Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma

ClinicalTrials.gov

2018-06-28

Metastatic Ewing Sarcoma; Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Neoplasm in the Bone Marrow; Metastatic Malignant Neoplasm in the Lung; Metastatic Peripheral Primitive Neuroectodermal Tumor of Bone; Peripheral Primitive Neuroectodermal Tumor of Soft Tissues

Tipifarnib in Treating Young Patients With Recurrent or Progressive High-Grade Glioma, Medulloblastoma, Primitive Neuroectodermal Tumor, or Brain Stem Glioma

ClinicalTrials.gov

2013-10-07

Childhood High-grade Cerebral Astrocytoma; Childhood Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

Endometrial endometrioid adenocarcinoma associated with primitive neuroectodermal tumour of the uterus: a poor prognostic subtype of uterine tumours.

PubMed

Bartosch, Carla; Vieira, Joana; Teixeira, Manuel R; Lopes, José Manuel

2011-12-01

Uterine primitive neuroectodermal tumours are extremely rare tumours. They can occur in pure form or combined with another component including endometrioid adenocarcinoma. We aimed to review the clinical impact of neuroectodermal phenotype in uterine tumours, after we recently diagnosed one such case. A 58-year-old female presented with irregular vaginal bleeding. Ultrasonography and CT showed the presence of a large uterine mass with irregular contours. At laparotomy it was found to extend to the right ureter, sigmoid colon and some small intestinal loops. Microscopic examination revealed that the tumour consisted of an endometrioid adenocarcinoma component merging with an extensive neuroectodermal component. No EWSR1 or FUS rearrangement was found in the two tumour components. The patient received two courses of chemotherapy but died 11 months after the initial diagnosis. We reviewed the morphological and molecular criteria for the diagnosis of uterine primitive neuroectodermal tumours published in the literature. We conclude that regardless of the detection of an EWSR1 rearrangement, the presence of a neuroectodermal differentiation component in these rare uterine tumours is a marker of aggressive behaviour, and its presence should be highlighted in the diagnosis.

Vismodegib and Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced or Metastatic Sarcoma

ClinicalTrials.gov

2016-06-09

Adult Alveolar Soft Part Sarcoma; Adult Angiosarcoma; Adult Desmoplastic Small Round Cell Tumor; Adult Epithelioid Hemangioendothelioma; Adult Epithelioid Sarcoma; Adult Extraskeletal Myxoid Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Mesenchymoma; Adult Malignant Peripheral Nerve Sheath Tumor; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Adult Unclassified Pleomorphic Sarcoma; Chondrosarcoma; Clear Cell Sarcoma of the Kidney; Conjunctival Kaposi Sarcoma; Dermatofibrosarcoma Protuberans; Gastrointestinal Stromal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Osteosarcoma; Ovarian Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Adult Unclassified Pleomorphic Sarcoma of Bone; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Kaposi Sarcoma; Recurrent Osteosarcoma; Recurrent Uterine Corpus Sarcoma; Small Intestine Leiomyosarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Uterine Sarcoma; Unclassified Pleomorphic Sarcoma of Bone

Imatinib Mesylate in Treating Patients With Relapsed or Refractory Solid Tumors of Childhood

ClinicalTrials.gov

2015-04-14

Childhood Desmoplastic Small Round Cell Tumor; Childhood Synovial Sarcoma; Gastrointestinal Stromal Tumor; Lung Metastases; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma

Study of Genistein in Pediatric Oncology Patients (UVA-Gen001)

ClinicalTrials.gov

2017-06-20

Lymphoma; Childhood Lymphoma; Solid Tumor; Childhood Solid Tumor; Neuroblastoma; Ewing Sarcoma; Hodgkin Lymphoma; Non-Hodgkin Lymphoma; Rhabdomyosarcoma; Soft Tissue Sarcoma; Medulloblastoma; Germ Cell Tumor; Wilms Tumor; Brain Neoplasms; Medulloblastoma, Childhood; Neuroectodermal Tumors, Primitive

Sorafenib in Treating Patients With Soft Tissue Sarcomas (Extremity Sarcoma Closed to Entry as of 5/30/07)

ClinicalTrials.gov

2014-04-01

Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Osteosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Osteosarcoma; Stage I Adult Soft Tissue Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

Primitive neuroectodermal tumour of the kidney: radiologic-pathological correlations.

PubMed

Chea, Y W; Agrawal, Rashi; Poh, Angeline C C

2008-06-01

A primitive neuroectodermal tumour of the kidney is a rare malignancy. We report the computed tomographic features and the histopathological correlation of such a tumour occurring in a middle-aged man. Although the radiological appearance has significant overlap with other renal tumours, this tumour should be included in the differential diagnosis of a large renal mass in younger patients.

The role of immunohistochemistry in medullomyoblastoma--a case series highlighting divergent differentiation.

PubMed

Sachdeva, Man Updesh S; Vankalakunti, Mahesha; Rangan, Aruna; Radotra, Bishan D; Chhabra, Rajesh; Vasishta, Rakesh K

2008-04-25

To analyse the histo-morphology of cases of medullomyoblastoma and identifying its divergent differentiation. A retrospective review of all cases reported as medulloblastoma between the period of Jan 2000 to Dec 2006 was carried out on Hematoxylin and eosin (H & E) stained slides. The cases were screened on light microscopy for primitive neuroectodermal component of a medulloblastoma accompanied by areas of "myoid" differentiation, identified on the basis of presence of strap cells (indicating a clear skeletal muscle differentiation) and/or large anaplastic cells with vescicular nuclei and moderate to abundant amount of eosinophilic cytoplasm. All these cases were subjected to a panel of immunohistochemical stains, including Desmin, GFAP, NFP, HMB45, SMA, S100, CK and EMA. Ultrastructural analysis was done on tissue obtained from paraffin blocks in 2 cases. Male predominance (M:F = 5:1) was noted with an incidence of five percent of all cases of medulloblastoma (6 out of 120 cases) over a period of 6 years. Primitive neuroectodermal areas were accompanied with areas of "myoid" differentiation, 5 cases showing strap cells. Two cases with epithelial and cartilaginous differentiation were seen. Three cases showed focal melanocytic differentiation, identified only on HMB45 immunostaining. Four cases showed glial differentiation. Neuronal differentiation again was very focally seen in two cases, of which one was identified only by NFP immunostain. Seventh case is included in the study, however it is not considered to calculate incidence as it occurred beyond the period of 6 years of records search. Medullomyoblastoma is a rare childhood tumor of cerebellum. Majority of cases reveal divergent differentiation, which are identified with the help of panel of immunostains indicating multi-potential nature of primitive neuroectodermal cells.

Primary extraskeletal Ewing's sarcoma/primitive neuroectodermal tumour of breast.

PubMed

Ikhwan, S M; Kenneth, V K T; Seoparjoo, A; Zin, A A M

2013-06-21

Primary primitive neuroectodermal tumour (PNET) and extraskeletal Ewing's sarcoma belongs to the Ewing's family of tumours. Primary tumours arising from breast are very rare. There are only a few case reports published on primary extraskeletal Ewing's sarcoma and PNET arising from breast. We present an extremely rare case of an inoperable primary Ewing's sarcoma arising from left breast with contralateral breast, lymphatic and lung metastasis.

Intensity-Modulated Radiation Therapy in Treating Younger Patients With Lung Metastases

ClinicalTrials.gov

2013-09-23

Adult Rhabdomyosarcoma; Lung Metastases; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Stage IV Adult Soft Tissue Sarcoma; Stage IV Wilms Tumor; Stage V Wilms Tumor; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific

Peripheral primitive neuroectodermal tumor of the vulva: report of a case with imprint cytology.

PubMed

Takeshima, N; Tabata, T; Nishida, H; Furuta, N; Tsuzuku, M; Hirai, Y; Hasumi, K

2001-01-01

Peripheral primitive neuroectodermal tumor (PNET) of the vulva is an extremely rare disease, and, to our knowledge, only two cases have been previously reported. A 45-year-old woman presented with a mass in the right labium major. Three years after removal of the tumor, she noticed a new lesion in the same place and underwent a partial vulvectomy. The imprint cytology of the recurrent tumor showed a monomorphic appearance, composed of small round cells with scant cytoplasm against a hemorrhagic background. These tumor cells were loosely connective, but rosettelike structures were observed focally. On pathologic examination, the neoplasm was composed of small round tumor cells showing sinusoidal, diffuse or micropapillary growth. Immunohistochemically, the neoplastic cells stained positively for neuron-specific enolase, vimentin and HBA 71 and negatively for cytokeratin, HBA 45 and muscle-specific actin. The morphologic characteristics of the disease were well expressed in the imprint cytology, and this influenced the selection of immunohistochemical studies. Cytologic examination for vulvar tumors, even imprint cytology, can be a useful tool in obtaining an accurate pathologic diagnosis of a rare disease, such as peripheral PNET.

[Primitive neuroectodermal tumor/Ewing's sarcoma of the penis in children: a case report and review of the literature].

PubMed

Zhang, Da-Wei; Jin, Mei; Zhou, Chun-Ju; Song, Hong-Cheng; Ma, Xiao-Li

2012-12-01

To investigate the clinical manifestations, pathological characteristics and treatment of primitive neuroectodermal tumor/Ewing's sarcoma (PNET/EWS) of the penis in children. We analyzed the clinical data of a case of PNET/EWS and reviewed relevant literature. The patient was a 5-year-old boy, admitted for penis swelling with pain for 11 months. Biopsy showed a small round cell tumor, CD99 positive by immunohistochemical staining, with EWS translocation by fluorescence in situ hybridization on molecular biological examination. The tumor was confirmed to be PNET/EWS of the penis, and disappeared after 45 weeks of chemotherapy and local radiotherapy. PNET/EWS of the penis is an extremely rare disease, with no specific clinical symptoms except penis enlargement with pain. Immunohistochemistry and molecular biological examination contribute to its diagnosis.

Stereotactic Radiosurgery in Treating Patients With Brain Tumors

ClinicalTrials.gov

2012-03-21

Adult Central Nervous System Germ Cell Tumor; Adult Malignant Meningioma; Adult Medulloblastoma; Adult Noninfiltrating Astrocytoma; Adult Oligodendroglioma; Adult Craniopharyngioma; Adult Meningioma; Brain Metastases; Adult Ependymoma; Adult Pineal Parenchymal Tumor; Adult Brain Stem Glioma; Adult Infiltrating Astrocytoma; Mixed Gliomas; Stage IV Peripheral Primitive Neuroectodermal Tumor

Expression of hydroxyindole-O-methyltransferase enzyme in the human central nervous system and in pineal parenchymal cell tumors.

PubMed

Fukuda, Takahiro; Akiyama, Nobutake; Ikegami, Masahiro; Takahashi, Hitoshi; Sasaki, Atsushi; Oka, Hidehiro; Komori, Takashi; Tanaka, Yuko; Nakazato, Youichi; Akimoto, Jiro; Tanaka, Masahiko; Okada, Yoshikazu; Saito, Saburo

2010-05-01

Pineal parenchymal tumor (PPT) cells usually show immunoreactivity for synaptophysin, neuron-specific enolase, neurofilament protein, class III beta-tubulin, tau protein, PGP9.5, chromogranin, serotonin, retinal S-antigen, and rhodopsin, but these markers are not specific for PPTs. Melatonin is produced and secreted mainly bypineal parenchymal cells; hydroxyindole-O-methyltransferase (HIOMT) catalyzes the final reaction in melatonin biosynthesis. We hypothesized that HIOMT could serve as a tumor marker of PPTs, and we investigated HIOMT localization and HIOMT expression in samples of normal human tissue and in PPTs, primitive neuroectodermal tumors, and medulloblastomas. In normal tissue, HIOMT was expressed in retinal cells, pineal parenchymal cells, neurons of the Edinger-Westphal nucleus, microglia, macrophages, thyroid follicular epithelium, principal and oxyphil cells of parathyroid gland, adrenal cortical cells, hepatic parenchymal cells, renal tubule epithelium, and enteroendocrine cells of stomach and duodenum. The HIOMT was also expressed in all 46 PPTs studied. The proportions of HIOMT-immunoreactive cells successively decreased in the following tumors: pineocytoma, pineal parenchymal tumor of intermediate differentiation, and pineoblastoma. A few HIOMT-immunoreactive cells were observed in one of 6 primitive neuroectodermal tumors and 23 of 42 medulloblastomas. These results indicate that HIOMT immunohistochemistry may be useful for the diagnosis of PPTs and be a prognostic factor in PPTs.

Depsipeptide (Romidepsin) in Treating Patients With Metastatic or Unresectable Soft Tissue Sarcoma

ClinicalTrials.gov

2017-05-18

Adult Alveolar Soft-part Sarcoma; Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Extraskeletal Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Fibrous Histiocytoma; Adult Malignant Hemangiopericytoma; Adult Malignant Mesenchymoma; Adult Neurofibrosarcoma; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Gastrointestinal Stromal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Adult Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

Alisertib in Treating Young Patients With Recurrent or Refractory Solid Tumors or Leukemia

ClinicalTrials.gov

2017-09-21

Hepatoblastoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Kidney Neoplasm; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma

Conservative multimodal management of a primitive neuroectodermal tumor of the thyroid.

PubMed

Natale, Romain; Thariat, Juliette; Vedrine, Pierre Olivier; Bozec, Alex; Peyrottes, Isabelle; Marcy, Pierre Yves; Haudebourg, Juliette; Pedeutour, Florence; Saâda, Esma; Thyss, Antoine

2013-04-15

Primitive neuroectodermal tumors (PNET) represent 1% of sarcomas. Head and neck peripheral PNETs have an intermediate prognosis between abdominopelvic disease and extremities. We here report the case of a 40-year old male who presented with primitive neuroectodermal tumor of the thyroid and was treated by multimodal treatment, including surgery, chemotherapy and intermediate dose radiotherapy. The patient is alive and fit with a functional larynx at 27 months. Multimodal treatments yield five-year survival rates of about 60%. Major drug regimens use vincristine, doxorubicin, ifosfamide or cyclophosphamide, dactinomycin and/or etoposide. Complete surgical excision is undertaken whenever possible to improve long-term survival. However, the relative radiosensitivity of tumors of the Ewing family, suggest multimodal treatment including adjuvant conformal radiotherapy in case of positive margins or poor response to chemotherapy rather than resection with 2-3 cm margins, which would imply laryngeal sacrifice for thyroid tumors. The role of expert rare tumor networks is crucial for optimal decision-making and management of such rare tumors on a case by case basis.

Fine-Needle Aspiration of Metastatic Central Type Primitive Neuroectodermal Tumors in Patients with a Germ Cell Tumor.

PubMed

Chen, Shaoxiong; Idrees, Muhammad; Lin, Jingmei; Wu, Howard H

2017-01-01

Central type primitive neuroectodermal tumors (PNET) are some of the most frequent somatic type tumors derived from germ cell tumors and can metastasize. We studied the cytomorphological features of metastatic central type PNET by fine-needle aspiration (FNA). A computerized search of our laboratory information system was performed for the 9-year period from 2005 through 2014 to identify all cytology cases in which a diagnosis of metastatic central type PNET had been rendered. A total of 5 FNA cases were collected and direct smears were reexamined. All patients had a history of testicular or ovarian germ cell tumors. Direct smears displayed single and clusters of atypical round to oval cells with scant to moderate cytoplasm. Abundant naked nuclei were present in Diff-Quik-stained smears with mild to marked crushed artifacts and nuclear molding. Tumor cells showed fine granular chromatin, nuclear size variation (up to 1:3), and one or more small nucleoli. Pseudorosettes (Homer Wright-like rosette) were noticed in 1 case. Tumor cells were commonly positive for synaptophysin. Metastatic PNET can be reliably diagnosed by FNA. Differential diagnoses include Ewing sarcoma/peripheral PNET, alveolar rhabdomyosarcoma, neuroblastoma, etc. It is important to be familiar with this entity to avoid diagnostic pitfalls. © 2017 S. Karger AG, Basel.

Efficacy of 68Ga-DOTATOC Positron Emission Tomography (PET) CT in Children and Young Adults With Brain Tumors

ClinicalTrials.gov

2017-04-27

Acoustic Schwannoma; Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Tumor; Adult Craniopharyngioma; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade I Meningioma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Subependymal Giant Cell Astrocytoma; Adult Subependymoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Childhood Supratentorial Ependymoma; Meningeal Melanocytoma; Newly Diagnosed Childhood Ependymoma; Recurrent Adult Brain Tumor; Recurrent Childhood Anaplastic Astrocytoma; Recurrent Childhood Anaplastic Oligoastrocytoma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Diffuse Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Fibrillary Astrocytoma; Recurrent Childhood Gemistocytic Astrocytoma; Recurrent Childhood Giant Cell Glioblastoma; Recurrent Childhood Glioblastoma; Recurrent Childhood Gliomatosis Cerebri; Recurrent Childhood Gliosarcoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Oligoastrocytoma; Recurrent Childhood Oligodendroglioma; Recurrent Childhood Pilocytic Astrocytoma; Recurrent Childhood Pilomyxoid Astrocytoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Pleomorphic Xanthoastrocytoma; Recurrent Childhood Protoplasmic Astrocytoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Anaplastic Oligodendroglioma; Untreated Childhood Brain Stem Glioma; Untreated Childhood Cerebellar Astrocytoma; Untreated Childhood Cerebral Astrocytoma; Untreated Childhood Diffuse Astrocytoma; Untreated Childhood Fibrillary Astrocytoma; Untreated Childhood Gemistocytic Astrocytoma; Untreated Childhood Giant Cell Glioblastoma; Untreated Childhood Glioblastoma; Untreated Childhood Gliomatosis Cerebri; Untreated Childhood Gliosarcoma; Untreated Childhood Medulloblastoma; Untreated Childhood Oligoastrocytoma; Untreated Childhood Oligodendroglioma; Untreated Childhood Pilocytic Astrocytoma; Untreated Childhood Pilomyxoid Astrocytoma; Untreated Childhood Pineoblastoma; Untreated Childhood Pleomorphic Xanthoastrocytoma; Untreated Childhood Protoplasmic Astrocytoma; Untreated Childhood Subependymal Giant Cell Astrocytoma; Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor; Untreated Childhood Visual Pathway and Hypothalamic Glioma; Untreated Childhood Visual Pathway Glioma

Bilateral Ewing Sarcoma/Primitive Neuroectodermal Tumor of the Breast: A Very Rare Entity and Review of the Literature

PubMed Central

Majid, N.; Amrani, M.; Ghissassi, I.; El Cadi, M.; El Bouzidi, M.; El Kabous, M.; Kherbach, A.; Errihani, H.

2013-01-01

Peripheral primitive neuroectodermal tumors (PNET) are rare malignant tumors, affecting mostly children and adolescents and have been described in breast in eight case reports only. In this paper, we present a case of bilateral mammary ES/PNET where distinction between primary and metastatic diseases was discussed through a literature review. The aim of this work is to demonstrate that although rare, the possibility of PNET should be kept in mind while evaluating a palpable breast abnormality in a young female. PMID:23819085

Primitive neuroectodermal tumor of the cervix uteri. A case report.

PubMed

Horn, L C; Fischer, U; Bilek, K

1997-02-01

Primitive neuroectodermal tumors (PNET) of the female genital tract are rare and more common in the ovary, but uncommon in the cervix uteri. A 26-year-old woman presented with suspect cervical smears. The conization specimen showed a small cell non-keratinised squamous cell carcinoma with involved margins. The patient underwent radical abdominal hysterectomy and pelvic lymphonodectomy. The microscopic examination showed a densely cellular tumor of small neuroendocrine cells with scanty cytoplasm and rosettes. Immunohistochemically, the cells were slightly positive for NSE and negative for S 100, GFAP, neurofilaments, squamous cell cytokeratin 1, vimentin, desmin and leukocyte common antigen. The diagnosis of PNET, stage pT1b1,N0, M0 was made. The patient underwent adjuvant pelvic radiation. Three years later, pulmonary metastases occured. Radiation therapy of the thorax and six courses of combination chemotherapy (5-FU and cis-platinium) could not prevent tumor progression. The patient died 4.2 years after diagnosis. The autopsy showed widespread lymphatic metastases and hepatic, pulmonal and skeletal metastases and a peritoneal carcinosis. The tumors are resistent to radio- and chemotherapy, and the prognosis is generally poor. Up to 15% foci of squamous or glandular differentiation occur in or adjacent to these tumors. So the authors favor the histogenesis from a pluripotent endocervical stem cell. The neuroendocrine component of mixed tumors improve the prognosis. Therefore, it is necessary to recognize this component.

Primary Ewing's sarcoma-primitive neuroectodermal tumor of the uterus: a case report and literature review.

PubMed

Park, Jeong-Yeol; Lee, Sun; Kang, Hyoung Jin; Kim, Hy-Sook; Park, Sang-Yoon

2007-08-01

Primary Ewing's sarcoma-primitive neuroectodermal tumor (ES-PNET) of the uterus is an extremely rare malignancy. A 30-year-old Korean woman presented with abnormal uterine bleeding with uterine enlargement. A computed tomography (CT) scan and magnetic resonance imaging (MRI) of the abdomen and pelvis showed a huge uterine mass measuring 18 x 20 x 21 cm, metastasis to both pelvic and para-aortic lymph nodes, and omental infiltration. The pathology report of the uterine mass described a uniformly hypercellular tumor, which was arranged in diffuse solid sheets of uniform, small, rounded, and sometimes spindle-shaped cells, with scanty cytoplasm. Immunohistochemically, the mass tested positive for vimentin, CD99, and chromogranin. The patient received several courses of combination chemotherapy and radiotherapy but died from tumor progression 16 months after the initial diagnosis. This is a rare case of primary uterine ES-PNET in a woman of reproductive age. A review of the literature indicates that primary uterine ES-PNET requires early diagnosis and multimodality treatment including surgery, chemotherapy, and radiotherapy. The behavior of this tumor is potentially aggressive.

Yoga Therapy in Treating Patients With Malignant Brain Tumors

ClinicalTrials.gov

2017-07-27

Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Tumor; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Recurrent Adult Brain Tumor

17-N-Allylamino-17-Demethoxygeldanamycin in Treating Patients With Advanced Epithelial Cancer, Malignant Lymphoma, or Sarcoma

ClinicalTrials.gov

2013-02-06

AIDS-related Peripheral/Systemic Lymphoma; AIDS-related Primary CNS Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Chondrosarcoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Osteosarcoma; Nodal Marginal Zone B-cell Lymphoma; Ovarian Sarcoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Osteosarcoma; Recurrent Small Lymphocytic Lymphoma; Recurrent Uterine Sarcoma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Stage IV Uterine Sarcoma; Unspecified Adult Solid Tumor, Protocol Specific

TCRαβ+/CD19+ Depleted Haploidentical HSCT + Zoledronate

ClinicalTrials.gov

2018-05-09

Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Hodgkin Lymphoma; Non-Hodgkin Lymphoma; Myelodysplastic Syndrome; Myeloproliferative Syndrome; Rhabdomyosarcoma; Ewing Sarcoma; Primitive Neuroectodermal Tumor; Osteosarcoma; Neuroblastoma

Vorinostat With or Without Isotretinoin in Treating Young Patients With Recurrent or Refractory Solid Tumors, Lymphoma, or Leukemia

ClinicalTrials.gov

2014-06-16

Childhood Acute Promyelocytic Leukemia (M3); Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Juvenile Myelomonocytic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Relapsing Chronic Myelogenous Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

AZD2171 in Treating Young Patients With Recurrent, Progressive, or Refractory Primary CNS Tumors

ClinicalTrials.gov

2016-03-04

Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Cerebral Anaplastic Astrocytoma; Childhood Cerebral Astrocytoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood Infratentorial Ependymoma; Childhood Oligodendroglioma; Childhood Spinal Cord Neoplasm; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Neoplasm; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway Glioma

Ewing sarcoma

MedlinePlus

Bone cancer - Ewing sarcoma; Ewing family of tumors; Primitive neuroectodermal tumors (PNET); Bone neoplasm - Ewing sarcoma ... adulthood. But it usually develops during puberty, when bones are growing rapidly. It is more common in ...

Positron Emission Tomography Using Fluorine F 18 EF5 to Find Oxygen in Tumor Cells of Patients Who Are Undergoing Surgery or Biopsy for Newly Diagnosed Brain Tumors

ClinicalTrials.gov

2013-01-15

Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Central Nervous System Germ Cell Tumor; Adult Choroid Plexus Tumor; Adult Craniopharyngioma; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade I Meningioma; Adult Grade II Meningioma; Adult Grade III Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Pilocytic Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Subependymoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Meningeal Melanocytoma

Imetelstat Sodium in Treating Younger Patients With Relapsed or Refractory Solid Tumors

ClinicalTrials.gov

2017-02-08

Childhood Hepatoblastoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Liver Cancer; Recurrent Childhood Rhabdomyosarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma

[Supratentorial primitive neuroectodermal tumor: a single center experience and comparison with the literature].

PubMed

Schmid, I; Stachel, D; Graubner, U B; Elsner, R; Schulze, S; Pöllinger, B; Goetz, C; Haas, R J

2005-01-01

Supratentorial primitive neuroectodermal tumors (stPNETs) are malignant tumors. We saw within three years six children with stPNETs. In four of the six children radical resection could be achieved. All had craniospinal irradiation and chemotherapy according to the HIT-91 protocol. The two children with incomplete resection died due to tumor progression after 7 and 10 months. Two of the 4 children with complete tumor resection had local relapses 8 months after diagnosis and died after 14 and 18 months. One child had a diffuse meningeal relapse 12 months after diagnosis. Despite (high-dose) systemic chemotherapy and intraventricular mafosfamide, he died 21 months after diagnosis due to tumor although remission could be achieved. Only one child is still in remission 86 months after diagnosis.

A practical approach to the clinical diagnosis of Ewing's sarcoma/primitive neuroectodermal tumour and other small round cell tumours sharing EWS rearrangement using new fluorescence in situ hybridisation probes for EWSR1 on formalin fixed, paraffin wax embedded tissue.

PubMed

Yamaguchi, U; Hasegawa, T; Morimoto, Y; Tateishi, U; Endo, M; Nakatani, F; Kawai, A; Chuman, H; Beppu, Y; Endo, M; Kurotaki, H; Furuta, K

2005-10-01

Over 90% of Ewing's sarcoma/primitive neuroectodermal tumour (ES/PNET) cases have the t(11;22) chromosomal rearrangement, which is also found in other small round cell tumours, including desmoplastic small round cell tumour (DSRCT) and clear cell sarcoma (CCS). Although this rearrangement can be analysed by fluorescence in situ hybridisation (FISH) using routinely formalin fixed, paraffin wax embedded (FFPE) tissues when fresh or frozen tissues are not available, a sensitive and convenient detection method is needed for routine clinical diagnosis. To investigate the usefulness of newly developed probes for detecting EWS rearrangement resulting from chromosomal translocations using FISH and FFPE tissue in the clinical diagnosis of ES/PNET, DSRCT, and CCS. Sixteen ES/PNETs, six DSRCTs, and six CCSs were studied. Three poorly differentiated synovial sarcomas, three alveolar rhabdomyosarcomas, and three neuroblastomas served as negative controls. Interphase FISH analysis was performed on FFPE tissue sections with a commercially available EWSR1 (22q12) dual colour, breakapart rearrangement probe. One fused signal and one split signal of orange and green, demonstrating rearrangement of the EWS gene, was detected in 14 of 16 ES/PNETs, all six DRSCTs, and five of six CCSs, but not in the negative controls. Interphase FISH using this newly developed probe is sensitive and specific for detecting the EWS gene on FFPE tissues and is of value in the routine clinical diagnosis of ES/PNET, DSRCT, and CCS.

Vorinostat Combined With Isotretinoin and Chemotherapy in Treating Younger Patients With Embryonal Tumors of the Central Nervous System

ClinicalTrials.gov

2018-05-16

Medulloblastoma; Pineoblastoma; Supratentorial Embryonal Tumor, Not Otherwise Specified; Untreated Childhood Medulloblastoma; Untreated Childhood Pineoblastoma; Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor

Episome-generated N-myc antisense RNA restricts the differentiation potential of primitive neuroectodermal cell lines.

PubMed Central

Whitesell, L; Rosolen, A; Neckers, L M

1991-01-01

Neuroectodermal tumors of childhood provide a unique opportunity to examine the role of genes potentially regulating neuronal growth and differentiation because many cell lines derived from these tumors are composed of at least two distinct morphologic cell types. These types display variant phenotypic characteristics and spontaneously interconvert, or transdifferentiate, in vitro. The factors that regulate transdifferentiation are unknown. Application of antisense approaches to the transdifferentiation process has allowed us to explore the precise role that N-myc may play in regulating developing systems. We now report construction of an episomally replicating expression vector designed to generate RNA antisense to part of the human N-myc gene. Such a vector is able to specifically inhibit N-myc expression in cell lines carrying both normal and amplified N-myc alleles. Inhibition of N-myc expression blocks transdifferentiation in these lines, with accumulation of cells of an intermediate phenotype. A concomitant decrease in growth rate but not loss of tumorigenicity was observed in the N-myc nonamplified cell line CHP-100. Vector-generated antisense RNA should allow identification of genes specifically regulated by the proto-oncogene N-myc. Images PMID:1996098

Palbociclib Isethionate in Treating Younger Patients With Recurrent, Progressive, or Refractory Central Nervous System Tumors

ClinicalTrials.gov

2017-09-27

Childhood Choroid Plexus Tumor; Childhood Ependymoblastoma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Recurrent Childhood Anaplastic Astrocytoma; Recurrent Childhood Anaplastic Oligoastrocytoma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Giant Cell Glioblastoma; Recurrent Childhood Glioblastoma; Recurrent Childhood Gliomatosis Cerebri; Recurrent Childhood Gliosarcoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor

Irinotecan in Treating Children With Refractory Solid Tumors

ClinicalTrials.gov

2013-06-13

Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood Infratentorial Ependymoma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Unspecified Childhood Solid Tumor, Protocol Specific

Oxaliplatin in Treating Young Patients With Recurrent Solid Tumors That Have Not Responded to Previous Treatment

ClinicalTrials.gov

2013-06-04

Childhood Central Nervous System Germ Cell Tumor; Childhood Extragonadal Germ Cell Tumor; Childhood Hepatoblastoma; Childhood Hepatocellular Carcinoma; Childhood High-grade Cerebral Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Malignant Ovarian Germ Cell Tumor; Childhood Malignant Testicular Germ Cell Tumor; Childhood Teratoma; Recurrent Adrenocortical Carcinoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Liver Cancer; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Colon Cancer; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Nasopharyngeal Cancer; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Rectal Cancer; Recurrent Renal Cell Cancer

Primitive Neuroectodermal Tumor Presenting with Diffuse Leptomeningeal Involvement in a 55-Year-Old Woman: A Case Report and Brief Summary of Current Diagnostic Tests and Treatment

PubMed Central

Kalidindi, Navya; Torres, Carlos H.; Michaud, Jean; Zwicker, Jocelyn Christine

2014-01-01

Primitive neuroectodermal tumors (PNETs) are typically present as masses in children and adolescents, but rarely in adults. Diagnoses, management strategies, and prognostication factors are not well established in adult cases of PNETs. We describe the case of a central nervous system PNET diagnosed in a 55-year-old woman presenting with a sudden onset of symptoms consisting of increased intracranial pressure and findings of diffuse leptomeningeal enhancement and a small medullary lesion seen on MRI. Amongst the small database of PNETs diagnosed in adults, our case report stands out as one of few cases describing a primarily leptomeningeal PNET diagnosed on biopsy. We also review the literature on PNETs presenting with diffuse leptomeningeal disease and the treatment of PNETs in the adult population. PMID:25202261

RO4929097, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Malignant Glioma

ClinicalTrials.gov

2015-09-28

Acoustic Schwannoma; Adult Anaplastic (Malignant) Meningioma; Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Brain Stem Glioma; Adult Choroid Plexus Neoplasm; Adult Craniopharyngioma; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade I Meningioma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Primary Melanocytic Lesion of Meninges; Adult Subependymal Giant Cell Astrocytoma; Adult Subependymoma; Adult Supratentorial Primitive Neuroectodermal Tumor; Malignant Adult Intracranial Hemangiopericytoma

Evaluating Dactinomycin and Vincristine in Young Patients With Cancer

ClinicalTrials.gov

2017-05-15

Childhood Acute Lymphoblastic Leukemia; Childhood Rhabdomyosarcoma; Childhood Soft Tissue Sarcoma; Ewing Sarcoma; Ewing Sarcoma of Bone; Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor (PNET); Unspecified Childhood Solid Tumor, Protocol Specific; Wilms Tumor and Other Childhood Kidney Tumors

Collecting and Storing Blood and Brain Tumor Tissue Samples From Children With Brain Tumors

ClinicalTrials.gov

2017-12-11

Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Newly Diagnosed Childhood Ependymoma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma

Embryonal tumor with abundant neuropil and true rosettes: a systematic literature review and report of 2 new cases.

PubMed

Alexiou, George A; Stefanaki, Kalliopi; Vartholomatos, George; Sfakianos, George; Prodromou, Neofytos; Moschovi, Maria

2013-12-01

Embryonal tumor with abundant neuropil and true rosettes has been recently defined as a distinct central nervous system embryonal neoplasm, although it was initially regarded as a subtype of central nervous system primitive neuroectodermal tumor. To date 70 cases have been reported. We have performed a literature review and we present 2 new cases. Analysis of the reported data revealed that radiotherapy, tumor excision and high-dose adjuvant chemotherapy with sequential autologous hematopoietic stem cell rescue have a prognostic significance.

Cilengitide in Treating Children With Refractory Primary Brain Tumors

ClinicalTrials.gov

2013-09-27

Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

Temozolomide and O6-Benzylguanine in Treating Children With Recurrent Brain Tumors

ClinicalTrials.gov

2013-09-27

Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

Lenalidomide in Treating Young Patients With Recurrent, Progressive, or Refractory CNS Tumors

ClinicalTrials.gov

2013-09-27

Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)

ClinicalTrials.gov

2018-06-25

Advanced Malignant Solid Neoplasm; Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma; Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma; BRAF NP_004324.2:p.V600X; Ependymoma; Ewing Sarcoma; Hepatoblastoma; Histiocytosis; Langerhans Cell Histiocytosis; Malignant Germ Cell Tumor; Malignant Glioma; Osteosarcoma; Peripheral Primitive Neuroectodermal Tumor; Recurrent Childhood Central Nervous System Neoplasm; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Malignant Solid Neoplasm; Recurrent Neuroblastoma; Refractory Central Nervous System Neoplasm; Refractory Malignant Solid Neoplasm; Refractory Neuroblastoma; Refractory Non-Hodgkin Lymphoma; Rhabdoid Tumor; Rhabdomyosarcoma; Soft Tissue Sarcoma; Wilms Tumor

Ispinesib in Treating Young Patients With Relapsed or Refractory Solid Tumors or Lymphoma

ClinicalTrials.gov

2013-01-15

Childhood Burkitt Lymphoma; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Spinal Cord Neoplasm; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Unspecified Childhood Solid Tumor, Protocol Specific

Ultrasound-guided core needle biopsy in diagnosis of abdominal and pelvic neoplasm in pediatric patients.

PubMed

Wang, Hailing; Li, Fangxuan; Liu, Juntian; Zhang, Sheng

2014-01-01

Ultrasound-guided core needle biopsy of abdominal and pelvic masses in adults has gained tremendous popularity. However, the application of the same treatment in children is not as popular because of apprehensions regarding inadequate tissues for the biopsy and accidental puncture of vital organs. Data of the application of ultrasound-guided core needle biopsy in 105 pediatric patients with clinically or ultrasound-diagnosed abdominopelvic masses were reviewed. Diagnostic procedures were conducted in our institution from May 2011 to May 2013. The biopsies were conducted on 86 malignant lesions and 19 benign lesions. 86 malignant tumors comprised neuroblastomas (30 cases), hepatoblastomas (15 cases), nephroblastomas (11 cases), and primitive neuroectodermal tumors/malignant small round cells (6 cases). Among malignant tumor cases, only a pelvic primitive neuroectodermal tumor did not receive a pathological diagnosis. Therefore, the biopsy accuracy was 98.8 % in malignant tumor. However, the biopsies for one neuroblastomas and one malignant small round cell tumor were inadequate for cytogenetic analysis. Therefore, 96.5 % of the malignant tumor patients received complete diagnosis via biopsy. 19 benign tumors comprised mature teratoma (10 cases), hemangioendothelioma (3 cases), paraganglioma (2 cases), and infection (2 cases). The diagnostic accuracy for benign neoplasm was 100 %. Five patients experienced postoperative complications, including pain (2 patients), bleeding from the biopsy site (2 patients), and wound infection (1 patient). Ultrasound-guided core needle biopsy is an efficient, minimally invasive, accurate, and safe diagnostic method that can be applied in the management of abdominal or pelvic mass of pediatric patients.

High-Dose Chemotherapy With or Without Total-Body Irradiation Followed by Autologous Stem Cell Transplant in Treating Patients With Hematologic Cancer or Solid Tumors

ClinicalTrials.gov

2018-04-05

Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor (PNET); Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Plasma Cell Neoplasm; Primary Systemic Amyloidosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Neuroblastoma; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Regional Neuroblastoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

Talazoparib and Temozolomide in Treating Younger Patients With Refractory or Recurrent Malignancies

ClinicalTrials.gov

2018-03-02

Adult Solid Neoplasm; Childhood Solid Neoplasm; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Central Nervous System Neoplasm; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Malignant Solid Neoplasm; Refractory Central Nervous System Neoplasm

Epidemiology, management and treatment outcome of medulloblastoma in singapore.

PubMed

Chan, Mei-Yoke; Teo, Wan-Yee; Seow, Wan-Tew; Tan, Ah-Moy

2007-05-01

Medulloblastoma/primitive neuroectodermal tumour is the most common type of malignant brain tumour in children. Long-term survival rates have improved over the years with a combination of surgical, radiotherapeutic and chemotherapeutic treatment modalities in the developed world. This paper aims to analyse the epidemiology and outcome of medulloblastoma in Singapore and compare our results with those reported in the literature. A 9-year retrospective study was done using data reported to the Singapore Children's Cancer Registry from June 1997 to June 2005. Only 39 children up to the age of 15 years diagnosed histologically with medulloblastoma or primitive neuroectodermal tumour arising from the cerebellum were included in the study. Follow-up data were collected up to June 2006 and analysed using SPSS v 13.0 software. Medulloblastoma/primitive neuroectodermal tumour was the most common type of brain tumour, accounting for 40.7% of all brain tumours diagnosed in children in Singapore. The 5-year event-free survival rate was 44.5%, while the 5- year overall survival rate was 51.5%. Nearly half (41%) of our patients had spinal metastasis at presentation and this was associated with a worse event-free survival (6.3% vs 71.9%, P = 0). Children under 36 months of age had a significantly poorer overall survival (28.8% vs 52.2%, P = 0.041). The outcome of medulloblastoma in Singapore was inferior to reported figures in the literature. We need to close identified gaps in care, like standardising assessment and treatment protocols, in order to improve our results. Research into molecular and genetic characteristics may also throw light on whether the disease is inherently more aggressive in our population.

Clinical analysis of primary primitive neuroectodermal tumors in the female genital tract.

PubMed

Xiao, Changji; Zhao, Jing; Guo, Peng; Wang, Dan; Zhao, Dachun; Ren, Tong; Yang, Jiaxin; Shen, Keng; Lang, Jinghe; Xiang, Yang; Cui, Quancai

2014-03-01

The aim of the study was to investigate the clinical manifestations, diagnosis, treatment, and prognosis of primitive neuroectodermal tumors (PNETs) in the female genital tract. From April 2001 to May 2013, the clinicopathologic characteristics, treatments, outcomes, and prognosis of 11 patients with PNET in the female genital tract were analyzed retrospectively at our hospital. The location of PNET in the 11 patients presented here included vulva (2 patients), cervix (2 patients), uterus and its ligament (5 patients), and the ovaries (2 patients). Ages ranged from 18 to 59 years (median, 31 years).The main clinical manifestations of PNET in the female genital tract are irregular vaginal bleeding (6 patients), pelvic mass, uterine enlargement, and rapidly increasing vulvar mass (8 patients), and vulvar pain and lower abdominal pain (5 patients). The CA125 levels of 8 patients were elevated before the operations and reduced to normal when the diseases were controlled, while the levels increased as the tumor was progressive. Results for the most commonly used immunohistochemistry studies revealed CD99 in 11 of the 11 tumors, synaptophysin in 6 of the 7 positive tumors, and neuron-specific enolase in 6 of the 6 tumors. Ten patients underwent surgical resection. Nine of them underwent preoperative or/and postoperative combination chemotherapy. The follow-up of 10 patients were available and ranged from 1 to 145 months (median, 30.5 months), 3 of whom experiencing recurrence. Primitive neuroectodermal tumor is very rare and can originate from any part of the female genital tract. The tumors had different manifestations but the same pathologic features. CA125 may be an important marker for prognosis and follow-up of PNET of the female internal genital tract.

Wild-Type Reovirus in Combination With Sargramostim in Treating Younger Patients With High-Grade Relapsed or Refractory Brain Tumors

ClinicalTrials.gov

2018-03-16

Childhood Astrocytoma; Childhood Atypical Teratoid/Rhabdoid Tumor; Diffuse Intrinsic Pontine Glioma; Glioma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Neoplasm; Recurrent Childhood Glioblastoma; Recurrent Childhood Medulloblastoma; Recurrent Primitive Neuroectodermal Tumor; Refractory Brain Neoplasm

Gadobutrol Versus Gadopentetate Dimeglumine or Gadobenate Dimeglumine Before DCE-MRI in Diagnosing Patients With Multiple Sclerosis, Grade II-IV Glioma, or Brain Metastases

ClinicalTrials.gov

2017-03-22

Adult Anaplastic (Malignant) Meningioma; Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Neoplasm; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Primary Melanocytic Lesion of Meninges; Adult Supratentorial Primitive Neuroectodermal Tumor; Malignant Adult Intracranial Hemangiopericytoma; Metastatic Malignant Neoplasm in the Brain; Multiple Sclerosis; Recurrent Adult Brain Neoplasm

A Case of Desmoplastic Small Round Cell Tumor.

PubMed

Reisner, David; Brahee, Deborah; Patel, Shweta; Hartman, Matthew

2015-08-01

Desmoplastic small round cell tumor is a rare, aggressive tumor primarily affecting young males. It is considered a childhood cancer, and is characterized by a unique chromosomal translocation which leads to failure to suppress tumor growth. It is classified as a soft tissue sarcoma, sharing some features with other small round cell tumors such as Ewing's Sarcoma and primitive neuroectodermal tumor. Typical imaging findings include multiple heterogeneous, lobular abdominal masses, which can grow very large. Often there is a dominant mass with additional peritoneal, omental, retroperitoneal and retrovesical masses. Prognosis is relatively poor with a 3 year survival rate of 50% in those treated aggressively with surgical resection, chemotherapy, and radiation therapy. The clinical presentation, imaging characteristics and pathology are discussed in regards to a recent case.

Study of Fixed vs. Flexible Filgrastim to Accelerate Bone Marrow Recovery After Chemotherapy in Children With Cancer

ClinicalTrials.gov

2017-03-28

Childhood Choroid Plexus Tumor; Childhood Medulloblastoma; Childhood Pineoblastoma; Childhood Soft Tissue Sarcoma; Childhood Supratentorial Primitive Neuroectodermal Tumor; Neuroblastoma; Osteosarcoma; Retinoblastoma; Wilms Tumor and Other Childhood Kidney Tumors; Recurrent/Refractory Childhood Hodgkin Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

Development of mediastinal lymphoma after radiotherapy for concurrent medulloblastoma and PNET in a patient with Gorlin syndrome.

PubMed

Jiang, Tao; Wang, Junmei; Wang, Ying; Li, Chunde

2016-08-12

Very young children with Gorlin syndrome are at risk for developing medulloblastoma. Patients with Gorlin syndrome may have multiple system abnormalities, including basal cell carcinomas, jaw cysts, desmoplastic medulloblastoma, palmar/plantar pits, rib abnormalities, and intracranial falx calcification. The early diagnosis of Gorlin syndrome in desmoplastic medulloblastoma patients is very important because these patients should receive chemotherapy as a first-line treatment and should avoid radiotherapy as much as possible. In the present study, a 5-year-old male patient had a concurrent cerebellar desmoplastic medulloblastoma and temporal primitive neuroectodermal tumor. Examinations of this patient revealed multiple café-au-lait spots, a jaw cyst, and a bifid rib. A molecular classification analysis revealed that the patient's cerebellar tumor was of the sonic hedgehog subtype. Twenty-seven months after tumor resection and cerebrospinal irradiation were performed, mediastinal lymphoma was found in the patient. The patient ultimately died of lymphoma. To the best of our knowledge, this is the first report of a concurrent medulloblastoma and primitive neuroectodermal tumor and the fourth report of multiple café-au-lait spots in a patient with Gorlin syndrome. This report is also the first account of the development of mediastinal lymphoma after spinal irradiation in a patient with Gorlin syndrome. Chemotherapy should be the first-line treatment for medulloblastoma patients with Gorlin syndrome. Young patients with medulloblastoma of the desmoplastic subtype and multiple café-au-lait spots should be thoroughly examined for Gorlin syndrome.

Primary Ewing's sarcoma/primitive neuroectodermal tumor of the ileum: case report of a 16-year-old Chinese female and literature review.

PubMed

Li, Teng; Zhang, Fang; Cao, Yarui; Ning, Shoubin; Bi, Yongmin; Xue, Weicheng; Ren, Li

2017-05-04

Ewing's sarcoma (ES) and primitive neuroectodermal tumors (PNET) are closely related tumors. Although soft tissue ES/PNET are common in clinical practice, they are rare in the small intestine. Because of the absence of characteristic clinical symptoms, they are easily misdiagnosed as other benign or malignant diseases. Here, we present the case of a 16-year-old female who complained of anemia and interval hematochezia. Her serum test results showed only a slight elevation of CA-125 and a low level of hemoglobin. Computer tomography and magnetic resonance imaging revealed a cystic and solid mass in the lower abdominal quadrant and pelvic region, which prompted suspicion of a malignant gastrointestinal stromal tumor of the small intestine. After resection, the tumor's histology and immunohistochemistry (positive for CD99, vimentin and synaptophysin) results suggested ES/PNET. Fluorescent in situ hybridization tests proved the breakpoint rearrangement of the EWSR1 gene in chr 22.Ultrastructural analysis revealed neurosecretory and glycogen granules in the tumor cell cytoplasm. Together, these data supported the diagnosis of a rare case of localized ES/PNET in the small intestine without adjuvant chemo- or radiotherapy. To our knowledge, this is the first report from China of a primary small bowel ES/PNET in the English-language literature. In addition, on the basis of findings from previous publications and the current case, the optimal treatment for localized gastrointestinal ES/PNET is discussed.

Surveillance imaging in children with malignant CNS tumors: low yield of spine MRI.

PubMed

Perreault, Sébastien; Lober, Robert M; Carret, Anne-Sophie; Zhang, Guohua; Hershon, Linda; Décarie, Jean-Claude; Vogel, Hannes; Yeom, Kristen W; Fisher, Paul G; Partap, Sonia

2014-02-01

Magnetic resonance imaging (MRI) is routinely obtained in patients with central nervous system (CNS) tumors, but few studies have been conducted to evaluate this practice. We assessed the benefits of surveillance MRI and more specifically spine MRI in a contemporary cohort. We evaluated MRI results of children diagnosed with CNS tumors from January 2000 to December 2011. Children with at least one surveillance MRI following the diagnosis of medulloblastoma (MB), atypical teratoid rhabdoid tumor (ATRT), pineoblastoma (PB), supratentorial primitive neuroectodermal tumor, supratentorial high-grade glioma (World Health Organization grade III-IV), CNS germ cell tumors or ependymoma were included. A total of 2,707 brain and 1,280 spine MRI scans were obtained in 258 patients. 97% of all relapses occurred in the brain and 3% were isolated to the spine. Relapse was identified in 226 (8%) brain and 48 (4%) spine MRI scans. The overall rate of detecting isolated spinal relapse was 9/1,000 and 7/1,000 for MB patients. MRI performed for PB showed the highest rate for detecting isolated spinal recurrence with 49/1,000. No initial isolated spinal relapse was identified in patients with glioma, supratentorial primitive neuroectodermal tumor and ATRT. Isolated spinal recurrences are infrequent in children with malignant CNS tumors and the yield of spine MRI is very low. Tailoring surveillance spine MRI to patients with higher spinal relapse risk such as PB, MB with metastatic disease and within 3 years of diagnosis could improve allocation of resources without compromising patient care.

ABT-888 and Temozolomide in Treating Young Patients With Recurrent or Refractory CNS Tumors

ClinicalTrials.gov

2014-07-07

Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Spinal Cord Neoplasm; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

131-I coupled to monoclonal antibodies as therapeutic agents for neuroectodermally derived tumors: fact or fiction?

PubMed

Kemshead, J T; Jones, D H; Lashford, L; Prichard, J; Gordon, I; Breatnach, F; Coakham, H B

1986-01-01

It has been suggested that monoclonal antibodies may be useful in targeting cytotoxic compounds to tumor cells. We have explored their use in targeting 131-I to highly radiosensitive primitive neural tumors such as neuroblastoma and pineoblastomas. Two routes of administration have been employed, intravenous and intrathecal. Our current experience in using radiolabelled antibodies is described, indicating toxicities seen and any therapeutic benefit observed. The results of the study suggest that if targeted radiation has a role in the treatment of these malignancies, it will be restricted to the eradication of small tumor masses from the body.

Cixutumumab and Temsirolimus in Treating Younger Patients With Recurrent or Refractory Sarcoma

ClinicalTrials.gov

2018-03-21

Childhood Alveolar Soft Part Sarcoma; Childhood Angiosarcoma; Childhood Epithelioid Sarcoma; Childhood Fibrosarcoma; Childhood Gliosarcoma; Childhood Leiomyosarcoma; Childhood Liposarcoma; Childhood Malignant Peripheral Nerve Sheath Tumor; Childhood Synovial Sarcoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Osteosarcoma; Rhabdomyosarcoma

Primary Pulmonary Ewing's Sarcoma/Primitive Neuroectodermal Tumor in a 67-year-old Man

PubMed Central

Lee, Yoon Young; Kim, Do Hoon; Lee, Ji Hye; Choi, Jong Sang; In, Kwang Ho; Oh, Yu Whan; Cho, Kyung Hwan

2007-01-01

Extraskeletal Ewing's sarcoma (EES) is a branch of neuroectodermal tumor (PNET), which is very rare soft tissue sarcoma. We report a case of EES/PNET arising is the lung of a 67-yr-old man. Computed tomography, bone scintigraphy, and positron emission tomography confirmed the mass to have a primary pulmonary origin. The mass showed positive reactivity in the Periodic Acid Schiff (PAS) stain and MIC-2 immunoreactivity in immunohistochemical stain. Fluorescence in situ hybridization (FISH) was performed, which revealed an EWSR1 (Ewing sarcoma breakpoint region 1) 22q12 rearrangement. The diagnosis was confirmed both pathologically and genetically. The mass lesion was resected, and the patient is currently undergoing chemotherapy. PMID:17923745

Thyroid-Stimulating Hormone Suppression for Protection Against Hypothyroidism Due to Craniospinal Irradiation for Childhood Medulloblastoma/Primitive Neuroectodermal Tumor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Massimino, Maura; Gandola, Lorenza; Collini, Paola

Purpose: Hypothyroidism is one of the earliest endocrine effects of craniospinal irradiation (CSI). The effects of radiation also depend on circulating thyroid-stimulating hormone (TSH), which acts as an indicator of thyrocyte function and is the most sensitive marker of thyroid damage. Hence, our study was launched in 1998 to evaluate the protective effect of TSH suppression during CSI for medulloblastoma/primitive neuroectodermal tumor. Patients and Methods: From Jan 1998 to Feb 2001, a total of 37 euthyroid children scheduled for CSI for medulloblastoma/primitive neuroectodermal tumor underwent thyroid ultrasound and free triiodothyronine (FT3), free thyroxine (FT4), and TSH evaluation at the beginningmore » and end of CSI. From 14 days before and up to the end of CSI, patients were administered L-thyroxine at suppressive doses; every 3 days, TSH suppression was checked to ensure a value <0.3 {mu}M/ml. During follow-up, blood tests and ultrasound were repeated after 1 year; primary hypothyroidism was considered an increased TSH level greater than normal range. CSI was done using a hyperfractionated accelerated technique with total doses ranging from 20.8-39 Gy; models were used to evaluate doses received by the thyroid bed. Results: Of 37 patients, 25 were alive a median 7 years after CSI. They were well matched for all clinical features, except that eight children underwent adequate TSH suppression during CSI, whereas 17 did not. Hypothyroidism-free survival rates were 70% for the 'adequately TSH-suppressed' group and 20% for the 'inadequately TSH-suppressed' group (p = 0.02). Conclusions: Thyroid-stimulating hormone suppression with L-thyroxine had a protective effect on thyroid function at long-term follow-up. This is the first demonstration that transient endocrine suppression of thyroid activity may protect against radiation-induced functional damage.« less

Cixutumumab in Treating Patients With Relapsed or Refractory Solid Tumors

ClinicalTrials.gov

2015-03-18

Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Childhood Hepatoblastoma; Childhood Synovial Sarcoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Adrenocortical Carcinoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Liver Cancer; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive; Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Retinoblastoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors

Tissue Elasticity Regulated Tumor Gene Expression: Implication for Diagnostic Biomarkers of Primitive Neuroectodermal Tumor

PubMed Central

Vu, Long T.; Keschrumrus, Vic; Zhang, Xi; Zhong, Jiang F.; Su, Qingning; Kabeer, Mustafa H.; Loudon, William G.; Li, Shengwen Calvin

2015-01-01

Background The tumor microenvironment consists of both physical and chemical factors. Tissue elasticity is one physical factor contributing to the microenvironment of tumor cells. To test the importance of tissue elasticity in cell culture, primitive neuroectodermal tumor (PNET) stem cells were cultured on soft polyacrylamide (PAA) hydrogel plates that mimics the elasticity of brain tissue compared with PNET on standard polystyrene (PS) plates. We report the molecular profiles of PNET grown on either PAA or PS. Methodology/Principal Findings A whole-genome microarray profile of transcriptional expression between the two culture conditions was performed as a way to probe effects of substrate on cell behavior in culture. The results showed more genes downregulated on PAA compared to PS. This led us to propose microRNA (miRNA) silencing as a potential mechanism for downregulation. Bioinformatic analysis predicted a greater number of miRNA binding sites from the 3' UTR of downregulated genes and identified as specific miRNA binding sites that were enriched when cells were grown on PAA—this supports the hypothesis that tissue elasticity plays a role in influencing miRNA expression. Thus, Dicer was examined to determine if miRNA processing was affected by tissue elasticity. Dicer genes were downregulated on PAA and had multiple predicted miRNA binding sites in its 3' UTR that matched the miRNA binding sites found enriched on PAA. Many differentially regulated genes were found to be present on PS but downregulated on PAA were mapped onto intron sequences. This suggests expression of alternative polyadenylation sites within intron regions that provide alternative 3' UTRs and alternative miRNA binding sites. This results in tissue specific transcriptional downregulation of mRNA in humans by miRNA. We propose a mechanism, driven by the physical characteristics of the microenvironment by which downregulation of genes occur. We found that tissue elasticity-mediated cytokines (TGFβ2 and TNFα) signaling affect expression of ECM proteins. Conclusions Our results suggest that tissue elasticity plays important roles in miRNA expression, which, in turn, regulate tumor growth or tumorigenicity. PMID:25774514

Hanging drop culture enhances differentiation of human adipose-derived stem cells into anterior neuroectodermal cells using small molecules.

PubMed

Amirpour, Noushin; Razavi, Shahnaz; Esfandiari, Ebrahim; Hashemibeni, Batoul; Kazemi, Mohammad; Salehi, Hossein

2017-06-01

Inspired by in vivo developmental process, several studies were conducted to design a protocol for differentiating of mesenchymal stem cells into neural cells in vitro. Human adipose-derived stem cells (hADSCs) as mesenchymal stem cells are a promising source for this purpose. At current study, we applied a defined neural induction medium by using small molecules for direct differentiation of hADSCs into anterior neuroectodermal cells. Anterior neuroectodermal differentiation of hADSCs was performed by hanging drop and monolayer protocols. At these methods, three small molecules were used to suppress the BMP, Nodal, and Wnt signaling pathways in order to obtain anterior neuroectodermal (eye field) cells from hADSCs. After two and three weeks of induction, the differentiated cells with neural morphology expressed anterior neuroectodermal markers such as OTX2, SIX3, β-TUB III and PAX6. The protein expression of such markers was confirmed by real time, RT-PCR and immunocytochemistry methods According to our data, it seems that the hanging drop method is a proper approach for neuroectodermal induction of hADSCs. Considering wide availability and immunosuppressive properties of hADSCs, these cells may open a way for autologous cell therapy of neurodegenerative disorders. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

FR901228 in Treating Children With Refractory or Recurrent Solid Tumors or Leukemia

ClinicalTrials.gov

2013-01-15

Blastic Phase Chronic Myelogenous Leukemia; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Chronic Myelogenous Leukemia; Childhood Craniopharyngioma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Spinal Cord Neoplasm; Childhood Supratentorial Ependymoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Refractory Chronic Lymphocytic Leukemia; Relapsing Chronic Myelogenous Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

"Pre-emptive strike"-the case for early treatment of hepatic sinusoidal obstruction syndrome with defibrotide.

PubMed

Rajagopal, Revathi; Phillips, Marianne B; Gottardo, Nicholas G

2018-07-01

The initial signs of hepatic sinusoidal obstruction syndrome (HSOS) can be challenging to recognize in children, especially outside the hematopoietic stem cell transplantation setting. To assist clinicians to promptly identify HSOS, the European Society for Blood and Marrow Transplantation has proposed pediatric HSOS diagnostic criteria which emphasize unexplained consumptive and transfusion-refractory thrombocytopenia. To highlight the importance of these "bellwether" early signs of HSOS and the efficacy of pre-emptive treatment with defibrotide, we describe the case of a child with a right 11th rib primitive neuroectodermal tumor who developed HSOS following focal radiotherapy and actinomycin-D treatment. © 2018 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.

Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)

ClinicalTrials.gov

2018-06-25

Advanced Malignant Solid Neoplasm; Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma; Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma; Deleterious ATM Gene Mutation; Deleterious BRCA1 Gene Mutation; Deleterious BRCA2 Gene Mutation; Deleterious RAD51C Gene Mutation; Deleterious RAD51D Gene Mutation; Histiocytosis; Low Grade Glioma; Malignant Glioma; Recurrent Childhood Central Nervous System Neoplasm; Recurrent Childhood Ependymoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Glioma; Recurrent Hepatoblastoma; Recurrent Langerhans Cell Histiocytosis; Recurrent Malignant Solid Neoplasm; Recurrent Medulloblastoma; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Refractory Central Nervous System Neoplasm; Refractory Langerhans Cell Histiocytosis; Refractory Malignant Solid Neoplasm; Refractory Neuroblastoma; Refractory Non-Hodgkin Lymphoma; Rhabdoid Tumor; Wilms Tumor

Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)

ClinicalTrials.gov

2018-06-25

Advanced Malignant Solid Neoplasm; Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma; Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma; FGFR1 Gene Mutation; FGFR2 Gene Mutation; FGFR3 Gene Mutation; FGFR4 Gene Mutation; Histiocytosis; Low Grade Glioma; Malignant Glioma; Recurrent Central Nervous System Neoplasm; Recurrent Childhood Ependymoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Hepatoblastoma; Recurrent Langerhans Cell Histiocytosis; Recurrent Malignant Solid Neoplasm; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Refractory Central Nervous System Neoplasm; Refractory Langerhans Cell Histiocytosis; Refractory Malignant Solid Neoplasm; Refractory Neuroblastoma; Refractory Non-Hodgkin Lymphoma; Rhabdoid Tumor; Stage III Soft Tissue Sarcoma AJCC v7; Stage IV Soft Tissue Sarcoma AJCC v7; Wilms Tumor

Multimodality Treatment in Ewing's Sarcoma Family Tumors of the Maxilla and Maxillary Sinus: Review of the Literature

PubMed Central

Mamot, Christoph; Krasniqi, Fatime; Metternich, Frank

2016-01-01

The Ewing sarcoma family of tumors (ESFT) encompasses a group of highly aggressive, morphologically similar, malignant neoplasms sharing a common spontaneous genetic translocation that affect mostly children and young adults. These predominantly characteristic, small round-cell tumors include Ewing's sarcoma of the bone and soft tissue, as well as primitive neuroectodermal tumors (PNETs) involving the bone, soft tissue, and thoracopulmonary region (Askin's tumor). Extraosseous ESFTs are extremely rare, especially in the head and neck region, where literature to date consists of sporadic case reports and very small series. We hereby present a review of the literature published on ESFTs reported in the maxilla and maxillary sinus region from 1968 to 2016. PMID:27413360

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)

ClinicalTrials.gov

2018-06-25

Advanced Malignant Solid Neoplasm; Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma; Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma; Childhood Langerhans Cell Histiocytosis; Histiocytic Sarcoma; Juvenile Xanthogranuloma; Malignant Glioma; Recurrent Central Nervous System Neoplasm; Recurrent Childhood Ependymoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma; Recurrent Glioma; Recurrent Hepatoblastoma; Recurrent Langerhans Cell Histiocytosis; Recurrent Malignant Solid Neoplasm; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Peripheral Primitive Neuroectodermal Tumor; Refractory Central Nervous System Neoplasm; Refractory Childhood Malignant Germ Cell Tumor; Refractory Langerhans Cell Histiocytosis; Refractory Malignant Solid Neoplasm; Refractory Neuroblastoma; Rhabdoid Tumor; Stage III Osteosarcoma AJCC v7; Stage III Soft Tissue Sarcoma AJCC v7; Stage IV Osteosarcoma AJCC v7; Stage IV Soft Tissue Sarcoma AJCC v7; Stage IVA Osteosarcoma AJCC v7; Stage IVB Osteosarcoma AJCC v7; Wilms Tumor

Integrative genomic analyses identify LIN28 and OLIG2 as markers of survival and metastatic potential in childhood central nervous system primitive neuro-ectodermal brain tumours

PubMed Central

Picard, Daniel; Miller, Suzanne; Hawkins, Cynthia E; Bouffet, Eric; Rogers, Hazel A; Chan, Tiffany SY; Kim, Seung-Ki; Ra, Young-Shin; Fangusaro, Jason; Korshunov, Andrey; Toledano, Helen; Nakamura, Hideo; Hayden, James T; Chan, Jennifer; Lafay-Cousin, Lucie; Hu, Ping X; Fan, Xing; Muraszko, Karin M; Pomeroy, Scott L; Lau, Ching C; Ng, Ho-Keung; Jones, Chris; Meter, Timothy Van; Clifford, Steven C; Eberhart, Charles; Gajjar, Amar; Pfister, Stefan M; Grundy, Richard G; Huang, Annie

2013-01-01

Background Childhood Central Nervous System Primitive Neuro-Ectodermal brain Tumours (CNS-PNETs) are highly aggressive brain tumours for which molecular features and best therapeutic strategy remains unknown. We interrogated a large cohort of these rare tumours in order to identify molecular markers that will enhance clinical management of CNS-PNET. Methods Transcriptional and copy number profiles from primary hemispheric CNS-PNETs were examined using clustering, gene and pathways enrichment analyses to discover tumour sub-groups and group-specific molecular markers. Immuno-histochemical and/or gene expression analyses were used to validate and examine the clinical significance of novel sub-group markers in 123 primary CNS-PNETs. Findings Three molecular sub-groups of CNS-PNETs distinguished by primitive neural (Group 1), oligo-neural (Group 2) and mesenchymal lineage (Group 3) gene expression signature were identified. Tumour sub-groups exhibited differential expression of cell lineage markers, LIN28 and OLIG2, and correlated with distinct demographics, survival and metastatic incidence. Group 1 tumours affected primarily younger females; male: female ratios were respectively 0.61 (median age 2.9 years; 95% CI: 2.4–5.2; p≤ 0.005), 1.25 (median age 7.9 years; 95% CI: 6–9.7) and 1.63 (median age 5.9 years; 95% CI: 4.9–7.8) for group 1, 2 and 3 patients. Overall outcome was poorest in group 1 patients which had a median survival of 0.8 years (95% CI: 0.47–1.2; p=0.019) as compared to 1.8 years (95% CI: 1.4–2.3) and 4.3 years; (95% CI: 0.82–7.8) respectively for group 2 and 3 patients. Group 3 tumours had the highest incidence of metastases at diagnosis; M0: M+ ratio were respectively 0.9 and 3.9 for group 3, versus group 1 and 2 tumours combined (p=0.037). Interpretation LIN28 and OLIG2 represent highly promising, novel diagnostic and prognostic molecular markers for CNS PNET that warrants further evaluation in prospective clinical trials. PMID:22691720

Intraventricular mass lesions at magnetic resonance imaging: iconographic essay - part 1*

PubMed Central

de Castro, Felipe Damásio; Reis, Fabiano; Guerra, José Guilherme Giocondo

2014-01-01

The present essay is illustrated with magnetic resonance images obtained at the authors' institution over the past 15 years and discusses the main imaging findings of intraventricular tumor-like lesions (ependymoma, pilocytic astrocytoma, central neurocytoma, ganglioglioma, choroid plexus papilloma, primitive neuroectodermal tumors, meningioma, epidermoid tumor). Such lesions represent a subgroup of intracranial lesions with unique characteristics and some image patterns that may facilitate the differential diagnosis. PMID:25741075

Conservative Treatment of Ewing's Sarcoma of the Uterus in Young Women.

PubMed

Loverro, Giuseppe; Resta, Leonardo; Di Naro, Edoardo; Caringella, Anna Maria; Mastrolia, Salvatore Andrea; Vicino, Mario; Tartagni, Massimo; Schonauer, Luca Maria

2015-01-01

Ewing sarcoma-primitive neuroectodermal tumors (ES/PNETs) constitute a family of neoplasms characterized by a continuum of neuroectodermal differentiations. ES/PNET of the uterus is rare. There are 48 cases of ES/PNET of the uterus published in the literature as far as we know. We describe a case of Ewing sarcoma of the uterus occurring in a 17-year-old woman presenting with a two-month history of pelvic pain. After surgical excision and microscopic, immunohistochemical, and electron microscopy examination, the diagnosis of Ewing sarcoma of the uterus was suggested. This report will discuss the diagnosis and surgical and clinical management of Ewing uterine sarcoma in young women, according to the available literature. In spite of the rarity of ES/PNETs, they should be taken into account in the differential diagnosis of uterine neoplasms in young women.

Immunohistochemical detection of FLI-1 protein expression: a study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing's sarcoma/primitive neuroectodermal tumor.

PubMed

Folpe, A L; Hill, C E; Parham, D M; O'Shea, P A; Weiss, S W

2000-12-01

The histologic and immunohistochemical differentiation of Ewing' s sarcoma/primitive neuroectodermal tumor (ES/PNET) from other small, blue, round cell tumors may be difficult. Despite initial promise, CD99 (MIC2) has not proven to be a specific marker. Approximately 90% of ES/PNET have a specific t(11; 22)(q24;q12) that results in fusion of the EWS and FLI-1 genes, and overexpression of FLI-1 protein. A recent study has shown immunohistochemical FLI-1 expression in five of seven of the ES/PNET cases tested. We evaluated FLI-1 expression in 132 well-characterized small, blue, round cell tumors. All tumors were immunostained for FLI-1 (1:40, Sc 356 polyclonal, Santa Cruz Biotechnology) using steam heat for epitope retrieval. Only nuclear staining was accepted as positive. Endothelial cells were strongly positive in all cases and served as an internal control. In many cases, a subset of lymphocytes also stained positive. No staining was seen in any other normal tissue. FLI-1 expression was seen in 29 of 41 (71%) ES/PNET, 7 of 8 (88%) lymphoblastic lymphomas, 0 of 8 poorly differentiated synovial sarcomas (PDSS), 0 of 32 rhabdomyosarcoma (RMS), 0 of 30 neuroblastomas, 0 of 8 esthesioneuroblastomas, 0 of 3 Wilms' tumors, 0 of 1 mesenchymal chondrosarcoma, and in 1 of 1 desmoplastic round cell tumor. This last case was known to have an EWS/WT-1 fusion. Although the EWS/FLI-1 fusion gene is specific for ES/PNET, FLI-1 protein expression is not. Significantly, the great majority of lymphoblastic lymphomas (also CD99-positive) are strongly FLI-1-positive. Immunohistochemical detection of FLI-1 may be valuable in confirming the diagnosis of ES/ PNET in cases in which molecular genetic evaluation is not feasible. FLI-1 protein expression is also helpful in distinguishing ES/PNET from other tumors that may be CD99-positive, such as PDSS and RMS. It is not surprising that some ES/ PNET are FLI-1-negative, because not all ES/PNET have the classic EWS/FLI-1, and some cases of ES/PNET may produce either low levels of protein or idiotypically different protein.

Vorinostat and Bortezomib in Treating Young Patients With Refractory or Recurrent Solid Tumors, Including Central Nervous System Tumors and Lymphoma

ClinicalTrials.gov

2013-07-01

Childhood Burkitt Lymphoma; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Germ Cell Tumor; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Medulloepithelioma; Childhood Meningioma; Childhood Mixed Glioma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Childhood Oligodendroglioma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)

ClinicalTrials.gov

2018-06-25

Advanced Malignant Solid Neoplasm; Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma; Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma; Malignant Glioma; NTRK1 Fusion Positive; NTRK2 Fusion Positive; NTRK3 Fusion Positive; Recurrent Central Nervous System Neoplasm; Recurrent Childhood Ependymoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma; Recurrent Glioma; Recurrent Hepatoblastoma; Recurrent Langerhans Cell Histiocytosis; Recurrent Malignant Solid Neoplasm; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Peripheral Primitive Neuroectodermal Tumor; Refractory Central Nervous System Neoplasm; Refractory Childhood Malignant Germ Cell Tumor; Refractory Langerhans Cell Histiocytosis; Refractory Malignant Solid Neoplasm; Refractory Neuroblastoma; Refractory Non-Hodgkin Lymphoma; Rhabdoid Tumor; Stage III Osteosarcoma AJCC v7; Stage III Soft Tissue Sarcoma AJCC v7; Stage IV Osteosarcoma AJCC v7; Stage IV Soft Tissue Sarcoma AJCC v7; Stage IVA Osteosarcoma AJCC v7; Stage IVB Osteosarcoma AJCC v7; Wilms Tumor

PI3K/mTOR Inhibitor LY3023414 in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)

ClinicalTrials.gov

2018-06-18

Advanced Malignant Solid Neoplasm; Ann Arbor Stage III Non-Hodgkin Lymphoma; Ann Arbor Stage IV Non-Hodgkin Lymphoma; Malignant Glioma; Recurrent Central Nervous System Neoplasm; Recurrent Childhood Ependymoma; Recurrent Ewing Sarcoma; Recurrent Glioma; Recurrent Hepatoblastoma; Recurrent Langerhans Cell Histiocytosis; Recurrent Malignant Germ Cell Tumor; Recurrent Malignant Solid Neoplasm; Recurrent Medulloblastoma; Recurrent Neuroblastoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Osteosarcoma; Recurrent Peripheral Primitive Neuroectodermal Tumor; Recurrent Rhabdomyosarcoma; Recurrent Soft Tissue Sarcoma; Refractory Central Nervous System Neoplasm; Refractory Langerhans Cell Histiocytosis; Refractory Malignant Germ Cell Tumor; Refractory Malignant Solid Neoplasm; Refractory Neuroblastoma; Refractory Non-Hodgkin Lymphoma; Rhabdoid Tumor; Stage III Osteosarcoma AJCC v7; Stage III Soft Tissue Sarcoma AJCC v7; Stage IV Osteosarcoma AJCC v7; Stage IV Soft Tissue Sarcoma AJCC v7; Stage IVA Osteosarcoma AJCC v7; Stage IVB Osteosarcoma AJCC v7; TSC1 Gene Mutation; TSC2 Gene Mutation; Wilms Tumor

Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC

PubMed Central

Swartling, Fredrik J.; Savov, Vasil; Persson, Anders I.; Chen, Justin; Hackett, Christopher S.; Northcott, Paul A.; Grimmer, Matthew R.; Lau, Jasmine; Chesler, Louis; Perry, Arie; Phillips, Joanna J.; Taylor, Michael D.; Weiss, William A.

2012-01-01

SUMMARY The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally-stabilized murine N-mycT58A into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem and forebrain. Transplantation of N-mycWT NSCs was insufficient for tumor formation. N-mycT58A cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating SHH-dependence and SHH-independence, respectively. These differences were regulated in-part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal. PMID:22624711

Vertebrate homologues of Frodo are dynamically expressed during embryonic development in tissues undergoing extensive morphogenetic movements.

PubMed

Hunter, Nina L; Hikasa, Hiroki; Dymecki, Susan M; Sokol, Sergei Y

2006-01-01

Frodo has been identified as a protein interacting with Dishevelled, an essential mediator of the Wnt signaling pathway, critical for the determination of cell fate and polarity in embryonic development. In this study, we use specific gene probes to characterize stage- and tissue-specific expression patterns of the mouse Frodo homologue and compare them with Frodo expression patterns in Xenopus embryos. In situ hybridization analysis of mouse Frodo transcripts demonstrates that, similar to Xenopus Frodo, mouse Frodo is expressed in primitive streak mesoderm, neuroectoderm, neural crest, presomitic mesoderm, and somites. In many cases, Frodo expression is confined to tissues undergoing extensive morphogenesis, suggesting that Frodo may be involved in the regulation of cell shape and motility. Highly conserved dynamic expression patterns of Frodo homologues indicate a similar function for these proteins in different vertebrates. 2005 Wiley-Liss, Inc.

Embryonal tumors with abundant neuropil and true rosettes: 2 illustrative cases and a review of the literature.

PubMed

Manjila, Sunil; Ray, Abhishek; Hu, Yin; Cai, Dan X; Cohen, Mark L; Cohen, Alan R

2011-01-01

Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a recently identified variant of primitive neuroectodermal tumor, with fewer than 50 cases reported in the literature to date. Histologically, this tumor has features of ependymoblastoma and neuroblastoma, demonstrating areas of fine fibrillary neuropil intermingled with ependymoblastic rosettes and zones of undifferentiated neuroepithelial cells. However, ETANTR is distinguished pathologically from other embryonal tumors by the striking abundance of neuropil. Clinically, ETANTRs have shown high malignant potential and poor clinical outcome despite aggressive treatment. The authors describe 2 illustrative surgical cases of ETANTR, one involving the longest reported survival in the literature to date. The other had a poor outcome despite high-dose adjuvant chemotherapy with sequential autologous hematopoietic stem cell rescue. The authors review the natural history and treatment strategies available for this unusual malignant pediatric brain tumor.

Ultrastructural findings in transplanted experimental brain tumors and their significance for the cytogenesis of such tumors.

PubMed

Mennel, H D

1988-01-01

Tumors induced by transplacental action in the spinal cord of rats were transplanted into the brains of the same rat strain. They were followed up by electron microscopy during the first ten passages. Three architectural features were detected: First pure tumor parts, second myelin breakdown and phagocytosis, and third the resulting accumulation of resting macrophages. Architecture two and three were interpreted as result of considerable phagocytotic activity of tumor cells localized within the white substance of the brain and spinal cord. Only architecture one was considered to represent proper tumor. Since this was low differentiated and partial astrocytic differentiation only occurred around vessels to remarkable extent, the thesis is put forward that these transplacentally induced tumors correspond to human primitive neuroectodermal tumors.

Congenital extraskeletal Ewing's sarcoma of chest wall--a rare case report.

PubMed

Atla, Bhagyalakshmi; Prasad, B Satya Vara; Sri, K Satya; Vandana, Geeta

2011-01-01

Congenital extraskeletal Ewing's sarcoma or peripheral primitive neuroectodermal tumor is an extremely uncommon and invariably fatal tumor. We report a case of extraskeletal congenital Ewing's sarcoma in a female fetus delivered at 34 weeks of gestation who died immediately after birth. In English literature, majority of cases of Ewing's sarcoma in neonates reported were skeletal. To the best of our knowledge, very few cases of extra-skeletal Ewing's sarcoma in neonates are reported in the literature.

Multiple Ewing Sarcoma/Primitive Neuroectodermal Tumors in the Mediastinum: A Case Report and Literature Review.

PubMed

Bae, Sung Hwan; Hwang, Jung Hwa; Da Nam, Bo; Kim, Hyun Jo; Kim, Ki-Up; Kim, Dong Won; Choi, In Ho

2016-02-01

Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET) are high-grade malignant neoplasms. These malignancies present very rare tumors of thoracopulmonary area and even rarer in the mediastinum. In our knowledge, ES/PNET presented with multiple mediastinal masses has not been reported previously. We experienced a case of a 42-year-old man presented with gradual onset of left-side pleuritic chest pain. A contrast-enhanced chest computed tomography (CT) scan showed separate 2 large heterogeneously enhancing masses in each anterior and middle mediastinum of the left hemithorax. Positron emission tomography-computed tomography (PET-CT) scan revealed high fluorodeoxyglucose (FDG) uptake in the mediastinal masses. After surgical excision for the mediastinal masses, both of the masses were diagnosed as the ES/PNET group of tumors on the histopathologic examination. The patient refused postoperative adjuvant chemotherapy and came back with local tumor recurrence and distant metastasis on 4-month follow-up after surgical resection. We report this uncommon form of ES/PNET. We are to raise awareness that this rare malignancy should be considered as a differential diagnosis of the malignant mediastinal tumors and which can be manifested as multiple masses in a patient. Understanding this rare entity of extra-skeletal ES/PNET and characteristic imaging findings can help radiologists and clinicians to approach proper diagnosis and better management for this highly malignant tumor.

Multiple Ewing Sarcoma/Primitive Neuroectodermal Tumors in the Mediastinum

PubMed Central

Bae, Sung Hwan; Hwang, Jung Hwa; Da Nam, Bo; Kim, Hyun Jo; Kim, Ki-Up; Kim, Dong Won; Choi, In Ho

2016-01-01

Abstract Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET) are high-grade malignant neoplasms. These malignancies present very rare tumors of thoracopulmonary area and even rarer in the mediastinum. In our knowledge, ES/PNET presented with multiple mediastinal masses has not been reported previously. We experienced a case of a 42-year-old man presented with gradual onset of left-side pleuritic chest pain. A contrast-enhanced chest computed tomography (CT) scan showed separate 2 large heterogeneously enhancing masses in each anterior and middle mediastinum of the left hemithorax. Positron emission tomography-computed tomography (PET-CT) scan revealed high fluorodeoxyglucose (FDG) uptake in the mediastinal masses. After surgical excision for the mediastinal masses, both of the masses were diagnosed as the ES/PNET group of tumors on the histopathologic examination. The patient refused postoperative adjuvant chemotherapy and came back with local tumor recurrence and distant metastasis on 4-month follow-up after surgical resection. We report this uncommon form of ES/PNET. We are to raise awareness that this rare malignancy should be considered as a differential diagnosis of the malignant mediastinal tumors and which can be manifested as multiple masses in a patient. Understanding this rare entity of extra-skeletal ES/PNET and characteristic imaging findings can help radiologists and clinicians to approach proper diagnosis and better management for this highly malignant tumor. PMID:26886614

Supratentorial primitive neuroectodermal tumors (S-PNET) in children: A prospective experience with adjuvant intensive chemotherapy and hyperfractionated accelerated radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Massimino, Maura; Gandola, Lorenza; Spreafico, Filippo

Purpose: Supratentorial primitive neuroectodermal tumors (S-PNET) are rare and have a grim prognosis, frequently taking an aggressive course with local relapse and metastatic spread. We report the results of a mono-institutional therapeutic trial. Methods and Materials: We enrolled 15 consecutive patients to preradiation chemotherapy (CT) consisting of high-dose methotrexate, high-dose etoposide, high-dose cyclophosphamide, and high-dose carboplatin, craniospinal irradiation (CSI) with hyperfractionated accelerated radiotherapy (HART) plus focal boost, maintenance with vincristine/lomustine or consolidation with high-dose thiotepa followed by autologous stem-cell rescue. Results: Median age was 9 years; 7 were male, 8 female. Site of disease was pineal in 3, elsewhere inmore » 12. Six patients were had no evidence of disease after surgery (NED). Of those with evidence of disease after surgery (ED), 2 had central nervous system spread. Of the 9 ED patients, 2 had complete response (CR) and 2 partial response (PR) after CT, 4 stable disease, and 1 progressive disease. Of the 7 ED patients before radiotherapy, 1 had CR, 4 PR, and 2 minor response, thus obtaining a 44% CR + PR after CT and 71% after HART. Because of rapid progression in 2 of the first 5 patients, high-dose thiotepa was systematically adopted after HART in the subsequent 10 patients. Six of 15 patients relapsed (4 locally, 1 locally with dissemination, 1 with dissemination) a mean of 6 months after starting CT, 2 developed second tumors; 5 of 6 relapsers died at a median of 13 months. Three-year progression-free survival, event-free survival, and overall survival were 54%, 34%, and 61%, respectively. Conclusion: Hyperfractionated accelerated RT was the main tool in obtaining responses in S-PNET; introducing the myeloablative phase improved the prognosis (3/10 vs. 3/5 relapses), though the outcome remained unsatisfactory despite the adoption of this intensive treatment.« less

Ewing's Sarcoma of the Adrenal Gland.

PubMed

Pal, Dilip Kumar; Chandra, Vipin; Ranjan, Kumar Rajiv; Chakrabortty, Debasis; Banerjee, Manju

2016-01-01

Ewing's sarcoma (ES) or primitive neuro-ectodermal tumor (PNET) typically occurs in long or flat bones, the chest wall, extra-skeletal soft tissue, and rarely in solid organs. Incidence of adrenal Ewing's sarcoma is very rare. Here we report a case of Ewing's sarcoma of the right adrenal gland in an 8-year-old girl who presented with an abdominal mass. The huge tumor was managed by preoperative neo-adjuvant chemotherapy followed by surgical resection. She died due to metastasis after five months of surgery.

Identification of Two Candidate Tumor Suppressor Genes on Chromosome 17p13.3: Assessment of Their Roles in Breast and Ovarian Carcinogenesis.

DTIC Science & Technology

1998-08-01

has also been reported in primitive neuroectodermal tumors (19), carcinoma of the cervix uteri (20), medulloblastoma, osteosarcoma (21), astrocytoma...Knudson, A. G., Jr. Oncogenes and tumor-suppressor genes. In: W. J. Hoskins, C. A. Perez, and R. C. Young (eds.), Principles and Practice of... Young , B. D., Nakayama, K., and Steiner, D. F. Processing of wild-type and mutant proinsulin-like growth factor-IA by subtilisin-related proprotein

Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas

ClinicalTrials.gov

2018-06-25

Metastatic Melanoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Hodgkin Lymphoma; Recurrent Malignant Solid Neoplasm; Recurrent Melanoma; Recurrent Neuroblastoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Osteosarcoma; Recurrent Rhabdomyosarcoma; Refractory Hodgkin Lymphoma; Refractory Malignant Solid Neoplasm; Refractory Non-Hodgkin Lymphoma; Stage III Cutaneous Melanoma AJCC v7; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7

Comparative expression analysis reveals lineage relationships between human and murine gliomas and a dominance of glial signatures during tumor propagation in vitro.

PubMed

Henriquez, Nico V; Forshew, Tim; Tatevossian, Ruth; Ellis, Matthew; Richard-Loendt, Angela; Rogers, Hazel; Jacques, Thomas S; Reitboeck, Pablo Garcia; Pearce, Kerra; Sheer, Denise; Grundy, Richard G; Brandner, Sebastian

2013-09-15

Brain tumors are thought to originate from stem/progenitor cell populations that acquire specific genetic mutations. Although current preclinical models have relevance to human pathogenesis, most do not recapitulate the histogenesis of the human disease. Recently, a large series of human gliomas and medulloblastomas were analyzed for genetic signatures of prognosis and therapeutic response. Using a mouse model system that generates three distinct types of intrinsic brain tumors, we correlated RNA and protein expression levels with human brain tumors. A combination of genetic mutations and cellular environment during tumor propagation defined the incidence and phenotype of intrinsic murine tumors. Importantly, in vitro passage of cancer stem cells uniformly promoted a glial expression profile in culture and in brain tumors. Gene expression profiling revealed that experimental gliomas corresponded to distinct subclasses of human glioblastoma, whereas experimental supratentorial primitive neuroectodermal tumors (sPNET) correspond to atypical teratoid/rhabdoid tumor (AT/RT), a rare childhood tumor. ©2013 AACR.

Vorinostat and Temozolomide in Treating Young Patients With Relapsed or Refractory Primary Brain Tumors or Spinal Cord Tumors

ClinicalTrials.gov

2013-05-01

Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Embryonal Tumor; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Extra-adrenal Paraganglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Spinal Cord Neoplasm; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

Temozolomide is an active agent in children with recurrent medulloblastoma/primitive neuroectodermal tumor: an Italian multi-institutional phase II trial.

PubMed

Cefalo, Graziella; Massimino, Maura; Ruggiero, Antonio; Barone, Giuseppe; Ridola, Vita; Spreafico, Filippo; Potepan, Paolo; Abate, Massimo E; Mascarin, Maurizio; Garrè, Maria Luisa; Perilongo, Giorgio; Madon, Enrico; Colosimo, Cesare; Riccardi, Riccardo

2014-05-01

The aim of this study was to assess the objective response rate (ORR) of children and young adults with recurrent medulloblastoma/primitive neuroectodermal tumor (MB/PNET) treated with temozolomide (TMZ). The secondary purpose was to analyze the toxicity profile of TMZ when administered orally for 5 days in 3 divided daily doses every 28 days. Forty-two patients with recurrent MB/PNET, aged 21 years and younger, were recruited. Patients were treated with oral TMZ. Starting doses ranged from 120 to 200 mg/m(2)/day based on previous treatments. A craniospinal MRI was performed prior to the first cycle of TMZ and following every 2 cycles of treatment. Median age was 10 years (range, 2-21 years). Forty of 42 patients were assessed for response and toxicity. The objective response rate was 42.5%: 6 patients achieved a complete response, 11 had a partial response, and 10 had stable disease. Progression-free survival rates for all patients at 6 and 12 months were 30% and 7.5%, respectively. Their median overall survival rates at 6 and 12 months were 42.5% and 17.5%, respectively. No major extrahematological effects or life-threatening events were reported. The most common grade 3/4 toxicity included thrombocytopenia (17.5%), neutropenia (7.5%), and anemia (2.5%). TMZ proved to be an effective agent in children and young adults with MB/PNET, heavily pre-treated, with a tolerable toxicity profile.

Nucleosome eviction along with H3K9ac deposition enhances Sox2 binding during human neuroectodermal commitment

PubMed Central

Du, Yanhua; Liu, Zhenping; Cao, Xinkai; Chen, Xiaolong; Chen, Zhenyu; Zhang, Xiaobai; Zhang, Xiaoqing; Jiang, Cizhong

2017-01-01

Neuroectoderm is an important neural precursor. However, chromatin remodeling and its epigenetic regulatory roles during the differentiation of human neuroectodermal cells (hNECs) from human embryonic stem cells (hESCs) remain largely unexplored. Here, we obtained hNECs through directed differentiation from hESCs, and determined chromatin states in the two cell types. Upon differentiation, H2A.Z-mediated nucleosome depletion leads to an open chromatin structure in promoters and upregulates expression of neuroectodermal genes. Increase in H3K9ac signals and decrease in H3K27me3 signals in promoters result in an active chromatin state and activate neuroectodermal genes. Conversely, decrease in H3K9ac signals and increase in H3K27me3 signals in promoters repress pluripotency genes. Moreover, H3K9ac signals facilitate the pluripotency factor Sox2 binding to target sites unique to hNECs. Knockdown of the acetyltransferase Kat2b erases H3K9ac signals, disrupts Sox2 binding, and fails the differentiation. Our results demonstrate a hierarchy of epigenetic regulation of gene expression during the differentiation of hNECs from hESCs through chromatin remodeling. PMID:28475175

Differentiation of neural crest stem cells from nasal mucosa into motor neuron-like cells.

PubMed

Bagher, Zohreh; Kamrava, Seyed Kamran; Alizadeh, Rafieh; Farhadi, Mohammad; Absalan, Moloud; Falah, Masoumeh; Faghihi, Faezeh; Zare-Sadeghi, Arash; Komeili, Ali

2018-05-25

Cell transplantation is a potential therapeutic approach for repairing neuropathological and neurodegenerative disorders of central nervous system by replacing the degenerated cells with new ones. Among a variety of stem cell candidates to provide these new cells, olfactory ectomesenchymal stem cells (OE-MSCs) have attracted a great attention due to their neural crest origin, easy harvest, high proliferation, and autologous transplantation. Since there is no report on differentiation potential of these cells into motor neuron-like cells, we evaluated this potential using Real-time PCR, flowcytometry and immunocytochemistry after the treatment with differentiation cocktail containing retinoic acid and Sonic Hedgehog. Immunocytochemistry staining of the isolated OE-MSCs demonstrated their capability to express nestin and vimentin, as the two markers of primitive neuroectoderm. The motor neuron differentiation of OE-MSCs resulted in changing their morphology into bipolar cells with high expression of motor neuron markers of ChAT, Hb-9 and Islet-1 at the level of mRNA and protein. Consequently, we believe that the OE-MSCs have great potential to differentiate into motor neuron-like cells and can be an ideal stem cell source for the treatment of motor neuron-related disorders of central nervous system. Copyright © 2018 Elsevier B.V. All rights reserved.

TFG-MET fusion in an infantile spindle cell sarcoma with neural features.

PubMed

Flucke, Uta; van Noesel, Max M; Wijnen, Marc; Zhang, Lei; Chen, Chun-Liang; Sung, Yun-Shao; Antonescu, Cristina R

2017-09-01

An increasing number of congenital and infantile sarcomas displaying a primitive, monomorphic spindle cell phenotype have been characterized to harbor recurrent gene fusions, including infantile fibrosarcoma and congenital spindle cell rhabdomyosarcoma. Here, we report an unusual spindle cell sarcoma presenting as a large and infiltrative pelvic soft tissue mass in a 4-month-old girl, which revealed a novel TFG-MET gene fusion by whole transcriptome RNA sequencing. The tumor resembled the morphology of an infantile fibrosarcoma with both fascicular and patternless growth, however, it expressed strong S100 protein immunoreactivity, while lacking SOX10 staining and retaining H3K27me3 expression. Although this immunoprofile suggested partial neural/neuroectodermal differentiation, overall features were unusual and did not fit into any known tumor types (cellular schwannoma, MPNST), raising the possibility of a novel pathologic entity. The TFG-MET gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital spindle cell sarcomas, with yet another example of kinase oncogenic activation through chromosomal translocation. The discovery of this new fusion is significant since the resulting MET activation can potentially be inhibited by targeted therapy, as MET inhibitors are presently available in clinical trials. © 2017 Wiley Periodicals, Inc.

Gamma-Secretase Inhibitor RO4929097 in Treating Young Patients With Relapsed or Refractory Solid Tumors, CNS Tumors, Lymphoma, or T-Cell Leukemia

ClinicalTrials.gov

2014-11-04

Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood Infratentorial Ependymoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Gonadotroph Adenoma; Pituitary Basophilic Adenoma; Pituitary Chromophobe Adenoma; Pituitary Eosinophilic Adenoma; Prolactin Secreting Adenoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Spinal Cord Neoplasm; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent Pituitary Tumor; Recurrent/Refractory Childhood Hodgkin Lymphoma; T-cell Childhood Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; TSH Secreting Adenoma; Unspecified Childhood Solid Tumor, Protocol Specific

Temozolomide is an active agent in children with recurrent medulloblastoma/primitive neuroectodermal tumor: an Italian multi-institutional phase II trial

PubMed Central

Cefalo, Graziella; Massimino, Maura; Ruggiero, Antonio; Barone, Giuseppe; Ridola, Vita; Spreafico, Filippo; Potepan, Paolo; Abate, Massimo E.; Mascarin, Maurizio; Garrè, Maria Luisa; Perilongo, Giorgio; Madon, Enrico; Colosimo, Cesare; Riccardi, Riccardo

2014-01-01

Background The aim of this study was to assess the objective response rate (ORR) of children and young adults with recurrent medulloblastoma/primitive neuroectodermal tumor (MB/PNET) treated with temozolomide (TMZ). The secondary purpose was to analyze the toxicity profile of TMZ when administered orally for 5 days in 3 divided daily doses every 28 days. Methods Forty-two patients with recurrent MB/PNET, aged 21 years and younger, were recruited. Patients were treated with oral TMZ. Starting doses ranged from 120 to 200 mg/m2/day based on previous treatments. A craniospinal MRI was performed prior to the first cycle of TMZ and following every 2 cycles of treatment. Results Median age was 10 years (range, 2–21 years). Forty of 42 patients were assessed for response and toxicity. The objective response rate was 42.5%: 6 patients achieved a complete response, 11 had a partial response, and 10 had stable disease. Progression-free survival rates for all patients at 6 and 12 months were 30% and 7.5%, respectively. Their median overall survival rates at 6 and 12 months were 42.5% and 17.5%, respectively. No major extrahematological effects or life-threatening events were reported. The most common grade 3/4 toxicity included thrombocytopenia (17.5%), neutropenia (7.5%), and anemia (2.5%). Conclusions TMZ proved to be an effective agent in children and young adults with MB/PNET, heavily pre-treated, with a tolerable toxicity profile. PMID:24482446

Clinical management of a unique case of PNET of the uterus during pregnancy, and review of the literature.

PubMed

De Nola, Rosalba; Di Naro, Edoardo; Schonauer, Luca Maria; Lucarelli, Giuseppe; Battaglia, Michele; Fiore, Maria Grazia; Mastrolia, Salvatore Andrea; Loverro, Giuseppe

2018-01-01

PNETs (primitive neuroectodermal tumors) are a family of highly malignant neoplasms characterized by small round cells of neuroepithelial origin. They usually involve bone and soft tissues, and have a higher incidence in childhood. In this case report, we describe the obstetric and oncological outcome of a huge mass diagnosed as a leiomyoma in a 39-year-old pregnant woman who complained of low back pain, dysuria, and urinary frequency at 22 weeks of gestation. During the 25th week of pregnancy, the patient was referred to our hospital at night with severe anemia and suspected hemoperitoneum. She underwent an emergency caesarean section, delivering a female fetus weighing 400 g, with an Apgar score of 7 at 1 minute and 9 at 5 minutes. During surgery, we found a huge uterine sarcoma-like metastatic tumor, invading the pelvic peritoneum and parametria bilaterally; the adnexae seemed disease-free. We performed a type B radical hysterectomy, bilateral salpingo-oophorectomy, pelvic peritonectomy, omentectomy, appendectomy, and excision of a bulky lymph node. Seven days after delivery, staging computed tomography (CT) scan demonstrated a large lombo-aortic lymph node compressing the left renal vein and we completed debulking with a second surgery, including diaphragmatic peritonectomy and excision of a huge lymph node by lombo-aortic lymphadenectomy, requiring partial reconstruction of an infiltrated renal vein. Ten days after the second surgery, echo-color Doppler showed a regular microcirculation in the left kidney. The patient was discharged after 10 days, and the baby after 1 month, both in good health.Histological examination revealed a uterine body cPNET (central primitive neuroectodermal tumor) orienting the clinical management toward chemotherapy with cisplatin and etoposide. PNETs are aggressive neoplasms, usually diagnosed at an advanced stage. Due to their low incidence, universally accepted guidelines are still unavailable. Radical surgery leaving no macroscopic residual disease is mandatory in advanced stages. A good fertility-sparing procedure can be performed only in young women at early stages of disease, when the wish for childbearing is not yet fulfilled. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Primitive Neuroectodermal Tumors of the Female Genital Tract: A Morphologic, Immunohistochemical, and Molecular Study of 19 Cases.

PubMed

Chiang, Sarah; Snuderl, Matija; Kojiro-Sanada, Sakiko; Quer Pi-Sunyer, Ariadna; Daya, Dean; Hayashi, Tohru; Bosincu, Luisanna; Ogawa, Fumihiro; Rosenberg, Andrew E; Horn, Lars-Christian; Wang, Lu; Iafrate, A John; Oliva, Esther

2017-06-01

Primary primitive neuroectodermal tumor (PNET) of the female genital tract is rare, and its proper classification remains unclear. The clinical, histologic, and immunophenotypic features as well as EWSR1 rearrangement status of 19 gynecologic PNETs, including 10 ovarian, 8 uterine, and 1 vulvar tumors, are herein reported. Patient age ranged from 12 to 68 years, with a median age of 20 and 51 years among those with ovarian and uterine PNETs, respectively. Morphologic features of central nervous system (CNS) tumors were seen in 15 PNETs, including 9 medulloblastomas, 3 ependymomas, 2 medulloepitheliomas, and 1 glioblastoma, consistent with central PNET. The remaining 4 PNETs were composed entirely of undifferentiated small round blue cells and were classified as Ewing sarcoma/peripheral PNET. Eight PNETs were associated with another tumor type, including 5 ovarian mature cystic teratomas, 2 endometrial low-grade endometrioid carcinomas, and a uterine carcinosarcoma. By immunohistochemistry, 17 PNETs expressed at least 1 marker of neuronal differentiation, including synaptophysin, NSE, CD56, S100, and chromogranin in 10, 8, 14, 8, and 1 tumors, respectively. GFAP was positive in 4 PNETs, all of which were of central type. Membranous CD99 and nuclear Fli-1 staining was seen in 10 and 16 tumors, respectively, and concurrent expression of both markers was seen in both central and Ewing sarcoma/peripheral PNETs. All tumors expressed vimentin, whereas keratin cocktail (CAM5.2, AE1/AE3) staining was only focally present in 4 PNETs. Fluorescence in situ hybridization was successful in all cases and confirmed EWSR1 rearrangement in 2 of 4 tumors demonstrating morphologic features of Ewing sarcoma/peripheral PNET and concurrent CD99 and Fli-1 expression. In conclusion, central and Ewing sarcoma/peripheral PNETs may be encountered in the female genital tract with central PNETs being more common. Central PNETs show a spectrum of morphologic features that overlaps with CNS tumors but lack EWSR1 rearrangements. GFAP expression supports a morphologic impression of central PNET and is absent in Ewing sarcoma/peripheral PNET. Ewing sarcoma/peripheral PNETs lack morphologic features of CNS tumors.

Primary Ewing's sarcoma of vulva: a case report and a review of the literature.

PubMed

Che, Shao-Min; Cao, Pei-Long; Chen, Hong-Wei; Liu, Zi; Meng, Du

2013-03-01

Ewing sarcomas/peripheral primitive neuroectodermal tumors (ES/pPNET) are extremely rare in the vulva. A review of the literature reveals only 14 previously reported possible cases. Here we reported a case of primary extraskeletal Ewing's sarcoma (EES) of the vulva in a 37-year-old woman. Characteristic histologic features of ES/pPNET were present in this case, including a monomorphic population of small round blue cells with cytoplasmic glycogen confirmed by periodic acid-Schiff, membrane staining with CD99 and nuclear staining with FLI-1. After surgery, the patient was found to have pulmonary metastasis and then received six cycles of polychemotherapy. She is still alive with stable disease after 1 year of follow up. Our findings underline the crucial role of immunohistochemical techniques in the differential diagnosis of small round cell tumors in these unusual locations. We also give a summary about the clinical and pathological features of the primary ES/pPNET in the vulva reported previously in the literature. © 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.

PDGF-C is an EWS/FLI induced transforming growth factor in Ewing Family Tumors

PubMed Central

Zwerner, Jeffrey P.; May, William A.

2013-01-01

The aberrant transcription factors associated with many human malignancies function by deregulation of tumorigenic pathways. However, identification of these pathways has come slowly. Virtually all cases of Ewing’s Sarcoma and peripheral Primitive Neuroectodermal Tumor (PNET) are associated with aberrant transcription factors which fuse amino-terminal EWS with the DNA binding moiety of an ETS transcription factor (FLI-1 in 90% of cases). Attempts to identify the downstream targets of these chimeras in the Ewing Family Tumors (EFT) on the basis of differential gene regulation have produced little association with tumor biology. As an alternative approach, we have used highly efficient retroviral systems to biologically screen cDNA derived from cells transformed by EWS/FLI-1. We have identified the recently described PDGF-C as target of EWS/ETS transcriptional deregulation. This transcriptional deregulation is specific to EWS/FLI. PDGF-C possesses substantial biologic activity in vitro and in vivo. It is expressed in EFT cell lines and in primary tumors. Within these EFT cell lines, PDGF-C expression is dependent upon EWS/FLI activity. These results suggest that PDGF-C may be a significant mediator of EWS/FLI driven oncogenesis. PMID:11313995

Small round blue cell tumors of the sinonasal tract: a differential diagnosis approach.

PubMed

Thompson, Lester Dr

2017-01-01

One of the most challenging diagnostic categories within tumors of the sinonasal tract is the small round blue cell tumors. Biopsies are usually small and limited, resulting in considerable diagnostic difficulty for practicing surgical pathologists. These tumors share several overlapping histologic and immunophenotypic findings while also showing considerable variation within and between cases. Specific tumor site of origin, imaging findings, and clinical findings must be combined with the histology and pertinent ancillary studies if the correct diagnosis is to be reached. Discrimination between neoplasms is critical as there are significant differences in therapy and overall outcome. It is important to have a well developed differential diagnosis for this category of tumors, where each of the diagnoses is considered, evaluated, and either confirmed or excluded from further consideration. In an undifferentiated tumor, showing a small round blue cell morphology, using the mnemonic 'MR SLEEP' helps to highlight tumors to consider: melanoma, mesenchymal chondrosarcoma, rhabdomyosarcoma, sinonasal undifferentiated carcinoma, squamous cell carcinoma (including NUT carcinoma), small cell osteosarcoma, lymphoma, esthesioneuroblastoma (olfactory neuroblastoma), Ewing sarcoma/primitive neuroectodermal tumor, pituitary adenoma, and plasmacytoma. A panel of pertinent immunohistochemistry studies, histochemistries and/or molecular tests should aid in reaching a diagnosis, especially when taking the pattern and intensity of reactions into consideration.

Ewing’s Sarcoma Family Tumors in the Jaws: Case Report, Immunohistochemical Analysis and Literature Review

PubMed Central

CASAROTO, ANA REGINA; SAMPIERI, MARCELO BONIFACIO DA SILVA; SOARES, CLEVERSON TEIXEIRA; SANTOS, PAULO SERGIO DA SILVA; YAEDU, RENATO YASSUTAKA FARIA; DAMANTE, JOSÉ HUMBERTO; LARA, VANESSA SOARES

2017-01-01

Due to the low incidence of the Ewing’s Sarcoma (ES) family tumors, the available epidemiology is likely to be unreliable, and at present, there are no standard diagnostic or clinical guidelines outlining their management. This report describes a case of peripheral primitive neuroectodermal tumor (ES/pPNET) which initially mimicked cystic lesions, and describes a comparison between ES and ES/pPNET in the jaws by the World Health Organization classification. This review addressed 63 cases published in the English literature between 1950 and 2016. The majority of cases were ES. Both ES and ES/pPNET mimicked other benign entities such as traumatic, cystic and inflammatory lesions. The patients who died of their disease had a history of metastatic tumors, and primary tumor located in the mandible and maxilla for ES and ES/pPNET, respectively. The differentiation of the ES family tumors from other small blue-cell tumors may be difficult and requires familiarity with histological and immunohistochemical features. PMID:28438883

Radiation Is an Important Component of Multimodality Therapy for Pediatric Non-Pineal Supratentorial Primitive Neuroectodermal Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

McBride, Sean M.; Daganzo, Sally M.; Banerjee, Anuradha

Purpose: To review a historical cohort of pediatric patients with supratentorial primitive neuroectodermal tumors (sPNET), to clarify the role of radiation in the treatment of these tumors. Patients and Methods: Fifteen children aged <18 years with non-pineal sPNETs diagnosed between 1992 and 2006 were identified. Initial therapy consisted of surgical resection and chemotherapy in all patients and up-front radiotherapy (RT) in 5 patients. Five patients had RT at the time of progression, and 5 received no RT whatever. Kaplan-Meier estimates of overall survival were then calculated. Results: The median follow-up from diagnosis for all patients was 31 months (range, 0.5-165more » months) and for surviving patients was 49 months (range, 10-165). Of the 5 patients who received up-front RT, all were alive without evidence of disease at a median follow-up of 50 months (range, 25-165 months). Only 5 of the 10 patients who did not receive up-front RT were alive at last follow-up. There was a statistically significant difference in overall survival between the patient group that received up-front RT and the group that did not (p = 0.048). In addition, we found a trend toward a statistically significant improvement in overall survival for those patients who received gross total resections (p = 0.10). Conclusions: Up-front RT and gross total resection may confer a survival benefit in patients with sPNET. Local failure was the dominant pattern of recurrence. Efforts should be made to determine patients most likely to have local failure exclusively or as a first recurrence, in order to delay or eliminate craniospinal irradiation.« less

Radiological features of primitive neuroectodermal tumors in intra-abdominal and retroperitoneal regions: A series of 18 cases

PubMed Central

Zhang, Youming; Xiao, Desheng; Yin, Hongling; Long, Xueying; Li, Li; Zai, Hongyan; Chen, Minfeng; Li, Wenzheng; Sun, Lunquan

2017-01-01

Objectives To characterize the imaging and clinicopathological features of primitive neuroectodermal tumors (PNETs) arising in intra-abdominal and retroperitoneal regions. Methods Eighteen patients with histopathologically proven intra-abdominal and retroperitoneal PNET were enrolled; computed tomography was performed for all cases, and magnetic resonance imaging was performed for a single case. Typical computed tomography and magnetic resonance imaging findings, including morphology, texture and enhancement features, as well as clinicopathological characteristics and prognosis data were retrospectively analyzed. Results Of eighteen PNET patients, fifteen were male and three were female, with a median age of 36 years (range, 2–65 years). The onset of symptoms was most often nonspecific and insidious. The mean tumor diameter was 7.2 cm (range, 3.0–12.1 cm), with necrosis in fifteen cases, cystic changes in eight, partition structure in five, calcification in five, hemorrhage in two, and mural nodules in one. Contrast enhanced computed tomography showed multiple tiny feeding arteries within the masses in six cases, resulting in a crab-like appearance, and mild ring enhancement pattern in five cases. Eleven cases showed surrounding invasion and metastasis. Of the eighteen PNET cases, nine cases showed smooth, well-defined margins, and nine cases had irregular, ill-defined margins. A median survival was 10.0±1.6 months. However, chemotherapy had efficacy on patients even those with advanced disease. Conclusions Primary intra-abdominal and retroperitoneal PNETs are rare, and imaging features documented here may help the diagnosis of this severe disease. Notably, two signs present in retroperitoneal PNET tumors, including a mild ring enhancement pattern and a crab-like appearance of the tiny feeding arteries, may have the potential to help us improve the ability to make a relatively reliable diagnosis. PMID:28319177

A Phase II Study of Preradiotherapy Chemotherapy Followed by Hyperfractionated Radiotherapy for Newly Diagnosed High-Risk Medulloblastoma/Primitive Neuroectodermal Tumor: A Report From the Children's Oncology Group (CCG 9931)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Allen, Jeffrey; Donahue, Bernadine; Mehta, Minesh

2009-07-15

Purpose: To verify feasibility and monitor progression-free survival and overall survival in children with high-risk medulloblastoma and noncerebellar primitive neuroectodermal tumors (PNETs) treated in a Phase II study with preradiotherapy chemotherapy (CHT) followed by high-dose, hyperfractionated craniospinal radiotherapy (CSRT). Methods and Materials: Eligibility criteria included age >3 years at diagnosis, medulloblastoma with either high M stage and/or >1.5 cm{sup 2} postoperative residual disease, and all patients with noncerebellar PNET. Treatment was initiated with five alternating monthly cycles of CHT (A [cisplatin, cyclophosphamide, etoposide, and vincristine], B [carboplatin and etoposide], A, B, and A) followed by hyperfractionated CSRT (40 Gy) withmore » a boost to the primary tumor (72 Gy) given in twice-daily 1-Gy fractions. Results: The valid study group consisted of 124 patients whose median age at diagnosis was 7.8 years. Eighty-four patients (68%) completed the entire protocol according to study guidelines (within 9 months), and the median time to complete CSRT was 1.6 months. Major reasons for failure to complete CHT included progressive disease (17%) and toxic death (2.4%). The 5-year progression-free survival and overall survival rates were 43% {+-} 5% and 52% {+-} 5%, respectively. No significant differences were detected in subset analysis related to response to CHT, site of primary tumor, postoperative residual disease, or M stage. Conclusions: The feasibility of this intensive multimodality protocol was confirmed, and response to pre-RT CHT did not impact on survival. Survival data from this protocol can not be compared with data from other studies, given the protocol design.« less

Proton Radiation Therapy for Pediatric Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumors: Outcomes for Very Young Children Treated With Upfront Chemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jimenez, Rachel B., E-mail: rbjimenez@partners.org; Sethi, Roshan; Depauw, Nicolas

Purpose: To report the early outcomes for very young children with medulloblastoma or supratentorial primitive neuroectodermal tumor (SPNET) treated with upfront chemotherapy followed by 3-dimensional proton radiation therapy (3D-CPT). Methods and Materials: All patients aged <60 months with medulloblastoma or SPNET treated with chemotherapy before 3D-CPT from 2002 to 2010 at our institution were included. All patients underwent maximal surgical resection, chemotherapy, and adjuvant 3D-CPT with either craniospinal irradiation followed by involved-field radiation therapy or involved-field radiation therapy alone. Results: Fifteen patients (median age at diagnosis, 35 months) were treated with high-dose chemotherapy and 3D-CPT. Twelve of 15 patients hadmore » medulloblastoma; 3 of 15 patients had SPNET. Median time from surgery to initiation of radiation was 219 days. Median craniospinal irradiation dose was 21.6 Gy (relative biologic effectiveness); median boost dose was 54.0 Gy (relative biologic effectiveness). At a median of 39 months from completion of radiation, 1 of 15 was deceased after a local failure, 1 of 15 had died from a non-disease-related cause, and the remaining 13 of 15 patients were alive without evidence of disease recurrence. Ototoxicity and endocrinopathies were the most common long-term toxicities, with 2 of 15 children requiring hearing aids and 3 of 15 requiring exogenous hormones. Conclusions: Proton radiation after chemotherapy resulted in good disease outcomes for a small cohort of very young patients with medulloblastoma and SPNET. Longer follow-up and larger numbers of patients are needed to assess long-term outcomes and late toxicity.« less

Immunohistochemical expression of WT1 by desmoplastic small round cell tumor: a comparative study with other small round cell tumors.

PubMed

Barnoud, R; Sabourin, J C; Pasquier, D; Ranchère, D; Bailly, C; Terrier-Lacombe, M J; Pasquier, B

2000-06-01

Desmoplastic small round cell tumors (DSRCTs) present a reciprocal chromosomal translocation, t(11;22)(p13;q12), that results in fusion of Ewing's sarcoma and Wilms' tumor (WT1) genes. The authors evaluated 15 DSRCTs and 71 other tumors often considered in the differential diagnosis for immunoreactivity using a polyclonal antibody directed against the WT1 part of the chimeric protein resulting from this translocation. WT1 immunostaining was performed on paraffin material using the WT(C-19) antibody after heat-antigen retrieval. All the DSRCTs (15 of 15, 100%) demonstrated strong WT1 nuclear immunoreactivity. Ten of 14 nephroblastomas (71%) disclosed WT1-positive nuclei in accordance with the staining reported by others, and rare and focal nuclear positivity was detected in two of 17 rhabdomyosarcomas. WT1 immunoreactivity was not observed in Ewing's sarcoma/primitive neuroectodermal tumors (zero of 21, 0%), neuroblastomas (zero of 17, 0%), or rhabdoid tumors of the kidney (zero of two, 0%). In nephroblastoma, differential diagnosis with DSRCT was not difficult: Clinical and morphologic data are not similar for these two entities. The current study validates WT1 immunoreactivity as a useful marker to separate DSRCT from other small round cell tumors.

Origin of Ameloblastoma From Basal Cells of the Oral Epithelium- Establishing the Relation Using Neuroectodermal Markers

PubMed Central

Suneela, S; Narayan, T V; Shreedhar, Balasundari; Mohanty, Leeky; Shenoy, Sadhana; Swaminathan, Uma

2014-01-01

Background and Objectives: Basal cell layer of the oral epithelium has been rightfully regarded as a potential source of odontogenic tumours and cysts, but, without substantial evidence. Also, whether the basal cell layer retains within it, some properties of ectomesenchyme, which was imbibed during the early embryogenesis and hence its neuroectodermal relation, is not known. Here, an attempt is made to establish the hidden neuroectodermal potential of the oral epithelium, especially the basal layer, by observing the expression of known neuroectodermal markers, NSE (Neuron Specific Enolase), Synaptophysin and CD99. The expression of the same markers has also been studied in Ameloblastoma, connecting it with oral epithelium, in turn establishing basal cell layer as a potential source of Ameloblastoma. Materials and Methods: Sections of formalin fixed, paraffin embedded tissue samples of 20 cases of Ameloblastoma and 10 cases of Normal Retromolar mucosa, were stained immunohistochemically with NSE, Synaptophysin, CD99 and also with CK-19 and evaluated for positive expression. Results: Positive reaction was obtained in all the cases of Ameloblastoma and NRM (Normal Retromolar mucosa) with NSE, all the cases of Ameloblastoma and eight cases of NRM with Synaptophysin and in six cases of Ameloblastoma and NRM with CD99. The staining was diffuse and more marked in case of NSE than Synaptophysin and CD99. CK19 staining done to assure that the tissue antigenicity was maintained was positive in all the samples. Interpretation and Conclusion: A strong relationship between the neuroectoderm, Ameloblastoma and the basal layer of the oral epithelium is established by the study. It favours the hypothesis that the basal cell layer of oral mucosa may be the sought out culprit in most cases of the Ameloblastomas, especially those occurring in the non-tooth bearing area. This would call for the need to incorporate additional therapy in the form of mucosal striping along with the conventional treatment. PMID:25478446

Central Diabetes Insipidus and Cisplatin-Induced Renal Salt Wasting Syndrome: A Challenging Combination.

PubMed

Cortina, Gerard; Hansford, Jordan R; Duke, Trevor

2016-05-01

We describe a 2-year-old female with a suprasellar primitive neuroectodermal tumor and central diabetes insipidus (DI) who developed polyuria with natriuresis and subsequent hyponatremia 36 hr after cisplatin administration. The marked urinary losses of sodium in combination with a negative sodium balance led to the diagnosis of cisplatin-induced renal salt wasting syndrome (RSWS). The subsequent clinical management is very challenging. Four weeks later she was discharged from ICU without neurological sequela. The combination of cisplatin-induced RSWS with DI can be confusing and needs careful clinical assessment as inaccurate diagnosis and management can result in increased neurological injury. © 2016 Wiley Periodicals, Inc.

PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis.

PubMed

Kendall, Genevieve C; Watson, Sarah; Xu, Lin; LaVigne, Collette A; Murchison, Whitney; Rakheja, Dinesh; Skapek, Stephen X; Tirode, Franck; Delattre, Olivier; Amatruda, James F

2018-06-05

Alveolar rhabdomyosarcoma is a pediatric soft-tissue sarcoma caused by PAX3/7-FOXO1 fusion oncogenes and is characterized by impaired skeletal muscle development. We developed human PAX3-FOXO1 -driven zebrafish models of tumorigenesis and found that PAX3-FOXO1 exhibits discrete cell lineage susceptibility and transformation. Tumors developed by 1.6-19 months and were primitive neuroectodermal tumors or rhabdomyosarcoma. We applied this PAX3-FOXO1 transgenic zebrafish model to study how PAX3-FOXO1 leverages early developmental pathways for oncogenesis and found that her3 is a unique target. Ectopic expression of the her3 human ortholog, HES3 , inhibits myogenesis in zebrafish and mammalian cells, recapitulating the arrested muscle development characteristic of rhabdomyosarcoma. In patients, HES3 is overexpressed in fusion-positive versus fusion-negative tumors. Finally, HES3 overexpression is associated with reduced survival in patients in the context of the fusion. Our novel zebrafish rhabdomyosarcoma model identifies a new PAX3-FOXO1 target, her3 / HES3 , that contributes to impaired myogenic differentiation and has prognostic significance in human disease. © 2018, Kendall et al.

Primary soft tissue Ewing's sarcoma of the maxillary sinus in elderly patients: presentation, management and prognosis.

PubMed

Dutta, M; Ghatak, S; Biswas, G; Sen, A

2014-06-01

Nonosseous or soft tissue Ewing's sarcoma is a rare form of Ewing's sarcoma/primitive neuroectodermal tumour that seldom affects the head and neck region. Involvement of the nose and paranasal sinuses is extremely uncommon, with only eight of such patients being reported to date, mostly affecting adolescents and young adults. To our knowledge, this study is the first comprehensive report of primary soft tissue Ewing's sarcoma involving the paranasal sinuses in an elderly patient who successfully completed treatment. We herein discuss the pathogenesis, management and factors affecting the prognosis of this rare group of tumours involving the nose and paranasal sinuses, in relation to the available literature.

Effusion cytomorphology of small round cell tumors.

PubMed

Ikeda, Katsuhide; Tsuta, Koji

2016-01-01

Small round cell tumors (SRCTs) are a group of tumors composed of small, round, and uniform cells with high nuclear/cytoplasmic (N/C) ratios. The appearance of SRCT neoplastic cells in the effusion fluid is very rare. We reported the cytomorphological findings of SRCTs in effusion cytology, and performed statistical and mathematical analyses for a purpose to distinguish SRCTs. We analyzed the cytologic findings of effusion samples from 40 SRCT cases and measured the lengths of the nuclei, cytoplasms, and the cell cluster areas. The SRCT cases included 14 Ewing sarcoma (EWS)/primitive neuroectodermal tumor cases, 5 synovial sarcoma cases, 6 rhabdomyosarcoma cases, 9 small cell lung carcinoma (SCLC) cases, and 6 diffuse large B-cell lymphoma (DLBL) cases. Morphologically, there were no significant differences in the nuclear and cytoplasmic lengths in cases of EWS, synovial sarcoma, and rhabdomyosarcoma. The cytoplasmic lengths in cases of SCLC and DLBL were smaller than those of EWS, synovial sarcoma, and rhabdomyosarcoma. The nuclear density of the cluster in SCLC was higher than that in other SRCTs, and cases of DLBL showed a lack of anisokaryosis and anisocytosis. We believe that it might be possible to diagnose DLBL and SCLC from cytologic analysis of effusion samples but it is very difficult to use this method to distinguish EWS, synovial sarcoma, and rhabdomyosarcoma. Statistical and mathematical analyses indicated that nuclear density and dispersion of nuclear and cytoplasmic sizes are useful adjuncts to conventional cytologic diagnostic criteria, which are acquired from experience.

Clinicopathological findings of primary esophageal malignant melanoma: report of six cases and review of literature.

PubMed

Zheng, Jinfeng; Mo, Haiying; Ma, Shufang; Wang, Zhenzheng

2014-01-01

We studied images and histopathological features of primary esophageal malignant melanoma to explore the clinical pathological features, diagnosis, differential diagnoses, and treatment. Immunolabelling was conducted on six cases of esophageal malignant melanoma using histological and immunohistochemical techniques. Combined with the related literature, the clinical manifestations, imaging, histopathological and immunohistochemical features, treatment, and prognosis of primary esophageal malignant melanoma were observed and analyzed. The six patients with primary esophageal malignant melanoma were all male with an average age of 63.4 years. Poor food intake was observed in all patients, and the symptoms showed progressive aggravation. Endoscopic feed tube revealed dark brown and black nodular and polypoid lesions, 1/4-1/2 loop cavity. Tumor histopathology revealed the following characteristics: tumor cells arranged in nests, sheets and cords, round or polygonal, abundant and red-stained cytoplasm, melanin granules in the cytoplasm, heterogeneous nucleus sizes, centered or deviated nuclei, clearly identifiable nucleoli, and apparent pathological mitosis. The immune phenotype was as follows: tumor cells had diffuse expression of HMB45, Melan A, and S100. The cells were CK negative, and the Ki67-positive cell number was 40%-45%. Primary esophageal malignant melanoma is rare with high malignancy and poor prognosis. Immunohistochemical staining is helpful for diagnosing this tumor. The differential diagnosis includes low differentiated carcinoma, primitive neuroectodermal tumor, esophageal sarcomatoid carcinoma, esophageal lymphoma, and other tumors.

MYCN induces neuroblastoma in primary neural crest cells.

PubMed

Olsen, R R; Otero, J H; García-López, J; Wallace, K; Finkelstein, D; Rehg, J E; Yin, Z; Wang, Y-D; Freeman, K W

2017-08-31

Neuroblastoma (NBL) is an embryonal cancer of the sympathetic nervous system (SNS), which causes 15% of pediatric cancer deaths. High-risk NBL is characterized by N-Myc amplification and segmental chromosomal gains and losses. Owing to limited disease models, the etiology of NBL is largely unknown, including both the cell of origin and the majority of oncogenic drivers. We have established a novel system for studying NBL based on the transformation of neural crest cells (NCCs), the progenitor cells of the SNS, isolated from mouse embryonic day 9.5 trunk neural tube explants. Based on pathology and gene expression analysis, we report the first successful transformation of wild-type NCCs into NBL by enforced expression of N-Myc, to generate phenotypically and molecularly accurate tumors that closely model human MYCN-amplified NBL. Using comparative genomic hybridization, we found that NCC-derived NBL tumors acquired copy number gains and losses that are syntenic to those observed in human MYCN-amplified NBL including 17q gain, 2p gain and loss of 1p36. When p53-compromised NCCs were transformed with N-Myc, we generated primitive neuroectodermal tumors with divergent differentiation including osteosarcoma. These subcutaneous tumors were metastatic to regional lymph nodes, liver and lung. Our novel experimental approach accurately models human NBL and establishes a new system with potential to study early stages of NBL oncogenesis, to functionally assess NBL oncogenic drivers and to characterize NBL metastasis.

Single cell cultures of Drosophila neuroectodermal and mesectodermal central nervous system progenitors reveal different degrees of developmental autonomy.

PubMed

Lüer, Karin; Technau, Gerhard M

2009-08-03

The Drosophila embryonic central nervous system (CNS) develops from two sets of progenitor cells, neuroblasts and ventral midline progenitors, which behave differently in many respects. Neuroblasts derive from the neurogenic region of the ectoderm and form the lateral parts of the CNS. Ventral midline precursors are formed by two rows of mesectodermal cells and build the CNS midline. There is plenty of evidence that individual identities are conferred to precursor cells by positional information in the ectoderm. It is unclear, however, how far the precursors can maintain their identities and developmental properties in the absence of normal external signals. To separate the respective contributions of autonomous properties versus extrinsic signals during their further development, we isolated individual midline precursors and neuroectodermal precursors at the pre-mitotic gastrula stage, traced their development in vitro, and analyzed the characteristics of their lineages in comparison with those described for the embryo. Although individually cultured mesectodermal cells exhibit basic characteristics of CNS midline progenitors, the clones produced by these progenitors differ from their in situ counterparts with regard to cell numbers, expression of molecular markers, and the separation of neuronal and glial fate. In contrast, clones derived from individually cultured precursors taken from specific dorsoventral zones of the neuroectoderm develop striking similarities to the lineages of neuroblasts that normally delaminate from these zones and develop in situ. This in vitro analysis allows for the first time a comparison of the developmental capacities in situ and in vitro of individual neural precursors of defined spatial and temporal origin. The data reveal that cells isolated at the pre-mitotic and pre-delamination stage express characteristics of the progenitor type appropriate to their site of origin in the embryo. However, presumptive neuroblasts, once specified in the neuroectoderm, exhibit a higher degree of autonomy regarding generation of their lineages compared to mesectodermal midline progenitors.

Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion

PubMed Central

Hussein, Deema; Punjaruk, Wiyada; Storer, Lisa C.D.; Shaw, Lucy; Ottoman, Ramadan; Peet, Andrew; Miller, Suzanne; Bandopadhyay, Gagori; Heath, Rachel; Kumari, Rajendra; Bowman, Karen J.; Braker, Paul; Rahman, Ruman; Jones, George D.D.; Watson, Susan; Lowe, James; Kerr, Ian D.; Grundy, Richard G.; Coyle, Beth

2011-01-01

Reliable model systems are needed to elucidate the role cancer stem cells (CSCs) play in pediatric brain tumor drug resistance. The majority of studies to date have focused on clinically distinct adult tumors and restricted tumor types. Here, the CSC component of 7 newly established primary pediatric cell lines (2 ependymomas, 2 medulloblastomas, 2 gliomas, and a CNS primitive neuroectodermal tumor) was thoroughly characterized. Comparison of DNA copy number with the original corresponding tumor demonstrated that genomic changes present in the original tumor, typical of that particular tumor type, were retained in culture. In each case, the CSC component was approximately 3–4-fold enriched in neurosphere culture compared with monolayer culture, and a higher capacity for multilineage differentiation was observed for neurosphere-derived cells. DNA content profiles of neurosphere-derived cells expressing the CSC marker nestin demonstrated the presence of cells in all phases of the cell cycle, indicating that not all CSCs are quiescent. Furthermore, neurosphere-derived cells demonstrated an increased resistance to etoposide compared with monolayer-derived cells, having lower initial DNA damage, potentially due to a combination of increased drug extrusion by ATP-binding cassette multidrug transporters and enhanced rates of DNA repair. Finally, orthotopic xenograft models reflecting the tumor of origin were established from these cell lines. In summary, these cell lines and the approach taken provide a robust model system that can be used to develop our understanding of the biology of CSCs in pediatric brain tumors and other cancer types and to preclinically test therapeutic agents. PMID:20978004

Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion.

PubMed

Hussein, Deema; Punjaruk, Wiyada; Storer, Lisa C D; Shaw, Lucy; Othman, Ramadhan; Ottoman, Ramadan; Peet, Andrew; Miller, Suzanne; Bandopadhyay, Gagori; Heath, Rachel; Kumari, Rajendra; Bowman, Karen J; Braker, Paul; Rahman, Ruman; Jones, George D D; Watson, Susan; Lowe, James; Kerr, Ian D; Grundy, Richard G; Coyle, Beth

2011-01-01

Reliable model systems are needed to elucidate the role cancer stem cells (CSCs) play in pediatric brain tumor drug resistance. The majority of studies to date have focused on clinically distinct adult tumors and restricted tumor types. Here, the CSC component of 7 newly established primary pediatric cell lines (2 ependymomas, 2 medulloblastomas, 2 gliomas, and a CNS primitive neuroectodermal tumor) was thoroughly characterized. Comparison of DNA copy number with the original corresponding tumor demonstrated that genomic changes present in the original tumor, typical of that particular tumor type, were retained in culture. In each case, the CSC component was approximately 3-4-fold enriched in neurosphere culture compared with monolayer culture, and a higher capacity for multilineage differentiation was observed for neurosphere-derived cells. DNA content profiles of neurosphere-derived cells expressing the CSC marker nestin demonstrated the presence of cells in all phases of the cell cycle, indicating that not all CSCs are quiescent. Furthermore, neurosphere-derived cells demonstrated an increased resistance to etoposide compared with monolayer-derived cells, having lower initial DNA damage, potentially due to a combination of increased drug extrusion by ATP-binding cassette multidrug transporters and enhanced rates of DNA repair. Finally, orthotopic xenograft models reflecting the tumor of origin were established from these cell lines. In summary, these cell lines and the approach taken provide a robust model system that can be used to develop our understanding of the biology of CSCs in pediatric brain tumors and other cancer types and to preclinically test therapeutic agents.

Treatment outcome and patterns of failure in patients of non-pineal supratentorial primitive neuroectodermal tumor: review of literature and clinical experience form a regional cancer center in north India.

PubMed

Biswas, Ahitagni; Mallick, Supriya; Purkait, Suvendu; Roy, Soumyajit; Sarkar, Chitra; Bakhshi, Sameer; Singh, Manmohan; Julka, Pramod Kumar; Rath, Goura Kishor

2015-07-01

Supra-tentorial primitive neuroectodermal tumors (SPNET) are high-grade, hemispheric tumors, which account for around 2-3 % of pediatric brain tumors. We herein intend to report the clinical features and treatment outcome of patients with nonpineal SPNET treated at our institute. Clinical data were collected by retrospective chart review from 2006 to 2012. Histopathology slides were reviewed, and relevant immunohistochemistry stains were done. Overall survival (OS), recurrence-free survival (RFS) and event-free survival (EFS) were analyzed by the Kaplan-Meier product-limit method. Fifteen patients met the study criterion (male: female = 2:1). Median age at presentation was 11 years (range 3-49 years). Surgical resection was gross total in 6 (40%) and subtotal in 8 (53.33%) patients. At presentation, two patients had leptomeningeal dissemination. Radiation therapy was delivered in 11 (73.33%) patients: craniospinal irradiation in 8 (36 Gy/20 fractions/4 weeks to the craniospinal axis followed by a local boost of 20 Gy/10 fractions/2 weeks) and focal RT in 3 patients. Systemic chemotherapy (median 6 cycles; range 1-16 cycles), given in 13 (86.67%) patients, included the VAC regimen (vincristine, adriamycin, cyclophosphamide) alternating with IE (ifosfamide,etoposide). After a median follow-up of 22.6 months (mean, 24.47 months), complete response and progressive disease were noted in 8 (53.33%) and 7 (46.67%) patients, respectively. Median OS was not reached, and estimated median EFS was noted to be 4.12 years (actuarial rate of EFS at 2 years, 55.2%). Maximal safe resection followed by craniospinal irradiation and systemic chemotherapy with 6-12 cycles of an alternating regimen of VAC and IE is a reasonable treatment strategy in patients with nonpineal SPNET.

Blue Cell Tumour at Unusual Site: Retropritoneal Ewings Sarcoma.

PubMed

Javalgi, Anita P; Karigoudar, Mahesh H; Palur, Katyayani

2016-04-01

Ewing's sarcoma is a highly malignant tumour of osseous or non-osseous origin, tremed as extra-skeletal Ewings sarcoma if arising from soft tissue. It is rare occurrence tumor most commonly occurring in paravertebral area, chest wall, head & neck and retroperitoneum. Reporting an interesting case of retroperitoneal Ewing's sarcoma in 39 years old female. Patient had complains of abdominal discomfort & vague pain since 2 months, following weakness in lower limb and loss of weight. On detail history and examination she was further referred to detail pathological and radiological investigations. Haematological profile, renal function test and liver function test were in normal limits. USG abdomen was normal, MRI showed a mass in pelvis retroperitoneum measuring 10x10cms, bilateral ovaries and tubes were normal. Because of retroperitoneal nature of tumor and suspicion of uterine sarcoma, laparotomy was performed. The large retroperitoneal mass adherent to posterior of uterus was excised and send for histopathological diagnosis. On gross and microscopy examination the diagnosis of blue cell tumor with PAS positivity, possibility of extraskeletal Ewing's sarcoma/primitive neuro-ectodermal tumor was made which was further confirmed by immunohistochemistry, positive for S100, Vementin and CD99 and negative for desmin and CK. Confirmed diagnosis help in accurate management and improves survival rate.

[Pineal anlage tumor in a 8-month-old boy. The first case reported in Spanish language].

PubMed

Rodríguez-Velasco, Alicia; Ramírez-Reyes, Alma Griselda

2014-01-01

The pineal anlage tumor is a very infrequent malign neoplasm. Even though it has been documented in literature, it is not listed yet in the World Health Organization's last nervous system classification (2007). It is a primitive pineal tumor with neuroepithelial and ectomesenchyme differentiation. Due to its low frequency, the understanding of its biological behavior and a suitable treatment are incomplete. In a search performed in PubMed with the term pineal anlage tumor, only seven informed cases were identified between 1989 and 2011. An 8-month-old infant was brought to medical attention because he had a progressive enlargement of the cephalic perimeter, and convergent strabismus of two months of evolution. A pineal tumor was identified. The histology showed glial tissue, ganglia cells, pigmented neuroepithelium and striate muscle cells. A ventriculoperitoneal derivation was done to diminish hydrocephalic pressure and also to led the complete surgical resection. The patient was treated with two courses of chemotherapy with carboplatine, ifosfamide and mesna. One year after the treatment, the patient is asymptomatic. This is the first case reported in Spanish language. Given that it is a really infrequent tumor, it could be misdiagnosed as teratome, melanotic or mesoblastic medulloblastoma, or a melanotic neuroectodermal tumor of childhood (melanotic prognoma).

Primary Ewing's Sarcoma/Primitive Neuroectodermal Tumor of Kidney with Caval Involvement in a Pregnant Woman.

PubMed

Ding, Yinghui; Huang, Zhenlin; Ding, Yafei; Jia, Zhankui; Gu, Chaohui; Xue, Rui; Yang, Jinjian

2016-01-01

In this article, we report the case of a woman in whom was found an abdominal mass during pregnancy and who underwent nephrectomy and extraction of the emboli after delivery. The kidney had a volume of 15 × 10 × 8 cm and pathological diagnosis was primary Ewing's sarcoma. The patient was treated with conventional chemotherapy for 1 year after surgery, at which time multiple metastases were found. From this case, we surmise that hormonal changes that occur during pregnancy may accelerate the growth of Ewing's sarcoma of the kidney, suggesting that renal tumors in pregnant women demand serious attention and that anti-cancer treatment should begin as soon as possible. © 2016 S. Karger AG, Basel.

p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells

PubMed Central

Harajly, Mohamad; Zalzali, Hasan; Nawaz, Zafar; Ghayad, Sandra E.; Ghamloush, Farah; Basma, Hussein; Zainedin, Samiha; Rabeh, Wissam; Jabbour, Mark; Tawil, Ayman; Badro, Danielle A.; Evan, Gerard I.

2015-01-01

The restoration of p53 has been suggested as a therapeutic approach in tumors. However, the timing of p53 restoration in relation to its efficacy during tumor progression still is unclear. We now show that the restoration of p53 in murine premalignant proliferating pineal lesions resulted in cellular senescence, while p53 restoration in invasive pineal tumors did not. The effectiveness of p53 restoration was not dependent on p19Arf expression but showed an inverse correlation with Mdm2 expression. In tumor cells, p53 restoration became effective when paired with either DNA-damaging therapy or with nutlin, an inhibitor of p53-Mdm2 interaction. Interestingly, the inactivation of p53 after senescence resulted in reentry into the cell cycle and rapid tumor progression. The evaluation of a panel of human supratentorial primitive neuroectodermal tumors (sPNET) showed low activity of the p53 pathway. Together, these data suggest that the restoration of the p53 pathway has different effects in premalignant versus invasive pineal tumors, and that p53 activation needs to be continually sustained, as reversion from senescence occurs rapidly with aggressive tumor growth when p53 is lost again. Finally, p53 restoration approaches may be worth exploring in sPNET, where the p53 gene is intact but the pathway is inactive in the majority of examined tumors. PMID:26598601

The antiretroviral nucleoside analogue Abacavir reduces cell growth and promotes differentiation of human medulloblastoma cells

PubMed Central

Rossi, Alessandra; Russo, Giuseppe; Puca, Andrew; La Montagna, Raffaele; Caputo, Mariella; Mattioli, Eliseo; Lopez, Massimo; Giordano, Antonio; Pentimalli, Francesca

2009-01-01

Abacavir is one of the most efficacious nucleoside analogues, with a well-characterized inhibitory activity on reverse transcriptase enzymes of retroviral origin, and has been clinically approved for the treatment of AIDS. Recently, Abacavir has been shown to inhibit also the human telomerase activity. Telomerase activity seems to be required in essentially all tumours for the immortalization of a subset of cells, including cancer stem cells. In fact, many cancer cells are dependent on telomerase for their continued replication and therefore telomerase is an attractive target for cancer therapy. Telomerase expression is upregulated in primary primitive neuroectodermal tumours and in the majority of medulloblastomas suggesting that its activation is associated with the development of these diseases. Therefore, we decided to test Abacavir activity on human medulloblastoma cell lines with high telomerase activity. We report that exposure to Abacavir induces a dose-dependent decrease in the proliferation rate of medulloblastoma cells. This is associated with a cell accumulation in the G2/M phase of the cell cycle in the Daoy cell line, and with increased cell death in the D283-MED cell line, and is likely to be dependent on the inhibition of telomerase activity. Interestingly, both cell lines showed features of senescence after Abacavir treatment. Moreover, following Abacavir exposure we detected, by immunofluorescence staining, increased protein expression of the glial marker glial fibrillary acidic protein (GFAP) and the neuronal marker synaptophysin (SYN) in both medulloblastoma cell lines. In conclusion, our results suggest that Abacavir reduces proliferation and induces differentiation of human medulloblastoma cells through the downregulation of telomerase activity. Thus, using Abacavir, alone or in combination with current therapies, might be an effective therapeutic strategy for the treatment of medulloblastoma. PMID:19358275

YKL-40 is differentially expressed in human embryonic stem cells and in cell progeny of the three germ layers.

PubMed

Brøchner, Christian B; Johansen, Julia S; Larsen, Lars A; Bak, Mads; Mikkelsen, Hanne B; Byskov, Anne Grete; Andersen, Claus Yding; Møllgård, Kjeld

2012-03-01

The secreted glycoprotein YKL-40 participates in cell differentiation, inflammation, and cancer progression. High YKL-40 expression is reported during early human development, but its functions are unknown. Six human embryonic stem cell (hESC) lines were cultured in an atmosphere of low or high oxygen tension, in culture medium with or without basic fibroblast growth factor, and on feeder layers comprising mouse embryonic fibroblasts or human foreskin fibroblasts to evaluate whether hESCs and their progeny produced YKL-40 and to characterize YKL-40 expression during differentiation. Secreted YKL-40 protein and YKL-40 mRNA expression were measured by enzyme-linked immunosorbent assay (ELISA) and quantitative RT-PCR. Serial-sectioned colonies were stained for YKL-40 protein and for pluripotent hESC (OCT4, NANOG) and germ layer (HNF-3β, PDX1, CD34, p63, nestin, PAX6) markers. Double-labeling showed YKL-40 expression in OCT4-positive hESCs, PAX6-positive neuroectodermal cells, and HNF-3β-positive endodermal cells. The differentiating progeny showed strong YKL-40 expression. Abrupt transition between YKL-40 and OCT4-positive hESCs and YKL-40-positive ecto- and neuroectodermal lineages was observed within the same epithelial-like layer. YKL-40-positive cells within deeper layers lacked contact with OCT4-positive cells. YKL-40 may be important in initial cell differentiation from hESCs toward ectoderm and neuroectoderm, with retained epithelial morphology, whereas later differentiation into endoderm and mesoderm involves a transition into the deeper layers of the colony.

MYCN induces neuroblastoma in primary neural crest cells

PubMed Central

Olsen, R R; Otero, J H; García-López, J; Wallace, K; Finkelstein, D; Rehg, J E; Yin, Z; Wang, Y-D; Freeman, K W

2017-01-01

Neuroblastoma (NBL) is an embryonal cancer of the sympathetic nervous system (SNS), which causes 15% of pediatric cancer deaths. High-risk NBL is characterized by N-Myc amplification and segmental chromosomal gains and losses. Owing to limited disease models, the etiology of NBL is largely unknown, including both the cell of origin and the majority of oncogenic drivers. We have established a novel system for studying NBL based on the transformation of neural crest cells (NCCs), the progenitor cells of the SNS, isolated from mouse embryonic day 9.5 trunk neural tube explants. Based on pathology and gene expression analysis, we report the first successful transformation of wild-type NCCs into NBL by enforced expression of N-Myc, to generate phenotypically and molecularly accurate tumors that closely model human MYCN-amplified NBL. Using comparative genomic hybridization, we found that NCC-derived NBL tumors acquired copy number gains and losses that are syntenic to those observed in human MYCN-amplified NBL including 17q gain, 2p gain and loss of 1p36. When p53-compromised NCCs were transformed with N-Myc, we generated primitive neuroectodermal tumors with divergent differentiation including osteosarcoma. These subcutaneous tumors were metastatic to regional lymph nodes, liver and lung. Our novel experimental approach accurately models human NBL and establishes a new system with potential to study early stages of NBL oncogenesis, to functionally assess NBL oncogenic drivers and to characterize NBL metastasis. PMID:28459463

Diagnostic utility of cyclin D1 in the diagnosis of small round blue cell tumors in children and adolescents.

PubMed

Magro, Gaetano; Salvatorelli, Lucia; Alaggio, Rita; D'Agata, Velia; Nicoletti, Ferdinando; Di Cataldo, Andrea; Parenti, Rosalba

2017-02-01

Small round blue cell tumors (SRBCTs) of children and adolescents are often diagnostically challenging lesions. With the increasing diagnostic approach based on small biopsies, there is the need of specific immunomarkers that can help in the differential diagnosis among the different tumor histotypes to assure the patient a correct diagnosis for proper treatment. Based on our recent studies showing cyclin D1 overexpression in both Ewing sarcoma/primitive peripheral neuroectodermal tumor (EWS/pPNET) and peripheral neuroblastic tumors (neuroblastoma and ganglioneuroblastoma), we immunohistochemically assessed cyclin D1 immunoreactivity in 128 cases of SRBCTs in children and adolescents to establish its potential utility in the differential diagnosis. All cases of EWS/pPNET and the undifferentiated/poorly differentiated neuroblastomatous component of all peripheral neuroblastic tumors exhibited strong and diffuse nuclear staining (>50% of neoplastic cells) for cyclin D1. In contrast, this marker was absent from rhabdomyosarcoma (regardless of subtype) and lymphoblastic lymphoma (either B- or T-cell precursors), whereas it was only focally detected (<5% of neoplastic cells) in some cases of Wilms tumor (blastemal component) and desmoplastic small round cell tumor. Our findings suggest that cyclin D1 can be exploitable as a diagnostic adjunct to conventional markers in confirming the diagnosis of EWS/pPNET or neuroblastoma/ganglioneuroblastoma. Its use in routine practice may also be helpful for those cases of SRBCT with undifferentiated morphology that are difficult to diagnose after application of the conventional markers. Copyright © 2016 Elsevier Inc. All rights reserved.

Treatment of Children With Central Nervous System Primitive Neuroectodermal Tumors/Pinealoblastomas in the Prospective Multicentric Trial HIT 2000 Using Hyperfractionated Radiation Therapy Followed by Maintenance Chemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gerber, Nicolas U., E-mail: nicolas.gerber@kispi.uzh.ch; Hoff, Katja von; Resch, Anika

Purpose: The prognosis for children with central nervous system primitive neuroectodermal tumor (CNS-PNET) or pinealoblastoma is still unsatisfactory. Here we report the results of patients between 4 and 21 years of age with nonmetastatic CNS-PNET or pinealoblastoma diagnosed from January 2001 to December 2005 and treated in the prospective GPOH-trial P-HIT 2000-AB4. Methods and Materials: After surgery, children received hyperfractionated radiation therapy (36 Gy to the craniospinal axis, 68 Gy to the tumor region, and 72 Gy to any residual tumor, fractionated at 2 × 1 Gy per day 5 days per week) accompanied by weekly intravenous administration of vincristine and followed by 8 cycles of maintenance chemotherapy (lomustine, cisplatin, andmore » vincristine). Results: Twenty-six patients (15 with CNS-PNET; 11 with pinealoblastoma) were included. Median age at diagnosis was 11.5 years old (range, 4.0-20.7 years). Gross total tumor resection was achieved in 6 and partial resection in 16 patients (indistinct, 4 patients). Median follow-up of the 15 surviving patients was 7.0 years (range, 5.2-10.0 years). The combined response rate to postoperative therapy was 17 of 20 (85%). Eleven of 26 patients (42%; 7 of 15 with CNS-PNET; 4 of 11 with pinealoblastoma) showed tumor progression or relapse at a median time of 1.3 years (range, 0.5-1.9 years). Five-year progression-free and overall survival rates (±standard error [SE]) were each 58% (±10%) for the entire cohort: CNS-PNET was 53% (±13); pinealoblastoma was 64% (±15%; P=.524 and P=.627, respectively). Conclusions: Postoperative hyperfractionated radiation therapy with local dose escalation followed by maintenance chemotherapy was feasible without major acute toxicity. Survival rates are comparable to those of a few other recent studies but superior to those of most other series, including the previous trial, HIT 1991.« less

Renal cell carcinoma and a constitutional t(11;22)(q23;q11.2): case report and review of the potential link between the constitutional t(11;22) and cancer.

PubMed

Doyen, Jérôme; Carpentier, Xavier; Haudebourg, Juliette; Hoch, Benjamin; Karmous-Benailly, Houda; Ambrosetti, Damien; Fabas, Thibault; Amiel, Jean; Lambert, Jean-Claude; Pedeutour, Florence

2012-11-01

We observed a t(11;22)(q23-24;q11.2-12) and monosomy 3 in renal tumor cells from a 72-year-old man. The hypothesis of a primitive peripheral neuroectodermal tumor (PPNET) located in the kidney was promptly excluded: Histologically, the tumor was a clear cell renal cell carcinoma (RCC) and we did not observe an EWSR1 gene rearrangement. The constitutional origin of this alteration was established. We report on the second case of RCC in a patient with a constitutional t(11;22). The t(11;22)(q23;q11.2) is the main recurrent germline translocation in humans. Unbalanced translocation can be transmitted to the progeny and can cause Emanuel syndrome. Our observation alerts cancer cytogeneticists to the fortuitous discovery of the constitutional t(11;22) in tumor cells. This translocation appears grossly similar to the t(11;22)(q24;q12) of PPNET and should be evoked if present in all cells of a tumor other than PPNET. This is important when providing appropriate genetic counseling. Moreover, the potential oncogenic role of the t(11;22) and its predisposing risk of cancer are under debate. The family history of the patient revealed a disabled brother who died at an early age from colon cancer and a sister with breast cancer. This observation reopens the issue of a link between the constitutional t(11;22) and cancer, and the utility of cancer prevention workups for t(11;22) carriers. Copyright © 2012 Elsevier Inc. All rights reserved.

Self-organization of neural patterns and structures in 3D culture of stem cells

NASA Astrophysics Data System (ADS)

Sasai, Yoshiki

2013-05-01

Over the last several years, much progress has been made for in vitro culture of mouse and human ES cells. Our laboratory focuses on the molecular and cellular mechanisms of neural differentiation from pluripotent cells. Pluripotent cells first become committed to the ectodermal fate and subsequently differentiate into uncommitted neuroectodermal cells. Both previous mammalian and amphibian studies on pluripotent cells have indicated that the neural fate is a sort of the basal direction of the differentiation of these cells while mesoendodermal differentiation requires extrinsic inductive signals. ES cells differentiate into neuroectodermal cells with a rostral-most character (telencephalon and hypothalamus) when they are cultured in the absence of strong patterning signals. In this talk, I first discuss this issue by referring to our recent data on the mechanism of spontaneous neural differentiation in serum-free culture of mouse ES cells. Then, I will talk about self-organization phenomena observed in 3D culture of ES cells, which lead to tissue-autonomous formation of regional structures such as layered cortical tissues. I also discuss our new attempt to monitor these in vitro morphogenetic processes by live imaging, in particular, self-organizing morphogenesis of the optic cup in three-dimensional cultures.

Unravelling the mystery of stem/progenitor cells in human breast milk.

PubMed

Fan, Yiping; Chong, Yap Seng; Choolani, Mahesh A; Cregan, Mark D; Chan, Jerry K Y

2010-12-28

Mammary stem cells have been extensively studied as a system to delineate the pathogenesis and treatment of breast cancer. However, research on mammary stem cells requires tissue biopsies which limit the quantity of samples available. We have previously identified putative mammary stem cells in human breast milk, and here, we further characterised the cellular component of human breast milk. We identified markers associated with haemopoietic, mesenchymal and neuro-epithelial lineages in the cellular component of human breast milk. We found 2.6 ± 0.8% (mean ± SEM) and 0.7 ± 0.2% of the whole cell population (WCP) were found to be CD133+ and CD34+ respectively, 27.8 ± 9.1% of the WCP to be positive for Stro-1 through flow-cytometry. Expressions of neuro-ectodermal stem cell markers such as nestin and cytokeratin 5 were found through reverse-transcription polymerase chain reaction (RT-PCR), and in 4.17 ± 0.2% and 0.9 ± 0.2% of the WCP on flow-cytometry. We also established the presence of a side-population (SP) (1.8 ± 0.4% of WCP) as well as CD133+ cells (1.7 ± 0.5% of the WCP). Characterisation of the sorted SP and non-SP, CD133+ and CD133- cells carried out showed enrichment of CD326 (EPCAM) in the SP cells (50.6 ± 8.6 vs 18.1 ± 6.0, P-value  = 0.02). However, culture in a wide range of in vitro conditions revealed the atypical behaviour of stem/progenitor cells in human breast milk; in that if they are present, they do not respond to established culture protocols of stem/progenitor cells. The identification of primitive cell types within human breast milk may provide a non-invasive source of relevant mammary cells for a wide-range of applications; even the possibility of banking one's own stem cell for every breastfeeding woman.

Unravelling the Mystery of Stem/Progenitor Cells in Human Breast Milk

PubMed Central

Fan, Yiping; Chong, Yap Seng; Choolani, Mahesh A.; Cregan, Mark D.; Chan, Jerry K. Y.

2010-01-01

Background Mammary stem cells have been extensively studied as a system to delineate the pathogenesis and treatment of breast cancer. However, research on mammary stem cells requires tissue biopsies which limit the quantity of samples available. We have previously identified putative mammary stem cells in human breast milk, and here, we further characterised the cellular component of human breast milk. Methodology/Principal Findings We identified markers associated with haemopoietic, mesenchymal and neuro-epithelial lineages in the cellular component of human breast milk. We found 2.6±0.8% (mean±SEM) and 0.7±0.2% of the whole cell population (WCP) were found to be CD133+ and CD34+ respectively, 27.8±9.1% of the WCP to be positive for Stro-1 through flow-cytometry. Expressions of neuro-ectodermal stem cell markers such as nestin and cytokeratin 5 were found through reverse-transcription polymerase chain reaction (RT-PCR), and in 4.17±0.2% and 0.9±0.2% of the WCP on flow-cytometry. We also established the presence of a side-population (SP) (1.8±0.4% of WCP) as well as CD133+ cells (1.7±0.5% of the WCP). Characterisation of the sorted SP and non-SP, CD133+ and CD133- cells carried out showed enrichment of CD326 (EPCAM) in the SP cells (50.6±8.6 vs 18.1±6.0, P-value  = 0.02). However, culture in a wide range of in vitro conditions revealed the atypical behaviour of stem/progenitor cells in human breast milk; in that if they are present, they do not respond to established culture protocols of stem/progenitor cells. Conclusions/Significance The identification of primitive cell types within human breast milk may provide a non-invasive source of relevant mammary cells for a wide-range of applications; even the possibility of banking one's own stem cell for every breastfeeding woman. PMID:21203434

A well-known lesion in an unusual location: infantile myofibroma of the eyelid: a case report and review of literature.

PubMed

Asadi Amoli, Fahimeh; Sina, Amir Hossein; Kasai, Aboulfazl; Ayan, Zahra

2010-01-01

Myofibroma is a neoplasia of myofibroblasts that can be solitary or multiple and it is found most commonly in the head & neck region including scalp, forehead, parotid region and oral cavity. In the eyelid it is rarely reported. It has a benign course in the solitary form and fatal in its multiple form. A 4 month male infant referred to Farabi hospital -the referral center for eye diseases- with a 2 month history of a mass in his eyelid with gradual enlargement with no other complaints. The only abnormal physical finding was a 2.5 cm mass in the eyelid. This mass was excised and sent to the hospital pathology laboratory. When confronting a spindle cell lesion with a nodular or multinodular growth pattern which appears biphasic due to alteration of light and dark staining areas, the surgical pathologist should think to the possibility of myofibroma. Its pattern of growth and architecture rules out the other differential diagnoses like nodular fasciitis, fibrous histiocytoma, infantile fibromatosis, and peripheral primitive neuroectodermal tumor, mesenchymal chondrosarcoma, malignant hemangiopericytoma, juvenile fibrosarcoma and poorly differentiated synovial sarcoma. In difficult cases immunohistochemical staining is helpful that is Vimentin & Actin positivity & Desmin, CK, EMA & S100 negativity.

Detection of EWS/FLI-1 fusion in non-Ewing soft tissue tumors.

PubMed

Trancău, I O; Huică, R; Surcel, M; Munteanu, A; Ursaciuc, C

2015-01-01

EWS/FLI-1 fusion mainly appears in Ewing's sarcoma or the primitive neuroectodermal tumors and represents a genomic marker for these tumors. However, it can appear with lower frequency in other soft tissue tumors. The paper investigates the presence of EWS/FLI-1 fusion in clinically diagnosed sarcoma belonging to different non-Ewing connective tissue tumors in order to search for a possible new biomarker valuable for investigators. 20 patients with soft tissue tumors, who underwent surgery, were tested. Intra-operative samples of normal and tumor tissue were collected for histopathological diagnosis and genetics determinations. The patients' RNA from tumor and normal peritumoral tissue was extracted and EWS/FLI-1 fusion screened by quantitative real-time PCR. The relative expression of the fusion in the tumor sample was compared to the similar expression in normal tissue. The amplification in the threshold zone was shown by 5 samples (25%): 2 clear cell sarcoma, 1 fibrosarcoma, 1 malignant tumor of nerve sheath, 1 metastatic adenocarcinoma. We differentiated between the unspecific amplification and concluded that these are weak positive results. Genomic investigation may establish the tumor malignancy and its possible affiliation earlier than histopathology. It can support the screening of EWS/FLI-1 fusion in a larger variety of clinically diagnosed soft tissue tumors.

Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants.

PubMed

Joseph, Nancy M; Phillips, Joanna; Dahiya, Sonika; M Felicella, Michelle; Tihan, Tarik; Brat, Daniel J; Perry, Arie

2013-03-01

Recent work has demonstrated that nearly all diffuse gliomas display nuclear immunoreactivity for the bHLH transcription factor OLIG2, and the R132H mutant isocitrate dehydrogenase 1 (IDH1) protein is expressed in the majority of diffuse gliomas other than primary glioblastoma. However, these antibodies have not been widely applied to rarer glioblastoma variants, which can be diagnostically challenging when the astrocytic features are subtle. We therefore surveyed the expression patterns of OLIG2 and IDH1 in 167 non-conventional glioblastomas, including 45 small cell glioblastomas, 45 gliosarcomas, 34 glioblastomas with primitive neuroectodermal tumor-like foci (PNET-like foci), 23 with an oligodendroglial component, 11 granular cell glioblastomas, and 9 giant cell glioblastomas. OLIG2 was strongly expressed in all glioblastomas with oligodendroglial component, 98% of small cell glioblastomas, and all granular cell glioblastomas, the latter being particularly helpful in ruling out macrophage-rich lesions. In 74% of glioblastomas with PNET-like foci, OLIG2 expression was retained in the PNET-like foci, providing a useful distinction from central nervous system PNETs. The glial component of gliosarcomas was OLIG2 positive in 93% of cases, but only 14% retained focal expression in the sarcomatous component; as such this marker would not reliably distinguish these from pure sarcoma in most cases. OLIG2 was expressed in 67% of giant cell glioblastomas. IDH1 was expressed in 55% of glioblastomas with oligodendroglial component, 15% of glioblastomas with PNET-like foci, 7% of gliosarcomas, and none of the small cell, granular cell, or giant cell glioblastomas. This provides further support for the notion that most glioblastomas with oligodendroglial component are secondary, while small cell glioblastomas, granular cell glioblastomas, and giant cell glioblastomas are primary variants. Therefore, in one of the most challenging differential diagnoses, IDH1 positivity could provide strong support for glioblastoma with oligodendroglial component, while essentially excluding small cell glioblastoma.

Perivascular Mesenchymal Stem Cells From the Adult Human Brain Harbor No Instrinsic Neuroectodermal but High Mesodermal Differentiation Potential.

PubMed

Lojewski, Xenia; Srimasorn, Sumitra; Rauh, Juliane; Francke, Silvan; Wobus, Manja; Taylor, Verdon; Araúzo-Bravo, Marcos J; Hallmeyer-Elgner, Susanne; Kirsch, Matthias; Schwarz, Sigrid; Schwarz, Johannes; Storch, Alexander; Hermann, Andreas

2015-10-01

Brain perivascular cells have recently been identified as a novel mesodermal cell type in the human brain. These cells reside in the perivascular niche and were shown to have mesodermal and, to a lesser extent, tissue-specific differentiation potential. Mesenchymal stem cells (MSCs) are widely proposed for use in cell therapy in many neurological disorders; therefore, it is of importance to better understand the "intrinsic" MSC population of the human brain. We systematically characterized adult human brain-derived pericytes during in vitro expansion and differentiation and compared these cells with fetal and adult human brain-derived neural stem cells (NSCs) and adult human bone marrow-derived MSCs. We found that adult human brain pericytes, which can be isolated from the hippocampus and from subcortical white matter, are-in contrast to adult human NSCs-easily expandable in monolayer cultures and show many similarities to human bone marrow-derived MSCs both regarding both surface marker expression and after whole transcriptome profile. Human brain pericytes showed a negligible propensity for neuroectodermal differentiation under various differentiation conditions but efficiently generated mesodermal progeny. Consequently, human brain pericytes resemble bone marrow-derived MSCs and might be very interesting for possible autologous and endogenous stem cell-based treatment strategies and cell therapeutic approaches for treating neurological diseases. Perivascular mesenchymal stem cells (MSCs) recently gained significant interest because of their appearance in many tissues including the human brain. MSCs were often reported as being beneficial after transplantation in the central nervous system in different neurological diseases; therefore, adult brain perivascular cells derived from human neural tissue were systematically characterized concerning neural stem cell and MSC marker expression, transcriptomics, and mesodermal and inherent neuroectodermal differentiation potential in vitro and in vivo after in utero transplantation. This study showed the lack of an innate neuronal but high mesodermal differentiation potential. Because of their relationship to mesenchymal stem cells, these adult brain perivascular mesodermal cells are of great interest for possible autologous therapeutic use. ©AlphaMed Press.

Guidelines for imaging retinoblastoma: imaging principles and MRI standardization.

PubMed

de Graaf, Pim; Göricke, Sophia; Rodjan, Firazia; Galluzzi, Paolo; Maeder, Philippe; Castelijns, Jonas A; Brisse, Hervé J

2012-01-01

Retinoblastoma is the most common intraocular tumor in children. The diagnosis is usually established by the ophthalmologist on the basis of fundoscopy and US. Together with US, high-resolution MRI has emerged as an important imaging modality for pretreatment assessment, i.e. for diagnostic confirmation, detection of local tumor extent, detection of associated developmental malformation of the brain and detection of associated intracranial primitive neuroectodermal tumor (trilateral retinoblastoma). Minimum requirements for pretreatment diagnostic evaluation of retinoblastoma or mimicking lesions are presented, based on consensus among members of the European Retinoblastoma Imaging Collaboration (ERIC). The most appropriate techniques for imaging in a child with leukocoria are reviewed. CT is no longer recommended. Implementation of a standardized MRI protocol for retinoblastoma in clinical practice may benefit children worldwide, especially those with hereditary retinoblastoma, since a decreased use of CT reduces the exposure to ionizing radiation.

Primitive erythrocytes are generated from hemogenic endothelial cells.

PubMed

Stefanska, Monika; Batta, Kiran; Patel, Rahima; Florkowska, Magdalena; Kouskoff, Valerie; Lacaud, Georges

2017-07-25

Primitive erythroblasts are the first blood cells generated during embryonic hematopoiesis. Tracking their emergence both in vivo and in vitro has remained challenging due to the lack of specific cell surface markers. To selectively investigate primitive erythropoiesis, we have engineered a new transgenic embryonic stem (ES) cell line, where eGFP expression is driven by the regulatory sequences of the embryonic βH1 hemoglobin gene expressed specifically in primitive erythroid cells. Using this ES cell line, we observed that the first primitive erythroblasts are detected in vitro around day 1.5 of blast colony differentiation, within the cell population positive for the early hematopoietic progenitor marker CD41. Moreover, we establish that these eGFP + cells emerge from a hemogenic endothelial cell population similarly to their definitive hematopoietic counterparts. We further generated a corresponding βH1-eGFP transgenic mouse model and demonstrated the presence of a primitive erythroid primed hemogenic endothelial cell population in the developing embryo. Taken together, our findings demonstrate that both in vivo and in vitro primitive erythrocytes are generated from hemogenic endothelial cells.

Discovery of survival factor for primitive chronic myeloid leukemia cells using induced pluripotent stem cells

PubMed Central

Suknuntha, Kran; Ishii, Yuki; Tao, Lihong; Hu, Kejin; McIntosh, Brian E.; Yang, David; Swanson, Scott; Stewart, Ron; Wang, Jean Y.J.; Thomson, James; Slukvin, Igor

2016-01-01

A definitive cure for chronic myeloid leukemia (CML) requires identifying novel therapeutic targets to eradicate leukemia stem cells (LSCs). However, the rarity of LSCs within the primitive hematopoietic cell compartment remains a major limiting factor for their study in humans. Here we show that primitive hematopoietic cells with typical LSC features, including adhesion defect, increased long-term survival and proliferation, and innate resistance to tyrosine kinase inhibitor (TKI) imatinib, can be generated de novo from reprogrammed primary CML cells. Using CML iPSC-derived primitive leukemia cells, we discovered olfactomedin 4 (OLFM4) as a novel factor that contributes to survival and growth of somatic lin−CD34+ cells from bone marrow of patients with CML in chronic phase, but not primitive hematopoietic cells from normal bone marrow. Overall, this study shows the feasibility and advantages of using reprogramming technology to develop strategies for targeting primitive leukemia cells. PMID:26561938

Microfluidic assay of the deformability of primitive erythroblasts.

PubMed

Zhou, Sitong; Huang, Yu-Shan; Kingsley, Paul D; Cyr, Kathryn H; Palis, James; Wan, Jiandi

2017-09-01

Primitive erythroblasts (precursors of red blood cells) enter vascular circulation during the embryonic period and mature while circulating. As a result, primitive erythroblasts constantly experience significant hemodynamic shear stress. Shear-induced deformation of primitive erythroblasts however, is poorly studied. In this work, we examined the deformability of primitive erythroblasts at physiologically relevant flow conditions in microfluidic channels and identified the regulatory roles of the maturation stage of primitive erythroblasts and cytoskeletal protein 4.1 R in shear-induced cell deformation. The results showed that the maturation stage affected the deformability of primitive erythroblasts significantly and that primitive erythroblasts at later maturational stages exhibited a better deformability due to a matured cytoskeletal structure in the cell membrane.

High-level expression of podoplanin in benign and malignant soft tissue tumors: immunohistochemical and quantitative real-time RT-PCR analysis.

PubMed

Xu, Yongjun; Ogose, Akira; Kawashima, Hiroyuki; Hotta, Tetsuo; Ariizumi, Takashi; Li, Guidong; Umezu, Hajime; Endo, Naoto

2011-03-01

Podoplanin is a 38 kDa mucin-type transmembrane glycoprotein that was first identified in rat glomerular epithelial cells (podocytes). It is expressed in normal lymphatic endothelium, but is absent from vascular endothelial cells. D2-40 is a commercially available mouse monoclonal antibody which binds to an epitope on human podoplanin. D2-40 immunoreactivity is therefore highly sensitive and specific for lymphatic endothelium. Recent investigations have shown widespread applications of immunohistochemical staining with D2-40 in evaluating podoplanin expression as an immunohistochemical marker for diagnosis and prognosis in various tumors. To determine whether the podoplanin (D2-40) antibody may be useful for the diagnosis of soft tissue tumors, 125 cases, including 4 kinds of benign tumors, 15 kinds of malignant tumors and 3 kinds of tumor-like lesions were immunostained using the D2-40 antibody. Total RNA was extracted from frozen tumor tissue obtained from 41 corresponding soft tissue tumor patients and 12 kinds of soft tissue tumor cell lines. Quantitative real-time PCR reactions were performed. Immunohistochemical and quantitative real-time RT-PCR analyses demonstrated the expression of the podoplanin protein and mRNA in the majority of benign and malignant soft tissue tumors and tumor-like lesions examined, with the exception of alveolar soft part sarcoma, embryonal and alveolar rhabdomyosarcoma, extraskeletal Ewing's sarcoma/peripheral primitive neuro-ectodermal tumor and lipoma, which were completely negative for podoplanin. Since it is widely and highly expressed in nearly all kinds of soft tissue tumors, especially in spindle cell sarcoma, myxoid type soft tissue tumors and soft tissue tumors of the nervous system, podoplanin is considered to have little value in the differential diagnosis of soft tissue tumors.

Auto Transplant for High Risk or Relapsed Solid or CNS Tumors

ClinicalTrials.gov

2018-04-24

Ewing's Family Tumors; Renal Tumors; Hepatoblastoma; Rhabdomyosarcoma; Soft Tissue Sarcoma; Primary Malignant Brain Neoplasms; Retinoblastoma; Medulloblastoma; Supra-tentorial Primative Neuro-Ectodermal Tumor (PNET); Atypical Teratoid/Rhabdoid Tumor (AT/RT); CNS Tumors; Germ Cell Tumors

Evolutionary constraint on Otx2 neuroectoderm enhancers-deep conservation from skate to mouse and unique divergence in teleost

PubMed Central

Kurokawa, Daisuke; Sakurai, Yusuke; Inoue, Ai; Nakayama, Rika; Takasaki, Nobuyoshi; Suda, Yoko; Miyake, Tsutomu; Amemiya, Chris T.; Aizawa, Shinichi

2006-01-01

Otx2 is a paired type homeobox gene that plays essential roles in each step and site of head development in vertebrates. In the mouse, Otx2 expression in the anterior neuroectoderm is regulated primarily by two distinct enhancers: anterior neuroectoderm (AN) and forebrain/midbrain (FM) enhancers at 92 kb and 75 kb 5′of the Otx2 locus, respectively. The AN enhancer has activity in the entire anterior neuroectoderm at headfold and early somite stages, whereas the FM enhancer is subsequently active in the future caudal forebrain and midbrain ectoderm. In tetrapods, both AN and FM enhancers are conserved, whereas the AN region is missing in teleosts, despite overt Otx2 expression in the anterior neuroectoderm. Here, we show that zebrafish and fugu FM regions drive expression not only in the forebrain and midbrain but also in the anterior neuroectoderm at headfold stage. The analysis of coelacanth and skate genomic Otx2 orthologues suggests that the utilization of the two enhancers, AN and FM, is an ancestral condition. In contrast, the AN enhancer has been specifically lost in the teleost lineage with a compensatory establishment of AN activity within the FM enhancer. Furthermore, the AN activity in the fish FM enhancer was established by recruiting upstream factors different from those that direct the tetrapod AN enhancer, yet zebrafish FM enhancer is active in both mouse and zebrafish anterior neuroectoderm at the headfold stage. PMID:17159156

Survival of patients with Ewing's sarcoma in Yazd-Iran.

PubMed

Akhavan, Ali; Binesh, Fariba; Shamshiri, Hadi; Ghanadi, Fazllolah

2014-01-01

The Ewing's sarcoma family is a group of small round cell tumors which accounts for 10-15% of all primary bone neoplasms. The aim of this study was to evaluate the survival of Ewing's sarcoma patients in our province and to determine of influencing factors. All patients with documented Ewing's sarcoma/ primitive neuroectodermal tumor(PNET) family pathology were enrolled in this study during a period of eight years. For all of them local and systemic therapy were carried out. Overall and event free survival and prognostic factors were evaluated. Thirty two patients were enrolled in the study. The median age was 17.5 years. Twenty (65.2%) were male and 9 (28.1%) were aged 14 years or less. Mean disease free survival was 26.8 (95%CI; 13.8-39.9) months and five year disease free survival was 26%. Mean overall survival was 38.7 months (95%CI; 25.9-50.6) and median overall survival was 24 months. Five year overall survival was 25%. From the variables evaluated , only presence of metastatic disease at presentation (p value=0. 028) and complete response (p value =0. 006) had significant relations to overall survival. Survival of Ewing's sarcoma in our province is disappointing. It seems to be mostly due to less effective treatment. Administration of adequate chemotherapy dosage, resection of tumor with negative margins and precise assessment of irradiation volume may prove helpful.

Increased p53 immunopositivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virus

PubMed Central

Eberhart, Charles G; Chaudhry, Aneeka; Daniel, Richard W; Khaki, Leila; Shah, Keerti V; Gravitt, Patti E

2005-01-01

Background p53 mutations are relatively uncommon in medulloblastoma, but abnormalities in this cell cycle pathway have been associated with anaplasia and worse clinical outcomes. We correlated p53 protein expression with pathological subtype and clinical outcome in 75 embryonal brain tumors. The presence of JC virus, which results in p53 protein accumulation, was also examined. Methods p53 protein levels were evaluated semi-quantitatively in 64 medulloblastomas, 3 atypical teratoid rhabdoid tumors (ATRT), and 8 supratentorial primitive neuroectodermal tumors (sPNET) using immunohistochemistry. JC viral sequences were analyzed in DNA extracted from 33 frozen medulloblastoma and PNET samples using quantitative polymerase chain reaction. Results p53 expression was detected in 18% of non-anaplastic medulloblastomas, 45% of anaplastic medulloblastomas, 67% of ATRT, and 88% of sPNET. The increased p53 immunoreactivity in anaplastic medulloblastoma, ATRT, and sPNET was statistically significant. Log rank analysis of clinical outcome revealed significantly shorter survival in patients with p53 immunopositive embryonal tumors. No JC virus was identified in the embryonal brain tumor samples, while an endogenous human retrovirus (ERV-3) was readily detected. Conclusion Immunoreactivity for p53 protein is more common in anaplastic medulloblastomas, ATRT and sPNET than in non-anaplastic tumors, and is associated with worse clinical outcomes. However, JC virus infection is not responsible for increased levels of p53 protein. PMID:15717928

Pineal tumors: analysis of treatment results in 20 patients.

PubMed

Amendola, Beatriz E; Wolf, Aizik; Coy, Sammie R; Amendola, Marco A; Eber, Daryl

2005-01-01

The authors evaluate their results when using gamma knife surgery (GKS) in the management of patients with tumors in the pineal region. This is a retrospective clinical evaluation of 20 patients with primary tumors of the pineal region treated with GKS from November 1994 through August 2003. There were 13 germ cell tumors, two pineoblastomas, two low-grade gliomas, one primitive neuroectodermal tumor, one teratoma, and one pineocytoma. There were 10 male and 10 female patients. Their median age was 15.5 years (range 5-71 years). The median margin dose was 11 Gy (range 8-20 Gy). The median target volume was 3.1 cm3 (range 0.1-49.9 cm3). Five patients received sequential systemic chemotherapy and four underwent adjuvant conventional radiation therapy. Seventeen (85%) of 20 patients are alive with a median survival of 30.4 months (range 0-85.7 months). Two patients required retreatment. Three patients died: one of unrelated causes, one who presented with extensive local disease, and the other of meningeal carcinomatosis with local control of the primary tumor. No complications from GKS were noted. This initial experience suggests that GKS is a valuable treatment modality for the management of pineal region tumors. This technique offers excellent local tumor control and minimal patient morbidity, allowing for immediate use of systemic chemotherapy and/or conventional radiation if indicated.

Round Cell Tumors: Classification and Immunohistochemistry.

PubMed

Sharma, Shweta; Kamala, R; Nair, Divya; Ragavendra, T Raju; Mhatre, Swapnil; Sabharwal, Robin; Choudhury, Basanta Kumar; Rana, Vivek

2017-01-01

Round cell tumors as the name suggest are comprised round cells with increased nuclear-cytoplasmic ratio. This group of tumor includes entities such as peripheral neuroectodermal tumor, rhabdomyosarcoma, synovial sarcoma, non-Hodgkin's lymphoma, neuroblastoma, hepatoblastoma, Wilms' tumor, and desmoplastic small round cell tumor. These round cells tumors are characterized by typical histological pattern, immunohistochemical, and electron microscopic features that can help in differential diagnosis. The present article describes the classification and explains the histopathology and immunohistochemistry of some important round cell tumors.

Human Epidermal Growth Factor Receptor 2 (HER2) –Specific Chimeric Antigen Receptor–Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma

PubMed Central

Ahmed, Nabil; Brawley, Vita S.; Hegde, Meenakshi; Robertson, Catherine; Ghazi, Alexia; Gerken, Claudia; Liu, Enli; Dakhova, Olga; Ashoori, Aidin; Corder, Amanda; Gray, Tara; Wu, Meng-Fen; Liu, Hao; Hicks, John; Rainusso, Nino; Dotti, Gianpietro; Mei, Zhuyong; Grilley, Bambi; Gee, Adrian; Rooney, Cliona M.; Brenner, Malcolm K.; Heslop, Helen E.; Wels, Winfried S.; Wang, Lisa L.; Anderson, Peter; Gottschalk, Stephen

2015-01-01

Purpose The outcome for patients with metastatic or recurrent sarcoma remains poor. Adoptive therapy with tumor-directed T cells is an attractive therapeutic option but has never been evaluated in sarcoma. Patients and Methods We conducted a phase I/II clinical study in which patients with recurrent/refractory human epidermal growth factor receptor 2 (HER2) –positive sarcoma received escalating doses (1 × 104/m2 to 1 × 108/m2) of T cells expressing an HER2-specific chimeric antigen receptor with a CD28.ζ signaling domain (HER2-CAR T cells). Results We enrolled 19 patients with HER2-positive tumors (16 osteosarcomas, one Ewing sarcoma, one primitive neuroectodermal tumor, and one desmoplastic small round cell tumor). HER2-CAR T-cell infusions were well tolerated with no dose-limiting toxicity. At dose level 3 (1 × 105/m2) and above, we detected HER2-CAR T cells 3 hours after infusion by quantitative polymerase chain reaction in 14 of 16 patients. HER2-CAR T cells persisted for at least 6 weeks in seven of the nine evaluable patients who received greater than 1 × 106/m2 HER2-CAR T cells (P = .005). HER2-CAR T cells were detected at tumor sites of two of two patients examined. Of 17 evaluable patients, four had stable disease for 12 weeks to 14 months. Three of these patients had their tumor removed, with one showing ≥ 90% necrosis. The median overall survival of all 19 infused patients was 10.3 months (range, 5.1 to 29.1 months). Conclusion This first evaluation of the safety and efficacy of HER2-CAR T cells in patients with cancer shows the cells can persist for 6 weeks without evident toxicities, setting the stage for studies that combine HER2-CAR T cells with other immunomodulatory approaches to enhance their expansion and persistence. PMID:25800760

Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma.

PubMed

Ahmed, Nabil; Brawley, Vita S; Hegde, Meenakshi; Robertson, Catherine; Ghazi, Alexia; Gerken, Claudia; Liu, Enli; Dakhova, Olga; Ashoori, Aidin; Corder, Amanda; Gray, Tara; Wu, Meng-Fen; Liu, Hao; Hicks, John; Rainusso, Nino; Dotti, Gianpietro; Mei, Zhuyong; Grilley, Bambi; Gee, Adrian; Rooney, Cliona M; Brenner, Malcolm K; Heslop, Helen E; Wels, Winfried S; Wang, Lisa L; Anderson, Peter; Gottschalk, Stephen

2015-05-20

The outcome for patients with metastatic or recurrent sarcoma remains poor. Adoptive therapy with tumor-directed T cells is an attractive therapeutic option but has never been evaluated in sarcoma. We conducted a phase I/II clinical study in which patients with recurrent/refractory human epidermal growth factor receptor 2 (HER2) -positive sarcoma received escalating doses (1 × 10(4)/m(2) to 1 × 10(8)/m(2)) of T cells expressing an HER2-specific chimeric antigen receptor with a CD28.ζ signaling domain (HER2-CAR T cells). We enrolled 19 patients with HER2-positive tumors (16 osteosarcomas, one Ewing sarcoma, one primitive neuroectodermal tumor, and one desmoplastic small round cell tumor). HER2-CAR T-cell infusions were well tolerated with no dose-limiting toxicity. At dose level 3 (1 × 10(5)/m(2)) and above, we detected HER2-CAR T cells 3 hours after infusion by quantitative polymerase chain reaction in 14 of 16 patients. HER2-CAR T cells persisted for at least 6 weeks in seven of the nine evaluable patients who received greater than 1 × 10(6)/m(2) HER2-CAR T cells (P = .005). HER2-CAR T cells were detected at tumor sites of two of two patients examined. Of 17 evaluable patients, four had stable disease for 12 weeks to 14 months. Three of these patients had their tumor removed, with one showing ≥ 90% necrosis. The median overall survival of all 19 infused patients was 10.3 months (range, 5.1 to 29.1 months). This first evaluation of the safety and efficacy of HER2-CAR T cells in patients with cancer shows the cells can persist for 6 weeks without evident toxicities, setting the stage for studies that combine HER2-CAR T cells with other immunomodulatory approaches to enhance their expansion and persistence. © 2015 by American Society of Clinical Oncology.

New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.

PubMed

Sturm, Dominik; Orr, Brent A; Toprak, Umut H; Hovestadt, Volker; Jones, David T W; Capper, David; Sill, Martin; Buchhalter, Ivo; Northcott, Paul A; Leis, Irina; Ryzhova, Marina; Koelsche, Christian; Pfaff, Elke; Allen, Sariah J; Balasubramanian, Gnanaprakash; Worst, Barbara C; Pajtler, Kristian W; Brabetz, Sebastian; Johann, Pascal D; Sahm, Felix; Reimand, Jüri; Mackay, Alan; Carvalho, Diana M; Remke, Marc; Phillips, Joanna J; Perry, Arie; Cowdrey, Cynthia; Drissi, Rachid; Fouladi, Maryam; Giangaspero, Felice; Łastowska, Maria; Grajkowska, Wiesława; Scheurlen, Wolfram; Pietsch, Torsten; Hagel, Christian; Gojo, Johannes; Lötsch, Daniela; Berger, Walter; Slavc, Irene; Haberler, Christine; Jouvet, Anne; Holm, Stefan; Hofer, Silvia; Prinz, Marco; Keohane, Catherine; Fried, Iris; Mawrin, Christian; Scheie, David; Mobley, Bret C; Schniederjan, Matthew J; Santi, Mariarita; Buccoliero, Anna M; Dahiya, Sonika; Kramm, Christof M; von Bueren, André O; von Hoff, Katja; Rutkowski, Stefan; Herold-Mende, Christel; Frühwald, Michael C; Milde, Till; Hasselblatt, Martin; Wesseling, Pieter; Rößler, Jochen; Schüller, Ulrich; Ebinger, Martin; Schittenhelm, Jens; Frank, Stephan; Grobholz, Rainer; Vajtai, Istvan; Hans, Volkmar; Schneppenheim, Reinhard; Zitterbart, Karel; Collins, V Peter; Aronica, Eleonora; Varlet, Pascale; Puget, Stephanie; Dufour, Christelle; Grill, Jacques; Figarella-Branger, Dominique; Wolter, Marietta; Schuhmann, Martin U; Shalaby, Tarek; Grotzer, Michael; van Meter, Timothy; Monoranu, Camelia-Maria; Felsberg, Jörg; Reifenberger, Guido; Snuderl, Matija; Forrester, Lynn Ann; Koster, Jan; Versteeg, Rogier; Volckmann, Richard; van Sluis, Peter; Wolf, Stephan; Mikkelsen, Tom; Gajjar, Amar; Aldape, Kenneth; Moore, Andrew S; Taylor, Michael D; Jones, Chris; Jabado, Nada; Karajannis, Matthias A; Eils, Roland; Schlesner, Matthias; Lichter, Peter; von Deimling, Andreas; Pfister, Stefan M; Ellison, David W; Korshunov, Andrey; Kool, Marcel

2016-02-25

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors. Copyright © 2016 Elsevier Inc. All rights reserved.

Primary Ewing Sarcoma of the Thyroid—Eight Cases in a Decade: A Case Report and Literature Review

PubMed Central

Kabata, Paweł; Kaniuka-Jakubowska, Sonia; Kabata, Wanda; Lakomy, Joanna; Biernat, Wojciech; Sworczak, Krzysztof; Jaśkiewicz, Janusz; Świerblewski, Maciej

2017-01-01

Sarcomas represent less than 1% of all malignant tumors found in the thyroid. Of these, primary extraosseoussarcoma has been reported only a few times in the past decade. We present the case of a 34-year-old male who had a fast-growing hard mass in the lower left neck. FNA was inconclusive. Core needle biopsy revealed the diagnosis of an Ewing sarcoma/primitive neuroectodermal tumor. Mutation of EWSR1 was confirmed using the FISH method. Following treatment by neoadjuvant chemotherapy, we observed clinical, radiological, and finally histopathological remission. This was followed by a left-sided isthmolobectomy with unilateral cervical lymph node dissection by lateral lymphadenectomy, which revealed no residual disease. Posttreatment radiotherapy was administered but discontinued upon the patient’s request. After 18 months of observation, the patient had no recurrence or metastasis and required l-thyroxine supplementation. We discuss our case using a comparative literature review to the few other known case reports. PMID:29163353

Bag3-Induced Autophagy Is Associated with Degradation of JCV Oncoprotein, T-Ag

PubMed Central

Sariyer, Ilker Kudret; Merabova, Nana; Patel, Prem Kumer; Knezevic, Tijana; Rosati, Alessandra; Turco, Maria C.; Khalili, Kamel

2012-01-01

JC virus, JCV, is a human neurotropic polyomavirus whose replication in glial cells causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). In addition, JCV possesses oncogenic activity and expression of its transforming protein, large T-antigen (T-Ag), in several experimental animals induces tumors of neural origin. Further, the presence of JCV DNA and T-Ag have been repeatedly observed in several human malignant tissues including primitive neuroectodermal tumors and glioblastomas. Earlier studies have demonstrated that Bag3, a member of the Bcl-2-associated athanogene (Bag) family of proteins, which is implicated in autophagy and apoptosis, is downregulated upon JCV infection of glial cells and that JCV T-Ag is responsible for suppressing the activity of the BAG3 promoter. Here, we investigated the possible impact of Bag3 on T-Ag expression in JCV-infected human primary glial cells as well as in cells derived from T-Ag-induced medulloblastoma in transgenic animals. Results from these studies revealed that overexpression of Bag3 drastically decreases the level of T-Ag expression by inducing the autophagic degradation of the viral protein. Interestingly, this event leads to the inhibition of JCV infection of glial cells, suggesting that the reduced levels of T-antigen seen upon the overexpression of Bag3 has a biological impact on the viral lytic cycle. Results from protein-protein interaction studies showed that T-Ag and Bag3 physically interact with each other through the zinc-finger of T-Ag and the proline rich domains of Bag3, and this interaction is important for the autophagic degradation of T-Ag. Our observations open a new avenue of research for better understanding of virus-host interaction by investigating the interplay between T-Ag and Bag3, and their impact on the development of JCV-associated diseases. PMID:22984599

Bag3-induced autophagy is associated with degradation of JCV oncoprotein, T-Ag.

PubMed

Sariyer, Ilker Kudret; Merabova, Nana; Patel, Prem Kumer; Knezevic, Tijana; Rosati, Alessandra; Turco, Maria C; Khalili, Kamel

2012-01-01

JC virus, JCV, is a human neurotropic polyomavirus whose replication in glial cells causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). In addition, JCV possesses oncogenic activity and expression of its transforming protein, large T-antigen (T-Ag), in several experimental animals induces tumors of neural origin. Further, the presence of JCV DNA and T-Ag have been repeatedly observed in several human malignant tissues including primitive neuroectodermal tumors and glioblastomas. Earlier studies have demonstrated that Bag3, a member of the Bcl-2-associated athanogene (Bag) family of proteins, which is implicated in autophagy and apoptosis, is downregulated upon JCV infection of glial cells and that JCV T-Ag is responsible for suppressing the activity of the BAG3 promoter. Here, we investigated the possible impact of Bag3 on T-Ag expression in JCV-infected human primary glial cells as well as in cells derived from T-Ag-induced medulloblastoma in transgenic animals. Results from these studies revealed that overexpression of Bag3 drastically decreases the level of T-Ag expression by inducing the autophagic degradation of the viral protein. Interestingly, this event leads to the inhibition of JCV infection of glial cells, suggesting that the reduced levels of T-antigen seen upon the overexpression of Bag3 has a biological impact on the viral lytic cycle. Results from protein-protein interaction studies showed that T-Ag and Bag3 physically interact with each other through the zinc-finger of T-Ag and the proline rich domains of Bag3, and this interaction is important for the autophagic degradation of T-Ag. Our observations open a new avenue of research for better understanding of virus-host interaction by investigating the interplay between T-Ag and Bag3, and their impact on the development of JCV-associated diseases.

Surface Antigens Common to Mouse Cleavage Embryos and Primitive Teratocarcinoma Cells in Culture

PubMed Central

Artzt, Karen; Dubois, Philippe; Bennett, Dorothea; Condamine, Hubert; Babinet, Charles; Jacob, François

1973-01-01

Syngeneic antisera have been produced in mouse strain 129/Sv-CP males against the primitive cells of teratocarcinoma. These sera react specifically with the primitive cells and are negative on various types of differentiated teratoma cells derived from the same original tumor. They are negative on all other mouse cells tested, with the exception of male germ cells and cleavage-stage embryos. Thus, teratoma cells possess cell-surface antigens in common with normal cleavage-stage embryos. Images PMID:4355379

Multi-processor including data flow accelerator module

DOEpatents

Davidson, George S.; Pierce, Paul E.

1990-01-01

An accelerator module for a data flow computer includes an intelligent memory. The module is added to a multiprocessor arrangement and uses a shared tagged memory architecture in the data flow computer. The intelligent memory module assigns locations for holding data values in correspondence with arcs leading to a node in a data dependency graph. Each primitive computation is associated with a corresponding memory cell, including a number of slots for operands needed to execute a primitive computation, a primitive identifying pointer, and linking slots for distributing the result of the cell computation to other cells requiring that result as an operand. Circuitry is provided for utilizing tag bits to determine automatically when all operands required by a processor are available and for scheduling the primitive for execution in a queue. Each memory cell of the module may be associated with any of the primitives, and the particular primitive to be executed by the processor associated with the cell is identified by providing an index, such as the cell number for the primitive, to the primitive lookup table of starting addresses. The module thus serves to perform functions previously performed by a number of sections of data flow architectures and coexists with conventional shared memory therein. A multiprocessing system including the module operates in a hybrid mode, wherein the same processing modules are used to perform some processing in a sequential mode, under immediate control of an operating system, while performing other processing in a data flow mode.

Non-neural ectoderm is really neural: evolution of developmental patterning mechanisms in the non-neural ectoderm of chordates and the problem of sensory cell homologies.

PubMed

Holland, Linda Z

2005-07-15

In chordates, the ectoderm is divided into the neuroectoderm and the so-called non-neural ectoderm. In spite of its name, however, the non-neural ectoderm contains numerous sensory cells. Therefore, the term "non-neural" ectoderm should be replaced by "general ectoderm." At least in amphioxus and tunicates and possibly in vertebrates as well, both the neuroectoderm and the general ectoderm are patterned anterior/posteriorly by mechanisms involving retinoic acid and Hox genes. In amphioxus and tunicates the ectodermal sensory cells, which have a wide range of ciliary and microvillar configurations, are mostly primary neurons sending axons to the CNS, although a minority lack axons. In contrast, vertebrate mechanosensory cells, called hair cells, are all secondary neurons that lack axons and have a characteristic eccentric cilium adjacent to a group of microvilli of graded lengths. It has been highly controversial whether the ectodermal sensory cells in the oral siphons of adult tunicates are homologous to vertebrate hair cells. In some species of tunicates, these cells appear to be secondary neurons, and microvillar and ciliary configurations of some of these cells approach those of vertebrate hair cells. However, none of the tunicate cells has all the characteristics of a hair cell, and there is a high degree of variation among ectodermal sensory cells within and between different species. Thus, similarities between the ectodermal sensory cells of any one species of tunicate and craniate hair cells may well represent convergent evolution rather than homology. Copyright 2005 Wiley-Liss, Inc.

Engineered Herpes Simplex Viruses for the Treatment of Malignant Peripheral Nerve Sheath Tumors

DTIC Science & Technology

2015-11-01

lines). This is an entry receptor usually limited to lymphoid cells has not been previously identified in neuroectodermal tissue. Year 3: As a... innate and adaptive immune 327 response. However, resistance is common in vitro and therefore, to the extent that tumor cell lines 328 maintain the...Handgretinger R, et al. Innate immune 461 defense defines susceptibility of sarcoma cells to measles vaccine virus-based oncolysis. J Virol. 462 2013;87

Extraosseous Primary Intracranial Ewing Sarcoma/peripheral Primitive Neuroectodermal Tumor: Series of Seven Cases and Review of Literature

PubMed Central

Singh, Amit Kumar; Srivastava, Arun Kumar; Pal, Lily; Sardhara, Jayesh; Yadav, Rajan; Singh, Shalini; Bhaisora, Kamlesh Singh; Das, Kuntal Kanti; Mehrotra, Anant; Sahu, Rabi Narayan; Jaiswal, Awadhesh Kumar; Behari, Sanjay

2018-01-01

Background: The Ewing sarcoma peripheral PNET (ES-pPNET) is very rare small round cell tumour that involves the CNS as either a primary dural neoplasm or by direct extension from contiguous bone or soft tissue. Materials and Methods: Biopsy proven cases of intracranial ES/pPNET with orbital involvement operated during Jan 2010-Jan 2014 were retrospectively included and their clinical data, operative and histological findings were reviewed from institutional oncology register. Results: seven patients (4 males; 3 female) were studied with mean age at presentation of 13 years. Six patients had orbital involvement in one or other form. Surgical excision was gross total in five, near total in one, and subtotal in one patient. All patients received adjuvant therapy, only chemotherapy in 2, only Radiotherapy in four, both in one. MRI characteristics were studied in six patients. Four patients died with average survival of 33.2 months and three patients are having Progression free survival of average 23.3 months. Conclusions: The EWS-pPNET is very rare tumour and very poorly described in literature. These tumours are showing special predilection for the frontotemporal dura and erode through the flat bone of cranium like orbital roof and lateral wall of the orbit. These tumours are aggressive, multi compartmental, vascular and very rapidly growing, so missing or overlooking the primary symptoms of dural stretching/bony involvement leads to delay in management and poor outcome. PMID:29682023

Context-specific function of the LIM homeobox 1 transcription factor in head formation of the mouse embryo.

PubMed

Fossat, Nicolas; Ip, Chi Kin; Jones, Vanessa J; Studdert, Joshua B; Khoo, Poh-Lynn; Lewis, Samara L; Power, Melinda; Tourle, Karin; Loebel, David A F; Kwan, Kin Ming; Behringer, Richard R; Tam, Patrick P L

2015-06-01

Lhx1 encodes a LIM homeobox transcription factor that is expressed in the primitive streak, mesoderm and anterior mesendoderm of the mouse embryo. Using a conditional Lhx1 flox mutation and three different Cre deleters, we demonstrated that LHX1 is required in the anterior mesendoderm, but not in the mesoderm, for formation of the head. LHX1 enables the morphogenetic movement of cells that accompanies the formation of the anterior mesendoderm, in part through regulation of Pcdh7 expression. LHX1 also regulates, in the anterior mesendoderm, the transcription of genes encoding negative regulators of WNT signalling, such as Dkk1, Hesx1, Cer1 and Gsc. Embryos carrying mutations in Pcdh7, generated using CRISPR-Cas9 technology, and embryos without Lhx1 function specifically in the anterior mesendoderm displayed head defects that partially phenocopied the truncation defects of Lhx1-null mutants. Therefore, disruption of Lhx1-dependent movement of the anterior mesendoderm cells and failure to modulate WNT signalling both resulted in the truncation of head structures. Compound mutants of Lhx1, Dkk1 and Ctnnb1 show an enhanced head truncation phenotype, pointing to a functional link between LHX1 transcriptional activity and the regulation of WNT signalling. Collectively, these results provide comprehensive insight into the context-specific function of LHX1 in head formation: LHX1 enables the formation of the anterior mesendoderm that is instrumental for mediating the inductive interaction with the anterior neuroectoderm and LHX1 also regulates the expression of factors in the signalling cascade that modulate the level of WNT activity. © 2015. Published by The Company of Biologists Ltd.

A zebrafish transgenic model of Ewing's sarcoma reveals conserved mediators of EWS-FLI1 tumorigenesis.

PubMed

Leacock, Stefanie W; Basse, Audrey N; Chandler, Garvin L; Kirk, Anne M; Rakheja, Dinesh; Amatruda, James F

2012-01-01

Ewing's sarcoma, a malignant bone tumor of children and young adults, is a member of the small-round-blue-cell tumor family. Ewing's sarcoma family tumors (ESFTs), which include peripheral primitive neuroectodermal tumors (PNETs), are characterized by chromosomal translocations that generate fusions between the EWS gene and ETS-family transcription factors, most commonly FLI1. The EWS-FLI1 fusion oncoprotein represents an attractive therapeutic target for treatment of Ewing's sarcoma. The cell of origin of ESFT and the molecular mechanisms by which EWS-FLI1 mediates tumorigenesis remain unknown, and few animal models of Ewing's sarcoma exist. Here, we report the use of zebrafish as a vertebrate model of EWS-FLI1 function and tumorigenesis. Mosaic expression of the human EWS-FLI1 fusion protein in zebrafish caused the development of tumors with histology strongly resembling that of human Ewing's sarcoma. The incidence of tumors increased in a p53 mutant background, suggesting that the p53 pathway suppresses EWS-FLI1-driven tumorigenesis. Gene expression profiling of the zebrafish tumors defined a set of genes that might be regulated by EWS-FLI1, including the zebrafish ortholog of a crucial EWS-FLI1 target gene in humans. Stable zebrafish transgenic lines expressing EWS-FLI1 under the control of the heat-shock promoter exhibit altered embryonic development and defective convergence and extension, suggesting that EWS-FLI1 interacts with conserved developmental pathways. These results indicate that functional targets of EWS-FLI1 that mediate tumorigenesis are conserved from zebrafish to human and provide a novel context in which to study the function of this fusion oncogene.

[Primitive cutaneous Ewing's sarcoma: a diagnostic and therapeutic dilemma].

PubMed

Delaplace, M; Mélard, P; Perrinaud, A; Goré, C; Vergier, B; Machet, L

2011-05-01

Ewing's sarcoma (or peripheral neuroectodermal tumour) is generally found in bone tissue, and a primary dermal site is extremely rare. We report a case of primary cutaneous Ewing's sarcoma in a 21-year-old woman. A 21-year-old woman presented with a scapular lesion that had been slowly developing for one year. The 1-cm lesion was removed and histological examination showed proliferation of small round cells in the dermis. Immunostaining revealed cytoplasmic membrane expression of CD99 and a negative immunoprofile for other small round-cell tumors. Ewing's sarcoma fusion gene transcripts were detected using fluorescence in situ hybridization (FISH). A staging examination revealed no other abnormalities. It was decided to treat the lesion as for osseous Ewing's sarcoma with wide resection followed by systemic adjuvant chemotherapy. Cutaneous Ewing's sarcoma raises concerns about diagnosis and treatment. Owing to the non-specificity of its clinical presentation, histology and immunoprofile, diagnosis of superficial Ewing's sarcoma is difficult and numerous differential diagnoses must be considered. When dealing with a surface tumour, the diagnosis of cutaneous Ewing's sarcoma must be considered. CD99 immunostaining and molecular testing for evidence of EWSR1 rearrangement are useful investigations to confirm the diagnosis. Furthermore, modalities of treatment must be carefully discussed. Cutaneous Ewing's sarcoma is currently treated in the same way as osseous Ewing's sarcoma (wide surgical excision, adjuvant radiotherapy when surgical margins are unsatisfactory, systemic adjuvant chemotherapy, and, in some cases, bone marrow transplant). However, some studies show a more favourable prognosis for cutaneous Ewing's sarcoma than for osseous Ewing's sarcoma. We may thus ask whether such aggressive multimodal treatment is needed. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Dynamic association with donor cell filopodia and lipid-modification are essential features of Wnt8a during patterning of the zebrafish neuroectoderm.

PubMed

Luz, Marta; Spannl-Müller, Stephanie; Özhan, Günes; Kagermeier-Schenk, Birgit; Rhinn, Muriel; Weidinger, Gilbert; Brand, Michael

2014-01-01

Wnt proteins are conserved signaling molecules that regulate pattern formation during animal development. Many Wnt proteins are post-translationally modified by addition of lipid adducts. Wnt8a provides a crucial signal for patterning the anteroposterior axis of the developing neural plate in vertebrates. However, it is not clear how this protein propagates from its source, the blastoderm margin, to the target cells in the prospective neural plate, and how lipid-modifications might influence Wnt8a propagation and activity. We have dynamically imaged biologically active, fluorescently tagged Wnt8a in living zebrafish embryos. We find that Wnt8a localizes to membrane-associated, punctate structures in live tissue. In Wnt8a expressing cells, these puncta are found on filopodial cellular processes, from where the protein can be released. In addition, Wnt8a is found colocalized with Frizzled receptor-containing clusters on signal receiving cells. Combining in vitro and in vivo assays, we compare the roles of conserved Wnt8a residues in cell and non-cell-autonomous signaling activity and secretion. Non-signaling Wnt8 variants show these residues can regulate Wnt8a distribution in producing cell membranes and filopodia as well as in the receiving tissue. Together, our results show that Wnt8a forms dynamic clusters found on filopodial donor cell and on signal receiving cell membranes. Moreover, they demonstrate a differential requirement of conserved residues in Wnt8a protein for distribution in producing cells and receiving tissue and signaling activity during neuroectoderm patterning.

Dynamic Association with Donor Cell Filopodia and Lipid-Modification Are Essential Features of Wnt8a during Patterning of the Zebrafish Neuroectoderm

PubMed Central

Luz, Marta; Spannl-Müller, Stephanie; Özhan, Günes; Kagermeier-Schenk, Birgit; Rhinn, Muriel; Weidinger, Gilbert; Brand, Michael

2014-01-01

Background Wnt proteins are conserved signaling molecules that regulate pattern formation during animal development. Many Wnt proteins are post-translationally modified by addition of lipid adducts. Wnt8a provides a crucial signal for patterning the anteroposterior axis of the developing neural plate in vertebrates. However, it is not clear how this protein propagates from its source, the blastoderm margin, to the target cells in the prospective neural plate, and how lipid-modifications might influence Wnt8a propagation and activity. Results We have dynamically imaged biologically active, fluorescently tagged Wnt8a in living zebrafish embryos. We find that Wnt8a localizes to membrane-associated, punctate structures in live tissue. In Wnt8a expressing cells, these puncta are found on filopodial cellular processes, from where the protein can be released. In addition, Wnt8a is found colocalized with Frizzled receptor-containing clusters on signal receiving cells. Combining in vitro and in vivo assays, we compare the roles of conserved Wnt8a residues in cell and non-cell-autonomous signaling activity and secretion. Non-signaling Wnt8 variants show these residues can regulate Wnt8a distribution in producing cell membranes and filopodia as well as in the receiving tissue. Conclusions Together, our results show that Wnt8a forms dynamic clusters found on filopodial donor cell and on signal receiving cell membranes. Moreover, they demonstrate a differential requirement of conserved residues in Wnt8a protein for distribution in producing cells and receiving tissue and signaling activity during neuroectoderm patterning. PMID:24427298

The mevalonate pathway regulates primitive streak formation via protein farnesylation

PubMed Central

Okamoto-Uchida, Yoshimi; Yu, Ruoxing; Miyamura, Norio; Arima, Norie; Ishigami-Yuasa, Mari; Kagechika, Hiroyuki; Yoshida, Suguru; Hosoya, Takamitsu; Nawa, Makiko; Kasama, Takeshi; Asaoka, Yoichi; Alois, Reiner Wimmer; Elling, Ulrich; Penninger, Josef M.; Nishina, Sachiko; Azuma, Noriyuki; Nishina, Hiroshi

2016-01-01

The primitive streak in peri-implantation embryos forms the mesoderm and endoderm and controls cell differentiation. The metabolic cues regulating primitive streak formation remain largely unknown. Here we utilised a mouse embryonic stem (ES) cell differentiation system and a library of well-characterised drugs to identify these metabolic factors. We found that statins, which inhibit the mevalonate metabolic pathway, suppressed primitive streak formation in vitro and in vivo. Using metabolomics and pharmacologic approaches we identified the downstream signalling pathway of mevalonate and revealed that primitive streak formation requires protein farnesylation but not cholesterol synthesis. A tagging-via-substrate approach revealed that nuclear lamin B1 and small G proteins were farnesylated in embryoid bodies and important for primitive streak gene expression. In conclusion, protein farnesylation driven by the mevalonate pathway is a metabolic cue essential for primitive streak formation. PMID:27883036

A simple and efficient method for deriving neurospheres from bone marrow stromal cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang Qin; Mu Jun; Li Qi

2008-08-08

Bone marrow stromal cells (MSCs) can be differentiated into neuronal and glial-like cell types under appropriate experimental conditions. However, previously reported methods are complicated and involve the use of toxic reagents. Here, we present a simplified and nontoxic method for efficient conversion of rat MSCs into neurospheres that express the neuroectodermal marker nestin. These neurospheres can proliferate and differentiate into neuron, astrocyte, and oligodendrocyte phenotypes. We thus propose that MSCs are an emerging model cell for the treatment of a variety of neurological diseases.

Primitive erythropoiesis is regulated by miR-126 via nonhematopoietic Vcam-1+ cells.

PubMed

Sturgeon, Christopher M; Chicha, Laurie; Ditadi, Andrea; Zhou, Qinbo; McGrath, Kathleen E; Palis, James; Hammond, Scott M; Wang, Shusheng; Olson, Eric N; Keller, Gordon

2012-07-17

Primitive erythropoiesis defines the onset of hematopoiesis in the yolk sac of the early embryo and is initiated by the emergence of progenitors assayed as colony-forming cells (EryP-CFCs). EryP-CFCs are detected for only a narrow window during embryonic development, suggesting that both their initiation and termination are tightly controlled. Using the embryonic stem differentiation system to model primitive erythropoiesis, we found that miR-126 regulates the termination of EryP-CFC development. Analyses of miR-126 null embryos revealed that this miR also regulates EryP-CFCs in vivo. We identified vascular cell adhesion molecule-1 (Vcam-1) expressed by a mesenchymal cell population as a relevant target of miR-126. Interaction of EryP-CFCs with Vcam-1 accelerated their maturation to ßh1-globin(+) and Ter119(+) cells through a Src family kinase. These findings uncover a cell nonautonomous regulatory pathway for primitive erythropoiesis that may provide insight into the mechanism(s) controlling the developmental switch from primitive to definitive hematopoiesis. Copyright © 2012 Elsevier Inc. All rights reserved.

A morphological analysis of the transition between the embryonic primitive intestine and yolk sac in bovine embryos and fetuses.

PubMed

Mançanares, Celina A F; Leiser, Rudolf; Favaron, Phelipe O; Carvalho, Ana F; Oliveira, Vanessa C De; Santos, José M Dos; Ambrósio, Carlos E; Miglino, Maria A

2013-07-01

The yolk sac (YS) is the main source of embryonic nutrition during the period when the placenta has not yet formed. It is also responsible for hematopoiesis because the blood cells develop from it as part of the primitive embryonic circulation. The objective of this study was to characterize the transitional area between the YS and primitive gut using the techniques of light microscopy, transmission electron microscopy, and immunohistochemistry to detect populations of pluripotent cells by labeling with Oct4 antibody. In all investigated embryos, serial sections were made to permit the identification of this small, restricted area. We identified the YS connection with the primitive intestine and found that it is composed of many blood islands, which correspond to the vessels covered by vitelline and mesenchymal cells. We identified large numbers of hemangioblasts inside the vessels. The mesenchymal layer was thin and composed of elongated cells, and the vitelline endodermal membrane was composed of large, mono- or binucleated cells. The epithelium of the primitive intestine comprised stratified columnar cells and undifferentiated mesenchymal cells. The transitional area between the YS and the primitive intestine was very thin and composed of cells with irregular shapes, which formed a delicate lumen containing hemangioblasts. In the mesenchyme of the transitional area, there were a considerable number of small vessels containing hemangioblasts. Using Oct4 as a primary antibody, we identified positive cells in the metanephros, primordial gonad, and hepatic parenchyma as well as in YS cells, suggesting that these regions contain populations of pluripotent cells. Copyright © 2013 Wiley Periodicals, Inc.

Antigen tissue distribution of Avian bornavirus (ABV) in psittacine birds with natural spontaneous proventricular dilatation disease and ABV genotype 1 infection.

PubMed

Wünschmann, Arno; Honkavuori, Kirsi; Briese, Thomas; Lipkin, W Ian; Shivers, Jan; Armien, Aníbal G

2011-07-01

Tissues of 10 psittacines from aviary 1 ("case birds") and 5 psittacines from different aviaries were investigated for the presence of Avian bornavirus (ABV) antigen by immunohistochemistry using a polyclonal serum specific for the viral nucleocapsid (N) protein. Seven of 10 case birds had clinical signs, and necropsy findings consistent with proventricular dilatation disease (PDD) while 3 case birds and the 5 birds from other aviaries did not exhibit signs and lesions of this disease. In birds with clinical signs of PDD, ABV antigen was largely limited to neuroectodermal cells including neurons, astroglia, and ependymal cells of the central nervous system, neurons of the peripheral nervous system, and adrenal cells. ABV antigen was present in the nuclei and cytoplasm of infected cells. In 2 case birds that lacked signs and lesions of PDD, viral antigen had a more widespread distribution and was present in nuclei and cytoplasm of epithelial cells of the alimentary and urogenital tract, retina, heart, skeletal muscle, and skin in addition to the mentioned neuroectodermal cells. ABV RNA was identified by reverse transcription polymerase chain reaction (RT-PCR) in tissues of all 7 case birds available for testing from aviary 1, including 4 birds with PDD lesions and the 3 birds without PDD lesions. Sequencing and phylogenetic analysis indicated the presence of ABV genotype 1 in all cases. Findings further substantiate a role of ABV in PDD of psittacine bird species.

Antigen tissue distribution of Avian bornavirus (ABV) in psittacine birds with natural spontaneous proventricular dilatation disease and ABV genotype 1 infection

PubMed Central

Wünschmann, Arno; Honkavuori, Kirsi; Briese, Thomas; Lipkin, W. Ian; Shivers, Jan; Armien, Aníbal G.

2014-01-01

Tissues of 10 psittacines from aviary 1 (“case birds”) and 5 psittacines from different aviaries were investigated for the presence of Avian bornavirus (ABV) antigen by immunohistochemistry using a polyclonal serum specific for the viral nucleocapsid (N) protein. Seven of 10 case birds had clinical signs, and necropsy findings consistent with proventricular dilatation disease (PDD) while 3 case birds and the 5 birds from other aviaries did not exhibit signs and lesions of this disease. In birds with clinical signs of PDD, ABV antigen was largely limited to neuroectodermal cells including neurons, astroglia, and ependymal cells of the central nervous system, neurons of the peripheral nervous system, and adrenal cells. ABV antigen was present in the nuclei and cytoplasm of infected cells. In 2 case birds that lacked signs and lesions of PDD, viral antigen had a more widespread distribution and was present in nuclei and cytoplasm of epithelial cells of the alimentary and urogenital tract, retina, heart, skeletal muscle, and skin in addition to the mentioned neuroectodermal cells. ABV RNA was identified by reverse transcription polymerase chain reaction (RT-PCR) in tissues of all 7 case birds available for testing from aviary 1, including 4 birds with PDD lesions and the 3 birds without PDD lesions. Sequencing and phylogenetic analysis indicated the presence of ABV genotype 1 in all cases. Findings further substantiate a role of ABV in PDD of psittacine bird species. PMID:21908314

Cytogenetically confirmed primary Ewing's sarcoma of the pancreas.

PubMed

Golhar, Ankush; Ray, Samrat; Haugk, Beate; Singhvi, Suresh Kumar

2017-05-04

Ewing's sarcoma is a highly aggressive malignant tumour most commonly affecting long bones in children and adolescents. It is part of the Ewing's sarcoma family of tumours (ESFTs) that also include peripheral primitive neuroectodermal tumour and Askin's tumours. ESFTs share common cytogenetic aberrations, antigenic profiles and proto-oncogene expression with an overall similar clinical course. In 99% of ESFTs, genetic translocation with molecular fusion involves the EWSR1 gene on 22q12. Approximately 30% of ESFTs are extraosseous, most commonly occurring in the soft tissues of extremities, pelvis, retroperitoneum and chest wall. Primary presentation in solid organs is very rare but has been described in multiple sites including the pancreas. Accurate diagnosis of a Ewing's sarcoma in a solid organ is critical in facilitating correct treatment. We report the case of a 17-year-old girl with cytogenetically confirmed primary pancreatic Ewing's sarcoma and provide a brief review of the published literature. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Protective, elective lung irradiation in non-metastatic Ewing's sarcoma.

PubMed

Marinova, L; Hristozova, I; Mihaylova, I; Perenovska, P

2015-07-01

Ewing's sarcoma in childhood is a disease from family of the peripheral primitive neuroectodermal tumours. For a period of 16 y (1984-2000), 34 children with Ewing's sarcoma were treated and followed in our department. Twenty-seven of these patients were without distant metastases. Complex treatment was applied to all these patients-chemotherapy VACA (vincristine, actinomycin D, cyclophosphamide, adriamycin), local radiotherapy to a total dose of 50-56 Gy +/- surgery. After, a local tumour control was achieved in 11 children with non-metastatic Ewing's sarcoma, elective whole lung irradiation to a total dose of 12-15 Gy was applied. Our experience in these 11 patients with non-metastatic Ewing's sarcoma, in whom elective lung irradiation was applied, showed significant reduction in the lung metastases, improved free of disease survival and overall survival. The achieved good treatment results necessitate extending this treatment approach through defining the risk groups of patients, suitable for elective lung radiotherapy combined with chemotherapy in non-metastatic Ewing's sarcoma. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Embryonal tumor with abundant neuropil and true rosettes: an autopsy case-based update and review of the literature.

PubMed

Adamek, Dariusz; Sofowora, Kolawole D; Cwiklinska, Magdalena; Herman-Sucharska, Izabela; Kwiatkowski, Stanislaw

2013-05-01

Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a rare subtype of primitive neuroectodermal tumors first reported in 2000. It is rare among the group of embryonal central nervous system tumors with approximately 50 reported cases. ETANTR has been suggested to be a separate entity among this group of tumors. Herein, we present only the second autopsy case of ETANTR, which occurred in a 17-month-old boy, and was located in the brainstem. The tumor was inoperable, and despite chemotherapy, the child died 3 months after initial hospitalization. A brain only autopsy was performed. Neuropathological and neuroimaging examinations suggest ETANTR grew by expansion rather than invasion distorting anatomical structures of the posterior fossa. We suggest that the characteristic histopathological picture of the tumor is the result of multifocal and dispersed germinative activity surrounded by mature neuropil-like areas. ETANTR is a pediatric tumor occurring in children under 4 with a significantly poor prognosis with more cases and research required to characterize this rare embryonal tumor.

The role of immunohistochemistry in the analysis of the spectrum of small round cell tumours at a tertiary care centre.

PubMed

D'cruze, Lawrence; Dutta, Ruma; Rao, Shalinee; R, Anuradha; Varadarajan, Suresh; Kuruvilla, Sarah

2013-07-01

The term, "Small Round - Cell Tumours" (SRCT) describes a group of highly aggressive malignant neoplasms which are composed predominantly of small and monotonous undifferentiated cells with high nucleocytoplasmic ratios. Immunohistochemistry (IHC) plays a crucial role in catagorizing the small round - cell tumours. This study was done to analyse the spectrum of small round cell tumours over a period of five years at a tertiary care centre and to study the relevance of immunohistochemistry in making precise diagnoses of the small round cell tumours. Formalin - fixed, paraffin - embedded sections of tumours which were diagnosed as small round cell tumours on small biopsies and resected specimens were retrieved from the files of the Department of Pathology of Sri Ramachandra Medical College and Research institute, in the period from January 2005 to December 2009. This study was confined to the bone and the soft tissues. Decalcification was performed on the bony tissues before the routine processing was done. The patients belonging to all age groups were included in this study. The small round cell tumours of the bone marrow, the spleen and the lymph node was excluded from our study. Immunohistochemical stains were performed to differentiate and categorise the small round blue cell tumours. The immunomarkers which were utilised in this study included CD45/LCA (the lymphocyte common antigen), CD20, CD3, CD99 (cluster of differentiation 99 also known as MIC2), desmin, EMA (epithelial membrane antigen), CK(cytokeratin), synaptophysin, chromogranin and GFAP (Glial fibrillary acidic protein). Forty three cases of small round cell tumours were analysed, which included 19 cases of NHL (non Hodgkin's lymphoma), 6 cases of Ewing/PNETs (primitive neuroectodermal tumours), 3 cases of atypical carcinoid, 3 cases of olfactory neuroblastoma, 2 cases each of rhabdomyosarcoma, Wilms tumour, neuroblastoma and synovial sarcoma and 1 case each of small cell osteosarcoma, small (oat) cell carcinoma, medulloblastoma and hepatoblastoma. By using a panel of monoclonal antibodies, we could arrive at a final diagnosis for all the 40 cases in which immunohistochemistry was performed. Our study showed that the use of immunohistochemistry was extremely beneficial. A majority of the small round cell tumours occurred between the ages of 15-45 years and the most common small round cell tumour was Non-Hodgkins lymphoma (extra lymphoreticular).

Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours

PubMed Central

2012-01-01

Background Ewing sarcoma/PNET is managed with treatment paradigms involving combinations of chemotherapy, surgery, and sometimes radiation. Although the 5-year survival rate of non-metastatic disease approaches 70%, those cases that are metastatic and those that recur have 5-year survival rates of less than 20%. Molecularly targeted treatments offer the potential to further improve treatment outcomes. Methods A PUBMED search was performed from 1997 to 2011. Published literature that included the topic of the Ewing sarcoma/PNET was also referenced. Results Insulin-like growth factor-1 receptor (IGF-1R) antagonists have demonstrated modest single agent efficacy in phase I/II clinical trials in Ewing sarcoma/PNET, but have a strong preclinical rationale. Based on in vitro and animal data, treatment using antisense RNA and cDNA oligonucleotides directed at silencing the EWS-FLI chimera that occurs in most Ewing sarcoma/PNET may have potential therapeutic importance. However drug delivery and degradation problems may limit this therapeutic approach. Protein-protein interactions can be targeted by inhibition of RNA helicase A, which binds to EWS/FLI as part of the transcriptional complex. Tumour necrosis factor related apoptosis inducing ligand induction using interferon has been used in preclinical models. Interferons may be incorporated into future chemotherapeutic treatment paradigms. Histone deacetylase inhibitors can restore TGF-β receptor II allowing TFF-β signalling, which appears to inhibit growth of Ewing sarcoma/PNET cell lines in vitro. Immunotherapy using allogeneic natural killer cells has activity in Ewing sarcoma/PNET cell lines and xenograft models. Finally, cyclin dependent kinase inhibitors such as flavopiridol may be clinically efficacious in relapsed Ewing sarcoma/PNET. Conclusion Preclinical evidence exists that targeted therapeutics may be efficacious in the ESFT. IGF-1R antagonists have demonstrated efficacy in phase I/II clinical trials, although predicting responses remains a challenge. The future treatment of Ewing sarcoma/PNET is likely to be improved by these scientific advances. PMID:22587874

Fine structures of embryonic discs of in vivo post-hatching porcine blastocysts at the pre-primitive streak stage.

PubMed

Xia, P; Liu, Z; Qin, P

2011-04-01

To date, reports about the ultrastructure of porcine embryonic discs have not shown details of the primitive streak. The main objective of this study was to examine the ultrastructure of interior and exterior embryonic discs in porcine in vivo blastocysts with diameters of 1, 3 and 9 mm using scanning electron microscopy and transmission electron microscopy. For the first time, we revealed the ultrastructure of the unusual group of cells in the pre-primitive streak area of embryonic discs. The cells were 1-2 μm in diameter, had high electron density and contained abundant, free ribosomes and endoplasmic reticulum. These primitive streak cells could represent original embryonic stem cells or represent a stem cell niche. The results also showed three types of cells on the exterior surface of the embryonic discs. Moreover, our results provided morphological evidence of condensed nuclei in the smooth cells on the surface of the embryonic disc. © 2010 Blackwell Verlag GmbH.

[Novel concepts in biology of diffuse endocrine system: results and future investigations].

PubMed

Iaglov, V V; Iaglova, N V

2012-01-01

Diffuse endocrine system is a largest part of endocrine system of vertebrates. Recend findings showed that DES-cells are not neuroectodermal but have ectodermal, mesodermal, and entodermal ontogeny. The article reviews novel concept of diffuse endocrine system anatomy and physiology, functional role of DES hormones and poorly investigated aspects like DES-cell morphology, hormones secretion in normal and pathologic conditions. Further research of diffuse endocrine system has a great significance for biochemistry, morphology, and clinical medicine.

Prostaglandin E2 alters Wnt-dependent migration and proliferation in neuroectodermal stem cells: implications for autism spectrum disorders

PubMed Central

2014-01-01

Prostaglandin E2 (PGE2) is a natural lipid-derived molecule that is involved in important physiological functions. Abnormal PGE2 signalling has been associated with pathologies of the nervous system. Previous studies provide evidence for the interaction of PGE2 and canonical Wnt signalling pathways in non-neuronal cells. Since the Wnt pathway is crucial in the development and organization of the brain, the main goal of this study is to determine whether collaboration between these pathways exists in neuronal cell types. We report that PGE2 interacts with canonical Wnt signalling through PKA and PI-3K in neuroectodermal (NE-4C) stem cells. We used time-lapse microscopy to determine that PGE2 increases the final distance from origin, path length travelled, and the average speed of migration in Wnt-activated cells. Furthermore, PGE2 alters distinct cellular phenotypes that are characteristic of Wnt-induced NE-4C cells, which corresponds to the modified splitting behaviour of the cells. We also found that in Wnt-induced cells the level of β-catenin protein was increased and the expression levels of Wnt-target genes (Ctnnb1, Ptgs2, Ccnd1, Mmp9) was significantly upregulated in response to PGE2 treatment. This confirms that PGE2 activated the canonical Wnt signalling pathway. Furthermore, the upregulated genes have been previously associated with ASD. Our findings show, for the first time, evidence for cross-talk between PGE2 and Wnt signalling in neuronal cells, where PKA and PI-3K might act as mediators between the two pathways. Given the importance of PGE2 and Wnt signalling in prenatal development of the nervous system, our study provides insight into how interaction between these two pathways may influence neurodevelopment. PMID:24656144

Prostaglandin E2 alters Wnt-dependent migration and proliferation in neuroectodermal stem cells: implications for autism spectrum disorders.

PubMed

Wong, Christine T; Ahmad, Eizaaz; Li, Hongyan; Crawford, Dorota A

2014-03-23

Prostaglandin E2 (PGE2) is a natural lipid-derived molecule that is involved in important physiological functions. Abnormal PGE2 signalling has been associated with pathologies of the nervous system. Previous studies provide evidence for the interaction of PGE2 and canonical Wnt signalling pathways in non-neuronal cells. Since the Wnt pathway is crucial in the development and organization of the brain, the main goal of this study is to determine whether collaboration between these pathways exists in neuronal cell types. We report that PGE2 interacts with canonical Wnt signalling through PKA and PI-3K in neuroectodermal (NE-4C) stem cells. We used time-lapse microscopy to determine that PGE2 increases the final distance from origin, path length travelled, and the average speed of migration in Wnt-activated cells. Furthermore, PGE2 alters distinct cellular phenotypes that are characteristic of Wnt-induced NE-4C cells, which corresponds to the modified splitting behaviour of the cells. We also found that in Wnt-induced cells the level of β-catenin protein was increased and the expression levels of Wnt-target genes (Ctnnb1, Ptgs2, Ccnd1, Mmp9) was significantly upregulated in response to PGE2 treatment. This confirms that PGE2 activated the canonical Wnt signalling pathway. Furthermore, the upregulated genes have been previously associated with ASD. Our findings show, for the first time, evidence for cross-talk between PGE2 and Wnt signalling in neuronal cells, where PKA and PI-3K might act as mediators between the two pathways. Given the importance of PGE2 and Wnt signalling in prenatal development of the nervous system, our study provides insight into how interaction between these two pathways may influence neurodevelopment.

Purification of zebrafish erythrocytes as a means of identifying a novel regulator of haematopoiesis.

PubMed

Kulkeaw, Kasem; Inoue, Tomoko; Ishitani, Tohru; Nakanishi, Yoichi; Zon, Leonard I; Sugiyama, Daisuke

2018-02-01

Zebrafish embryos are useful to study haematopoietic gene function in vertebrates, although lack of antibodies to zebrafish proteins has limited the purification of specific cell populations. Here, we purified primitive zebrafish erythrocytes using 1, 5-bis{[2-(di-methylamino)ethyl]amino}-4, 8-dihydroxyanthracene-9, 10-dione (DRAQ5 TM ), a DNA-staining fluorescent dye. At 48-h post-fertilization, we sorted small-sized cells from embryos using forward scatter and found that they consisted of DRAQ5 high and DRAQ5 low populations. DRAQ5 high cells contained haemoglobin, lacked myeloperoxidase activity and expressed high levels of embryonic globin (hbae3 and hbbe1.1) mRNA, all characteristics of primitive erythrocytes. Following DRAQ5 TM analysis of gata1:dsRed transgenic embryos, we purified primitive DRAQ5 high dsRed+ erythrocytes from haematopoietic progenitor cells. Using this method, we identified docking protein 2 (Dok2) as functioning in differentiation of primitive erythrocytes. We conclude that DRAQ5 TM -based flow cytometry enables purification of primitive zebrafish erythrocytes. © 2017 John Wiley & Sons Ltd.

EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation

PubMed Central

Richter, Günther H. S.; Plehm, Stephanie; Fasan, Annette; Rössler, Sabine; Unland, Rebekka; Bennani-Baiti, Idriss M.; Hotfilder, Marc; Löwel, Diana; von Luettichau, Irene; Mossbrugger, Ilona; Quintanilla-Martinez, Leticia; Kovar, Heinrich; Staege, Martin S.; Müller-Tidow, Carsten; Burdach, Stefan

2009-01-01

Ewing tumors (ET) are highly malignant, localized in bone or soft tissue, and are molecularly defined by ews/ets translocations. DNA microarray analysis revealed a relationship of ET to both endothelium and fetal neural crest. We identified expression of histone methyltransferase enhancer of Zeste, Drosophila, Homolog 2 (EZH2) to be increased in ET. Suppressive activity of EZH2 maintains stemness in normal and malignant cells. Here, we found EWS/FLI1 bound to the EZH2 promoter in vivo, and induced EZH2 expression in ET and mesenchymal stem cells. Down-regulation of EZH2 by RNA interference in ET suppressed oncogenic transformation by inhibiting clonogenicity in vitro. Similarly, tumor development and metastasis was suppressed in immunodeficient Rag2−/−γC−/− mice. EZH2-mediated gene silencing was shown to be dependent on histone deacetylase (HDAC) activity. Subsequent microarray analysis of EZH2 knock down, HDAC-inhibitor treatment and confirmation in independent assays revealed an undifferentiated phenotype maintained by EZH2 in ET. EZH2 regulated stemness genes such as nerve growth factor receptor (NGFR), as well as genes involved in neuroectodermal and endothelial differentiation (EMP1, EPHB2, GFAP, and GAP43). These data suggest that EZH2 might have a central role in ET pathology by shaping the oncogenicity and stem cell phenotype of this tumor. PMID:19289832

Incidence and survival of children with central nervous system primitive tumors in the French National Registry of Childhood Solid Tumors.

PubMed

Desandes, Emmanuel; Guissou, Sandra; Chastagner, Pascal; Lacour, Brigitte

2014-07-01

Central nervous system (CNS) tumors are the second most common childhood malignancy. The French National Registry of Childhood Solid Tumors (NRCST) makes it possible to describe this variety of distinct tumor types and to provide incidence and survival data in France on a nationwide basis. All children aged 0-14 years, who were registered with a primary CNS tumor in the NRCST of France between 2000 and 2008, were identified. Tumors were classified according to the International Classification of Childhood Cancer, third edition. Approximately 57% of pediatric CNS tumors were gliomas, with astrocytomas of the pilocytic type predominating. Distributions of subtypes by age showed that primitive neuroectodermal tumors and ependymomas mainly occurred in children aged <5 years. The mean annual incidence rate of CNS tumors was 39 per million. No statistically significant change in time trends of incidence rate was observed during 2000-2008. For all tumors combined, overall survival was 84.8% (95% CI, 83.7%-85.9%) at 1 year and 72.9% (95% CI, 71.5%-74.3%) at 5 years. Survival time trends were studied in a multivariate analysis observing a reduction in the risk of death in periods of diagnosis 2003-2005 (HR = 0.8; 95% CI, 0.7–0.9) and 2006-2008 (HR = 0.7; 95% CI, 0.6-0.9) compared with 2000-2002. The stable incidence rates during the last 10 years could indicate that major changes in environmental risk factors are unlikely, but the ongoing need for population-based surveillance remains relevant. Results indicate a positive trend in the survival probability still persistent in the 2000s.

BMPs regulate msx gene expression in the dorsal neuroectoderm of Drosophila and vertebrates by distinct mechanisms.

PubMed

Esteves, Francisco F; Springhorn, Alexander; Kague, Erika; Taylor, Erika; Pyrowolakis, George; Fisher, Shannon; Bier, Ethan

2014-09-01

In a broad variety of bilaterian species the trunk central nervous system (CNS) derives from three primary rows of neuroblasts. The fates of these neural progenitor cells are determined in part by three conserved transcription factors: vnd/nkx2.2, ind/gsh and msh/msx in Drosophila melanogaster/vertebrates, which are expressed in corresponding non-overlapping patterns along the dorsal-ventral axis. While this conserved suite of "neural identity" gene expression strongly suggests a common ancestral origin for the patterning systems, it is unclear whether the original regulatory mechanisms establishing these patterns have been similarly conserved during evolution. In Drosophila, genetic evidence suggests that Bone Morphogenetic Proteins (BMPs) act in a dosage-dependent fashion to repress expression of neural identity genes. BMPs also play a dose-dependent role in patterning the dorsal and lateral regions of the vertebrate CNS, however, the mechanism by which they achieve such patterning has not yet been clearly established. In this report, we examine the mechanisms by which BMPs act on cis-regulatory modules (CRMs) that control localized expression of the Drosophila msh and zebrafish (Danio rerio) msxB in the dorsal central nervous system (CNS). Our analysis suggests that BMPs act differently in these organisms to regulate similar patterns of gene expression in the neuroectoderm: repressing msh expression in Drosophila, while activating msxB expression in the zebrafish. These findings suggest that the mechanisms by which the BMP gradient patterns the dorsal neuroectoderm have reversed since the divergence of these two ancient lineages.

BMPs Regulate msx Gene Expression in the Dorsal Neuroectoderm of Drosophila and Vertebrates by Distinct Mechanisms

PubMed Central

Esteves, Francisco F.; Taylor, Erika; Pyrowolakis, George; Fisher, Shannon; Bier, Ethan

2014-01-01

In a broad variety of bilaterian species the trunk central nervous system (CNS) derives from three primary rows of neuroblasts. The fates of these neural progenitor cells are determined in part by three conserved transcription factors: vnd/nkx2.2, ind/gsh and msh/msx in Drosophila melanogaster/vertebrates, which are expressed in corresponding non-overlapping patterns along the dorsal-ventral axis. While this conserved suite of “neural identity” gene expression strongly suggests a common ancestral origin for the patterning systems, it is unclear whether the original regulatory mechanisms establishing these patterns have been similarly conserved during evolution. In Drosophila, genetic evidence suggests that Bone Morphogenetic Proteins (BMPs) act in a dosage-dependent fashion to repress expression of neural identity genes. BMPs also play a dose-dependent role in patterning the dorsal and lateral regions of the vertebrate CNS, however, the mechanism by which they achieve such patterning has not yet been clearly established. In this report, we examine the mechanisms by which BMPs act on cis-regulatory modules (CRMs) that control localized expression of the Drosophila msh and zebrafish (Danio rerio) msxB in the dorsal central nervous system (CNS). Our analysis suggests that BMPs act differently in these organisms to regulate similar patterns of gene expression in the neuroectoderm: repressing msh expression in Drosophila, while activating msxB expression in the zebrafish. These findings suggest that the mechanisms by which the BMP gradient patterns the dorsal neuroectoderm have reversed since the divergence of these two ancient lineages. PMID:25210771

[Outstanding problems of normal and pathological morphology of the diffuse endocrine system].

PubMed

Iaglov, V V; Iaglova, N V

2011-01-01

The diffuse endocrine system (DES)--a mosaic-cellular endoepithelial gland--is the biggest part of the human endocrine system. Scientists used to consider cells of DES as neuroectodermal. According to modem data cells of DES are different cytogenetic types because they develop from the different embryonic blastophyllum. So that any hormone-active tumors originated from DES of the digestive, respiratory and urogenital system shouldn't be considered as neuroendocrinal tumors. The basic problems of DES morphology and pathology are the creation of scientifically substantiated histogenetic classification of DES tumors.

MicroRNA Signatures as Biomarkers and Therapeutic Target for CNS Embryonal Tumors: The Pros and the Cons

PubMed Central

Shalaby, Tarek; Fiaschetti, Giulio; Baumgartner, Martin; Grotzer, Michael A.

2014-01-01

Embryonal tumors of the central nervous system represent a heterogeneous group of childhood cancers with an unknown pathogenesis; diagnosis, on the basis of histological appearance alone, is controversial and patients’ response to therapy is difficult to predict. They encompass medulloblastoma, atypical teratoid/rhabdoid tumors and a group of primitive neuroectodermal tumors. All are aggressive tumors with the tendency to disseminate throughout the central nervous system. The large amount of genomic and molecular data generated over the last 5–10 years encourages optimism that new molecular targets will soon improve outcomes. Recent neurobiological studies have uncovered the key role of microRNAs (miRNAs) in embryonal tumors biology and their potential use as biomarkers is increasingly being recognized and investigated. However the successful use of microRNAs as reliable biomarkers for the detection and management of pediatric brain tumors represents a substantial challenge. This review debates the importance of miRNAs in the biology of central nervous systemembryonal tumors focusing on medulloblastoma and atypical teratoid/rhabdoid tumors and highlights the advantages as well as the limitations of their prospective application as biomarkers and candidates for molecular therapeutic targets. PMID:25421247

A case-control study of childhood brain tumors and fathers' hobbies: a Children's Oncology Group study.

PubMed

Rosso, Andrea L; Hovinga, Mary E; Rorke-Adams, Lucy B; Spector, Logan G; Bunin, Greta R

2008-12-01

A comprehensive case-control study was conducted to evaluate parental risk factors for medulloblastoma (MB) and primitive neuroectodermal tumor (PNET). This analysis was conducted to evaluate associations between fathers' hobbies and risk of their children developing MB/PNET. The hobbies chosen for study were those with similar exposures as occupations associated with childhood cancers. Cases were 318 subjects under six years of age at diagnosis between 1991 and 1997 and registered with the Children's Cancer Group. An equal number of controls were selected through random digit dialing and individually matched to cases. In multivariate analyses, a significant association was seen for lawn care with pesticides [during pregnancy: odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.5; after birth: OR = 1.8, 95% CI: 1.2, 2.8] and a weak association was seen for stripping paint [during pregnancy: OR = 1.4, 95% CI: 0.8, 2.6; after birth: OR = 1.4, 95% CI: 0.7, 2.6]. This study suggests that household exposures from hobbies, particularly pesticides, may increase risk of MB/PNET in children; previous research has been mostly limited to occupational exposures.

A CASE-CONTROL STUDY OF CHILDHOOD BRAIN TUMORS AND FATHERS’ HOBBIES — A CHILDREN’S ONCOLOGY GROUP STUDY

PubMed Central

Rosso, Andrea L.; Hovinga, Mary E.; Rorke-Adams, Lucy B.; Spector, Logan G.; Bunin, Greta R.

2009-01-01

Objective A comprehensive case-control study was conducted to evaluate parental risk factors for medulloblastoma (MB) and primitive neuroectodermal tumor (PNET). This analysis was conducted to evaluate associations between fathers’ hobbies and risk of their children developing MB/PNET. The hobbies chosen for study were those with similar exposures as occupations associated with childhood cancers. Methods Cases were 318 subjects under 6 years of age at diagnosis between 1991-1997 and registered with the Children’s Cancer Group. An equal number of controls were selected through random digit dialing and individually matched to cases. Results In multivariate analyses, a significant association was seen for lawn care with pesticides [during pregnancy: odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.5; after birth: OR = 1.8, 95% CI: 1.2, 2.8] and a weak association was seen for stripping paint [during pregnancy: OR = 1.4, 95% CI: 0.8, 2.6; after birth: OR = 1.4, 95% CI: 0.7, 2.6]. Conclusions This study suggests that household exposures from hobbies, particularly pesticides, may increase risk of MB/PNET in children; previous research has been mostly limited to occupational exposures. PMID:18560982

The effect of Bcr-Abl protein tyrosine kinase on maturation and proliferation of primitive haematopoietic cells.

PubMed Central

Buckle, A. M.; Mottram, R.; Pierce, A.; Lucas, G. S.; Russell, N.; Miyan, J. A.; Whetton, A. D.

2000-01-01

BACKGROUND: Chronic Myeloid Leukaemia (CML) is characterised by the chromosomal translocation resulting in expression of the Bcr-Abl protein tyrosine kinase (PTK) in early stem cells and their progeny. However the precise nature of Bcr-Abl effects in primitive CML stem cells remains a matter of active debate. MATERIALS AND METHODS: Extremely primitive Bcr-Abl fusion positive cells were purified from patients with CML using multiparameter flow cytometric analysis of CD34, Thy, and lineage marker (Lin) expression, plus rhodamine-123 (Rh-123) brightness. Progenitor cells of increasing maturity were examined for cycling status by flow cytometry and their proliferative status directly correlated with cell phenotype. The activation status of a key transcription factor, signal transducers and activators of transcription (STAT-5), was also analyzed by immunocytochemistry. RESULTS: The most primitive stem cells currently defined (CD34+Lin-Thy+ Rh-1231o) were present as a lower proportion of the stem cell compartment (CD34+Lin-) of CML patients at presentation than of normal individuals (2.3% +/- 0.4 compared with 5.1% +/- 0.6 respectively). Conversely there was a significantly higher proportion of the more mature cells (CD34+Lin-Thy-Rh-123 hi) in CML patients than in normal individuals (79.3 +/- 1.8 compared with 70.9 +/- 3.3). No primitive subpopulation of CML CD34+Lin- cells was cycling to a significantly greater degree than cells from normal donors, in fact, late progenitor cells (CD34+Lin+) were cycling significantly less in CML samples than normal samples. STAT5, however, was observed to be activated in CML cells. CONCLUSIONS: We conclude that no subpopulation of CML stem cells displays significantly increased cell cycling. Thus, increased cycling cannot be a direct consequence of Bcr-Abl PTK acquisition in highly enriched stem cells from patients with CML. In vivo CML need not be considered a disease of unbridled stem cell proliferation, but a subtle defect in the balance between self renewal and maturation. PMID:11126203

Primitive Sca-1 Positive Bone Marrow HSC in Mouse Model of Aplastic Anemia: A Comparative Study through Flowcytometric Analysis and Scanning Electron Microscopy

PubMed Central

Chatterjee, Sumanta; Basak, Pratima; Das, Prosun; Das, Madhurima; Pereira, Jacintha Archana; Dutta, Ranjan Kumar; Chaklader, Malay; Chaudhuri, Samaresh; Law, Sujata

2010-01-01

Self-renewing Hematopoietic Stem Cells (HSCs) are responsible for reconstitution of all blood cell lineages. Sca-1 is the “stem cell antigen” marker used to identify the primitive murine HSC population, the expression of which decreases upon differentiation to other mature cell types. Sca-1+ HSCs maintain the bone marrow stem cell pool throughout the life. Aplastic anemia is a disease considered to involve primary stem cell deficiency and is characterized by severe pancytopenia and a decline in healthy blood cell generation system. Studies conducted in our laboratory revealed that the primitive Sca-1+ BM-HSCs (bone marrow hematopoietic stem cell) are significantly affected in experimental Aplastic animals pretreated with chemotherapeutic drugs (Busulfan and Cyclophosphamide) and there is increased Caspase-3 activity with consecutive high Annexin-V positivity leading to premature apoptosis in the bone marrow hematopoietic stem cell population in Aplastic condition. The Sca-1bright, that is, “more primitive” BM-HSC population was more affected than the “less primitive” BM-HSC Sca-1dim  population. The decreased cell population and the receptor expression were directly associated with an empty and deranged marrow microenvironment, which is evident from scanning electron microscopy (SEM). The above experimental evidences hint toward the manipulation of receptor expression for the benefit of cytotherapy by primitive stem cell population in Aplastic anemia cases. PMID:21048851

The Role of H1 Linker Histone Subtypes in Preserving the Fidelity of Elaboration of Mesendodermal and Neuroectodermal Lineages during Embryonic Development

PubMed Central

Nguyen, Giang D.; Gokhan, Solen; Molero, Aldrin E.; Yang, Seung-Min; Kim, Byung-Ju; Skoultchi, Arthur I.; Mehler, Mark F.

2014-01-01

H1 linker histone proteins are essential for the structural and functional integrity of chromatin and for the fidelity of additional epigenetic modifications. Deletion of H1c, H1d and H1e in mice leads to embryonic lethality by mid-gestation with a broad spectrum of developmental alterations. To elucidate the cellular and molecular mechanisms underlying H1 linker histone developmental functions, we analyzed embryonic stem cells (ESCs) depleted of H1c, H1d and H1e subtypes (H1-KO ESCs) by utilizing established ESC differentiation paradigms. Our study revealed that although H1-KO ESCs continued to express core pluripotency genes and the embryonic stem cell markers, alkaline phosphatase and SSEA1, they exhibited enhanced cell death during embryoid body formation and during specification of mesendoderm and neuroectoderm. In addition, we demonstrated deregulation in the developmental programs of cardiomyocyte, hepatic and pancreatic lineage elaboration. Moreover, ectopic neurogenesis and cardiomyogenesis occurred during endoderm-derived pancreatic but not hepatic differentiation. Furthermore, neural differentiation paradigms revealed selective impairments in the specification and maturation of glutamatergic and dopaminergic neurons with accelerated maturation of glial lineages. These impairments were associated with deregulation in the expression profiles of pro-neural genes in dorsal and ventral forebrain-derived neural stem cell species. Taken together, these experimental observations suggest that H1 linker histone proteins are critical for the specification, maturation and fidelity of organ-specific cellular lineages derived from the three cardinal germ layers. PMID:24802750

Maternal xNorrin, a Canonical Wnt Signaling Agonist and TGF-β Antagonist, Controls Early Neuroectoderm Specification in Xenopus

PubMed Central

Xu, Suhong; Cheng, Feng; Liang, Juan; Wu, Wei; Zhang, Jian

2012-01-01

Dorsal–ventral specification in the amphibian embryo is controlled by β-catenin, whose activation in all dorsal cells is dependent on maternal Wnt11. However, it remains unknown whether other maternally secreted factors contribute to β-catenin activation in the dorsal ectoderm. Here, we show that maternal Xenopus Norrin (xNorrin) promotes anterior neural tissue formation in ventralized embryos. Conversely, when xNorrin function is inhibited, early canonical Wnt signaling in the dorsal ectoderm and the early expression of the zygotic neural inducers Chordin, Noggin, and Xnr3 are severely suppressed, causing the loss of anterior structures. In addition, xNorrin potently inhibits BMP- and Nodal/Activin-related functions through direct binding to the ligands. Moreover, a subset of Norrin mutants identified in humans with Norrie disease retain Wnt activation but show defective inhibition of Nodal/Activin-related signaling in mesoderm induction, suggesting that this disinhibition causes Norrie disease. Thus, xNorrin is an unusual molecule that acts on two major signaling pathways, Wnt and TGF-β, in opposite ways and is essential for early neuroectoderm specification. PMID:22448144

Epidemiological data and case load spectrum of patients presenting to bone and soft tissue disease management group at a tertiary cancer center.

PubMed

Gulia, A; Puri, A; Chorge, S; Panda, P K

2016-01-01

This study was conducted to know the spectrum and number of bone and soft tissue (BST) tumors presenting to our institute. We needed to assess the gap between the number of patients seen and infrastructure available, and based on this information, help formulate guidelines for optimum utilization of resources and to provide best possible evidence-based cancer care. This is a prospective observational study (epidemiological). This study included all new patients seen in BST-disease management group (DMG) in the year 2010. An audit form was devised to capture all the relevant information. A comparison of our data with other national and international studies was also done. Out of total 31,951 new patients registered at our institute, 2007 patients availed BST-DMG services. Sixty percent were bone tumors and 36% were soft tissue tumors. In bone tumor, 66% were malignant, 15% were benign, and 19% were non-neoplastic. Osteosarcoma (43%) was the most common malignant tumor followed by primitive neuroectodermal tumor/Ewing's (27%) and chondrosarcoma (11%). Giant cell tumor was the most common benign bone tumor. Eighty-one percent of all soft tissue lesions were malignant, of which 75% were of mesenchymal origin and 25% were of cutaneous origin. This is an attempt to document the epidemiology of musculoskeletal tumors presenting to our institution while guiding the institute to frame and implement disease-specific protocols and generate further research questions. Continued data collection and follow-up can provide valuable information on long-term survival and treatment-related toxicities. This data (within limitations) may be extrapolated to national level to identify the need for infrastructure and human resources.

The case for DNA methylation based molecular profiling to improve diagnostic accuracy for central nervous system embryonal tumors (not otherwise specified) in adults.

PubMed

Halliday, Gail C; Junckerstorff, Reimar C; Bentel, Jacqueline M; Miles, Andrew; Jones, David T W; Hovestadt, Volker; Capper, David; Endersby, Raelene; Cole, Catherine H; van Hagen, Tom; Gottardo, Nicholas G

2018-01-01

Central nervous system primitive neuro-ectodermal tumors (CNS-PNETs), have recently been re-classified in the most recent 2016 WHO Classification into a standby catch all category, "CNS Embryonal Tumor, not otherwise specified" (CNS embryonal tumor, NOS) based on epigenetic, biologic and histopathologic criteria. CNS embryonal tumors (NOS) are a rare, histologically and molecularly heterogeneous group of tumors that predominantly affect children, and occasionally adults. Diagnosis of this entity continues to be challenging and the ramifications of misdiagnosis of this aggressive class of brain tumors are significant. We report the case of a 45-year-old woman who was diagnosed with a central nervous system embryonal tumor (NOS) based on immunohistochemical analysis of the patient's tumor at diagnosis. However, later genome-wide methylation profiling of the diagnostic tumor undertaken to guide treatment, revealed characteristics most consistent with IDH-mutant astrocytoma. DNA sequencing and immunohistochemistry confirmed the presence of IDH1 and ATRX mutations resulting in a revised diagnosis of high-grade small cell astrocytoma, and the implementation of a less aggressive treatment regime tailored more appropriately to the patient's tumor type. This case highlights the inadequacy of histology alone for the diagnosis of brain tumours and the utility of methylation profiling and integrated genomic analysis for the diagnostic verification of adults with suspected CNS embryonal tumor (NOS), and is consistent with the increasing realization in the field that a combined diagnostic approach based on clinical, histopathological and molecular data is required to more accurately distinguish brain tumor subtypes and inform more effective therapy. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Assessment of the number, biomass, and cell size of bacteria in different soils using the "cascade" filtration method

NASA Astrophysics Data System (ADS)

Polyanskaya, L. M.; Pinchuk, I. P.; Zvyagintsev, D. G.

2015-03-01

Soddy-podzolic, gray forest, brown forest, primitive Antarctic soils, typical chernozems, and solonchaks were studied. Many ultrafine bacterial cells, along with fine ones, were found in all the soils studied. The gray forest, brown forest, and primitive Antarctic soils were especially distinguished in this respect. Formerly, in the works on soil microbiology, the fact of the cell size reduction was insufficiently taken into account because of the absence of reliable methods. A decrease in the number and biomass of bacteria down the profile in all the soils, except for the solonchak, was shown. In the solonchak, the bacterial number and biomass increases with decreasing salinity of the soil horizons. The bacterial biomass mainly depends on the predominance of cells of definite sizes (0.38 and 0.23 μm). In the B1fungi horizon of the primitive Antarctic soil, a considerable number of large (1.85 μm) bacterial cells was recorded, and this resulted in the maximal microbial biomass in this horizon. The data on the average volume of a cell correlate with those on the number and biomass of bacteria. The largest diameters of cells were registered in the humus and B1fungi horizons of the primitive Antarctic soil.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meijne, E.I.; van der Winden-van Groenewegen, R.J.; Ploemacher, R.E.

The sensitivity for x-irradiation of a series of hematopoietic stem cell populations has been determined. The most primitive cells identified, cells with marrow-repopulating ability (MRA), showed the highest degree of radioresistance. These MRA cells which generate many secondary day-twelve spleen colony-forming units (MRA(CFU-S-12)) or colony-forming units in culture (MRA(CFU-C)) in the marrow of primary recipients had Do values equal to 1.18 and 1.13 Gy, respectively. The more mature CFU-S-12 had intermediate radiosensitivity (Do = 0.94 Gy), whereas the less primitive CFU-S-7 were the most radiosensitive (Do = 0.71 Gy). The in vitro colony-forming precursor cells (CFU-C) showed low radiosensitivity. Thesemore » data clearly show that the most primitive hematopoietic stem cell measured is less sensitive to ionizing radiation than generally has been assumed on the basis of measurements on CFU-S-7 or CFU-S-12.« less

The cryopreservation protocol optimal for progenitor recovery is not optimal for preservation of marrow repopulating ability.

PubMed

Balint, B; Ivanović, Z; Petakov, M; Taseski, J; Jovcić, G; Stojanović, N; Milenković, P

1999-03-01

The efficiency of five different cryopreservation protocols (our original controlled-rate and noncontrolled-rate protocols) was evaluated on the basis of the recovery after thawing of very primitive pluripotent hemopoietic stem cells (MRA(CFU-GM), pluripotent progenitors (CFU-Sd12) and committed granulocyte-monocyte progenitors (CFU-GM) in mouse bone marrow. Although the nucleated cell recovery and viability determined immediately after the thawing and washing of the cells were found to be similar, whether controlled-rate or noncontrolled-rate cryopreservation protocols were used, the recovery of MRA(CFU-GM), CFU-Sd12 and CFU-GM varied depending on the type of protocol and the cryoprotector (DMSO) concentrations used. It was shown that the controlled-rate protocol was more efficient, enabling better MRA(CFU-GM), CFU-Sd12 and CFU-GM recovery from frozen samples. The most efficient was the controlled-rate protocol of cryopreservation designed to compensate for the release of fusion heat, which enabled a better survival of CFU-Sd12 and CFU-GM when combined with a lower (5%) DMSO concentration. On the contrary, a satisfactory survival rate of very primitive stem cells (MRA(CFU-GM)) was achieved only when 10% DMSO was included with a five-step protocol of cryopreservation. These results point to adequately used controlled-rate freezing as essential for a highly efficient cryopreservation of some of the categories of hematopoietic stem and progenitor cells. At the same time, it was obvious that a higher DMSO concentration was necessary for the cryopreservation of very primitive stem cells, but not, however, for more mature progenitor cells (CFU-S, CFU-GM). These results imply the existence of a mechanism that decreases the intracellular concentration of DMSO in primitive MRA cells, which is not the case for less primitive progenitors.

CD34 Antigen and the MPL Receptor Expression Defines a Novel Class of Human Cord Blood-Derived Primitive Hematopoietic Stem Cells.

PubMed

Matsuoka, Yoshikazu; Takahashi, Masaya; Sumide, Keisuke; Kawamura, Hiroshi; Nakatsuka, Ryusuke; Fujioka, Tatsuya; Sonoda, Yoshiaki

2017-06-09

In the murine hematopoietic stem cell (HSC) compartment, thrombopoietin (THPO)/MPL (THPO receptor) signaling plays an important role in the maintenance of adult quiescent HSCs. However, the role of THPO/MPL signaling in the human primitive HSC compartment has not yet been elucidated. We have identified very primitive human cord blood (CB)-derived CD34- severe combined immunodeficiency (SCID)-repopulating cells (SRCs) using the intra-bone marrow injection method. In this study, we investigated the roles of the MPL expression in the human primitive HSC compartment. The SRC activities of the highly purified CB-derived 18Lin-CD34+/-MPL+/- cells were analyzed using NOG mice. In the primary recipient mice, nearly all mice that received CD34+/-MPL+/- cells were repopulated with human CD45+ cells. Nearly all of these mice that received CD34+MPL+/- and CD34-MPL- cells showed a secondary repopulation. Interestingly, the secondary recipient mice that received CD34+/-MPL- cells showed a distinct tertiary repopulation. These results clearly indicate that the CD34+/- SRCs not expressing MPL sustain a long-term (LT) (>1 year) human cell repopulation in NOG mice. Moreover, CD34- SRCs generate CD34+CD38-CD90+ SRCs in vitro and in vivo. These findings provide a new concept that CD34-MPL- SRCs reside at the apex of the human HSC hierarchy.

A newborn with neurocutaneous melanocytosis and Dandy-Walker malformation.

PubMed

De Cock, Jens; Snauwaert, Julie; Van Rompaey, Walter; Morren, Marie-Anne; Demaerel, Philippe

2014-03-01

Neurocutaneous melanocytosis is a rare congenital dysplasia of the neuroectodermal melanocyte precursor cells that leads to proliferation of melanin-producing cells in the skin and leptomeninges. We describe a newborn with a giant congenital melanocytic nevus on his back, buttocks, and thighs. His brain magnetic resonance imaging study revealed bilateral T1 hyperintense lesions in the cerebellum and in the amygdala, hydrocephalus, and a Blake's pouch cyst, consistent with neurocutaneous melanocytosis and Dandy-Walker malformation. Neurocutaneous melanocytosis has a wide clinical spectrum that includes hydrocephalus, epilepsy, cranial nerve palsy, increased intracranial pressure, and sensorimotor deficits. Copyright © 2014. Published by Elsevier Inc.

Cinemicrographic study of the cell movement in the primitive-streak-stage mouse embryo.

PubMed

Nakatsuji, N; Snow, M H; Wylie, C C

1986-07-01

Migration of the mesoderm cells in the primitive-streak-stage mouse embryo was directly studied by cinemicrography using whole embryo culture and Nomarski differential interference contrast optics. Relative transparency and small size of the early mouse embryos enabled direct observation of the individual cells and their cell processes. Seven-day-old mouse embryos were isolated and cultured in a small chamber in a medium consisting of 50% rat serum and 50% Dulbecco's modified minimum essential medium. The mesoderm cells move away from the primitive streak in both anterior and antimesometrial (distal) directions at a mean velocity of 46 micron h-1. They extend cell processes and constantly change cell shape. They do not translocate extensively as isolated single cells, but usually maintain attachment to other mesoderm cells. They show frequent cell division preceded by rounding up of the cell bodies, and accompanied by vigorous blebbing before and after cytokinesis. This study shows that it is possible to examine the motility of embryonic cells inside the mammalian embryo by direct observation if the embryo is small and transparent enough for the use of the Nomarski optics.

Efficient conservative ADER schemes based on WENO reconstruction and space-time predictor in primitive variables

NASA Astrophysics Data System (ADS)

Zanotti, Olindo; Dumbser, Michael

2016-01-01

We present a new version of conservative ADER-WENO finite volume schemes, in which both the high order spatial reconstruction as well as the time evolution of the reconstruction polynomials in the local space-time predictor stage are performed in primitive variables, rather than in conserved ones. To obtain a conservative method, the underlying finite volume scheme is still written in terms of the cell averages of the conserved quantities. Therefore, our new approach performs the spatial WENO reconstruction twice: the first WENO reconstruction is carried out on the known cell averages of the conservative variables. The WENO polynomials are then used at the cell centers to compute point values of the conserved variables, which are subsequently converted into point values of the primitive variables. This is the only place where the conversion from conservative to primitive variables is needed in the new scheme. Then, a second WENO reconstruction is performed on the point values of the primitive variables to obtain piecewise high order reconstruction polynomials of the primitive variables. The reconstruction polynomials are subsequently evolved in time with a novel space-time finite element predictor that is directly applied to the governing PDE written in primitive form. The resulting space-time polynomials of the primitive variables can then be directly used as input for the numerical fluxes at the cell boundaries in the underlying conservative finite volume scheme. Hence, the number of necessary conversions from the conserved to the primitive variables is reduced to just one single conversion at each cell center. We have verified the validity of the new approach over a wide range of hyperbolic systems, including the classical Euler equations of gas dynamics, the special relativistic hydrodynamics (RHD) and ideal magnetohydrodynamics (RMHD) equations, as well as the Baer-Nunziato model for compressible two-phase flows. In all cases we have noticed that the new ADER schemes provide less oscillatory solutions when compared to ADER finite volume schemes based on the reconstruction in conserved variables, especially for the RMHD and the Baer-Nunziato equations. For the RHD and RMHD equations, the overall accuracy is improved and the CPU time is reduced by about 25 %. Because of its increased accuracy and due to the reduced computational cost, we recommend to use this version of ADER as the standard one in the relativistic framework. At the end of the paper, the new approach has also been extended to ADER-DG schemes on space-time adaptive grids (AMR).

Experimental analysis of control mechanisms in somite segmentation in avian embryos. II. Reduction of material in the gastrula stages of the chick.

PubMed

Bellairs, R; Veini, M

1984-02-01

A new theory of control of somite segmentation in chick embryos is proposed. This supposses that tiny clusters of already programmed cells are present throughout the presumptive somite area at stage 4, but that in order to fulfill their destiny they probably depend on the addition of further cells from the primitive streak. Evidence is based on the two groups of experiments: a) Experiments involving transection across the primitive streak at various stages, (which results in a 'tail' which possesses mesodermal derivatives) and across the segmental plate (which results in a 'tail' lacking mesodermal derivatives). b) Experiments in which parts of embryos have been explanted with or without their primitive streak. It is suggested that the initial clusters of pre-programmed cells move further and further posteriorly, developing into somitomeres (the precursors of true somites) only as they receive re-inforcements from the primitive streak or, ultimately, from the tail bud.

CD34 Antigen and the MPL Receptor Expression Defines a Novel Class of Human Cord Blood-Derived Primitive Hematopoietic Stem Cells

PubMed Central

Matsuoka, Yoshikazu; Takahashi, Masaya; Sumide, Keisuke; Kawamura, Hiroshi; Nakatsuka, Ryusuke; Fujioka, Tatsuya; Sonoda, Yoshiaki

2017-01-01

In the murine hematopoietic stem cell (HSC) compartment, thrombopoietin (THPO)/MPL (THPO receptor) signaling plays an important role in the maintenance of adult quiescent HSCs. However, the role of THPO/MPL signaling in the human primitive HSC compartment has not yet been elucidated. We have identified very primitive human cord blood (CB)-derived CD34– severe combined immunodeficiency (SCID)-repopulating cells (SRCs) using the intra-bone marrow injection method. In this study, we investigated the roles of the MPL expression in the human primitive HSC compartment. The SRC activities of the highly purified CB-derived 18Lin–CD34+/–MPL+/– cells were analyzed using NOG mice. In the primary recipient mice, nearly all mice that received CD34+/–MPL+/– cells were repopulated with human CD45+ cells. Nearly all of these mice that received CD34+MPL+/– and CD34–MPL– cells showed a secondary repopulation. Interestingly, the secondary recipient mice that received CD34+/–MPL– cells showed a distinct tertiary repopulation. These results clearly indicate that the CD34+/– SRCs not expressing MPL sustain a long-term (LT) (>1 year) human cell repopulation in NOG mice. Moreover, CD34– SRCs generate CD34+CD38–CD90+ SRCs in vitro and in vivo. These findings provide a new concept that CD34–MPL– SRCs reside at the apex of the human HSC hierarchy. PMID:27938494

Endometrial stromal sarcoma involving the urinary bladder: a study of 6 cases.

PubMed

Tian, Wei; Latour, Mathieu; Epstein, Jonathan I

2014-07-01

Endometrial stromal sarcoma (ESS) involving the urinary bladder is very rare, with no prior series reported. We identified 6 cases of low-grade ESS involving the bladder at our institution (1998 to 2013), 5 of them consults. The median age at bladder involvement was 60 years (range, 44 to 77 y). One patient presented with bladder involvement at initial diagnosis of ESS. The remaining 5 cases with bladder involvement presented 7 to 30 years (mean 18 y) after a known diagnosis of ESS (n=2) or after a remote history of hysterectomy with an uncertain diagnosis (n=3). The location of bladder involvement included dome (n=1), trigone (n=2), diffuse (n=1), and unknown (n=2). Two cases demonstrated worm-like infiltrating tumor nests classic of low-grade ESS with little stromal reaction with retraction artifact mimicking vascular invasion. One case originating from the ovary showed focal glandular differentiation in the bladder, resembling endometriosis. Two cases had abundant keloidal collagen formation, arranged haphazardly or in a sunburst pattern. One case showed primitive cells infiltrating entirely hyalinized stroma, after chemotherapy given for a misdiagnosis of urothelial carcinoma. CD31 was negative in all cases, except for 1 case with obvious large vessel invasion. The differential diagnosis included a large nested variant of urothelial carcinoma, carcinoid tumor, synovial sarcoma, solitary fibrous tumor, Ewing sarcoma/primitive neuroectodermal tumors, and endometriosis. CD10 was strongly positive in 5 cases, and 1 case had very focal, moderate staining. Estrogen receptor showed strong and diffuse staining in all 6 cases. Progesterone receptor showed moderate to strong staining in 5 cases and focal staining in 1 case. One case showed PAX8 expression, and 2 cases showed p16 nuclear and cytoplasmic expression. CD56 showed weak to strong staining in 4 cases. Two cases had diffuse synaptophysin, and 1 case had focal p63 positivity. GATA-3, CD34, and CD99 were negative in all cases. The Ki-67 index was 1% to 10% (mean 4%). The mitotic count was 0 to 3/10 HPF (mean <1/10 HPF). Two patients had metastases to pelvic lymph nodes, and 1 had possible lung metastasis. Three patients were treated with Megace and 1 with Arimidex after surgery. Follow-up averaged 19 years (0 to 33 y) after the initial diagnosis of ESS or hysterectomy and 3.5 years (0 to 11 y) after bladder surgery. ESS involving the bladder is extremely rare with a very long interval from onset to bladder involvement. In female patients, low-grade spindle cell lesions involving the bladder should include ESS in the differential diagnosis.

Cell Aggregation-induced FGF8 Elevation Is Essential for P19 Cell Neural Differentiation

PubMed Central

Wang, Chen; Xia, Caihong; Bian, Wei; Liu, Li; Lin, Wei; Chen, Ye-Guang; Ang, Siew-Lan

2006-01-01

FGF8, a member of the fibroblast growth factor (FGF) family, has been shown to play important roles in different developing systems. Mouse embryonic carcinoma P19 cells could be induced by retinoic acid (RA) to differentiate into neuroectodermal cell lineages, and this process is cell aggregation dependent. In this report, we show that FGF8 expression is transiently up-regulated upon P19 cell aggregation, and the aggregation-dependent FGF8 elevation is pluripotent stem cell related. Overexpressing FGF8 promotes RA-induced monolayer P19 cell neural differentiation. Inhibition of FGF8 expression by RNA interference or blocking FGF signaling by the FGF receptor inhibitor, SU5402, attenuates neural differentiation of the P19 cell. Blocking the bone morphogenetic protein (BMP) pathway by overexpressing Smad6 in P19 cells, we also show that FGF signaling plays a BMP inhibition–independent role in P19 cell neural differentiation. PMID:16641368

Two different pathways for the transport of primitive and definitive blood cells from the yolk sac to the embryo in humans.

PubMed

Pereda, Jaime; Monge, Juan I; Niimi, Gen

2010-08-01

During the early human embryonic period nutrients and blood cells are temporarily provided by the extraembryonic yolk sac (YS). The YS before week six is involved not only in primitive but also in definitive erythropoiesis. While the destiny of primitive erythroid cells that fill the blood vessels of the YS is well known, the final destination of erythrocytes present in the endodermal vesicular system is unknown. In the present study we have investigated, step by step, the destiny of the erythrocytes present in the endodermal vesicles during the embryonic period. Twelve human YSs and their corresponding yolk stalks were analyzed between weeks 4 and 7 of embryonic age by light and scanning electron microscopy. It is shown that erythrocytes (according to their size and morphological features) located within the endodermal vesicles of the YS wall are pulled out through endodermal pits into the YS cavity, from where they reach the lumen of the primitive gut of the embryo through the vitelline duct, a temporary pathway communicating both compartments. During the study period no erythrocytes were seen within the embryo's vascular network where only primitive erythroblasts were identified. Our results indicate that the vitelline duct plays an important transient role as a pathway for the transport of nutrients and blood cells between the YS and the embryo before week five of embryonic development that ends just at the time when YS-embryo circulation becomes established. (c) 2010 Wiley-Liss, Inc.

Evidence of Mobilization of Pluripotent Stem Cells into Peripheral Blood of Patients with Myocardial Ischemia

PubMed Central

Abdel-Latif, Ahmed; Zuba-Surma, Ewa K.; Ziada, Khaled M.; Kucia, Magdalena; Cohen, Donald A.; Kaplan, Alan M.; Zant, Gary Van; Selim, Samy; Smyth, Susan S.; Ratajczak, Mariusz Z.

2010-01-01

Objective The ischemic myocardium releases multiple chemotactic factors responsible for the mobilization and recruitment of bone marrow-derived cells to injured myocardium. However, the mobilization of primitive pluripotent stem cells (PSCs) enriched in Very Small Embryonic-Like stem cells (VSELs) in various cardiac ischemic scenarios is not well understood. Methods Fifty four ischemic heart disease patients, including subjects with stable angina, non-ST elevation (NSTME) myocardial infarction (MI) and ST elevation myocardial infarction (STEMI), and twelve matched controls were enrolled. The absolute numbers of circulating stem/primitive cells in samples of peripheral blood (PB) were quantitated by Image Stream Analysis and conventional flow cytometry. Gene expression of PSC (Oct-4 and Nanog), early cardiomyocyte (Nkx-2.5 and GATA-4), and endothelial (vWF) markers was analyzed by real-time PCR. Results The absolute numbers of PSCs, stem cell populations enriched in VSELs and hematopoietic stem cells (HSCs) present in PB were significantly higher in STEMI patients at presentation and declined over time. There was a corresponding increase in pluripotent, cardiac and endothelial gene expression in unfractionated PB cells and sorted PB-derived primitive CD34+ cells. The absolute numbers of circulating VSELs and HSCs in STEMI correlated negatively with patients' age. Conclusions Myocardial ischemia mobilizes primitive PSCs including pluripotent VSELs into the circulation. The peak of mobilization occurs within 12 hours in patients presenting with STEMI, which may represent a therapeutic window for future clinical applications. Reduced stem cell mobilization with advancing age could explain, in part, the observation that age is associated with poor prognosis in patients with MI. PMID:20800644

Melanotic neuroectodermal tumour of infancy at the anterior fontanelle.

PubMed

Nishio, S; Morioka, T; Murakami, N; Fukui, M; Inamitsu, T; Ishihara, S

1999-03-01

We describe a 4-month-old girl presenting with a melanotic neuroectodermal tumour of infancy at the anterior fontanelle. According to the neuroimaging findings, this tumour was found to lie epidurally, adherent to the dura mater, with thickening of the adjacent frontal bone. The tumour was dense on CT, while MRI showed a major part of the tumour to be isointense with cerebral cortex on both T1- and T2-weighted images. The neuroimaging and clinical features are briefly discussed.

ECK, a human EPH-related gene, maps to 1p36.1, a common region of alteration in human cancers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sulman, E.P.; Brodeur, G.M.; Ikegaki, N.

1997-03-01

Mouse eck, a member of the EPH gene family, has been mapped to mouse chromosome 4. The syntenic relationship between this chromosome and human chromosome 1 suggests that the human ECK gene maps to the distal short arm of human chromosome 1 (1p). Since this region is frequently deleted or altered in certain tumors of neuroectodermal origin, it is important to define the specific chromosomal localization of the human ECK gene. PCR screening of a rodent-human somatic cell hybrid panel by ECK-specific primers showed that ECK is indeed localized to human chromosome 1. Additional PCR screening of a regional screeningmore » panel for chromosome 1p indicated that ECK is localized to 1p36, distal to FUCA1. Furthermore, fluorescence in situ hybridization analysis with an ECK-specific P1 clone showed that ECK maps proximal to genetic marker D1S228. Taken together, the data suggest that ECK maps to 1p36.1, a region that is frequently deleted in neuroblastoma, melanoma, and other neuroectodermal tumors. 23 refs., 3 figs.« less

SJDAWN: St. Jude Children's Research Hospital Phase 1 Study Evaluating Molecularly-Driven Doublet Therapies for Children and Young Adults With Recurrent Brain Tumors

ClinicalTrials.gov

2018-04-09

Anaplastic Astrocytoma; Anaplastic Ependymoma; Anaplastic Ganglioglioma; Anaplastic Meningioma; Anaplastic Oligodendroglioma; Pleomorphic Xanthoastrocytoma, Anaplastic; Atypical Teratoid/Rhabdoid Tumor; Brain Cancer; Brain Tumor; Central Nervous System Neoplasms; Choroid Plexus Carcinoma; CNS Embryonal Tumor With Rhabdoid Features; Ganglioneuroblastoma of Central Nervous System; CNS Tumor; Embryonal Tumor of CNS; Ependymoma; Glioblastoma; Glioma; Glioma, Malignant; Medulloblastoma; Medulloblastoma; Unspecified Site; Medulloepithelioma; Neuroepithelial Tumor; Neoplasms; Neoplasms, Neuroepithelial; Papillary Tumor of the Pineal Region (High-grade Only); Pediatric Brain Tumor; Pineal Parenchymal Tumor of Intermediate Differentiation (High-grade Only); Pineoblastoma; Primitive Neuroectodermal Tumor; Recurrent Medulloblastoma; Refractory Brain Tumor; Neuroblastoma. CNS; Glioblastoma, IDH-mutant; Glioblastoma, IDH-wildtype; Medulloblastoma, Group 3; Medulloblastoma, Group 4; Glioma, High Grade; Neuroepithelial Tumor, High Grade; Medulloblastoma, SHH-activated and TP53 Mutant; Medulloblastoma, SHH-activated and TP53 Wildtype; Medulloblastoma, Chromosome 9q Loss; Medulloblastoma, Non-WNT Non-SHH, NOS; Medulloblastoma, Non-WNT/Non-SHH; Medulloblastoma, PTCH1 Mutation; Medulloblastoma, WNT-activated; Ependymoma, Recurrent; Glioma, Recurrent High Grade; Glioma, Recurrent Malignant; Embryonal Tumor, NOS; Glioma, Diffuse Midline, H3K27M-mutant; Embryonal Tumor With Multilayered Rosettes (ETMR); Ependymoma, NOS, WHO Grade III; Ependymoma, NOS, WHO Grade II; Medulloblastoma, G3/G4; Ependymoma, RELA Fusion Positive

Neuropathology of genetically engineered mice: consensus report and recommendations from an international forum.

PubMed

Weiss, William A; Israel, Mark; Cobbs, Charles; Holland, Eric; James, C David; Louis, David N; Marks, Cheryl; McClatchey, Andrea I; Roberts, Tim; Van Dyke, Terry; Wetmore, Cynthia; Chiu, Ing-Ming; Giovannini, Marco; Guha, Abhijit; Higgins, Robert J; Marino, Silvia; Radovanovic, Ivan; Reilly, Karlyne; Aldape, Ken

2002-10-24

The Mouse Models of Cancer Consortium of the NCI sponsored a meeting of neuropathologists and veterinary pathologists in New York City in November of 2000. A rapidly growing number of genetically engineered mice (GEM) predisposed to tumors of the nervous system have led to a concomitant need for neuropathological evaluation and validation of these models. A panel of 13 pathologists reviewed material representing most of the available published and unpublished GEM models of medulloblastoma, primitive neuroectodermal tumor, astrocytoma, oligodendroglioma, mixed glioma, and tumors of the peripheral nerve. The GEM tumors were found to have many similarities and some distinct differences with respect to human disease. After review of the biology and pathology for all models presented, participants were split into groups reflective of clinical expertise in human pathology, tumor biology, neuroimaging, or treatment/intervention. Recommendations were made detailing an extensive and complete neuropathological characterization of animals. Importance was placed on including information on strains, tumor clonality, and examination for genetic mutation or altered gene expression characteristics of the corresponding human malignancy. Specific proposals were made to incorporate GEM models in emerging neuroradiological modalities. Recommendations were also made for preclinical validation of these models in cancer therapeutics, and for incorporation of surrogate markers of tumor burden to facilitate preclinical evaluation of new therapies.

Evolutionary conservation of the presumptive neural plate markers AmphiSox1/2/3 and AmphiNeurogenin in the invertebrate chordate amphioxus

NASA Technical Reports Server (NTRS)

Holland, L. Z.; Schubert, M.; Holland, N. D.; Neuman, T.

2000-01-01

Amphioxus, as the closest living invertebrate relative of the vertebrates, can give insights into the evolutionary origin of the vertebrate body plan. Therefore, to investigate the evolution of genetic mechanisms for establishing and patterning the neuroectoderm, we cloned and determined the embryonic expression of two amphioxus transcription factors, AmphiSox1/2/3 and AmphiNeurogenin. These genes are the earliest known markers for presumptive neuroectoderm in amphioxus. By the early neurula stage, AmphiNeurogenin expression becomes restricted to two bilateral columns of segmentally arranged neural plate cells, which probably include precursors of motor neurons. This is the earliest indication of segmentation in the amphioxus nerve cord. Later, expression extends to dorsal cells in the nerve cord, which may include precursors of sensory neurons. By the midneurula, AmphiSox1/2/3 expression becomes limited to the dorsal part of the forming neural tube. These patterns resemble those of their vertebrate and Drosophila homologs. Taken together with the evolutionarily conserved expression of the dorsoventral patterning genes, BMP2/4 and chordin, in nonneural and neural ectoderm, respectively, of chordates and Drosophila, our results are consistent with the evolution of the chordate dorsal nerve cord and the insect ventral nerve cord from a longitudinal nerve cord in a common bilaterian ancestor. However, AmphiSox1/2/3 differs from its vertebrate homologs in not being expressed outside the CNS, suggesting that additional roles for this gene have evolved in connection with gene duplication in the vertebrate lineage. In contrast, expression in the midgut of AmphiNeurogenin together with the gene encoding the insulin-like peptide suggests that amphioxus may have homologs of vertebrate pancreatic islet cells, which express neurogenin3. In addition, AmphiNeurogenin, like its vertebrate and Drosophila homologs, is expressed in apparent precursors of epidermal chemosensory and possibly mechanosensory cells, suggesting a common origin for protostome and deuterostome epidermal sensory cells in the ancestral bilaterian. Copyright 2000 Academic Press.

[Undifferentiated soft tissue tumor with rhabdoid phenotype (extra-renal rhabdoid tumor). Report of a congenital case associated with medulloblastoma in a brother].

PubMed

Costes, V; Medioni, D; Durand, L; Sarran, N; Marguerite, G; Baldet, P

1997-03-01

We report a case of congenital cervical rhabdoid tumor with association of a medulloblastoma in a brother. The immunohistochemical features of this tumor are compatible with a neuroectodermal differentiation (MIC 2+, Leu 7+). Extrarenal rhabdoid tumors share a common morphology but do not represent a single entity with only one histogenesis. Most of them are now considered to be of neuroectodermal origin. In our case, the association with a medulloblastoma in a brother seems to confirm this concept.

Why are hematopoietic stem cells so 'sexy'? on a search for developmental explanation.

PubMed

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.

Evaluating Interaction of Cord Blood Hematopoietic Stem/Progenitor Cells with Functionally Integrated Three-Dimensional Microenvironments.

PubMed

Mokhtari, Saloomeh; Baptista, Pedro M; Vyas, Dipen A; Freeman, Charles Jordan; Moran, Emma; Brovold, Matthew; Llamazares, Guillermo A; Lamar, Zanneta; Porada, Christopher D; Soker, Shay; Almeida-Porada, Graça

2018-03-01

Despite advances in ex vivo expansion of cord blood-derived hematopoietic stem/progenitor cells (CB-HSPC), challenges still remain regarding the ability to obtain, from a single unit, sufficient numbers of cells to treat an adolescent or adult patient. We and others have shown that CB-HSPC can be expanded ex vivo in two-dimensional (2D) cultures, but the absolute percentage of the more primitive stem cells decreases with time. During development, the fetal liver is the main site of HSPC expansion. Therefore, here we investigated, in vitro, the outcome of interactions of primitive HSPC with surrogate fetal liver environments. We compared bioengineered liver constructs made from a natural three-dimensional-liver-extracellular-matrix (3D-ECM) seeded with hepatoblasts, fetal liver-derived (LvSt), or bone marrow-derived stromal cells, to their respective 2D culture counterparts. We showed that the inclusion of cellular components within the 3D-ECM scaffolds was necessary for maintenance of HSPC viability in culture, and that irrespective of the microenvironment used, the 3D-ECM structures led to the maintenance of a more primitive subpopulation of HSPC, as determined by flow cytometry and colony forming assays. In addition, we showed that the timing and extent of expansion depends upon the biological component used, with LvSt providing the optimal balance between preservation of primitive CB HSPC and cellular differentiation. Stem Cells Translational Medicine 2018;7:271-282. © 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

[The value of immunohistochemistry using SMARCA4/BRG1 in the diagnosis of small cell ovarian carcinoma hypercalcemic type. A report of two cases].

PubMed

Ruiz-García, Gema; Torroba-Carón, M Amparo; Ferri-Ñíguez, Belén; Lencina-Guardiola, Miriam; García-Molina, Francisco; Martínez-Barba, Enrique

Small cell carcinoma of ovary-hypercalcemic type is an undifferentiated carcinoma. We describe two cases in women aged 32 and 29. Both presented with large masses and complete surgical extirpation was impossible. Histologically, the images were similar, with diffuse cell proliferation, accompanied by the presence of follicle-like spaces. In both cases it was necessary to make a differential diagnosis with entities such as adult or juvenile granulosa cell tumour, small cell carcinoma of pulmonary type, dysgerminoma and even peripheral neuroectodermal tumour. The absence of SMARCA4/BRG1 immunostaining proved very useful in the diagnosis of hypercalcemic small cell ovarian carcinoma. Copyright © 2017 Sociedad Española de Anatomía Patológica. Publicado por Elsevier España, S.L.U. All rights reserved.

Hard Spheres on the Primitive Surface

NASA Astrophysics Data System (ADS)

Dotera, Tomonari; Takahashi, Yusuke

2015-03-01

Recently hierarchical structures associated with the gyroid in several soft-matter systems have been reported. One of fundamental questions is regular arrangement or tiling on minimal surfaces. We have found certain numbers of hard spheres per unit cell on the gyroid surface are entropically self-organized. Here, new results for the primitive surface are presented. 56/64/72 per unit cell on the primitive minimal surface are entropically self-organized. Numerical evidences for the fluid-solid transition as a function of hard sphere radius are obtained in terms of the acceptance ratio of Monte Carlo moves and order parameters. These arrangements, which are the extensions of the hexagonal arrangement on a flat surface, can be viewed as hyperbolic tiling on the Poincaré disk with a negative Gaussian curvature.

The Spemann organizer meets the anterior-most neuroectoderm at the equator of early gastrulae in amphibian species

PubMed Central

Yanagi, Takanori; Ito, Kenta; Nishihara, Akiha; Minamino, Reika; Mori, Shoko; Sumida, Masayuki; Hashimoto, Chikara

2015-01-01

The dorsal blastopore lip (known as the Spemann organizer) is important for making the body plan in amphibian gastrulation. The organizer is believed to involute inward and migrate animally to make physical contact with the prospective head neuroectoderm at the blastocoel roof of mid- to late-gastrula. However, we found that this physical contact was already established at the equatorial region of very early gastrula in a wide variety of amphibian species. Here we propose a unified model of amphibian gastrulation movement. In the model, the organizer is present at the blastocoel roof of blastulae, moves vegetally to locate at the region that lies from the blastocoel floor to the dorsal lip at the onset of gastrulation. The organizer located at the blastocoel floor contributes to the anterior axial mesoderm including the prechordal plate, and the organizer at the dorsal lip ends up as the posterior axial mesoderm. During the early step of gastrulation, the anterior organizer moves to establish the physical contact with the prospective neuroectoderm through the “subduction and zippering” movements. Subduction makes a trench between the anterior organizer and the prospective neuroectoderm, and the tissues face each other via the trench. Zippering movement, with forming Brachet's cleft, gradually closes the gap to establish the contact between them. The contact is completed at the equator of early gastrulae and it continues throughout the gastrulation. After the contact is established, the dorsal axis is formed posteriorly, but not anteriorly. The model also implies the possibility of constructing a common model of gastrulation among chordate species. PMID:25754292

Genetic control of Drosophila nerve cord development

NASA Technical Reports Server (NTRS)

Skeath, James B.; Thor, Stefan

2003-01-01

The Drosophila ventral nerve cord has been a central model system for studying the molecular genetic mechanisms that control CNS development. Studies show that the generation of neural diversity is a multistep process initiated by the patterning and segmentation of the neuroectoderm. These events act together with the process of lateral inhibition to generate precursor cells (neuroblasts) with specific identities, distinguished by the expression of unique combinations of regulatory genes. The expression of these genes in a given neuroblast restricts the fate of its progeny, by activating specific combinations of downstream genes. These genes in turn specify the identity of any given postmitotic cell, which is evident by its cellular morphology and choice of neurotransmitter.

β-Globin-Expressing Definitive Erythroid Progenitor Cells Generated from Embryonic and Induced Pluripotent Stem Cell-Derived Sacs.

PubMed

Fujita, Atsushi; Uchida, Naoya; Haro-Mora, Juan J; Winkler, Thomas; Tisdale, John

2016-06-01

Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent a potential alternative source for red blood cell transfusion. However, when using traditional methods with embryoid bodies, ES cell-derived erythroid cells predominantly express embryonic type ɛ-globin, with lesser fetal type γ-globin and very little adult type β-globin. Furthermore, no β-globin expression is detected in iPS cell-derived erythroid cells. ES cell-derived sacs (ES sacs) have been recently used to generate functional platelets. Due to its unique structure, we hypothesized that ES sacs serve as hemangioblast-like progenitors capable to generate definitive erythroid cells that express β-globin. With our ES sac-derived erythroid differentiation protocol, we obtained ∼120 erythroid cells per single ES cell. Both primitive (ɛ-globin expressing) and definitive (γ- and β-globin expressing) erythroid cells were generated from not only ES cells but also iPS cells. Primitive erythropoiesis is gradually switched to definitive erythropoiesis during prolonged ES sac maturation, concurrent with the emergence of hematopoietic progenitor cells. Primitive and definitive erythroid progenitor cells were selected on the basis of glycophorin A or CD34 expression from cells within the ES sacs before erythroid differentiation. This selection and differentiation strategy represents an important step toward the development of in vitro erythroid cell production systems from pluripotent stem cells. Further optimization to improve expansion should be required for clinical application. Stem Cells 2016;34:1541-1552. © 2016 AlphaMed Press.

Efficacy of vincristine and etoposide with escalating cyclophosphamide in poor-prognosis pediatric brain tumors1

PubMed Central

Ziegler, David S.; Cohn, Richard J.; McCowage, Geoffrey; Alvaro, Frank; Oswald, Cecilia; Mrongovius, Robert; White, Les

2006-01-01

The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Children’s Cancer Study Group—VETOPEC I, Baby Brain 91, and VETOPEC II—have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors treated with these intensive VETOPEC-based protocols to assess the response, toxicity, and survival. We also assessed whether the use of very high dose chemotherapy with stem cell rescue improved the response rate or affected toxicity. Seventy-one brain tumor patients were treated with VETOPEC-based protocols. Of the 54 patients evaluable for tumor response, 17 had a complete response (CR) and 20 a partial response (PR) to treatment, which yielded an overall response rate of 69%. The CR + PR was 83% (19/23) for medulloblastomas, 56% (5/9) for primitive neuroectodermal tumors, 55% (6/11) for grade 3 and 4 astrocytomas, and 80% (6/8) for ependymomas. At a median follow-up of 36 months, overall survival for the entire cohort of 71 patients was 32%, with event-free survival of 13%. There were no toxic deaths within the PBSC-supported VETOPEC II cohort, despite higher CPA doses, compared with 7% among the non-PBSC patients. This regimen produces high response rates in a variety of very poor prognosis pediatric brain tumors. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. With PBSC rescue in the VETOPEC II study, hematologic toxicity was no longer a limiting factor. The response rates observed support further development of this chemotherapy regimen. PMID:16443948

Performance characteristics of a reverse transcriptase-polymerase chain reaction assay for the detection of tumor-specific fusion transcripts from archival tissue.

PubMed

Fritsch, Michael K; Bridge, Julia A; Schuster, Amy E; Perlman, Elizabeth J; Argani, Pedram

2003-01-01

Pediatric small round cell tumors still pose tremendous diagnostic problems. In difficult cases, the ability to detect tumor-specific gene fusion transcripts for several of these neoplasms, including Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/PNET), synovial sarcoma (SS), alveolar rhabdomyosarcoma (ARMS), and desmoplastic small round cell tumor (DSRCT) using reverse transcriptase-polymerase chain reaction (RT-PCR), can be extremely helpful. Few studies to date, however, have systematically examined several different tumor types for the presence of multiple different fusion transcripts in order to determine the specificity and sensitivity of the RT-PCR method, and no study has addressed this issue for formalin-fixed material. The objectives of this study were to address the specificity, sensitivity, and practicality of such an assay applied strictly to formalin-fixed tissue blocks. Our results demonstrate that, for these tumors, the overall sensitivity for detecting each fusion transcript is similar to that reported in the literature for RT-PCR on fresh or formalin-fixed tissues. The specificity of the assay is very high, being essentially 100% for each primer pair when interpreting the results from visual inspection of agarose gels. However, when these same agarose gels were examined using Southern blotting, a small number of tumors also yielded reproducibly detectable weak signals for unexpected fusion products, in addition to a strong signal for the expected fusion product. Fluorescence in situ hybridization (FISH) studies in one such case indicated that a rearrangement that would account for the unexpected fusion was not present, while another case was equivocal. The overall specificity for each primer pair used in this assay ranged from 94 to 100%. Therefore, RT-PCR using formalin-fixed paraffin-embedded tissue sections can be used to detect chimeric transcripts as a reliable, highly sensitive, and highly specific diagnostic assay. However, we strongly suggest that the final interpretation of the results from this assay be viewed in light of the other features of the case, including clinical history, histology, and immunohistochemistry, by the diagnostic pathologist. Additional studies such as FISH may be useful in clarifying the nature of equivocal or unexpected results.

Isolation and characterisation of cancer stem cells from canine osteosarcoma.

PubMed

Wilson, H; Huelsmeyer, M; Chun, R; Young, K M; Friedrichs, K; Argyle, D J

2008-01-01

There is increasing evidence that cancer is a stem cell disease. This study sought to isolate and characterise cancer stem cells from canine osteosarcoma. One human and three canine cell lines were cultured in non-adherent culture conditions using serum-starved, semi-solid media. Primitive sarcosphere colonies from all cell lines were identified under these conditions and were characterised using molecular and cytochemical techniques for embryonic stem cell markers. Expression of the embryonic stem cell-associated genes Nanog, Oct4 and STAT3 indicated a primitive phenotype. Sarcospheres could be reproduced consistently when passaged multiple times and produced adherent cell cultures when returned to normal growth conditions. Similarities between human and canine osteosarcoma cell lines add credence to the potential of the dog as a model for human disease.

Melanotic neuroectodermal tumor of the neurocranium in infancy.

PubMed

Walsh, J W; Strand, R D

1982-01-01

Melanotic neuroectodermal tumors of the neurocranium are a rare but life-threatening disorder of infancy. 11 previously reported cases are reviewed in terms of clinical presentation, radiological diagnosis, and management. A twelfth case, a 4-month-old infant who developed three discrete sites of tumor unilaterally in the neurocranium is presented. Several hypotheses for the mechanism of formation of these tumors are reviewed. The authors propose that the mechanism of formation involves a dysontogenesis of neural crest tissue and that these tumors form, at least in part, from fragments of melanin-containing arachnoid villi which are displaced during embryonic development.

A cellular automaton model for neurogenesis in Drosophila

NASA Astrophysics Data System (ADS)

Luthi, Pascal O.; Chopard, Bastien; Preiss, Anette; Ramsden, Jeremy J.

1998-07-01

A cellular automaton (CA) is constructed for the formation of the central nervous system of the Drosophila embryo. This is an experimentally well-studied system in which complex interactions between neighbouring cells appear to drive their differentiation into different types. It appears that all the cells initially have the potential to become neuroblasts, and all strive to this end, but those which differentiate first block their as yet undifferentiated neighbours from doing so. The CA makes use of observational evidence for a lateral inhibition mechanism involving signalling products S of the ‘proneural’ or neuralizing genes. The key concept of the model is that cells are continuously producing S, but the production rate is lowered by inhibitory signals received from neighbouring cells which have advanced further along the developmental pathway. Comparison with experimental data shows that it well accounts for the observed proportion of neuroectodermal cells delaminating as neuroblasts.

Targeting Aberrant Glutathione Metabolism to Eradicate Human Acute Myelogenous Leukemia Cells*

PubMed Central

Pei, Shanshan; Minhajuddin, Mohammad; Callahan, Kevin P.; Balys, Marlene; Ashton, John M.; Neering, Sarah J.; Lagadinou, Eleni D.; Corbett, Cheryl; Ye, Haobin; Liesveld, Jane L.; O'Dwyer, Kristen M.; Li, Zheng; Shi, Lei; Greninger, Patricia; Settleman, Jeffrey; Benes, Cyril; Hagen, Fred K.; Munger, Joshua; Crooks, Peter A.; Becker, Michael W.; Jordan, Craig T.

2013-01-01

The development of strategies to eradicate primary human acute myelogenous leukemia (AML) cells is a major challenge to the leukemia research field. In particular, primitive leukemia cells, often termed leukemia stem cells, are typically refractory to many forms of therapy. To investigate improved strategies for targeting of human AML cells we compared the molecular mechanisms regulating oxidative state in primitive (CD34+) leukemic versus normal specimens. Our data indicate that CD34+ AML cells have elevated expression of multiple glutathione pathway regulatory proteins, presumably as a mechanism to compensate for increased oxidative stress in leukemic cells. Consistent with this observation, CD34+ AML cells have lower levels of reduced glutathione and increased levels of oxidized glutathione compared with normal CD34+ cells. These findings led us to hypothesize that AML cells will be hypersensitive to inhibition of glutathione metabolism. To test this premise, we identified compounds such as parthenolide (PTL) or piperlongumine that induce almost complete glutathione depletion and severe cell death in CD34+ AML cells. Importantly, these compounds only induce limited and transient glutathione depletion as well as significantly less toxicity in normal CD34+ cells. We further determined that PTL perturbs glutathione homeostasis by a multifactorial mechanism, which includes inhibiting key glutathione metabolic enzymes (GCLC and GPX1), as well as direct depletion of glutathione. These findings demonstrate that primitive leukemia cells are uniquely sensitive to agents that target aberrant glutathione metabolism, an intrinsic property of primary human AML cells. PMID:24089526

A gene trap transposon eliminates haematopoietic expression of zebrafish Gfi1aa, but does not interfere with haematopoiesis.

PubMed

Thambyrajah, Roshana; Ucanok, Deniz; Jalali, Maryam; Hough, Yasmin; Wilkinson, Robert Neil; McMahon, Kathryn; Moore, Chris; Gering, Martin

2016-09-01

A transposon-mediated gene trap screen identified the zebrafish line qmc551 that expresses a GFP reporter in primitive erythrocytes and also in haemogenic endothelial cells, which give rise to haematopoietic stem and progenitor cells (HSPCs) that seed sites of larval and adult haematopoiesis. The transposon that mediates this GFP expression is located in intron 1 of the gfi1aa gene, one of three zebrafish paralogs that encode transcriptional repressors homologous to mammalian Gfi1 and Gfi1b proteins. In qmc551 transgenics, GFP expression is under the control of the endogenous gfi1aa promoter, recapitulates early gfi1aa expression and allows live observation of gfi1aa promoter activity. While the transposon integration interferes with the expression of gfi1aa mRNA in haematopoietic cells, homozygous qmc551 fish are viable and fertile, and display normal primitive and definitive haematopoiesis. Retained expression of Gfi1b in primitive erythrocytes and up-regulation of Gfi1ab at the onset of definitive haematopoiesis in homozygous qmc551 carriers, are sufficient to allow normal haematopoiesis. This finding contradicts previously published morpholino data that suggested an essential role for zebrafish Gfi1aa in primitive erythropoiesis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Orbital infantile myofibroma: a case report and clinicopathologic review of 24 cases from the literature.

PubMed

Mynatt, Corey J; Feldman, Kenneth A; Thompson, Lester D R

2011-09-01

Isolated orbital infantile myofibroma are rare tumors in the head and neck. The mass-like clinical presentation and variable histologic features result in frequent misdiagnosis and potentially inappropriate clinical management. There are only a few reported cases in the English literature. Twenty-four patients with orbital infantile myofibroma or myofibromatosis were compiled from the English literature (Medline 1960-2011) and integrated with this case report. The patients included 14 males and 10 females, aged newborn to 10 years (mean, 34.8 months), who presented with a painless mass in the infra- or supraorbital regions, usually increasing in size andassociated with exophthalmos (n = 5). Females were on average older than their male counterparts (38.9 vs. 31.9 months, respectively; P = 0.71). The tumors were twice as frequent on the left (n = 16) than right (n = 8). Patients experienced symptoms for an average of 2.7 months before clinical presentation. The tumors involved the bone (n = 17) or the soft tissues (n = 7) of the orbit, with extension into the nasal or oral cavity (n = 3). The mean size was 3.0 cm, with a statistically significant difference between males and females (mean: 3.9 vs. 1.82; P = 0.0047), but without any differences based on age at presentation (P = 0.25), duration of symptoms (P = 0.66), or bone or soft tissue involvement (P = 0.51). Grossly, all tumors were well-circumscribed, firm to rubbery, homogenous, and white-grey. Histologically, the tumors were biphasic, showing whorled and nodular areas of fusiform cells with extracellular collagen, mixed with a population of small, primitive-appearing, darkly staining cells. Necrosis was not present, but mitoses could be seen. Tumors with immunohistochemistry performed showed strong and diffuse smooth muscle actin and vimentin immunoreactivity, but were negative with muscle specific actin, desmin, MYOD1, myogenin, S100 protein, GFAP, keratin, CD31, 34, Factor VIIIR-Ag, and CD45RB. The principle histologic differential diagnosis includes juvenile hyaline fibromatosis, fibrous hamartoma of infancy, fibromatosis coli, leiomyoma, infantile hemangiopericytoma, infantile fibrosarcoma, Ewing sarcoma/primitive neuroectodermal tumor, and lymphoma. All patients were managed with surgery. Recurrences developed in two patients at 4 and 6 months, respectively. Follow-up data was available on all but two patients (n = 22). These patients were either alive without evidence of disease (n = 18), alive but with disease (n = 3), or had died unrelated to this disease (i.e., neuroblastoma, n = 1). Orbital infantile myofibroma is a rare tumor, presenting in infancy as an enlarging mass of the orbit, with characteristic histomorphologic and immunophenotypic features. Orbital disease is usually isolated rather than part of systemic disease, and shows an excellent long-term prognosis, making appropriate separation from other conditions important.

Childhood cancer incidence trends in association with US folic acid fortification (1986-2008).

PubMed

Linabery, Amy M; Johnson, Kimberly J; Ross, Julie A

2012-06-01

Epidemiologic evidence indicates that prenatal vitamin supplementation reduces risk for some childhood cancers; however, a systematic evaluation of population-based childhood cancer incidence trends after fortification of enriched grain products with folic acid in the United States in 1996-1998 has not been previously reported. Here we describe temporal trends in childhood cancer incidence in association with US folic acid fortification. Using Surveillance, Epidemiology, and End Results program data (1986-2008), we calculated incidence rate ratios and 95% confidence intervals to compare pre- and postfortification cancer incidence rates in children aged 0 to 4 years. Incidence trends were also evaluated by using joinpoint and loess regression models. From 1986 through 2008, 8829 children aged 0 to 4 years were diagnosed with malignancies, including 3790 and 3299 in utero during the pre- and postfortification periods, respectively. Pre- and postfortification incidence rates were similar for all cancers combined and for most specific cancer types. Rates of Wilms tumor (WT), primitive neuroectodermal tumors (PNETs), and ependymomas were significantly lower postfortification. Joinpoint regression models detected increasing WT incidence from 1986 through 1997 followed by a sizable decline from 1997 through 2008, and increasing PNET incidence from 1986 through 1993 followed by a sharp decrease from 1993 through 2008. Loess curves indicated similar patterns. These results provide support for a decrease in WT and possibly PNET incidence, but not other childhood cancers, after US folic acid fortification.

Formation and Rupture of the Internal Carotid Artery Aneurysm after Multiple Courses of Intensity-Modulated Radiation Therapy for Management of the Skull Base Ewing Sarcoma/PNET: Case Report.

PubMed

Tamura, Manabu; Kogo, Kasei; Masuo, Osamu; Oura, Yoshinori; Matsumoto, Hiroyuki; Fujita, Koji; Nakao, Naoyuki; Uematsu, Yuji; Itakura, Toru; Chernov, Mikhail; Hayashi, Motohiro; Muragaki, Yoshihiro; Iseki, Hiroshi

2013-12-01

Background Aneurysm formation after stereotactic irradiation of skull base tumors is rare. The formation and rupture of an internal carotid artery (ICA) aneurysm in a patient with skull base Ewing sarcoma/primitive neuroectodermal tumor (PNET), who underwent surgery followed by multiple courses of intensity-modulated radiation therapy (IMRT) and chemotherapy, is described. Case Description A 25-year-old man presented with a sinonasal tumor with intraorbital and intracranial growth. At that time cerebral angiography did not reveal any vascular abnormalities. The lesion was resected subtotally. Histopathologic diagnosis was Ewing sarcoma/PNET. The patient underwent multiple courses of chemotherapy and three courses of IMRT at 3, 28, and 42 months after initial surgery. The total biologically effective dose delivered to the right ICA was 220.2 Gy. Seven months after the third IMRT, the patient experienced profound nasal bleeding that resulted in hypovolemic shock. Angiography revealed a ruptured right C4-C5 aneurysm and irregular stenotic changes of the ICA. Lifesaving endovascular trapping of the right ICA was done. The patient recovered well after surgery but died due to tumor recurrence 6 months later. Conclusion Excessive irradiation of the ICA may occasionally result in aneurysm formation, which should be borne in mind during stereotactic irradiation of malignant skull base tumors.

Metabolic brain imaging correlated with clinical features of brain tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alavi, J.; Alavi, A.; Dann, R.

1985-05-01

Nineteen adults with brain tumors have been studied with positron emission tomography utilizing FDG. Fourteen had biopsy proven cerebral malignant glioma, one each had meningioma, hemangiopericytoma, primitive neuroectodermal tumor (PNET), two had unbiopsied lesions, and one patient had an area of biopsy proven radiation necrosis. Three different patterns of glucose metabolism are observed: marked increase in metabolism at the site of the known tumor in (10 high grade gliomas and the PNET), lower than normal metabolism at the tumor (in 1 grade II glioma, 3 grade III gliomas, 2 unbiopsied low density nonenhancing lesions, and the meningioma), no abnormality (1more » enhancing glioma, the hemangiopericytoma and the radiation necrosis.) The metabolic rate of the tumor or the surrounding brain did not appear to be correlated with the history of previous irradiation or chemotherapy. Decreased metabolism was frequently observed in the rest of the affected hemisphere and in the contralateral cerebellum. Tumors of high grade or with enhancing CT characteristics were more likely to show increased metabolism. Among the patients with proven gliomas, survival after PETT scan tended to be longer for those with low metabolic activity tumors than for those with highly active tumors. The authors conclude that PETT may help to predict the malignant potential of tumors, and may add useful clinical information to the CT scan.« less

[A new entity in WHO classification of tumors of the central nervous system--embryonic tumor with abundant neuropil and true rosettes: case report and review of literature].

PubMed

Ryzhova, M V; Zheludkova, O G; Ozerov, S S; Shishkina, L V; Panina, T N; Gorelyshev, S K; Novikov, A I; Melikian, A G; Kushel', Iu V; Korshunov, A E

2011-01-01

Embryonic tumor with abundant neuropil and true rosettes (ETANTR) is a very aggressive rare tumor with unique histologic and molecular features occurring in very young children. At present approximately 80 cases of ETANTR have been documented in the literature since first description in 2000. We report seven patients with ETANTR below 4 years of age who underwent surgical resection in the Burdenko Neurosurgery Institute between 2005 and 2010. Four children have received different modality chemotherapy and radiotherapy and two patients were treated by chemotherapy alone. One child did not receive any adjuvant treatment. All children had local relapses, two of them were operated twice. A 2 year old girl underwent subtotal resection thrice. Histological examination showed that all tumors were composed of true multilayered rosettes admixed with large areas of paucicellular neuropil. By analysis of recurrences we have found that large areas of neuropil and number of true rosettes were lost and tumors acquired a resemblance to central nervous system primitive neuroectodermal tumors. In four cases frozen tumor material was available for array-based comparative genomic hybridization, which discovered trisomy of chromosome 2 and amplification at the 19q13.42 chromosome locus. Fluorescence in situ hybridization revealed amplification at the 19q13.42 chromosome locus in all cases.

PMS2 mutations in childhood cancer.

PubMed

De Vos, Michel; Hayward, Bruce E; Charlton, Ruth; Taylor, Graham R; Glaser, Adam W; Picton, Susan; Cole, Trevor R; Maher, Eamonn R; McKeown, Carole M E; Mann, Jill R; Yates, John R; Baralle, Diana; Rankin, Julia; Bonthron, David T; Sheridan, Eamonn

2006-03-01

Until recently, the PMS2 DNA mismatch repair gene has only rarely been implicated as a cancer susceptibility locus. New studies have shown, however, that earlier analyses of this gene have had technical limitations and also that the genetic behavior of mutant PMS2 alleles is unusual, in that, unlike MLH1 or MSH2 mutations, PMS2 mutations show low heterozygote penetrance. As a result, a dominantly inherited cancer predisposition has not been a feature reported in families with PMS2 mutations. Such families have instead been ascertained through childhood-onset cancers in homozygotes or through apparently sporadic colorectal cancer in heterozygotes. We present further information on the phenotype associated with homozygous PMS2 deficiency in 13 patients from six families of Pakistani origin living in the United Kingdom. This syndrome is characterized by café-au-lait skin pigmentation and a characteristic tumor spectrum, including leukemias, lymphomas, cerebral malignancies (such as supratentorial primitive neuroectodermal tumors, astrocytomas, and glioblastomas), and colorectal neoplasia with an onset in early adult life. We present evidence for a founder effect in five families, all of which carried the same R802-->X mutation (i.e., arginine-802 to stop) in PMS2. This cancer syndrome can be mistaken for neurofibromatosis type 1, with important management implications including the risk of the disorder occurring in siblings and the likelihood of tumor development in affected individuals.

Large-scale production of embryonic red blood cells from human embryonic stem cells.

PubMed

Olivier, Emmanuel N; Qiu, Caihong; Velho, Michelle; Hirsch, Rhoda Elison; Bouhassira, Eric E

2006-12-01

To develop a method to produce in culture large number of erythroid cells from human embryonic stem cells. Human H1 embryonic stem cells were differentiated into hematopoietic cells by coculture with a human fetal liver cell line, and the resulting CD34-positive cells were expanded in vitro in liquid culture using a three-step method. The erythroid cells produced were then analyzed by light microscopy and flow cytometry. Globin expression was characterized by quantitative reverse-transcriptase polymerase chain reaction and by high-performance liquid chromatography. CD34-positive cells produced from human embryonic stem cells could be efficiently differentiated into erythroid cells in liquid culture leading to a more than 5000-fold increase in cell number. The erythroid cells produced are similar to primitive erythroid cells present in the yolk sac of early human embryos and did not enucleate. They are fully hemoglobinized and express a mixture of embryonic and fetal globins but no beta-globin. We have developed an experimental protocol to produce large numbers of primitive erythroid cells starting from undifferentiated human embryonic stem cells. As the earliest human erythroid cells, the nucleated primitive erythroblasts, are not very well characterized because experimental material at this stage of development is very difficult to obtain, this system should prove useful to answer a number of experimental questions regarding the biology of these cells. In addition, production of mature red blood cells from human embryonic stem cells is of great potential practical importance because it could eventually become an alternate source of cell for transfusion.

Treatment and Clinical Outcomes of Patients with Teratoma with Somatic-Type Malignant Transformation: An International Collaboration.

PubMed

Giannatempo, Patrizia; Pond, Gregory R; Sonpavde, Guru; Albany, Costantine; Loriot, Yohann; Sweeney, Christopher J; Salvioni, Roberto; Colecchia, Maurizio; Nicolai, Nicola; Raggi, Daniele; Rice, Kevin R; Flack, Chandra K; El Mouallem, Nemer R; Feldman, Hope; Fizazi, Karim; Einhorn, Lawrence H; Foster, Richard S; Necchi, Andrea; Cary, Clint

2016-07-01

We assessed prognostic factors, treatments and outcomes in patients with teratoma with malignant transformation, a rare occurrence among germ cell tumors. Data on patients diagnosed with teratoma with malignant transformation between June 1981 and August 2014 were collected across 5 referral centers. Chemotherapy was dichotomized as based on germ cell tumor or teratoma with malignant transformation. Cox analyses were done to evaluate prognostic factors of overall survival, the primary end point. Each factor was evaluated in a univariable model. Forward stepwise selection was used to construct an optimal model. Among 320 patients the tumor primary site was gonadal in 287 (89.7%), retroperitoneal in 17 (5.3%) and mediastinal in 16 (5%). Teratoma with malignant transformation and germ cell tumor were diagnosed concurrently in 130 patients (40.6%). A total of 49 patients (16.8%) initially presented with clinical stage I. The remaining patients were at good (123 or 42.3%), intermediate (42 or 14.4%) and poor (77 or 26.5%) risk for metastasis according to IGCCCG (International Germ Cell Cancer Collaborative Group). First line chemotherapy was given for germ cell tumor in 159 patients (49.7%), chemotherapy for teratoma with malignant transformation was performed in 14 (4.4%) and only surgery was done in 147 (45.9%). Median followup was 25.1 months (IQR 5.4-63.8). Five-year overall survival was 83.4% (95% CI 61.3 to 93.5) in patients with clinical stage I and it was also worse than expected in those with metastasis. On multivariable analyses nonprimitive neuroectodermal tumor histology (overall p = 0.004), gonadal primary tumor (p = 0.005) and fewer prior chemotherapy regimens (p <0.001) were independent predictors of better overall survival. Chemotherapy was not independently prognostic. Less heavily pretreated teratoma with malignant transformation with a gonadal primary tumor and nonprimitive neuroectodermal tumor histology appears to be associated with longer overall survival. Generally, teratoma with malignant transformation had a worse prognosis than germ cell tumor. Uncertainties persist regarding optimal chemotherapy. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

CD71(high) population represents primitive erythroblasts derived from mouse embryonic stem cells.

PubMed

Chao, Ruihua; Gong, Xueping; Wang, Libo; Wang, Pengxiang; Wang, Yuan

2015-01-01

The CD71/Ter119 combination has been widely used to reflect dynamic maturation of erythrocytes in vivo. However, because CD71 is expressed on all proliferating cells, it is unclear whether it can be utilized as an erythrocyte-specific marker during differentiation of embryonic stem cells (ESCs). In this study, we revealed that a population expressing high level of CD71 (CD71(high)) during mouse ESC differentiation represented an in vitro counterpart of yolk sac-derived primitive erythroblasts (EryPs) isolated at 8.5days post coitum. In addition, these CD71(high) cells went through "maturational globin switching" and enucleated during terminal differentiation in vitro that were similar to the yolk sac-derived EryPs in vivo. We further demonstrated that the formation of CD71(high) population was regulated differentially by key factors including Scl, HoxB4, Eaf1, and Klf1. Taken together, our study provides a technical advance that allows efficient segregation of EryPs from differentiated ESCs in vitro for further understanding molecular regulation during primitive erythropoiesis. Copyright © 2014. Published by Elsevier B.V.

Attributed relational graphs for cell nucleus segmentation in fluorescence microscopy images.

PubMed

Arslan, Salim; Ersahin, Tulin; Cetin-Atalay, Rengul; Gunduz-Demir, Cigdem

2013-06-01

More rapid and accurate high-throughput screening in molecular cellular biology research has become possible with the development of automated microscopy imaging, for which cell nucleus segmentation commonly constitutes the core step. Although several promising methods exist for segmenting the nuclei of monolayer isolated and less-confluent cells, it still remains an open problem to segment the nuclei of more-confluent cells, which tend to grow in overlayers. To address this problem, we propose a new model-based nucleus segmentation algorithm. This algorithm models how a human locates a nucleus by identifying the nucleus boundaries and piecing them together. In this algorithm, we define four types of primitives to represent nucleus boundaries at different orientations and construct an attributed relational graph on the primitives to represent their spatial relations. Then, we reduce the nucleus identification problem to finding predefined structural patterns in the constructed graph and also use the primitives in region growing to delineate the nucleus borders. Working with fluorescence microscopy images, our experiments demonstrate that the proposed algorithm identifies nuclei better than previous nucleus segmentation algorithms.

Application of infrared spectroscopy in the identification of Ewing sarcoma: A preliminary report

NASA Astrophysics Data System (ADS)

Chaber, Radosław; Łach, Kornelia; Szmuc, Kamil; Michalak, Elżbieta; Raciborska, Anna; Mazur, Damian; Machaczka, Maciej; Cebulski, Józef

2017-06-01

Fourier transform infrared (FTIR) spectroscopy is a highly sensitive, non-invasive analytical technique that can provide information about molecular changes in a biological sample. FTIR spectrum is a sum of the frequencies of many biomolecules which reveals a biochemical fingerprint for mineral identification, and can be analyzed for information about the mineral structure of malignant cells. This gives us the potential to differentiate tumor cells from normal cells in the early stage of relapse, before the tumor cells would be detectable in light microscopy. Ewing sarcoma (ES) is the second most common malignant bone tumor found in children and adolescents. ES affects annually almost 3 persons/1,000,000 mostly children and young adults under 20 years of age annually. ES originates from primitive, low-differentiated neuroectodermal cells. The current standard of therapy for ES is the surgical resection of the primary tumor and metastasis in combination with the chemo- and radiotherapy. The aim of this study was to compare the spectra of ES bone samples and the spectra of normal bone tissues, analyzed before and after induction chemotherapy, by means of FTIR spectroscopy. Six patients with ES affecting bones aged 5.5-16.5 years (median age 11.2 years), who were treated between 2011 and 2015, were included to the study. In all analyzed patients, the diagnosis of ES and the assessment of response to the chemotherapy were performed according to the Euro-EWING-2008 protocol. The Fourier transform infrared spectroscope (FT-IR; Vertex 70v from Bruker) was used in this study. Tissue specimens were applied to the attenuated total reflection (ATR) in the infrared (IR) radiation from the mid-infrared range using a single-reflection snap ATR crystal diamond. In the FTIR spectra we observed a shift in the wave number of the phosphate ion (from 3 to 26 [cm-1]) associated with the presence of tumor tissue. After chemotherapy, a change of the FTIR spectrum was associated with the ES's histopathological response. In patients with a high ratio of the necrotic cells in the tumor (>90% of cells) after chemotherapy, we showed a shift of the peak ⧹ absorption bands to the higher wave numbers. In contrast, in patients with a poor chemotherapy response (<30% of necrotic cells in the tumor), we observed a decline in the peak absorption bands to the lower wave numbers. The results showed that analysis of the spectrum changes of tissue specimens in ES can be helpful in the assessment of clinical response to cancer therapy. It seems that FTIR spectroscopy is a valuable tool for his purpose. The issue awaits full elucidation in further studies on larger groups of patients with ES.

Tubulin post-translational modifications in the primitive protist Trichomonas vaginalis.

PubMed

Delgado-Viscogliosi, P; Brugerolle, G; Viscogliosi, E

1996-01-01

Using several specific monoclonal antibodies, we investigated the occurrence and distribution of different post-translationally modified tubulin during interphase and division of the primitive flagellated protist Trichomonas vaginalis. Immunoblotting and immunofluorescence experiments revealed that interphasic microtubular structures of T. vaginalis contained acetylated and glutamylated but non-tyrosinated and non-glycylated [Brugerolle and Adoutte, 1988: Bio Systems 21: 255-268] tubulin. Immunofluorescence studies performed on dividing cells showed that the extranuclear mitotic spindle (or paradesmosis) was acetylated and glutamylated, which contrast with the ephemeral nature of this structure. Newly formed short axostyles also contained acetylated and glutamylated tubulin suggesting that both post-translational modifications might take place very early after assembly of microtubular structures. Our results indicate that acetylation and glutamylation of tubulin appeared early in the history of eukaryotes and could reflect the occurrence of post-translational modifications of tubulin in the primitive eukaryotic cells. These cells probably had a highly ordered cross-linked microtubular cytoskeleton in which microtubules showed a low level of subunit exchange dynamics.

Transduction of Human Primitive Repopulating Hematopoietic Cells With Lentiviral Vectors Pseudotyped With Various Envelope Proteins

PubMed Central

Kim, Yoon-Sang; Wielgosz, Matthew M; Hargrove, Phillip; Kepes, Steven; Gray, John; Persons, Derek A; Nienhuis, Arthur W

2010-01-01

Lentiviral vectors are useful for transducing primitive hematopoietic cells. We examined four envelope proteins for their ability to mediate lentiviral transduction of mobilized human CD34+ peripheral blood cells. Lentiviral particles encoding green fluorescent protein (GFP) were pseudotyped with the vesicular stomatitis virus envelope glycoprotein (VSV-G), the amphotropic (AMPHO) murine leukemia virus envelope protein, the endogenous feline leukemia viral envelope protein or the feline leukemia virus type C envelope protein. Because the relative amount of genome RNA per ml was similar for each pseudotype, we transduced CD34+ cells with a fixed volume of each vector preparation. Following an overnight transduction, CD34+ cells were transplanted into immunodeficient mice which were sacrificed 12 weeks later. The average percentages of engrafted human CD45+ cells in total bone marrow were comparable to that of the control, mock-transduced group (37–45%). Lenti-particles pseudotyped with the VSV-G envelope protein transduced engrafting cells two- to tenfold better than particles pseudotyped with any of the γ-retroviral envelope proteins. There was no correlation between receptor mRNA levels for the γ-retroviral vectors and transduction efficiency of primitive hematopoietic cells. These results support the use of the VSV-G envelope protein for the development of lentiviral producer cell lines for manufacture of clinical-grade vector. PMID:20372106

Targeting the aryl hydrocarbon receptor nuclear translocator complex with DMOG and Stemregenin 1 improves primitive hematopoietic stem cell expansion.

PubMed

Jackson, Carlo Stephan; Durandt, Chrisna; Janse van Rensburg, Ilse; Praloran, Vincent; Brunet de la Grange, Philippe; Pepper, Michael Sean

2017-05-01

Culture conditions used for the expansion of hematopoietic stem and progenitor cells (HSCs and HPCs, collectively HSPCs) should ideally favor the self renewal of long-term HSCs. At 20% O 2 , the synthesis of HIF-1α is balanced by its hydroxylation and proteasomal degradation. This favors HSPC differentiation, but can be prevented by culturing CD34+ cord blood cells in the presence of dimethyloxaloylglycine (DMOG). This differentiation may also be reduced by culturing the cells in the presence of Stemregenin 1, an antagonist of the aryl hydrocarbon receptor (AhR). The objective of this study was to investigate how hypoxia, DMOG and Stemregenin 1 might affect the expansion of HSPCs with the aim of identifying optimal conditions for expansion in culture. It was found that DMOG decreased proliferation but was effective in preserving the number of cells in the primitive hematopoietic sub-populations in vitro. The effect of DMOG was similar to hypoxia, although differences were observed with regard to the side population and CD34+ sub-populations. Stemregenin 1 on the other hand increased the size of the primitive as well as the other HSC sub-populations. The use of Stemregenin 1 with DMOG increased the proportion of primitive HSCs to 3.54% compared to 2.61% for Stemregenin 1 alone. In vivo engraftment studies confirmed these findings and showed that fewer cells (3710) are required for long-term engraftment when HSCs are grown in Stemregenin 1 together with hypoxia than in Stemregenin 1 under conditions of normoxia (13430). Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

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

PubMed Central

Aubé, Michel; Lafrance, Matthieu; Brodeur, Isabelle; Delisle, Marie-Chantal; Carreau, Madeleine

2003-01-01

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. PMID:12809565

Individual blastomeres of 16- and 32-cell mouse embryos are able to develop into foetuses and mice.

PubMed

Tarkowski, Andrzej K; Suwińska, Aneta; Czołowska, Renata; Ożdżeński, Wacław

2010-12-15

Cell and developmental studies have clarified how, by the time of implantation, the mouse embryo forms three primary cell lineages: epiblast (EPI), primitive endoderm (PE), and trophectoderm (TE). However, it still remains unknown when cells allocated to these three lineages become determined in their developmental fate. To address this question, we studied the developmental potential of single blastomeres derived from 16- and 32-cell stage embryos and supported by carrier, tetraploid blastomeres. We were able to generate singletons, identical twins, triplets, and quadruplets from individual inner and outer cells of 16-cell embryos and, sporadically, foetuses from single cells of 32-cell embryos. The use of embryos constitutively expressing GFP as the donors of single diploid blastomeres enabled us to identify their cell progeny in the constructed 2n↔4n blastocysts. We showed that the descendants of donor blastomeres were able to locate themselves in all three first cell lineages, i.e., epiblast, primitive endoderm, and trophectoderm. In addition, the application of Cdx2 and Gata4 markers for trophectoderm and primitive endoderm, respectively, showed that the expression of these two genes in the descendants of donor blastomeres was either down- or up-regulated, depending on the cell lineage they happened to occupy. Thus, our results demonstrate that up to the early blastocysts stage, the destiny of at least some blastomeres, although they have begun to express markers of different lineage, is still labile. Copyright © 2010 Elsevier Inc. All rights reserved.

Characterization of selected elementary motion detector cells to image primitives.

PubMed

Benson, Leslie A; Barrett, Steven F; Wright, Cameron H G

2008-01-01

Developing a visual sensing system, complete with motion processing hardware and software would have many applications to current technology. It could be mounted on many autonomous vehicles to provide information about the navigational environment, as well as obstacle avoidance features. Incorporating the motion processing capabilities into the sensor requires a new approach to the algorithm implementation. This research, and that of many others, have turned to nature for inspiration. Elementary motion detector (EMD) cells are involved in a biological preprocessing network to provide information to the motion processing lobes of the house degrees y Musca domestica. This paper describes the response of the photoreceptor inputs to the EMDs. The inputs to the EMD components are tested as they are stimulated with varying image primitives. This is the first of many steps in characterizing the EMD response to image primitives.

The evolution of nervous system patterning: insights from sea urchin development

PubMed Central

Angerer, Lynne M.; Yaguchi, Shunsuke; Angerer, Robert C.; Burke, Robert D.

2011-01-01

Recent studies of the sea urchin embryo have elucidated the mechanisms that localize and pattern its nervous system. These studies have revealed the presence of two overlapping regions of neurogenic potential at the beginning of embryogenesis, each of which becomes progressively restricted by separate, yet linked, signals, including Wnt and subsequently Nodal and BMP. These signals act to specify and localize the embryonic neural fields – the anterior neuroectoderm and the more posterior ciliary band neuroectoderm – during development. Here, we review these conserved nervous system patterning signals and consider how the relationships between them might have changed during deuterostome evolution. PMID:21828090

Spontaneous circulation of myeloid-lymphoid-initiating cells and SCID-repopulating cells in sickle cell crisis.

PubMed

Lamming, Christopher E D; Augustin, Lance; Blackstad, Mark; Lund, Troy C; Hebbel, Robert P; Verfaillie, Catherine M

2003-03-01

The only curative therapy for sickle cell disease (SCD) is allogeneic hematopoietic stem cell (HSC) transplantation. Gene therapy approaches for autologous HSC transplantation are being developed. Although earlier engraftment is seen when cells from GCSF-mobilized blood are transplanted than when bone marrow is transplanted, administration of GCSF to patients with SCD can cause significant morbidity. We tested whether primitive hematopoietic progenitors are spontaneously mobilized in the blood of patients with SCD during acute crisis (AC-SCD patients). The frequency of myeloid-lymphoid-initiating cells (ML-ICs) and SCID-repopulating cells (SRCs) was significantly higher in blood from AC-SCD patients than in blood from patients with steady-state SCD or from normal donors. The presence of SRCs in peripheral blood was not associated with detection of long-term culture-initiating cells, consistent with the notion that SRCs are more primitive than long-term culture-initiating cells. As ML-ICs and SRCs were both detected in blood of AC-SCD patients only, these assays may both measure primitive progenitors. The frequency of ML-ICs also correlated with increases in stem cell factor, GCSF, and IL-8 levels in AC-SCD compared with steady-state SCD and normal-donor sera. Because significant numbers of ML-ICs and SRCs are mobilized in the blood without exogenous cytokine treatment during acute crisis of SCD, collection of peripheral blood progenitors during crisis may yield a source of autologous HSCs suitable for ex-vivo correction by gene therapy approaches and subsequent transplantation.

The Coherent Interlayer Resistance of a Single, Misoriented Interface between Two Graphite Stacks

NASA Astrophysics Data System (ADS)

Lake, Roger K.; Habib, K. M. Masum; Sylvia, Somaia; Ge, Supeng; Neupane, Mahesh

2014-03-01

The coherent, interlayer resistance of a misoriented, rotated interface between two stacks of AB graphite is determined for a variety of misorientation angles ranging from 0° to 27 .29° . The quantum-resistance of the ideal AB stack is on the order of 1 to 10 m Ωμm2 depending on the Fermi energy. For small rotation angles <= 7 .34° , the coherent interlayer resistance exponentially approaches the ideal quantum resistance at energies away from the charge neutrality point. Over a range of intermediate angles, the resistance increases exponentially with primitive cell size for minimum size cells. A change of misorientation angle by one degree can increase the primitive cell size by three orders of magnitude. These large cell sizes may not follow the exponential trend of the minimal cells especially at energies a few hundred meV away from the charge neutrality point. At such energies, their coherent interlayer resistance is likely to coincide with that of a nearby rotation angle with a much smaller primitive cell. The energy dependence of the interlayer transmission is described and analyzed. This work was supported in part by FAME, one of six centers of STARnet, a Semiconductor Research Corporation program sponsored by MARCO and DARPA.

Local bone marrow renin-angiotensin system in primitive, definitive and neoplastic haematopoiesis.

PubMed

Haznedaroglu, Ibrahim C; Beyazit, Yavuz

2013-03-01

The locally active ligand peptides, mediators, receptors and signalling pathways of the haematopoietic BM (bone marrow) autocrine/paracrine RAS (renin-angiotensin system) affect the essential steps of definitive blood cell production. Haematopoiesis, erythropoiesis, myelopoiesis, formation of monocytic and lymphocytic lineages, thrombopoiesis and other stromal cellular elements are regulated by the local BM RAS. The local BM RAS is present and active even in primitive embryonic haematopoiesis. ACE (angiotensin-converting enzyme) is expressed on the surface of the first endothelial and haematopoietic cells, forming the marrow cavity in the embryo. ACE marks early haematopoietic precursor cells and long-term blood-forming CD34(+) BM cells. The local autocrine tissue BM RAS may also be active in neoplastic haematopoiesis. Critical RAS mediators such as renin, ACE, AngII (angiotensin II) and angiotensinogen have been identified in leukaemic blast cells. The local tissue RAS influences tumour growth and metastases in an autocrine and paracrine fashion via the modulation of numerous carcinogenic events, such as angiogenesis, apoptosis, cellular proliferation, immune responses, cell signalling and extracellular matrix formation. The aim of the present review is to outline the known functions of the local BM RAS within the context of primitive, definitive and neoplastic haematopoiesis. Targeting the actions of local RAS molecules could represent a valuable therapeutic option for the management of neoplastic disorders.

Comparison of Gene Expression in Human Embryonic Stem Cells, hESC-Derived Mesenchymal Stem Cells and Human Mesenchymal Stem Cells.

PubMed

Barbet, Romain; Peiffer, Isabelle; Hatzfeld, Antoinette; Charbord, Pierre; Hatzfeld, Jacques A

2011-01-01

We present a strategy to identify developmental/differentiation and plasma membrane marker genes of the most primitive human Mesenchymal Stem Cells (hMSCs). Using sensitive and quantitative TaqMan Low Density Arrays (TLDA) methodology, we compared the expression of 381 genes in human Embryonic Stem Cells (hESCs), hESC-derived MSCs (hES-MSCs), and hMSCs. Analysis of differentiation genes indicated that hES-MSCs express the sarcomeric muscle lineage in addition to the classical mesenchymal lineages, suggesting they are more primitive than hMSCs. Transcript analysis of membrane antigens suggests that IL1R1(low), BMPR1B(low), FLT4(low), LRRC32(low), and CD34 may be good candidates for the detection and isolation of the most primitive hMSCs. The expression in hMSCs of cytokine genes, such as IL6, IL8, or FLT3LG, without expression of the corresponding receptor, suggests a role for these cytokines in the paracrine control of stem cell niches. Our database may be shared with other laboratories in order to explore the considerable clinical potential of hES-MSCs, which appear to represent an intermediate developmental stage between hESCs and hMSCs.

Krüppel-Like Factor 1 (KLF1), KLF2, and Myc Control a Regulatory Network Essential for Embryonic Erythropoiesis

PubMed Central

Pang, Christopher J.; Lemsaddek, Wafaa; Alhashem, Yousef N.; Bondzi, Cornelius; Redmond, Latasha C.; Ah-Son, Nicolas; Dumur, Catherine I.; Archer, Kellie J.; Haar, Jack L.

2012-01-01

The Krüppel-like factor 1 (KLF1) and KLF2 positively regulate embryonic β-globin expression and have additional overlapping roles in embryonic (primitive) erythropoiesis. KLF1−/− KLF2−/− double knockout mice are anemic at embryonic day 10.5 (E10.5) and die by E11.5, in contrast to single knockouts. To investigate the combined roles of KLF1 and KLF2 in primitive erythropoiesis, expression profiling of E9.5 erythroid cells was performed. A limited number of genes had a significantly decreasing trend of expression in wild-type, KLF1−/−, and KLF1−/− KLF2−/− mice. Among these, the gene for Myc (c-Myc) emerged as a central node in the most significant gene network. The expression of the Myc gene is synergistically regulated by KLF1 and KLF2, and both factors bind the Myc promoters. To characterize the role of Myc in primitive erythropoiesis, ablation was performed specifically in mouse embryonic proerythroblast cells. After E9.5, these embryos exhibit an arrest in the normal expansion of circulating red cells and develop anemia, analogous to KLF1−/− KLF2−/− embryos. In the absence of Myc, circulating erythroid cells do not show the normal increase in α- and β-like globin gene expression but, interestingly, have accelerated erythroid cell maturation between E9.5 and E11.5. This study reveals a novel regulatory network by which KLF1 and KLF2 regulate Myc to control the primitive erythropoietic program. PMID:22566683

Is alkaline phosphatase the smoking gun for highly refractory primitive leukemic cells?

PubMed Central

Rico, Laura G.; Juncà, Jordi; Ward, Mike D.; Bradford, Jolene; Petriz, Jordi

2016-01-01

With the aim to detect candidate malignant primitive progenitor populations, we modified an original alkaline phosphatase (ALP) stem cell detection method based on the identification of alkaline phosphatase fluorescent cells in combination with flow cytometry immunophenotyping. Over a period of one year, we have been using this technique to study its activity in patients with leukemia and lymphoma, showing that changes in the alkaline phosphatase levels can be used to detect rare populations of highly refractory malignant cells. By screening different blood cancers, we have observed that this activity is not always restricted to CD34+ leukemic cells, and can be overexpressed in CD34 negative leukemia. We have verified that this method gives accurate and reproducible measurements and our preliminary results suggest that CD34+/ALPhigh cells appear to sustain leukemogenesis over time. PMID:27732563

Primitive macrophages control HSPC mobilization and definitive haematopoiesis.

PubMed

Travnickova, Jana; Tran Chau, Vanessa; Julien, Emmanuelle; Mateos-Langerak, Julio; Gonzalez, Catherine; Lelièvre, Etienne; Lutfalla, Georges; Tavian, Manuela; Kissa, Karima

2015-02-17

In vertebrates, haematopoietic stem/progenitor cells (HSPCs) first emerge in the aorta-gonad-mesonephros (AGM) before colonizing transitory and subsequently definitive haematopoietic organs allowing haematopoiesis throughout adult life. Here we identify an unexpected primitive macrophage population accumulated in the dorsal mesenteric mesoderm surrounding the dorsal aorta of the human embryo and study its function in the transparent zebrafish embryo. Our study reveals dynamic interactions occurring between the HSPCs and primitive macrophages in the AGM. Specific chemical and inducible genetic depletion of macrophages or inhibition of matrix metalloproteinases (Mmps) leads to an accumulation of HSPCs in the AGM and a decrease in the colonization of haematopoietic organs. Finally, in vivo zymography demonstrates the function of primitive macrophages in extracellular matrix degradation, which allows HSPC migration through the AGM stroma, their intravasation, leading to the colonization of haematopoietic organs and the establishment of definitive haematopoiesis.

Neocortical layers I and II of the hedgehog (Erinaceus europaeus). I. Intrinsic organization.

PubMed

Valverde, F; Facal-Valverde, M V

1986-01-01

The intrinsic organization and interlaminar connections in neocortical layers I and II have been studied in adult hedgehogs (Erinaceus europaeus) using the Golgi method. Layer I contains a dense plexus of horizontal fibers, the terminal dendritic bouquets of pyramidal cells of layer II and of underlying layers, and varieties of intrinsic neurons. Four main types of cells were found in layer I. Small horizontal cells represent most probably persisting foetal horizontal cells described for other mammals. Large horizontal cells, tufted cells, and spinous horizontal cells were also found in this layer. Layer II contains primitive pyramidal cells representing the most outstanding feature of the neocortex of the hedgehog. Most pyramidal cells in layer II have two, three or more apical dendrites, richly covered by spines predominating over the basal dendrites. These cells resemble pyramidal cells found in the piriform cortex, hippocampus and other olfactory areas. It is suggested that the presence of these neurons reflects the retention of a primitive character in neocortical evolution. Cells with intrinsic axons were found among pyramidal cells in layer II. These have smooth dendrites penetrating layer I and local axons forming extremely complex terminal arborizations around the bodies and proximal dendritic portions of pyramidal cells. They most probably effect numerous axo-somatic contacts resembling basket cells. The similarity of some axonal terminals with the chandelier type of axonal arborization is discussed. Other varieties of cells located in deep cortical layers and having ascending axons for layers I and II were also studied. It is concluded that the two first neocortical layers represent a level of important integration in this primitive mammal.

Spontaneous circulation of myeloid-lymphoid–initiating cells and SCID-repopulating cells in sickle cell crisis

PubMed Central

Lamming, Christopher E.D.; Augustin, Lance; Blackstad, Mark; Lund, Troy C.; Hebbel, Robert P.; Verfaillie, Catherine M.

2003-01-01

The only curative therapy for sickle cell disease (SCD) is allogeneic hematopoietic stem cell (HSC) transplantation. Gene therapy approaches for autologous HSC transplantation are being developed. Although earlier engraftment is seen when cells from GCSF-mobilized blood are transplanted than when bone marrow is transplanted, administration of GCSF to patients with SCD can cause significant morbidity. We tested whether primitive hematopoietic progenitors are spontaneously mobilized in the blood of patients with SCD during acute crisis (AC-SCD patients). The frequency of myeloid-lymphoid–initiating cells (ML-ICs) and SCID-repopulating cells (SRCs) was significantly higher in blood from AC-SCD patients than in blood from patients with steady-state SCD or from normal donors. The presence of SRCs in peripheral blood was not associated with detection of long-term culture–initiating cells, consistent with the notion that SRCs are more primitive than long-term culture–initiating cells. As ML-ICs and SRCs were both detected in blood of AC-SCD patients only, these assays may both measure primitive progenitors. The frequency of ML-ICs also correlated with increases in stem cell factor, GCSF, and IL-8 levels in AC-SCD compared with steady-state SCD and normal-donor sera. Because significant numbers of ML-ICs and SRCs are mobilized in the blood without exogenous cytokine treatment during acute crisis of SCD, collection of peripheral blood progenitors during crisis may yield a source of autologous HSCs suitable for ex-vivo correction by gene therapy approaches and subsequent transplantation. PMID:12639987

Importance of Sox2 in maintenance of cell proliferation and multipotency of mesenchymal stem cells in low-density culture.

PubMed

Yoon, D S; Kim, Y H; Jung, H S; Paik, S; Lee, J W

2011-10-01

This study has aimed to repopulate 'primitive' cells from late-passage mesenchymal stem cells (MSCs) of poor multipotentiality and low cell proliferation rate, by simply altering plating density. Effects of low density culture compared t high density culture on late-passage bone marrow (BM)-derived MSCs and pluripotency markers of multipotentiality were investigated. Cell proliferation, gene expression, RNA interference and differentiation potential were assayed. We repopulated 'primitive' cells by replating late-passage MSCs at low density (17 cells/cm(2) ) regardless of donor age. Repopulated MSCs from low-density culture were smaller cells with spindle shaped morphology compared to MSCs from high-density culture. The latter had enhanced colony-forming ability, proliferation rate, and adipogenic and chondrogenic potential. Strong expression of osteogenic-related genes (Cbfa1, Dlx5, alkaline phosphatase and type Ι collagen) in late-passage MSCs was reduced by replating at low density, whereas expression of three pluripotency markers (Sox2, Nanog and Oct-4), Osterix and Msx2 reverted to levels of early-passage MSCs. Knockdown of Sox2 and Msx2 but not Nanog, using RNA interference, showed significant decrease in colony-forming ability. Specifically, knockdown of Sox2 significantly inhibited multipotentiality and cell proliferation. Our data suggest that plating density should be considered to be a critical factor for enrichment of 'primitive' cells from heterogeneous BM and that replicative senescence and multipotentiality of MSCs during in vitro expansion may be predominantly regulated through Sox2. © 2011 Blackwell Publishing Ltd.

Generation of neural progenitor cells by chemical cocktails and hypoxia

PubMed Central

Cheng, Lin; Hu, Wenxiang; Qiu, Binlong; Zhao, Jian; Yu, Yongchun; Guan, Wuqiang; Wang, Min; Yang, Wuzhou; Pei, Gang

2014-01-01

Neural progenitor cells (NPCs) can be induced from somatic cells by defined factors. Here we report that NPCs can be generated from mouse embryonic fibroblasts by a chemical cocktail, namely VCR (V, VPA, an inhibitor of HDACs; C, CHIR99021, an inhibitor of GSK-3 kinases and R, Repsox, an inhibitor of TGF-β pathways), under a physiological hypoxic condition. These chemical-induced NPCs (ciNPCs) resemble mouse brain-derived NPCs regarding their proliferative and self-renewing abilities, gene expression profiles, and multipotency for different neuroectodermal lineages in vitro and in vivo. Further experiments reveal that alternative cocktails with inhibitors of histone deacetylation, glycogen synthase kinase, and TGF-β pathways show similar efficacies for ciNPC induction. Moreover, ciNPCs can also be induced from mouse tail-tip fibroblasts and human urinary cells with the same chemical cocktail VCR. Thus our study demonstrates that lineage-specific conversion of somatic cells to NPCs could be achieved by chemical cocktails without introducing exogenous factors. PMID:24638034

Progenitors of the protochordate ocellus as an evolutionary origin of the neural crest

PubMed Central

2013-01-01

The neural crest represents a highly multipotent population of embryonic stem cells found only in vertebrate embryos. Acquisition of the neural crest during the evolution of vertebrates was a great advantage, providing Chordata animals with the first cellular cartilage, bone, dentition, advanced nervous system and other innovations. Today not much is known about the evolutionary origin of neural crest cells. Here we propose a novel scenario in which the neural crest originates from neuroectodermal progenitors of the pigmented ocelli in Amphioxus-like animals. We suggest that because of changes in photoreception needs, these multipotent progenitors of photoreceptors gained the ability to migrate outside of the central nervous system and subsequently started to give rise to neural, glial and pigmented progeny at the periphery. PMID:23575111

Impact of modeled microgravity on migration, differentiation, and cell cycle control of primitive human hematopoietic progenitor cells.

PubMed

Plett, P Artur; Abonour, Rafat; Frankovitz, Stacy M; Orschell, Christie M

2004-08-01

Migration, proliferation, and differentiation of bone marrow (BM) hematopoietic stem cells (HSC) are important factors in maintaining hematopoietic homeostasis. Homeostatic control of erythrocytes and lymphocytes is perturbed in humans exposed to microgravity (micro-g), resulting in space flight-induced anemia and immunosuppression. We sought to determine whether any of these anomalies can be explained by micro-g-induced changes in migration, proliferation, and differentiation of human BM CD34+ cells, and whether such changes can begin to explain any of the shifts in hematopoietic homeostasis observed in astronauts. BM CD34+ cells were cultured in modeled micro-g (mmicro-g) using NASA's rotating wall vessels (RWV), or in control cultures at earth gravity for 2 to 18 days. Cells were harvested at different times and CD34+ cells assessed for migration potential, cell-cycle kinetics and regulatory proteins, and maturation status. Culture of BM CD34+ cells in RWV for 2 to 3 days resulted in a significant reduction of stromal cell-derived factor 1 (SDF-1alpha)-directed migration, which correlated with decreased expression of F-actin. Modeled micro-g induced alterations in cell-cycle kinetics that were characterized by prolonged S phase and reduced cyclin A expression. Differentiation of primitive CD34+ cells cultured for 14 to 18 days in RWV favored myeloid cell development at the expense of erythroid development, which was significantly reduced compared to controls. These results illustrate that mmicro-g significantly inhibits the migration potential, cell-cycle progression, and differentiation patterns of primitive BM CD34+ cells, which may contribute to some of the hematologic abnormalities observed in humans during space flight.

Msx1-modulated muscle satellite cells retain a primitive state and exhibit an enhanced capacity for osteogenic differentiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ding, Ke, E-mail: dingke@med.uestc.edu.cn; Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072; Department of Orthopaedics, Southwest Hospital, Third Military Medical University, Chongqing 400038

Multipotent muscle satellite cells (MuSCs) have been identified as potential seed cells for bone tissue engineering. However, MuSCs exhibit a rapid loss of stemness after in vitro culturing, thereby compromising their therapeutic efficiency. Muscle segment homeobox gene 1 (msx1) has been found to induce the dedifferentiation of committed progenitor cells, as well as terminally differentiated myotubes. In this study, a Tet-off retroviral gene delivery system was used to modulate msx1 expression. After ten passages, MuSCs that did not express msx-1 (e.g., the non-msx1 group) were compared with MuSCs with induced msx-1 expression (e.g., the msx1 group). The latter group exhibitedmore » a more juvenile morphology, it contained a significantly lower percentage of senescent cells characterized by positive β-galactosidase staining, and it exhibited increased proliferation and a higher proliferation index. Immunocytochemical stainings further detected a more primitive gene expression profile for the msx1 group, while osteogenic differentiation assays and ectopic bone formation assays demonstrated an improved capacity for the msx1 group to undergo osteogenic differentiation. These results suggest that transient expression of msx1 in MuSCs can retain a primitive state, thereby enhancing their capacity for osteogenic differentiation and restoring the potential for MuSCs to serve as seed cells for bone tissue engineering.« less

Msx1-modulated muscle satellite cells retain a primitive state and exhibit an enhanced capacity for osteogenic differentiation.

PubMed

Ding, Ke; Liu, Wen-Ying; Zeng, Qiang; Hou, Fang; Xu, Jian-Zhong; Yang, Zhong

2017-03-01

Multipotent muscle satellite cells (MuSCs) have been identified as potential seed cells for bone tissue engineering. However, MuSCs exhibit a rapid loss of stemness after in vitro culturing, thereby compromising their therapeutic efficiency. Muscle segment homeobox gene 1 (msx1) has been found to induce the dedifferentiation of committed progenitor cells, as well as terminally differentiated myotubes. In this study, a Tet-off retroviral gene delivery system was used to modulate msx1 expression. After ten passages, MuSCs that did not express msx-1 (e.g., the non-msx1 group) were compared with MuSCs with induced msx-1 expression (e.g., the msx1 group). The latter group exhibited a more juvenile morphology, it contained a significantly lower percentage of senescent cells characterized by positive β-galactosidase staining, and it exhibited increased proliferation and a higher proliferation index. Immunocytochemical stainings further detected a more primitive gene expression profile for the msx1 group, while osteogenic differentiation assays and ectopic bone formation assays demonstrated an improved capacity for the msx1 group to undergo osteogenic differentiation. These results suggest that transient expression of msx1 in MuSCs can retain a primitive state, thereby enhancing their capacity for osteogenic differentiation and restoring the potential for MuSCs to serve as seed cells for bone tissue engineering. Copyright © 2017 Elsevier Inc. All rights reserved.

Disruption of IKAROS activity in primitive chronic-phase CML cells mimics myeloid disease progression

PubMed Central

Beer, Philip A.; Knapp, David J. H. F.; Miller, Paul H.; Kannan, Nagarajan; Sloma, Ivan; Heel, Kathy; Babovic, Sonja; Bulaeva, Elizabeth; Rabu, Gabrielle; Terry, Jefferson; Druker, Brian J.; Loriaux, Marc M.; Loeb, Keith R.; Radich, Jerald P.; Erber, Wendy N.

2015-01-01

Without effective therapy, chronic-phase chronic myeloid leukemia (CP-CML) evolves into an acute leukemia (blast crisis [BC]) that displays either myeloid or B-lymphoid characteristics. This transition is often preceded by a clinically recognized, but biologically poorly characterized, accelerated phase (AP). Here, we report that IKAROS protein is absent or reduced in bone marrow blasts from most CML patients with advanced myeloid disease (AP or BC). This contrasts with primitive CP-CML cells and BCR-ABL1–negative acute myeloid leukemia blasts, which express readily detectable IKAROS. To investigate whether loss of IKAROS contributes to myeloid disease progression in CP-CML, we examined the effects of forced expression of a dominant-negative isoform of IKAROS (IK6) in CP-CML patients’ CD34+ cells. We confirmed that IK6 disrupts IKAROS activity in transduced CP-CML cells and showed that it confers on them features of AP-CML, including a prolonged increased output in vitro and in xenografted mice of primitive cells with an enhanced ability to differentiate into basophils. Expression of IK6 in CD34+ CP-CML cells also led to activation of signal transducer and activator of transcription 5 and transcriptional repression of its negative regulators. These findings implicate loss of IKAROS as a frequent step and potential diagnostic harbinger of progressive myeloid disease in CML patients. PMID:25370416

Apical constriction is driven by a pulsatile apical myosin network in delaminating Drosophila neuroblasts.

PubMed

An, Yanru; Xue, Guosheng; Shaobo, Yang; Mingxi, Deng; Zhou, Xiaowei; Yu, Weichuan; Ishibashi, Toyotaka; Zhang, Lei; Yan, Yan

2017-06-15

Cell delamination is a conserved morphogenetic process important for the generation of cell diversity and maintenance of tissue homeostasis. Here, we used Drosophila embryonic neuroblasts as a model to study the apical constriction process during cell delamination. We observe dynamic myosin signals both around the cell adherens junctions and underneath the cell apical surface in the neuroectoderm. On the cell apical cortex, the nonjunctional myosin forms flows and pulses, which are termed medial myosin pulses. Quantitative differences in medial myosin pulse intensity and frequency are crucial to distinguish delaminating neuroblasts from their neighbors. Inhibition of medial myosin pulses blocks delamination. The fate of a neuroblast is set apart from that of its neighbors by Notch signaling-mediated lateral inhibition. When we inhibit Notch signaling activity in the embryo, we observe that small clusters of cells undergo apical constriction and display an abnormal apical myosin pattern. Together, these results demonstrate that a contractile actomyosin network across the apical cell surface is organized to drive apical constriction in delaminating neuroblasts. © 2017. Published by The Company of Biologists Ltd.

Basic and clinical aspects of malignant melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nathanson, L.

1987-01-01

This book contains the following 10 chapters: The role of oncogenes in the pathogenesis of malignant melanoma; Laminin and fibronectin modulate the metastatic activity of melanoma cells; Structure, function and biosynthesis of ganglioside antigens associated with human tumors derived from the neuroectoderm; Epidemiology of ocular melanoma; Malignant melanoma: Prognostic factors; Endocrine influences on the natural history of human malignant melanoma; Psychosocial factors associated with prognostic indicators, progression, psychophysiology, and tumor-host response in cutaneous malignant melanoma; Central nervous system metastases in malignant melanoma; Interferon trials in the management of malignant melanoma and other neoplasms: an overview; and The treatment of malignantmore » melanoma by fast neutrons.« less

Essential roles for Cdx in murine primitive hematopoiesis.

PubMed

Brooke-Bisschop, Travis; Savory, Joanne G A; Foley, Tanya; Ringuette, Randy; Lohnes, David

2017-02-15

The Cdx transcription factors play essential roles in primitive hematopoiesis in the zebrafish where they exert their effects, in part, through regulation of hox genes. Defects in hematopoiesis have also been reported in Cdx mutant murine embryonic stem cell models, however, to date no mouse model reflecting the zebrafish Cdx mutant hematopoietic phenotype has been described. This is likely due, in part, to functional redundancy among Cdx members and the early lethality of Cdx2 null mutants. To circumvent these limitations, we used Cre-mediated conditional deletion to assess the impact of concomitant loss of Cdx1 and Cdx2 on murine primitive hematopoiesis. We found that Cdx1/Cdx2 double mutants exhibited defects in primitive hematopoiesis and yolk sac vasculature concomitant with reduced expression of several genes encoding hematopoietic transcription factors including Scl/Tal1. Chromatin immunoprecipitation analysis revealed that Scl was occupied by Cdx2 in vivo, and Cdx mutant hematopoietic yolk sac differentiation defects could be rescued by expression of exogenous Scl. These findings demonstrate critical roles for Cdx members in murine primitive hematopoiesis upstream of Scl. Copyright © 2017 Elsevier Inc. All rights reserved.

The Evolution of the Earliest Cells.

ERIC Educational Resources Information Center

Schopf, J. William

1978-01-01

Describes the unicellular microorganisms of three billion years ago. Explains how these primitive cells gave rise to biochemical systems and the present oxygen-rich atmosphere. Numerous diagrams, charts, and illustrations. (MA)

Childhood Cancer Incidence Trends in Association With US Folic Acid Fortification (1986–2008)

PubMed Central

Johnson, Kimberly J.; Ross, Julie A.

2012-01-01

OBJECTIVE: Epidemiologic evidence indicates that prenatal vitamin supplementation reduces risk for some childhood cancers; however, a systematic evaluation of population-based childhood cancer incidence trends after fortification of enriched grain products with folic acid in the United States in 1996–1998 has not been previously reported. Here we describe temporal trends in childhood cancer incidence in association with US folic acid fortification. METHODS: Using Surveillance, Epidemiology, and End Results program data (1986–2008), we calculated incidence rate ratios and 95% confidence intervals to compare pre- and postfortification cancer incidence rates in children aged 0 to 4 years. Incidence trends were also evaluated by using joinpoint and loess regression models. RESULTS: From 1986 through 2008, 8829 children aged 0 to 4 years were diagnosed with malignancies, including 3790 and 3299 in utero during the pre- and postfortification periods, respectively. Pre- and postfortification incidence rates were similar for all cancers combined and for most specific cancer types. Rates of Wilms tumor (WT), primitive neuroectodermal tumors (PNETs), and ependymomas were significantly lower postfortification. Joinpoint regression models detected increasing WT incidence from 1986 through 1997 followed by a sizable decline from 1997 through 2008, and increasing PNET incidence from 1986 through 1993 followed by a sharp decrease from 1993 through 2008. Loess curves indicated similar patterns. CONCLUSIONS: These results provide support for a decrease in WT and possibly PNET incidence, but not other childhood cancers, after US folic acid fortification. PMID:22614769

Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group.

PubMed

Geyer, J Russell; Sposto, Richard; Jennings, Mark; Boyett, James M; Axtell, Richard A; Breiger, David; Broxson, Emmett; Donahue, Bernadine; Finlay, Jonathan L; Goldwein, Joel W; Heier, Linda A; Johnson, Dennis; Mazewski, Claire; Miller, Douglas C; Packer, Roger; Puccetti, Diane; Radcliffe, Jerilynn; Tao, May Lin; Shiminski-Maher, Tania

2005-10-20

To evaluate response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors and to estimate control intervals without irradiation in children with no residual tumor after initial surgery and induction chemotherapy and with delayed irradiation in patients with residual tumor or metastatic disease at diagnosis. Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide). Maintenance chemotherapy began after induction in children without progressive disease. Children with no residual tumors after induction therapy and no metastatic disease at diagnosis were not to receive radiation therapy unless their tumors progressed. Two hundred ninety-nine infants were enrolled. Forty-two percent of patients responded to induction chemotherapy. At 5 years from study entry, the EFS rate was 27% +/- 3%, and the survival rate was 43% +/- 3%. There was no significant difference between the two arms in terms of response rate or EFS. For medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, and rhabdoid tumors, 5-year EFS rates were 32% +/- 5%, 17% +/- 6%, and 32% +/- 6%, and 14% +/- 7%, respectively. Fifty-eight percent of patients who were alive 5 years after study entry had not received radiation therapy. Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.

A germline mutation of CDKN2A and a novel RPLP1-C19MC fusion detected in a rare melanotic neuroectodermal tumor of infancy: a case report.

PubMed

Barnes, David J; Hookway, Edward; Athanasou, Nick; Kashima, Takeshi; Oppermann, Udo; Hughes, Simon; Swan, Daniel; Lueerssen, Dietrich; Anson, John; Hassan, A Bassim

2016-08-12

Melanotic neuroectodermal tumor of infancy (MNTI) is exceptionally rare and occurs predominantly in the head and neck (92.8 % cases). The patient reported here is only the eighth case of MNTI presenting in an extremity, and the first reported in the fibula. A 2-month-old female presented with a mass arising in the fibula. Exhaustive genomic, transcriptomic, epigenetic and pathological characterization was performed on the excised primary tumor and a derived cell line. Whole-exome analysis of genomic DNA from both the tumor and blood indicated no somatic, non-synonymous coding mutations within the tumor, but a heterozygous, unique germline, loss of function mutation in CDKN2A (p16(INK4A), D74A). SNP-array CGH on DNA samples revealed the tumor to be euploid, with no detectable gene copy number variants. Multiple chromosomal translocations were identified by RNA-Seq, and fusion genes included RPLP1-C19MC, potentially deregulating the C19MC cluster, an imprinted locus containing microRNA genes reactivated by gene fusion in embryonal tumors with multilayered rosettes. Since the presumed cell of origin of MNTI is from the neural crest, we also compared gene expression with a dataset from human neural crest cells and identified 185 genes with significantly different expression. Consistent with the melanotic phenotype of the tumor, elevated expression of tyrosinase was observed. Other highly expressed genes encoded muscle proteins and modulators of the extracellular matrix. A derived MNTI cell line was sensitive to inhibitors of lysine demethylase, but not to compounds targeting other epigenetic regulators. In the absence of somatic copy number variations or mutations, the fully transformed phenotype of the MNTI may have arisen in infancy because of the combined effects of a germline CDKN2A mutation, tumor promoting somatic fusion genes and epigenetic deregulation. Very little is known about the etiology of MNTI and this report advances knowledge of these rare tumors by providing the first comprehensive genomic, transcriptomic and epigenetic characterization of a case.

Combination Adenovirus + Pembrolizumab to Trigger Immune Virus Effects

ClinicalTrials.gov

2018-06-20

Brain Cancer; Brain Neoplasm; Glioma; Glioblastoma; Gliosarcoma; Malignant Brain Tumor; Neoplasm, Neuroepithelial; Neuroectodermal Tumors; Neoplasm by Histologic Type; Neoplasm, Nerve Tissue; Nervous System Diseases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Das, Amitabh, E-mail: amitabhdas.kn@gmail.com; Chai, Jin Choul, E-mail: jincchai@gmail.com; Jung, Kyoung Hwa, E-mail: khjung2@gmail.com

JMJD2A is a lysine trimethyl-specific histone demethylase that is highly expressed in a variety of tumours. The role of JMJD2A in tumour progression remains unclear. The objectives of this study were to identify JMJD2A-regulated genes and understand the function of JMJD2A in p53-null neuroectodermal stem cells (p53{sup −/−} NE-4Cs). We determined the effect of LPS as a model of inflammation in p53{sup −/−} NE-4Cs and investigated whether the epigenetic modifier JMJD2A alter the expression of tumourigenic inflammatory genes. Global gene expression was measured in JMJD2A knockdown (kd) p53{sup −/−} NE-4Cs and in LPS-stimulated JMJD2A-kd p53{sup −/−} NE-4C cells. JMJD2A attenuationmore » significantly down-regulated genes were Cdca2, Ccnd2, Ccnd1, Crebbp, IL6rα, and Stat3 related with cell cycle, proliferation, and inflammatory-disease responses. Importantly, some tumour-suppressor genes including Dapk3, Timp2 and TFPI were significantly up-regulated but were not affected by silencing of the JMJD2B. Furthermore, we confirmed the attenuation of JMJD2A also down-regulated Cdca2, Ccnd2, Crebbp, and Rest in primary NSCs isolated from the forebrains of E15 embryos of C57/BL6J mice with effective p53 inhibitor pifithrin-α (PFT-α). Transcription factor (TF) motif analysis revealed known binding patterns for CDC5, MYC, and CREB, as well as three novel motifs in JMJD2A-regulated genes. IPA established molecular networks. The molecular network signatures and functional gene-expression profiling data from this study warrants further investigation as an effective therapeutic target, and studies to elucidate the molecular mechanism of JMJD2A-kd-dependent effects in neuroectodermal stem cells should be performed. - Highlights: • Significant up-regulation of epigenetic modifier JMJD2A mRNA upon LPS treatment. • Inhibition of JMJD2A attenuated key inflammatory and tumourigenic genes. • Establishing IPA based functional genomics in JMJD2A-attenuated p53{sup −/−} NE4C cells. • Finding JMJD2A-based molecular targets and crucial pathways in p53{sup −/−} NE4C cells.« less

DNA methylation in schizophrenia in different patient-derived cell types.

PubMed

Vitale, Alejandra M; Matigian, Nicholas A; Cristino, Alexandre S; Nones, Katia; Ravishankar, Sugandha; Bellette, Bernadette; Fan, Yongjun; Wood, Stephen A; Wolvetang, Ernst; Mackay-Sim, Alan

2017-01-01

DNA methylation of gene promoter regions represses transcription and is a mechanism via which environmental risk factors could affect cells during development in individuals at risk for schizophrenia. We investigated DNA methylation in patient-derived cells that might shed light on early development in schizophrenia. Induced pluripotent stem cells may reflect a "ground state" upon which developmental and environmental influences would be minimal. Olfactory neurosphere-derived cells are an adult-derived neuro-ectodermal stem cell modified by developmental and environmental influences. Fibroblasts provide a non-neural control for life-long developmental and environmental influences. Genome-wide profiling of DNA methylation and gene expression was done in these three cell types from the same individuals. All cell types had distinct, statistically significant schizophrenia-associated differences in DNA methylation and linked gene expression, with Gene Ontology analysis showing that the differentially affected genes clustered in networks associated with cell growth, proliferation, and movement, functions known to be affected in schizophrenia patient-derived cells. Only five gene loci were differentially methylated in all three cell types. Understanding the role of epigenetics in cell function in the brain in schizophrenia is likely to be complicated by similar cell type differences in intrinsic and environmentally induced epigenetic regulation.

Ultrastrukturelle Untersuchungen zur Morphologie und Genese der Spermien von Archaeogastropoda

NASA Astrophysics Data System (ADS)

Kohnert, R.; Storch, V.

1983-03-01

The sperm cells of Patella coerulea (Patellacea), Monodonta turbinata, and Gibbula tumida (Trochacea) were investigated by means of transmission electron microscopy. They belong to the primitive type (sensu Franzén) and have more features in common with primitive Bivalvia sperms than with Neritacea. Their head contains an apical acrosome and a roundish nucleus followed by 4 or 5 mitochondria and a centriolar apparatus which consists of two centrioles, one of which bears a flagellum. The sperm cells of Monodonta and Gibbula are very similar to each other and differ mainly in size; Patella exhibits more differences (very small acrosome, subacrosomal space, variable number of spherical mitochondria (origin of spermic dimorphism ?). The development of the sperm cells shows no peculiarities.

Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function.

PubMed

Takata, Kazuyuki; Kozaki, Tatsuya; Lee, Christopher Zhe Wei; Thion, Morgane Sonia; Otsuka, Masayuki; Lim, Shawn; Utami, Kagistia Hana; Fidan, Kerem; Park, Dong Shin; Malleret, Benoit; Chakarov, Svetoslav; See, Peter; Low, Donovan; Low, Gillian; Garcia-Miralles, Marta; Zeng, Ruizhu; Zhang, Jinqiu; Goh, Chi Ching; Gul, Ahmet; Hubert, Sandra; Lee, Bernett; Chen, Jinmiao; Low, Ivy; Shadan, Nurhidaya Binte; Lum, Josephine; Wei, Tay Seok; Mok, Esther; Kawanishi, Shohei; Kitamura, Yoshihisa; Larbi, Anis; Poidinger, Michael; Renia, Laurent; Ng, Lai Guan; Wolf, Yochai; Jung, Steffen; Önder, Tamer; Newell, Evan; Huber, Tara; Ashihara, Eishi; Garel, Sonia; Pouladi, Mahmoud A; Ginhoux, Florent

2017-07-18

Tissue macrophages arise during embryogenesis from yolk-sac (YS) progenitors that give rise to primitive YS macrophages. Until recently, it has been impossible to isolate or derive sufficient numbers of YS-derived macrophages for further study, but data now suggest that induced pluripotent stem cells (iPSCs) can be driven to undergo a process reminiscent of YS-hematopoiesis in vitro. We asked whether iPSC-derived primitive macrophages (iMacs) can terminally differentiate into specialized macrophages with the help of growth factors and organ-specific cues. Co-culturing human or murine iMacs with iPSC-derived neurons promoted differentiation into microglia-like cells in vitro. Furthermore, murine iMacs differentiated in vivo into microglia after injection into the brain and into functional alveolar macrophages after engraftment in the lung. Finally, iPSCs from a patient with familial Mediterranean fever differentiated into iMacs with pro-inflammatory characteristics, mimicking the disease phenotype. Altogether, iMacs constitute a source of tissue-resident macrophage precursors that can be used for biological, pathophysiological, and therapeutic studies. Copyright © 2017 Elsevier Inc. All rights reserved.

Studying the hopping parameters of half-Heusler NaAuS using maximally localized Wannier function

NASA Astrophysics Data System (ADS)

Sihi, Antik; Lal, Sohan; Pandey, Sudhir K.

2018-04-01

Here, the electronic behavior of half-Heusler NaAuS is studied using PBEsol exchange correlation functional by plotting the band structure curve. These bands are reproduced using maximally localized Wannier function using WANNIER90. Tight-binding bands are nicely matched with density functional theory bands. By fitting the tight-binding model, hopping parameter for NaAuS is obtained by including Na 2s, 2p, Au 6s, 5p, 5d and S 3s, 3p orbitals within the energy interval of -5 to 16 eV around the Fermi level. In present study, hopping integrals for NaAuS are computed for the first primitive unit cell atoms as well as the first nearest neighbor primitive unit cell. The most dominating hopping integrals are found for Na (3s) - S (3s), Na (2px) - S (2px), Au (6s) - S (3px), Au (6s) - S (3py) and Au (6s) - S (3pz) orbitals. The hopping integrals for the first nearest neighbor primitive unit cell are also discussed in this manuscript. In future, these hopping integrals are very important to find the topological invariant for NaAuS compound.

Pathological features of olfactory neuroblastoma in an axolotl (Ambystoma mexicanum).

PubMed

Shioda, Chieko; Uchida, Kazuyuki; Nakayama, Hiroyuki

2011-08-01

A one-year-old, female Mexican axolotl (Ambystoma mexicanum) had a rough-surfaced, polypoid, pink tumor mass of approximately 10 mm in diameter in the oral cavity. Histologically, the tumor extended from the ethmoturbinate region and into the oral cavity and had replaced some of the maxillary bone tissue. The tumor mass was composed of a lobular architecture of small round-shaped tumor cells with occasional Flexner-Wintersteiner-like rosette formation. There were no metastatic lesions in the other organs. Immunohistochemically, the tumor cells were partly positive for several neural markers (class III beta-tubulin, S-100 protein, and doublecortin) and intensely positive for an epithelial marker (cytokeratin AE1/AE3). These results suggest that the present tumor originated from neuroectodermal tissue. Considering the location and histological and immunohistochemical features of the tumor, a diagnosis of olfactory neuroblastoma was made.

Enforced expression of KDR receptor promotes proliferation, survival and megakaryocytic differentiation of TF1 progenitor cell line.

PubMed

Coppola, S; Narciso, L; Feccia, T; Bonci, D; Calabrò, L; Morsilli, O; Gabbianelli, M; De Maria, R; Testa, U; Peschle, C

2006-01-01

Vascular endothelial growth factor (VEGF) receptor-2/kinase insert domain-containing receptor (KDR) is expressed in primitive hematopoietic cells, in megakaryocytes and platelets. In primitive hematopoiesis KDR mediates cell survival via autocrine VEGF, while its effect on cell growth and differentiation has not been elucidated. We induced enforced KDR expression in the granulocyte macrophage-colony-stimulating factor (GM-CSF)-dependent TF1 progenitor cell line (TF1-KDR), treated the cells with VEGF and analyzed their response. In GM-CSF-deprived cells, VEGF induces cell proliferation and protection against apoptosis, followed by enhanced expression of megakaryocytic (MK) markers. Combined with GM-CSF, VEGF induces a mild proliferative stimulus, followed by cell adherence, accumulation in G0/G1, massive MK differentiation and Fas-mediated apoptosis. Accordingly, we observed that MK-differentiating cells, derived from hematopoietic progenitors, produce VEGF, express KDR, inhibition of which reduces MK differentiation, indicating a key role of KDR in megakaryopoiesis. In conclusion, TF1-KDR cells provide a reliable model to investigate the biochemical and molecular mechanisms underlying hematopoietic progenitor proliferation, survival and MK differentiation.

Microsatellite analysis of loss of heterozygosity on chromosomes 9q, 11p and 17p in medulloblastomas.

PubMed

Albrecht, S; von Deimling, A; Pietsch, T; Giangaspero, F; Brandner, S; Kleihues, P; Wiestler, O D

1994-02-01

Medulloblastoma (MB) is a primitive neuroectodermal tumour of the cerebellum whose pathogenesis is poorly understood. Previous studies suggest a role for loci on chromosomes 11p and 17p in the pathogenesis of MB. Evidence for another potential MB locus has recently emerged from studies on Gorlin syndrome (GS), an autosomal dominant syndrome with multiple basal cell carcinomas, epithelial jaw cysts, and skeletal anomalies. Since GS can be associated with MB, we examined sporadic (non-GS) cases of MB for evidence of loss of heterozygosity (LOH) on chromosome 9 where a putative GS locus has been localized to band q31. Nineteen paired blood and MB DNA specimens from 16 patients (11 primary tumours, two primary with recurrent tumours, one primary tumour and cell line, two cell lines) were studied by PCR analysis of microsatellites at D9S55 (9p12), D9S15 (9q13-q21.1), D9S127 (9q21.1-21.3), D9S12 (9q22.3), D9S58 (9q22.3-q31), D9S109 (9q31), D9S53 (9q31), GSN (9q33), D9S60 (9q33-q34), D9S65 (9q33-q34), ASS (9q34), D9S67 (9q34.3), TH (11p15.5), D11S490 (11q23.3), D17S261 (17p11.2-12), D17S520 (17p12), TP53 (17p13.1), D17S5 (17p13.3), D17S515 (17q22-qter), and by RFLP analysis at the WT-1 locus (11p13). Only two tumours had LOH on 9q. One was non-informative at D9S15, D9S65, and GSN but showed LOH at D9S127, D9S12, D9S58, D9S109, D9S53, D9S60, ASS, and D9S67. The other was uninterpretable at D9S65 and non-informative at D9S15, D9S58, D9S53, and D9S67 but exhibited LOH at D9S127, D9S12, D9S109, GSN, D9S60, and ASS. Both these cases were informative at D9S55 without LOH.(ABSTRACT TRUNCATED AT 250 WORDS)

Dual mTORC2/mTORC1 targeting results in potent suppressive effects on acute myeloid leukemia (AML) progenitors*

PubMed Central

Altman, Jessica K.; Sassano, Antonella; Kaur, Surinder; Glaser, Heather; Kroczynska, Barbara; Redig, Amanda J.; Russo, Suzanne; Barr, Sharon; Platanias, Leonidas C.

2011-01-01

Purpose To determine whether mTORC2 and RI-mTORC1 complexes are present in AML cells and to examine the effects of dual mTORC2/mTORC1 inhibition on primitive AML leukemic progenitors. Experimental Design Combinations of different experimental approaches were used, including immunoblotting to detect phosphorylated/activated forms of elements of the mTOR pathway in leukemic cell lines and primary AML blasts; cell proliferation assays; direct assessment of mRNA translation in polysomal fractions of leukemic cells; and clonogenic assays in methylcellulose to evaluate leukemic progenitor colony formation. Results mTORC2 complexes are active in AML cells and play critical roles in leukemogenesis. Rapamycin insensitive (RI) mTORC1 complexes are also formed and regulate the activity of the translational repressor 4E-BP1 in AML cells. OSI-027, blocks mTORC1 and mTORC2 activities and suppresses mRNA translation of cyclin D1 and other genes that mediate proliferative responses in AML cells. Moreover, OSI-027 acts as a potent suppressor of primitive leukemic precursors from AML patients and is much more effective than rapamycin in eliciting antileukemic effects in vitro. Conclusions Dual targeting of mTORC2 and mTORC1 results in potent suppressive effects on primitive leukemic progenitors from AML patients. Inhibition of the mTOR catalytic site with OSI-027 results in suppression of both mTORC2 and RI-mTORC1 complexes and elicits much more potent antileukemic responses than selective mTORC1 targeting with rapamycin. PMID:21415215

The ocular pathology of Norrie disease in a fetus of 11 weeks' gestational age.

PubMed

Parsons, M A; Curtis, D; Blank, C E; Hughes, H N; McCartney, A C

1992-01-01

The ocular pathology of Norrie disease was studied for the first time in a fetus of 11 weeks' gestation, following prenatal diagnosis using genetic markers for Norrie disease and elective abortion. The eyes were histologically normal, with no evidence of primary neuroectodermal maldevelopment of the retina, previously postulated to be the cause of the ocular changes. We believe that the retinal and other manifestations of Norrie disease are the result of a primary abnormality of vascular proliferation, probably in relation to persistent hyperplastic primary vitreous after approximately 14 weeks' gestation. We postulate that the ocular and otological effects of Norrie disease may be due to a genetically mediated abnormality of secretion of, or sensitivity to, angiogenic growth factors at endodermal-neuroectodermal interfaces during fetal and postnatal development.

The Composition and Organization of Cytoplasm in Prebiotic Cells

PubMed Central

Trevors, Jack T.

2011-01-01

This article discusses the hypothesized composition and organization of cytoplasm in prebiotic cells from a theoretical perspective and also based upon what is currently known about bacterial cytoplasm. It is unknown if the first prebiotic, microscopic scale, cytoplasm was initially contained within a primitive, continuous, semipermeable membrane, or was an uncontained gel substance, that later became enclosed by a continuous membrane. Another possibility is that the first cytoplasm in prebiotic cells and a primitive membrane organized at the same time, permitting a rapid transition to the first cell(s) capable of growth and division, thus assisting with the emergence of life on Earth less than a billion years after the formation of the Earth. It is hypothesized that the organization and composition of cytoplasm progressed initially from an unstructured, microscopic hydrogel to a more complex cytoplasm, that may have been in the volume magnitude of about 0.1–0.2 μm3 (possibly less if a nanocell) prior to the first cell division. PMID:21673913

Lysophosphatidic acid acts as a nutrient-derived developmental cue to regulate early hematopoiesis

PubMed Central

Li, Haisen; Yue, Rui; Wei, Bin; Gao, Ge; Du, Jiulin; Pei, Gang

2014-01-01

Primitive hematopoiesis occurs in the yolk sac blood islands during vertebrate embryogenesis, where abundant phosphatidylcholines (PC) are available as important nutrients for the developing embryo. However, whether these phospholipids also generate developmental cues to promote hematopoiesis is largely unknown. Here, we show that lysophosphatidic acid (LPA), a signaling molecule derived from PC, regulated hemangioblast formation and primitive hematopoiesis. Pharmacological and genetic blockage of LPA receptor 1 (LPAR1) or autotoxin (ATX), a secretory lysophospholipase that catalyzes LPA production, inhibited hematopoietic differentiation of mouse embryonic stem cells and impaired the formation of hemangioblasts. Mechanistic experiments revealed that the regulatory effect of ATX-LPA signaling was mediated by PI3K/Akt-Smad pathway. Furthermore, during in vivo embryogenesis in zebrafish, LPA functioned as a developmental cue for hemangioblast formation and primitive hematopoiesis. Taken together, we identified LPA as an important nutrient-derived developmental cue for primitive hematopoiesis as well as a novel mechanism of hemangioblast regulation. PMID:24829209

Lysophosphatidic acid acts as a nutrient-derived developmental cue to regulate early hematopoiesis.

PubMed

Li, Haisen; Yue, Rui; Wei, Bin; Gao, Ge; Du, Jiulin; Pei, Gang

2014-06-17

Primitive hematopoiesis occurs in the yolk sac blood islands during vertebrate embryogenesis, where abundant phosphatidylcholines (PC) are available as important nutrients for the developing embryo. However, whether these phospholipids also generate developmental cues to promote hematopoiesis is largely unknown. Here, we show that lysophosphatidic acid (LPA), a signaling molecule derived from PC, regulated hemangioblast formation and primitive hematopoiesis. Pharmacological and genetic blockage of LPA receptor 1 (LPAR1) or autotoxin (ATX), a secretory lysophospholipase that catalyzes LPA production, inhibited hematopoietic differentiation of mouse embryonic stem cells and impaired the formation of hemangioblasts. Mechanistic experiments revealed that the regulatory effect of ATX-LPA signaling was mediated by PI3K/Akt-Smad pathway. Furthermore, during in vivo embryogenesis in zebrafish, LPA functioned as a developmental cue for hemangioblast formation and primitive hematopoiesis. Taken together, we identified LPA as an important nutrient-derived developmental cue for primitive hematopoiesis as well as a novel mechanism of hemangioblast regulation. © 2014 The Authors.

Transcriptional Networks in Single Perivascular Cells Sorted from Human Adipose Tissue Reveal a Hierarchy of Mesenchymal Stem Cells.

PubMed

Hardy, W Reef; Moldovan, Nicanor I; Moldovan, Leni; Livak, Kenneth J; Datta, Krishna; Goswami, Chirayu; Corselli, Mirko; Traktuev, Dmitry O; Murray, Iain R; Péault, Bruno; March, Keith

2017-05-01

Adipose tissue is a rich source of multipotent mesenchymal stem-like cells, located in the perivascular niche. Based on their surface markers, these have been assigned to two main categories: CD31 - /CD45 - /CD34 + /CD146 - cells (adventitial stromal/stem cells [ASCs]) and CD31 - /CD45 - /CD34 - /CD146 + cells (pericytes [PCs]). These populations display heterogeneity of unknown significance. We hypothesized that aldehyde dehydrogenase (ALDH) activity, a functional marker of primitivity, could help to better define ASC and PC subclasses. To this end, the stromal vascular fraction from a human lipoaspirate was simultaneously stained with fluorescent antibodies to CD31, CD45, CD34, and CD146 antigens and the ALDH substrate Aldefluor, then sorted by fluorescence-activated cell sorting. Individual ASCs (n = 67) and PCs (n = 73) selected from the extremities of the ALDH-staining spectrum were transcriptionally profiled by Fluidigm single-cell quantitative polymerase chain reaction for a predefined set (n = 429) of marker genes. To these single-cell data, we applied differential expression and principal component and clustering analysis, as well as an original gene coexpression network reconstruction algorithm. Despite the stochasticity at the single-cell level, covariation of gene expression analysis yielded multiple network connectivity parameters suggesting that these perivascular progenitor cell subclasses possess the following order of maturity: (a) ALDH br ASC (most primitive); (b) ALDH dim ASC; (c) ALDH br PC; (d) ALDH dim PC (least primitive). This order was independently supported by specific combinations of class-specific expressed genes and further confirmed by the analysis of associated signaling pathways. In conclusion, single-cell transcriptional analysis of four populations isolated from fat by surface markers and enzyme activity suggests a developmental hierarchy among perivascular mesenchymal stem cells supported by markers and coexpression networks. Stem Cells 2017;35:1273-1289. © 2017 AlphaMed Press.

Transplanted Dental Pulp Stem Cells Migrate to Injured Area and Express Neural Markers in a Rat Model of Cerebral Ischemia.

PubMed

Zhang, Xuemei; Zhou, Yinglian; Li, Hulun; Wang, Rui; Yang, Dan; Li, Bing; Cao, Xiaofang; Fu, Jin

2018-01-01

Ischemic stroke is a major cause of disability and mortality worldwide, while effective restorative treatments are limited at present. Stem cell transplantation holds therapeutic potential for ischemic vascular diseases and may provide an opportunity for neural regeneration. Dental pulp stem cells (DPSCs) origin from neural crest and have neuro-ectodermal features including proliferation and multilineage differentiation potentials. The rat model of middle cerebral artery occlusion (MCAO) was used to evaluate whether intravenous administration of DPSCs can reduce infarct size and to estimate the migration and trans-differentiation into neuron-like cells in focal cerebral ischemia models. Brain tissues were collected at 4 weeks following cell transplantation and analyzed with immunofluorescence, immunohistochemistry and real-time polymerase chain reaction (RT-PCR) methods. Intravenously administration of rat-derived DPSCs were found to migrate into the boundary of ischemic areas and expressed neural specific markers, reducing infarct volume and cerebral edema. These results suggest that DPSCs treatment may serve as a potential therapy for clinical stroke patients in the future. © 2018 The Author(s). Published by S. Karger AG, Basel.

3D Culture for Self-Formation of the Cerebellum from Human Pluripotent Stem Cells Through Induction of the Isthmic Organizer.

PubMed

Muguruma, Keiko

2017-01-01

Pluripotent stem cells (PSCs) possess self-organizing abilities in 3D culture. This property has been demonstrated in recent studies, including the generation of various neuroectodermal and endodermal tissues. For example, PSCs are able to differentiate into specific type of neural tissues, such as the neocortex and the optic cup, in response to local positional information brought about by signals during embryogenesis. In contrast, the generation of cerebellar tissue from PSCs requires a secondary induction by a signaling center, called the isthmic organizer, which first appears in the cell aggregate in 3D culture. Such developmental complexity of cerebellum has hampered establishment of effective differentiation culture system from PSCs, thus far.We recently reported that cerebellar neurons are generated from human PSCs (hPSCs). In this chapter, we describe an efficient protocol for differentiation of 3D cerebellar neuroepithelium from hPSCs. We also describe the protocols for further differentiation into specific neurons in the cerebellar cortex, such as Purkinje cells and the granule cells.

Morphology of isolated mouse inner cell masses developing in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wiley, L.M.; Spindle, A.I.; Pedersen, R.A.

1978-01-01

The purpose of this study was to examine the developmental capacity of the mouse inner cell mass (ICM) in the absence of the trophoblast. ICMs were isolated from blastocysts by immunosurgery and cultured under conditions that support egg cylinder formation by intact blastocysts. After 2 or 3 days of culture, the ICMs consisted of an outer layer of endoderm and an inner layer of ectoderm that had cavitated centrally. By 4 or 5 days of culture, 25 to 60% of these ICMs had developed into paired cysts, apparently by secondary cavity formation. The inner cell layer surrounding this secondary cavitymore » resembled the extraembryonic ectoderm of cultured egg cylinders. By 6 days of culture, 60% of the ICMs had expanded into yolk sac-like structures that subsequently produced capillaries containing blood cells. The ICMs appeared to develop mesoderm in two distinct ways. A few of them developed mesoderm as a third layer of cells in the cleft separating endoderm and ectoderm, presumably by migrating from the inner, ectodermal layer, through the primitive streak, as in the intact egg cylinder. In the rest of the ICMs the embryonic ectoderm gradually differentiated into mesoderm while still in the inner layer, without primitive streak formation. We suggest, therefore, that the continuous presence of the trophoblast or of its derivatives is not required for the cytodifferentiation of mesoderm although it may be important in establishing embryonic polarity or in providinginductive signals necessary for the morphogenetic aspects of mesoderm differentiation, specifically primitive streak formation.« less

The ECM moves during primitive streak formation--computation of ECM versus cellular motion.

PubMed

Zamir, Evan A; Rongish, Brenda J; Little, Charles D

2008-10-14

Galileo described the concept of motion relativity--motion with respect to a reference frame--in 1632. He noted that a person below deck would be unable to discern whether the boat was moving. Embryologists, while recognizing that embryonic tissues undergo large-scale deformations, have failed to account for relative motion when analyzing cell motility data. A century of scientific articles has advanced the concept that embryonic cells move ("migrate") in an autonomous fashion such that, as time progresses, the cells and their progeny assemble an embryo. In sharp contrast, the motion of the surrounding extracellular matrix scaffold has been largely ignored/overlooked. We developed computational/optical methods that measure the extent embryonic cells move relative to the extracellular matrix. Our time-lapse data show that epiblastic cells largely move in concert with a sub-epiblastic extracellular matrix during stages 2 and 3 in primitive streak quail embryos. In other words, there is little cellular motion relative to the extracellular matrix scaffold--both components move together as a tissue. The extracellular matrix displacements exhibit bilateral vortical motion, convergence to the midline, and extension along the presumptive vertebral axis--all patterns previously attributed solely to cellular "migration." Our time-resolved data pose new challenges for understanding how extracellular chemical (morphogen) gradients, widely hypothesized to guide cellular trajectories at early gastrulation stages, are maintained in this dynamic extracellular environment. We conclude that models describing primitive streak cellular guidance mechanisms must be able to account for sub-epiblastic extracellular matrix displacements.

The neonatal marmoset monkey ovary is very primitive exhibiting many oogonia

PubMed Central

Fereydouni, B; Drummer, C; Aeckerle, N; Schlatt, S; Behr, R

2014-01-01

Oogonia are characterized by diploidy and mitotic proliferation. Human and mouse oogonia express several factors such as OCT4, which are characteristic of pluripotent cells. In human, almost all oogonia enter meiosis between weeks 9 and 22 of prenatal development or undergo mitotic arrest and subsequent elimination from the ovary. As a consequence, neonatal human ovaries generally lack oogonia. The same was found in neonatal ovaries of the rhesus monkey, a representative of the old world monkeys (Catarrhini). By contrast, proliferating oogonia were found in adult prosimians (now called Strepsirrhini), which is a group of ‘lower’ primates. The common marmoset monkey (Callithrix jacchus) belongs to the new world monkeys (Platyrrhini) and is increasingly used in reproductive biology and stem cell research. However, ovarian development in the marmoset monkey has not been widely investigated. Herein, we show that the neonatal marmoset ovary has an extremely immature histological appearance compared with the human ovary. It contains numerous oogonia expressing the pluripotency factors OCT4A, SALL4, and LIN28A (LIN28). The pluripotency factor-positive germ cells also express the proliferation marker MKI67 (Ki-67), which has previously been shown in the human ovary to be restricted to premeiotic germ cells. Together, the data demonstrate the primitiveness of the neonatal marmoset ovary compared with human. This study may introduce the marmoset monkey as a non-human primate model to experimentally study the aspects of primate primitive gonad development, follicle assembly, and germ cell biology in vivo. PMID:24840529

All of the human beta-type globin genes compete for LCR enhancer activity in embryonic erythroid cells of yeast artificial chromosome transgenic mice.

PubMed

Okamura, Eiichi; Matsuzaki, Hitomi; Campbell, Andrew D; Engel, James Douglas; Fukamizu, Akiyoshi; Tanimoto, Keiji

2009-12-01

In primitive erythroid cells of human beta-globin locus transgenic mice (TgM), the locus control region (LCR)-proximal epsilon- and gamma-globin genes are transcribed, whereas the distal delta- and beta-globin genes are silent. It is generally accepted that the beta-globin gene is competitively suppressed by gamma-globin gene expression at this developmental stage. Previously, however, we observed that epsilon-globin gene expression was severely attenuated when its distance from the LCR was extended, implying that beta-globin gene might also be silenced because of its great distance from the LCR. Here, to clarify the beta-globin gene silencing mechanism, we established TgM lines carrying either gamma- or epsilon- plus gamma-globin promoter deletions, without significantly altering the distance between the beta-globin gene and the LCR. Precocious expression of delta- and beta-globin genes was observed in primitive erythroid cells of mutant, but not wild-type TgM, which was most evident when both the epsilon and gamma promoters were deleted. Thus, we clearly demonstrated that the repression of the delta- and beta-globin genes in primitive erythroid cells is dominated by competitive silencing by the epsilon- and gamma-globin gene promoters, and that epsilon- and the other beta-like globin genes might be activated by two distinct mechanisms by the LCR.

HURTLE CELLS IMMUNOHISTOCHEMICAL ACTIVITIES IN HASHIMOTO THYROIDITIS PARENCHYMA.

PubMed

Tsagareli, Z; Kvachadze, T; Melikadze, E; Metreveli, L; Nikobadze, E; Gogiashvili, L

2016-11-01

The present study was designed to evaluate the participation and utility of Hǘrtle cells morphological requirment and transformation under Hashimoto autoimmune thyroiditis versus Riedel´s struma. Several markers have been evaluated to detect induced activities of Hǘrtle cells. Study subject - specimens (tissue fragments) collected from TG surgery (thyroidectomy) for mollecular (receptor) diagnosis of Hǘrtle cells activities using routine histological and immunohistochemical samples. 89 cases were selected in Hashimoto thyroiditis diagnosis with Hǘrtle cells history (adenoma and adenomatous grouth of oncocytes). Markers as: TSH receptors, TTF-1, S-100 protein, also anti-TPO and anti-TG levels in blood plasm were detected. It was shown that solid cell claster-nests like agregation of oncocytes and adenomatous growth foci in parafollicular areas with anti-TPO and anti-TG antibodies levels arising while Riedel´s struma shown only large intra- and extra glandular inflammatory proliferative fibrosing process. Large positive expression of TTF-1 and S-100 protein and the negative reaction of TSH receptor factor suggest that Thyroid parenchyma disorganization and mollecular biological atypia with Hǘrtle cells are proceses due to hypothyreoidismus, as well as neuroectodermal cells prominent activities in 70% of Hashimoto cases.

SIRT1 deficiency compromises mouse embryonic stem cell hematopoietic differentiation, and embryonic and adult hematopoiesis in the mouse

PubMed Central

Ou, Xuan; Chae, Hee-Don; Wang, Rui-Hong; Shelley, William C.; Cooper, Scott; Taylor, Tammi; Kim, Young-June; Deng, Chu-Xia; Yoder, Mervin C.

2011-01-01

SIRT1 is a founding member of a sirtuin family of 7 proteins and histone deacetylases. It is involved in cellular resistance to stress, metabolism, differentiation, aging, and tumor suppression. SIRT1−/− mice demonstrate embryonic and postnatal development defects. We examined hematopoietic and endothelial cell differentiation of SIRT1−/− mouse embryonic stem cells (ESCs) in vitro, and hematopoietic progenitors in SIRT1+/++/−, and −/− mice. SIRT1−/− ESCs formed fewer mature blast cell colonies. Replated SIRT1−/− blast colony-forming cells demonstrated defective hematopoietic potential. Endothelial cell production was unaltered, but there were defects in formation of a primitive vascular network from SIRT1−/−-derived embryoid bodies. Development of primitive and definitive progenitors derived from SIRT1−/− ESCs were also delayed and/or defective. Differentiation delay/defects were associated with delayed capacity to switch off Oct4, Nanog and Fgf5 expression, decreased β-H1 globin, β-major globin, and Scl gene expression, and reduced activation of Erk1/2. Ectopic expression of SIRT1 rescued SIRT1−/− ESC differentiation deficiencies. SIRT1−/− yolk sacs manifested fewer primitive erythroid precursors. SIRT1−/− and SIRT1+/− adult marrow had decreased numbers and cycling of hematopoietic progenitors, effects more apparent at 5%, than at 20%, oxygen tension, and these progenitors survived less well in vitro under conditions of delayed growth factor addition. This suggests a role for SIRT1 in ESC differentiation and mouse hematopoiesis. PMID:20966168

Indian hedgehog signaling from endothelial cells is required for sclera and retinal pigment epithelium development in the mouse eye.

PubMed

Dakubo, Gabriel D; Mazerolle, Chantal; Furimsky, Marosh; Yu, Chuan; St-Jacques, Benoit; McMahon, Andrew P; Wallace, Valerie A

2008-08-01

The development of extraocular orbital structures, in particular the choroid and sclera, is regulated by a complex series of interactions between neuroectoderm, neural crest and mesoderm derivatives, although in many instances the signals that mediate these interactions are not known. In this study we have investigated the function of Indian hedgehog (Ihh) in the developing mammalian eye. We show that Ihh is expressed in a population of non-pigmented cells located in the developing choroid adjacent to the RPE. The analysis of Hh mutant mice demonstrates that the RPE and developing scleral mesenchyme are direct targets of Ihh signaling and that Ihh is required for the normal pigmentation pattern of the RPE and the condensation of mesenchymal cells to form the sclera. Our findings also indicate that Ihh signals indirectly to promote proliferation and photoreceptor specification in the neural retina. This study identifies Ihh as a novel choroid-derived signal that regulates RPE, sclera and neural retina development.

Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes.

PubMed

Barshad, Gilad; Blumberg, Amit; Cohen, Tal; Mishmar, Dan

2018-06-14

Oxidative phosphorylation (OXPHOS), a fundamental energy source in all human tissues, requires interactions between mitochondrial (mtDNA)- and nuclear (nDNA)-encoded protein subunits. Although such interactions are fundamental to OXPHOS, bi-genomic coregulation is poorly understood. To address this question, we analyzed ∼8500 RNA-seq experiments from 48 human body sites. Despite well-known variation in mitochondrial activity, quantity, and morphology, we found overall positive mtDNA-nDNA OXPHOS genes' co-expression across human tissues. Nevertheless, negative mtDNA-nDNA gene expression correlation was identified in the hypothalamus, basal ganglia, and amygdala (subcortical brain regions, collectively termed the "primitive" brain). Single-cell RNA-seq analysis of mouse and human brains revealed that this phenomenon is evolutionarily conserved, and both are influenced by brain cell types (involving excitatory/inhibitory neurons and nonneuronal cells) and by their spatial brain location. As the "primitive" brain is highly oxidative, we hypothesized that such negative mtDNA-nDNA co-expression likely controls for the high mtDNA transcript levels, which enforce tight OXPHOS regulation, rather than rewiring toward glycolysis. Accordingly, we found "primitive" brain-specific up-regulation of lactate dehydrogenase B ( LDHB ), which associates with high OXPHOS activity, at the expense of LDHA , which promotes glycolysis. Analyses of co-expression, DNase-seq, and ChIP-seq experiments revealed candidate RNA-binding proteins and CEBPB as the best regulatory candidates to explain these phenomena. Finally, cross-tissue expression analysis unearthed tissue-dependent splice variants and OXPHOS subunit paralogs and allowed revising the list of canonical OXPHOS transcripts. Taken together, our analysis provides a comprehensive view of mito-nuclear gene co-expression across human tissues and provides overall insights into the bi-genomic regulation of mitochondrial activities. © 2018 Barshad et al.; Published by Cold Spring Harbor Laboratory Press.

The birth of embryonic pluripotency

PubMed Central

Boroviak, Thorsten; Nichols, Jennifer

2014-01-01

Formation of a eutherian mammal requires concurrent establishment of embryonic and extraembryonic lineages. The functions of the trophectoderm and primitive endoderm are to enable implantation in the maternal uterus, axis specification and delivery of nutrients. The pluripotent epiblast represents the founding cell population of the embryo proper, which is protected from ectopic and premature differentiation until it is required to respond to inductive cues to form the fetus. While positional information plays a major role in specifying the trophoblast lineage, segregation of primitive endoderm from epiblast depends upon gradual acquisition of transcriptional identity, directed but not initiated by fibroblast growth factor (FGF) signalling. Following early cleavage divisions and formation of the blastocyst, cells of the inner cell mass lose totipotency. Developing epiblast cells transiently attain the state of naive pluripotency and competence to self-renew in vitro as embryonic stem cells and in vivo by means of diapause. This property is lost after implantation as the epiblast epithelializes and becomes primed in preparation for gastrulation and subsequent organogenesis. PMID:25349450

The Modern Primitives: Applying New Technological Approaches to Explore the Biology of the Earliest Red Blood Cells

PubMed Central

Fraser, Stuart T.

2013-01-01

One of the most critical stages in mammalian embryogenesis is the independent production of the embryo's own circulating, functional red blood cells. Correspondingly, erythrocytes are the first cell type to become functionally mature during embryogenesis. Failure to achieve this invariably leads to in utero lethality. The recent application of technologies such as transcriptome analysis, flow cytometry, mutant embryo analysis, and transgenic fluorescent gene expression reporter systems has shed new light on the distinct erythroid lineages that arise early in development. Here, I will describe the similarities and differences between the distinct erythroid populations that must form for the embryo to survive. While much of the focus of this review will be the poorly understood primitive erythroid lineage, a discussion of other erythroid and hematopoietic lineages, as well as the cell types making up the different niches that give rise to these lineages, is essential for presenting an appropriate developmental context of these cells. PMID:24222861

Primitive control of cellular metabolism

NASA Technical Reports Server (NTRS)

Mitz, M. A.

1974-01-01

It is pointed out that control substances must have existed from the earliest times in the evolution of life and that the same control mechanisms must exist today. The investigation reported is concerned with the concept that carbon dioxide is a primitive regulator of cell function. The effects of carbon dioxide on cellular materials are examined, taking into account questions of solubilization, dissociation, changes of charge, stabilization, structural changes, wettability, the exclusion of other gases, the activation of compounds, changes in plasticity, and changes in membrane permeability.

Friend of GATA (FOG) Interacts with the Nucleosome Remodeling and Deacetylase Complex (NuRD) to Support Primitive Erythropoiesis in Xenopus laevis

PubMed Central

Mimoto, Mizuho S.; Christian, Jan L.

2012-01-01

Friend of GATA (FOG) plays many diverse roles in adult and embryonic hematopoiesis, however the mechanisms by which it functions and the roles of potential interaction partners are not completely understood. Previous work has shown that overexpression of FOG in Xenopus laevis causes loss of blood suggesting that in contrast to its role in mammals, FOG might normally function to repress erythropoiesis in this species. Using loss-of-function analysis, we demonstrate that FOG is essential to support primitive red blood cell (RBC) development in Xenopus. Moreover, we show that it is specifically required to prevent excess apoptosis of circulating primitive RBCs and that in the absence of FOG, the pro-apoptotic gene Bim-1 is strongly upregulated. To identify domains of FOG that are essential for blood development and, conversely, to begin to understand the mechanism by which overexpressed FOG represses primitive erythropoiesis, we asked whether FOG mutants that are unable to interact with known co-factors retain their ability to rescue blood formation in FOG morphants and whether they repress erythropoiesis when overexpressed in wild type embryos. We find that interaction of FOG with the Nucleosome Remodeling and Deacetylase complex (NuRD), but not with C-terminal Binding Protein, is essential for normal primitive RBC development. In contrast, overexpression of all mutant and wild type constructs causes a comparable repression of primitive erythropoiesis. Together, our data suggest that a requirement for FOG and its interaction with NuRD during primitive erythropoiesis are conserved in Xenopus and that loss of blood upon FOG overexpression is due to a dominant-interfering effect. PMID:22235346

Oparin's coacervates as an important milestone in chemical evolution

NASA Astrophysics Data System (ADS)

Kolb, Vera M.

2015-09-01

Although Oparin's coacervate model for the origin of life by chemical evolution is almost 100 years old, it is still valid. However, the structure of his originally proposed coacervate is not considered prebiotic, based on some recent developments in prebiotic chemistry. We have remedied this deficiency of the Oparin's model, by substituting his coacervate with a prebiotically feasible one. Oparin's coacervates are aqueous structures, but have a boundary with the rest of the aqueous medium. They exhibit properties of self-replication, and provide a path to a primitive metabolism, via chemical competition and thus a primitive selection. Thus, coacervates are good models for proto-cells. We review here some salient points of Oparin's model and address also some philosophical views on the beginning of natural selection in primitive chemical systems.

Characterization of Epithelial Progenitors in Normal Human Palatine Tonsils and Their HPV16 E6/E7-Induced Perturbation

PubMed Central

Kang, Sung Yoon Catherine; Kannan, Nagarajan; Zhang, Lewei; Martinez, Victor; Rosin, Miriam P.; Eaves, Connie J.

2015-01-01

Summary Human palatine tonsils are oropharyngeal lymphoid tissues containing multiple invaginations (crypts) in which the continuity of the outer surface epithelium is disrupted and the isolated epithelial cells intermingle with other cell types. We now show that primitive epithelial cells detectable in vitro in 2D colony assays and in a 3D culture system are CD44+NGFR+ and present in both surface and crypt regions. Transcriptome analysis indicated a high similarity between CD44+NGFR+ cells in both regions, although those isolated from the crypt contained a higher proportion of the most primitive (holo)clonogenic cells. Lentiviral transduction of CD44+NGFR+ cells from both regions with human papillomavirus 16-encoded E6/E7 prolonged their growth in 2D cultures and caused aberrant differentiation in 3D cultures. Our findings therefore reveal a shared, site-independent, hierarchical organization, differentiation potential, and transcriptional profile of normal human tonsillar epithelial progenitor cells. They also introduce a new model for investigating the mechanisms of their transformation. PMID:26527383

Clinical, Pathological, and Surgical Outcomes for Adult Pineoblastomas.

PubMed

Gener, Melissa A; Conger, Andrew R; Van Gompel, Jamie; Ariai, Mohammad S; Jentoft, Mark; Meyer, Fredric B; Cardinal, Jeremy S; Bonnin, José M; Cohen-Gadol, Aaron A

2015-12-01

Pineoblastomas are uncommon primitive neuroectodermal tumors that occur mostly in children; they are exceedingly rare in adults. Few published reports have compared the various aspects of these tumors between adults and children. The authors report a series of 12 pineoblastomas in adults from 2 institutions over 24 years. The clinical, radiologic, and pathologic features and clinical outcomes were compared with previously reported cases in children and adults. Patient age ranged from 24 to 81 years, and all but 1 patient exhibited symptoms of obstructive hydrocephalus. Three patients underwent gross total resection, and subtotal resection was performed in 3 patients. Diagnostic biopsy specimens were obtained in an additional 6 patients. Pathologically, the tumors had the classical morphologic and immunohistochemical features of pineoblastomas. Postoperatively, 10 patients received radiotherapy, and 5 patients received chemotherapy. Compared with previously reported cases, several differences were noted in clinical outcomes. Of the 12 patients, only 5 (42%) died of their disease (average length of survival, 118 months); 5 patients (42%) are alive with no evidence of disease (average length of follow-up, 92 months). One patient died of unrelated causes, and one was lost to follow-up. Patients with subtotal resections or diagnostic biopsies did not suffer a worse prognosis. Of the 9 patients with biopsy or subtotal resection, 4 are alive, 4 died of their disease, and 1 died of an unrelated hemorrhagic cerebral infarction. Although this series is small, the data suggest that pineoblastomas in adults have a less aggressive clinical course than in children. Copyright © 2015 Elsevier Inc. All rights reserved.

Apparent diffusion coefficient in glioblastoma with PNET-like components, a GBM variant.

PubMed

Ali, Saad; Joseph, Nancy M; Perry, Arie; Barajas, Ramon F; Cha, Soonmee

2014-09-01

Glioblastoma (GBM) with primitive neuroectodermal tumor (PNET)-like (GBM-PNET) components is a rare variant of GBM. Recent studies describe PNET-like clinical behavior in these patients-with significantly increased propensity for CSF dissemination and a benefit of "PNET-like" chemotherapy. The imaging appearance of GBM-PNET is not well-described and given areas of marked cellularity in the PNET components one might expect significantly reduced diffusion on MRI. The purpose of this study is to quantitatively evaluate the diffusion characteristics in GBM-PNET and compare them with conventional GBMs. Nine patients with surgical specimens yielding GBM-PNET were identified from the UCSF Pathology files. MR images of these patients were reviewed retrospectively. DWI (diffusion-weighted imaging) sequences were analyzed with multiple regions of interests placed within the tumor, and ADC (apparent diffusion coefficient) values were measured. Results were compared to previously published ADC values in pathology-proven conventional GBM cases from our institution. Reduced ADC was seen in GBM-PNET (mean 581 × 10(-6) mm(2)/s, range 338-817) compared to previously published mean of 1,030 × 10(-6) mm(2)/s in the enhancing components of conventional GBMs. We report substantially reduced ADC values in GBM-PNETs compared to conventional GBMs. If demonstrated in a larger sample, when areas of marked reduced diffusion are seen in a suspected GBM, MRI may appropriately direct tissue sampling and can advocate a thorough search for PNET-like components on histopathology. These patients may have a higher chance of developing CSF dissemination and may benefit from "PNET-like" platinum-based chemotherapy.

Carbon Ion Radiotherapy for Unresectable Retroperitoneal Sarcomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Serizawa, Itsuko, E-mail: s_itsuko@nirs.go.j; Kagei, Kenji; Kamada, Tadashi

2009-11-15

Purpose: To evaluate the applicability of carbon ion radiotherapy (CIRT) for unresectable retroperitoneal sarcomas with regard to normal tissue morbidity and local tumor control. Methods and Materials: From May 1997 to February 2006, 24 patients (17 male and 7 female) with unresectable retroperitoneal sarcoma received CIRT. Age ranged from 16 to 77 years (median, 48.6 years). Of the patients, 16 had primary disease and 8 recurrent disease. Histologic diagnoses were as follows: malignant fibrous histiocytoma in 6, liposarcoma in 3, malignant peripheral nerve sheath tumor in 3, Ewing/primitive neuroectodermal tumor (PNET) in 2, and miscellaneous in 10 patients. The histologicmore » grades were as follows: Grade 3 in 15, Grade 2-3 in 2, Grade 2 in 3, and unknown in 4. Clinical target volumes ranged between 57 cm{sup 3} and 1,194 cm{sup 3} (median 525 cm{sup 3}). The delivered carbon ion dose ranged from 52.8 to 73.6 GyE in 16 fixed fractions over 4 weeks. Results: The median follow-up was 36 months (range, 6-143 months). The overall survival rates at 2 and 5 years were 75% and 50%, respectively. The local control rates at 2 and 5 years were 77% and 69%. No complications of the gastrointestinal tract were encountered. No other toxicity greater than Grade 2 was observed. Conclusions: Use of CIRT is suggested to be effective and safe for retroperitoneal sarcomas. The results obtained with CIRT were a good overall survival rate and local control, notwithstanding the fact that most patients were not eligible for surgical resection and had high-grade sarcomas.« less

Teleost growth factor independence (gfi) genes differentially regulate successive waves of hematopoiesis.

PubMed

Cooney, Jeffrey D; Hildick-Smith, Gordon J; Shafizadeh, Ebrahim; McBride, Paul F; Carroll, Kelli J; Anderson, Heidi; Shaw, George C; Tamplin, Owen J; Branco, Diana S; Dalton, Arthur J; Shah, Dhvanit I; Wong, Clara; Gallagher, Patrick G; Zon, Leonard I; North, Trista E; Paw, Barry H

2013-01-15

Growth Factor Independence (Gfi) transcription factors play essential roles in hematopoiesis, differentially activating and repressing transcriptional programs required for hematopoietic stem/progenitor cell (HSPC) development and lineage specification. In mammals, Gfi1a regulates hematopoietic stem cells (HSC), myeloid and lymphoid populations, while its paralog, Gfi1b, regulates HSC, megakaryocyte and erythroid development. In zebrafish, gfi1aa is essential for primitive hematopoiesis; however, little is known about the role of gfi1aa in definitive hematopoiesis or about additional gfi factors in zebrafish. Here, we report the isolation and characterization of an additional hematopoietic gfi factor, gfi1b. We show that gfi1aa and gfi1b are expressed in the primitive and definitive sites of hematopoiesis in zebrafish. Our functional analyses demonstrate that gfi1aa and gfi1b have distinct roles in regulating primitive and definitive hematopoietic progenitors, respectively. Loss of gfi1aa silences markers of early primitive progenitors, scl and gata1. Conversely, loss of gfi1b silences runx-1, c-myb, ikaros and cd41, indicating that gfi1b is required for definitive hematopoiesis. We determine the epistatic relationships between the gfi factors and key hematopoietic transcription factors, demonstrating that gfi1aa and gfi1b join lmo2, scl, runx-1 and c-myb as critical regulators of teleost HSPC. Our studies establish a comparative paradigm for the regulation of hematopoietic lineages by gfi transcription factors. Copyright © 2012 Elsevier Inc. All rights reserved.

Identification of centromere regions in chromosomes of a unicellular red alga, Cyanidioschyzon merolae.

PubMed

Kanesaki, Yu; Imamura, Sousuke; Matsuzaki, Motomichi; Tanaka, Kan

2015-05-08

To investigate the evolution of centromere architecture in plant cells, it is important to identify centromere regions of primitive algae, such as Cyanidioschyzon merolae. In a previous genome project, in silico analysis predicted an AT-rich region in each chromosome as putative centromere regions. Here, we identified a centromere position in each chromosome by ChIP-on-chip analysis using an anti-CENP-A antibody. The identified centromeres were of the regional type, about 2-3 kb in length and contained no consensus or repeat elements. Centromeres in primitive eukaryotic plant cells may have originated from these regional type centromeres. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

On cat's eyes and multiple disjoint cells natural convection flow in tall tilted cavities

NASA Astrophysics Data System (ADS)

Báez, Elsa; Nicolás, Alfredo

2014-10-01

Natural convection fluid flow in air-filled tall tilted cavities is studied numerically with a direct projection method applied on the unsteady Boussinesq approximation in primitive variables. The study is focused on the so called cat's eyes and multiple disjoint cells as the aspect ratio A and the angle of inclination ϕ of the cavity vary. Results have already been reported with primitive and stream function-vorticity variables. The former are validated with the latter ones, which in turn were validated through mesh size and time-step independence studies. The new results complemented with the previous ones lead to find out the fluid motion and heat transfer invariant properties of this thermal phenomenon, which is the novelty here.

Cellular reprogramming in skin cancer.

PubMed

Song, Ihn Young; Balmain, Allan

2015-06-01

Early primitive stem cells have long been viewed as the cancer cells of origin (tumor initiating target cells) due to their intrinsic features of self-renewal and longevity. However, emerging evidence suggests a surprising capacity for normal committed cells to function as reserve stem cells upon reprogramming as a consequence of tissue damage resulting in inflammation and wound healing. This results in an alternative concept positing that tumors may originate from differentiated cells that can re-acquire stem cell properties due to genetic or epigenetic reprogramming. It is likely that both models are correct, and that a continuum of potential cells of origin exists, ranging from early primitive stem cells to committed progenitor or even terminally differentiated cells. A combination of the nature of the target cell and the specific types of gene mutations introduced determine tumor cell lineage, as well as potential for malignant conversion. Evidence from mouse skin models of carcinogenesis suggests that initiated cells at different stages within a stem cell hierarchy have varying degrees of requirement for reprogramming (e.g. inflammation stimuli), depending on their degree of differentiation. This article will present evidence in favor of these concepts that has been developed from studies of several mouse models of skin carcinogenesis. Copyright © 2014 Elsevier Ltd. All rights reserved.

A recursive vesicle-based model protocell with a primitive model cell cycle

NASA Astrophysics Data System (ADS)

Kurihara, Kensuke; Okura, Yusaku; Matsuo, Muneyuki; Toyota, Taro; Suzuki, Kentaro; Sugawara, Tadashi

2015-09-01

Self-organized lipid structures (protocells) have been proposed as an intermediate between nonliving material and cellular life. Synthetic production of model protocells can demonstrate the potential processes by which living cells first arose. While we have previously described a giant vesicle (GV)-based model protocell in which amplification of DNA was linked to self-reproduction, the ability of a protocell to recursively self-proliferate for multiple generations has not been demonstrated. Here we show that newborn daughter GVs can be restored to the status of their parental GVs by pH-induced vesicular fusion of daughter GVs with conveyer GVs filled with depleted substrates. We describe a primitive model cell cycle comprising four discrete phases (ingestion, replication, maturity and division), each of which is selectively activated by a specific external stimulus. The production of recursive self-proliferating model protocells represents a step towards eventual production of model protocells that are able to mimic evolution.

18F-FDG PET/CT in a cardiac metastasis in a patient with history of malignant neuroectodermal tumour of the chest wall: Case report and review of the literature.

PubMed

Marroquín, J A; Hernández, A C; Pilkington, J P; Saviatto, A; Tabuenca, M J; Estenoz, J M

The case presented is a 25-year-old male with a malignant neuroectodermal tumour on the left chest wall (Askin tumour), treated with surgery after neoadyuvant chemotherapy and followed by consolidation chemotherapy. After 9 years of disease free survival, the patient developed an acute pulmonary embolism. The echocardiogram, thoracic CT, and cardiac MRI scans revealed a mass in the right atrium. Recurrence of an Askin tumour versus an atrium myxoma was suspected. 18 F-FDG PET/CT showed an intense hypermetabolic right atrium mass with extension to the right ventricle highly suggestive of malignancy. The result of the histopathology examination after biopsy and subsequently exeresis of the right atrium mass was consistent with a metastasis of the primary tumour. Copyright © 2017 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

Correct Patterning of the Primitive Streak Requires the Anterior Visceral Endoderm

PubMed Central

Stuckey, Daniel W.; Di Gregorio, Aida; Clements, Melanie; Rodriguez, Tristan A.

2011-01-01

Anterior-posterior axis specification in the mouse requires signalling from a specialised extra-embryonic tissue called the anterior visceral endoderm (AVE). AVE precursors are induced at the distal tip of the embryo and move to the prospective anterior. Embryological and genetic analysis has demonstrated that the AVE is required for anterior patterning and for correctly positioning the site of primitive streak formation by inhibiting Nodal activity. We have carried out a genetic ablation of the Hex-expressing cells of the AVE (Hex-AVE) by knocking the Diphtheria toxin subunit A into the Hex locus in an inducible manner. Using this model we have identified that, in addition to its requirement in the anterior of the embryo, the Hex-AVE sub-population has a novel role between 5.5 and 6.5dpc in patterning the primitive streak. Embryos lacking the Hex-AVE display delayed initiation of primitive streak formation and miss-patterning of the anterior primitive streak. We demonstrate that in the absence of the Hex-AVE the restriction of Bmp2 expression to the proximal visceral endoderm is also defective and expression of Wnt3 and Nodal is not correctly restricted to the posterior epiblast. These results, coupled with the observation that reducing Nodal signalling in Hex-AVE ablated embryos increases the frequency of phenotypes observed, suggests that these primitive streak patterning defects are due to defective Nodal signalling. Together, our experiments demonstrate that the AVE is not only required for anterior patterning, but also that specific sub-populations of this tissue are required to pattern the posterior of the embryo. PMID:21445260

THE CELLULAR ORIGIN OF HUMAN IMMUNOGLOBULINS (γ2, γ1M, γ1A)

PubMed Central

Mellors, Robert C.; Korngold, Leonhard

1963-01-01

A study was made of the cellular origin of human immunoglobulins (γ2, γ1M, γ1A). The results indicated that two closely related families of cells form immunoglobulins in human lymphoid tissue: germinal (reticular) centers and plasma cells. Thus their cellular origin in addition to their known antigenic relations further justifies placing the immunoglobulins in one family of proteins. Immunoglobulins were also formed to a small extent in primitive reticular cells which resembled those of germinal centers but were separated from them. Possibly such cells were undergoing transition to the much more numerous plasma cells with which they were commonly associated. The mantles of small lymphocytes which surrounded germinal centers did not contain detectable quantities of immunoglobulins. While in general only one type of immunoglobulin was present in an individual cell or germinal center, γ2- and γ1M-globulin were identified on occasion in the same plasma cell and germinal center. A peculiarity of the fetal thymus gland was the presence of immunoglobulin, mainly γ1M, in a small number of cells of small and intermediate size and primitive reticular appearance and in Hassall's corpuscles. PMID:14077999

Self-organization of neural tissue architectures from pluripotent stem cells.

PubMed

Karus, Michael; Blaess, Sandra; Brüstle, Oliver

2014-08-15

Despite being a subject of intensive research, the mechanisms underlying the formation of neural tissue architectures during development of the central nervous system remain largely enigmatic. So far, studies into neural pattern formation have been restricted mainly to animal experiments. With the advent of pluripotent stem cells it has become possible to explore early steps of nervous system development in vitro. These studies have unraveled a remarkable propensity of primitive neural cells to self-organize into primitive patterns such as neural tube-like rosettes in vitro. Data from more advanced 3D culture systems indicate that this intrinsic propensity for self-organization can even extend to the formation of complex architectures such as a multilayered cortical neuroepithelium or an entire optic cup. These novel experimental paradigms not only demonstrate the enormous self-organization capacity of neural stem cells, they also provide exciting prospects for studying the earliest steps of human neural tissue development and the pathogenesis of brain malformations in reductionist in vitro paradigms. © 2014 Wiley Periodicals, Inc.

A Quantitative Proteomic Analysis of Hemogenic Endothelium Reveals Differential Regulation of Hematopoiesis by SOX17

PubMed Central

Clarke, Raedun L.; Robitaille, Aaron M.; Moon, Randall T.; Keller, Gordon

2015-01-01

Summary The in vitro derivation of hematopoietic stem cells (HSCs) from pluripotent stem cells (PSCs) is complicated by the existence of multiple overlapping embryonic blood cell programs called primitive, erythromyeloid progenitor (EMP), and definitive. As HSCs are only generated during the definitive stage of hematopoiesis, deciphering the regulatory pathways that control the emergence of this program and identifying markers that distinguish it from the other programs are essential. To identify definitive specific pathways and marker sets, we used label-free proteomics to determine the proteome of embryo-derived and mouse embryonic stem cell-derived VE-CADHERIN+CD45− definitive hematopoietic progenitors. With this approach, we identified Stat1 as a marker that distinguishes the definitive erythroid lineage from the primitive- and EMP-derived lineages. Additionally, we provide evidence that the generation of the Stat1+ definitive lineage is dependent on Sox17. These findings establish an approach for monitoring the emergence of definitive hematopoiesis in the PSC differentiation cultures. PMID:26267830

Understanding Microbial Sensing in Inflammatory Bowel Disease Using Click Chemistry

DTIC Science & Technology

2017-10-01

pathogens and commensals. However, the technology available to track these molecules in host cells and tissues remains primitive. To address this...live, luminal bacteria into specific host intestinal immune cells and their subsequent degradation in host phagocytes. Notably, this approach also...click-chemistry, bacterial cell wall, bacterial outer membrane, peptidoglycan, lipopolysaccharide, endotoxin, capsular polysaccharide, inflammatory

Understanding Microbial Sensing in Inflammatory Bowel Disease Using Click Chemistry

DTIC Science & Technology

2017-10-01

both pathogens and commensals. However, the technology available to track these molecules in host cells and tissues remains primitive. To address this...from live, luminal bacteria into specific host intestinal immune cells and their subsequent degradation in host phagocytes. Notably, this approach...Bioorthogonal click-chemistry, bacterial cell wall, bacterial outer membrane, peptidoglycan, lipopolysaccharide, endotoxin, capsular polysaccharide

Expression of the Intermediate Filament Nestin in Gastrointestinal Stromal Tumors and Interstitial Cells of Cajal

PubMed Central

Tsujimura, Tohru; Makiishi-Shimobayashi, Chiaki; Lundkvist, Johan; Lendahl, Urban; Nakasho, Keiji; Sugihara, Ayako; Iwasaki, Teruo; Mano, Masayuki; Yamada, Naoko; Yamashita, Kunihiro; Toyosaka, Akihiro; Terada, Nobuyuki

2001-01-01

It has recently been proposed that gastrointestinal stromal tumors (GISTs) originate from stem cells that differentiate toward a phenotype of interstitial cells of Cajal (ICCs). Nestin is a newly identified intermediate filament protein, and is predominantly expressed in immature cells, such as neuroectodermal stem cells and skeletal muscle progenitor cells, and tumors originating from these cells. In this study, we examined, using immunohistochemistry, the nestin expression in GISTs and ICCs to clarify the origin of GISTs. Strong immunoreactivity for nestin was observed in all 18 GISTs, and its expression was confirmed by Western blot and Northern blot analyses. In contrast, three leiomyomas and a schwannoma that developed in the gastrointestinal tract showed no apparent immunoreactivity for nestin. Among 17 mesenchymal tumors (seven leiomyosarcomas, five malignant peripheral nerve sheath tumors, and five fibrosarcomas) that occurred in sites other than the gastrointestinal tract, only two malignant peripheral nerve sheath tumors were moderately immunoreactive for nestin. Furthermore, with fluorescence double immunostaining of the normal small intestine, nestin expression was demonstrated in ICCs. These results show that nestin may be a useful marker for diagnosis of GISTs, and support the current hypothesis that GISTs are tumors of stem cells that differentiate toward an ICC phenotype. PMID:11238030

Septic disruption of lactiferous ducts with heterogeneous carcinoma of the breast in a lactating woman.

PubMed

Naim, Mohammed; John, Vanesa T; Gaur, Kavita; Anees, Afzal

2010-08-06

This report documents the diagnostic histopathological features of heterogeneous breast carcinoma following sepsis and disruption of the lactiferous ducts in a lactating woman and discusses the pathogenesis. Sections from the nipple revealed disrupted collecting lactiferous ducts presenting with intraduct precarcinoma and carcinoma of the epidermoid type, and attached reparative sprouts lined by lactiferous cells. Breast lobules showed generalised benign adenotic change with various foci of carcinoma microscopically identifiable as intraduct primitive lactiferal ectodermal carcinoma, lactating carcinoma, primitive neuroendocrine carcinoma and myoepithelioid granulomatous carcinoma. The findings led to the conclusion that the lactiferous ducts are susceptible to sepsis and disruption, which may predispose a patient to breast carcinoma. The pattern of carcinoma suggested that lactiferous epithelial cells behaved colonially, with different metaplastic changes, precarcinoma and carcinoma.

Adipogenic placenta-derived mesenchymal stem cells are not lineage restricted by withdrawing extrinsic factors: developing a novel visual angle in stem cell biology.

PubMed

Hu, C; Cao, H; Pan, X; Li, J; He, J; Pan, Q; Xin, J; Yu, X; Li, J; Wang, Y; Zhu, D; Li, L

2016-03-17

Current evidence implies that differentiated bone marrow mesenchymal stem cells (BMMSCs) can act as progenitor cells and transdifferentiate across lineage boundaries. However, whether this unrestricted lineage has specificities depending on the stem cell type is unknown. Placental-derived mesenchymal stem cells (PDMSCs), an easily accessible and less invasive source, are extremely useful materials in current stem cell therapies. No studies have comprehensively analyzed the transition in morphology, surface antigens, metabolism and multilineage potency of differentiated PDMSCs after their dedifferentiation. In this study, we showed that after withdrawing extrinsic factors, adipogenic PDMSCs reverted to a primitive cell population and retained stem cell characteristics. The mitochondrial network during differentiation and dedifferentiation may serve as a marker of absent or acquired pluripotency in various stem cell models. The new population proliferated faster than unmanipulated PDMSCs and could be differentiated into adipocytes, osteocytes and hepatocytes. The cell adhesion molecules (CAMs) signaling pathway and extracellular matrix (ECM) components modulate cell behavior and enable the cells to proliferate or differentiate during the differentiation, dedifferentiation and redifferentiation processes in our study. These observations indicate that the dedifferentiated PDMSCs are distinguishable from the original PDMSCs and may serve as a novel source in stem cell biology and cell-based therapeutic strategies. Furthermore, whether PDMSCs differentiated into other lineages can be dedifferentiated to a primitive cell population needs to be investigated.

Very small embryonic-like stem cells: implications in reproductive biology.

PubMed

Bhartiya, Deepa; Unni, Sreepoorna; Parte, Seema; Anand, Sandhya

2013-01-01

The most primitive germ cells in adult mammalian testis are the spermatogonial stem cells (SSCs) whereas primordial follicles (PFs) are considered the fundamental functional unit in ovary. However, this central dogma has recently been modified with the identification of a novel population of very small embryonic-like stem cells (VSELs) in the adult mammalian gonads. These stem cells are more primitive to SSCs and are also implicated during postnatal ovarian neo-oogenesis and primordial follicle assembly. VSELs are pluripotent in nature and characterized by nuclear Oct-4A, cell surface SSEA-4, and other pluripotent markers like Nanog, Sox2, and TERT. VSELs are considered to be the descendants of epiblast stem cells and possibly the primordial germ cells that persist into adulthood and undergo asymmetric cell division to replenish the gonadal germ cells throughout life. Elucidation of their role during infertility, endometrial repair, superovulation, and pathogenesis of various reproductive diseases like PCOS, endometriosis, cancer, and so on needs to be addressed. Hence, a detailed review of current understanding of VSEL biology is pertinent, which will hopefully open up new avenues for research to better understand various reproductive processes and cancers. It will also be relevant for future regenerative medicine, translational research, and clinical applications in human reproduction.

Stretching morphogenesis of the roof plate and formation of the central canal.

PubMed

Kondrychyn, Igor; Teh, Cathleen; Sin, Melvin; Korzh, Vladimir

2013-01-01

Neurulation is driven by apical constriction of actomyosin cytoskeleton resulting in conversion of the primitive lumen into the central canal in a mechanism driven by F-actin constriction, cell overcrowding and buildup of axonal tracts. The roof plate of the neural tube acts as the dorsal morphogenetic center and boundary preventing midline crossing by neural cells and axons. The roof plate zebrafish transgenics expressing cytosolic GFP were used to study and describe development of this structure in vivo for a first time ever. The conversion of the primitive lumen into the central canal causes significant morphogenetic changes of neuroepithelial cells in the dorsal neural tube. We demonstrated that the roof plate cells stretch along the D-V axis in parallel with conversion of the primitive lumen into central canal and its ventral displacement. Importantly, the stretching of the roof plate is well-coordinated along the whole spinal cord and the roof plate cells extend 3× in length to cover 2/3 of the neural tube diameter. This process involves the visco-elastic extension of the roof place cytoskeleton and depends on activity of Zic6 and the Rho-associated kinase (Rock). In contrast, stretching of the floor plate is much less extensive. The extension of the roof plate requires its attachment to the apical complex of proteins at the surface of the central canal, which depends on activity of Zic6 and Rock. The D-V extension of the roof plate may change a range and distribution of morphogens it produces. The resistance of the roof plate cytoskeleton attenuates ventral displacement of the central canal in illustration of the novel mechanical role of the roof plate during development of the body axis.

Stretching Morphogenesis of the Roof Plate and Formation of the Central Canal

PubMed Central

Kondrychyn, Igor; Teh, Cathleen; Sin, Melvin; Korzh, Vladimir

2013-01-01

Background Neurulation is driven by apical constriction of actomyosin cytoskeleton resulting in conversion of the primitive lumen into the central canal in a mechanism driven by F-actin constriction, cell overcrowding and buildup of axonal tracts. The roof plate of the neural tube acts as the dorsal morphogenetic center and boundary preventing midline crossing by neural cells and axons. Methodology/Principal Findings The roof plate zebrafish transgenics expressing cytosolic GFP were used to study and describe development of this structure in vivo for a first time ever. The conversion of the primitive lumen into the central canal causes significant morphogenetic changes of neuroepithelial cells in the dorsal neural tube. We demonstrated that the roof plate cells stretch along the D–V axis in parallel with conversion of the primitive lumen into central canal and its ventral displacement. Importantly, the stretching of the roof plate is well-coordinated along the whole spinal cord and the roof plate cells extend 3× in length to cover 2/3 of the neural tube diameter. This process involves the visco-elastic extension of the roof place cytoskeleton and depends on activity of Zic6 and the Rho-associated kinase (Rock). In contrast, stretching of the floor plate is much less extensive. Conclusions/Significance The extension of the roof plate requires its attachment to the apical complex of proteins at the surface of the central canal, which depends on activity of Zic6 and Rock. The D–V extension of the roof plate may change a range and distribution of morphogens it produces. The resistance of the roof plate cytoskeleton attenuates ventral displacement of the central canal in illustration of the novel mechanical role of the roof plate during development of the body axis. PMID:23409159

In vitro differentiation of human umbilical cord blood-derived mesenchymal stem cells into hepatocyte-like cells.

PubMed

Hong, Seung Hyun; Gang, Eun Ji; Jeong, Ju Ah; Ahn, Chiyoung; Hwang, Soo Han; Yang, Il Ho; Park, Hwon Kyum; Han, Hoon; Kim, Hoeon

2005-05-20

In addition to long-term self-renewal capability, human mesenchymal stem cells (MSCs) possess versatile differentiation potential ranging from mesenchyme-related multipotency to neuroectodermal and endodermal competency. Of particular concern is hepatogenic potential that can be used for liver-directed stem cell therapy and transplantation. In this study, we have investigated whether human umbilical cord blood (UCB)-derived MSCs are also able to differentiate into hepatocyte-like cells. MSCs isolated from UCB were cultured under the pro-hepatogenic condition similar to that for bone marrow (BM)-derived MSCs. Expression of a variety of hepatic lineage markers was analyzed by flow cytometry, RT-PCR, Western blot, and immunofluorescence. The functionality of differentiated cells was assessed by their ability to incorporate DiI-acetylated low-density lipoprotein (DiI-Ac-LDL). As the cells were morphologically transformed into hepatocyte-like cells, they expressed Thy-1, c-Kit, and Flt-3 at the cell surface, as well as albumin, alpha-fetoprotein, and cytokeratin-18 and 19 in the interior. Moreover, about a half of the cells were found to acquire the capability to transport DiI-Ac-LDL. Based on these observations, and taking into account immense advantages of UCB over other stem cell sources, we conclude that UCB-derived MSCs retain hepatogenic potential suitable for cell therapy and transplantation against intractable liver diseases.

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

PubMed

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.

Chemotaxis of primitive hematopoietic cells in response to stromal cell–derived factor-1

PubMed Central

Jo, Deog-Yeon; Rafii, Shahin; Hamada, Tsuneyoshi; Moore, Malcolm A.S.

2000-01-01

Stromal cell–derived factor-1 (SDF-1) provides a potent chemotactic stimulus for CD34+ hematopoietic cells. We cultured mobilized peripheral blood (PB) and umbilical cord blood (CB) for up to 5 weeks and examined the migratory activity of cobblestone area–forming cells (CAFCs) and long-term culture–initiating cells (LTC-ICs) in a transwell assay. In this system, SDF-1 or MS-5 marrow stromal cells placed in the lower chamber induced transmembrane and transendothelial migration by 2- and 5-week-old CAFCs and LTC-ICs in 3 hours. Transmigration was blocked by preincubation of input CD34+ cells with antibody to CXCR4. Transendothelial migration of CB CAFCs and LTC-ICs was higher than that of PB. We expanded CD34+ cells from CB in serum-free medium with thrombopoietin, flk-2 ligand, and c-kit ligand, with or without IL-3 and found that CAFCs cultured in the absence of IL-3 had a chemotactic response equivalent to noncultured cells, even after 5 weeks. However, addition of IL-3 to the culture reduced this response by 20–50%. These data indicate that SDF-1 induces chemotaxis of primitive hematopoietic cells signaling through CXCR4 and that the chemoattraction could be downmodulated by culture ex vivo. PMID:10619866

"Somatic-type" malignancies arising from testicular germ cell tumors: a clinicopathologic study of 124 cases with emphasis on glandular tumors supporting frequent yolk sac tumor origin.

PubMed

Magers, Martin J; Kao, Chia-Sui; Cole, Cristina D; Rice, Kevin R; Foster, Richard S; Einhorn, Lawrence H; Ulbright, Thomas M

2014-10-01

Somatic-type malignancies (SMs) in patients with testicular germ cell tumors (GCT) are rare and mostly attributed to "transformation" of teratoma, although yolk sac tumor (YST) origin has also been proposed. We studied 124 cases of "SM" of testicular GCT origin from 106 patients to evaluate their morphology, immunohistochemical features (especially the utility of SALL4), and relationship to YST. Primitive neuroectodermal and nephroblastomatous tumors were excluded because of prior studies. Patients ranged in age from 15 to 68 years (mean, 33 y). The tumors ranged from 0.7 to 30 cm (mean, 7.6 cm) and involved the retroperitoneum (64%), abdomen/pelvis (10%), lung (10%), mediastinum (6%), supraclavicular region/neck (4%), testis (4%), and thigh (1%). Most initial diagnoses were sarcomas (n=68) or carcinomas (n=51). On review and immunohistochemical analysis, 7 of 45 adenocarcinomas were reclassified as glandular YSTs (GYST) on the basis of glypican-3 (GPC3) and/or α-fetoprotein positivity and scant/absent reactivity for EMA and CK7. These occasionally (29%) had subnuclear and sometimes supranuclear vacuoles (endometrioid-like), whereas adenocarcinomas were more frequently mucinous (17%) or enteric-type (11%) than endometrioid-like (9%). Both expressed CDX2 frequently (83% and 63%, respectively). MUC protein 2, 4, 5, and 6 expression was more common in adenocarcinomas (7% to 36%) than in GYSTs (0% to 20%) but was infrequent. Both were often positive for SALL4, BerEP4, and MOC31; all were negative for TTF-1. On follow-up (GYST: range, 23 to 169 mo; mean, 81mo; adenocarcinoma: range, 1 to 170 mo; mean, 55 mo), 50% and 33% of patients with GYST and adenocarcinoma, respectively, died of disease. We reclassified 26 of 76 sarcomatoid tumors as sarcomatoid YSTs (SYST) on the basis of positive reactivity for both AE1/3 and GPC3. These tumors often had spindled and epithelioid cells in a fibromyxoid stroma. SYSTs were often (60%) SALL4 positive, whereas sarcomas were all negative. On follow-up (SYST: range, 1 to 259 mo; mean, 62 mo; sarcoma: range, 1 to 327 mo; mean, 70 mo), 50% and 29% of patients with SYST and sarcoma, respectively, died of disease, with most mortality occurring in those with high-grade tumors. We conclude that, on the basis of a panel of immunoreactivities, a significant number of "SMs" in testicular GCT patients are more accurately classified as either GYSTs or SYSTs. Ambiguous glandular tumors should be evaluated for GPC3, α-fetoprotein, CK7, and EMA reactivity and sarcomatoid ones for GPC3, AE1/3, and SALL4 reactivity.

Unprecedented Cell-Selection Using Ultra-Quick Freezing Combined with Aquaporin Expression

PubMed Central

Kato, Yasuhiro; Miyauchi, Takayuki; Abe, Youichiro; Kojić, Dušan; Tanaka, Manami; Chikazawa, Nana; Nakatake, Yuhki; Ko, Shigeru B. H.; Kobayashi, Daisuke; Hazama, Akihiro; Fujiwara, Shoko; Uchida, Tatsuya; Yasui, Masato

2014-01-01

Freezing is usually used for preservation and storage of biological samples; however, this process may have some adverse effects such as cell membrane damage. Aquaporin (AQP), a water channel protein, has been suggested to play some roles for cryopreservation although its molecular mechanism remains unclear. Here we show that membrane damage caused by ultra-quick freezing is rescued by the expression of AQP4. We next examine if the expression of AQP combined with ultra-quick freezing can be used to select cells efficiently under freezing conditions where most cells are died. CHO cells stably expressing AQP4 were exclusively selected from mixed cell cultures. Having identified the increased expression of AQP4 during ES cell differentiation into neuro-ectoderm using bioinformatics, we confirmed the improved survival of differentiated ES cells with AQP4 expression. Finally we show that CHO cells transiently transfected with Endothelin receptor A and Aqp4 were also selected and concentrated by multiple cycles of freezing/thawing, which was confirmed with calcium imaging in response to endothelin. Furthermore, we found that the expression of AQP enables a reduction in the amount of cryoprotectants for freezing, thereby decreasing osmotic stress and cellular toxicity. Taken together, we propose that this simple but efficient and safe method may be applicable to the selection of mammalian cells for applications in regenerative medicine as well as cell-based functional assays or drug screening protocols. PMID:24558371

Structure and function of primitive immunoglobulin superfamily neural cell adhesion molecules: a lesson from studies on planarian.

PubMed

Fusaoka, Eri; Inoue, Takeshi; Mineta, Katsuhiko; Agata, Kiyokazu; Takeuchi, Kosei

2006-05-01

Precise wiring and proper remodeling of the neural network are essential for its normal function. The freshwater planarian is an attractive animal in which to study the formation and maintenance of the neural network due to its high regenerative capability and developmental plasticity. Although a recent study revealed that homologs of netrin and its receptors are required for regeneration and maintenance of the planarian central nervous system (CNS), the roles of cell adhesion in the formation and maintenance of the planarian neural network remain poorly understood. In the present study, we found primitive immunoglobulin superfamily cell adhesion molecules (IgCAMs) in a planarian that are homologous to vertebrate neural IgCAMs. We identified planarian orthologs of NCAM, L1CAM, contactin and DSCAM, and designated them DjCAM, DjLCAM, DjCTCAM and DjDSCAM, respectively. We further confirmed that they function as cell adhesion molecules using cell aggregation assays. DjCAM and DjDSCAM were found to be differentially expressed in the CNS. Functional analyses using RNA interference revealed that DjCAM is partly involved in axon formation, and that DjDSCAM plays crucial roles in neuronal cell migration, axon outgrowth, fasciculation and projection.

Acute erythremic myelosis (true erythroleukaemia): a variant of AML FAB-M6.

PubMed

Hasserjian, R P; Howard, J; Wood, A; Henry, K; Bain, B

2001-03-01

Classic erythroleukaemia (acute myeloid leukaemia M6, or M6 AML) is defined as an excess of myeloblasts in an erythroid predominant background. Leukaemia variants in which the primitive blast cells are demonstrably erythroid are extremely rare and poorly characterised. Variably referred to as "true erythroleukaemia" or "acute erythremic myelosis", they are often included within the M6 AML category even though they do not meet strict criteria for this type of AML. Two cases of acute erythroid neoplasia are presented with clinical, morphological, immunophenotypic, and cytogenetic analysis. Both patients presented with profound anaemia, one in a setting of long standing myelodysplasia. Bone marrow examination revealed a predominant population of highly dysplastic erythroid cells in both cases. In one case, the liver was infiltrated by neoplastic erythroid cells. Both patients died within four months of diagnosis. This report illustrates that cases of acute leukaemia occur in which the dominant neoplastic cell is a primitive erythroid cell without an accompanying increase in myeloblasts. This does not preclude the neoplastic clone originating in a multipotent haemopoietic stem cell, as suggested by cases arising in patients with myelodysplasia. Acute erythremic myelosis should be recognised as a distinct variant of M6 AML.

Attenuation of Neurovirulence, Biodistribution, and Shedding of a Poliovirus:Rhinovirus Chimera after Intrathalamic Inoculation in Macaca fascicularis

PubMed Central

Dobrikova, Elena Y.; Goetz, Christian; Walters, Robert W.; Lawson, Sarah K.; Peggins, James O.; Muszynski, Karen; Ruppel, Sheryl; Poole, Karyol; Giardina, Steven L.; Vela, Eric M.; Estep, James E.

2012-01-01

A dependence of poliovirus on an unorthodox translation initiation mode can be targeted selectively to drive viral protein synthesis and cytotoxicity in malignant cells. Transformed cells are naturally susceptible to poliovirus, due to widespread ectopic upregulation of the poliovirus receptor, Necl-5, in ectodermal/neuroectodermal cancers. Viral tumor cell killing and the host immunologic response it engenders produce potent, lasting antineoplastic effects in animal tumor models. Clinical application of this principle depends on unequivocal demonstration of safety in primate models for paralytic poliomyelitis. We conducted extensive dose-range-finding, toxicity, biodistribution, shedding, and neutralizing antibody studies of the prototype oncolytic poliovirus recombinant, PVS-RIPO, after intrathalamic inoculation in Macaca fascicularis. These studies suggest that intracerebral PVS-RIPO inoculation does not lead to viral propagation in the central nervous system (CNS), does not cause histopathological CNS lesions or neurological symptoms that can be attributed to the virus, is not associated with extraneural virus dissemination or replication and does not induce shedding of virus with stool. Intrathalamic PVS-RIPO inoculation induced neutralizing antibody responses against poliovirus serotype 1 in all animals studied. PMID:22171271

Update on the management of unusual neuroendocrine tumors: pheochromocytoma and paraganglioma, medullary thyroid cancer and adrenocortical carcinoma.

PubMed

Strosberg, Jonathan R

2013-02-01

Pheochromocytomas, paragangliomas, and medullary thyroid carcinomas (MTCs) originate in cells that share a common neuroectodermal origin. Like other neuroendocrine neoplasms, they are characterized by a propensity to secrete amines (epinephrine and norepinephrine) and peptide hormones (calcitonin). Improved understanding of underlying molecular pathways, such as mutations of the RET (rearranged during transfection) proto-oncogene, has led to new rational targeted therapies. Adrenocortical carcinomas (ACCs) originate in the steroid hormone-producing adrenal cortex. While tumors of the adrenal cortex are not, strictly speaking, part the "diffuse neuroendocrine system," they are often included in neuroendocrine tumor guidelines due to their orphan status. In this update on management of unusual neuroendocrine tumors, we review the biology and treatment of these rare neoplasms. Copyright © 2013 Elsevier Inc. All rights reserved.

Differential expression of two scribble isoforms during Drosophila embryogenesis.

PubMed

Li, M; Marhold, J; Gatos, A; Török, I; Mechler, B M

2001-10-01

The tumour suppressor gene scribble (scrib) is required for epithelial polarity and growth control in Drosophila. Here, we report the identification and embryonic expression pattern of two Scrib protein isoforms resulting from alternative splicing during scrib transcription. Both proteins are first ubiquitously expressed during early embryogenesis. Then, during morphogenesis each Scrib protein displays a specific pattern of expression in the central and peripheral nervous systems, CNS and PNS, respectively. During germ band extension, the expression of the longer form Scrib1 occurs predominantly in the neuroblasts derived from the neuro-ectoderm and becomes later restricted to CNS neurones as well as to the pole cells in the gonads. By contrast, the shorter form Scrib2 is strongly expressed in the PNS and a subset of CNS neurones.

Downstream targets of HOXB4 in a cell line model of primitive hematopoietic progenitor cells.

PubMed

Lee, Han M; Zhang, Hui; Schulz, Vincent; Tuck, David P; Forget, Bernard G

2010-08-05

Enforced expression of the homeobox transcription factor HOXB4 has been shown to enhance hematopoietic stem cell self-renewal and expansion ex vivo and in vivo. To investigate the downstream targets of HOXB4 in hematopoietic progenitor cells, HOXB4 was constitutively overexpressed in the primitive hematopoietic progenitor cell line EML. Two genome-wide analytical techniques were used: RNA expression profiling using microarrays and chromatin immunoprecipitation (ChIP)-chip. RNA expression profiling revealed that 465 gene transcripts were differentially expressed in KLS (c-Kit(+), Lin(-), Sca-1(+))-EML cells that overexpressed HOXB4 (KLS-EML-HOXB4) compared with control KLS-EML cells that were transduced with vector alone. In particular, erythroid-specific gene transcripts were observed to be highly down-regulated in KLS-EML-HOXB4 cells. ChIP-chip analysis revealed that the promoter region for 1910 genes, such as CD34, Sox4, and B220, were occupied by HOXB4 in KLS-EML-HOXB4 cells. Side-by-side comparison of the ChIP-chip and RNA expression profiling datasets provided correlative information and identified Gp49a and Laptm4b as candidate "stemness-related" genes. Both genes were highly ranked in both dataset lists and have been previously shown to be preferentially expressed in hematopoietic stem cells and down-regulated in mature hematopoietic cells, thus making them attractive candidates for future functional studies in hematopoietic cells.

From catʼs eyes to multiple disjoint natural convection flow in tall tilted cavities: A direct primitive variables approach

NASA Astrophysics Data System (ADS)

Báez, Elsa; Nicolás, Alfredo

2013-11-01

Natural convection fluid flow in air-filled tall tilted cavities is studied numerically with a new direct projection method on the Boussinesq approximation in primitive variables. The study deals with “cat's eyes” instabilities and multiple disjoint cells as the aspect ratio A and the angle of inclination ϕ of the cavity vary. The flows are validated with those reported before using the stream function-vorticity variables. New cases, A=12 and 20 varying ϕ, lead to get more insight on the physical phenomenon.

Cell fate regulation in early mammalian development

NASA Astrophysics Data System (ADS)

Oron, Efrat; Ivanova, Natalia

2012-08-01

Preimplantation development in mammals encompasses a period from fertilization to implantation and results in formation of a blastocyst composed of three distinct cell lineages: epiblast, trophectoderm and primitive endoderm. The epiblast gives rise to the organism, while the trophectoderm and the primitive endoderm contribute to extraembryonic tissues that support embryo development after implantation. In many vertebrates, such as frog or fish, maternally supplied lineage determinants are partitioned within the egg. Cell cleavage that follows fertilization results in polarization of these factors between the individual blastomeres, which become restricted in their developmental fate. In contrast, the mouse oocyte and zygote lack clear polarity and, until the eight-cell stage, individual blastomeres retain the potential to form all lineages. How are cell lineages specified in the absence of a maternally supplied blueprint? This is a fundamental question in the field of developmental biology. The answer to this question lies in understanding the cell-cell interactions and gene networks involved in embryonic development prior to implantation and using this knowledge to create testable models of the developmental processes that govern cell fates. We provide an overview of classic and contemporary models of early lineage development in the mouse and discuss the emerging body of work that highlights similarities and differences between blastocyst development in the mouse and other mammalian species.

Comparison of endoscope- versus microscope-assisted resection of deep-seated intracranial lesions using a minimally invasive port retractor system.

PubMed

Hong, Christopher S; Prevedello, Daniel M; Elder, J Bradley

2016-03-01

Tubular brain retractors may improve access to deep-seated brain lesions while potentially reducing the risks of collateral neurological injury associated with standard microsurgical approaches. Here, microscope-assisted resection of lesions using tubular retractors is assessed to determine if it is superior to endoscope-assisted surgery due to the technological advancements associated with modern tubular ports and surgical microscopes. Following institutional approval of the tubular port, data obtained from the initial 20 patients to undergo transportal resection of deep-seated brain lesions were analyzed in this study. The pathological entities of the resected tissues included metastatic tumors (8 patients), glioma (7), meningioma (1), neurocytoma (1), radiation necrosis (1), primitive neuroectodermal tumor (1), and hemangioblastoma (1). Surgery incorporated endoscopic (5 patients) or microscopic (15) assistance. The locations included the basal ganglia (11 patients), cerebellum (4), frontal lobe (2), temporal lobe (2), and parietal lobe (1). Cases were reviewed for neurological outcomes, extent of resection (EOR), and complications. Technical data for the port, surgical microscope, and endoscope were analyzed. EOR was considered total in 14 (70%), near total (> 95%) in 4 (20%), and subtotal (< 90%) in 2 (10%) of 20 patients. Incomplete resection was associated with the basal ganglia location (p < 0.05) and use of the endoscope (p < 0.002). Four of 5 (80%) endoscope-assisted cases were near-total (2) or subtotal (2) resection. Histopathological diagnosis, presenting neurological symptoms, and demographics were not associated with EOR. Complication rates were low and similar between groups. Initial experience with tubular retractors favors use of the microscope rather than the endoscope due to a wider and 3D field of view. Improved microscope optics and tubular retractor design allows for binocular vision with improved lighting for the resection of deep-seated brain lesions.

Medulloblastoma in children and adolescents: a systematic review of contemporary phase I and II clinical trials and biology update.

PubMed

Bautista, Francisco; Fioravantti, Victoria; de Rojas, Teresa; Carceller, Fernando; Madero, Luis; Lassaletta, Alvaro; Moreno, Lucas

2017-11-01

Survival rates for patients with medulloblastoma have improved in the last decades but for those who relapse outcome is dismal and new approaches are needed. Emerging drugs have been tested in the last two decades within the context of phase I/II trials. In parallel, advances in genetic profiling have permitted to identify key molecular alterations for which new strategies are being developed. We performed a systematic review focused on the design and outcome of early-phase trials evaluating new agents in patients with relapsed medulloblastoma. PubMed, clinicaltrials.gov, and references from selected studies were screened to identify phase I/II studies with reported results between 2000 and 2015 including patients with medulloblastoma aged <18 years. A total of 718 studies were reviewed and 78 satisfied eligibility criteria. Of those, 69% were phase I; 31% phase II. Half evaluated conventional chemotherapeutics and 35% targeted agents. Overall, 662 patients with medulloblastoma/primitive neuroectodermal tumors were included. The study designs and the response assessments were heterogeneous, limiting the comparisons among trials and the correct identification of active drugs. Median (range) objective response rate (ORR) for patients with medulloblastoma in phase I/II studies was 0% (0-100) and 6.5% (0-50), respectively. Temozolomide containing regimens had a median ORR of 16.5% (0-100). Smoothened inhibitors trials had a median ORR of 8% (3-8). Novel drugs have shown limited activity against relapsed medulloblastoma. Temozolomide might serve as backbone for new combinations. Novel and more homogenous trial designs might facilitate the development of new drugs. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Clinical features and outcomes in patients with extraskeletal Ewing sarcoma

PubMed Central

Applebaum, Mark A.; Worch, Jennifer; Matthay, Katherine K.; Goldsby, Robert; Neuhaus, John; West, Daniel C.; DuBois, Steven G.

2010-01-01

Background Ewing sarcoma can arise in either bone or soft tissue locations. We sought to investigate if patient characteristics, treatment strategies, and outcomes differ between skeletal Ewing sarcoma and extraskeletal Ewing sarcoma (EES). Procedure Patients < 40 years of age with Ewing sarcoma or peripheral primitive neuroectodermal tumor (PNET) reported to the US SEER database from 1973 to 2007 were evaluated based on skeletal (n=1519) vs. extraskeletal (n=683) site of origin. Patient characteristics were compared using Fisher exact tests. Overall survival was estimated by Kaplan-Meier methods and compared using log-rank tests and Cox models. Results Patients with EES had a higher mean age (19.5 vs. 16.3 years; p < 0.001) and were less likely to be male (53.4% vs. 63.3%; p < 0.001) or white (84.8% vs. 92.5%; p < 0.001) compared to patients with skeletal tumors. Extraskeletal tumors were more likely to arise in axial locations (72.9% vs. 54.2%; p = 0.001), though less likely to arise specifically in the pelvis (19.8% vs. 26.6%; p < 0.001). Metastatic status or tumor size did not differ by group. Five-year overall survival was superior for localized EES compared to localized skeletal tumors (69.7% vs. 62.6%; p = 0.02). The hazard ratio for death in patients with localized skeletal tumors compared to localized EES was 2.36 (95% CI 1.61-3.44) beyond 24 months from initial diagnosis. Conclusions Patient characteristics and outcomes differ among patients with EES compared to patients with skeletal Ewing sarcoma. These findings may have important implications for patient care. PMID:21692057

Outcome of Children With Metastatic Medulloblastoma Treated With Carboplatin During Craniospinal Radiotherapy: A Children's Oncology Group Phase I/II Study

PubMed Central

Jakacki, Regina I.; Burger, Peter C.; Zhou, Tianni; Holmes, Emiko J.; Kocak, Mehmet; Onar, Arzu; Goldwein, Joel; Mehta, Minesh; Packer, Roger J.; Tarbell, Nancy; Fitz, Charles; Vezina, Gilbert; Hilden, Joanne; Pollack, Ian F.

2012-01-01

Purpose We evaluated the feasibility of administering carboplatin as a radiosensitizer during craniospinal radiation therapy (CSRT) to patients with high-risk medulloblastomas (MBs) and supratentorial primitive neuroectodermal tumors, and we report the outcome in the subset with metastatic (M+) MB. Patients and Methods After surgery, patients received 36 Gy CSRT with boosts to sites of disease. During radiation, patients received 15 to 30 doses of carboplatin (30-45 mg/m2/dose), along with vincristine (VCR) once per week for 6 weeks. Patients on regimen A received 6 months of maintenance chemotherapy (MC) with cyclophosphamide and VCR. Once the recommended phase II dose (RP2D) of carboplatin was determined, cisplatin was added to the MC (regimen B). Results In all, 161 eligible patients (median age, 8.7 years; range, 3.1 to 21.6 years) were enrolled. Myelosuppression was dose limiting and 35 mg/m2/dose × 30 was determined to be the RP2D of carboplatin. Twenty-nine (36%) of 81 patients with M+ MB had diffuse anaplasia. Four patients were taken off study within 11 months of completing radiotherapy for presumed metastatic progression and are long-term survivors following palliative chemotherapy. Excluding these four patients, 5-year overall survival ± SE and progression-free survival ± SE for M+ patients treated at the RP2D on regimen A was 82% ± 9% and 71% ± 11% versus 68% ± 10% and 59% ± 10% on regimen B (P = .36). There was no difference in survival by M stage. Anaplasia was a negative predictor of outcome. Conclusion The use of carboplatin as a radiosensitizer is a promising strategy for patients with M+ MB. Early progression should be confirmed by biopsy. PMID:22665539

Proton Therapy in Children: A Systematic Review of Clinical Effectiveness in 15 Pediatric Cancers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leroy, Roos, E-mail: Roos.leroy@kce.fgov.be; Benahmed, Nadia; Hulstaert, Frank

Because it spares many normal tissues and reduces the integral dose, proton therapy (PT) is the preferred tumor irradiation technique for treating childhood cancer. However, to the best of our knowledge, no systematic review of the clinical effectiveness of PT in children has been reported in the scientific literature. A systematic search for clinical outcome studies on PT published between 2007 and 2015 was performed in Medline (through OVID), EMBASE, and the Cochrane Library. Twenty-three primary studies were identified, including approximately 650 patients overall. The median/mean follow-up times were limited (range, 19-91 months). None of the studies were randomized, 2 weremore » comparative, and 20 were retrospective. Most suffered from serious methodologic limitations, yielding a very low level of clinical evidence for the outcomes in all indications. For example, for retinoblastoma, very low-level evidence was found that PT might decrease the incidence of second malignancies. For chondrosarcoma, chordoma, craniopharyngioma, ependymoma, esthesioneuroblastoma, Ewing sarcoma, central nervous system germinoma, glioma, medulloblastoma, osteosarcoma, and rhabdomyosarcoma, there was insufficient evidence to either support or refute PT in children. For pelvic sarcoma (ie, nonrhabdomyosarcoma and non-Ewing sarcoma), pineal parenchymal tumor, primitive neuroectodermal tumor, and “adult-type” soft tissue sarcoma, no studies were identified that fulfilled the inclusion criteria. Although there is no doubt that PT reduces the radiation dose to normal tissues and organs, to date the critical clinical data on the long-term effectiveness and harm associated with the use of PT in the 15 pediatric cancers under investigation are lacking. High-quality clinical research in this area is needed.« less

Prolonged Growth Hormone/Insulin/Insulin-like Growth Factor Nutrient Response Signaling Pathway as a Silent Killer of Stem Cells and a Culprit in Aging.

PubMed

Ratajczak, Mariusz Z; Bartke, Andrzej; Darzynkiewicz, Zbigniew

2017-08-01

The dream of slowing down the aging process has always inspired mankind. Since stem cells are responsible for tissue and organ rejuvenation, it is logical that we should search for encoded mechanisms affecting life span in these cells. However, in adult life the hierarchy within the stem cell compartment is still not very well defined, and evidence has accumulated that adult tissues contain rare stem cells that possess a broad trans-germ layer differentiation potential. These most-primitive stem cells-those endowed with pluripotent or multipotent differentiation ability and that give rise to other cells more restricted in differentiation, known as tissue-committed stem cells (TCSCs) - are of particular interest. In this review we present the concept supported by accumulating evidence that a population of so-called very small embryonic-like stem cells (VSELs) residing in adult tissues positively impacts the overall survival of mammals, including humans. These unique cells are prevented in vertebrates from premature depletion by decreased sensitivity to growth hormone (GH), insulin (INS), and insulin-like growth factor (IGF) signaling, due to epigenetic changes in paternally imprinted genes that regulate their resistance to these factors. In this context, we can envision nutrient response GH/INS/IGF signaling pathway as a lethal factor for these most primitive stem cells and an important culprit in aging.

Resolving early mesoderm diversification through single-cell expression profiling.

PubMed

Scialdone, Antonio; Tanaka, Yosuke; Jawaid, Wajid; Moignard, Victoria; Wilson, Nicola K; Macaulay, Iain C; Marioni, John C; Göttgens, Berthold

2016-07-14

In mammals, specification of the three major germ layers occurs during gastrulation, when cells ingressing through the primitive streak differentiate into the precursor cells of major organ systems. However, the molecular mechanisms underlying this process remain unclear, as numbers of gastrulating cells are very limited. In the mouse embryo at embryonic day 6.5, cells located at the junction between the extra-embryonic region and the epiblast on the posterior side of the embryo undergo an epithelial-to-mesenchymal transition and ingress through the primitive streak. Subsequently, cells migrate, either surrounding the prospective ectoderm contributing to the embryo proper, or into the extra-embryonic region to form the yolk sac, umbilical cord and placenta. Fate mapping has shown that mature tissues such as blood and heart originate from specific regions of the pre-gastrula epiblast, but the plasticity of cells within the embryo and the function of key cell-type-specific transcription factors remain unclear. Here we analyse 1,205 cells from the epiblast and nascent Flk1(+) mesoderm of gastrulating mouse embryos using single-cell RNA sequencing, representing the first transcriptome-wide in vivo view of early mesoderm formation during mammalian gastrulation. Additionally, using knockout mice, we study the function of Tal1, a key haematopoietic transcription factor, and demonstrate, contrary to previous studies performed using retrospective assays, that Tal1 knockout does not immediately bias precursor cells towards a cardiac fate.

A recursive vesicle-based model protocell with a primitive model cell cycle

PubMed Central

Kurihara, Kensuke; Okura, Yusaku; Matsuo, Muneyuki; Toyota, Taro; Suzuki, Kentaro; Sugawara, Tadashi

2015-01-01

Self-organized lipid structures (protocells) have been proposed as an intermediate between nonliving material and cellular life. Synthetic production of model protocells can demonstrate the potential processes by which living cells first arose. While we have previously described a giant vesicle (GV)-based model protocell in which amplification of DNA was linked to self-reproduction, the ability of a protocell to recursively self-proliferate for multiple generations has not been demonstrated. Here we show that newborn daughter GVs can be restored to the status of their parental GVs by pH-induced vesicular fusion of daughter GVs with conveyer GVs filled with depleted substrates. We describe a primitive model cell cycle comprising four discrete phases (ingestion, replication, maturity and division), each of which is selectively activated by a specific external stimulus. The production of recursive self-proliferating model protocells represents a step towards eventual production of model protocells that are able to mimic evolution. PMID:26418735

Origin and specification of type II neuroblasts in the Drosophila embryo.

PubMed

Álvarez, José-Andrés; Díaz-Benjumea, Fernando J

2018-04-05

In Drosophila , neural stem cells or neuroblasts (NBs) acquire different identities according to their site of origin in the embryonic neuroectoderm. Their identity determines the number of times they will divide and the types of daughter cells they will generate. All NBs divide asymmetrically, with type I NBs undergoing self-renewal and generating another cell that will divide only once more. By contrast, a small set of NBs in the larval brain, type II NBs, divides differently, undergoing self-renewal and generating an intermediate neural progenitor (INP) that continues to divide asymmetrically several more times, generating larger lineages. In this study, we have analysed the origin of type II NBs and how they are specified. Our results indicate that these cells originate in three distinct clusters in the dorsal protocerebrum during stage 12 of embryonic development. Moreover, it appears that their specification requires the combined action of EGFR signalling and the activity of the related genes buttonhead and Drosophila Sp1 In addition, we also show that the INPs generated in the embryo enter quiescence at the end of embryogenesis, resuming proliferation during the larval stage. © 2018. Published by The Company of Biologists Ltd.

Brain and Retinal Pericytes: Origin, Function and Role

PubMed Central

Trost, Andrea; Lange, Simona; Schroedl, Falk; Bruckner, Daniela; Motloch, Karolina A.; Bogner, Barbara; Kaser-Eichberger, Alexandra; Strohmaier, Clemens; Runge, Christian; Aigner, Ludwig; Rivera, Francisco J.; Reitsamer, Herbert A.

2016-01-01

Pericytes are specialized mural cells located at the abluminal surface of capillary blood vessels, embedded within the basement membrane. In the vascular network these multifunctional cells fulfil diverse functions, which are indispensable for proper homoeostasis. They serve as microvascular stabilizers, are potential regulators of microvascular blood flow and have a central role in angiogenesis, as they for example regulate endothelial cell proliferation. Furthermore, pericytes, as part of the neurovascular unit, are a major component of the blood-retina/brain barrier. CNS pericytes are a heterogenic cell population derived from mesodermal and neuro-ectodermal germ layers acting as modulators of stromal and niche environmental properties. In addition, they display multipotent differentiation potential making them an intriguing target for regenerative therapies. Pericyte-deficiencies can be cause or consequence of many kinds of diseases. In diabetes, for instance, pericyte-loss is a severe pathological process in diabetic retinopathy (DR) with detrimental consequences for eye sight in millions of patients. In this review, we provide an overview of our current understanding of CNS pericyte origin and function, with a special focus on the retina in the healthy and diseased. Finally, we highlight the role of pericytes in de- and regenerative processes. PMID:26869887

In Pursuit of Prostate Cancer Stem Cells

DTIC Science & Technology

2007-01-01

cells with different tumorigenicities and primitiveness in human PCa xenografts and cell lines. In this study, we seek to reevaluate the relevancy...us prostatospheres and establish primary xenografts in order to carry out our proposed experiments. Preliminary in vitro experiments indicate that...LIMITATION OF ABSTRACT 18 . NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT U b. ABSTRACT U c. THIS PAGE U UU 31

In vitro long-term culture of human primitive hematopoietic cells supported by murine stromal cell line MS-5.

PubMed

Nishi, N; Ishikawa, R; Inoue, H; Nishikawa, M; Yoneya, T; Kakeda, M; Tsumura, H; Ohashi, H; Mori, K J

1997-04-01

When Lin-CD34+CD38- cells from normal human cord blood were cocultured with MS-5, colony forming cells were maintained for over 8 weeks. Prevention of contact between MS-5 and Lin-CD34+CD38- cells by using a membrane filter was negligible for this activity, indicating that the activity of MS-5 on human primitive hematopoietic cells may be due to soluble factor(s) secreted from MS-5. We tried to purify this activity by a [3H]TdR incorporation assay. The activity was found in 150 kD fraction and was neutralized with anti-mSCF (stem cell factor) antibody. Another 20-30 kD fraction synergized with mSCF to stimulate the growth of Lin-CD34+CD38- cells but failed alone. This fraction supported the growth of the G-CSF (granulocyte-colony stimulating factor)-dependent cell line FD/GR3, FDC-P2 transfected with mG-CSF receptor cDNA. This synergy was canceled in the presence of soluble mG-CSF receptor. Addition of anti-mSCF antibody and soluble mG-CSF receptor to the culture completely abrogated the activity of MS-5-culture supernatant. These results indicate the activity of MS-5 on Lin-CD34+CD38- cells is due to synergistic effect of mSCF and mG-CSF.

Optimizing homeostatic cell renewal in hierarchical tissues

PubMed Central

Fider, Nicole A.

2018-01-01

In order to maintain homeostasis, mature cells removed from the top compartment of hierarchical tissues have to be replenished by means of differentiation and self-renewal events happening in the more primitive compartments. As each cell division is associated with a risk of mutation, cell division patterns have to be optimized, in order to minimize or delay the risk of malignancy generation. Here we study this optimization problem, focusing on the role of division tree length, that is, the number of layers of cells activated in response to the loss of terminally differentiated cells, which is related to the balance between differentiation and self-renewal events in the compartments. Using both analytical methods and stochastic simulations in a metapopulation-style model, we find that shorter division trees are advantageous if the objective is to minimize the total number of one-hit mutants in the cell population. Longer division trees on the other hand minimize the accumulation of two-hit mutants, which is a more likely evolutionary goal given the key role played by tumor suppressor genes in cancer initiation. While division tree length is the most important property determining mutant accumulation, we also find that increasing the size of primitive compartments helps to delay two-hit mutant generation. PMID:29447149

Identification of progenitor cancer stem cell in lentigo maligna melanoma.

PubMed

Bongiorno, M R; Doukaki, S; Malleo, F; Aricò, M

2008-07-01

The potential role of stem cells in neoplasia has aroused considerable interest over the past few years. A number of known biologic characteristics of melanomas support the theory that they may originate in a mutated stem cell. Melanocytic stem cell markers have been described recently. Moreover, the CD133 cells that show surface markers for CD34 are stem cells primitive. These stem cells are capable of differentiating into neurons, glia, keratinocytes, smooth muscle cells, and melanocytes in vitro. The identification of cancer stem/initiating cells with a crucial role in tumor formation may open up new pharmacologic perspectives. The purpose of this study is to detect the expression of CD133 and CD34, two putative markers of cancer stem cells in the lentigo maligna melanoma. Thirty cases of lentigo maligna melanoma were analyzed using indirect immunohistochemical staining. The vast majority of the samples analyzed showed the presence of rare cells, which were clearly positive for CD133 and CD34. Strong CD133 and CD34 staining was found in the outer root sheath of the mid-lower hair follicles, intermixed with atypical melanocytes extending along layers of the hair follicles. A number of these staminal cells were adjacent and intermixed with melanoma cells. This study supports the stem cell origin of this tumor and suggests that the precursor of the melanoma in question is a stem-like cell rather than the primitive melanoblast committed to be exclusively involved in melanocytic differentiation.

Distribution and Characterization of Progenitor Cells within the Human Filum Terminale

PubMed Central

Jaff, Nasren; Ossoinak, Amina; Jansson, Katarina; Hägerstrand, Anders; Johansson, Clas B.; Brundin, Lou; Svensson, Mikael

2011-01-01

Background Filum terminale (FT) is a structure that is intimately associated with conus medullaris, the most caudal part of the spinal cord. It is well documented that certain regions of the adult human central nervous system contains undifferentiated, progenitor cells or multipotent precursors. The primary objective of this study was to describe the distribution and progenitor features of this cell population in humans, and to confirm their ability to differentiate within the neuroectodermal lineage. Methodology/Principal Findings We demonstrate that neural stem/progenitor cells are present in FT obtained from patients treated for tethered cord. When human or rat FT-derived cells were cultured in defined medium, they proliferated and formed neurospheres in 13 out of 21 individuals. Cells expressing Sox2 and Musashi-1 were found to outline the central canal, and also to be distributed in islets throughout the whole FT. Following plating, the cells developed antigen profiles characteristic of astrocytes (GFAP) and neurons (β-III-tubulin). Addition of PDGF-BB directed the cells towards a neuronal fate. Moreover, the cells obtained from young donors shows higher capacity for proliferation and are easier to expand than cells derived from older donors. Conclusion/Significance The identification of bona fide neural progenitor cells in FT suggests a possible role for progenitor cells in this extension of conus medullaris and may provide an additional source of such cells for possible therapeutic purposes. Filum terminale, human, progenitor cells, neuron, astrocytes, spinal cord. PMID:22096566

In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors

PubMed Central

Richter, Maximilian; Saydaminova, Kamola; Yumul, Roma; Krishnan, Rohini; Liu, Jing; Nagy, Eniko-Eva; Singh, Manvendra; Izsvák, Zsuzsanna; Cattaneo, Roberto; Uckert, Wolfgang; Palmer, Donna; Ng, Philip; Haworth, Kevin G.; Kiem, Hans-Peter; Ehrhardt, Anja; Papayannopoulou, Thalia

2016-01-01

Current protocols for hematopoietic stem/progenitor cell (HSPC) gene therapy, involving the transplantation of ex vivo genetically modified HSPCs are complex and not without risk for the patient. We developed a new approach for in vivo HSPC transduction that does not require myeloablation and transplantation. It involves subcutaneous injections of granulocyte-colony-stimulating factor/AMD3100 to mobilize HSPCs from the bone marrow (BM) into the peripheral blood stream and the IV injection of an integrating, helper-dependent adenovirus (HD-Ad5/35++) vector system. These vectors target CD46, a receptor that is uniformly expressed on HSPCs. We demonstrated in human CD46 transgenic mice and immunodeficient mice with engrafted human CD34+ cells that HSPCs transduced in the periphery home back to the BM where they stably express the transgene. In hCD46 transgenic mice, we showed that our in vivo HSPC transduction approach allows for the stable transduction of primitive HSPCs. Twenty weeks after in vivo transduction, green fluorescent protein (GFP) marking in BM HSPCs (Lin−Sca1+Kit− cells) in most of the mice was in the range of 5% to 10%. The percentage of GFP-expressing primitive HSPCs capable of forming multilineage progenitor colonies (colony-forming units [CFUs]) increased from 4% of all CFUs at week 4 to 16% at week 12, indicating transduction and expansion of long-term surviving HSPCs. Our approach was well tolerated, did not result in significant transduction of nonhematopoietic tissues, and was not associated with genotoxicty. The ability to stably genetically modify HSPCs without the need of myeloablative conditioning is relevant for a broader clinical application of gene therapy. PMID:27554082

Ciliary photoreceptors in the cerebral eyes of a protostome larva

PubMed Central

2011-01-01

Background Eyes in bilaterian metazoans have been described as being composed of either ciliary or rhabdomeric photoreceptors. Phylogenetic distribution, as well as distinct morphologies and characteristic deployment of different photopigments (ciliary vs. rhabdomeric opsins) and transduction pathways argue for the co-existence of both of these two photoreceptor types in the last common bilaterian ancestor. Both receptor types exist throughout the Bilateria, but only vertebrates are thought to use ciliary photoreceptors for directional light detection in cerebral eyes, while all other invertebrate bilaterians studied utilize rhabdomeric photoreceptors for this purpose. In protostomes, ciliary photoreceptors that express c-opsin have been described only from a non-visual deep-brain photoreceptor. Their homology with vertebrate rods and cones of the human eye has been hypothesized to represent a unique functional transition from non-visual to visual roles in the vertebrate lineage. Results To test the hypothesis that protostome cerebral eyes employ exclusively rhabdomeric photoreceptors, we investigated the ultrastructure of the larval eyes in the brachiopod Terebratalia transversa. We show that these pigment-cup eyes consist of a lens cell and a shading pigment cell, both of which are putative photoreceptors, deploying a modified, enlarged cilium for light perception, and have axonal connections to the larval brain. Our investigation of the gene expression patterns of c-opsin, Pax6 and otx in these eyes confirms that the larval eye spots of brachiopods are cerebral eyes that deploy ciliary type photoreceptors for directional light detection. Interestingly, c-opsin is also expressed during early embryogenesis in all potential apical neural cells, becoming restricted to the anterior neuroectoderm, before expression is initiated in the photoreceptor cells of the eyes. Coincident with the expression of c-opsin in the presumptive neuroectoderm, we found that middle gastrula stage embryos display a positive photoresponse behavior, in the absence of a discrete shading pigment or axonal connections between cells. Conclusions Our results indicate that the dichotomy in the deployment of ciliary and rhabdomeric photoreceptors for directional light detection is not as clear-cut as previously thought. Analyses of brachiopod larval eyes demonstrate that the utilization of c-opsin expressing ciliary photoreceptors in cerebral eyes is not limited to vertebrates. The presence of ciliary photoreceptor-based eyes in protostomes suggests that the transition between non-visual and visual functions of photoreceptors has been more evolutionarily labile than previously recognized, and that co-option of ciliary and rhabdomeric photoreceptor cell types for directional light detection has occurred multiple times during animal evolution. In addition, positive photoresponse behavior in gastrula stage embryos suggests that a discrete shading pigment is not requisite for directional photoreception in metazoans. Scanning photoreception of light intensities mediating cell-autonomous changes of ciliary movement may represent an ancient mechanism for regulating locomotory behavior, and is likely to have existed prior to the evolution of eye-mediated directional light detection employing axonal connections to effector cells and a discreet shading pigment. PMID:21362157

Defined culture medium for stem cell differentiation: applicability of serum-free conditions in the mouse embryonic stem cell test.

PubMed

Riebeling, Christian; Schlechter, Katharina; Buesen, Roland; Spielmann, Horst; Luch, Andreas; Seiler, Andrea

2011-06-01

The embryonic stem cell test (EST) is a validated method to assess the developmental toxicity potency of chemicals. It was developed to reduce animal use and allow faster testing for hazard assessment. The cells used in this method are maintained and differentiated in media containing foetal calf serum. This animal product is of considerable variation in quality, and individual batches require extensive testing for their applicability in the EST. Moreover, its production involves a large number of foetuses and possible animal suffering. We demonstrate the serum-free medium and feeder cell-free maintenance of the mouse embryonic stem cell line D3 and investigate the use of specific growth factors for induction of cardiac differentiation. Using a combination of bone morphogenetic protein-2, bone morphogenetic protein-4, activin A and ascorbic acid, embryoid bodies efficiently differentiated into contracting myocardium. Additionally, examining levels of intracellular marker proteins by flow cytometry not only confirmed differentiation into cardiomyocytes, but demonstrated significant differentiation into neuronal cells in the same time frame. Thus, this approach might allow for simultaneous detection of developmental effects on both early mesodermal and neuroectodermal differentiation. The serum-free conditions for maintenance and differentiation of D3 cells described here enhance the transferability and standardisation and hence the performance of the EST. Copyright © 2011 Elsevier Ltd. All rights reserved.

Globin switches in yolk sac-like primitive and fetal-like definitive red blood cells produced from human embryonic stem cells.

PubMed

Qiu, Caihong; Olivier, Emmanuel N; Velho, Michelle; Bouhassira, Eric E

2008-02-15

We have previously shown that coculture of human embryonic stem cells (hESCs) for 14 days with immortalized fetal hepatocytes yields CD34(+) cells that can be expanded in serum-free liquid culture into large numbers of megaloblastic nucleated erythroblasts resembling yolk sac-derived cells. We show here that these primitive erythroblasts undergo a switch in hemoglobin (Hb) composition during late terminal erythroid maturation with the basophilic erythroblasts expressing predominantly Hb Gower I (zeta(2)epsilon(2)) and the orthochromatic erythroblasts hemoglobin Gower II (alpha(2)epsilon(2)). This suggests that the switch from Hb Gower I to Hb Gower II, the first hemoglobin switch in humans is a maturation switch not a lineage switch. We also show that extending the coculture of the hESCs with immortalized fetal hepatocytes to 35 days yields CD34(+) cells that differentiate into more developmentally mature, fetal liver-like erythroblasts, that are smaller, express mostly fetal hemoglobin, and can enucleate. We conclude that hESC-derived erythropoiesis closely mimics early human development because the first 2 human hemoglobin switches are recapitulated, and because yolk sac-like and fetal liver-like cells are sequentially produced. Development of a method that yields erythroid cells with an adult phenotype remains necessary, because the most mature cells that can be produced with current systems express less than 2% adult beta-globin mRNA.

Formation and specification of a Drosophila dopaminergic precursor cell.

PubMed

Watson, Joseph D; Crews, Stephen T

2012-09-01

Dopaminergic neurons play important roles in animal behavior, including motivation, reward and locomotion. The Drosophila dopaminergic H-cell interneuron is an attractive system for studying the genetics of neural development because analysis is focused on a single neuronal cell type. Here we provide a mechanistic understanding of how MP3, the precursor to the H-cell, forms and acquires its identity. We show that the gooseberry/gooseberry-neuro (gsb/gsb-n) transcription factor genes act to specify MP3 cell fate. It is proposed that single-minded commits neuroectodermal cells to a midline fate, followed by a series of signaling events that result in the formation of a single gsb(+)/gsb-n(+) MP3 cell per segment. The wingless signaling pathway establishes a midline anterior domain by activating expression of the forkhead transcription factors sloppy paired 1 and sloppy paired 2. This is followed by hedgehog signaling that activates gsb/gsb-n expression in a subgroup of anterior cells. Finally, Notch signaling results in the selection of a single MP3, with the remaining cells becoming midline glia. In MP3, gsb/gsb-n direct H-cell development, in large part by activating expression of the lethal of scute and tailup H-cell regulatory genes. Thus, a series of signaling and transcriptional events result in the specification of a unique dopaminergic precursor cell. Additional genetic experiments indicate that the molecular mechanisms that govern MP3/H-cell development might also direct the development of non-midline dopaminergic neurons.

Formation and specification of a Drosophila dopaminergic precursor cell

PubMed Central

Watson, Joseph D.; Crews, Stephen T.

2012-01-01

Dopaminergic neurons play important roles in animal behavior, including motivation, reward and locomotion. The Drosophila dopaminergic H-cell interneuron is an attractive system for studying the genetics of neural development because analysis is focused on a single neuronal cell type. Here we provide a mechanistic understanding of how MP3, the precursor to the H-cell, forms and acquires its identity. We show that the gooseberry/gooseberry-neuro (gsb/gsb-n) transcription factor genes act to specify MP3 cell fate. It is proposed that single-minded commits neuroectodermal cells to a midline fate, followed by a series of signaling events that result in the formation of a single gsb+/gsb-n+ MP3 cell per segment. The wingless signaling pathway establishes a midline anterior domain by activating expression of the forkhead transcription factors sloppy paired 1 and sloppy paired 2. This is followed by hedgehog signaling that activates gsb/gsb-n expression in a subgroup of anterior cells. Finally, Notch signaling results in the selection of a single MP3, with the remaining cells becoming midline glia. In MP3, gsb/gsb-n direct H-cell development, in large part by activating expression of the lethal of scute and tailup H-cell regulatory genes. Thus, a series of signaling and transcriptional events result in the specification of a unique dopaminergic precursor cell. Additional genetic experiments indicate that the molecular mechanisms that govern MP3/H-cell development might also direct the development of non-midline dopaminergic neurons. PMID:22874915

Gut endoderm takes flight from the wings of mesoderm.

PubMed

McDonald, Angela C H; Rossant, Janet

2014-12-01

The endoderm layer destined to be primitive gut is a mosaic of earlier visceral endoderm and definitive endoderm that arises later, during gastrulation. Live imaging now reveals that in mouse embryos, definitive endoderm cells egress from underlying mesoderm and intercalate into the overlying cell layer. This process requires SOX17-mediated control of basement membrane organization.

Granulocyte-colony stimulating factor and stem cell factor are the crucial factors in long-term culture of human primitive hematopoietic cells supported by a murine stromal cell line.

PubMed

Nishi, N; Ishikawa, R; Inoue, H; Nishikawa, M; Kakeda, M; Yoneya, T; Tsumura, H; Ohashi, H; Yamaguchi, Y; Motoki, K; Sudo, T; Mori, K J

1996-09-01

The findings that murine marrow stromal cell line MS-5 supported the proliferation of human lineage-negative (Lin-) CD34+CD38- bone marrow cells in long-term culture have been reported. In this study, we analyzed this proliferating activity of MS-5-conditioned medium (CM) on human primitive hematopoietic cells. When Lin-CD34+CD38- cells of normal human cord blood cells were co-cultured with MS-5, colony forming cells (CFCs) were maintained over 7 weeks in vitro. Prevention of contact between MS-5 and Lin-CD34+CD38- cells by using membrane filter (0.45 micron) was negligible for this activity. This indicated that the activity of MS-5 on human primitive hematopoietic cells is a soluble factor(s) secreted from MS-5, which is not induced by the contact between MS-5 and Lin-CD34+CD38- cells. We tried to purify this soluble activity. An active material with a molecular weight of about 150 kDa, determined by gel filtration chromatography, solely supported the growth of Lin-CD34+CD38- cells and Mo7e, a human megakaryocytic cell line. This activity not only reacted with anti-mouse stem cell factor (mSCF) antibody on Western blots, but it was also neutralized in the presence of anti-mSCF antibody. Another active material with a molecular weight of about 20-30 kDa synergized with mSCF to stimulate the growth of Lin-CD34+CD38- cells but failed to do so alone, although this synergy was inhibited in the presence of soluble mouse granulocyte-colony stimulating factor (mG-CSF) receptor, which is a chimeric protein consisting of the extracellular domain of mG-CSF receptor and the Fe region of human IgG1. In addition, the latter molecule supported the growth of the G-CSF dependent cell line FD/GR3, which is a murine myeloid leukemia cell line, FDC-P2, transfected with mG-CSF receptor cDNA. Adding of anti-mSCF antibody and soluble mG-CSF receptor to the culture completely abrogated the activity of MS-5-CM. Recombinant (r) mSCF and rmG-CSF had synergistic activity on the growth of Lin-CD34+CD38- cells. These results indicated that the activity on Lin-CD34+CD38- cells included in MS-5-CM is based upon the synergistic effects of mSCF and mG-CSF.

Unified structure theory of icosahedral quasicrystals: Evidence from neutron powder diffraction patterns that AlCrFeMnSi, AlCuLiMg, and TiNiFeSi icosahedral quasicrystals are twins of cubic crystals containing about 820 or 1012 atoms in a primitive unit cube

PubMed Central

Pauling, Linus

1988-01-01

A unified structure theory of icosahedral quasicrystals, combining the twinned-cubic-crystal theory and the Penrose-tiling-six-dimensional-projection theory, is described. Values of the primitive-cubic lattice constant for several quasicrystals are evaluated from x-ray and neutron diffraction data. The fact that the low-angle diffraction maxima can be indexed with cubic unit cells provides additional support for the twinned-cubic-crystal theory of icosahedral quasicrystals. PMID:16593990

Spectrum of hemoglobinopathies among the primitive tribes: a multicentric study in India.

PubMed

Mohanty, Dipika; Mukherjee, Malay B; Colah, Roshan B; Wadia, Mahrukh; Ghosh, Kanjaksha; Chottray, Guru Prasad; Jain, Dipty; Italia, Yazdi; Ashokan, Kumar S; Kaul, Rajni; Shukla, Deepak K; Muthuswamy, Vasantha

2015-03-01

We evaluated the spectrum of hemoglobinopathies among the primitive tribal groups from 4 states in India. A total of 15,200 individuals from 14 primitive tribal groups were studied by automated high-performance liquid chromatography. The hemoglobin S (HbS) allele frequency varied from 0.011 to 0.120 and the β-thalassemia allele frequency from 0.005 to 0.024. It is interesting to note that a very high HbS allele frequency was observed among the Dravidian (0.060-0.120) and Indo-European (0.060-0.076) as compared with Austro-Asiatic (0.011-0.022) speaking tribal groups. Although statistical analysis of the data did not show any ethnic differences within the states, regional differences were observed between the states for both HbS and β-thalassemia traits. HbS was found to be the most common hemoglobinopathy followed by β-thalassemia. A health plan for identifying sickle-cell homozygotes in the neonatal period with proper medical intervention is desirable. © 2013 APJPH.

Oxygen and the evolution of metabolic pathways

NASA Technical Reports Server (NTRS)

Jahnke, L. L.

1986-01-01

While a considerable amount of evidence has been accumulated about the history of oxygen on this planet, little is known about the relative amounts to which primitive cells might have been exposed. One clue may be found in the metabolic pathways of extant microorganisms. While eucaryotes are principally aerobic organisms, a number are capable of anaerobic growth by fermentation. One such eucaryotic microorganism, Saccharomyces cerevisiae, will grow in the complete absence of oxygen when supplemented with unsaturated fatty acid and sterol. Oxygen-requiring enzymes are involved in the synthesis of both of these compounds. Studies have demonstrated that the oxidative desaturation of palmitic acid and the conversion of squalene to sterols occur in the range of 10-(3) to 10(-2) PAL. Thus, if the oxygen requirements of these enzymatic processes are an indication, eucaryotes might be more primitive than anticipated from the microfossil record. Results of studies on the oxygen requirements for sterol and unsaturated fatty acid synthesis in a more primitive procaryotic system are also discussed.

Immunocytochemical location of pituitary cells containing ACTH, alpha-MSH, and beta-endorphin in Acipenser transmontanus, Lepisosteus spatula, and Amia calva.

PubMed

Joss, J M; Dores, R M; Crim, J W; Beshaw, M

1990-06-01

This immunocytochemical study of the pituitaries of the primitive actinopterygians, Acipenser transmontanus, Lepisosteus spatula, and Amia calva, showed a strict delineation between the hormonal fragments of proopiomelanocorticotropin (POMC) produced by corticotropes of the pars distalis and the melanotropes of the pars intermedia. Corticotropes were immunoreactive only for ACTH and not to either of the further degradation products, alpha-MSH or beta-endorphin. Melanotropes were shown to be immunoreactive to all three antisera but it is argued that immunoreactivity of melanotropes to ACTH antiserum is due to that antiserum's cross-reactivity with the cleavage product corticotropin-like intermediate peptide. The PAS positivity of both the corticotropes and the melanotropes of all three primitive fish argues for an ancient origin of a carbohydrate component of POMC and for its loss or reduction in teleosts where these cells are PAS negative.

Ripple/Carcinoid pattern sebaceoma with apocrine differentiation.

PubMed

Misago, Noriyuki; Narisawa, Yutaka

2011-02-01

Sebaceoma is a benign sebaceous neoplasm, which has been reported to show characteristic growth patterns, such as, ripple, labyrinthine/sinusoidal, and carcinoid-like patterns. Another recent finding regarding in sebaceoma is the observation of apocrine differentiation within the sebaceoma lesion. This report describes a case of carcinoid (a partial ripple and labyrinthine) pattern sebaceoma with apocrine differentiation with a literature review and immunohistochemical studies. The various characteristic growth patterns in sebaceoma were suggested to simply be variations of the same growth pattern arranged in cords, namely, a unified term "ripple/carcinoid pattern." The primitive sebaceous germinative cells in sebaceoma may still have the ability to undergo apocrine differentiation. Most of the reports so far on sebaceoma with apocrine differentiation, including the present case, describe a ripple/carcinoid pattern, thus suggesting that ripple/carcinoid pattern sebaceoma is composed of more primitive sebaceous germinative cells than conventional sebaceoma.

Proceedings of the Midwinter Conference of Immunologists (28th) Held in Pacific Grove, California on 28-31 January 1989 (Lymphocyte Differentiation)

DTIC Science & Technology

1989-02-24

N. Witte Sf-ak-r’." OWEN N. WITTE University of California, Los Angeles, CA "Oncogene Interactions with Primitive Lymphoid Cells" DAVID BALTIMORE The...as Schwann cells, myotubes and astroglial cells. Neurons use different receptors to interact with different cell types. Different neu-ons also differ...controlled by a clock in the progenitor cell that is driven by platelet- derived growth factor (PDGF) secreted by type-i astrocytes. Type-2 astrocyte

Clonal and molecular analysis of the prospective anterior neural boundary in the mouse embryo

PubMed Central

Cajal, Marieke; Lawson, Kirstie A.; Hill, Bill; Moreau, Anne; Rao, Jianguo; Ross, Allyson; Collignon, Jérôme; Camus, Anne

2012-01-01

In the mouse embryo the anterior ectoderm undergoes extensive growth and morphogenesis to form the forebrain and cephalic non-neural ectoderm. We traced descendants of single ectoderm cells to study cell fate choice and cell behaviour at late gastrulation. In addition, we provide a comprehensive spatiotemporal atlas of anterior gene expression at stages crucial for anterior ectoderm regionalisation and neural plate formation. Our results show that, at late gastrulation stage, expression patterns of anterior ectoderm genes overlap significantly and correlate with areas of distinct prospective fates but do not define lineages. The fate map delineates a rostral limit to forebrain contribution. However, no early subdivision of the presumptive forebrain territory can be detected. Lineage analysis at single-cell resolution revealed that precursors of the anterior neural ridge (ANR), a signalling centre involved in forebrain development and patterning, are clonally related to neural ectoderm. The prospective ANR and the forebrain neuroectoderm arise from cells scattered within the same broad area of anterior ectoderm. This study establishes that although the segregation between non-neural and neural precursors in the anterior midline ectoderm is not complete at late gastrulation stage, this tissue already harbours elements of regionalisation that prefigure the later organisation of the head. PMID:22186731

Derivation and characterisation of the human embryonic stem cell lines, NOTT1 and NOTT2.

PubMed

Priddle, Helen; Allegrucci, Cinzia; Burridge, Paul; Munoz, Maria; Smith, Nigel M; Devlin, Lyndsey; Sjoblom, Cecilia; Chamberlain, Sarah; Watson, Sue; Young, Lorraine E; Denning, Chris

2010-04-01

The ability to maintain human embryonic stem cells (hESCs) during long-term culture and yet induce differentiation to multiple lineages potentially provides a novel approach to address various biomedical problems. Here, we describe derivation of hESC lines, NOTT1 and NOTT2, from human blastocysts graded as 3BC and 3CB, respectively. Both lines were successfully maintained as colonies by mechanical passaging on mouse embryonic feeder cells or as monolayers by trypsin-passaging in feeder-free conditions on Matrigel. Undifferentiated cells retained expression of pluripotency markers (OCT4, NANOG, SSEA-4, TRA-1-60 and TRA-1-81), a stable karyotype during long-term culture and could be transfected efficiently with plasmid DNA and short interfering RNA. Differentiation via formation of embryoid bodies resulted in expression of genes associated with early germ layers and terminal lineage specification. The electrophysiology of spontaneously beating NOTT1-derived cardiomyocytes was recorded and these cells were shown to be pharmacologically responsive. Histological examination of teratomas formed by in vivo differentiation of both lines in severe immunocompromised mice showed complex structures including cartilage or smooth muscle (mesoderm), luminal epithelium (endoderm) and neuroectoderm (ectoderm). These observations show that NOTT1 and NOTT2 display the accepted characteristics of hESC pluripotency.

Merkel cell carcinoma occurring in a black woman: a case report.

PubMed

Kadiri, Selma; Aissa, Abdellah; Berhili, Soufiane; Khmou, Mouna; Elmajjaoui, Sanaa; Kebdani, Tayeb; El Khannoussi, Basma; Elkacemi, Hanan; Benjaafar, Noureddine

2017-01-31

Merkel cell carcinoma is a rare, very aggressive neuroectodermal tumor of the skin. It is typically located on sun-exposed skin and frequently found in white men aged between 70 and 80 years. We report a case of a 58-year-old black woman diagnosed with Merkel cell carcinoma of the posterior face of the right elbow. She had biopsy excision and was lost to follow-up. Four months later, she presented with recurrent disease on the inferior third of the right arm with three ipsilateral axillary lymph node metastases. Amputation of the right arm and ipsilateral axillary lymph node dissection were performed, followed by adjuvant radiotherapy. Six months later, the patient died as a result of respiratory failure caused by lung metastasis. To the best of our knowledge, no specific studies have been done comparing the course and the characteristics of Merkel cell carcinoma in white and black populations, and no similar case has been reported in the literature. The Merkel cell carcinoma is very rare in black people. As described elsewhere in the literature, our patient had a poor outcome despite radical management. To date, to the best of our knowledge, there has been no comparison of the prognosis of this tumor in white and black populations.

Tumor spheroid model for the biologically targeted radiotherapy of neuroblastoma micrometastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walker, K.A.; Mairs, R.; Murray, T.

Neuroblastoma is a pediatric malignancy with a poor prognosis at least partly attributable to an early pattern of dissemination. New approaches to treatment of micrometastases include targeted radiotherapy using radiolabeled antibodies or molecules which are taken up preferentially by tumor cells. Multicellular tumor spheroids (MTS) resemble micrometastases during the avascular phase of their development. A human neuroblastoma cell line (NBl-G) was grown as MTS and incubated briefly with a radiolabeled monoclonal antibody ({sup 131}I-UJ13A) directed against neuroectodermal antigens. Spheroid response was evaluated in terms of regrowth delay or proportion sterilized. A dose-response relationship was demonstrated in terms of {sup 131}Imore » activity or duration of incubation. Control experiments using unlabeled UJ13A, radiolabeled nonspecific antibody (T2.10), radiolabeled human serum albumin, and radiolabeled sodium iodide showed these to be relatively ineffective compared to {sup 131}I-UJ13A. The cell line NBl-G grown as MTS has also been found to preferentially accumulate the radiolabeled catecholamine precursor molecule m-({sup 131}I)iodobenzylguanidine compared to cell lines derived from other tumor types. NBl-G cells grown as MTS provide a promising laboratory model for targeted radiotherapy of neuroblastoma micrometastases using radiolabeled antibodies or m-iodobenzylguanidine.« less

Characterization of a Weak Allele of Zebrafish cloche Mutant

PubMed Central

Ma, Ning; Huang, Zhibin; Chen, Xiaohui; He, Fei; Wang, Kun; Liu, Wei; Zhao, Linfeng; Xu, Xiangmin; Liao, Wangjun; Ruan, Hua; Luo, Shenqiu; Zhang, Wenqing

2011-01-01

Hematopoiesis is a complicated and dynamic process about which the molecular mechanisms remain poorly understood. Danio rerio (zebrafish) is an excellent vertebrate system for studying hematopoiesis and developmental mechanisms. In the previous study, we isolated and identified a cloche 172 (clo 172) mutant, a novel allele compared to the original cloche (clo) mutant, through using complementation test and initial mapping. Here, according to whole mount in-situ hybridization, we report that the endothelial cells in clo 172 mutant embryos, although initially developed, failed to form the functional vascular system eventually. In addition, further characterization indicates that the clo 172 mutant exhibited weaker defects instead of completely lost in primitive erythroid cells and definitive hematopoietic cells compared with the clo s5 mutant. In contrast, primitive myeloid cells were totally lost in clo 172 mutant. Furthermore, these reappeared definitive myeloid cells were demonstrated to initiate from the remaining hematopoietic stem cells (HSCs) in clo 172 mutant, confirmed by the dramatic decrease of lyc in clo 172 runx1w84x double mutant. Collectively, the clo 172 mutant is a weak allele compared to the clo s5 mutant, therefore providing a model for studying the early development of hematopoietic and vascular system, as well as an opportunity to further understand the function of the cloche gene. PMID:22132109

Stem cell sources for regenerative medicine.

PubMed

Riazi, Ali M; Kwon, Sarah Y; Stanford, William L

2009-01-01

Tissue-resident stem cells or primitive progenitors play an integral role in homeostasis of most organ systems. Recent developments in methodologies to isolate and culture embryonic and somatic stem cells have many new applications poised for clinical and preclinical trials, which will enable the potential of regenerative medicine to be realized. Here, we overview the current progress in therapeutic applications of various stem cells and discuss technical and social hurdles that must be overcome for their potential to be realized.

Design of a nanocomposite substrate inducing adult stem cell assembly and progression toward an Epiblast-like or Primitive Endoderm-like phenotype via mechanotransduction.

PubMed

Morena, Francesco; Armentano, Ilaria; Montanucci, Pia; Argentati, Chiara; Fortunati, Elena; Montesano, Simona; Bicchi, Ilaria; Pescara, Teresa; Pennoni, Ilaria; Mattioli, Samantha; Torre, Luigi; Latterini, Loredana; Emiliani, Carla; Basta, Giuseppe; Calafiore, Riccardo; Kenny, Josè Maria; Martino, Sabata

2017-11-01

This work shows that the active interaction between human umbilical cord matrix stem cells and Poly (l-lactide)acid (PLLA) and PLLA/Multi Walled Carbon Nanotubes (MWCNTs) nanocomposite films results in the stem cell assembly as a spheroid conformation and affects the stem cell fate transition. We demonstrated that spheroids directly respond to a tunable surface and the bulk properties (electric, dielectric and thermal) of plain and nanocomposite PLLA films by triggering a mechanotransduction axis. This stepwise process starts from tethering of the cells' focal adhesion proteins to the surface, together with the adherens junctions between cells. Both complexes transmit traction forces to F-Actin stress fibres that link Filamin-A and Myosin-IIA proteins, generating a biological scaffold, with increased stiffening conformation from PLLA to PLLA/MWCNTs, and enable the nucleoskeleton proteins to boost chromatin reprogramming processes. Herein, the opposite expression of NANOG and GATA6 transcription factors, together with other lineage specification related proteins, steer spheroids toward an Epiblast-like or Primitive Endoderm-like lineage commitment, depending on the absence or presence of 1 wt% MWCNTs, respectively. This work represents a pioneering effort to create a stem cell/material interface that can model the stem cell fate transition under growth culture conditions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Integration and long distance axonal regeneration in the central nervous system from transplanted primitive neural stem cells.

PubMed

Zhao, Jiagang; Sun, Woong; Cho, Hyo Min; Ouyang, Hong; Li, Wenlin; Lin, Ying; Do, Jiun; Zhang, Liangfang; Ding, Sheng; Liu, Yizhi; Lu, Paul; Zhang, Kang

2013-01-04

Spinal cord injury (SCI) results in devastating motor and sensory deficits secondary to disrupted neuronal circuits and poor regenerative potential. Efforts to promote regeneration through cell extrinsic and intrinsic manipulations have met with limited success. Stem cells represent an as yet unrealized therapy in SCI. Recently, we identified novel culture methods to induce and maintain primitive neural stem cells (pNSCs) from human embryonic stem cells. We tested whether transplanted human pNSCs can integrate into the CNS of the developing chick neural tube and injured adult rat spinal cord. Following injection of pNSCs into the developing chick CNS, pNSCs integrated into the dorsal aspects of the neural tube, forming cell clusters that spontaneously differentiated into neurons. Furthermore, following transplantation of pNSCs into the lesioned rat spinal cord, grafted pNSCs survived, differentiated into neurons, and extended long distance axons through the scar tissue at the graft-host interface and into the host spinal cord to form terminal-like structures near host spinal neurons. Together, these findings suggest that pNSCs derived from human embryonic stem cells differentiate into neuronal cell types with the potential to extend axons that associate with circuits of the CNS and, more importantly, provide new insights into CNS integration and axonal regeneration, offering hope for repair in SCI.

On Synchronization Primitive Systems.

DTIC Science & Technology

The report studies the question: what synchronization primitive should be used to handle inter-process communication. A formal model is presented...between these synchronization primitives. Although only four synchronization primitives are compared, the general methods can be used to compare other... synchronization primitives. Moreover, in the definitions of these synchronization primitives, conditional branches are explicitly allowed. In addition

In vitro long-term development of cultured inner ear stem cells of newborn rat.

PubMed

Carricondo, Francisco; Iglesias, Mari Cruz; Rodríguez, Fernando; Poch-Broto, Joaquin; Gil-Loyzaga, Pablo

2010-10-01

The adult mammalian auditory receptor lacks any ability to repair and/or regenerate after injury. However, the late developing cochlea still contains some stem-cell-like elements that might be used to regenerate damaged neurons and/or cells of the organ of Corti. Before their use in any application, stem cell numbers need to be amplified because they are usually rare in late developing and adult tissues. The numerous re-explant cultures required for the progressive amplification process can result in a spontaneous differentiation process. This aspect has been implicated in the tumorigenicity of stem cells when transplanted into a tissue. The aim of this study has been to determine whether cochlear stem cells can proliferate and differentiate spontaneously in long-term cultures without the addition of any factor that might influence these processes. Cochlear stem cells, which express nestin protein, were cultured in monolayers and fed with DMEM containing 5% FBS. They quickly organized themselves into typical spheres exhibiting a high proliferation rate, self-renewal property, and differentiation ability. Secondary cultures of these stem cell spheres spontaneously differentiated into neuroectodermal-like cells. The expression of nestin, glial-fibrillary-acidic protein, vimentin, and neurofilaments was evaluated to identify early differentiation. Nestin expression appeared in primary and secondary cultures. Other markers were also identified in differentiating cells. Further research might demonstrate the spontaneous differentiation of cochlear stem cells and their teratogenic probability when they are used for transplantation.

Resolving Early Mesoderm Diversification through Single Cell Expression Profiling

PubMed Central

Wilson, Nicola K.; Macaulay, Iain C.; Marioni, John C.; Göttgens, Berthold

2016-01-01

Summary In mammals, specification of the three major germ layers occurs during gastrulation, when cells ingressing through the primitive streak differentiate into the precursor cells of major organ systems. However, the molecular mechanisms underlying this process remain unclear, as numbers of gastrulating cells are very limited. In the E6.5 mouse embryo, cells located at the junction between the extra-embryonic region and the epiblast on the posterior side of the embryo undergo an epithelial-to-mesenchymal transition (EMT) and ingress through the primitive streak (PS). Subsequently, cells migrate, either surrounding the prospective ectoderm contributing to the embryo proper, or into the extra-embryonic region to form the yolk sac (YS), umbilical cord and placenta. Fate mapping has shown that mature tissues such as blood and heart originate from specific regions of the pre-gastrula epiblast1 but the plasticity of cells within the embryo and the function of key cell type-specific transcription factors remain unclear. Here we analyse 1,205 cells from the epiblast and nascent Flk1+ mesoderm of gastrulating mouse embryos using single cell RNA-sequencing, representing the first transcriptome-wide in vivo view of early mesoderm formation during mammalian gastrulation. Additionally, using knock-out mice, we study the function of Tal1, a key hematopoietic transcription factor (TF), and demonstrate, contrary to previous studies performed using retrospective assays2,3, that Tal1 knock out does not immediately bias precursor cells towards a cardiac fate. PMID:27383781

Co-ordinated ocular development from human iPS cells and recovery of corneal function.

PubMed

Hayashi, Ryuhei; Ishikawa, Yuki; Sasamoto, Yuzuru; Katori, Ryosuke; Nomura, Naoki; Ichikawa, Tatsuya; Araki, Saori; Soma, Takeshi; Kawasaki, Satoshi; Sekiguchi, Kiyotoshi; Quantock, Andrew J; Tsujikawa, Motokazu; Nishida, Kohji

2016-03-17

The eye is a complex organ with highly specialized constituent tissues derived from different primordial cell lineages. The retina, for example, develops from neuroectoderm via the optic vesicle, the corneal epithelium is descended from surface ectoderm, while the iris and collagen-rich stroma of the cornea have a neural crest origin. Recent work with pluripotent stem cells in culture has revealed a previously under-appreciated level of intrinsic cellular self-organization, with a focus on the retina and retinal cells. Moreover, we and others have demonstrated the in vitro induction of a corneal epithelial cell phenotype from pluripotent stem cells. These studies, however, have a single, tissue-specific focus and fail to reflect the complexity of whole eye development. Here we demonstrate the generation from human induced pluripotent stem cells of a self-formed ectodermal autonomous multi-zone (SEAM) of ocular cells. In some respects the concentric SEAM mimics whole-eye development because cell location within different zones is indicative of lineage, spanning the ocular surface ectoderm, lens, neuro-retina, and retinal pigment epithelium. It thus represents a promising resource for new and ongoing studies of ocular morphogenesis. The approach also has translational potential and to illustrate this we show that cells isolated from the ocular surface ectodermal zone of the SEAM can be sorted and expanded ex vivo to form a corneal epithelium that recovers function in an experimentally induced animal model of corneal blindness.

CD34+ Testicular Stromal Cells Support Long-Term Expansion of Embryonic and Adult Stem and Progenitor Cells

PubMed Central

Kim, Jiyeon; Seandel, Marco; Falciatori, Ilaria; Wen, Duancheng; Rafii, Shahin

2010-01-01

Stem cells reside in specialized microenvironments created by supporting stromal cells that orchestrate self-renewal and lineage-specific differentiation. However, the precise identity of the cellular and molecular pathways that support self-renewal of stem cells is not known. For example, long-term culture of prototypical stem cells, such as adult spermatogonial stem and progenitor cells (SPCs), in vitro has been impeded by the lack of an optimal stromal cell line that initiates and sustains proliferation of these cells. Indeed, current methods, including the use of mouse embryonic fibroblasts (MEFs), have not been efficient and have generally led to inconsistent results. Here, we report the establishment of a novel CD34-positive cell line, referred to as JK1, derived from mouse testicular stromal cells that not only facilitated long-term SPC culture but also allowed faithful generation of SPCs and multipotent stem cells. SPCs generated on JK1 maintained key features of germ line stem cells, including expression of PLZF, DAZL, and GCNA. Furthermore, these feeders also promoted the long-term cultivation of other types of primitive cells including multi-potent adult spermatogonial-derived stem cells, pluripotent murine embryonic stem cells, and embryonic germ cells derived from primordial germ cells. Stem cells could be passaged serially and still maintained expression of characteristic markers such as OCT4 and NANOG in vitro, as well as the ability to generate all three germ layers in vivo. These results indicate that the JK1 cell line is capable of promoting long-term culture of primitive cells. As such, this cell line allows for identification of stromal-derived factors that support long-term proliferation of various types of stem cells and constitutes a convenient alternative to other types of feeder layers. PMID:18669907

Clonal analysis identifies hemogenic endothelium as the source of the blood-endothelial common lineage in the mouse embryo

PubMed Central

Padrón-Barthe, Laura; Temiño, Susana; Villa del Campo, Cristina; Carramolino, Laura; Isern, Joan

2014-01-01

The first blood and endothelial cells of amniote embryos appear in close association in the blood islands of the yolk sac (YS). This association and in vitro lineage analyses have suggested a common origin from mesodermal precursors called hemangioblasts, specified in the primitive streak during gastrulation. Fate mapping and chimera studies, however, failed to provide strong evidence for a common origin in the early mouse YS. Additional in vitro studies suggest instead that mesodermal precursors first generate hemogenic endothelium, which then generate blood cells in a linear sequence. We conducted an in vivo clonal analysis to determine the potential of individual cells in the mouse epiblast, primitive streak, and early YS. We found that early YS blood and endothelial lineages mostly derive from independent epiblast populations, specified before gastrulation. Additionally, a subpopulation of the YS endothelium has hemogenic activity and displays characteristics similar to those found later in the embryonic hemogenic endothelium. Our results show that the earliest blood and endothelial cell populations in the mouse embryo are specified independently, and that hemogenic endothelium first appears in the YS and produces blood precursors with markers related to definitive hematopoiesis. PMID:25139355

MiRNA-mediated regulation of cell signaling and homeostasis in the early mouse embryo.

PubMed

Pernaute, Barbara; Spruce, Thomas; Rodriguez, Tristan A; Manzanares, Miguel

2011-02-15

At the time of implantation the mouse embryo is composed of three tissues the epiblast, trophectoderm and primitive endoderm. As development progresses the epiblast goes on to form the foetus whilst the trophectoderm and primitive endoderm give rise to extra-embryonic structures with important roles in embryo patterning and nutrition. Dramatic changes in gene expression occur during early embryo development and these require regulation at different levels. miRNAs are small non coding RNAs that have emerged over the last decade as important post-transcriptional repressors of gene expression. The roles played by miRNAs during early mammalian development are only starting to be elucidated. In order to gain insight into the function of miRNAs in the different lineages of the early mouse embryo we have analysed in depth the phenotype of embryos and extra-embryonic stem cells mutant for the miRNA maturation protein Dicer. This study revealed that miRNAs are involved in regulating cell signaling and homeostasis in the early embryo. Specifically, we identified a role for miRNAs in regulating the Erk signaling pathway in the extra-embryonic endoderm, cell cycle progression in extra-embryonic tissues and apoptosis in the epiblast.

Notochord Morphogenesis in Mice: Current Understanding & Open Questions

PubMed Central

Balmer, Sophie; Nowotschin, Sonja; Hadjantonakis, Anna-Katerina

2016-01-01

The notochord is the structure which defines chordates. It is a rod-like mesodermal structure that runs the anterior-posterior length of the embryo, adjacent to the ventral neural tube. The notochord plays a critical role in embryonic tissue patterning, for example the dorsal-ventral patterning of the neural tube. The cells that will come to form the notochord are specified at gastrulation. Axial mesodermal cells arising at the anterior primitive streak migrate anteriorly as the precursors of the notochord and populate the notochordal plate. Interestingly, even though a lot of interest has centered on investigating the functional and structural roles of the notochord, we still have a very rudimentary understanding of notochord morphogenesis. The events driving the formation of the notochord are rapid, taking place over the period of approximately a day in mice. In this commentary we provide an overview of our current understanding of mouse notochord morphogenesis, from the initial specification of axial mesendodermal cells at the primitive streak, the emergence of these cells at the midline on the surface of the embryo, to their submergence and organization of the stereotypically positioned notochord. We will also discuss some key open questions. PMID:26845388

The physics of cellular synthesis, growth and division

NASA Technical Reports Server (NTRS)

Pollard, E. C.

1974-01-01

Three areas of research in NASA'S University Program are described. Primitive terrestrial living cells were studied as a guide to the kind of cells to look for in extraterrestrial life. Experiments in zero gravity conditions are described with emphasis upon effects on small organisms. The effects of ionizing radiation on cells are studied so that it will be possible to predict dosages which can be tolerated by humans with no permanent damage.

[Clinicopathologic study of sinonasal teratocarcinosarcoma and its contrast with olfactory neuroblastoma].

PubMed

Li, Xue; Liu, Hong-Gang; Xie, Xin-Ji; Han, Yi-Ding; Li, Ming

2008-07-01

To study the clinicopathologic features, diagnosis and differential diagnosis of sinonasal teratocarcinosarcoma (SNTCS) and olfactory neuroblastoma (ONB), and to discuss the histogenesis and possible relationship between SNTCS and ONB. Seven cases of SNTCS and 34 cases of ONB were retrieved from the pathological archives together with one case each of malignant teratoma and immature embryonic tissue at 8 weeks were collected from Beijing Tongren Hospital. The clinicopathologic features were analyzed and immunohistochemical staining was performed on paraffin sections. Six of the SNTCS patients were male and one was female. The patients age range was 25 to 69 years (mean age 46). Four cases were initial presentation and three were recurrences. Histologically, the tumor shows multiple tissue components derived from three germ layers. There were mixture of teratoma-like tissue and carcinosarcoma. The components include fetal clear cell squamous epithelium derived from ectoderm. Glandular and tubular structures and ciliated columnar epithelium derived from endoderm. Fibroblasts, striated muscle, smooth muscle, cartilage and osteoid matrix derived from mesoderm. The carcinoma component exhibited mostly adenocarcinoma and squamous cell carcinoma, whereas the sarcoma component mostly exhibited rhabdomyosarcoma, leiomyosarcoma, and fibrosarcoma. In addition, carcinoid, and primitive mesenchymal tissue and the ONB component were also seen. The morphological characteristics of SNTCS comprised fetal clear cell squamous epithelium, carcinosarcoma and the ONB component. By immunohistochemistry, the epithelial component and cells with epithelium differentiation were positive for cytokeratin (pan) and EMA. The ONB component was positive for Syn, NSE, CD99, NF and CgA to different degrees. Neurofibril bundles were positive for S-100, and Flexner-Wintersteiner rosettes expressed cytokeratin (pan) and EMA. The spindle cells expressed vimentin, SMA, desmin, myosin and myoglobin. The primitive mesenchymal tissue expressed vimentin, and the mucoid materials and glycogen were positive for PAS. GFAP was negative in all cases. The 34 cases of ONB, included 18 men and 16 women, the age ranged from 12 to 72 years (mean 42.8 years). Microscopically, the tumor shows epithelial nests, net of angioma-like fibrous connective tissues, small round and spindle cells, glandular, squamous-like cells, and cells of rhabdomyoblastic differentiation, Homer-Wright and Flexner rosette, bundles of neurofibrils, etc. NSE and CgA were expressed in small cells. S-100 protein was positive in the areas of bunches of neurofibril. Cytokeratin (pan) was positive in epithelial cells. Myoglobin was positive in the cells of rhabdomyoblastic differentiation. The single case of immature malignant teratoma exhibited primitive nerve tissue, but fetal clear cell squamous epithelium was not found. In the immature embryonic tissue, rudimentary organs were formed, with fetal clear cell squamous epithelium lining present on the nasal and oral cavities surface. SNTCS is a rare and aggressive malignant neoplasm. Most of ONB are low-grade malignant tumors. Morphological differences are the most important basis to make differentiate SNTCS from ONB. As SNTCS may demonstrate a multiplicity of structures and pleomorphism, inadequate sampling at biopsy, therefore, may lead to errors in diagnosis. No evidence show that SNTCS are derived from germ cells and sinonasal teratoid carcinosarcoma may be a more proper name. SNTCS probably arises from primitive totipotential cells of olfactory/sinonasal membrane, and the relationship between SNTCS and ONB needs further study.

An Animal Model to Investigate the Potential for Breast Cancer Metastatic Dissemination Following Surgery Intervention on the Primitive Tumor

DTIC Science & Technology

2010-09-01

cancer cells at the plasma membrane level were measured by cell surface biotinylation, using a dedicated kit (cat. #89881) obtained from Pierce...each form of the receptor at the plasma membrane of transfected cells was confirmed by isolation of cell surface proteins obtained by biotinylation...this receptor to interact with both plasma membrane-bound and soluble FKN. Based on our study, it seems reasonable to postulate that the dissemination

Single-lineage transcriptome analysis reveals key regulatory pathways in primitive erythroid progenitors in the mouse embryo

PubMed Central

Isern, Joan; He, Zhiyong; Fraser, Stuart T.; Nowotschin, Sonja; Ferrer-Vaquer, Anna; Moore, Rebecca; Hadjantonakis, Anna-Katerina; Schulz, Vincent; Tuck, David; Gallagher, Patrick G.

2011-01-01

Primitive erythroid (EryP) progenitors are the first cell type specified from the mesoderm late in gastrulation. We used a transgenic reporter to image and purify the earliest blood progenitors and their descendants from developing mouse embryos. EryP progenitors exhibited remarkable proliferative capacity in the yolk sac immediately before the onset of circulation, when these cells comprise nearly half of all cells of the embryo. Global expression profiles generated at 24-hour intervals from embryonic day 7.5 through 2.5 revealed 2 abrupt changes in transcript diversity that coincided with the entry of EryPs into the circulation and with their late maturation and enucleation, respectively. These changes were paralleled by the expression of critical regulatory factors. Experiments designed to test predictions from these data demonstrated that the Wnt-signaling pathway is active in EryP progenitors, which display an aerobic glycolytic profile and the numbers of which are regulated by transforming growth factor-β1 and hypoxia. This is the first transcriptome assembled for a single hematopoietic lineage of the embryo over the course of its differentiation. PMID:21263157

Early Lineage Priming by Trisomy of Erg Leads to Myeloproliferation in a Down Syndrome Model

PubMed Central

Ng, Ashley P.; Hu, Yifang; Metcalf, Donald; Hyland, Craig D.; Ierino, Helen; Phipson, Belinda; Wu, Di; Baldwin, Tracey M.; Kauppi, Maria; Kiu, Hiu; Di Rago, Ladina; Hilton, Douglas J.; Smyth, Gordon K.; Alexander, Warren S.

2015-01-01

Down syndrome (DS), with trisomy of chromosome 21 (HSA21), is the commonest human aneuploidy. Pre-leukemic myeloproliferative changes in DS foetal livers precede the acquisition of GATA1 mutations, transient myeloproliferative disorder (DS-TMD) and acute megakaryocytic leukemia (DS-AMKL). Trisomy of the Erg gene is required for myeloproliferation in the Ts(1716)65Dn DS mouse model. We demonstrate here that genetic changes specifically attributable to trisomy of Erg lead to lineage priming of primitive and early multipotential progenitor cells in Ts(1716)65Dn mice, excess megakaryocyte-erythroid progenitors, and malignant myeloproliferation. Gene expression changes dependent on trisomy of Erg in Ts(1716)65Dn multilineage progenitor cells were correlated with those associated with trisomy of HSA21 in human DS hematopoietic stem and primitive progenitor cells. These data suggest a role for ERG as a regulator of hematopoietic lineage potential, and that trisomy of ERG in the context of DS foetal liver hemopoiesis drives the pre-leukemic changes that predispose to subsequent DS-TMD and DS-AMKL. PMID:25973911

Loss of alleles from the distal short arm of chromosome 1 occurs late in melanoma tumor progression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dracopoli, N.C.; Harnett, P.; Bale, S.J.

The gene for familial malignant melanoma and its precursor lesion, the dysplastic nevus, has been assigned to a region of the distal short arm of chromosome 1, which is frequently involved in karyotypic abnormalities in melanoma cells. The authors have examined loci on chromosome 1p for loss-of-constitutional heterozygosity in 35 melanomas and 21 melanoma cell lines to analyze the role of these abnormalities in melanocyte transformation. Loss-of-heterozygosity at loci on chromosome 1p was identified in 15/35 (43%) melanomas and 11/21 (52%) melanoma cell lines. Analysis of multiple metastases derived from the same patient and of melanoma and lymphoblastoid samples frommore » a family with hereditary melanoma showed that the loss-of-heterozygosity at loci on distal 1p is a late event in tumor progression, rather than the second mutation that would occur if melanoma were due to a cellular recessive mechanism. Comparisons with neuroblastoma and multiple endocrine neoplasia (MEN2) suggest that the frequent 1p loss-of-heterozygosity in these malignancies is a common late event of neuroectodermal tumor progression.« less

Efficient and rapid derivation of primitive neural stem cells and generation of brain subtype neurons from human pluripotent stem cells.

PubMed

Yan, Yiping; Shin, Soojung; Jha, Balendu Shekhar; Liu, Qiuyue; Sheng, Jianting; Li, Fuhai; Zhan, Ming; Davis, Janine; Bharti, Kapil; Zeng, Xianmin; Rao, Mahendra; Malik, Nasir; Vemuri, Mohan C

2013-11-01

Human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, are unique cell sources for disease modeling, drug discovery screens, and cell therapy applications. The first step in producing neural lineages from hPSCs is the generation of neural stem cells (NSCs). Current methods of NSC derivation involve the time-consuming, labor-intensive steps of an embryoid body generation or coculture with stromal cell lines that result in low-efficiency derivation of NSCs. In this study, we report a highly efficient serum-free pluripotent stem cell neural induction medium that can induce hPSCs into primitive NSCs (pNSCs) in 7 days, obviating the need for time-consuming, laborious embryoid body generation or rosette picking. The pNSCs expressed the neural stem cell markers Pax6, Sox1, Sox2, and Nestin; were negative for Oct4; could be expanded for multiple passages; and could be differentiated into neurons, astrocytes, and oligodendrocytes, in addition to the brain region-specific neuronal subtypes GABAergic, dopaminergic, and motor neurons. Global gene expression of the transcripts of pNSCs was comparable to that of rosette-derived and human fetal-derived NSCs. This work demonstrates an efficient method to generate expandable pNSCs, which can be further differentiated into central nervous system neurons and glia with temporal, spatial, and positional cues of brain regional heterogeneity. This method of pNSC derivation sets the stage for the scalable production of clinically relevant neural cells for cell therapy applications in good manufacturing practice conditions.

Bone marrow-on-a-chip: Long-term culture of human haematopoietic stem cells in a three-dimensional microfluidic environment.

PubMed

Sieber, Stefan; Wirth, Lorenz; Cavak, Nino; Koenigsmark, Marielle; Marx, Uwe; Lauster, Roland; Rosowski, Mark

2018-02-01

Multipotent haematopoietic stem and progenitor cells (HSPCs) are the source for all blood cell types. The bone marrow stem cell niche in which the HSPCs are maintained is known to be vital for their maintenance. Unfortunately, to date, no in vitro model exists that accurately mimics the aspects of the bone marrow niche and simultaneously allows the long-term culture of HSPCs. In this study, a novel three-dimensional coculture model is presented, based on a hydroxyapatite coated zirconium oxide scaffold, comprising of human mesenchymal stromal cells (MSCs) and cord blood derived HSPCs, enabling successful HSPC culture for a time span of 28 days within the microfluidic multiorgan chip. The HSPCs were found to stay in their primitive state (CD34 + CD38 - ) and capable of granulocyte, erythrocyte, macrophage, megakaryocyte colony formation. Furthermore, a microenvironment was formed bearing molecular and structural similarity to the in vivo bone marrow niche containing extracellular matrix and signalling molecules known to play an important role in HSPC homeostasis. Here, a novel human in vitro bone marrow model is presented for the first time, capable of long-term culture of primitive HSPCs in a microfluidic environment. Copyright © 2017 John Wiley & Sons, Ltd.

The metastatic infiltration at the metastasis/brain parenchyma-interface is very heterogeneous and has a significant impact on survival in a prospective study

PubMed Central

Siam, Laila; Bleckmann, Annalen; Chaung, Han-Ning; Mohr, Alexander; Klemm, Florian; Barrantes-Freer, Alonso; Blazquez, Raquel; Wolff, Hendrik A.; Lüke, Florian; Rohde, Veit; Stadelmann, Christine; Pukrop, Tobias

2015-01-01

The current approach to brain metastases resection is macroscopic removal of metastasis until reaching the glial pseudo-capsule (gross total resection (GTR)). However, autopsy studies demonstrated infiltrating metastatic cells into the parenchyma at the metastasis/brain parenchyma (M/BP)-interface. Aims/Methods: To analyze the astrocyte reaction and metastatic infiltration pattern at the M/BP-interface with an organotypic brain slice coculture system. Secondly, to evaluate the significance of infiltrating metastatic tumor cells in a prospective biopsy study. Therefore, after GTR, biopsies were obtained from the brain parenchyma beyond the glial pseudo-capsule and analyzed histomorphologically. Results: The coculture revealed three types of cancer cell infiltration. Interestingly, the astrocyte reaction was significantly different in the coculture with a benign, neuroectodermal-derived cell line. In the prospective biopsy study 58/167 (34.7%) samples revealed infiltrating metastatic cells. Altogether, 25/39 patients (64.1%) had proven to exhibit infiltration in at least one biopsy specimen with significant impact on survival (OS) (3.4 HR; p = 0.009; 2-year OS was 6.6% versus 43.5%). Exceptionally, in the non-infiltrating cohort three patients were long-term survivors. Conclusions: Metastatic infiltration has a significant impact on prognosis. Secondly, the astrocyte reaction at the M/BP-interface is heterogeneous and supports our previous concept of the organ-specific defense against metastatic (organ-foreign) cells. PMID:26299612

Humic First Theory: A New Theory on the Origin of Life

NASA Astrophysics Data System (ADS)

Daei, Mohammad Ali; Daei, Manijeh; Daei, Bijan

2017-04-01

In 1953, Miller & Urey through a brilliant experiment demonstrated that the building blocks of life could evolve in primitive earth conditions [1]. During the recent years scientists revealed that organic matters are not very rare compounds in comets, asteroids, and meteorites which have bombarded the ancient earth repeatedly [2]. So simple organic molecules on early earth could be quite enough to start chemical evolution and steadily, proceeded to the very simple form of life. Many theories have tried to explain how life emerged from non life, but failed, largely due to the lack of a distinct methodology. There is a huge gap between the simple building blocks, like amino acid, sugar, and lipid molecules, to a living cell with a very sophisticated structure and organization. It is unacceptable to fill this great distance, only by accidental reactions in a passive media (primitive soap) even, over a very long time. Obviously, manufacturing of a primitive cell required a natural factory with rather firm and resistant basement, plenty of organic and inorganic raw materials and qualified production line, plus some sources of energy. There were plenty of solar energy and water in the early Earth, but what about the other factors? Availability of essential minerals was not guaranteed at all, in primitive earth which covered with bare, dead rocks. While we are not able today, to multiply any microorganisms in ideal conditions of modern laboratory in the absence of only one of essential nutrients or elements, how can we expect primitive cells appear on early earth conditions without the support of soluble minerals and organic matters? Ideal production line must be active and protective, have catalyzing ability, could provide numerous opportunities for interaction between basic bio molecules (mainly RNA and proteins) and above all, have capability to react with different sources of energy. There are strong evidences that show only some form of stable, rich and active organic matter like modern "humic substances" could perform this great and complicated duty. A mass of warm, wet clay mixed with enough humic substances (HS) in suitable PH, could provide all above requirements, and promote biochemical evolution step by step toward a functional primitive cell. HS are fluorescent compounds and could transform UV radiation to usable light. In addition these protective materials could provide chemical energy plus balanced minerals and organic molecules. While everything in non living world is reducing energy, HS can collect more and more material and energy like a living organism. Fortunately, there are reliable evidences that HS could be accessible on ancient Earth. In fact Ziechman et al [7], in 1994 by finding humic material in Miller's experimental vessels proved that humic substances could be generated on early Earth conditions by polymerizing simple organic molecules. Our investigations show elemental selection and also chairal selection for life are proportionately tailored to Humic materials. For example nearly all heavy metals make insoluble compounds with HS, hence omitted from life processes. In contrast all essential elements have appropriate affinity and workability with HS. There is reliable evidence that shows HS prefer left amino acids and right sugars. As you see many signs and symptoms are referring to "humic substances" as the mother of life, at least on this planet.

Shape-Shifted Red Blood Cells: A Novel Red Blood Cell Stage?

PubMed Central

Chico, Verónica; Puente-Marin, Sara; Ciordia, Sergio; Mena, María Carmen; Carracedo, Begoña; Mercado, Luis; Coll, Julio

2018-01-01

Primitive nucleated erythroid cells in the bloodstream have long been suggested to be more similar to nucleated red cells of fish, amphibians, and birds than the red cells of fetal and adult mammals. Rainbow trout Ficoll-purified red blood cells (RBCs) cultured in vitro undergo morphological changes, especially when exposed to stress, and enter a new cell stage that we have coined shape-shifted RBCs (shRBCs). We have characterized these shRBCs using transmission electron microscopy (TEM) micrographs, Wright–Giemsa staining, cell marker immunostaining, and transcriptomic and proteomic evaluation. shRBCs showed reduced density of the cytoplasm, hemoglobin loss, decondensed chromatin in the nucleus, and striking expression of the B lymphocyte molecular marker IgM. In addition, shRBCs shared some features of mammalian primitive pyrenocytes (extruded nucleus surrounded by a thin rim of cytoplasm and phosphatidylserine (PS) exposure on cell surface). These shRBCs were transiently observed in heat-stressed rainbow trout bloodstream for three days. Functional network analysis of combined transcriptomic and proteomic studies resulted in the identification of proteins involved in pathways related to the regulation of cell morphogenesis involved in differentiation, cellular response to stress, and immune system process. In addition, shRBCs increased interleukin 8 (IL8), interleukin 1 β (IL1β), interferon ɣ (IFNɣ), and natural killer enhancing factor (NKEF) protein production in response to viral hemorrhagic septicemia virus (VHSV). In conclusion, shRBCs may represent a novel cell stage that participates in roles related to immune response mediation, homeostasis, and the differentiation and development of blood cells. PMID:29671811

Shape-Shifted Red Blood Cells: A Novel Red Blood Cell Stage?

PubMed

Chico, Verónica; Puente-Marin, Sara; Nombela, Iván; Ciordia, Sergio; Mena, María Carmen; Carracedo, Begoña; Villena, Alberto; Mercado, Luis; Coll, Julio; Ortega-Villaizan, María Del Mar

2018-04-19

Primitive nucleated erythroid cells in the bloodstream have long been suggested to be more similar to nucleated red cells of fish, amphibians, and birds than the red cells of fetal and adult mammals. Rainbow trout Ficoll-purified red blood cells (RBCs) cultured in vitro undergo morphological changes, especially when exposed to stress, and enter a new cell stage that we have coined shape-shifted RBCs (shRBCs). We have characterized these shRBCs using transmission electron microscopy (TEM) micrographs, Wright⁻Giemsa staining, cell marker immunostaining, and transcriptomic and proteomic evaluation. shRBCs showed reduced density of the cytoplasm, hemoglobin loss, decondensed chromatin in the nucleus, and striking expression of the B lymphocyte molecular marker IgM. In addition, shRBCs shared some features of mammalian primitive pyrenocytes (extruded nucleus surrounded by a thin rim of cytoplasm and phosphatidylserine (PS) exposure on cell surface). These shRBCs were transiently observed in heat-stressed rainbow trout bloodstream for three days. Functional network analysis of combined transcriptomic and proteomic studies resulted in the identification of proteins involved in pathways related to the regulation of cell morphogenesis involved in differentiation, cellular response to stress, and immune system process. In addition, shRBCs increased interleukin 8 (IL8), interleukin 1 β (IL1β), interferon ɣ (IFNɣ), and natural killer enhancing factor (NKEF) protein production in response to viral hemorrhagic septicemia virus (VHSV). In conclusion, shRBCs may represent a novel cell stage that participates in roles related to immune response mediation, homeostasis, and the differentiation and development of blood cells.

Novel Target for Ameliorating Pain and Other Problems after SCI: Spontaneous Activity in Nociceptors

DTIC Science & Technology

2016-06-01

BSCB will permit blood-borne mye- loid and lymphoid immune cells to enter the spinal cord parenchyma and exert direct inflammatory actions on central...primitive innate immune system is the first line of defense against pathogens and toxins; it is always present and it depends upon diverse cell types that...adaptive immune system, the innate immune system does not em- ploy antigen-specific humoral and cell -mediated immunity mecha- nisms. Two innate immune

Using Depth Recovery in Humans

DTIC Science & Technology

1988-07-07

presence of oriented luminance discontinuities or "edges" in the image data (Marr & Poggio, i976; Dey, 1975; Nelson, 1975 & 1977; Marr, Palm & Poggio, 1978...primitives, namely computational expense, is rapidly diminishing as we continue to benefit from dramatic advances in signal processing hardware...dimensional weighting function of simple cells are well fitted by Gabor functions. Pollen & Ronner (1981) demonstrated that simple cells which are tuned to

The molecular characterization of porcine egg precursor cells

PubMed Central

Tsai, Te-Sha; Johnson, Jacqueline; White, Yvonne; John, Justin C.

2017-01-01

Female-factor infertility can be caused by poor oocyte quality and depleted ovarian reserves. Egg precursor cells (EPCs), isolated from the ovarian cortex, have the potential to be used to overcome female infertility. We aimed to define the origins of EPCs by analyzing their gene expression profiles and mtDNA content using a mini-pig model. We characterized FAC-sorted DDX4+-derived porcine EPCs by performing RNA-sequencing and determined that they utilize pathways important for cell cycle and proliferation, which supports the existence of adult mitotically active oogonial cells. Expression of the pluripotent markers Sox2 and Oct4, and the primitive germ cell markers Blimp1 and Stella were not detected. However, Nanog and Ddx4 were expressed, as were the primitive germ cell markers Fragilis, c-Kit and Tert. Moreover, porcine EPCs expressed self-renewal and proliferation markers including Myc, Esrrb, Id2, Klf4, Klf5, Stat3, Fgfr1, Fgfr2 and Il6st. The presence of Zp1, Zp2, Zp3 and Nobox were not detected, indicating that porcine EPCs are not indicative of mature primordial oocytes. We performed mitochondrial DNA Next Generation Sequencing and determined that one mtDNA variant harbored by EPCs was present in oocytes, preimplantation embryos and somatic tissues over three generations in our mini-pig model indicating the potential germline origin of EPCs. PMID:28969006

DNase I hypersensitivity and epsilon-globin transcriptional enhancement are separable in locus control region (LCR) HS1 mutant human beta-globin YAC transgenic mice.

PubMed

Shimotsuma, Motoshi; Okamura, Eiichi; Matsuzaki, Hitomi; Fukamizu, Akiyoshi; Tanimoto, Keiji

2010-05-07

Expression of the five beta-like globin genes (epsilon, Ggamma, Agamma, delta, beta) in the human beta-globin locus depends on enhancement by the locus control region, which consists of five DNase I hypersensitive sites (5'HS1 through 5'HS5). We report here a novel enhancer activity in 5'HS1 that appears to be potent in transfected K562 cells. Deletion analyses identified a core activating element that bound to GATA-1, and a two-nucleotide mutation that disrupted GATA-1 binding in vitro abrogated 5'HS1 enhancer activity in transfection experiments. To determine the in vivo role of this GATA site, we generated multiple lines of human beta-globin YAC transgenic mice bearing the same two-nucleotide mutation. In the mutant mice, epsilon-, but not gamma-globin, gene expression in primitive erythroid cells was severely attenuated, while adult beta-globin gene expression in definitive erythroid cells was unaffected. Interestingly, DNaseI hypersensitivity near the 5'HS1 mutant sequence was eliminated in definitive erythroid cells, whereas it was only mildly affected in primitive erythroid cells. We therefore conclude that, although the GATA site in 5'HS1 is critical for efficient epsilon-globin gene expression, hypersensitive site formation per se is independent of 5'HS1 function, if any, in definitive erythroid cells.

Niche displacement of human leukemic stem cells uniquely allows their competitive replacement with healthy HSPCs

PubMed Central

Boyd, Allison L.; Campbell, Clinton J.V.; Hopkins, Claudia I.; Fiebig-Comyn, Aline; Russell, Jennifer; Ulemek, Jelena; Foley, Ronan; Leber, Brian; Xenocostas, Anargyros; Collins, Tony J.

2014-01-01

Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) is currently the leading strategy to manage acute myeloid leukemia (AML). However, treatment-related morbidity limits the patient generalizability of HSCT use, and the survival of leukemic stem cells (LSCs) within protective areas of the bone marrow (BM) continues to lead to high relapse rates. Despite growing appreciation for the significance of the LSC microenvironment, it has remained unresolved whether LSCs preferentially situate within normal HSC niches or whether their niche requirements are more promiscuous. Here, we provide functional evidence that the spatial localization of phenotypically primitive human AML cells is restricted to niche elements shared with their normal counterparts, and that their intrinsic ability to initiate and retain occupancy of these niches can be rivaled by healthy hematopoietic stem and progenitor cells (HSPCs). When challenged in competitive BM repopulation assays, primary human leukemia-initiating cells (L-ICs) can be consistently outperformed by HSPCs for BM niche occupancy in a cell dose-dependent manner that ultimately compromises long-term L-IC renewal and subsequent leukemia-initiating capacity. The effectiveness of this approach could be demonstrated using cytokine-induced mobilization of established leukemia from the BM that facilitated the replacement of BM niches with transplanted HSPCs. These findings identify a functional vulnerability of primitive leukemia cells, and suggest that clinical development of these novel transplantation techniques should focus on the dissociation of L-IC–niche interactions to improve competitive replacement with healthy HSPCs during HSCT toward increased survival of patients. PMID:25180064

Specification of embryonic stem cell-derived tissues into eye fields by Wnt signaling using rostral diencephalic tissue-inducing culture.

PubMed

Sakakura, Eriko; Eiraku, Mototsugu; Takata, Nozomu

2016-08-01

The eyes are subdivided from the rostral diencephalon in early development. How the neuroectoderm regulates this subdivision, however, is largely unknown. Taking advantage of embryonic stem cell (ESC) culture using a Rax reporter line to monitor rostral diencephalon formation, we found that ESC-derived tissues at day 7 grown in Glasgow Minimum Expression Media (GMEM) containing knockout serum replacement (KSR) exhibited higher levels of expression of axin2, a Wnt target gene, than those grown in chemically defined medium (CDM). Surprisingly, Wnt agonist facilitated eye field-like tissue specification in CDM. In contrast, the addition of Wnt antagonist diminished eye field tissue formation in GMEM+KSR. Furthermore, the morphological formation of the eye tissue anlage, including the optic vesicle, was accompanied by Wnt signaling activation. Additionally, using CDM culture, we developed an efficient method for generating Rax+/Chx10+ retinal progenitors, which could become fully stratified retina. Here we provide a new avenue for exploring the mechanisms of eye field specification in vitro. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

An immunohistochemical study of neuropeptides and neuronal cytoskeletal proteins in the neuroepithelial component of a spontaneous murine ovarian teratoma. Primitive neuroepithelium displays immunoreactivity for neuropeptides and neuron-associated beta-tubulin isotype.

PubMed Central

Caccamo, D. V.; Herman, M. M.; Frankfurter, A.; Katsetos, C. D.; Collins, V. P.; Rubinstein, L. J.

1989-01-01

Approximately one third of the female mice of the LTXBO strain develop spontaneous ovarian teratomas. These tumors contain a large neuroepithelial component, which includes primitive neural structures resembling embryonic neural tubes (medulloepithelial rosettes), ependymoblastic and ependymal rosettes, neuroblasts, mature ganglionic neurons, myelinated neurites, and astrocytes. The purpose of this study was to characterize these tumors according to the immunohistochemical location of some well-characterized trophic and regulatory neuropeptides and neurotransmitters, several neuronal-associated cytoskeletal proteins, and other proteins indicative of neuronal and glial differentiation. Medulloepithelial rosettes showed focal serotonin-like, opioid peptide-like and gamma-amino butyric acid-like immunoreactivity, and displayed immunostaining for the neuron-associated class III beta-tubulin isotype. The mature ganglion cells were also immunoreactive for these markers, and, in addition, for somatostatin, cholecystokinin, bombesin, glucagon, vasoactive intestinal peptide, and neuropeptide Y. Mature ganglion cells were also immunoreactive for proteins associated with the neuronal cytoskeleton (including microtubule-associated proteins, MAP2 and tau, and higher molecular weight phosphorylated and non-phosphorylated neurofilament subunits), neuron-specific enolase, and synaptophysin. Undifferentiated stem cells, ependymoblastic and ependymal rosettes, and astroglia all stained with a monoclonal antibody that recognizes all mammalian beta-tubulin isotypes, but did not react with antibodies to neuronal-associated cytoskeletal proteins or neuropeptides. Neuropeptide-like immunoreactivity and demonstration of the class III beta-tubulin isotype indicate early neuronal commitment in neoplastic primitive neuroepithelium. These patterns of immunoreactivity closely follow those encountered in the normal neurocytogenesis of the mammalian and avian forebrain, and increase the precision with which the early stages of progressive neuroepithelial differentiation can be analyzed in human embryonal tumors of the CNS. Images Figure 1 Figure 2 Figure 3 PMID:2817080

Epidermal differentiation in embryos of the tuatara Sphenodon punctatus (Reptilia, Sphenodontidae) in comparison with the epidermis of other reptiles.

PubMed

Alibardi, L; Gill, B J

2007-07-01

Studying the epidermis in primitive reptiles can provide clues regarding evolution of the epidermis during land adaptation in vertebrates. With this aim, the development of the skin of the relatively primitive reptile Sphenodon punctatus in representative embryonic stages was studied by light and electron microscopy and compared with that of other reptiles previously studied. The dermis organizes into a superficial and deep portion when the epidermis starts to form the first layers. At embryonic stages comparable with those of lizards, only one layer of the inner periderm is formed beneath the outer periderm. This also occurs in lizards and snakes so far studied. The outer and inner periderm form the embryonic epidermis and accumulate thick, coarse filaments (25-30 nm thick) and sparse alpha-keratin filaments as in other reptiles. Beneath the embryonic epidermis an oberhautchen and beta-cells form small horny tips that represent overlapping borders along the margin of beta-cells that overlap other beta-cells (in a tile-like arrangement). The tips resemble those of agamine lizards but at a small scale, forming a lamellate-spinulated pattern as previously described in adult epidermis. The embryonic epidermis matures by the dispersion of coarse filaments among keratin at the end of embryonic development and is shed around hatching. The presence of these matrix organelles in the embryonic epidermis of this primitive reptile further indicates that amniote epidermis acquired interkeratin matrix proteins early for land adaptation. Unlike the condition in lizards and snakes, a shedding complex is not formed in the epidermis of embryonic S. punctatus that is like that of the adult. Therefore, as in chelonians and crocodilians, the epidermis of S. punctatus also represents an initial stage that preceded the evolution of the shedding complex for moulting.

Epidermal differentiation in embryos of the tuatara Sphenodon punctatus (Reptilia, Sphenodontidae) in comparison with the epidermis of other reptiles

PubMed Central

Alibardi, L; Gill, B J

2007-01-01

Studying the epidermis in primitive reptiles can provide clues regarding evolution of the epidermis during land adaptation in vertebrates. With this aim, the development of the skin of the relatively primitive reptile Sphenodon punctatus in representative embryonic stages was studied by light and electron microscopy and compared with that of other reptiles previously studied. The dermis organizes into a superficial and deep portion when the epidermis starts to form the first layers. At embryonic stages comparable with those of lizards, only one layer of the inner periderm is formed beneath the outer periderm. This also occurs in lizards and snakes so far studied. The outer and inner periderm form the embryonic epidermis and accumulate thick, coarse filaments (25–30 nm thick) and sparse alpha-keratin filaments as in other reptiles. Beneath the embryonic epidermis an oberhautchen and beta-cells form small horny tips that represent overlapping borders along the margin of beta-cells that overlap other beta-cells (in a tile-like arrangement). The tips resemble those of agamine lizards but at a small scale, forming a lamellate-spinulated pattern as previously described in adult epidermis. The embryonic epidermis matures by the dispersion of coarse filaments among keratin at the end of embryonic development and is shed around hatching. The presence of these matrix organelles in the embryonic epidermis of this primitive reptile further indicates that amniote epidermis acquired interkeratin matrix proteins early for land adaptation. Unlike the condition in lizards and snakes, a shedding complex is not formed in the epidermis of embryonic S. punctatus that is like that of the adult. Therefore, as in chelonians and crocodilians, the epidermis of S. punctatus also represents an initial stage that preceded the evolution of the shedding complex for moulting. PMID:17532799

Positional cloning identifies zebrafish one-eyed pinhead as a permissive EGF-related ligand required during gastrulation.

PubMed

Zhang, J; Talbot, W S; Schier, A F

1998-01-23

The zebrafish one-eyed pinhead (oep) mutation disrupts embryonic development, resulting in cyclopia and defects in endoderm, prechordal plate, and ventral neuroectoderm formation. We report the molecular isolation of oep using a positional cloning approach. The oep gene encodes a novel EGF-related protein with similarity to the EGF-CFC proteins cripto, cryptic, and FRL-1. Wild-type oep protein contains a functional signal sequence and is membrane-associated. Following ubiquitous maternal and zygotic expression, highest levels of oep mRNA are found in the gastrula margin and in axial structures and forebrain. Widespread misexpression of both membrane-attached and secreted forms of oep rescues prechordal plate and forebrain development in mutant embryos but does not lead to the ectopic induction of these cell types in wild-type fish. These results establish an essential but permissive role for an EGF-related ligand during vertebrate gastrulation.

Secure Heterogeneous Multicore Platform Through Diversity and Redundancy

DTIC Science & Technology

2012-03-31

implementation detects synchronization in this way. If a programmer uses custom synchronization primitives , our approach assumes that such primitives ... synchronization primitives . Primitives such as barriers and spinlocks explicitly enforce a pre- determined ordering among threads. Therefore, the outcome of...these synchronization operations are deterministic. In the discussion, we will refer to these primitives as ordering synchronization operations. On the

HOXB4 overexpression mediates very rapid stem cell regeneration and competitive hematopoietic repopulation.

PubMed

Antonchuk, J; Sauvageau, G; Humphries, R K

2001-09-01

Hox transcription factors have emerged as important regulators of hematopoiesis. In particular, we have shown that overexpression of HOXB4 in mouse bone marrow can greatly enhance the level of hematopoietic stem cell (HSC) regeneration achieved at late times (> 4 months) posttransplantation. The objective of this study was to resolve if HOXB4 increases the rate and/or duration of HSC regeneration, and also to see if this enhancement was associated with impaired production of end cells or would lead to competitive reconstitution of all compartments. Retroviral vectors were generated with the GFP reporter gene +/- HOXB4 to enable the isolation and direct tracking of transduced cells in culture or following transplantation. Stem cell recovery was measured by limit dilution assay for long-term competitive repopulating cells (CRU). HOXB4-overexpressing cells have enhanced growth in vitro, as demonstrated by their rapid dominance in mixed cultures and their shortened population doubling time. Furthermore, HOXB4-transduced cells have a marked competitive repopulating advantage in vivo in both primitive and mature compartments. CRU recovery in HOXB4 recipients was extremely rapid, reaching 25% of normal by 14 days posttransplant or some 80-fold greater than control transplant recipients, and attaining normal numbers by 12 weeks. Mice transplanted with even higher numbers of HOXB4-transduced CRU regenerated up to but not beyond the normal CRU levels. HOXB4 is a potent enhancer of primitive hematopoietic cell growth, likely by increasing self-renewal probability but without impairing homeostatic control of HSC population size or the rate of production and maintenance of mature end cells.

Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling

PubMed Central

Franco, Claudio A; Jones, Martin L; Bernabeu, Miguel O; Vion, Anne-Clemence; Barbacena, Pedro; Fan, Jieqing; Mathivet, Thomas; Fonseca, Catarina G; Ragab, Anan; Yamaguchi, Terry P; Coveney, Peter V; Lang, Richard A; Gerhardt, Holger

2016-01-01

Endothelial cells respond to molecular and physical forces in development and vascular homeostasis. Deregulation of endothelial responses to flow-induced shear is believed to contribute to many aspects of cardiovascular diseases including atherosclerosis. However, how molecular signals and shear-mediated physical forces integrate to regulate vascular patterning is poorly understood. Here we show that endothelial non-canonical Wnt signalling regulates endothelial sensitivity to shear forces. Loss of Wnt5a/Wnt11 renders endothelial cells more sensitive to shear, resulting in axial polarization and migration against flow at lower shear levels. Integration of flow modelling and polarity analysis in entire vascular networks demonstrates that polarization against flow is achieved differentially in artery, vein, capillaries and the primitive sprouting front. Collectively our data suggest that non-canonical Wnt signalling stabilizes forming vascular networks by reducing endothelial shear sensitivity, thus keeping vessels open under low flow conditions that prevail in the primitive plexus. DOI: http://dx.doi.org/10.7554/eLife.07727.001 PMID:26845523

Principles determining the structure of high-pressure forms of metals: The structures of cesium(IV) and cesium(V)

PubMed Central

Pauling, Linus

1989-01-01

Consideration of the relation between bond length and bond number and the average atomic volume for different ways of packing atoms leads to the conclusion that the average ligancy of atoms in a metal should increase when a phase change occurs on increasing the pressure. Minimum volume for each value of the ligancy results from triangular coordination polyhedra (with triangular faces), such as the icosahedron and the Friauf polyhedron. Electron transfer may permit atoms of an element to assume different ligancies. Application of these principles to Cs(IV) and Cs(V), which were previously assigned structures with ligancy 8 and 6, respectively, has led to the assignment to Cs(IV) of a primitive cubic unit cell with a = 16.11 Å and with about 122 atoms in the cube and to Cs(V) of a primitive cubic unit cell resembling that of Mg32(Al,Zn)49, with a = 16.97 Å and with 162 atoms in the cube. PMID:16578839

A network of epigenetic regulators guides developmental haematopoiesis in vivo.

PubMed

Huang, Hsuan-Ting; Kathrein, Katie L; Barton, Abby; Gitlin, Zachary; Huang, Yue-Hua; Ward, Thomas P; Hofmann, Oliver; Dibiase, Anthony; Song, Anhua; Tyekucheva, Svitlana; Hide, Winston; Zhou, Yi; Zon, Leonard I

2013-12-01

The initiation of cellular programs is orchestrated by key transcription factors and chromatin regulators that activate or inhibit target gene expression. To generate a compendium of chromatin factors that establish the epigenetic code during developmental haematopoiesis, a large-scale reverse genetic screen was conducted targeting orthologues of 425 human chromatin factors in zebrafish. A set of chromatin regulators was identified that target different stages of primitive and definitive blood formation, including factors not previously implicated in haematopoiesis. We identified 15 factors that regulate development of primitive erythroid progenitors and 29 factors that regulate development of definitive haematopoietic stem and progenitor cells. These chromatin factors are associated with SWI/SNF and ISWI chromatin remodelling, SET1 methyltransferase, CBP-p300-HBO1-NuA4 acetyltransferase, HDAC-NuRD deacetylase, and Polycomb repressive complexes. Our work provides a comprehensive view of how specific chromatin factors and their associated complexes play a major role in the establishment of haematopoietic cells in vivo.

Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM.

PubMed

Hayward, A R; Levy, J; Facchetti, F; Notarangelo, L; Ochs, H D; Etzioni, A; Bonnefoy, J Y; Cosyns, M; Weinberg, A

1997-01-15

We report an association between X-linked immunodeficiency with hyper-IgM (XHIM) and carcinomas affecting the liver, pancreas, biliary tree, and associated neuroectodermal endocrine cells. The tumors were fatal in eight of nine cases and in most instances were preceded by chronic cholangiopathy and/or cirrhosis. An additional group of subjects with XHIM had chronic inflammation of the liver or bile ducts but no malignancy. Many patients with XHIM were infected with cryptosporidia. CD40 is normally expressed on regenerating or inflammed bile duct epithelium. A CD40+ hepatocellular carcinoma cell line, HepG2, susceptible to cryptosporidia and CMV infection became resistant when cell surface CD40 was cross-linked by a CD40 ligand fusion protein. Apoptosis was triggered in HepG2 cells if protein synthesis was blocked by cycloheximide or if the cells were infected by cryptosporidia. Ligation of CD40 on biliary epithelium may contribute to defense against infection by intracellular pathogens. We propose that the CD40 ligand mutations that cause XHIM deprive the biliary epithelium of one line of defense against intracellular pathogens and that malignant transformation in the biliary tree follows chronic infection or inflammation. The resulting tumors may then progress without check by an effective immune response. Patients with XHIM who have abnormal liver function tests should be considered at increased risk for cholangiopathy or malignancy.

Zebrafish numb and numblike are involved in primitive erythrocyte differentiation.

PubMed

Bresciani, Erica; Confalonieri, Stefano; Cermenati, Solei; Cimbro, Simona; Foglia, Efrem; Beltrame, Monica; Di Fiore, Pier Paolo; Cotelli, Franco

2010-12-13

Notch signaling is an evolutionarily conserved regulatory circuitry implicated in cell fate determination in various developmental processes including hematopoietic stem cell self-renewal and differentiation of blood lineages. Known endogenous inhibitors of Notch activity are Numb-Nb and Numblike-Nbl, which play partially redundant functions in specifying and maintaining neuronal differentiation. Nb and Nbl are expressed in most tissues including embryonic and adult hematopoietic tissues in mice and humans, suggesting possible roles for these proteins in hematopoiesis. We employed zebrafish to investigate the possible functional role of Numb and Numblike during hematopoiesis, as this system allows a detailed analysis even in embryos with severe defects that would be lethal in other organisms. Here we describe that nb/nbl knockdown results in severe reduction or absence of embryonic erythrocytes in zebrafish. Interestingly, nb/nbl knocked-down embryos present severe downregulation of the erythroid transcription factor gata1. This results in erythroblasts which fail to mature and undergo apoptosis. Our results indicate that Notch activity is increased in embryos injected with nb/nbl morpholino, and we show that inhibition of Notch activation can partially rescue the hematopoietic phenotype. Our results provide the first in vivo evidence of an involvement of Numb and Numblike in zebrafish erythroid differentiation during primitive hematopoiesis. Furthermore, we found that, at least in part, the nb/nbl morphant phenotype is due to enhanced Notch activation within hematopoietic districts, which in turn results in primitive erythroid differentiation defects.

Undifferentiated myxoid lipoblastoma with PLAG1-HAS2 fusion in an infant; morphologically mimicking primitive myxoid mesenchymal tumor of infancy (PMMTI)--diagnostic importance of cytogenetic and molecular testing and literature review.

PubMed

Warren, Mikako; Turpin, Brian K; Mark, Melissa; Smolarek, Teresa A; Li, Xia

2016-01-01

Lipoblastoma is a benign myxoid neoplasm arising in young children that typically demonstrates adipose differentiation. It is often morphologically indistinguishable from primitive myxoid mesenchymal tumor of infancy (PMMTI), which is characterized by a well-circumscribed myxoid mass with a proliferation of primitive mesenchymal cells with mild cytologic atypia. PMMTI occurs in the first year of life and is known to have locally aggressive behavior. No specific genetic rearrangements have been reported to date. In contrast, the presence of PLAG1 (Pleomorphic Adenoma Gene 1) rearrangement is diagnostic for lipoblastoma. We hereby demonstrate the combined application of multiple approaches to tackle the diagnostic challenges of a rapidly growing neck tumor in a 3-month-old female. An incisional tumor biopsy had features of an undifferentiated, myxoid mesenchymal neoplasm mimicking PMMTI. However, tumor cells showed diffuse nuclear expression by immunohistochemical (IHC) stain. Conventional cytogenetic and fluorescence in situ hybridization (FISH) analyses as well as next generation sequencing (NGS) demonstrated evidence of PLAG1 rearrangement, confirming the diagnosis of lipoblastoma. This experience warrants that undifferentiated myxoid lipoblastoma can mimic PMMTI, and the combination of cytogenetic and molecular approaches is essential to distinguish these two myxoid neoplasms. Literature on lipoblastomas with relevant molecular and cytogenetic findings is summarized. Our case is the first lipoblastoma diagnosed with a PLAG1 fusion defined by NGS technology. Copyright © 2016 Elsevier Inc. All rights reserved.

Electrospun Collagen/Silk Tissue Engineering Scaffolds: Fiber Fabrication, Post-Treatment Optimization, and Application in Neural Differentiation of Stem Cells

NASA Astrophysics Data System (ADS)

Zhu, Bofan

Biocompatible scaffolds mimicking the locally aligned fibrous structure of native extracellular matrix (ECM) are in high demand in tissue engineering. In this thesis research, unidirectionally aligned fibers were generated via a home-built electrospinning system. Collagen type I, as a major ECM component, was chosen in this study due to its support of cell proliferation and promotion of neuroectodermal commitment in stem cell differentiation. Synthetic dragline silk proteins, as biopolymers with remarkable tensile strength and superior elasticity, were also used as a model material. Good alignment, controllable fiber size and morphology, as well as a desirable deposition density of fibers were achieved via the optimization of solution and electrospinning parameters. The incorporation of silk proteins into collagen was found to significantly enhance mechanical properties and stability of electrospun fibers. Glutaraldehyde (GA) vapor post-treatment was demonstrated as a simple and effective way to tune the properties of collagen/silk fibers without changing their chemical composition. With 6-12 hours GA treatment, electrospun collagen/silk fibers were not only biocompatible, but could also effectively induce the polarization and neural commitment of stem cells, which were optimized on collagen rich fibers due to the unique combination of biochemical and biophysical cues imposed to cells. Taken together, electrospun collagen rich composite fibers are mechanically strong, stable and provide excellent cell adhesion. The unidirectionally aligned fibers can accelerate neural differentiation of stem cells, representing a promising therapy for neural tissue degenerative diseases and nerve injuries.

JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo

PubMed Central

Gallipoli, Paolo; Cook, Amy; Rhodes, Susan; Hopcroft, Lisa; Wheadon, Helen; Whetton, Anthony D.; Jørgensen, Heather G.; Bhatia, Ravi

2014-01-01

Chronic myeloid leukemia (CML) stem cell survival is not dependent on BCR-ABL protein kinase and treatment with ABL tyrosine kinase inhibitors cures only a minority of CML patients, thus highlighting the need for novel therapeutic targets. The Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)5 pathway has recently been explored for providing putative survival signals to CML stem/progenitor cells (SPCs) with contradictory results. We investigated the role of this pathway using the JAK2 inhibitor, ruxolitinib (RUX). We demonstrated that the combination of RUX, at clinically achievable concentrations, with the specific and potent tyrosine kinase inhibitor nilotinib, reduced the activity of the JAK2/STAT5 pathway in vitro relative to either single agent alone. These effects correlated with increased apoptosis of CML SPCs in vitro and a reduction in primitive quiescent CML stem cells, including NOD.Cg-Prkdcscid IL2rgtm1Wjl /SzJ mice repopulating cells, induced by combination treatment. A degree of toxicity toward normal SPCs was observed with the combination treatment, although this related to mature B-cell engraftment in NOD.Cg-Prkdcscid IL2rgtm1Wjl /SzJ mice with minimal effects on primitive CD34+ cells. These results support the JAK2/STAT5 pathway as a relevant therapeutic target in CML SPCs and endorse the current use of nilotinib in combination with RUX in clinical trials to eradicate persistent disease in CML patients. PMID:24957147

IGF-1 Signaling Plays an Important Role in the Formation of Three-Dimensional Laminated Neural Retina and Other Ocular Structures From Human Embryonic Stem Cells.

PubMed

Mellough, Carla B; Collin, Joseph; Khazim, Mahmoud; White, Kathryn; Sernagor, Evelyne; Steel, David H W; Lako, Majlinda

2015-08-01

We and others have previously demonstrated that retinal cells can be derived from human embryonic stem cells (hESCs) and induced pluripotent stem cells under defined culture conditions. While both cell types can give rise to retinal derivatives in the absence of inductive cues, this requires extended culture periods and gives lower overall yield. Further understanding of this innate differentiation ability, the identification of key factors that drive the differentiation process, and the development of clinically compatible culture conditions to reproducibly generate functional neural retina is an important goal for clinical cell based therapies. We now report that insulin-like growth factor 1 (IGF-1) can orchestrate the formation of three-dimensional ocular-like structures from hESCs which, in addition to retinal pigmented epithelium and neural retina, also contain primitive lens and corneal-like structures. Inhibition of IGF-1 receptor signaling significantly reduces the formation of optic vesicle and optic cups, while exogenous IGF-1 treatment enhances the formation of correctly laminated retinal tissue composed of multiple retinal phenotypes that is reminiscent of the developing vertebrate retina. Most importantly, hESC-derived photoreceptors exhibit advanced maturation features such as the presence of primitive rod- and cone-like photoreceptor inner and outer segments and phototransduction-related functional responses as early as 6.5 weeks of differentiation, making these derivatives promising candidates for cell replacement studies and in vitro disease modeling. © 2015 AlphaMed Press.

Spindle Cell Epithelioma of the Vagina Shows Immunohistochemical Staining Supporting Its Origin From a Primitive/Progenitor Cell Population

DTIC Science & Technology

2001-04-01

broader spectrum of immunohistochemical stains is presented that supports the origin of these tumors from a progenitor cell popula- tion. REPORT OF A CASE ...with S100 protein, with coexpression of cytokeratins and vimentin and expression of estrogen and progesterone receptors, as previously reported in...SCEVs. In addition, diffuse expres- sion of CD34, CD99, and Bcl-2 immunohistochemical stains was found, which has not previously been reported . The

Interlaminar differences in the pyramidal cell phenotype in parietal cortex of an Indian bat, cynopterus sphinx.

PubMed

Srivastava, U C; Pathak, S V

2010-10-30

To study interlaminar phenotypic variations in the pyramidal neurons of parietal isocortex in bat (Cynopterus sphinx), Golgi and Nissl methods have been employed. The parietal isocortex is relatively thin in the bat as compared to prototheria with layer III, V and VI accounting for more than two—thirds of total cortical thickness. Thick cell free layer I and thinnest accentuated layer II are quite in connotation with other chiropterids. Poor demarcation of layer III/IV in the present study is also in connotation with primitive eutherian mammal (i.e. prototherian) and other chiropterids. Most of the pyramidal cells in the different layers of the parietal isocortex are of typical type as seen in other eutherians but differ significantly in terms of soma shape and size, extent of dendritic arbor, diameter of dendrites and spine density. Percentage of pyramidal neurons, diameter of apical dendrite and spine density on apical dendrite appear to follow an increasing trend from primitive to advanced mammals; but extent of dendrites are probably governed by the specific life patterns of these mammals. It is thus concluded that 'typical' pyramidal neurons in parietal isocortex are similar in therians but different from those in prototherians. It is possible that these cells might have arisen among early eutherians after divergence from prototherian stock.

Notochord morphogenesis in mice: Current understanding & open questions.

PubMed

Balmer, Sophie; Nowotschin, Sonja; Hadjantonakis, Anna-Katerina

2016-05-01

The notochord is a structure common to all chordates, and the feature that the phylum Chordata has been named after. It is a rod-like mesodermal structure that runs the anterior-posterior length of the embryo, adjacent to the ventral neural tube. The notochord plays a critical role in embryonic tissue patterning, for example the dorsal-ventral patterning of the neural tube. The cells that will come to form the notochord are specified at gastrulation. Axial mesodermal cells arising at the anterior primitive streak migrate anteriorly as the precursors of the notochord and populate the notochordal plate. Yet, even though a lot of interest has centered on investigating the functional and structural roles of the notochord, we still have a very rudimentary understanding of notochord morphogenesis. The events driving the formation of the notochord are rapid, taking place over the period of approximately a day in mice. In this commentary, we provide an overview of our current understanding of mouse notochord morphogenesis, from the initial specification of axial mesendodermal cells at the primitive streak, the emergence of these cells at the midline on the surface of the embryo, to their submergence and organization of the stereotypically positioned notochord. We will also discuss some key open questions. Developmental Dynamics 245:547-557, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Amphioxus and lamprey AP-2 genes: implications for neural crest evolution and migration patterns

NASA Technical Reports Server (NTRS)

Meulemans, Daniel; Bronner-Fraser, Marianne

2002-01-01

The neural crest is a uniquely vertebrate cell type present in the most basal vertebrates, but not in cephalochordates. We have studied differences in regulation of the neural crest marker AP-2 across two evolutionary transitions: invertebrate to vertebrate, and agnathan to gnathostome. Isolation and comparison of amphioxus, lamprey and axolotl AP-2 reveals its extensive expansion in the vertebrate dorsal neural tube and pharyngeal arches, implying co-option of AP-2 genes by neural crest cells early in vertebrate evolution. Expression in non-neural ectoderm is a conserved feature in amphioxus and vertebrates, suggesting an ancient role for AP-2 genes in this tissue. There is also common expression in subsets of ventrolateral neurons in the anterior neural tube, consistent with a primitive role in brain development. Comparison of AP-2 expression in axolotl and lamprey suggests an elaboration of cranial neural crest patterning in gnathostomes. However, migration of AP-2-expressing neural crest cells medial to the pharyngeal arch mesoderm appears to be a primitive feature retained in all vertebrates. Because AP-2 has essential roles in cranial neural crest differentiation and proliferation, the co-option of AP-2 by neural crest cells in the vertebrate lineage was a potentially crucial event in vertebrate evolution.

Post-transcriptional regulation in hematopoiesis: RNA binding proteins take control.

PubMed

de Rooij, Laura P M H; Chan, Derek C H; Keyvani Chahi, Ava; Hope, Kristin J

2018-06-13

Normal hematopoiesis is sustained through a carefully orchestrated balance between hematopoietic stem cell (HSC) self-renewal and differentiation. The functional importance of this axis is underscored by the severity of disease phenotypes initiated by abnormal HSC function, including myelodysplastic syndromes and hematopoietic malignancies. Major advances in the understanding of transcriptional regulation of primitive hematopoietic cells have been achieved, however, the post-transcriptional regulatory layer that may impinge on their behavior remains underexplored by comparison. Key players at this level include RNA binding proteins (RBPs), which execute precise and highly coordinated control of gene expression through modulation of RNA properties that include its splicing, polyadenylation, localization, degradation or translation. With the recent identification of RBPs having essential roles in regulating proliferation and cell fate decisions in other systems, there has been an increasing appreciation of the importance of post-transcriptional control at the stem cell level. Here we discuss our current understanding of RBP-driven post-transcriptional regulation in HSC, its implications for normal, perturbed and malignant hematopoiesis, as well as the most recent technological innovations aimed at RBP-RNA network characterization at the systems level. Emerging evidence highlights RBP-driven control as an underappreciated feature of primitive hematopoiesis, the greater understanding of which has important clinical implications.

Cell differentiation: therapeutical challenges in diabetes.

PubMed

Roche, Enrique; Vicente-Salar, Nestor; Arribas, Maribel; Paredes, Beatriz

2012-01-01

Stem cells, derived from either embryonic or adult tissues, are considered to be potential sources of insulin-secreting cells to be transplanted into type 1 and advanced stages of type 2 diabetic patients. Many laboratories have considered this possibility, resulting in a large amount of published protocols, with a wide degree of complexity among them. Our group was the first to report that it was possible to obtain insulin-secreting cells from mouse embryonic stem cells, proving the feasibility of this new challenge. The same observation was immediately reported using human embryonic stem cells. However, the resulting cell product was not properly characterised, affecting the reproducibility of the protocol by other groups. A more elaborated protocol was developed by Lumelsky and co-workers, demonstrating that neuroectodermal cells could be an alternative source for insulin-producing cells. However, the resulting cells of this protocol produced low amounts of the hormone. This aimed other groups to perform key changes in order to improve the insulin content of the resulting cells. Recently, Baetge's group has published a new protocol based on the knowledge accumulated in pancreatic development. In this protocol, human embryonic stem cells were differentiated into islet-like structures through a five step protocol, emulating the key steps during embryonic development of the endocrine pancreas. The final cell product, however, seemed to be in an immature state, thus further improvement is required. Despite this drawback, the protocol represents the culmination of work performed by different groups and offers new research challenges for the investigators in this exciting field. Concerning adult stem cells, the possibility of identifying pancreatic precursors or of reprogramming extrapancreatic derived cells are key possibilities that may circumvent the problems that appear when using embryonic stem cells, such as immune rejection and tumour formation.

A novel gene's role in an ancient mechanism: secreted Frizzled-related protein 1 is a critical component in the anterior-posterior Wnt signaling network that governs the establishment of the anterior neuroectoderm in sea urchin embryos.

PubMed

Khadka, Anita; Martínez-Bartolomé, Marina; Burr, Stephanie D; Range, Ryan C

2018-01-01

The anterior neuroectoderm (ANE) in many deuterostome embryos (echinoderms, hemichordates, urochordates, cephalochordates, and vertebrates) is progressively restricted along the anterior-posterior axis to a domain around the anterior pole. In the sea urchin embryo, three integrated Wnt signaling branches (Wnt/β-catenin, Wnt/JNK, and Wnt/PKC) govern this progressive restriction process, which begins around the 32- to 60-cell stage and terminates by the early gastrula stage. We previously have established that several secreted Wnt modulators of the Dickkopf and secreted Frizzled-related protein families (Dkk1, Dkk3, and sFRP-1/5) are expressed within the ANE and play important roles in modulating the Wnt signaling network during this process. In this study, we use morpholino and dominant-negative interference approaches to characterize the function of a novel Frizzled-related protein, secreted Frizzled-related protein 1 (sFRP-1), during ANE restriction. sFRP-1 appears to be related to a secreted Wnt modulator, sFRP3/4, that is essential to block Wnt signaling and establish the ANE in vertebrates. Here, we show that the sea urchin sFRP3/4 orthologue is not expressed during ANE restriction in the sea urchin embryo. Instead, our results indicate that ubiquitously expressed maternal sFRP-1 and Fzl1/2/7 signaling act together as early as the 32- to 60-cell stage to antagonize the ANE restriction mechanism mediated by Wnt/β-catenin and Wnt/JNK signaling. Then, starting from the blastula stage, Fzl5/8 signaling activates zygotic sFRP-1 within the ANE territory, where it works with the secreted Wnt antagonist Dkk1 (also activated by Fzl5/8 signaling) to antagonize Wnt1/Wnt8-Fzl5/8-JNK signaling in a negative feedback mechanism that defines the outer ANE territory boundary. Together, these data indicate that maternal and zygotic sFRP-1 protects the ANE territory by antagonizing the Wnt1/Wnt8-Fzl5/8-JNK signaling pathway throughout ANE restriction, providing precise spatiotemporal control of the mechanism responsible for the establishment of the ANE territory around the anterior pole of the sea urchin embryo.

Dynamic Primitives of Motor Behavior

PubMed Central

Hogan, Neville; Sternad, Dagmar

2013-01-01

We present in outline a theory of sensorimotor control based on dynamic primitives, which we define as attractors. To account for the broad class of human interactive behaviors—especially tool use—we propose three distinct primitives: submovements, oscillations and mechanical impedances, the latter necessary for interaction with objects. Due to fundamental features of the neuromuscular system, most notably its slow response, we argue that encoding in terms of parameterized primitives may be an essential simplification required for learning, performance, and retention of complex skills. Primitives may simultaneously and sequentially be combined to produce observable forces and motions. This may be achieved by defining a virtual trajectory composed of submovements and/or oscillations interacting with impedances. Identifying primitives requires care: in principle, overlapping submovements would be sufficient to compose all observed movements but biological evidence shows that oscillations are a distinct primitive. Conversely, we suggest that kinematic synergies, frequently discussed as primitives of complex actions, may be an emergent consequence of neuromuscular impedance. To illustrate how these dynamic primitives may account for complex actions, we briefly review three types of interactive behaviors: constrained motion, impact tasks, and manipulation of dynamic objects. PMID:23124919

Automated single cell sorting and deposition in submicroliter drops

NASA Astrophysics Data System (ADS)

Salánki, Rita; Gerecsei, Tamás; Orgovan, Norbert; Sándor, Noémi; Péter, Beatrix; Bajtay, Zsuzsa; Erdei, Anna; Horvath, Robert; Szabó, Bálint

2014-08-01

Automated manipulation and sorting of single cells are challenging, when intact cells are needed for further investigations, e.g., RNA or DNA sequencing. We applied a computer controlled micropipette on a microscope admitting 80 PCR (Polymerase Chain Reaction) tubes to be filled with single cells in a cycle. Due to the Laplace pressure, fluid starts to flow out from the micropipette only above a critical pressure preventing the precise control of drop volume in the submicroliter range. We found an anomalous pressure additive to the Laplace pressure that we attribute to the evaporation of the drop. We have overcome the problem of the critical dropping pressure with sequentially operated fast fluidic valves timed with a millisecond precision. Minimum drop volume was 0.4-0.7 μl with a sorting speed of 15-20 s per cell. After picking NE-4C neuroectodermal mouse stem cells and human primary monocytes from a standard plastic Petri dish we could gently deposit single cells inside tiny drops. 94 ± 3% and 54 ± 7% of the deposited drops contained single cells for NE-4C and monocytes, respectively. 7.5 ± 4% of the drops contained multiple cells in case of monocytes. Remaining drops were empty. Number of cells deposited in a drop could be documented by imaging the Petri dish before and after sorting. We tuned the adhesion force of cells to make the manipulation successful without the application of microstructures for trapping cells on the surface. We propose that our straightforward and flexible setup opens an avenue for single cell isolation, critically needed for the rapidly growing field of single cell biology.

Long-term hematopoietic stem cell damage in a murine model of the hematopoietic syndrome of the acute radiation syndrome.

PubMed

Chua, Hui Lin; Plett, P Artur; Sampson, Carol H; Joshi, Mandar; Tabbey, Rebeka; Katz, Barry P; MacVittie, Thomas J; Orschell, Christie M

2012-10-01

Residual bone marrow damage (RBMD) persists for years following exposure to radiation and is believed to be due to decreased self-renewal potential of radiation-damaged hematopoietic stem cells (HSC). Current literature has examined primarily sublethal doses of radiation and time points within a few months of exposure. In this study, the authors examined RBMD in mice surviving lethal doses of total body ionizing irradiation (TBI) in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS). Survivors were analyzed at various time points up to 19 mo post-TBI for hematopoietic function. The competitive bone marrow (BM) repopulating potential of 150 purified c-Kit+ Sca-1+ lineage- CD150+ cells (KSLCD150+) remained severely deficient throughout the study compared to KSLCD150+ cells from non-TBI age-matched controls. The minimal engraftment from these TBI HSCs is predominantly myeloid, with minimal production of lymphocytes both in vitro and in vivo. All classes of blood cells as well as BM cellularity were significantly decreased in TBI mice, especially at later time points as mice aged. Primitive BM hematopoietic cells (KSLCD150+) displayed significantly increased cell cycling in TBI mice at all time points, which may be a physiological attempt to maintain HSC numbers in the post-irradiation state. Taken together, these data suggest that the increased cycling among primitive hematopoietic cells in survivors of lethal radiation may contribute to long-term HSC exhaustion and subsequent RBMD, exacerbated by the added insult of aging at later time points.

What Everyone Should Know about Archeans

ERIC Educational Resources Information Center

Freeland, Peter

2013-01-01

For many years biologists supposed that one group of microorganisms, which they called archaebacteria, were an ancient and primitive type of bacteria. Following biochemical analysis of their RNA and other cell components, it soon became clear that their distinct features merited classification in a separate domain, the archea. From an evolutionary…

HEPATOBLASTOMAS IN THE MUMMICHOG, FUNDULUS HETEROCLITUS (L.), FROM A CREOSOTE-CONTAMINATED ENVIRONMENT: A HISTOLOGIC, ULTRASTRUCTURAL AND IMMUNOHISTOCHEMICAL STUDY

EPA Science Inventory

A detailed histologic and ultrastructural description of two cases of hepatoblastoma, a primitive liver cell neoplasm, is provided from mummichog, Fundulus heteroclitus(L.), inhabiting a creosote-contaminated site in the Elizabeth River, Virginia, USA. Both neoplasms were multifo...

Postirradiation malignant fibrous histiocytoma of the lung. Demonstration of alpha 1-antitrypsin-like material in neoplastic cells.

PubMed

Chowdhury, L N; Swerdlow, M A; Jao, W; Kathpalia, S; Desser, R K

1980-12-01

A metastasizing fibrous histiocytoma arising in the lung of a patient who received radiation therapy and long-term chemotherapy for malignant lymphoma is presented. Ultrastructural studies revealed fibroblast-like and histiocyte-like cells, cells of intermediate type showing ultrastructural features of both fibroblast-like and histiocyte-like cells, primitive mesenchymal cells, multinucleate tumor cells, and xanthomatous cells. The neoplastic cells showed dilated rough endoplasmic reticula with intracisternal accumulation of electron-dense material forming lattice-like structures. Direct immunofluorescence staining of the neoplastic cells using antihuman alpha 1-antitrypsin showed specific activity, with fluorescent deposits exhibiting interlacing globular formations. These findings and their implications are discussed.

Molecular Features of Neural Stem Cells Enable their Enrichment Using Pharmacological Inhibitors of Survival-Promoting Kinases

PubMed Central

Brazel, Christine Y.; Alaythan, Abdulaziz A.; Felling, Ryan J.; Calderon, Frances; Levison, Steven W.

2013-01-01

Isolating a pure population of neural stem cells (NSCs) has been difficult since no exclusive surface markers have been identified for panning or FACS purification. Moreover, additional refinements for maintaining NSCs in culture are required, since NSCs generate a variety of neural precursors (NPs) as they proliferate. Here, we demonstrate that postnatal rat NPs express low levels of pro-apoptotic molecules and resist PI3K and ERK1/2 inhibition as compared to late oligodendrocyte progenitors. Furthermore, maintaining SVZ precursors in LY294002 and PD98059, inhibitors of PI3K and ERK1/2 signaling, eliminated lineage-restricted precursors as revealed by enrichment for Nestin+/SOX-2+ cells. The cells that survived formed neurospheres and 89% of these neurospheres were tripotential, generating neurons, astrocytes and oligodendrocytes. Without this enrichment step, less than 50% of the NPs were Nestin+/SOX-2+ and 42% of the neurospheres were tripotential. Additionally, neurospheres enriched using this procedure produced 3-times more secondary neurospheres, supporting the conclusion that this procedure enriches for NSCs. A number of genes that enhance survival were more highly expressed in neurospheres compared to late oligodendrocyte progenitors. Altogether, these studies demonstrate that primitive neural precursors can be enriched using a relatively simple and inexpensive means that will facilitate cell replacement strategies using stem cells as well as other studies whose goal is to reveal the fundamental properties of primitive neural precursors. PMID:24032666

Common tree shrews and primates share leukocyte membrane antigens.

PubMed

Palley, L S; Schlossman, S F; Letvin, N L

1984-01-01

Monoclonal antibodies reactive with human peripheral blood lymphocyte and myeloid cell surface antigens were utilized to study the phylogeny of the common tree shrew. Blood cells from the common tree shrew, but not the bat or short-tailed shrew, react with certain of these antibodies. These data strengthen the argument that the Tupaiidae are primitive primates rather than insectivores. They also indicate that this approach should be useful for further work in taxonomic systemization.

Cell lineage allocation in equine blastocysts produced in vitro under varying glucose concentrations.

PubMed

Choi, Young-Ho; Ross, Pablo; Velez, Isabel C; Macías-García, B; Riera, Fernando L; Hinrichs, Katrin

2015-07-01

Equine embryos develop in vitro in the presence of high glucose concentrations, but little is known about their requirements for development. We evaluated the effect of glucose concentrations in medium on blastocyst development after ICSI. In experiment 1, there were no significant differences in rates of blastocyst formation among embryos cultured in our standard medium (DMEM/F-12), which contained >16 mM glucose, and those cultured in a minimal-glucose embryo culture medium (<1 mM; Global medium, GB), with either 0 added glucose for the first 5 days, then 20 mM (0-20) or 20 mM for the entire culture period (20-20). In experiment 2, there were no significant differences in the rates of blastocyst development (31-46%) for embryos cultured in four glucose treatments in GB (0-10, 0-20, 5-10, or 5-20). Blastocysts were evaluated by immunofluorescence for lineage-specific markers. All cells stained positively for POU5F1. An inner cluster of cells was identified that included presumptive primitive endoderm cells (GATA6-positive) and presumptive epiblast (EPI) cells. The 5-20 treatment resulted in a significantly lower number of presumptive EPI-lineage cells than the 0-20 treatment did. GATA6-positive cells appeared to be allocated to the primitive endoderm independent of the formation of an inner cell mass, as was previously hypothesized for equine embryos. These data demonstrate that equine blastocyst development is not dependent on high glucose concentrations during early culture; rather, environmental glucose may affect cell allocation. They also present the first analysis of cell lineage allocation in in vitro-fertilized equine blastocysts. These findings expand our understanding of the factors that affect embryo development in the horse. © 2015 Society for Reproduction and Fertility.

Lens epithelial cells derived from alphaB-crystallin knockout mice demonstrate hyperproliferation and genomic instability.

PubMed

Andley, U P; Song, Z; Wawrousek, E F; Brady, J P; Bassnett, S; Fleming, T P

2001-01-01

alphaB-crystallin is a member of the small heat shock protein family and can act as a molecular chaperone preventing the in vitro aggregation of other proteins denatured by heat or other stress conditions. Expression of alphaB-crystallin increases in cells exposed to stress and enhanced in tumors of neuroectodermal origin and in many neurodegenerative diseases. In the present study, we examined the properties of lens epithelial cells derived from mice in which the alphaB-crystallin gene had been knocked out. Primary rodent cells immortalize spontaneously in tissue culture with a frequency of 10(-5) to 10(-6). Primary lens epithelial cells derived from alphaB-crystallin-/- mice produced hyperproliferative clones at a frequency of 7.6 x 10(-2), four orders of magnitude greater than predicted by spontaneous immortalization (1). Hyperproliferative alphaB-crystallin-/- cells were shown to be truly immortal since they have been passaged for more than 100 population doublings without any diminution in growth potential. In striking contrast to the wild-type cells, which were diploid, the alphaB-crystallin-/- cultures had a high proportion of tetraploid and higher ploidy cells, indicating that the loss of alphaB-crystallin is associated with an increase in genomic instability. Further evidence of genomic instability of alphaB-crystallin-/- cells was observed when primary cultures were infected with Ad12-SV40 hybrid virus. In striking contrast to wild-type cells, alphaB-crystallin-/- cells expressing SV40 T antigen exhibited a widespread cytocidal response 2 to 3 days after attaining confluence, indicating that SV40 T antigen enhanced the intrinsic genomic instability of alphaB-crystallin-/- lens epithelial cells. These observations suggest that the widely distributed molecular chaperone alphaB-crystallin may play an important nuclear role in maintaining genomic integrity.

Neurogenic transdifferentiation of human adipose-derived stem cells? A critical protocol reevaluation with special emphasis on cell proliferation and cell cycle alterations.

PubMed

Kompisch, Kai Michael; Lange, Claudia; Steinemann, Doris; Skawran, Britta; Schlegelberger, Brigitte; Müller, Reinhard; Schumacher, Udo

2010-11-01

Adipose-derived stem cells (ASCs) are reported to display multilineage differentiation potential, including neuroectodermal pathways. The aim of the present study was to critically re-evaluate the potential neurogenic (trans-)differentiation capacity of ASCs using a neurogenic induction protocol based on the combination of isobutylmethylxanthine (IBMX), indomethacin and insulin. ASCs isolated from lipo-aspirate samples of five healthy female donors were characterized and potential neurogenic (trans-)differentiation was assessed by means of immunohistochemistry and gene expression analyses. Cell proliferation and cell cycle alterations were studied, and the expression of CREB/ATF transcription factors was analyzed. ASCs expressed CD59, CD90 and CD105, and were tested negative for CD34 and CD45. Under neurogenic induction, ASCs adopted a characteristic morphology comparable to neur(on)al progenitors and expressed musashi1, β-III-tubulin and nestin. Gene expression analyses revealed an increased expression of β-III-tubulin, GFAP, vimentin and BDNF, as well as SOX4 in induced ASCs. Cell proliferation was significantly reduced under neurogenic induction; cell cycle analyses showed a G2-cell cycle arrest accompanied by differential expression of key regulators of cell cycle progression. Differential expression of CREB/ATF transcription factors could be observed on neurogenic induction, pointing to a decisive role of the cAMP-CREB/ATF system. Our findings may point to a potential neurogenic (trans-)differentiation of ASCs into early neur(on)al progenitors, but do not present definite evidence for it. Especially, the adoption of a neural progenitor cell-like morphology must not automatically be misinterpreted as a specific characteristic of a respective (trans-)differentiation process, as this may as well be caused by alterations of cell cycle progression.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hua Chiaho, E-mail: Chia-Ho.Hua@stjude.org; Merchant, Thomas E.; Gajjar, Amar

Purpose: To characterize therapy-induced changes in normal-appearing brainstems of childhood brain tumor patients by serial diffusion tensor imaging (DTI). Methods and Materials: We analyzed 109 DTI studies from 20 brain tumor patients, aged 4 to 23 years, with normal-appearing brainstems included in the treatment fields. Those with medulloblastomas, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors (n = 10) received postoperative craniospinal irradiation (23.4-39.6 Gy) and a cumulative dose of 55.8 Gy to the primary site, followed by four cycles of high-dose chemotherapy. Patients with high-grade gliomas (n = 10) received erlotinib during and after irradiation (54-59.4 Gy). Parametricmore » maps of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were computed and spatially registered to three-dimensional radiation dose data. Volumes of interest included corticospinal tracts, medial lemnisci, and the pons. Serving as an age-related benchmark for comparison, 37 DTI studies from 20 healthy volunteers, aged 6 to 25 years, were included in the analysis. Results: The median DTI follow-up time was 3.5 years (range, 1.6-5.0 years). The median mean dose to the pons was 56 Gy (range, 7-59 Gy). Three patterns were seen in longitudinal FA and apparent diffusion coefficient changes: (1) a stable or normal developing time trend, (2) initial deviation from normal with subsequent recovery, and (3) progressive deviation without evidence of complete recovery. The maximal decline in FA often occurred 1.5 to 3.5 years after the start of radiation therapy. A full recovery time trend could be observed within 4 years. Patients with incomplete recovery often had a larger decline in FA within the first year. Radiation dose alone did not predict long-term recovery patterns. Conclusions: Variations existed among individual patients after therapy in longitudinal evolution of brainstem white matter injury and recovery. Early response in brainstem anisotropy may serve as an indicator of the recovery time trend over 5 years after radiation therapy.« less

Skull base bony lesions: Management nuances; a retrospective analysis from a Tertiary Care Centre

PubMed Central

Singh, Amit Kumar; Srivastava, Arun Kumar; Sardhara, Jayesh; Bhaisora, Kamlesh Singh; Das, Kuntal Kanti; Mehrotra, Anant; Sahu, Rabi Narayan; Jaiswal, Awadhesh Kumar; Behari, Sanjay

2017-01-01

Background: Skull base lesions are not uncommon, but their management has been challenging for surgeons. There is large no of bony tumors at the skull base which has not been studied in detail as a group. These tumors are difficult not only because of their location but also due to their variability in the involvement of important local structure. Through this retrospective analysis from a Tertiary Care Centre, we are summarizing the details of skull base bony lesions and its management nuances. Materials and Methods: The histopathologically, radiologically, and surgically proven cases of skull base bony tumors or lesions involving bone were analyzed from the neurosurgery, neuropathology record of our Tertiary Care Institute from January 2009 to January 2014. All available preoperative and postoperative details were noted from their case files. The extent of excision was ascertained from operation records and postoperative magnetic resonance imaging if available. Results: We have surgically managed 41 cases of skull base bony tumors. It includes 11 patients of anterior skull base, 13 middle skull base, and 17 posterior skull base bony tumors. The most common bony tumor was chordoma 15 (36.6%), followed by fibrous dysplasia 5 (12.2%), chondrosarcoma (12.2%), and ewings sarcoma-peripheral primitive neuroectodermal tumor (EWS-pPNET) five cases (12.2%) each. There were more malignant lesions (n = 29, 70.7%) at skull base than benign (n = 12, 29.3%) lesions. The surgical approach employed depended on location of tumor and pathology. Total mortality was 8 (20%) of whom 5 patients were of histological proven EWS-pPNET. Conclusions: Bony skull base lesion consists of wide variety of lesions, and requires multispecialty management. The complex lesions required tailored approaches surgery of these lesions. With the advent of microsurgical and endoscopic techniques, and use of navigation better outcomes are being seen, but these lesions require further study for development of proper management plan. PMID:28761532

Long-term neurologic health and psychosocial function of adult survivors of childhood medulloblastoma/PNET: a report from the Childhood Cancer Survivor Study.

PubMed

King, Allison A; Seidel, Kristy; Di, Chongzhi; Leisenring, Wendy M; Perkins, Stephanie Mabry; Krull, Kevin R; Sklar, Charles A; Green, Daniel M; Armstrong, Gregory T; Zeltzer, Lonnie K; Wells, Elizabeth; Stovall, Marilyn; Ullrich, Nicole J; Oeffinger, Kevin C; Robison, Leslie L; Packer, Roger J

2017-05-01

Medulloblastoma is the most common malignant childhood brain tumor, although long-term risks for chronic neurologic health and psychosocial functioning in aging adult survivors are incompletely characterized. The Childhood Cancer Survivor Study (CCSS) includes 380 five-year survivors of medulloblastoma/primitive neuroectodermal tumor (PNET; median age at follow-up: 30 y, interquartile range 24-36) and sibling comparison (n = 4031). Cumulative incidence of neurologic health conditions was reported. Cox regression models provided hazard ratios (HRs) and 95% CIs. Cross-sectional outcomes were assessed using generalized linear models. Compared with siblings, survivors were at increased risk of late-onset hearing loss (HR: 36.0, 95% CI: 23.6-54.9), stroke (HR: 33.9, 95% CI: 17.8-64.7), seizure (HR: 12.8, 95% CI: 9.0-18.1), poor balance (HR: 10.4, 95% CI: 6.7-15.9), tinnitus (HR: 4.8, 95% CI: 3.5-6.8), and cataracts (HR: 31.8, 95% CI: 16.7-60.5). Temporal/frontal lobe radiotherapy of 50 Gy or more increased risk for hearing loss (HR: 1.9, 95% CI: 1.1-1.3), seizure (HR: 2.1, 95% CI: 1.1-3.9), stroke (HR: 3.5, 95% CI: 1.3-9.1), and tinnitus (HR: 2.0, 95% CI: 1.0-3.9). Survivors were less likely than siblings to earn a college degree (relative risk [RR]: 0.49, 95% CI: 0.39-0.60), marry (RR: 0.35, 95% CI: 0.29-0.42), and live independently (RR: 0.58, 95% CI: 0.52-0.66). Adult survivors of childhood medulloblastoma/PNET demonstrate pronounced risk for hearing impairment, stroke, lower educational attainment, and social independence. Interventions to support survivors should be a high priority. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Vertebral Body Growth After Craniospinal Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hartley, Katherine A.; Li Chenghong; Laningham, Fred H.

2008-04-01

Purpose: To estimate the effects of radiotherapy and clinical factors on vertebral growth in patients with medulloblastoma and supratentorial primitive neuroectodermal tumors treated with craniospinal irradiation (CSI) and chemotherapy. Methods and Materials: The height of eight individual or grouped vertebral bodies (C3, C3-C4, T4, T4-T5, C6-T3, T4-T7, L3, L1-L5) was measured before and after CSI (23.4 or 36-39.6 Gy) in 61 patients. Of the 61 patients, 40 were boys and 21 were girls (median age, 7 years; range, 3-13 years), treated between October 1996 and October 2003. Sagittal T{sub 1}-weighted magnetic resonance images were used for the craniocaudal measurements. Themore » measurements numbered 275 (median, 5/patient; range, 3-7). The median follow-up after CSI was 44.1 months (range, 13.8-74.9 months). Results: Significant growth was observed in all measured vertebrae. Excluding C3-C4, the growth rate of the grouped vertebrae was affected by age, gender, and CSI dose (risk classification). The risk classification alone affected the growth rates of C3 (p = 0.002) and L3 (p = 0.02). Before CSI, the length of all vertebral bodies was an increasing function of age (p <0.0001). The C3 length before CSI was affected by gender and risk classification: C3 was longer for female (p = 0.07) and high-risk (p = 0.07) patients. Conclusion: All vertebrae grew significantly after CSI, with the vertebrae of the boys and younger patients growing at a rate greater than that of their counterparts. The effect of age was similar across all vertebrae, and gender had the greatest effect on the growth of the lower cervical and upper thoracic vertebrae. The effect of the risk classification was greatest in the lumbar spine by a factor of {<=}10.« less

Infant brain tumors: incidence, survival, and the role of radiation based on Surveillance, Epidemiology, and End Results (SEER) Data.

PubMed

Bishop, Andrew J; McDonald, Mark W; Chang, Andrew L; Esiashvili, Natia

2012-01-01

To evaluate the incidence of infant brain tumors and survival outcomes by disease and treatment variables. The Surveillance, Epidemiology, and End Results (SEER) Program November 2008 submission database provided age-adjusted incidence rates and individual case information for primary brain tumors diagnosed between 1973 and 2006 in infants less than 12 months of age. Between 1973 and 1986, the incidence of infant brain tumors increased from 16 to 40 cases per million (CPM), and from 1986 to 2006, the annual incidence rate averaged 35 CPM. Leading histologies by annual incidence in CPM were gliomas (13.8), medulloblastoma and primitive neuroectodermal tumors (6.6), and ependymomas (3.6). The annual incidence was higher in whites than in blacks (35.0 vs. 21.3 CPM). Infants with low-grade gliomas had the highest observed survival, and those with atypical teratoid rhabdoid tumors (ATRTs) or primary rhabdoid tumors of the brain had the lowest. Between 1979 and 1993, the annual rate of cases treated with radiation within the first 4 months from diagnosis declined from 20.5 CPM to <2 CPM. For infants with medulloblastoma, desmoplastic histology and treatment with both surgery and upfront radiation were associated with improved survival, but on multivariate regression, only combined surgery and radiation remained associated with improved survival, with a hazard ratio for death of 0.17 compared with surgery alone (p = 0.005). For ATRTs, those treated with surgery and upfront radiation had a 12-month survival of 100% compared with 24.4% for those treated with surgery alone (p = 0.016). For ependymomas survival was higher in patients treated in more recent decades (p = 0.001). The incidence of infant brain tumors has been stable since 1986. Survival outcomes varied markedly by histology. For infants with medulloblastoma and ATRTs, improved survival was observed in patients treated with both surgery and early radiation compared with those treated with surgery alone. Copyright © 2012 Elsevier Inc. All rights reserved.

The Late Devonian Gogo Formation Lägerstatte of Western Australia: Exceptional Early Vertebrate Preservation and Diversity

NASA Astrophysics Data System (ADS)

Long, John A.; Trinajstic, Kate

2010-05-01

The Gogo Formation of Western Australia preserves a unique Late Devonian (Frasnian) reef fauna. The exceptional three-dimensional preservation of macrofossils combined with unprecedented soft-tissue preservation (including muscle bundles, nerve cells, and umbilical structures) has yielded a particularly rich assemblage with almost 50 species of fishes described. The most significant discoveries have contributed to resolving placoderm phylogeny and elucidating their reproductive physiology. Specifically, these discoveries have produced data on the oldest known vertebrate embryos; the anatomy of the primitive actinopterygian neurocranium and phylogeny of the earliest actinopterygians; the histology, radiation, and plasticity of dipnoan (lungfish) dental and cranial structures; the anatomy and functional morphology of the extinct onychodonts; and the anatomy of the primitive tetrapodomorph head and pectoral fin.

Neuromuscular transmission in a primitive insect: modulation by octopamine, and catch-like tension.

PubMed

Hoyle, G

1984-01-01

The third pair of legs of the primitive New Zealand orthopteran insect, the " weta ", has and innervation and muscle cell distribution exactly similar to that of locusts, but wetas do not jump. Neuromuscular transmission to the slow excitatory axon ( SETi ) is potentiated more than 10-fold by the natural modulator octopamine (OCT). A brief burst of SETi impulses following infusion of as little as 10(-8) M OCT is followed by a very long-lasting plateau of catch-like tension (CT). The plateau is abruptly relaxed by a single inhibitory impulse, or even by a single SETi impulse if this arrives no sooner than about 30 sec following excitation. CT is used by wetas in a defense posture. Locusts and grasshoppers have a different type of modulation by OCT.

Hair Cell Heterogeneity in the Goldfish Saccule

NASA Technical Reports Server (NTRS)

Saidel, William M.; Lanford, Pamela J.; Yan, Hong Y.; Popper, Arthur N.

1995-01-01

A set of cytological studies performed in the utricle and saccule of Astronotus ocellatus (Teleostei, Percomorphi, Cichlidae) identified two basic types of hair cells and others with some intermediate characteristics. This paper reports on applying the same techniques to the saccule of Carassius auratus (Teleostei, Otophysi, Cyprinidae) and demonstrates similar types of hair cells to those found in Astronotus. Since Carassius and Astronous are species of extreme taxonomic distance within the Euteteostei, two classes of mechanoreceptive hair cells are likely to represent the primitive condition for sensory receptors in the euteleost inner ear and perhaps in all bony fish ears.

Crystallization and preliminary crystallographic analysis of the cellulose biosynthesis-related protein CMCax from Acetobacter xylinum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kawano, Shin; Yasutake, Yoshiaki; Tajima, Kenji

2005-02-01

The cellulose biosynthesis-related protein CMCax from A. xylinum has been purified and crystallized. The crystals of CMCax belong to the primitive hexagonal space group P6{sub 1} or P6{sub 5}, with unit-cell parameters a = b = 89.1, c = 94.2 Å.

Proton Transports in Pure Liquid Water Characterized by Melted Ice Lattice Model

NASA Astrophysics Data System (ADS)

Jie, Binbin; Sah, Chihtang

Basic water properties have not been understood for 200 years. Our Melted Ice Lattice model accounts for the 2 basic properties of pure water, the ion product (pH) and mobilities. It has HCP primitive unit cells, each with 4H2O, based on the 1933 Bernal-Fowler model, verified by 1935 Pauling residual entropy theory of 1928-1935 Giauque experimental low temperature specific heat measurements. Our 2 ion species are point-mass protons p + and p-, for mass and electricity transport. Three protonic thermal activation energies are obtained from pH and p + and p- mobilities vs T (0-100OC). Proton transport is analyzed in 3 proton-phonon collision steps: proton detrapping by protonic phonon absorption, proton scattering by oxygenic (water) phonons, and proton trapping with protonic phonon emission. Distinction between Potential and Kinetic Energy Bands of protons (Fermions) and phonons (Bosons) is noted. Experimental protonic activation energies are the phonon energies given by the spring-mass vibration frequencies of lattice, wn = (kn/mn)1/2 . n is the proton-mass unit of the synchronized vibrating particles in the primitive unit cells.

Human Pluripotent Stem Cell Based Developmental Toxicity Assays for Chemical Safety Screening and Systems Biology Data Generation.

PubMed

Shinde, Vaibhav; Klima, Stefanie; Sureshkumar, Perumal Srinivasan; Meganathan, Kesavan; Jagtap, Smita; Rempel, Eugen; Rahnenführer, Jörg; Hengstler, Jan Georg; Waldmann, Tanja; Hescheler, Jürgen; Leist, Marcel; Sachinidis, Agapios

2015-06-17

Efficient protocols to differentiate human pluripotent stem cells to various tissues in combination with -omics technologies opened up new horizons for in vitro toxicity testing of potential drugs. To provide a solid scientific basis for such assays, it will be important to gain quantitative information on the time course of development and on the underlying regulatory mechanisms by systems biology approaches. Two assays have therefore been tuned here for these requirements. In the UKK test system, human embryonic stem cells (hESC) (or other pluripotent cells) are left to spontaneously differentiate for 14 days in embryoid bodies, to allow generation of cells of all three germ layers. This system recapitulates key steps of early human embryonic development, and it can predict human-specific early embryonic toxicity/teratogenicity, if cells are exposed to chemicals during differentiation. The UKN1 test system is based on hESC differentiating to a population of neuroectodermal progenitor (NEP) cells for 6 days. This system recapitulates early neural development and predicts early developmental neurotoxicity and epigenetic changes triggered by chemicals. Both systems, in combination with transcriptome microarray studies, are suitable for identifying toxicity biomarkers. Moreover, they may be used in combination to generate input data for systems biology analysis. These test systems have advantages over the traditional toxicological studies requiring large amounts of animals. The test systems may contribute to a reduction of the costs for drug development and chemical safety evaluation. Their combination sheds light especially on compounds that may influence neurodevelopment specifically.

Neurenteric Cyst or Neuroendodermal Cyst? Immunohistochemical Study and Pathogenesis.

PubMed

Chen, Chun-Ting; Lai, Hung-Yi; Jung, Shih-Ming; Lee, Ching-Yi; Wu, Chieh-Tsai; Lee, Shih-Tseng

2016-12-01

Neurenteric cysts are rare central nervous system lesions derived from an endodermal origin. There is no consensus concerning pathogenesis because of the paucity of occurrences. We report an immunohistochemical study of 10 cases with neurenteric cysts and postulate its pathogenesis. Ten patients underwent surgical treatment for neurenteric cysts from 1995 to 2015. We retrospectively reviewed clinical, radiologic, operative, and pathologic findings for these patients. Immunohistochemical stains were completed in all cases to distinguish cell type and origin. Three cell types were identified: pseudostratified-ciliated, goblet-columnar, and simple cuboidal cells. All cases were positive for cytokeratin 7, and negative for cytokeratin 20, caudal-type homeobox 2, mucin 2, thyroid transcription factor 1, human chorionic gonadotropin, placental alkaline phosphatase, and cluster of differentiation 31. Four of them had positive staining for mucin 5AC, with expression only in goblet-columnar cells. According to the immunohistochemical results, the cells resembled the respiratory tract (pseudostratified-ciliated), stomach (goblet-columnar), and respiratory bronchioles (simple cuboidal). Seventy-five percent of cases with recurrence had a goblet-columnar component, emphasizing the importance of total resection of the cyst and complete pathologic examination. We postulate that the cystic tumor was derived from multipotent endodermal cells that migrated and traveled along the neuroectoderm, with incomplete differentiation into various cell types as a result of an unsuitable microenvironment. Because the neurenteric canal was only the channel of migration rather than a component of the cysts, the term neuroendodermal cysts is more precise in presenting the embryopathogenesis. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Potentiation of cytotoxic chemotherapy by growth hormone-releasing hormone agonists.

PubMed

Jaszberenyi, Miklos; Rick, Ferenc G; Popovics, Petra; Block, Norman L; Zarandi, Marta; Cai, Ren-Zhi; Vidaurre, Irving; Szalontay, Luca; Jayakumar, Arumugam R; Schally, Andrew V

2014-01-14

The dismal prognosis of malignant brain tumors drives the development of new treatment modalities. In view of the multiple activities of growth hormone-releasing hormone (GHRH), we hypothesized that pretreatment with a GHRH agonist, JI-34, might increase the susceptibility of U-87 MG glioblastoma multiforme (GBM) cells to subsequent treatment with the cytotoxic drug, doxorubicin (DOX). This concept was corroborated by our findings, in vivo, showing that the combination of the GHRH agonist, JI-34, and DOX inhibited the growth of GBM tumors, transplanted into nude mice, more than DOX alone. In vitro, the pretreatment of GBM cells with JI-34 potentiated inhibitory effects of DOX on cell proliferation, diminished cell size and viability, and promoted apoptotic processes, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, ApoLive-Glo multiplex assay, and cell volumetric assay. Proteomic studies further revealed that the pretreatment with GHRH agonist evoked differentiation decreasing the expression of the neuroectodermal stem cell antigen, nestin, and up-regulating the glial maturation marker, GFAP. The GHRH agonist also reduced the release of humoral regulators of glial growth, such as FGF basic and TGFβ. Proteomic and gene-expression (RT-PCR) studies confirmed the strong proapoptotic activity (increase in p53, decrease in v-myc and Bcl-2) and anti-invasive potential (decrease in integrin α3) of the combination of GHRH agonist and DOX. These findings indicate that the GHRH agonists can potentiate the anticancer activity of the traditional chemotherapeutic drug, DOX, by multiple mechanisms including the induction of differentiation of cancer cells.

Zeb2 Regulates Cell Fate at the Exit from Epiblast State in Mouse Embryonic Stem Cells.

PubMed

Stryjewska, Agata; Dries, Ruben; Pieters, Tim; Verstappen, Griet; Conidi, Andrea; Coddens, Kathleen; Francis, Annick; Umans, Lieve; van IJcken, Wilfred F J; Berx, Geert; van Grunsven, Leo A; Grosveld, Frank G; Goossens, Steven; Haigh, Jody J; Huylebroeck, Danny

2017-03-01

In human embryonic stem cells (ESCs) the transcription factor Zeb2 regulates neuroectoderm versus mesendoderm formation, but it is unclear how Zeb2 affects the global transcriptional regulatory network in these cell-fate decisions. We generated Zeb2 knockout (KO) mouse ESCs, subjected them as embryoid bodies (EBs) to neural and general differentiation and carried out temporal RNA-sequencing (RNA-seq) and reduced representation bisulfite sequencing (RRBS) analysis in neural differentiation. This shows that Zeb2 acts preferentially as a transcriptional repressor associated with developmental progression and that Zeb2 KO ESCs can exit from their naïve state. However, most cells in these EBs stall in an early epiblast-like state and are impaired in both neural and mesendodermal differentiation. Genes involved in pluripotency, epithelial-to-mesenchymal transition (EMT), and DNA-(de)methylation, including Tet1, are deregulated in the absence of Zeb2. The observed elevated Tet1 levels in the mutant cells and the knowledge of previously mapped Tet1-binding sites correlate with loss-of-methylation in neural-stimulating conditions, however, after the cells initially acquired the correct DNA-methyl marks. Interestingly, cells from such Zeb2 KO EBs maintain the ability to re-adapt to 2i + LIF conditions even after prolonged differentiation, while knockdown of Tet1 partially rescues their impaired differentiation. Hence, in addition to its role in EMT, Zeb2 is critical in ESCs for exit from the epiblast state, and links the pluripotency network and DNA-methylation with irreversible commitment to differentiation. Stem Cells 2017;35:611-625. © 2016 The Authors Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Absence of suppressor of cytokine signalling 3 reduces self-renewal and promotes differentiation in murine embryonic stem cells.

PubMed

Forrai, Ariel; Boyle, Kristy; Hart, Adam H; Hartley, Lynne; Rakar, Steven; Willson, Tracy A; Simpson, Ken M; Roberts, Andrew W; Alexander, Warren S; Voss, Anne K; Robb, Lorraine

2006-03-01

Leukemia inhibitory factor (LIF) is required to maintain pluripotency and permit self-renewal of murine embryonic stem (ES) cells. LIF binds to a receptor complex of LIFR-beta and gp130 and signals via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, with signalling attenuated by suppressor of cytokine signalling (SOCS) proteins. Recent in vivo studies have highlighted the role of SOCS-3 in the negative regulation of signalling via gp130. To determine the role of SOCS-3 in ES cell biology, SOCS-3-null ES cell lines were generated. When cultured in LIF levels that sustain self-renewal of wild-type cells, SOCS-3-null ES cell lines exhibited less self-renewal and greater differentiation into primitive endoderm. The absence of SOCS-3 enhanced JAK-STAT and extracellular signal-related kinase 1/2 (ERK-1/2)-mitogen-activated protein kinase (MAPK) signal transduction via gp130, with higher levels of phosphorylated STAT-1, STAT-3, SH-2 domain-containing cytoplasmic protein tyrosine phosphatase 2 (SHP-2), and ERK-1/2 in steady state and in response to LIF stimulation. Attenuation of ERK signalling by the addition of MAPK/ERK kinase (MEK) inhibitors to SOCS-3-null ES cell cultures rescued the differentiation phenotype, but did not restore proliferation to wild-type levels. In summary, SOCS-3 plays a crucial role in the regulation of the LIF signalling pathway in murine ES cells. Its absence perturbs the balance between activation of the JAK-STAT and SHP-2-ERK-1/2-MAPK pathways, resulting in less self-renewal and a greater potential for differentiation into the primitive endoderm lineage.

Evaluating structural pattern recognition for handwritten math via primitive label graphs

NASA Astrophysics Data System (ADS)

Zanibbi, Richard; Mouchère, Harold; Viard-Gaudin, Christian

2013-01-01

Currently, structural pattern recognizer evaluations compare graphs of detected structure to target structures (i.e. ground truth) using recognition rates, recall and precision for object segmentation, classification and relationships. In document recognition, these target objects (e.g. symbols) are frequently comprised of multiple primitives (e.g. connected components, or strokes for online handwritten data), but current metrics do not characterize errors at the primitive level, from which object-level structure is obtained. Primitive label graphs are directed graphs defined over primitives and primitive pairs. We define new metrics obtained by Hamming distances over label graphs, which allow classification, segmentation and parsing errors to be characterized separately, or using a single measure. Recall and precision for detected objects may also be computed directly from label graphs. We illustrate the new metrics by comparing a new primitive-level evaluation to the symbol-level evaluation performed for the CROHME 2012 handwritten math recognition competition. A Python-based set of utilities for evaluating, visualizing and translating label graphs is publicly available.

Neuronal differentiation of stem cells isolated from adult muscle.

PubMed

Romero-Ramos, Marina; Vourc'h, Patrick; Young, Henry E; Lucas, Paul A; Wu, Young; Chivatakarn, Onanong; Zaman, Rumina; Dunkelman, Noushin; el-Kalay, Mohammad A; Chesselet, Marie-Françoise

2002-09-15

Lineage uncommitted pluripotent stem cells reside in the connective tissue of skeletal muscle. The present study was carried out with pluripotent stem cells (PPSCs) isolated from 6-month old rat muscle. Before differentiation, these cells were vimentin+, CD90+, CD45-, and varied in their expression of CD34. The PPSCs were expanded as non-adherent aggregates under similar conditions to those used to generate neurospheres from embryonic or neural stem cells. The PPSC-derived neurospheres were positive for nestin, an early marker present in neuronal precursors, and expressed the two alternative mRNA forms of the neuroectodermal marker Pax-6, as well as mRNA for Oct-4, a gene related to the pluripotentiality of stem cells. To confirm their neural potential, PPSC-derived neurospheres were plated on coated coverslips under varying conditions: Neurobasal medium with N2 or B27, and either NT3 or BDNF. After 4-6 days the cells expressed neuronal (Tuj1+, NF68), astrocytic (GFAP) and oligodendrocytic (MOSP+, MBP+) markers, both by immunocytochemistry and RT-PCR. In addition, PPSCs were cultured as monolayers under adherent conditions, exposed to growth factors and defined differentiating conditions for 5 hr, and subsequently kept for 2 days in a maturation medium. At this point they gave rise to a mixed population of early neural progenitors (Nestin+ or NG2+), immature and mature neurons (Tuj1+ and NF145+) and myelin producing oligodendrocytes (CNPase + and MOSP+). Our study shows that PPSCs present in adult muscle can overcome germ lineage restrictions and express the molecular characteristics of brain cells. Therefore, PPSCs isolated from adult muscle could provide a novel source for autologous cell replacement in neurodegenerative and demyelinating diseases. Copyright 2002 Wiley-Liss, Inc.

Downregulation of Axl in non-MYCN amplified neuroblastoma cell lines reduces migration.

PubMed

Duijkers, Floor A M; Meijerink, Jules P P; Pieters, Rob; van Noesel, Max M

2013-05-25

Neuroblastomas (NBL) are common pediatric solid tumors with a variable clinical course. At diagnosis half of all neuroblastoma patients presents with metastatic disease. The mechanisms of metastasis are largely unknown. Gene expression profiles (HU133plus2.0 arrays, Affymetrix) of 17 NBL and 5 peripheral neuro-ectodermal cell lines were used to identify a subgroup of non-MYCN amplified (non-NMA) NBL cell lines with a distinct gene expression profile and characterized by high expression of AXL. Axl is a tyrosine kinase receptor which plays a role in the metastatic process of several types of cancer. We hypothesized that Axl contributes to the metastasizing potential of non-NMA NBL and tested if AXL silencing diminishes malignant properties of high Axl expressing cell lines. AXL was silenced in two non-NMA NBL cell lines by using a lentiviral shRNA construct that was able to transduce these cell lines with more than 90% infection efficiency. Axl mRNA and protein level were efficiently knocked-down resulting in a decrease of migration of Axl positive cell lines GI-M-EN and SH-EP-2, and decreased invasion of GI-M-EN. Morphologically, Axl knockdown induced more rounded cells with a loss of contact. Intracellularly, we observed induction of stress fibers (immunofluorescence F-actin). These changes in cytoskeleton were associated with decreased migration, but were not accompanied by changes in genes involved in epithelial to mesenchymal transition such as CDH2, VIM or MMP9. No effects were observed for cell proliferation, apoptosis or downstream pathways. In conclusion, AXL is identified as a possible mediator of NBL metastasis. Copyright © 2013 Elsevier B.V. All rights reserved.

Intracardiac heterotopia--mesenchymal and endodermal.

PubMed Central

Ariza, S; Rafel, E; Castillo, J A; Garcia-Canton, J A

1978-01-01

A case is reported of an intracardiac 'epithelial heterotopia' with a predominant mesenchymal component. This is thought to have resulted from the differentiation of aberrant primitive cell(s) displaced into the heart during its development. Though microscopically resembling a myxoma, this lesion is clearly distinguished by the presence of glandular structures. The myxoid component exhibited a startling invasiveness which resulted in occlusion of the superior vena cava, causing symptoms very early in life and death at the age of 6 months. Images PMID:637987

Transitional cell carcinoma of the retrorectal space arisen in tailgut cyst: a case report and review of the literature.

PubMed

Vinciguerra, Gian Luca Rampioni; Mercantini, Paolo; La Torre, Marco; Pilozzi, Emanuela; Ziparo, Vincenzo; Vecchione, Andrea

2014-05-01

Tailgut cysts, also known as retrorectal cystic hamartomas, are congenital lesions derived by an abnormal remnant of the postanal primitive hindgut, consisting of unilocular or multilocular cysts usually lined by squamous, transitional, or glandular epithelium. Malignant transformation is an uncommon event, and it mainly involves the neuroendocrine or glandular epithelium; other histotypes are sporadic. Here, we report, for the first time, the clinicopathological features of a transitional cell carcinoma that arose in a tailgut cyst.

In vitro cementoblast-like differentiation of postmigratory neural crest-derived p75{sup +} stem cells with dental follicle cell conditioned medium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wen, Xiujie; Liu, Luchuan; Deng, Manjing

Cranial neural crest-derived cells (CNCCs) play important role in epithelial–mesenchymal interactions during tooth morphogenesis. However, the heterogeneity of CNCCs and their tendency to spontaneously differentiate along smooth muscle or osteoblast lineages in vitro limit further understanding of their biological properties. We studied the differentiation properties of isolated rat embryonic postmigratory CNCCs, expressing p75 neurotrophin receptor (p75NTR). These p75NTR positive (p75{sup +}) CNCCs, isolated using fluorescence activated cell sorter, exhibited fibroblast-like morphology and characteristics of mesenchymal stem cells. Incubation of p75{sup +} CNCCs in dental follicle cell conditioned medium (DFCCM) combined with dentin non-collagenous proteins (dNCPs), altered their morphological features tomore » cementoblast-like appearance. These cells also showed low proliferative activity, high ALP activity and significantly increased calcified nodule formation. Markers related to mineralization or specific to cementoblast lineage were highly expressed in dNCPs/DFCCM-treated p75{sup +} cells, suggesting their differentiation along cementoblast-like lineage. p75{sup +} stem cells selected from postmigratory CNCCs represent a pure stem cell population and could be used as a stem cell model for in vitro studies due to their intrinsic ability to differentiate to neuronal cells and transform from neuroectoderm to ectomesenchyme. They can provide a potential stem cell resource for tooth engineering studies and help to further investigate mechanisms of epithelial–mesenchymal interactions in tooth morphogenesis. - Highlights: • Cranial neural crest-derived cells (CNCCs) take part in tooth morphogenesis. • positive (p75{sup +}) CNCCs are fibroblast-like and resemble mesenchymal stem cells. • p75{sup +} CNCCs in dental follicle cell medium (DFCCM/dNCP) appear like cementoblasts. • DFCCM/dNCP-treated p75{sup +} cells express cementoblast specific mineralization markers. • p75{sup +} cells are pure stem cells and able to differentiate to neuronal cells.« less

Interpreting the universal phylogenetic tree

NASA Technical Reports Server (NTRS)

Woese, C. R.

2000-01-01

The universal phylogenetic tree not only spans all extant life, but its root and earliest branchings represent stages in the evolutionary process before modern cell types had come into being. The evolution of the cell is an interplay between vertically derived and horizontally acquired variation. Primitive cellular entities were necessarily simpler and more modular in design than are modern cells. Consequently, horizontal gene transfer early on was pervasive, dominating the evolutionary dynamic. The root of the universal phylogenetic tree represents the first stage in cellular evolution when the evolving cell became sufficiently integrated and stable to the erosive effects of horizontal gene transfer that true organismal lineages could exist.

Manipulation of immune system via immortal bone marrow stem cells.

PubMed

Ruedl, Christiane; Khameneh, Hanif Javanmard; Karjalainen, Klaus

2008-09-01

Extensive amplification of hematopoietic stem cells (HSCs) and their multipotent primitive progenitors (MPPs) in culture would greatly benefit not only clinical transplantation but also provide a potential tool to manipulate all cellular lineages derived from these cells for gene therapy and experimental purposes. Here, we demonstrate that mouse bone marrow cultures containing cells engineered to over-express NUP98-HOXB4 fusion protein support self-renewal of physiologically normal HSC and MPP for several weeks leading practically to their unlimited expansion. This allows time consuming and cumulative in vitro experimental manipulations without sacrificing their ability to differentiate in vivo or in vitro to any hematopoietic lineage.

A GRFa2/Prop1/stem (GPS) cell niche in the pituitary.

PubMed

Garcia-Lavandeira, Montse; Quereda, Víctor; Flores, Ignacio; Saez, Carmen; Diaz-Rodriguez, Esther; Japon, Miguel A; Ryan, Aymee K; Blasco, Maria A; Dieguez, Carlos; Malumbres, Marcos; Alvarez, Clara V

2009-01-01

The adult endocrine pituitary is known to host several hormone-producing cells regulating major physiological processes during life. Some candidates to progenitor/stem cells have been proposed. However, not much is known about pituitary cell renewal throughout life and its homeostatic regulation during specific physiological changes, such as puberty or pregnancy, or in pathological conditions such as tumor development. We have identified in rodents and humans a niche of non-endocrine cells characterized by the expression of GFRa2, a Ret co-receptor for Neurturin. These cells also express b-Catenin and E-cadherin in an oriented manner suggesting a planar polarity organization for the niche. In addition, cells in the niche uniquely express the pituitary-specific transcription factor Prop1, as well as known progenitor/stem markers such as Sox2, Sox9 and Oct4. Half of these GPS (GFRa2/Prop1/Stem) cells express S-100 whereas surrounding elongated cells in contact with GPS cells express Vimentin. GFRa2+-cells form non-endocrine spheroids in culture. These spheroids can be differentiated to hormone-producing cells or neurons outlining the neuroectoderm potential of these progenitors. In vivo, GPSs cells display slow proliferation after birth, retain BrdU label and show long telomeres in its nuclei, indicating progenitor/stem cell properties in vivo. Our results suggest the presence in the adult pituitary of a specific niche of cells characterized by the expression of GFRa2, the pituitary-specific protein Prop1 and stem cell markers. These GPS cells are able to produce different hormone-producing and neuron-like cells and they may therefore contribute to postnatal pituitary homeostasis. Indeed, the relative abundance of GPS numbers is altered in Cdk4-deficient mice, a model of hypopituitarism induced by the lack of this cyclin-dependent kinase. Thus, GPS cells may display functional relevance in the physiological expansion of the pituitary gland throughout life as well as protection from pituitary disease.

A GRFa2/Prop1/Stem (GPS) Cell Niche in the Pituitary

PubMed Central

Garcia-Lavandeira, Montse; Quereda, Víctor; Flores, Ignacio; Saez, Carmen; Diaz-Rodriguez, Esther; Japon, Miguel A.; Ryan, Aymee K.; Blasco, Maria A.; Dieguez, Carlos; Malumbres, Marcos; Alvarez, Clara V.

2009-01-01

Background The adult endocrine pituitary is known to host several hormone-producing cells regulating major physiological processes during life. Some candidates to progenitor/stem cells have been proposed. However, not much is known about pituitary cell renewal throughout life and its homeostatic regulation during specific physiological changes, such as puberty or pregnancy, or in pathological conditions such as tumor development. Principal Findings We have identified in rodents and humans a niche of non-endocrine cells characterized by the expression of GFRa2, a Ret co-receptor for Neurturin. These cells also express b-Catenin and E-cadherin in an oriented manner suggesting a planar polarity organization for the niche. In addition, cells in the niche uniquely express the pituitary-specific transcription factor Prop1, as well as known progenitor/stem markers such as Sox2, Sox9 and Oct4. Half of these GPS (GFRa2/Prop1/Stem) cells express S-100 whereas surrounding elongated cells in contact with GPS cells express Vimentin. GFRa2+-cells form non-endocrine spheroids in culture. These spheroids can be differentiated to hormone-producing cells or neurons outlining the neuroectoderm potential of these progenitors. In vivo, GPSs cells display slow proliferation after birth, retain BrdU label and show long telomeres in its nuclei, indicating progenitor/stem cell properties in vivo. Significance Our results suggest the presence in the adult pituitary of a specific niche of cells characterized by the expression of GFRa2, the pituitary-specific protein Prop1 and stem cell markers. These GPS cells are able to produce different hormone-producing and neuron-like cells and they may therefore contribute to postnatal pituitary homeostasis. Indeed, the relative abundance of GPS numbers is altered in Cdk4-deficient mice, a model of hypopituitarism induced by the lack of this cyclin-dependent kinase. Thus, GPS cells may display functional relevance in the physiological expansion of the pituitary gland throughout life as well as protection from pituitary disease. PMID:19283075

Immune-related zinc finger gene ZFAT is an essential transcriptional regulator for hematopoietic differentiation in blood islands

PubMed Central

Tsunoda, Toshiyuki; Takashima, Yasuo; Tanaka, Yoko; Fujimoto, Takahiro; Doi, Keiko; Hirose, Yumiko; Koyanagi, Midori; Yoshida, Yasuhiro; Okamura, Tadashi; Kuroki, Masahide; Sasazuki, Takehiko; Shirasawa, Senji

2010-01-01

TAL1 plays pivotal roles in vascular and hematopoietic developments through the complex with LMO2 and GATA1. Hemangioblasts, which have a differentiation potential for both endothelial and hematopoietic lineages, arise in the primitive streak and migrate into the yolk sac to form blood islands, where primitive hematopoiesis occurs. ZFAT (a zinc-finger gene in autoimmune thyroid disease susceptibility region / an immune-related transcriptional regulator containing 18 C2H2-type zinc-finger domains and one AT-hook) was originally identified as an immune-related transcriptional regulator containing 18 C2H2-type zinc-finger domains and one AT-hook, and is highly conserved among species. ZFAT is thought to be a critical transcription factor involved in immune-regulation and apoptosis; however, developmental roles for ZFAT remain unknown. Here we show that Zfat-deficient (Zfat−/−) mice are embryonic-lethal, with impaired differentiation of hematopoietic progenitor cells in blood islands, where ZFAT is exactly expressed. Expression levels of Tal1, Lmo2, and Gata1 in Zfat−/− yolk sacs are much reduced compared with those of wild-type mice, and ChIP-PCR analysis revealed that ZFAT binds promoter regions for these genes in vivo. Furthermore, profound reduction in TAL1, LMO2, and GATA1 protein expressions are observed in Zfat−/− blood islands. Taken together, these results suggest that ZFAT is indispensable for mouse embryonic development and functions as a critical transcription factor for primitive hematopoiesis through direct-regulation of Tal1, Lmo2, and Gata1. Elucidation of ZFAT functions in hematopoiesis might lead to a better understanding of transcriptional networks in differentiation and cellular programs of hematopoietic lineage and provide useful information for applied medicine in stem cell therapy. PMID:20660741

Use of Optical Storage Devices as Shared Resources in Local Area Networks

DTIC Science & Technology

1989-09-01

13 3. SERVICE CALLS FOR MS-DOS CD-ROM EXTENSIONS . 14 4. MS-DOS PRIMITIVE GROUPS ....................... 15 5. RAM USAGE FOR VARIOUS LAN...17 2. Service Call Translation to DOS Primitives ............. 19 3. MS-DOS Device Drivers ............................. 21 4. MS-DOS/ROM...directed to I/O devices will be referred to as primitive instruction groups). These primitive instruction groups include keyboard, video, disk, serial

Zeb2 Regulates Cell Fate at the Exit from Epiblast State in Mouse Embryonic Stem Cells

PubMed Central

Stryjewska, Agata; Dries, Ruben; Pieters, Tim; Verstappen, Griet; Conidi, Andrea; Coddens, Kathleen; Francis, Annick; Umans, Lieve; van IJcken, Wilfred F. J.; Berx, Geert; van Grunsven, Leo A.; Grosveld, Frank G.; Goossens, Steven; Haigh, Jody J.

2016-01-01

Abstract In human embryonic stem cells (ESCs) the transcription factor Zeb2 regulates neuroectoderm versus mesendoderm formation, but it is unclear how Zeb2 affects the global transcriptional regulatory network in these cell‐fate decisions. We generated Zeb2 knockout (KO) mouse ESCs, subjected them as embryoid bodies (EBs) to neural and general differentiation and carried out temporal RNA‐sequencing (RNA‐seq) and reduced representation bisulfite sequencing (RRBS) analysis in neural differentiation. This shows that Zeb2 acts preferentially as a transcriptional repressor associated with developmental progression and that Zeb2 KO ESCs can exit from their naïve state. However, most cells in these EBs stall in an early epiblast‐like state and are impaired in both neural and mesendodermal differentiation. Genes involved in pluripotency, epithelial‐to‐mesenchymal transition (EMT), and DNA‐(de)methylation, including Tet1, are deregulated in the absence of Zeb2. The observed elevated Tet1 levels in the mutant cells and the knowledge of previously mapped Tet1‐binding sites correlate with loss‐of‐methylation in neural‐stimulating conditions, however, after the cells initially acquired the correct DNA‐methyl marks. Interestingly, cells from such Zeb2 KO EBs maintain the ability to re‐adapt to 2i + LIF conditions even after prolonged differentiation, while knockdown of Tet1 partially rescues their impaired differentiation. Hence, in addition to its role in EMT, Zeb2 is critical in ESCs for exit from the epiblast state, and links the pluripotency network and DNA‐methylation with irreversible commitment to differentiation. Stem Cells 2017;35:611–625 PMID:27739137

QCAPUF: QCA-based physically unclonable function as a hardware security primitive

NASA Astrophysics Data System (ADS)

Abutaleb, M. M.

2018-04-01

Physically unclonable functions (PUFs) are increasingly used as innovative security primitives to provide the hardware authentication and identification as well as the secret key generation based on unique and random variations in identically fabricated devices. Security and low power have appeared to become two crucial necessities to modern designs. As an emerging nanoelectronic technology, a quantum-dot cellular automata (QCA) can achieve ultra-low power consumption as well as an extremely small area for implementing digital designs. However, there are various classes of permanent defects that can happen during the manufacture of QCA devices. The recent extensive research has been focused on how to eliminate errors in QCA structures resulting from fabrication variances. By a completely different vision, to turn this disadvantage into an advantage, this paper presents a novel QCA-based PUF (QCAPUF) architecture to exploit the unique physical characteristics of fabricated QCA cells in order to produce different hardware fingerprint instances. This architecture is composed of proposed logic and interconnect blocks that have critical vulnerabilities and perform unexpected logical operations. The behaviour of QCAPUF is thoroughly analysed through physical relations and simulations. Results confirm that the proposed QCAPUF has state of the art PUF characteristics in the QCA technology. This paper will serve as a basis for further research into QCA-based hardware security primitives and applications.

Method for concurrent execution of primitive operations by dynamically assigning operations based upon computational marked graph and availability of data

NASA Technical Reports Server (NTRS)

Mielke, Roland V. (Inventor); Stoughton, John W. (Inventor)

1990-01-01

Computationally complex primitive operations of an algorithm are executed concurrently in a plurality of functional units under the control of an assignment manager. The algorithm is preferably defined as a computationally marked graph contianing data status edges (paths) corresponding to each of the data flow edges. The assignment manager assigns primitive operations to the functional units and monitors completion of the primitive operations to determine data availability using the computational marked graph of the algorithm. All data accessing of the primitive operations is performed by the functional units independently of the assignment manager.

How to Spot a Primitive Black Hole

NASA Image and Video Library

2010-03-17

These two data plots from NASA Spitzer Space Telescope show a primitive supermassive black hole top compared to a typical one; usually, dust tori are missing and only gas disks are observed in primitive black holes.

Functional characterization of individual human hematopoietic stem cells cultured at limiting dilution on supportive marrow stromal layers.

PubMed Central

Sutherland, H J; Lansdorp, P M; Henkelman, D H; Eaves, A C; Eaves, C J

1990-01-01

A major goal of current hematopoiesis research is to develop in vitro methods suitable for the measurement and characterization of stem cells with long-term in vivo repopulating potential. Previous studies from several centers have suggested the presence in normal human or murine marrow of a population of very primitive cells that are biologically, physically, and pharmacologically different from cells detectable by short-term colony assays and that can give rise to the latter in long-term cultures (LTCs) containing a competent stromal cell layer. In this report, we show that such cultures can be used to provide a quantitative assay for human "LTC-initiating cells" based on an assessment of the number of clonogenic cells present after 5-8 weeks. Production of derivative clonogenic cells is shown to be absolutely dependent on the presence of a stromal cell feeder. When this requirement is met, the clonogenic cell output (determined by assessment of 5-week-old cultures) is linearly related to the input cell number over a wide range of cell concentrations. Using limiting dilution analysis techniques, we have established the frequency of LTC-initiating cells in normal human marrow to be approximately 1 per 2 X 10(4) cells and in a highly purified CD34-positive subpopulation to be approximately 1 per 50-100 cells. The proliferative capacity exhibited by individual LTC-initiating cells cultured under apparently identical culture conditions was found to be highly variable. Values for the number of clonogenic cells per LTC-initiating cell in 5-week-old cultures ranged from 1 to 30 (the average being 4) with similar levels being detected in positive 8-week-old cultures. Some LTC-initiating cells are multipotent as evidenced by their generation of erythroid as well as granulopoietic progeny. The availability of a system for quantitative analysis of the proliferative and differentiative behavior of this newly defined compartment of primitive human hematopoietic cells should facilitate future studies of specific genetic or microenvironmental parameters involved in the regulation of these cells. Images PMID:2333304

Versatility of `hemorheologic fitness' according to exercise intensity: emphasis on the "healthy primitive lifestyle"

NASA Astrophysics Data System (ADS)

Brun, Jean-Frédéric; Varlet-Marie, Emmanuelle; Chevance, Guillaume; Pollatz, Marion; Fedou, Christine; de Mauverger, Eric Raynaud

2014-05-01

We recently proposed a unifying hypothesis to reconcile unexpected findings in exercise hemorheology and the classical concepts of "hemorheologic fitness" and the "triphasic effects of exercise", based on the "healthy primitive lifestyle" paradigm. This paradigm assumes that evolution has selected genetic polymorphisms leading to insulin resistance as an adaptative strategy to cope with continuous low intensity physical activity and a special alimentation moderately high in protein, rich in low glycemic index carbohydrates, and poor in saturated fat. According to this protocol the true physiological picture would be that of an individual whose exercise and nutritional habits are close from this lifestyle, both sedentary subjects and trained athletes representing situations on the edge of this model. Unfortunately samples of people truly adhering to this ancestral lifestyle are hard to obtain. In order to address this picture we tried to compare databases obtained with our preceding published studies. As a model of the "healthy primitive lifestyle" we selected patients trained at low intensity (LI) and given an advice of protein intake around 1.2 g/kg/day. Results show a continuum for plasma viscosity which seems to be lower in athletes than LI-trained and even more sedentaries. When sedentary subjects become obese the most obvious characteristic is an increase in red blood cell (RBC) aggregation correlated to the size of fat stores. It is clear that 3 months of LI are not a perfect model of "healthy primitive lifestyle", but these data suggest that the most important effect of LI regular exercise is to decrease plasma viscosity and that sedentarity increases RBC aggregation mostly when it results in increased fat storage.

A key heterogeneous structure of fractal networks based on inverse renormalization scheme

NASA Astrophysics Data System (ADS)

Bai, Yanan; Huang, Ning; Sun, Lina

2018-06-01

Self-similarity property of complex networks was found by the application of renormalization group theory. Based on this theory, network topologies can be classified into universality classes in the space of configurations. In return, through inverse renormalization scheme, a given primitive structure can grow into a pure fractal network, then adding different types of shortcuts, it exhibits different characteristics of complex networks. However, the effect of primitive structure on networks structural property has received less attention. In this paper, we introduce a degree variance index to measure the dispersion of nodes degree in the primitive structure, and investigate the effect of the primitive structure on network structural property quantified by network efficiency. Numerical simulations and theoretical analysis show a primitive structure is a key heterogeneous structure of generated networks based on inverse renormalization scheme, whether or not adding shortcuts, and the network efficiency is positively correlated with degree variance of the primitive structure.

Developmental characteristics of somatic cell hybrids between totipotent mouse teratocarcinoma and rat intestinal villus cells.

PubMed

van der Kamp, A W; Roza-de Jongh, E J; Houwen, R H; Magrane, G G; van Dongen, J M; Evans, M J

1984-09-01

Hybrids between mouse PCC4-azal teratocarcinoma cells and rat epithelial intestinal villus cells (PCI hybrids) are phenotypically teratocarcinoma cells. They express several teratocarcinoma-specific traits but do not express functions specific for differentiated cells. Tumour formation is partially or completely suppressed. Some of the hybrids show more extensive differentiation both in vitro and in vivo than the PCC4-azal parental line. The hybrids are capable of endoderm formation in monolayer cultures and of the formation of embryoid bodies in suspension cultures. Two of the tumour-forming hybrids generate derivatives of all three germ layers, whereas differentiation in the PCC4-azal tumours is restricted to the formation of primitive neuronal tissues.

A mutli-technique search for the most primitive CO chondrites

NASA Astrophysics Data System (ADS)

Alexander, C. M. O'D.; Greenwood, R. C.; Bowden, R.; Gibson, J. M.; Howard, K. T.; Franchi, I. A.

2018-01-01

As part of a study to identify the most primitive COs and to look for weakly altered CMs amongst the COs, we have conducted a multi-technique study of 16 Antarctic meteorites that had been classified as primitive COs. For this study, we have determined: (1) the bulk H, C and N abundances and isotopes, (2) bulk O isotopic compositions, (3) bulk modal mineralogies, and (4) for some selected samples the abundances and compositions of their insoluble organic matter (IOM). Two of the 16 meteorites do appear to be CMs - BUC 10943 seems to be a fairly typical CM, while MIL 090073 has probably been heated. Of the COs, DOM 08006 appears to be the most primitive CO identified to date and is quite distinct from the other members of its pairing group. The other COs fall into two groups that are less primitive than DOM 08006 and ALH 77307, the previously most primitive CO. The first group is composed of members of the DOM 08004 pairing group, except DOM 08006. The second group is composed of meteorites belonging to the MIL 03377 and MIL 07099 pairing groups. These two pairing groups should probably be combined. There is a dichotomy in the bulk O isotopes between the primitive (all Antarctic finds) and the more metamorphosed COs (mostly falls). This dichotomy can only partly be explained by the terrestrial weathering experienced by the primitive Antarctic samples. It seems that the more equilibrated samples interacted to a greater extent with 16O-poor material, probably water, than the more primitive meteorites.

Human Pluripotent Stem Cells Differentiated in Fully Defined Medium Generate Hematopoietic CD34+ and CD34− Progenitors with Distinct Characteristics

PubMed Central

Chicha, Laurie; Feki, Anis; Boni, Alessandro; Irion, Olivier; Hovatta, Outi; Jaconi, Marisa

2011-01-01

Background Differentiation of pluripotent stem cells in vitro provides a powerful means to investigate early developmental fates, including hematopoiesis. In particular, the use of a fully defined medium (FDM) would avoid biases induced by unidentified factors contained in serum, and would also allow key molecular mediators involved in such a process to be identified. Our goal was to induce in vitro, the differentiation of human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) into morphologically and phenotypically mature leukocytes and erythrocytes, in the complete absence of serum and feeder cells. Methodology/Principal Findings ESC and iPSC were sequentially induced in liquid cultures for 4 days with bone morphogenic protein-4, and for 4 days with FLT3-ligand, stem cell factor, thrombopoietin and vascular endothelium growth factor. Cell differentiation status was investigated by both mRNA expression and FACS expression profiles. Cells were further sorted and assayed for their hematopoietic properties in colony-forming unit (CFU) assays. In liquid cultures, cells progressively down-modulated Oct-4 expression while a sizeable cell fraction expressed CD34 de novo. SCL/Tal1 and Runx1 transcripts were exclusively detected in CD34+ cells. In clonal assays, both ESC and iPSC-derived cells generated CFU, albeit with a 150-fold lower efficacy than cord blood (CB) CD34+ cells. ESC-derived CD34+ cells generated myeloid and fully hemoglobinized erythroid cells whereas CD34− cells almost exclusively generated small erythroid colonies. Both ESC and iPSC-derived erythroid cells expressed embryonic and fetal globins but were unable to synthesize adult β-globin in contrast with CB cells, suggesting that they had differentiated from primitive rather than from definitive hematopoietic progenitors. Conclusions/Significance Short-term, animal protein-free culture conditions are sufficient to sustain the differentiation of human ESC and iPSC into primitive hematopoietic progenitors, which, in turn, produce more mature blood cell types. However, additional factors have yet to be identified to allow their differentiation into definitive erythroid cultures. PMID:21364915

Human pluripotent stem cells differentiated in fully defined medium generate hematopoietic CD34- and CD34+ progenitors with distinct characteristics.

PubMed

Chicha, Laurie; Feki, Anis; Boni, Alessandro; Irion, Olivier; Hovatta, Outi; Jaconi, Marisa

2011-02-25

Differentiation of pluripotent stem cells in vitro provides a powerful means to investigate early developmental fates, including hematopoiesis. In particular, the use of a fully defined medium (FDM) would avoid biases induced by unidentified factors contained in serum, and would also allow key molecular mediators involved in such a process to be identified. Our goal was to induce in vitro, the differentiation of human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) into morphologically and phenotypically mature leukocytes and erythrocytes, in the complete absence of serum and feeder cells. ESC and iPSC were sequentially induced in liquid cultures for 4 days with bone morphogenic protein-4, and for 4 days with FLT3-ligand, stem cell factor, thrombopoietin and vascular endothelium growth factor. Cell differentiation status was investigated by both mRNA expression and FACS expression profiles. Cells were further sorted and assayed for their hematopoietic properties in colony-forming unit (CFU) assays. In liquid cultures, cells progressively down-modulated Oct-4 expression while a sizeable cell fraction expressed CD34 de novo. SCL/Tal1 and Runx1 transcripts were exclusively detected in CD34(+) cells. In clonal assays, both ESC and iPSC-derived cells generated CFU, albeit with a 150-fold lower efficacy than cord blood (CB) CD34(+) cells. ESC-derived CD34(+) cells generated myeloid and fully hemoglobinized erythroid cells whereas CD34(-) cells almost exclusively generated small erythroid colonies. Both ESC and iPSC-derived erythroid cells expressed embryonic and fetal globins but were unable to synthesize adult β-globin in contrast with CB cells, suggesting that they had differentiated from primitive rather than from definitive hematopoietic progenitors. Short-term, animal protein-free culture conditions are sufficient to sustain the differentiation of human ESC and iPSC into primitive hematopoietic progenitors, which, in turn, produce more mature blood cell types. However, additional factors have yet to be identified to allow their differentiation into definitive erythroid cultures.

A monoclonal antibody inhibits calcium accumulation and skeleton formation in cultured embryonic cells of the sea urchin.

PubMed

Carson, D D; Farach, M C; Earles, D S; Decker, G L; Lennarz, W J

1985-06-01

The assembly of the spicules (primitive skeleton) of the sea urchin embryo is being studied in primary mesenchyme cells cultured in vitro. A monoclonal antibody (1223) has been prepared that inhibits the deposition of CaCO3 into the spicules. This antibody reacts with a 130,000 Mr cell-surface protein that is concentrated on the surface of approximately 5% of the cells of dissociated gastrula stage embryos. When primary mesenchyme cells in the embryo or cells cultured in vitro are examined, the 1223 antigen is detected on the surface of the cells and on the extracellular material associated with the spicule. We conclude that the 1223 antibody recognizes a cell-surface protein that plays an essential role in spicule formation.

Miscellaneous rare paratesticular tumors.

PubMed

Henley, J D; Ferry, J; Ulbright, T M

2000-11-01

A few uncommon but distinctive tumors may preferentially involve the paratestis. The 3 unusual tumors that represent the focus of this discussion are the ovarian-type epithelial tumors (OTET), the desmoplastic small round cell tumor (DSRCT), and the melanotic neuroectodermal tumor of infancy (MNTI). The OTETs are testicular homologues of their more common namesake counterparts that arise in the ovary. Most frequent of these are serous tumors of borderline malignancy, with fewer cases of serous carcinomas or other forms of mullerian differentiation. DSRCT is an increasingly recognized, aggressive, "small blue cell" neoplasm with distinctive clinical and pathologic features. These polyphenotypic tumors characteristically, but not invariably, arise in intimate association with the serosal membrane of the peritoneal cavity and harbor a signature translocation-t(11;22)(p13,q12). In the paratestis they often involve the surface of the epididymis. The MNTI is an enigmatic, histologically distinctive, low-grade neoplasm occasionally encountered in the epididymis. Recognition of its features is essential to avoid misdiagnosis as a more aggressive "small blue cell" neoplasm and consequent therapeutic mismanagement. Primary hematopoietic tumors of the paratesticular structures are rare. There appears to be a tendency for young men to have low-grade lymphomas with an indolent course and older patients to develop higher-grade tumors. Plasmacytoma and granulocytic sarcoma of the paratestis are even more rare and are often susceptible to misinterpretation. Finally, metastatic tumors and a variety of other very rare neoplasms are discussed.

Spontaneous encapsulation and concentration of biological macromolecules in liposomes: an intriguing phenomenon and its relevance in origins of life.

PubMed

de Souza, Tereza Pereira; Fahr, Alfred; Luisi, Pier Luigi; Stano, Pasquale

2014-12-01

One of the main open questions in origin of life research focuses on the formation, by self-organization, of primitive cells composed by macromolecular compounds enclosed within a semi-permeable membrane. A successful experimental strategy for studying the emergence and the properties of primitive cells relies on a synthetic biology approach, consisting in the laboratory assembly of cell models of minimal complexity (semi-synthetic minimal cells). Despite the recent advancements in the construction and characterization of synthetic cells, an important physical aspect related to their formation is still not well known, namely, the mechanism of solute entrapment inside liposomes (in particular, the entrapment of macromolecules). In the past years, we have investigated this phenomenon and here we shortly review our experimental results. We show how the detailed cryo-transmission electron microscopy analyses of liposome populations created in the presence of ferritin (taken as model protein) or ribosomes have revealed that a small fraction of liposomes contains a high number of solutes, against statistical expectations. The local (intra-liposomal) macromolecule concentration in these liposomes largely exceeds the bulk concentration. A similar behaviour is observed when multi-molecular reaction mixtures are used, whereby the reactions occur effectively only inside those liposomes that have entrapped high number of molecules. If similar mechanisms operated in early times, these intriguing results support a scenario whereby the formation of lipid compartments plays an important role in concentrating the components of proto-metabolic systems-in addition to their well-known functions of confinement and protection.

ACME: Automated Cell Morphology Extractor for Comprehensive Reconstruction of Cell Membranes

PubMed Central

Mosaliganti, Kishore R.; Noche, Ramil R.; Xiong, Fengzhu; Swinburne, Ian A.; Megason, Sean G.

2012-01-01

The quantification of cell shape, cell migration, and cell rearrangements is important for addressing classical questions in developmental biology such as patterning and tissue morphogenesis. Time-lapse microscopic imaging of transgenic embryos expressing fluorescent reporters is the method of choice for tracking morphogenetic changes and establishing cell lineages and fate maps in vivo. However, the manual steps involved in curating thousands of putative cell segmentations have been a major bottleneck in the application of these technologies especially for cell membranes. Segmentation of cell membranes while more difficult than nuclear segmentation is necessary for quantifying the relations between changes in cell morphology and morphogenesis. We present a novel and fully automated method to first reconstruct membrane signals and then segment out cells from 3D membrane images even in dense tissues. The approach has three stages: 1) detection of local membrane planes, 2) voting to fill structural gaps, and 3) region segmentation. We demonstrate the superior performance of the algorithms quantitatively on time-lapse confocal and two-photon images of zebrafish neuroectoderm and paraxial mesoderm by comparing its results with those derived from human inspection. We also compared with synthetic microscopic images generated by simulating the process of imaging with fluorescent reporters under varying conditions of noise. Both the over-segmentation and under-segmentation percentages of our method are around 5%. The volume overlap of individual cells, compared to expert manual segmentation, is consistently over 84%. By using our software (ACME) to study somite formation, we were able to segment touching cells with high accuracy and reliably quantify changes in morphogenetic parameters such as cell shape and size, and the arrangement of epithelial and mesenchymal cells. Our software has been developed and tested on Windows, Mac, and Linux platforms and is available publicly under an open source BSD license (https://github.com/krm15/ACME). PMID:23236265

Dynamic primitives in the control of locomotion.

PubMed

Hogan, Neville; Sternad, Dagmar

2013-01-01

Humans achieve locomotor dexterity that far exceeds the capability of modern robots, yet this is achieved despite slower actuators, imprecise sensors, and vastly slower communication. We propose that this spectacular performance arises from encoding motor commands in terms of dynamic primitives. We propose three primitives as a foundation for a comprehensive theoretical framework that can embrace a wide range of upper- and lower-limb behaviors. Building on previous work that suggested discrete and rhythmic movements as elementary dynamic behaviors, we define submovements and oscillations: as discrete movements cannot be combined with sufficient flexibility, we argue that suitably-defined submovements are primitives. As the term "rhythmic" may be ambiguous, we define oscillations as the corresponding class of primitives. We further propose mechanical impedances as a third class of dynamic primitives, necessary for interaction with the physical environment. Combination of these three classes of primitive requires care. One approach is through a generalized equivalent network: a virtual trajectory composed of simultaneous and/or sequential submovements and/or oscillations that interacts with mechanical impedances to produce observable forces and motions. Reliable experimental identification of these dynamic primitives presents challenges: identification of mechanical impedances is exquisitely sensitive to assumptions about their dynamic structure; identification of submovements and oscillations is sensitive to their assumed form and to details of the algorithm used to extract them. Some methods to address these challenges are presented. Some implications of this theoretical framework for locomotor rehabilitation are considered.

A simple physical mechanism enables homeostasis in primitive cells

NASA Astrophysics Data System (ADS)

Engelhart, Aaron E.; Adamala, Katarzyna P.; Szostak, Jack W.

2016-05-01

The emergence of homeostatic mechanisms that enable maintenance of an intracellular steady state during growth was critical to the advent of cellular life. Here, we show that concentration-dependent reversible binding of short oligonucleotides, of both specific and random sequence, can modulate ribozyme activity. In both cases, catalysis is inhibited at high concentrations, and dilution activates the ribozyme via inhibitor dissociation, thus maintaining near-constant ribozyme specific activity throughout protocell growth. To mimic the result of RNA synthesis within non-growing protocells, we co-encapsulated high concentrations of ribozyme and oligonucleotides within fatty acid vesicles, and ribozyme activity was inhibited. Following vesicle growth, the resulting internal dilution produced ribozyme activation. This simple physical system enables a primitive homeostatic behaviour: the maintenance of constant ribozyme activity per unit volume during protocell volume changes. We suggest that such systems, wherein short oligonucleotides reversibly inhibit functional RNAs, could have preceded sophisticated modern RNA regulatory mechanisms, such as those involving miRNAs.

How many theories for the origin of /proto/life

NASA Technical Reports Server (NTRS)

Fox, S. W.

1980-01-01

The sequence of primordial chemical events leading to contemporary metabolism is considered, taking into account primordial reactants, amino acids, proteinoid, protocells, ATP, polynucleotides, and protein. The right kind of matter, thermal copolyamino acids, can organize itself into cell-like structures, in the absence of discrete lipid, when triggered to do so by water. Another unpredicted result of examination of the microsystems formed was the step-by-step realization that the component processes of a primitive form of replication were latent in the proteinoid microsystems. At the present time, four modes of primitive replication of proteinoid microsystems have been identified, plus one that has the appearance of protosexual reproduction. Two main conceptual pathways have received attention. One is the proteinoid theory, derived from experiments. The other is the DNA-first theory, for which attempts at conceptual construction and experimental support continue to be sought.

The origin and early evolution of life on earth

NASA Technical Reports Server (NTRS)

Oro, J.; Miller, Stanley L.; Lazcano, Antonio

1990-01-01

Results of the studies that have provided insights into the cosmic and primitive earth environments are reviewed with emphasis on those environments in which life is thought to have originated. The evidence bearing on the antiquity of life on the earth and the prebiotic significance of organic compounds found in interstellar clouds and in primitive solar-system bodies such as comets, dark asteroids, and carbonaceous chondrites are assessed. The environmental models of the Hadean and early Archean earth are discussed, as well as the prebiotic formation of organic monomers and polymers essential to life. The processes that may have led to the appearance in the Archean of the first cells are considered, and possible effects of these processes on the early steps of biological evolution are analyzed. The significance of these results to the study of the distribution of life in the universe is evaluated.

Models of glycolysis: Glyceraldehyde as a source of energy and monomers for prebiotic condensation reactions

NASA Technical Reports Server (NTRS)

Weber, A. L.

1986-01-01

All organisms require energy in a chemical form for maintenance and growth. In contemporary life this chemical energy is obtained by the synthesis of the phosphoanhydride bonds of ATP. Among the biological processes that yield ATP, fermentation is generally considered primitive, because it operates under anaerobic conditions by substrate-level phosphorylation which does not require compartmentation by membranes. Fermentation by the glycolytic pathway, which is found in almost every living cell, is an especially attractive energy source for primitive life. Glycolysis not only produces useful chemical energy (ATP), but intermediates of this pathway are also involved in amino acid synthesis and photosynthetic carbon-fixation. It is believed that energy and substrates needed for the origin of life were provided by nonenzymatic chemical reactions that resemble the enzyme-mediated reactions of glycolysis. These nonenzymatic reactions would have provided a starting point for the evolutionary development of glycolysis.

Inhibiting Low-Frequency Vibrations Explains Exceptionally High Electron Mobility in 2,5-Difluoro-7,7,8,8-tetracyanoquinodimethane (F2-TCNQ) Single Crystals.

PubMed

Chernyshov, Ivan Yu; Vener, Mikhail V; Feldman, Elizaveta V; Paraschuk, Dmitry Yu; Sosorev, Andrey Yu

2017-07-06

Organic electronics requires materials with high charge mobility. Despite decades of intensive research, charge transport in high-mobility organic semiconductors has not been well understood. In this Letter, we address the physical mechanism underlying the exceptionally high band-like electron mobility in F 2 -TCNQ (2,5-difluoro-7,7,8,8-tetracyanoquinodimethane) single crystals among a crystal family of similar compounds F n -TCNQ (n = 0, 2, 4) using a combined experimental and theoretical approach. While electron transfer integrals and reorganization energies did not show outstanding features for F 2 -TCNQ, Raman spectroscopy and solid-state DFT indicated that the frequency of the lowest vibrational mode is nearly twice higher in the F 2 -TCNQ crystal than in TCNQ and F 4 -TCNQ. This phenomenon is explained by the specific packing motif of F 2 -TCNQ with only one molecule per primitive cell so that electron-phonon interaction decreases and the electron mobility increases. We anticipate that our findings will encourage investigators for the search and design of organic semiconductors with one molecule per primitive cell and/or the poor low-frequency vibrational spectrum.

Co-evolution of breast-to-brain metastasis and neural progenitor cells.

PubMed

Neman, Josh; Choy, Cecilia; Kowolik, Claudia M; Anderson, Athena; Duenas, Vincent J; Waliany, Sarah; Chen, Bihong T; Chen, Mike Y; Jandial, Rahul

2013-08-01

Brain colonization by metastatic tumor cells offers a unique opportunity to investigate microenvironmental influences on the neoplastic process. The bi-directional interplay of breast cancer cells (mesodermal origin) and brain cells (neuroectodermal origin) is poorly understood and rarely investigated. In our patients undergoing neurosurgical resection of breast-to-brain metastases, specimens from the tumor/brain interface exhibited increased active gliosis as previously described. In addition, our histological characterization revealed infiltration of neural progenitor cells (NPCs) both outside and inside the tumor margin, leading us to investigate the cellular and molecular interactions between NPCs and metastases. Since signaling by the TGF-β superfamily is involved in both developmental neurobiology and breast cancer pathogenesis, we examined the role of these proteins in the context of brain metastases. The brain-metastatic breast cancer cell line MDA-MB-231Br (231Br) expressed BMP-2 at significantly higher levels compared to its matched primary breast cancer cell line MDA-MB-231 (231). Co-culturing was used to examine bi-directional cellular effects and the relevance of BMP-2 overexpression. When co-cultured with NPCs, 231 (primary) tumor cells failed to proliferate over 15 days. However, 231Br (brain metastatic) tumor cells co-cultured with NPCs escaped growth inhibition after day 5 and proliferated, occurring in parallel with NPC differentiation into astrocytes. Using shRNA and gene knock-in, we then demonstrated BMP-2 secreted by 231Br cells mediated NPC differentiation into astrocytes and concomitant tumor cell proliferation in vitro. In xenografts, overexpression of BMP-2 in primary breast cancer cells significantly enhanced their ability to engraft and colonize the brain, thereby creating a metastatic phenotype. Conversely, BMP-2 knockdown in metastatic breast cancer cells significantly diminished engraftment and colonization. The results suggest metastatic tumor cells create a permissive neural niche by steering NPC differentiation toward astrocytes through paracrine BMP-2 signaling.