpopulation of marrow stem cells exhibiting a disappearance half time of 9.5 h. Splenectomy did not change the apparent rate of stem cell removal from the blood.

  16. Proton radiation therapy for retinoblastoma: Comparison of various intraocular tumor locations and beam arrangements

    International Nuclear Information System (INIS)

    Krengli, Marco; Hug, Eugen B.; Adams, Judy A.; Smith, Alfred R.; Tarbell, Nancy J.; Munzenrider, John E.

    2005-01-01

    Purpose: To study the optimization of proton beam arrangements for various intraocular tumor locations; and to correlate isodose distributions with various target and nontarget structures. Methods and materials: We considered posterior-central, nasal, and temporal tumor locations, with straight, intrarotated, or extrarotated eye positions. Doses of 46 cobalt grey equivalent (CGE) to gross tumor volume (GTV) and 40 CGE to clinical target volume (CTV) (2 CGE per fraction) were assumed. Using three-dimensional planning, we compared isodose distributions for lateral, anterolateral oblique, and anteromedial oblique beams and dose-volume histograms of CTVs, GTVs, lens, lacrimal gland, bony orbit, and soft tissues. Results: All beam arrangements fully covered GTVs and CTVs with optimal lens sparing. Only 15% of orbital bone received doses ≥20 CGE with a lateral beam, with 20-26 CGE delivered to two of three growth centers. The anterolateral oblique approach with an intrarotated eye resulted in additional reduction of bony volume and exposure of only one growth center. No appreciable dose was delivered to the contralateral eye, brain tissue, or pituitary gland. Conclusions: Proton therapy achieved homogeneous target coverage with true lens sparing. Doses to orbit structures, including bony growth centers, were minimized with different beam arrangements and eye positions. Proton therapy could reduce the risks of second malignancy and cosmetic and functional sequelae

  17. The continuum of stem cell transdifferentiation: possibility of hematopoietic stem cell plasticity with concurrent CD45 expression.

    Science.gov (United States)

    Udani, V M

    2006-02-01

    Recent years have seen a surge of scientific research examining adult stem cell plasticity. For example, the hematopoietic stem cell has been shown to give rise to skin, respiratory epithelium, intestinal epithelium, renal epithelium, liver parenchyma, pancreas, skeletal muscle, vascular endothelium, myocardium, and central nervous system (CNS) neurons. The potential for such stem cell plasticity seems to be enhanced by stressors such as injury and neoplasia. Interestingly, recent studies have demonstrated that hematopoietic stem cells may be able to adopt certain nonhematopoietic phenotypes, such as endothelial, neural, or skeletal muscle phenotypes, without entirely losing their initial hematopoietic identity. We propose that transdifferentiation can, in certain conditions, be a partial rather than a complete event, and we encourage further investigation into the phenomenon of a stem cell simultaneously expressing phenotypic features of two distinct cell fates.

  18. Lung function after allogeneic hematopoietic stem cell transplantation in children

    DEFF Research Database (Denmark)

    Uhlving, Hilde Hylland; Larsen Bang, Cæcilie; Christensen, Ib Jarle

    2013-01-01

    Reduction in pulmonary function (PF) has been reported in up to 85% of pediatric patients during the first year after hematopoietic stem cell transplantation (HSCT). Our understanding of the etiology for this decrease in lung function is, however, sparse. The aim of this study was to describe PF...

  19. Allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies: Hospital Israelita Albert Einstein experience

    Directory of Open Access Journals (Sweden)

    Juliana Folloni Fernandes

    2011-06-01

    Full Text Available Objective: To report the experience of a tertiary care hospital withallogeneic hematopoietic stem cell transplantation in children withprimary immunodeficiencies. Methods: Seven patients with primaryimmunodeficiencies (severe combined immunodeficiency: n = 2;combined immunodeficiency: n = 1; chronic granulomatous disease:n = 1; hyper-IgM syndrome: n = 2; and IPEX syndrome: n = 1who underwent eight hematopoietic stem cell transplants (HSCTin a single center, from 2007 to 2010, were studied. Results: Twopatients received transplants from HLA-identical siblings; the othersix transplants were done with unrelated donors (bone marrow: n= 1; cord blood: n = 5. All patients had pre-existing infectionsbefore hematopoietic stem cell transplants. One patient receivedonly anti-thymocyte globulin prior to transplant, three transplantswere done with reduced intensity conditioning regimens and fourtransplants were done after myeloablative therapy. Two patientswere not evaluable for engraftment due to early death. Three patientsengrafted, two had primary graft failure and one received a secondtransplant with posterior engraftment. Two patients died of regimenrelated toxicity (hepatic sinusoidal obstruction syndrome; one patient died of progressive respiratory failure due to Parainfluenza infection diagnosed prior to transplant. Four patients are alive and well from 60 days to 14 months after transplant. Conclusion: Patients’ status prior to transplant is the most important risk factor on the outcome of hematopoietic stem cell transplants in the treatment of these diseases. Early diagnosis and the possibility of a faster referral of these patients for treatment in reference centers may substantially improve their survival and quality of life.

  20. Cord Blood-Derived Hematopoietic Stem/Progenitor Cells: Current Challenges in Engraftment, Infection, and Ex Vivo Expansion

    Directory of Open Access Journals (Sweden)

    Katsuhiro Kita

    2011-01-01

    Full Text Available Umbilical cord blood has served as an alternative to bone marrow for hematopoietic transplantation since the late 1980s. Numerous clinical studies have proven the efficacy of umbilical cord blood. Moreover, the possible immaturity of cells in umbilical cord blood gives more options to recipients with HLA mismatch and allows for the use of umbilical cord blood from unrelated donors. However, morbidity and mortality rates associated with hematopoietic malignancies still remain relatively high, even after cord blood transplantation. Infections and relapse are the major causes of death after cord blood transplantation in patients with hematopoietic diseases. Recently, new strategies have been introduced to improve these major problems. Establishing better protocols for simple isolation of primitive cells and ex vivo expansion will also be very important. In this short review, we discuss several recent promising findings related to the technical improvement of cord blood transplantation.

  1. Nuclear adaptor Ldb1 regulates a transcriptional program essential for the maintenance of hematopoietic stem cells.

    Science.gov (United States)

    Li, LiQi; Jothi, Raja; Cui, Kairong; Lee, Jan Y; Cohen, Tsadok; Gorivodsky, Marat; Tzchori, Itai; Zhao, Yangu; Hayes, Sandra M; Bresnick, Emery H; Zhao, Keji; Westphal, Heiner; Love, Paul E

    2011-02-01

    The nuclear adaptor Ldb1 functions as a core component of multiprotein transcription complexes that regulate differentiation in diverse cell types. In the hematopoietic lineage, Ldb1 forms a complex with the non-DNA-binding adaptor Lmo2 and the transcription factors E2A, Scl and GATA-1 (or GATA-2). Here we demonstrate a critical and continuous requirement for Ldb1 in the maintenance of both fetal and adult mouse hematopoietic stem cells (HSCs). Deletion of Ldb1 in hematopoietic progenitors resulted in the downregulation of many transcripts required for HSC maintenance. Genome-wide profiling by chromatin immunoprecipitation followed by sequencing (ChIP-Seq) identified Ldb1 complex-binding sites at highly conserved regions in the promoters of genes involved in HSC maintenance. Our results identify a central role for Ldb1 in regulating the transcriptional program responsible for the maintenance of HSCs.

  2. Progressive maturation toward hematopoietic stem cells in the mouse embryo aorta

    NARCIS (Netherlands)

    Boisset, Jean-Charles; Clapes, Thomas; Klaus, Anna; Papazian, Natalie; Onderwater, Jos; Mommaas-Kienhuis, Mieke; Cupedo, Tom; Robin, Catherine

    2015-01-01

    Clusters of cells attached to the endothelium of the main embryonic arteries were first observed a century ago. Present in most vertebrate species, such clusters, or intraaortic hematopoietic clusters (IAHCs), derive from specialized hemogenic endothelial cells and contain the first few

  3. ES-cell derived hematopoietic cells induce transplantation tolerance.

    Directory of Open Access Journals (Sweden)

    Sabrina Bonde

    Full Text Available BACKGROUND: Bone marrow cells induce stable mixed chimerism under appropriate conditioning of the host, mediating the induction of transplantation tolerance. However, their strong immunogenicity precludes routine use in clinical transplantation due to the need for harsh preconditioning and the requirement for toxic immunosuppression to prevent rejection and graft-versus-host disease. Alternatively, embryonic stem (ES cells have emerged as a potential source of less immunogenic hematopoietic progenitor cells (HPCs. Up till now, however, it has been difficult to generate stable hematopoietic cells from ES cells. METHODOLOGY/PRINCIPAL FINDINGS: Here, we derived CD45(+ HPCs from HOXB4-transduced ES cells and showed that they poorly express MHC antigens. This property allowed their long-term engraftment in sublethally irradiated recipients across MHC barriers without the need for immunosuppressive agents. Although donor cells declined in peripheral blood over 2 months, low level chimerism was maintained in the bone marrow of these mice over 100 days. More importantly, chimeric animals were protected from rejection of donor-type cardiac allografts. CONCLUSIONS: Our data show, for the first time, the efficacy of ES-derived CD45(+ HPCs to engraft in allogenic recipients without the use of immunosuppressive agents, there by protecting cardiac allografts from rejection.

  4. Changing patterns of radiosensitivity of hematopoietic progenitors from chronically irradiated dogs prone either to aplastic anemia or to myeloproliferative disease

    International Nuclear Information System (INIS)

    Seed, T.M.; Kaspar, L.V.

    1990-01-01

    Hematopoietic patterns have been assessed in chronic 60 Co gamma irradiated dogs during preclinical phases of evolving aplastic anemia (AA) or myeloproliferative disease (MPD), principally myeloid leukemia. The results support the concept that acquired radioresistance of vital granulocyte/monocyte lineage-committed hematopoietic progenitors is temporally, perhaps causally, linked to the processes mediating hematopoietic recovery and accommodation under chronic irradiation, and in turn to preclinical events of evolving MPD. In addition, the marked differential responses of progenitors to gamma and neutron irradiation in vitro might suggest differences in the nature of cellular lesions elicited by chronic gamma irradiation, in vivo. (author)

  5. Changing patterns of radiosensitivity of hematopoietic progenitors from chronically irradiated dogs prone either to aplastic anemia or to myeloproliferative disease

    Energy Technology Data Exchange (ETDEWEB)

    Seed, T.M.; Kaspar, L.V. (Oak Ridge National Lab., TN (USA))

    1990-01-01

    Hematopoietic patterns have been assessed in chronic {sup 60}Co gamma irradiated dogs during preclinical phases of evolving aplastic anemia (AA) or myeloproliferative disease (MPD), principally myeloid leukemia. The results support the concept that acquired radioresistance of vital granulocyte/monocyte lineage-committed hematopoietic progenitors is temporally, perhaps causally, linked to the processes mediating hematopoietic recovery and accommodation under chronic irradiation, and in turn to preclinical events of evolving MPD. In addition, the marked differential responses of progenitors to gamma and neutron irradiation in vitro might suggest differences in the nature of cellular lesions elicited by chronic gamma irradiation, in vivo. (author).

  6. Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice

    Directory of Open Access Journals (Sweden)

    Pasupathi Sundaramoorthy

    2017-11-01

    Full Text Available Abstract Background Radiation exposure poses a significant threat to public health. Hematopoietic injury is one of the major manifestations of acute radiation sickness. Protection and/or mitigation of hematopoietic stem cells (HSCs from radiation injury is an important goal in the development of medical countermeasure agents (MCM. We recently identified thioredoxin (TXN as a novel molecule that has marked protective and proliferative effects on HSCs. In the current study, we investigated the effectiveness of TXN in rescuing mice from a lethal dose of total body radiation (TBI and in enhancing hematopoietic reconstitution following a lethal dose of irradiation. Methods We used in-vivo and in-vitro methods to understand the biological and molecular mechanisms of TXN on radiation mitigation. BABL/c mice were used for the survival study and a flow cytometer was used to quantify the HSC population and cell senescence. A hematology analyzer was used for the peripheral blood cell count, including white blood cells (WBCs, red blood cells (RBCs, hemoglobin, and platelets. Colony forming unit (CFU assay was used to study the colongenic function of HSCs. Hematoxylin and eosin staining was used to determine the bone marrow cellularity. Senescence-associated β-galactosidase assay was used for cell senescence. Western blot analysis was used to evaluate the DNA damage and senescence protein expression. Immunofluorescence staining was used to measure the expression of γ-H2AX foci for DNA damage. Results We found that administration of TXN 24 h following irradiation significantly mitigates BALB/c mice from TBI-induced death: 70% of TXN-treated mice survived, whereas only 25% of saline-treated mice survived. TXN administration led to enhanced recovery of peripheral blood cell counts, bone marrow cellularity, and HSC population as measured by c-Kit+Sca-1+Lin– (KSL cells, SLAM + KSL cells and CFUs. TXN treatment reduced cell senescence and radiation

  7. Dynamic changes in mouse hematopoietic stem cell numbers during aging

    NARCIS (Netherlands)

    de Haan, G; Van Zant, G

    1999-01-01

    To address the fundamental question of whether or not stem cell populations age, we performed quantitative measurements of the cycling status and frequency of hematopoietic stem cells in long-lived C57BL/6 (B6) and short-lived DBA/2 (DBA) mice at different developmental and aging stages. The

  8. Molecular mechanism behind the synergistic activity of diphenylmethyl selenocyanate and Cisplatin against murine tumor model.

    Science.gov (United States)

    Chakraborty, Pramita; Roy, Somnath Singha; Bhattacharya, Sudin

    2015-01-01

    Various preclinical, clinical and epidemiological studies have already well established the cancer chemopreventive and chemoprotective potential of selenium compounds. In addition to its protective efficacy, recent studies have also proved the abilities of selenium compounds to induce cell death specifically in malignant cells. Therefore, our intention is to improve the therapeutic efficacy of an alkylating agent, cisplatin, by the adjuvant use of an organoselenium compound, diphenylmethyl selenocyanate (DMSE). It was observed that combined treatment decreased the tumor burden significantly through reactive oxygen species generation and modulation of antioxidant and detoxifying enzyme system in tumor cells. These activities ultimately led to significant DNA damage and apoptosis in tumor cells. Study of the molecular pathway disclosed that the adjuvant treatment caused induction of p53, Bax and suppressed Bcl-2 followed by the activation of caspase cascade. Furthermore, a concomitant decrease in cisplatin-induced nephrotoxicity and hematopoietic toxicity by DMSE might also have enhanced the efficacy of cisplatin and provided survival advantage to the host. Results suggested that the combination treatment with DMSE and cisplatin may offer potential therapeutic benefit, and utilization of cisplatin in cancer chemotherapy exempt of its limitations.

  9. A telomerase em células-tronco hematopoéticas Telomerase in hematopoietic stem cells

    Directory of Open Access Journals (Sweden)

    Silvana Perini

    2008-02-01

    Full Text Available A proliferação das células-tronco hematopoéticas sofre a perda dos telômeros a cada divisão celular. Alguns autores discordam quanto à perda ou não do potencial proliferativo e capacidade de auto-renovação das células mais diferenciadas. Revisaremos aqui o papel da telomerase na biologia do sistema hematopoético, na diferenciação normal ou maligna, assim como no envelhecimento das células-tronco hematopoéticas. A constante renovação celular requerida pela hematopoese confere às células-tronco embrionárias, assim como à maioria das células tumorais, um aumento da capacidade proliferativa marcada pela detecção da enzima telomerase e possível manutenção dos telômeros. Estudos clínicos se farão necessários para esclarecer melhor a atividade da telomerase em células-tronco hematopoéticas, seu possível uso como marcador de diagnóstico e seu uso a fim de propósitos prognósticos.Hematopoietic stem cell proliferation leads to telomere length decreases at each cellular division. Some authors disagree about the telomere influence on the reduction of the proliferative potential and capacity of self renewal. Here we review telomerase function in the biology of the hematopoietic system, in normal or differentiation and its influence on the ageing of hematopoietic stem cells. The constant cellular renewal required to maintain the hematopoietic system, provides embryonic stem cells, as well as malignant cells, an increased proliferative capacity. This is marked by the detection of telomerase enzyme activity and possible telomere maintenance. Clinical trials will be required to clarify telomerase activity in hematopoietic stem cells, its possible use as a diagnostic marker and its use for prognostic purposes.

  10. Evaluation of Three Cases Using a Novel Titanium Mesh System-Skull-Fit with Orbital Wall (Skull-Fit WOW)-For Cranial Base Reconstructions.

    Science.gov (United States)

    Hattori, Noriko; Nakajima, Hideo; Tamada, Ikkei; Sakamoto, Yoshiaki; Ohira, Takayuki; Yoshida, Kazunari; Kawase, Takeshi; Kishi, Kazuo

    2011-09-01

    Cranial base reconstructions associated with tumor resections around the orbital wall often require that both the upper and lateral orbital walls be reconstructed during a single procedure. Previously, we used titanium mesh plates that were preoperatively fabricated based on three-dimensional models. Although these plates are precise and do not increase the probability of infection, we still had to use autologous bones to reconstruct the orbital walls. Recently, we developed a new titanium mesh plate-called Skull-Fit(®)-with orbital wall (Skull-Fit WOW(®)), enabling us to reconstruct the cranial base and orbital walls without bone grafts. Here, we report on three reconstruction cases in which the novel titanium mesh-orbital wall system was used. In all three cases, the customized titanium mesh system performed satisfactorily with little, if any, complications.

  11. Treatment Effects and Sequelae of Radiation Therapy for Orbital Mucosa-Associated Lymphoid Tissue Lymphoma

    International Nuclear Information System (INIS)

    Hata, Masaharu; Omura, Motoko; Koike, Izumi; Tomita, Naoto; Iijima, Yasuhito; Tayama, Yoshibumi; Odagiri, Kazumasa; Minagawa, Yumiko; Ogino, Ichiro; Inoue, Tomio

    2011-01-01

    Purpose: Among extranodal lymphomas, orbital mucosa-associated lymphoid tissue (MALT) lymphoma is a relatively rare presentation. We performed a review to ascertain treatment efficacy and toxicity of radiation therapy for orbital MALT lymphoma. We also evaluated changes in visual acuity after irradiation. Methods and Materials: Thirty patients with orbital MALT lymphoma underwent radiation therapy with curative intent. Clinical stages at diagnosis were stage I E A in 29 patients and stage II E A in 1 patient. Total doses of 28.8 to 45.8 Gy (median, 30 Gy) in 15 to 26 fractions (median, 16 fractions) were delivered to the tumors. Results: All irradiated tumors were controlled during the follow-up period of 2 to 157 months (median, 35 months) after treatment. Two patients had relapses that arose in the cervical lymph node and the ipsilateral palpebral conjunctiva outside the radiation field at 15 and 67 months after treatment, respectively. The 5-year local progression-free and relapse-free rates were 100% and 96%, respectively. All 30 patients are presently alive; the overall and relapse-free survival rates at 5 years were 100% and 96%, respectively. Although 5 patients developed cataracts of grade 2 at 8 to 45 months after irradiation, they underwent intraocular lens implantation, and their eyesight recovered. Additionally, there was no marked deterioration in the visual acuity of patients due to irradiation, with the exception of cataracts. No therapy-related toxicity of grade 3 or greater was observed. Conclusions: Radiation therapy was effective and safe for patients with orbital MALT lymphoma. Although some patients developed cataracts after irradiation, visual acuity was well preserved.

  12. Treatment Effects and Sequelae of Radiation Therapy for Orbital Mucosa-Associated Lymphoid Tissue Lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Hata, Masaharu, E-mail: mhata@syd.odn.ne.jp [Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa (Japan); Omura, Motoko; Koike, Izumi [Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa (Japan); Tomita, Naoto [Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa (Japan); Iijima, Yasuhito [Department of Ophthalmology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa (Japan); Tayama, Yoshibumi; Odagiri, Kazumasa; Minagawa, Yumiko [Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa (Japan); Ogino, Ichiro [Department of Radiation Oncology, Yokohama City University Medical Center, Yokohama, Kanagawa (Japan); Inoue, Tomio [Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa (Japan)

    2011-12-01

    Purpose: Among extranodal lymphomas, orbital mucosa-associated lymphoid tissue (MALT) lymphoma is a relatively rare presentation. We performed a review to ascertain treatment efficacy and toxicity of radiation therapy for orbital MALT lymphoma. We also evaluated changes in visual acuity after irradiation. Methods and Materials: Thirty patients with orbital MALT lymphoma underwent radiation therapy with curative intent. Clinical stages at diagnosis were stage I{sub E}A in 29 patients and stage II{sub E}A in 1 patient. Total doses of 28.8 to 45.8 Gy (median, 30 Gy) in 15 to 26 fractions (median, 16 fractions) were delivered to the tumors. Results: All irradiated tumors were controlled during the follow-up period of 2 to 157 months (median, 35 months) after treatment. Two patients had relapses that arose in the cervical lymph node and the ipsilateral palpebral conjunctiva outside the radiation field at 15 and 67 months after treatment, respectively. The 5-year local progression-free and relapse-free rates were 100% and 96%, respectively. All 30 patients are presently alive; the overall and relapse-free survival rates at 5 years were 100% and 96%, respectively. Although 5 patients developed cataracts of grade 2 at 8 to 45 months after irradiation, they underwent intraocular lens implantation, and their eyesight recovered. Additionally, there was no marked deterioration in the visual acuity of patients due to irradiation, with the exception of cataracts. No therapy-related toxicity of grade 3 or greater was observed. Conclusions: Radiation therapy was effective and safe for patients with orbital MALT lymphoma. Although some patients developed cataracts after irradiation, visual acuity was well preserved.

  13. Why are hematopoietic stem cells so 'sexy'? on a search for developmental explanation.

    Science.gov (United States)

    Ratajczak, M Z

    2017-08-01

    Evidence has accumulated that normal human and murine hematopoietic stem cells express several functional pituitary and gonadal sex hormones, and that, in fact, some sex hormones, such as androgens, have been employed for many years to stimulate hematopoiesis in patients with bone marrow aplasia. Interestingly, sex hormone receptors are also expressed by leukemic cell lines and blasts. In this review, I will discuss the emerging question of why hematopoietic cells express these receptors. A tempting hypothetical explanation for this phenomenon is that hematopoietic stem cells are related to subpopulation of migrating primordial germ cells. To support of this notion, the anatomical sites of origin of primitive and definitive hematopoiesis during embryonic development are tightly connected with the migratory route of primordial germ cells: from the proximal epiblast to the extraembryonic endoderm at the bottom of the yolk sac and then back to the embryo proper via the primitive streak to the aorta-gonado-mesonephros (AGM) region on the way to the genital ridges. The migration of these cells overlaps with the emergence of primitive hematopoiesis in the blood islands at the bottom of the yolk sac, and definitive hematopoiesis that occurs in hemogenic endothelium in the embryonic dorsal aorta in AGM region.

  14. Normal hematopoietic stem cell function in mice with enforced expression of the Hippo signaling effector YAP1.

    Directory of Open Access Journals (Sweden)

    Lina Jansson

    Full Text Available The Hippo pathway has recently been implicated in the regulation of organ size and stem cells in multiple tissues. The transcriptional cofactor yes-associated protein 1 (Yap1 is the most downstream effector of Hippo signaling and is functionally repressed by the upstream components of the pathway. Overexpression of YAP1 stimulates proliferation of stem and progenitor cells in many tissues, consistent with inhibition of Hippo signaling. To study the role of Hippo signaling in hematopoietic stem cells (HSCs, we created a transgenic model with inducible YAP1 expression exclusively within the hematopoietic system. Following 3 months induction, examination of blood and bone marrow in the induced mice revealed no changes in the distribution of the hematopoietic lineages compared to control mice. Moreover, the progenitor cell compartment was unaltered as determined by colony forming assays and immunophenotyping. To address whether YAP1 affects the quantity and function of HSCs we performed competitive transplantation experiments. We show that ectopic YAP1 expression does not influence HSC function neither during steady state nor in situations of hematopoietic stress. This is in sharp contrast to effects seen on stem- and progenitor cells in other organs and suggests highly tissue specific functions of the Hippo pathway in regulation of stem cells.

  15. DAS181 Treatment of Severe Parainfluenza Virus 3 Pneumonia in Allogeneic Hematopoietic Stem Cell Transplant Recipients Requiring Mechanical Ventilation

    Directory of Open Access Journals (Sweden)

    B. Dhakal

    2016-01-01

    Full Text Available Parainfluenza virus (PIV may cause life-threatening pneumonia in allogeneic hematopoietic stem cell transplant (HSCT recipients. Currently, there are no proven effective therapies. We report the use of inhaled DAS181, a novel sialidase fusion protein, for treatment of PIV type 3 pneumonia in two allogeneic hematopoietic SCT recipients with respiratory failure.

  16. Generation of axolotl hematopoietic chimeras

    Directory of Open Access Journals (Sweden)

    David Lopez

    2015-02-01

    Full Text Available Wound repair is an extremely complex process that requires precise coordination between various cell types including immune cells.  Unfortunately, in mammals this usually results in scar formation instead of restoration of the original fully functional tissue, otherwise known as regeneration.  Various animal models like frogs and salamanders are currently being studied to determine the intracellular and intercellular pathways, controlled by gene expression, that elicit cell proliferation, differentiation, and migration of cells during regenerative healing.  Now, the necessary genetic tools to map regenerative pathways are becoming available for the axolotl salamander, thus allowing comparative studies between scarring and regeneration.  Here, we describe in detail three methods to produce axolotl hematopoietic cell-tagged chimeras for the study of hematopoiesis and regeneration.

  17. ERS orbit control

    Science.gov (United States)

    Rosengren, Mats

    1991-12-01

    The European remote sensing mission orbit control is addressed. For the commissioning phase, the orbit is defined by the following requirements: Sun synchronous, local time of descending node 10:30; three days repeat cycle with 43 orbital revolutions; overhead Venice tower (12.508206 deg east, 45.314222 deg north). The launch, maneuvers for the initial acquisition of the operational orbit, orbit maintenance maneuvers, evaluation of the orbit control, and the drift of the inclination are summarized.

  18. Wnt5a regulates hematopoietic stem cell proliferation and repopulation through the Ryk receptor.

    Science.gov (United States)

    Povinelli, Benjamin J; Nemeth, Michael J

    2014-01-01

    Proper regulation of the balance between hematopoietic stem cell (HSC) proliferation, self-renewal, and differentiation is necessary to maintain hematopoiesis throughout life. The Wnt family of ligands has been implicated as critical regulators of these processes through a network of signaling pathways. Previously, we have demonstrated that the Wnt5a ligand can induce HSC quiescence through a noncanonical Wnt pathway, resulting in an increased ability to reconstitute hematopoiesis. In this study, we tested the hypothesis that the Ryk protein, a Wnt ligand receptor that can bind the Wnt5a ligand, regulated the response of HSCs to Wnt5a. We observed that inhibiting Ryk blocked the ability of Wnt5a to induce HSC quiescence and enhance short-term and long-term hematopoietic repopulation. We found that Wnt5a suppressed production of reactive oxygen species, a known inducer of HSC proliferation. The ability of Wnt5a to inhibit ROS production was also regulated by Ryk. From these data, we propose that Wnt5a regulates HSC quiescence and hematopoietic repopulation through the Ryk receptor and that this process is mediated by suppression of reactive oxygen species. © 2013 AlphaMed Press.

  19. Pre-malignant lymphoid cells arise from hematopoietic stem/progenitor cells in chronic lymphocytic leukemia.

    Science.gov (United States)

    Kikushige, Yoshikane; Miyamoto, Toshihiro

    2015-11-01

    Human malignancies progress through a multistep process that includes the development of critical somatic mutations over the clinical course. Recent novel findings have indicated that hematopoietic stem cells (HSCs), which have the potential to self-renew and differentiate into multilineage hematopoietic cells, are an important cellular target for the accumulation of critical somatic mutations in hematological malignancies and play a central role in myeloid malignancy development. In contrast to myeloid malignancies, mature lymphoid malignancies, such as chronic lymphocytic leukemia (CLL), are thought to originate directly from differentiated mature lymphocytes; however, recent compelling data have shown that primitive HSCs and hematopoietic progenitor cells contribute to the pathogenesis of mature lymphoid malignancies. Several representative mutations of hematological malignancies have been identified within the HSCs of CLL and lymphoma patients, indicating that the self-renewing long-lived fraction of HSCs can serve as a reservoir for the development of oncogenic events. Novel mice models have been established as human mature lymphoma models, in which specific oncogenic events target the HSCs and immature progenitor cells. These data collectively suggest that HSCs can be the cellular target involved in the accumulation of oncogenic events in the pathogenesis of mature lymphoid and myeloid malignancies.

  20. Brief Reports: Nfix Promotes Survival of Immature Hematopoietic Cells via Regulation of c-Mpl.

    Science.gov (United States)

    Hall, Trent; Walker, Megan; Ganuza, Miguel; Holmfeldt, Per; Bordas, Marie; Kang, Guolian; Bi, Wenjian; Palmer, Lance E; Finkelstein, David; McKinney-Freeman, Shannon

    2018-02-12

    Hematopoietic stem and progenitor cells (HSPCs) are necessary for life-long blood production and replenishment of the hematopoietic system during stress. We recently reported that nuclear factor I/X (Nfix) promotes HSPC survival post-transplant. Here, we report that ectopic expression of Nfix in primary mouse HSPCs extends their ex vivo culture from about 20 to 40 days. HSPCs overexpressing Nfix display hypersensitivity to supportive cytokines and reduced apoptosis when subjected to cytokine deprivation relative to controls. Ectopic Nfix resulted in elevated levels of c-Mpl transcripts and cell surface protein on primary murine HSPCs as well as increased phosphorylation of STAT5, which is known to be activated down-stream of c-MPL. Blocking c-MPL signaling by removal of thrombopoietin or addition of a c-MPL neutralizing antibody negated the antiapoptotic effect of Nfix overexpression on cultured HSPCs. Furthermore, NFIX was capable of binding to and transcriptionally activating a proximal c-Mpl promoter fragment. In sum, these data suggest that NFIX-mediated upregulation of c-Mpl transcription can protect primitive hematopoietic cells from stress ex vivo. Stem Cells 2018. © AlphaMed Press 2018.

  1. Body composition of Fanconi anemia patients after hematopoietic stem cell transplantation

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    Priscilla Peixoto Policarpo da Silva

    Full Text Available Abstract Introduction: Fanconi anemia is a rare genetic disease linked to bone marrow failure; a possible treatment is hematopoietic stem cell transplantation. Changes in the nutritional status of Fanconi anemia patients are not very well known. This study aimed to characterize body composition of adult, children and adolescent patients with Fanconi anemia who were submitted to hematopoietic stem cell transplantation or not. Methods: This cross-sectional study enrolled 63 patients (29 adults and 34 children and adolescents. Body composition was assessed based on diverse methods, including triceps skin fold, arm circumference, arm muscle area and bioelectrical impedance analysis, as there is no established consensus for this population. Body mass index was also considered as reference according to age. Results: Almost half (48.3% of the transplanted adult patients were underweight considering body mass index whereas eutrophic status was observed in 66.7% of the children and adolescents submitted to hematopoietic stem cell transplantation and in 80% of those who were not. At least 50% of all groups displayed muscle mass depletion. Half of the transplanted children and adolescents presented short/very short stature for age. Conclusion: All patients presented low muscle stores, underweight was common in adults, and short stature was common in children and adolescents. More studies are needed to detect whether muscle mass loss measured at the early stages of treatment results in higher risk of mortality, considering the importance of muscle mass as an essential body component to prevent mortality related to infectious and non-infectious diseases and the malnutrition inherent to Fanconi anemia.

  2. Reduced Erg Dosage Impairs Survival of Hematopoietic Stem and Progenitor Cells.

    Science.gov (United States)

    Xie, Ying; Koch, Mia Lee; Zhang, Xin; Hamblen, Melanie J; Godinho, Frank J; Fujiwara, Yuko; Xie, Huafeng; Klusmann, Jan-Henning; Orkin, Stuart H; Li, Zhe

    2017-07-01

    ERG, an ETS family transcription factor frequently overexpressed in human leukemia, has been implicated as a key regulator of hematopoietic stem cells. However, how ERG controls normal hematopoiesis, particularly at the stem and progenitor cell level, and how it contributes to leukemogenesis remain incompletely understood. Using homologous recombination, we generated an Erg knockdown allele (Erg kd ) in which Erg expression can be conditionally restored by Cre recombinase. Erg kd/kd animals die at E10.5-E11.5 due to defects in endothelial and hematopoietic cells, but can be completely rescued by Tie2-Cre-mediated restoration of Erg in these cells. In Erg kd/+ mice, ∼40% reduction in Erg dosage perturbs both fetal liver and bone marrow hematopoiesis by reducing the numbers of Lin - Sca-1 + c-Kit + (LSK) hematopoietic stem and progenitor cells (HSPCs) and megakaryocytic progenitors. By genetic mosaic analysis, we find that Erg-restored HSPCs outcompete Erg kd/+ HSPCs for contribution to adult hematopoiesis in vivo. This defect is in part due to increased apoptosis of HSPCs with reduced Erg dosage, a phenotype that becomes more drastic during 5-FU-induced stress hematopoiesis. Expression analysis reveals that reduced Erg expression leads to changes in expression of a subset of ERG target genes involved in regulating survival of HSPCs, including increased expression of a pro-apoptotic regulator Bcl2l11 (Bim) and reduced expression of Jun. Collectively, our data demonstrate that ERG controls survival of HSPCs, a property that may be used by leukemic cells. Stem Cells 2017;35:1773-1785. © 2017 AlphaMed Press.

  3. Pulmonary candidiasis after hematopoietic stem cell transplantation: thin-section CT findings.

    Science.gov (United States)

    Franquet, Tomás; Müller, Nestor L; Lee, Kyung S; Oikonomou, Anastasia; Flint, Julia D

    2005-07-01

    To retrospectively evaluate thin-section computed tomographic (CT) findings in hematopoietic stem cell transplant (ie, bone marrow transplant) patients with histopathologically proved pulmonary candidiasis. Ethical approval was obtained from the institutional review board of each of the three institutions; informed consent was not required. The study included 17 hematopoietic stem cell transplant recipients with proved pulmonary candidiasis. Histopathologic specimens were acquired at transbronchial biopsy (n = 8), open lung biopsy (n = 6), and autopsy (n = 3). The patients included seven men and 10 women (age range, 20-62 years; mean age, 37 years). The thin-section CT scans were retrospectively reviewed by two thoracic radiologists for the presence, appearance, and distribution of parenchymal abnormalities. Multiple nodules were present in 15 (88%) patients, including centrilobular nodules and tree-in-bud pattern in seven (41%) patients. Nodules were bilateral in 12 patients and unilateral in three. An associated halo of ground-glass opacity was identified in five (33%) patients. Nodules were the only CT finding in five patients (29%). Areas of air-space consolidation were identified in 11 (65%) patients. Areas of ground-glass opacity were seen in six (35%) of 17 patients and were always associated with other abnormalities. Other less common CT findings included pleural effusion (n = 3), thickening of the bronchial walls (n = 2), and cavitation (n = 1). The most common thin-section CT findings of pulmonary candidiasis in hematopoietic stem cell transplant patients are multiple bilateral nodular opacities often associated with areas of consolidation. Copyright RSNA, 2005

  4. Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells

    Science.gov (United States)

    Gori, Jennifer L.; Butler, Jason M.; Chan, Yan-Yi; Chandrasekaran, Devikha; Poulos, Michael G.; Ginsberg, Michael; Nolan, Daniel J.; Elemento, Olivier; Wood, Brent L.; Adair, Jennifer E.; Rafii, Shahin; Kiem, Hans-Peter

    2015-01-01

    Pluripotent stem cells (PSCs) represent an alternative hematopoietic stem cell (HSC) source for treating hematopoietic disease. The limited engraftment of human PSC–derived (hPSC-derived) multipotent progenitor cells (MPP) has hampered the clinical application of these cells and suggests that MPP require additional cues for definitive hematopoiesis. We hypothesized that the presence of a vascular niche that produces Notch ligands jagged-1 (JAG1) and delta-like ligand-4 (DLL4) drives definitive hematopoiesis. We differentiated hes2 human embryonic stem cells (hESC) and Macaca nemestrina–induced PSC (iPSC) line-7 with cytokines in the presence or absence of endothelial cells (ECs) that express JAG1 and DLL4. Cells cocultured with ECs generated substantially more CD34+CD45+ hematopoietic progenitors compared with cells cocultured without ECs or with ECs lacking JAG1 or DLL4. EC-induced cells exhibited Notch activation and expressed HSC-specific Notch targets RUNX1 and GATA2. EC-induced PSC-MPP engrafted at a markedly higher level in NOD/SCID/IL-2 receptor γ chain–null (NSG) mice compared with cytokine-induced cells, and low-dose chemotherapy-based selection further increased engraftment. Long-term engraftment and the myeloid-to-lymphoid ratio achieved with vascular niche induction were similar to levels achieved for cord blood–derived MPP and up to 20-fold higher than those achieved with hPSC-derived MPP engraftment. Our findings indicate that endothelial Notch ligands promote PSC-definitive hematopoiesis and production of long-term engrafting CD34+ cells, suggesting these ligands are critical for HSC emergence. PMID:25664855

  5. Computed tomography and histopathological findings in pseudotumors of the orbit

    International Nuclear Information System (INIS)

    Ishibashi, Yasuhiko; Watanabe, Takao; Yoshimoto, Takashi; Suzuki, Jiro

    1981-01-01

    The CT scan findings of 4 cases of orbital tumor, in which transcranial orbital decompression was performed because of no improvement by medication, were reported. The first case was a 71-year-old female with exophthalmos, decreased vision and ocular movement disturbance of the left eye. CT scan demonstrated an abnormal high density area in the left retrobulbar region with a thickened medial rectal muscle. Specimens were taken from a thickened medial rectal muscle. The histological examination revealed angitis. The second case was a 38-year-old female with exophthalmos, blepharoptosis, chemosis, decreased vision and ocular movement disturbance of the left eye. CT scan showed exophthalmos of the left eye, but no focal abnormality. Specimens were taken from fatty tissue-in the left retrobulbar region. The histological examination revealed no abnormal inflammatory changes. The third case was a 37-year-old female with orbital pain, exophthalmos and ocular movement disturbance of the right eye. CT scan demonstrated a growing abnormal high density area in the right retrobulbar region. Specimens were taken from the abnormal tissue in the right retrobulbar region. The histological examination revealed inflammatory changes of muscle and nerve. The forth case was a 61-year-old male with diplopia and exophthalmos. CT scan demonstrated an abnormal high density area in the left retrobulbar region. Specimens were taken from an abnormal tissue in the left retrobulbar region lying against the lateral wall of the orbit. The histological examination revealed severe infiltrations with lymphocytes and plasma cells. Transcranial orbital decompression improved the exophthalmos and ocular movement in all cases. (author)

  6. Computed tomography and histopathological findings in pseudotumors of the orbit

    Energy Technology Data Exchange (ETDEWEB)

    Ishibashi, Y.; Watanabe, T.; Yoshimoto, T.; Suzuki, J. (Tohoku Univ., Sendai (Japan). School of Medicine)

    1981-09-01

    The CT scan findings of 4 cases of orbital tumor, in which transcranial orbital decompression was performed because of no improvement by medication, were reported. The first case was a 71-year-old female with exophthalmos, decreased vision and ocular movement disturbance of the left eye. CT scan demonstrated an abnormal high density area in the left retrobulbar region with a thickened medial rectal muscle. Specimens were taken from a thickened medial rectal muscle. The histological examination revealed angitis. The second case was a 38-year-old female with exophthalmos, blepharoptosis, chemosis, decreased vision and ocular movement disturbance of the left eye. CT scan showed exophthalmos of the left eye, but no focal abnormality. Specimens were taken from fatty tissue in the left retrobulbar region. The histological examination revealed no abnormal inflammatory changes. The third case was a 37-year-old female with orbital pain, exophthalmos and ocular movement disturbance of the right eye. CT scan demonstrated a growing abnormal high density area in the right retrobulbar region. Specimens were taken from the abnormal tissue in the right retrobulbar region. The histological examination revealed inflammatory changes of muscle and nerve. The forth case was a 61-year-old male with diplopia and exophthalmos. CT scan demonstrated an abnormal high density area in the left retrobulbar region. Specimens were taken from an abnormal tissue in the left retrobulbar region lying against the lateral wall of the orbit. The histological examination revealed severe infiltrations with lymphocytes and plasma cells. Transcranial orbital decompression improved the exophthalmos and ocular movement in all cases.

  7. Oral changes in individuals undergoing hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Regina Haddad Barrach

    2015-04-01

    Full Text Available INTRODUCTION: Patients undergoing hematopoietic stem cell transplantation receive high doses of chemotherapy and radiotherapy, which cause severe immunosuppression.OBJECTIVE: To report an oral disease management protocol before and after hematopoietic stem cell transplantation.METHODS: A prospective study was carried out with 65 patients aged > 18 years, with hematological diseases, who were allocated into two groups: A (allogeneic transplant, 34 patients; B (autologous transplant, 31 patients. A total of three dental status assessments were performed: in the pre-transplantation period (moment 1, one week after stem cell infusion (moment 2, and 100 days after transplantation (moment 3. In each moment, oral changes were assigned scores and classified as mild, moderate, and severe risks.RESULTS: The most frequent pathological conditions were gingivitis, pericoronitis in the third molar region, and ulcers at the third moment assessments. However, at moments 2 and 3, the most common disease was mucositis associated with toxicity from the drugs used in the immunosuppression.CONCLUSION: Mucositis accounted for the increased score and potential risk of clinical complications. Gingivitis, ulcers, and pericoronitis were other changes identified as potential risk factors for clinical complications.

  8. [Hematopoietic cells raising with plerixafor in non-Hodgkin lymphoma].

    Science.gov (United States)

    Pérez-Lozano, Uendy; Tripp-Villanueva, Francisco; Ramírez-Alvarado, Aline; Vela-Ojeda, Jorge; Limón-Flores, Alejandro; Kramis-Cerezo, José Luis

    2012-01-01

    bone marrow autologous transplantation (BMAT) has proven benefits in patients treated for non-Hodgkin's lymphoma (NHL). Plerixafor is an inhibitor of CXCR4 receptor. The aim was to report the raise of hematopoietic cells with plerixafor in patients with NHL. patient 1 with follicular NHL, GI, intermediate FLIPI, CD20+, CD45+, BCL-2+, who reached complete response after three chemotherapy regimes. Mobilization failed after use of filgrastim (G-CSF) alone and G-CSF + cyclophosphamide. A new attempt was made with G-CSF + plerixafor (G-CSF, 10 μg/kg for 7 days + plerixafor, 240 μg/kg in days 4 to 7). Patient 2 with follicular NHL and CD20+ reached complete remission with MINE after therapeutic failure with other regimes, but develops severe marrow toxicity. Mobilization was supported with G-CSF 10 μg/kg/d + plerixafor in days 4 and 5. In case one, proper cell counts where obtained after three aphaeresis. In the second case, two harvests add of 2.7 × 106/kg were obtained. plerixafor raised the hematopoietic stem cells in peripheral blood and improves mobilization of proper cell population.

  9. Developmental Vitamin D Availability Impacts Hematopoietic Stem Cell Production

    Directory of Open Access Journals (Sweden)

    Mauricio Cortes

    2016-10-01

    Full Text Available Vitamin D insufficiency is a worldwide epidemic affecting billions of individuals, including pregnant women and children. Despite its high incidence, the impact of active vitamin D3 (1,25(OHD3 on embryonic development beyond osteo-regulation remains largely undefined. Here, we demonstrate that 1,25(OHD3 availability modulates zebrafish hematopoietic stem and progenitor cell (HSPC production. Loss of Cyp27b1-mediated biosynthesis or vitamin D receptor (VDR function by gene knockdown resulted in significantly reduced runx1 expression and Flk1+cMyb+ HSPC numbers. Selective modulation in vivo and in vitro in zebrafish indicated that vitamin D3 acts directly on HSPCs, independent of calcium regulation, to increase proliferation. Notably, ex vivo treatment of human HSPCs with 1,25(OHD3 also enhanced hematopoietic colony numbers, illustrating conservation across species. Finally, gene expression and epistasis analysis indicated that CXCL8 (IL-8 was a functional target of vitamin D3-mediated HSPC regulation. Together, these findings highlight the relevance of developmental 1,25(OHD3 availability for definitive hematopoiesis and suggest potential therapeutic utility in HSPC expansion.

  10. Umbilical cord blood banking in the worldwide hematopoietic stem cell transplantation system: perspectives for Ukraine.

    Science.gov (United States)

    Kalynychenko, T O

    2017-09-01

    Significant progress in the promotion of procedural technologies associated with the transplantation of hematopoietic stem cells caused a rapid increase in activity. The exchange of hematopoietic stem cells for unrelated donor transplantations is now much easier due to the relevant international professional structures and organizations established to support cooperation and standard setting, as well as rules for the functioning of both national donor registries and cord blood banks. These processes are increasing every year and are contributing to the outpacing rates of development in this area. Products within their country should be regulated by the competent government authorities. This study analyzes the work of international and national levels of support for transplantation activity in the field of unrelated hematopoietic stem cell transplantation, the standardization order of technologies, as well as data that justify the need to create a network of donated umbilical cord blood banks in Ukraine as a factor in the development of allogeneic transplantation. This will promote the accessibility of international standards for the treatment of serious diseases for Ukrainian citizens.

  11. A Typical Presentation of Orbital Pseudotumor Mimicking Orbital Cellulitis

    Directory of Open Access Journals (Sweden)

    J. Ayatollahi

    2013-10-01

    Full Text Available Introduction: Orbital pseudotumor, also known as idiopathic orbital inflammatory syndrome (IOIS, is a benign, non- infective inflammatory condition of the orbit without identifiable local or systemic causes. The disease may mimics a variety of pathologic conditions. We pre-sent a case of pseudotumor observed in a patient admitted under the name of orbital celluli-ties. Case Report: A 26-year-old woman reffered to our hospital with the history of left ocular pain and headache 2 days before her visit.. Ophthalmological examination of the patient was normal except for the redness and lid edema, mild chemosis and conjunctival injection. Gen-eral assessment was normal but a low grade fever was observed. She was hospitalized as an orbital cellulitis patient. She was treated with intravenous antibiotics. On the third day , sud-denly diplopia, proptosis in her left eye and ocular pain in her right side appeared. MRI re-vealed bilateral enlargement of extraocular muscles. Diagnosis of orbital pseudotumor was made and the patient was treated with oral steroid.She responded promptly to the treatment. Antibiotics were discontinued and steroid was tapered in one month period under close fol-low up. Conclusion: The clinical features of orbital pseudotumor vary widely . Orbital pseudotumor and orbital cellulitis can occasionally demonstrate overlapping features.. Despite complete physical examination and appropriate imaging, sometimes correct diagnosis of the disease would be difficult (Sci J Hamadan Univ Med Sci 2013; 20 (3:256-259

  12. Lymphomas or leukemia presenting as ovarian tumors. An analysis of 42 cases.

    Science.gov (United States)

    Osborne, B M; Robboy, S J

    1983-11-15

    Forty cases of ovarian lymphoma and two of extramedullary leukemia were examined with emphasis on histologic types correlated with age, modes of presentation, operative findings, including frequency of bilaterality and omental spread, clinical course following therapy, and problems in differential diagnosis. Although most cases were referred with diagnoses other than lymphoma (granulosa cell tumor or dysgerminoma, occasionally anaplastic tumor, Krukenberg tumor, or metastatic breast carcinoma), utilization of sections cut at 4 mu and stained with hematoxylin and eosin, or sections stained by the methyl green pyronine (MGP), naphthol-ASD esterase (NASD) or periodic acid-Schiff (PAS) methods helped bring out the lymphoid or hematopoietic nature of the cells. Sixteen patients were under 20 years of age. They had small noncleaved cell lymphoma (undifferentiated Burkitt's and non-Burkitt's, 10 cases), diffuse immunoblastic large cell lymphoma (4 cases), or acute granulocytic leukemia (2 cases). Twenty-six patients were 29 to 74 years of age and had diffuse large cell lymphoma (10 cases), diffuse immunoblastic large cell lymphoma (9 cases), follicular (nodular) lymphoma (6 cases) or small noncleaved cell lymphoma (1 case). Pain with an abdominal or pelvic mass was the most common presentation. Nine tumors were discovered during investigation of other gynecologic complaints. At laparotomy, the tumors in 55% of cases involved both ovaries, and in 64% also involved extragonadal sites (usually omentum, fallopian tubes, or lymph nodes). Seventeen patients had tumor affecting one ovary, seven of these without any evidence of extragonadal spread. Forty-two percent (15) of 37 patients with follow-up were alive after 2 years. Only nine patients survived more than 5 years; two subsequently died of lymphoma. Favorable prognostic features included: (1) FIGO stage IA; (2) unilateral ovarian involvement; (3) focal involvement of one ovary; and (4) follicular (nodular) lymphoma.

  13. Intrathymic injection of hematopoietic progenitor cells establishes functional T cell development in a mouse model of severe combined immunodeficiency

    Directory of Open Access Journals (Sweden)

    Andrea Z. Tuckett

    2017-05-01

    Full Text Available Abstract Background Even though hematopoietic stem cell transplantation can be curative in patients with severe combined immunodeficiency, there is a need for additional strategies boosting T cell immunity in individuals suffering from genetic disorders of lymphoid development. Here we show that image-guided intrathymic injection of hematopoietic stem and progenitor cells in NOD-scid IL2rγnull mice is feasible and facilitates the generation of functional T cells conferring protective immunity. Methods Hematopoietic stem and progenitor cells were isolated from the bone marrow of healthy C57BL/6 mice (wild-type, Luciferase+, CD45.1+ and injected intravenously or intrathymically into both male and female, young or aged NOD-scid IL2rγnull recipients. The in vivo fate of injected cells was analyzed by bioluminescence imaging and flow cytometry of thymus- and spleen-derived T cell populations. In addition to T cell reconstitution, we evaluated mice for evidence of immune dysregulation based on diabetes development and graft-versus-host disease. T cell immunity following intrathymic injection of hematopoietic stem and progenitor cells in NOD-scid IL2rγnull mice was assessed in a B cell lymphoma model. Results Despite the small size of the thymic remnant in NOD-scid IL2rγnull mice, we were able to accomplish precise intrathymic delivery of hematopoietic stem and progenitor cells by ultrasound-guided injection. Thymic reconstitution following intrathymic injection of healthy allogeneic hematopoietic cells was most effective in young male recipients, indicating that even in the setting of severe immunodeficiency, sex and age are important variables for thymic function. Allogeneic T cells generated in intrathymically injected NOD-scid IL2rγnull mice displayed anti-lymphoma activity in vivo, but we found no evidence for severe auto/alloreactivity in T cell-producing NOD-scid IL2rγnull mice, suggesting that immune dysregulation is not a major concern

  14. The Polycomb Group Protein L3MBTL1 Represses a SMAD5-Mediated Hematopoietic Transcriptional Program in Human Pluripotent Stem Cells

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    Fabiana Perna

    2015-04-01

    Full Text Available Epigenetic regulation of key transcriptional programs is a critical mechanism that controls hematopoietic development, and, thus, aberrant expression patterns or mutations in epigenetic regulators occur frequently in hematologic malignancies. We demonstrate that the Polycomb protein L3MBTL1, which is monoallelically deleted in 20q- myeloid malignancies, represses the ability of stem cells to drive hematopoietic-specific transcriptional programs by regulating the expression of SMAD5 and impairing its recruitment to target regulatory regions. Indeed, knockdown of L3MBTL1 promotes the development of hematopoiesis and impairs neural cell fate in human pluripotent stem cells. We also found a role for L3MBTL1 in regulating SMAD5 target gene expression in mature hematopoietic cell populations, thereby affecting erythroid differentiation. Taken together, we have identified epigenetic priming of hematopoietic-specific transcriptional networks, which may assist in the development of therapeutic approaches for patients with anemia.

  15. Deadly Sunflower Orbits

    Science.gov (United States)

    Hamilton, Douglas P.

    2018-04-01

    Solar radiation pressure is usually very effective at removing hazardous millimeter-sized debris from distant orbits around asteroidsand other small solar system bodies (Hamilton and Burns 1992). Theprimary loss mechanism, driven by the azimuthal component of radiationpressure, is eccentricity growth followed by a forced collision withthe central body. One large class of orbits, however, neatly sidestepsthis fate. Orbits oriented nearly perpendicular to the solar directioncan maintain their face-on geometry, oscillating slowly around a stableequilibrium orbit. These orbits, designated sunflower orbits, arerelated to terminator orbits studied by spacecraft mission designers(Broschart etal. 2014).Destabilization of sunflower orbits occurs only for particles smallenough that radiation pressure is some tens of percent the strength ofthe central body's direct gravity. This greatly enhanced stability,which follows from the inability of radiation incident normal to theorbit to efficiently drive eccentricities, presents a threat tospacecraft missions, as numerous dangerous projectiles are potentiallyretained in orbit. We have investigated sunflower orbits insupport of the New Horizons, Aida, and Lucy missions and find thatthese orbits are stable for hazardous particle sizes at asteroids,comets, and Kuiper belt objects of differing dimensions. Weinvestigate the sources and sinks for debris that might populate suchorbits, estimate timescales and equilibrium populations, and willreport on our findings.

  16. Generation of induced pluripotent stem cells as a potential source of hematopoietic stem cells for transplant in PNH patients.

    Science.gov (United States)

    Phondeechareon, Tanapol; Wattanapanitch, Methichit; U-Pratya, Yaowalak; Damkham, Chanapa; Klincumhom, Nuttha; Lorthongpanich, Chanchao; Kheolamai, Pakpoom; Laowtammathron, Chuti; Issaragrisil, Surapol

    2016-10-01

    Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by lack of CD55 and CD59 on blood cell membrane leading to increased sensitivity of blood cells to complement. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for PNH, however, lack of HLA-matched donors and post-transplant complications are major concerns. Induced pluripotent stem cells (iPSCs) derived from patients are an attractive source for generating autologous HSCs to avoid adverse effects resulting from allogeneic HSCT. The disease involves only HSCs and their progeny; therefore, other tissues are not affected by the mutation and may be used to produce disease-free autologous HSCs. This study aimed to derive PNH patient-specific iPSCs from human dermal fibroblasts (HDFs), characterize and differentiate to hematopoietic cells using a feeder-free protocol. Analysis of CD55 and CD59 expression was performed before and after reprogramming, and hematopoietic differentiation. Patients' dermal fibroblasts expressed CD55 and CD59 at normal levels and the normal expression remained after reprogramming. The iPSCs derived from PNH patients had typical pluripotent properties and differentiation capacities with normal karyotype. After hematopoietic differentiation, the differentiated cells expressed early hematopoietic markers (CD34 and CD43) with normal CD59 expression. The iPSCs derived from HDFs of PNH patients have normal levels of CD55 and CD59 expression and hold promise as a potential source of HSCs for autologous transplantation to cure PNH patients.

  17. Hematopoietic microenvironment. Origin, lineage, and transplantability of the stromal cells in long-term bone marrow cultures from chimeric mice

    International Nuclear Information System (INIS)

    Perkins, S.; Fleischman, R.A.

    1988-01-01

    Studies of bone marrow transplant patients have suggested that the stromal cells of the in vitro hematopoietic microenvironment are transplantable into conditioned recipients. Moreover, in patients with myeloproliferative disorders, all of the stromal cells, which include presumptive endothelial cells, appear to be derived from hematopoietic precursors. To confirm these findings, we have constructed two chimeric mouse models: (a) traditional radiation chimeras, and (b) fetal chimeras, produced by placental injection of bone marrow into genetically anemic Wx/Wv fetuses, a technique that essentially precludes engraftment of nonhematopoietic cells. Using two-color indirect immunofluorescence, the stromal cells in long-term bone marrow culture derived from these chimeras were analyzed for donor or host origin by strain-specific H-2 antigens, and for cell lineage by a variety of other specific markers. 75-95% of the stromal cells were shown to be hematopoietic cells of the monocyte-macrophage lineage, based upon donor origin, phagocytosis, and expression of specific hematopoietic surface antigens. The remaining 5-25% of the stromal cells were exclusively host in origin. Apart from occasional fat cells, these cells uniformly expressed collagen type IV, laminin, and a surface antigen associated with endothelial cells. Since these endothelial-like cells are not transplantable into radiation or fetal chimeras, they are not derived from hematopoietic stem cells. The contrast between our findings and human studies suggests either unexpected species differences in the origin of stromal lineages or limitations in the previous methodology used to detect nonhematopoietic stromal cells

  18. Incidence of enhancement of the optic nerve/sheath complex in fat-suppression orbit MRI

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ho Kyu; Yoon, Kwon Ha; Choi, Choong Gon; Suh, Dae Chul [Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    1995-04-15

    To elucidate the incidence of Gd-DTPA enhancement of the optic nerve/sheath complex (ONC) in patients with various ophthalmopathies using fat-suppression MRI. Orbit MRI with fat-suppression technique (ChemSat) was performed in 58 patients with normal and various orbital lesions. The fat-suppression MR was done with and without Gd-DTPA injection in all cases. MR findings were reviewed retrospectively in a blind fashion with respect to presence or absence of contrast enhancement of the ONC. Contrast enhancement of the ONC was seen in 86% (6/7) of cavernous sinus lesions, 80% (8/10) of intraconal lesions excluding the ONC, 57% (16/28) of ONC lesions, 38% (3/8) of ocular lesions, and 2% (1/55) of normal orbits. The ONC enhancement was the most common in optic nerve/sheath tumors (10/10), and pseudotumors (6/6), cavernous sinus dural arteriovenous malformations (3/3) and cavernous sinus thrombosis (2/2), and less frequently seen in optic neuritis (3/14). Enhancement of the ONC may be seen in lesions of the cavernous sinus and orbit other than optic nerve/sheath lesion.

  19. CT findings of malignant nasal cavity tumors

    International Nuclear Information System (INIS)

    Ku, Young Mi; Chun, Kyung Ah; Choi, Kyu Ho; Yu, Won Jong; Kim, Young Joo; Kim, Sung Hoon; Park, Seog Hee; Shinn, Kyung Sub

    1997-01-01

    To evaluate the CT findings of malignant nasal cavity tumors. Retrospective analysis was performed on 20 patients with pathologically-proven malignant nasal cavity tumors. Using CT, we analysed their location, extent of bone destruction and of involvement of adjacent structures, and enhancing pattern. A total of 20 cases included nine squamous cell carcinomas, three olfactory neuroblastomas, three lymphomas, two polymorphic reticulosis, one adenoid cystic carcinoma, one undifferentiated carcinoma and one metastasis from renal cell carcinoma. All cases except one adenoid cystic carcinoma and one squamous cell carcinoma revealed bone destruction or erosion. Aggressive bone destruction and irregular enhancement were seen in eight cases of squamous cell carcinoma, seven cases of which showed involvement of the adjacent paranasal sinuses, nasopharynx, and orbit. Olfactory neuroblastomas were centered in the superior nasal cavity and the adjacent ethmoid sinus, and erosion or destruction of the cribriform plate had occurred. Lymphomas showed bilateral involvement, with uniform contrast enhancement. Polymorphic reticuloses showed perforation or erosion of the nasal septum, with bilateral involvement of the nasal cavity. The location, presence of bone destruction, involvement of adjacent structures, and enhancement pattern of tumor on CT can be helpful for the differential diagnosis of malignant nasal cavity tumors

  20. Allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies: Hospital Israelita Albert Einstein experience.

    Science.gov (United States)

    Fernandes, Juliana Folloni; Kerbauy, Fabio Rodrigues; Ribeiro, Andreza Alice Feitosa; Kutner, Jose Mauro; Camargo, Luis Fernando Aranha; Stape, Adalberto; Troster, Eduardo Juan; Zamperlini-Netto, Gabriele; Azambuja, Alessandra Milani Prandini de; Carvalho, Bruna; Dorna, Mayra de Barros; Vilela, Marluce Dos Santos; Jacob, Cristina Miuki Abe; Costa-Carvalho, Beatriz Tavares; Cunha, Jose Marcos; Carneiro-Sampaio, Magda Maria; Hamerschlak, Nelson

    2011-06-01

    To report the experience of a tertiary care hospital with allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies. Seven pediatric patients with primary immunodeficiencies (severe combined immunodeficiency: n = 2; combined immunodeficiency: n = 1; chronic granulomatous disease: n = 1; hyper-IgM syndrome: n = 2; and IPEX syndrome: n = 1) who underwent eight hematopoietic stem cell transplants in a single center, from 2007 to 2010, were studied. Two patients received transplants from HLA-identical siblings; the other six transplants were done with unrelated donors (bone marrow: n = 1; cord blood: n = 5). All patients had pre-existing infections before hematopoietic stem cell transplants. One patient received only anti-thymocyte globulin prior to transplant, three transplants were done with reduced intensity conditioning regimens and four transplants were done after myeloablative therapy. Two patients were not evaluated for engraftment due to early death. Three patients engrafted, two had primary graft failure and one received a second transplant with posterior engraftment. Two patients died of regimen related toxicity (hepatic sinusoidal obstruction syndrome); one patient died of progressive respiratory failure due to Parainfluenza infection present prior to transplant. Four patients are alive and well from 60 days to 14 months after transplant. Patients' status prior to transplant is the most important risk factor on the outcome of hematopoietic stem cell transplants in the treatment of these diseases. Early diagnosis and the possibility of a faster referral of these patients for treatment in reference centers may substantially improve their survival and quality of life.

  1. Orbits

    CERN Document Server

    Xu, Guochang

    2008-01-01

    This is the first book of the satellite era which describes orbit theory with analytical solutions of the second order with respect to all possible disturbances. Based on such theory, the algorithms of orbits determination are completely revolutionized.

  2. Sonic Hedgehog Signaling Regulates Hematopoietic Stem/Progenitor Cell Activation during the Granulopoietic Response to Systemic Bacterial Infection.

    Science.gov (United States)

    Shi, Xin; Wei, Shengcai; Simms, Kevin J; Cumpston, Devan N; Ewing, Thomas J; Zhang, Ping

    2018-01-01

    Activation and reprogramming of hematopoietic stem/progenitor cells play a critical role in the granulopoietic response to bacterial infection. Our current study determined the significance of Sonic hedgehog (SHH) signaling in the regulation of hematopoietic precursor cell activity during the host defense response to systemic bacterial infection. Bacteremia was induced in male Balb/c mice via intravenous injection (i.v.) of Escherichia coli (5 × 10 7 CFUs/mouse). Control mice received i.v. saline. SHH protein level in bone marrow cell (BMC) lysates was markedly increased at both 24 and 48 h of bacteremia. By contrast, the amount of soluble SHH ligand in marrow elutes was significantly reduced. These contrasting alterations suggested that SHH ligand release from BMCs was reduced and/or binding of soluble SHH ligand to BMCs was enhanced. At both 12 and 24 h of bacteremia, SHH mRNA expression by BMCs was significantly upregulated. This upregulation of SHH mRNA expression was followed by a marked increase in SHH protein expression in BMCs. Activation of the ERK1/2-SP1 pathway was involved in mediating the upregulation of SHH gene expression. The major cell type showing the enhancement of SHH expression in the bone marrow was lineage positive cells. Gli1 positioned downstream of the SHH receptor activation serves as a key component of the hedgehog (HH) pathway. Primitive hematopoietic precursor cells exhibited the highest level of baseline Gli1 expression, suggesting that they were active cells responding to SHH ligand stimulation. Along with the increased expression of SHH in the bone marrow, expression of Gli1 by marrow cells was significantly upregulated at both mRNA and protein levels following bacteremia. This enhancement of Gli1 expression was correlated with activation of hematopoietic stem/progenitor cell proliferation. Mice with Gli1 gene deletion showed attenuation in activation of marrow hematopoietic stem/progenitor cell proliferation and inhibition

  3. Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Cartier, Nathalie; Hacein-Bey-Abina, Salima; Bartholomae, Cynthia C; Bougnères, Pierre; Schmidt, Manfred; Kalle, Christof Von; Fischer, Alain; Cavazzana-Calvo, Marina; Aubourg, Patrick

    2012-01-01

    X-linked adrenoleukodystrophy (X-ALD) is a severe genetic demyelinating disease caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. When performed at an early stage of the disease, allogeneic hematopoietic stem cell transplantation (HCT) can arrest the progression of cerebral demyelinating lesions. To overcome the limitations of allogeneic HCT, hematopoietic stem cell (HSC) gene therapy strategy aiming to perform autologous transplantation of lentivirally corrected cells was developed. We demonstrated the preclinical feasibility of HSC gene therapy for ALD based on the correction of CD34+ cells from X-ALD patients using an HIV1-derived lentiviral vector. These results prompted us to initiate an HSC gene therapy trial in two X-ALD patients who had developed progressive cerebral demyelination, were candidates for allogeneic HCT, but had no HLA-matched donors or cord blood. Autologous CD34+ cells were purified from the peripheral blood after G-CSF stimulation, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1 cDNA, and then reinfused into the patients after they had received full myeloablative conditioning. Over 3 years of follow-up, the hematopoiesis remained polyclonal in the two patients treated with 7-14% of granulocytes, monocytes, and T and B lymphocytes expressing the lentivirally encoded ALD protein. There was no evidence of clonal dominance or skewing based on the retrieval of lentiviral insertion repertoire in different hematopoietic lineages by deep sequencing. Cerebral demyelination was arrested 14 and 16months, respectively, in the two treated patients, without further progression up to the last follow-up, a clinical outcome that is comparable to that observed after allogeneic HCT. Longer follow-up of these two treated patients and HSC gene therapy performed in additional ALD patients are however needed to evaluate the safety and efficacy of lentiviral HSC

  4. A SYSTEM AND A DEVICE FOR ISOLATING CIRCULATING TUMOR CELLS FROM THE PERIPHERAL BLOOD IN VIVO

    Directory of Open Access Journals (Sweden)

    Michal Mego

    2015-08-01

    Full Text Available Circulating tumor cells (CTC play a crucial role in disseminating tumors and in the metastatic cascade. CTCs are found only in small numbers, and the limited amount of isolated CTCs makes it impossible to characterize them closely. This paper presents a proposal for a new system for isolating CTCs from the peripheral blood in vivo. The system enables CTCs to be isolated from the whole blood volume for further research and applications. The proposed system consists of magnetic nanoparticles covered by monoclonal antibodies against a common epithelial antigen, large supermagnets, which are used to control the position of the nanoparticles within the human body, and a special wire made of a magnetic core wrapped in a non-magnetic shell. The system could be used not only for isolating CTCs, but also for in vivo isolation of other rare cells from the peripheral blood, including hematopoietic and/or mesenchymal stem cells, with applications in regenerative medicine and/or in stem cell transplantation.

  5. Progression and CSF Inflammation after Eradication of Oligoclonal Bands in an MS Patient Treated with Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma

    DEFF Research Database (Denmark)

    Braendstrup, P; Langkilde, Annika; Schreiber, K

    2012-01-01

    Allogeneic hematopoietic cell transplantation (allo-HCT) has been proposed as treatment for multiple sclerosis (MS) and other autoimmune diseases.......Allogeneic hematopoietic cell transplantation (allo-HCT) has been proposed as treatment for multiple sclerosis (MS) and other autoimmune diseases....

  6. PRDM11 is dispensable for the maintenance and function of hematopoietic stem and progenitor cells

    DEFF Research Database (Denmark)

    Thoren, Lina A; Fog, Cathrine K; Jensen, Klaus T

    2013-01-01

    Hematopoietic stem cells (HSC)(1) supply organisms with life-long output of mature blood cells. To do so, the HSC pool size has to be maintained by HSC self-renewing divisions. PRDM3 and PRDM16 have been documented to regulate HSC self-renewal, maintenance and function. We found Prdm11 to have...... similar expression patterns in the hematopoietic stem and progenitor cell (HSPC) compartments as Prdm3 and Prdm16. Therefore, we undertook experiments to test if PRDM11 regulates HSC self-renewal, maintenance and function by investigating the Prdm11(-/-) mice. Our data shows that phenotypic HSPCs...

  7. Differential Reponses of Hematopoietic Stem and Progenitor Cells to mTOR Inhibition

    Directory of Open Access Journals (Sweden)

    Aimin Yang

    2015-01-01

    Full Text Available Abnormal activation of the mammalian target of rapamycin (mTOR signaling pathway has been observed in a variety of human cancers. Therefore, targeting of the mTOR pathway is an attractive strategy for cancer treatment and several mTOR inhibitors, including AZD8055 (AZD, a novel dual mTORC1/2 inhibitor, are currently in clinical trials. Although bone marrow (BM suppression is one of the primary side effects of anticancer drugs, it is not known if pharmacological inhibition of dual mTORC1/2 affects BM hematopoietic stem and progenitor cells (HSPCs function and plasticity. Here we report that dual inhibition of mTORC1/2 by AZD or its analogue (KU-63794 depletes mouse BM Lin−Sca-1+c-Kit+ cells in cultures via the induction of apoptotic cell death. Subsequent colony-forming unit (CFU assays revealed that inhibition of mTORC1/2 suppresses the clonogenic function of hematopoietic progenitor cells (HPCs in a dose-dependent manner. Surprisingly, we found that dual inhibition of mTORC1/2 markedly inhibits the growth of day-14 cobblestone area-forming cells (CAFCs but enhances the generation of day-35 CAFCs. Given the fact that day-14 and day-35 CAFCs are functional surrogates of HPCs and hematopoietic stem cells (HSCs, respectively, these results suggest that dual inhibition of mTORC1/2 may have distinct effects on HPCs versus HSCs.

  8. Comparative study of hematopoietic stem and progenitor cells between sexes in mice under physiological conditions along time.

    Science.gov (United States)

    Gasco, Samanta; Rando, Amaya; Zaragoza, Pilar; García-Redondo, Alberto; Calvo, Ana Cristina; Osta, Rosario

    2017-12-01

    Hematopoietic stem and progenitor cells (HSPCs) are attractive targets in regenerative medicine, although the differences in their homeostatic maintenance between sexes along time are still under debate. We accurately monitored hematopoietic stem cells (HSCs), common lymphoid progenitors (CLPs), and common myeloid progenitors (CMPs) frequencies by flow cytometry, by performing serial peripheral blood extractions from male and female B6SJL wild-type mice and found no significant differences. Only modest differences were found in the gene expression profile of Slamf1 and Gata2. Our findings suggest that both sexes could be used indistinctly to perform descriptive studies in the murine hematopoietic system, especially for flow cytometry studies in peripheral blood. This would allow diminishing the number of animals needed for the experimental procedures. In addition, the use of serial extractions in the same animals drastically decreases the number of animals needed. © 2017 International Federation for Cell Biology.

  9. Pluripotent stem cell models of Shwachman-Diamond syndrome reveal a common mechanism for pancreatic and hematopoietic dysfunction

    Science.gov (United States)

    Tulpule, Asmin; Kelley, James M.; Lensch, M. William; McPherson, Jade; Park, In Hyun; Hartung, Odelya; Nakamura, Tomoka; Schlaeger, Thorsten M.; Shimamura, Akiko; Daley, George Q.

    2013-01-01

    Summary Shwachman-Diamond syndrome (SDS), a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency and hematopoietic dysfunction, is caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. We created human pluripotent stem cell models of SDS by knock-down of SBDS in human embryonic stem cells (hESCs) and generation of induced pluripotent stem cell (iPSC) lines from two SDS patients. SBDS-deficient hESCs and iPSCs manifest deficits in exocrine pancreatic and hematopoietic differentiation in vitro, enhanced apoptosis and elevated protease levels in culture supernatants, which could be reversed by restoring SBDS protein expression through transgene rescue or by supplementing culture media with protease inhibitors. Protease-mediated auto-digestion provides a mechanistic link between the pancreatic and hematopoietic phenotypes in SDS, highlighting the utility of hESCs and iPSCs in obtaining novel insights into human disease. PMID:23602541

  10. Long-term expression of human adenosine deaminase in mice transplanted with retrovirus-infected hematopoietic stem cells

    International Nuclear Information System (INIS)

    Lim, B.; Apperley, J.F.; Orkin, S.H.; Williams, D.A.

    1989-01-01

    Long-term stable expression of foreign genetic sequences transferred into hematopoietic stem cells by using retroviral vectors constitutes a relevant model for somatic gene therapy. Such stability of expression may depend on vector design, including the presence or absence of specific sequences within the vector, in combination with the nature and efficiency of infection of the hematopoietic target cells. The authors have previously reported successful transfer of human DNA encoding adenosine deaminase (ADA) into CFU-S (colony-forming unit-spleen) stem cells using simplified recombinant retroviral vectors. Human ADA was expressed in CFU-S-derived spleen colonies at levels near to endogenous enzyme. However, because of the lack of an efficient dominant selectable marker and low recombinant viral titers, stability of long-term expression of human ADA was not examined. They report here the development of an efficient method of infection of hematopoietic stem cells (HSC) without reliance on in vitro selection. Peripheral blood samples of 100% of mice transplanted with HSC infected by this protocol exhibit expression of human ADA 30 days after transplantation. Some mice (6 of 13) continue to express human ADA in all lineages after complete hematopoietic reconstitution (4 months). The use of recombinant retroviral vectors that efficiently transfer human ADA cDNA into HSC leading to stable expression of functional ADA in reconstituted mice, provides an experimental framework for future development of approaches to somatic gene therapy

  11. Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations.

    Science.gov (United States)

    Andersson, Anna; Olofsson, Tor; Lindgren, David; Nilsson, Björn; Ritz, Cecilia; Edén, Patrik; Lassen, Carin; Råde, Johan; Fontes, Magnus; Mörse, Helena; Heldrup, Jesper; Behrendtz, Mikael; Mitelman, Felix; Höglund, Mattias; Johansson, Bertil; Fioretos, Thoas

    2005-12-27

    Global expression profiles of a consecutive series of 121 childhood acute leukemias (87 B lineage acute lymphoblastic leukemias, 11 T cell acute lymphoblastic leukemias, and 23 acute myeloid leukemias), six normal bone marrows, and 10 normal hematopoietic subpopulations of different lineages and maturations were ascertained by using 27K cDNA microarrays. Unsupervised analyses revealed segregation according to lineages and primary genetic changes, i.e., TCF3(E2A)/PBX1, IGH@/MYC, ETV6(TEL)/RUNX1(AML1), 11q23/MLL, and hyperdiploidy (>50 chromosomes). Supervised discriminatory analyses were used to identify differentially expressed genes correlating with lineage and primary genetic change. The gene-expression profiles of normal hematopoietic cells were also studied. By using principal component analyses (PCA), a differentiation axis was exposed, reflecting lineages and maturation stages of normal hematopoietic cells. By applying the three principal components obtained from PCA of the normal cells on the leukemic samples, similarities between malignant and normal cell lineages and maturations were investigated. Apart from showing that leukemias segregate according to lineage and genetic subtype, we provide an extensive study of the genes correlating with primary genetic changes. We also investigated the expression pattern of these genes in normal hematopoietic cells of different lineages and maturations, identifying genes preferentially expressed by the leukemic cells, suggesting an ectopic activation of a large number of genes, likely to reflect regulatory networks of pathogenetic importance that also may provide attractive targets for future directed therapies.

  12. PRIMARY ENDOPROSTHETIC REPLACEMENT OF THE ANOPHTHALMIC ORBIT IN PATIENTS WITH UVEAL MELANOMA: SIX-YEAR FOLLOW-UP RESULTS

    Directory of Open Access Journals (Sweden)

    A. A. Yarovoy

    2012-01-01

    Full Text Available A locomotor stump was formed in 36 patients (28 women and 8 men, by implanting an endoprosthesis for enucleation of the eyeball with uveal melanoma (UM. The indication for endoprosthesis implantation was no signs of extrabulbar growth. A modified 17–19 mm silicone implant covered with strips from a dura mater graft and medical mesh fabric was used as an orbital implant. The follow-up was 3 to 72 months (mean 32.5 months. All the patients achieved a satisfactory cosmetic effect. None patient was found to have a recurrent orbital tumor. Out of the complications, anterior implant surface denudation was noted in 4 patients. Two patients developed metastases. The absence of recurrent orbital UM at a 6-year follow-up enables primary endoprosthetic replacement of the orbit for UM to be regarded as a safe and reasonable method for patient cosmetic rehabilitation. 

  13. Potential role of immunoablation and hematopoietic cell transplantation in the treatment of early diabetes type 1.

    Science.gov (United States)

    Snarski, Emilian; Milczarczyk, Alicja; Franek, Edward; Jedrzejczak, Wieslaw

    2010-01-01

    Immunoablation with autologous hematopoietic cell transplantation has shown some effectiveness in the treatment of autoimmune diseases as diverse as aplastic anemia, systemic lupus erythematosus, multiple sclerosis and Crohn's disease. It has been recently shown that this treatment might prevent or delay development of diabetes type 1. The majority of more than 30 patients with early diabetes type 1 who underwent immunoablation and hematopoietic cell transplantation in various centers in the world achieved durable remission of diabetes and independence of exogenous insulin. This review summarizes advantages and risks of this treatment of early diabetes type 1.

  14. Maxillary brown tumor as initial presentation of parathyroid adenoma: A case report

    Directory of Open Access Journals (Sweden)

    Hon-Ke Sia

    2012-07-01

    Full Text Available Brown tumor is a rare late-stage skeletal change caused by long-term stimulation of excess parathyroid hormone. It is not neoplastic, but a reparative cellular process. Common sites of brown tumor are the ribs, clavicle, long bones and pelvic girdle. Solitary maxillary brown tumor as initial presentation of primary hyperparathyroidism is rare; it is often accompanied by brown tumors of the other facial bones. Here, we present the first case of solitary maxillary brown tumor in a 29-year-old ethnic Chinese woman with initial presentation of a large tumor filling the left maxillary sinus. Underlying long-standing primary hyperparathyroidism caused by a large parathyroid adenoma was finally diagnosed. Brown tumor tends to be misdiagnosed as malignancy, and delayed diagnosis of the underlying hyperparathyroidism is common. Our case validates the suggestion that young women have a higher probability of brown tumor. Biopsy of the suspicious bone tumor and blood tests for calcium and parathyroid hormone level are crucial and essential to reach the correct diagnosis. Most brown tumors show spontaneous regression after parathyroidectomy. However, direct excision of the brown tumor may be indicated to avoid the risk of facial deformity and orbital compression at a special anatomical site, as in our case.

  15. Polypropylene Darning: A New Alternative for Reconstruction of Orbital Floor after Total Maxillectomy.

    Science.gov (United States)

    Sharma, Prashant

    2015-06-01

    Removal of orbital floor is an integral part of total (radical) maxillectomy (type IIIa), which if not managed properly, may lead to some eye related distressing complications like diplopia, eyelid malposition, epiphora, dacryocystitis, enopthalmos and ectoprion. Among all, diplopia is the most distressing complication which hampers daily activity. Various options for orbital floor reconstruction are available like titanium sheet, polypropylene mesh, non-vascularized or vascularized bone graft, pedicled flaps, micro-vascular free flaps, prosthesis placement, and split skin graft followed by obturator placement. Till date no-body has tried stabilization of eye ball by 'darning' the orbital floor using non-absorbable suture. 'Polypropylene suture darning' is an easy to learn, novel method with equally good results. Five patients with potentially resectable tumors underwent total maxillectomy. I used polypropylene 3-0 round body suture and 'darning' was done at orbital floor, incorporating periosteum (if remaining) and peri-orbital fat into the sutures. Muscle flaps were done to provide bulk and palatal reconstruction. Assessment of patients was done post-operatively at day-5 i.e., before discharge and at 1 month after surgery, and also in further follow up visits. The results were very good in terms of clear vision & eye movements (directly related to 'darning'), and the aesthetic look of patients and bilateral symmetry were satisfactory (not related to darning). Darning of orbital floor by polypropylene after total maxillectomy is an easy to learn and cost-effective method of reconstruction with good results.

  16. Todralazine protects zebra fish from lethal doses of ionizing radiation: role of hematopoietic stem cell expansion

    International Nuclear Information System (INIS)

    Dimri, Manali; Joshi, Jaidev; Indracanti, Prem Kumar

    2013-01-01

    Radiation induced cell killing and hematopoietic stem cell depletion leads to compromised immune functions and opportunistic infections which significantly affect the recovery and survival upon irradiation. Any agent which can expand residual hematopoietic stem cells in irradiated organism can render protection from the effects of lethal doses of ionizing radiation. Johns Hopkins Clinical compound library (JHCCL) was screened for protection against lethal doses of ionizing radiation using developing zebra fish as a model organism. Modulation of radiation induced reactive oxygen species by the small molecules were done by DCFDA staining and for visual identification and quantification of apoptosis acridine orange assay, flow cytometry were employed respectively. Hematopoietic stem cell expansion potential was assessed by quantifying runx1 expression, a marker for definitive stem cells, were done by RT-PCR and by the kinetics of recovery from chemically induced anaemia. Todralazine hydrochloride from JHCCL exhibited promising results with potential anti radiation effects. A dose of 5μM was found to be the most effective and has rendered significant organ and whole body protection (100% survival advantage over a period of 6 days) against 20 Gy. However todralazine did not modulated radiation induced free radicals (monitored within 2 h of irradiation) and apoptosis in zebra fish embryos analysed at 8 and 24h post irradiation. Flow cytometric quantification of pre G1 population suggested the same. Chemoinformatics approaches were further carried out to elucidate possible targets which are contributing to its radioprotection potential. Structural similarity search suggested several targets and possible hematopoietic stem cell expanding potential. Treatment of zebra fish embryos with todralazine has lead to significant proliferation of hematopoietic stem cell as indicated by increase in expression of runx1. HSC expanding potential of todralazine was further supported by

  17. Local orbitals by minimizing powers of the orbital variance

    DEFF Research Database (Denmark)

    Jansik, Branislav; Høst, Stinne; Kristensen, Kasper

    2011-01-01

    's correlation consistent basis sets, it is seen that for larger penalties, the virtual orbitals become more local than the occupied ones. We also show that the local virtual HF orbitals are significantly more local than the redundant projected atomic orbitals, which often have been used to span the virtual...

  18. Melanotic neuroectodermal tumor of infancy

    Energy Technology Data Exchange (ETDEWEB)

    Song, Haeng Un; Koh, Kwang Joon [School of Dentistry, Chonbuk National University, Cheonju (Korea, Republic of)

    2002-09-15

    The melanotic neuroectodermal tumor of infancy is a rare neoplasm arising in the first year of life. A 33-day-old female infant had an enlarged alveolar ridge on the right anterior maxilla. Intraoral examination revealed a nonulcerative swelling at the site. An intraoral radiograph showed an ill-defined radiolucency on the right anterior maxilla and displacement of primary incisors from their alveolar sockets. CT scans revealed an expansion of the surrounding bone and partial destruction of the anterior wall of the premaxilla. Histopathologic examination showed the cytoplasm of neuroblastic cells and eosinophilic, epithelioid cells frequently contained a dark brown granular pigment that stained positively to vimentin and HMB45, focally positive to NSE and cytokeratin. Four weeks after the operation, CT scans showed a rapidly growing soft tissue mass occupying right maxillary sinus encroaching to the orbit and nasal cavity. The final diagnosis was made as a malignant melanotic neuroectodermal tumor of infancy.

  19. Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions.

    Science.gov (United States)

    Karigane, Daiki; Takubo, Keiyo

    2017-07-01

    Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.

  20. Expression of NR1I3 in mouse lung tumors induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone

    International Nuclear Information System (INIS)

    Fukumasu, H.; Cordeiro, Y.G.; Rochetti, A.L.; Barra, C.N.; Sámora, T.S.; Strefezzi, R.F.; Dagli, M.L.Z.

    2015-01-01

    Nuclear receptor subfamily 1, group I, member 3 (NR1I3) is reported to be a possible novel therapeutic target for some cancers, including lung, brain and hematopoietic tumors. Here, we characterized expression of NR1I3 in a mouse model of lung carcinogenesis induced by 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone (NNK), the most potent tobacco carcinogen. Lung tumors were collected from mice treated with NNK (400 mg/kg) and euthanized after 52 weeks. Benign and malignant lesions were formalin-fixed and paraffin-embedded for histology and immunohistochemistry, with samples snap-frozen for mRNA analysis. Immunohistochemically, we found that most macrophages and type I and II pneumocytes expressed NR1I3, whereas fibroblasts and endothelial cells were NR1I3 − . Compared with benign lesions, malignant lesions had less NR1I3 + tumor cells. Gene expression analysis also showed an inverse correlation between NR1I3 mRNA expression and tumor size (P=0.0061), suggesting that bigger tumors expressed less NR1I3 transcripts, in accordance with our immunohistochemical NR1I3 tests. Our results indicate that NR1I3 expression decreased during progression of malignant lung tumors induced by NNK in mice

  1. Expression of NR1I3 in mouse lung tumors induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone

    Energy Technology Data Exchange (ETDEWEB)

    Fukumasu, H.; Cordeiro, Y.G.; Rochetti, A.L.; Barra, C.N.; Sámora, T.S.; Strefezzi, R.F. [Laboratório de Oncologia Comparada e Translacional, Departmento de Medicina Veterinária, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Pirassununga, SP (Brazil); Dagli, M.L.Z. [Laboratório de Oncologia Experimental e Comparada, Departmento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP (Brazil)

    2015-02-13

    Nuclear receptor subfamily 1, group I, member 3 (NR1I3) is reported to be a possible novel therapeutic target for some cancers, including lung, brain and hematopoietic tumors. Here, we characterized expression of NR1I3 in a mouse model of lung carcinogenesis induced by 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone (NNK), the most potent tobacco carcinogen. Lung tumors were collected from mice treated with NNK (400 mg/kg) and euthanized after 52 weeks. Benign and malignant lesions were formalin-fixed and paraffin-embedded for histology and immunohistochemistry, with samples snap-frozen for mRNA analysis. Immunohistochemically, we found that most macrophages and type I and II pneumocytes expressed NR1I3, whereas fibroblasts and endothelial cells were NR1I3{sup −}. Compared with benign lesions, malignant lesions had less NR1I3{sup +} tumor cells. Gene expression analysis also showed an inverse correlation between NR1I3 mRNA expression and tumor size (P=0.0061), suggesting that bigger tumors expressed less NR1I3 transcripts, in accordance with our immunohistochemical NR1I3 tests. Our results indicate that NR1I3 expression decreased during progression of malignant lung tumors induced by NNK in mice.

  2. The Chromatin Remodeler BPTF Activates a Stemness Gene-Expression Program Essential for the Maintenance of Adult Hematopoietic Stem Cells

    Directory of Open Access Journals (Sweden)

    Bowen Xu

    2018-03-01

    Full Text Available Summary: Self-renewal and differentiation of adult stem cells are tightly regulated partly through configuration of chromatin structure by chromatin remodelers. Using knockout mice, we here demonstrate that bromodomain PHD finger transcription factor (BPTF, a component of the nucleosome remodeling factor (NURF chromatin-remodeling complex, is essential for maintaining the population size of hematopoietic stem/progenitor cells (HSPCs, including long-term hematopoietic stem cells (HSCs. Bptf-deficient HSCs are defective in reconstituted hematopoiesis, and hematopoietic-specific knockout of Bptf caused profound defects including bone marrow failure and anemia. Genome-wide transcriptome profiling revealed that BPTF loss caused downregulation of HSC-specific gene-expression programs, which contain several master transcription factors (Meis1, Pbx1, Mn1, and Lmo2 required for HSC maintenance and self-renewal. Furthermore, we show that BPTF potentiates the chromatin accessibility of key HSC “stemness” genes. These results demonstrate an essential requirement of the chromatin remodeler BPTF and NURF for activation of “stemness” gene-expression programs and proper function of adult HSCs. : Wang and colleagues show that a chromatin remodeler, BPTF, sustains appropriate functions of hematopoietic stem/progenitor cells (HSPCs. BPTF loss causes bone marrow failure and anemia. The authors further define a BPTF-dependent gene-expression program in HSPCs, which contains key HSC stemness factors. These results demonstrate an essential requirement of the BPTF-associated chromatin remodelers for HSC functionality and adult hematopoiesis. Keywords: Bptf, hematopoietic stem cells, chromatin remodeler, Meis1, Pbx1, Mn1, DNA accessibility, NURF, AP1 complex

  3. Mutual Interference between Cytomegalovirus and Reconstitution of Protective Immunity after Hematopoietic Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Matthias J. Reddehase

    2016-08-01

    Full Text Available Hematopoietic cell transplantation (HCT is a therapy option for aggressive forms of hematopoietic malignancies that are resistant to standard antitumoral therapies. Hematoablative treatment preceding HCT, however, opens a ‘window of opportunity’ for latent cytomegalovirus (CMV by releasing it from immune control with the consequence of reactivation of productive viral gene expression and recurrence of infectious virus. A ‘window of opportunity’ for the virus represents a ‘window of risk’ for the patient. In the interim between HCT and reconstitution of antiviral immunity, primarily mediated by CD8+ T cells, initially low amounts of reactivated virus can expand exponentially, disseminate to essentially all organs, and cause multiple organ CMV disease, with interstitial pneumonia (CMV-IP representing the most severe clinical manifestation. Here I will review predictions originally made in the mouse model of experimental HCT and murine CMV infection, some of which have already paved the way to translational preclinical research and promising clinical trials of a pre-emptive cytoimmunotherapy of human CMV disease. Specifically, the mouse model has been pivotal in providing ‘proof of concept’ for preventing CMV disease after HCT by adoptive transfer of preselected, virus epitope-specific effector and memory CD8+ T cells bridging the critical interim. CMV, however, is not a ‘passive antigen’ but is a pathogen that actively interferes with the reconstitution of protective immunity by infecting bone marrow stromal cells that otherwise form niches for hematopoiesis by providing the structural microenvironment and by producing hematopoietically active cytokines, the hemopoietins. Depending on the precise conditions of HCT, reduced homing of transplanted hematopoietic stem- and progenitor cells to infected bone marrow stroma and impaired colony growth and lineage differentiation can lead to ‘graft failure’. In consequence

  4. Synergistic actions of hematopoietic and mesenchymal stem/progenitor cells in vascularizing bioengineered tissues.

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    Eduardo K Moioli

    Full Text Available Poor angiogenesis is a major road block for tissue repair. The regeneration of virtually all tissues is limited by angiogenesis, given the diffusion of nutrients, oxygen, and waste products is limited to a few hundred micrometers. We postulated that co-transplantation of hematopoietic and mesenchymal stem/progenitor cells improves angiogenesis of tissue repair and hence the outcome of regeneration. In this study, we tested this hypothesis by using bone as a model whose regeneration is impaired unless it is vascularized. Hematopoietic stem/progenitor cells (HSCs and mesenchymal stem/progenitor cells (MSCs were isolated from each of three healthy human bone marrow samples and reconstituted in a porous scaffold. MSCs were seeded in micropores of 3D calcium phosphate (CP scaffolds, followed by infusion of gel-suspended CD34(+ hematopoietic cells. Co-transplantation of CD34(+ HSCs and CD34(- MSCs in microporous CP scaffolds subcutaneously in the dorsum of immunocompromised mice yielded vascularized tissue. The average vascular number of co-transplanted CD34(+ and MSC scaffolds was substantially greater than MSC transplantation alone. Human osteocalcin was expressed in the micropores of CP scaffolds and was significantly increased upon co-transplantation of MSCs and CD34(+ cells. Human nuclear staining revealed the engraftment of transplanted human cells in vascular endothelium upon co-transplantation of MSCs and CD34(+ cells. Based on additional in vitro results of endothelial differentiation of CD34(+ cells by vascular endothelial growth factor (VEGF, we adsorbed VEGF with co-transplanted CD34(+ and MSCs in the microporous CP scaffolds in vivo, and discovered that vascular number and diameter further increased, likely owing to the promotion of endothelial differentiation of CD34(+ cells by VEGF. Together, co-transplantation of hematopoietic and mesenchymal stem/progenitor cells may improve the regeneration of vascular dependent tissues such as bone

  5. Evaluation of Three Cases Using a Novel Titanium Mesh System—Skull-Fit® with Orbital Wall (Skull-Fit WOW®)—For Cranial Base Reconstructions

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    Hattori, Noriko; Nakajima, Hideo; Tamada, Ikkei; Sakamoto, Yoshiaki; Ohira, Takayuki; Yoshida, Kazunari; Kawase, Takeshi; Kishi, Kazuo

    2011-01-01

    Cranial base reconstructions associated with tumor resections around the orbital wall often require that both the upper and lateral orbital walls be reconstructed during a single procedure. Previously, we used titanium mesh plates that were preoperatively fabricated based on three-dimensional models. Although these plates are precise and do not increase the probability of infection, we still had to use autologous bones to reconstruct the orbital walls. Recently, we developed a new titanium mesh plate—called Skull-Fit®—with orbital wall (Skull-Fit WOW®), enabling us to reconstruct the cranial base and orbital walls without bone grafts. Here, we report on three reconstruction cases in which the novel titanium mesh-orbital wall system was used. In all three cases, the customized titanium mesh system performed satisfactorily with little, if any, complications. PMID:22451827

  6. Hematopoietic stem cells transplant in patients with common variable immunodeficiency. Is a therapeutic option?

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    Julio César Cambray-Gutiérrez

    2017-02-01

    Full Text Available Background: Patients with common variable immunodeficiency show higher incidence of sinopulmonary and gastrointestinal infections, as well as lymphoproliferative and autoimmune diseases. The treatment of choice is replacement therapy with human gamma-globulin. Hematopoietic stem cell transplantation is a non-conventional therapeutic modality. Clinical case: Twenty-six-year old woman with no family or hereditary history of primary immune deficiencies or consanguinity, with repeated episodes of otitis, sinusitis, gastroenteritis and bronchitis since childhood. At adolescence, she was diagnosed with common variable immunodeficiency; she was prescribed intravenous gamma-globulin, broad-spectrum antimicrobials and macrolides. At 22 years of age, she underwent hematopoietic stem cell transplantation owing to continued severe infections. At 4 months, post-transplantation she was diagnosed with hypothyroidism and ovarian insufficiency. During the following 3 years, she had no infections, but at 25 years of age she had immune thrombocytopenic purpura diagnosed, which persists together with Raynaud’s disease and upper respiratory tract persistent infections. At the moment of this report she is being treated with intravenous gamma-globulin and receiving prophylaxis with clarithromycin, without steroids or danazol. Conclusions: Given the high rate of morbidity and mortality associated and immune reconstitution failure, hematopoietic stem cell transplantation should be carefully evaluated in patients with treatment-unresponsive infections or lymphoproliferative disorders.

  7. Gastroesophageal reflux disease and its association with bronchiolitis obliterans syndrome in allogeneic hematopoietic stem cell transplant recipients.

    Science.gov (United States)

    Khalid, Mohammed; Aljurf, Mahmoud; Saleemi, Sarfraz; Khan, Mohammed Qaseem; Khan, Basha; Ahmed, Shad; Ibrahim, Khalid El Tayeb; Mobeireek, Abdullah; Al Mohareb, Fahad; Chaudhri, Naeem

    2013-06-01

    Bronchiolitis obliterans syndrome is a significant postallogeneic hematopoietic stem cell transplant problem. Recent data in lung transplant patients suggest an association with gastroesophageal reflux disease and bronchiolitis obliterans syndrome. We studied posthematopoietic stem cell transplant patients with bronchiolitis obliterans syndrome for gastroesophageal reflux disease and its response to a proton pump inhibitor. Seven postallogeneic hematopoietic stem cell transplant patients with bronchiolitis obliterans syndrome were studied. Gastroesophageal reflux disease was assessed by 24-hour pH monitoring with a Bravo catheter-free radio pH capsule. Patients with positive gastroesophageal reflux disease were started on omeprazole. Pretreatment and posttreatment pulmonary function tests were done at 3-month intervals. Of 7 patients, 5 had positive results for gastroesophageal reflux disease (71%). Omeprazole had a disease-stabilizing effect on the patients' pulmonary function tests. Our study shows a significant association between bronchiolitis obliterans syndrome and gastroesophageal reflux disease in postallogeneic hematopoietic stem cell transplant patients. Use of omeprazole may have a disease-stabilizing effect in short-term follow-up.

  8. The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease.

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    Singbrant, Sofie; Wall, Meaghan; Moody, Jennifer; Karlsson, Göran; Chalk, Alistair M; Liddicoat, Brian; Russell, Megan R; Walkley, Carl R; Karlsson, Stefan

    2014-04-01

    The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced a gene signature associated with hematopoietic stem cells and myeloid differentiation, as well as hepatocyte growth factor signaling. Here we demonstrate that, in contrast to what has generally been assumed, the significant impact of SKI on hematopoiesis is independent of its ability to inhibit TGF-beta signaling. Instead, myeloid progenitors expressing SKI are partially dependent on functional hepatocyte growth factor signaling. Collectively our results demonstrate that SKI is an important regulator of hematopoietic stem cell activity and its overexpression leads to myeloproliferative disease.

  9. Pleiotrophin Regulates the Retention and Self-Renewal of Hematopoietic Stem Cells in the Bone Marrow Vascular Niche

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    Heather A. Himburg

    2012-10-01

    Full Text Available The mechanisms through which the bone marrow (BM microenvironment regulates hematopoietic stem cell (HSC fate remain incompletely understood. We examined the role of the heparin-binding growth factor pleiotrophin (PTN in regulating HSC function in the niche. PTN−/− mice displayed significantly decreased BM HSC content and impaired hematopoietic regeneration following myelosuppression. Conversely, mice lacking protein tyrosine phosphatase receptor zeta, which is inactivated by PTN, displayed significantly increased BM HSC content. Transplant studies revealed that PTN action was not HSC autonomous, but rather was mediated by the BM microenvironment. Interestingly, PTN was differentially expressed and secreted by BM sinusoidal endothelial cells within the vascular niche. Furthermore, systemic administration of anti-PTN antibody in mice substantially impaired both the homing of hematopoietic progenitor cells to the niche and the retention of BM HSCs in the niche. PTN is a secreted component of the BM vascular niche that regulates HSC self-renewal and retention in vivo.

  10. Quality of life of patients with graft-versus-host disease (GvHD post-hematopoietic stem cell transplantation

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    Sibéli de Fátima Ferraz Simão Proença

    Full Text Available Abstract OBJECTIVE Assessing the quality of life of adult patients with hematological cancer in the 100 days after transplantation of hematopoietic stem cells and verifying whether the variable graft-versus-host disease (GvHD is predictive of worse results. METHOD An observational correlational and quantitative study with 36 adult participants diagnosed with hematologic cancer who underwent hematopoietic stem cell transplantation from September 2013 to June 2015. RESULT The mean age was 37 years, 52.78% were female, and 61.11% were diagnosed with leukemia. Quality of life scores showed a significant impact between pre-transplantation and pre-hospital discharge, and also within the 100 days post-transplantation. The statistical analysis between the scores for the groups with and without GvHD showed a significant difference between the presence of the complication and worse results. CONCLUSION Quality of life is altered as a result of hematopoietic stem cells transplantation, especially in patients who have graft-versus-host disease.

  11. Integrated analysis of hematopoietic differentiation outcomes and molecular characterization reveals unbiased differentiation capacity and minor transcriptional memory in HPC/HSC-iPSCs.

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    Gao, Shuai; Hou, Xinfeng; Jiang, Yonghua; Xu, Zijian; Cai, Tao; Chen, Jiajie; Chang, Gang

    2017-01-23

    Transcription factor-mediated reprogramming can reset the epigenetics of somatic cells into a pluripotency compatible state. Recent studies show that induced pluripotent stem cells (iPSCs) always inherit starting cell-specific characteristics, called epigenetic memory, which may be advantageous, as directed differentiation into specific cell types is still challenging; however, it also may be unpredictable when uncontrollable differentiation occurs. In consideration of biosafety in disease modeling and personalized medicine, the availability of high-quality iPSCs which lack a biased differentiation capacity and somatic memory could be indispensable. Herein, we evaluate the hematopoietic differentiation capacity and somatic memory state of hematopoietic progenitor and stem cell (HPC/HSC)-derived-iPSCs (HPC/HSC-iPSCs) using a previously established sequential reprogramming system. We found that HPC/HSCs are amenable to being reprogrammed into iPSCs with unbiased differentiation capacity to hematopoietic progenitors and mature hematopoietic cells. Genome-wide analyses revealed that no global epigenetic memory was detectable in HPC/HSC-iPSCs, but only a minor transcriptional memory of HPC/HSCs existed in a specific tetraploid complementation (4 N)-incompetent HPC/HSC-iPSC line. However, the observed minor transcriptional memory had no influence on the hematopoietic differentiation capacity, indicating the reprogramming of the HPC/HSCs was nearly complete. Further analysis revealed the correlation of minor transcriptional memory with the aberrant distribution of H3K27me3. This work provides a comprehensive framework for obtaining high-quality iPSCs from HPC/HSCs with unbiased hematopoietic differentiation capacity and minor transcriptional memory.

  12. Transgene expression, but not gene delivery, is improved by adhesion-assisted lipofection of hematopoietic cells.

    Science.gov (United States)

    Keller, H; Yunxu, C; Marit, G; Pla, M; Reiffers, J; Thèze, J; Froussard, P

    1999-05-01

    In contrast to adherent cells, cells growing in suspension and particularly hematopoietic cells, are notoriously difficult to transfect in vitro using nonviral approaches. In the present study, the effect of cell adhesion on gene transfer efficacy was investigated by allowing hematopoietic cells to bind to an adherent cell monolayer (ACM) before being subjected to cationic liposome-mediated DNA transfer. Human CD34 and T CD4 cell lines were cultivated on an ACM constituted of murine fibroblast NIH3T3 cells and transfected with a plasmid carrying the beta-galactosidase gene. X-gal staining showed that up to 27% of the cells expressed the transgene. In contrast, less than 0.1% of these cells were positively transfected in suspension. This adhesion-assisted lipofection (AAL) procedure was also successfully tested on blood lymphocytes, since it resulted in up to 30% of transfected human primary T lymphocytes. Flow cytometry analysis performed on T lymphocyte subsets revealed that 8 and 9%, respectively, of CD4 and CD8 cells could be transfected with a plasmid carrying the green fluorescent protein gene. Other adherent cells, such as MS5 murine stromal cells or HeLa epithelial cells, were also a compatible matrix for AAL. Moreover, the pCMV beta plasmid was present in similar amounts in the nuclei of TF1 cells transfected in suspension or with the AAL procedure. These data raise the possibility that cell matrix/hematopoietic cell interactions might govern expression of the transgene in hematopoietic cells growing usually in suspension, but not endocytosis of liposome/DNA particles and plasmid migration ot the cell nucleus.

  13. Phenotypic and Functional Changes Induced in Hematopoietic Stem/Progenitor Cells After Gamma-Ray Radiation Exposure

    International Nuclear Information System (INIS)

    Simonnet, A.J.; Nehme, J.; Leboulch, Ph.; Tronik-Le Roux, D.; Simonnet, A.J.; Nehme, J.; Leboulch, Ph.; Tronik-Le Roux, D.; Vaigot, P.; Vaigot, P.; Barroca, V.; Barroca, V.; Leboulch, Ph.

    2009-01-01

    Ionizing radiation (IR) exposure causes rapid and acute bone marrow (BM) suppression that is reversible for nonlethal doses. Evidence is accumulating that IR can also provoke long-lasting residual hematopoietic injury. To better understand these effects, we analyzed phenotypic and functional changes in the stem/progenitor compartment of irradiated mice over a 10-week period. We found that hematopoietic stem cells (HSCs) identified by their repopulating ability continued to segregate within the Hoechst dye excluding 'side population (SP)' early after IR exposure. However, transient phenotypic changes were observed within this cell population: Sca-1 (S) and c-Kit (K) expression levels were increased and severely reduced, respectively, with a concurrent increase in the proportion of SPSK cells positive for established indicators of the presence of HSCs: CD150 and CD105. Ten weeks after IR exposure, expression of Sca-1 and c-Kit at the SP cell surface returned to control levels, and BM cellularity of irradiated mice was restored. However, the c-Kit + Sca-1 + Lin -/low (KSL) stem/progenitor compartment displayed major phenotypic modifications, including an increase and a severe decrease in the frequencies of CD150 + Flk2 - and CD150 - Flk2 + cells, respectively. CD150 + KSL cells also showed impaired reconstituting ability, an increased tendency to apoptosis, and accrued DNA damage. Finally, 15 weeks after exposure, irradiated mice, but not age matched controls, allowed engraftment and significant hematopoietic contribution from transplanted con-genic HSCs without additional host conditioning. These results provide novel insight in our understanding of immediate and delayed IR-induced hematopoietic injury and highlight similarities between HSCs of young irradiated and old mice. (authors)

  14. Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration.

    Science.gov (United States)

    Yan, Xiao; Himburg, Heather A; Pohl, Katherine; Quarmyne, Mamle; Tran, Evelyn; Zhang, Yurun; Fang, Tiancheng; Kan, Jenny; Chao, Nelson J; Zhao, Liman; Doan, Phuong L; Chute, John P

    2016-11-01

    Imprinted genes are differentially expressed by adult stem cells, but their functions in regulating adult stem cell fate are incompletely understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an imprinted gene, regulates hematopoietic stem cell (HSC) self-renewal and regeneration. Deletion of the maternal allele of Grb10 in mice (Grb10 m/+ mice) substantially increased HSC long-term repopulating capacity, as compared to that of Grb10 +/+ mice. After total body irradiation (TBI), Grb10 m/+ mice demonstrated accelerated HSC regeneration and hematopoietic reconstitution, as compared to Grb10 +/+ mice. Grb10-deficient HSCs displayed increased proliferation after competitive transplantation or TBI, commensurate with upregulation of CDK4 and Cyclin E. Furthermore, the enhanced HSC regeneration observed in Grb10-deficient mice was dependent on activation of the Akt/mTORC1 pathway. This study reveals a function for the imprinted gene Grb10 in regulating HSC self-renewal and regeneration and suggests that the inhibition of Grb10 can promote hematopoietic regeneration in vivo. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  15. [Clinical roles of vitamins in hematopoietic disorders].

    Science.gov (United States)

    Matsuda, M; Kanamaru, A

    1999-10-01

    Vitamins are essential organisms which promote various metabolisms and physiological systems. Several vitamins play important roles in hematopoietic system. Vitamin B12, C and folic acid are associated with DNA synthesis of erythroid nucleus, the deficiency of which causes the megaloblastic anemia. Some megaloblatic anemia and sideroblastic anemia might response to vitamin B1 and B6, respectively. Vitamin K participates in some coagulation factors in coagulation-fibrinogenolysis system. It has been reported that vitamins A, D and K potentially differentiate leukemic cells and then induce the apoptosis, suggesting that they would be new therapeutic agents in acute leukemia.

  16. Apoptosis-Related Gene Expression Profiling in Hematopoietic Cell Fractions of MDS Patients

    NARCIS (Netherlands)

    MC Langemeijer, Saskia; Mariani, Niccolo; Knops, Ruth; Gilissen, Christian; Woestenenk, Rob; de Witte, Theo; Huls, Gerwin; van der Reijden, Bert A.; Jansen, Joop H.

    2016-01-01

    Although the vast majority of patients with a myelodysplastic syndrome (MDS) suffer from cytopenias, the bone marrow is usually normocellular or hypercellular. Apoptosis of hematopoietic cells in the bone marrow has been implicated in this phenomenon. However, in MDS it remains only partially

  17. Desensitization for solid organ and hematopoietic stem cell transplantation.

    Science.gov (United States)

    Zachary, Andrea A; Leffell, Mary S

    2014-03-01

    Desensitization protocols are being used worldwide to enable kidney transplantation across immunologic barriers, i.e. antibody to donor HLA or ABO antigens, which were once thought to be absolute contraindications to transplantation. Desensitization protocols are also being applied to permit transplantation of HLA mismatched hematopoietic stem cells to patients with antibody to donor HLA, to enhance the opportunity for transplantation of non-renal organs, and to treat antibody-mediated rejection. Although desensitization for organ transplantation carries an increased risk of antibody-mediated rejection, ultimately these transplants extend and enhance the quality of life for solid organ recipients, and desensitization that permits transplantation of hematopoietic stem cells is life saving for patients with limited donor options. Complex patient factors and variability in treatment protocols have made it difficult to identify, precisely, the mechanisms underlying the downregulation of donor-specific antibodies. The mechanisms underlying desensitization may differ among the various protocols in use, although there are likely to be some common features. However, it is likely that desensitization achieves a sort of immune detente by first reducing the immunologic barrier and then by creating an environment in which an autoregulatory process restricts the immune response to the allograft. © 2014 The Authors. Immunological Reviews Published by John Wiley & Sons Ltd.

  18. An In Vitro Study of Differentiation of Hematopoietic Cells to Endothelial Cells

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    Qi Ru Wang

    2011-01-01

    medium (ECCM. BM-EPCs were characterized in terms of phenotype, lineage potential, and their functional properties. Endothelial cell colonies derived from BM-EPC were cultured with ECCM for 3 months. Cultured EPC colony cells expressed endothelial cell markers and formed the capillary-like network in vitro. EPC colony cells expressed differential proliferative capacity; some of the colonies exhibited a high proliferative potential (HPP capacity up to 20 population doublings. More importantly, these HPP-EPCs expressed hematopoietic marker CD45, exhibited endocytic activities, and preserved some of the myeloid cell activity. In addition, the HPP-EPCs secrete various growth factors including VEGF and GM-CSF into the culture medium. The results demonstrate that these EPCs were primarily derived from hematopoietic origin of early precursor cells and maintained high proliferative potential capacity, a feature with a significant potential in the application of cell therapy in ischemic diseases.

  19. Orbital Dynamics of Low-Earth Orbit Laser-Propelled Space Vehicles

    International Nuclear Information System (INIS)

    Yamakawa, Hiroshi; Funaki, Ikkoh; Komurasaki, Kimiya

    2008-01-01

    Trajectories applicable to laser-propelled space vehicles with a laser station in low-Earth orbit are investigated. Laser vehicles are initially located in the vicinity of the Earth-orbiting laser station in low-earth orbit at an altitude of several hundreds kilometers, and are accelerated by laser beaming from the laser station. The laser-propelled vehicles start from low-earth orbit and finally escape from the Earth gravity well, enabling interplanetary trajectories and planetary exploration

  20. Catalase inhibits ionizing radiation-induced apoptosis in hematopoietic stem and progenitor cells.

    Science.gov (United States)

    Xiao, Xia; Luo, Hongmei; Vanek, Kenneth N; LaRue, Amanda C; Schulte, Bradley A; Wang, Gavin Y

    2015-06-01

    Hematologic toxicity is a major cause of mortality in radiation emergency scenarios and a primary side effect concern in patients undergoing chemo-radiotherapy. Therefore, there is a critical need for the development of novel and more effective approaches to manage this side effect. Catalase is a potent antioxidant enzyme that coverts hydrogen peroxide into hydrogen and water. In this study, we evaluated the efficacy of catalase as a protectant against ionizing radiation (IR)-induced toxicity in hematopoietic stem and progenitor cells (HSPCs). The results revealed that catalase treatment markedly inhibits IR-induced apoptosis in murine hematopoietic stem cells and hematopoietic progenitor cells. Subsequent colony-forming cell and cobble-stone area-forming cell assays showed that catalase-treated HSPCs can not only survive irradiation-induced apoptosis but also have higher clonogenic capacity, compared with vehicle-treated cells. Moreover, transplantation of catalase-treated irradiated HSPCs results in high levels of multi-lineage and long-term engraftments, whereas vehicle-treated irradiated HSPCs exhibit very limited hematopoiesis reconstituting capacity. Mechanistically, catalase treatment attenuates IR-induced DNA double-strand breaks and inhibits reactive oxygen species. Unexpectedly, we found that the radioprotective effect of catalase is associated with activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway and pharmacological inhibition of STAT3 abolishes the protective activity of catalase, suggesting that catalase may protect HSPCs against IR-induced toxicity via promoting STAT3 activation. Collectively, these results demonstrate a previously unrecognized mechanism by which catalase inhibits IR-induced DNA damage and apoptosis in HSPCs.