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Sample records for anaplastic spindle cell

  1. Anaplastic Large Cell Lymphoma

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    Anaplastic Large Cell Lymphoma Overview Lymphoma is the most common blood cancer. The two main forms of lymphoma are ... organs, and can accumulate to form tumors. Anaplastic large cell lymphoma (ALCL) is arare type of NHL, ...

  2. Pathobiology of Anaplastic Large Cell Lymphoma

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    Pier Paolo Piccaluga

    2010-01-01

    Full Text Available The authors revise the concept of anaplastic large cell lymphoma (ALCL in the light of the recently updated WHO classification of Tumors of Hematopoietic and Lymphoid Tissues both on biological and clinical grounds. The main histological findings are illustrated with special reference to the cytological spectrum that is indeed characteristic of the tumor. The phenotype is reported in detail: the expression of the ALK protein as well as the chromosomal abnormalities is discussed with their potential pathogenetic implications. The clinical features of ALCL are presented by underlining the difference in terms of response to therapy and survival between the ALK-positive and ALK-negative forms. Finally, the biological rationale for potential innovative targeted therapies is presented.

  3. The Spindle Cell Neoplasms of the Oral Cavity

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    Shamim, Thorakkal

    2015-01-01

    Spindle cell neoplasms are defined as neoplasms that consist of spindle-shaped cells in the histopathology. Spindle cell neoplasms can affect the oral cavity. In the oral cavity, the origin of the spindle cell neoplasms may be traced to epithelial, mesenchymal and odontogenic components. This article aims to review the spindle cell neoplasms of the oral cavity with emphasis on histopathology.

  4. Retropharyngeal spindle cell/plemorphic lipoma

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    Lee, Hyun Kyung; Hwang, Seung Bae; Chung, Gyung Ho; Hong, Ki Hwang; Jang, Kyu Yun [Chonbuk National University Medical School and Hospital, Jeonju (Korea, Republic of)

    2013-06-15

    Spindle cell/pleomorphic lipoma is an uncommon benign adipose tissue tumor most frequently arising from the subcutaneous tissue of the back, shoulder, head and neck, and extremities. The deep cervical spaces are the rarely affected locations. Herein we report on the imaging findings of spindle cell/pleomorphic lipoma involving the retropharyngeal space in an elderly woman.

  5. Research progresses in the pathogenesis of anaplastic large cell lymphoma

    Institute of Scientific and Technical Information of China (English)

    Xiao-Lan Shi; Xiao-Wen Tang; De-Pei Wu

    2011-01-01

    Anaplastic large cell lymphoma (ALCL) is a distinct subset of T-cell non-Hodgkin's lymphoma. As a consequence of its low incidence, general pathogenic consideration of ALCL is lacking. In this review, we summarize the pathogenesis, epidemiology, clinical manifestations, and treatment of ALCL, so as to better understand key stages of the development of this disease and provide valuable information for future treatment.

  6. Spindle cell lipoma of the posterior axilla: a case report

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    Lee, Jee Young; Suh, Kyung Jin; Kim, Sang Yoon [Dongguk University Hospital, Cheonan (Korea, Republic of)

    2008-07-15

    Spindle cell lipoma is characterized by different cell components, mature adipocytes, spindle cells and collagen bundles, and it presents as a well-defined benign fatty mass on the posterior neck or upper back of middle aged men. As a result of the various ratios of non-adipose tissue, it is difficult to differentiate spindle cell lipoma from liposarcoma. To the best of our knowledge, the imaging features of spindle cell lipoma have not been reported in Korea. We report here on the imaging findings of a histologically confirmed spindle cell lipoma in the subcutaneous layer of the posterior axilla.

  7. Spindle cell carcinoma of the nasal cavity

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    Mark D DeLacure

    2013-02-01

    Full Text Available Spindle cell carcinoma (SpCC is a unique variant of squamous cell carcinoma (SCC. SpCC confined to the nasal cavity is extremely rare, with only one case having been previously reported. We present a case report of nasal cavity SpCC and review the literature on this rare entity. A 29-year-old male presented with intermittent epistaxis from the left nasal cavity. On physical examination, the patient had an ulcerated mass in the left nasal vestibule and a biopsy showed a proliferation of spindle and epitheliod cells. The patient underwent wide local excision of the mass via a lateral alotomy approach and reconstruction with a composite conchal bowl skin and cartilage graft. Histologically, the mass had dyplastic squamous epithelium and spindle-shaped cells admixed with epitheliod cells. Immunohistochemistry was only positive for pancytokeratin AE1/AE3 and vimentin. Six months after surgery, the patient continues to have no evidence of disease. On literature review, only one previous case of SpCC confined to the nasal cavity was identified. We present a rare case of nasal cavity SpCC. No definite treatment protocol exists for this unique entity, but we believe that this tumor should primarily be treated with aggressive, wide local excision. Adjuvant radiation and/or chemotherapy have also been used anecdotally.

  8. Breast spindle cell tumours: about eight cases

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    Abd El All Howayda S

    2006-07-01

    Full Text Available Abstract Background Breast spindle cell tumours (BSCTs, although rare, represent a heterogeneous group with different treatment modalities. This work was undertaken to evaluate the utility of fine needle aspiration cytology (FNAC, histopathology and immunohistochemistry (IHC in differentiating BSCTs. Methods FNAC of eight breast masses diagnosed cytologically as BSCTs was followed by wide excision biopsy. IHC using a panel of antibodies against vimentin, pan-cytokeratin, s100, desmin, smooth muscle actin, CD34, and CD10 was evaluated to define their nature. Results FNAC defined the tumors as benign (n = 4, suspicious (n = 2 and malignant (n = 3, based on the cytopathological criteria of malignancy. Following wide excision biopsy, the tumors were reclassified into benign (n = 5 and malignant (n = 3. In the benign group, the diagnosis was raised histologically and confirmed by IHC for 3 cases (one spindle cell lipoma, one myofibroblastoma and one leiomyoma. For the remaining two cases, the diagnosis was set up after IHC (one fibromatosis and one spindle cell variant of adenomyoepithelioma. In the malignant group, a leiomyosarcoma was diagnosed histologically, while IHC was crucial to set up the diagnosis of one case of spindle cell carcinoma and one malignant myoepithelioma. Conclusion FNAC in BSCTs is an insufficient tool and should be followed by wide excision biopsy. The latter technique differentiate benign from malignant BSCTs and is able in 50% of the cases to set up the definite diagnosis. IHC is of value to define the nature of different benign lesions and is mandatory in the malignant ones for optimal treatment. Awareness of the different types of BSCTs prevents unnecessary extensive therapeutic regimes.

  9. A cell cycle timer for asymmetric spindle positioning.

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    Erin K McCarthy Campbell

    2009-04-01

    Full Text Available The displacement of the mitotic spindle to one side of a cell is important for many cells to divide unequally. While recent progress has begun to unveil some of the molecular mechanisms of mitotic spindle displacement, far less is known about how spindle displacement is precisely timed. A conserved mitotic progression mechanism is known to time events in dividing cells, although this has never been linked to spindle displacement. This mechanism involves the anaphase-promoting complex (APC, its activator Cdc20/Fizzy, its degradation target cyclin, and cyclin-dependent kinase (CDK. Here we show that these components comprise a previously unrecognized timer for spindle displacement. In the Caenorhabditis elegans zygote, mitotic spindle displacement begins at a precise time, soon after chromosomes congress to the metaphase plate. We found that reducing the function of the proteasome, the APC, or Cdc20/Fizzy delayed spindle displacement. Conversely, inactivating CDK in prometaphase caused the spindle to displace early. The consequence of experimentally unlinking spindle displacement from this timing mechanism was the premature displacement of incompletely assembled components of the mitotic spindle. We conclude that in this system, asymmetric positioning of the mitotic spindle is normally delayed for a short time until the APC inactivates CDK, and that this delay ensures that the spindle does not begin to move until it is fully assembled. To our knowledge, this is the first demonstration that mitotic progression times spindle displacement in the asymmetric division of an animal cell. We speculate that this link between the cell cycle and asymmetric cell division might be evolutionarily conserved, because the mitotic spindle is displaced at a similar stage of mitosis during asymmetric cell divisions in diverse systems.

  10. Anaplastic large cell lymphoma: A single institution experience from India

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    K C Lakshmaiah

    2013-01-01

    Full Text Available Background: Systemic anaplastic large cell lymphoma (ALCL accounts for 2-8% of non-Hodgkin′s lymphoma in adults and 10-15% in children. While there is ample data in the world literature about the clinical features and outcome of this disease, prognosis in Indian patients is largely unknown. Objective: To study the clinical, pathologic profile and outcome ALCL. Materials and Methods: Fifty patients who had pathologically proven diagnosis of systemic ALCL at our institute from June 2003 to May 2011 were included for retrospective analysis. This included 30 cases of anaplastic lymphoma kinase+ (ALK+, ALCL and 20 cases of anaplastic lymphoma kinase- (ALK−, ALCL. The hospital protocol for treatment of these patients included CHOP chemotherapy regimen in >15 years of age and MCP842 protocol with vinblastine for 1 year in <15 years of age. Event free survival was noted. These outcomes were correlated with ALK status, International Prognostic Index (IPI score, and stage at presentation. Results: At a median follow-up of 36 months (range: 6-72 months ALK− ALCL had a poor outcome. The 3 year event free survival in pediatric ALCL was 66.7%. In adults, this was 60% ALK+ ALCL was 60% and 20% in ALK− ALCL. Conclusions: Systemic ALCL is an aggressive disease. CD3 + positivity is commonly seen in ALK− ALCL and ALK+, epithelial membrane antigen + positivity is seen in ALK+ ALCL. ALK− ALCL, advanced stage III, IV and high IPI score were associated with poor prognosis. The demographic profile and outcome in our study was similar to the world literature. With new drugs like crizotinib and brentuximab vedotin the future looks very promising.

  11. Anaplastic lymphoma kinase negative anaplastic large cell lymphoma of hard palate as first clinical manifestation of acquired immune deficiency syndrome.

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    Narwal, Anjali; Yadav, Achla Bharti; Prakash, Sant; Gupta, Shally

    2016-01-01

    Anaplastic large cell lymphoma (ALCL) is an uncommon disease, accounting for <5% of all cases of non-Hodgkin's lymphoma. We report a case of 48-year-old male who presented a clinically benign swelling in the right anterior palatal region since last 2 months. Radiographic evaluation showed no bone loss in palatal area. Histological and radiological examination was in favor of a peripheral reactive lesion like pyogenic granuloma or a benign salivary gland tumor. Immunohistochemistry confirmed the diagnosis of anaplastic lymphoma kinase-negative (ALK(-)) ALCL. Further laboratory tests ELISA for human immunodeficiency virus (HIV) and CD4 cell count was done which showed positivity for HIV. To the best of our knowledge, it is the first case of ALK(-) ALCL in the hard palate presenting as the first clinical manifestation of acquired immune deficiency syndrome. PMID:27041916

  12. Anaplastic lymphoma kinase negative anaplastic large cell lymphoma of hard palate as first clinical manifestation of acquired immune deficiency syndrome

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    Anjali Narwal

    2016-01-01

    Full Text Available Anaplastic large cell lymphoma (ALCL is an uncommon disease, accounting for <5% of all cases of non-Hodgkin's lymphoma. We report a case of 48-year-old male who presented a clinically benign swelling in the right anterior palatal region since last 2 months. Radiographic evaluation showed no bone loss in palatal area. Histological and radiological examination was in favor of a peripheral reactive lesion like pyogenic granuloma or a benign salivary gland tumor. Immunohistochemistry confirmed the diagnosis of anaplastic lymphoma kinase-negative (ALK(− ALCL. Further laboratory tests ELISA for human immunodeficiency virus (HIV and CD4 cell count was done which showed positivity for HIV. To the best of our knowledge, it is the first case of ALK(− ALCL in the hard palate presenting as the first clinical manifestation of acquired immune deficiency syndrome.

  13. MicroRNA Expression Profiling Identifies Molecular Diagnostic Signatures for Anaplastic Large Cell Lymphoma

    DEFF Research Database (Denmark)

    Liu, Cuiling; Iqbal, Javeed; Teruya-Feldstein, Julie;

    2013-01-01

    Anaplastic large-cell lymphomas (ALCLs) encompass at least 2 systemic diseases distinguished by the presence or absence of anaplastic lymphoma kinase (ALK) expression. We performed genome-wide microRNA (miRNA) profiling on 33 ALK-positive (ALK[+]) ALCLs, 25 ALK-negative (ALK[-]) ALCLs, 9 angioimm...

  14. ALK signaling and target therapy in anaplastic large cell lymphoma

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    Fabrizio eTabbo

    2012-05-01

    Full Text Available The discovery by Morris SW et al. in 1994 of the genes contributing to the t(2;5(p23;q35 translocation has put the foundation for a molecular based recognition of Anaplastic Large Cell Lymphoma (ALCL and pointed out the need for a further stratification of T-cell neoplasia. Likewise the detection of ALK genetic lesions among many human cancers has defined unique subsets of cancer patients, providing new opportunities for innovative therapeutic interventions. The objective of this review is to appraise the molecular mechanisms driving ALK-mediated transformation, and to maintain the neoplastic phenotype. The understanding of these events will allow the design and implementation of novel tailored strategies for a well-defined subset of cancer patients.

  15. Primary cutaneous anaplastic large-cell lymphoma: a case report.

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    Cao, Can; Zeng, Kang; Wang, Menglei; Han, Kai; Peng, Yusheng; Xiong, Hao; Wang, Qi; Li, Qian; Wang, Qian; Li, Li

    2016-07-01

    Primary cutaneous anaplastic large-cell lymphoma (PCALCL) is a part of the spectrum of CD30+ lymphoproliferative cutaneous processes. The characteristics include single or multifocal nodules that ulcerate as skin lesion, slow disease progression, autoregressive, and recurrent in few years. The present study report the case of a 16-year-old boy presenting PCALCL with single nodules, ulcer, keloid, and scab in his right-side face. He showed a good response to the treatment with systemic chemotherapy and dermatoplasty, and regained confidence after the appearance of recovery. There is no relapse of the primary lesion and organs involved till now. The chemotherapy combining with surgical excision and dermatoplasty is a good method for PCALCL, per the lesion biopsy and positron emission tomography-computed tomography before and after treatment. PMID:26970422

  16. Undifferentiated (Spindle Cell Pancreatic Carcinoma: A Case Report with Osteochondroid Differentiation

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    Xing Wang

    2015-05-01

    Full Text Available Context Undifferentiated (spindle cell carcinomas of the pancreas are rare anaplastic variants of pancreatic ductal adenocarcinoma with a frequency of 2% of pancreatic exocrine tumors. Their clinicopathological features are limited and obtained by few previously case reports. We report a case of undifferentiated pancreatic carcinoma with a rare focal osteochondroid differentiation. Case report A sixty-six-year-old woman was admitted to our hospital for abdominal pain and nonspecific nausea for almost 40 days. Imaging studies revealed a well-defined cystic–solid mass with heterogeneous density involving the tail of the pancreas. We performed an en bloc distal pancreatectomy with splenectomy for radical excision, as well as regional lymphadenectomy. The resected specimen revealed a 4.0×5.0 cm exophytic clear-bordered neoplasm of the tail of the pancreas containing necrotic and calcified areas, without splenic invasion. The lymph node involvement was not detected (0/5 and the surgical margins were negative. Microscopy showed pleomorphism with giantcells, spindle-shaped cells with anaplasia, and osteochondroid differentiation. A diagnosis of undifferentiated (spindle cell carcinoma of the pancreas with focal osteochondroid differentiation was made. The patient declined chemotherapy and extended lymphadenectomy. She suffered from liver and lymph nodes metastasis 9 months after surgery, and she subsequently died 4 months later due to high tumor burden. Conclusions Undifferentiated pancreatic carcinoma with osteochondroid differentiation is rare but associated with extremely poor prognosis. It should be included in the differential diagnosis of pancreatic mass lesions.

  17. Association of Systemic Anaplastic Large Cell Lymphoma and Active Toxoplasmosis in a Child

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    Sayyahfar, Shirin; Karimi, Abdollah; Gharib, Atoosa; Fahimzad, Alireza

    2015-01-01

    Introduction: Anaplastic large cell lymphoma is a subset of non-Hodgkin lymphoma and an unusual disease in children. Case Presentation: Herein we have reported a 7- year- old girl with a large necrotic skin ulcer on the chest caused by systemic form of anaplastic large-cell lymphoma and simultaneous active toxoplasmosis diagnosed by PCR on lymph node specimen. There were few reports showing a role for toxoplasma infection to cause some malignancies such as lymphoma in adults. Conclusions: Bas...

  18. Cell adhesion molecule control of planar spindle orientation.

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    Tuncay, Hüseyin; Ebnet, Klaus

    2016-03-01

    Polarized epithelial cells align the mitotic spindle in the plane of the sheet to maintain tissue integrity and to prevent malignant transformation. The orientation of the spindle apparatus is regulated by the immobilization of the astral microtubules at the lateral cortex and depends on the precise localization of the dynein-dynactin motor protein complex which captures microtubule plus ends and generates pulling forces towards the centrosomes. Recent developments indicate that signals derived from intercellular junctions are required for the stable interaction of the dynein-dynactin complex with the cortex. Here, we review the molecular mechanisms that regulate planar spindle orientation in polarized epithelial cells and we illustrate how different cell adhesion molecules through distinct and non-overlapping mechanisms instruct the cells to align the mitotic spindle in the plane of the sheet. PMID:26698907

  19. Abnormal number cell division of human thyroid anaplastic carcinoma cell line, SW 1736

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    Keiichi Ikeda

    2015-12-01

    Full Text Available Cell division, during which a mother cell usually divides into two daughter cells during one cell cycle, is the most important physiological event of cell biology. We observed one-to-four cell division during imaging of live SW1736 human thyroid anaplastic carcinoma cells transfected with a plasmid expressing the hybrid protein of green fluorescent protein and histone 2B (plasmid eGFP-H2B. Analysis of the images revealed a mother cell divided into four daughter cells. And one of the abnormally divided daughter cells subsequently formed a dinucleate cell.

  20. MR imaging features of spindle cell lipoma

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    Kirwadi, Anand; Abdul-Halim, Rehan; Highland, Adrian; Kotnis, Nikhil [Sheffield Teaching Hospitals NHS Trust, Radiology Department, Sheffield (United Kingdom); Fernando, Malee [Sheffield Teaching Hospitals NHS Trust, Histopathology Department, Sheffield (United Kingdom)

    2014-02-15

    To assess the MR imaging features of spindle cell lipomas (SCL) and to compare these appearances directly with the histopathological findings. A retrospective review of our soft tissue tumor database was performed. This yielded 1,327 histologically proven lipomas, of which 25 were confirmed as being SCLs. Fourteen of the 25 patients had MR examinations available for review and only these patients were included in our study. Lesions were assessed at MR examination for the degree of internal fat signal content with grade 0 representing 0 % fat signal and grade 4 100 % fat signal. The degree of fat suppression and contrast-enhancement pattern were also recorded. The excision specimens were independently reviewed by a consultant histopathologist. The histology specimens were assessed for the amount of internal fat and non-adipose tissue and graded using the same scale applied for the imaging. Where core needle biopsy (CNB) was performed, the CNB specimens were also examined for positive features of SCL. In our study, 93 % (13/14) of our patients were male and the average age was 58 years. 65 % (9/14) of the lesions presented in the upper back, shoulder, or neck. All lesions were subcutaneous. 35 % (5/14) of the SCLs demonstrated grade 3 (>75 %) or grade 4 (100 %) fat signal on MR examination. 35 % (5/14) of the lesions had grade 2 (25-75 %) fat signal and 29 % (4/14) of the lesions demonstrated grade 0 (0 %) or grade 1 (<25 %) fat signal. 43 % (6/14) of lesions demonstrated homogenous fat suppression, 28 % (4/14) showed focal areas of high internal signal, and 28 % (4/14) had diffuse internal high signal on fluid-sensitive fat-saturated sequences. 86 % (6/7) of the cases demonstrated septal/nodular enhancement. The diagnosis was evident on the CNB specimen in 100 % (9/9) cases. The histopathology fat content grade was in agreement with the imaging grade in 86 % (12/14) cases. The internal signal pattern of SCL can range broadly, with low fat content lesions seen almost

  1. Neutrophil rich anaplastic large cell lymphoma presented as cutaneous nodules in an adolescent

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    @@ Anaplastic large cell lymphoma (ALCL),a type of lymphoma,was first described by Stain in 1985 and included in non-Hodgkin lymphoma according to REAL classification since 1998.In the absence of necrosis,neutrophils infiltration in non-Hodgkin lymphoma is uncommon.Mann et all had previously reported neutrophil rich ALCL as a variant of ALCL.In this paper,we describe a neutrophil rich,anaplastic large cell lymphoma (ALCL) which presented as cutaneous nodules in an adolescent.

  2. Spindle cell sarcoma of the penis. A case report

    International Nuclear Information System (INIS)

    A 75-year-old man, with a past history of radiation therapy for prostatic carcinoma ten years ago, was referred to our hospital with complaints of penile tumor. After pathological examination by core biopsy, the patient was treated by radical penectomy for a penile tumor. Pathological examinations demonstrated that the tumor was composed of pleomorphic spindle cells without any differentiation tendency and diagnosed as spindle cell sarcoma. Although the patient had a past history of radiation therapy for the prostate, the causal relation of development of penile sarcoma with the radiation therapy was uncertain because the main tumor was very near but outside of the irradiation field. The sarcoma rarely occurs in the penis, and this is the first report of penile spindle cell sarcoma, to our knowledge. (author)

  3. Large cell anaplastic medulloblastoma metastatic to the scalp: tumor and derived stem-like cells features

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    Mastronuzzi, Angela; Miele, Evelina; Po, Agnese; Antonelli, Manila; Buttarelli, Francesca Romana; Colafati, Giovanna Stefania; Del Bufalo, Francesca; Faedda, Roberta; Spinelli, Gian Paolo; Carai, Andrea; Giangaspero, Felice; Gulino, Alberto; Locatelli, Franco; Ferretti, Elisabetta

    2014-01-01

    Background Extraneural metastases (ENM) rarely occur in medulloblastoma (MBL) patients and only few cases of subcutaneous localizations have been described. ENM indicate an aggressive disease associated with a worse prognosis. The characterization of metastatic tumours might be useful to understand their pathogenesis and to identify the most appropriate therapeutic strategies. Case presentation We present the case of a child with Large Cell Anaplastic (LC/A) MBL, who developed multiple subcut...

  4. Imaging characteristics of spindle cell lipoma and its variants

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    Khashper, Alla; Zheng, Jiamin [McGill University Health Centre, Department of Radiology, Montreal, QC (Canada); Nahal, Ayoub [McGill University Health Centre, Department of Pathology, Montreal, QC (Canada); Discepola, Federico [Jewish General Hospital, Department of Radiology, Montreal, QC (Canada)

    2014-05-15

    A spindle cell lipoma (SCL) is a relatively common tumor that can be challenging to the radiologist, pathologist, or surgeon to diagnose, particularly when internal fat content is scant or absent. Although these lesions may be found at various locations, the typical presentation for this lesion is a well-circumscribed and non-aggressive subcutaneous mass in the posterior neck presenting in a middle-aged to elderly man. In this article, the typical and atypical imaging characteristics of a spindle cell lipoma (SCL) will be reviewed. Knowledge of the common imaging and pathologic features of SCLs can help suggest the diagnosis and guide patient management. (orig.)

  5. Cardiac anaplastic large cell lymphoma in an 8-year old boy

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    Melchior Lauten

    2014-01-01

    Full Text Available We report on an 8 year old boy with primary cardiac anaplastic large cell lymphoma (ALCL, in whom the diagnosis was challenging and who was treated with modified chemotherapy without radiation therapy according to the ALCL 99 study protocol [1]. Two years and 4 months after completion of therapy the boy is in complete remission with normal cardiac function.

  6. Cardiac anaplastic large cell lymphoma in an 8-year old boy

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    Melchior Lauten; Simon Vieth; Christopher Hart; Wilhelm Wössmann; Birte Tröger; Christoph Härtel; Martin Bethge; André Schrauder; Gunnar Cario

    2014-01-01

    We report on an 8 year old boy with primary cardiac anaplastic large cell lymphoma (ALCL), in whom the diagnosis was challenging and who was treated with modified chemotherapy without radiation therapy according to the ALCL 99 study protocol [1]. Two years and 4 months after completion of therapy the boy is in complete remission with normal cardiac function.

  7. Galectin-1-mediated cell adhesion, invasion and cell death in human anaplastic large cell lymphoma: Regulatory roles of cell surface glycans

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    Suzuki, Osamu; Abe, Masafumi

    2014-01-01

    Galectin-1 is known to be one of the extracellular matrix proteins. To elucidate the biological roles of galectin-1 in cell adhesion and invasion of human anaplastic large cell lymphoma, we performed cell adhesion and invasion assays using the anaplastic large cell lymphoma cell line H-ALCL, which was previously established in our laboratory. From the cell surface lectin array, treatment with neuraminidase from Arthrobacter ureafaciens which cleaves all linkage types of cell surface sialic ac...

  8. Cell shape impacts on the positioning of the mitotic spindle with respect to the substratum.

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    Lázaro-Diéguez, Francisco; Ispolatov, Iaroslav; Müsch, Anne

    2015-04-01

    All known mechanisms of mitotic spindle orientation rely on astral microtubules. We report that even in the absence of astral microtubules, metaphase spindles in MDCK and HeLa cells are not randomly positioned along their x-z dimension, but preferentially adopt shallow β angles between spindle pole axis and substratum. The nonrandom spindle positioning is due to constraints imposed by the cell cortex in flat cells that drive spindles that are longer and/or wider than the cell's height into a tilted, quasidiagonal x-z position. In rounder cells, which are taller, fewer cortical constraints make the x-z spindle position more random. Reestablishment of astral microtubule-mediated forces align the spindle poles with cortical cues parallel to the substratum in all cells. However, in flat cells, they frequently cause spindle deformations. Similar deformations are apparent when confined spindles rotate from tilted to parallel positions while MDCK cells progress from prometaphase to metaphase. The spindle disruptions cause the engagement of the spindle assembly checkpoint. We propose that cell rounding serves to maintain spindle integrity during its positioning. PMID:25657320

  9. Detection of an early adult T-cell leukemia-lymphoma clone in lymph nodes with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma involvement.

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    Tokunaga, Masahito; Yoshida, Noriaki; Nakano, Nobuaki; Kubota, Ayumu; Takeuchi, Shogo; Takatsuka, Yoshifusa; Seto, Masao; Utsunomiya, Atae

    2016-04-01

    A 58-year-old man was admitted to our hospital with systemic lymphadenopathy and was diagnosed with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALCL) by lymph node biopsy. Although he was a human T-cell leukemia virus type I (HTLV-1) carrier, Southern blot analysis of the lymph node did not show monoclonal integration of HTLV-1 provirus deoxyribonucleic acid (DNA). He achieved complete remission after chemotherapy and subsequently, autologous peripheral blood stem cell transplantation (auto-PBSCT) was performed. Fifteen months after the auto-PBSCT, abnormal lymphocytes in the peripheral blood gradually increased. Southern blot analysis revealed monoclonal integration of HTLV-1 provirus DNA and monoclonal rearrangement of TRB. He was diagnosed with chronic type adult T-cell leukemia-lymphoma (ATL), which immediately progressed to the acute type. He died of tumor progression despite intensive chemotherapy. We analyzed genomic alterations of the ALCL and ATL cells using array comparative genomic hybridization. We found that the genomic alteration pattern differed between the two diseases. T-cell receptor clonality analysis using polymerase chain reaction (PCR) showed that the T-cell clone of the ATL was present in the lymph nodes with ALCL involvement, but not in peripheral blood. This finding suggests that lymph nodes can serve as a niche for ATL development. PMID:26874918

  10. CD30-Positive Anaplastic Lymphoma Kinase-Negative Systemic Anaplastic Large-Cell Lymphoma in a 9-Year-Old Boy

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    Kim, Jeong Eun; Oh, Eui Hyun; Ro, Young Suck

    2016-01-01

    Anaplastic large-cell lymphoma (ALCL) is a CD30-positive T-cell/null-cell lymphoma that is clinically classified into either primary cutaneous ALCL or systemic ALCL (S-ALCL) sub-types. Because 90% of childhood S-ALCL cases are anaplastic lymphoma kinase (ALK)-positive, there is a lack of data on ALK-negative S-ALCL cases among pediatric patients. Herein, we report a rare case of ALK-negative S-ALCL in a 9-year-old Korean boy who initially presented with itchy erythematous maculopapules and an erosive nodule on the trunk area. We emphasize the need of high index of suspicion of an underlying malignant disease in the presence of refractory eczematous lesions. PMID:27274637

  11. Radiation-induced spindle cell sarcoma: A rare case report

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    Khan Mubeen

    2009-01-01

    Full Text Available Ionizing radiation has been known to induce malignant transformation in human beings. Radiation-induced sarcomas are a late sequel of radiation therapy. Most sarcomas have been reported to occur after exposure to a radiation dose of 55 Gray (Gy and above, with a dose ranging from 16 to 112 Gys. Spindle cell sarcomas, arising after radiotherapy given to treat the carcinoma of head and neck region is a very uncommon sequel. This is a rare case report of spindle cell sarcoma of left maxilla, in a 24-year-old male, occurring as a late complication of radiotherapy with Cobalt-60 given for the treatment of retinoblastoma of the left eye 21 years back.

  12. ALK-positive anaplastic large cell lymphoma with soft tissue involvement in a young woman

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    Gao KH

    2016-07-01

    Full Text Available Kehai Gao, Hongtao Li, Caihong Huang, Huazhuang Li, Jun Fang, Chen Tian Department of Orthopaedics, Yidu Central Hospital, Shandong, People’s Republic of China Introduction: Anaplastic large cell lymphoma (ALCL is a type of non-Hodgkin lymphoma that has strong expression of CD30. ALCL can sometimes involve the bone marrow, and in advanced stages, it can produce destructive extranodal lesions. But anaplastic large cell lymphoma kinase (ALK+ ALCL with soft tissue involvement is very rare.Case report: A 35-year-old woman presented with waist pain for over 1 month. The biopsy of soft tissue lesions showed that these cells were positive for ALK-1, CD30, TIA-1, GranzymeB, CD4, CD8, and Ki67 (90%+ and negative for CD3, CD5, CD20, CD10, cytokeratin (CK, TdT, HMB-45, epithelial membrane antigen (EMA, and pan-CK, which identified ALCL. After six cycles of Hyper-CVAD/MA regimen, she achieved partial remission. Three months later, she died due to disease progression.Conclusion: This case illustrates the unusual presentation of ALCL in soft tissue with a bad response to chemotherapy. Because of the tendency for rapid progression, ALCL in young adults with extranodal lesions are often treated with high-grade chemotherapy, such as Hyper-CVAD/MA. Keywords: anaplastic large cell lymphoma, ALK+, soft tissue involvement, Hyper-CVAD/MA

  13. Fission yeast cells undergo nuclear division in the absence of spindle microtubules.

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    Stefania Castagnetti

    Full Text Available Mitosis in eukaryotic cells employs spindle microtubules to drive accurate chromosome segregation at cell division. Cells lacking spindle microtubules arrest in mitosis due to a spindle checkpoint that delays mitotic progression until all chromosomes have achieved stable bipolar attachment to spindle microtubules. In fission yeast, mitosis occurs within an intact nuclear membrane with the mitotic spindle elongating between the spindle pole bodies. We show here that in fission yeast interference with mitotic spindle formation delays mitosis only briefly and cells proceed to an unusual nuclear division process we term nuclear fission, during which cells perform some chromosome segregation and efficiently enter S-phase of the next cell cycle. Nuclear fission is blocked if spindle pole body maturation or sister chromatid separation cannot take place or if actin polymerization is inhibited. We suggest that this process exhibits vestiges of a primitive nuclear division process independent of spindle microtubules, possibly reflecting an evolutionary intermediate state between bacterial and Archeal chromosome segregation where the nucleoid divides without a spindle and a microtubule spindle-based eukaryotic mitosis.

  14. A rare case of ALK negative CD30+ primary cutaneous anaplastic large cell lymphoma in a young adult

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    H B Sridevi

    2015-01-01

    Full Text Available Cutaneous anaplastic large cell lymphoma can present either as a primary disease or as secondary to a pre-existing systemic anaplastic lymphoma. Distinguishing primary cutaneous anaplastic lymphoma (PC-ALCL from its systemic counterpart requires a complete clinical and laboratory workup. We hereby report a case of PC-ALCL in a young adult, who presented with unusual rapidly progressive ulcerated mass in the neck. Biopsy showed anaplastic large cells, which were strongly positive for CD30 and CD25 but ALK1 gene product was negative. Clinical examination and computed tomography (CT scan ruled out extracutaneous involvement. Chemotherapy with 6 cycles of CHOP regimen was planned and on follow-up, a complete remission of the lesion was attained.

  15. Synchronous Occurrence of Primary Cutaneous Anaplastic Large Cell Lymphoma and Squamous Cell Carcinoma

    Science.gov (United States)

    Park, Ji-Hye; Lee, Jae Ho; Lim, Youngkyoung; Lee, You Jin

    2016-01-01

    CD30+ lymphoproliferative disorders (LPD) represent a spectrum of T-cell lymphoma including lymphomatoid papulosis and anaplastic large cell lymphoma (ALCL). Epidermis overlying cutaneous CD30+ LPD often shows epidermal hyperplasia, hyperkeratosis, crusting, and ulceration and it is difficult to distinguish from carcinoma such as keratoacanthoma (KA) or squamous cell carcinoma (SCC). Several cases of pseudocarcinomatous hyperplasia mimicking KA or SCC in CD30+ LPD have been reported. The relationship between CD30+ LPD and epithelial proliferations has not yet well understood. It was reported that a variety of mediators, including epidermal growth factor (EGF), transforming growth factor-α and EGFR from CD30+ LPD could attribute to epidermal hyperplasia. However, separate and distinct SCC occurring in CD30+ LPD has rarely been reported. Herein, we present a rare case of coexistence of SCC and cutaneous ALCL located on the same region. PMID:27489433

  16. Asymmetric division of cyst stem cells in Drosophila testis is ensured by anaphase spindle repositioning

    OpenAIRE

    Cheng, Jun; Tiyaboonchai, Amita; Yamashita, Yukiko M.; Hunt, Alan J.

    2011-01-01

    Many stem cells divide asymmetrically to balance self-renewal and differentiation. In Drosophila testes, two stem cell populations, germline stem cells (GSCs) and somatic cyst stem cells (CySCs), cohere and regulate one another. Here, we report that CySCs divide asymmetrically through repositioning the mitotic spindle around anaphase. CySC spindle repositioning requires functional centrosomes, Dynein and the actin-membrane linker Moesin. Anaphase spindle repositioning is required to achieve h...

  17. Automated three-dimensional single cell phenotyping of spindle dynamics, cell shape, and volume

    CERN Document Server

    Plumb, Kemp; Pelletier, Vincent; Kilfoil, Maria L

    2015-01-01

    We present feature finding and tracking algorithms in 3D in living cells, and demonstrate their utility to measure metrics important in cell biological processes. We developed a computational imaging hybrid approach that combines automated three-dimensional tracking of point-like features with surface determination from which cell (or nuclear) volume, shape, and planes of interest can be extracted. After validation, we applied the technique to real space context-rich dynamics of the mitotic spindle, and cell volume and its relationship to spindle length, in dividing living cells. These methods are additionally useful for automated segregation of pre-anaphase and anaphase spindle populations in budding yeast. We found that genetic deletion of the yeast kinesin-5 mitotic motor cin8 leads to large mother and daughter cells that were indistinguishable based on size, and that in those cells the spindle length becomes uncorrelated with cell size. The technique can be used to visualize and quantify tracked feature c...

  18. Cytotoxic effects of Gemcitabine-loaded liposomes in human anaplastic thyroid carcinoma cells

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    Rotiroti Domenicoantonio

    2004-09-01

    Full Text Available Abstract Background Identification of effective systemic antineoplastic drugs against anaplastic thyroid carcinomas has particularly important implications. In fact, the efficacy of the chemotherapeutic agents presently used in these tumours, is strongly limited by their low therapeutic index. Methods In this study gemcitabine was entrapped within a pegylated liposomal delivery system to improve the drug antitumoral activity, thus exploiting the possibility to reduce doses to be administered in cancer therapy. The cytotoxic effects of free or liposome-entrapped gemcitabine was evaluated against a human thyroid tumour cell line. ARO cells, derived from a thyroid anaplastic carcinoma, were exposed to different concentrations of the drug. Liposomes formulations were made up of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/cholesterol/1,2-distearoyl-sn-glycero-3-phosphoethanolamine-MPEG (8:3:1 molar ratio. Cell viability was assessed by both trypan bleu dye exclusion assay and fluorimetric analysis of cell DNA content. Results A cytotoxic effect of free gemcitabine was present only after 72 h incubation (ARO cell mortality increased of approximately 4 fold over control at 1 μM, 7 fold at 100 μM. When gemcitabine was encapsulated in liposomes, a significant effect was observed by using lower concentrations of the drug (increased cell mortality of 2.4 fold vs. control at 0.3 μM and earlier exposure time (24 h. Conclusion These findings show that, in vitro against human thyroid cancer cells, the gemcitabine incorporation within liposomes enhances the drug cytotoxic effect with respect to free gemcitabine, thus suggesting a more effective drug uptake inside the cells. This may allow the use of new formulations with lower dosages (side effect free for the treatment of anaplastic human thyroid tumours.

  19. Cytotoxic effects of Gemcitabine-loaded liposomes in human anaplastic thyroid carcinoma cells

    International Nuclear Information System (INIS)

    Identification of effective systemic antineoplastic drugs against anaplastic thyroid carcinomas has particularly important implications. In fact, the efficacy of the chemotherapeutic agents presently used in these tumours, is strongly limited by their low therapeutic index. In this study gemcitabine was entrapped within a pegylated liposomal delivery system to improve the drug antitumoral activity, thus exploiting the possibility to reduce doses to be administered in cancer therapy. The cytotoxic effects of free or liposome-entrapped gemcitabine was evaluated against a human thyroid tumour cell line. ARO cells, derived from a thyroid anaplastic carcinoma, were exposed to different concentrations of the drug. Liposomes formulations were made up of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/cholesterol/ 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-MPEG (8:3:1 molar ratio). Cell viability was assessed by both trypan bleu dye exclusion assay and fluorimetric analysis of cell DNA content. A cytotoxic effect of free gemcitabine was present only after 72 h incubation (ARO cell mortality increased of approximately 4 fold over control at 1 μM, 7 fold at 100 μM). When gemcitabine was encapsulated in liposomes, a significant effect was observed by using lower concentrations of the drug (increased cell mortality of 2.4 fold vs. control at 0.3 μM) and earlier exposure time (24 h). These findings show that, in vitro against human thyroid cancer cells, the gemcitabine incorporation within liposomes enhances the drug cytotoxic effect with respect to free gemcitabine, thus suggesting a more effective drug uptake inside the cells. This may allow the use of new formulations with lower dosages (side effect free) for the treatment of anaplastic human thyroid tumours

  20. Combination therapy with brentuximab vedotin and cisplatin/cytarabine in a patient with primarily refractory anaplastic lymphoma kinase positive anaplastic large cell lymphoma

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    Heidegger S

    2014-06-01

    Full Text Available Simon Heidegger,1 Ambros Beer,2 Eva Geissinger,3 Andreas Rosenwald,3 Christian Peschel,1 Ingo Ringshausen,1 Ulrich Keller11III Medical Department, 2Nuclear Medicine Department, Technische Universität München, Munich, Germany; 3Institute of Pathology, University of Würzburg, Würzburg, GermanyAbstract: Anaplastic large cell lymphoma (ALCL is a common subtype of the heterogeneous group of peripheral T-cell lymphomas, which is characterized by large pleomorphic cells with strong expression of CD30. Translocations involving ALK, the anaplastic lymphoma kinase gene, are associated with a favorable clinical outcome. Such ALK-positive ALCLs are usually responsive to a multidrug chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone. However, there is no general consensus on the optimal therapy for relapsed or refractory ALCL. We report the case of a 24-year-old male suffering from ALK-positive ALCL with an uncommon manifestation of only extranodal disease in the gastric cardia region that showed primary refractoriness to standard CHOP chemotherapy. A combination therapy consisting of the anti-CD30 drug conjugate, brentuximab vedotin, and classical lymphoma salvage regimen DHAP (cisplatin, high-dose cytarabine and dexamethasone was administered. Following two treatment cycles in 21-day intervals, the lymphoma showed considerable regression based on imaging diagnostics and no evidence of vital lymphoma in a subsequent biopsy. We did not observe any increase in toxicity; in particular, polyneuropathy and febrile neutropenia were not observed. In summary, we report that the antibody-drug conjugate brentuximab vedotin and a classical regimen used for aggressive lymphoma, DHAP, could be combined as salvage therapy in a case of refractory ALK-positive ALCL. Phase I/II studies will be required for safety and efficacy analysis.Keywords: anaplastic large cell lymphoma (ALCL, refractory/relapsed lymphoma, anti-CD30 drug conjugate, DHAP

  1. Spindle cell hemangioma: Unusual presentation of an uncommon tumor

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    Olalere Omoyosola Gbolahan

    2015-01-01

    Full Text Available Spindle cell hemangioma (SCH is an uncommon tumor that usually presents as subcutaneous or deep dermal nodule affecting the extremities and is typically <2 cm in size. A few cases have been reported in the head and neck region. To the best of the authors' knowledge, there are no previous reports of SCH occurring in the orbit in the English literature. We, therefore, report the case of a large SCH involving the right orbit of a healthy 9-year-old Nigerian girl.

  2. Specific polar subpopulations of astral microtubules control spindle orientation and symmetric neural stem cell division.

    Science.gov (United States)

    Mora-Bermúdez, Felipe; Matsuzaki, Fumio; Huttner, Wieland B

    2014-01-01

    Mitotic spindle orientation is crucial for symmetric vs asymmetric cell division and depends on astral microtubules. Here, we show that distinct subpopulations of astral microtubules exist, which have differential functions in regulating spindle orientation and division symmetry. Specifically, in polarized stem cells of developing mouse neocortex, astral microtubules reaching the apical and basal cell cortex, but not those reaching the central cell cortex, are more abundant in symmetrically than asymmetrically dividing cells and reduce spindle orientation variability. This promotes symmetric divisions by maintaining an apico-basal cleavage plane. The greater abundance of apical/basal astrals depends on a higher concentration, at the basal cell cortex, of LGN, a known spindle-cell cortex linker. Furthermore, newly developed specific microtubule perturbations that selectively decrease apical/basal astrals recapitulate the symmetric-to-asymmetric division switch and suffice to increase neurogenesis in vivo. Thus, our study identifies a novel link between cell polarity, astral microtubules, and spindle orientation in morphogenesis. PMID:24996848

  3. SPINDLE CELL SARCOMA OF VAGINA- A CASE REPORT

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    Sankareswari

    2013-04-01

    Full Text Available ABSTRACT : Malignant tumors of vagina are rare accounting for 1 to 4 % of all genital malignancies. Rarest of rare is spindle cell sarcoma of vagina having a very poor prognosis. 47yrs old, regularly menstruating woman, completed f amily, presented with hard painful ulcerated swelling near the vaginal introitus and l ower vaginal wall of 4 months duration. On examination, 2x4cms sized ulcerated growth with exc avated base, covered with necrotic material, present in the left antero-lateral lower e nd of vagina, inner to hymenal ring which was tender, hard, indurated, infiltrating, fixed to bas e and did not bleed to touch. Another nodule of size 1x1cm tender, hard, fixed and necrotic was pres ent below the external urethral meatus. HPE revealed Amelanotic malignant melanoma of vagin a. Immunohistochemistry revealed Spindle cell sarcoma of vagina. Tumor board recommen ded neo-adjuvant chemotherapy and radiotherapy (CT + EBRT. Of the recommended 50Gy, s he completed 46Gy in 23days and 1 course of chemotherapy (VAC. On review after 9 mont hs, the lesion disappeared clinically and she was advised to complete the treatment. Inspite o f radio and chemotherapy secondaries to lungs and brain could not be prevented and the patien t expired 20 months after the final diagnosis

  4. Indium-111-oxine labeled leukocyte uptake in Ki-1-positive anaplastic large cell lymphoma

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    Chiu, W.; Amodio, J.B.; Scharf, S.C. (New York Univ., NY (United States). Dept. of Radiology); Rivlin, K.A. (Department of Hematology and Oncology, New York Univ. Medical Center, NY (United States)); Desai, P. (Department of Pathology, Hospital for Joint Diseases-Orthopaedic Inst., New York, NY (United States)); Breuer, F. (Department of Pathology, Lenox Hill Hospital, New York, NY (United States))

    1999-08-01

    Indium-111-oxine labeled leukocyte ([sup 111]In-WBC) scintigraphy is well known for its ability to localize in areas of active infection, but not in areas of lymphomatous involvement. We present a case of Ki-1-positive anaplastic large-cell lymphoma that was initially thought to be a case of multifocal osteomyelitis because of positive uptake on a [sup 111]In-WBC scan. The areas of abnormal uptake on the indium scan were demonstrated histopathologically to be sites of lymphomatous involvement in bone. (orig.) With 4 figs., 3 refs.

  5. Indium-111-oxine labeled leukocyte uptake in Ki-1-positive anaplastic large cell lymphoma

    International Nuclear Information System (INIS)

    Indium-111-oxine labeled leukocyte (111In-WBC) scintigraphy is well known for its ability to localize in areas of active infection, but not in areas of lymphomatous involvement. We present a case of Ki-1-positive anaplastic large-cell lymphoma that was initially thought to be a case of multifocal osteomyelitis because of positive uptake on a 111In-WBC scan. The areas of abnormal uptake on the indium scan were demonstrated histopathologically to be sites of lymphomatous involvement in bone. (orig.)

  6. Multidisciplinaly total-cell-kill treatment of bronchogenic small cell anaplastic carcinoma

    International Nuclear Information System (INIS)

    Survival time of the patients with bronchogenic small cell anaplastic cancer was studied. Combined treatment with six-drug combination chemotherapy ''METVFC'' (mitomycin C + cyclophosphamide + toyomycin + vincristine + 5-FU + cytosine arabinoside) and radiotherapy (5,000 rads in total) was given to 14 cases of limited disease of small cell carcinoma. Median survival was 8 months, one year and two year survival rates were 47% and 27%, respectively. Combined treatment with METVFC and small dose radiotherapy of 100 or 200 rads irradiation 4 hours before chemotherapy, followed by remission consolidation of 3,000 -- 4,000 rads radiotherapy, thereafter second line chemotherapy of ''COAM'' (cyclophosphamide + vincristine + ACNU + methotrexate) was given to 4 cases of limited disease of small cell carcinoma. All cases survived more than 1.5 years and two of them have retained complete remission more than 1.5 years. There are 6 cases with small cell carcinoma survived more than 3 years out of total 128 cases. They are all those of limited disease. They received combined treatment of chemotherapy and radiotherapy simultaneously or alternatively, followed by remission maintenance chemotherapy. One case of them died from cancer. Two cases died from another disease without lung cancer. Three cases survived healthy more than 3 to 8 years. In the limited disease, small cell carcinoma of the lung might be curable if the complete remission could continue more than three years. (author)

  7. Chromokinesin: Kinesin superfamily regulating cell division through chromosome and spindle.

    Science.gov (United States)

    Zhong, Ai; Tan, Fu-Qing; Yang, Wan-Xi

    2016-09-01

    Material transportation is essential for appropriate cellular morphology and functions, especially during cell division. As a motor protein moving along microtubules, kinesin has several intracellular functions. Many kinesins play important roles in chromosome condensation and separation and spindle organization during the cell cycle. Some of them even can directly bind to chromosomes, as a result, these proteins are called chromokinesins. Kinesin-4 and kinesin-10 family are two major families of chromokinesin and many members can regulate some processes, both in mitosis and meiosis. Their functions have been widely studied. Here, we summarize current knowledge about known chromokinesins and introduce their intracellular features in accordance with different families. Furthermore, we have also introduced some new-found but unconfirmed kinesins which may have a relationship with chromosomes or the cell cycle. PMID:27196062

  8. Targeted therapy for Hodgkin lymphoma and systemic anaplastic large cell lymphoma: focus on brentuximab vedotin

    Directory of Open Access Journals (Sweden)

    Chen X

    2013-12-01

    Full Text Available Xueyan Chen, Lorinda A Soma, Jonathan R FrommDepartment of Laboratory Medicine, University of Washington Medical Center, Seattle, WA, USAAbstract: Despite the relative success of chemotherapy for Hodgkin lymphoma (HL and systemic anaplastic large cell lymphoma (ALCL, novel therapeutic agents are needed for refractory or relapsed patients. Targeted immunotherapy has emerged as a novel treatment option for these patients. Although unconjugated anti-cluster of differentiation (CD30 antibodies showed minimal antitumor activity in early clinical trials, development of antibody–drug conjugates (ADCs appears promising. Brentuximab vedotin is an ADC composed of an anti-CD30 antibody linked to a potent microtubule-disrupting agent monomethyl auristatin E (MMAE. It has the ability to target CD30-positive tumor cells and, once bound to CD30, brentuximab vedotin is internalized and MMAE is released to induce cell cycle arrest and apoptosis. In two phase II trials, objective response was reported in 75% and 86% of patients with refractory or relapsed HL and systemic ALCL, respectively, with an acceptable toxicity profile. Based on these studies, the US Food and Drug Administration (FDA granted accelerated approval of brentuximab vedotin in August 2011 for the treatment of refractory and relapsed HL and ALCL. We review the key characteristics of brentuximab vedotin, clinical data supporting its therapeutic efficacy, and current ongoing trials to explore its utility in other CD30-positive malignancies.Keywords: classical Hodgkin lymphoma, systemic anaplastic large cell lymphoma, CD30, brentuximab vedotin, SGN-35

  9. A novel Patient Derived Tumorgraft model with TRAF1-ALK Anaplastic Large Cell Lymphoma translocation

    Science.gov (United States)

    Abate, Francesco; Todaro, Maria; van der Krogt, Jo-Anne; Boi, Michela; Landra, Indira; Machiorlatti, Rodolfo; Tabbo’, Fabrizio; Messana, Katia; Barreca, Antonella; Novero, Domenico; Gaudiano, Marcello; Aliberti, Sabrina; Di Giacomo, Filomena; Tousseyn, Thomas; Lasorsa, Elena; Crescenzo, Ramona; Bessone, Luca; Ficarra, Elisa; Acquaviva, Andrea; Rinaldi, Andrea; Ponzoni, Maurilio; Longo, Dario Livio; Aime, Silvio; Cheng, Mangeng; Ruggeri, Bruce; Piccaluga, Pier Paolo; Pileri, Stefano; Tiacci, Enrico; Falini, Brunangelo; Pera-Gresely, Benet; Cerchietti, Leandro; Iqbal, Javeed; Chan, Wing C; Shultz, Leonard D.; Kwee, Ivo; Piva, Roberto; Wlodarska, Iwona; Rabadan, Raul; Bertoni, Francesco; Inghirami, Giorgio

    2016-01-01

    Although Anaplastic Large Cell Lymphomas (ALCL) carrying Anaplastic Lymphoma Kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human Patient Derived Tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and of NFkB pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells lacking PRDM1/Blimp-1 and with c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to down-regulation of p50/p52 and lymphoma growth inhibition. Moreover a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Moreover, a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, but the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable to validate the role of druggable molecules, predict therapeutic responses and are helpful tools for the implementation of patient specific therapies. PMID:25533804

  10. Large cell anaplastic medulloblastoma metastatic to the scalp: tumor and derived stem-like cells features

    International Nuclear Information System (INIS)

    Extraneural metastases (ENM) rarely occur in medulloblastoma (MBL) patients and only few cases of subcutaneous localizations have been described. ENM indicate an aggressive disease associated with a worse prognosis. The characterization of metastatic tumours might be useful to understand their pathogenesis and to identify the most appropriate therapeutic strategies. We present the case of a child with Large Cell Anaplastic (LC/A) MBL, who developed multiple subcutaneous metastases in the scalp area after a ventriculo-peritoneal shunting procedure. The disease rapidly progressed and the child died despite chemotherapy and primary tumour surgical debulking. We molecularly classified the tumour as a group 3 MBL; in addition, we derived stem-like cells (SLC) from a metastatic lesion. Primary tumour, metastases and SLC were further analysed, particularly focusing on features linked to the cutaneous dissemination. Indeed, molecules involved in angiogenesis, cell invasion and epidermal growth factor signalling resulted highly expressed. The present report describes a very rare case of subcutaneous metastatic MBL. The tumour, metastases and SLC have been clinically, pathologically and molecularly characterized. Our case is an example of multidisciplinary approach aiming to characterize MBL aggressive behaviour

  11. Management of small-cell anaplastic carcinoma, 1980-1982

    International Nuclear Information System (INIS)

    The author gives an updated report on the management of small-cell carcinoma of the lung, particularly on staging and therapy. He presents and discusses data accumulated from the literature published in 1980 and 1981 and finishes with 9 conclusions regarding treatment of these carcinomas. Of interest are the following: combined use of chemotherapy and radiotherapy is clearly superior to radiotherapy alone; prophylactic brain irradiation decreases the incidence of brain metastases, but it does not change the overall median survival. It should probably be restricted to patients who have achieved complete remission; radiotherapy to the primary tumor and including the regional lymph nodes decreases the rate of local recurrence, but it does not influence the median survival when given with combination chemotherapy. The morbidity of the combined modality of therapy is considerably higher than when using chemotherapy alone. Whether the percentage of long-term remission survivors is higher when the combined modality of therapy is used, is still uncertain. (C.F.)

  12. Clinical features and treatment results in children with anaplastic large cell lymphoma.

    Science.gov (United States)

    Ataş, Erman; Kutluk, M Tezer; Akyüz, Canan; Kale, Gülsev; Varan, Ali; Yalçın, Bilgehan; Aydın, Burça; Büyükpamukçu, Münevver

    2015-01-01

    Anaplastic large cell lymphoma (ALCL) tends to have frequent relapse and good response to salvage chemotherapy. The frequency of ALCL among 1486 Non-Hodgkin's lymphoma (NHL) cases followed-up since 1972 was 1.5%, however, the percentage was 9.3% in cases diagnosed after 2000. Event-free survival (EFS) and overall survival (OS) rates for 23 children were 32.2% and 72.8% at 3 years, respectively. Disseminated diseases, no response to first line treatment, anaplastic lymphoma kinase (ALK) negativity were found as significant predictors on survival of ALCL. The proper diagnosis and early referral is essential in these children for a better survival rate. The children with ALK negative status should be monitored carefully because of the poor prognostic factors, and treated differently. The survival rates in this study are need of further improvement since the survival rates with current protocols are achievable at a level more than 80%. This is mainly related with late referral of those children with advanced disease. PMID:27411412

  13. A Report of a Rare Case of Anaplastic Large Cell Lymphoma of the Oral Cavity

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    Prasad G Kango

    2012-01-01

    Full Text Available Case history: Malignant lymphoma is a neoplastic proliferative process of the lymphopoietic portion of the reticuloendothelial system that involves cells of either the lymphocytic or histiocytic series in varying degrees of differentiation and occurs in an essentially homogenous population of a single cell type. The character of histologic involvement is either diffuse (uniform or nodular and the distribution of involvement may be regional or systemic (generalized, the process basically being multicentric. A case of oral cavity lymphoma was detected and after various panel of imunnohistochemical (IHC markers it was diagnosed as Anaplastic large cell lymphomas (ALCL of oral cavity. Conclusion: Lymphoma of oral regions are very rare and ALCL is rarest. It is of utmost importance to do the IHC, so that the prognosis of the lesion is known at the earliest. In this case since it was detected at a later stage the outcome was fatal.

  14. Isolated cutaneous involvement in a child with nodal anaplastic large cell lymphoma

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    Vibhu Mendiratta

    2016-01-01

    Full Text Available Non-Hodgkin lymphoma is a common childhood T-cell and B-cell neoplasm that originates primarily from lymphoid tissue. Cutaneous involvement can be in the form of a primary extranodal lymphoma, or secondary to metastasis from a non-cutaneous location. The latter is uncommon, and isolated cutaneous involvement is rarely reported. We report a case of isolated secondary cutaneous involvement from nodal anaplastic large cell lymphoma (CD30 + and ALK + in a 7-year-old boy who was on chemotherapy. This case is reported for its unusual clinical presentation as an acute febrile, generalized papulonodular eruption that mimicked deep fungal infection, with the absence of other foci of systemic metastasis.

  15. Primary pancreatic anaplastic large cell lymphoma, ALK negative:A case report

    Institute of Scientific and Technical Information of China (English)

    Christos G Savopoulos; NE Tsesmeli; GD Kaiafa; AT Zantidis; MT Bobos; AI Hatzitolios; ST Papavramidis; IS Kostopoulos

    2005-01-01

    We present the fourth case of a primary pancreatic anaplastic large cell lymphoma (ALCL), ALK-. An 80-year-old man was admitted to our clinic for further investigation of a fever of unknown origin. He noted anorexia, weight loss and fatigue. His laboratory tests showed anemia and a great elevation of ESR, LDH, and β2 microglobulin. In CT and MRI scan, a soft tissue mass in the pancreas was observed. A repeated endoscopy after his admission revealed an ulcerated mass-like deformity of the duodenal bulb. Explorative laparotomy confirmed a diffuse spread of an unresectable malignant pancreatic mass extending to the adjacent organs. Duodenal and surgical biopsies identified an ALCL of T-cell lineage, ALK-. The patient died in the Intensive Care Unit due to hemodynamic instability.Our case is the first one indicating that primary pancreatic lymphoma should be suspected in a patient with pancreatic mass and elevated serum LDH and β2 microglobulin.

  16. Iodide uptake in human anaplastic thyroid carcinoma cells after transfer of the human thyroid peroxidase gene

    International Nuclear Information System (INIS)

    Human thyroperoxidase (hTPO) is critical for the accumulation of iodide in thyroid tissues. Poorly differentiated and anaplastic thyroid tumours which lack thyroid-specific gene expression fail to accumulate iodide and, therefore, do not respond to iodine-131 therapy. We consequently investigated whether transfer of the hTPO gene is sufficient to restore the iodide-trapping capacity in undifferentiated thyroid and non-thyroid tumour cells. The human anaplastic thyroid carcinoma cell lines C643 and SW1736, the rat Morris hepatoma cell line MH3924A and the rat papillary thyroid carcinoma cell line L2 were used as in vitro model systems. Employing a bicistronic retroviral vector based on the myeloproliferative sarcoma virus for the transfer of the hTPO and the neomycin resistance gene, the C643 cells and SW1736 cells were transfected while the L2 cells and MH3924A cells were infected with retroviral particles. Seven recombinant C643 and seven SW1736 cell lines as well as four recombinant L2 and four MH3924A cell lines were established by neomycin selection. They were studied for hTPO expression using an antibody-based luminescence kit, followed by determination of the enzyme activity in the guaiacol assay and of the iodide uptake capacity in the presence of Na125I. Genetically modified cell lines expressed up to 1,800 times more hTPO as compared to wild type tumour cells. The level of hTPO expression varied significantly between individual neomycin-resistant cell lines, suggesting that the recombinant retroviral DNA was integrated at different sites of the cellular genome. The accumulation of iodide, however, was not significantly enhanced in individual recombinant cell lines, irrespective of low or high hTPO expression. Moreover, there was no correlation between hTPO expression and enzyme activity in individual cell lines. The transduction of the hTPO gene per se is not sufficient to restore iodide trapping in non-iodide-concentrating tumour cells. Future studies

  17. Anaplastic large cell lymphoma ALK-negative clinically mimicking alcoholic hepatitis – a review

    Directory of Open Access Journals (Sweden)

    Fernando Peixoto Ferraz de Campos

    2013-10-01

    Full Text Available Anaplastic large cell lymphoma (ALCL, described less than 30 years ago by Karl Lennert and Herald Stein in Kiel, West Germany, is a T-cell or null non-Hodgkin lymphoma, with distinctive morphology (hallmark cells, prominent sinus and/or perivascular growth pattern, characteristic immunophenotype (CD30+, cytotoxic granules protein+, CD3–/+ and specific genetic features as translocations involving the receptor tyrosine kinase called anaplastic lymphoma kinase (ALK on 2p23 and variable partners genes, which results in the expression of ALK fusion protein. The absence of ALK expression is also observed and is associated with poorer prognosis that seen with ALK expression. ALK-negative ALCL is more frequent in adults, with both nodal and extra nodal clinical presentation and includes several differential diagnoses with other CD30+ lymphomas. Liver involvement by ALCL is rare and is generally seen as mass formation; the diffuse pattern of infiltration is even more unusual. The authors present a case of a 72-year-old man who presented clinical symptoms of acute hepatic failure. The patient had a long history of alcohol abuse and the diagnosis of alcoholic hepatitis was highly considered, although the serum lactic dehydrogenase (LDH value was highly elevated. The clinical course was fulminant leading to death on the fourth day of hospitalization. Autopsy demonstrated diffuse neoplastic hepatic infiltration as well as splenic, pulmonary, bone marrow, and minor abdominal lymph nodes involvement by the tumor. Based on morphological, immunophenotypical, and immunohistochemical features, a diagnosis of ALK- negative ALCL was concluded. When there is marked elevation of LDH the possibility of lymphoma, ALCL and other types, should be the principal diagnosis to be considered.

  18. CD13-positive anaplastic large cell lymphoma of T-cell origin--a diagnostic and histogenetic problem.

    Science.gov (United States)

    Popnikolov, N K; Payne, D A; Hudnall, S D; Hawkins, H K; Kumar, M; Norris, B A; Elghetany, M T

    2000-12-01

    The expression of myelomonocytic-associated antigens in anaplastic large cell lymphomas (ALCLs), particularly those presenting in extranodal sites, can make their distinction from extramedullary myeloid cell tumors (EMCTs) or histiocytic tumors problematic. Yet, this distinction is clinically significant because of its therapeutic and prognostic implications. Herein, we describe a case of extranodal anaplastic lymphoma kinase-positive CD30-positive ALCL of T-cell origin in a 12-year-old boy, which was initially called an EMCT because of the expression of CD13 and HLA-DR detected by flow cytometry and the absence of other T-cell-related surface markers. However, the detection of cytoplasmic CD3 by flow cytometry prompted further studies. The tumor was composed of large cells with abundant slightly eosinophilic vacuolated cytoplasm and ovoid or reniform nuclei with a few small nucleoli. Using immunohistochemistry, the tumor was positive for CD45, CD30, CD45RO, and CD43 with a strong cytoplasmic and nuclear anaplastic lymphoma kinase stain. The tumor cells showed a T-cell clonal genotype. Electron microscopy revealed no ultrastructural features of myelomonocytic or histiocytic origin. The patient responded well to the chemotherapy and was in complete remission for 10 months at the time of submission of this manuscript. Review of the literature showed inconsistencies regarding the diagnosis, nomenclature, and, therefore, treatment and prognosis of these tumors. In addition, the CD13 expression in ALCL raises some histogenetic questions and may indicate origin from a pluripotent stem cell, misprogramming during malignant transformation, or a microenvironmental effect on lymphoid cell expression of surface antigens. Therefore, ALCL should be considered in the differential diagnosis of EMCTs or histiocytic tumors, particularly when surface marker lineage assignment is ambiguous. PMID:11100061

  19. Aurora A kinase regulates proper spindle positioning in C. elegans and in human cells.

    Science.gov (United States)

    Kotak, Sachin; Afshar, Katayon; Busso, Coralie; Gönczy, Pierre

    2016-08-01

    Accurate spindle positioning is essential for error-free cell division. The one-cell Caenorhabditis elegans embryo has proven instrumental for dissecting mechanisms governing spindle positioning. Despite important progress, how the cortical forces that act on astral microtubules to properly position the spindle are modulated is incompletely understood. Here, we report that the PP6 phosphatase PPH-6 and its associated subunit SAPS-1, which positively regulate pulling forces acting on spindle poles, associate with the Aurora A kinase AIR-1 in C. elegans embryos. We show that acute inactivation of AIR-1 during mitosis results in excess pulling forces on astral microtubules. Furthermore, we uncover that AIR-1 acts downstream of PPH-6-SAPS-1 in modulating spindle positioning, and that PPH-6-SAPS-1 negatively regulates AIR-1 localization at the cell cortex. Moreover, we show that Aurora A and the PP6 phosphatase subunit PPP6C are also necessary for spindle positioning in human cells. There, Aurora A is needed for the cortical localization of NuMA and dynein during mitosis. Overall, our work demonstrates that Aurora A kinases and PP6 phosphatases have an ancient function in modulating spindle positioning, thus contributing to faithful cell division. PMID:27335426

  20. Small cell anaplastic carcinoma of primary lung tumor in a miniature schnauzer dog

    International Nuclear Information System (INIS)

    A seven-year-old male, an intact miniature Schnauzer dog with history of vomiting, abdominal distention, anorexia, and dyspnea was referred for further evaluation and treatment. Thoracic radiographs showed the well marginated solitary mass with soft density in the right caudal lung field, and abdominal radiographs showed signs of ascites, such as abdominal distention and moderate serosal detail loss. On ultrasonograph and computed tomograph, it was observed that the mass compressed the caudal vena cava (CVC) and adhered to the heart. Exploratory thoracotomy was performed, and then it was showed that mass adhered heart, CVC, and diaphragm. The mass was fully rejected although adhered part of CVC could not be completely rejected. On histopathological findings, the mass was diagnosed as small-cell anaplastic carcinoma

  1. Clonal heterogeneity of small-cell anaplastic carcinoma of the lung demonstrated by flow-cytometric DNA analysis

    DEFF Research Database (Denmark)

    Vindeløv, L L; Hansen, H H; Christensen, I J;

    1980-01-01

    Flow-cytometric DNA analysis yields information on ploidy and proliferative characteristics of a cell population. The analysis was implemented on small-cell anaplastic carcinoma of the lung using a rapid detergent technique for the preparation of fine-needle aspirates for DNA determination and a...... newly developed procedure for storing aspirates at -80 degrees. Thirty-eight different metastases in 30 consecutive patients with small-cell anaplastic carcinoma of the lung were examined with a total of 273 fine-needle aspirations. The results on ploidy are reported in this paper. The degree of...... contamination of the aspirates with normal cells was determined by differential counts. The ratio of the peak channel numbers for the G1 phase of the tumor cells to that of the diploid standard (DNA index) was calculated and used for ploidy identification. Twenty-nine patients were evaluable with respect to DNA...

  2. Three Years Sustained Complete Remission Achieved in a Primary Refractory ALK-Positive Anaplastic T Large Cell Lymphoma Treated with Crizotinib

    Science.gov (United States)

    Mahuad, Carolina Valeria; Repáraz, María de los Ángeles Vicente; Zerga, Marta E.; Aizpurua, María Florencia; Casali, Claudia; Garate, Gonzalo

    2016-01-01

    The prognosis of the primary refractory anaplastic lymphoma kinase (ALK+) anaplastic T large cell lymphoma is ominous. The identification of molecular targets with potential to drive oncogenesis remains a cornerstone for the designing of new selective cancer therapies. Crizotinib is a selective ATP-competitive inhibitor for ALK, approved for its use in lung cancer with rearrangements on ALK gene. The reported cases describe the use of crizotinib as a bridging strategy prior to allotransplantation; there are no reported prolonged survivals under monotherapy with Crizotinib. We report a case of a primary refractory ALK+ anaplastic large-cell lymphoma that sustains complete response after 3 years of crizotinib monotherapy.

  3. Three Years Sustained Complete Remission Achieved in a Primary Refractory ALK-Positive Anaplastic T Large Cell Lymphoma Treated with Crizotinib.

    Science.gov (United States)

    Mahuad, Carolina Valeria; Repáraz, María de Los Ángeles Vicente; Zerga, Marta E; Aizpurua, María Florencia; Casali, Claudia; Garate, Gonzalo

    2016-06-28

    The prognosis of the primary refractory anaplastic lymphoma kinase (ALK+) anaplastic T large cell lymphoma is ominous. The identification of molecular targets with potential to drive oncogenesis remains a cornerstone for the designing of new selective cancer therapies. Crizotinib is a selective ATP-competitive inhibitor for ALK, approved for its use in lung cancer with rearrangements on ALK gene. The reported cases describe the use of crizotinib as a bridging strategy prior to allotransplantation; there are no reported prolonged survivals under monotherapy with Crizotinib. We report a case of a primary refractory ALK+ anaplastic large-cell lymphoma that sustains complete response after 3 years of crizotinib monotherapy. PMID:27441079

  4. Regulation of spindle orientation and neural stem cell fate in the Drosophila optic lobe

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    Brand Andrea H

    2007-01-01

    Full Text Available Abstract Background The choice of a stem cell to divide symmetrically or asymmetrically has profound consequences for development and disease. Unregulated symmetric division promotes tumor formation, whereas inappropriate asymmetric division affects organ morphogenesis. Despite its importance, little is known about how spindle positioning is regulated. In some tissues cell fate appears to dictate the type of cell division, whereas in other tissues it is thought that stochastic variation in spindle position dictates subsequent sibling cell fate. Results Here we investigate the relationship between neural progenitor identity and spindle positioning in the Drosophila optic lobe. We use molecular markers and live imaging to show that there are two populations of progenitors in the optic lobe: symmetrically dividing neuroepithelial cells and asymmetrically dividing neuroblasts. We use genetically marked single cell clones to show that neuroepithelial cells give rise to neuroblasts. To determine if a change in spindle orientation can trigger a neuroepithelial to neuroblast transition, we force neuroepithelial cells to divide along their apical/basal axis by misexpressing Inscuteable. We find that this does not induce neuroblasts, nor does it promote premature neuronal differentiation. Conclusion We show that symmetrically dividing neuroepithelial cells give rise to asymmetrically dividing neuroblasts in the optic lobe, and that regulation of spindle orientation and division symmetry is a consequence of cell type specification, rather than a mechanism for generating cell type diversity.

  5. {sup 18}F-FDG PET in Patients with Primary Systemic Anaplastic Large Cell Lymphoma: Differential Features According to Expression of Anaplastic Lymphoma Kinase

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Dong Yun; Lee, Jong Jin; Park, Seol Hoon; Chae, Sunyoung; Kim, Shin; Yoon, Dok Hyun; Suh, Cheolwon; Huh, Jooryung; Ryu, Jinsook [Univ. of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2013-12-15

    Primary systemic anaplastic large cell lymphoma (ALCL) is divided into two entities according to the expression of anaplastic lymphoma kinase (ALK). We investigated {sup 18}F-fluorodeoxyglucose positron emission tomography ({sup 18}F-FDG PET) findings in primary systemic ALCL according to ALK expression. Thirty-seven patients who had baseline PET before CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone)-based chemotherapy were enrolled. Among them, patients who underwent interim and/or post-therapy PET were further investigated for the treatment response and survival analysis. Baseline PET was analyzed visually and semi-quantitatively using peak SUV, and interim and post-therapy PETs were visually analyzed. All cases were {sup 18}F-FDG-avid on baseline PET. The peak SUV of ALK-positive ALCL (n =16, 18.7±10.5) was higher than that of ALK-negative ALCL (n =21, 10.0±4.9) (P =0.006). In ALK-negative ALCL, complete response (CR) rate in negative-interim PET was higher than positive-interim PET (100 % vs 37.5 %, P=0.02); however, there was no such difference in ALK-positive ALCL (100 % vs 75 %, P =0.19). The 3-year progression-free survival (PFS) was not significantly different between ALK-positive and ALK-negative ALCL (72.7 % vs 47.6 %, P =0.34). In ALK-negative ALCL, negative interim and post-therapy PET patients had better 3-year PFS than positive interim (83.3 % vs 25.0 %, P =0.06) and post-therapy PET patients (70.0%vs 20.0 %, P =0.04). In contrast, ALK-positive ALCL had no such differences between PFS and PET results. On baseline PET, all cases showed {sup 18}F-FDG avidity, and ALK expression was related to higher {sup 18}F-FDG uptake. ALK-positive patients tend to have better PFS than ALK-negative patients. Negative-interim PET was a good indicator of CR, and interim or post-therapy PET was helpful for predicting the prognosis only in the ALK-negative group.

  6. A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells.

    Science.gov (United States)

    Hehnly, Heidi; Canton, David; Bucko, Paula; Langeberg, Lorene K; Ogier, Leah; Gelman, Irwin; Santana, L Fernando; Wordeman, Linda; Scott, John D

    2015-01-01

    Correct orientation of the mitotic spindle in stem cells underlies organogenesis. Spindle abnormalities correlate with cancer progression in germ line-derived tumors. We discover a macromolecular complex between the scaffolding protein Gravin/AKAP12 and the mitotic kinases, Aurora A and Plk1, that is down regulated in human seminoma. Depletion of Gravin correlates with an increased mitotic index and disorganization of seminiferous tubules. Biochemical, super-resolution imaging, and enzymology approaches establish that this Gravin scaffold accumulates at the mother spindle pole during metaphase. Manipulating elements of the Gravin-Aurora A-Plk1 axis prompts mitotic delay and prevents appropriate assembly of astral microtubules to promote spindle misorientation. These pathological responses are conserved in seminiferous tubules from Gravin(-/-) mice where an overabundance of Oct3/4 positive germ line stem cells displays randomized orientation of mitotic spindles. Thus, we propose that Gravin-mediated recruitment of Aurora A and Plk1 to the mother (oldest) spindle pole contributes to the fidelity of symmetric cell division. PMID:26406118

  7. P-glycoprotein Mediates Ceritinib Resistance in Anaplastic Lymphoma Kinase-rearranged Non-small Cell Lung Cancer

    OpenAIRE

    Ryohei Katayama; Takuya Sakashita; Noriko Yanagitani; Hironori Ninomiya; Atsushi Horiike; Luc Friboulet; Gainor, Justin F.; Noriko Motoi; Akito Dobashi; Seiji Sakata; Yuichi Tambo; Satoru Kitazono; Shigeo Sato; Sumie Koike; John Iafrate, A.

    2015-01-01

    The anaplastic lymphoma kinase (ALK) fusion oncogene is observed in 3%–5% of non-small cell lung cancer (NSCLC). Crizotinib and ceritinib, a next-generation ALK tyrosine kinase inhibitor (TKI) active against crizotinib-refractory patients, are clinically available for the treatment of ALK-rearranged NSCLC patients, and multiple next-generation ALK-TKIs are currently under clinical evaluation. These ALK-TKIs exhibit robust clinical activity in ALK-rearranged NSCLC patients; however, the emerge...

  8. ALK-positive anaplastic large cell lymphoma with prominent bone involvement in a 13-year-old boy

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    Tian C

    2016-01-01

    Full Text Available Chen Tian, Yong Yu, Hongliang Yang, Lei Zhu, Yafei Wang, Yizhuo Zhang Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of China Introduction: Anaplastic lymphoma kinase-positive (ALK+ anaplastic large cell lymphoma (ALCL is a type of non-Hodgkin lymphoma, which has strong expression of cluster of differentiation (CD-30 and ALK. ALCL sometimes can involve the bone marrow, and in advanced stages, it can produce destructive bone lesions. But ALK+ ALCL with prominent bone involvement is very rare, especially in children. Case report: A 13-year-old boy presented with waist pain and low-grade fever for 8 months. The biopsy of soft tissue lesions around the thoracic spine showed that these cells were positive for ALK-1, CD30, leukocyte common antigen, CD3, CD4, and CD8, as well as being negative for epithelial membrane antigen and pan-cytokeratin, which revealed ALCL. After six cycles of a regimen consisting of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate and cytarabine (hyper-CVAD/MA and autologous hematopoietic stem cell transplantation, he achieved complete remission (CR. Conclusion: It is generally believed that the regimen consisting of cyclophosphamide, hydroxydaunorubicin (doxorubicin, vincristine, and prednisolone (CHOP is also applicable to ALCL. Because of the tendency of rapid progression and the frequency of B symptoms, ALCL in children and young adults is treated with high-grade chemotherapy such as hyper-CVAD/MA. Keywords: anaplastic large cell lymphoma, anaplastic lymphoma kinase, bone involvement, hyper-CVAD/MA

  9. Clinical and laboratory characteristics of systemic anaplastic large cell lymphoma in Chinese patients

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    Wang Yan-Fang

    2012-07-01

    Full Text Available Abstract Background Systemic anaplastic large cell lymphoma (S-ALCL is a rare disease with a highly variable prognosis and no standard chemotherapy regimen. Anaplastic lymphoma kinase (ALK has been reported as an important prognostic factor correlated with S-ALCL in many but not all studies. In our study, we retrospectively analyzed 92 patients with S-ALCL from the Peking University Lymphoma Center for clinical and molecular prognostic factors to make clear the role of ALK and other prognostic factors in Han Chinese S-ALCL. Results The majority of Chinese S-ALCL patients were young male patients (median age 26, male/female ratio 1.7 and the median age was younger than previous reports regardless of ALK expression status. The only statistically significant different clinical characteristic in S-ALCL between ALK positive (ALK+ and ALK negative (ALK- was age, with a younger median age of 22 for ALK+ compared with 30 for ALK-. However, when pediatric patients (≤18 were excluded, there was no age difference between ALK+ and ALK-. The groups did not differ in the proportion of males, those with clinical stage III/IV (49 vs 51% or those with extranodal disease (53 vs 59%. Of 73 evaluable patients, the 3-year and 5-year survival rates were 60% and 47%, respectively. Univariate analysis showed that three factors: advanced stage III/IV, lack of expression of ALK, and high Ki-67 expression, were associated with treatment failure in patients with S-ALCL. However, ALK expression correlated with improved survival only in patients younger than 14 years, while not in adult patients. In multivariate analysis, only clinical stage was an independent prognostic factor for survival. Expressions of Wilms tumor 1 (WT1 and B-cell lymphoma 2 protein (BCL-2 correlated with the expression of ALK, but they did not have prognostic significance. High Ki-67 expression was also a poor prognostic factor. Conclusions Our results show that ALK expression alone is not

  10. Prognostic significance and therapeutic potential of the activation of anaplastic lymphoma kinase/protein kinase B/mammalian target of rapamycin signaling pathway in anaplastic large cell lymphoma

    International Nuclear Information System (INIS)

    Activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway has been demonstrated to be involved in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated tumorigenesis in anaplastic large cell lymphoma (ALCL) and correlated with unfavorable outcome in certain types of other cancers. However, the prognostic value of AKT/mTOR activation in ALCL remains to be fully elucidated. In the present study, we aim to address this question from a clinical perspective by comparing the expressions of the AKT/mTOR signaling molecules in ALCL patients and exploring the therapeutic significance of targeting the AKT/mTOR pathway in ALCL. A cohort of 103 patients with ALCL was enrolled in the study. Expression of ALK fusion proteins and the AKT/mTOR signaling phosphoproteins was studied by immunohistochemical (IHC) staining. The pathogenic role of ALK fusion proteins and the therapeutic significance of targeting the ATK/mTOR signaling pathway were further investigated in vitro study with an ALK + ALCL cell line and the NPM-ALK transformed BaF3 cells. ALK expression was detected in 60% of ALCLs, of which 79% exhibited the presence of NPM-ALK, whereas the remaining 21% expressed variant-ALK fusions. Phosphorylation of AKT, mTOR, 4E-binding protein-1 (4E-BP1), and 70 kDa ribosomal protein S6 kinase polypeptide 1 (p70S6K1) was detected in 76%, 80%, 91%, and 93% of ALCL patients, respectively. Both phospho-AKT (p-AKT) and p-mTOR were correlated to ALK expression, and p-mTOR was closely correlated to p-AKT. Both p-4E-BP1 and p-p70S6K1 were correlated to p-mTOR, but were not correlated to the expression of ALK and p-AKT. Clinically, ALK + ALCL occurred more commonly in younger patients, and ALK + ALCL patients had a much better prognosis than ALK-ALCL cases. However, expression of p-AKT, p-mTOR, p-4E-BP1, or p-p70S6K1 did not have an impact on the clinical outcome. Overexpression of NPM-ALK in a nonmalignant murine pro-B lymphoid cell line, BaF3, induced the

  11. A nanocomplex that is both tumor cell-selective and cancer gene-specific for anaplastic large cell lymphoma

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    Zu Youli

    2011-01-01

    Full Text Available Abstract Background Many in vitro studies have demonstrated that silencing of cancerous genes by siRNAs is a potential therapeutic approach for blocking tumor growth. However, siRNAs are not cell type-selective, cannot specifically target tumor cells, and therefore have limited in vivo application for siRNA-mediated gene therapy. Results In this study, we tested a functional RNA nanocomplex which exclusively targets and affects human anaplastic large cell lymphoma (ALCL by taking advantage of the abnormal expression of CD30, a unique surface biomarker, and the anaplastic lymphoma kinase (ALK gene in lymphoma cells. The nanocomplexes were formulated by incorporating both ALK siRNA and a RNA-based CD30 aptamer probe onto nano-sized polyethyleneimine-citrate carriers. To minimize potential cytotoxicity, the individual components of the nanocomplexes were used at sub-cytotoxic concentrations. Dynamic light scattering showed that formed nanocomplexes were ~140 nm in diameter and remained stable for more than 24 hours in culture medium. Cell binding assays revealed that CD30 aptamer probes selectively targeted nanocomplexes to ALCL cells, and confocal fluorescence microscopy confirmed intracellular delivery of the nanocomplex. Cell transfection analysis showed that nanocomplexes silenced genes in an ALCL cell type-selective fashion. Moreover, exposure of ALCL cells to nanocomplexes carrying both ALK siRNAs and CD30 RNA aptamers specifically silenced ALK gene expression, leading to growth arrest and apoptosis. Conclusions Taken together, our findings indicate that this functional RNA nanocomplex is both tumor cell type-selective and cancer gene-specific for ALCL cells.

  12. Breast Implant Informed Consent Should Include the Risk of Anaplastic Large Cell Lymphoma.

    Science.gov (United States)

    Clemens, Mark W; Miranda, Roberto N; Butler, Charles E

    2016-04-01

    Breast implant-associated anaplastic large cell lymphoma (ALCL) is a rare T-cell lymphoma arising around breast implants. Public awareness has increased following a safety communication warning of the association of breast implant-associated ALCL by the U.S. Food and Drug Administration in 2011. Difficulty with determining an accurate assessment of risk, including diagnosis, or standardized treatment regimen has led surgeons to commonly omit preoperative discussion of this rare and frequently misunderstood cancer. Risk disclosure is a form of respect for patient autonomy, and informed consent has positive practical and moral consequences for the practice of plastic surgery. A model of breast implant-associated ALCL informed consent implementation and health care provider education are reviewed with 1-year process follow-up at a tertiary cancer center. Breast implant-associated ALCL should be included during preoperative counseling on the risks of breast implantation when obtaining informed consent. Pertinent aspects of decision-making include disease awareness, presenting symptoms, and resources for concerned patients. Education of health care professionals and provision of patient-focused materials ensures effectiveness of the informed consent process. PMID:27018666

  13. Pleomorphic xanthoastrocytoma with anaplastic features

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    Cheng ZHI

    2015-08-01

    Full Text Available Objective  To explore the clinical pathological characteristics, immunophenotyping, diagnosis and differential diagnosis and prognosis of pleomorphic xanthoastrocytoma (PXA with anaplastic features.  Methods  HE staining was used for histological observation. The expressions of glial fibrillary acidic protein (GFAP, vimentin (Vim, CD34, epithelial membrane antigen (EMA, progestrone receptor (PR, neurofilment protein (NF, neuronal nuclei (NeuN, synaptophysin (Syn, Nestin (Nes, S-100 protein (S-100, P53 and Ki-67 labeling index were detected by immunohistochemical method. BRAF mutation was detected by polymerase chain reaction (PCR amplification.  Results  A 43-year-old male patient presented with repeatedly paroxysmal tic of limbs and disturbance of consciousness. Cranial MRI revealed multiple abnormal signals in left temporo-occipito-parietal lobe and posterior horn of lateral ventricle, with unclear borderline and cystic degeneration. Surgical removal of the lesion was performed. Histologically, the tumor was biphasic. One part was composed of spindle cells arranged in fascicles or as running water, with weird multinuclear giant cells. Abundant vacuolated lipidized cytoplasm could be seen. Mitosis and "map"-like necrosis were noted. Another part revealed the tumor cells were consistent in size and uniform in distribution, with loose background tissue. Immunohistochemistry showed tumor cells were diffusely positive for GFAP, Vim, S-100, Nes, CD34 and P53, and negative for EMA, Syn, NeuN and NF. Ki-67 labeling index was about 15%. Reticular fiber staining showed abundant reticular fibers in the tumor tissue. BRAF mutation detected by PCR amplification was not found.  Conclusions  Classified as grade Ⅱ in the World Health Organization (WHO classification, the prognosis of PXA is good. A diagnosis of PXA with anaplastic features should be considered when the tumor demonstrates mitotic activity > 5/10 high power field (HPF and/or areas of

  14. Pulmonary sclerosing hemangioma presenting with dense spindle stroma cells: a potential diagnostic pitfall

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    Lin Xu-Yong

    2012-12-01

    Full Text Available Abstract Pulmonary sclerosing hemangioma (PSH is an uncommon pulmonary tumor. Histologically, PSH typically consists of two types of cells, surface cuboidal cells and polygonal cells, four architectural patterns including papillary, sclerotic, solid, and hemorrhagic. Herein, we present a case of PSH in a 59-year-old Chinese female. The tumor was predominantly composed of solid area presenting with diffuse spindle cells rather than polygonal cells. Focally, classical papillary and sclerotic area could be seen. Immunohistochemical staining showed that the spindle cells were positive for TTF-1, EMA, Actin(SM and Vimentin, and negative for cytokeratin, cytokeratin7, cytokeratin5/6, surfactant apoprotein A, surfactant apoprotein B, CD34, CD99, S-100, HMB45, Desmin, Synaptophysin, CD56, ALK and Calretinin. The immunophenotype of the dense spindle cells in this case was similar to that of the polygonal cells, and thus the spindle cells may be the variants of polygonal cells. Based on morphologic features and the immunohistochemical profile, the tumor was diagnosed as a PSH. The significance of spindle cells change is unclear for us. To our knowledge, this is the first reported case of PSH showing dense spindle cells in solid area. This case represents a potential diagnostic pitfall, as it may be misdiagnosed as a mesenchymal tumor such as inflammatory myofibroblastic tumor, synovial sarcoma, solitary fibrous tumor, leiomyoma, or even mesothelioma, especially if the specimen is limited or from fine- needle aspiration. Virtual slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1235401622806126

  15. Successful treatment in a child with anaplastic large cell lymphoma and coexistence of pulmonary tuberculosis.

    Science.gov (United States)

    Baka, Margarita; Doganis, Dimitrios; Pourtsidis, Apostolos; Tsolia, Maria; Bouhoutsou, Despina; Varvoutsi, Maria; Strantzia, Katerina; Kosmidis, Helen

    2013-01-01

    A 13-year-old girl was admitted to our department with a history of severe pain of her left axilla and fever. On physical examination, a block of lymph nodes in her left axilla, diffuse papular rash, and red-violet swelling of her supraclavicular and subclavian region were noted. Imaging investigations revealed left axillar and supraclavicular lymphadenopathy and a small nodular shade in the upper lobe of her left lung. A biopsy from an axillary lymph node established the diagnosis of anaplastic large cell lymphoma (ALCL), whereas DNA of Mycobacterium tuberculosis was detected by polymerase chain reaction (PCR) in the same tissue biopsy. Patient was started on chemotherapy for ALCL and achieved remission of all initially involved fields. Nevertheless, two new nodular lesions were detected in the left lower lobe. Biopsy revealed granulomas, and PCR was positive for M. tuberculosis. Our patient received treatment with the combination of isoniazid and rifampin (12 months), pyrazinamide (the first 2 months), and maintenance chemotherapy for her ALCL for one year simultaneously. Four years later, she is disease free for both mycobacterial infection and lymphoma. We are reporting this successful management of mycobacterial infection in a patient with ALCL despite intensive chemotherapy that the patient received at the same time. PMID:23841007

  16. Successful Treatment in a Child with Anaplastic Large Cell Lymphoma and Coexistence of Pulmonary Tuberculosis

    Directory of Open Access Journals (Sweden)

    Margarita Baka

    2013-01-01

    Full Text Available A 13-year-old girl was admitted to our department with a history of severe pain of her left axilla and fever. On physical examination, a block of lymph nodes in her left axilla, diffuse papular rash, and red-violet swelling of her supraclavicular and subclavian region were noted. Imaging investigations revealed left axillar and supraclavicular lymphadenopathy and a small nodular shade in the upper lobe of her left lung. A biopsy from an axillary lymph node established the diagnosis of anaplastic large cell lymphoma (ALCL, whereas DNA of Mycobacterium tuberculosis was detected by polymerase chain reaction (PCR in the same tissue biopsy. Patient was started on chemotherapy for ALCL and achieved remission of all initially involved fields. Nevertheless, two new nodular lesions were detected in the left lower lobe. Biopsy revealed granulomas, and PCR was positive for M. tuberculosis. Our patient received treatment with the combination of isoniazid and rifampin (12 months, pyrazinamide (the first 2 months, and maintenance chemotherapy for her ALCL for one year simultaneously. Four years later, she is disease free for both mycobacterial infection and lymphoma. We are reporting this successful management of mycobacterial infection in a patient with ALCL despite intensive chemotherapy that the patient received at the same time.

  17. Infectious Mimicry Complicates Diagnosis in Hemophagocytic Syndrome Caused by Anaplastic Large-Cell Lymphoma

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    Michael J. Peluso

    2012-01-01

    Full Text Available Hemophagocytic syndrome (HPS arises secondary to genetic, rheumatologic, neoplastic, and infectious causes. We discuss a patient whose presentation was consistent with systemic infection but was discovered to have HPS of unknown etiology. The presenting symptoms, as well as unremarkable malignancy and rheumatologic workups, led to the pursuit of an infectious cause, but the patient was ultimately discovered to have an occult anaplastic large-cell lymphoma (ALCL. This case demonstrates the diagnostic challenges that result from infectious mimicry in the context of HPS—first, in distinguishing noninfectious HPS from the systemic inflammation that can result from a widespread infectious process, second, in the identification of the precipitating cause of HPS. While evidence of these challenges has been suggested by the limited literature on HPS and ALCL, our case illustrates the diagnostic dilemma that arises when tissue biopsy does not quickly reveal an etiology. It is important that all physicians be aware that HPS can mimic infection and be prepared to redirect the workup when an infectious etiology for HPS cannot be identified.

  18. Current Status of Targeted Therapy for Anaplastic Lymphoma Kinase in Non-small Cell Lung Cancer

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    Li MA

    2014-12-01

    Full Text Available The rate of the anaplastic lymphoma kinase (ALK gene rearrangements in non-small cell lung cancer (NSCLC tissues is 3%-5%. The first-in-class ALK tyrosine kinase inhibitor, crizotinib, can effectively target these tumors represent a significant advance in the evolution of personalized medicine for NSCLC. A randomized phase III clinical trial in which superiority of crizotinib over chemotherapy was seen in previously treated ALK-positive NSCLC patients demonstrated durable responses and well tolerance in the majority of ALK-positive NSCLC patients treated with crizotinib. However, despite the initial responses, most patients develop acquired resistance to crizotinib. Several novel therapeutic approaches targeting ALK-positive NSCLC are currently under evaluation in clinical trials, including second-generation ALK inhibitors, such as LDK378, CH5424802 (RO5424802, and AP26113, and new agents shock protein 90 inhibitors. This review aims to present the current knowledge on this fusion gene, the treatment advances, and novel drug clinical trials in ALK rearranged NSCLC.

  19. ULTRASONOGRAPHIC FEATURES OF CANINE GASTROINTESTINAL STROMAL TUMORS COMPARED TO OTHER GASTROINTESTINAL SPINDLE CELL TUMORS.

    Science.gov (United States)

    Hobbs, Joshua; Sutherland-Smith, James; Penninck, Dominique; Jennings, Samuel; Barber, Lisa; Barton, Bruce

    2015-01-01

    Canine gastrointestinal stromal tumors (GISTs) are a recent subtype of gastrointestinal spindle cell tumor recognized with the increasing use of immunohistochemistry. To our knowledge, no imaging features have been described in immunostochemically confirmed canine GISTs. The objective of this retrospective, cross-sectional study was to describe ultrasonographic features of canine GISTs compared with other spindle cell tumors. Thirty-seven dogs with an ultrasonographically visible gastrointestinal mass and a histopathologic diagnosis of spindle cell neoplasia were examined. Immunohistochemistry staining was performed for retrieved tissue samples to further differentiate the tumor type and each sample was interpreted by a single veterinary pathologist. Ultrasonographic features recorded examined included mass echogenicity, homogeneity, presence of cavitation, layer of origin, bowel wall symmetry, and loss of wall layering, location, size, vascularity, and evidence of perforation or ulceration. Tumor types included 19 GISTs, eight leiomyosarcomas, six leiomyomas, and four nonspecified sarcomas. Gastrointestinal stromal tumors were significantly more likely to be associated (P < 0.03) with abdominal effusion than other tumor types. There was overlap between the anatomical locations of all tumors types with the exception of the cecum where all eight tumors identified were GISTs. Besides location, there were no unique ultrasound features of GISTs that would allow distinction from other gastrointestinal spindle cell tumors. Similar to previous studies, GISTs appeared to be the most common spindle cell tumor associated with the cecum in our sample of dogs. The high frequency of abdominal effusion with GIST's was of unknown etiology could possibly have been due to septic peritonitis. PMID:25846814

  20. Cep55 regulates spindle organization and cell cycle progression in meiotic oocyte.

    Science.gov (United States)

    Xu, Zhao-Yang; Ma, Xue-Shan; Qi, Shu-Tao; Wang, Zhen-Bo; Guo, Lei; Schatten, Heide; Sun, Qing-Yuan; Sun, Ying-Pu

    2015-01-01

    Cep55 is a relatively novel member of the centrosomal protein family. Here, we show that Cep55 is expressed in mouse oocytes from the germinal vesicle (GV) to metaphase II (MII) stages. Immuostaining and confocal microscopy as well as time lapse live imaging after injection of mRNA encoding fusion protein of Cep55 and GFP identified that Cep55 was localized to the meiotic spindle, especially to the spindle poles at metaphase, while it was concentrated at the midbody in telophase in meiotic oocytes. Knockdown of Cep55 by specific siRNA injection caused the dissociation of γ-tubulin from the spindle poles, resulting in severely defective spindles and misaligned chromosomes, leading to metaphase I arrest and failure of first polar body (PB1) extrusion. Correspondingly, cyclin B accumulation and spindle assembly checkpoint (SAC) activation were observed in Cep55 knockdown oocytes. Our results suggest that Cep55 may act as an MTOC-associated protein regulating spindle organization, and thus cell cycle progression during mouse oocyte meiotic maturation. PMID:26582107

  1. Sialylation by β-galactoside α-2,6-sialyltransferase and N-glycans regulate cell adhesion and invasion in human anaplastic large cell lymphoma

    OpenAIRE

    Suzuki, Osamu; Abe, Masafumi; HASHIMOTO, YUKO

    2015-01-01

    The interaction between cell surface glycans and extracellular matrix (ECM) including galectins is known to be closely associated with tumor cell adhesion, invasion and metastasis. We analyzed the roles of cell surface sialylation or glycosylation in galectin or ECM-mediated cell adhesion and invasion of human malignant lymphoma cells. Neuraminidase from Arthrobacter ureafaciens (AU) treatment resulted in reduction of cell adhesion to galectin-8 in human anaplastic large cell lymphoma (H-ALCL...

  2. Radmis, a novel mitotic spindle protein that functions in cell division of neural progenitors.

    Directory of Open Access Journals (Sweden)

    Takahito Yumoto

    Full Text Available Developmental dynamics of neural stem/progenitor cells (NSPCs are crucial for embryonic and adult neurogenesis, but its regulatory factors are not fully understood. By differential subtractive screening with NSPCs versus their differentiated progenies, we identified the radmis (radial fiber and mitotic spindle/ckap2l gene, a novel microtubule-associated protein (MAP enriched in NSPCs. Radmis is a putative substrate for the E3-ubiquitin ligase, anaphase promoting complex/cyclosome (APC/C, and is degraded via the KEN box. Radmis was highly expressed in regions of active neurogenesis throughout life, and its distribution was dynamically regulated during NSPC division. In embryonic and perinatal brains, radmis localized to bipolar mitotic spindles and radial fibers (basal processes of dividing NSPCs. As central nervous system development proceeded, radmis expression was lost in most brain regions, except for several neurogenic regions. In adult brain, radmis expression persisted in the mitotic spindles of both slowly-dividing stem cells and rapid amplifying progenitors. Overexpression of radmis in vitro induced hyper-stabilization of microtubules, severe defects in mitotic spindle formation, and mitotic arrest. In vivo gain-of-function using in utero electroporation revealed that radmis directed a reduction in NSPC proliferation and a concomitant increase in cell cycle exit, causing a reduction in the Tbr2-positive basal progenitor population and shrinkage of the embryonic subventricular zone. Besides, radmis loss-of-function by shRNAs induced the multipolar mitotic spindle structure, accompanied with the catastrophe of chromosome segregation including the long chromosome bridge between two separating daughter nuclei. These findings uncover the indispensable role of radmis in mitotic spindle formation and cell-cycle progression of NSPCs.

  3. Diffuse large B cell lymphoma of thyroid as a masquerader of anaplastic carcinoma of thyroid, diagnosed by FNA: a case report

    Directory of Open Access Journals (Sweden)

    Dehghani Mehdi

    2006-01-01

    Full Text Available Abstract Background Both thyroid lymphoma and anaplastic carcinoma of thyroid present with rapidly growing mass in eldery patients. Anaplastic carcinoma has high mortality rate and combination of surgery, radiation therapy and multidrug chemotherapy are the best chance for cure. Prognosis of thyroid lymphoma is excellent and chemotherapy for widespred lymphoms and radiotherapy with or without adjuvant chemotherapy for tumors localized to the gland, are the treatment of choice. Case report This article reports a 70 year old man presenting with diffuse neck swelling and hoarseness of few weeks duration. Fine needle aspiration was done and reported as anaplastic carcinoma of thyroid which thyroidectomy was planned. The slides were sent for second opinion. After review, with initial diagnosis of anaplastic carcinoma versus lymphoma, immunocytochemical study was performed. Smears were positive for B cell markers and negative for cytokeratin, so with the impression of diffuse large B cell lymphoma, the patient received two courses of chemotherapy by which the tumor disappeared during two weaks. Conclusion Despite previous reports, stating easy diagnosis of high-grade thyroid lymphoma on the grounds of cytomorphological features we like to emphasize, overlapping cytologic features of the curable high grade thyroid lymphoma form noncurable anaplastic thyroid carcinoma and usefulness of immunocytochemistry to differentiate these two disease.

  4. Anaplastic astrocytoma.

    Science.gov (United States)

    Grimm, Sean A; Chamberlain, Marc C

    2016-07-01

    Anaplastic astrocytoma (AA) is a diffusely infiltrating, malignant, astrocytic, primary brain tumor. AA is currently defined by histology although future classification schemes will include molecular alterations. AA can be separated into subgroups, which share similar molecular profiles, age at diagnosis and median survival, based on 1p/19q co-deletion status and IDH mutation status. AA with co-deletion of chromosomes 1p and 19q and IDH mutation have the best prognosis. AA with IDH mutation and no 1p/19q co-deletion have intermediate prognosis and AA with wild-type IDH have the worst prognosis and share many molecular alterations with glioblastoma. Treatment of noncodeleted AA based on preliminary results from the CATNON clinical trial consists of maximal safe resection followed by radiotherapy with post-radiotherapy temozolomide (TMZ) chemotherapy. The role of concurrent TMZ and whether IDH1 subgroups benefit from TMZ is currently being evaluated in the recently completed randomized, prospective Phase III clinical trial, CATNON. PMID:27230974

  5. The transforming parasite Theileria co-opts host cell mitotic and central spindles to persist in continuously dividing cells.

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    Conrad von Schubert

    Full Text Available The protozoan parasite Theileria inhabits the host cell cytoplasm and possesses the unique capacity to transform the cells it infects, inducing continuous proliferation and protection against apoptosis. The transforming schizont is a multinucleated syncytium that resides free in the host cell cytoplasm and is strictly intracellular. To maintain transformation, it is crucial that this syncytium is divided over the two daughter cells at each host cell cytokinesis. This process was dissected using different cell cycle synchronization methods in combination with the targeted application of specific inhibitors. We found that Theileria schizonts associate with newly formed host cell microtubules that emanate from the spindle poles, positioning the parasite at the equatorial region of the mitotic cell where host cell chromosomes assemble during metaphase. During anaphase, the schizont interacts closely with host cell central spindle. As part of this process, the schizont recruits a host cell mitotic kinase, Polo-like kinase 1, and we established that parasite association with host cell central spindles requires Polo-like kinase 1 catalytic activity. Blocking the interaction between the schizont and astral as well as central spindle microtubules prevented parasite segregation between the daughter cells during cytokinesis. Our findings provide a striking example of how an intracellular eukaryotic pathogen that evolved ways to induce the uncontrolled proliferation of the cells it infects usurps the host cell mitotic machinery, including Polo-like kinase 1, one of the pivotal mitotic kinases, to ensure its own persistence and survival.

  6. A rare spindle-cell variant of non-Hodgkin's lymphoma of the mandible

    Science.gov (United States)

    Srikant, N; Yinti, Shanmukha Raviteja; Baliga, Mohan; Kini, Hema

    2016-01-01

    A 64-year-old male farmer presented with a rapidly progressive swelling of the left mandible since 6 months. The swelling was firm to hard, diffuse, nontender, obliterating the vestibule with paresthesia of lower lip. The cone beam computed tomography imaging revealed an ill-defined, moth-eaten radiolucency with destruction of the buccal and lingual cortical plates. The rapid growth and aggressive behavior of the lesion coupled with guidance from the patient's previous reports from the incisional biopsy and fine needle aspiration cytology warranted a mandibular resection. Microscopic examination showed an encapsulated lesion situated in the connective tissue containing a mixture of proliferating spindle-shaped cells arranged in fascicles and round cells infiltrating into the connective tissue stroma and bone. The neoplastic cells exhibited atypical features such as pleomorphism, hyperchromatism and increased mitotic figures with noncleaved nuclei. A working diagnosis of a spindle-cell sarcoma was arrived at with various differentials provided such as fibrosarcoma, rhabdomyosarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, Langerhans cell histiocytosis and lymphoma and stating the need for immunohistochemistry to subtype the tumor. The neoplastic cells were negative for Van Gieson's stain and Masson's trichrome. Immunohistochemical analysis performed using desmin, smooth muscle actin, S-100 and CD1a in a bid to determine the phenotype of the tumor and rule out the previously stated differentials were all negative for the lesion. Lymphoid markers such as leukocyte common antigen and CD20 (cluster differentiation marker for B-cells) showed positivity in spindle-shaped cells as well as round cells indicating the tumor to be a lymphoproliferative lesion of B-cell type. A final diagnosis of “spindle-cell variant of non-Hodgkin's lymphoma” was rendered based on the immunohistochemical profile. PMID:27194875

  7. Spindle Cell Carcinoma of the Larynx: A Confusing Diagnosis for the Pathologist and Clinician

    Science.gov (United States)

    Bostanci, Asli; Ozbilim, Gulay; Turhan, Murat

    2015-01-01

    Laryngeal spindle cell carcinoma (SpCC) is an uncommon subtype of squamous cell carcinoma which represents 0.5% of all laryngeal squamous cell carcinomas. It is a biphasic tumor consisting of the combination of a malignant mesenchymal spindle cell component and a squamous cell component that includes dysplasia, carcinoma in situ, or invasive carcinoma. Although it has aggressive biological features, the probability of making a diagnosis in the early stages is high as it often leads to obstructive symptoms in the early period. Due to its low incidence, there is no clear consensus on prognostic factors and optimal treatment strategies yet. In this paper, a 60-year-old laryngeal SpCC case that was effectively treated with wide local excision followed by adjuvant radiotherapy was presented with the literature. PMID:26788392

  8. Spindle Cell Carcinoma of the Larynx: A Confusing Diagnosis for the Pathologist and Clinician

    Directory of Open Access Journals (Sweden)

    Asli Bostanci

    2015-01-01

    Full Text Available Laryngeal spindle cell carcinoma (SpCC is an uncommon subtype of squamous cell carcinoma which represents 0.5% of all laryngeal squamous cell carcinomas. It is a biphasic tumor consisting of the combination of a malignant mesenchymal spindle cell component and a squamous cell component that includes dysplasia, carcinoma in situ, or invasive carcinoma. Although it has aggressive biological features, the probability of making a diagnosis in the early stages is high as it often leads to obstructive symptoms in the early period. Due to its low incidence, there is no clear consensus on prognostic factors and optimal treatment strategies yet. In this paper, a 60-year-old laryngeal SpCC case that was effectively treated with wide local excision followed by adjuvant radiotherapy was presented with the literature.

  9. SPINDLE CELL CARCINOMA OF MAXILLA:CASE REPORT OF A RARE ENTITY AND REVIEW OF LITERATURE

    Directory of Open Access Journals (Sweden)

    Ajish M. Saji

    2013-07-01

    Full Text Available Spindle cell Carcinoma is a rare biphasic neoplasm consisting of epithelial andmesenchymal components and accounts for less than 1% of all tumours of oralregion. It is a rare aggressive variant of squamous cell carcinoma which frequentlyrecurs and metastasizes with poor prognosis compared to classical squamous cellcarcinoma. The biologic behaviour is comparable to poorly differentiated SquamousCell Carcinoma. The 5 year disease free survival rate is approximately 30% for all OralTumors. The variants of squamous cell carcinoma frequently arise in mucosa of upperaerodigestive tract. The most common site in head and neck region is in larynx andhypopharynx; the oral cavity being rarely affected. This biphasic malignant neoplasmoften assumes a sarcomatous appearance and may present diagnostic difficulty. Hencecareful histopathologic analysis is warranted. We report a rare case of spindle cellcarcinoma in unusual location with immunohistochemical findings and review of theliterature.

  10. Non-anaplastic peripheral T cell lymphoma in children and adolescents-an international review of 143 cases.

    Science.gov (United States)

    Mellgren, K; Attarbaschi, A; Abla, O; Alexander, S; Bomken, S; Bubanska, E; Chiang, A; Csóka, M; Fedorova, A; Kabickova, E; Kapuscinska-Kemblowska, L; Kobayashi, R; Krenova, Z; Meyer-Wentrup, F; Miakova, N; Pillon, M; Plat, G; Uyttebroeck, A; Williams, D; Wróbel, G; Kontny, U

    2016-08-01

    Peripheral T cell lymphomas (PTCL) are rare in children and adolescents, and data about outcome and treatment results are scarce. The present study is a joint, international, retrospective analysis of 143 reported cases of non-anaplastic PTCL in patients event-free survival was (pEFS) 0.45 ± 0.05. Patients with SP TCL had a good outcome with 5-year pOS of 0.78 ± 0.1 while patients with HS TCL were reported with 5-year pOS of only 0.13 ± 0.12. Twenty-five percent of the patients were reported to have a pre-existing condition, and this group had a dismal outcome with 5-year pOS of 0.29 ± 0.09. The distribution of non-anaplastic PTCL subtypes in pediatric and adolescent patients differs from what is reported in adult patients. Overall outcome depends on the subtype with some doing better than others. Pre-existing conditions are frequent and associated with poor outcomes. There is a clear need for subtype-based treatment recommendations for children and adolescents with PTCL. PMID:27270301

  11. Galectin-1-mediated cell adhesion, invasion and cell death in human anaplastic large cell lymphoma: regulatory roles of cell surface glycans.

    Science.gov (United States)

    Suzuki, Osamu; Abe, Masafumi

    2014-05-01

    Galectin-1 is known to be one of the extracellular matrix proteins. To elucidate the biological roles of galectin-1 in cell adhesion and invasion of human anaplastic large cell lymphoma, we performed cell adhesion and invasion assays using the anaplastic large cell lymphoma cell line H-ALCL, which was previously established in our laboratory. From the cell surface lectin array, treatment with neuraminidase from Arthrobacter ureafaciens which cleaves all linkage types of cell surface sialic acid enhanced Arachis hypogaea (PNA), Helix pomatia (HPA) and Phaseolus vulgaris-L (L-PHA) lectin binding reactivity to cell surface of lymphoma cells suggesting that neuraminidase removes cell surface sialic acid. In cell adhesion and invasion assays treatment with neuraminidase markedly enhanced cell adhesion to galectin-1 and decreased cell invasive capacity through galectin-1. α2,6-linked sialic acid may be involved in masking the effect of the interaction between galectin-1 and cell surface glycans. H-ALCL cells expressed the β-galactoside-α2,6-sialyltransferase ST6Gal1. On resialylation assay by recombinant ST6Gal1 with CMP-Neu5Ac, α2,6-resialylation of L-PHA reactive oligosaccharide by ST6Gal1 resulted in inhibition of H-ALCL cell adhesion to galectin-1 compared to the desialylated H-ALCL cells. On knockdown experiments, knockdown of ST6Gal1 dramatically enhanced cell adhesion to galectin-1. N-glycosylation inhibitor swainsonine treatment resulted in enhancement of cell adhesion to galectin-1. In glycomic analysis using the lectin blocking assay treatment with PNA, Artocarpus integrifolia (Jacalin), Glycine max (SBA), Helix pomatia (HPA), Vicia villosa (VVA), Ulex europaeus (UEA-1), Triticum vulgaris (WGA), Canavalia ensiformis (ConA), Phaseolus vulgaris-L (L-PHA), Phaseolus vulgaris-E4 (E-PHA), Datura stramonium (DSA) lectins resulted in modulation of lymphoma cell to galectin-1 suggesting that several types of glycans may regulate cell adhesion to galectin-1 by

  12. Surgical and medical management of a uterine spindle cell tumor in an African hedgehog (Atelerix albiventris).

    Science.gov (United States)

    Done, Lisa B; Deem, Sharon L; Fiorello, Christine V

    2007-12-01

    A 5-yr-old female African hedgehog (Ateleris albiventris) presented with hematuria. Vulvar culture results revealed a 4+ growth of Enterococcus sp. and gamma-Streptococcus sp. susceptible to trimethoprim sulfa and enrofloxacin. Ultrasound evaluation of the abdomen revealed an unidentifiable tubular structure in the region of the reproductive tract. An exploratory laparotomy and ovariohysterectomy were performed. Pathologic studies of the uterus showed a uterine spindle cell tumor, uterine endometrial polyp, uterine adenomyosis, and a possible acute infarct resulting in uterine wall necrosis. Hematuria did not reoccur, and the hedgehog lived for another 19 mo until she died from an oral squamous cell carcinoma. To date, this is the first report of a uterine spindle cell tumor in an African hedgehog. PMID:18229871

  13. Primary histiocytic sarcoma arising in the head and neck with predominant spindle cell component

    Directory of Open Access Journals (Sweden)

    Zhao XF

    2007-02-01

    Full Text Available Abstract This is the first case report of Histiocytic Sarcoma (HS with predominant spindle cell component occurring in the head and neck region of a 41-year-old man. The tumor was composed of sheets of large round to oval cells with pleomorphic vesicular nuclei, prominent nucleoli and abundant eosinophilic cytoplasm. Multinucleated forms, numerous mitoses, and tumor necrosis were also noted. Sheets, fascicles, and whorls of spindle cells with spindled to ovoid vesicular nuclei, small to medium-sized distinct nucleoli, and eosinophilic cytoplasm were frequently observed. Immunohistochemical staining in the tumor cells was positive for CD163, CD68, lysozyme, CD45, and NSE. Focal expression of CD4 and S-100 was also noted. Electron microscopy demonstrated an abundance of lysosomes in the cytoplasm of tumor cells. Chromosome study revealed a 57–80 hyperdiploid [7]/46, XY [13] karyotype, including 3 to 4 copies of various chromosomes. The immunohistochemical and ultrastructural findings confirmed the diagnosis of HS.

  14. Mixed Large Cell Neuroendocrine Carcinoma and Adenocarcinoma with Spindle Cell and Clear Cell Features in the Extrahepatic Bile Duct

    OpenAIRE

    John Wysocki; Rishi Agarwal; Laura Bratton; Jeremy Nguyen; Mandy Crause Weidenhaft; Nathan Shores; Kimbrell, Hillary Z.

    2014-01-01

    Mixed adenoneuroendocrine carcinomas, spindle cell carcinomas, and clear cell carcinomas are all rare tumors in the biliary tract. We present the first case, to our knowledge, of an extrahepatic bile duct carcinoma composed of all three types. A 65-year-old man with prior cholecystectomy presented with painless jaundice, vomiting, and weight loss. CA19-9 and alpha-fetoprotein (AFP) were elevated. Cholangioscopy revealed a friable mass extending from the middle of the common bile duct to the c...

  15. A case report of spindle cell myoepithelioma with extensive lipomatous metaplasia and thick collagen bundles in the submandibular gland.

    Science.gov (United States)

    Kwon, Mi Jung; Kim, Hye Jeong; Park, Bumjung; Cho, Seong Jin; Shin, Hyung Sik; Park, Hye-Rim; Min, Soo Kee; Seo, Jinwon; Min, Kyueng-Whan; Nam, Eun Sook

    2016-09-01

    Spindle cell myoepithelioma with extensive lipomatous metaplasia and thick collagen bundles has not yet been described, and there are no published reports on its cytological appearance in fine-needle aspiration (FNA). A 49-year-old man presented with a painless mass in the right submandibular area that had been gradually enlarging for a period of 5 years. The cytologic smears showed fascicles of cohesive spindle cells as well as individual bland cells with bipolar naked nuclei in a fibrillary background. Brightly eosinophilic bundles were intermingled with spindle cells and fat-like vacuoles. The FNA results were suggestive of neurogenic tumor. Patient underwent submandibular gland resection. Grossly, the cut surface showed a well-encapsulated, yellowish-white, soft, elastic mass, measuring 2.8 × 1.9 × 1.5 cm. The tumor consisted of uniform bland spindle cells arranged in short fascicles admixed with adipocyte-like cells and transversing thick collagen bundles, which demonstrated immunoreactivity for myoepithelial markers and ultrastructural features characteristic of myoepithelial cells, suggesting the presence of lipomatous metaplasia. The FNA cytology of spindle cell myoepithelioma with extensive lipometaplasia mimicked that of neurogenic tumor or lipomatous mesenchymal tumor. This case represents the first description of submandibular gland myoepithelioma with lipometaplasia, which is characterized by the coexistence of spindle cells, collagen bundles, and fat-like vacuoles in a fibrillary background. Diagn. Cytopathol. 2016;44:764-769. © 2016 Wiley Periodicals, Inc. PMID:27307392

  16. In vitro identification and characterization of CD133(pos cancer stem-like cells in anaplastic thyroid carcinoma cell lines.

    Directory of Open Access Journals (Sweden)

    Giovanni Zito

    Full Text Available BACKGROUND: Recent publications suggest that neoplastic initiation and growth are dependent on a small subset of cells, termed cancer stem cells (CSCs. Anaplastic Thyroid Carcinoma (ATC is a very aggressive solid tumor with poor prognosis, characterized by high dedifferentiation. The existence of CSCs might account for the heterogeneity of ATC lesions. CD133 has been identified as a stem cell marker for normal and cancerous tissues, although its biological function remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: ATC cell lines ARO, KAT-4, KAT-18 and FRO were analyzed for CD133 expression. Flow cytometry showed CD133(pos cells only in ARO and KAT-4 (64+/-9% and 57+/-12%, respectively. These data were confirmed by qRT-PCR and immunocytochemistry. ARO and KAT-4 were also positive for fetal marker oncofetal fibronectin and negative for thyrocyte-specific differentiating markers thyroglobulin, thyroperoxidase and sodium/iodide symporter. Sorted ARO/CD133(pos cells exhibited higher proliferation, self-renewal, colony-forming ability in comparison with ARO/CD133(neg. Furthermore, ARO/CD133(pos showed levels of thyroid transcription factor TTF-1 similar to the fetal thyroid cell line TAD-2, while the expression in ARO/CD133(neg was negligible. The expression of the stem cell marker OCT-4 detected by RT-PCR and flow cytometry was markedly higher in ARO/CD133(pos in comparison to ARO/CD133(neg cells. The stem cell markers c-KIT and THY-1 were negative. Sensitivity to chemotherapy agents was investigated, showing remarkable resistance to chemotherapy-induced apoptosis in ARO/CD133(pos when compared with ARO/CD133(neg cells. CONCLUSIONS/SIGNIFICANCE: We describe CD133(pos cells in ATC cell lines. ARO/CD133(pos cells exhibit stem cell-like features--such as high proliferation, self-renewal ability, expression of OCT-4--and are characterized by higher resistance to chemotherapy. The simultaneous positivity for thyroid specific factor TTF-1 and onfFN suggest

  17. The effect of 17-allylamino-17-demethoxygeldanamycin alone or in combination with paclitaxel on anaplastic thyroid carcinoma cells.

    Science.gov (United States)

    Kim, Si Hyoung; Kang, Jun Goo; Kim, Chul Sik; Ihm, Sung-Hee; Choi, Moon Gi; Yoo, Hyung Joon; Lee, Seong Jin

    2015-04-01

    The effect of 17-allylamino-17-demethoxygeldanamycin (17-AAG), an hsp90 inhibitor, alone or in combination with paclitaxel on survival of anaplastic thyroid carcinoma (ATC) was evaluated. In 8505C and CAL62 cells, after treatment of 17-AAG, cell viability decreased, and the percentage of dead cells increased. 17-AAG did not cause cleavage of caspase-3 protein, and change expression of IAPs. Pretreatment of z-VAD-fmk did not alter cell viability and the percentage of dead cells. In 17-AAG-treated cells, knockdown of p53 rescued growth inhibition, while cycloheximide attenuated cell death. When cells were treated with both 17-AAG and paclitaxel, all of the combination index values were higher than 1, indicating antagonism between 17-AAG and paclitaxel. In 17-AAG- and paclitaxel-treated cells, compared with paclitaxel alone-treated cells, the protein levels of hsp90, hsp70, and hsc70 increased. In conclusion, our results suggest that 17-AAG induces non-apoptotic cell death requiring de novo protein synthesis in ATC cells. Moreover, these results demonstrate that 17-AAG antagonizes paclitaxel with concomitant alterations in hsp90 client proteins in ATC cells. PMID:25096912

  18. Mucinous tubular and spindle cell carcinoma of the kidney associated with tuberculosis

    Directory of Open Access Journals (Sweden)

    Saloua Krichen Makni

    2011-01-01

    Full Text Available Mucinous tubular and spindle cell carcinomas (MTSCC are low-grade renal epi-thelial neoplasms with approximately 100 documented cases reported in the literature. We report a case of MTSCC in a 79-year-old patient in association with a renal tuberculosis infection that has never been reported. Further investigations are needed to determine the frequency and true prognosis of these tumors.

  19. Pax7 Shows Higher Satellite Cell Frequencies and Concentrations Within Intrafusal Fibers of Muscle Spindles

    OpenAIRE

    Kirkpatrick, Lisa J.; Allouh, Mohammed Z.; Nightingale, Chantale N.; Devon, Heidi G.; Yablonka-Reuveni, Zipora; Rosser, Benjamin W. C.

    2008-01-01

    Intrafusal fibers within muscle spindles make up a small subpopulation of muscle fibers. These proprioceptive fibers differ from most extrafusal fibers because, even in maturity, their diameters remain small, and they retain expression of developmental myosins. Although both extrafusal and intrafusal fibers contain satellite cells (SCs), comparatively little is known about intrafusal SCs. Analyzing chicken fast-phasic posterior (PLD) and slow-tonic anterior (ALD) latissimus dorsi muscles, we ...

  20. “Low-Fat” Pseudoangiomatous Spindle Cell Lipoma: A Rare Variant With Loss of 13q14 Region

    OpenAIRE

    Forcucci, Jessica A.; Sugianto, Jessica Z.; Wolff, Daynna J.; Maize, John C.; Ralston, Jonathan S.

    2015-01-01

    Abstract: Spindle cell and pleomorphic lipoma constitute a spectrum of lipomatous lesions with characteristic clinical, morphologic, immunohistochemical, and molecular features. Multiple variants have been previously described including vascular, fibrous, plexiform, and those with significantly less fat termed “low-fat” and “fat-free” by Folpe. Cytogenetically, spindle cell lipomas frequently display monoallelic loss of 13q14 region, an abnormality also found in cellular angiofibroma and mamm...

  1. Locally advanced breast implant associated anaplastic large cell lymphoma: A case report of successful treatment with radiation and chemotherapy

    Directory of Open Access Journals (Sweden)

    Christopher Fleighton Estes

    2015-02-01

    Full Text Available The development of breast implant associated anaplastic large cell lymphoma (ALCL is a rare phenomenon. A typical presentation is an effusion associated with a breast implant. Less commonly, disease can become more advanced locoregionally or distantly. The optimal treatment schema is a topic of debate: localized ALCL can potentially be cured with implant removal alone, while other cases in the literature, including those that are more advanced, have been treated with varying combinations of surgery, chemotherapy, and external beam radiotherapy. This is a case report of breast implant ALCL with pathologically proven lymph node involvement, the fifth such patient reported. Our patient experienced a favorable outcome with radiation therapy and chemotherapy.

  2. Alectinib-Induced Alopecia in a Patient with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer

    Science.gov (United States)

    Koizumi, Tomonobu; Fukushima, Toshirou; Gomi, Daisuke; Kobayashi, Takashi; Sekiguchi, Nodoka; Sakamoto, Akiyuki; Sasaki, Shigeru; Mamiya, Keiko

    2016-01-01

    Alectinib, a novel alternative anaplastic lymphoma kinase (ALK) inhibitor, is highly effective against ALK-positive non-small cell lung cancer (NSCLC) and is well tolerated. Molecular targeted agents generally have little contribution to alopecia. We encountered a case of alopecia that developed gradually over 2 months after initiation of alectinib administration for the treatment of ALK-positive NSCLC. The patient had no history of alopecia in previous treatments of cisplatin + pemetrexed and crizotinib. The present case indicates that alopecia should be taken into consideration as toxicity during alectinib treatment, which could adversely affect the psychological and emotional condition and quality of life even in patients treated with specific molecular targeted agents. PMID:27194980

  3. Aberrant expression and biological significance of Sox2, an embryonic stem cell transcriptional factor, in ALK-positive anaplastic large cell lymphoma

    International Nuclear Information System (INIS)

    Sox2 (sex-determining region Y-Box) is one of the master transcriptional factors that are important in maintaining the pluripotency of embryonic stem cells (ESCs). In line with this function, Sox2 expression is largely restricted to ESCs and somatic stem cells. We report that Sox2 is expressed in cell lines and tumor samples derived from ALK-positive anaplastic large cell lymphoma (ALK+ALCL), for which the normal cellular counterpart is believed to be mature T-cells. The expression of Sox2 in ALK+ALCL can be attributed to nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), the oncogenic fusion protein carrying a central pathogenetic role in these tumors. By confocal microscopy, Sox2 protein was detectable in virtually all cells in ALK+ALCL cell lines. However, the transcriptional activity of Sox2, as assessed using a Sox2-responsive reporter construct, was detectable only in a small proportion of cells. Importantly, downregulation of Sox2 using short interfering RNA in isolated Sox2active cells, but not Sox2inactive cells, resulted in a significant decrease in cell growth, invasiveness and tumorigenicity. To conclude, ALK+ALCL represents the first example of a hematologic malignancy that aberrantly expresses Sox2, which represents a novel mechanism by which NPM-ALK mediates tumorigenesis. We also found that the transcriptional activity and oncogenic effects of Sox2 can be heterogeneous in cancer cells

  4. Sarcomatoid (Spindle Cell Carcinoma of Tongue: A Report of Two Cases

    Directory of Open Access Journals (Sweden)

    Montserrat Reyes

    2015-01-01

    Full Text Available Sarcomatoid Carcinoma (SC is an unusual and aggressive variant of squamous cell carcinoma, which frequently recurs and metastasizes; for this reason, the right diagnosis is very important. It is considered to be a biphasic tumor made up of cells from squamous and spindle cells carcinoma with a sarcomatous aspect, but of epithelial origin. The diagnosis often represents a clinical-pathological challenge where the study with immunohistochemical technique (IHC is key to the histopathological diagnosis. The reported cases related to oral mucosa are limited. In this work we present two SC cases where the use of IHC allowed us to achieve a conclusive diagnosis.

  5. Biomarkers Provide Clues to Early Events in the Pathogenesis of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

    Science.gov (United States)

    Kadin, Marshall E; Deva, Anand; Xu, Haiying; Morgan, John; Khare, Pranay; MacLeod, Roderick A F; Van Natta, Bruce W; Adams, William P; Brody, Garry S; Epstein, Alan L

    2016-07-01

    Almost 200 women worldwide have been diagnosed with breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). The unique location and specific lymphoma type strongly suggest an etio-pathologic link between breast implants and BIA-ALCL. It is postulated that chronic inflammation via bacterial infection may be an etiological factor. BIA-ALCL resembles primary cutaneous ALCL (pcALCL) in morphology, activated T-cell phenotype, and indolent clinical course. Gene expression array analysis, flow cytometry, and immunohistochemistry were used to study pcALCL and BIA-ALCL cell lines. Clinical samples were also studied to characterize transcription factor and cytokine profiles of tumor cells and surrounding lymphocytes. BIA-ALCL and pcALCL were found to have common expression of transcription factors SOCS3, JunB, SATB1, and a cytokine profile suggestive of a Th1 phenotype. Similar patterns were observed in a CD30+ cutaneous lymphoproliferative disorder (LPD). The patterns of cytokine and transcription factor expression suggest that BIA-ALCL is likely to arise from chronic bacterial antigen stimulation of T-cells. Further analysis of cytokine and transcription factor profiles may allow early detection and treatment of BIA-ALCL leading to better prognosis and survival. LEVEL OF EVIDENCE 5: Risk. PMID:26979456

  6. Inhibition of clathrin by pitstop 2 activates the spindle assembly checkpoint and induces cell death in dividing HeLa cancer cells

    Directory of Open Access Journals (Sweden)

    Smith Charlotte M

    2013-01-01

    Full Text Available Abstract Background During metaphase clathrin stabilises the mitotic spindle kinetochore(K-fibres. Many anti-mitotic compounds target microtubule dynamics. Pitstop 2™ is the first small molecule inhibitor of clathrin terminal domain and inhibits clathrin-mediated endocytosis. We investigated its effects on a second function for clathrin in mitosis. Results Pitstop 2 did not impair clathrin recruitment to the spindle but disrupted its function once stationed there. Pitstop 2 trapped HeLa cells in metaphase through loss of mitotic spindle integrity and activation of the spindle assembly checkpoint, phenocopying clathrin depletion and aurora A kinase inhibition. Conclusions Pitstop 2 is therefore a new tool for investigating clathrin spindle dynamics. Pitstop 2 reduced viability in dividing HeLa cells, without affecting dividing non-cancerous NIH3T3 cells, suggesting that clathrin is a possible novel anti-mitotic drug target.

  7. Galpha/LGN-mediated asymmetric spindle positioning does not lead to unequal cleavage of the mother cell in 3-D cultured MDCK cells

    OpenAIRE

    Xiao, Zhuoni; Wan, Qingwen; Du, Quansheng; Zheng, Zhen

    2012-01-01

    The position of the mitotic spindle plays a key role in spatial control of cell division. It is generally believed that when a spindle is positioned asymmetrically in a dividing cell, the resulting daughter cells are usually unequal in size due to eccentric cleavage of the mother cell. Molecular mechanisms underlying the generation of unequal sized daughter cells have been extensively studied in Drosophila neuroblast and C elegans zygote where the Gα subunit of the heterotrimeric G proteins a...

  8. miR-4295 promotes cell proliferation and invasion in anaplastic thyroid carcinoma via CDKN1A

    Energy Technology Data Exchange (ETDEWEB)

    Shao, Mingchen; Geng, Yiwei [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Laboratory of Tumor Biology, Zhengzhou University, Zhengzhou (China); Lu, Peng [Gastrointestinal Surgery Department, People' s Hospital of Zhengzhou, Zhengzhou (China); Xi, Ying [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Laboratory of Tumor Biology, Zhengzhou University, Zhengzhou (China); Wei, Sidong [Liver Transplantation Hepatobiliary Surgery Department, People' s Hospital of Zhengzhou, Zhengzhou (China); Wang, Liuxing; Fan, Qingxia [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Laboratory of Tumor Biology, Zhengzhou University, Zhengzhou (China); Ma, Wang, E-mail: doctormawang@126.com [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Laboratory of Tumor Biology, Zhengzhou University, Zhengzhou (China)

    2015-09-04

    MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. However, the role of microRNAs in anaplastic thyroid carcinoma (ATC), has remained elusive. Here, we identified that miR-4295 promotes ATC cell proliferation by negatively regulates its target gene CDKN1A. In ATC cell lines, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-4295, while miR-4295 inhibitor significantly inhibited the cell proliferation. Transwell assay showed that miR-4295 mimics significantly promoted the migration and invasion of ATC cells, whereas miR-4295 inhibitors significantly reduced cell migration and invasion. luciferase assays confirmed that miR-4295 directly bound to the 3'untranslated region of CDKN1A, and western blotting showed that miR-4295 suppressed the expression of CDKN1A at the protein levels. This study indicated that miR-4295 negatively regulates CDKN1A and promotes proliferation and invasion of ATC cell lines. Thus, miR-4295 may represent a potential therapeutic target for ATC intervention. - Highlights: • miR-4295 mimics promote the proliferation and invasion of ATC cells. • miR-4295 inhibitors inhibit the proliferation and invasion of ATC cells. • miR-4295 targets 3′UTR of CDKN1A in ATC cells. • miR-4295 negatively regulates CDKN1A in ATC cells.

  9. miR-4295 promotes cell proliferation and invasion in anaplastic thyroid carcinoma via CDKN1A

    International Nuclear Information System (INIS)

    MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. However, the role of microRNAs in anaplastic thyroid carcinoma (ATC), has remained elusive. Here, we identified that miR-4295 promotes ATC cell proliferation by negatively regulates its target gene CDKN1A. In ATC cell lines, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-4295, while miR-4295 inhibitor significantly inhibited the cell proliferation. Transwell assay showed that miR-4295 mimics significantly promoted the migration and invasion of ATC cells, whereas miR-4295 inhibitors significantly reduced cell migration and invasion. luciferase assays confirmed that miR-4295 directly bound to the 3'untranslated region of CDKN1A, and western blotting showed that miR-4295 suppressed the expression of CDKN1A at the protein levels. This study indicated that miR-4295 negatively regulates CDKN1A and promotes proliferation and invasion of ATC cell lines. Thus, miR-4295 may represent a potential therapeutic target for ATC intervention. - Highlights: • miR-4295 mimics promote the proliferation and invasion of ATC cells. • miR-4295 inhibitors inhibit the proliferation and invasion of ATC cells. • miR-4295 targets 3′UTR of CDKN1A in ATC cells. • miR-4295 negatively regulates CDKN1A in ATC cells

  10. Mixed Large Cell Neuroendocrine Carcinoma and Adenocarcinoma with Spindle Cell and Clear Cell Features in the Extrahepatic Bile Duct

    Directory of Open Access Journals (Sweden)

    John Wysocki

    2014-01-01

    Full Text Available Mixed adenoneuroendocrine carcinomas, spindle cell carcinomas, and clear cell carcinomas are all rare tumors in the biliary tract. We present the first case, to our knowledge, of an extrahepatic bile duct carcinoma composed of all three types. A 65-year-old man with prior cholecystectomy presented with painless jaundice, vomiting, and weight loss. CA19-9 and alpha-fetoprotein (AFP were elevated. Cholangioscopy revealed a friable mass extending from the middle of the common bile duct to the common hepatic duct. A bile duct excision was performed. Gross examination revealed a 3.6 cm intraluminal polypoid tumor. Microscopically, the tumor had foci of conventional adenocarcinoma (CK7-positive and CA19-9-postive surrounded by malignant-appearing spindle cells that were positive for cytokeratins and vimentin. Additionally, there were separate areas of large cell neuroendocrine carcinoma (LCNEC. Foci of clear cell carcinoma merged into both the LCNEC and the adenocarcinoma. Tumor invaded through the bile duct wall with extensive perineural and vascular invasion. Circumferential margins were positive. The patient’s poor performance status precluded adjuvant therapy and he died with recurrent and metastatic disease 5 months after surgery. This is consistent with the reported poor survival rates of biliary mixed adenoneuroendocrine carcinomas.

  11. Locally Advanced Breast Implant-Associated Anaplastic Large-Cell Lymphoma: A Case Report of Successful Treatment with Radiation and Chemotherapy

    OpenAIRE

    Estes, Christopher F.; Zhang, Da; Reyes, Ruben; Korentager, Richard; McGinness, Marilee; Lominska, Christopher

    2015-01-01

    The development of breast implant-associated anaplastic large-cell lymphoma (ALCL) is a rare phenomenon. A typical presentation is an effusion associated with a breast implant. Less commonly, disease can be more advanced locoregionally or distantly. The optimal treatment schema is a topic of debate: localized ALCL can potentially be cured with implant removal alone, while other cases in the literature, including those that are more advanced, have been treated with varying combinations of surg...

  12. Spindle cell carcinoma of the breast as complex cystic lesion:a case report

    Institute of Scientific and Technical Information of China (English)

    Masahiro Kitada; Satoshi Hayashi; Yoshinari Matsuda; Kei Ishibashi; Keisuke Oikawa; Naoyuki Miyokawa

    2014-01-01

    Spindle cell carcinoma of the breast is a rare tumor. hTis tumor can proliferate rapidly and cause cystic changes because of internal tissue necrosis. We evaluated a 54-year-old woman with right breast lump. Mammography showed a category four mass with a diameter of 2.5 cm. Ultrasonography (US) revealed a complex cystic lesion, and ifne-needle aspiration (FNA) cytology demonstrated bloody fluid and malignant cells. Partial breast resection and sentinel lymph node biopsy were performed. Immunohistology revealed spindle cells with positive results for cytokeratin (AE1/AE3) and vimentin, partially positive results for s-100, and negative results for desmin and α-actin. The pathological stage was IIA, and biochemical characterization showed that the tumor was triple negative. Six courses of FEC-100 chemotherapy (5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) were administered. Radiotherapy was performed. hTis case is discussed with reference to the literature.

  13. Mucinous tubular and spindle cell carcinoma of kidney: A rare case report and review of the literature

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    Geramizadeh Bita

    2009-10-01

    Full Text Available Low grade mucinous tubular and spindle cell carcinoma of kidney was newly established as a distinct renal cell carcinoma in the World Health Organization (WHO classification of 2004. Until now, less than 60 cases have been reported and the largest series represented approximately 15 patients with this type of tumor. Herein, we report a case of mucinous tubular and spindle cell carcinoma in a 63-year-old male presented with right flank pain which was diagnosed after nephrectomy. Pathologists should consider this diagnosis and its spectrum of histopathologic features in mind to ensure an accurate diagnosis.

  14. P-glycoprotein Mediates Ceritinib Resistance in Anaplastic Lymphoma Kinase-rearranged Non-small Cell Lung Cancer

    Science.gov (United States)

    Katayama, Ryohei; Sakashita, Takuya; Yanagitani, Noriko; Ninomiya, Hironori; Horiike, Atsushi; Friboulet, Luc; Gainor, Justin F.; Motoi, Noriko; Dobashi, Akito; Sakata, Seiji; Tambo, Yuichi; Kitazono, Satoru; Sato, Shigeo; Koike, Sumie; John Iafrate, A.; Mino-Kenudson, Mari; Ishikawa, Yuichi; Shaw, Alice T.; Engelman, Jeffrey A.; Takeuchi, Kengo; Nishio, Makoto; Fujita, Naoya

    2015-01-01

    The anaplastic lymphoma kinase (ALK) fusion oncogene is observed in 3%–5% of non-small cell lung cancer (NSCLC). Crizotinib and ceritinib, a next-generation ALK tyrosine kinase inhibitor (TKI) active against crizotinib-refractory patients, are clinically available for the treatment of ALK-rearranged NSCLC patients, and multiple next-generation ALK-TKIs are currently under clinical evaluation. These ALK-TKIs exhibit robust clinical activity in ALK-rearranged NSCLC patients; however, the emergence of ALK-TKI resistance restricts the therapeutic effect. To date, various secondary mutations or bypass pathway activation-mediated resistance have been identified, but large parts of the resistance mechanism are yet to be identified. Here, we report the discovery of p-glycoprotein (P-gp/ABCB1) overexpression as a ceritinib resistance mechanism in ALK-rearranged NSCLC patients. P-gp exported ceritinib and its overexpression conferred ceritinib and crizotinib resistance, but not to PF-06463922 or alectinib, which are next-generation ALK inhibitors. Knockdown of ABCB1 or P-gp inhibitors sensitizes the patient-derived cancer cells to ceritinib, in vitro and in vivo. P-gp overexpression was identified in three out of 11 cases with in ALK-rearranged crizotinib or ceritinib resistant NSCLC patients. Our study suggests that alectinib, PF-06463922, or P-gp inhibitor with ceritinib could overcome the ceritinib or crizotinib resistance mediated by P-gp overexpression. PMID:26870817

  15. P-glycoprotein Mediates Ceritinib Resistance in Anaplastic Lymphoma Kinase-rearranged Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Ryohei Katayama

    2016-01-01

    Full Text Available The anaplastic lymphoma kinase (ALK fusion oncogene is observed in 3%–5% of non-small cell lung cancer (NSCLC. Crizotinib and ceritinib, a next-generation ALK tyrosine kinase inhibitor (TKI active against crizotinib-refractory patients, are clinically available for the treatment of ALK-rearranged NSCLC patients, and multiple next-generation ALK-TKIs are currently under clinical evaluation. These ALK-TKIs exhibit robust clinical activity in ALK-rearranged NSCLC patients; however, the emergence of ALK-TKI resistance restricts the therapeutic effect. To date, various secondary mutations or bypass pathway activation-mediated resistance have been identified, but large parts of the resistance mechanism are yet to be identified. Here, we report the discovery of p-glycoprotein (P-gp/ABCB1 overexpression as a ceritinib resistance mechanism in ALK-rearranged NSCLC patients. P-gp exported ceritinib and its overexpression conferred ceritinib and crizotinib resistance, but not to PF-06463922 or alectinib, which are next-generation ALK inhibitors. Knockdown of ABCB1 or P-gp inhibitors sensitizes the patient-derived cancer cells to ceritinib, in vitro and in vivo. P-gp overexpression was identified in three out of 11 cases with in ALK-rearranged crizotinib or ceritinib resistant NSCLC patients. Our study suggests that alectinib, PF-06463922, or P-gp inhibitor with ceritinib could overcome the ceritinib or crizotinib resistance mediated by P-gp overexpression.

  16. Crizotinib as a personalized alternative for targeted anaplastic lymphoma kinase rearrangement in previously treated patients with non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Guo L

    2015-10-01

    Full Text Available Liting Guo,1,* Haijun Zhang,1,* Weiwei Shao,2 Baoan Chen1 1Department of Hematology and Oncology (Key Department of Jiangsu Medicine, The Affiliated Zhongda Hospital, Medical School of Southeast University, Nanjing, 2Department of Pathology, the First People’s Hospital of Yancheng, Yancheng, Jiangsu, People’s Republic of China *These authors contributed equally to this work Abstract: Crizotinib, the first clinically designed and synthesized as a tyrosine kinase inhibitor targeting mesenchymal–epithelial transition factor, indicating marked anticancer activity in patients with advanced, anaplastic lymphoma kinase-positive non-small-cell lung cancer, was approved by the US Food and Drug Administration in 2011. In this review, we focus on the efficacy of crizotinib compared with chemotherapy in advanced anaplastic lymphoma kinase-positive lung cancer and present the role of crizotinib as a personalized alternative in previously treated patients with non-small-cell lung cancer. Keywords: crizotinib, anaplastic lymphoma kinase rearrangement, non-small-cell lung cancer 

  17. Stable kinetochore–microtubule attachment is sufficient to silence the spindle assembly checkpoint in human cells

    Science.gov (United States)

    Tauchman, Eric C.; Boehm, Frederick J.; DeLuca, Jennifer G.

    2015-01-01

    During mitosis, duplicated sister chromatids attach to microtubules emanating from opposing sides of the bipolar spindle through large protein complexes called kinetochores. In the absence of stable kinetochore–microtubule attachments, a cell surveillance mechanism known as the spindle assembly checkpoint (SAC) produces an inhibitory signal that prevents anaphase onset. Precisely how the inhibitory SAC signal is extinguished in response to microtubule attachment remains unresolved. To address this, we induced formation of hyper-stable kinetochore–microtubule attachments in human cells using a non-phosphorylatable version of the protein Hec1, a core component of the attachment machinery. We find that stable attachments are sufficient to silence the SAC in the absence of sister kinetochore bi-orientation and strikingly in the absence of detectable microtubule pulling forces or tension. Furthermore, we find that SAC satisfaction occurs despite the absence of large changes in intra-kinetochore distance, suggesting that substantial kinetochore stretching is not required for quenching the SAC signal. PMID:26620470

  18. Step by step approach to rare breast lesions containing spindle cells.

    Science.gov (United States)

    Ünal, Betül; Erdoğan, Gülgün; Karaveli, Fatma Şeyda

    2015-01-01

    Differential diagnosis of spindle cell lesions of breast is challenging for certain reasons. The most important reason is the presence of cytological atypia and mitosis in all three conditions: reactive, benign, and malignant. Patients diagnosed with benign and malignant tumor/tumor-like lesions that had spindle cell components following the histopathological examination were included in the study. The patients' medical records were accessed to obtain the clinical history, follow-up notes, and radiological findings. Following histopathological, immunohistochemical, and clinical evaluations, the patients were diagnosed as follows: pseudoangiomatous stromal hyperplasia (PASH), bilateral desmoid-type fibromatosis (FM), adenomyoepithelioma (AME), myofibroblastoma (MFB), malignant phyllodes tumor (MF), high-grade AS, post-chemotherapy osteosarcoma (OS) + Paget's disease, and metaplastic carcinoma (MC). An algorithmic approach should be used in the diagnosis; cellular structure, presence and grade of atypia, growth pattern, mitotic activity, immunohistochemical staining, and clinical and radiological features should be evaluated together. Detection of some molecular changes can be useful in differential diagnosis. PMID:26558181

  19. A nuclear circularity-based classifier for diagnostic distinction of desmoplastic from spindle cell melanoma in digitized histological images

    Directory of Open Access Journals (Sweden)

    Manuel Schöchlin

    2014-01-01

    Full Text Available Context: Distinction of spindle cell melanoma (SM and desmoplastic melanoma (DM is clinically important due to differences in metastatic rate and prognosis; however, histological distinction is not always straightforward. During a routine review of cases, we noted differences in nuclear circularity between SM and DM. Aim: The primary aim in our study was to determine whether these differences in nuclear circularity, when assessed using a basic ImageJ-based threshold extraction, can serve as a diagnostic classifier to distinguish DM from SM. Settings and Design: Our retrospective analysis of an established patient cohort (SM n = 9, DM n = 9 was employed to determine discriminatory power. Subjects and Methods: Regions of interest (total n = 108; 6 images per case were selected from scanned H and E-stained histological sections, and nuclear circularity was extracted and quantified by computational image analysis using open source tools (plugins for ImageJ. Statistical Analysis: Using analysis of variance, t-tests, and Fisher′s exact tests, we compared extracted quantitative shape measures; statistical significance was defined as P < 0.05. Results: Classifying circularity values into four shape categories (spindled, elongated, oval, round demonstrated significant differences in the spindled and round categories. Paradoxically, DM contained more spindled nuclei than SM (P = 0.011 and SM contained more round nuclei than DM (P = 0.026. Performance assessment using a combined shape-classification of the round and spindled fractions showed 88.9% accuracy and a Youden index of 0.77. Conclusions: Spindle cell melanoma and DM differ significantly in their nuclear morphology with respect to fractions of round and spindled nuclei. Our study demonstrates that quantifying nuclear circularity can be used as an adjunct diagnostic tool for distinction of DM and SM.

  20. DNA damage response and spindle assembly checkpoint function throughout the cell cycle to ensure genomic integrity.

    Directory of Open Access Journals (Sweden)

    Katherine S Lawrence

    2015-04-01

    Full Text Available Errors in replication or segregation lead to DNA damage, mutations, and aneuploidies. Consequently, cells monitor these events and delay progression through the cell cycle so repair precedes division. The DNA damage response (DDR, which monitors DNA integrity, and the spindle assembly checkpoint (SAC, which responds to defects in spindle attachment/tension during metaphase of mitosis and meiosis, are critical for preventing genome instability. Here we show that the DDR and SAC function together throughout the cell cycle to ensure genome integrity in C. elegans germ cells. Metaphase defects result in enrichment of SAC and DDR components to chromatin, and both SAC and DDR are required for metaphase delays. During persistent metaphase arrest following establishment of bi-oriented chromosomes, stability of the metaphase plate is compromised in the absence of DDR kinases ATR or CHK1 or SAC components, MAD1/MAD2, suggesting SAC functions in metaphase beyond its interactions with APC activator CDC20. In response to DNA damage, MAD2 and the histone variant CENPA become enriched at the nuclear periphery in a DDR-dependent manner. Further, depletion of either MAD1 or CENPA results in loss of peripherally associated damaged DNA. In contrast to a SAC-insensitive CDC20 mutant, germ cells deficient for SAC or CENPA cannot efficiently repair DNA damage, suggesting that SAC mediates DNA repair through CENPA interactions with the nuclear periphery. We also show that replication perturbations result in relocalization of MAD1/MAD2 in human cells, suggesting that the role of SAC in DNA repair is conserved.

  1. Eosinophilic and neutrophilic leukemoid reaction in a woman with spindle cell sarcoma: a case report

    Directory of Open Access Journals (Sweden)

    Lauter Carl B

    2010-10-01

    Full Text Available Abstract Introduction We report a case of a patient with marked eosinophilia and neutrophilia as a manifestation of a spindle cell sarcoma. Case presentation A 41-year-old African American woman presented with an enlarging, painful mass in her right knee area. Four years previously, she had had a mass similar to this diagnosed as an osteosarcoma, and had undergone a radical resection and hinge-knee replacement. Before the surgery, she was treated with neoadjuvant docetaxel and gemcitabine. A biopsy was taken from the recurrent mass, and histological examination revealed high-grade soft-tissue sarcoma. The patient received no further treatment. Complete blood counts revealed a white blood cell (WBC count of 13.6 to 17.9 × 109/L, with neutrophils being 8.2 to 10.9 × 109/L and eosinophils 1.8 to 1.9 × 109/L. At readmission six months later, WBC was 126.7 × 109/L, with neutrophils being 57.02 × 109/L and eosinophils 60.82 × 109/L. The eosinophils peaked at 77.79 × 109/L two days later. Evaluations for allergies, infection, and autoimmune mechanisms were negative. Bone marrow revealed increased eosinophils without blasts. After resection, blood counts abruptly decreased to the normal range. Pathology confirmed high-grade spindle cell sarcoma. Approximately one year after resection, the patient was readmitted with metastatic disease to her lungs. During this presentation, her eosinophil and neutrophil count was again increased. WBC was 107.8 × 109/L, with eosinophil count of 47.43 × 109/L and neutrophil count of 44.10 × 109/L. Interleukin-5 was normal, and granulocyte–macrophage colony-stimulating factor (GM-CSF was elevated at 208.8 (normal Conclusion In our case, the patient had eosinophilia and neutrophilia associated with a spindle cell sarcoma, possibly representing a paraneoplastic syndrome secondary to GM-CSF. There were no signs of infectious, allergic, or autoimmune causes for the eosinophilia or neutrophilia. Even though the

  2. Anaplastic lymphoma kinase status in rhabdomyosarcomas.

    Science.gov (United States)

    Yoshida, Akihiko; Shibata, Tatsuhiro; Wakai, Susumu; Ushiku, Tetsuo; Tsuta, Koji; Fukayama, Masashi; Makimoto, Atsushi; Furuta, Koh; Tsuda, Hitoshi

    2013-06-01

    Rhabdomyosarcoma is a rare soft tissue sarcoma that typically affects children, adolescents, and young adults. Despite treatment via a multidisciplinary approach, the prognosis of advance-stage rhabdomyosarcomas remains poor, and a new treatment strategy is needed. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is a potential target for specific inhibitors. In this study, we investigated 116 rhabdomyosarcomas using a polymer-based ALK immunostaining method and correlated the results with clinicopathological parameters. In addition, we examined ALK status using dual-color fluorescence in situ hybridization, PCR, and sequencing. In immunohistochemical analysis, ALK was detected in 2 (6%) of 33 embryonal rhabdomyosarcomas, 42 (69%) of 61 alveolar rhabdomyosarcomas, and 0 (0%) of 22 other subtypes, including pleomorphic, adult-spindle-cell/sclerosing, and epithelioid variants. Compared with ALK-negative alveolar rhabdomyosarcomas, ALK-positive ones are presented with metastatic spread more frequently and showed a greater extent of myogenin reactivity. Overall survival was not associated with ALK expression. FOXO1 rearrangement was significantly associated with ALK immunoreactivity. The median ALK copy number was greater in ALK-positive tumors than in ALK-negative tumors. Most (93%) cases tested showed no selective increase in the ALK gene dosage. ALK selective amplification and low-level selective gain were noted in one and three cases, respectively. Further, a high-polysomy pattern (≥4 ALK copies in ≥40% of cells) was observed in seven cases. A significant increase in the ALK copy number was exclusive to the ALK-immunopositive cohort, but it was uncommon, accounting for only 30% of the 37 ALK-positive rhabdomyosarcomas. ALK gene rearrangement was not observed in either cohort, while an ALK somatic mutation (I1277T) was found in one ALK-negative embryonal case. Although it remains controversial whether ALK expression without gene rearrangement

  3. The Spindle Assembly Checkpoint Safeguards Genomic Integrity of Skeletal Muscle Satellite Cells

    Directory of Open Access Journals (Sweden)

    Swapna Kollu

    2015-06-01

    Full Text Available To ensure accurate genomic segregation, cells evolved the spindle assembly checkpoint (SAC, whose role in adult stem cells remains unknown. Inducible perturbation of a SAC kinase, Mps1, and its downstream effector, Mad2, in skeletal muscle stem cells shows the SAC to be critical for normal muscle growth, repair, and self-renewal of the stem cell pool. SAC-deficient muscle stem cells arrest in G1 phase of the cell cycle with elevated aneuploidy, resisting differentiation even under inductive conditions. p21CIP1 is responsible for these SAC-deficient phenotypes. Despite aneuploidy’s correlation with aging, we find that aged proliferating muscle stem cells display robust SAC activity without elevated aneuploidy. Thus, muscle stem cells have a two-step mechanism to safeguard their genomic integrity. The SAC prevents chromosome missegregation and, if it fails, p21CIP1-dependent G1 arrest limits cellular propagation and tissue integration. These mechanisms ensure that muscle stem cells with compromised genomes do not contribute to tissue homeostasis.

  4. Extrinsic apoptotic pathways: A new potential "Target" for more sufficient therapy in a case of cutaneous anaplastic large CD30+ ALK-T--cell lymphoma

    Directory of Open Access Journals (Sweden)

    Georgi Tchernev

    2011-01-01

    Full Text Available The primary cutaneous T-cell lymphomas (CTCL represent a clonal T-lymphocyte proliferation infiltrating the skin. CD30+ T-cell lymphomas present clinically as nodules with a diameter between 1 and 15 cm, mostly in elderly patients. The role of the CD30 molecule in patients suffering from T-cell lymphomas is not completely clear yet. The signal transduction pathway which includes CD30 seems to play a key role in tumor progression. In certain forms of T-cellular lymphomas, the interaction between CD30/CD30-ligand is able to provoke apoptosis of the "tumor lymphocytes". The modern conceptions of the pathogenesis of T-cell lymphomas include disorders in the pathways involved in programmed cellular death and disregulation in the expression of certain of its regulatory molecules. We are presenting an unusual case of a female patient with a primary cutaneous form of CD30 + /ALK− anaplastic large T-cell lymphoma. Upon the introduction of systemic PUVA, (psoralen plus ultraviolet light radiation combined with beam therapy, a complete remission could be noticed. Eight months later, we observed a local recurrence, which was overcome by CHOP chemotherapy (Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin, Vincristin (Oncovin®, Predniso(lon. Six months later, new cutaneous lesions had been noticed again. A new therapeutic hope for the patients with anaplastic large CTCL is actually based on the influence of the activity of the different apoptotic pathways. Death ligands, including tumor necrosis factor (TNF-α, CD95L/FasL, and TRAIL, mediate also some important safeguard mechanisms against tumor growth in patients with CD30 + cutaneous anaplastic large T-cell lymphomas and critically contribute to lymphocyte homeostasis.

  5. The Wnt pathway controls cell death engulfment, spindle orientation, and migration through CED-10/Rac.

    Directory of Open Access Journals (Sweden)

    Juan Cabello

    2010-02-01

    Full Text Available Wnt signalling pathways have extremely diverse functions in animals, including induction of cell fates or tumours, guidance of cell movements during gastrulation, and the induction of cell polarity. Wnt can induce polar changes in cellular morphology by a remodelling of the cytoskeleton. However, how activation of the Frizzled receptor induces cytoskeleton rearrangement is not well understood. We show, by an in depth 4-D microscopy analysis, that the Caenorhabditis elegans Wnt pathway signals to CED-10/Rac via two separate branches to regulate modulation of the cytoskeleton in different cellular situations. Apoptotic cell clearance and migration of the distal tip cell require the MOM-5/Fz receptor, GSK-3 kinase, and APC/APR-1, which activate the CED-2/5/12 branch of the engulfment machinery. MOM-5 (Frizzled thus can function as an engulfment receptor in C. elegans. Our epistatic analyses also suggest that the two partially redundant signalling pathways defined earlier for engulfment may act in a single pathway in early embryos. By contrast, rearrangement of mitotic spindles requires the MOM-5/Fz receptor, GSK-3 kinase, and beta-catenins, but not the downstream factors LIT-1/NLK or POP-1/Tcf. Taken together, our results indicate that in multiple developmental processes, CED-10/Rac can link polar signals mediated by the Wnt pathway to rearrangements of the cytoskeleton.

  6. Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells.

    Science.gov (United States)

    Giladi, Moshe; Schneiderman, Rosa S; Voloshin, Tali; Porat, Yaara; Munster, Mijal; Blat, Roni; Sherbo, Shay; Bomzon, Zeev; Urman, Noa; Itzhaki, Aviran; Cahal, Shay; Shteingauz, Anna; Chaudhry, Aafia; Kirson, Eilon D; Weinberg, Uri; Palti, Yoram

    2015-01-01

    Tumor Treating Fields (TTFields) are low intensity, intermediate frequency, alternating electric fields. TTFields are a unique anti-mitotic treatment modality delivered in a continuous, noninvasive manner to the region of a tumor. It was previously postulated that by exerting directional forces on highly polar intracellular elements during mitosis, TTFields could disrupt the normal assembly of spindle microtubules. However there is limited evidence directly linking TTFields to an effect on microtubules. Here we report that TTFields decrease the ratio between polymerized and total tubulin, and prevent proper mitotic spindle assembly. The aberrant mitotic events induced by TTFields lead to abnormal chromosome segregation, cellular multinucleation, and caspase dependent apoptosis of daughter cells. The effect of TTFields on cell viability and clonogenic survival substantially depends upon the cell division rate. We show that by extending the duration of exposure to TTFields, slowly dividing cells can be affected to a similar extent as rapidly dividing cells. PMID:26658786

  7. Brentuximab vedotin in children and adolescents with Hodgkin’s lymphoma and anaplastic large cell lymphoma – literature review and own experience

    OpenAIRE

    N. V. Myakova; D. A. Evstratov; D. S. Abramov; D. M. Konovalov; A. V. Pshonkin; D. V. Litvinov

    2016-01-01

    Despite significant advances in the treatment of lymphomas in children remain a small proportion of patients with refractory or recurrent disease. An effective approach to the treatment of such patients – not only is the second line chemotherapy, but the use of the new targeted therapies. An example of this approach is the use of brentuximab vedotin (antibody-drug conjugate directed to the CD30) in relapsed Hodgkin’s lymphoma and anaplastic large cell lymphoma. Literature review and own exper...

  8. Effects of BP-14, a novel cyclin-dependent kinase inhibitor, on anaplastic thyroid cancer cells

    Czech Academy of Sciences Publication Activity Database

    Allegri, L.; Baldan, F.; Mio, F.; Puppin, C.; Russo, D.; Kryštof, Vladimír; Damante, G.

    2016-01-01

    Roč. 35, č. 4 (2016), s. 2413-2418. ISSN 1021-335X R&D Projects: GA ČR(CZ) GA15-15264S Institutional support: RVO:61389030 Keywords : mTOR * thyroid cancer * cell proliferation Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.301, year: 2014

  9. Non-anaplastic peripheral T-cell lymphoma in children and adolescents--a retrospective analysis of the NHL-BFM study group.

    Science.gov (United States)

    Kontny, Udo; Oschlies, Ilske; Woessmann, Willi; Burkhardt, Birgit; Lisfeld, Jasmin; Salzburg, Janina; Janda, Ales; Attarbaschi, Andishe; Niggli, Felix; Zimmermann, Martin; Reiter, Alfred; Klapper, Wolfram

    2015-03-01

    Mature (peripheral) T-cell lymphoma (PTCL) other than anaplastic large cell lymphoma is a heterogeneous group of diseases and exceedingly rare in children and adolescents. Survival rates range between 46% and 85%. This study reports the disease characteristics, treatment and outcome of all patients with the diagnosis of mature TCL registered in the Berlin-Frankfurt-Munster non-Hodgkin lymphoma database between 1986 and 2012. All diagnoses were centrally reviewed and revised by clinico-pathological correlation according to the criteria of the current World Health Organization classification. Of the 69 patients originally registered as having PTCL, the diagnosis was confirmed in 38 of them. Most patients were treated with an anaplastic large cell lymphoma (ALCL)-like therapy regimen. Patients with PTCL-not otherwise specified comprised the largest group and showed a 5-year event-free survival rate of 61 ± 11%. Patients suffering from Natural Killer/T-cell- and hepatosplenic TCL had the poorest outcome. Our results suggest that the outcomes of children with mature TCL other than ALCL depend on the subtype and are worse than in all other paediatric lymphomas. The clinical experience presented in this largest study on paediatric mature TCL may serve as basis for future collaborative international prospective clinical trials. PMID:25395120

  10. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma.

    Science.gov (United States)

    Crescenzo, Ramona; Abate, Francesco; Lasorsa, Elena; Tabbo', Fabrizio; Gaudiano, Marcello; Chiesa, Nicoletta; Di Giacomo, Filomena; Spaccarotella, Elisa; Barbarossa, Luigi; Ercole, Elisabetta; Todaro, Maria; Boi, Michela; Acquaviva, Andrea; Ficarra, Elisa; Novero, Domenico; Rinaldi, Andrea; Tousseyn, Thomas; Rosenwald, Andreas; Kenner, Lukas; Cerroni, Lorenzo; Tzankov, Alexander; Ponzoni, Maurilio; Paulli, Marco; Weisenburger, Dennis; Chan, Wing C; Iqbal, Javeed; Piris, Miguel A; Zamo', Alberto; Ciardullo, Carmela; Rossi, Davide; Gaidano, Gianluca; Pileri, Stefano; Tiacci, Enrico; Falini, Brunangelo; Shultz, Leonard D; Mevellec, Laurence; Vialard, Jorge E; Piva, Roberto; Bertoni, Francesco; Rabadan, Raul; Inghirami, Giorgio

    2015-04-13

    A systematic characterization of the genetic alterations driving ALCLs has not been performed. By integrating massive sequencing strategies, we provide a comprehensive characterization of driver genetic alterations (somatic point mutations, copy number alterations, and gene fusions) in ALK(-) ALCLs. We identified activating mutations of JAK1 and/or STAT3 genes in ∼20% of 88 [corrected] ALK(-) ALCLs and demonstrated that 38% of systemic ALK(-) ALCLs displayed double lesions. Recurrent chimeras combining a transcription factor (NFkB2 or NCOR2) with a tyrosine kinase (ROS1 or TYK2) were also discovered in WT JAK1/STAT3 ALK(-) ALCL. All these aberrations lead to the constitutive activation of the JAK/STAT3 pathway, which was proved oncogenic. Consistently, JAK/STAT3 pathway inhibition impaired cell growth in vitro and in vivo. PMID:25873174

  11. Aurora A Kinase Regulates Mammary Epithelial Cell Fate by Determining Mitotic Spindle Orientation in a Notch-Dependent Manner

    Directory of Open Access Journals (Sweden)

    Joseph L. Regan

    2013-07-01

    Full Text Available Cell fate determination in the progeny of mammary epithelial stem/progenitor cells remains poorly understood. Here, we have examined the role of the mitotic kinase Aurora A (AURKA in regulating the balance between basal and luminal mammary lineages. We find that AURKA is highly expressed in basal stem cells and, to a lesser extent, in luminal progenitors. Wild-type AURKA expression promoted luminal cell fate, but expression of an S155R mutant reduced proliferation, promoted basal fate, and inhibited serial transplantation. The mechanism involved regulation of mitotic spindle orientation by AURKA and the positioning of daughter cells after division. Remarkably, this was NOTCH dependent, as NOTCH inhibitor blocked the effect of wild-type AURKA expression on spindle orientation and instead mimicked the effect of the S155R mutant. These findings directly link AURKA, NOTCH signaling, and mitotic spindle orientation and suggest a mechanism for regulating the balance between luminal and basal lineages in the mammary gland.

  12. Spindle cell lipoma of the head and neck: CT and MR imaging findings

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Jin Wook [Sungkyunkwan University School of Medicine, Department of Radiology, Samsung Medical Center, Seoul (Korea, Republic of); Ajou University School of Medicine, Department of Radiology, Suwon (Korea, Republic of); Kim, Hyung-Jin; Kim, Hye Jung; Cha, Ji Hoon; Kim, Sung Tae [Sungkyunkwan University School of Medicine, Department of Radiology, Samsung Medical Center, Seoul (Korea, Republic of); Kim, Jinna [Yonsei University College of Medicine, Department of Radiology, Seoul (Korea, Republic of)

    2013-01-15

    Spindle cell lipoma (SCL) is an uncommon benign lipomatous tumor, most commonly occurring in the posterior neck and shoulder. The purpose of this study was to investigate the CT and MR imaging features of SCL in the head and neck. CT (n = 5) and MR (n = 3) images of seven patients (five men and two women; mean age, 54 years) with surgically proven SCL in the head and neck were retrospectively reviewed. The location and morphologic characteristics of SCL were documented as well. Six lesions were well-defined and located in the subcutaneous fat of the posterior neck (n = 4), anterior neck (n = 1), and buccal space (n = 1). One lesion was ill-defined and located deeply in the supraclavicular fossa, infiltrating the adjacent shoulder muscles. Intratumoral fat was identified in five lesions in various amounts. Compared with the adjacent subcutaneous fat, intratumoral fat was slightly hyperattenuated on CT scans and slightly hypointense on T1-weighted MR images. In five of six lesions in which postcontrast CT and/or MR images were obtained, significant enhancement was seen in the nonadipose component of the lesion. Various components of the adipose and nonadipose tissues may cause difficulty differentiating between SCL and other adipocytic tumors including liposarcoma radiologically. Although nonspecific, the radiologist should know the various imaging features of SCL, because the tumor can be cured by simple excision. (orig.)

  13. h-prune affects anaplastic thyroid cancer invasion and metastasis.

    Science.gov (United States)

    Nambu, Junko; Kobayashi, Tsuyoshi; Hashimoto, Masakazu; Tashiro, Hirotaka; Sugino, Keizo; Shimamoto, Fumio; Kikuchi, Akira; Ohdan, Hideki

    2016-06-01

    Anaplastic thyroid cancer is one of the most aggressive human malignancies and is resistant to multimodal treatments. The expression of h-prune, the human homologue of Drosophila prune, has been reported to be correlated with progression and aggressiveness in various cancers including breast, colorectal and pancreatic cancers. We examined the role of h-prune in anaplastic thyroid cancer cell migration, invasion and metastasis. Immunohistochemical analysis of h-prune was performed with 15 surgically resected specimens of anaplastic thyroid cancers. To investigate cell motility, Boyden chamber, wound healing and matrigel invasion assays were performed using cells from anaplastic thyroid cancer cell lines. A murine orthotopic thyroid cancer model was used to investigate metastatic ability. In the immunohistochemical analysis, only weak focal or no staining of h-prune was observed in non-tumor tissue. In contrast, diffuse staining of h-prune was observed in anaplastic thyroid cancer and lymph node metastasis samples. Both inhibition of h-prune phosphodiesterase activity with dipyridamole and small interfering RNA for h-prune suppressed 8505C and KTC-3 cell motility. In addition, treatment with dipyridamole and decreased expression of h-prune suppressed tumor invasion and pulmonary metastasis in a NOD/Shi-scid, IL-2Rγnull (NOG) mouse orthotopic thyroid cancer model. In conclusion, h-prune is frequently expressed in anaplastic thyroid cancer cells and lymph nodes metastasis, and promotes migration and invasion of anaplastic thyroid cancer cells and metastasis in an anaplastic thyroid cancer model. Thus, h-prune shows promise as a targeting candidate against anaplastic thyroid cancer. PMID:27109060

  14. Effect of Spindle Checkpoint on Akt2-mediated Paclitaxel-resistance in A2780 Ovarian Cancer Cells

    Institute of Scientific and Technical Information of China (English)

    周婷; 鲍引娣; 叶双梅; 翁丹卉; 陈刚; 卢运萍; 马丁; 王世宣

    2010-01-01

    Recent evidence has suggested that Akt2 plays an important role in the protection of cells from paclitaxel(PTX)-induced apoptosis and control of the cell cycle.In addition,some scholars suggested that the PTX sensitivity depends on a functional spindle assembly checkpoint.In the present study,we investigated the role of the Akt2/Bub1 cross-talking in apoptosis and cell cycle after exposure of the A2780 ovarian cancer cells to paclitaxel(PTX).Recombinant expression plasmid WT-Akt2 was transfected into A2780 ...

  15. Eu/Tb codoped spindle-shaped fluorinated hydroxyapatite nanoparticles for dual-color cell imaging

    Science.gov (United States)

    Ma, Baojin; Zhang, Shan; Qiu, Jichuan; Li, Jianhua; Sang, Yuanhua; Xia, Haibing; Jiang, Huaidong; Claverie, Jerome; Liu, Hong

    2016-06-01

    Lanthanide doped fluorinated hydroxyapatite (FAp) nanoparticles are promising cell imaging nanomaterials but they are excited at wavelengths which do not match the light sources usually found in a commercial confocal laser scanning microscope (CLSM). In this work, we have successfully prepared spindle-shaped Eu/Tb codoped FAp nanoparticles by a hydrothermal method. Compared with single Eu doped FAp, Eu/Tb codoped FAp can be excited by a 488 nm laser, and exhibit both green and red light emission. By changing the amounts of Eu and Tb peaks, the emission in the green region (500-580 nm) can be decreased to the benefit of the emission in the red region (580-720 nm), thus reaching a balanced dual color emission. Using MC3T3-E1 cells co-cultured with Eu/Tb codoped FAp nanoparticles, it is observed that the nanoparticles are cytocompatible even at a concentration as high as 800 μg ml-1. The Eu/Tb codoped FAp nanoparticles are located in the cytoplasm and can be monitored by dual color--green and red imaging with a single excitation light at 488 nm. At a concentration of 200 μg ml-1, the cytoplasm is saturated in 8 hours, and Eu/Tb codoped FAp nanoparticles retain their fluorescence for at least 3 days. The cytocompatible Eu/Tb codoped FAp nanoparticles with unique dual color emission will be of great use for cell and tissue imaging.Lanthanide doped fluorinated hydroxyapatite (FAp) nanoparticles are promising cell imaging nanomaterials but they are excited at wavelengths which do not match the light sources usually found in a commercial confocal laser scanning microscope (CLSM). In this work, we have successfully prepared spindle-shaped Eu/Tb codoped FAp nanoparticles by a hydrothermal method. Compared with single Eu doped FAp, Eu/Tb codoped FAp can be excited by a 488 nm laser, and exhibit both green and red light emission. By changing the amounts of Eu and Tb peaks, the emission in the green region (500-580 nm) can be decreased to the benefit of the emission in the

  16. Human ASPM participates in spindle organisation, spindle orientation and cytokinesis

    Directory of Open Access Journals (Sweden)

    Woods C Geoffrey

    2010-11-01

    Full Text Available Abstract Background Mutations in the Abnormal Spindle Microcephaly related gene (ASPM are the commonest cause of autosomal recessive primary microcephaly (MCPH a disorder characterised by a small brain and associated mental retardation. ASPM encodes a mitotic spindle pole associated protein. It is suggested that the MCPH phenotype arises from proliferation defects in neural progenitor cells (NPC. Results We show that ASPM is a microtubule minus end-associated protein that is recruited in a microtubule-dependent manner to the pericentriolar matrix (PCM at the spindle poles during mitosis. ASPM siRNA reduces ASPM protein at the spindle poles in cultured U2OS cells and severely perturbs a number of aspects of mitosis, including the orientation of the mitotic spindle, the main determinant of developmental asymmetrical cell division. The majority of ASPM depleted mitotic cells fail to complete cytokinesis. In MCPH patient fibroblasts we show that a pathogenic ASPM splice site mutation results in the expression of a novel variant protein lacking a tripeptide motif, a minimal alteration that correlates with a dramatic decrease in ASPM spindle pole localisation. Moreover, expression of dominant-negative ASPM C-terminal fragments cause severe spindle assembly defects and cytokinesis failure in cultured cells. Conclusions These observations indicate that ASPM participates in spindle organisation, spindle positioning and cytokinesis in all dividing cells and that the extreme C-terminus of the protein is required for ASPM localisation and function. Our data supports the hypothesis that the MCPH phenotype caused by ASPM mutation is a consequence of mitotic aberrations during neurogenesis. We propose the effects of ASPM mutation are tolerated in somatic cells but have profound consequences for the symmetrical division of NPCs, due to the unusual morphology of these cells. This antagonises the early expansion of the progenitor pool that underpins cortical

  17. Spectrotemporal receptive fields during spindling and non-spindling epochs in cat primary auditory cortex.

    Science.gov (United States)

    Britvina, T; Eggermont, J J

    2008-07-17

    It was often thought that synchronized rhythmic epochs of spindle waves disconnect thalamo-cortical system from incoming sensory signals. The present study addresses this issue by simultaneous extracellular action potential and local field potential (LFP) recordings from primary auditory cortex of ketamine-anesthetized cats during spindling activity. We compared cortical spectrotemporal receptive fields (STRF) obtained during spindling and non-spindling epochs. The basic spectro-temporal parameters of "spindling" and "non-spindling" STRFs were similar. However, the peak-firing rate at the best frequency was significantly enhanced during spindling epochs. This enhancement was mainly caused by the increased probability of a stimulus to evoke spikes (effectiveness of stimuli) during spindling as compared with non-spindling epochs. Augmented LFPs associated with effective stimuli and increased single-unit pair correlations during spindling epochs suggested higher synchrony of thalamo-cortical inputs during spindling that resulted in increased effectiveness of stimuli presented during spindling activity. The neuronal firing rate, both stimulus-driven and spontaneous, was higher during spindling as compared with non-spindling epochs. Overall, our results suggests that thalamic cells during spindling respond to incoming stimuli-related inputs and, moreover, cause more powerful stimulus-related or spontaneous activation of the cortex. PMID:18515012

  18. Anaplastic astrocytoma in the spinal cord of an African pygmy hedgehog (Atelerix albiventris).

    Science.gov (United States)

    Gibson, C J; Parry, N M A; Jakowski, R M; Eshar, D

    2008-11-01

    A 2-year-old, female hedgehog presented with an 8-month history of progressive, ascending paresis/paralysis and was tentatively diagnosed with wobbly hedgehog syndrome. She died awaiting further diagnostic tests, and the owners consented to postmortem examination. Grossly, the bladder was large and flaccid and the cervical and lumbar spinal cord were regionally enlarged, light grey, and friable with multifocal hemorrhages. The thoracic spinal cord was grossly normal. Microscopically all regions of the spinal cord had similar changes, although the cervical and lumbar sections were most severely affected. These regions were completely effaced by a moderately cellular infiltration of highly pleomorphic polygonal to spindle shaped cells, mineralization, and necrosis, which were most consistent with anaplastic astrocytoma. The thoracic spinal cord white matter was similarly infiltrated by the neoplastic cells, with perivascular extension into the otherwise normal grey matter. A diagnosis of anaplastic astrocytoma was confirmed using immunohistochemical stains that were positive for glial fibrillary acidic protein and S100. PMID:18984799

  19. Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells.

    Directory of Open Access Journals (Sweden)

    William T Silkworth

    Full Text Available Many cancer cells display a CIN (Chromosome Instability phenotype, by which they exhibit high rates of chromosome loss or gain at each cell cycle. Over the years, a number of different mechanisms, including mitotic spindle multipolarity, cytokinesis failure, and merotelic kinetochore orientation, have been proposed as causes of CIN. However, a comprehensive theory of how CIN is perpetuated is still lacking. We used CIN colorectal cancer cells as a model system to investigate the possible cellular mechanism(s underlying CIN. We found that CIN cells frequently assembled multipolar spindles in early mitosis. However, multipolar anaphase cells were very rare, and live-cell experiments showed that almost all CIN cells divided in a bipolar fashion. Moreover, fixed-cell analysis showed high frequencies of merotelically attached lagging chromosomes in bipolar anaphase CIN cells, and higher frequencies of merotelic attachments in multipolar vs. bipolar prometaphases. Finally, we found that multipolar CIN prometaphases typically possessed gamma-tubulin at all spindle poles, and that a significant fraction of bipolar metaphase/early anaphase CIN cells possessed more than one centrosome at a single spindle pole. Taken together, our data suggest a model by which merotelic kinetochore attachments can easily be established in multipolar prometaphases. Most of these multipolar prometaphase cells would then bi-polarize before anaphase onset, and the residual merotelic attachments would produce chromosome mis-segregation due to anaphase lagging chromosomes. We propose this spindle pole coalescence mechanism as a major contributor to chromosome instability in cancer cells.

  20. THE MORPHOLOGICAL CHANGES IN MUSCLE SPINDLES AND ALTERATIONS IN CELL ACTIVITY OF THE RATS' RED NUCLEUS AFTER 2 WEEKS' SIMULATED WEIGHTLESSNESS

    Institute of Scientific and Technical Information of China (English)

    Zhu Yongjin; Fan Xiaoli; Wu Sudi; Li Qiang

    2006-01-01

    Objective To study the morphological changes of soleus muscle spindle and electrical activity of neurons in Red Nucleus(RN) of the rat after 2 weeks' simulated weightlessness, and to reveal the interaction between proprioceptive inputs of muscle spindles and reciprocal alterations in RN under simulated weightlessness. Methods Twenty female rats were exposed to weightlessness simulated by tail-suspension for 14 days (SW-14d). Body weight(200-220g) matched female rats were control group(Con). The morphological changes in isolated muscle spindle of soleus muscle, the discharges of red nucleus neurons were observed after 14d tail-suspensions by silver staining and extracellular recording respectively. Results Compared with control group ,the nerve ending of muscle spindle in SW-14d was distorted, degenerated and dissolved; the diameters of intrafusal fibers and capsule in equatorial region of soleus muscle spindles were diminished(P<0.05). The spontaneous cell activity and discharge of RN neurons (spikes/s) induced by afferent firing from muscle spindles after injection of succinylcholine were reduced after 2 weeks' simulated weightlessness respectively (18.44±5.96 vs. 10.19±6.88, 32.50±8.08 vs. 16.86±5.97, P<0.01). Conclusion The degeneration of muscle spindle induced by simulated weightlessness may be one of the causes that led to alterations in discharges of RN.

  1. TrkAIII Promotes Microtubule Nucleation and Assembly at the Centrosome in SH-SY5Y Neuroblastoma Cells, Contributing to an Undifferentiated Anaplastic Phenotype

    Directory of Open Access Journals (Sweden)

    Antonietta R. Farina

    2013-01-01

    Full Text Available The alternative TrkAIII splice variant is expressed by advanced stage human neuroblastomas (NBs and exhibits oncogenic activity in NB models. In the present study, employing stable transfected cell lines and assays of indirect immunofluorescence, immunoprecipitation, Western blotting, microtubule regrowth, tubulin kinase, and tubulin polymerisation, we report that TrkAIII binds α-tubulin and promotes MT nucleation and assembly at the centrosome. This effect depends upon spontaneous TrkAIII activity, TrkAIII localisation to the centrosome and pericentrosomal area, and the capacity of TrkAIII to bind, phosphorylate, and polymerise tubulin. We propose that this novel role for TrkAIII contributes to MT involvement in the promotion and maintenance of an undifferentiated anaplastic NB cell morphology by restricting and augmenting MT nucleation and assembly at the centrosomal MTOC.

  2. Locally advanced breast implant-associated anaplastic large-cell lymphoma: a case report of successful treatment with radiation and chemotherapy.

    Science.gov (United States)

    Estes, Christopher F; Zhang, Da; Reyes, Ruben; Korentager, Richard; McGinness, Marilee; Lominska, Christopher

    2015-01-01

    The development of breast implant-associated anaplastic large-cell lymphoma (ALCL) is a rare phenomenon. A typical presentation is an effusion associated with a breast implant. Less commonly, disease can be more advanced locoregionally or distantly. The optimal treatment schema is a topic of debate: localized ALCL can potentially be cured with implant removal alone, while other cases in the literature, including those that are more advanced, have been treated with varying combinations of surgery, chemotherapy, and external beam radiotherapy. This is a case report of breast implant ALCL with pathologically proven lymph node involvement, the fifth such patient reported. Our patient experienced a favorable outcome with radiation therapy and chemotherapy. PMID:25741471

  3. Energy and protein intake and nutritional status in non-surgically treated patients with small cell anaplastic carcinoma of the lung

    International Nuclear Information System (INIS)

    The spontaneous food intake and nutritional status was assessed in 23 patients with small cell anaplastic carcinoma of the lung before and two times during a treatment period of 6 weeks. Radiation therapy was given for 2 weeks followed by a course of chemotherapy and another 2 weeks of radiation therapy. The energy intake decreased during the treatment from 146 to 130 per cent of basal metabolic rate (p>0.10). The protein intake remained unchanged (mean 0.9 g/kg body weight).There were insignificant and small losses of weight, body fat, free body mass and arm muscle circumference, and no changes were seen in serum albumin and serum transferrin. However, 6 patients suffered a weight loss of 5 per cent or more. No correlation existed between the nutritional parameters measured before treatment and the changes during treatment. Patients who suffered a loss of body weight could therefore not be singled out before the treatment. (orig.)

  4. Anaplastic, plasmablastic, and plasmacytic plasmacytomas of mice: relationships to human plasma cell neoplasms and late-stage differentiation of normal B cells.

    Science.gov (United States)

    Qi, Chen-Feng; Zhou, Jeff X; Lee, Chang Hoon; Naghashfar, Zohreh; Xiang, Shao; Kovalchuk, Alexander L; Fredrickson, Torgny N; Hartley, Janet W; Roopenian, Derry C; Davidson, Wendy F; Janz, Siegfried; Morse, Herbert C

    2007-03-15

    We have compared histologic features and gene expression profiles of newly identified plasmacytomas from NFS.V(+) congenic mice with plasmacytomas of IL6 transgenic, Fasl mutant, and SJL-beta2M(-/-) mice. NFS.V(+) tumors comprised an overlapping morphologic spectrum of high-grade/anaplastic, intermediate-grade/plasmablastic, and low-grade/plasmacytic cases with similarities to subsets of human multiple myeloma and plasmacytoma. Microarray and immunohistochemical analyses of genes expressed by the most prevalent tumors, plasmablastic plasmacytomas, showed them to be most closely related to immunoblastic lymphomas, less so to plasmacytomas of Fasl mutant and SJL mice, and least to plasmacytic plasmacytomas of IL6 transgenic mice. Plasmablastic tumors seemed to develop in an inflammatory environment associated with gene signatures of T cells, natural killer cells, and macrophages not seen with plasmacytic plasmacytomas. Plasmablastic plasmacytomas from NFS.V(+) and SJL-beta2M(-/-) mice did not have structural alterations in Myc or T(12;15) translocations and did not express Myc at high levels, regular features of transgenic and pristane-induced plasmacytomas. These findings imply that, as for human multiple myeloma, Myc-independent routes of transformation contribute to the pathogenesis of these tumors. These findings suggest that plasma cell neoplasms of mice and humans exhibit similar degrees of complexity. Mouse plasmacytomas, previously considered to be homogeneous, may thus be as diverse as their human counterparts with respect to oncogenic mechanisms of plasma cell transformation. Selecting specific types of mouse plasmacytomas that relate most closely to subtypes of human multiple myeloma may provide new opportunities for preclinical testing of drugs for treatment of the human disease. PMID:17363561

  5. The heat shock protein 90 inhibitor SNX5422 has a synergistic activity with histone deacetylase inhibitors in induction of death of anaplastic thyroid carcinoma cells.

    Science.gov (United States)

    Kim, Si Hyoung; Kang, Jun Goo; Kim, Chul Sik; Ihm, Sung-Hee; Choi, Moon Gi; Yoo, Hyung Joon; Lee, Seong Jin

    2016-02-01

    The influence of the heat shock protein 90 (hsp90) inhibitor SNX5422 alone or in combination with the histone deacetylase (HDAC) inhibitors PXD101, suberoylanilide hydroxamic acid (SAHA), and trichostatin A (TSA) on survival of anaplastic thyroid carcinoma (ATC) cells was investigated. In 8505C and CAL62 cells, SNX5422 caused cell death with concomitant changes in the expression of hsp90 client proteins. After treatment of both SNX5422 and PXD101, SAHA and TSA, compared with treatment of SNX5422 alone, cell viability was diminished, whereas inhibition rate and cytotoxic activity were enhanced. All of the combination index values were lower than 1.0, suggesting the synergism between SNX5422 and PXD101, SAHA and TSA in induction of cell death. In cells treated with both SNX5422 and PXD101, SAHA and TSA, compared with cells treated with SNX5422 alone, the protein levels of Akt, phospho-4EBP1, phospho-S6 K, and survivin were diminished, while those of γH2AX, acetyl. histone H3, acetyl. histone H4, cleaved PARP, and cleaved caspase-3 were enhanced. In conclusion, these results demonstrate that SNX5422 has a cytotoxic activity in conjunction with alterations in the expression of hsp90 client proteins in ATC cells. Moreover, SNX5422 synergizes with HDAC inhibitors in induction of cytotoxicity accompanied by the suppression of PI3K/Akt/mTOR signaling and survivin, and the overexpression of DNA damage-related proteins in ATC cells. PMID:26219406

  6. The dichloromethane extract of the ethnomedicinal plant Neurolaena lobata inhibits NPM/ALK expression which is causal for anaplastic large cell lymphomagenesis.

    Science.gov (United States)

    Unger, Christine; Popescu, Ruxandra; Giessrigl, Benedikt; Laimer, Daniela; Heider, Susanne; Seelinger, Mareike; Diaz, Rene; Wallnöfer, Bruno; Egger, Gerda; Hassler, Melanie; Knöfler, Martin; Saleh, Leila; Sahin, Emine; Grusch, Michael; Fritzer-Szekeres, Monika; Dolznig, Helmut; Frisch, Richard; Kenner, Lukas; Kopp, Brigitte; Krupitza, Georg

    2013-01-01

    The present study investigates extracts of Neuolaena lobata, an anti-protozoan ethnomedicinal plant of the Maya, regarding its anti-neoplastic properties. Firstly, extracts of increasing polarity were tested in HL-60 cells analyzing inhibition of cell proliferation and apoptosis induction. Secondly, the most active extract was further tested in anaplastic large cell lymphoma (ALCL) cell lines of human and mouse origin. The dichloromethane extract inhibited proliferation of HL-60, human and mouse ALCL cells with an IC50 of ~2.5, 3.7 and 2.4 µg/ml, respectively and arrested cells in the G2/M phase. The extract induced the checkpoint kinases Chk1 and Chk2 and perturbed the orchestrated expression of the Cdc25 family of cell cycle phosphatases which was paralleled by the activation of p53, p21 and downregulation of c-Myc. Importantly, the expression of NPM/ALK and its effector JunB were drastically decreased, which correlated with the activation of caspase 3. Subsequently also platelet derived growth factor receptor β was downregulated, which was recently shown to be transcriptionally controlled by JunB synergizing with ALK in ALCL development. We show that a traditional healing plant extract downregulates various oncogenes, induces tumor suppressors, inhibits cell proliferation and triggers apoptosis of malignant cells. The discovery of the 'Active Principle(s)' is warranted. PMID:23135783

  7. The Clathrin-dependent Spindle Proteome.

    Science.gov (United States)

    Rao, Sushma R; Flores-Rodriguez, Neftali; Page, Scott L; Wong, Chin; Robinson, Phillip J; Chircop, Megan

    2016-08-01

    The mitotic spindle is required for chromosome congression and subsequent equal segregation of sister chromatids. These processes involve a complex network of signaling molecules located at the spindle. The endocytic protein, clathrin, has a "moonlighting" role during mitosis, whereby it stabilizes the mitotic spindle. The signaling pathways that clathrin participates in to achieve mitotic spindle stability are unknown. Here, we assessed the mitotic spindle proteome and phosphoproteome in clathrin-depleted cells using quantitative MS/MS (data are available via ProteomeXchange with identifier PXD001603). We report a spindle proteome that consists of 3046 proteins and a spindle phosphoproteome consisting of 5157 phosphosites in 1641 phosphoproteins. Of these, 2908 (95.4%) proteins and 1636 (99.7%) phosphoproteins are known or predicted spindle-associated proteins. Clathrin-depletion from spindles resulted in dysregulation of 121 proteins and perturbed signaling to 47 phosphosites. The majority of these proteins increased in mitotic spindle abundance and six of these were validated by immunofluorescence microscopy. Functional pathway analysis confirmed the reported role of clathrin in mitotic spindle stabilization for chromosome alignment and highlighted possible new mechanisms of clathrin action. The data also revealed a novel second mitotic role for clathrin in bipolar spindle formation. PMID:27174698

  8. Taxifolin enhances andrographolide-induced mitotic arrest and apoptosis in human prostate cancer cells via spindle assembly checkpoint activation.

    Directory of Open Access Journals (Sweden)

    Zhong Rong Zhang

    Full Text Available Andrographolide (Andro suppresses proliferation and triggers apoptosis in many types of cancer cells. Taxifolin (Taxi has been proposed to prevent cancer development similar to other dietary flavonoids. In the present study, the cytotoxic and apoptotic effects of the addition of Andro alone and Andro and Taxi together on human prostate carcinoma DU145 cells were assessed. Andro inhibited prostate cancer cell proliferation by mitotic arrest and activation of the intrinsic apoptotic pathway. Although the effect of Taxi alone on DU145 cell proliferation was not significant, the combined use of Taxi with Andro significantly potentiated the anti-proliferative effect of increased mitotic arrest and apoptosis by enhancing the cleavage of poly(ADP-ribose polymerase, and caspases-7 and -9. Andro together with Taxi enhanced microtubule polymerization in vitro, and they induced the formation of twisted and elongated spindles in the cancer cells, thus leading to mitotic arrest. In addition, we showed that depletion of MAD2, a component in the spindle assembly checkpoint (SAC, alleviated the mitotic block induced by the two compounds, suggesting that they trigger mitotic arrest by SAC activation. This study suggests that the anti-cancer activity of Andro can be significantly enhanced in combination with Taxi by disrupting microtubule dynamics and activating the SAC.

  9. Epigenetic Silencing of the Proapoptotic Gene BIM in Anaplastic Large Cell Lymphoma through an MeCP2/SIN3a Deacetylating Complex

    Directory of Open Access Journals (Sweden)

    Rocco Piazza

    2013-05-01

    Full Text Available BIM is a proapoptotic member of the Bcl-2 family. Here, we investigated the epigenetic status of the BIM locus in NPM/ALK+ anaplastic large cell lymphoma (ALCL cell lines and in lymph node biopsies from NPM/ALK+ ALCL patients. We show that BIM is epigenetically silenced in cell lines and lymph node specimens and that treatment with the deacetylase inhibitor trichostatin A restores the histone acetylation, strongly upregulates BIM expression, and induces cell death. BIM silencing occurs through recruitment of MeCP2 and the SIN3a/histone deacetylase 1/2 (HDAC1/2 corepressor complex. This event requires BIM CpG methylation/demethylation with 5-azacytidine that leads to detachment of the MeCP2 corepressor complex and reacetylation of the histone tails. Treatment with the ALK inhibitor PF2341066 or with an inducible shRNA targeting NPM/ALK does not restore BIM locus reacetylation; however, enforced expression of NPM/ALK in an NPM/ALK-negative cell line significantly increases the methylation at the BIM locus. This study demonstrates that BIM is epigenetically silenced in NPM/ALK-positive cells through recruitment of the SIN3a/HDAC1/2 corepressor complex and that NPM/ALK is dispensable to maintain BIM epigenetic silencing but is able to act as an inducer of BIM methylation.

  10. Lobatin B inhibits NPM/ALK and NF-κB attenuating anaplastic-large-cell-lymphomagenesis and lymphendothelial tumour intravasation.

    Science.gov (United States)

    Kiss, Izabella; Unger, Christine; Huu, Chi Nguyen; Atanasov, Atanas Georgiev; Kramer, Nina; Chatruphonprasert, Waranya; Brenner, Stefan; McKinnon, Ruxandra; Peschel, Andrea; Vasas, Andrea; Lajter, Ildiko; Kain, Renate; Saiko, Philipp; Szekeres, Thomas; Kenner, Lukas; Hassler, Melanie R; Diaz, Rene; Frisch, Richard; Dirsch, Verena M; Jäger, Walter; de Martin, Rainer; Bochkov, Valery N; Passreiter, Claus M; Peter-Vörösmarty, Barbara; Mader, Robert M; Grusch, Michael; Dolznig, Helmut; Kopp, Brigitte; Zupko, Istvan; Hohmann, Judit; Krupitza, Georg

    2015-01-28

    An apolar extract of the traditional medicinal plant Neurolaena lobata inhibited the expression of the NPM/ALK chimera, which is causal for the majority of anaplastic large cell lymphomas (ALCLs). Therefore, an active principle of the extract, the furanoheliangolide sesquiterpene lactone lobatin B, was isolated and tested regarding the inhibition of ALCL expansion and tumour cell intravasation through the lymphendothelium. ALCL cell lines, HL-60 cells and PBMCs were treated with plant compounds and the ALK inhibitor TAE-684 to measure mitochondrial activity, proliferation and cell cycle progression and to correlate the results with protein- and mRNA-expression of selected gene products. Several endpoints indicative for cell death were analysed after lobatin B treatment. Tumour cell intravasation through lymphendothelial monolayers was measured and potential causal mechanisms were investigated analysing NF-κB- and cytochrome P450 activity, and 12(S)-HETE production. Lobatin B inhibited the expression of NPM/ALK, JunB and PDGF-Rβ, and attenuated proliferation of ALCL cells by arresting them in late M phase. Mitochondrial activity remained largely unaffected upon lobatin B treatment. Nevertheless, caspase 3 became activated in ALCL cells. Also HL-60 cell proliferation was attenuated whereas PBMCs of healthy donors were not affected by lobatin B. Additionally, tumour cell intravasation, which partly depends on NF-κB, was significantly suppressed by lobatin B most likely due to its NF-κB-inhibitory property. Lobatin B, which was isolated from a plant used in ethnomedicine, targets malignant cells by at least two properties: I) inhibition of NPM/ALK, thereby providing high specificity in combating this most prevalent fusion protein occurring in ALCL; II) inhibition of NF-κB, thereby not affecting normal cells with low constitutive NF-κB activity. This property also inhibits tumour cell intravasation into the lymphatic system and may provide an option to manage this

  11. Dysphonia in geriatric cases always needs fiberoptic laryngoscopy/bronchoscopy: Spindle cell carcinoma of larynx, a rare entity

    Directory of Open Access Journals (Sweden)

    Shivaji Patil

    2016-01-01

    Full Text Available Spindle cell (sarcomatoid carcinoma is a rare variant of squamous cell carcinoma (SCC. It compromises of 2–3% of laryngeal cancers. Tumor arises from the oral cavity, tonsil larynx, and pharynx. Tumor is majority times misdiagnosed as reactive lesions or mesenchymal malignancies. It is considered to be a biphasic tumor that is composed of an SCC (in situ or invasive and spindle cell carcinoma (SpCC with sarcomatous appearance. In this case report, 61-year-male with minimal throat pain and acute onset dysphonia misdiagnosed and treated as a case of bronchial asthma with gastroesophageal reflux confirmed to have exophytic laryngeal growth is the cause for clinical presentation. We performed fiberoptic laryngoscopy and diagnosed to have SpCC of larynx. High index of suspicion is a must in geriatric cases with documented history of smoking and fiberoptic laryngoscopy/bronchoscopy found to be crucial in the evaluation. Histopathology expertise in surgical oncology is essential while planning treatment.

  12. Spindle Bursts in Neonatal Rat Cerebral Cortex.

    Science.gov (United States)

    Yang, Jenq-Wei; Reyes-Puerta, Vicente; Kilb, Werner; Luhmann, Heiko J

    2016-01-01

    Spontaneous and sensory evoked spindle bursts represent a functional hallmark of the developing cerebral cortex in vitro and in vivo. They have been observed in various neocortical areas of numerous species, including newborn rodents and preterm human infants. Spindle bursts are generated in complex neocortical-subcortical circuits involving in many cases the participation of motor brain regions. Together with early gamma oscillations, spindle bursts synchronize the activity of a local neuronal network organized in a cortical column. Disturbances in spindle burst activity during corticogenesis may contribute to disorders in cortical architecture and in the activity-dependent control of programmed cell death. In this review we discuss (i) the functional properties of spindle bursts, (ii) the mechanisms underlying their generation, (iii) the synchronous patterns and cortical networks associated with spindle bursts, and (iv) the physiological and pathophysiological role of spindle bursts during early cortical development. PMID:27034844

  13. Thrombospondin-1 silencing down-regulates integrin expression levels in human anaplastic thyroid cancer cells with BRAFV600E: new insights in the host tissue adaptation and homeostasis of tumor microenvironment

    OpenAIRE

    CarmeloNucera; PeterM.Sadow; JackLawler

    2013-01-01

    Background and Rationale: Anaplastic thyroid cancer (ATC) is characterized by pleomorphic cells, has a poor prognosis, is highly devastating disease, and is not curable. No reliable biomarkers of metastatic potential, helpful for early diagnosis of ATC and therapeutic response have been found yet. Thrombospondin-1 (TSP-1) plays a fundamental role in cancer progression by regulating cell stromal cross talk in the tumor microenvironment. Goals: Our goal was to understand whether TSP-1 could...

  14. Are there sufficient diagnostic criteria for bronchial atypical carcinoid? A case report of bronchial pigmented spindle cell carcinoid with a review of the literature

    Directory of Open Access Journals (Sweden)

    Piotr Lewitowicz

    2014-09-01

    Full Text Available Here we present a case of a 42-year-old female patient with pigmented spindle cell variant of bronchial carcinoid. The aim of this study was not only to record a rare variant of this tumour but also to highlight the differences in diagnostic criteria of gastrointestinal and bronchopulmonary-thymic neuroendocrine neoplasms. Ki-67 index is a discriminating factor in differential diagnosis between gastrointestinal neuroendocrine tumours (NETs and, only optionally, in bronchopulmonary-thymic tumours. Since diagnosis is currently based on mitotic activity, optionally Ki-67 index and tumour necrosis, a rare variant of NET, spindle cell carcinoids with cellular atypia could be potential pitfalls for diagnostic controversies or mistakes. Nevertheless, the presented case of typical carcinoid with spindle cell component and mild to moderate cellular atypia has been classified according current WHO criteria as a typical carcinoid.

  15. Case report: a unique pediatric case of a primary CD8 expressing ALK-1 positive anaplastic large cell lymphoma of skeletal muscle

    Directory of Open Access Journals (Sweden)

    Gaiser Timo

    2012-04-01

    Full Text Available Abstract Primary involvement of skeletal muscle is a very rare event in ALK-1 positive anaplastic large cell lymphoma (ALCL. We describe a case of a 10-year old boy presenting with a three week history of pain and a palpable firm swelling at the dorsal aspect of the left thigh. Histological examination of the lesion revealed a tumoral and diffuse polymorphic infiltration of the muscle by large lymphoid cells. Tumor cells displayed eccentric, lobulated "horse shoe" or "kidney-shape" nuclei. The cells showed immunohistochemical positivity for CD30, ALK-1, CD2, CD3, CD7, CD8, and Perforin. Fluorescence in situ hybridization analysis revealed a characteristic rearrangement of the ALK-1 gene in 2p23 leading to the diagnosis of ALK-1 positive ALCL. Chemotherapy according to the ALCL-99-NHL-BFM protocol was initiated and resulted in a complete remission after two cycles. This case illustrates the unusual presentation of a pediatric ALCL in soft tissue with a good response to chemotherapy.

  16. Diffuse large B cell lymphoma of thyroid as a masquerader of anaplastic carcinoma of thyroid, diagnosed by FNA: a case report

    OpenAIRE

    Dehghani Mehdi; Omidvari Shapour; Daneshbod Yahya; Daneshbod Khosrow; Negahban Shahrzad

    2006-01-01

    Abstract Background Both thyroid lymphoma and anaplastic carcinoma of thyroid present with rapidly growing mass in eldery patients. Anaplastic carcinoma has high mortality rate and combination of surgery, radiation therapy and multidrug chemotherapy are the best chance for cure. Prognosis of thyroid lymphoma is excellent and chemotherapy for widespred lymphoms and radiotherapy with or without adjuvant chemotherapy for tumors localized to the gland, are the treatment of choice. Case report Thi...

  17. Bilayer hollow/spindle-like anatase TiO2 photoanode for high efficiency dye-sensitized solar cells

    Science.gov (United States)

    Wang, Guanxi; Zhu, Xunjin; Yu, Jiaguo

    2015-03-01

    Derived from a hollow TiO2 nanoparticle (HNP) as underlayer and a TiO2 spindle (SP) as light scattering overlayer, a new bilayer single-crystalline photoanode (HNP/SP) is fabricated for dye-sensitized solar cell (DSSC) application. The prepared bilayer TiO2 photoanode and two comparative HNP/HNP and SP/SP ones are fully characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, UV-vis absorption spectroscopy and N2 adsorption-desorption isotherms. An overall photoelectric conversion efficiency of 8.65% has been achieved for HNP/SP DSSC, which is 25% higher than that of HNP/HNP DSSC, and also far superior to that of SP/SP or conventional P25 DSSC. The improved photovoltaic performance of HNP/SP DSSC is attributed to the synergic effects, i.e. the single-crystalline bilayer structure favoring for rapid interfacial electron transport, the relatively large specific surface area of HNP for effective dye adsorption, and the 1D geometry of single-crystalline TiO2 spindles for direct electron transport pathway and strong light scattering effect.

  18. Mucinous tubular and spindle cell carcinoma of the kidney: Diagnosis by fine needle aspiration and review of the literature

    Directory of Open Access Journals (Sweden)

    Jiang Huimiao

    2015-01-01

    Full Text Available Renal mucinous tubular and spindle cell carcinoma (MTSCC was recently described as a distinct subtype of renal cell carcinoma (RCC in the 2004 World Health Organization classification of kidney tumors. MTSCC is a rare low grade malignancy with < 100 cases reported in the literature. To the best of our knowledge, there are 5 case reports with a total of 6 patients describing its diagnosis by fine needle aspiration (FNA. All of these cases were diagnosed as conventional RCC on FNA. Subsequent excisions proved them to be MTSCC. We herein report a case in a 67-year-old male. He presented with abdominal pain and was found to have a new colon adenocarcinoma with metastasis to the liver and lungs. The extent of disease made the patient ineligible for surgical excision, and he received chemotherapy. Work-up also revealed a kidney mass which was later biopsied by FNA and core biopsy. The tumor was composed of epithelial and spindled cell components embedded in a myxoid background. It was positive for CK7, AMCAR, vimentin, and epithelial membrane antigen. The tumor was diagnosed as MTSCC. One year later the kidney mass remained stable. However, the patient developed new metastasis to the liver from colonic primary. The kidney mass was not resected. Although rarely encountered in FNA cytology of the kidney, we believe the cytologic features of this tumor are distinctive and are different from conventional and other subtypes of RCC. Therefore, its accurate diagnosis on FNA is possible once pathologists are aware that MTSCC should be considered in the differential diagnosis of kidney tumors.

  19. Spindle formation and microtubule organization during first division in reconstructed rat embryos produced by somatic cell nuclear transfer.

    Science.gov (United States)

    Tomioka, Ikuo; Mizutani, Eiji; Yoshida, Tomoyuki; Sugawara, Atsushi; Inai, Kentaro; Sasada, Hiroshi; Sato, Eimei

    2007-08-01

    The present study was conducted to demonstrate the spindle formation and behavior of chromosomes and microtubules during first division in reconstructed rat embryos produced by somatic cell nuclear transfer (SCNT) with cumulus cell nuclei. To demonstrate the effect of oocyte aging after ovulation on the cleavage of SCNT embryos, micromanipulation was carried out 11, 15 and 18 h after injection of hCG. SCNT oocytes were activated by incubation in culture medium supplemented with 5 microM ionomycin for 5 min followed by treatment with 2 mM 6-dimethylaminopurine (6-DMAP) in mR1ECM for 2-3 h. For immunocytochemical observation, the SCNT embryos were incubated with monoclonal anti-alpha-tubulin antibody and then fluorescein isothiocyanate (FITC)-conjugated goat anti-mouse IgG. Cleavage rates were significantly higher for oocytes collected after 15 and 18 h rather than for those collected 11 h after injection of hCG (56 and 53%, respectively vs. 28%; P<0.05). Premature chromosome condensation occurred before activation of the SCNT oocytes, but adequate spindle formation was only rarely observed. The distribution of microtubules in SCNT embryos after activation was different from those of fertilized and parthenogenic oocytes, i.e., a dense microtubule organization shaped like a ring was observed. Eighteen to 20 h post-activation, most SCNT embryos were in the 2-cell stage, but no nucleoli were clearly visible, which was quite different from the fertilized oocytes. In addition, first division with and without small cellular bodies containing DNA was observed in the rat SCNT embryos in some cases. The present study suggests that reorganization of transferred nuclei in rat SCNT embryos may be inadequate in terms of formation of the mitotic assembly and nucleolar reorganization. PMID:17446658

  20. 伴鳞样成分的甲状腺间变性癌临床病理分析%Clinicopathologic Analysis of Anaplastic Thyroid Carcinoma with Squamoid Cell Component

    Institute of Scientific and Technical Information of China (English)

    潘毅; 孙保存

    2011-01-01

    目的:探讨伴鳞样成分的甲状腺间变性癌(anaplastic thyroid carcinoma with squamoid cell component,ATC-SCC)的诊断、鉴别诊断及临床病理特征.方法:回顾性分析85例少见甲状腺肿瘤的临床病理资料,通过HE切片进行形态学观察,对5例ATC-SCC,6例甲状腺鳞状细胞癌(squamous cell carcinoma,SCC),8例甲状腺呈胸腺样分化癌(carcinoma showing thymus-like ele?ments,CASTLE)和2 例甲状腺降钙素阴性的神经内分泌肿瘤(calcitonin-negative neuroendocrine tumor of the thyroid gland,CNNETT)进行9项免疫组织化学染色,包括Cytokeratin(CK)、Vimentin(VM)、Chromogranin A(CgA)、Synaptophysin(SYN)、CD117、CD5、Calcitonin(CT)、Thyroglobulin(TG)和Thyroid transcription factor-1(TTF-1),并对结果进行分析.结果:5例ATC-SCC中,男性2例,女性3例;年龄41~79岁,平均年龄53.2岁;肿物位于左腺叶3例,右腺叶2例.临床表现为无痛性颈部肿物.肿物通常体积较大,质地硬实,与周围组织粘连.镜下可见肿瘤组织由梭形细胞、多形性巨细胞、破骨样细胞和鳞状上皮样细胞以不同比例混合而成,并可见胞浆红染的横纹肌样细胞及大片坏死.免疫组织化学染色显示5例ATC-SCC的肿瘤细胞CK和VM均阳性.鳞状上皮样细胞为主要成分时需要与SCC、CASTLE和CNNETT进行鉴别.结论:ATC-SCC多见于老年人,女性较多见,生长迅速,常扩展至甲状腺外累犯颈部软组织,预后非常差,手术和放化疗相结合是治疗ATC-SCC的基本原则.%Objective: To investigate the clinicopathologic features, diagnosis, and differential diagnosis of anaplastic thyroid carcinoma with squamoid cell component ( ATC-SCC ).Methods: The data of 85 cases with rare thyroid neoplasms were retrospectively analyzed.Morphological observation of the sections from all cases was conducted after H&E staining.Five cases of ATC-SCC, 6 cases of thyroid squamous cell carcinoma ( TSCC ), 8 cases of with thyroid carcinoma showing thymus

  1. Rapid and dramatic response to alectinib in an anaplastic lymphoma kinase rearranged non-small-cell lung cancer patient who is critically ill.

    Science.gov (United States)

    Yoshida, Tatsuya; Hida, Toyoaki; Yatabe, Yasushi

    2016-07-01

    Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have shown promising clinical activity in the treatment of non-small-cell lung cancer (NSCLC) that harbors ALK rearrangement. The next-generation ALK-TKI, alectinib, has been reported to have potent efficacy in ALK-positive NSCLC patients including on mutations that confer resistance to crizotinib, which was the first ALK-TKI approved for ALK-positive NSCLC. The efficacy and safety of ALK-TKIs, including crizotinib and alectinib, as the first-line treatment in critically ill patients is unclear. We report one ALK-positive NSCLC patient with poor performance status (PS) and disseminated intravascular coagulation because of respiratory failure and multiple metastases, and experienced the rapid and dramatic response to alectinib without adverse events that can lead to discontinuation and dose reduction of the drug. After a couple of months of treatment with alectinib, radiological review indicated a complete response. The present case is the first reported case of rapid and marked response to alectinib in ALK-positive NSCLC patients who had poor PS and severe organ dysfunction, such as disseminated intravascular coagulation. Further investigation of the safety and efficacy of ALK-TKI for ALK-positive NSCLC patients who are critically ill is warranted. PMID:26938871

  2. Role of immunohistochemistry and fluorescence in-situ hybridization (FISH in the diagnosis of spindle and round cell tumors of the kidney

    Directory of Open Access Journals (Sweden)

    M. Abbas

    2015-09-01

    Conclusion: In summary we advise an immunohistochemical panel for round/spindle cell tumors of the kidney and for unclear cases we advise to add (FISH to get the correct diagnosis, as they are completely different regarding surgical approach and post-operative adjuvant therapy.

  3. Mammalian neurogenesis requires Treacle-Plk1 for precise control of spindle orientation, mitotic progression, and maintenance of neural progenitor cells.

    Directory of Open Access Journals (Sweden)

    Daisuke Sakai

    Full Text Available The cerebral cortex is a specialized region of the brain that processes cognitive, motor, somatosensory, auditory, and visual functions. Its characteristic architecture and size is dependent upon the number of neurons generated during embryogenesis and has been postulated to be governed by symmetric versus asymmetric cell divisions, which mediate the balance between progenitor cell maintenance and neuron differentiation, respectively. The mechanistic importance of spindle orientation remains controversial, hence there is considerable interest in understanding how neural progenitor cell mitosis is controlled during neurogenesis. We discovered that Treacle, which is encoded by the Tcof1 gene, is a novel centrosome- and kinetochore-associated protein that is critical for spindle fidelity and mitotic progression. Tcof1/Treacle loss-of-function disrupts spindle orientation and cell cycle progression, which perturbs the maintenance, proliferation, and localization of neural progenitors during cortical neurogenesis. Consistent with this, Tcof1(+/- mice exhibit reduced brain size as a consequence of defects in neural progenitor maintenance. We determined that Treacle elicits its effect via a direct interaction with Polo-like kinase1 (Plk1, and furthermore we discovered novel in vivo roles for Plk1 in governing mitotic progression and spindle orientation in the developing mammalian cortex. Increased asymmetric cell division, however, did not promote increased neuronal differentiation. Collectively our research has therefore identified Treacle and Plk1 as novel in vivo regulators of spindle fidelity, mitotic progression, and proliferation in the maintenance and localization of neural progenitor cells. Together, Treacle and Plk1 are critically required for proper cortical neurogenesis, which has important implications in the regulation of mammalian brain size and the pathogenesis of congenital neurodevelopmental disorders such as microcephaly.

  4. Targeting Transforming Growth Factor-Beta1 (TGF-β1) Inhibits Tumorigenesis of Anaplastic Thyroid Carcinoma Cells Through ERK1/2-NFκkB-PUMA Signaling.

    Science.gov (United States)

    Yin, Qiang; Liu, Shan; Dong, Anbing; Mi, Xiufang; Hao, Fengyun; Zhang, Kejun

    2016-01-01

    BACKGROUND The transforming growth factor-beta (TGF-β) signaling pathway plays a critical role in promoting tumor growth. TGF-β1was found to be overexpressed in anaplastic thyroid cancer (ATC). We therefore tested our hypothesis that targeting TGF-β1 inhibits tumorigenesis of ATC cells. MATERIAL AND METHODS Effects of TGF-β1 stimulation or TGF-β1 inhibition by small interfering RNA (TGF-β1siRNA) on proliferation, colony formation, and apoptosis in 8505C cells in vitro was detected using siRNAs and inhibitors to examine the TGF-β1 signaling pathway. A subcutaneously implanted tumor model of 8505C cells in nude mice was used to assess the effects of TGF-β1 inhibition on tumorigenesis development. RESULTS TGF-β1siRNAs decreased proliferation and colony formation, and increased apoptosis in 8505C cells in vitro and inhibited tumor growth in vivo. TGF-β1siRNA inhibited phosphorylation ERK1/2 (pERK1/2) and increased p65-dependant PUMA mRNA and protein expression. Knockdown of p65 or PUMA by siRNA reduced TGF-β1siRNA-induced apoptosis, as well as caspase-3 and PARP activation. Upregulation of p65 or PUMA expression by TGF-β1siRNA requires pERK1/2 inhibition. TGF-β1 shRNA inhibited tumor growth in vivo. CONCLUSIONS Therapies targeting the TGF-β1 pathway may be more effective to prevent primary tumor formation. The ability of this therapy to decrease tumorigenesis may be related to ERK1/2/NF-κB/PUMA signaling. PMID:27356491

  5. When the genome plays dice: circumvention of the spindle assembly checkpoint and near-random chromosome segregation in multipolar cancer cell mitoses.

    Directory of Open Access Journals (Sweden)

    David Gisselsson

    Full Text Available BACKGROUND: Normal cell division is coordinated by a bipolar mitotic spindle, ensuring symmetrical segregation of chromosomes. Cancer cells, however, occasionally divide into three or more directions. Such multipolar mitoses have been proposed to generate genetic diversity and thereby contribute to clonal evolution. However, this notion has been little validated experimentally. PRINCIPAL FINDINGS: Chromosome segregation and DNA content in daughter cells from multipolar mitoses were assessed by multiphoton cross sectioning and fluorescence in situ hybridization in cancer cells and non-neoplastic transformed cells. The DNA distribution resulting from multipolar cell division was found to be highly variable, with frequent nullisomies in the daughter cells. Time-lapse imaging of H2B/GFP-labelled multipolar mitoses revealed that the time from the initiation of metaphase to the beginning of anaphase was prolonged and that the metaphase plates often switched polarity several times before metaphase-anaphase transition. The multipolar metaphase-anaphase transition was accompanied by a normal reduction of cellular cyclin B levels, but typically occurred before completion of the normal separase activity cycle. Centromeric AURKB and MAD2 foci were observed frequently to remain on the centromeres of multipolar ana-telophase chromosomes, indicating that multipolar mitoses were able to circumvent the spindle assembly checkpoint with some sister chromatids remaining unseparated after anaphase. Accordingly, scoring the distribution of individual chromosomes in multipolar daughter nuclei revealed a high frequency of nondisjunction events, resulting in a near-binomial allotment of sister chromatids to the daughter cells. CONCLUSION: The capability of multipolar mitoses to circumvent the spindle assembly checkpoint system typically results in a near-random distribution of chromosomes to daughter cells. Spindle multipolarity could thus be a highly efficient

  6. Paracetamol-induced spindle disturbances in V79 cells with and without expression of human CYP1A2

    DEFF Research Database (Denmark)

    Jensen, K G; Poulsen, H E; Doehmer, J;

    1996-01-01

    Spindle disturbing effects in terms of c-mitosis and cytotoxicity of paracetamol were investigated in two Chinese hamster V79 cell lines, one of which (V79MZh1A2) was transfected with human CYP1A2. This enzyme catalyses the oxidative formation of the reactive paracetamol metabolite, NAPQI, believed...... to initiate hepatoxicity by covalent binding to proteins after overdose. In the native V79 cell line paracetamol increased c-mitosis frequency in a concentration dependent manner from 8.7 + or - 3.5% (control) to 66 + or - 18% at 20 mM. A significant increase to 13.3 + or - 3.5% was first seen at 2.......5 mM in the native cell line (P<0.05). In the V79MZh1A2 cells the concentration-effect curve was slightly shifted to the left (P<0.05) with c-mitosis frequency increased to 12.1 + or - 2.6% (P<0.05) at 1 mM paracetamol. At 5 mM paracetamol the c-mitosis frequency was 14.4 + or - 5.0% and 19.0 + or - 3...

  7. Methylglyoxal Induced Basophilic Spindle Cells with Podoplanin at the Surface of Peritoneum in Rat Peritoneal Dialysis Model

    Directory of Open Access Journals (Sweden)

    Ichiro Hirahara

    2015-01-01

    Full Text Available Peritoneal dialysis (PD is a common treatment for patients with reduced or absent renal function. Long-term PD leads to peritoneal injury with structural changes and functional decline. At worst, peritoneal injury leads to encapsulating peritoneal sclerosis (EPS, which is a serious complication of PD. In order to carry out PD safely, it is important to define the mechanism of progression of peritoneal injury and EPS. We prepared rat models of peritoneal injury by intraperitoneal administration of glucose degradation products, such as methylglyoxal (MGO or formaldehyde (FA, chlorhexidine gluconate (CG, and talc. In rats treated with MGO, peritoneal fibrous thickening with the appearance of basophilic spindle cells with podoplanin, cytokeratin, and α-smooth muscle actin at the surface of the peritoneum was observed. These cells may have been derived from mesothelial cells by epithelial-to-mesenchymal transition. In FA- or CG-treated rats, the peritoneum was thickened, and mesothelial cells were absent at the surface of the peritoneum. The CG- or MGO-treated rats presented with a so-called abdominal cocoon. In the talc-treated rats, extensive peritoneal adhesion and peritoneal thickening were observed. MGO-induced peritoneal injury model may reflect human histopathology and be suitable to analyze the mechanism of progression of peritoneal injury and EPS.

  8. Methylglyoxal Induced Basophilic Spindle Cells with Podoplanin at the Surface of Peritoneum in Rat Peritoneal Dialysis Model.

    Science.gov (United States)

    Hirahara, Ichiro; Sato, Hideki; Imai, Toshimi; Onishi, Akira; Morishita, Yoshiyuki; Muto, Shigeaki; Kusano, Eiji; Nagata, Daisuke

    2015-01-01

    Peritoneal dialysis (PD) is a common treatment for patients with reduced or absent renal function. Long-term PD leads to peritoneal injury with structural changes and functional decline. At worst, peritoneal injury leads to encapsulating peritoneal sclerosis (EPS), which is a serious complication of PD. In order to carry out PD safely, it is important to define the mechanism of progression of peritoneal injury and EPS. We prepared rat models of peritoneal injury by intraperitoneal administration of glucose degradation products, such as methylglyoxal (MGO) or formaldehyde (FA), chlorhexidine gluconate (CG), and talc. In rats treated with MGO, peritoneal fibrous thickening with the appearance of basophilic spindle cells with podoplanin, cytokeratin, and α-smooth muscle actin at the surface of the peritoneum was observed. These cells may have been derived from mesothelial cells by epithelial-to-mesenchymal transition. In FA- or CG-treated rats, the peritoneum was thickened, and mesothelial cells were absent at the surface of the peritoneum. The CG- or MGO-treated rats presented with a so-called abdominal cocoon. In the talc-treated rats, extensive peritoneal adhesion and peritoneal thickening were observed. MGO-induced peritoneal injury model may reflect human histopathology and be suitable to analyze the mechanism of progression of peritoneal injury and EPS. PMID:26064894

  9. The tyrosine phosphatase Shp2 interacts with NPM-ALK and regulates anaplastic lymphoma cell growth and migration

    DEFF Research Database (Denmark)

    Voena, Claudia; Conte, Chiara; Ambrogio, Chiara; Boeri Erba, Elisabetta; Boccalatte, Francesco; Mohammed, Shabaz; Jensen, Ole N; Palestro, Giorgio; Inghirami, Giorgio; Chiarle, Roberto

    2007-01-01

    , leading to increased cell growth, resistance to apoptosis, and changes in morphology and migration of transformed cells. To search for new NPM-ALK interacting molecules, we developed a mass spectrometry-based proteomic approach in HEK293 cells expressing an inducible NPM-ALK and identified the tyrosine...

  10. Measuring mitotic spindle dynamics in budding yeast

    Science.gov (United States)

    Plumb, Kemp

    In order to carry out its life cycle and produce viable progeny through cell division, a cell must successfully coordinate and execute a number of complex processes with high fidelity, in an environment dominated by thermal noise. One important example of such a process is the assembly and positioning of the mitotic spindle prior to chromosome segregation. The mitotic spindle is a modular structure composed of two spindle pole bodies, separated in space and spanned by filamentous proteins called microtubules, along which the genetic material of the cell is held. The spindle is responsible for alignment and subsequent segregation of chromosomes into two equal parts; proper spindle positioning and timing ensure that genetic material is appropriately divided amongst mother and daughter cells. In this thesis, I describe fluorescence confocal microscopy and automated image analysis algorithms, which I have used to observe and analyze the real space dynamics of the mitotic spindle in budding yeast. The software can locate structures in three spatial dimensions and track their movement in time. By selecting fluorescent proteins which specifically label the spindle poles and cell periphery, mitotic spindle dynamics have been measured in a coordinate system relevant to the cell division. I describe how I have characterised the accuracy and precision of the algorithms by simulating fluorescence data for both spindle poles and the budding yeast cell surface. In this thesis I also describe the construction of a microfluidic apparatus that allows for the measurement of long time-scale dynamics of individual cells and the development of a cell population. The tools developed in this thesis work will facilitate in-depth quantitative analysis of the non-equilibrium processes in living cells.

  11. Anaplastic lymphoma kinase gene rearrangements in patients with advanced-stage non-small-cell lung cancer: CT characteristics and response to chemotherapy

    International Nuclear Information System (INIS)

    Few articles have been published on the imaging findings of anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). To investigate the radiological findings of ALK-positive NSCLC in the advanced stage, CT scans were examined. In addition, the response to chemotherapy was evaluated. Of the 36 patients with ALK-rearranged NSCLC, a mass and a nodule were identified in 17 (47.2%) and 16 (44.4%), respectively, indicating that more than 40% had a small-sized tumor. Overall, 31 (86.1%) patients had lymphadenopathy, seven (19.4%) had extranodal lymph node invasion, and three (8.3%) had lymphangitis. A pleural effusion was seen in 15 patients (41.7%). All but one patient had no ground-glass opacity (GGO) lesions, indicating that most ALK-positive tumors showed a solid growth pattern without GGO on CT. Twenty were evaluable for response to chemotherapy; 10 (50.0%) had a partial response (PR), nine (45.0%) had stable disease (SD), and one (5.0%) had progressive disease (PD) with first-line chemotherapy. With second-line chemotherapy, five (26.3%) had PR, 11 (57.9%) had SD, and three (15.8%) had PD. The five patients with PR were all treated by using crizotinib. Time to progression was 8.2 months with first-line chemotherapy, and 6.0 months with second-line chemotherapy. Advanced-stage ALK-positive tumors have a relatively aggressive phenotype, which cannot be inferred from the size of the tumor alone. ALK-positive patients have a good response to first-line cytotoxic drugs and to crizotinib as second-line therapy, but a relatively poor response to cytotoxic drugs as second-line therapy

  12. Clinicopathologic characteristics andtherapeutic responses ofChinese patients withnon-small cell lung cancer who harbor an anaplastic lymphoma kinase rearrangement

    Institute of Scientific and Technical Information of China (English)

    ShaFu; HaiYunWang; FangWang; MaYanHuang; LingDeng; XiaoZhang; ZuLuYe; JianYong Shao

    2015-01-01

    Introduction:The rearrangement of the anaplastic lymphoma kinase (ALK) gene accounts for approximately 1%–6%of lung adenocarcinoma cases and deifnes a molecular subgroup of tumors characterized by clinical sensitivity toALK inhibitors such as crizotinib. This study aimed to identify the relationship betweenALK rearrangement and the clinico‑pathologic characteristics of non‑small cell lung cancer (NSCLC) and to analyze the therapeutic responses of crizotinib and conventional chemotherapy toALK rearrangement in NSCLC patients. Methods:A total of 487 lung cancer patients who underwent testing forALK rearrangement in our department were included in this study.ALK rearrangement was examined by using lfuorescence insitu hybridization (FISH) assay. Results:Among the 487 patients, 44 (9.0%) were diagnosed withALK rearrangement by using FISH assay. In 123 patients with adenocarcinoma who were non‑smokers and of a young age (≤58years old), the frequency ofALK rearrangement was 20.3% (25/123). Short overall survival (OS) was associated with non‑adenocarcinoma tumor type (P=0.006), poorly differentiated tumors (P=0.001), advanced‑stage tumors (P<0.001), smoking history (P=0.008), and wild‑type epidermal growth factor receptor (EGFR) (P=0.008). Moreover, patients with poorly differentiated and advanced‑stage tumors had a shorter time to cancer progression compared with those with well differentiated (P=0.023) and early‑stage tumors (P=0.001), respectively. Conclusions:ALK‑rearranged NSCLC tends to occur in younger individuals who are either non‑smokers or light smokers with adenocarcinoma. Patients withALK rearrangement might beneift fromALK inhibitor therapy.

  13. Primary anaplastic large cell lymphoma of the breast arising in reconstruction mammoplasty capsule of saline filled breast implant after radical mastectomy for breast cancer: an unusual case presentation

    Directory of Open Access Journals (Sweden)

    Sur Monalisa

    2009-04-01

    Full Text Available Abstract Background Primary non-Hodgkin lymphoma (NHL of the breast represents 0.04–0.5% of malignant lesions of the breast and accounts for 1.7–2.2% of extra-nodal NHL. Most primary cases are of B-cell phenotype and only rare cases are of T-cell phenotype. Anaplastic large cell lymphoma (ALCL is a rare T-cell lymphoma typically seen in children and young adults with the breast being one of the least common locations. There are a total of eleven cases of primary ALCL of the breast described in the literature. Eight of these cases occurred in proximity to breast implants, four in relation to silicone breast implant and three in relation to saline filled breast implant with three out of the eight implant related cases having previous history of breast cancer treated surgically. Adjuvant postoperative chemotherapy is given in only one case. Secondary hematological malignancies after breast cancer chemotherapy have been reported in literature. However in contrast to acute myeloid leukemia (AML, the association between lymphoma and administration of chemotherapy has never been clearly demonstrated. Case Presentation In this report we present a case of primary ALCL of the breast arising in reconstruction mamoplasty capsule of saline filled breast implant after radical mastectomy for infiltrating ductal carcinoma followed by postoperative chemotherapy twelve years ago. Conclusion Primary ALK negative ALCL arising at the site of saline filled breast implant is rare. It is still unclear whether chemotherapy and breast implantation increases risk of secondary hematological malignancies significantly. However, it is important to be aware of these complications and need for careful pathologic examination of tissue removed for implant related complications to make the correct diagnosis for further patient management and treatment. It is important to be aware of this entity at this site as it can be easily misdiagnosed on histologic grounds and to exclude

  14. Role of immunohistochemistry and fluorescence in-situ hybridization (FISH) in the diagnosis of spindle and round cell tumors of the kidney

    International Nuclear Information System (INIS)

    Spindle cell/mesenchymal tumors of the kidney are rare. The diagnosis is supported mainly by the application of ancillary techniques such as immunohistochemistry (IH) and in-situ hybridization (FISH). An accurate diagnosis is essential because early management by complete resection and adjuvant chemotherapy improves the prognosis dramatically. Synovial sarcoma and primitive neuroectodermal tumor/Ewing sarcoma are infrequent malignancies which usually present in soft tissues but rarely in the kidney. The challenge for the pathologists is to histologically differentiate between different types of sarcomas such as PNET/Ewing’s sarcoma, sarcomatous dedifferentiated renal cell carcinoma, metastasis, non-Hodgkin’s lymphoma, nephroblastoma and angiomyolipoma. Methods We report from our experience six exemplary rare cases that presented in the kidney as spindle/round cell tumors. Results We have arrived at the accurate diagnosis after performing a large panel of IH and FISH. Conclusion In summary we advise an immunohistochemical panel for round/spindle cell tumors of the kidney and for unclear cases we advise to add (FISH) to get the correct diagnosis, as they are completely different regarding surgical approach and post-operative adjuvant therapy

  15. Visualizing the spindle checkpoint in Drosophila spermatocytes

    Science.gov (United States)

    Rebollo, Elena; González, Cayetano

    2000-01-01

    The spindle assembly checkpoint detects defects in spindle structure or in the alignment of the chromosomes on the metaphase plate and delays the onset of anaphase until defects are corrected. Thus far, the evidence regarding the presence of a spindle checkpoint during meiosis in male Drosophila has been indirect and contradictory. On the one hand, chromosomes without pairing partners do not prevent meiosis progression. On the other hand, some conserved components of the spindle checkpoint machinery are expressed in these cells and behave as their homologue proteins do in systems with an active spindle checkpoint. To establish whether the spindle checkpoint is active in Drosophila spermatocytes we have followed meiosis progression by time-lapse microscopy under conditions where the checkpoint is likely to be activated. We have found that the presence of a relatively high number of misaligned chromosomes or a severe disruption of the meiotic spindle results in a significant delay in the time of entry into anaphase. These observations provide the first direct evidence substantiating the activity of a meiotic spindle checkpoint in male Drosophila. PMID:11256627

  16. The spindle protein CHICA mediates localization of the chromokinesin Kid to the mitotic spindle

    NARCIS (Netherlands)

    Santamaria, Anna; Nagel, Susanna; Sillje, Herman H W; Nigg, Erich A

    2008-01-01

    Microtubule-based motor proteins provide essential forces for bipolar organization of spindle microtubules and chromosome movement, prerequisites of chromosome segregation during the cell cycle. Here, we describe the functional characterization of a novel spindle protein, termed "CHICA," that was or

  17. The budding yeast protein kinase Ipl1/Aurora allows the absence of tension to activate the spindle checkpoint

    OpenAIRE

    Biggins, Sue; Murray, Andrew W.

    2001-01-01

    The spindle checkpoint prevents cell cycle progression in cells that have mitotic spindle defects. Although several spindle defects activate the spindle checkpoint, the exact nature of the primary signal is unknown. We have found that the budding yeast member of the Aurora protein kinase family, Ipl1p, is required to maintain a subset of spindle checkpoint arrests. Ipl1p is required to maintain the spindle checkpoint that is induced by overexpression of the protein kinase Mps1. Inactivating I...

  18. Trading in your spindles for blebs: the amoeboid tumor cell phenotype in prostate cancer

    Directory of Open Access Journals (Sweden)

    Samantha Morley

    2014-08-01

    Full Text Available Prostate cancer (PCa remains a principal cause of mortality in developed countries. Because no clinical interventions overcome resistance to androgen ablation therapy, management of castration resistance and metastatic disease remains largely untreatable. Metastasis is a multistep process in which tumor cells lose cell-cell contacts, egress from the primary tumor, intravasate, survive shear stress within the vasculature and extravasate into tissues to colonize ectopic sites. Tumor cells reestablish migratory behaviors employed during nonneoplastic processes such as embryonic development, leukocyte trafficking and wound healing. While mesenchymal motility is an established paradigm of dissemination, an alternate, 'amoeboid' phenotype is increasingly appreciated as relevant to human cancer. Here we discuss characteristics and pathways underlying the phenotype, and highlight our findings that the cytoskeletal regulator DIAPH3 governs the mesenchymal-amoeboid transition. We also describe our identification of a new class of tumor-derived microvesicles, large oncosomes, produced by amoeboid cells and with potential clinical utility in prostate and other cancers.

  19. Tipping the spindle into the right position.

    Science.gov (United States)

    Akhmanova, Anna; van den Heuvel, Sander

    2016-05-01

    The position of the mitotic spindle determines the cleavage plane in animal cells, but what controls spindle positioning? Kern et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201510117) demonstrate that the microtubule plus end-associated SKAP/Astrin complex participates in this process, possibly by affecting dynein-dependent pulling forces exerted on the tips of astral microtubules. PMID:27138251

  20. Thrombospondin-1 Silencing Down-Regulates Integrin Expression Levels in Human Anaplastic Thyroid Cancer Cells with BRAFV600E: New Insights in the Host Tissue Adaptation and Homeostasis of Tumor Microenvironment

    Science.gov (United States)

    Duquette, Mark; Sadow, Peter M.; Lawler, Jack; Nucera, Carmelo

    2013-01-01

    Background and Rationale: Anaplastic thyroid cancer (ATC) is characterized by pleomorphic cells, has a poor prognosis, is highly devastating disease, and is not curable. No reliable biomarkers of metastatic potential, helpful for early diagnosis of ATC and therapeutic response have been found yet. Thrombospondin-1 (TSP-1) plays a fundamental role in cancer progression by regulating cell stromal cross-talk in the tumor microenvironment. Goals: Our goal was to understand whether TSP-1 could affect protein levels of its integrin receptors (e.g., ITGα3, α6, and β1) and cell morphology in BRAFV600E-ATC cells in vitro and in vivo. Experimental Design: Anaplastic thyroid cancer-derived cell cultures and western blotting were used to assess integrin protein expression upon TSP-1 silencing. Immunohistochemistry was performed on orthotopic primary human ATC and metastatic ATC in lung tissue to compare TSP-1 and integrin protein expression levels. Results: TSP-1 knock-down down-regulates ITGα3, α6, and β1 in BRAFV600E-human ATC cells. BRAFV600E-ATC cells with TSP-1 knock-down were rounded compared to control cells, which displayed a spread morphology. TSP-1 knock-down also reduced TSP-1, ITGα3, α6, and β1 protein expression levels in vivo in the ATC microenvironment, which is enriched in stromal and inflammatory cells. Conclusion: TSP-1 silencing causes changes in ITG levels and ATC cell morphology. The assessment of TSP-1 and ITG levels might contribute to earlier metastatic potential of BRAFV600E-positive aggressive thyroid cancers, and allow improved patient selection for clinical trials. PMID:24348463

  1. Giant Cell Tumor Presenting as A Spindle Shaped Tumor Arising From the Costovertebral Junction at D7, d8, d9 Levels

    Science.gov (United States)

    Upadhyaya, Mihir; Kale, Sachin; Chaudhary, Prasad; Dhar, Sanjay

    2016-01-01

    Introduction: Giant cell tumor accounts for 5 to 9 percent of all primary bony tumors. Giant cell tumors are usually found in the long bones, most often the distal femur, proximal tibia, distal radius and rarely arising from the ribs. In this paper, we describe a case of giant cell tumor presented at an unusual location of the costovertebral junction as a dumbbell shaped tumor. Case Report: Authors report a case of a 27 year old male patient with a giant cell tumor arising from the costovertebral junction at D7, D8, and D9 levels compressing the cord. Well-defined osteolysis with nonsclerotic borders were visualized on radiographs and CT scan images. Intermediate signal intensity on T1 sequences and central high signal and peripheral intermediate signal intensity on T2 sequences was visualized on MRI images. CT guided biopsy was reported as a moderately vascular lesion with spindle cell neoplasm suggestive of schwannoma. The cord was decompressed, tumor mass was surgically resected and stabilization with instrumentation was done. Histopatholgy was suggestive of giant cell tumor. Conclusion: Giant cell tumor may be included in the differential diagnosis in a well-defined lytic lesion when involving the costovertebral junction presenting as a spindle cell tumor on biopsy reports. PMID:27299118

  2. Mitotic spindle perturbations

    NARCIS (Netherlands)

    Tame, M.A.

    2016-01-01

    Microtubules are major components of the cytoskeleton and form the bipolar spindle apparatus during mitosis. The mitotic spindle consists of highly dynamic microtubule polymers that are under constant modulation, controlled by multiple motor proteins and microtubule-associated proteins. This tight s

  3. Primary spindle cell sarcoma of the prostate and 18 F-fluorodeoxyglucose-positron-emission tomography/computed tomography findings

    Directory of Open Access Journals (Sweden)

    Hakan Öztürk

    2015-01-01

    Conclusion: Spindle sarcomas of the prostate have quite aggressive nature and they have high potential to metastase. Average life expectancy is <1 year and the prognosis is poor. CTx and radiation therapy can′t yield curative effects due to poor differentiation.

  4. [Successful long-term control of recurrent primary central nervous system anaplastic large cell lymphoma after autologous hematopoietic stem cell transplantation with concurrent whole brain and spinal cord radiotherapy].

    Science.gov (United States)

    Hiroshima, Yuki; Kaiume, Hiroko; Kirihara, Takehiko; Takeda, Wataru; Kurihara, Taro; Sato, Keijiro; Shimizu, Ikuo; Ueki, Toshimitsu; Sumi, Masahiko; Ueno, Mayumi; Ichikawa, Naoaki; Asano, Naoko; Watanabe, Masahide; Kobayashi, Hikaru

    2015-12-01

    A 24-year-old woman was hospitalized with seizures in 2002. Magnetic resonance imaging demonstrated an intraspinal mass and inhomogeneous gadolinium enhancement along the cerebrospinal meninges. Cerebrospinal fluid (CSF) cytology showed large atypical cells expressing CD2, cytoplasmic CD3, CD7, CD13 and CD30. The patient was finally diagnosed with primary central nervous system anaplastic large cell lymphoma (ALCL). She completed 5 courses of methotrexate (MTX)/ procarbazine (PCZ)/ vincristine (VCR) (MPV) chemotherapy, followed by 2 courses of high dose cytarabine (AraC) and achieved a complete remission. In 2003, she suffered from headache. CSF analysis showed atypical lymphoid cells expressing CD 30. First CNS relapse was diagnosed. She then underwent autologous peripheral blood stem cell transplantation (auto-PBSCT) after administration of thiotepa, buslfan, and cyclophosphamide. However, second CNS relapse occurred in 2004. She received 5 courses of MPV chemotherapy followed by 36 Gy of craniospinal irradiation. Although there was no recurrence of the CNS disease, a third relapse was detected in the right breast in 2009. Pathological and immunohistochemistry analysis revealed ALK-1 positive ALCL. She was treated with 6 courses of cyclophosphamide/adriamycin/vincristine/predonine (CHOP) chemotherapy and 30.6 Gy of local radiation therapy. She has remained in remission for 6 years, to date, since the last therapy and has an excellent quality of life. PMID:26725359

  5. Downregulation of nucleolar and spindle-associated protein 1 expression suppresses cell migration, proliferation and invasion in renal cell carcinoma.

    Science.gov (United States)

    Fang, Lu; Zhang, Meng; Chen, Lei; Xiong, Hu; Ge, Yukun; Lu, Wei; Wu, Xun; Heng, Baoli; Yu, Dexin; Wu, Song

    2016-09-01

    Nucleolar and spindle-associated protein 1 (NUSAP1) is a microtubule-binding protein that plays an essential role in mitosis and cancer. Previous studies have demonstrated that NUSAP1 expression is relatively elevated in several malignancies. However, the biological roles of NUSAP1 in renal cell carcinoma (RCC) remain unknown. In the present study, we firstly performed reverse transcription‑polymerase chain reaction (RT-PCR) and western blot analysis to reveal that the expression of NUSAP1 was relatively elevated in clear cell RCC (ccRCC) tissue specimens and RCC cell lines. Immunohistochemical analysis showed that upregulation of NUSAP1 was significantly correlated with Fuhrman grade (P<0.001), tumor size (P=0.016), clinical stage (P<0.001) and distant metastasis (P=0.023). Additionally, high expression of NUSAP1 was closely associated with a shorter overall survival time of the ccRCC patients (P=0.006). Furthermore, we investigated the biological behaviors of RCC cells in vitro, and we identified that NUSAP1 depletion inhibited RCC cell migration, proliferation and invasion, and apoptosis was induced and the cell cycle was arrested. On the basis of our studies, NUSAP1 was identified as a potential prognostic indicator and a novel therapeutic target for RCC patients. PMID:27461786

  6. Airborne urban particles (Milan winter-PM2.5) cause mitotic arrest and cell death: Effects on DNA, mitochondria, AhR binding and spindle organization

    International Nuclear Information System (INIS)

    Highlights: → PM2.5 induces mitotic arrest in BEAS-2B cells. → PM2.5 induces DNA damage and activates DNA damage response. → AhR regulated genes (Cyp1A1, Cyp1B1 and AhRR) are upregulated after PM exposure. → Mitotic spindle assembly is perturbed in PM exposed cells. - Abstract: Airborne particulate matter (PM) is considered to be an important contributor to lung diseases. In the present study we report that Milan winter-PM2.5 inhibited proliferation in human bronchial epithelial cells (BEAS-2B) by inducing mitotic arrest. The cell cycle arrest was followed by an increase in mitotic-apoptotic cells, mitotic slippage and finally an increase in 'classical' apoptotic cells. Exposure to winter-PM10 induced only a slight effect which may be due to the presence of PM2.5 in this fraction while pure combustion particles failed to disturb mitosis. Fewer cells expressing the mitosis marker phospho-histone H3 compared to cells with condensed chromosomes, suggest that PM2.5 induced premature mitosis. PM2.5 was internalized into the cells and often localized in laminar organelles, although particles without apparent plasma membrane covering were also seen. In PM-containing cells mitochondria and lysosomes were often damaged, and in mitotic cells fragmented chromosomes often appeared. PM2.5 induced DNA strands breaks and triggered a DNA-damage response characterized by increased phosphorylation of ATM, Chk2 and H2AX; as well as induced a marked increase in expression of the aryl hydrocarbon receptor (AhR)-regulated genes, CYP1A1, CYP1B1 and AhRR. Furthermore, some disturbance of the organization of microtubules was indicated. It is hypothesized that the induced mitotic arrest and following cell death was due to a premature chromosome condensation caused by a combination of DNA, mitochondrial and spindle damage.

  7. MelanA-negative spindle-cell associated melanoma, a distinct inflammatory phenotype correlated with dense infiltration of CD163 macrophages and loss of E-cadherin

    DEFF Research Database (Denmark)

    Bønnelykke-Behrndtz, Marie L; Steiniche, Torben; Damsgaard, Tine E;

    2015-01-01

    inflammatory heterogeneity of melanoma, which may have important diagnostic, prognostic and therapeutic implications for the patients. We show that melanomas harbour cell clones that bear strong resemblance to tumour-associated macrophages, a pivotal player in a tumour-supporting microenvironment......A-negative clone next to a MelanA-positive clone. Interestingly, MelanA-negative clones correlated significantly with an augmented inflammatory response of tumour-infiltrating macrophages (CD163+), complete loss of E-cadherin and a spindle-shaped morphology, irrespective of ulcerated status. These cases show the...

  8. Pins homolog LGN regulates meiotic spindle organization in mouse oocytes

    Institute of Scientific and Technical Information of China (English)

    Xinzheng Guo; Shaorong Gao

    2009-01-01

    Mouse oocytes undergo polarization during meiotic maturation, and this polarization is essential for asymmetric cell divisions that maximize retention of maternal components required for early development. Without conventional centrosomes, the meiotic spindle has less focused poles and is barrel-shaped. The migration of meiotic spindles to the cortex is accompanied by a local reorganization and polarization of the cortex. LGN is a conserved protein involved in cell polarity and regulation of spindle organization. In the present study, we characterized the localization dynam-ics of LGN during mouse oocyte maturation and analyzed the effects of LGN upregulation and downregulation on meiotic spindle organization. At the germinal vesicle stage, LGN is distributed both cytoplasmically and at the cor-tex. During maturation, LGN localizes to the meiotic spindle apparatus and cortical LGN becomes less concentrated at the actin cap region. Excessive LGN induces meiotic spindle organization defects by elongating the spindle and enhancing pole focusing, whereas depletion of LGN by RNA interference results in meiotic spindle deformation and chromosome misalignment. Furthermore, the N-terminus of LGN has the ability of full-length LGN to regulate spin-dle organization, whereas the C-terminus of LGN controls cortical localization and polarization. Our results reveal that LGN is cortically polarized in mouse oocytes and is critical for meiotic spindle organization.

  9. Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells

    OpenAIRE

    Moshe Giladi; Schneiderman, Rosa S; Tali Voloshin; Yaara Porat; Mijal Munster; Roni Blat; Shay Sherbo; Zeev Bomzon; Noa Urman; Aviran Itzhaki; Shay Cahal; Anna Shteingauz; Aafia Chaudhry; Kirson, Eilon D.; Uri Weinberg

    2015-01-01

    Tumor Treating Fields (TTFields) are low intensity, intermediate frequency, alternating electric fields. TTFields are a unique anti-mitotic treatment modality delivered in a continuous, noninvasive manner to the region of a tumor. It was previously postulated that by exerting directional forces on highly polar intracellular elements during mitosis, TTFields could disrupt the normal assembly of spindle microtubules. However there is limited evidence directly linking TTFields to an effect on mi...

  10. A novel dendritic nanocarrier of polyamidoamine-polyethylene glycol-cyclic RGD for “smart” small interfering RNA delivery and in vitro antitumor effects by human ether-à-go-go-related gene silencing in anaplastic thyroid carcinoma cells

    Directory of Open Access Journals (Sweden)

    Li G

    2013-03-01

    Full Text Available Guanhua Li,1,2 Zuojun Hu,1 Henghui Yin,1 Yunjian Zhang,1 Xueling Huang,1 Shenming Wang,1 Wen Li2 1Department of Vascular and Thyroid Surgery, 2Key Laboratory of Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China Abstract: The application of RNA interference techniques is promising in gene therapeutic approaches, especially for cancers. To improve safety and efficiency of small interfering RNA (siRNA delivery, a triblock dendritic nanocarrier, polyamidoamine-polyethylene glycol-cyclic RGD (PAMAM-PEG-cRGD, was developed and studied as an siRNA vector targeting the human ether-à-go-go-related gene (hERG in human anaplastic thyroid carcinoma cells. Structure characterization, particle size, zeta potential, and gel retardation assay confirmed that complete triblock components were successfully synthesized with effective binding capacity of siRNA in this triblock nanocarrier. Cytotoxicity data indicated that conjugation of PEG significantly alleviated cytotoxicity when compared with unmodified PAMAM. PAMAM-PEG-cRGD exerted potent siRNA cellular internalization in which transfection efficiency measured by flow cytometry was up to 68% when the charge ratio (N/P ratio was 3.5. Ligand-receptor affinity together with electrostatic interaction should be involved in the nano-siRNA endocytosis mechanism and we then proved that attachment of cRGD enhanced cellular uptake via RGD-integrin recognition. Gene silencing was evaluated by reverse transcription polymerase chain reaction and PAMAM-PEG-cRGD-siRNA complex downregulated the expression of hERG to 26.3% of the control value. Furthermore, gene knockdown of hERG elicited growth suppression as well as activated apoptosis by means of abolishing vascular endothelial growth factor secretion and triggering caspase-3 cascade in anaplastic thyroid carcinoma cells. Our study demonstrates that this novel triblock polymer, PAMAM-PEG-cRGD, exhibits negligible

  11. Mechanical stability of bipolar spindle assembly

    Science.gov (United States)

    Malgaretti, Paolo; Muhuri, Sudipto

    2016-07-01

    Assembly and stability of mitotic spindle are governed by the interplay of various intra-cellular forces, e.g. the forces generated by motor proteins by sliding overlapping anti-parallel microtubules (MTs) polymerized from the opposite centrosomes, the interaction of kinetochores with MTs, and the interaction of MTs with the chromosome arms. We study the mechanical behavior and stability of spindle assembly within the framework of a minimal model which includes all these effects. For this model, we derive a closed-form analytical expression for the force acting between the centrosomes as a function of their separation distance and we show that an effective potential can be associated with the interactions at play. We obtain the stability diagram of spindle formation in terms of parameters characterizing the strength of motor sliding, repulsive forces generated by polymerizing MTs, and the forces arising out of the interaction of MTs with kinetochores. The stability diagram helps in quantifying the relative effects of the different interactions and elucidates the role of motor proteins in formation and inhibition of spindle structures during mitotic cell division. We also predict a regime of bistability for a certain parameter range, wherein the spindle structure can be stable for two different finite separation distances between centrosomes. This occurrence of bistability also suggests the mechanical versatility of such self-assembled spindle structures.

  12. Attachment issues : kinetochore transformations and spindle checkpoint silencing

    NARCIS (Netherlands)

    Etemad, Banafsheh; Kops, Geert Jpl

    2016-01-01

    Cell division culminates in the segregation of duplicated chromosomes in opposite directions prior to cellular fission. This process is guarded by the spindle assembly checkpoint (SAC), which prevents the anaphase of cell division until stable connections between spindle microtubules and the kinetoc

  13. Carcinoma fusocelular de cavidad oral: Revisión de 9 casos Spindle cell carcinoma of the oral cavity: A review of 9 cases

    Directory of Open Access Journals (Sweden)

    G. Gómez Oliveira

    2006-02-01

    Full Text Available El carcinoma fusocelular es una variedad maligna y poco frecuente del carcinoma de células escamosas. Es una tumoración constituida por una doble proliferación celular: una sarcomatosa de células fusocelulares y otra carcinomatosa de células epiteliales. Aunque puede afectar a cualquier parte del organismo, es más frecuente encontrarla en vías aerodigestivas superiores. Afecta con mayor frecuencia a varones entre la 6ª y 7ª décadas de la vida. Tiene un comportamiento agresivo con tendencia a la recurrencia. El alcohol y tabaco han sido identificados como los factores de riesgo más importantes. Su diagnóstico histológico es complicado y muchas veces es necesario recurrir a técnicas de inmunohistoquímica y al uso del microscopio electrónico. En la actualidad, se le atribuye un origen epitelial. El objetivo de este trabajo es presentar una revisión de 9 casos de carcinoma fusocelular localizados en cavidad oral recogidos en nuestro servicio entre los años 1985 a 2004, describiendo su comportamiento clínico y tratando de comprender la patogenia de esta controvertida estirpe tumoral.Spindle cell carcinoma is a malignant and rare variant of squamous cell carcinoma. The histological pattern is composed of a double cell proliferation: a sarcomatous component made up of spindle-shaped cells and a carcinomatous component made up of epithelial cells. Nearly all the anatomy of the body can be affected by these tumors although the most common location is the upper aerodigestive tract. With regard to sex distribution, it is more frequent in males than in females in their sixth and seventh decades of life. Its behavior is aggressive and it tends to recur after treatment. The most important risk factors are alcohol and tobacco. The histological diagnosis is complicated, so immunohistochemical techniques and the use of electron microscopy are usually necessary. Nowadays, its epithelial origin is accepted. The aim of this article is to report a

  14. A pathway containing the Ipl1/Aurora protein kinase and the spindle midzone protein Ase1 regulates yeast spindle assembly

    OpenAIRE

    Kotwaliwale, Chitra V.; Frei, Stéphanie Buvelot; Stern, Bodo M.; Biggins, Sue

    2007-01-01

    It is critical to elucidate the pathways that mediate spindle assembly and therefore ensure accurate chromosome segregation during cell division. Our studies of a unique allele of the budding yeast Ipl1/Aurora protein kinase revealed that it is required for centrosome-mediated spindle assembly in the absence of the BimC motor protein Cin8. In addition, we found that the Ase1 spindle midzone-associated protein is required for bipolar spindle assembly. The cin8 ipl1 and cin8 ase1 double mutant ...

  15. Anaplastic thyroid cancer, tumorigenesis and therapy.

    LENUS (Irish Health Repository)

    O'Neill, J P

    2010-03-01

    Anaplastic thyroid cancer (ATC) is a fatal endocrine malignancy. Current therapy fails to significantly improve survival. Recent insights into thyroid tumorigenesis, post-malignant dedifferentiation and mode of metastatic activity offer new therapeutic strategies.

  16. Anaplastic myeloma in systemic lupus erythematosus.

    Science.gov (United States)

    Butler, R C; Thomas, S M; Thompson, J M; Keat, A C

    1984-01-01

    We describe a patient with systemic lupus erythematosus who developed an unusual form of anaplastic myeloma. Possible relationships between the two disease, and the role played by immunosuppressive therapy, are discussed. Images PMID:6476924

  17. Absence of anaplastic lymphoma kinase-1 expression in inflammatory myofibroblastic tumors of the central nervous system: Does it signify a different nosologic entity from its systemic counterpart?

    Directory of Open Access Journals (Sweden)

    Aparna Govindan

    2014-01-01

    Full Text Available Background and Aim: Inflammatory myofibroblastic tumors (IMFTs are uncommon neoplasms of the central nervous system (CNS of intermediate grade biologic potential. Anaplastic lymphoma kinase (ALK-1, a diagnostic marker of anaplastic large cell lymphoma, is also expressed in a subset of IMFTs and appears to have prognostic significance. Though, few studies have evaluated expression of ALK-1 in IMFTs of the CNS. This retrospective study was undertaken to evaluate the expression of ALK-1 expression in IMFT of CNS by immunohistochemistry and correlate with the clinical, radiological and pathologic features. Materials and Methods: Five cases diagnosed as IMFT/inflammatory pseudotumour/plasma cell granuloma, diagnosed in CNS over 10 year period (1998-2007 were retrieved from the archives of Department of Neuropathology of a tertiary referralcenter. The clinical profile and imaging features were collected from the case records. Hematoxylin and eosin stained sections were reviewed with immunohistochemistry for smooth muscle actin (SMA, vimentin, desmin, ALK-1, p53, MIB-1, CD68, leukocyte common antigen, CD3, and CD20. Results: All five cases of IMFTs presented as dural-based space occupying or en-plaque lesions. Histologically, four cases had combined plasma cell granuloma-fibrous histiocytoma morphology, and one had fibrous histiocytoma-like morphology. Immunohistochemically, SMA was strongly positive in spindle cell component of the tumors confirming diagnosis. ALK-1 expression could not be detected by immunohistochemistry in any of the cases. Conclusion: Further studies analyzing ALK-1 gene mutation and rearrangements are required to determine pathogenetic role, if any, in CNS IMFTs.

  18. Leptomeningeal metastases from anaplastic thyroid carcinoma

    International Nuclear Information System (INIS)

    Anaplastic thyroid carcinoma is an extremely aggressive neoplasm that accounts for 1-3% of all thyroid cancers. ' Most patients have metastatic disease at presentation and die in a short period of time, often with uncontrolled local disease. We report a case of anaplastic thyroid cancer characterised by good response to initial treatment both locally and in distant metastases, and the subsequent development of refractory metastatic disease in an unusual site, the leptomeninges

  19. Clinicopathologic Features of Gastrointestinal Tract Involvement of Anaplastic Large Cell Lymphoma%累及胃肠道的间变性大细胞淋巴瘤的临床病理学特点

    Institute of Scientific and Technical Information of China (English)

    孙健; 周皎琳; 陈杰; 卢朝辉

    2012-01-01

    Objective To investigate the clinicopathological characteristics of gastrointestinal tract involvement of anaplastic large cell lymphoma ( ALCL ). Methods The clinicopathological features of four patients with ALCL that involved gastrointestinal tract were retrospectively analyzed using immunohistochemical study, T-cell receptor gene rearrangement analysis, and evaluation for Epstein Barr virus infection status. Results Most tumor cells in all these four cases are large and highly pleomorphic, and all four cases were classified as the "common pattern" ALCL Tumor cells in all four tumors expressed CD30, and expressed at least one cytotoxic maker. Two patients were confirmed to be with anaplastic lymphoma kinase ( ALK) -positive ALCL, and four patients were negative during in situ hybridization for Epstein-Barr virus-encoded RNA but showed clonal T-cell receptor gene rearrangement. Conclusion Gastrointestinal tract involvement of ALCL has the unique clinicopathological features.%目的 总结累及胃肠道的间变性大细胞淋巴瘤(ALCL)的临床病理学特点.方法 收集整理4例累及胃肠道的ALCL病例标本,对其进行临床病理分析、免疫组织化学检测、EB病毒编码的RNA (EBER)原位杂交检测及T细胞受体(TCR)基因重排检测.结果 4例病例中,肿瘤细胞均以多形性大细胞为主,归为普通型ALCL;均表现为弥漫、较强地表达CD30,且至少表达1种细胞毒性抗原;2例为间变性淋巴瘤激酶(ALK)阳性ALCL;4例EBER原位杂交检测均为阴性且均存在TCR基因克隆性重排.结论 累及胃肠道的ALCL具有独特的临床病理特点.

  20. Human Nek7-interactor RGS2 is required for mitotic spindle organization.

    Science.gov (United States)

    de Souza, Edmarcia Elisa; Hehnly, Heidi; Perez, Arina Marina; Meirelles, Gabriela Vaz; Smetana, Juliana Helena Costa; Doxsey, Stephen; Kobarg, Jörg

    2015-01-01

    The mitotic spindle apparatus is composed of microtubule (MT) networks attached to kinetochores organized from 2 centrosomes (a.k.a. spindle poles). In addition to this central spindle apparatus, astral MTs assemble at the mitotic spindle pole and attach to the cell cortex to ensure appropriate spindle orientation. We propose that cell cycle-related kinase, Nek7, and its novel interacting protein RGS2, are involved in mitosis regulation and spindle formation. We found that RGS2 localizes to the mitotic spindle in a Nek7-dependent manner, and along with Nek7 contributes to spindle morphology and mitotic spindle pole integrity. RGS2-depletion leads to a mitotic-delay and severe defects in the chromosomes alignment and congression. Importantly, RGS2 or Nek7 depletion or even overexpression of wild-type or kinase-dead Nek7, reduced γ-tubulin from the mitotic spindle poles. In addition to causing a mitotic delay, RGS2 depletion induced mitotic spindle misorientation coinciding with astral MT-reduction. We propose that these phenotypes directly contribute to a failure in mitotic spindle alignment to the substratum. In conclusion, we suggest a molecular mechanism whereupon Nek7 and RGS2 may act cooperatively to ensure proper mitotic spindle organization. PMID:25664600

  1. A versatile multivariate image analysis pipeline reveals features of Xenopus extract spindles.

    Science.gov (United States)

    Grenfell, Andrew W; Strzelecka, Magdalena; Crowder, Marina E; Helmke, Kara J; Schlaitz, Anne-Lore; Heald, Rebecca

    2016-04-11

    Imaging datasets are rich in quantitative information. However, few cell biologists possess the tools necessary to analyze them. Here, we present a large dataset ofXenopusextract spindle images together with an analysis pipeline designed to assess spindle morphology across a range of experimental conditions. Our analysis of different spindle types illustrates how kinetochore microtubules amplify spindle microtubule density. Extract mixing experiments reveal that some spindle features titrate, while others undergo switch-like transitions, and multivariate analysis shows the pleiotropic morphological effects of modulating the levels of TPX2, a key spindle assembly factor. We also apply our pipeline to analyze nuclear morphology in human cell culture, showing the general utility of the segmentation approach. Our analyses provide new insight into the diversity of spindle types and suggest areas for future study. The approaches outlined can be applied by other researchers studying spindle morphology and adapted with minimal modification to other experimental systems. PMID:27044897

  2. Spindle cell sarcoma of pulmonary artery mimicking thromboembolism with lung metastasis detected in fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography

    International Nuclear Information System (INIS)

    Pulmonary artery sarcoma (PAS), although rare, must be considered in the differential diagnosis of pulmonary thromboembolism (PTE). This tumor is highly malignant and the prognosis is very poor. As much as the standardized uptake values (SUVs) at fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) have helped in differentiating between benign and malignant tumors, visualization of a low-attenuation filling defect within a pulmonary artery on contrast-enhanced chest computed tomography (CT) can be suggestive of a malignancy, such as PAS, if the lesion shows high FDG uptake at PET. We present a case of PAS that showed high FDG uptake on integrated FDG PET/CT and with lung metastasis. Patient underwent endoscopic bronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA), which confirmed spindle cell sarcoma

  3. Linfoma de células fusiformes: relato anatomopatológico de um caso com apresentação pulmonar Spindle cell lymphoma: a case with pulmonary presentation

    Directory of Open Access Journals (Sweden)

    Túlio Geraldo de Souza e Souza

    2006-02-01

    Full Text Available São raros os linfomas que se apresentam com padrão histológico de células fusiformes. Relatamos um caso de tumor pulmonar isolado em homem de 74 anos, diagnosticado em biópsia de agulha como neoplasia maligna de células fusiformes. Na ocasião, o estudo imuno-histoquímico favoreceu pseudotumor inflamatório. Sete meses após, o paciente foi laparotomizado devido a tumor perfurado intestinal. Os estudos anatomopatológico e imuno-histoquímico estabeleceram o diagnóstico de linfoma B difuso de grandes células. A revisão do tumor pulmonar revelou positividade franca para CD45 e CD20, confirmando o diagnóstico de Linfoma B de células fusiformes. Esta publicação visa a alertar para essa incomum apresentação dos linfomas, que necessita ser considerada, no diagnóstico diferencial de neoplasias de células fusiformes.This paper reports a rare malignant lymphoma with histological spindle-cell pattern. Seventy four year-old man presented with lung tumor. A diagnostic of spindle-cell malignant neoplasia was made and immunohistochemical studies were suggestive of inflammatory pseudotumor. Three months later, the patient returned to our service with acute abdomen. The surgery showed small Intestinal perforation associated with tumor. Microscopic examination and immunohistochemical studies revealed Diffuse B-large cell lymphoma. After the diagnostic of the intestinal tumor, the lung tumor was reviewed, showing positivity for CD45 and CD20 antibodies. This result supports the diagnostic of Spindle B-cell lymphoma, in the lung tumor. The aim of this report is to alert pathologists about this rare spindle cell pattern presentation of lymphomas, that must be differentiated from true sarcomas and others spindle-cell neoplasias.

  4. Successful fabrication of a convex platform PMMA cell-counting slide using a high-precision perpendicular dual-spindle CNC machine tool

    International Nuclear Information System (INIS)

    This study presents a novel approach to the fabrication of a biomedical-mold for producing convex platform PMMA (poly-methyl-meth-acrylate) slides for counting cells. These slides allow for the microscopic examination of urine sediment cells. Manufacturing of such slides incorporates three important procedures: (1) the development of a tabletop high-precision dual-spindle CNC (computerized numerical control) machine tool; (2) the formation of a boron-doped polycrystalline composite diamond (BD-PCD) wheel-tool on the machine tool developed in procedure (1); and (3) the cutting of a multi-groove-biomedical-mold array using the formed diamond wheel-tool in situ on the developed machine. The machine incorporates a hybrid working platform providing wheel-tool thinning using spark erosion to cut, polish, and deburr microgrooves on NAK80 steel directly. With consideration given for the electrical conductive properties of BD-PCD, the diamond wheel-tool is thinned to a thickness of 5 µm by rotary wire electrical discharge machining. The thinned wheel-tool can grind microgrooves 10 µm wide. An embedded design, which inserts a close fitting precision core into the biomedical-mold to create step-difference (concave inward) of 50 µm in height between the core and the mold, is also proposed and realized. The perpendicular dual-spindles and precision rotary stage are features that allow for biomedical-mold machining without the necessity of uploading and repositioning materials until all tasks are completed. A PMMA biomedical-slide with a plurality of juxtaposed counting chambers is formed and its usefulness verified. (paper)

  5. Successful fabrication of a convex platform PMMA cell-counting slide using a high-precision perpendicular dual-spindle CNC machine tool

    Science.gov (United States)

    Chen, Shun-Tong; Chang, Chih-Hsien

    2013-12-01

    This study presents a novel approach to the fabrication of a biomedical-mold for producing convex platform PMMA (poly-methyl-meth-acrylate) slides for counting cells. These slides allow for the microscopic examination of urine sediment cells. Manufacturing of such slides incorporates three important procedures: (1) the development of a tabletop high-precision dual-spindle CNC (computerized numerical control) machine tool; (2) the formation of a boron-doped polycrystalline composite diamond (BD-PCD) wheel-tool on the machine tool developed in procedure (1); and (3) the cutting of a multi-groove-biomedical-mold array using the formed diamond wheel-tool in situ on the developed machine. The machine incorporates a hybrid working platform providing wheel-tool thinning using spark erosion to cut, polish, and deburr microgrooves on NAK80 steel directly. With consideration given for the electrical conductive properties of BD-PCD, the diamond wheel-tool is thinned to a thickness of 5 µm by rotary wire electrical discharge machining. The thinned wheel-tool can grind microgrooves 10 µm wide. An embedded design, which inserts a close fitting precision core into the biomedical-mold to create step-difference (concave inward) of 50 µm in height between the core and the mold, is also proposed and realized. The perpendicular dual-spindles and precision rotary stage are features that allow for biomedical-mold machining without the necessity of uploading and repositioning materials until all tasks are completed. A PMMA biomedical-slide with a plurality of juxtaposed counting chambers is formed and its usefulness verified.

  6. PTEN regulates EG5 to control spindle architecture and chromosome congression during mitosis.

    Science.gov (United States)

    He, Jinxue; Zhang, Zhong; Ouyang, Meng; Yang, Fan; Hao, Hongbo; Lamb, Kristy L; Yang, Jingyi; Yin, Yuxin; Shen, Wen H

    2016-01-01

    Architectural integrity of the mitotic spindle is required for efficient chromosome congression and accurate chromosome segregation to ensure mitotic fidelity. Tumour suppressor PTEN has multiple functions in maintaining genome stability. Here we report an essential role of PTEN in mitosis through regulation of the mitotic kinesin motor EG5 for proper spindle architecture and chromosome congression. PTEN depletion results in chromosome misalignment in metaphase, often leading to catastrophic mitotic failure. In addition, metaphase cells lacking PTEN exhibit defects of spindle geometry, manifested prominently by shorter spindles. PTEN is associated and co-localized with EG5 during mitosis. PTEN deficiency induces aberrant EG5 phosphorylation and abrogates EG5 recruitment to the mitotic spindle apparatus, leading to spindle disorganization. These data demonstrate the functional interplay between PTEN and EG5 in controlling mitotic spindle structure and chromosome behaviour during mitosis. We propose that PTEN functions to equilibrate mitotic phosphorylation for proper spindle formation and faithful genomic transmission. PMID:27492783

  7. The effect of low level laser on anaplastic thyroid cancer

    Science.gov (United States)

    Rhee, Yun-Hee; Moon, Jeon-Hwan; Ahn, Jin-Chul; Chung, Phil-Sang

    2015-02-01

    Low-level laser therapy (LLLT) is a non-thermal phototherapy used in several medical applications, including wound healing, reduction of pain and amelioration of oral mucositis. Nevertheless, the effects of LLLT upon cancer or dysplastic cells have been so far poorly studied. Here we report that the effects of laser irradiation on anaplastic thyroid cancer cells leads to hyperplasia. 650nm of laser diode was performed with a different time interval (0, 15, 30, 60J/cm2 , 25mW) on anaplastic thyroid cancer cell line FRO in vivo. FRO was orthotopically injected into the thyroid gland of nude mice and the irradiation was performed with the same method described previously. After irradiation, the xenograft evaluation was followed for one month. The thyroid tissues from sacrificed mice were undergone to H&E staining and immunohistochemical staining with HIF-1α, Akt, TGF-β1. We found the aggressive proliferation of FRO on thyroid gland with dose dependent. In case of 60 J/ cm2 of energy density, the necrotic bodies were found in a center of the thyroid. The phosphorylation of HIF-1α and Akt was detected in the thyroid gland, which explained the survival signaling of anaplastic cancer cell was turned on the thyroid gland. Furthermore, TGF-β1 expression was decreased after irradiation. In this study, we demonstrated that insufficient energy density irradiation occurred the decreasing of TGF-β1 which corresponding to the phosphorylation of Akt/ HIF-1α. This aggressive proliferation resulted to the hypoxic condition of tissue for angiogenesis. We suggest that LLLT may influence to cancer aggressiveness associated with a decrease in TGF-β1 and increase in Akt/HIF-1α.

  8. Rab11 endosomes contribute to mitotic spindle organization and orientation.

    Science.gov (United States)

    Hehnly, Heidi; Doxsey, Stephen

    2014-03-10

    During interphase, Rab11-GTPase-containing endosomes recycle endocytic cargo. However, little is known about Rab11 endosomes in mitosis. Here, we show that Rab11 localizes to the mitotic spindle and regulates dynein-dependent endosome localization at poles. We found that mitotic recycling endosomes bind γ-TuRC components and associate with tubulin in vitro. Rab11 depletion or dominant-negative Rab11 expression disrupts astral microtubules, delays mitosis, and redistributes spindle pole proteins. Reciprocally, constitutively active Rab11 increases astral microtubules, restores γ-tubulin spindle pole localization, and generates robust spindles. This suggests a role for Rab11 activity in spindle pole maturation during mitosis. Rab11 depletion causes misorientation of the mitotic spindle and the plane of cell division. These findings suggest a molecular mechanism for the organization of astral microtubules and the mitotic spindle through Rab11-dependent control of spindle pole assembly and function. We propose that Rab11 and its associated endosomes cocontribute to these processes through retrograde transport to poles by dynein. PMID:24561039

  9. A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically-Modified Neural Stem Cells Expressing E.Coli Cytosine Deaminase for Treatment of Recurrent High Grade Gliomas

    Science.gov (United States)

    2015-03-02

    Adult Anaplastic Astrocytoma; Recurrent Grade III Glioma; Recurrent Grade IV Glioma; Adult Anaplastic Oligodendroglioma; Adult Brain Tumor; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Recurrent Adult Brain Tumor; Adult Anaplastic Oligoastrocytoma; Recurrent High Grade Glioma

  10. Use of EF5 to Measure the Oxygen Level in Tumor Cells of Patients Undergoing Surgery or Biopsy for Newly Diagnosed Supratentorial Malignant Glioma

    Science.gov (United States)

    2013-01-15

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Diffuse Astrocytoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Subependymoma

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

    International Nuclear Information System (INIS)

    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. 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. 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. 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

  12. CD105 expression on CD34-negative spindle-shaped stromal cells of primary tumor is an unfavorable prognostic marker in early breast cancer patients.

    Science.gov (United States)

    Martinez, Leandro Marcelo; Labovsky, Vivian; Calcagno, María de Luján; Davies, Kevin Mauro; Garcia Rivello, Hernán; Rivello, Hernán Garcia; Bianchi, Maria Silvia; Wernicke, Alejandra; Vallone, Valeria Beatriz Fernández; Fernández Vallone, Valeria Beatriz; Chasseing, Norma Alejandra

    2015-01-01

    Several studies have confirmed that the breast tumor microenvironment drives cancer progression and metastatic development. The aim of our research was to investigate the prognostic significance of the breast tumor microenvironment in untreated early breast cancer patients. Therefore, we analyzed the association of the expression of α-SMA, FSP, CD105 and CD146 in CD34-negative spindle-shaped stromal cells, not associated with the vasculature, in primary breast tumors with classical prognostic marker levels, metastatic recurrence, local relapse, disease-free survival, metastasis-free survival and the overall survival of patients. In the same way, we evaluated the association of the amount of intra-tumor stroma, fibroblasts, collagen deposition, lymphocytic infiltration and myxoid changes in these samples with the clinical-pathological data previously described. This study is the first to demonstrate the high CD105 expression in this stromal cell type as a possible independent marker of unfavorable prognosis in early breast cancer patients. Our study suggests that this new finding can be useful prognostic marker in the clinical-pathological routine. PMID:25803686

  13. 18F-fluorodeoxyglucose-positron-emission tomography/computed tomography staging of mucinous tubular and spindle cell carcinoma of the kidney

    International Nuclear Information System (INIS)

    Mucinous tubular and spindle cell carcinoma of the kidney (MTSCC-K) is an extremely rare carcinoma of the kidney, which develops by malignant differentiation of the collecting ducts or the loop of Henle. The tumor can occur at all ages, with 4 times higher prevalence in females than in males. A 62-year-old female patient presented with an asymptomatic mass lesion in the left kidney. The ultrasound revealed a hyperechogenic mass lesion measuring 4 cm in diameter and centrally located in the left kidney. Computed tomography (CT) revealed an isodense mass lesion measuring 4 cm in diameter and posterolaterally located in the left kidney. Magnetic resonance imaging revealed a renal mass of 4 cm in diameter with hypervascular contrast uptake. For primary staging, 18F-fluorodeoxyglucose-positron-emission tomography (18FDG-PET)/CT revealed left renal cell carcinoma (RCC) with a maximum standard uptake value of 6.7. The patient underwent transperitoneal radical nephrectomy. The immunohistochemical examination revealed MTSCC-K. 18FDG-PET/CT provides 81-89% sensitivity and 83-100% specificity in primary staging of the renal cancers, in diagnosing metastatic RCC, and monitoring the response to therapy. Its use in the staging of MTSCC of the kidney has not been previously described in the literature. This case highlights the usefulness of 18FDG-PET/CT in the staging of this rare tumor

  14. Intercentrosomal angular separation during mitosis plays a crucial role for maintaining spindle stability

    Science.gov (United States)

    Sutradhar, S.; Basu, S.; Paul, R.

    2015-10-01

    Cell division through proper spindle formation is one of the key puzzles in cell biology. In most mammalian cells, chromosomes spontaneously arrange to achieve a stable bipolar spindle during metaphase which eventually ensures proper segregation of the DNA into the daughter cells. In this paper, we present a robust three-dimensional mechanistic model to investigate the formation and maintenance of a bipolar mitotic spindle in mammalian cells under different physiological constraints. Using realistic parameters, we test spindle viability by measuring the spindle length and studying the chromosomal configuration. The model strikingly predicts a feature of the spindle instability arising from the insufficient intercentrosomal angular separation and impaired sliding of the interpolar microtubules. In addition, our model successfully reproduces chromosomal patterns observed in mammalian cells, when activity of different motor proteins is perturbed.

  15. Regulation of mitotic spindle orientation: an integrated view.

    Science.gov (United States)

    di Pietro, Florencia; Echard, Arnaud; Morin, Xavier

    2016-08-01

    Mitotic spindle orientation is essential for cell fate decisions, epithelial maintenance, and tissue morphogenesis. In most animal cell types, the dynein motor complex is anchored at the cell cortex and exerts pulling forces on astral microtubules to position the spindle. Early studies identified the evolutionarily conserved Gαi/LGN/NuMA complex as a key regulator that polarizes cortical force generators. In recent years, a combination of genetics, biochemistry, modeling, and live imaging has contributed to decipher the mechanisms of spindle orientation. Here, we highlight the dynamic nature of the assembly of this complex and discuss the molecular regulation of its localization. Remarkably, a number of LGN-independent mechanisms were described recently, whereas NuMA remains central in most pathways involved in recruiting force generators at the cell cortex. We also describe the emerging role of the actin cortex in spindle orientation and discuss how dynamic astral microtubule formation is involved. We further give an overview on instructive external signals that control spindle orientation in tissues. Finally, we discuss the influence of cell geometry and mechanical forces on spindle orientation. PMID:27432284

  16. F-actin asymmetry and the endoplasmic reticulum-associated TCC-1 protein contribute to stereotypic spindle movements in the Caenorhabditis elegans embryo

    NARCIS (Netherlands)

    Berends, C.W.H.; Muñoz, J.; Portegijs, V.C.; Schmidt, R.; Grigoriev, I.S.; Boxem, M.; Akhmanova, A.S.; Heck, A.J.R.; van den Heuvel, S.

    2013-01-01

    The microtubule spindle apparatus dictates the plane of cell cleavage in animal cells. During development, dividing cells control the position of the spindle to determine the size, location, and fate of daughter cells. Spindle positioning depends on pulling forces that act between the cell periphery

  17. Kinase signaling in the spindle checkpoint.

    Science.gov (United States)

    Kang, Jungseog; Yu, Hongtao

    2009-06-01

    The spindle checkpoint is a cell cycle surveillance system that ensures the fidelity of chromosome segregation. In mitosis, it elicits the "wait anaphase" signal to inhibit the anaphase-promoting complex or cyclosome until all chromosomes achieve bipolar microtubule attachment and align at the metaphase plate. Because a single kinetochore unattached to microtubules activates the checkpoint, the wait anaphase signal is thought to be generated by this kinetochore and is then amplified and distributed throughout the cell to inhibit the anaphase-promoting complex/cyclosome. Several spindle checkpoint kinases participate in the generation and amplification of this signal. Recent studies have begun to reveal the activation mechanisms of these checkpoint kinases. Increasing evidence also indicates that the checkpoint kinases not only help to generate the wait anaphase signal but also actively correct kinetochore-microtubule attachment defects. PMID:19228686

  18. A transmembrane inner nuclear membrane protein in the mitotic spindle

    OpenAIRE

    Figueroa, Ricardo; Gudise, Santhosh; Larsson, Veronica; Hallberg, Einar

    2010-01-01

    We have recently characterized a novel transmembrane protein of the inner nuclear membrane of mammalian cells. The protein has two very interesting features. First, despite being an integral membrane protein it is able to concentrate in the membranes colocalizing with the mitotic spindle in metaphase and anaphase. Hence, the protein was named Samp1, Spindle associated membrane protein 1. Secondly, it displays a functional connection to centrosomes. This article discusses various aspects of Sa...

  19. Mitotic Spindle Positioning in Saccharomyces cerevisiae Is Accomplished by Antagonistically Acting Microtubule Motor Proteins

    OpenAIRE

    Cottingham, Frank R.; Hoyt, M. Andrew

    1997-01-01

    Proper positioning of the mitotic spindle is often essential for cell division and differentiation processes. The asymmetric cell division characteristic of budding yeast, Saccharomyces cerevisiae, requires that the spindle be positioned at the mother–bud neck and oriented along the mother–bud axis. The single dynein motor encoded by the S. cerevisiae genome performs an important but nonessential spindle-positioning role. We demonstrate that kinesin-related Kip3p makes a major contribution to...

  20. CENP-W plays a role in maintaining bipolar spindle structure.

    Directory of Open Access Journals (Sweden)

    Agnieszka Kaczmarczyk

    Full Text Available The CENP-W/T complex was previously reported to be required for mitosis. HeLa cells depleted of CENP-W displayed profound mitotic defects, with mitotic timing delay, disorganized prometaphases and multipolar spindles as major phenotypic consequences. In this study, we examined the process of multipolar spindle formation induced by CENP-W depletion. Depletion of CENP-W in HeLa cells labeled with histone H2B and tubulin fluorescent proteins induced rapid fragmentation of originally bipolar spindles in a high proportion of cells. CENP-W depletion was associated with depletion of Hec1 at kinetochores. The possibility of promiscuous centrosomal duplication was ruled out by immunofluorescent examination of centrioles. However, centrioles were frequently observed to be abnormally split. In addition, a large proportion of the supernumerary poles lacked centrioles, but were positively stained with different centrosomal markers. These observations suggested that perturbation in spindle force distribution caused by defective kinetochores could contribute to a mechanical mechanism for spindle pole disruption. 'Spindle free' nocodazole arrested cells did not exhibit pole fragmentation after CENP-W depletion, showing that pole fragmentation is microtubule dependent. Inhibition of centrosome separation by monastrol reduced the incidence of spindle pole fragmentation, indicating that Eg5 plays a role in spindle pole disruption. Surprisingly, CENP-W depletion rescued the monopolar spindle phenotype of monastrol treatment, with an increased frequency of bipolar spindles observed after CENP-W RNAi. We overexpressed the microtubule cross-linking protein TPX2 to create spindle poles stabilized by the microtubule cross-linking activity of TPX2. Spindle pole fragmentation was suppressed in a TPX2-dependent fashion. We propose that CENP-W, by influencing proper kinetochore assembly, particularly microtubule docking sites, can confer spindle pole resistance to traction

  1. Spindle neurons of the human anterior cingulate cortex

    Science.gov (United States)

    Nimchinsky, E. A.; Vogt, B. A.; Morrison, J. H.; Hof, P. R.; Bloom, F. E. (Principal Investigator)

    1995-01-01

    The human anterior cingulate cortex is distinguished by the presence of an unusual cell type, a large spindle neuron in layer Vb. This cell has been noted numerous times in the historical literature but has not been studied with modern neuroanatomic techniques. For instance, details regarding the neuronal class to which these cells belong and regarding their precise distribution along both ventrodorsal and anteroposterior axes of the cingulate gyrus are still lacking. In the present study, morphological features and the anatomic distribution of this cell type were studied using computer-assisted mapping and immunocytochemical techniques. Spindle neurons are restricted to the subfields of the anterior cingulate cortex (Brodmann's area 24), exhibiting a greater density in anterior portions of this area than in posterior portions, and tapering off in the transition zone between anterior and posterior cingulate cortex. Furthermore, a majority of the spindle cells at any level is located in subarea 24b on the gyral surface. Immunocytochemical analysis revealed that the neurofilament protein triple was present in a large percentage of these neurons and that they did not contain calcium-binding proteins. Injections of the carbocyanine dye DiI into the cingulum bundle revealed that these cells are projection neurons. Finally, spindle cells were consistently affected in Alzheimer's disease cases, with an overall loss of about 60%. Taken together, these observations indicate that the spindle cells of the human cingulate cortex represent a morphological subpopulation of pyramidal neurons whose restricted distribution may be associated with functionally distinct areas.

  2. TCF12 is mutated in anaplastic oligodendroglioma

    OpenAIRE

    Labreche, Karim; Simeonova, Iva; Kamoun, Aurélie; Gleize, Vincent; Chubb, Daniel; Letouzé, Eric; Riazalhosseini, Yasser; Dobbins, Sara E; Elarouci, Nabila; Ducray, Francois; De Reyniès, Aurélien; Zelenika, Diana; Wardell, Christopher P.; Frampton, Mathew; Saulnier, Olivier

    2015-01-01

    Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosomes 1p/19q co-deletion and an IDH mutation. Here we analysed 51 AO by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall, 7.5% of AO are mutated for TCF12...

  3. Contribution of noncentrosomal microtubules to spindle assembly in Drosophila spermatocytes.

    Directory of Open Access Journals (Sweden)

    Elena Rebollo

    2004-01-01

    Full Text Available Previous data suggested that anastral spindles, morphologically similar to those found in oocytes, can assemble in a centrosome-independent manner in cells that contain centrosomes. It is assumed that the microtubules that build these acentrosomal spindles originate over the chromatin. However, the actual processes of centrosome-independent microtubule nucleation, polymerisation, and sorting have not been documented in centrosome-containing cells. We have identified two experimental conditions in which centrosomes are kept close to the plasma membrane, away from the nuclear region, throughout meiosis I in Drosophila spermatocytes. Time-lapse confocal microscopy of these cells labelled with fluorescent chimeras reveals centrosome-independent microtubule nucleation, growth, and sorting into a bipolar spindle array over the nuclear region, away from the asters. The onset of noncentrosomal microtubule nucleation is significantly delayed with respect to nuclear envelope breakdown and coincides with the end of chromosome condensation. It takes place in foci that are close to the membranes that ensheath the nuclear region, not over the condensed chromosomes. Metaphase plates are formed in these spindles, and, in a fraction of them, some degree of polewards chromosome segregation takes place. In these cells that contain both membrane-bound asters and an anastral spindle, the orientation of the cytokinesis furrow correlates with the position of the asters and is independent of the orientation of the spindle. We conclude that the fenestrated nuclear envelope may significantly contribute to the normal process of spindle assembly in Drosophila spermatocytes. We also conclude that the anastral spindles that we have observed are not likely to provide a robust back-up able to ensure successful cell division. We propose that these anastral microtubule arrays could be a constitutive component of wild-type spindles, normally masked by the abundance of centrosome

  4. The deafferented reticular thalamic nucleus generates spindle rhythmicity.

    Science.gov (United States)

    Steriade, M; Domich, L; Oakson, G; Deschênes, M

    1987-01-01

    The hypothesis that nucleus reticularis thalami (RE) is the generator of spindle rhythmicity during electroencephalogram (EEG) synchronization was tested in acutely prepared cats. Unit discharges and focal waves were extracellularly recorded in the rostral pole of RE nucleus, which was completely disconnected by transections from all other thalamic nuclei. In some experiments, additional transections through corona radiata created a triangular island in which the rostral RE pole survived with the caudate nucleus, putamen, basal forebrain nuclei, prepyriform area, and the adjacent cortex. Similar results were obtained in two types of experiments: brain stem-transected preparations that exhibited spontaneous spindle sequences, and animals under ketamine anesthesia in which transient spindling was repeatedly precipitated during recording by very low doses of a short-acting barbiturate. Both spindle-related rhythms (7- to 16-Hz waves grouped in sequences that recur with a rhythm of 0.1-0.3 Hz) are seen in focal recordings of the deafferented RE nucleus. The presence of spindling rhythmicity in the disconnected RE nucleus contrasts with total absence of spindles in cortical EEG leads and in thalamic recordings behind the transection. Oscillations within the same frequency range as that of spontaneous spindles can be evoked in the deafferented RE nucleus by subcortical white matter stimulation. In deafferented RE cells, the burst structure consists of an initially biphasic acceleration-deceleration pattern, eventually leading to a long-lasting tonic tail. Quantitative group data show that the burst parameters of disconnected RE cells are very similar to those of RE neurons with intact connections. In the deafferented RE nucleus, spike bursts of RE neurons recur periodically (0.1-0.3 Hz) in close time-relation with simultaneously recorded focal spindle sequences. The burst occurrence of deafferented RE cells is greatly reduced after systemic administration of bicuculline

  5. CENP-32 is required to maintain centrosomal dominance in bipolar spindle assembly.

    Science.gov (United States)

    Ohta, Shinya; Wood, Laura; Toramoto, Iyo; Yagyu, Ken-Ichi; Fukagawa, Tatsuo; Earnshaw, William C

    2015-04-01

    Centrosomes nucleate spindle formation, direct spindle pole positioning, and are important for proper chromosome segregation during mitosis in most animal cells. We previously reported that centromere protein 32 (CENP-32) is required for centrosome association with spindle poles during metaphase. In this study, we show that CENP-32 depletion seems to release centrosomes from bipolar spindles whose assembly they had previously initiated. Remarkably, the resulting anastral spindles function normally, aligning the chromosomes to a metaphase plate and entering anaphase without detectable interference from the free centrosomes, which appear to behave as free asters in these cells. The free asters, which contain reduced but significant levels of CDK5RAP2, show weak interactions with spindle microtubules but do not seem to make productive attachments to kinetochores. Thus CENP-32 appears to be required for centrosomes to integrate into a fully functional spindle that not only nucleates astral microtubules, but also is able to nucleate and bind to kinetochore and central spindle microtubules. Additional data suggest that NuMA tethers microtubules at the anastral spindle poles and that augmin is required for centrosome detachment after CENP-32 depletion, possibly due to an imbalance of forces within the spindle. PMID:25657325

  6. Clinical analysis of primary anaplastic carcinoma of the small intestine

    Institute of Scientific and Technical Information of China (English)

    Tsutomu Namikawa; Kazuhiro Hanazaki

    2009-01-01

    Primary anaplastic carcinoma is a rare variant of small intestinal cancer. Most reports of primary anaplastic carcinoma of the small intestine are isolated case reports, therefore the clinicopathological features, therapeutic management, and surgical outcome of this tumor type remain unclear. This review analyzes the available clinical characteristics of primary anaplastic carcinoma of the small intestine and investigates key differences from differentiated adenocarcinoma of the small intestine. A Medline search was performed using the keywords 'small intestine' and 'anaplastic carcinoma' or 'undifferentiated carcinoma'. Additional articles were obtained from references with in the papers identified by the Medline search. The literature revealed a poor prognosis for patients who underwent surgical resection for anaplastic carcinoma of the small intestine, which gave a 3-year overall survival rate of 10.8% and a median survival time of 5.0 mo. The literature suggests that anaplastic carcinoma is markedly more aggressive than differentiated adenocarcinoma of the small intestine. Surgical resection with the aim of complete tumor removal provides the only beneficial therapeutic option for patients with anaplastic carcinoma of the small intestine, because chemotherapy and radiation therapy have no significant effect on the rate of survival. However, despite complete tumor resection, most patients with anaplastic carcinoma of the small intestine are at great risk of disease recurrence. Multicenter clinical trials are expected to provide additional therapeutic strategies and establish the efficacy of multimodality adjuvant therapy. This report also highlights the importance of a systematic diagnostic approach for anaplastic carcinoma of the small intestine.

  7. The forces that center the mitotic spindle in the C. elegans embryo

    OpenAIRE

    Garzon-Coral, Carlos

    2015-01-01

    The precise positioning of the mitotic spindle to the cell center during mitosis is a fundamental process for chromosome segregation and the division plane definition. Despite its importance, the mechanism for spindle centering remains elusive. To study this mechanism, the dynamic of the microtubules was characterized at the bulk and at the cortex in the C. elegans embryo. Then, this dynamic was correlated to the centering forces of the spindle that were studied by applying calibrated magneti...

  8. A Kinesin Mutant with an Atypical Bipolar Spindle Undergoes Normal Mitosis

    OpenAIRE

    Marcus, A. I.; Li, W.; Ma, H; Cyr, R. J.

    2003-01-01

    Motor proteins have been implicated in various aspects of mitosis, including spindle assembly and chromosome segregation. Here, we show that acentrosomal Arabidopsis cells that are mutant for the kinesin, ATK1, lack microtubule accumulation at the predicted spindle poles during prophase and have reduced spindle bipolarity during prometaphase. Nonetheless, all abnormalities are rectified by anaphase and chromosome segregation appears normal. We conclude that ATK1 is required for normal microtu...

  9. csi2p modulates microtubule dynamics and organizes the bipolar spindle for chromosome segregation

    OpenAIRE

    Costa, Judite; Fu, Chuanhai; Khare, V. Mohini; Tran, Phong T.

    2014-01-01

    Proper chromosome segregation is of paramount importance for proper genetic inheritance. Defects in chromosome segregation can lead to aneuploidy, which is a hallmark of cancer cells. Eukaryotic chromosome segregation is accomplished by the bipolar spindle. Additional mechanisms, such as the spindle assembly checkpoint and centromere positioning, further help to ensure complete segregation fidelity. Here we present the fission yeast csi2 +. csi2p localizes to the spindle poles, where it regul...

  10. A 16-Gene Signature Distinguishes Anaplastic Astrocytoma from Glioblastoma

    OpenAIRE

    Soumya Alige Mahabala Rao; Sujaya Srinivasan; Irene Rosita Pia Patric; Alangar Sathyaranjandas Hegde; Bangalore Ashwathnarayanara Chandramouli; Arivazhagan Arimappamagan; Vani Santosh; Paturu Kondaiah; Manchanahalli R Sathyanarayana Rao; Kumaravel Somasundaram

    2014-01-01

    Anaplastic astrocytoma (AA; Grade III) and glioblastoma (GBM; Grade IV) are diffusely infiltrating tumors and are called malignant astrocytomas. The treatment regimen and prognosis are distinctly different between anaplastic astrocytoma and glioblastoma patients. Although histopathology based current grading system is well accepted and largely reproducible, intratumoral histologic variations often lead to difficulties in classification of malignant astrocytoma samples. In order to obtain a mo...

  11. Microtubule Dynamics and Oscillating State for Mitotic Spindle

    CERN Document Server

    Rashid-Shomali, Safura

    2010-01-01

    We present a physical mechanism that can cause the mitotic spindle to oscillate. The driving force for this mechanism emerges from the polymerization of astral microtubules interacting with the cell cortex. We show that Brownian ratchet model for growing microtubules reaching the cell cortex, mediate an effective mass to the spindle body and therefore force it to oscillate. We compare the predictions of this mechanism with the previous mechanisms which were based on the effects of motor proteins. Finally we combine the effects of microtubules polymerization and motor proteins, and present the detailed phase diagram for possible oscillating states.

  12. Nap sleep spindle correlates of intelligence

    OpenAIRE

    Ujma, Péter P.; Róbert Bódizs; Ferenc Gombos; Johannes Stintzing; Konrad, Boris N.; Lisa Genzel; Axel Steiger; Martin Dresler

    2015-01-01

    Sleep spindles are thalamocortical oscillations in non-rapid eye movement (NREM) sleep, that play an important role in sleep-related neuroplasticity and offline information processing. Several studies with full-night sleep recordings have reported a positive association between sleep spindles and fluid intelligence scores, however more recently it has been shown that only few sleep spindle measures correlate with intelligence in females, and none in males. Sleep spindle regulation underlies a...

  13. Visualizing the spindle checkpoint in Drosophila spermatocytes

    OpenAIRE

    Rebollo, Elena; González, Cayetano

    2000-01-01

    The spindle assembly checkpoint detects defects in spindle structure or in the alignment of the chromosomes on the metaphase plate and delays the onset of anaphase until defects are corrected. Thus far, the evidence regarding the presence of a spindle checkpoint during meiosis in male Drosophila has been indirect and contradictory. On the one hand, chromosomes without pairing partners do not prevent meiosis progression. On the other hand, some conserved components of the spindle checkpoint ma...

  14. Noninvasive three-dimensional live imaging methodology for the spindles at meiosis and mitosis

    Science.gov (United States)

    Zheng, Jing-gao; Huo, Tiancheng; Tian, Ning; Chen, Tianyuan; Wang, Chengming; Zhang, Ning; Zhao, Fengying; Lu, Danyu; Chen, Dieyan; Ma, Wanyun; Sun, Jia-lin; Xue, Ping

    2013-05-01

    The spindle plays a crucial role in normal chromosome alignment and segregation during meiosis and mitosis. Studying spindles in living cells noninvasively is of great value in assisted reproduction technology (ART). Here, we present a novel spindle imaging methodology, full-field optical coherence tomography (FF-OCT). Without any dye labeling and fixation, we demonstrate the first successful application of FF-OCT to noninvasive three-dimensional (3-D) live imaging of the meiotic spindles within the mouse living oocytes at metaphase II as well as the mitotic spindles in the living zygotes at metaphase and telophase. By post-processing of the 3-D dataset obtained with FF-OCT, the important morphological and spatial parameters of the spindles, such as short and long axes, spatial localization, and the angle of meiotic spindle deviation from the first polar body in the oocyte were precisely measured with the spatial resolution of 0.7 μm. Our results reveal the potential of FF-OCT as an imaging tool capable of noninvasive 3-D live morphological analysis for spindles, which might be useful to ART related procedures and many other spindle related studies.

  15. Carfilzomib potentiates CUDC-101-induced apoptosis in anaplastic thyroid cancer

    Science.gov (United States)

    Zhang, Lisa; Boufraqech, Myriem; Lake, Ross; Kebebew, Electron

    2016-01-01

    Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies, with no effective treatment currently available. Previously, we identified agents active against ATC cells, both in vitro and in vivo, using quantitative high-throughput screening of 3282 clinically approved drugs and small molecules. Here, we report that combining two of these active agents, carfilzomib, a second-generation proteasome inhibitor, and CUDC-101, a histone deacetylase and multi-kinase inhibitor, results in increased, synergistic activity in ATC cells. The combination of carfilzomib and CUDC-101 synergistically inhibited cellular proliferation and caused cell death in multiple ATC cell lines harboring various driver mutations observed in human ATC tumors. This increased anti-ATC effect was associated with a synergistically enhanced G2/M cell cycle arrest and increased caspase 3/7 activity induced by the drug combination. Mechanistically, treatment with carfilzomib and CUDC-101 increased p21 expression and poly (ADP-ribose) polymerase protein cleavage. Our results suggest that combining carfilzomib and CUDC-101 would offer an effective therapeutic strategy to treat ATC. PMID:26934320

  16. Synergistic role of fission yeast Alp16GCP6 and Mzt1MOZART1 in γ-tubulin complex recruitment to mitotic spindle pole bodies and spindle assembly.

    Science.gov (United States)

    Masuda, Hirohisa; Toda, Takashi

    2016-06-01

    In fission yeast, γ-tubulin ring complex (γTuRC)-specific components Gfh1(GCP4), Mod21(GCP5), and Alp16(GCP6) are nonessential for cell growth. Of these deletion mutants, only alp16Δ shows synthetic lethality with temperature-sensitive mutants of Mzt1(MOZART1), a component of the γTuRC required for recruitment of the complex to microtubule-organizing centers. γ-Tubulin small complex levels at mitotic spindle pole bodies (SPBs, the centrosome equivalent in fungi) and microtubule levels for preanaphase spindles are significantly reduced in alp16Δ cells but not in gfh1Δ or mod21Δ cells. Furthermore, alp16Δ cells often form monopolar spindles and frequently lose a minichromosome when the spindle assembly checkpoint is inactivated. Alp16(GCP6) promotes Mzt1-dependent γTuRC recruitment to mitotic SPBs and enhances spindle microtubule assembly in a manner dependent on its expression levels. Gfh1(GCP4) and Mod21(GCP5) are not required for Alp16(GCP6)-dependent γTuRC recruitment. Mzt1 has an additional role in the activation of the γTuRC for spindle microtubule assembly. The ratio of Mzt1 to γTuRC levels for preanaphase spindles is higher than at other stages of the cell cycle. Mzt1 overproduction enhances spindle microtubule assembly without affecting γTuRC levels at mitotic SPBs. We propose that Alp16(GCP6) and Mzt1 act synergistically for efficient bipolar spindle assembly to ensure faithful chromosome segregation. PMID:27053664

  17. Anaplastic thyroid carcinoma: outcome and prognostic factors

    International Nuclear Information System (INIS)

    Purpose: Anaplastic carcinoma of the thyroid has been described as a rapidly progressive disease. We assessed the outcome and prognostic factors in patients with anaplastic thyroid carcinoma at our institution. Materials and Methods: Between 1975 and 1995, 37 patients were seen and treated at our institution with pathologically proven anaplastic carcinoma of the thyroid gland. Patients ranged in age from 49 to 97 years old (median 73 years) and females were represented in a 2:1 ratio. Many patients had history of prior benign thyroid disease (17) or low grade malignancy (6). Other medical illnesses were frequently present in these patients, including 5 with diabetes, 1 scleroderma, 1 sarcoidosis and 1 polycythemia vera. 12 patients had metastatic disease at presentation. 26 patients had locally advanced (T4) disease. The time from diagnosis to treatment was never longer than 1 month. Management was most often with biopsy only (22 patients) and local irradiation (34 patients, median dose 52.5 Gy). 15 patients had primary surgical resection, one of which had negative surgical margins. 11 patients received chemotherapy, 9 with Adriamycin-based regimens. Follow-up ranged from 4 months to 11 years, with a mean of 11 months. Results: 26 patients had a local response, either partial or complete, to their treatment regimen. However, systemic disease was an important cause of failure. 9 patients (24%) survived at least one year from diagnosis; 3 (8%) survived beyond two years. The development of metastases occurred quickly in originally localized disease, at a median of 2 months. Metastases occurred most commonly in the lung (11 of 14 cases), but also occured in brain (2), liver (1), bone (1) and pericardium (1). Performance status, sex, metastatic disease, hyperfractionation, treatment modalities, RT dose, age and response to treatment were assessed as prognostic factors for survival. On univariate analysis, age over 70 (p=.004) and failure to attain a complete response to

  18. Anaplastic Medullary Ependymoma Presenting as Subarachnoid Hemorrhage

    Directory of Open Access Journals (Sweden)

    Nicolas Nicastro

    2013-01-01

    Full Text Available A-41-year old man presented with violent thunderclap headache and a bilateral proprioceptive sensibility deficit of the upper limbs. Cerebral CT scan and MRI were negative. Lumbar puncture confirmed subarachnoid hemorrhage (SAH, but cerebral angiography was negative. Three months later, the patient presented with paraparesis, and a thorough work-up revealed a diffuse, anaplastic extramedullary C7-D10 ependymoma with meningeal carcinomatosis considered the source of hemorrhage. The patient went through a D5-D8 laminectomy, temozolomide chemotherapy, and radiotherapy. The situation remained stable for a few months. In this paper, we would like to emphasize that spinal masses should be considered in cases of SAH with negative diagnostic findings for aneurysms or arteriovenous malformation.

  19. Equilibria of idealized confined astral microtubules and coupled spindle poles.

    Directory of Open Access Journals (Sweden)

    Ivan V Maly

    Full Text Available Positioning of the mitotic spindle through the interaction of astral microtubules with the cell boundary often determines whether the cell division will be symmetric or asymmetric. This process plays a crucial role in development. In this paper, a numerical model is presented that deals with the force exerted on the spindle by astral microtubules that are bent by virtue of their confinement within the cell boundary. It is found that depending on parameters, the symmetric position of the spindle can be stable or unstable. Asymmetric stable equilibria also exist, and two or more stable positions can exist simultaneously. The theory poses new types of questions for experimental research. Regarding the cases of symmetric spindle positioning, it is necessary to ask whether the microtubule parameters are controlled by the cell so that the bending mechanics favors symmetry. If they are not, then it is necessary to ask what forces external to the microtubule cytoskeleton counteract the bending effects sufficiently to actively establish symmetry. Conversely, regarding the cases with asymmetry, it is now necessary to investigate whether the cell controls the microtubule parameters so that the bending favors asymmetry apart from any forces that are external to the microtubule cytoskeleton.

  20. Interphase adhesion geometry is transmitted to an internal regulator for spindle orientation via caveolin-1

    OpenAIRE

    Matsumura, Shigeru; Kojidani, Tomoko; Kamioka, Yuji; Uchida, Seiichi; Haraguchi, Tokuko; Kimura, Akatsuki; Toyoshima, Fumiko

    2016-01-01

    Despite theoretical and physical studies implying that cell-extracellular matrix adhesion geometry governs the orientation of the cell division axis, the molecular mechanisms that translate interphase adhesion geometry to the mitotic spindle orientation remain elusive. Here, we show that the cellular edge retraction during mitotic cell rounding correlates with the spindle axis. At the onset of mitotic cell rounding, caveolin-1 is targeted to the retracting cortical region at the proximal end ...

  1. Automated high-throughput quantification of mitotic spindle positioning from DIC movies of Caenorhabditis embryos.

    Directory of Open Access Journals (Sweden)

    David Cluet

    Full Text Available The mitotic spindle is a microtubule-based structure that elongates to accurately segregate chromosomes during anaphase. Its position within the cell also dictates the future cell cleavage plan, thereby determining daughter cell orientation within a tissue or cell fate adoption for polarized cells. Therefore, the mitotic spindle ensures at the same time proper cell division and developmental precision. Consequently, spindle dynamics is the matter of intensive research. Among the different cellular models that have been explored, the one-cell stage C. elegans embryo has been an essential and powerful system to dissect the molecular and biophysical basis of spindle elongation and positioning. Indeed, in this large and transparent cell, spindle poles (or centrosomes can be easily detected from simple DIC microscopy by human eyes. To perform quantitative and high-throughput analysis of spindle motion, we developed a computer program ACT for Automated-Centrosome-Tracking from DIC movies of C. elegans embryos. We therefore offer an alternative to the image acquisition and processing of transgenic lines expressing fluorescent spindle markers. Consequently, experiments on large sets of cells can be performed with a simple setup using inexpensive microscopes. Moreover, analysis of any mutant or wild-type backgrounds is accessible because laborious rounds of crosses with transgenic lines become unnecessary. Last, our program allows spindle detection in other nematode species, offering the same quality of DIC images but for which techniques of transgenesis are not accessible. Thus, our program also opens the way towards a quantitative evolutionary approach of spindle dynamics. Overall, our computer program is a unique macro for the image- and movie-processing platform ImageJ. It is user-friendly and freely available under an open-source licence. ACT allows batch-wise analysis of large sets of mitosis events. Within 2 minutes, a single movie is processed

  2. A Balance between Nuclear and Cytoplasmic Volumes Controls Spindle Length

    Czech Academy of Sciences Publication Activity Database

    Nováková, Lucia; Kovačovicová, Kristina; Dang-Nguyen, T.; Šodek, Martin; Škultéty, M.; Anger, Martin

    2016-01-01

    Roč. 11, č. 2 (2016), e0149535-e0149535. E-ISSN 1932-6203 R&D Projects: GA ČR GAP502/12/2201 Institutional support: RVO:67985904 Keywords : mitotoc spindle * size * cells Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.234, year: 2014

  3. A 16-gene signature distinguishes anaplastic astrocytoma from glioblastoma.

    Directory of Open Access Journals (Sweden)

    Soumya Alige Mahabala Rao

    Full Text Available Anaplastic astrocytoma (AA; Grade III and glioblastoma (GBM; Grade IV are diffusely infiltrating tumors and are called malignant astrocytomas. The treatment regimen and prognosis are distinctly different between anaplastic astrocytoma and glioblastoma patients. Although histopathology based current grading system is well accepted and largely reproducible, intratumoral histologic variations often lead to difficulties in classification of malignant astrocytoma samples. In order to obtain a more robust molecular classifier, we analysed RT-qPCR expression data of 175 differentially regulated genes across astrocytoma using Prediction Analysis of Microarrays (PAM and found the most discriminatory 16-gene expression signature for the classification of anaplastic astrocytoma and glioblastoma. The 16-gene signature obtained in the training set was validated in the test set with diagnostic accuracy of 89%. Additionally, validation of the 16-gene signature in multiple independent cohorts revealed that the signature predicted anaplastic astrocytoma and glioblastoma samples with accuracy rates of 99%, 88%, and 92% in TCGA, GSE1993 and GSE4422 datasets, respectively. The protein-protein interaction network and pathway analysis suggested that the 16-genes of the signature identified epithelial-mesenchymal transition (EMT pathway as the most differentially regulated pathway in glioblastoma compared to anaplastic astrocytoma. In addition to identifying 16 gene classification signature, we also demonstrated that genes involved in epithelial-mesenchymal transition may play an important role in distinguishing glioblastoma from anaplastic astrocytoma.

  4. Complex Commingling: Nucleoporins and the Spindle Assembly Checkpoint

    Directory of Open Access Journals (Sweden)

    Ikram Mossaid

    2015-11-01

    Full Text Available The segregation of the chromosomes during mitosis is an important process, in which the replicated DNA content is properly allocated into two daughter cells. To ensure their genomic integrity, cells present an essential surveillance mechanism known as the spindle assembly checkpoint (SAC, which monitors the bipolar attachment of the mitotic spindle to chromosomes to prevent errors that would result in chromosome mis-segregation and aneuploidy. Multiple components of the nuclear pore complex (NPC, a gigantic protein complex that forms a channel through the nuclear envelope to allow nucleocytoplasmic exchange of macromolecules, were shown to be critical for faithful cell division and implicated in the regulation of different steps of the mitotic process, including kinetochore and spindle assembly as well as the SAC. In this review, we will describe current knowledge about the interconnection between the NPC and the SAC in an evolutional perspective, which primarily relies on the two mitotic checkpoint regulators, Mad1 and Mad2. We will further discuss the role of NPC constituents, the nucleoporins, in kinetochore and spindle assembly and the formation of the mitotic checkpoint complex during mitosis and interphase.

  5. The Case of the Disappearing Spindle Burst

    Directory of Open Access Journals (Sweden)

    Alexandre Tiriac

    2016-01-01

    Full Text Available Sleep spindles are brief cortical oscillations at 10–15 Hz that occur predominantly during non-REM (quiet sleep in adult mammals and are thought to contribute to learning and memory. Spindle bursts are phenomenologically similar to sleep spindles, but they occur predominantly in early infancy and are triggered by peripheral sensory activity (e.g., by retinal waves; accordingly, spindle bursts are thought to organize neural networks in the developing brain and establish functional links with the sensory periphery. Whereas the spontaneous retinal waves that trigger spindle bursts in visual cortex are a transient feature of early development, the myoclonic twitches that drive spindle bursts in sensorimotor cortex persist into adulthood. Moreover, twitches—and their associated spindle bursts—occur exclusively during REM (active sleep. Curiously, despite the persistence of twitching into adulthood, twitch-related spindle bursts have not been reported in adult sensorimotor cortex. This raises the question of whether such spindle burst activity does not occur in adulthood or, alternatively, occurs but has yet to be discovered. If twitch-related spindle bursts do occur in adults, they could contribute to the calibration, maintenance, and repair of sensorimotor systems.

  6. The Case of the Disappearing Spindle Burst.

    Science.gov (United States)

    Tiriac, Alexandre; Blumberg, Mark S

    2016-01-01

    Sleep spindles are brief cortical oscillations at 10-15 Hz that occur predominantly during non-REM (quiet) sleep in adult mammals and are thought to contribute to learning and memory. Spindle bursts are phenomenologically similar to sleep spindles, but they occur predominantly in early infancy and are triggered by peripheral sensory activity (e.g., by retinal waves); accordingly, spindle bursts are thought to organize neural networks in the developing brain and establish functional links with the sensory periphery. Whereas the spontaneous retinal waves that trigger spindle bursts in visual cortex are a transient feature of early development, the myoclonic twitches that drive spindle bursts in sensorimotor cortex persist into adulthood. Moreover, twitches-and their associated spindle bursts-occur exclusively during REM (active) sleep. Curiously, despite the persistence of twitching into adulthood, twitch-related spindle bursts have not been reported in adult sensorimotor cortex. This raises the question of whether such spindle burst activity does not occur in adulthood or, alternatively, occurs but has yet to be discovered. If twitch-related spindle bursts do occur in adults, they could contribute to the calibration, maintenance, and repair of sensorimotor systems. PMID:27119028

  7. NuMA-microtubule interactions are critical for spindle orientation and the morphogenesis of diverse epidermal structures

    Science.gov (United States)

    Seldin, Lindsey; Muroyama, Andrew; Lechler, Terry

    2016-01-01

    Mitotic spindle orientation is used to generate cell fate diversity and drive proper tissue morphogenesis. A complex of NuMA and dynein/dynactin is required for robust spindle orientation in a number of cell types. Previous research proposed that cortical dynein/dynactin was sufficient to generate forces on astral microtubules (MTs) to orient the spindle, with NuMA acting as a passive tether. In this study, we demonstrate that dynein/dynactin is insufficient for spindle orientation establishment in keratinocytes and that NuMA’s MT-binding domain, which targets MT tips, is also required. Loss of NuMA-MT interactions in skin caused defects in spindle orientation and epidermal differentiation, leading to neonatal lethality. In addition, we show that NuMA-MT interactions are also required in adult mice for hair follicle morphogenesis and spindle orientation within the transit-amplifying cells of the matrix. Loss of spindle orientation in matrix cells results in defective differentiation of matrix-derived lineages. Our results reveal an additional and direct function of NuMA during mitotic spindle positioning, as well as a reiterative use of spindle orientation in the skin to build diverse structures. DOI: http://dx.doi.org/10.7554/eLife.12504.001 PMID:26765568

  8. NuMA-microtubule interactions are critical for spindle orientation and the morphogenesis of diverse epidermal structures.

    Science.gov (United States)

    Seldin, Lindsey; Muroyama, Andrew; Lechler, Terry

    2016-01-01

    Mitotic spindle orientation is used to generate cell fate diversity and drive proper tissue morphogenesis. A complex of NuMA and dynein/dynactin is required for robust spindle orientation in a number of cell types. Previous research proposed that cortical dynein/dynactin was sufficient to generate forces on astral microtubules (MTs) to orient the spindle, with NuMA acting as a passive tether. In this study, we demonstrate that dynein/dynactin is insufficient for spindle orientation establishment in keratinocytes and that NuMA's MT-binding domain, which targets MT tips, is also required. Loss of NuMA-MT interactions in skin caused defects in spindle orientation and epidermal differentiation, leading to neonatal lethality. In addition, we show that NuMA-MT interactions are also required in adult mice for hair follicle morphogenesis and spindle orientation within the transit-amplifying cells of the matrix. Loss of spindle orientation in matrix cells results in defective differentiation of matrix-derived lineages. Our results reveal an additional and direct function of NuMA during mitotic spindle positioning, as well as a reiterative use of spindle orientation in the skin to build diverse structures. PMID:26765568

  9. Next generation spindles for micromilling.

    Energy Technology Data Exchange (ETDEWEB)

    Pathak, Jay P. (Machine Tool Research Center, University of Florida, Gainesville, FL); Payne, Scott W. T. (Machine Tool Research Center, University of Florida, Gainesville, FL); Gill, David Dennis; Ziegert, John C. (Machine Tool Research Center, University of Florida, Gainesville, FL); Jokiel, Bernhard, Jr.

    2004-12-01

    There exists a wide variety of important applications for micro- and meso-scale mechanical systems in the commercial and defense sectors, which require high-strength materials and complex geometries that cannot be produced using current MEMS fabrication technologies. Micromilling has great potential to fill this void in MEMS technology by adding the capability of free form machining of complex 3D shapes from a wide variety and combination of traditional, well-understood engineering alloys, glasses and ceramics. Inefficiencies in micromilling result from the relationships between a cutting tool's breaking strength, the applied cutting force, and the metal removal rate. Because machining times in mesofeatures scale inversely to the part size, a feature 1/10th as large will take 10 times as long to machine. Also, required chip sizes of 1 m or less are cut with tools having edge radius of 2-3 m, the cutting edge effectively has a highly negative rake angle, cutting forces are increased significantly causing chip loads to be further reduced and the machining takes even longer than predicted above. However, cutting forces do not increase with cutting speed, so faster spindles with reduced tool runout are the path to achieve efficient mesoscale milling. This research explored the development of new ultra-high speed micromilling spindles. A novel air-bearing spindle design is discussed that will run at very high speeds (450,000 rpm) and provide very minimal runout allowing the best use of micromilling cutters and reducing overall machining time drastically. Two generations of this spindle design were completed; one with an air bearing supported tool shaft and one with a novel rolling element bearing supported tool shaft. Both designs utilized friction-drive systems that relied on diameter differences between the drive wheel (operating at speeds up to 90,000 rpm) and the tool shaft to achieve high rotational tool speeds. Runout, stiffness, and machining tests were

  10. A Minus-End–directed Kinesin with Plus-End Tracking Protein Activity Is Involved in Spindle MorphogenesisV⃞

    OpenAIRE

    Ambrose, J. Christian; Li, Wuxing; Marcus, Adam; Ma, Hong; Cyr, Richard

    2005-01-01

    Diverse kinesin motor proteins are involved in spindle function; however, the mechanisms by which they are targeted to specific sites within spindles are not well understood. Here, we show that a fusion between yellow fluorescent protein (YFP) and a minus-end–directed Kinesin-14 (C-terminal family) from Arabidopsis, ATK5, localizes to mitotic spindle midzones and regions rich in growing plus-ends within phragmoplasts. Notably, in Arabidopsis interphase cells, YFP::ATK5 localizes to microtubul...

  11. EB1 is required for spindle symmetry in mammalian mitosis.

    Directory of Open Access Journals (Sweden)

    Anke Brüning-Richardson

    Full Text Available Most information about the roles of the adenomatous polyposis coli protein (APC and its binding partner EB1 in mitotic cells has come from siRNA studies. These suggest functions in chromosomal segregation and spindle positioning whose loss might contribute to tumourigenesis in cancers initiated by APC mutation. However, siRNA-based approaches have drawbacks associated with the time taken to achieve significant expression knockdown and the pleiotropic effects of EB1 and APC gene knockdown. Here we describe the effects of microinjecting APC- or EB1- specific monoclonal antibodies and a dominant-negative EB1 protein fragment into mammalian mitotic cells. The phenotypes observed were consistent with the roles proposed for EB1 and APC in chromosomal segregation in previous work. However, EB1 antibody injection also revealed two novel mitotic phenotypes, anaphase-specific cortical blebbing and asymmetric spindle pole movement. The daughters of microinjected cells displayed inequalities in microtubule content, with the greatest differences seen in the products of mitoses that showed the severest asymmetry in spindle pole movement. Daughters that inherited the least mobile pole contained the fewest microtubules, consistent with a role for EB1 in processes that promote equality of astral microtubule function at both poles in a spindle. We propose that these novel phenotypes represent APC-independent roles for EB1 in spindle pole function and the regulation of cortical contractility in the later stages of mitosis. Our work confirms that EB1 and APC have important mitotic roles, the loss of which could contribute to CIN in colorectal tumour cells.

  12. Uncovering the molecular machinery of the human spindle--an integration of wet and dry systems biology.

    Science.gov (United States)

    Rojas, Ana M; Santamaria, Anna; Malik, Rainer; Jensen, Thomas Skøt; Körner, Roman; Morilla, Ian; de Juan, David; Krallinger, Martin; Hansen, Daniel Aaen; Hoffmann, Robert; Lees, Jonathan; Reid, Adam; Yeats, Corin; Wehner, Anja; Elowe, Sabine; Clegg, Andrew B; Brunak, Søren; Nigg, Erich A; Orengo, Christine; Valencia, Alfonso; Ranea, Juan A G

    2012-01-01

    The mitotic spindle is an essential molecular machine involved in cell division, whose composition has been studied extensively by detailed cellular biology, high-throughput proteomics, and RNA interference experiments. However, because of its dynamic organization and complex regulation it is difficult to obtain a complete description of its molecular composition. We have implemented an integrated computational approach to characterize novel human spindle components and have analysed in detail the individual candidates predicted to be spindle proteins, as well as the network of predicted relations connecting known and putative spindle proteins. The subsequent experimental validation of a number of predicted novel proteins confirmed not only their association with the spindle apparatus but also their role in mitosis. We found that 75% of our tested proteins are localizing to the spindle apparatus compared to a success rate of 35% when expert knowledge alone was used. We compare our results to the previously published MitoCheck study and see that our approach does validate some findings by this consortium. Further, we predict so-called "hidden spindle hub", proteins whose network of interactions is still poorly characterised by experimental means and which are thought to influence the functionality of the mitotic spindle on a large scale. Our analyses suggest that we are still far from knowing the complete repertoire of functionally important components of the human spindle network. Combining integrated bio-computational approaches and single gene experimental follow-ups could be key to exploring the still hidden regions of the human spindle system. PMID:22427808

  13. Dynamic Response Analysis of Motorized Spindle System

    Institute of Scientific and Technical Information of China (English)

    ZHANG Li; LUO Yi-chao; XU Juan; XIAO Ru-feng; LI Xian-hui

    2013-01-01

    As to motorized spindle system, this paper builds a simplified 3D model of spindle and bearing, performs structure modal analysis, reveals its dynamic characteristics under the free model;furthermore, modifies bearing radial stiffness and number of model, and studies the change of modal parameters. On this basis, through the harmonic response analysis of the finite element model, dy-namic response characteristic caused by imbalance of monitored spindle system and law of vibration response to different amount of unbalance is analyzed.

  14. A ligand-independent integrin β1 mechanosensory complex guides spindle orientation.

    Science.gov (United States)

    Petridou, Nicoletta I; Skourides, Paris A

    2016-01-01

    Control of spindle orientation is a fundamental process for embryonic development, morphogenesis and tissue homeostasis, while defects are associated with tumorigenesis and other diseases. Force sensing is one of the mechanisms through which division orientation is determined. Here we show that integrin β1 plays a critical role in this process, becoming activated at the lateral regions of the cell cortex in a ligand-independent manner. This activation is force dependent and polar, correlating with the spindle capture sites. Inhibition of integrin β1 activation on the cortex and disruption of its asymmetric distribution leads to spindle misorientation, even when cell adhesion is β1 independent. Examining downstream targets reveals that a cortical mechanosensory complex forms on active β1, and regulates spindle orientation irrespective of cell context. We propose that ligand-independent integrin β1 activation is a conserved mechanism that allows cell responses to external stimuli. PMID:26952307

  15. F-actin mechanics control spindle centring in the mouse zygote

    Science.gov (United States)

    Chaigne, Agathe; Campillo, Clément; Voituriez, Raphaël; Gov, Nir S.; Sykes, Cécile; Verlhac, Marie-Hélène; Terret, Marie-Emilie

    2016-01-01

    Mitotic spindle position relies on interactions between astral microtubules nucleated by centrosomes and a rigid cortex. Some cells, such as mouse oocytes, do not possess centrosomes and astral microtubules. These cells rely only on actin and on a soft cortex to position their spindle off-centre and undergo asymmetric divisions. While the first mouse embryonic division also occurs in the absence of centrosomes, it is symmetric and not much is known on how the spindle is positioned at the exact cell centre. Using interdisciplinary approaches, we demonstrate that zygotic spindle positioning follows a three-step process: (1) coarse centring of pronuclei relying on the dynamics of an F-actin/Myosin-Vb meshwork; (2) fine centring of the metaphase plate depending on a high cortical tension; (3) passive maintenance at the cell centre. Altogether, we show that F-actin-dependent mechanics operate the switch between asymmetric to symmetric division required at the oocyte to embryo transition.

  16. Using Photobleaching to Measure Spindle Microtubule Dynamics in Primary Cultures of Dividing Drosophila Meiotic Spermatocytes

    OpenAIRE

    Savoian, Matthew S.

    2015-01-01

    In dividing animal cells, a microtubule (MT)-based bipolar spindle governs chromosome movement. Current models propose that the spindle facilitates and/or generates translocating forces by regionally depolymerizing the kinetochore fibers (k-fibers) that bind each chromosome. It is unclear how conserved these sites and the resultant chromosome-moving mechanisms are between different dividing cell types because of the technical challenges of quantitatively studying MTs in many specimens. In par...

  17. Meiosis in a triploid hybrid of Gossypium: high frequency of secondary bipolar spindles at metaphase II

    Indian Academy of Sciences (India)

    Mosareza Vafaie-Tabar; Shanti Chandrashekaran

    2007-01-01

    Studies on meiosis in pollen mother cells (PMCs) of a triploid interspecific hybrid ($3x = 39$ chromosomes, AAD) between tetraploid Gossypium hirsutum ($4n = 2x = 52$,AADD) and diploid G. arboreum ($2n = 2x = 26$,AA) are reported. During meiotic metaphase I, 13 AA bivalents and 13 D univalents are expected in the hybrid. However, only 28% of the PMCs had this expected configuration. The rest of the PMCs had between 8 and 12 bivalents and between 12 and 17 univalents. Univalents lagged at anaphase I, and at metaphase II one or a group of univalents remained scattered in the cytoplasm and failed to assemble at a single metaphase plate. Primary bipolar spindles organized around the bivalents and multivalents. In addition to the primary spindle, several secondary and smaller bipolar spindles organized themselves around individual univalents and groups of univalents. Almost all (97%) of the PMCs showed secondary spindles. Each spindle functioned independently and despite their multiple numbers in a cell, meiosis I proceeded normally, with polyad formation. These observations strongly support the view that in plant meiocytes bilateral kinetochore symmetry is not required for establishing a bipolar spindle and that single unpaired chromosomes can initiate and stabilize the formation of a functional bipolar spindle.

  18. The emerging pathogenic and therapeutic importance of the anaplastic lymphoma kinase gene.

    LENUS (Irish Health Repository)

    Kelleher, Fergal C

    2012-02-01

    The anaplastic lymphoma kinase gene (ALK) is a gene on chromosome 2p23 that has expression restricted to the brain, testis and small intestine but is not expressed in normal lymphoid tissue. It has similarity to the insulin receptor subfamily of kinases and is emerging as having increased pathologic and potential therapeutic importance in malignant disease. This gene was originally established as being implicated in the pathogenesis of rare diseases including inflammatory myofibroblastic tumour (IMT) and ALK-positive anaplastic large cell lymphoma, which is a subtype of non-Hodgkin\\'s lymphoma. Recently the number of diseases in which ALK is implicated in their pathogenesis has increased. In 2007, an inversion of chromosome 2 involving ALK and a fusion partner gene in a subset of non-small cell lung cancer was discovered. In 2008, publications emerged implicating ALK in familial and sporadic cases of neuroblastoma, a childhood cancer of the sympatho-adrenal system. Chromosomal abnormalities involving ALK are translocations, amplifications or mutations. Chromosomal translocations are the longest recognised ALK genetic abnormality. When translocations occur a fusion gene is created between ALK and a gene partner. This has been described in ALK-positive anaplastic large cell lymphoma in which ALK is fused to NPM (nucleolar protein gene) and in non-small cell lung cancer where ALK is fused to EML4 (Echinoderm microtubule-associated protein 4). The most frequently described partner genes in inflammatory myofibroblastic tumour are tropomyosin 3\\/4 (TMP3\\/4), however in IMTs a diversity of ALK fusion partners have been found, with the ability to homodimerise a common characteristic. Point mutations and amplification of the ALK gene occur in the childhood cancer neuroblastoma. Therapeutic targeting of ALK fusion genes using tyrosine kinase inhibition, vaccination using an ALK specific antigen and treatment using viral vectors for RNAi are emerging potential therapeutic

  19. Anaplastic carcinoma following well-differentiated thyroid cancer: etiological considerations

    International Nuclear Information System (INIS)

    Most cases of anaplastic thyroid carcinoma can be pathologically and often historically associated with the presence of low-grade (differentiated) cancer in the thyroid. That radiation therapy to the differentiated tumor plays an etiologic role in the transformation of a differentiated to an undifferentiated tumor has been suggested. If such therapy can be implicated, is there a difference in risk between external radiotherapy or radioactive iodine. Review of the literature discloses that more anaplastic carcinoma of the thyroid develop in patients without a history of prior radiation than in individuals who have received radiation. We report our recent experience with two patients who demonstrated the sequence of well-differentiated followed by anaplastic thyroid cancer subsequent to radiation and review the question

  20. The actin-binding ERM protein Moesin directly regulates spindle assembly and function during mitosis.

    Science.gov (United States)

    Vilmos, Péter; Kristó, Ildikó; Szikora, Szilárd; Jankovics, Ferenc; Lukácsovich, Tamás; Kari, Beáta; Erdélyi, Miklós

    2016-06-01

    Ezrin-Radixin-Moesin proteins are highly conserved, actin-binding cytoskeletal proteins that play an essential role in microvilli formation, T-cell activation, and tumor metastasis by linking actin filaments to the plasma membrane. Recent studies demonstrated that the only Ezrin-Radixin-Moesin protein of Drosophila melanogaster, Moesin, is involved in mitotic spindle function through stabilizing cell shape and microtubules at the cell cortex. We previously observed that Moesin localizes to the mitotic spindle; hence, we tested for the biological significance of this surprising localization and investigated whether it plays a direct role in spindle function. To separate the cortical and spindle functions of Moesin during mitosis we combined cell biological and genetic methods. We used early Drosophila embryos, in which mitosis occurs in the absence of a cell cortex, and found in vivo evidence for the direct requirement of Moesin in mitotic spindle assembly and function. We also found that the accumulation of Moesin precedes the construction of the microtubule spindle, and the fusiform structure formed by Moesin persists even after the microtubules have disassembled. PMID:27006187

  1. Nap sleep spindle correlates of intelligence

    NARCIS (Netherlands)

    Ujma, P.P.; Bodizs, R.; Gombos, F.; Stintzing, J.; Konrad, B.N.; Genzel, L.; Steiger, A.; Dresler, M.

    2015-01-01

    Sleep spindles are thalamocortical oscillations in non-rapid eye movement (NREM) sleep, that play an important role in sleep-related neuroplasticity and offline information processing. Several studies with full-night sleep recordings have reported a positive association between sleep spindles and fl

  2. Optimization Study of the Efficient Spindle

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    In the field of yam dyeing, the most generally employed method is a type of package dyeing which uses a package of cheese stacked on a spindle made of a perforated robe. Spindles up to now, have been designed without considering the characteristics of dyeing liquid, focusing only on the geometric configuration which cause many problems such as lack of level dyeing. To improve the level dyeing and find the appropriate spindle configuration for the most effective dyeing process, this study examines the spindle flow-field in detail, using a computational method. Flow characteristics inside the spindle have been investigated with varying in porosity, porous diameter and the velocity of the flow. The results show that the total pressure of the flow through the spindle is used to overcom e body force. The characteristics of the flow from the porous spindle could also be observed. Based on the results from this study, an effective spindle configuration for level-dyeing has been proposed.

  3. Clathrin is spindle-associated but not essential for mitosis.

    Directory of Open Access Journals (Sweden)

    Joana Borlido

    Full Text Available Clathrin is a multimeric protein involved in vesicle coat assembly. Recently clathrin distribution was reported to change during the cell cycle and was found to associate with the mitotic spindle. Here we test whether the recruitment of clathrin to the spindle is indicative of a critical functional contribution to mitosis.Previously a chicken pre-B lymphoma cell line (DKO-R was developed in which the endogenous clathrin heavy chain alleles were replaced with the human clathrin heavy chain under the control of a tetracycline-regulatable promoter. Receptor-mediated and fluid-phase endocytosis were significantly inhibited in this line following clathrin knockout, and we used this to explore the significance of clathrin heavy chain expression for cell cycle progression. We confirmed using confocal microscopy that clathrin colocalised with tubulin at mitotic spindles. Using a propidium iodide flow cytometric assay we found no statistical difference in the cell cycle distribution of the knockout cells versus the wild-type. Additionally, we showed that the ploidy and the recovery kinetics following cell cycle arrest with nocodazole were unchanged by repressing clathrin heavy chain expression.We conclude that the association of clathrin with the mitotic spindle and the contribution of clathrin to endocytosis are evolutionarily conserved. However we find that the contribution of clathrin to mitosis is less robust and dependent on cellular context. In other cell-lines silencing RNA has been used by others to knockdown clathrin expression resulting in an increase in the mitotic index of the cells. We show an effect on the G2/M phase population of clathrin knockdown in HEK293 cells but show that repressing clathrin expression in the DKO-R cell-line has no effect on the size of this population. Consequently this work highlights the need for a more detailed molecular understanding of the recruitment and function of clathrin at the spindle, since the

  4. DDA3 targets Cep290 into the centrosome to regulate spindle positioning.

    Science.gov (United States)

    Song, Haiyu; Park, Ji Eun; Jang, Chang-Young

    The centrosome is an important cellular organelle which nucleates microtubules (MTs) to form the cytoskeleton during interphase and the mitotic spindle during mitosis. The Cep290 is one of the centrosomal proteins and functions in cilia formation. Even-though it is in the centrosome, the function of Cep290 in mitosis had not yet been evaluated. In this study, we report a novel function of Cep290 that is involved in spindle positioning. Cep290 was identified as an interacting partner of DDA3, and we confirmed that Cep290 specifically localizes in the mitotic centrosome. Depletion of Cep290 caused a reduction of the astral spindle, leading to misorientation of the mitotic spindle. MT polymerization also decreased in Cep290-depleted cells, suggesting that Cep290 is involved in spindle nucleation. Furthermore, DDA3 stabilizes and transports Cep290 to the centrosome. Therefore, we concluded that DDA3 controls astral spindle formation and spindle positioning by targeting Cep290 to the centrosome. PMID:25998387

  5. Presence of anaplastic lymphoma kinase in inflammatory breast cancer.

    Science.gov (United States)

    Robertson, Fredika M; Petricoin Iii, Emanuel F; Van Laere, Steven J; Bertucci, Francois; Chu, Khoi; Fernandez, Sandra V; Mu, Zhaomei; Alpaugh, Katherine; Pei, Jianming; Circo, Rita; Wulfkuhle, Julia; Ye, Zaiming; Boley, Kimberly M; Liu, Hui; Moraes, Ricardo; Zhang, Xuejun; Demaria, Ruggero; Barsky, Sanford H; Sun, Guoxian; Cristofanilli, Massimo

    2013-01-01

    Although Inflammatory Breast Cancer (IBC) is recognized as the most metastatic variant of locally advanced breast cancer, the molecular basis for the distinct clinical presentation and accelerated program of metastasis of IBC is unknown. Reverse phase protein arrays revealed activation of the receptor tyrosine kinase, anaplastic lymphoma kinase (ALK) and biochemically-linked downstream signaling molecules including JAK1/STAT3, AKT, mTor, PDK1, and AMPKβ in pre-clinical models of IBC. To evaluate the clinical relevance of ALK in IBC, analysis of 25 IBC patient tumors using the FDA approved diagnostic test for ALK genetic abnormalities was performed. These studies revealed that 20/25 (80%) had either increased ALK copy number, low level ALK gene amplification, or ALK gene expression, with a prevalence of ALK alterations in basal-like IBC. One of 25 patients was identified as having an EML4-ALK translocation. The generality of gains in ALK copy number in basal-like breast tumors with IBC characteristics was demonstrated by analysis of 479 breast tumors using the TGCA data-base and our newly developed 79 IBC-like gene signature. The small molecule dual tyrosine kinase cMET/ALK inhibitor, Crizotinib (PF-02341066/Xalkori®, Pfizer Inc), induced both cytotoxicity (IC50 = 0.89 μM) and apoptosis, with abrogation of pALK signaling in IBC tumor cells and in FC-IBC01 tumor xenograft model, a new IBC model derived from pleural effusion cells isolated from an ALK(+) IBC patient. Based on these studies, IBC patients are currently being evaluated for the presence of ALK genetic abnormalities and when eligible, are being enrolled into clinical trials evaluating ALK targeted therapeutics. PMID:24102046

  6. 肾脏黏液性管状和梭形细胞癌4例报告%Clinical and pathological characteristics of renal mucinous tubular and spindle cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    王俊生; 林云华; 商建峰; 勇强; 姜永光

    2011-01-01

    目的 探讨肾脏黏液性管状和梭形细胞癌的临床病理特征.方法 回顾分析4例肾脏黏液性管状和梭形细胞癌患者的临床资料.女性3例,男性1例;年龄35~56岁,平均41岁;左肾2例,右肾2例;肾上极3例,肾下极1例;肿瘤直径3.5~6.5cm,平均5.5cm;无明显临床症状及体征,均为体检发现.B超检查提示,2例肾囊实性占位,为良性肿瘤;2例为厚壁型肾囊肿.CT检查提示,3例肾囊实性占位,为良性肿瘤;1例为厚壁型肾囊肿.2例行MRI检查提示,肾脏囊实性占位,为良性肿瘤.结果 4例患者均予手术治疗,术中发现肿块与肾组织的界限清楚,易分离;肿块呈囊实性,囊壁厚薄均匀,组织致密且内壁光滑.术后病理组织学检查示:2例为低度恶性上皮细胞肿瘤,1例为恶性肿瘤(透明细胞癌不排除),另1例为肾脏黏液性管状和梭形细胞癌.结论 肾脏黏液性管状和梭形细胞癌是一种具有良性肿瘤生长特性的低度恶性倾向的肿瘤.%Objective To explore the clinical and pathological characteristics of renal mucinous tubular and spindle cell carcinoma. Methods Clinical data of 4 patients including 3 female and 1 male aged from 35 to 56 were analyzed retrospectively. Among the 4 cases, two tumors were in the left side and two in right. Three tumors located in the upper part of kidneys, one in the lower part. The size of tumors ranged from 3.5 to 6.5 cm. There was no obvious symptom or physical sign in all cases and the tumors were detected during healthy examination. In B type untrasonography, two patients showed cystsolid tumor and two showed thick-wall cyst of kidney. In CT scan, three patients showed cystsolid tumor and one showed thick-wall cyst of kidney. In MRI scan, two patients showed cystsolid tumor. All the imaging examinations indicated the lump was benign. Results There were clear boundaries between the tumors and normal kidney tissue and the lesions were easy to be separated

  7. Attachment issues: kinetochore transformations and spindle checkpoint silencing.

    Science.gov (United States)

    Etemad, Banafsheh; Kops, Geert J P L

    2016-04-01

    Cell division culminates in the segregation of duplicated chromosomes in opposite directions prior to cellular fission. This process is guarded by the spindle assembly checkpoint (SAC), which prevents the anaphase of cell division until stable connections between spindle microtubules and the kinetochores of all chromosomes are established. The anaphase inhibitor is generated at unattached kinetochores and inhibitor production is prevented when microtubules are captured. Understanding the molecular changes in the kinetochore that are evoked by microtubule attachments is crucial for understanding the mechanisms of SAC signaling and silencing. Here, we highlight the most recent findings on these events, pinpoint some remaining mysteries, and argue for incorporating holistic views of kinetochore dynamics in order to understand SAC silencing. PMID:26947988

  8. Mechanism of the mitotic kinesin CENP-E in tethering kinetochores to spindle microtubules

    OpenAIRE

    Kim, Yumi

    2009-01-01

    The mitotic kinesin CENP-E is an essential kinetochore motor that directly contributes to the capture and stabilization of spindle microtubules by kinetochores. Although it has been well established that CENP-E is essential for metaphase chromosome alignment and reduction of CENP-E leads to high rates of whole chromosome missegregation in cells, its properties as a microtubule- dependent motor, the mechanism by which CENP-E contributes to the dynamic linkage between kinetochores and spindle m...

  9. Mitotic spindle asymmetry in rodents and primates: 2D vs. 3D measurement methodologies

    OpenAIRE

    Delphine eDelaunay; Robini, Marc C.; Colette eDehay

    2015-01-01

    Recent data have uncovered that spindle size asymmetry (SSA) is a key component of asymmetric cell division (ACD) in the mouse cerebral cortex (Delaunay et al., 2014). In the present study we show that SSA is independent of spindle orientation and also occurs during cortical progenitor divisions in the ventricular zone (VZ) of the macaque cerebral cortex, pointing to a conserved mechanism in the mammalian lineage. Because SSA magnitude is smaller in cortical precursors than in invertebrate ne...

  10. Chromosome misalignments induce spindle-positioning defects.

    Science.gov (United States)

    Tame, Mihoko A; Raaijmakers, Jonne A; Afanasyev, Pavel; Medema, René H

    2016-03-01

    Cortical pulling forces on astral microtubules are essential to position the spindle. These forces are generated by cortical dynein, a minus-end directed motor. Previously, another dynein regulator termed Spindly was proposed to regulate dynein-dependent spindle positioning. However, the mechanism of how Spindly regulates spindle positioning has remained elusive. Here, we find that the misalignment of chromosomes caused by Spindly depletion is directly provoking spindle misorientation. Chromosome misalignments induced by CLIP-170 or CENP-E depletion or by noscapine treatment are similarly accompanied by severe spindle-positioning defects. We find that cortical LGN is actively displaced from the cortex when misaligned chromosomes are in close proximity. Preventing the KT recruitment of Plk1 by the depletion of PBIP1 rescues cortical LGN enrichment near misaligned chromosomes and re-establishes proper spindle orientation. Hence, KT-enriched Plk1 is responsible for the negative regulation of cortical LGN localization. In summary, we uncovered a compelling molecular link between chromosome alignment and spindle orientation defects, both of which are implicated in tumorigenesis. PMID:26882550

  11. Successful radiopeptide targeting of metastatic anaplastic meningioma: Case report

    Directory of Open Access Journals (Sweden)

    Biersack Hans-Jürgen

    2011-08-01

    Full Text Available Abstract A patient with anaplastic meningioma and lung metastases resistant to conventional treatment underwent radiopeptide therapy with 177Lu- DOTA-octreotate in our institute. The treatment resulted in significant improvement in patient's quality of life and inhibition of tumor progression. This case may eventually help to establish the value of radiopeptide therapy in patients with this rare condition.

  12. Successful radiopeptide targeting of metastatic anaplastic meningioma: Case report

    International Nuclear Information System (INIS)

    A patient with anaplastic meningioma and lung metastases resistant to conventional treatment underwent radiopeptide therapy with 177Lu- DOTA-octreotate in our institute. The treatment resulted in significant improvement in patient's quality of life and inhibition of tumor progression. This case may eventually help to establish the value of radiopeptide therapy in patients with this rare condition

  13. Spindle activity phase-locked to sleep slow oscillations.

    Science.gov (United States)

    Klinzing, Jens G; Mölle, Matthias; Weber, Frederik; Supp, Gernot; Hipp, Jörg F; Engel, Andreas K; Born, Jan

    2016-07-01

    The right hemisphere did not reveal any signs of a concurrent lateralization of spindle activity co-occurring with these SOs. Our data are consistent with the concept of the neocortical SO exerting top-down control over thalamic spindle generation. However, they call into question the notion that SOs locally coordinate spindles and thereby inform spindle-related memory processing. PMID:27103135

  14. Semaphorin-Plexin Signaling Controls Mitotic Spindle Orientation during Epithelial Morphogenesis and Repair

    DEFF Research Database (Denmark)

    Xia, Jingjing; Swiercz, Jakub M.; Bañón-Rodríguez, Inmaculada;

    2015-01-01

    Morphogenesis, homeostasis, and regeneration of epithelial tissues rely on the accurate orientation of cell divisions, which is specified by the mitotic spindle axis. To remain in the epithelial plane, symmetrically dividing epithelial cells align their mitotic spindle axis with the plane. Here, we...... show that this alignment depends on epithelial cell-cell communication via semaphorin-plexin signaling. During kidney morphogenesis and repair, renal tubular epithelial cells lacking the transmembrane receptor Plexin-B2 or its semaphorin ligands fail to correctly orient the mitotic spindle, leading to...... severe defects in epithelial architecture and function. Analyses of a series of transgenic and knockout mice indicate that Plexin-B2 controls the cell division axis by signaling through its GTPase-activating protein (GAP) domain and Cdc42. Our data uncover semaphorin-plexin signaling as a central...

  15. Thirty-nine cases of intracranial hemangiopericytoma and anaplastic hemangiopericytoma: A retrospective review of MRI features and pathological findings

    International Nuclear Information System (INIS)

    Objective: To retrospectively review the imaging features of surgically and pathologically confirmed intracranial hemangiopericytoma and anaplastic hemangiopericytoma. Methods: Thirty-nine cases of surgically and pathologically confirmed hemangiopericytoma and anaplastic hemangiopericytoma were analyzed retrospectively. The MRI features were compared with pathological findings in all cases. Results: Of the 39 cases, 21 were anaplastic hemangiopericytoma (WHO grade III) and the remaining cases were hemangiopericytoma (WHO grade II); all lesions were solitary. MRI of anaplastic hemangiopericytoma showed that 20 cases were lobulated, and nine grew cross-leaf. The lesions showed mixed iso-high-low signal (n = 20) or iso-signal (n = 1) on plain T1WI, and mixed high-low signal (n = 20) or iso-signal (n = 1) on plain T2WI. After contrast injection, marked heterogeneous enhancement was seen in 19 cases. Significant necrosis and cystic changes were seen in 16 cases, and the “dural tail sign” was found in two cases. Ten cases had bony destruction, and 16 showed significant peritumoral edema. In 18 cases of hemangiopericytoma, nine were oval-shaped and three grew cross-leaf. The lesions showed mixed iso-low signal (n = 10) or iso-signal (n = 8) on plain T1WI, and mixed iso-high signal (n = 10) or iso-signal (n = 8) on plain T2WI. After contrast injection, significant uniform enhancement was seen in 10 cases. Significant necrosis and cystic changes were seen in seven cases, and “dural tail sign” was seen in six cases. Two cases had bony destruction. No case showed significant peritumoral edema. Pathological immunohistochemical Ki67 staining showed a concentration of ∼18.4% positive cells in anaplastic hemangiopericytoma, whereas in hemangiopericytoma it was 7.12%. Conclusion: Imaging findings of intracranial anaplastic hemangiopericytoma had more pronounced lobulation, cross-leaf growth tendency, more and easier bleeding, more necrosis, more cystic changes giving

  16. An astral simulacrum of the central spindle accounts for normal, spindle-less, and anucleate cytokinesis in echinoderm embryos.

    Science.gov (United States)

    Su, Kuan-Chung; Bement, William M; Petronczki, Mark; von Dassow, George

    2014-12-15

    Cytokinesis in animal cells depends on spindle-derived spatial cues that culminate in Rho activation, and thereby actomyosin assembly, in a narrow equatorial band. Although the nature, origin, and variety of such cues have long been obscure, one component is certainly the Rho activator Ect2. Here we describe the behavior and function of Ect2 in echinoderm embryos, showing that Ect2 migrates from spindle midzone to astral microtubules in anaphase and that Ect2 shapes the pattern of Rho activation in incipient furrows. Our key finding is that Ect2 and its binding partner Cyk4 accumulate not only at normal furrows, but also at furrows that form in the absence of associated spindle, midzone, or chromosomes. In all these cases, the cell assembles essentially the same cytokinetic signaling ensemble—opposed astral microtubules decorated with Ect2 and Cyk4. We conclude that if multiple signals contribute to furrow induction in echinoderm embryos, they likely converge on the same signaling ensemble on an analogous cytoskeletal scaffold. PMID:25298401

  17. Characterization of ring-like F-actin structure as a mechanical partner for spindle positioning in mitosis.

    Directory of Open Access Journals (Sweden)

    Huan Lu

    Full Text Available Proper spindle positioning and orientation are essential for accurate mitosis which requires dynamic interactions between microtubule and actin filament (F-actin. Although mounting evidence demonstrates the role of F-actin in cortical cytoskeleton dynamics, it remains elusive as to the structure and function of F-actin-based networks in spindle geometry. Here we showed a ring-like F-actin structure surrounding the mitotic spindle which forms since metaphase and maintains in MG132-arrested metaphase HeLa cells. This cytoplasmic F-actin structure is relatively isotropic and less dynamic. Our computational modeling of spindle position process suggests a possible mechanism by which the ring-like F-actin structure can regulate astral microtubule dynamics and thus mitotic spindle orientation. We further demonstrated that inhibiting Plk1, Mps1 or Myosin, and disruption of microtubules or F-actin polymerization perturbs the formation of the ring-like F-actin structure and alters spindle position and symmetric division. These findings reveal a previously unrecognized but important link between mitotic spindle and ring-like F-actin network in accurate mitosis and enables the development of a method to theoretically illustrate the relationship between mitotic spindle and cytoplasmic F-actin.

  18. Delay of HeLa cell cleavage into interphase using dihydrocytochalasin B: retention of a postmitotic spindle and telophase disc correlates with synchronous cleavage recovery

    OpenAIRE

    1995-01-01

    The molecular signals that determine the position and timing of the cleavage furrow during mammalian cell cytokinesis are presently unknown. We have studied in detail the effect of dihydrocytochalasin B (DCB), a drug that interferes with actin assembly, on specific late mitotic events in synchronous HeLa cells. When cleavage furrow formation is blocked at 10 microM DCB, cells return to interphase by the criteria of reformation of nuclei with lamin borders, degradation of the cyclin B componen...

  19. P21-activated kinase 4 (PAK4) is required for metaphase spindle positioning and anchoring.

    Science.gov (United States)

    Bompard, G; Rabeharivelo, G; Cau, J; Abrieu, A; Delsert, C; Morin, N

    2013-02-14

    The oncogenic kinase PAK4 was recently found to be involved in the regulation of the G1 phase and the G2/M transition of the cell cycle. We have also identified that PAK4 regulates Ran GTPase activity during mitosis. Here, we show that after entering mitosis, PAK4-depleted cells maintain a prolonged metaphase-like state. In these cells, chromosome congression to the metaphase plate occurs with normal kinetics but is followed by an extended period during which membrane blebbing and spindle rotation are observed. These bipolar PAK4-depleted metaphase-like spindles have a defective astral microtubule (MT) network and are not centered in the cell but are in close contact with the cell cortex. As the metaphase-like state persists, centrosome fragmentation occurs, chromosomes scatter from the metaphase plate and move toward the spindle poles with an active spindle assembly checkpoint, a phenotype that is reminiscent of cohesion fatigue. PAK4 also regulates the acto-myosin cytoskeleton and we report that PAK4 depletion results in the induction of cortical membrane blebbing during prometaphase arrest. However, we show that membrane blebs, which are strongly enriched in phospho-cofilin, are not responsible for the poor anchoring of the spindle. As PAK4 depletion interferes with the localization of components of the dynein/dynactin complexes at the kinetochores and on the astral MTs, we propose that loss of PAK4 could induce a change in the activities of motor proteins. PMID:22450748

  20. New spindle morphogenesis model by Dynein,Nudel, and the spindle matrix

    Institute of Scientific and Technical Information of China (English)

    Wei-Lih Lee; Patricia Wadsworth

    2009-01-01

    @@ It is well established that the mi-totic spindle, the organeile responsible for chromosome segregation during mitosis, is built from microtubules, motor proteins, and associated struc-tural and regulatory molecules. More controversial is the existence and identity of non-microtubule spindle components, collectively referred to as the matrix.

  1. Anaplastic cerebral hemangiopericytoma: Rare variant of a rare disease

    Directory of Open Access Journals (Sweden)

    Purnima Thakur

    2015-01-01

    Full Text Available Intracranial hemangiopericytoma (HPC is a rare tumor of central nervous system, anaplastic type (grade 3 being the rarest. HPC closely mimics meningiomas in clinical and radiological features, thus, its diagnosis and treatment is a challenge. We report a rare case of histopathologically diagnosed anaplastic HPC of frontal lobe of the brain. A lady in her 60′s presented with neurological signs of impaired memory, headache, decreased vision and slurring of speech that gradually progressed to aphasia over a period of 2 months. A space occupying lesion was identified on magnetic resonance imaging in the left frontal region. Left frontal craniotomy and Simpson grade 1 excision of the tumor was done. Postoperative radiotherapy was administered in view of positive margins on histopathological specimen. We describe the clinical, radiological, and histological features of this tumor, its outcome on completion of treatment and on subsequent follow-up along with a review of the literature.

  2. Malignant Trigeminal Nerve Sheath Tumor and Anaplastic Astrocytoma Collision Tumor with High Proliferative Activity and Tumor Suppressor P53 Expression

    Directory of Open Access Journals (Sweden)

    Maher Kurdi

    2014-01-01

    Full Text Available Background. The synchronous development of two primary brain tumors of distinct cell of origin in close proximity or in contact with each other is extremely rare. We present the first case of collision tumor with two histological distinct tumors. Case Presentation. A 54-year-old woman presented with progressive atypical left facial pain and numbness for 8 months. MRI of the brain showed left middle cranial fossa heterogeneous mass extending into the infratemporal fossa. At surgery, a distinct but intermingled intra- and extradural tumor was demonstrated which was completely removed through left orbitozygomatic-temporal craniotomy. Histopathological examination showed that the tumor had two distinct components: malignant nerve sheath tumor of the trigeminal nerve and temporal lobe anaplastic astrocytoma. Proliferative activity and expressed tumor protein 53 (TP53 gene mutations were demonstrated in both tumors. Conclusions. We describe the first case of malignant trigeminal nerve sheath tumor (MTNST and anaplastic astrocytoma in collision and discuss the possible hypothesis of this rare occurrence. We propose that MTNST, with TP53 mutation, have participated in the formation of anaplastic astrocytoma, or vice versa.

  3. Mitotic spindle asymmetry in rodents and primates:2D versus 3D measurement methodologies

    Directory of Open Access Journals (Sweden)

    Delphine eDelaunay

    2015-02-01

    Full Text Available Recent data have uncovered that spindle size asymmetry (SSA is a key component of asymmetric cell division in the mouse cerebral cortex (Delaunay et al., 2014. In the present study we show that SSA also occurs during cortical progenitor divisions in the ventricular zone of the macaque cerebral cortex, pointing to a conserved mechanism in the mammalian lineage. Because SSA magnitude is smaller in cortical precursors than in invertebrate neuroblasts, the unambiguous demonstration of volume differences between the two half spindles is considered to require 3D reconstruction of the mitotic spindle (Delaunay et al., 2014. Although straightforward, the 3D analysis of SSA is time consuming, which is likely to hinder SSA identification and prevent further explorations of SSA related mechanisms in generating asymmetric cell division. We therefore set out to develop an alternative method for accurately measuring spindle asymmetry. Based on the mathematically demonstrated linear relationship between 2D and 3D analysis, we show that 2D assessment of spindle size in metaphase cells is as accurate and reliable as 3D reconstruction provided a specific procedure is applied. We have examined the experimental accuracy of the two methods by applying them to different sets of in vivo and in vitro biological data, including mouse and primate cortical precursors. Linear regression analysis demonstrates that the results from 2D and 3D reconstructions are equally powerful. We therefore provide a reliable and efficient technique to measure SSA in mammalian cells.

  4. Anaplastic carcinoma following well-differentiated thyroid cancer: etiological considerations.

    OpenAIRE

    Kapp, D S; LiVolsi, V. A.; Sanders, M M

    1982-01-01

    Most cases of anaplastic thyroid carcinoma can be pathologically and often historically associated with the presence of low-grade (differentiated) cancer in the thyroid. That radiation therapy to the differentiated tumor plays an etiologic role in the transformation of a differentiated to an undifferentiated tumor has been suggested. If such therapy can be implicated, is there a difference in risk between external radiotherapy or radioactive iodine? Review of the literature discloses that mor...

  5. Anaplastic Thyroid Carcinoma Following Radioactive Iodine Therapy for Graves' Disease

    OpenAIRE

    Kim, Sun Hwa; Kim, Hee Young; Jung, Kwang Yoon; Choi, Dong Seop; Kim, Sin Gon

    2013-01-01

    Radioactive iodine (RAI) therapy has been used as a treatment option for Graves' disease, and it has been widely accepted to be safe. On the other hand, some evidence suggests that RAI therapy is possibly associated with a small increased risk of thyroid cancer. Herein, we report a rare case of anaplastic thyroid carcinoma (ATC) associated with Graves' disease, following RAI treatment. A 42-year-old woman had been diagnosed with Graves' disease and although she was treated with an antithyroid...

  6. Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies

    OpenAIRE

    Smallridge, Robert C.; Marlow, Laura A.; Copland, John A.

    2008-01-01

    Anaplastic thyroid cancer (ATC) is a rare malignancy. While external beam radiation therapy has improved locoregional control, the median survival of ∼ 4 months has not changed in more than half a century due to uncontrolled systemic metastases. The objective of this study was to review the literature in order to identify potential new strategies for treating this highly lethal cancer. PubMed searches were the principal source of articles reviewed. The molecular pathogenesis of ATC includes m...

  7. Anaplastic thyroid cancer Irish epidemiology and novel chemotherapeutic strategies

    OpenAIRE

    O'Neill, James Paul

    2009-01-01

    This body of work was conducted over a four year period. Within this timeframe we have conducted a National Epidemiology project, established a National Head and Neck Cancer database and completed Oncology laboratory investigations. Anaplastic thyroid cancer (ATC) is the most aggressive endocrine disease in nature. Within the thyroid gland a heterogeneous group of neoplasms may develop. These can range from well differentiated tumours with an excellent prognosis, to ATC tumours which prese...

  8. Ovarian mucinous cystadenoma with mural nodule of anaplastic carcinoma.

    OpenAIRE

    Hong, S. R.; Chun, Y. K.; Kim, Y. J.; Lim, K. T.; Kim, H S

    1998-01-01

    The occurrence of malignant mural nodule in benign cystic common epithelial tumor of the ovary have been reported in only three cases; the case one was mucinous cystadenoma with a mural nodule of fibrosarcoma and the others were of carcinomas. Our case was another rare case of ovarian mucinous cystadenoma with mural nodule of anaplastic carcinoma in a 42-year-old woman. The cystadenoma had an unilocular cystic cavity and a mural nodule with thick multinodular solid wall. The internal cystic w...

  9. Presence of anaplastic lymphoma kinase in inflammatory breast cancer

    OpenAIRE

    Robertson, Fredika M; Petricoin III, Emanuel F.; van Laere, Steven J; Bertucci, Francois; Chu, Khoi; Fernandez, Sandra V.; Mu, Zhaomei; Alpaugh, Katherine; Pei, Jianming; Circo, Rita; Wulfkuhle, Julia; Ye, Zaiming; Boley, Kimberly M; Liu, Hui; Moraes, Ricardo

    2013-01-01

    Although Inflammatory Breast Cancer (IBC) is recognized as the most metastatic variant of locally advanced breast cancer, the molecular basis for the distinct clinical presentation and accelerated program of metastasis of IBC is unknown. Reverse phase protein arrays revealed activation of the receptor tyrosine kinase, anaplastic lymphoma kinase (ALK) and biochemically-linked downstream signaling molecules including JAK1/STAT3, AKT, mTor, PDK1, and AMPKβ in pre-clinical models of IBC. To evalu...

  10. Constitutive Cdk2 activity promotes aneuploidy while altering the spindle assembly and tetraploidy checkpoints

    DEFF Research Database (Denmark)

    Jahn, Stephan C; Corsino, Patrick E; Davis, Bradley J;

    2013-01-01

    The cell has many mechanisms for protecting the integrity of its genome. These mechanisms are often weakened or absent in many cancers, leading to high rates of chromosomal instability in tumors. Control of the cell cycle is crucial for the function of these checkpoints, and is frequently lost in...... instability. Expression of these complexes in the MCF10A cell line leads to retinoblastoma protein (Rb) hyperphosphorylation, a subsequent increase in proliferation rate, and increased expression of the spindle assembly checkpoint protein Mad2. This results in a strengthening of the spindle assembly...

  11. DNA methylation alterations in grade II- and anaplastic pleomorphic xanthoastrocytoma

    International Nuclear Information System (INIS)

    Pleomorphic xanthoastrocytoma (PXA) is a rare WHO grade II tumor accounting for less than 1% of all astrocytomas. Malignant transformation into PXA with anaplastic features, is unusual and correlates with poorer outcome of the patients. Using a DNA methylation custom array, we have quantified the DNA methylation level on the promoter sequence of 807 cancer-related genes of WHO grade II (n = 11) and III PXA (n = 2) and compared to normal brain tissue (n = 10) and glioblastoma (n = 87) samples. DNA methylation levels were further confirmed on independent samples by pyrosequencing of the promoter sequences. Increasing DNA promoter hypermethylation events were observed in anaplastic PXA as compared with grade II samples. We further validated differential hypermethylation of CD81, HCK, HOXA5, ASCL2 and TES on anaplastic PXA and grade II tumors. Moreover, these epigenetic alterations overlap those described in glioblastoma patients, suggesting common mechanisms of tumorigenesis. Even taking into consideration the small size of our patient populations, our data strongly suggest that epigenome-wide profiling of PXA is a valuable tool to identify methylated genes, which may play a role in the malignant progression of PXA. These methylation alterations may provide useful biomarkers for decision-making in those patients with low-grade PXA displaying a high risk of malignant transformation

  12. High Temperature Resistant Exhaust Valve Spindle

    DEFF Research Database (Denmark)

    Bihlet, Uffe Ditlev

    O5 and Na2SO4 condense on the spindle, causing hot corrosion. Current industry standards can withstand service temperatures of up to 500°C for the spindle seat and 700°C for the spindle bottom. This project was tasked with increasing these temperatures 50°C each. Literature review as well as an in......-situ corrosion test revealed that the most resistant alloy in such an environment is Alloy 657 (Ni-based, 49 wt% Cr, 1.5 wt% Nb). This alloy is suitable for the spindle bottom, but not for the spindle seat, as it is too weak. Thermodynamic calculations suggested that it was possible to modify the chemistry of...... the current valve seat alloy, Alloy 718 (Ni-based, 19 wt% Cr, 18 wt% Fe, 5.1 wt% Nb, 3 wt% Mo, 1 wt% Ti and 0.6 wt% Al), and thereby to obtain a more hot corrosion resistant alloy. To validate these calculations, 16 Ni-based alloys, containing 40 wt% Cr and Nb, Ta and Ti in varying levels, were...

  13. Successful treatment with carboplatin and nanoparticle albumin-bound paclitaxel in a patient with pulmonary spindle cell carcinoma

    Directory of Open Access Journals (Sweden)

    Takahiro Tsuji

    2015-01-01

    Discussion: Preclinical models suggested that nab-PTX may reach the tumor microenvironment more efficiently than solvent-based paclitaxel (sb-PTX and be preferentially taken up by cancer cells. Considering that there is no effective treatment for patients with pulmonary SpCC, nab-PTX may merit further investigation in patients with pulmonary SpCC.

  14. Pins is not required for spindle orientation in the Drosophila wing disc.

    Science.gov (United States)

    Bergstralh, Dan T; Lovegrove, Holly E; Kujawiak, Izabela; Dawney, Nicole S; Zhu, Jinwei; Cooper, Samantha; Zhang, Rongguang; St Johnston, Daniel

    2016-07-15

    In animal cells, mitotic spindles are oriented by the dynein/dynactin motor complex, which exerts a pulling force on astral microtubules. Dynein/dynactin localization depends on Mud/NUMA, which is typically recruited to the cortex by Pins/LGN. In Drosophila neuroblasts, the Inscuteable/Baz/Par-6/aPKC complex recruits Pins apically to induce vertical spindle orientation, whereas in epithelial cells Dlg recruits Pins laterally to orient the spindle horizontally. Here we investigate division orientation in the Drosophila imaginal wing disc epithelium. Live imaging reveals that spindle angles vary widely during prometaphase and metaphase, and therefore do not reliably predict division orientation. This finding prompted us to re-examine mutants that have been reported to disrupt division orientation in this tissue. Loss of Mud misorients divisions, but Inscuteable expression and aPKC, dlg and pins mutants have no effect. Furthermore, Mud localizes to the apical-lateral cortex of the wing epithelium independently of both Pins and cell cycle stage. Thus, Pins is not required in the wing disc because there are parallel mechanisms for Mud localization and hence spindle orientation, making it a more robust system than in other epithelia. PMID:27287805

  15. F-actin asymmetry and the endoplasmic reticulum-associated TCC-1 protein contribute to stereotypic spindle movements in the Caenorhabditis elegans embryo

    OpenAIRE

    Berends, C.W.H.; Muñoz, J.; Portegijs, V.C.; Schmidt, R.; Grigoriev, I.S.; Boxem, M.; Akhmanova, A.S.; Heck, A.J.R.; Van den Heuvel, S.

    2013-01-01

    The microtubule spindle apparatus dictates the plane of cell cleavage in animal cells. During development, dividing cells control the position of the spindle to determine the size, location, and fate of daughter cells. Spindle positioning depends on pulling forces that act between the cell periphery and astral microtubules. This involves dynein recruitment to the cell cortex by a heterotrimeric G-protein α subunit in complex with a TPR-GoLoco motif protein (GPR-1/2, Pins, LGN) and coiled-coil...

  16. F-actin asymmetry and the endoplasmic reticulum–associated TCC-1 protein contribute to stereotypic spindle movements in the Caenorhabditis elegans embryo

    OpenAIRE

    2013-01-01

    The microtubule spindle apparatus dictates the plane of cell cleavage in animal cells. During development, dividing cells control the position of the spindle to determine the size, location, and fate of daughter cells. Spindle positioning depends on pulling forces that act between the cell periphery and astral microtubules. This involves dynein recruitment to the cell cortex by a heterotrimeric G-protein α subunit in complex with a TPR-GoLoco motif protein (GPR-1/2, Pins, LGN) and coiled-coil...

  17. Cenp-meta is required for sustained spindle checkpoint

    Directory of Open Access Journals (Sweden)

    Thomas Rubin

    2014-05-01

    Full Text Available Cenp-E is a kinesin-like motor protein required for efficient end-on attachment of kinetochores to the spindle microtubules. Cenp-E immunodepletion in Xenopus mitotic extracts results in the loss of mitotic arrest and massive chromosome missegregation, whereas its depletion in mammalian cells leads to chromosome segregation defects despite the presence of a functional spindle assembly checkpoint (SAC. Cenp-meta has previously been reported to be the Drosophila homolog of vertebrate Cenp-E. In this study, we show that cenp-metaΔ mutant neuroblasts arrest in mitosis when treated with colchicine. cenp-metaΔ mutant cells display a mitotic delay. Yet, despite the persistence of the two checkpoint proteins Mad2 and BubR1 on unattached kinetochores, these cells eventually enter anaphase and give rise to highly aneuploid daughter cells. Indeed, we find that cenp-metaΔ mutant cells display a slow but continuous degradation of cyclin B, which eventually triggers the mitotic exit observed. Thus, our data provide evidence for a role of Cenp-meta in sustaining the SAC response.

  18. Mechanical stability of bipolar spindle assembly

    CERN Document Server

    Malgaretti, Paolo

    2016-01-01

    Assembly and stability of mitotic spindle is governed by the interplay of various intra-cellular forces, e.g. the forces generated by motor proteins by sliding overlapping anti-parallel microtubules (MTs) polymerized from the opposite centrosomes, the interaction of kinetochores with MTs, and the interaction of MTs with the chromosomes arms. We study the mechanical behavior and stability of spindle assembly within the framework of a minimal model which includes all these effects. For this model, we derive a closed--form analytical expression for the force acting between the centrosomes as a function of their separation distance and we show that an effective potential can be associated with the interactions at play. We obtain the stability diagram of spindle formation in terms of parameters characterizing the strength of motor sliding, repulsive forces generated by polymerizing MTs, and the forces arising out of interaction of MTs with kinetochores. The stability diagram helps in quantifying the relative effec...

  19. Functions of spindle check-point and its relationship to chromosome instability

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    It is generally believed that the equal distribution of genetic materials to two daughter cells during mitosis is the key to cell health and development. During the dynamic process, spindle checkpoint plays a very important role in chromosome movements and final sister chromatid separation. The equal and precise segregation of chromosomes contributes to the genomic stability while aberrant separations result in chromosome instability that causes pathogenesis of certain diseases such as Down's syndrome and cancers. Kinetochore and its regulatory proteins consist of the spindle checkpoint and determine the spatial and temporal orders of chromosome segregation.

  20. MLL5 maintains spindle bipolarity by preventing aberrant cytosolic aggregation of PLK1.

    Science.gov (United States)

    Zhao, Wei; Liu, Jie; Zhang, Xiaoming; Deng, Lih-Wen

    2016-03-28

    Faithful chromosome segregation with bipolar spindle formation is critical for the maintenance of genomic stability. Perturbation of this process often leads to severe mitotic failure, contributing to tumorigenesis. MLL5 has been demonstrated to play vital roles in cell cycle progression and the maintenance of genomic stability. Here, we identify a novel interaction between MLL5 and PLK1 in the cytosol that is crucial for sustaining spindle bipolarity during mitosis. Knockdown of MLL5 caused aberrant PLK1 aggregation that led to acentrosomal microtubule-organizing center (aMTOC) formation and subsequent spindle multipolarity. Further molecular studies revealed that the polo-box domain (PBD) of PLK1 interacted with a binding motif on MLL5 (Thr887-Ser888-Thr889), and this interaction was essential for spindle bipolarity. Overexpression of wild-type MLL5 was able to rescue PLK1 mislocalization and aMTOC formation in MLL5-KD cells, whereas MLL5 mutants incapable of interacting with the PBD failed to do so. We thus propose that MLL5 preserves spindle bipolarity through maintaining cytosolic PLK1 in a nonaggregated form. PMID:27002166

  1. A Bipolar Spindle of Antiparallel ParM Filaments Drives Bacterial Plasmid Segregation

    DEFF Research Database (Denmark)

    Gayathri, P; Fujii, T; Møller-Jensen, Jakob;

    2012-01-01

    To ensure their stable inheritance by daughter cells during cell division, bacterial low copy-number plasmids make simple DNA segregating machines that use an elongating protein filament between sister plasmids. In the ParMRC system of Escherichia coli R1 plasmid, ParM, an actin-like protein, forms...... the spindle between ParRC complexes on sister plasmids. Using a combination of structural work and total internal reflection fluorescence microscopy, we show that ParRC bound and could accelerate growth at only one end of polar ParM filaments, mechanistically resembling eukaryotic formins. The architecture...... of ParM filaments enabled two ParRC-bound filaments to associate in an antiparallel orientation, forming a bipolar spindle. The spindle elongated as a bundle of at least two antiparallel filaments, thereby pushing two plasmid clusters toward the poles....

  2. Smurf2 as a novel mitotic regulator: From the spindle assembly checkpoint to tumorigenesis

    Directory of Open Access Journals (Sweden)

    Moore Finola E

    2009-07-01

    Full Text Available Abstract The execution of the mitotic program with high fidelity is dependent upon precise spatiotemporal regulation of posttranslational protein modifications. For example, the timely polyubiquitination of critical mitotic regulators by Anaphase Promoting Complex/Cyclosome (APC/C is essential for the metaphase to anaphase transition and mitotic exit. The spindle assembly checkpoint prevents unscheduled activity of APC/C-Cdc20 in early mitosis, allowing bipolar attachment of kinetochores to mitotic spindle and facilitating equal segregation of sister chromatids. The critical effector of the spindle checkpoint, Mitotic arrest deficient 2 (Mad2, is recruited to unattached kinetochores forming a complex with other regulatory proteins to efficiently and cooperatively inhibit APC/C-Cdc20. A weakened and/or dysfunctional spindle checkpoint has been linked to the development of genomic instability in both cell culture and animal models, and evidence suggests that aberrant regulation of the spindle checkpoint plays a critical role in human carcinogenesis. Recent studies have illuminated a network of both degradative and non-degradative ubiquitination events that regulate the metaphase to anaphase transition and mitotic exit. Within this context, our recent work showed that the HECT (Homologous to E6-AP C-terminus-family E3 ligase Smurf2 (Smad specific ubiquitin regulatory factor 2, known as a negative regulator of transforming growth factor-beta (TGF-β signaling, is required for a functional spindle checkpoint by promoting the functional localization and stability of Mad2. Here we discuss putative models explaining the role of Smurf2 as a new regulator in the spindle checkpoint. The dynamic mitotic localization of Smurf2 to the centrosome and other critical mitotic structures provides implications about mitotic checkpoint control dependent on various ubiquitination events. Finally, deregulated Smurf2 activity may contribute to carcinogenesis by

  3. Optogenetically induced sleep spindle rhythms alter sleep architectures in mice

    OpenAIRE

    Kim, Angela; Latchoumane, Charles; Lee, Soojung; Kim, Guk Bae; Cheong, Eunji; Augustine, George J.; Shin, Hee-Sup

    2012-01-01

    Sleep spindles are rhythmic patterns of neuronal activity generated within the thalamocortical circuit. Although spindles have been hypothesized to protect sleep by reducing the influence of external stimuli, it remains to be confirmed experimentally whether there is a direct relationship between sleep spindles and the stability of sleep. We have addressed this issue by using in vivo photostimulation of the thalamic reticular nucleus of mice to generate spindle oscillations that are structura...

  4. Sleep Spindles as Facilitators of Memory Formation and Learning

    OpenAIRE

    Ulrich, Daniel

    2016-01-01

    Over the past decades important progress has been made in understanding the mechanisms of sleep spindle generation. At the same time a physiological role of sleep spindles is starting to be revealed. Behavioural studies in humans and animals have found significant correlations between the recall performance in different learning tasks and the amount of sleep spindles in the intervening sleep. Concomitant neurophysiological experiments showed a close relationship between sleep spindles and oth...

  5. Management of anaplastic lymphoma kinase positive orbito-conjunctival inflammatory myofibroblastic tumor with crizotinib.

    Science.gov (United States)

    Kiratli, Hayyam; Uzun, Salih; Varan, Ali; Akyüz, Canan; Orhan, Diclehan

    2016-06-01

    Inflammatory myofibroblastic tumor (IMT) is a distinct mesenchymal neoplasm of myofibroblastic spindle cells associated with an inflammatory infiltrate formed by lymphocytes, eosinophils, and plasma cells in a myxoid or collagenous stroma. This tumor has a predilection for children and young adults and most commonly occurs in the lungs, retroperitoneum, abdomen, and pelvis. Ocular and orbital involvement is exceedingly rare. We describe a case of IMT in a 7-year-old girl involving the cornea, conjunctiva, and the anterior orbit treated with crizotinib, resulting in complete tumor remission. PMID:27312965

  6. Spindle epithelial tumor with thymus-like differentiation of thyroid gland: Report of two cases with follow-up

    Directory of Open Access Journals (Sweden)

    Nisa Azizun

    2010-10-01

    Full Text Available Spindle epithelial tumor with thymus-like differentiation (SETTLE is a rare malignant thyroid tumor showing thymic or related branchial pouch differentiation. The tumors are composed predominantly of spindle cells along with focal epithelial component and ductular formations. SETTLE occurs in young patients, with indolent growth and a tendency to develop delayed blood-borne metastases. We herein report two cases of SETTLE with a follow-up period of 64 months and 30 months, respectively.

  7. Urinary bladder urothelial carcinoma with expression of KIT and PDGFRA and showing diverse differentiations into plasmacytoid, clear cell, acantholytic, nested, and spindle variants, and into adenocarcinoma, signet-ring cell carcinoma, small cell carcinoma, large cell carcinoma, and pleomorphic carcinoma

    OpenAIRE

    Terada, Tadashi

    2013-01-01

    Various tumors can arise in the urinary bladder (UB); most common is urothelial carcinoma (UC). UC of the UB have many variants. Other types of carcinomas such as adenocarcinoma (AC) and small cell carcinoma (SmCC) can occur in UB carcinomas. Expression of KIT and PDGFRA has not been reported. A 66-year-old man admitted to our hospital because of hematuria. Cystoscopy revealed papillary invasive tumor and a transurethral bladder tumorectomy (TUR-BT) was performed. The TUR-BT showed UC, AC, Sm...

  8. Cortical Anaplastic Ependymoma with Significant Desmoplasia: A Case Report and Literature Review

    Science.gov (United States)

    Elsharkawy, Alaa Eldin; Abuamona, Raid; Bergmann, Markus; Salem, Shadi; Gafumbegete, Evariste; Röttger, Ernst

    2013-01-01

    Ectopic brain anaplastic ependymomas with no connection to the ventricles are rare. We present a rare case of a 25-year-old male who presented with generalized convulsions. Computed tomography (CT), Magnetic Resonance Imaging (MRI), and magnetic resonance spectroscopy (MRS) showed characters of an intra- and extra-axial lesion. Intraoperatively, the lesion was a cortical solid mass that had no connections to the dura or to the ventricle. The histological diagnosis showed an anaplastic ependymoma with WHO grade III with distinctive desmoplasia. A literature review of ectopic anaplastic ependymomas regarding their clinical presentations, management, and prognostic factors was performed. There is a need to establish a clinically based histopathological grading system for anaplastic ependymomas. Ectopic anaplastic ependymomas should be included in the preoperative differential diagnosis. PMID:24455359

  9. Cortical Anaplastic Ependymoma with Significant Desmoplasia: A Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Alaa Eldin Elsharkawy

    2013-01-01

    Full Text Available Ectopic brain anaplastic ependymomas with no connection to the ventricles are rare. We present a rare case of a 25-year-old male who presented with generalized convulsions. Computed tomography (CT, Magnetic Resonance Imaging (MRI, and magnetic resonance spectroscopy (MRS showed characters of an intra- and extra-axial lesion. Intraoperatively, the lesion was a cortical solid mass that had no connections to the dura or to the ventricle. The histological diagnosis showed an anaplastic ependymoma with WHO grade III with distinctive desmoplasia. A literature review of ectopic anaplastic ependymomas regarding their clinical presentations, management, and prognostic factors was performed. There is a need to establish a clinically based histopathological grading system for anaplastic ependymomas. Ectopic anaplastic ependymomas should be included in the preoperative differential diagnosis.

  10. The role of p53 in the response to mitotic spindle damage

    International Nuclear Information System (INIS)

    The p53 tumour suppressor protein has defined roles in G1/S and G2/M cell cycle checkpoint in response to a range of cellular stresses including DNA damage, dominant oncogene expression, hypoxia, metabolic changes and viral infection. In addition to these responses, p53 can also be activated when damage occurs to the mitotic spindle. Initially, spindle damage activates a p53-independent checkpoint which functions at the metaphase-anaphase transition and prevents cells from progressing through mitosis until the completion of spindle formation. Cells eventually escape from this block (a process termed 'mitotic slippage'), and an aberrant mitosis ensues in which sister chromatids fail to segregate properly. After a delay period, p53 responds to this mitotic failure by instituting a G1-like growth arrest, with an intact nucleus containing 4N DNA, but without the cells undergoing division. Cells lacking wild-type p53 are still able to arrest transiently at mitosis, and also fail to undergo division, underscoring that the delay in mitosis is p53-independent. However, these cells are not prevented from re-entering the cell cycle and can reduplicate their DNA unchecked, leading to polyploidy. Additionally, p53-null cells which experience spindle failure often show the appearance of micronuclei arising from poorly segregated chromosomes which have de-condensed and been enclosed in a nuclear envelope. The ability of p53 to prevent their formation suggests an additional G2 involvement which prevents nuclear breakdown prior to mitosis. The molecular mechanism by which p53 is able to sense mitotic failure is still unknown, but may be linked to the ability of p53 to regulate duplication of the centrosome, the organelle which nucleates spindle formation. (authors)

  11. Combination chemotherapy (COMP protocol) and radiotherapy of anaplastic supratentorial gliomas

    International Nuclear Information System (INIS)

    Postoperative survival time and recurrence-free intervals in 116 consecutive patients with supratentorial grade III and IV gliomas (glioblastomas, gliosarcomas, anaplastic astrocytomas, and ependymomas) were compared in unselected groups receiving different forms of treatment. Postoperative high-voltage radiotherapy (31 patients, dosage 4,000-6,000 rads) and combined chemotherapy consisting of CCNU, vincristine, amethopterine, and procarbazine in 15-day circles (COMP protocol) (12 patients) showed the same median survival time of 10.6 months and comparable recurrence-free intervals of 6.8 and 7.0 months, respectively. These results were significantly different from a control group (39 patients) receiving best postoperative supportive (conventional) care (median survival 5.4 months, free interval 3.7 months). Combination of postoperative radiotherapy with simultaneous polychemotherapy (COMP protocol), evaluated in 18 patients, did not significantly change the recurrence-free interval (median 7.0 months), but increased the median survival time to 12.9 months, which was significantly superior to the two other treatment groups. The toxic side effects of COMP therapy were moderate and essentially haematological. In general, simultaneous radiation and chemical treatment was well tolerated after major tumour resection. These preliminary results of postoperative combination of radiation and polychemotherapy for anaplastic supratentorial gliomas appear encouraging, but further trials for optimization of combined therapeutic strategies are warranted. (author)

  12. Using Photobleaching to Measure Spindle Microtubule Dynamics in Primary Cultures of Dividing Drosophila Meiotic Spermatocytes.

    Science.gov (United States)

    Savoian, Matthew S

    2015-07-01

    In dividing animal cells, a microtubule (MT)-based bipolar spindle governs chromosome movement. Current models propose that the spindle facilitates and/or generates translocating forces by regionally depolymerizing the kinetochore fibers (k-fibers) that bind each chromosome. It is unclear how conserved these sites and the resultant chromosome-moving mechanisms are between different dividing cell types because of the technical challenges of quantitatively studying MTs in many specimens. In particular, our knowledge of MT kinetics during the sperm-producing male meiotic divisions remains in its infancy. In this study, I use an easy-to-implement photobleaching-based assay for measuring spindle MT dynamics in primary cultures of meiotic spermatocytes isolated from the fruit fly Drosophila melanogaster. By use of standard scanning confocal microscopy features, fiducial marks were photobleached on fluorescent protein (FP)-tagged MTs. These were followed by time-lapse imaging during different division stages, and their displacement rates were calculated using public domain software. I find that k-fibers continually shorten at their poles during metaphase and anaphase A through the process of MT flux. Anaphase chromosome movement is complemented by Pac-Man, the shortening of the k-fiber at its chromosomal interface. Thus, Drosophila spermatocytes share the sites of spindle dynamism and mechanisms of chromosome movement with mitotic cells. The data reveal the applicability of the photobleaching assay for measuring MT dynamics in primary cultures. This approach can be readily applied to other systems. PMID:25802491

  13. Material Choice for spindle of machine tools

    International Nuclear Information System (INIS)

    The requirements of contemporary industry and the flashing development of modern sciences impose restrictions on the majority of the elements of machines; the resulting financial constraints can be satisfied by a better output of the production equipment. As for those concerning the design, the resistance and the correct operation of the product, these require the development of increasingly precise parts, therefore the use of increasingly powerful tools [5]. The precision of machining and the output of the machine tools are generally determined by the precision of rotation of the spindle, indeed, more this one is large more the dimensions to obtain are in the zone of tolerance and the defects of shape are minimized. During the development of the machine tool, the spindle which by definition is a rotating shaft receiving and transmitting to the work piece or the cutting tool the rotational movement, must be designed according to certain optimal parameters to be able to ensure the precision required. This study will be devoted to the choice of the material of the spindle fulfilling the imposed requirements of precision.

  14. Simplified Dynamic Analysis of Grinders Spindle Node

    Science.gov (United States)

    Demec, Peter

    2014-12-01

    The contribution deals with the simplified dynamic analysis of surface grinding machine spindle node. Dynamic analysis is based on the use of the transfer matrix method, which is essentially a matrix form of method of initial parameters. The advantage of the described method, despite the seemingly complex mathematical apparatus, is primarily, that it does not require for solve the problem of costly commercial software using finite element method. All calculations can be made for example in MS Excel, which is advantageous especially in the initial stages of constructing of spindle node for the rapid assessment of the suitability its design. After detailing the entire structure of spindle node is then also necessary to perform the refined dynamic analysis in the environment of FEM, which it requires the necessary skills and experience and it is therefore economically difficult. This work was developed within grant project KEGA No. 023TUKE-4/2012 Creation of a comprehensive educational - teaching material for the article Production technique using a combination of traditional and modern information technology and e-learning.

  15. Presence of Meiotic Spindles Indicates Early Cleavage of Embryos

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective To assess whether the detection of the meiotic spindle could anticipate the appearance of early cleavage.Methods Oocytes were obtained from stimulated ovaries of consenting patients undergoing oocytes retrieval for ICSI.Spindles were imaged with the Polscope.After ICSI,oocytes with or without spindles were cultured for examination of early cleavage and embryo development.A total of 328 oocytes from 50 cycles were examined with the Polscope and inseminated by ICSI.Results Spindles were imaged in 81.7% of oocytes.After ICSI,more oocytes with spindles (78.4%) fertilized normally than oocytes without spindles (53.3%)(P<0.001).At 25-27 h post ICSI.more fertilized oocytes developed from oocytes with spindles (81.9%) were detected early cleavage than those from oocytes without spindles(28.1%)(P<0.001).Significantly more embryos with early cleavage (82.2%) developed to high quality embryos at d 3 compared with the embryos without early cleavage(48.3%)(P=0.001).The value of rs related to the relationship between spindles and early cleavage was 0.420(P<0.0001).Conclusion The existing of the early cleavage may have a predictive value on the opportunity of high quality embryos and the existing of the spindle may have a predictive value in the appearance of early cleavage.

  16. Temozolomide Treatment for Pediatric Refractory Anaplastic Ependymoma with Low MGMT Protein Expression.

    Science.gov (United States)

    Komori, Kazutoshi; Yanagisawa, Ryu; Miyairi, Yosuke; Sakashita, Kazuo; Shiohara, Masaaki; Fujihara, Ikuko; Morita, Daisuke; Nakamura, Tomohiko; Ogiso, Yoshifumi; Sano, Kenji; Shirahata, Mitsuaki; Fukuoka, Kohei; Ichimura, Koichi; Shigeta, Hiroaki

    2016-01-01

    The benefit of postoperative chemotherapy for anaplastic ependymoma remains unknown. We report two pediatric patients with refractory anaplastic ependymoma treated with temozolomide (TMZ). We did not detect O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation in tumor samples; however, MGMT protein expression was low. With TMZ treatment, one patient had a 7-month complete remission; the other, stable disease for 15 months. Three other patients did not respond to TMZ; two had high and one low MGMT expression, and two showed no MGMT promoter methylation. These findings suggest that TMZ may be effective for pediatric refractory anaplastic ependymoma with low MGMT protein expression. PMID:26305586

  17. Concomitant occurrence of EGFR (epidermal growth factor receptor) and KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutations in an ALK (anaplastic lymphoma kinase)-positive lung adenocarcinoma patient with acquired resistance to crizotinib

    DEFF Research Database (Denmark)

    Rossing, Henrik H; Grauslund, Morten; Urbanska, Edyta M;

    2013-01-01

    events behind crizotinib-resistance currently remain largely uncharacterized. Thus, we report on an anaplastic lymphoma kinase-positive non-small cell lung carcinoma patient with concomitant occurrence of epidermal growth factor receptor and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations...

  18. Anaplastic thyroid carcinoma: 91 patients treated by surgery and radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Junor, E.J.; Paul, J.; Reed, N.S. (Beatson Oncology Centre, Glasgow (United Kingdom))

    1992-04-01

    Ninety-one patients with histologically proven anaplastic carcinoma of the thyroid were referred to the Beatson Oncology Centre between 1961 and 1986. The female:male ratio was 2.4:1 and the median age at presentation was 70 (range 38-92) years. All patients had a thyroid mass at presentation and the most common symptoms were dyspnoea, dyspnagia and dysphonia. Five patients had a total thyroidectomy and 28 partial thyroidectomy. Ninety five per cent of patients received external beam radiotherapy. Results show dyspnoea to be the only symptom strongly influencing survival. Total or partial thyroidectomy is associated with increased survival. This association is most marked for patients presenting without dyspnoea. Eighty per cent of patients responded to radiotherapy. (Author).

  19. Anaplastic thyroid carcinoma: 91 patients treated by surgery and radiotherapy

    International Nuclear Information System (INIS)

    Ninety-one patients with histologically proven anaplastic carcinoma of the thyroid were referred to the Beatson Oncology Centre between 1961 and 1986. The female:male ratio was 2.4:1 and the median age at presentation was 70 (range 38-92) years. All patients had a thyroid mass at presentation and the most common symptoms were dyspnoea, dyspnagia and dysphonia. Five patients had a total thyroidectomy and 28 partial thyroidectomy. Ninety five per cent of patients received external beam radiotherapy. Results show dyspnoea to be the only symptom strongly influencing survival. Total or partial thyroidectomy is associated with increased survival. This association is most marked for patients presenting without dyspnoea. Eighty per cent of patients responded to radiotherapy. (Author)

  20. Anaplastic thyroid carcinoma: 91 patients treated by surgery and radiotherapy.

    Science.gov (United States)

    Junor, E J; Paul, J; Reed, N S

    1992-04-01

    Ninety-one patients with histologically proven anaplastic carcinoma of the thyroid were referred to the Beatson Oncology Centre between 1961 and 1986. The female:male ratio was 2.4:1 and the median age at presentation was 70 (range 38-92) years. All patients had a thyroid mass at presentation and the most common symptoms were dyspnoea, dysphagia and dysphonia. Five patients had a total thyroidectomy and 28 partial thyroidectomy. Ninety five per cent of patients received external beam radiotherapy. Results show dyspnoea to be the only symptom strongly influencing survival. Total or partial thyroidectomy is associated with increased survival. This association is most marked for patients presenting without dyspnoea. Eighty per cent of patients responded to radiotherapy. PMID:1582515

  1. A SUMOylation Motif in Aurora-A: Implications in Spindle Dynamics and Oncogenesis

    Directory of Open Access Journals (Sweden)

    MarcosMalumbres

    2011-12-01

    Full Text Available Aurora-A is a serine/threonine kinase that plays critical roles in centrosome maturation, spindle dynamics and chromosome orientation and is frequently found overexpressed in human cancers. In this work, we show that Aurora-A interacts with the SUMO conjugating enzyme UBC9 and co-localizes with SUMO-1 in mitotic cells. Aurora-A can be SUMOylated in vitro and mutation in the highly conserved SUMOylation residue lysine 249 results in the induction of mitotic defects characterized by defective and multipolar spindles. The Aurora-AK249R mutant has normal kinase activity but it displays altered dynamics at the mitotic spindle. In addition, ectopic expression of the Aurora-AK249R mutant results in a significant increase in the susceptibility to malignant transformation induced by the Ras oncogene and an increased protection against apoptosis in tumor cells treated with mitotic poisons. These data suggest that modification by SUMO residues may control Aurora-A function at the spindle and suggest that deficient SUMOylation of this kinase may have relevant implications in tumor development or cancer therapy.

  2. The effect of magnesium on mitotic spindle formation in Schizosaccharomyces pombe.

    Science.gov (United States)

    Uz, Gulsen; Sarikaya, Aysegul Topal

    2016-01-01

    Magnesium (Mg2+), an essential ion for cells and biological systems, is involved in a variety of cellular processes, including the formation and breakdown of microtubules. The results of a previous investigation suggested that as cells grow the intracellular Mg2+ concentration falls, thereby stimulating formation of the mitotic spindle. In the present work, we used a Mg2+-deficient Schizosaccharomyces pombe strain GA2, in which two essential membrane Mg2+ transporter genes (homologs of ALR1 and ALR2 in Saccharomyces cerevisae) were deleted, and its parental strain Sp292, to examine the extent to which low Mg2+ concentrations can affect mitotic spindle formation. The two S. pombe strains were transformed with a plasmid carrying a GFP-α2-tubulin construct to fluorescently label microtubules. Using the free Mg2+-specific fluorescent probe mag-fura-2, we confirmed that intracellular free Mg2+ levels were lower in GA2 than in the parental strain. Defects in interphase microtubule organization, a lower percentage of mitotic spindle formation and a reduced mitotic index were also observed in the GA2 strain. Although there was interphase microtubule polymerization, the lower level of mitotic spindle formation in the Mg2+-deficient strain suggested a greater requirement for Mg2+ in this phenomenon than previously thought. PMID:27560651

  3. Genomic Landscape of poorly Differentiated and Anaplastic Thyroid Carcinoma.

    Science.gov (United States)

    Xu, Bin; Ghossein, Ronald

    2016-09-01

    Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are aggressive thyroid tumors associated with a high mortality rate of 38-57 % and almost 100 % respectively. Several recent studies utilizing next generation sequencing techniques have shed lights on the molecular pathogenesis of these tumors, providing evidence to support a stepwise tumoral progression from well-differentiated to poorly differentiated, and finally to anaplastic thyroid carcinomas. While BRAF (V600E) and RAS mutations remain the main drivers in aggressive thyroid carcinoma, PDTC and ATC gains additional mutations, e.g., TERT promoter mutation, TP53 mutation, as well as frequent alterations in PIK3CA-PTEN-AKT-mTOR pathway, SWI-SNF complex, histomethyltransferases, and mismatch repair genes. RAS-mutated PDTCs are commonly associated with a histologic phenotype defined by Turin proposal, high frequency of distant metastasis, high thyroid differentiation score, and a RAS-like gene expression profile, whereas BRAF-mutated PDTCs are usually defined solely by the Memorial Sloan Kettering Cancer Center (MSKCC) criteria with a propensity for nodal metastasis and are less differentiated with a BRAF-like expression signature. Such demarcation is largely lost in ATC which is characterized by genomic complexity, heavy mutation burden, and profound undifferentiation. Additionally, several molecular events, e.g., EIF1AX mutation, mutation burden, and chromosome 1q gain in PDTCs, as well as EIF1AX mutation, chromosome 13q loss, and 20q gains in ATCs, may serve as adverse prognostic markers predicting poor clinical outcome. PMID:27372303

  4. Small molecule inhibitor of formin homology 2 domains (SMIFH2 reveals the roles of the formin family of proteins in spindle assembly and asymmetric division in mouse oocytes.

    Directory of Open Access Journals (Sweden)

    Hak-Cheol Kim

    Full Text Available Dynamic actin reorganization is the main driving force for spindle migration and asymmetric cell division in mammalian oocytes. It has been reported that various actin nucleators including Formin-2 are involved in the polarization of the spindle and in asymmetric cell division. In mammals, the formin family is comprised of 15 proteins. However, their individual roles in spindle migration and/or asymmetric division have not been elucidated yet. In this study, we employed a newly developed inhibitor for formin family proteins, small molecule inhibitor of formin homology 2 domains (SMIFH2, to assess the functions of the formin family in mouse oocyte maturation. Treatment with SMIFH2 during in vitro maturation of mouse oocytes inhibited maturation by decreasing cytoplasmic and cortical actin levels. In addition, treatment with SMIFH2, especially at higher concentrations (500 μM, impaired the proper formation of meiotic spindles, indicating that formins play a role in meiotic spindle formation. Knockdown of the mDia2 formins caused a similar decrease in oocyte maturation and abnormal spindle morphology, mimicking the phenotype of SMIFH2-treated cells. Collectively, these results suggested that besides Formin-2, the other proteins of the formin, including mDia family play a role in asymmetric division and meiotic spindle formation in mammalian oocytes.

  5. A Protein Interaction Map of the Mitotic Spindle

    OpenAIRE

    Wong, Jonathan; Nakajima, Yuko; Westermann, Stefan; Shang, Ching; Kang, Jung-seog; Goodner, Crystal; Houshmand, Pantea; Fields, Stanley; Chan, Clarence S.M.; Drubin, David; Barnes, Georjana; Hazbun, Tony

    2007-01-01

    The mitotic spindle consists of a complex network of proteins that segregates chromosomes in eukaryotes. To strengthen our understanding of the molecular composition, organization, and regulation of the mitotic spindle, we performed a system-wide two-hybrid screen on 94 proteins implicated in spindle function in Saccharomyces cerevisiae. We report 604 predominantly novel interactions that were detected in multiple screens, involving 303 distinct prey proteins. We uncovered a pattern of extens...

  6. Role of fungal dynein in hyphal growth, microtubule organization, spindle pole body motility and nuclear migration.

    Science.gov (United States)

    Inoue, S; Turgeon, B G; Yoder, O C; Aist, J R

    1998-06-01

    Cytoplasmic dynein is a microtubule-associated motor protein with several putative subcellular functions. Sequencing of the gene (DHC1) for cytoplasmic dynein heavy chain of the filamentous ascomycete, Nectria haematococca, revealed a 4,349-codon open reading frame (interrupted by two introns) with four highly conserved P-loop motifs, typical of cytoplasmic dynein heavy chains. The predicted amino acid sequence is 78.0% identical to the cytoplasmic dynein heavy chain of Neurospora crassa, 70.2% identical to that of Aspergillus nidulans and 24.8% identical to that of Saccharomyces cerevisiae. The genomic copy of DHC1 in N. haematococca wild-type strain T213 was disrupted by inserting a selectable marker into the central motor domain. Mutants grew at 33% of the wild-type rate, forming dense compact colonies composed of spiral and highly branched hyphae. Major cytological phenotypes included (1) absence of aster-like arrays of cytoplasmic microtubules focused at the spindle pole bodies of post-mitotic and interphase nuclei, (2) limited post-mitotic nuclear migration, (3) lack of spindle pole body motility at interphase, (4) failure of spindle pole bodies to anchor interphase nuclei, (5) nonuniform distribution of interphase nuclei and (6) small or ephemeral Spitzenkörper at the apices of hyphal tip cells. Microtubule distribution in the apical region of tip cells of the mutant was essentially normal. The nonuniform distribution of nuclei in hyphae resulted primarily from a lack of both post-mitotic nuclear migration and anchoring of interphase nuclei by the spindle pole bodies. The results support the hypothesis that DHC1 is required for the motility and functions of spindle pole bodies, normal secretory vesicle transport to the hyphal apex and normal hyphal tip cell morphogenesis. PMID:9580563

  7. Long-term control of disseminated pleomorphic xanthoastrocytoma with anaplastic features by means of stereotactic irradiation

    OpenAIRE

    Koga, Tomoyuki; Morita, Akio; Maruyama, Keisuke; Tanaka, Minoru; Ino, Yasushi; Shibahara, Junji; Louis, David N.; Reifenberger, Guido; Itami, Jun; Hara, Ryusuke; SAITO, Nobuhito; Todo, Tomoki

    2009-01-01

    Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic neoplasm of the brain. Some PXAs are accompanied by anaplastic features and are difficult to manage because of frequent recurrences that lead to early death. No previous reports have demonstrated consistent efficacy of adjuvant radiotherapy or chemotherapy for this disease. We report a case of PXA with anaplastic features treated with stereotactic irradiation (STI) that resulted in long-term control of repeatedly recurring nodules throu...

  8. Cortical Anaplastic Ependymoma with Significant Desmoplasia: A Case Report and Literature Review

    OpenAIRE

    Alaa Eldin Elsharkawy; Raid Abuamona; Markus Bergmann; Shadi Salem; Evariste Gafumbegete; Ernst Röttger

    2013-01-01

    Ectopic brain anaplastic ependymomas with no connection to the ventricles are rare. We present a rare case of a 25-year-old male who presented with generalized convulsions. Computed tomography (CT), Magnetic Resonance Imaging (MRI), and magnetic resonance spectroscopy (MRS) showed characters of an intra- and extra-axial lesion. Intraoperatively, the lesion was a cortical solid mass that had no connections to the dura or to the ventricle. The histological diagnosis showed an anaplastic ependym...

  9. Focused Ultrasound Surgery for the Treatment of Recurrent Anaplastic Astrocytoma: A Preliminary Report

    Science.gov (United States)

    Park, Jung-Wuk; Jung, Shin; Jung, Tae-Young; Lee, Min-Cheol

    2006-05-01

    Anaplastic glioma is a highly aggressive tumor in the central nervous system. The conventional treatment for patients with anaplstic glioma consists of the combination of surgery, chemotherapy and radiotherapy. However, the effect of the currently available therapies is limited, and the prognosis is very poor in these patients. The purpose of this abstract is to introduce our preliminary experience of using focused ultrasound surgery (FUS) for the treatment of patients with recurrent anaplastic astrocytoma.

  10. Dynamic Localization of the Human Papillomavirus Type 11 Origin Binding Protein E2 through Mitosis While in Association with the Spindle Apparatus

    OpenAIRE

    Dao, Luan D.; Duffy, Aaron; Van Tine, Brian A.; Wu, Shwu-Yuan; Chiang, Cheng-Ming; Broker, Thomas R.; Chow, Louise T.

    2006-01-01

    Papillomaviral DNA replicates as extrachromosomal plasmids in squamous epithelium. Viral DNA must segregate equitably into daughter cells to persist in dividing basal/parabasal cells. We have previously reported that the viral origin binding protein E2 of human papillomavirus types 11 (HPV-11), 16, and 18 colocalized with the mitotic spindles. In this study, we show the localization of the HPV-11 E2 protein to be dynamic. It colocalized with the mitotic spindles during prophase and metaphase....

  11. Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas.

    Science.gov (United States)

    Boström, J; Meyer-Puttlitz, B; Wolter, M; Blaschke, B; Weber, R G; Lichter, P; Ichimura, K; Collins, V P; Reifenberger, G

    2001-08-01

    We investigated 67 meningothelial tumors (20 benign meningiomas, 34 atypical meningiomas, and 13 anaplastic meningiomas) for losses of genetic information from chromosome arms 1p and 9p, as well as for deletion, mutation, and expression of the tumor suppressor genes CDKN2A (p16(INKa)/MTS1), p14(ARF), CDKN2B (p15(INK4b)/MTS2) (all located at 9p21) and CDKN2C (1p32). Comparative genomic hybridization and microsatellite analysis showed losses on 1p in 11 anaplastic meningiomas (85%), 23 atypical meningiomas (68%), and 5 benign meningiomas (25%). One atypical meningioma with loss of heterozygosity on 1p carried a somatic CDKN2C mutation (c.202C>T: R68X). Losses on 9p were found in five anaplastic meningiomas (38%), six atypical meningiomas (18%), and one benign meningioma (5%). Six anaplastic meningiomas (46%) and one atypical meningioma (3%) showed homozygous deletions of the CDKN2A, p14(ARF), and CDKN2B genes. Two anaplastic meningiomas carried somatic point mutations in CDKN2A (c.262G>T: E88X and c.262G>A: E88K) and p14(ARF) (c.305G>T: G102V and c.305G>A: G102E). One anaplastic meningioma, three atypical meningiomas, and one benign meningioma without a demonstrated homozygous deletion or mutation of CDKN2A, p14(ARF), or CDKN2B lacked detectable transcripts from at least one of these genes. Hypermethylation of CDKN2A, p14(ARF), and CDKN2B could be demonstrated in one of these cases. Taken together, our results indicate that CDKN2C is rarely altered in meningiomas. However, the majority of anaplastic meningiomas either show homozygous deletions of CDKN2A, p14(ARF), and CDKN2B, mutations in CDKN2A and p14(ARF), or lack of expression of one or more of these genes. Thus, inactivation of the G(1)/S-phase cell-cycle checkpoint is an important aberration in anaplastic meningiomas. PMID:11485924

  12. v-Src causes delocalization of Mklp1, Aurora B, and INCENP from the spindle midzone during cytokinesis failure

    Energy Technology Data Exchange (ETDEWEB)

    Soeda, Shuhei [Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8675 (Japan); Nakayama, Yuji, E-mail: nakayama@mb.kyoto-phu.ac.jp [Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8675 (Japan); Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414 (Japan); Honda, Takuya; Aoki, Azumi; Tamura, Naoki; Abe, Kohei; Fukumoto, Yasunori [Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8675 (Japan); Yamaguchi, Naoto, E-mail: nyama@faculty.chiba-u.jp [Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8675 (Japan)

    2013-06-10

    Src-family tyrosine kinases are aberrantly activated in cancers, and this activation is associated with malignant tumor progression. v-Src, encoded by the v-src transforming gene of the Rous sarcoma virus, is a mutant variant of the cellular proto-oncogene c-Src. Although investigations with temperature sensitive mutants of v-Src have shown that v-Src induces many oncogenic processes, the effects on cell division are unknown. Here, we show that v-Src inhibits cellular proliferation of HCT116, HeLa S3 and NIH3T3 cells. Flow cytometry analysis indicated that inducible expression of v-Src results in an accumulation of 4N cells. Time-lapse analysis revealed that binucleation is induced through the inhibition of cytokinesis, a final step of cell division. The localization of Mklp1, which is essential for cytokinesis, to the spindle midzone is inhibited in v-Src-expressing cells. Intriguingly, Aurora B, which regulates Mklp1 localization at the midzone, is delocalized from the spindle midzone and the midbody but not from the metaphase chromosomes upon v-Src expression. Mklp2, which is responsible for the relocation of Aurora B from the metaphase chromosomes to the spindle midzone, is also lost from the spindle midzone. These results suggest that v-Src inhibits cytokinesis through the delocalization of Mklp1 and Aurora B from the spindle midzone, resulting in binucleation. -- Highlights: • v-Src inhibits cell proliferation of HCT116, HeLa S3 and NIH3T3 cells. • v-Src induces binucleation together with cytokinesis failure. • v-Src causes delocalization of Mklp1, Aurora B and INCENP from the spindle midzone.

  13. A bone metastases model of anaplastic thyroid carcinoma in athymic nude mice

    International Nuclear Information System (INIS)

    Anaplastic thyroid carcinoma (ATC), an aggressive form of thyroid cancer, represents less than 2% of all thyroid cancers. The survival of patients with ATC remains low especially when accompanied with bone metastasis. This study aims to establish a reproducible animal model of bone metastasis of ATC which may be useful for further research on novel treatment strategy. Eight 6-8 week old female athymic nude mice were randomly selected. ATC cell line ARO cells were injected into the left ventricular cavity of each mouse respectively. Each mouse was imaged using a dedicated small-animal PET/CT scanner after successful injection of [18F]-FDG under deep anesthesia. Pathological examination was carried out to confirm the bone metastases of ATC. Histopathology established ATC bone metastases in five nude mice’s tibia. Similarly, PET image displayed significantly increased radioactivity (P<0.01) in the established bone metastasis compared with the control normal tibia. Both micro-PET/CT and histomorphometric measurement confirmed the bone metastases model of ATC in nude mice by left ventricular cavity injection of ARO cell line. The bone metastases model of ATC will thus facilitate the understanding of its pathogenesis and aid in the development of novel therapies.

  14. Gem GTPase acts upstream Gmip/RhoA to regulate cortical actin remodeling and spindle positioning during early mitosis.

    Science.gov (United States)

    Andrieu, Guillaume; Quaranta, Muriel; Leprince, Corinne; Cuvillier, Olivier; Hatzoglou, Anastassia

    2014-11-01

    Gem is a small guanosine triphosphate (GTP)-binding protein within the Ras superfamily, involved in the regulation of voltage-gated calcium channel activity and cytoskeleton reorganization. Gem overexpression leads to stress fiber disruption, actin and cell shape remodeling and neurite elongation in interphase cells. In this study, we show that Gem plays a crucial role in the regulation of cortical actin cytoskeleton that undergoes active remodeling during mitosis. Ectopic expression of Gem leads to cortical actin disruption and spindle mispositioning during metaphase. The regulation of spindle positioning by Gem involves its downstream effector Gmip. Knockdown of Gmip rescued Gem-induced spindle phenotype, although both Gem and Gmip accumulated at the cell cortex. In addition, we implicated RhoA GTPase as an important effector of Gem/Gmip signaling. Inactivation of RhoA by overexpressing dominant-negative mutant prevented normal spindle positioning. Introduction of active RhoA rescued the actin and spindle positioning defects caused by Gem or Gmip overexpression. These findings demonstrate a new role of Gem/Gmip/RhoA signaling in cortical actin regulation during early mitotic stages. PMID:25173885

  15. Central Spindle Self-Organization and Cytokinesis in Artificially Activated Sea Urchin Eggs.

    Science.gov (United States)

    Henson, John H; Buckley, Mary W; Yeterian, Mesrob; Weeks, Richard M; Simerly, Calvin R; Shuster, Charles B

    2016-04-01

    The ability of microtubules of the mitotic apparatus to control the positioning and initiation of the cleavage furrow during cytokinesis was first established from studies on early echinoderm embryos. However, the identity of the microtubule population that imparts cytokinetic signaling is unclear. The two main--and not necessarily mutually exclusive--candidates are the central spindle and the astral rays. In the present study, we examined cytokinesis in ammonia-activated sea urchin eggs, which lack paternally derived centrosomes and undergo mitosis mediated by unusual anastral, bipolar mini-spindles. Live cell imaging and immunolabeling for microtubules and the centralspindlin constituent and kinesin-related protein, MKLP1, demonstrated that furrowing in ammonia-activated eggs was associated with aligned arrays of centralspindlin-linked, opposed bundles of antiparallel microtubules. These autonomous, zipper-like arrays were not associated with a mitotic apparatus, but did possess characteristics similar to the central spindle region of control, fertilized embryos. Our results highlight the self-organizing nature of the central spindle region and its ability to induce cytokinesis-like furrowing, even in the absence of a complete mitotic apparatus. PMID:27132131

  16. Concomitant binding of Afadin to LGN and F-actin directs planar spindle orientation.

    Science.gov (United States)

    Carminati, Manuel; Gallini, Sara; Pirovano, Laura; Alfieri, Andrea; Bisi, Sara; Mapelli, Marina

    2016-02-01

    Polarized epithelia form by oriented cell divisions in which the mitotic spindle aligns parallel to the epithelial plane. To orient the mitotic spindle, cortical cues trigger the recruitment of NuMA-dynein-based motors, which pull on astral microtubules via the protein LGN. We demonstrate that the junctional protein Afadin is required for spindle orientation and correct epithelial morphogenesis of Caco-2 cysts. Molecularly, Afadin binds directly and concomitantly to F-actin and to LGN. We determined the crystallographic structure of human Afadin in complex with LGN and show that it resembles the LGN-NuMA complex. In mitosis, Afadin is necessary for cortical accumulation of LGN and NuMA above the spindle poles, in an F-actin-dependent manner. Collectively, our results depict Afadin as a molecular hub governing the enrichment of LGN and NuMA at the cortex. To our knowledge, Afadin is the first-described mechanical anchor between dynein and cortical F-actin. PMID:26751642

  17. PLK1-dependent activation of LRRK1 regulates spindle orientation by phosphorylating CDK5RAP2.

    Science.gov (United States)

    Hanafusa, Hiroshi; Kedashiro, Shin; Tezuka, Motohiro; Funatsu, Motoki; Usami, Satoshi; Toyoshima, Fumiko; Matsumoto, Kunihiro

    2015-08-01

    Correct formation of the cell division axis requires the initial precise orientation of the mitotic spindle. Proper spindle orientation depends on centrosome maturation, and Polo-like kinase 1 (PLK1) is known to play a crucial role in this process. However, the molecular mechanisms that function downstream of PLK1 are not well understood. Here we show that LRRK1 is a PLK1 substrate that is phosphorylated on Ser 1790. PLK1 phosphorylation is required for CDK1-mediated activation of LRRK1 at the centrosomes, and this in turn regulates mitotic spindle orientation by nucleating the growth of astral microtubules from the centrosomes. Interestingly, LRRK1 in turn phosphorylates CDK5RAP2(Cep215), a human homologue of Drosophila Centrosomin (Cnn), in its γ-tubulin-binding motif, thus promoting the interaction of CDK5RAP2 with γ-tubulin. LRRK1 phosphorylation of CDK5RAP2 Ser 140 is necessary for CDK5RAP2-dependent microtubule nucleation. Thus, our findings provide evidence that LRRK1 regulates mitotic spindle orientation downstream of PLK1 through CDK5RAP2-dependent centrosome maturation. PMID:26192437

  18. Anastral spindle assembly and γ-tubulin in Drosophila oocytes

    Directory of Open Access Journals (Sweden)

    Hallen Mark A

    2011-01-01

    Full Text Available Abstract Background Anastral spindles assemble by a mechanism that involves microtubule nucleation and growth from chromatin. It is still uncertain whether γ-tubulin, a microtubule nucleator essential for mitotic spindle assembly and maintenance, plays a role. Not only is the requirement for γ-tubulin to form anastral Drosophila oocyte meiosis I spindles controversial, but its presence in oocyte meiosis I spindles has not been demonstrated and is uncertain. Results We show, for the first time, using a bright GFP fusion protein and live imaging, that the Drosophila maternally-expressed γTub37C is present at low levels in oocyte meiosis I spindles. Despite this, we find that formation of bipolar meiosis I spindles does not require functional γTub37C, extending previous findings by others. Fluorescence photobleaching assays show rapid recovery of γTub37C in the meiosis I spindle, similar to the cytoplasm, indicating weak binding by γTub37C to spindles, and fits of a new, potentially more accurate model for fluorescence recovery yield kinetic parameters consistent with transient, diffusional binding. Conclusions The FRAP results, together with its mutant effects late in meiosis I, indicate that γTub37C may perform a role subsequent to metaphase I, rather than nucleating microtubules for meiosis I spindle formation. Weak binding to the meiosis I spindle could stabilize pre-existing microtubules or position γ-tubulin for function during meiosis II spindle assembly, which follows rapidly upon oocyte activation and completion of the meiosis I division.

  19. 131I therapy for hyperthyroidism and consequent appearing of anaplastic carcinoma of the thyroid: simple case-report or real pathophysiologic link?

    Directory of Open Access Journals (Sweden)

    G. Scanelli

    2013-05-01

    Full Text Available BACKGROUND 131I is usually employed for the therapy of hyperfunctioning thyroid diseases. This β-emitting radioisotope acts releasing its radiations in small tissue volumes, but it is mandatory to consider, also for the small doses, the carcinogenic risk, well documented with the high 131I dosages used to cure differentiated thyroid cancers. METHODS We describe a case of anaplastic thyroid carcinoma appeared 4 years after therapy with 131I for Graves’ disease. The patient was treated both surgically and with thyonamides for Graves’ disease 20 years before; thereafter she underwent simple nephrectomy owing to Grawitz disease. After some years of well being, she was treated with 131I for a relapse of Graves’ disease. Four years later, she was treated with interleukin-2 and TNF-α, owing to distant metastases (pancreas, liver and lung of Grawitz cancer. Some months later, because of a rapid enlargement of the thyroid gland, she was thyroidectomized and anaplastic thyroid cancer was histologically documented. DISCUSSION AND CONCLUSIONS It is very difficult to investigate the possible transformation of a benign thyroid lesion to a malignant one, and data from the literature are conflicting. Fractioned doses of 131I are known to induce less cancers than high doses: they allow DNA to repair. Nevertheless, in patients with altered or non valid genetic repair’s mechanisms (i.e. patients with p53 mutations and, for this reason, prone to develop cancers, even low doses of 131I can induce carcinogenetic effects. In a patient with a history of cancer, who subsequently develops hyperthyroidism, even low doses of 131I can induce anaplastic thyroid cancer; in these subjects, therefore, other treatments than 131I could be preferred for the therapy of Graves’ disease. In our peculiar case, moreover, some studies have noteworthy demonstrated that certain cytokines (IL-1, TGF-β1 e TNF-α can, rather than inhibit, induce anaplastic thyroid cancer cells

  20. Short exposure to paclitaxel induces multipolar spindle formation and aneuploidy through promotion of acentrosomal pole assembly

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Paclitaxel is a widely used microtubule drug and cancer medicine. Here we report that by short exposure to paclitaxel at a low dose, multipolar spindles were induced in mitotic cells without centrosome amplification. Both TPX2 depletion and Aurora-A overexpression antagonized the multipolarity. Live cell imaging showed that some paclitaxel-treated cells accomplished multipolar cell division and a portion of the daughter cells went on to the next round of mitosis. The surviving cells grew into clones with varied genome content. The results indicated that an aneuploidy population could be induced by short exposure to paclitaxel at a low dose, implicating potential side effects of paclitaxel.

  1. Testing for anaplastic lymphoma kinase rearrangement to target crizotinib therapy: oncology, pathology and health economic perspectives.

    Science.gov (United States)

    Lee, James A; Bubendorf, Lukas; Stahel, Rolf; Peters, Solange

    2013-05-01

    Crizotinib is a first-in-class oral anaplastic lymphoma kinase (ALK) inhibitor targeting ALK-rearranged non-small-cell lung cancer. The therapy was approved by the US FDA in August 2011 and received conditional marketing approval by the European Commission in October 2012 for advanced non-small-cell lung cancer. A break-apart FISH-based assay was jointly approved with crizotinib by the FDA. This assay and an immunohistochemistry assay that uses a D5F3 rabbit monoclonal primary antibody were also approved for marketing in Europe in October 2012. While ALK rearrangement has relatively low prevalence, a clinical benefit is exhibited in more than 85% of patients with median progression-free survival of 8-10 months. In this article, the authors summarize the therapy and alternative test strategies for identifying patients who are likely to respond to therapy, including key issues for effective and efficient testing. The key economic considerations regarding the joint companion diagnostic and therapy are also presented. Given the observed clinical benefit and relatively high cost of crizotinib therapy, companion diagnostics should be evaluated relative to response to therapy versus correlation alone whenever possible, and both high inter-rater reliability and external quality assessment programs are warranted. PMID:23617353

  2. IL-6 and mouse oocyte spindle.

    Directory of Open Access Journals (Sweden)

    Jashoman Banerjee

    Full Text Available Interleukin 6 (IL-6 is considered a major indicator of the acute-phase inflammatory response. Endometriosis and pelvic inflammation, diseases that manifest elevated levels of IL-6, are commonly associated with higher infertility. However, the mechanistic link between elevated levels of IL-6 and poor oocyte quality is still unclear. In this work, we explored the direct role of this cytokine as a possible mediator for impaired oocyte spindle and chromosomal structure, which is a critical hurdle in the management of infertility. Metaphase-II mouse oocytes were exposed to recombinant mouse IL-6 (50, 100 and 200 ng/mL for 30 minutes and subjected to indirect immunofluorescent staining to identify alterations in the microtubule and chromosomal alignment compared to untreated controls. The deterioration in microtubule and chromosomal alignment were evaluated utilizing both fluorescence and confocal microscopy, and were quantitated with a previously reported scoring system. Our results showed that IL-6 caused a dose-dependent deterioration in microtubule and chromosomal alignment in the treated oocytes as compared to the untreated group. Indeed, IL-6 at a concentration as low as 50 ng/mL caused deterioration in the spindle structure in 60% of the oocytes, which increased significantly (P<0.0001 as IL-6 concentration was increased. In conclusion, elevated levels of IL-6 associated with endometriosis and pelvic inflammation may reduce the fertilizing capacity of human oocyte through a mechanism that involves impairment of the microtubule and chromosomal structure.

  3. Tumor-associated macrophages (TAMs form an interconnected cellular supportive network in anaplastic thyroid carcinoma.

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    Bernard Caillou

    Full Text Available BACKGROUND: A relationship between the increased density of tumor-associated macrophages (TAMs and decreased survival was recently reported in thyroid cancer patients. Among these tumors, anaplastic thyroid cancer (ATC is one of the most aggressive solid tumors in humans. TAMs (type M2 have been recognized as promoting tumor growth. The purpose of our study was to analyze with immunohistochemistry the presence of TAMs in a series of 27 ATC. METHODOLOGY/PRINCIPAL FINDINGS: Several macrophages markers such as NADPH oxidase complex NOX2-p22phox, CD163 and CD 68 were used. Immunostainings showed that TAMs represent more than 50% of nucleated cells in all ATCs. Moreover, these markers allowed the identification of elongated thin ramified cytoplasmic extensions, bestowing a "microglia-like" appearance on these cells which we termed "Ramified TAMs" (RTAMs. In contrast, cancer cells were totally negative. Cellular stroma was highly simplified since apart from cancer cells and blood vessels, RTAMs were the only other cellular component. RTAMs were evenly distributed and intermingled with cancer cells, and were in direct contact with other RTAMs via their ramifications. Moreover, RTAMs displayed strong immunostaining for connexin Cx43. Long chains of interconnected RTAMs arose from perivascular clusters and were dispersed within the tumor parenchyma. When expressed, the glucose transporter Glut1 was found in RTAMs and blood vessels, but rarely in cancer cells. CONCLUSION: ATCs display a very dense network of interconnected RTAMs in direct contact with intermingled cancer cells. To our knowledge this is the first time that such a network is described in a malignant tumor. This network was found in all our studied cases and appeared specific to ATC, since it was not found in differentiated thyroid cancers specimens. Taken together, these results suggest that RTAMs network is directly related to the aggressiveness of the disease via metabolic and trophic

  4. Sleep spindles and intelligence: evidence for a sexual dimorphism

    NARCIS (Netherlands)

    Ujma, P.P.; Konrad, B.N.; Genzel, L.; Bleifuss, A.; Simor, P.; Potari, A.; Kormendi, J.; Gombos, F.; Steiger, A.; Bodizs, R.; Dresler, M.

    2014-01-01

    Sleep spindles are thalamocortical oscillations in nonrapid eye movement sleep, which play an important role in sleep-related neuroplasticity and offline information processing. Sleep spindle features are stable within and vary between individuals, with, for example, females having a higher number o

  5. Sleep Spindles as Biomarker for Early Detection of Neurodegenerative Disorders

    DEFF Research Database (Denmark)

    2015-01-01

    The present invention relates to the use of sleep spindles as a novel biomarker for early diagnosis of synucleinopathies, in particular Parkinson's disease (PD). The method is based on automatic detection of sleep spindles. The method may be combined with measurements of one or more further...

  6. In-silico modeling of the mitotic spindle assembly checkpoint.

    Directory of Open Access Journals (Sweden)

    Bashar Ibrahim

    Full Text Available BACKGROUND: The Mitotic Spindle Assembly Checkpoint ((MSAC is an evolutionary conserved mechanism that ensures the correct segregation of chromosomes by restraining cell cycle progression from entering anaphase until all chromosomes have made proper bipolar attachments to the mitotic spindle. Its malfunction can lead to cancer. PRINCIPLE FINDINGS: We have constructed and validated for the human (MSAC mechanism an in silico dynamical model, integrating 11 proteins and complexes. The model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. Originating from the biochemical reactions for the underlying molecular processes, non-linear ordinary differential equations for the concentrations of 11 proteins and complexes of the (MSAC are derived. Most of the kinetic constants are taken from literature, the remaining four unknown parameters are derived by an evolutionary optimization procedure for an objective function describing the dynamics of the APC:Cdc20 complex. MCC:APC dissociation is described by two alternatives, namely the "Dissociation" and the "Convey" model variants. The attachment of the kinetochore to microtubuli is simulated by a switching parameter silencing those reactions which are stopped by the attachment. For both, the Dissociation and the Convey variants, we compare two different scenarios concerning the microtubule attachment dependent control of the dissociation reaction. Our model is validated by simulation of ten perturbation experiments. CONCLUSION: Only in the controlled case, our models show (MSAC behaviour at meta- to anaphase transition in agreement with experimental observations. Our simulations revealed that for (MSAC activation, Cdc20 is not fully sequestered; instead APC is inhibited by MCC binding.

  7. Sleep spindles predict stress-related increases in sleep disturbances

    Directory of Open Access Journals (Sweden)

    Thien Thanh eDang-Vu

    2015-02-01

    Full Text Available Background and Aim: Predisposing factors place certain individuals at higher risk for insomnia, especially in the presence of precipitating conditions such as stressful life events. Sleep spindles have been shown to play an important role in the preservation of sleep continuity. Lower spindle density might thus constitute an objective predisposing factor for sleep reactivity to stress. The aim of this study was therefore to evaluate the relationship between baseline sleep spindle density and the prospective change in insomnia symptoms in response to a standardized academic stressor. Methods: 12 healthy students had a polysomnography (PSG recording during a period of lower stress at the beginning of the academic semester, along with an assessment of insomnia complaints using the Insomnia Severity Index (ISI. They completed a second ISI assessment at the end of the semester, a period coinciding with the week prior to final examinations and thus higher stress. Spindle density, amplitude, duration and frequency, as well as sigma power were computed from C4-O2 electroencephalography (EEG derivation during stages N2-N3 of non-rapid-eye-movement (NREM sleep, across the whole night and for each NREM sleep period. To test for the relationship between spindle density and changes in insomnia symptoms in response to academic stress, spindle measurements at baseline were correlated with changes in ISI across the academic semester.Results: Spindle density (as well as spindle amplitude and sigma power, particularly during the first NREM sleep period, negatively correlated with changes in ISI (p < 0.05. Conclusion: Lower spindle activity, especially at the beginning of the night, prospectively predicted larger increases in insomnia symptoms in response to stress. This result indicates that individual differences in sleep spindle activity contribute to the differential vulnerability to sleep disturbances in the face of precipitating factors.

  8. Mitotic Spindle Asymmetry: A Wnt/PCP-Regulated Mechanism Generating Asymmetrical Division in Cortical Precursors

    Directory of Open Access Journals (Sweden)

    Delphine Delaunay

    2014-01-01

    Full Text Available The regulation of asymmetric cell division (ACD during corticogenesis is incompletely understood. We document that spindle-size asymmetry (SSA between the two poles occurs during corticogenesis and parallels ACD. SSA appears at metaphase and is maintained throughout division, and we show it is necessary for proper neurogenesis. Imaging of spindle behavior and division outcome reveals that neurons preferentially arise from the larger-spindle pole. Mechanistically, SSA magnitude is controlled by Wnt7a and Vangl2, both members of the Wnt/planar cell polarity (PCP-signaling pathway, and relayed to the cell cortex by P-ERM proteins. In vivo, Vangl2 and P-ERM downregulation promotes early cell-cycle exit and prevents the proper generation of late-born neurons. Thus, SSA is a core component of ACD that is conserved in invertebrates and vertebrates and plays a key role in the tight spatiotemporal control of self-renewal and differentiation during mammalian corticogenesis.

  9. Anaplastic carcinoma of the pancreas: Is there a role for palliative surgical procedure?

    Directory of Open Access Journals (Sweden)

    Rajan Vaithianathan

    2014-01-01

    Full Text Available Anaplastic carcinoma (AC or undifferentiated carcinoma of the pancreas is a rare variant among the malignant pancreatic neoplasms. These tumors have a poor prognosis with survival measured in months. The role of surgical palliation to improve the quality of life is not well defined in these patients. We report a case of AC of pancreas in a 65-year-old male patient. Patient had upper abdominal pain with frequent bilious vomiting. Computed tomography scan of the abdomen showed a mass in the body of pancreas with possible infiltration of duodenojejunal flexure (DJF. Laparotomy revealed an inoperable mass with posterior fixity and involvement of the DJF. Patient underwent a palliative duodenojejunostomy. Tissue biopsy from the tumor showed pleomorphic type AC with giant cells. Patient had good symptomatic relief from profuse vomiting and progressed well at follow up. AC of pancreas is a rare and aggressive malignancy with dismal outlook. If obstructive symptoms are present due to duodenal involvement, a palliative bypass may be a worthwhile surgical option in selected cases.

  10. Anaplastic Lymphoma Kinase Rearrangement in Digestive Tract Cancer: Implication for Targeted Therapy in Chinese Population.

    Directory of Open Access Journals (Sweden)

    Jianming Ying

    Full Text Available Anaplastic lymphoma kinase (ALK rearrangements define a subgroup of lung cancer which is eligible to targeted kinase inhibition. The aim of this study is to observe the incidence rate of ALK fusion in a large cohort of Chinese digestive tract cancer patients.Tissue microarray (TMA was constructed from 808 digestive tract cancer cases, including 169 esophageal squamous cell carcinoma, 182 gastric cancer and 457 colorectal cancer (CRC cases. We tested all cases for ALK expression via a fully automated immunohistochemistry (IHC assay. The IHC-positive cases were subjected to fluorescence in situ hybridization (FISH, real-time polymerase chain reaction (qRT-PCR, target gene enrichment and sequencing for confirmation of ALK gene rearrangement and discovery of novel fusion partner.Among the tested cases, 2 (0.44% CRC cases showed positive both by IHC and FISH. By qRT-PCR, EML4-ALK fusion was found in one IHC-positive CRC case. In another IHC-positive CRC case, target gene enrichment and sequencing revealed ALK was fused to a novel partner, spectrin beta non-erythrocytic 1 (SPTBN1. One gastric cancer case showed partially positive IHC result, but no fusion was found by FISH and gene sequencing.The incidence rate of ALK gene fusion in Chinese CRC patients was 0.44%,but not detectable in gastric and esophageal cancers. The novel SPTBN1 -ALK fusion, together with other ALK fusion genes, may become a potential target for anti-ALK therapy.

  11. Polyglutamylated Tubulin Binding Protein C1orf96/CSAP Is Involved in Microtubule Stabilization in Mitotic Spindles

    Science.gov (United States)

    Ohta, Shinya; Hamada, Mayako; Sato, Nobuko; Toramoto, Iyo

    2015-01-01

    The centrosome-associated C1orf96/Centriole, Cilia and Spindle-Associated Protein (CSAP) targets polyglutamylated tubulin in mitotic microtubules (MTs). Loss of CSAP causes critical defects in brain development; however, it is unclear how CSAP association with MTs affects mitosis progression. In this study, we explored the molecular mechanisms of the interaction of CSAP with mitotic spindles. Loss of CSAP caused MT instability in mitotic spindles and resulted in mislocalization of Nuclear protein that associates with the Mitotic Apparatus (NuMA), with defective MT dynamics. Thus, CSAP overload in the spindles caused extensive MT stabilization and recruitment of NuMA. Moreover, MT stabilization by CSAP led to high levels of polyglutamylation on MTs. MT depolymerization by cold or nocodazole treatment was inhibited by CSAP binding. Live-cell imaging analysis suggested that CSAP-dependent MT-stabilization led to centrosome-free MT aster formation immediately upon nuclear envelope breakdown without γ-tubulin. We therefore propose that CSAP associates with MTs around centrosomes to stabilize MTs during mitosis, ensuring proper bipolar spindle formation and maintenance. PMID:26562023

  12. Topography of age-related changes in sleep spindles.

    Science.gov (United States)

    Martin, Nicolas; Lafortune, Marjolaine; Godbout, Jonathan; Barakat, Marc; Robillard, Rebecca; Poirier, Gaétan; Bastien, Célyne; Carrier, Julie

    2013-02-01

    Aging induces multiple changes to sleep spindles, which may hinder their alleged functional role in memory and sleep protection mechanisms. Brain aging in specific cortical regions could affect the neural networks underlying spindle generation, yet the topography of these age-related changes is currently unknown. In the present study, we analyzed spindle characteristics in 114 healthy volunteers aged between 20 and 73 years over 5 anteroposterior electroencephalography scalp derivations. Spindle density, amplitude, and duration were higher in young subjects than in middle-aged and elderly subjects in all derivations, but the topography of age effects differed drastically. Age-related decline in density and amplitude was more prominent in anterior derivations, whereas duration showed a posterior prominence. Age groups did not differ in all-night spindle frequency for any derivation. These results show that age-related changes in sleep spindles follow distinct topographical patterns that are specific to each spindle characteristic. This topographical specificity may provide a useful biomarker to localize age-sensitive changes in underlying neural systems during normal and pathological aging. PMID:22809452

  13. F-actin asymmetry and the endoplasmic reticulum-associated TCC-1 protein contribute to stereotypic spindle movements in the Caenorhabditis elegans embryo.

    Science.gov (United States)

    Berends, Christian W H; Muñoz, Javier; Portegijs, Vincent; Schmidt, Ruben; Grigoriev, Ilya; Boxem, Mike; Akhmanova, Anna; Heck, Albert J R; van den Heuvel, Sander

    2013-07-01

    The microtubule spindle apparatus dictates the plane of cell cleavage in animal cells. During development, dividing cells control the position of the spindle to determine the size, location, and fate of daughter cells. Spindle positioning depends on pulling forces that act between the cell periphery and astral microtubules. This involves dynein recruitment to the cell cortex by a heterotrimeric G-protein α subunit in complex with a TPR-GoLoco motif protein (GPR-1/2, Pins, LGN) and coiled-coil protein (LIN-5, Mud, NuMA). In this study, we searched for additional factors that contribute to spindle positioning in the one-cell Caenorhabditis elegans embryo. We show that cortical actin is not needed for Gα-GPR-LIN-5 localization and pulling force generation. Instead, actin accumulation in the anterior actually reduces pulling forces, possibly by increasing cortical rigidity. Examining membrane-associated proteins that copurified with GOA-1 Gα, we found that the transmembrane and coiled-coil domain protein 1 (TCC-1) contributes to proper spindle movements. TCC-1 localizes to the endoplasmic reticulum membrane and interacts with UNC-116 kinesin-1 heavy chain in yeast two-hybrid assays. RNA interference of tcc-1 and unc-116 causes similar defects in meiotic spindle positioning, supporting the concept of TCC-1 acting with kinesin-1 in vivo. These results emphasize the contribution of membrane-associated and cortical proteins other than Gα-GPR-LIN-5 in balancing the pulling forces that position the spindle during asymmetric cell division. PMID:23699393

  14. Sleep spindling and fluid intelligence across adolescent development: sex matters

    Directory of Open Access Journals (Sweden)

    Róbert eBódizs

    2014-11-01

    Full Text Available Evidence supports the intricate relationship between sleep electroencephalogram (EEG spindling and cognitive abilities in children and adults. Although sleep EEG changes during adolescence index fundamental brain reorganization, a detailed analysis of sleep spindling and the spindle-intelligence relationship was not yet provided for adolescents. Therefore, adolescent development of sleep spindle oscillations were studied in a home polysomnographic study focusing on the effects of chronological age and developmentally acquired overall mental efficiency (fluid IQ with sex as a potential modulating factor. Subjects were 24 healthy adolescents (12 males with an age range of 15–22 years (mean: 18 years and fluid IQ of 91-126 (mean: 104.12, Raven Progressive Matrices Test. Slow spindles (SSs and fast spindles (FSs were analyzed in 21 EEG derivations by using the individual adjustment method. A significant age-dependent increase in average FS density (r = .57; p = .005 was found. Moreover, fluid IQ correlated with FS density (r = .43; p = .04 and amplitude (r = .41; p = .049. The latter effects were entirely driven by particularly reliable FS-IQ correlations in females [r = .80 (p = .002 and r = .67 (p = .012, for density and amplitude, respectively]. Region-specific analyses revealed that these correlations peak in the fronto-central regions. The control of the age-dependence of FS measures and IQ scores did not considerably reduce the spindle-IQ correlations with respect to FS density. The only positive spindle-index of fluid IQ in males turned out to be the frequency of FSs (r = .60, p = .04. Increases in FS density during adolescence may index reshaped structural connectivity related to white matter maturation in the late developing human brain. The continued development over this age range of cognitive functions is indexed by specific measures of sleep spindling unravelling gender differences in adolescent brain maturation and perhaps cognitive

  15. Microcystin-LR induces mitotic spindle assembly disorders in Vicia faba by protein phosphatase inhibition and not reactive oxygen species induction.

    Science.gov (United States)

    Garda, Tamás; Kónya, Zoltán; Tándor, Ildikó; Beyer, Dániel; Vasas, Gábor; Erdődi, Ferenc; Vereb, György; Papp, Georgina; Riba, Milán; M-Hamvas, Márta; Máthé, Csaba

    2016-07-20

    We aimed to reveal the mechanisms of mitotic spindle anomalies induced by microcystin-LR (MCY-LR), a cyanobacterial toxin in Vicia faba, a well-known model in plant cell and molecular biology. MCY-LR inhibits type 1 and 2A phosphoserine/threonine specific protein phosphatases (PP1 and PP2A) and induces reactive oxygen species (ROS) formation. The cytoskeleton is one of the main targets of the cyanotoxin during cytopathogenesis. Histochemical-immunohistochemical and biochemical methods were used. A significant number of MCY-LR induced spindle alterations are described for the first time. Disrupted, multipolar spindles and missing kinetochore fibers were detected both in metaphase and anaphase cells. Additional polar microtubule (MT) bundles, hyperbundling of spindle MTs, monopolar spindles, C-S- shaped, additional and asymmetric spindles were detected in metaphase, while midplane kinetochore fibers were detected in anaphase cells only. Several spindle anomalies induced mitotic disorders, i.e. they occurred concomitantly with altered sister chromatid separation. Alterations were dependent on the MCY-LR dose and exposure time. Under long-term (2 and mainly 6 days') exposure they were detected in the concentration range of 0.1-20μgmL(-1) MCY-LR that inhibited PP1 and PP2A significantly without significant ROS induction. Elevated peroxidase/catalase activities indicated that MCY-LR treated V. faba plants showed efficient defense against oxidative stress. Thus, although the elevation of ROS is known to induce cytoskeletal aberrations in general, this study shows that long-term protein phosphatase inhibition is the primary cause of MCY-LR induced spindle disorders. PMID:27186862

  16. A Single-phase Spindle Motor Design for DVD Application

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    A. single phase brushless spindle motor with innovative design has been deyeloped for application in a DVD drive. The methods used to reduce the cogging torque and to improve the dynamic performance of this new design motor are proposed in this paper. The single phase brushless spindle motor is usually applied for cooling fan, pump and blower before the performance is improved by the reengineering process. The stator configuration and the drive circuit have been remodeled in order to meet the requirements of the spindle motor used in the DVD applications.

  17. 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

    Science.gov (United States)

    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

  18. Uncovering the Molecular Machinery of the Human Spindle-An Integration of Wet and Dry Systems Biology

    DEFF Research Database (Denmark)

    Rojas, Ana M.; Santamaria, Anna; Malik, Rainer;

    2012-01-01

    The mitotic spindle is an essential molecular machine involved in cell division, whose composition has been studied extensively by detailed cellular biology, high-throughput proteomics, and RNA interference experiments. However, because of its dynamic organization and complex regulation it is dif...

  19. Mad2 binding to Mad1 and Cdc20, rather than oligomerization, is required for the spindle checkpoint

    DEFF Research Database (Denmark)

    Sironi, L; Melixetian, M; Faretta, M;

    2001-01-01

    Mad2 is a key component of the spindle checkpoint, a device that controls the fidelity of chromosome segregation in mitosis. The ability of Mad2 to form oligomers in vitro has been correlated with its ability to block the cell cycle upon injection into Xenopus embryos. Here we show that Mad2 forms...

  20. Meningiomas with Rhabdoid or Papillary Components : Prognosis and Comparison with Anaplastic Meningiomas.

    Science.gov (United States)

    Kim, Jeong-Kwon; Jung, Tae-Young; Jung, Shin; Lee, Kyung-Hwa; Kim, Seul-Kee; Lee, Eun Jung

    2016-07-01

    Papillary and rhabdoid meningiomas are pathologically World Health Organization (WHO) grade III. Any correlation between clinical prognosis and pathologic component is not clear. We analyzed the prognoses of patients with meningiomas with a rhabdoid or papillary component compared to those of patients with anaplastic meningiomas. From 1994 to June 2013, 14 anaplastic meningiomas, 6 meningiomas with a rhabdoid component, and 5 meningiomas with papillary component were pathologically diagnosed. We analyzed magnetic resonance imaging (MRI) findings, extent of removal, adjuvant treatment, progression-free survival (PFS), overall survival (OS), and pathologic features of 14 anaplastic meningiomas (group A), 5 meningiomas with a predominant (≥50%) papillary or rhabdoid component (group B1), and 6 meningiomas without a predominant (aggressive behavior than group B2 tumors. In group B2 cases, the pathologic findings of non-rhabdoid/papillary portion could be considered for further adjuvant treatment. PMID:27446516

  1. The Aurora B kinase in chromosome biorientation and spindle checkpoint signalling

    Directory of Open Access Journals (Sweden)

    Veronica eKrenn

    2015-10-01

    Full Text Available Aurora B, a member of the Aurora family of serine/threonine protein kinases, is a key player in chromosome segregation. As part of a macromolecular complex known as the chromosome passenger complex, Aurora B concentrates early during mitosis in the proximity of centromeres and kinetochores, the sites of attachment of chromosomes to spindle microtubules. There, it contributes to a number of processes that impart fidelity to cell division, including kinetochore stabilization, kinetochore-microtubule attachment, and the regulation of a surveillance mechanism named the spindle assembly checkpoint. In the regulation of these processes, Aurora B is the fulcrum of a remarkably complex network of interactions that feed back on its localization and activation state. In this review we discuss the multiple roles of Aurora B during mitosis, focusing in particular on its role at centromeres and kinetochores. Many details of the network of interactions at these locations remain poorly understood, and we focus here on several crucial outstanding questions.

  2. Meiosis I in Xenopus oocytes is not error-prone despite lacking spindle assembly checkpoint.

    Science.gov (United States)

    Liu, Dandan; Shao, Hua; Wang, Hongmei; Liu, X Johné

    2014-01-01

    The spindle assembly checkpoint, SAC, is a surveillance mechanism to control the onset of anaphase during cell division. SAC prevents anaphase initiation until all chromosome pairs have achieved bipolar attachment and aligned at the metaphase plate of the spindle. In doing so, SAC is thought to be the key mechanism to prevent chromosome nondisjunction in mitosis and meiosis. We have recently demonstrated that Xenopus oocyte meiosis lacks SAC control. This prompted the question of whether Xenopus oocyte meiosis is particularly error-prone. In this study, we have karyotyped a total of 313 Xenopus eggs following in vitro oocyte maturation. We found no hyperploid egg, out of 204 metaphase II eggs with countable chromosome spreads. Therefore, chromosome nondisjunction is very rare during Xenopus oocyte meiosis I, despite the lack of SAC. PMID:24646611

  3. The Mother Centriole Appendage Protein Cenexin Modulates Lumen Formation through Spindle Orientation.

    Science.gov (United States)

    Hung, Hui-Fang; Hehnly, Heidi; Doxsey, Stephen

    2016-03-21

    Establishing apical-basal polarity is instrumental in the functional shaping of a solitary lumen within an acinus. By exploiting micropatterned slides, wound healing assays, and three-dimensional culture systems, we identified a mother centriole subdistal appendage protein, cenexin, as a critical player in symmetric lumen expansion through the control of microtubule organization. In this regard, cenexin was required for both centrosome positioning in interphase cells and proper spindle orientation during mitosis. In contrast, the essential mother centriole distal appendage protein CEP164 did not play a role in either process, demonstrating the specificity of subdistal appendages for these events. Importantly, upon closer examination we found that cenexin depletion decreased astral microtubule length, disrupted astral microtubule minus-end organization, and increased levels of the polarity protein NuMA at the cell cortex. Interestingly, spindle misorientation and NuMA mislocalization were reversed by treatment with a low dose of the microtubule-stabilizing agent paclitaxel. Taken together, these results suggest that cenexin modulates microtubule organization and stability to mediate spindle orientation. PMID:26948879

  4. Immunoexpression of TTF-1 and Ki-67 in a coexistent anaplastic and follicular thyroid cancer with rare long-life surviving.

    Directory of Open Access Journals (Sweden)

    Jerzy Sowinski

    2009-01-01

    Full Text Available We report the immunohistochemical diagnosis, including TTF-1 (thyroid transcription factor 1 and Ki-67, of a rare mixed thyroid neoplasm composed of minimally invasive well differentiated follicular areas and highly aggressive undifferentiated anaplastic areas. A 75 old female presented to our clinic with a rapidly growing neck mass. Considering the dynamics of the disease and the multiple challenges presented by the patient: advanced age, tumor size, history of a longstanding goiter we decided to transfer her to the department of surgery. The intraoperative findings were an enlarged right lobe with tracheal and surrounding tissues infiltration. Total thyroidectomy, radical neck lymph nodes dissection and tracheostomy were performed. The histopathological and immunohistochemical examination revealed a coexistent anaplastic and follicular thyroid carcinoma. The proliferation index Ki-67, a cell proliferation marker, was found to be significantly higher in the anaplastic areas (30 +/- 5% in the comparison with the follicular areas (2 +/- 1%. The evaluation of the thyroid transcription factor 1 (TTF-1 expression revealed a correlation with the tumor cells aggressiveness accordingly to the cancer areas. After a radical surgery an external adjuvant radiation was applied. The patient is alive and more than five years after diagnosis she presented an increase of the serum thyroglobulin level suggesting, probably, a recurrence of the follicular form of the cancer. According to our survey we suggest that in thyroid cancers TTF-1 and Ki-67 could provides useful information on the differentiation activities of thyroid tumor cells and may be helpful to distinguish well differentiated and undifferentiated areas in a mixed thyroid cancer.

  5. A Novel Pathway that Coordinates Mitotic Exit with Spindle Position

    OpenAIRE

    Nelson, Scott A.; Cooper, John A.

    2007-01-01

    In budding yeast, the spindle position checkpoint (SPC) delays mitotic exit until the mitotic spindle moves into the neck between the mother and bud. This checkpoint works by inhibiting the mitotic exit network (MEN), a signaling cascade initiated and controlled by Tem1, a small GTPase. Tem1 is regulated by a putative guanine exchange factor, Lte1, but the function and regulation of Lte1 remains poorly understood. Here, we identify novel components of the checkpoint that operate upstream of L...

  6. Focal adhesions control cleavage furrow shape and spindle tilt during mitosis

    Science.gov (United States)

    Taneja, Nilay; Fenix, Aidan M.; Rathbun, Lindsay; Millis, Bryan A.; Tyska, Matthew J.; Hehnly, Heidi; Burnette, Dylan T.

    2016-01-01

    The geometry of the cleavage furrow during mitosis is often asymmetric in vivo and plays a critical role in stem cell differentiation and the relative positioning of daughter cells during development. Early observations of adhesive cell lines revealed asymmetry in the shape of the cleavage furrow, where the bottom (i.e., substrate attached side) of the cleavage furrow ingressed less than the top (i.e., unattached side). This data suggested substrate attachment could be regulating furrow ingression. Here we report a population of mitotic focal adhesions (FAs) controls the symmetry of the cleavage furrow. In single HeLa cells, stronger adhesion to the substrate directed less ingression from the bottom of the cell through a pathway including paxillin, focal adhesion kinase (FAK) and vinculin. Cell-cell contacts also direct ingression of the cleavage furrow in coordination with FAs in epithelial cells—MDCK—within monolayers and polarized cysts. In addition, mitotic FAs established 3D orientation of the mitotic spindle and the relative positioning of mother and daughter centrosomes. Therefore, our data reveals mitotic FAs as a key link between mitotic cell shape and spindle orientation, and may have important implications in our understanding stem cell homeostasis and tumorigenesis. PMID:27432211

  7. Dgp71WD is required for the assembly of the acentrosomal Meiosis I spindle, and is not a general targeting factor for the γ-TuRC

    Directory of Open Access Journals (Sweden)

    Richard F. Reschen

    2012-03-01

    Dgp71WD/Nedd1 proteins are essential for mitotic spindle formation. In human cells, Nedd1 targets γ-tubulin to both centrosomes and spindles, but in other organisms the function of Dgp71WD/Nedd1 is less clear. In Drosophila cells, Dgp71WD plays a major part in targeting γ-tubulin to spindles, but not centrosomes, while in Xenopus egg extracts, Nedd1 acts as a more general microtubule (MT organiser that can function independently of γ-tubulin. The interpretation of these studies, however, is complicated by the fact that some residual Dgp71WD/Nedd1 is likely present in the cells/extracts analysed. Here we generate a Dgp71WD null mutant lacking all but the last 12 nucleotides of coding sequence. The complete loss of Dgp71WD has no quantifiable effect on γ-tubulin or Centrosomin recruitment to the centrosome in larval brain cells. The recruitment of γ-tubulin to spindle MTs, however, is severely impaired, and spindle MT density is reduced in a manner that is indistinguishable from cells lacking Augmin or γ-TuRC function. In contrast, the absence of Dgp71WD leads to defects in the assembly of the acentrosomal female Meiosis I spindle that are more severe than those seen in Augmin or γ-TuRC mutants, indicating that Dgp71WD has additional functions that are independent of these complexes in oocytes. Moreover, the localisation of bicoid RNA during oogenesis, which requires γ-TuRC function, is unperturbed in Dgp71WD120 mutants. Thus, Dgp71WD is not simply a general cofactor required for γ-TuRC and/or Augmin targeting, and it appears to have a crucial role independent of these complexes in the acentrosomal Meiosis I spindle.

  8. Selective detection of Escherichia coli DNA using fluorescent carbon spindles.

    Science.gov (United States)

    Roy, Anurag; Chatterjee, Sabyasachi; Pramanik, Srikrishna; Devi, Parukuttyamma Sujatha; Suresh Kumar, Gopinatha

    2016-04-28

    We investigate the interaction of hydrophilic blue emitting carbon spindles with various deoxyribonucleic acids (DNA) having different base pair compositions, such as Herring testes (HT), calf thymus (CT), Escherichia coli (EC) and Micrococcus lysodeikticus (ML) DNA, to understand the mode of interaction. Interestingly, the fluorescent carbon spindles selectively interacted with E. coli DNA resulting in enhanced fluorescence of the former. Interaction of the same carbon with other DNAs exhibited insignificant changes in fluorescence. In addition, in the presence of EC DNA, the D band in the Raman spectrum attributed to the defect state completely disappeared, resulting in enhanced crystallinity. Microscopy images confirmed the wrapping of DNA on the carbon spindles leading to the assembly of spindles in the form of flowers. Dissociation of double-stranded DNA occurred upon interaction with carbon spindles, resulting in selective E. coli DNA interaction. The carbon spindles also exhibited a similar fluorescence enhancement upon treating with E. coli bacteria. These results confirm the possibility of E. coli detection in water and other liquid foods using such fluorescent carbon. PMID:27081680

  9. Signal transmission from motor axons to group Ia muscle spindle afferents: frequency responses and second-order non-linearities.

    Science.gov (United States)

    Windhorst, U; Kokkoroyiannis, T; Laouris, Y; Meyer-Lohmann, J

    1994-03-01

    Spinal recurrent inhibition via Renshaw cells and proprioceptive feedback via skeletal muscle and muscle spindle afferents have been hypothesized to constitute a compound feedback system [Windhorst (1989) Afferent Control of Posture and Locomotion; Windhorst (1993) Robots and Biological Systems--Towards a New Bionics]. To assess their detailed functions, it is necessary to know their dynamic characteristics. Previously we have extensively described the properties of signal transmission from motor axons to Renshaw cells using random motor axon stimulation and data analysis methods based thereupon. Using the same methods, we here compare these properties, in the cat, with those between motor axons and group Ia muscle spindle afferents in terms of frequency responses and nonlinear features. The frequency responses depend on the mean rate (carrier rate) of activation of motor axons and on the strength of coupling between motor units and spindles. In general, they are those of a second-order low-pass system with a cut-off at fairly low frequencies. This contrasts with the dynamics of motor axon-Renshaw cell couplings which are those of a much broader band-pass with its peak in the range of c. 2-15 Hz [Christakos (1987) Neuroscience 23, 613-623]. The second-order non-linearities in motor unit-muscle spindle signal lines are much more diverse than those in motor axon-Renshaw cell couplings. Although the average strength of response declines with mean stimulus rate in both subsystems, there is no systematic relationship between the amount of non-linearity and the average response in the former, whilst there is in the latter. The qualitative appearance of motor unit-muscle spindle non-linearities was complicated as was the average response to motor unit twitches. Thus, whilst Renshaw cells appear to dynamically reflect motor output rather faithfully, muscle spindles seem to signal local muscle fibre length changes and their dynamics. This would be consistent with the

  10. p600 regulates spindle orientation in apical neural progenitors and contributes to neurogenesis in the developing neocortex

    Directory of Open Access Journals (Sweden)

    Camille Belzil

    2014-05-01

    Full Text Available Apical neural progenitors (aNPs drive neurogenesis by means of a program consisting of self-proliferative and neurogenic divisions. The balance between these two manners of division sustains the pool of apical progenitors into late neurogenesis, thereby ensuring their availability to populate the brain with terminal cell types. Using knockout and in utero electroporation mouse models, we report a key role for the microtubule-associated protein 600 (p600 in the regulation of spindle orientation in aNPs, a cellular event that has been associated with cell fate and neurogenesis. We find that p600 interacts directly with the neurogenic protein Ndel1 and that aNPs knockout for p600, depleted of p600 by shRNA or expressing a Ndel1-binding p600 fragment all display randomized spindle orientation. Depletion of p600 by shRNA or expression of the Ndel1-binding p600 fragment also results in a decreased number of Pax6-positive aNPs and an increased number of Tbr2-positive basal progenitors destined to become neurons. These Pax6-positive aNPs display a tilted mitotic spindle. In mice wherein p600 is ablated in progenitors, the production of neurons is significantly impaired and this defect is associated with microcephaly. We propose a working model in which p600 controls spindle orientation in aNPs and discuss its implication for neurogenesis.

  11. An integrated texton and bag of words classifier for identifying anaplastic medulloblastomas.

    Science.gov (United States)

    Galaro, Joseph; Judkins, Alexander R; Ellison, David; Baccon, Jennifer; Madabhushi, Anant

    2011-01-01

    In this paper we present a combined Bag of Words and texton based classifier for differentiating anaplastic and non-anaplastic medulloblastoma on digitized histopathology. The hypothesis behind this work is that histological image signatures may reflect different levels of aggressiveness of the disease and that texture based approaches can help discriminate between more aggressive and less aggressive phenotypes of medulloblastoma. The bag of words approach attempts to model the occurrence of differently expressed image features. In this work we choose to model the image features via textons which can quantitatively capture and model texture appearance in the images. The texton-based features, obtained via two methods, the Haar Wavelet responses and MR8 filter bank, provide spatial orientation and rotation invariant attributes. Applying these features to the bag of words framework yields textural representations that can be used in conjunction with a classifier (κ-nearest neighbor) or a content based image retrieval system. Over multiple runs of randomized cross validation, a κ-NN classifier in conjunction with Haar wavelets and the texton, bag of words approach yielded a mean classification accuracy of 80, an area under the precision recall curve of 87 and an area under the ROC curve of 83 in distinguishing between anaplastic and non-anaplastic medulloblastomas on a cohort of 36 patient studies. PMID:22255080

  12. Hemorrhagic cerebellar anaplastic glioma appearing 12 years after prophylactic cranial radiotherapy for acute lymphocytic leukemia

    International Nuclear Information System (INIS)

    A radiation-induced cerebellar glioma is extremely rare, and the etiology of such a tumor is unknown. We report a rare case of hemorrhagic cerebellar anaplastic glioma occurring 12 years after prophylactic cranial radiotherapy for acute lymphocytic leukemia. We discuss the etiologies of the radiation-induced hemorrhagic cerebellar glioma as a secondary malignancy after radiotherapy. (author)

  13. Impact of histopathological transformation and overall survival in patients with progressive anaplastic glioma.

    Science.gov (United States)

    Ho, Allen L; Koch, Matthew J; Tanaka, Shota; Eichler, April F; Batchelor, Tracy T; Tanboon, Jantima; Louis, David N; Cahill, Daniel P; Chi, Andrew S; Curry, William T

    2016-09-01

    Progression of anaplastic glioma (World Health Organization [WHO] grade III) is typically determined radiographically, and transformation to glioblastoma (GB) (WHO grade IV) is often presumed at that time. However, the frequency of actual histopathologic transformation of anaplastic glioma and the subsequent clinical impact is unclear. To determine these associations, we retrospectively reviewed all anaplastic glioma patients who underwent surgery at our center at first radiographic progression, and we examined the effects of histological diagnosis, clinical history, and molecular factors on transformation rate and survival. We identified 85 anaplastic glioma (39 astrocytoma, 24 oligodendroglioma, 22 oligoastrocytoma), of which 38.8% transformed to GB. Transformation was associated with shorter overall survival (OS) from the time of diagnosis (3.4 vs. 10.9years, p=0.0005) and second surgery (1.0 vs. 3.5years, p<0.0001). Original histologic subtype did not significantly impact the risk of transformation or OS. No other factors, including surgery, adjuvant therapy or molecular markers, significantly affected the risk of transformation. However, mutations in isocitrate dehydrogenase 1 (IDH1) was associated with longer time to progression (median 4.6 vs. 1.4years, p=0.008) and OS (median 10.0 vs. 4.2years, p=0.046). At radiographic progression, tissue diagnosis may be warranted as histologic grade may provide valuable prognostic information and affect therapeutic clinical trial selection criteria for this patient population. PMID:27279154

  14. The Chromokinesin Kid Is Required for Maintenance of Proper Metaphase Spindle SizeD⃞

    OpenAIRE

    Tokai-Nishizumi, Noriko; Ohsugi, Miho; Suzuki, Emiko; Yamamoto, Tadashi

    2005-01-01

    The human chromokinesin Kid/kinesin-10, a plus end-directed microtubule (MT)-based motor with both microtubule- and DNA-binding domains, is required for proper chromosome alignment at the metaphase plate. Here, we performed RNA interference experiments to deplete endogenous Kid from HeLa cells and confirmed defects in metaphase chromosome arm alignment in Kid-depleted cells. In addition, we noted a shortening of the spindle length, resulting in a pole-to-pole distance only 80% of wild type. T...

  15. B-type nuclear lamin and the nuclear pore complex Nup107-160 influences maintenance of the spindle envelope required for cytokinesis in Drosophila male meiosis.

    Science.gov (United States)

    Hayashi, Daisuke; Tanabe, Karin; Katsube, Hiroka; Inoue, Yoshihiro H

    2016-01-01

    In higher eukaryotes, nuclear envelope (NE) disassembly allows chromatin to condense and spindle microtubules to access kinetochores. The nuclear lamina, which strengthens the NE, is composed of a polymer meshwork made of A- and B-type lamins. We found that the B-type lamin (Lam) is not fully disassembled and continues to localize along the spindle envelope structure during Drosophila male meiosis I, while the A-type lamin (LamC) is completely dispersed throughout the cytoplasm. Among the nuclear pore complex proteins, Nup107 co-localized with Lam during this meiotic division. Surprisingly, Lam depletion resulted in a higher frequency of cytokinesis failure in male meiosis. We also observed the similar meiotic phenotype in Nup107-depleted cells. Abnormal localization of Lam was found in the Nup-depleted cells at premeiotic and meiotic stages. The central spindle microtubules became abnormal and recruitment of a contractile ring component to the cleavage sites was disrupted in Lam-depleted cells and Nup107-depleted cells. Therefore, we speculate that both proteins are required for a reinforcement of the spindle envelope, which supports the formation of central spindle microtubules essential for cytokinesis in Drosophila male meiosis. PMID:27402967

  16. B-type nuclear lamin and the nuclear pore complex Nup107-160 influences maintenance of the spindle envelope required for cytokinesis in Drosophila male meiosis

    Science.gov (United States)

    Hayashi, Daisuke; Tanabe, Karin; Katsube, Hiroka

    2016-01-01

    ABSTRACT In higher eukaryotes, nuclear envelope (NE) disassembly allows chromatin to condense and spindle microtubules to access kinetochores. The nuclear lamina, which strengthens the NE, is composed of a polymer meshwork made of A- and B-type lamins. We found that the B-type lamin (Lam) is not fully disassembled and continues to localize along the spindle envelope structure during Drosophila male meiosis I, while the A-type lamin (LamC) is completely dispersed throughout the cytoplasm. Among the nuclear pore complex proteins, Nup107 co-localized with Lam during this meiotic division. Surprisingly, Lam depletion resulted in a higher frequency of cytokinesis failure in male meiosis. We also observed the similar meiotic phenotype in Nup107-depleted cells. Abnormal localization of Lam was found in the Nup-depleted cells at premeiotic and meiotic stages. The central spindle microtubules became abnormal and recruitment of a contractile ring component to the cleavage sites was disrupted in Lam-depleted cells and Nup107-depleted cells. Therefore, we speculate that both proteins are required for a reinforcement of the spindle envelope, which supports the formation of central spindle microtubules essential for cytokinesis in Drosophila male meiosis. PMID:27402967

  17. Topography-specific spindle frequency changes in Obstructive Sleep Apnea

    Directory of Open Access Journals (Sweden)

    V Suzana

    2012-07-01

    Full Text Available Abstract Background Sleep spindles, as detected on scalp electroencephalography (EEG, are considered to be markers of thalamo-cortical network integrity. Since obstructive sleep apnea (OSA is a known cause of brain dysfunction, the aim of this study was to investigate sleep spindle frequency distribution in OSA. Seven non-OSA subjects and 21 patients with OSA (11 mild and 10 moderate were studied. A matching pursuit procedure was used for automatic detection of fast (≥13Hz and slow (Hz spindles obtained from 30min samples of NREM sleep stage 2 taken from initial, middle and final night thirds (sections I, II and III of frontal, central and parietal scalp regions. Results Compared to non-OSA subjects, Moderate OSA patients had higher central and parietal slow spindle percentage (SSP in all night sections studied, and higher frontal SSP in sections II and III. As the night progressed, there was a reduction in central and parietal SSP, while frontal SSP remained high. Frontal slow spindle percentage in night section III predicted OSA with good accuracy, with OSA likelihood increased by 12.1%for every SSP unit increase (OR 1.121, 95% CI 1.013 - 1.239, p=0.027. Conclusions These results are consistent with diffuse, predominantly frontal thalamo-cortical dysfunction during sleep in OSA, as more posterior brain regions appear to maintain some physiological spindle frequency modulation across the night. Displaying changes in an opposite direction to what is expected from the aging process itself, spindle frequency appears to be informative in OSA even with small sample sizes, and to represent a sensitive electrophysiological marker of brain dysfunction in OSA.

  18. Multi-frequency auditory stimulation disrupts spindling activity in anesthetized animals.

    Science.gov (United States)

    Britvina, T; Eggermont, J J

    2008-02-01

    It is often implied that during the occurrence of spindle oscillations, thalamocortical neurons do not respond to signals from the outside world. Since recording of sound-evoked activity from cat auditory cortex is common during spindling this implies that sound stimulation changes the spindle-related brain state. Local field potentials and multi-unit activity recorded from cat primary auditory cortex under ketamine anesthesia during successive silence-stimulus-silence conditions were used to investigate the effect of sound on cortical spindle oscillations. Multi-frequency stimulation suppresses spindle waves, as shown by the decrease of spectral power within the spindle frequency range during stimulation as compared with the previous silent period. We show that the percentage suppression is independent of the power of the spindle waves during silence, and that the suppression of spindle power occurs very fast after stimulus onset. The global inter-spindle rhythm was not disturbed during stimulation. Spectrotemporal and correlation analysis revealed that beta waves (15-26 Hz), and to a lesser extent delta waves, were modulated by the same inter-spindle rhythm as spindle oscillations. The suppression of spindle power during stimulation had no effect on the spatial correlation of spindle waves. Firing rates increased under stimulation and spectro-temporal receptive fields could reliably be obtained. The possible mechanism of suppression of spindle waves is discussed and it is suggested that suppression likely occurs through activity of the specific auditory pathway. PMID:18164553

  19. Stereotactic Radiation Therapy can Safely and Durably Control Sites of Extra-Central Nervous System Oligoprogressive Disease in Anaplastic Lymphoma Kinase-Positive Lung Cancer Patients Receiving Crizotinib

    Energy Technology Data Exchange (ETDEWEB)

    Gan, Gregory N., E-mail: gregory.gan@ucdenver.edu [Department of Radiation Oncology, University of Colorado, Aurora, Colorado (United States); Weickhardt, Andrew J.; Scheier, Benjamin; Doebele, Robert C. [Department of Medical Oncology, University of Colorado, Aurora, Colorado (United States); Gaspar, Laurie E.; Kavanagh, Brian D. [Department of Radiation Oncology, University of Colorado, Aurora, Colorado (United States); Camidge, D. Ross [Department of Medical Oncology, University of Colorado, Aurora, Colorado (United States)

    2014-03-15

    Purpose: To analyze the durability and toxicity of radiotherapeutic local ablative therapy (LAT) applied to extra-central nervous system (eCNS) disease progression in anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC) patients. Methods and Materials: Anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib and manifesting ≤4 discrete sites of eCNS progression were classified as having oligoprogressive disease (OPD). If subsequent progression met OPD criteria, additional courses of LAT were considered. Crizotinib was continued until eCNS progression was beyond OPD criteria or otherwise not suitable for further LAT. Results: Of 38 patients, 33 progressed while taking crizotinib. Of these, 14 had eCNS progression meeting OPD criteria suitable for radiotherapeutic LAT. Patients with eCNS OPD received 1-3 courses of LAT with radiation therapy. The 6- and 12-month actuarial local lesion control rates with radiation therapy were 100% and 86%, respectively. The 12-month local lesion control rate with single-fraction equivalent dose >25 Gy versus ≤25 Gy was 100% versus 60% (P=.01). No acute or late grade >2 radiation therapy-related toxicities were observed. Median overall time taking crizotinib among those treated with LAT versus those who progressed but were not suitable for LAT was 28 versus 10.1 months, respectively. Patients continuing to take crizotinib for >12 months versus ≤12 months had a 2-year overall survival rate of 72% versus 12%, respectively (P<.0001). Conclusions: Local ablative therapy safely and durably eradicated sites of individual lesion progression in anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib. A dose–response relationship for local lesion control was observed. The suppression of OPD by LAT in patients taking crizotinib allowed an extended duration of exposure to crizotinib, which was associated with longer overall survival.

  20. Stereotactic Radiation Therapy can Safely and Durably Control Sites of Extra-Central Nervous System Oligoprogressive Disease in Anaplastic Lymphoma Kinase-Positive Lung Cancer Patients Receiving Crizotinib

    International Nuclear Information System (INIS)

    Purpose: To analyze the durability and toxicity of radiotherapeutic local ablative therapy (LAT) applied to extra-central nervous system (eCNS) disease progression in anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC) patients. Methods and Materials: Anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib and manifesting ≤4 discrete sites of eCNS progression were classified as having oligoprogressive disease (OPD). If subsequent progression met OPD criteria, additional courses of LAT were considered. Crizotinib was continued until eCNS progression was beyond OPD criteria or otherwise not suitable for further LAT. Results: Of 38 patients, 33 progressed while taking crizotinib. Of these, 14 had eCNS progression meeting OPD criteria suitable for radiotherapeutic LAT. Patients with eCNS OPD received 1-3 courses of LAT with radiation therapy. The 6- and 12-month actuarial local lesion control rates with radiation therapy were 100% and 86%, respectively. The 12-month local lesion control rate with single-fraction equivalent dose >25 Gy versus ≤25 Gy was 100% versus 60% (P=.01). No acute or late grade >2 radiation therapy-related toxicities were observed. Median overall time taking crizotinib among those treated with LAT versus those who progressed but were not suitable for LAT was 28 versus 10.1 months, respectively. Patients continuing to take crizotinib for >12 months versus ≤12 months had a 2-year overall survival rate of 72% versus 12%, respectively (P<.0001). Conclusions: Local ablative therapy safely and durably eradicated sites of individual lesion progression in anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib. A dose–response relationship for local lesion control was observed. The suppression of OPD by LAT in patients taking crizotinib allowed an extended duration of exposure to crizotinib, which was associated with longer overall survival

  1. Sleep Spindle Deficit in Schizophrenia: Contextualization of Recent Findings.

    Science.gov (United States)

    Castelnovo, Anna; D'Agostino, Armando; Casetta, Cecilia; Sarasso, Simone; Ferrarelli, Fabio

    2016-08-01

    Sleep spindles are wax and waning brain oscillations at a frequency range of 11-16 Hz, lasting 0.5-2 s, that define non-rapid eye movement sleep stage 2. Over the past few years, several independent studies pointed to a decrease of sleep spindles in schizophrenia. The aim of this review is to contextualize these findings within the growing literature on these oscillations across other neuro-psychiatric disorders. Indeed, spindles reflect the coordinated activity of thalamocortical networks, and their abnormality can be observed in a variety of conditions that disrupt local or global thalamocortical connectivity. Although the broad methodological variability across studies limits the possibility of drawing firm conclusions, impaired spindling activity has been observed in several neurodevelopmental and neurodegenerative disorders. Despite such lack of specificity, schizophrenia remains the only condition with a typical late adolescence to young adulthood onset in which impaired spindling has been consistently reported. Further research is necessary to clearly define the pathogenetic mechanisms that lead to this deficit and the validity of its widespread use as a clinical biomarker. PMID:27299655

  2. Combination Chemotherapy and Lenalidomide in Treating Patients With Newly Diagnosed Stage II-IV Peripheral T-cell Non-Hodgkin's Lymphoma

    Science.gov (United States)

    2015-10-02

    Anaplastic Large Cell Lymphoma, ALK-Negative; Anaplastic Large Cell Lymphoma, ALK-Positive; Hepatosplenic T-Cell Lymphoma; Peripheral T-Cell Lymphoma, Not Otherwise Specified; Stage II Angioimmunoblastic T-cell Lymphoma; Stage II Enteropathy-Associated T-Cell Lymphoma; Stage III Angioimmunoblastic T-cell Lymphoma; Stage III Enteropathy-Associated T-Cell Lymphoma; Stage IV Angioimmunoblastic T-cell Lymphoma; Stage IV Enteropathy-Associated T-Cell Lymphoma

  3. The SUMO protease SENP1 is required for cohesion maintenance and mitotic arrest following spindle poison treatment

    Energy Technology Data Exchange (ETDEWEB)

    Era, Saho [Fondazione IFOM, Istituto FIRC di Oncologia Molecolare, IFOM-IEO campus, Via Adamello 16, 20139 Milan (Italy); Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501 (Japan); Abe, Takuya; Arakawa, Hiroshi [Fondazione IFOM, Istituto FIRC di Oncologia Molecolare, IFOM-IEO campus, Via Adamello 16, 20139 Milan (Italy); Kobayashi, Shunsuke [Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501 (Japan); Szakal, Barnabas [Fondazione IFOM, Istituto FIRC di Oncologia Molecolare, IFOM-IEO campus, Via Adamello 16, 20139 Milan (Italy); Yoshikawa, Yusuke; Motegi, Akira; Takeda, Shunichi [Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501 (Japan); Branzei, Dana, E-mail: dana.branzei@ifom.eu [Fondazione IFOM, Istituto FIRC di Oncologia Molecolare, IFOM-IEO campus, Via Adamello 16, 20139 Milan (Italy)

    2012-09-28

    Highlights: Black-Right-Pointing-Pointer SENP1 knockout chicken DT40 cells are hypersensitive to spindle poisons. Black-Right-Pointing-Pointer Spindle poison treatment of SENP1{sup -/-} cells leads to increased mitotic slippage. Black-Right-Pointing-Pointer Mitotic slippage in SENP1{sup -/-} cells associates with apoptosis and endoreplication. Black-Right-Pointing-Pointer SENP1 counteracts sister chromatid separation during mitotic arrest. Black-Right-Pointing-Pointer Plk1-mediated cohesion down-regulation is involved in colcemid cytotoxicity. -- Abstract: SUMO conjugation is a reversible posttranslational modification that regulates protein function. SENP1 is one of the six SUMO-specific proteases present in vertebrate cells and its altered expression is observed in several carcinomas. To characterize SENP1 role in genome integrity, we generated Senp1 knockout chicken DT40 cells. SENP1{sup -/-} cells show normal proliferation, but are sensitive to spindle poisons. This hypersensitivity correlates with increased sister chromatid separation, mitotic slippage, and apoptosis. To test whether the cohesion defect had a causal relationship with the observed mitotic events, we restored the cohesive status of sister chromatids by introducing the TOP2{alpha}{sup +/-} mutation, which leads to increased catenation, or by inhibiting Plk1 and Aurora B kinases that promote cohesin release from chromosomes during prolonged mitotic arrest. Although TOP2{alpha} is SUMOylated during mitosis, the TOP2{alpha}{sup +/-} mutation had no obvious effect. By contrast, inhibition of Plk1 or Aurora B rescued the hypersensitivity of SENP1{sup -/-} cells to colcemid. In conclusion, we identify SENP1 as a novel factor required for mitotic arrest and cohesion maintenance during prolonged mitotic arrest induced by spindle poisons.

  4. The SUMO protease SENP1 is required for cohesion maintenance and mitotic arrest following spindle poison treatment

    International Nuclear Information System (INIS)

    Highlights: ► SENP1 knockout chicken DT40 cells are hypersensitive to spindle poisons. ► Spindle poison treatment of SENP1−/− cells leads to increased mitotic slippage. ► Mitotic slippage in SENP1−/− cells associates with apoptosis and endoreplication. ► SENP1 counteracts sister chromatid separation during mitotic arrest. ► Plk1-mediated cohesion down-regulation is involved in colcemid cytotoxicity. -- Abstract: SUMO conjugation is a reversible posttranslational modification that regulates protein function. SENP1 is one of the six SUMO-specific proteases present in vertebrate cells and its altered expression is observed in several carcinomas. To characterize SENP1 role in genome integrity, we generated Senp1 knockout chicken DT40 cells. SENP1−/− cells show normal proliferation, but are sensitive to spindle poisons. This hypersensitivity correlates with increased sister chromatid separation, mitotic slippage, and apoptosis. To test whether the cohesion defect had a causal relationship with the observed mitotic events, we restored the cohesive status of sister chromatids by introducing the TOP2α+/− mutation, which leads to increased catenation, or by inhibiting Plk1 and Aurora B kinases that promote cohesin release from chromosomes during prolonged mitotic arrest. Although TOP2α is SUMOylated during mitosis, the TOP2α+/− mutation had no obvious effect. By contrast, inhibition of Plk1 or Aurora B rescued the hypersensitivity of SENP1−/− cells to colcemid. In conclusion, we identify SENP1 as a novel factor required for mitotic arrest and cohesion maintenance during prolonged mitotic arrest induced by spindle poisons.

  5. Mitotic spindle organization by dynein & kinetochores

    NARCIS (Netherlands)

    Raaijmakers, J.A.

    2014-01-01

    The human body contains an estimated 37 trillion cells. Although most cells in the body are non-dividing, approximately 300 billion new cells are produced every day. This is important for the maintenance of our tissues but also for the repair of tissues when they are damaged. To prepare for cell div

  6. An anillin-Ect2 complex stabilizes central spindle microtubules at the cortex during cytokinesis.

    Directory of Open Access Journals (Sweden)

    Paul Frenette

    Full Text Available Cytokinesis occurs due to the RhoA-dependent ingression of an actomyosin ring. During anaphase, the Rho GEF (guanine nucleotide exchange factor Ect2 is recruited to the central spindle via its interaction with MgcRacGAP/Cyk-4, and activates RhoA in the central plane of the cell. Ect2 also localizes to the cortex, where it has access to RhoA. The N-terminus of Ect2 binds to Cyk-4, and the C-terminus contains conserved DH (Dbl homologous and PH (Pleckstrin Homology domains with GEF activity. The PH domain is required for Ect2's cortical localization, but its molecular function is not known. In cultured human cells, we found that the PH domain interacts with anillin, a contractile ring protein that scaffolds actin and myosin and interacts with RhoA. The anillin-Ect2 interaction may require Ect2's association with lipids, since a novel mutation in the PH domain, which disrupts phospholipid association, weakens their interaction. An anillin-RacGAP50C (homologue of Cyk-4 complex was previously described in Drosophila, which may crosslink the central spindle to the cortex to stabilize the position of the contractile ring. Our data supports an analogous function for the anillin-Ect2 complex in human cells and one hypothesis is that this complex has functionally replaced the Drosophila anillin-RacGAP50C complex. Complexes between central spindle proteins and cortical proteins could regulate the position of the contractile ring by stabilizing microtubule-cortical interactions at the division plane to ensure the generation of active RhoA in a discrete zone.

  7. Dynamic Analysis of Axial Magnetic Forces for DVD Spindle Motors

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The axial magnetic force, induced by the complicated flux linkage distribution from rotor magnet and stator slotted, is constructed by different relative heights and calculated by 3D finite element method (FEM) to analyze the dynamic characteristics for a DVD spindle motor. The axial magnetic force is designed to provide an axial stiffness and govern the natural frequency of the dynamic performance. According to the simulation results and experimental measurements, the dynamic behaviors are significantly improved with a variation of relative height of rotor magnet and stator slotted on a DVD spindle motor.

  8. Nonadiabatic scattering and transport at the spindle cusp

    International Nuclear Information System (INIS)

    When magnetohydrodynamics is used to describe plasma flow across a separatrix to open field lines, the transport is modeled by a diffusion equation with a sink for particles on the open lines. In that case, it is assumed that plasma is carried to and from the separatrix by diffusive processes. The purpose of this note is to discuss the nonadiabatic processes occurring at a spindle cusp to transfer plasma across a separatrix. After an ion is delivered to the vicinity of the separatrix by diffusion it enters the spindle cusp and will skip back and forth across the separatrix, producing a structured transport not seen with MHD

  9. Moderate intensity static magnetic fields affect mitotic spindles and increase the antitumor efficacy of 5-FU and Taxol.

    Science.gov (United States)

    Luo, Yan; Ji, Xinmiao; Liu, Juanjuan; Li, Zhiyuan; Wang, Wenchao; Chen, Wei; Wang, Junfeng; Liu, Qingsong; Zhang, Xin

    2016-06-01

    Microtubules are the fundamental components in mitotic spindle, which plays essential roles in cell division. It was well known that purified microtubules could be affected by static magnetic fields (SMFs) in vitro because of the diamagnetic anisotropy of tubulin. However, whether these effects lead to cell division defects was unknown. Here we find that 1T SMFs induce abnormal mitotic spindles and increase mitotic index. Synchronization experiments show that SMFs delay cell exit from mitosis and cause mitotic arrest. These mimic the cellular effects of a microtubule-targeting drug Paclitaxel (Taxol), which is frequently used in combination with 5-Fluorouracil (5-FU) and Cisplatin in cancer treatment. Using four different human cancer cell lines, HeLa, HCT116, CNE-2Z and MCF7, we find that SMFs increase the antitumor efficacy of 5-FU or 5-FU/Taxol, but not Cisplatin, which indicates that the SMF-induced combinational effects with chemodrugs are drug-specific. Our study not only reveals the effect of SMFs on microtubules to cause abnormal mitotic spindles and delay cells exit from mitosis, but also implies the potential applications of SMFs in combination with chemotherapy drugs 5-FU or 5-FU/Taxol, but not with Cisplatin in cancer treatment. PMID:26775206

  10. Fibrillarin redistributes to the spindle poles and partially colocalizes with NuMA during mitosis

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Fibrillarin, a major protein in the nucleolus, is known to redistribute during mitosis from the nucleolus to the cytosol, and is related to the dynamics of post-mitotic reassembly of the nucleolus. To better understand the dynamic behavior and the relationship with other cytoplasmic structures, we have now expressed fibrillarin-pDsRed1 fusion protein in HeLa cells. The results showed that a part of fibrillarin was associated with mitotic spindle poles in the mitotic cells. Nocodazole-induced microtubule depolymerization resulted in fibrillarin redistribution throughout the cytoplasm, and removal of nocodazole resulted in relocalization of fibrillarin at the polar region during the mitotic spindles reassembly. In a mitotic cell free system, fibrillarin was found in the center of taxol-induced microtubule asters. Moreover, fibrillarin was found to colocalize with the nuclear mitotic apparatus protein (NuMA) at the poles of mitotic cells. Therefore, it is postulated that the polar redistribution of fibrillarin is mediated by microtubules.

  11. Transformation of p53-positive papillary thyroid carcinoma to anaplastic carcinoma of the liver following postoperative radioactive iodine-131 therapy

    OpenAIRE

    Takeshita, Yumie; Takamura, Toshinari; Minato, Hiroshi; Misu, Hirofumi; Ando, Hitoshi; Yamashita, Tatsuya; IKEDA, HIROKO; Nakanuma, Yasuni; Kaneko, Shuichi

    2008-01-01

    Multiple liver metastases were incidentally detected in the lobe of the liver of an 81-year-old woman following total thyroidectomy and ablative radioactive iodine administration for the treatment of papillary thyroid carcinoma. A biopsy specimen taken from the metastatic liver tumor was histologically diagnosed as anaplastic carcinoma. Immunohistochemical staining for p53 was positive in both the primary tumor and liver biopsy specimens. We considered this to have been caused by anaplastic t...

  12. The budding yeast Ipl1/Aurora protein kinase regulates mitotic spindle disassembly

    OpenAIRE

    Buvelot, Stéphanie; Tatsutani, Sean Y.; Vermaak, Danielle; Biggins, Sue

    2003-01-01

    Ipl1p is the budding yeast member of the Aurora family of protein kinases, critical regulators of genomic stability that are required for chromosome segregation, the spindle checkpoint, and cytokinesis. Using time-lapse microscopy, we found that Ipl1p also has a function in mitotic spindle disassembly that is separable from its previously identified roles. Ipl1–GFP localizes to kinetochores from G1 to metaphase, transfers to the spindle after metaphase, and accumulates at the spindle midzone ...

  13. Stiffness Identification of Spindle-Toolholder Joint Based on Finite Difference Technique and Residual Compensation Theory

    OpenAIRE

    Zhifeng Liu; Xiaolei Song; Yongsheng Zhao; Ligang Cai; Hongsheng Guo; Jianchuan Ma

    2013-01-01

    The chatter vibration in high-speed machining mostly originates from the flexible connection of spindle and toolholder. Accurate identification of spindle-toolholder joint is crucial to predict machining stability of spindle system. This paper presents an enhanced stiffness identification method for the spindle-toolholder joint, in which the rotational degree of freedom (RDOF) is included. RDOF frequency response functions (FRFs) are formulated based on finite difference technique to construc...

  14. Human Muscle Spindle Sensitivity Reflects the Balance of Activity between Antagonistic Muscles

    OpenAIRE

    Dimitriou, Michael

    2014-01-01

    Muscle spindles are commonly considered as stretch receptors encoding movement, but the functional consequence of their efferent control has remained unclear. The "alpha-gamma coactivation" hypothesis states that activity in a muscle is positively related to the output of its spindle afferents. However, in addition to the above, possible reciprocal inhibition of spindle controllers entails a negative relationship between contractile activity in one muscle and spindle afferent output from its ...

  15. Radiation-induced spinal cord anaplastic astrocytoma subsequent to radiotherapy for testicular seminoma. Case report

    International Nuclear Information System (INIS)

    A 54-year-old man presented with a very rare case of radiation-induced intramedullary spinal cord anaplastic astrocytoma, which developed 37 years after radiotherapy for testicular seminoma. The patient presented with weakness and numbness of the left lower extremity that had gradually aggravated for 3 months. Magnetic resonance imaging demonstrated an intramedullary mass lesion with syringomyelia at the T9 to T12 levels. Subtotal removal of the tumor was performed using standard microsurgical technique. Histological examination revealed anaplastic astrocytoma. Although radiotherapy was seriously considered, chemotherapy was employed as adjuvant therapy considering the previous treatment. Although his neurological status improved transiently after surgery, relentless neurological decline occurred and resulted in death 9 months following surgery. Considering that subtotal removal of the tumor and chemotherapy had little influence on the quality of life and the length of survival in our case, cordectomy may be the optimum treatment for patients with radiation-induced spinal intramedullary malignant astrocytoma. (author)

  16. Timely anaphase onset requires a novel spindle and kinetochore complex comprising Ska1 and Ska2

    NARCIS (Netherlands)

    Hanisch, Anja; Silljé, Herman H W; Nigg, Erich A

    2006-01-01

    Chromosome segregation during mitosis requires chromosomes to undergo bipolar attachment on spindle microtubules (MTs) and subsequent silencing of the spindle checkpoint. Here, we describe the identification and characterisation of a novel spindle and kinetochore (KT)-associated complex that is requ

  17. Involvement of Spindles in Memory Consolidation Is Slow Wave Sleep-Specific

    Science.gov (United States)

    Cox, Roy; Hofman, Winni F.; Talamini, Lucia M.

    2012-01-01

    Both sleep spindles and slow oscillations have been implicated in sleep-dependent memory consolidation. Whereas spindles occur during both light and deep sleep, slow oscillations are restricted to deep sleep, raising the possibility of greater consolidation-related spindle involvement during deep sleep. We assessed declarative memory retention…

  18. Acute Hydrocephalus due to Secondary Leptomeningeal Dissemination of an Anaplastic Oligodendroglioma

    OpenAIRE

    Friederike Knerlich-Lukoschus; Heinz-Herrmann Hugo; Stark, Andreas M.; H. Maximilian Mehdorn

    2009-01-01

    Secondary leptomeningeal dissemination of oligodendroglioma is very rare. We report the case of a 38-year-old Caucasian male who presented with acute hydrocephalus. 8 months before, the patient had undergone craniotomy for right frontal anaplastic oligodendroglioma, WHO grade III. By that time, there was no evidence of tumor dissemination. MRI now ruled out local tumor progression but revealed meningeal contrast enhancement along the medulla, the myelon, and the cauda equina. Repeated lumbar ...

  19. Development of anaplastic Wilms tumor and subsequent relapse in a child with diaphanospondylodysostosis.

    Science.gov (United States)

    Tasian, Sarah K; Kim, Grace E; Miniati, Douglas N; DuBois, Steven G

    2012-10-01

    Diaphanospondylodysostosis (DSD) is a rare skeletal dysplasia syndrome resulting from disordered mesenchymal differentiation. Children with DSD generally die in utero or during the first month of life from severe thoracic insufficiency syndrome. An association of DSD with nephroblastomatosis has been observed, but the natural history of such nephroblastomatosis remains poorly characterized due to the rarity of the underlying condition. We describe a patient with DSD who developed bilateral hyperplastic nephroblastomatosis that ultimately evolved into therapy-resistant anaplastic Wilms tumor (nephroblastoma). PMID:22469945

  20. COMBINED CHEMOTHERAPY INCLUDING PROCARBAZINE (NATULAN IN THE TREATMENT OF ANAPLASTIC OLIGODENDROGLIOMAS

    Directory of Open Access Journals (Sweden)

    D. R. Naskhletashvili

    2012-01-01

    Full Text Available Our investigation has demonstrated the high efficiency of combined chemotherapy (CT including procarbazine + lomustine or procarbazine + lomustine + vincristine in patients with anaplastic oligodendrogliomas. Postoperative CT has been recently recommended for patients with deletion of chromosomes 1p and 19q, by taking into account the good prognosis of a therapeutic effect, better parameters of time till progression in this patient group, and a risk for cognitive impairments after brain radiotherapy.

  1. AT-36PANOBINOSTAT IN COMBINATION WITH BEVACIZUMAB FOR RECURRENT GLIOBLASTOMA AND ANAPLASTIC GLIOMA

    OpenAIRE

    Lee, Eudocia; Reardon, David; Schiff, David; Drappatz, Jan; Muzikansky, Alona; Grimm, Sean; Norden, Andrew; Nayak, Lakshmi; Beroukhim, Rameen; Rinne, Mikael; Chi, Andrew; Batchelor, Tracy; Hempfling, Kelly; McCluskey, Christine; Smith, Katrina

    2014-01-01

    Bevacizumab is frequently used to treat recurrent high-grade gliomas, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects in glioma models and may work synergistically with bevacizumab. We conducted a multicenter phase II trial of panobinostat in combination with bevacizumab. Two cohorts were enrolled: one with recurrent glioblastoma (GBM) as the primary study and one with recurrent anaplastic glioma (AG) as...

  2. A Time-Resolved Luminescence Biosensor Assay for Anaplastic Lymphoma Kinase (ALK) Activity†

    OpenAIRE

    Cui, Wei; Parker, Laurie L.

    2014-01-01

    A novel time-resolved luminescence biosensor assay for anaplastic lymphoma kinase (ALK) was developed. We used a straightforward strategy to modify a known ALK substrate into a peptide biosensor that can accommodate terbium luminescence sensitization upon its phosphorylation by ALK. Since this strategy is generalizable, this high-throughput screening compatible assay serves as an example for development of other kinase assays that employ terbium luminescence as a read-out.

  3. A mitotic SKAP isoform regulates spindle positioning at astral microtubule plus ends.

    Science.gov (United States)

    Kern, David M; Nicholls, Peter K; Page, David C; Cheeseman, Iain M

    2016-05-01

    The Astrin/SKAP complex plays important roles in mitotic chromosome alignment and centrosome integrity, but previous work found conflicting results for SKAP function. Here, we demonstrate that SKAP is expressed as two distinct isoforms in mammals: a longer, testis-specific isoform that was used for the previous studies in mitotic cells and a novel, shorter mitotic isoform. Unlike the long isoform, short SKAP rescues SKAP depletion in mitosis and displays robust microtubule plus-end tracking, including localization to astral microtubules. Eliminating SKAP microtubule binding results in severe chromosome segregation defects. In contrast, SKAP mutants specifically defective for plus-end tracking facilitate proper chromosome segregation but display spindle positioning defects. Cells lacking SKAP plus-end tracking have reduced Clasp1 localization at microtubule plus ends and display increased lateral microtubule contacts with the cell cortex, which we propose results in unbalanced dynein-dependent cortical pulling forces. Our work reveals an unappreciated role for the Astrin/SKAP complex as an astral microtubule mediator of mitotic spindle positioning. PMID:27138257

  4. Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Purcell, James W; Davis, Jefferson; Reddy, Mamatha; Martin, Shamra; Samayoa, Kimberly; Vo, Hung; Thomsen, Karen; Bean, Peter; Kuo, Wen Lin; Ziyad, Safiyyah; Billig, Jessica; Feiler, Heidi S; Gray, Joe W; Wood, Kenneth W; Cases, Sylvaine

    2009-06-10

    Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein (KSP), a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have demonstrated a 9% response rate in patients with locally advanced or metastatic breast cancer, and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer we explored the activity of ispinesib alone and in combination several therapies approved for the treatment of breast cancer. We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo, and tested the ability of ispinesib to enhance the anti-tumor activity of approved therapies. In vitro, ispinesib displayed broad anti-proliferative activity against a panel of 53 breast cell-lines. In vivo, ispinesib produced regressions in each of five breast cancer models, and tumor free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the anti-tumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine, and exhibited activity comparable to paclitaxel and ixabepilone. These findings support further clinical exploration of KSP inhibitors for the treatment of breast cancer.

  5. Spindle Oscillations in Sleep Disorders: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Oren M. Weiner

    2016-01-01

    Full Text Available Measurement of sleep microarchitecture and neural oscillations is an increasingly popular technique for quantifying EEG sleep activity. Many studies have examined sleep spindle oscillations in sleep-disordered adults; however reviews of this literature are scarce. As such, our overarching aim was to critically review experimental studies examining sleep spindle activity between adults with and without different sleep disorders. Articles were obtained using a systematic methodology with a priori criteria. Thirty-seven studies meeting final inclusion criteria were reviewed, with studies grouped across three categories: insomnia, hypersomnias, and sleep-related movement disorders (including parasomnias. Studies of patients with insomnia and sleep-disordered breathing were more abundant relative to other diagnoses. All studies were cross-sectional. Studies were largely inconsistent regarding spindle activity differences between clinical and nonclinical groups, with some reporting greater or less activity, while many others reported no group differences. Stark inconsistencies in sample characteristics (e.g., age range and diagnostic criteria and methods of analysis (e.g., spindle bandwidth selection, visual detection versus digital filtering, absolute versus relative spectral power, and NREM2 versus NREM3 suggest a need for greater use of event-based detection methods and increased research standardization. Hypotheses regarding the clinical and empirical implications of these findings, and suggestions for potential future studies, are also discussed.

  6. Modelling muscle spindle dynamics for a proprioceptive prosthesis.

    Science.gov (United States)

    Williams, Ian; Constandinou, Timothy G

    2013-01-01

    Muscle spindles are found throughout our skeletal muscle tissue and continuously provide us with a sense of our limbs' position and motion (proprioception). This paper advances a model for generating artificial muscle spindle signals for a prosthetic limb, with the aim of one day providing amputees with a sense of feeling in their artificial limb. By utilising the Opensim biomechanical modelling package the relationship between a joint's angle and the length of surrounding muscles is estimated for a prosthetic limb. This is then applied to the established Mileusnic model to determine the associated muscle spindle firing pattern. This complete system model is then reduced to allow for a computationally efficient hardware implementation. This reduction is achieved with minimal impact on accuracy by selecting key mono-articular muscles and fitting equations to relate joint angle to muscle length. Parameter values fitting the Mileusnic model to human spindles are then proposed and validated against previously published human neural recordings. Finally, a model for fusimotor signals is also proposed based on data previously recorded from reduced animal experiments. PMID:24110089

  7. Screening tomato germplasm for resistance to potato spindle tuber viroid

    Science.gov (United States)

    In recent years, several outbreaks of a potentially devastating viroid disease on tomato in North America have caused serious concerns to tomato growers and vegetable seed industry. Several closely related viroids in the genus Pospiviroid have been identified on tomato. Among them, Potato spindle t...

  8. Potato spindle tuber viroid: the simplicity paradox resolved?

    Science.gov (United States)

    Taxonomy: Potato spindle tuber viroid (PSTVd) is the type species of the genus Posipiviroid, family Pospiviroidae. An absence of hammerhead ribozymes and the presence of a 'central conserved region' distinguish PSTVd and related viroids from members of a second viroid family, the Avsunviroidae. ...

  9. Experimental study on bearing preload optimum of machine tool spindle

    International Nuclear Information System (INIS)

    An experimental study is conducted to investigate the possibility and the effect of temperature rise and vibration level of bearing by adjusting axial preloads and radial loads in spindle bearing test rig. The shaft of the test rig is driven by a motorized high speed spindle at the range of 0∼20000 rpm. The axial preloads and radial loads on bearings are controlled by using hydraulic pressure which can be adjusted automatically. Temperature rise and radial vibration of test bearings are measured by thermocouples and Polytec portable laser vibrometer PDV100. Experiment shows that the temperature rise of bearings is nonlinear varying with the increase of radial loads, but temperature rise almost increases linearly with the increase of axial preload and rotating speed. In this paper, an alternate axial preload is used for bearings. When the rotating speed passes through the critical speed of the shaft, axial preload of bearings will have a remarkable effect. The low preload could reduce bearing vibration and temperature rise for bearings as well. At the others speed, the high preload could improve the vibration performance of high speed spindle and the bearing temperature was lower than that of the constant pressure preload spindle.

  10. A case of adult onset medulloblastoma during maintenance chemotherapy for anaplastic astrocytoma one year after radiotherapy.

    Science.gov (United States)

    Takeshi, Nishimoto; Kazuhiko, Sugiyama; Koji, Iida; Toshikazu, Hidaka; Kaoru, Kurisu

    2013-01-01

    Multiple primitive intracranial tumors with different histological characteristics are uncommon. Although coexistence of a medulloblastoma with glial tumors has been reported in children, medulloblastoma is rarely found in adults, especially those older than 40 years of age. We present an extremely rare case of a medulloblastoma developing in a 40-year-old male undergoing maintenance chemotherapy for anaplastic astrocytoma for 21 months after radiotherapy. Initially, he complained of intractable epilepsy characterized by complex partial seizures. Magnetic resonance imaging (MRI) revealed a slightly enhanced mass lesion in the left insula region. He underwent subtotal removal of the tumor and it was histologically diagnosed as anaplastic astrocytoma. After 19 months of treatment with temozolomide (TMZ) and radiotherapy, he presented with vertigo and headache. A homogeneously enhanced mass had developed in the left cerebellar hemisphere. He received gross total resection of the second tumor, pathologically diagnosed as medulloblastoma. In conclusion, this is the first case report of an adult medulloblastoma coexisting with anaplastic astrocytoma. PMID:24101275

  11. Anaplastic transformation of metastatic papillary thyroid carcinoma at shoulder mimicking soft tissue sarcoma

    Directory of Open Access Journals (Sweden)

    Seema Kaushal

    2011-01-01

    Full Text Available A 52-year-old woman presented with fracture upper end of the left humerus after trivial trauma and aspiration cytology from the lytic lesion in the upper humerus seen on X-ray revealed a metastatic papillary carcinoma from the thyroid. Total thyroidectomy confirmed the papillary carcinoma thyroid. Post-operatively, she was given radioactive iodine (I-131 ablation therapy for 8 years and was asymptomatic during this period; however, for the last 1 year, she has been complaining of swelling in the shoulder, which did not respond to palliative radiotherapy and rapidly increased in size. Disarticulation of the shoulder joint was performed, which showed anaplastic carcinoma on histopathological examination. Anaplastic transformation of papillary carcinoma at the metastatic sites is well documented in the literature and is rare. However, the same has not been reported at the shoulder and from India before. Although soft tissue sarcomas are most common at this site, however, the possibility of anaplastic transformation should be kept in the differential diagnosis of rapidly enlarging painful mass in a known case of metastatic thyroid carcinoma to prevent misdiagnosis.

  12. Self-organization mechanisms in the assembly and maintenance of bipolar spindles

    Science.gov (United States)

    Burbank, Kendra Stewart

    Anastral, meiotic spindles are thought to be organized differently from astral, mitotic spindles, but the field has lacked basic structural information required to describe and model them, including the location of microtubule nucleating sites and minus ends. How the various components of spindles act together to establish and maintain the dynamic bipolar structure of spindles is not understood. We measure the distributions of oriented microtubules (MTs) in metaphase anastral spindles in Xenopus extracts by fluorescence speckle microscopy and cross-correlation analysis. We localized plus ends by tubulin incorporation and combined this with the orientation data to infer the localization of minus ends. We find that minus ends are localized throughout the spindle, sparsely at the equator and at higher concentrations near the poles. This dads to the surprising conclusion that spindles contained many short MTs, not connected to the spindle poles. Based on these data, we propose a slide-and-cluster model based on four known molecular activities: MT nucleation near chromosomes, the sliding of MTs by a plus-enddirected motor, the clustering of their minus ends by a minus-end-directed motor, and the loss of MTs by dynamic instability. This work demonstrates how the interplay between two types of motors together with continual nucleation of MTs by chromosomes could organize the MTs into spindles. Our model applies to overlapping, nonkinetochore MTs in anastral spindles, and perhaps also to interpolar MTs in astral spindles. We show mathematically that the slide-and-cluster mechanism robustly forms bipolar spindles a stable steady-state length, sometimes with sharp poles. This model accounts for several experimental observations that were difficult to explain with existing models, and is the first self contained model for anastral spindle assembly, MT sliding (known as poleward flux), and spindle bistability. Our experimental results support the slide-and-cluster scenario

  13. TTF-1-positive oncocytic sellar tumor with follicle formation/ependymal differentiation: non-adenomatous tumor capable of two different interpretations as a pituicytoma or a spindle cell oncocytoma.

    Science.gov (United States)

    Yoshimoto, Toyoki; Takahashi-Fujigasaki, Junko; Inoshita, Naoko; Fukuhara, Noriaki; Nishioka, Hiroshi; Yamada, Shozo

    2015-07-01

    We describe herein the unique case of a 70-year-old male with a TTF-1-positive non-adenomatous sellar tumor that has unusual morphological and immunohistochemical features. MRI examination detected a 2-cm sellar mass that was enhanced heterogeneously. By histology, the tumor was composed of epithelioid and oncocytic cells arranged in a trabecular pattern with occasional luminal structures. The lesion was diffusely immunopositive for thyroid transcription factor-1 (TTF-1) and vimentin but negative for S100 protein and GFAP. Immunoreactivity for epithelial membrane antigen, low molecular weight cytokeratin (CAM 5.2), and neuronal markers was also observed in the tumor cells. By electron microscopy, the tumor cells were filled with abundant mitochondria and extended microvillous projections into small extracellular and intracellular lumens. TTF-1 is considered to be an excellent marker of pituicytes, specialized glia of the neurohypophysis. This case can be regarded as a variant of pituicytoma, showing both ependymal differentiation and oncocytic changes. However, the immunoprofile was not completely consistent with a pituicyte lineage; the epithelial features suggested a possibility of folliculostellate cell origin. TTF-1-positive sellar neoplasms might therefore have variable morphological and immunohistochemical profiles. For suitable classification of TTF-1 positive sellar neoplasms, their histological features should be carefully re-evaluated. PMID:25893822

  14. Mechanisms of daughter cell-size control during cell division.

    Science.gov (United States)

    Kiyomitsu, Tomomi

    2015-05-01

    Daughter cell size is tightly regulated during cell division. In animal cells, the position of the anaphase spindle specifies the cell cleavage site to dictate the relative size of the daughter cells. Although spindle orientation is regulated by dynein-dependent cortical pulling forces exerted on astral microtubules in many cell types, it was unclear how these forces are precisely regulated to center or displace the spindle. Recently, intrinsic signals derived from chromosomes or spindle poles have been demonstrated to regulate dynein-dependent pulling forces in symmetrically dividing cells. Unexpectedly, myosin-dependent contractile forces have also been shown to control spindle position by altering the cellular boundaries during anaphase. In this review, I discuss how dynein- and myosin-dependent forces are coordinately regulated to control daughter cell size. PMID:25548067

  15. Inter-expert and intra-expert reliability in sleep spindle scoring

    DEFF Research Database (Denmark)

    Wendt, Sabrina Lyngbye; Welinder, Peter; Sørensen, Helge Bjarup Dissing;

    2015-01-01

    with higher reliability than the estimation of spindle duration. Reliability of sleep spindle scoring can be improved by using qualitative confidence scores, rather than a dichotomous yes/no scoring system. Conclusions We estimate that 2–3 experts are needed to build a spindle scoring dataset with...... ‘substantial’ reliability (κ: 0.61–0.8), and 4 or more experts are needed to build a dataset with ‘almost perfect’ reliability (κ: 0.81–1). Significance Spindle scoring is a critical part of sleep staging, and spindles are believed to play an important role in development, aging, and diseases of the nervous......Objectives To measure the inter-expert and intra-expert agreement in sleep spindle scoring, and to quantify how many experts are needed to build a reliable dataset of sleep spindle scorings. Methods The EEG dataset was comprised of 400 randomly selected 115 s segments of stage 2 sleep from 110...

  16. Sleep Spindles as an Electrographic Element: Description and Automatic Detection Methods

    Science.gov (United States)

    Maquet, Pierre

    2016-01-01

    Sleep spindle is a peculiar oscillatory brain pattern which has been associated with a number of sleep (isolation from exteroceptive stimuli, memory consolidation) and individual characteristics (intellectual quotient). Oddly enough, the definition of a spindle is both incomplete and restrictive. In consequence, there is no consensus about how to detect spindles. Visual scoring is cumbersome and user dependent. To analyze spindle activity in a more robust way, automatic sleep spindle detection methods are essential. Various algorithms were developed, depending on individual research interest, which hampers direct comparisons and meta-analyses. In this review, sleep spindle is first defined physically and topographically. From this general description, we tentatively extract the main characteristics to be detected and analyzed. A nonexhaustive list of automatic spindle detection methods is provided along with a description of their main processing principles. Finally, we propose a technique to assess the detection methods in a robust and comparable way.

  17. Sleep Spindles as an Electrographic Element: Description and Automatic Detection Methods

    Directory of Open Access Journals (Sweden)

    Dorothée Coppieters ’t Wallant

    2016-01-01

    Full Text Available Sleep spindle is a peculiar oscillatory brain pattern which has been associated with a number of sleep (isolation from exteroceptive stimuli, memory consolidation and individual characteristics (intellectual quotient. Oddly enough, the definition of a spindle is both incomplete and restrictive. In consequence, there is no consensus about how to detect spindles. Visual scoring is cumbersome and user dependent. To analyze spindle activity in a more robust way, automatic sleep spindle detection methods are essential. Various algorithms were developed, depending on individual research interest, which hampers direct comparisons and meta-analyses. In this review, sleep spindle is first defined physically and topographically. From this general description, we tentatively extract the main characteristics to be detected and analyzed. A nonexhaustive list of automatic spindle detection methods is provided along with a description of their main processing principles. Finally, we propose a technique to assess the detection methods in a robust and comparable way.

  18. Developmental Changes in Sleep Spindle Characteristics and Sigma Power across Early Childhood.

    Science.gov (United States)

    McClain, Ian J; Lustenberger, Caroline; Achermann, Peter; Lassonde, Jonathan M; Kurth, Salome; LeBourgeois, Monique K

    2016-01-01

    Sleep spindles, a prominent feature of the non-rapid eye movement (NREM) sleep electroencephalogram (EEG), are linked to cognitive abilities. Early childhood is a time of rapid cognitive and neurophysiological maturation; however, little is known about developmental changes in sleep spindles. In this study, we longitudinally examined trajectories of multiple sleep spindle characteristics (i.e., spindle duration, frequency, integrated spindle amplitude, and density) and power in the sigma frequency range (10-16 Hz) across ages 2, 3, and 5 years (n = 8; 3 males). At each time point, nocturnal sleep EEG was recorded in-home after 13-h of prior wakefulness. Spindle duration, integrated spindle amplitude, and sigma power increased with age across all EEG derivations (C3A2, C4A1, O2A1, and O1A2; all ps ontogenesis in early childhood and may help identify electrophysiological features related to healthy and aberrant brain maturation. PMID:27110405

  19. A novel, diffusely infiltrative xenograft model of human anaplastic oligodendroglioma with mutations in FUBP1, CIC, and IDH1.

    Directory of Open Access Journals (Sweden)

    Barbara Klink

    Full Text Available Oligodendroglioma poses a biological conundrum for malignant adult human gliomas: it is a tumor type that is universally incurable for patients, and yet, only a few of the human tumors have been established as cell populations in vitro or as intracranial xenografts in vivo. Their survival, thus, may emerge only within a specific environmental context. To determine the fate of human oligodendroglioma in an experimental model, we studied the development of an anaplastic tumor after intracranial implantation into enhanced green fluorescent protein (eGFP positive NOD/SCID mice. Remarkably after nearly nine months, the tumor not only engrafted, but it also retained classic histological and genetic features of human oligodendroglioma, in particular cells with a clear cytoplasm, showing an infiltrative growth pattern, and harboring mutations of IDH1 (R132H and of the tumor suppressor genes, FUBP1 and CIC. The xenografts were highly invasive, exhibiting a distinct migration and growth pattern around neurons, especially in the hippocampus, and following white matter tracts of the corpus callosum with tumor cells accumulating around established vasculature. Although tumors exhibited a high growth fraction in vivo, neither cells from the original patient tumor nor the xenograft exhibited significant growth in vitro over a six-month period. This glioma xenograft is the first to display a pure oligodendroglioma histology and expression of R132H. The unexpected property, that the cells fail to grow in vitro even after passage through the mouse, allows us to uniquely investigate the relationship of this oligodendroglioma with the in vivo microenvironment.

  20. A comparison of two sleep spindle detection methods based on all night averages: individually adjusted versus fixed frequencies

    Directory of Open Access Journals (Sweden)

    Péter Przemyslaw Ujma

    2015-02-01

    Full Text Available Sleep spindles are frequently studied for their relationship with state and trait cognitive variables, and they are thought to play an important role in sleep-related memory consolidation. Due to their frequent occurrence in NREM sleep, the detection of sleep spindles is only feasible using automatic algorithms, of which a large number is available. We compared subject averages of the spindle parameters computed by a fixed frequency (11-13 Hz for slow spindles, 13-15 Hz for fast spindles automatic detection algorithm and the individual adjustment method (IAM, which uses individual frequency bands for sleep spindle detection. Fast spindle duration and amplitude are strongly correlated in the two algorithms, but there is little overlap in fast spindle density and slow spindle parameters in general. The agreement between fixed and manually determined sleep spindle frequencies is limited, especially in case of slow spindles. This is the most likely reason for the poor agreement between the two detection methods in case of slow spindle parameters. Our results suggest that while various algorithms may reliably detect fast spindles, a more sophisticated algorithm primed to individual spindle frequencies is necessary for the detection of slow spindles as well as individual variations in the number of spindles in general.

  1. Development of anaplastic lymphoma kinase (ALK inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer

    Directory of Open Access Journals (Sweden)

    Iwama E

    2014-03-01

    Full Text Available Eiji Iwama,1,2 Isamu Okamoto,3 Taishi Harada,2 Koichi Takayama,2 Yoichi Nakanishi2,3 1Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences, Kyushu University, 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan Abstract: The fusion of echinoderm microtubule-associated protein-like 4 with anaplastic lymphoma kinase (ALK was identified as a transforming gene for lung cancer in 2007. This genetic rearrangement accounts for 2%–5% of non-small-cell lung cancer (NSCLC cases, occurring predominantly in younger individuals with adenocarcinoma who are never- or light smokers. A small-molecule tyrosine-kinase inhibitor of ALK, crizotinib, was rapidly approved by the US Food and Drug Administration on the basis of its pronounced clinical activity in patients with ALK rearrangement-positive NSCLC. Next-generation ALK inhibitors, such as alectinib, LDK378, and AP26113, are also being developed in ongoing clinical trials. In addition, the improvement and validation of methods for the detection of ALK rearrangement in NSCLC patients will be key to the optimal clinical use of ALK inhibitors. We here summarize recent progress in the development of new ALK inhibitors and in the molecular diagnosis of ALK rearrangement-positive NSCLC. Keywords: ALK, rearrangement, NSCLC, ALK inhibitor, targeted therapy, diagnosis

  2. Human papillomavirus type 16 E7 oncoprotein engages but does not abrogate the mitotic spindle assembly checkpoint

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Yueyang [Division of Infectious Diseases, Brigham and Women' s Hospital and Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115 (United States); Munger, Karl, E-mail: kmunger@rics.bwh.harvard.edu [Division of Infectious Diseases, Brigham and Women' s Hospital and Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115 (United States)

    2012-10-10

    The mitotic spindle assembly checkpoint (SAC) ensures faithful chromosome segregation during mitosis by censoring kinetochore-microtubule interactions. It is frequently rendered dysfunctional during carcinogenesis causing chromosome missegregation and genomic instability. There are conflicting reports whether the HPV16 E7 oncoprotein drives chromosomal instability by abolishing the SAC. Here we report that degradation of mitotic cyclins is impaired in cells with HPV16 E7 expression. RNAi-mediated depletion of Mad2 or BubR1 indicated the involvement of the SAC, suggesting that HPV16 E7 expression causes sustained SAC engagement. Mutational analyses revealed that HPV16 E7 sequences that are necessary for retinoblastoma tumor suppressor protein binding as well as sequences previously implicated in binding the nuclear and mitotic apparatus (NuMA) protein and in delocalizing dynein from the mitotic spindle contribute to SAC engagement. Importantly, however, HPV16 E7 does not markedly compromise the SAC response to microtubule poisons.

  3. Dynein Light Intermediate Chain 2 Facilitates the Metaphase to Anaphase Transition by Inactivating the Spindle Assembly Checkpoint.

    Directory of Open Access Journals (Sweden)

    Sagar P Mahale

    Full Text Available The multi-functional molecular motor cytoplasmic dynein performs diverse essential roles during mitosis. The mechanistic importance of the dynein Light Intermediate Chain homologs, LIC1 and LIC2 is unappreciated, especially in the context of mitosis. LIC1 and LIC2 are believed to exist in distinct cytoplasmic dynein complexes as obligate subunits. LIC1 had earlier been reported to be required for metaphase to anaphase progression by inactivating the kinetochore-microtubule attachment-sensing arm of the spindle assembly checkpoint (SAC. However, the functional importance of LIC2 during mitosis remains elusive. Here we report prominent novel roles for the LIC2 subunit of cytoplasmic dynein in regulating the spindle assembly checkpoint. LIC2 depletion in mammalian cells led to prolonged metaphase arrest in the presence of an active SAC and also to stretched kinetochores, thus implicating it in SAC inactivation. Quantitative fluorescence microscopy of SAC components revealed accumulation of both attachment- and tension-sensing checkpoint proteins at metaphase kinetochores upon LIC2 depletion. These observations support a stronger and more diverse role in checkpoint inactivation for LIC2 in comparison to its close homolog LIC1. Our study uncovers a novel functional hierarchy during mitotic checkpoint inactivation between the closely related but homologous LIC subunits of cytoplasmic dynein. These subtle functional distinctions between dynein subpopulations could be exploited to study specific aspects of the spindle assembly checkpoint, which is a key mediator of fidelity in eukaryotic cell division.

  4. Dynein Light Intermediate Chain 2 Facilitates the Metaphase to Anaphase Transition by Inactivating the Spindle Assembly Checkpoint

    Science.gov (United States)

    Mahale, Sagar P.; Sharma, Amit; Mylavarapu, Sivaram V. S.

    2016-01-01

    The multi-functional molecular motor cytoplasmic dynein performs diverse essential roles during mitosis. The mechanistic importance of the dynein Light Intermediate Chain homologs, LIC1 and LIC2 is unappreciated, especially in the context of mitosis. LIC1 and LIC2 are believed to exist in distinct cytoplasmic dynein complexes as obligate subunits. LIC1 had earlier been reported to be required for metaphase to anaphase progression by inactivating the kinetochore-microtubule attachment-sensing arm of the spindle assembly checkpoint (SAC). However, the functional importance of LIC2 during mitosis remains elusive. Here we report prominent novel roles for the LIC2 subunit of cytoplasmic dynein in regulating the spindle assembly checkpoint. LIC2 depletion in mammalian cells led to prolonged metaphase arrest in the presence of an active SAC and also to stretched kinetochores, thus implicating it in SAC inactivation. Quantitative fluorescence microscopy of SAC components revealed accumulation of both attachment- and tension-sensing checkpoint proteins at metaphase kinetochores upon LIC2 depletion. These observations support a stronger and more diverse role in checkpoint inactivation for LIC2 in comparison to its close homolog LIC1. Our study uncovers a novel functional hierarchy during mitotic checkpoint inactivation between the closely related but homologous LIC subunits of cytoplasmic dynein. These subtle functional distinctions between dynein subpopulations could be exploited to study specific aspects of the spindle assembly checkpoint, which is a key mediator of fidelity in eukaryotic cell division. PMID:27441562

  5. Downregulation of Protein 4.1R impairs centrosome function,bipolar spindle organization and anaphase

    Energy Technology Data Exchange (ETDEWEB)

    Spence, Jeffrey R.; Go, Minjoung M.; Bahmanyar, S.; Barth,A.I.M.; Krauss, Sharon Wald

    2006-03-17

    Centrosomes nucleate and organize interphase MTs and areinstrumental in the assembly of the mitotic bipolar spindle. Here wereport that two members of the multifunctional protein 4.1 family havedistinct distributions at centrosomes. Protein 4.1R localizes to maturecentrioles whereas 4.1G is a component of the pericentriolar matrixsurrounding centrioles. To selectively probe 4.1R function, we used RNAinterference-mediated depletion of 4.1R without decreasing 4.1Gexpression. 4.1R downregulation reduces MT anchoring and organization atinterphase and impairs centrosome separation during prometaphase.Metaphase chromosomes fail to properly condense/align and spindleorganization is aberrant. Notably 4.1R depletion causes mislocalizationof its binding partner NuMA (Nuclear Mitotic Apparatus Protein),essential for spindle pole focusing, and disrupts ninein. Duringanaphase/telophase, 4.1R-depleted cells have lagging chromosomes andaberrant MT bridges. Our data provide functional evidence that 4.1R makescrucial contributions to centrosome integrity and to mitotic spindlestructure enabling mitosis and anaphase to proceed with the coordinatedprecision required to avoid pathological events.

  6. The discovery and eradication of potato spindle tuber viroid in Canada.

    Science.gov (United States)

    Singh, Rudra P

    2014-12-01

    In 1960s, potato spindle tuber was thought to be a viral disease. In 1971, the agent of the disease was characterised as a low-molecular weight infectious ribonucleic acid (RNA), which was named as 'viroid', specifically Potato spindle tuber viroid (PSTVd)). Since then, more than 30 plant diseases in horticultural and ornamental plants have been shown to be caused by different viroids globally. Viroids are single-stranded RNA, covalently closed circular molecule, without any protein coat. They are the smallest known plant pathogen containing RNA genome ranging from 246 nucleotides (Coconut cadang-cadang viroid) to 399 nucleotides (Chrysanthemum chlorotic mottle viroid). Some viroids are located in the plant cell nucleus (pospiviroids) and others in the chloroplast (avsunviroids). With the recognition of pathogenic nature of viroid, specific detection methodologies were developed, which enabled detection of PSTVd in seed-potato tubers prior to their planting in the field, and thus PSTVd was prevented from spreading the disease. As a result, PSTVd was eradicated from Canada in late 1980s. Viroids similar to PSTVd (Pospiviroid) have been discovered and they are detected in symptomless ornamental plants. Although, PSTVd has been eradicated from Canada, there is a strong possibility of viroid introduction from other plants besides potato and tomato and causing PSTVd like diseases. PMID:25674616

  7. Sleep spindle alterations in patients with Parkinson's disease

    DEFF Research Database (Denmark)

    Christensen, Julie Anja Engelhard; Nikolic, Miki; Warby, Simon C.;

    2015-01-01

    The aim of this study was to identify changes of sleep spindles (SS) in the EEG of patients with Parkinson's disease (PD). Five sleep experts manually identified SS at a central scalp location (C3-A2) in 15 PD and 15 age- and sex-matched control subjects. Each SS was given a confidence score, and...... automatic detection of SS in patients with PD or other neurodegenerative disorders (NDDs)....

  8. Automatic sleep spindle detection and genetic influence estimation using continuous wavelet transform

    Directory of Open Access Journals (Sweden)

    Marek Adamczyk

    2015-11-01

    Full Text Available Mounting evidence for the role of sleep spindles for neuroplasticity led to an increased interest in these NREM sleep oscillations. It has been hypothesized that fast and slow spindles might play a different role in memory processing. Here we present a new sleep spindle detection algorithm utilizing a continuous wavelet transform and individual adjustment of slow and fast spindle frequency ranges. 18 nap recordings of 10 subjects were used for algorithm validation. Our method was compared with human scorer and commercially available SIESTA spindle detector. For the validation set, mean agreement between our detector and human scorer measured during sleep stage 2 using kappa coefficient was 0.45, whereas mean agreement between our detector and SIESTA algorithm was 0.62. Our algorithm was also applied to sleep-related memory consolidation data previously analyzed with SIESTA detector and confirmed previous findings of significant correlation between spindle density and declarative memory consolidation. Then, we applied our method to a study in monozygotic (MZ and dizygotic (DZ twins examining the heritability of slow and fast sleep spindle parameters. Our analysis revealed strong genetic influence of all slow spindle parameters, weaker genetic effect on fast spindles and no effects on fast spindle density and number during stage 2 sleep.

  9. FDG PET staging compared to C.T. in children with Hodgkin's disease or anaplastic lymphoma

    International Nuclear Information System (INIS)

    The accuracy of initial staging in Hodgkin's disease and anaplastic lymphoma is very important since treatment depends on the initial staging disease. An error of assessment can have serious consequences on evolution and survival. To judge PET scan performances initial staging was done on our patients by both conventional imaging and PET scan. Methods: 21 children (10 girls, 11 boys), median age 14,9 years (8 to 22) had a PET scan for the initial staging (17 Hodgkin's disease, 4 anaplastic lymphomas). Conventional staging for imaging included: Thorax x-ray, thorax and abdomen C.T., abdominal echography, and also two bone marrow biopsies. Others exams were done in accordance with special clinical data. PET scan was done on a C PET scan ADAC one hour after IV injection of 2 MBq/Kg of 18 FDG. C.T. and PET scan images were revised blindly and separately by radiologist and nuclearist with no knowledge of clinical data. Results: the staging by C.I. and PET scan were concordant in 84% of cases. In 16% of cases PET scan displayed localisation not seen by C.I., particularly bone lesions. The staging changed grading status from stage III to stage IV. The clinical cases will be presented. PET scan upgrading were confirmed by resonance imaging or bone scintigraphy. The change of stage led in each child an intensification of chemotherapy (6 courses instead of 4). Conclusion: FDG PET is a useful diagnostic tool in children with Hodgkin's disease or anaplastic lymphoma to achieve with a single exam an accurate staging allowing to choose the best treatment

  10. THE ASSOCIATION OF WELL-DIFFERENTIATED THYROID-CARCINOMA WITH INSULAR OR ANAPLASTIC THYROID-CARCINOMA - EVIDENCE FOR DEDIFFERENTIATION IN TUMOR PROGRESSION

    NARCIS (Netherlands)

    van der Laan, Bernard F.A.M.; FREEMAN, JL; TSANG, RW; ASA, SL

    1993-01-01

    The sequence of tumorigenesis in the thyroid is unclear. It has been proposed that anaplastic carcinomas of the thyroid develop by dedifferentiation in pre-existing differentiated carcinomas. We reviewed all anaplastic and insular (poorly differentiated) thyroid carcinomas in a consultation practice

  11. Micronucleus test and metaphase analyses in mice exposed to known and suspected spindle poisons.

    Science.gov (United States)

    Marrazzini, A; Betti, C; Bernacchi, F; Barrai, I; Barale, R

    1994-11-01

    Micronucleus (Mn) and metaphase chromosome analyses were performed in mouse bone marrow cells with two known and eight suspected mitotic spindle poisons. Polychromatic (PCEs) and normochromatic (NCEs) erythrocytes were scored for presence of Mn, while structural (CAs) and numerical chromosome aberrations (NCAs), i.e. hyperploid cells, were evaluated by metaphase analysis. CAs were scored in first, and NCAs in the second metaphases, identified by BrdUrd differential staining. Hydroquinone induced Mn, NCAs and CAs; colchicine, vinblastine and, to a lesser extent, chloral hydrate, diazepam and econazole induced both Mn and NCAs; cadmium chloride and thimerosal induced Mn and CAs, while pyrimethamine and thiabendazole induced Mn only. The proposed stepwise protocol allowed satisfactory statistical evaluation of the effects induced with a reduction in the number of animals killed. An acceptable agreement was found between induction of Mn and NCAs, suggesting a possible use of the Mn test for revealing compounds with aneugenic properties. PMID:7854141

  12. Distribution of potato spindle tuber viroid in reproductive organs of petunia during its developmental stages.

    Science.gov (United States)

    Matsushita, Yosuke; Tsuda, Shinya

    2014-09-01

    Embryo infection is important for efficient seed transmission of viroids. To identify the major pattern of seed transmission of viroids, we used in situ hybridization to histochemically analyze the distribution of Potato spindle tuber viroid (PSTVd) in each developmental stage of petunia (flowering to mature seed stages). In floral organs, PSTVd was present in the reproductive tissues of infected female × infected male and infected female × healthy male but not of healthy female × infected male before embryogenesis. After pollination, PSTVd was detected in the developed embryo and endosperm in all three crosses. These findings indicate that PSTVd is indirectly delivered to the embryo through ovule or pollen during the development of reproductive tissues before embryogenesis but not directly through maternal tissues as cell-to-cell movement during embryogenesis. PMID:25116641

  13. Emergency total thyroidectomy for bleeding anaplastic thyroid carcinoma: A viable option for palliation

    Directory of Open Access Journals (Sweden)

    Sunil Kumar

    2011-01-01

    Full Text Available Anaplastic thyroid carcinoma (ATC is a rare and highly aggressive thyroid neoplasm. Bleeding from tumor is an uncommon, but potentially life-threatening complication requiring sophisticated intervention facilities which are not usually available at odd hours in emergency. We report the case of a 45-year-old woman who presented with exsanguinating hemorrhage from ATC and was treated by emergency total thyroidectomy. The patient is well three months postoperatively. Emergency total thyroidectomy is a viable option for palliation in ATC presenting with bleeding.

  14. A significant response to sunitinib in a patient with anaplastic thyroid carcinoma

    Directory of Open Access Journals (Sweden)

    Enrique Grande

    2013-01-01

    Full Text Available Anaplastic thyroid cancer (ATC is a rare disease with an incidence of less than three cases per million of habitants in western countries. ATC accounts for 1-10% of all tumors derived from the thyroid gland. Classic chemotherapy approach based on platinum and anthracyclines regimens have been considered standard for the last decades. Novel multitarget agents have shown promising responses; however, no positive randomized clinical trials are available up to now. To our knowledge, the case we are presenting here is the first reported case showing clinical and visual activity using sunitinib as a salvage treatment in an ATC patient who was not fit to receive systemic chemotherapy treatment.

  15. Investigation of the results of therapy of anaplastic thyroid gland carcinomas

    International Nuclear Information System (INIS)

    The results of the treatment of 28 patients with an anaplastic thyroid gland carcinoma are investigated, to see whether an optimal therapy is indicated. The execution of an operation before radiotherapy does not appear to improve the prognosis (statistically this conclusion is not wholly justified). The presence of metastases at the beginning of the therapy gave rise to a worse prognosis than the absence of metastases. The combination treatment of chemotherapy and either surgery or radiotherapy was only applied to two patients so no conclusions can be made about its benefit. (C.F.)

  16. Evaluation of Lentiviral-Mediated Expression of Sodium Iodide Symporter in Anaplastic Thyroid Cancer and the Efficacy of In Vivo Imaging and Therapy

    Directory of Open Access Journals (Sweden)

    Chien-Chih Ke

    2011-01-01

    Full Text Available Anaplastic thyroid carcinoma (ATC is one of the most deadly cancers. With intensive multimodalities of treatment, the survival remains low. ATC is not sensitive to 131I therapy due to loss of sodium iodide symporter (NIS gene expression. We have previously generated a stable human NIS-expressing ATC cell line, ARO, and the ability of iodide accumulation was restored. To make NIS-mediated gene therapy more applicable, this study aimed to establish a lentiviral system for transferring hNIS gene to cells and to evaluate the efficacy of in vitro and in vivo radioiodide accumulation for imaging and therapy. Lentivirus containing hNIS cDNA were produced to transduce ARO cells which do not concentrate iodide. Gene expression, cell function, radioiodide imaging and treatment were evaluated in vitro and in vivo. Results showed that the transduced cells were restored to express hNIS and accumulated higher amount of radioiodide than parental cells. Therapeutic dose of 131I effectively inhibited the tumor growth derived from transduced cells as compared to saline-treated mice. Our results suggest that the lentiviral system efficiently transferred and expressed hNIS gene in ATC cells. The transduced cells showed a promising result of tumor imaging and therapy.

  17. Primary nodal peripheral T-cell lymphomas: diagnosis and therapeutic considerations

    Directory of Open Access Journals (Sweden)

    Luis Alberto de Pádua Covas Lage

    2015-08-01

    Full Text Available Nodal peripheral T-cell lymphomas are a rare group of neoplasms derived from post-thymic and activated T lymphocytes. A review of scientific articles listed in PubMed, Lilacs, and the Cochrane Library databases was performed using the term "peripheral T-cell lymphomas". According to the World Health Organization classification of hematopoietic tissue tumors, this group of neoplasms consists of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS, angioimmunoblastic T-cell lymphoma (AITL, anaplastic large cell lymphoma-anaplastic lymphoma kinase positive (ALCL-ALK+, and a provisional entity called anaplastic large cell lymphoma-anaplastic lymphoma kinase negative (ALCL-ALK-. Because the treatment and prognoses of these neoplasms involve different principles, it is essential to distinguish each one by its clinical, immunophenotypic, genetic, and molecular features. Except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, which has no adverse international prognostic index, the prognosis of nodal peripheral T-cell lymphomas is worse than that of aggressive B-cell lymphomas. Chemotherapy based on anthracyclines provides poor outcomes because these neoplasms frequently have multidrug-resistant phenotypes. Based on this, the current tendency is to use intensified cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP regimens with the addition of new drugs, and autologous hematopoietic stem cell transplantation. This paper describes the clinical features and diagnostic methods, and proposes a therapeutic algorithm for nodal peripheral T-cell lymphoma patients.

  18. EFFECT OF ANGELICA SINENSIS ON AFFERENT DISCHARGE OF SINGLE MUSCLE SPINDLE IN TOADS

    Institute of Scientific and Technical Information of China (English)

    高云芳; 樊小力

    2004-01-01

    Objective In drugs for invigorating blood circulation, to find a herb that can stimulate afferent discharge of muscle spindle. Methods A single muscle spindle was isolated from sartorial muscle of toad. Using air-gap technique, afferent discharge of the muscle spindle was recorded. Effects of Angelica Sinensis, Salvia Miltiorrhiza, and Safflower on afferent discharge of the muscle spindle were observed. Results Angelica Sinensis could distinctly increase afferent discharge frequency of the muscle spindle, and this increase was dose-dependent. But Salvia Miltiorrhiza and Safflower had no this excitatory effect. Conclusion It is known that Angelica Sinensis can invigorate blood circulation, and we have found its excitatory effect on muscle spindle which makes it possible to serve people with muscle atrophy if more evidences from clinical experiments are available.

  19. The Significance of Sigma Neurofeedback Training on Sleep Spindles and Aspects of Declarative Memory

    OpenAIRE

    Berner, I.; Schabus, M; Wienerroither, T.; Klimesch, W.

    2006-01-01

    The functional significance of sleep spindles for overnight memory consolidation and general learning aptitude as well as the effect of four 10-minute sessions of spindle frequency (11.6–16 Hz, sigma) neurofeedback-training on subsequent sleep spindle activity and overnight performance change was investigated. Before sleep, subjects were trained on a paired-associate word list task after having received either neurofeedback training (NFT) or pseudofeedback training (PFT).

  20. The role of muscle spindles in the development of the monosynaptic stretch reflex

    OpenAIRE

    Wang, Zhi; Li, LingYing; Frank, Eric

    2012-01-01

    Muscle sensory axons induce the development of specialized intrafusal muscle fibers in muscle spindles during development, but the role that the intrafusal fibers may play in the development of the central projections of these Ia sensory axons is unclear. In the present study, we assessed the influence of intrafusal fibers in muscle spindles on the formation of monosynaptic connections between Ia (muscle spindle) sensory axons and motoneurons (MNs) using two transgenic strains of mice. Deleti...

  1. A comparative evaluation of supervised and unsupervised representation learning approaches for anaplastic medulloblastoma differentiation

    Science.gov (United States)

    Cruz-Roa, Angel; Arevalo, John; Basavanhally, Ajay; Madabhushi, Anant; González, Fabio

    2015-01-01

    Learning data representations directly from the data itself is an approach that has shown great success in different pattern recognition problems, outperforming state-of-the-art feature extraction schemes for different tasks in computer vision, speech recognition and natural language processing. Representation learning applies unsupervised and supervised machine learning methods to large amounts of data to find building-blocks that better represent the information in it. Digitized histopathology images represents a very good testbed for representation learning since it involves large amounts of high complex, visual data. This paper presents a comparative evaluation of different supervised and unsupervised representation learning architectures to specifically address open questions on what type of learning architectures (deep or shallow), type of learning (unsupervised or supervised) is optimal. In this paper we limit ourselves to addressing these questions in the context of distinguishing between anaplastic and non-anaplastic medulloblastomas from routine haematoxylin and eosin stained images. The unsupervised approaches evaluated were sparse autoencoders and topographic reconstruct independent component analysis, and the supervised approach was convolutional neural networks. Experimental results show that shallow architectures with more neurons are better than deeper architectures without taking into account local space invariances and that topographic constraints provide useful invariant features in scale and rotations for efficient tumor differentiation.

  2. Research on Control System of Spindle Drive for High Speed Spinning Machine

    Institute of Scientific and Technical Information of China (English)

    魏建

    2001-01-01

    Through analyzing the principle of spindle drive of winding mechanism for high speed spinning machine,the article not only describes a kind of mode of spindle drive for take-up motion on the basis of control method of constant velocity winding, but also introduces the design technique of software and hardware for the control system of mechatronics of spindle drive mode for take- up motion on the basis of constant velocity winding for high speed spinning machine with single-chip microcomputer. The mathematical model to describe the spindle rotating speed is established. It is an important technology for high speed spinning machine and provides a feasible application way.

  3. An Overview of the Spindle Assembly Checkpoint Status in Oral Cancer

    Science.gov (United States)

    Teixeira, José Henrique; Silva, Patrícia Manuela; Reis, Rita Margarida; Moura, Inês Moranguinho; Marques, Sandra; Fonseca, Joana; Monteiro, Luís Silva; Bousbaa, Hassan

    2014-01-01

    Abnormal chromosome number, or aneuploidy, is a common feature of human solid tumors, including oral cancer. Deregulated spindle assembly checkpoint (SAC) is thought as one of the mechanisms that drive aneuploidy. In normal cells, SAC prevents anaphase onset until all chromosomes are correctly aligned at the metaphase plate thereby ensuring genomic stability. Significantly, the activity of this checkpoint is compromised in many cancers. While mutations are rather rare, many tumors show altered expression levels of SAC components. Genomic alterations such as aneuploidy indicate a high risk of oral cancer and cancer-related mortality, and the molecular basis of these alterations is largely unknown. Yet, our knowledge on the status of SAC components in oral cancer remains sparse. In this review, we address the state of our knowledge regarding the SAC defects and the underlying molecular mechanisms in oral cancer, and discuss their therapeutic relevance, focusing our analysis on the core components of SAC and its target Cdc20. PMID:24995269

  4. Anaplastic Thyroid Carcinoma: A ceRNA Analysis Pointed to a Crosstalk between SOX2, TP53, and microRNA Biogenesis

    Directory of Open Access Journals (Sweden)

    Walter Arancio

    2015-01-01

    Full Text Available It has been suggested that cancer stem cells (CSC may play a central role in oncogenesis, especially in undifferentiated tumours. Anaplastic thyroid carcinoma (ATC has characteristics suggestive of a tumour enriched in CSC. Previous studies suggested that the stem cell factor SOX2 has a preeminent hierarchical role in determining the characteristics of stem cells in SW1736 ATC cell line. In detail, silencing SOX2 in SW1736 is able to suppress the expression of the stem markers analysed, strongly sensitizing the line to treatment with chemotherapeutic agents. Therefore, in order to further investigate the role of SOX2 in ATC, a competing endogenous RNA (ceRNA analysis was conducted in order to isolate new functional partners of SOX2. Among the interactors, of particular interest are genes involved in the biogenesis of miRNAs (DICER1, RNASEN, and EIF2C2, in the control cell cycle (TP53, CCND1, and in mitochondrial activity (COX8A. The data suggest that stemness, microRNA biogenesis and functions, p53 regulatory network, cyclin D1, and cell cycle control, together with mitochondrial activity, might be coregulated.

  5. Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951

    NARCIS (Netherlands)

    M.C.M. Kouwenhoven (Mathilde); T.S. Gorlia (Thierry); J.M. Kros (Johan); A. Ibdaih (Ahmed); A. Brandes (Alba); J.E.C. Bromberg (Jacolien); K. Mokhtari (Karima); S.G. van Duinen (Sjoerd); J.L.J.M. Teepen; P. Wesseling (Pieter); F. Vandenbos (Fanny); W. Grisold (Wolfgang); L. Sipos (László); R.O. Mirimanoff; C.J. Vecht (Charles); A. Allgeier (Anouk); D. Lacombe (Denis); M.J. van den Bent (Martin)

    2009-01-01

    textabstractRecent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated whether the assessment of 1p/19q codeletion, polysomy of chromosome 7, epidermal growth f

  6. Detection of novel and potentially actionable anaplastic lymphoma kinase (ALK) rearrangement in colorectal adenocarcinoma by immunohistochemistry screening

    OpenAIRE

    Lee, Jeeyun; Kim, Hee Cheol; Hong, Jung Yong; Wang, Kai; Kim, Sun Young; Jang, Jiryeon; Kim, Seung Tae; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Park, Young Suk; Lee, Jiyun; Lee, Woo Yong; Park, Yoon Ah; Huh, Jung Wook

    2015-01-01

    Purpose Anaplastic lymphoma kinase (ALK) rearrangement has been detected in colorectal carcinoma (CRC) using advanced molecular diagnostics tests including exon scanning, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). We investigated if immunohistochemistry (IHC) can be used to detect ALK rearrangement in gastrointestinal malignancies. Experimental designs Tissue microarrays (TMAs) from consecutive gastric carcinoma (GC) and CRC patients who underwent surgica...

  7. Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951.

    Science.gov (United States)

    Kouwenhoven, Mathilde C M; Gorlia, Thierry; Kros, Johan M; Ibdaih, Ahmed; Brandes, Alba A; Bromberg, Jacolien E C; Mokhtari, Karima; van Duinen, Sjoerd G; Teepen, Johannes L; Wesseling, Pieter; Vandenbos, Fanny; Grisold, Wolfgang; Sipos, László; Mirimanoff, Rene; Vecht, Charles J; Allgeier, Anouk; Lacombe, Denis; van den Bent, Martin J

    2009-12-01

    Recent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated whether the assessment of 1p/19q codeletion, polysomy of chromosome 7, epidermal growth factor receptor (EGFR) gene amplification (EGFR(amp)), and loss of chromosome 10 or 10q offers additional prognostic information to the histological diagnosis and would allow molecular subtyping. For this study, we used the clinical data and tumor samples of the patients included in multicenter prospective phase III European Organisation for Research and Treatment of Cancer (EORTC) study 26951 on the effects of adjuvant procarbazine, chloroethyl cyclohexylnitrosourea (lomustine), and vincristine chemotherapy in anaplastic oligodendroglial tumors. Fluorescence in situ hybridization was used to assess copy number aberrations of chromosome 1p, 19q, 7, 10, and 10q and EGFR. Three different analyses were performed: on all included patients based on local pathology diagnosis, on the patients with confirmed anaplastic oligodendroglial tumors on central pathology review, and on this latter group but after excluding anaplastic oligoastrocytoma (AOA) with necrosis. As a reference set for glioblastoma multiforme (GBM), patients from the prospective randomized phase III study on GBM (EORTC 26981) were used as a benchmark. In 257 of 368 patients, central pathology review confirmed the presence of an anaplastic oligodendroglial tumor. Tumors with combined 1p and 19q loss (1p(loss)19q(loss)) were histopathologically diagnosed as anaplastic oligodendroglioma, were more frequently located in the frontal lobe, and had a better outcome. Anaplastic oligodendroglial tumors with EGFR(amp) were more frequently AOA, were more often localized outside the frontal lobe, and had a survival similar to that for GBM. Survival of patients with AOA harboring necrosis was in a similar range as for GBM, while patients

  8. Impact of 1p/19q Codeletion and Histology on Outcomes of Anaplastic Gliomas Treated With Radiation Therapy and Temozolomide

    Energy Technology Data Exchange (ETDEWEB)

    Speirs, Christina K.; Simpson, Joseph R.; Robinson, Clifford G.; DeWees, Todd A. [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Tran, David D.; Linette, Gerry [Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Chicoine, Michael R.; Dacey, Ralph G.; Rich, Keith M.; Dowling, Joshua L.; Leuthardt, Eric C.; Zipfel, Gregory J.; Kim, Albert H. [Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri (United States); Huang, Jiayi, E-mail: jhuang@radonc.wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States)

    2015-02-01

    Purpose: Anaplastic gliomas represent a heterogeneous group of primary high-grade brain tumors, and the optimal postoperative treatment remains controversial. In this report, we present our institutional data on the clinical outcomes of radiation therapy (RT) plus temozolomide (RT + TMZ) for anaplastic gliomas, stratified by histology and 1p/19q codeletion. Methods and Materials: A single-institution retrospective review was conducted of patients with supratentorial anaplastic oligodendroglioma (AO), mixed anaplastic oligoastrocytoma (AOA), and anaplastic astrocytoma (AA). After surgery, RT was delivered at a median total dose of 60 Gy (range, 31.6-63 Gy) in daily fractions. All patients received standard concurrent TMZ, with or without adjuvant TMZ. Histological/molecular subtypes were defined as codeleted AO/AOA, non-codeleted AO/AOA, and AA. Results: From 2000 to 2012, 111 cases met study criteria and were evaluable. Codeleted AO/AOA had superior overall survival (OS) to non-codeleted AO/AOA (91% vs 68% at 5 years, respectively, P=.02), whereas progression-free survival (PFS) was not significantly different (70% vs 46% at 5 years, respectively, P=.10). AA had inferior OS to non-codeleted AO/AOA (37% vs 68% at 5 years, respectively, P=.007) and inferior PFS (27% vs 46%, respectively, P=.03). On multivariate analysis, age, performance status, and histological or molecular subtype were independent predictors for both PFS and OS. Compared to historical controls, RT + TMZ provided comparable OS to RT with procarbazine, lomustine, and vincristine (RT + PCV) for codeleted AO/AOA, superior OS to RT alone for non-codeleted AO/AOA, and similar OS to RT alone for AA. Conclusions: RT + TMZ may be a promising treatment for both codeleted and non-codeleted AO/AOA, but its role for AA remains unclear.

  9. Impact of 1p/19q Codeletion and Histology on Outcomes of Anaplastic Gliomas Treated With Radiation Therapy and Temozolomide

    International Nuclear Information System (INIS)

    Purpose: Anaplastic gliomas represent a heterogeneous group of primary high-grade brain tumors, and the optimal postoperative treatment remains controversial. In this report, we present our institutional data on the clinical outcomes of radiation therapy (RT) plus temozolomide (RT + TMZ) for anaplastic gliomas, stratified by histology and 1p/19q codeletion. Methods and Materials: A single-institution retrospective review was conducted of patients with supratentorial anaplastic oligodendroglioma (AO), mixed anaplastic oligoastrocytoma (AOA), and anaplastic astrocytoma (AA). After surgery, RT was delivered at a median total dose of 60 Gy (range, 31.6-63 Gy) in daily fractions. All patients received standard concurrent TMZ, with or without adjuvant TMZ. Histological/molecular subtypes were defined as codeleted AO/AOA, non-codeleted AO/AOA, and AA. Results: From 2000 to 2012, 111 cases met study criteria and were evaluable. Codeleted AO/AOA had superior overall survival (OS) to non-codeleted AO/AOA (91% vs 68% at 5 years, respectively, P=.02), whereas progression-free survival (PFS) was not significantly different (70% vs 46% at 5 years, respectively, P=.10). AA had inferior OS to non-codeleted AO/AOA (37% vs 68% at 5 years, respectively, P=.007) and inferior PFS (27% vs 46%, respectively, P=.03). On multivariate analysis, age, performance status, and histological or molecular subtype were independent predictors for both PFS and OS. Compared to historical controls, RT + TMZ provided comparable OS to RT with procarbazine, lomustine, and vincristine (RT + PCV) for codeleted AO/AOA, superior OS to RT alone for non-codeleted AO/AOA, and similar OS to RT alone for AA. Conclusions: RT + TMZ may be a promising treatment for both codeleted and non-codeleted AO/AOA, but its role for AA remains unclear

  10. Sleep Spindles Characteristics in Insomnia Sufferers and Their Relationship with Sleep Misperception

    Directory of Open Access Journals (Sweden)

    Marie-Pier Normand

    2016-01-01

    Full Text Available Cortical hyperarousal is higher in insomnia sufferers (INS than in good sleepers (GS and could be related to an alteration in sleep protection mechanisms, like reduced density or altered characteristics in sleep spindles. The deficient sleep protection mechanisms might in turn enhance underestimation of sleep. This study’s objective was to document sleep spindles characteristics in INS compared with GS and to investigate their potential role in sleep consolidation and misperception. Seventeen individuals with paradoxical insomnia (PARA-I, 24 individuals with psychophysiological insomnia (PSY-I, and 29 GS completed four consecutive polysomnographic nights in laboratory. Sleep spindles were detected automatically during stage 2 and SWS (3-4 on night 3. Number, density, duration, frequency, and amplitude of sleep spindles were calculated. A misperception index was used to determine the degree of discrepancy between subjective and objective total sleep times. Kruskal-Wallis H tests and post hoc tests revealed that PARA-I had significantly shorter sleep spindles than GS but that PSY-I and GS did not differ on spindles length. A standard multiple regression model revealed that neither sleep spindles characteristics nor objective sleep measures were predictive of sleep misperception. A longer duration of spindles could reflect a higher gating process but this hypothesis still needs to be confirmed in replication studies.

  11. Aurora A, MCAK, and Kif18b promote Eg5-independent spindle formation

    NARCIS (Netherlands)

    van Heesbeen, Roy G H P; Raaijmakers, Jonne A; Tanenbaum, Marvin E; Halim, Vincentius A; Lelieveld, Daphne; Lieftink, Cor; Heck, Albert J R; Egan, David A; Medema, René H

    2016-01-01

    Inhibition of the microtubule (MT) motor protein Eg5 results in a mitotic arrest due to the formation of monopolar spindles, making Eg5 an attractive target for anti-cancer therapies. However, Eg5-independent pathways for bipolar spindle formation exist, which might promote resistance to treatment w

  12. An allometric analysis of the number of muscle spindles in mammalian skeletal muscles.

    Science.gov (United States)

    Banks, R W

    2006-06-01

    An allometric analysis of the number of muscle spindles in relation to muscle mass in mammalian (mouse, rat, guinea-pig, cat, human) skeletal muscles is presented. It is shown that the trend to increasing number as muscle mass increases follows an isometric (length) relationship between species, whereas within a species, at least for the only essentially complete sample (human), the number of spindles scales, on average, with the square root rather than the cube root of muscle mass. An attempt is made to reconcile these apparently discrepant relationships. Use of the widely accepted spindle density (number of spindles g(-1) of muscle) as a measure of relative abundance of spindles in different muscles is shown to be grossly misleading. It is replaced with the residuals of the linear regression of ln spindle number against ln muscle mass. Significant differences in relative spindle abundance as measured by residuals were found between regional groups of muscles: the greatest abundance is in axial muscles, including those concerned with head position, whereas the least is in muscles of the shoulder girdle. No differences were found between large and small muscles operating in parallel, or between antigravity and non-antigravity muscles. For proximal vs. distal muscles, spindles were significantly less abundant in the hand than the arm, but there was no difference between the foot and the leg. PMID:16761976

  13. Sleep Spindles Characteristics in Insomnia Sufferers and Their Relationship with Sleep Misperception

    Science.gov (United States)

    2016-01-01

    Cortical hyperarousal is higher in insomnia sufferers (INS) than in good sleepers (GS) and could be related to an alteration in sleep protection mechanisms, like reduced density or altered characteristics in sleep spindles. The deficient sleep protection mechanisms might in turn enhance underestimation of sleep. This study's objective was to document sleep spindles characteristics in INS compared with GS and to investigate their potential role in sleep consolidation and misperception. Seventeen individuals with paradoxical insomnia (PARA-I), 24 individuals with psychophysiological insomnia (PSY-I), and 29 GS completed four consecutive polysomnographic nights in laboratory. Sleep spindles were detected automatically during stage 2 and SWS (3-4) on night 3. Number, density, duration, frequency, and amplitude of sleep spindles were calculated. A misperception index was used to determine the degree of discrepancy between subjective and objective total sleep times. Kruskal-Wallis H tests and post hoc tests revealed that PARA-I had significantly shorter sleep spindles than GS but that PSY-I and GS did not differ on spindles length. A standard multiple regression model revealed that neither sleep spindles characteristics nor objective sleep measures were predictive of sleep misperception. A longer duration of spindles could reflect a higher gating process but this hypothesis still needs to be confirmed in replication studies.

  14. Dynamic characteristics of hard disk drive spindles supported by hydrodynamic bearings

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Most hard disk spindles currently used are supported by grease lubricated deep-groove ball bearings.However, in the trend of increasing spindle speed and reducing size and cost, the shortcomings of ball bearing spin-dles, such as high non-repeatable run out, high acoustic noise and short life time at high running speed, make themunsuitable for high performance hard disk drives (HDD). On the contrary, the dynamic characteristics of hydrody-namic bearing spindles are superior to that of ball bearing spindles. Therefore, they are considered to be the substi-tute of ball bearing spindles in HDD. In this paper, a simulative setup of HDD is build up. The dynamic characteristicsof liquid lubricated spiral groove bearing(SGB) spindles are studied. The effects of both operating condition andbearing clearance are investigated. It is found that running speed of the spindle has significant influence on its dy-namic performance, while the load has little influence. The effect of clearance is also evident.

  15. The product of the spindle formation gene sad1+ associates with the fission yeast spindle pole body and is essential for viability

    OpenAIRE

    1995-01-01

    Spindle formation in fission yeast occurs by the interdigitation of two microtubule arrays extending from duplicated spindle pole bodies which span the nuclear membrane. By screening a bank of temperature-sensitive mutants by anti-tubulin immunofluorescence microscopy, we previously identified the sad1.1 mutation (Hagan, I., and M. Yanagida. 1990. Nature (Lond.). 347:563-566). Here we describe the isolation and characterization of the sad1+ gene. We show that the sad1.1 mutation affected both...

  16. Metronomic chemotherapy in anaplastic thyroid carcinoma: A potentially feasible alternative to therapeutic nihilism

    Directory of Open Access Journals (Sweden)

    Swaroop Revannasiddaiah

    2015-01-01

    Full Text Available Anaplastic thyroid carcinoma (ATC is one of the most aggressive malignancies and prognostic outlook remains very dismal. Treatment most often is palliative in intent attempting to relieve the patients from local compressive symptoms in the neck. Radical surgery, radiotherapy (RT, and chemotherapy have not been tested in large prospective trials, and current evidence from retrospective series and small trials indicate only marginal survival benefits. Given the poor prognostic and therapeutic outlook, patients must be encouraged to be actively involved in the decision making process. We report the case of an elderly patient who had no response to palliative RT, and was treated with oral metronomic chemotherapy. The response to oral metronomic chemotherapy was dramatic, and the patient has enjoyed complete freedom from symptoms as well as radiologically exhibits a complete regression. Thus, we document the first ever use of a simple, cost-effective, and convenient oral metronomic chemotherapeutic regimen delivering a remarkable response in an elderly patient with ATC.

  17. Metronomic chemotherapy in anaplastic thyroid carcinoma: a potentially feasible alternative to therapeutic nihilism.

    Science.gov (United States)

    Revannasiddaiah, Swaroop; Madabhavi, Irappa; Bodh, Anita; Thakur, Priyanka; Sharma, Mukesh

    2015-01-01

    Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies and prognostic outlook remains very dismal. Treatment most often is palliative in intent attempting to relieve the patients from local compressive symptoms in the neck. Radical surgery, radiotherapy (RT), and chemotherapy have not been tested in large prospective trials, and current evidence from retrospective series and small trials indicate only marginal survival benefits. Given the poor prognostic and therapeutic outlook, patients must be encouraged to be actively involved in the decision making process. We report the case of an elderly patient who had no response to palliative RT, and was treated with oral metronomic chemotherapy. The response to oral metronomic chemotherapy was dramatic, and the patient has enjoyed complete freedom from symptoms as well as radiologically exhibits a complete regression. Thus, we document the first ever use of a simple, cost-effective, and convenient oral metronomic chemotherapeutic regimen delivering a remarkable response in an elderly patient with ATC. PMID:26009682

  18. Novel benzimidazole inhibitors bind to a unique site in the kinesin spindle protein motor domain.

    Science.gov (United States)

    Sheth, Payal R; Shipps, Gerald W; Seghezzi, Wolfgang; Smith, Catherine K; Chuang, Cheng-Chi; Sanden, David; Basso, Andrea D; Vilenchik, Lev; Gray, Kimberly; Annis, D Allen; Nickbarg, Elliott; Ma, Yao; Lahue, Brian; Herbst, Ronald; Le, Hung V

    2010-09-28

    Affinity selection-mass spectrometry (AS-MS) screening of kinesin spindle protein (KSP) followed by enzyme inhibition studies and temperature-dependent circular dichroism (TdCD) characterization was utilized to identify a series of benzimidazole compounds. This series also binds in the presence of Ispinesib, a known anticancer KSP inhibitor in phase I/II clinical trials for breast cancer. TdCD and AS-MS analyses support simultaneous binding implying existence of a novel non-Ispinesib binding pocket within KSP. Additional TdCD analyses demonstrate direct binding of these compounds to Ispinesib-resistant mutants (D130V, A133D, and A133D + D130V double mutant), further strengthening the hypothesis that the compounds bind to a distinct binding pocket. Also importantly, binding to this pocket causes uncompetitive inhibition of KSP ATPase activity. The uncompetitive inhibition with respect to ATP is also confirmed by the requirement of nucleotide for binding of the compounds. After preliminary affinity optimization, the benzimidazole series exhibited distinctive antimitotic activity as evidenced by blockade of bipolar spindle formation and appearance of monoasters. Cancer cell growth inhibition was also demonstrated either as a single agent or in combination with Ispinesib. The combination was additive as predicted by the binding studies using TdCD and AS-MS analyses. The available data support the existence of a KSP inhibitory site hitherto unknown in the literature. The data also suggest that targeting this novel site could be a productive strategy for eluding Ispinesib-resistant tumors. Finally, AS-MS and TdCD techniques are general in scope and may enable screening other targets in the presence of known drugs, clinical candidates, or tool compounds that bind to the protein of interest in an effort to identify potency-enhancing small molecules that increase efficacy and impede resistance in combination therapy. PMID:20718440

  19. Expert and crowd-sourced validation of an individualized sleep spindle detection method employing complex demodulation and individualized normalization

    Directory of Open Access Journals (Sweden)

    Stuart Fogel

    2015-09-01

    Full Text Available A spindle detection method was developed that: 1 extracts the signal of interest (i.e., spindle-related phasic changes in sigma relative to ongoing “background” sigma activity using complex demodulation, 2 accounts for variations of spindle characteristics across the night, scalp derivations and between individuals, and 3 employs a minimum number of sometimes arbitrary, user-defined parameters. Complex demodulation was used to extract instantaneous power in the spindle band. To account for intra- and inter-individual differences, the signal was z-score transformed using a 60s sliding window, per channel, over the course of the recording. Spindle events were detected with a z-score threshold corresponding to a low probability (e.g., 99th percentile. Spindle characteristics, such as amplitude, duration and oscillatory frequency, were derived for each individual spindle following detection, which permits spindles to be subsequently and flexibly categorized as slow or fast spindles from a single detection pass. Spindles were automatically detected in 15 young healthy subjects. Two experts manually identified spindles from C3 during Stage 2 sleep, from each recording; one employing conventional guidelines, and the other, identifying spindles with the aid of a sigma (11-16 Hz filtered channel. These spindles were then compared between raters and to the automated detection to identify the presence of true positives, true negatives, false positives and false negatives. This method of automated spindle detection resolves or avoids many of the limitations that complicate automated spindle detection, and performs well compared to a group of non-experts, and importantly, has good external validity with respect to the extant literature in terms of the characteristics of automatically detected spindles.

  20. Chemoradiation for anaplastic oligodendrogliomas: clinical outcomes and prognostic value of molecular markers.

    Science.gov (United States)

    Minniti, Giuseppe; Arcella, Antonella; Scaringi, Claudia; Lanzetta, Gaetano; Di Stefano, Domenica; Scarpino, Stefania; Pace, Andrea; Giangaspero, Felice; Osti, Mattia Falchetto; Enrici, Riccardo Maurizi

    2014-01-01

    Combination of procarbazine, lomustine and vincristine (PCV) with radiation therapy (RT) has been associated with longer survival in patients with anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA), especially in those with chromosome 1p/19q codeletion. We report a multicenter retrospective study of 84 consecutive adult patients with AO and AOA treated with RT plus concomitant and adjuvant temozolomide (TMZ) between February 2004 and January 2011. Correlations between chromosome 1p/19q codeletion, isocitrate dehydrogenase1 (IDH1) mutation, and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with survival outcomes have been analyzed. For all 84 patients the median overall survival (OS) and progression-free survival rates were 55.6 and 45.2 months, respectively. Grade 3 or 4 hematological toxicity occurred in 17 % of patients. Chromosome 1p/19q codeletion was detected in 57 %, IDH1 mutation in 63 %, and MGMT promoter methylation in 74 % of evaluable patients. In multivariate analysis the presence of chromosome 1p/19q codeletion was associated with significant survival benefit (median OS 34 months in noncodeleted tumors and not reached in codeleted tumors; HR 0.16, 95 % CI 0.03-0.45; P = 0.005). IDH1 mutation was also of prognostic significance for longer survival (P = 0.001; HR 0.20, 95 % 0.06-0.41), whereas MGMT promoter methylation was only of borderline significance. The study indicates that RT with concomitant and adjuvant TMZ is a relatively safe treatment associated with longer survival in patients with 1p/19q codeleted and IDH1 mutated tumors. Results from ongoing randomized studies will be essential to clarify if RT plus TMZ may provide survival as good as or better than RT combined with PCV for patients with AO and AOA. PMID:24162810

  1. Mdb1, a fission yeast homolog of human MDC1, modulates DNA damage response and mitotic spindle function.

    Directory of Open Access Journals (Sweden)

    Yi Wei

    Full Text Available During eukaryotic DNA damage response (DDR, one of the earliest events is the phosphorylation of the C-terminal SQ motif of histone H2AX (H2A in yeasts. In human cells, phosphorylated H2AX (γH2AX is recognized by MDC1, which serves as a binding platform for the accumulation of a myriad of DDR factors on chromatin regions surrounding DNA lesions. Despite its important role in DDR, no homolog of MDC1 outside of metazoans has been described. Here, we report the characterization of Mdb1, a protein from the fission yeast Schizosaccharomyces pombe, which shares significant sequence homology with human MDC1 in their C-terminal tandem BRCT (tBRCT domains. We show that in vitro, recombinant Mdb1 protein binds a phosphorylated H2A (γH2A peptide, and the phospho-specific binding requires two conserved phospho-binding residues in the tBRCT domain of Mdb1. In vivo, Mdb1 forms nuclear foci at DNA double strand breaks (DSBs induced by the HO endonuclease and ionizing radiation (IR. IR-induced Mdb1 focus formation depends on γH2A and the phospho-binding residues of Mdb1. Deleting the mdb1 gene does not overtly affect DNA damage sensitivity in a wild type background, but alters the DNA damage sensitivity of cells lacking another γH2A binder Crb2. Overexpression of Mdb1 causes severe DNA damage sensitivity in a manner that requires the interaction between Mdb1 and γH2A. During mitosis, Mdb1 localizes to spindles and concentrates at spindle midzones at late mitosis. The spindle midzone localization of Mdb1 requires its phospho-binding residues, but is independent of γH2A. Loss of Mdb1 or mutating its phospho-binding residues makes cells more resistant to the microtubule depolymerizing drug thiabendazole. We propose that Mdb1 performs dual roles in DDR and mitotic spindle regulation.

  2. Phase II Pediatric Study With Dabrafenib in HGG Patients

    Science.gov (United States)

    2016-03-09

    Anaplastic Astrocytoma; Glioblastoma; Giant Cell Glioblastoma; Gliosarcoma; Anaplastic Oligodendroglioma; Anaplastic Oligoastrocytoma; Anaplastic Ependymoma; Choroid Plexus Carcinoma; Anaplastic Ganglioglioma; Pineal Parenchymal Tumor; Pineoblastoma; Medulloblastoma; PNET; Rhabdoid Tumor; Perineurioma; MPNST; Malignant Meningloma; Anaplastic Hemangiopericytoma

  3. Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: A report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial

    NARCIS (Netherlands)

    H.J. Dubbink (Erik Jan); P.N. Atmodimedjo; J.M. Kros (Johan); P.J. French (Pim); M. Sanson (Marc); A. Idbaih (Ahmed); P. Wesseling (Pieter); R. Enting (Roelien); W.G.M. Spliet (Wim); C.C. Tijssen (Cees); W.N.M. Dinjens (Winand); T.S. Gorlia (Thierry); M.J. van den Bent (Martin)

    2016-01-01

    textabstractBackground Histopathological diagnosis of diffuse gliomas is subject to interobserver variation and correlates modestly with major prognostic and predictive molecular abnormalities. We investigated a series of patients with locally diagnosed anaplastic oligodendroglial tumors included in

  4. Ipl1p-dependent phosphorylation of Mad3p is required for the spindle checkpoint response to lack of tension at kinetochores

    OpenAIRE

    King, Emma M J; Rachidi, Najma; Morrice, Nick; Hardwick, Kevin G.; Stark, Michael J. R.

    2007-01-01

    The spindle checkpoint delays anaphase onset until all chromosomes are correctly attached to microtubules. Ipl1 protein kinase (Aurora B) is required to correct inappropriate kinetochore-microtubule attachments and for the response to lack of tension between sister kinetochores. Here we identify residues in the checkpoint protein Mad3p that are phosphorylated by Ipl1p. When phosphorylation of Mad3p at two sites is prevented, the cell's response to reduced kinetochore tension is dramatically c...

  5. Sleep spindles and hippocampal functional connectivity in human NREM sleep.

    Science.gov (United States)

    Andrade, Kátia C; Spoormaker, Victor I; Dresler, Martin; Wehrle, Renate; Holsboer, Florian; Sämann, Philipp G; Czisch, Michael

    2011-07-13

    We investigated human hippocampal functional connectivity in wakefulness and throughout non-rapid eye movement sleep. Young healthy subjects underwent simultaneous EEG and functional magnetic resonance imaging (fMRI) measurements at 1.5 T under resting conditions in the descent to deep sleep. Continuous 5 min epochs representing a unique sleep stage (i.e., wakefulness, sleep stages 1 and 2, or slow-wave sleep) were extracted. fMRI time series of subregions of the hippocampal formation (HF) (cornu ammonis, dentate gyrus, and subiculum) were extracted based on cytoarchitectonical probability maps. We observed sleep stage-dependent changes in HF functional coupling. The HF was integrated to variable strength in the default mode network (DMN) in wakefulness and light sleep stages but not in slow-wave sleep. The strongest functional connectivity between the HF and neocortex was observed in sleep stage 2 (compared with both slow-wave sleep and wakefulness). We observed a strong interaction of sleep spindle occurrence and HF functional connectivity in sleep stage 2, with increased HF/neocortical connectivity during spindles. Moreover, the cornu ammonis exhibited strongest functional connectivity with the DMN during wakefulness, while the subiculum dominated hippocampal functional connectivity to frontal brain regions during sleep stage 2. Increased connectivity between HF and neocortical regions in sleep stage 2 suggests an increased capacity for possible global information transfer, while connectivity in slow-wave sleep is reflecting a functional system optimal for segregated information reprocessing. Our data may be relevant to differentiating sleep stage-specific contributions to neural plasticity as proposed in sleep-dependent memory consolidation. PMID:21753010

  6. Rotation of Meiotic Spindle Is Controlled by Microfilaments in Mouse Oocytes

    Institute of Scientific and Technical Information of China (English)

    Da-YuanChen; Jin-SongLi; LiLian; LeiLei; Zhi-MingHan; Qing-YuanSun

    2005-01-01

    The completion of meiosis requires the spatial and temporal coordination of cytokinesis and karyokirlesis. During meiotic maturation, many events, such as formation, location, and rotation of the meiotic spindle as well as chromosomal movement,Polar body extrusion,and pronuclear migration,are dependent on regulation of the cytoskeleton system.To study functions of microfilaments in meiosis,we induced metaphase Ⅱ(MII)mouse oocytes to resume meiosis by in vitro fertilization or parthenogenetic activation,and we treated such oocytes with cytochalasin B(CB).The changes of the meiotic spindle,as visualized in preparations stained for β-tubulin and chromation,were observed by fluorescent confocal microscopy.The meiotic spindle of Mll oocytes was observed to be parallel to the plasmalemma.After meiosis had resumed,the spindle rotated to the vertical position so that the second polar body could be extruded into the perivitelline space.When meiosis resumed and oocytes were treated with 10μg/ml of CB,the spindle rotation was inhibited.Consequently,the oocyte formed an extra pronucleus instead of extruding a second polar body.These results indicate that spindle rotation is essential for polar body extrusion;it is the microfilaments that play a crucial role in regulating rotation of the meiotic spindle.

  7. A new method to measure circular runout of end-milling spindle based on cutting mark

    Science.gov (United States)

    Zhou, Jianlai; Liu, Shuchun

    2008-12-01

    A practical method is introduced to measure the circular runout of a end-milling spindle system at high speed rotations without the need of a reference sphere. A workpiece is held on a linear slide which moves along the axial direction of the spindle. The spindle is then programmed to run at a specific speed. A very sharp edge cutter must be used and the depth of cut will be very shallow in order to keep the cutting force very small. The workpiece is then fed into the end mill in order to make a cutting mark of teens μm in depth. The cutting marks are circular, and their diameters are related to the circular runout of the spindle system. The cutting mark that is generated at a specific speed is expected to contain information about the spindle circular runout at this speed. In practice the cutting marks are not perfectly circular. Therefore, a best-fit circle of a cutting mark is needed to determine its diameter. A high-resolution edge detector machine is used for this purpose. Quantitative precision analysis was carried out to confirm the accuracy and repeatability of this new measurement technique. It is demonstrated that this technique for the measurement of spindle circular runout is an effective tool in verifying the actual running accuracy of spindles at their actual operating speeds and can be accomplished without the need for a reference sphere.

  8. Automatic sleep spindle detection: Benchmarking with fine temporal resolution using open science tools

    Directory of Open Access Journals (Sweden)

    Christian O'Reilly

    2015-06-01

    Full Text Available Sleep spindle properties index cognitive faculties such as memory consolidation and diseases such as major depression. For this reason, scoring sleep spindle properties in polysomnographic recordings has become an important activity in both research and clinical settings. The tediousness of this manual task has motivated efforts for its automation. Although some progress has been made, increasing the temporal accuracy of spindle scoring and improving the performance assessment methodology are two aspects needing more attention. In this paper, four open-access automated spindle detectors with fine temporal resolution are proposed and tested against expert scoring of two proprietary and two open-access databases. Results highlight several findings: 1 that expert scoring and polysomnographic databases are important confounders when comparing the performance of spindle detectors tested using different databases or scorings; 2 because spindles are sparse events, specificity estimates are potentially misleading for assessing automated detector performance; 3 reporting the performance of spindle detectors exclusively with sensitivity and specificity estimates, as is often seen in the literature, is insufficient; including sensitivity, precision and a more comprehensive statistic such as Matthew’s correlation coefficient, F1-score, or Cohen’s κ is necessary for adequate evaluation; 4 reporting statistics for some reasonable range of decision thresholds provides a much more complete and useful benchmarking; 5 performance differences between tested automated detectors were found to be similar to those between available expert scorings; 6 much more development is needed to effectively compare the performance of spindle detectors developed by different research teams. Finally, this work clarifies a long-standing but only seldom posed question regarding whether expert scoring truly is a reliable gold standard for sleep spindle assessment.

  9. Human chromokinesins promote chromosome congression and spindle microtubule dynamics during mitosis.

    Science.gov (United States)

    Wandke, Cornelia; Barisic, Marin; Sigl, Reinhard; Rauch, Veronika; Wolf, Frank; Amaro, Ana C; Tan, Chia H; Pereira, Antonio J; Kutay, Ulrike; Maiato, Helder; Meraldi, Patrick; Geley, Stephan

    2012-09-01

    Chromokinesins are microtubule plus end-directed motor proteins that bind to chromosome arms. In Xenopus egg cell-free extracts, Xkid and Xklp1 are essential for bipolar spindle formation but the functions of the human homologues, hKID (KIF22) and KIF4A, are poorly understood. By using RNAi-mediated protein knockdown in human cells, we find that only co-depletion delayed progression through mitosis in a Mad2-dependent manner. Depletion of hKID caused abnormal chromosome arm orientation, delayed chromosome congression, and sensitized cells to nocodazole. Knockdown of KIF4A increased the number and length of microtubules, altered kinetochore oscillations, and decreased kinetochore microtubule flux. These changes were associated with failures in establishing a tight metaphase plate and an increase in anaphase lagging chromosomes. Co-depletion of both chromokinesins aggravated chromosome attachment failures, which led to mitotic arrest. Thus, hKID and KIF4A contribute independently to the rapid and correct attachment of chromosomes by controlling the positioning of chromosome arms and the dynamics of microtubules, respectively. PMID:22945934

  10. Regulation of spindle pole body assembly and cytokinesis by the centrin-binding protein Sfi1 in fission yeast.

    Science.gov (United States)

    Lee, I-Ju; Wang, Ning; Hu, Wen; Schott, Kersey; Bähler, Jürg; Giddings, Thomas H; Pringle, John R; Du, Li-Lin; Wu, Jian-Qiu

    2014-09-15

    Centrosomes play critical roles in the cell division cycle and ciliogenesis. Sfi1 is a centrin-binding protein conserved from yeast to humans. Budding yeast Sfi1 is essential for the initiation of spindle pole body (SPB; yeast centrosome) duplication. However, the recruitment and partitioning of Sfi1 to centrosomal structures have never been fully investigated in any organism, and the presumed importance of the conserved tryptophans in the internal repeats of Sfi1 remains untested. Here we report that in fission yeast, instead of doubling abruptly at the initiation of SPB duplication and remaining at a constant level thereafter, Sfi1 is gradually recruited to SPBs throughout the cell cycle. Like an sfi1Δ mutant, a Trp-to-Arg mutant (sfi1-M46) forms monopolar spindles and exhibits mitosis and cytokinesis defects. Sfi1-M46 protein associates preferentially with one of the two daughter SPBs during mitosis, resulting in a failure of new SPB assembly in the SPB receiving insufficient Sfi1. Although all five conserved tryptophans tested are involved in Sfi1 partitioning, the importance of the individual repeats in Sfi1 differs. In summary, our results reveal a link between the conserved tryptophans and Sfi1 partitioning and suggest a revision of the model for SPB assembly. PMID:25031431

  11. Centromere-tethered Mps1 pombe homolog (Mph1) kinase is a sufficient marker for recruitment of the spindle checkpoint protein Bub1, but not Mad1.

    Science.gov (United States)

    Ito, Daisuke; Saito, Yu; Matsumoto, Tomohiro

    2012-01-01

    The spindle checkpoint delays the onset of anaphase until all of the chromosomes properly achieve bipolar attachment to the spindle. It has been shown that unattached kinetochores are the site that emits a signal for activation of the checkpoint. Although the components of the checkpoint such as Bub1, Mad1 and Mad2 selectively accumulate at unattached kinetochores, the answer to how they recognize unattached kinetochores has remained elusive. Mps1 pombe homolog (Mph1) kinase has been shown to function upstream of most of the components of the checkpoint and thus it is thought to recognize unattached kinetochores by itself and recruit other components. In this study we have expressed a fusion protein of Mph1 and Ndc80 (a kinetochore protein of the outer plate) and shown that the fusion protein arrests cell cycle progression in a spindle-checkpoint\\x{2013}dependent manner in fission yeast. When expression of Mad2 is turned off, the cells grow normally with Mph1 constitutively localized at centromeres/kinetochores. Under this condition, Bub1 can be found with Mph1 throughout the cell cycle, indicating that localization of Mph1 at centromeres/kinetochores is sufficient to recruit Bub1. In contrast, Mad1 is found to transiently localize at kinetochores, which are presumably unattached to the spindle, but soon it dissociates from kinetochores. We propose that Mph1 is a sufficient marker for recruitment of Bub1. Mad1, in contrast, requires an additional condition/component for stable association with kinetochores. PMID:22184248

  12. Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951

    OpenAIRE

    Kouwenhoven, Mathilde C. M.; Gorlia, Thierry; Kros, Johan M; Ibdaih, Ahmed; Brandes, Alba A.; Bromberg, Jacolien E.C.; Mokhtari, Karima; van Duinen, Sjoerd G.; Teepen, Johannes L.; Wesseling, Pieter; Vandenbos, Fanny; Grisold, Wolfgang; Sipos, László; Mirimanoff, Rene; Vecht, Charles J

    2009-01-01

    Recent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated whether the assessment of 1p/19q codeletion, polysomy of chromosome 7, epidermal growth factor receptor (EGFR) gene amplification (EGFRamp), and loss of chromosome 10 or 10q offers additional prognostic information to the histological diagnosis and would allow molecular subtyping. For this study, ...

  13. An infant with hyperalertness, hyperkinesis, and failure to thrive: a rare diencephalic syndrome due to hypothalamic anaplastic astrocytoma

    OpenAIRE

    Stival, Alessia; Lucchesi, Maurizio; Farina, Silvia; Buccoliero, Anna Maria; Castiglione, Francesca; Genitori, Lorenzo; de Martino, Maurizio; Sardi, Iacopo

    2015-01-01

    Background Diencephalic Syndrome is a rare clinical condition of failure to thrive despite a normal caloric intake, hyperalertness, hyperkinesis, and euphoria usually associated with low-grade hypothalamic astrocytomas. Case presentation We reported an unusual case of diencephalic cachexia due to hypothalamic anaplastic astrocytoma (WHO-grade III). Baseline endocrine function evaluation was performed in this patient before surgery. After histological diagnosis, he enrolled to a chemotherapy p...

  14. The kinetochore protein Kis1/Eic1/Mis19 ensures the integrity of mitotic spindles through maintenance of kinetochore factors Mis6/CENP-I and CENP-A.

    Science.gov (United States)

    Hirai, Hayato; Arai, Kunio; Kariyazono, Ryo; Yamamoto, Masayuki; Sato, Masamitsu

    2014-01-01

    Microtubules play multiple roles in a wide range of cellular phenomena, including cell polarity establishment and chromosome segregation. A number of microtubule regulators have been identified, including microtubule-associated proteins and kinases, and knowledge of these factors has contributed to our molecular understanding of microtubule regulation of each relevant cellular process. The known regulators, however, are insufficient to explain how those processes are linked to one another, underscoring the need to identify additional regulators. To find such novel mechanisms and microtubule regulators, we performed a screen that combined genetics and microscopy for fission yeast mutants defective in microtubule organization. We isolated approximately 900 mutants showing defects in either microtubule organization or the nuclear envelope, and these mutants were classified into 12 categories. We particularly focused on one mutant, kis1, which displayed spindle defects in early mitosis. The kis1 mutant frequently failed to assemble a normal bipolar spindle. The responsible gene encoded a kinetochore protein, Mis19 (also known as Eic1), which localized to the interface of kinetochores and spindle poles. We also found that the inner kinetochore proteins Mis6/CENP-I and Cnp1/CENP-A were delocalized from kinetochores in the kis1 cells and that kinetochore-microtubule attachment was defective. Another mutant, mis6, also displayed similar spindle defects. We conclude that Kis1 is required for inner kinetochore organization, through which Kis1 ensures kinetochore-microtubule attachment and spindle integrity. Thus, we propose an unexpected relationship between inner kinetochore organization and spindle integrity. PMID:25375240

  15. The kinetochore protein Kis1/Eic1/Mis19 ensures the integrity of mitotic spindles through maintenance of kinetochore factors Mis6/CENP-I and CENP-A.

    Directory of Open Access Journals (Sweden)

    Hayato Hirai

    Full Text Available Microtubules play multiple roles in a wide range of cellular phenomena, including cell polarity establishment and chromosome segregation. A number of microtubule regulators have been identified, including microtubule-associated proteins and kinases, and knowledge of these factors has contributed to our molecular understanding of microtubule regulation of each relevant cellular process. The known regulators, however, are insufficient to explain how those processes are linked to one another, underscoring the need to identify additional regulators. To find such novel mechanisms and microtubule regulators, we performed a screen that combined genetics and microscopy for fission yeast mutants defective in microtubule organization. We isolated approximately 900 mutants showing defects in either microtubule organization or the nuclear envelope, and these mutants were classified into 12 categories. We particularly focused on one mutant, kis1, which displayed spindle defects in early mitosis. The kis1 mutant frequently failed to assemble a normal bipolar spindle. The responsible gene encoded a kinetochore protein, Mis19 (also known as Eic1, which localized to the interface of kinetochores and spindle poles. We also found that the inner kinetochore proteins Mis6/CENP-I and Cnp1/CENP-A were delocalized from kinetochores in the kis1 cells and that kinetochore-microtubule attachment was defective. Another mutant, mis6, also displayed similar spindle defects. We conclude that Kis1 is required for inner kinetochore organization, through which Kis1 ensures kinetochore-microtubule attachment and spindle integrity. Thus, we propose an unexpected relationship between inner kinetochore organization and spindle integrity.

  16. Centrioles in the cell cycle. I. Epithelial cells

    OpenAIRE

    1982-01-01

    A study was made of the structure of the centrosome in the cell cycle in a nonsynchronous culture of pig kidney embryo (PE) cells. In the spindle pole of the metaphase cell there are two mutually perpendicular centrioles (mother and daughter) which differ in their ultrastructure. An electron-dense halo, which surrounds only the mother centriole and is the site where spindle microtubules converge, disappears at the end of telophase. In metaphase and anaphase, the mother centriole is situated p...

  17. Sleep-spindle detection: crowdsourcing and evaluating performance of experts, non-experts and automated methods

    DEFF Research Database (Denmark)

    Warby, Simon C.; Wendt, Sabrina Lyngbye; Welinder, Peter;

    2014-01-01

    crowdsource spindle identification by human experts and non-experts, and we compared their performance with that of automated detection algorithms in data from middle- to older-aged subjects from the general population. We also refined methods for forming group consensus and evaluating the performance of...... that crowdsourcing the scoring of sleep data is an efficient method to collect large data sets, even for difficult tasks such as spindle identification. Further refinements to spindle detection algorithms are needed for middle- to older-aged subjects....... event detectors in physiological data such as electroencephalographic recordings from polysomnography. Compared to the expert group consensus gold standard, the highest performance was by individual experts and the non-expert group consensus, followed by automated spindle detectors. This analysis showed...

  18. Chromosome position at the spindle equator is regulated by chromokinesin and a bipolar microtubule array.

    Science.gov (United States)

    Takagi, Jun; Itabashi, Takeshi; Suzuki, Kazuya; Ishiwata, Shin'ichi

    2013-01-01

    The chromosome alignment is mediated by polar ejection and poleward forces acting on the chromosome arm and kinetochores, respectively. Although components of the motile machinery such as chromokinesin have been characterized, their dynamics within the spindle is poorly understood. Here we show that a quantum dot (Qdot) binding up to four Xenopus chromokinesin (Xkid) molecules behaved like a nanosize chromosome arm in the meiotic spindle, which is self-organized in cytoplasmic egg extracts. Xkid-Qdots travelled long distances along microtubules by changing several tracks, resulting in their accumulation toward and distribution around the metaphase plate. The analysis indicated that the direction of motion and velocity depend on the distribution of microtubule polarity within the spindle. Thus, this mechanism is governed by chromokinesin motors, which is dependent on symmetrical microtubule orientation that may allow chromosomes to maintain their position around the spindle equator until correct microtubule-kinetochore attachment is established. PMID:24077015

  19. Research Progress of Key Technology of High-Speed and High Precision Motorized Spindles

    Institute of Scientific and Technical Information of China (English)

    XIONG Wan-li; MI Hai-qing; HUANG Hon-gwu

    2005-01-01

    High speed machining and high precision machining are two tendencies of the manufacturing technology worldwide. The motorized spindle is the core component of the machine tools for achieving the high speed and high precise machining, which affects the general development level of the machine tools to a great extent. Progress of the key techniques is reviewed in this paper, in which the high speed and high precision spindle bearings, the dynamical and thermal characteristics of spindles, the design technique of the high frequency motors and the drivers, the anti-electromagnetic damage technique of the motors, and the machining and assembling technique are involved. Finally, tha development tendencies of the motorized spindles are presented.

  20. MINITYPE MACHINING SYSTEM FOR DIAMOND LAPPING & POLISHING BY USING BRUSHLESS DIRECT CURRENT MOTOR AS PRECISE SPINDLE

    Institute of Scientific and Technical Information of China (English)

    FU Huinan; CHEN Dongsheng; ZHAO Yong; LIN Binquan

    2008-01-01

    A minitype precise spindle system which can machine precisely and stably in the process of diamond lapping and polishing is designed. In such minitype spindle system, the brushless DC spindle motor is used to drive the lapping finish table, which is built with fluid dynamic bearings. Some measures have been taken to make the lapping system dynamic balance, and a servo controller which can adjust the speed of motor from 1 200 r/min to 5 400 r/min is designed. Experiments show that the spindle system is reliable and stable for diamond polishing, and the detection results by atomic force microscope(AFM) show that the surfaces of diamond edge's Ra is 6.725 nm and whole diamond average Ra is 3.25 nm.

  1. Sleep Spindles Characteristics in Insomnia Sufferers and Their Relationship with Sleep Misperception

    OpenAIRE

    Normand, Marie-Pier; St-Hilaire, Patrick; Célyne H. Bastien

    2016-01-01

    Cortical hyperarousal is higher in insomnia sufferers (INS) than in good sleepers (GS) and could be related to an alteration in sleep protection mechanisms, like reduced density or altered characteristics in sleep spindles. The deficient sleep protection mechanisms might in turn enhance underestimation of sleep. This study’s objective was to document sleep spindles characteristics in INS compared with GS and to investigate their potential role in sleep consolidation and misperception. Sevente...

  2. An AFM-based methodology for measuring axial and radial error motions of spindles

    International Nuclear Information System (INIS)

    This paper presents a novel atomic force microscopy (AFM)-based methodology for measurement of axial and radial error motions of a high precision spindle. Based on a modified commercial AFM system, the AFM tip is employed as a cutting tool by which nano-grooves are scratched on a flat surface with the rotation of the spindle. By extracting the radial motion data of the spindle from the scratched nano-grooves, the radial error motion of the spindle can be calculated after subtracting the tilting errors from the original measurement data. Through recording the variation of the PZT displacement in the Z direction in AFM tapping mode during the spindle rotation, the axial error motion of the spindle can be obtained. Moreover the effects of the nano-scratching parameters on the scratched grooves, the tilting error removal method for both conditions and the method of data extraction from the scratched groove depth are studied in detail. The axial error motion of 124 nm and the radial error motion of 279 nm of a commercial high precision air bearing spindle are achieved by this novel method, which are comparable with the values provided by the manufacturer, verifying this method. This approach does not need an expensive standard part as in most conventional measurement approaches. Moreover, the axial and radial error motions of the spindle can both be obtained, indicating that this is a potential means of measuring the error motions of the high precision moving parts of ultra-precision machine tools in the future. (paper)

  3. Sources of innervation of the neuromuscular spindles in sternomastoid and trapezius.

    OpenAIRE

    FitzGerald, M J; Comerford, P T; Tuffery, A R

    1982-01-01

    The sources of innervation of neuromuscular spindles in sternomastoid and trapezius have been investigated in rats and mice, by degeneration experiments. The entire motor supply, both extrafusal and intrafusal, to both muscles, was from the spinal accessory nerve. The sensory supply to the spindles in sternomastoid and rostral trapezius was from cervical spinal nerves, and to those in the caudal trapezius was from thoracic spinal nerves.

  4. Somatic and intramuscular distribution of muscle spindles and their relation to muscular angiotypes.

    Science.gov (United States)

    Kokkorogiannis, Theodoros

    2004-07-21

    The distribution pattern of muscle spindles in the skeletal musculature has been reviewed in a large number of muscles (using the literature data especially from cat and man), and the relation of spindle content to muscle mass was quantitatively examined in 36 cat and 140 human muscles. In both species, the number of spindles increases with increasing muscle mass in a power law fashion of the form y=bx+a, whereby y denotes the logarithm of spindle content within a muscle, and x is the logarithm of muscle mass. For the cat, slope b and intercept a were estimated as 0.39 and 1.53, and for man as 0.48 and 1.33, respectively. The results show that the spindle content of a muscle may be related to its mass, confirming a similar analysis made previously by Banks and Stacey (Mechano receptors, Plenum Press, New York, 1988, pp. 263-269) in a different data set. With regard to the histological profile of muscle fibers, (as it is already well documented by many groups) muscle spindles tend to be located in deeper muscle regions where oxidative fibers predominate, and are far scarcer in superficial and flat muscle regions where glycolytic fibers predominate. These discrete muscle regions differ also in the properties of the vessel tree supplying them, for which the term oxidative and glycolytic "angiotype" has been used. The results from these three aspects of analysis (relation to muscle mass, relation to muscle regions with high oxidative index and relation to muscle regions with dense vascular supply) were combined with histological findings showing that spindles may be in systematic anatomical contact to intramuscular vessels. Based on these data a hypothesis is proposed according to which, both the number and intramuscular placement of muscle spindles are related to the oxidative angiotype supplying the muscle territories rich in oxidative fibers. The hypothesis is discussed. PMID:15207480

  5. Muscle spindles in the jaw-closer muscles of the domestic cat.

    OpenAIRE

    Burhanudin, R; McDonald, F.; Rowlerson, A.

    1996-01-01

    The objectives of this study were to identify the exact location of spindles in jaw-closer muscles of the cat, to count the total number of spindles and to compare their distribution with the distribution of slow extrafusal fibres. The jaw-closer muscle group with all the skeletal attachments intact was fixed in a modified Carnoy solution, decalcified and processed through to wax. Complete series of sections were cut transverse, sagittal and perpendicular to the anterior temporalis muscle. At...

  6. High-Speed Spindle Fault Diagnosis with the Empirical Mode Decomposition and Multiscale Entropy Method

    OpenAIRE

    Nan-Kai Hsieh; Wei-Yen Lin; Hong-Tsu Young

    2015-01-01

    The root mean square (RMS) value of a vibration signal is an important indicator used to represent the amplitude of vibrations in evaluating the quality of high-speed spindles. However, RMS is unable to detect a number of common fault characteristics that occur prior to bearing failure. Extending the operational life and quality of spindles requires reliable fault diagnosis techniques for the analysis of vibration signals from three axes. This study used empirical mode decomposition to decomp...

  7. Spike Sorting of Muscle Spindle Afferent Nerve Activity Recorded with Thin-Film Intrafascicular Electrodes

    OpenAIRE

    Milan Djilas; Christine Azevedo-Coste; David Guiraud; Ken Yoshida

    2010-01-01

    Afferent muscle spindle activity in response to passive muscle stretch was recorded in vivo using thin-film longitudinal intrafascicular electrodes. A neural spike detection and classification scheme was developed for the purpose of separating activity of primary and secondary muscle spindle afferents. The algorithm is based on the multiscale continuous wavelet transform using complex wavelets. The detection scheme outperforms the commonly used threshold detection, especially with recordings ...

  8. Impaired Prefrontal Sleep Spindle Regulation of Hippocampal-Dependent Learning in Older Adults

    OpenAIRE

    Mander, Bryce A.; Rao, Vikram; Lu, Brandon; Saletin, Jared M.; Ancoli-Israel, Sonia; Jagust, William J.; Walker, Matthew P.

    2013-01-01

    A hallmark feature of cognitive aging is a decline in the ability to form new memories. Parallel to these cognitive impairments are marked disruptions in sleep physiology. Despite recent evidence in young adults establishing a role for sleep spindles in restoring hippocampal-dependent memory formation, the possibility that disrupted sleep physiology contributes to age-related decline in hippocampal-dependent learning remains unknown. Here, we demonstrate that reduced prefrontal sleep spindles...

  9. Control of position and movement is simplified by combined muscle spindle and Golgi tendon organ feedback

    OpenAIRE

    Kistemaker, D.A.; Soest, van, R.W.M.; Wong, J D; Kurtzer, I; Gribble, P.L.

    2012-01-01

    Whereas muscle spindles play a prominent role in current theories of human motor control, Golgi tendon organs (GTO) and their associated tendons are often neglected. This is surprising since there is ample evidence that both tendons and GTOs contribute importantly to neuromusculoskeletal dynamics. Using detailed musculoskeletal models, we provide evidence that simple feedback using muscle spindles alone results in very poor control of joint position and movement since muscle sp...

  10. Comparison of primary thyroid lymphoma with anaplastic thyroid carcinoma on computed tomographic imaging

    Energy Technology Data Exchange (ETDEWEB)

    Ishikawa, Hitoshi; Mitsuhashi, Norio; Niibe, Hideo [Gunma Univ., Maebashi (Japan). School of Medicine; Tamaki, Yoshio; Takahashi, Mitsuhiro; Higuchi, Keiko; Sakaino, Kouji; Nonaka, Tetsuo; Shioya, Mariko [Gunma Cancer Center, Ota (Japan)

    2002-02-01

    Primary non-Hodgkin's lymphoma (LY) and anaplastic carcinoma (AC) of the thyroid gland are rare malignant tumors, and the initial symptoms of these diseases are very similar. The aim of our study was to compare the characteristics of the two diseases using computed tomographic (CT) scans in order to make an accurate differential diagnosis. Ten patients with LY and 10 with AC were analyzed. Differences in the CT findings of the two diseases were evaluated before treatment and statistically tested with either Student's t-test or the chi-square test. In the analysis of characteristics of CT imaging, the existence of calcification and necrosis, and heterogeneous tumor were dominant findings in AC, and there was a statistically significant difference in frequency between the two diseases (p<0.01). Calcification detected in AC was usually multiple and/or gross (mean size: {phi}8.2 mm). All lymphadenopathies were delineated as having the same homogeneous attenuation as the tumors in the thyroid gland in LY, but were shown as irregular rim enhancement in AC. The CT features of the two diseases are characteristic in terms of calcification, necrosis, and tumor composition. Evaluation by means of CT imaging is useful in distinguishing between LY and AC. (author)

  11. Identifying the association between contrast enhancement pattern, surgical resection, and prognosis in anaplastic glioma patients

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yinyan; Jiang, Tao [Capital Medical University, Department of Neurosurgery, Beijing Tiantan Hospital, Beijing (China); Capital Medical University, Beijing Neurosurgical Institute, Beijing (China); Wang, Kai; Li, Shaowu; Ma, Jun [Capital Medical University, Department of Neuroradiology, Beijing Tiantan Hospital, Beijing (China); Wang, Jiangfei [Capital Medical University, Department of Neurosurgery, Beijing Tiantan Hospital, Beijing (China); Dai, Jianping [Capital Medical University, Beijing Neurosurgical Institute, Beijing (China); Capital Medical University, Department of Neuroradiology, Beijing Tiantan Hospital, Beijing (China)

    2016-04-15

    Contrast enhancement observable on magnetic resonance (MR) images reflects the destructive features of malignant gliomas. This study aimed to investigate the relationship between radiologic patterns of tumor enhancement, extent of resection, and prognosis in patients with anaplastic gliomas (AGs). Clinical data from 268 patients with histologically confirmed AGs were retrospectively analyzed. Contrast enhancement patterns were classified based on preoperative T1-contrast MR images. Univariate and multivariate analyses were performed to evaluate the prognostic value of MR enhancement patterns on progression-free survival (PFS) and overall survival (OS). The pattern of tumor contrast enhancement was associated with the extent of surgical resection in AGs. A gross total resection was more likely to be achieved for AGs with focal enhancement than those with diffuse (p = 0.001) or ring-like (p = 0.024) enhancement. Additionally, patients with focal-enhanced AGs had a significantly longer PFS and OS than those with diffuse (log-rank, p = 0.025 and p = 0.031, respectively) or ring-like (log-rank, p = 0.008 and p = 0.011, respectively) enhanced AGs. Furthermore, multivariate analysis identified the pattern of tumor enhancement as a significant predictor of PFS (p = 0.016, hazard ratio [HR] = 1.485) and OS (p = 0.030, HR = 1.446). Our results suggested that the contrast enhancement pattern on preoperative MR images was associated with the extent of resection and predictive of survival outcomes in AG patients. (orig.)

  12. Effectiveness of interferon-beta and temozolomide combination therapy against temozolomide-refractory recurrent anaplastic astrocytoma

    Directory of Open Access Journals (Sweden)

    Arai Hajime

    2007-08-01

    Full Text Available Abstract Background Malignant gliomas recur even after extensive surgery and chemo-radiotherapy. Although a relatively novel chemotherapeutic agent, temozolomide (TMZ, has demonstrated promising activity against recurrent glioma, the effects last only a few months and drug resistance develops thereafter in most cases. Induction of O6-methylguanine-DNA methyltransferase (MGMT in tumors is considered to be responsible for resistance to TMZ. Interferon-beta has been reported to suppress MGMT in an experimental glioma model. Here we report a patient with TMZ-refractory anaplastic astrocytoma (AA who was treated successfully with a combination of interferon-beta and TMZ. Case presentation A patient with recurrent AA after radiation-chemotherapy and stereotactic radiotherapy was treated with TMZ. After 6 cycles, the tumor became refractory to TMZ, and the patient was treated with interferon-beta at 3 × 106 international units/body, followed by 5 consecutive days of 200 mg/m2 TMZ in cycles of 28 days. After the second cycle the tumor decreased in size by 50% (PR. The tumor showed further shrinkage after 8 months and the patient's KPS improved from 70% to 100%. The immunohistochemical study of the initial tumor specimen confirmed positive MGMT protein expression. Conclusion It is considered that interferon-beta pre-administration increased the TMZ sensitivity of the glioma, which had been refractory to TMZ monotherapy.

  13. The 14-3-3 protein PAR-5 regulates the asymmetric localization of the LET-99 spindle positioning protein.

    Science.gov (United States)

    Wu, Jui-Ching; Espiritu, Eugenel B; Rose, Lesilee S

    2016-04-15

    PAR proteins play important roles in establishing cytoplasmic polarity as well as regulating spindle positioning during asymmetric division. However, the molecular mechanisms by which the PAR proteins generate asymmetry in different cell types are still being elucidated. Previous studies in Caenorhabditis elegans revealed that PAR-3 and PAR-1 regulate the asymmetric localization of LET-99, which in turn controls spindle positioning by affecting the distribution of the conserved force generating complex. In wild-type embryos, LET-99 is localized in a lateral cortical band pattern, via inhibition at the anterior by PAR-3 and at the posterior by PAR-1. In this report, we show that the 14-3-3 protein PAR-5 is also required for cortical LET-99 asymmetry. PAR-5 associated with LET-99 in pull-down assays, and two PAR-5 binding sites were identified in LET-99 using the yeast two-hybrid assay. Mutation of these sites abolished binding in yeast and altered LET-99 localization in vivo: LET-99 was present at the highest levels at the posterior pole of the embryo instead of a band in par-5 embryos. Together the results indicate that PAR-5 acts in a mechanism with PAR-1 to regulate LET-99 cortical localization. PMID:26921457

  14. The Contribution of Thalamocortical Core and Matrix Pathways to Sleep Spindles.

    Science.gov (United States)

    Piantoni, Giovanni; Halgren, Eric; Cash, Sydney S

    2016-01-01

    Sleep spindles arise from the interaction of thalamic and cortical neurons. Neurons in the thalamic reticular nucleus (TRN) inhibit thalamocortical neurons, which in turn excite the TRN and cortical neurons. A fundamental principle of anatomical organization of the thalamocortical projections is the presence of two pathways: the diffuse matrix pathway and the spatially selective core pathway. Cortical layers are differentially targeted by these two pathways with matrix projections synapsing in superficial layers and core projections impinging on middle layers. Based on this anatomical observation, we propose that spindles can be classified into two classes, those arising from the core pathway and those arising from the matrix pathway, although this does not exclude the fact that some spindles might combine both pathways at the same time. We find evidence for this hypothesis in EEG/MEG studies, intracranial recordings, and computational models that incorporate this difference. This distinction will prove useful in accounting for the multiple functions attributed to spindles, in that spindles of different types might act on local and widespread spatial scales. Because spindle mechanisms are often hijacked in epilepsy and schizophrenia, the classification proposed in this review might provide valuable information in defining which pathways have gone awry in these neurological disorders. PMID:27144033

  15. On the Free Vibration Modeling of Spindle Systems: A Calibrated Dynamic Stiffness Matrix

    Directory of Open Access Journals (Sweden)

    Omar Gaber

    2014-01-01

    Full Text Available The effect of bearings on the vibrational behavior of machine tool spindles is investigated. This is done through the development of a calibrated dynamic stiffness matrix (CDSM method, where the bearings flexibility is represented by massless linear spring elements with tuneable stiffness. A dedicated MATLAB code is written to develop and to assemble the element stiffness matrices for the system’s multiple components and to apply the boundary conditions. The developed method is applied to an illustrative example of spindle system. When the spindle bearings are modeled as simply supported boundary conditions, the DSM model results in a fundamental frequency much higher than the system’s nominal value. The simply supported boundary conditions are then replaced by linear spring elements, and the spring constants are adjusted such that the resulting calibrated CDSM model leads to the nominal fundamental frequency of the spindle system. The spindle frequency results are also validated against the experimental data. The proposed method can be effectively applied to predict the vibration characteristics of spindle systems supported by bearings.

  16. A curved edge diffraction-utilized displacement sensor for spindle metrology

    Science.gov (United States)

    Lee, ChaBum; Mahajan, Satish M.; Zhao, Rui; Jeon, Seongkyul

    2016-07-01

    This paper presents a new dimensional metrological sensing principle for a curved surface based on curved edge diffraction. Spindle error measurement technology utilizes a cylindrical or spherical target artifact attached to the spindle with non-contact sensors, typically a capacitive sensor (CS) or an eddy current sensor, pointed at the artifact. However, these sensors are designed for flat surface measurement. Therefore, measuring a target with a curved surface causes error. This is due to electric fields behaving differently between a flat and curved surface than between two flat surfaces. In this study, a laser is positioned incident to the cylindrical surface of the spindle, and a photodetector collects the total field produced by the diffraction around the target surface. The proposed sensor was compared with a CS within a range of 500 μm. The discrepancy between the proposed sensor and CS was 0.017% of the full range. Its sensing performance showed a resolution of 14 nm and a drift of less than 10 nm for 7 min of operation. This sensor was also used to measure dynamic characteristics of the spindle system (natural frequency 181.8 Hz, damping ratio 0.042) and spindle runout (22.0 μm at 2000 rpm). The combined standard uncertainty was estimated as 85.9 nm under current experiment conditions. It is anticipated that this measurement technique allows for in situ health monitoring of a precision spindle system in an accurate, convenient, and low cost manner.

  17. A curved edge diffraction-utilized displacement sensor for spindle metrology.

    Science.gov (United States)

    Lee, ChaBum; Mahajan, Satish M; Zhao, Rui; Jeon, Seongkyul

    2016-07-01

    This paper presents a new dimensional metrological sensing principle for a curved surface based on curved edge diffraction. Spindle error measurement technology utilizes a cylindrical or spherical target artifact attached to the spindle with non-contact sensors, typically a capacitive sensor (CS) or an eddy current sensor, pointed at the artifact. However, these sensors are designed for flat surface measurement. Therefore, measuring a target with a curved surface causes error. This is due to electric fields behaving differently between a flat and curved surface than between two flat surfaces. In this study, a laser is positioned incident to the cylindrical surface of the spindle, and a photodetector collects the total field produced by the diffraction around the target surface. The proposed sensor was compared with a CS within a range of 500 μm. The discrepancy between the proposed sensor and CS was 0.017% of the full range. Its sensing performance showed a resolution of 14 nm and a drift of less than 10 nm for 7 min of operation. This sensor was also used to measure dynamic characteristics of the spindle system (natural frequency 181.8 Hz, damping ratio 0.042) and spindle runout (22.0 μm at 2000 rpm). The combined standard uncertainty was estimated as 85.9 nm under current experiment conditions. It is anticipated that this measurement technique allows for in situ health monitoring of a precision spindle system in an accurate, convenient, and low cost manner. PMID:27475601

  18. Sleep Spindle Characteristics in Children with Neurodevelopmental Disorders and Their Relation to Cognition

    Science.gov (United States)

    Wise, Merrill S.

    2016-01-01

    Empirical evidence indicates that sleep spindles facilitate neuroplasticity and “off-line” processing during sleep, which supports learning, memory consolidation, and intellectual performance. Children with neurodevelopmental disorders (NDDs) exhibit characteristics that may increase both the risk for and vulnerability to abnormal spindle generation. Despite the high prevalence of sleep problems and cognitive deficits in children with NDD, only a few studies have examined the putative association between spindle characteristics and cognitive function. This paper reviews the literature regarding sleep spindle characteristics in children with NDD and their relation to cognition in light of what is known in typically developing children and based on the available evidence regarding children with NDD. We integrate available data, identify gaps in understanding, and recommend future research directions. Collectively, studies are limited by small sample sizes, heterogeneous populations with multiple comorbidities, and nonstandardized methods for collecting and analyzing findings. These limitations notwithstanding, the evidence suggests that future studies should examine associations between sleep spindle characteristics and cognitive function in children with and without NDD, and preliminary findings raise the intriguing question of whether enhancement or manipulation of sleep spindles could improve sleep-dependent memory and other aspects of cognitive function in this population.

  19. The Contribution of Thalamocortical Core and Matrix Pathways to Sleep Spindles

    Science.gov (United States)

    Piantoni, Giovanni; Halgren, Eric; Cash, Sydney S.

    2016-01-01

    Sleep spindles arise from the interaction of thalamic and cortical neurons. Neurons in the thalamic reticular nucleus (TRN) inhibit thalamocortical neurons, which in turn excite the TRN and cortical neurons. A fundamental principle of anatomical organization of the thalamocortical projections is the presence of two pathways: the diffuse matrix pathway and the spatially selective core pathway. Cortical layers are differentially targeted by these two pathways with matrix projections synapsing in superficial layers and core projections impinging on middle layers. Based on this anatomical observation, we propose that spindles can be classified into two classes, those arising from the core pathway and those arising from the matrix pathway, although this does not exclude the fact that some spindles might combine both pathways at the same time. We find evidence for this hypothesis in EEG/MEG studies, intracranial recordings, and computational models that incorporate this difference. This distinction will prove useful in accounting for the multiple functions attributed to spindles, in that spindles of different types might act on local and widespread spatial scales. Because spindle mechanisms are often hijacked in epilepsy and schizophrenia, the classification proposed in this review might provide valuable information in defining which pathways have gone awry in these neurological disorders.

  20. Katanin maintains meiotic metaphase chromosome alignment and spindle structure in vivo and has multiple effects on microtubules in vitro.

    Science.gov (United States)

    McNally, Karen; Berg, Evan; Cortes, Daniel B; Hernandez, Veronica; Mains, Paul E; McNally, Francis J

    2014-04-01

    Assembly of Caenorhabditis elegans female meiotic spindles requires both MEI-1 and MEI-2 subunits of the microtubule-severing ATPase katanin. Strong loss-of-function mutants assemble apolar intersecting microtubule arrays, whereas weaker mutants assemble bipolar meiotic spindles that are longer than wild type. To determine whether katanin is also required for spindle maintenance, we monitored metaphase I spindles after a fast-acting mei-1(ts) mutant was shifted to a nonpermissive temperature. Within 4 min of temperature shift, bivalents moved off the metaphase plate, and microtubule bundles within the spindle lengthened and developed a high degree of curvature. Spindles eventually lost bipolar structure. Immunofluorescence of embryos fixed at increasing temperature indicated that MEI-1 was lost from spindle microtubules before loss of ASPM-1, indicating that MEI-1 and ASPM-1 act independently at spindle poles. We quantified the microtubule-severing activity of purified MEI-1/MEI-2 complexes corresponding to six different point mutations and found a linear relationship between microtubule disassembly rate and meiotic spindle length. Previous work showed that katanin is required for severing at points where two microtubules intersect in vivo. We show that purified MEI-1/MEI-2 complexes preferentially sever at intersections between two microtubules and directly bundle microtubules in vitro. These activities could promote parallel/antiparallel microtubule organization in meiotic spindles. PMID:24501424