WorldWideScience

Sample records for human clear cell

  1. Clear cell chondrosarcoma

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, R.; David, R.; Cierney, G. III

    1985-01-01

    The clinical, radiologic, and histopathologic features of three cases of clear cell chondrosarcoma are described. On radiographs, this rather benign-appearing tumor resembles a chondroblastoma when it occurs at the end of a long bone, and may occasionally show a calcified matrix. However, it has distinctive tumor cells with a centrally placed vesicular nucleus surrounded by clear cytoplasm. The lesion has a low-grade malignancy and is amenable to en bloc surgical resection, which results in a much better prognosis than that of conventional chondrosarcoma.

  2. Elevated cyclin E level in human clear cell renal cell carcinoma: possible causes and consequences.

    Science.gov (United States)

    Nauman, Alicja; Turowska, Olga; Poplawski, Piotr; Master, Adam; Tanski, Zbigniew; Puzianowska-Kuznicka, Monika

    2007-01-01

    The expression of cyclin E gene (CCNE) in relation to the expression of its major regulatory protein, E2F1, was examined in clear cell renal cell carcinomas (ccRCC). We show that the overexpression of E2F1 is accompanied by the significant increase of the mean amounts of cyclin E mRNA, as well as of total cyclin E protein and its low molecular weight forms in cancer tissues as compared to peritumoral controls. A significant increase of the mean amount of total cyclin E was found in peritumoral tissues compared to cancer-free kidneys, suggesting that cancer cells might secrete factors having a profound influence on the metabolism of neighbouring tissues. A significant, positive correlations between E2F1 protein and total cyclin E mRNA, as well as between E2F1 protein and full length cyclin E protein were found in cancer-free kidneys and in peritumoral tissues, but not in ccRCCs. The overexpression of cyclin E positively correlated with the decreasing degree of tumor differentiation, implicating a role for cyclin E in the promotion of tumorigenesis.

  3. Vasoactive intestinal peptide induces oxidative stress and suppresses metastatic potential in human clear cell renal cell carcinoma.

    Science.gov (United States)

    Vacas, Eva; Bajo, Ana M; Schally, Andrew V; Sánchez-Chapado, Manuel; Prieto, Juan C; Carmena, María J

    2013-01-30

    Molecular mechanisms involved in progression of clear-cell renal-cell carcinomas (ccRCCs) are poorly understood. A common genetic mutation found in ccRCC is the loss of the von Hippel-Lindau (VHL) gene, which contributes to cancer progression and metastasis. We investigated VIP effects on metastatic and angiogenic factors in human VHL-null A498 ccRCC and HK2 renal cells. VIP increased adhesion but decreased expression of metalloproteinases, MMP2 and MMP9, as well as cell migration and VEGF expression and secretion in A498 but not in HK2 cells. VIP enhanced ROS levels and decreased nuclear levels of β-catenin and NFκB p50-subunit in A498 cells, suggesting neuropeptide involvement in the observed decrease of metastatic ability in clear-cell carcinoma. VIP effects in A498 cells were blocked by the VPAC(1/2)-receptor antagonist JV-1-53. In conclusion, present data point to a role of VIP in preventing invasion and metastasis in ccRCCs and support its potential therapeutic usefulness in this disease.

  4. Ultrastructural appearance and cytoskeletal architecture of the clear, chromophilic, and chromophobe types of human renal cell carcinoma in vitro.

    Science.gov (United States)

    Gerharz, C D; Moll, R; Störkel, S; Ramp, U; Thoenes, W; Gabbert, H E

    1993-03-01

    The clear, chromophilic, and chromophobe types of human renal cell carcinoma have been defined as distinct morphological entities and can be clearly separated by differences of ultrastructural appearance, cytoskeletal architecture, enzyme synthesis, and cytogenetic aberrations. In this report, the cytomorphological aspects of these tumor types are compared in vitro, showing that essential ultrastructural and cytoskeletal characteristics of each tumor type are expressed even after prolonged in vitro cultivation. The pattern of intermediate filament proteins of each tumor type was preserved in vitro, permitting the separation of exclusively cytokeratin-positive chromophobe tumor cells from clear and chromophilic tumor cells with a co-expression of vimentin and cytokeratins. In vitro, the chromophobe tumor cells continued to exhibit abundant cytoplasmatic microvesicles and sparsely distributed "studded" vesicles, which are known to be characteristic features of this tumor type in vivo. This observation confirmed the structural similarity of the chromophobe cell to the 'intercalated cell' of the cortical collecting duct and provided further evidence for the histogenetic derivation of this tumor subtype from the collecting duct system.

  5. pVHL co-ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear-cell renal cell carcinoma

    DEFF Research Database (Denmark)

    Struckmann, K; Mertz, Kd; Steu, S;

    2008-01-01

    Loss of pVHL function, characteristic for clear-cell renal cell carcinoma (ccRCC), causes increased expression of CXCR4 chemokine receptor, which triggers expression of metastasis-associated MMP2/MMP9 in different human cancers. The impact of pVHL on MMP2/MMP9 expression and their relationship...

  6. Odontogenic ghost cell tumour with clear cell components: clear cell odontogenic ghost cell tumour?

    Science.gov (United States)

    Yoon, Jung Hoon; Ahn, Sang Gun; Kim, Su Gwan; Kim, Jin

    2004-07-01

    A case of odontogenic ghost cell tumour (OGCT) with clear cell components was encountered in the mandible of a 63-year-old man. The tumour revealed ameloblastomatous-type epithelial components accompanied by clusters of ghost cells and dentinoid juxtaposed to the odontogenic epithelium. In addition, some areas of the tumour tissue showed sheets and islands of clear, glycogen containing epithelial cells, which were separated by a thin fibrous connective tissue stroma. Both ameloblastic and clear cells exhibited positive immunoreactivities for cytokeratin 19 and AE1/3. It is not known whether this tumour represents a clear cell change of a pre-existing OGCT or a separate and distinct neoplasm derived de novo from the odontogenic epithelium. This tumour was given the term 'clear cell OGCT' because it captures the clear cell components, which is one of the most prominent distinguishing features of the tumour.

  7. Genetic alterations in the human kidney clear cell carcinoma line Рпоч1-КК

    Directory of Open Access Journals (Sweden)

    A. A. Lushnikova

    2016-01-01

    Full Text Available Continuous cell line Рпоч1-КК from the сollection of N. N. Blokhin Russian Cancer Research Center refers to the kidney clear cell carcinoma subtypе. It is useful for study of carcinogenesis and molecular targets for targeted therapy.Objective. Analysis of the genetic alterations in a stable cell culture Рпоч1-КК to characterize this model cell line.Results. Alterations in VHL (exons 1, 2 and 3 and TP53 genes (exons 6–10 were identified by amplification of genomic DNA followed by fragment analysis polymerase chain reaction and direct Sanger sequencing. An extended deletion in exon 1 in combination with mutation in exon 7 of VHL gene and 2 polymorphisms in exon 4 of TP53 gene were reveated. Such simultaneous alterations in 2 suppressor genes maight be one of the causes of aggressive tumor growth and its resistance to standard therapy.

  8. Unusual clear cell variant of epithelioid mesothelioma.

    Science.gov (United States)

    Dessy, E; Falleni, M; Braidotti, P; Del Curto, B; Panigalli, T; Pietra, G G

    2001-12-01

    Clear cell mesothelioma is an extremely rare neoplasm of the pleura, which can easily be mistaken for a metastasis of clear cell carcinoma to the pleura. We report here the histochemical, immunohistochemical, and ultrastructural aspects of a new case of clear cell pleural mesothelioma in a 52-year-old man with no known asbestos exposure. He was admitted to the hospital for recurrent pleural effusion, which was negative for neoplastic cells at the cytologic examination. A partial decortication of the right pleura was performed. The morphologic, immunohistochemical, and ultrastructural features reported for this case are consistent with the diagnosis of clear cell mesothelioma. The differential diagnosis and immunohistochemical features in comparison with other clear cell neoplasms are discussed.

  9. Malignant Clear Cell Hidradenoma of the Breast

    Science.gov (United States)

    Rahal, Ahmad K.; Reddy, Pavan S; Kallail, K. James

    2017-01-01

    A 58-year-old female had a mass in the right breast palpable beneath the areola. A mammogram revealed a 1.5-centimeter soft tissue density that was confirmed with a subsequent ultrasound. The patient underwent a core needle biopsy which was initially reported as a moderately differentiated invasive ductal carcinoma. Immunohistochemical analysis revealed negative staining for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2), mammaglobin, and gross cystic disease fluid protein 15 (GCDFP-15). A wide local excision of the mass was performed. The pathology report stated the tumor had an infiltrative growth pattern with a desmoplastic stromal response with enhanced epithelial atypia consistent with malignant transformation of a nodular clear cell hidradenoma. Clear cell hidradenoma is a very rare tumor originating from the sweat gland and has a propensity for the face and extremities. The malignant variant of this tumor is extremely rare and has been reported to originate from the breast in few cases. This case represents the difficulty in diagnosing this tumor along with the radiographic and histologic features that can distinguish this malignancy from other entities.

  10. Clear cell myoepithelial carcinoma ex pleomorphic adenoma

    Directory of Open Access Journals (Sweden)

    Nikhil R Rabade

    2014-01-01

    Full Text Available Pleomorphic adenoma is the most common epithelial neoplasm of lacrimal gland. A clear cell myoepithelial carcinoma arising in the background of pleomorphic adenoma is common in the salivary glands but very rare in the lacrimal glands. We report the case of a 27 year old man whose lacrimal gland pleomorphic adenoma recurred several times over a period of four years and ultimately evolved into a clear cell myoepithelial carcinoma ex pleomorphic adenoma.

  11. Expression of the vitamin D receptor, 25-hydroxylases, 1alpha-hydroxylase and 24-hydroxylase in the human kidney and renal clear cell cancer

    DEFF Research Database (Denmark)

    Blomberg Jensen, Martin; Andersen, Claus B.; Nielsen, John E

    2010-01-01

    The vitamin D receptor (VDR), CYP27B1 and CYP24A1 are expressed in the human kidney, but the segmental expression of the 25-hydroxylases is unknown. A comprehensive analysis of CYP2R1, CYP27A1, CYP27B1, VDR and CYP24A1 expression in normal kidney and renal clear cell cancer (CCc) would reveal...... the segmental location of expression, and clarify whether the reported loss of VDR in CCc is coincident with alterations of vitamin D metabolism....

  12. Expression of the vitamin D receptor, 25-hydroxylases, 1alpha-hydroxylase and 24-hydroxylase in the human kidney and renal clear cell cancer

    DEFF Research Database (Denmark)

    Blomberg Jensen, Martin; Andersen, Claus B.; Nielsen, John E;

    2010-01-01

    The vitamin D receptor (VDR), CYP27B1 and CYP24A1 are expressed in the human kidney, but the segmental expression of the 25-hydroxylases is unknown. A comprehensive analysis of CYP2R1, CYP27A1, CYP27B1, VDR and CYP24A1 expression in normal kidney and renal clear cell cancer (CCc) would reveal...... the segmental location of expression, and clarify whether the reported loss of VDR in CCc is coincident with alterations of vitamin D metabolism....

  13. The management of clear cell sarcoma

    NARCIS (Netherlands)

    Kuiper, DR; Hoekstra, HJ; Veth, RPH; Wobbes, T

    2003-01-01

    Clear cell sarcoma is a rare soft tissue tumour, constituting approximately 1% of all soft tissue sarcomas. Prognosis is reported to be poor due to the great propensity to metastasise regionally and distantly. In this paper, we report the surgical experience of two university hospitals. Both disease

  14. An Immune Atlas of Clear Cell Renal Cell Carcinoma.

    Science.gov (United States)

    Chevrier, Stéphane; Levine, Jacob Harrison; Zanotelli, Vito Riccardo Tomaso; Silina, Karina; Schulz, Daniel; Bacac, Marina; Ries, Carola Hermine; Ailles, Laurie; Jewett, Michael Alexander Spencer; Moch, Holger; van den Broek, Maries; Beisel, Christian; Stadler, Michael Beda; Gedye, Craig; Reis, Bernhard; Pe'er, Dana; Bodenmiller, Bernd

    2017-05-04

    Immune cells in the tumor microenvironment modulate cancer progression and are attractive therapeutic targets. Macrophages and T cells are key components of the microenvironment, yet their phenotypes and relationships in this ecosystem and to clinical outcomes are ill defined. We used mass cytometry with extensive antibody panels to perform in-depth immune profiling of samples from 73 clear cell renal cell carcinoma (ccRCC) patients and five healthy controls. In 3.5 million measured cells, we identified 17 tumor-associated macrophage phenotypes, 22 T cell phenotypes, and a distinct immune composition correlated with progression-free survival, thereby presenting an in-depth human atlas of the immune tumor microenvironment in this disease. This study revealed potential biomarkers and targets for immunotherapy development and validated tools that can be used for immune profiling of other tumor types. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  15. Pediatric spinal clear cell meningioma. Case report.

    Science.gov (United States)

    Colen, Chaim B; Rayes, Mahmoud; McClendon, Jamal; Rabah, Raja; Ham, Steven D

    2009-01-01

    In this report the authors describe a unique case of spinal clear cell meningioma in a 13-year-old girl. Clear cell meningiomas (CCMs) are not uncommon. To the authors' knowledge, 14 cases of pediatric CCM occurring in the spinal canal have been reported. Factors lending resistance to meningioma initiation and invasion are analyzed. This 13-year-old girl presented with pain radiating down her left leg. Admission MR imaging showed an inhomogeneous enhancing intradural-extramedullary mass at the L4-5 level. Resection revealed a CCM, and radiotherapy was subsequently administered. Postoperatively there has been no recurrence in > 2 years. In this paper the authors report a case of CCM and provide a comprehensive literature review on this disease. Current recommendations for its management are still debatable, especially in the pediatric population, and the authors propose an algorithm for its treatment and surveillance.

  16. Clear cell odontogenic carcinoma: A rare case

    Directory of Open Access Journals (Sweden)

    Garima Jain

    2015-01-01

    Full Text Available Clear cell odontogenic carcinoma is a rare neoplasm with very few cases reported in the literature. We report a case of a 50-year-old female patient with the malignancy at a less common location. Diagnosis was given based on the histopathologic findings. The demographic data and understanding for this tumor needs to be strengthened by reporting all new cases, which are diagnosed, in literature.

  17. [Clear cell carcinoma of the parotid gland].

    Science.gov (United States)

    Mazouzi, A; Benjelloun, H; Benchekroun, N; Acharki, A; Benider, A

    2005-06-01

    Clear cell carcinomas of the parotid gland are hardly reported only fifty cases are known. They are characterized by a proliferation of acinic epithelial cells and of clear myo epithelial cells. What makes them remarkable is a slow process of evolution. Three cases which were treated in the Ibn Rochd center of oncology are gathered from the 1999-2003 period into a review in order to discover the epidemic and anatomopathological characteristics of these tumours. The goal of study is to contribute to a best knowledge of the clinical features, pare clinical, anatomopathological and therapeutic characteristic of this tumour. Two men, aged of 62 and 71 and a 82-years-old-woman were concerned. Growing cervical mass was the most revealing symptom. The diagnosis was established by the parotid biopsy in 2 cases and after surgery in the third case. The treatment consisted in a total parotidectomy with conservation of the facial nerve and postoperative radiation at the extend of 65 Gy for the first patient. After 12 months the patient is still alive. As for the two other patients, given the extend of advancement of the tumour, palliative treatment was decided. It resulted in stabilization of the disease and a receding of 22 months for one patient and no trace of the second one because of a loss of the evolutionary pursuit. With an in-depth analysis we can notice that clear cell carcinomas of the parotid gland are rare and mostly occur to old patients. Immunohistochemistry is the essential first step to sort these tumour with other salivary ones. Basic treatment is surgery. Radiation therapy linked to surgery seems to improve the local control of the disease. The prognosis remains relatively good despite discusses. Because of the few published cases, it's hard to analyze these tumours.

  18. Clear cell carcinoma of the female genital tract (not everything is as clear as it seems).

    Science.gov (United States)

    Offman, Saul L; Longacre, Teri A

    2012-09-01

    Clear cell carcinoma has a storied history in the female genital tract. From the initial designation of ovarian clear cell adenocarcinoma as "mesonephroma" to the linkage between vaginal clear cell carcinoma and diethylstilbestrol exposure in utero, gynecologic tract clear cell tumors have puzzled investigators, posed therapeutic dilemmas for oncologists, and otherwise presented major differential diagnostic challenges for pathologists. One of the most common errors in gynecologic pathology is misdiagnosis of clear cell carcinoma, on both frozen section and permanent section. Given the poor response to platinum-based chemotherapy for advanced-stage disease and increased risk of thromboembolism, accurate diagnosis of clear cell carcinoma is important in the female genital tract. This review (1) presents the clinical and pathologic features of female genital tract clear cell carcinomas; (2) highlights recent molecular developments; (3) identifies areas of potential diagnostic confusion; and (4) presents solutions for these diagnostic problems where they exist.

  19. Clear cell renal cell tumors: Not all that is "clear" is cancer.

    Science.gov (United States)

    Williamson, Sean R; Cheng, Liang

    2016-07-01

    Continued improvement of our understanding of the clinical, histologic, and genetic features of renal cell tumors has progressively evolved renal tumor classification, revealing an expanding array of distinct tumor types with different implications for prognosis, patient counseling, and treatment. Although clear cell renal cell carcinoma is unequivocally the most common adult renal tumor, there is growing evidence that some "clear cell" renal neoplasms, such as exemplified by multilocular cystic clear cell renal neoplasm of low malignant potential (formerly multilocular cystic renal cell carcinoma), do not have the same potential for insidious progression and metastasis, warranting reclassification as low malignant potential tumors or benign neoplasms. Still other novel tumor types such as clear cell papillary renal cell carcinoma have been more recently recognized, which similarly have shown a conspicuous absence of aggressive behavior to date, suggesting that these too may be recategorized as noncancerous or may be premalignant neoplasms. This importance for prognosis is increasingly significant in the modern era, in which renal masses are increasingly found incidentally by imaging techniques at a small tumor size, raising consideration for less aggressive management options guided by renal mass biopsy diagnosis, including imaging surveillance, tumor ablation, or partial nephrectomy.

  20. An unusual case of clear cell meningioma

    Directory of Open Access Journals (Sweden)

    Deb Prabal

    2009-01-01

    Full Text Available Clear-cell meningioma (CCM is an uncommon, aggressive variant of meningioma, usually affecting younger females and having predilection for infratentorial locations. We present a rare case of recurrent supratentorial CCM in a 58-year-old male. Ten years back, he had an intra-axial tumor in the left occipital lobe, which was managed by surgical excision and radiotherapy. Currently, the patient presented with sudden severe headache along with speech and vision disturbances. Neuroimaging revealed an extra-axial parietooccipital tumor, with intratumoural bleed. Histopathology of both tumors showed features of CCM, immunopositive for epithelial membrane antigen (EMA and vimentin. This case illustrates multiple unusual features of a rare variant of meningioma in the form of affection of an adult age group, supratentorial location, recurrence, and intratumoral bleed. It also highlights the importance of incorporating immunohistochemistry in the diagnostic workup, to exclude CCM mimics, each having distinctive biological behavior, and prognostic outcome, and warranting different therapeutic protocols.

  1. An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma

    National Research Council Canada - National Science Library

    Hakimi, A Ari; Reznik, Ed; Lee, Chung-Han; Creighton, Chad J; Brannon, A Rose; Luna, Augustin; Aksoy, B Arman; Liu, Eric Minwei; Shen, Ronglai; Lee, William; Chen, Yang; Stirdivant, Steve M; Russo, Paul; Chen, Ying-Bei; Tickoo, Satish K; Reuter, Victor E; Cheng, Emily H; Sander, Chris; Hsieh, James J

    2016-01-01

    .... We performed metabolomic profiling on 138 matched clear cell renal cell carcinoma (ccRCC)/normal tissue pairs and found that ccRCC is characterized by broad shifts in central carbon metabolism, one-carbon metabolism, and antioxidant response...

  2. Water-Clear Cell Adenoma of the Mediastinal Parathyroid Gland.

    Science.gov (United States)

    Arik, Deniz; Dündar, Emine; Yilmaz, Evrim; Sivrikoz, Cumhur

    2017-10-06

    Water-clear cell adenoma of the parathyroid gland is a rare neoplasm that consists of cells with abundant clear-pink cytoplasm. There have only been 19 cases reported in the English literature. Here we report a case of water-clear cell adenoma of the mediastinal parathyroid gland. A 70-year-old male patient presented to the hospital with back pain and a mediastinal mass 6 cm in size was detected. After excision and microscopic evaluation, uniform, large clear cells with fine cytoplasmic vacuolization, without nuclear atypia, and arranged in solid and acinar patterns were revealed. The cells formed nests that were separated by fine fibrovascular septae and stained positively with anti-parathyroid hormone. To the best of our knowledge, this has not been previously reported in this location. In the differential diagnosis of clear cell lesions of the mediastinum, water-clear cell parathyroid adenoma should be considered.

  3. Incidentally detected clear cell renal cell carcinoma with rhabdoid differentiation

    Directory of Open Access Journals (Sweden)

    Venkatesh Krishnamoorthy

    2016-01-01

    Full Text Available Renal cell carcinoma with rhabdoid differentiation (RCC-R has an aggressive biologic behavior and poor prognosis. A recent consensus statement of the International Society of Urological Pathology (ISUP proposed a nucleolar grading system (ISUP grade for RCC to replace Fuhrman system and recommended reporting the presence of rhabdoid differentiation and considering tumors with rhabdoid differentiation to be ISUP Grade 4. We report a case of incidentally detected clear cell RCC-R in a 52-year-old man. This is one of the earliest cases of RCC-R (pT1b detected and first such case from Indian subcontinent.

  4. Incidentally detected clear cell renal cell carcinoma with rhabdoid differentiation.

    Science.gov (United States)

    Krishnamoorthy, Venkatesh; Gowda, Kiran Krishne; Rao, Raman Narayana

    2016-01-01

    Renal cell carcinoma with rhabdoid differentiation (RCC-R) has an aggressive biologic behavior and poor prognosis. A recent consensus statement of the International Society of Urological Pathology (ISUP) proposed a nucleolar grading system (ISUP grade) for RCC to replace Fuhrman system and recommended reporting the presence of rhabdoid differentiation and considering tumors with rhabdoid differentiation to be ISUP Grade 4. We report a case of incidentally detected clear cell RCC-R in a 52-year-old man. This is one of the earliest cases of RCC-R (pT1b) detected and first such case from Indian subcontinent.

  5. Clear cell hepatocellular carcinoma: Back to the basics for diagnosis

    Directory of Open Access Journals (Sweden)

    Puja Sakhuja

    2015-01-01

    Full Text Available Hepatocellular carcinoma (HCC is a common cancer world-wide with a higher incidence in Asia. Clear cell variant of HCC (CCHCC has a frequency ranging from 0.4% to 37%. The presence of 90-100% clear cells is rare. In the present case, a 35-year-old female patient presented with fever and a large abdominal mass in the right hypochondrium. Histology of the tumor revealed >95% clear cells and after taking multiple sections from different areas of tumor only few scattered cells with eosinophilic cytoplasm were found. Immunohistochemistry with Hep Par 1, Glypican 3 and polyclonal carcinoembryonic antigen were negative as were all other markers for metastatic clear cell tumors. Histological diagnosis was based on routine H and E sections showing a histological pattern of architecture with thickened trabeculae. We describe a rare case of CCHCC with >95% clear cells and no immunoreactivity in tumor cells in a non-cirrhotic liver.

  6. Glycogen-rich clear cell carcinoma of the breast

    DEFF Research Database (Denmark)

    Sørensen, Flemming Brandt; Paulsen, S M

    1987-01-01

    The light microscopic, immunohistochemical and ultrastructural features of a clear cell carcinoma of the breast have been studied. Both intraductal and invasive components were found. Histochemistry showed large amounts of intracytoplasmic glycogen and sparse neutral mucin in the tumour. The tumo...... was classified as a mucin-containing variant of glycogen-rich, clear cell carcinoma of the breast....

  7. An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma.

    Science.gov (United States)

    Hakimi, A Ari; Reznik, Ed; Lee, Chung-Han; Creighton, Chad J; Brannon, A Rose; Luna, Augustin; Aksoy, B Arman; Liu, Eric Minwei; Shen, Ronglai; Lee, William; Chen, Yang; Stirdivant, Steve M; Russo, Paul; Chen, Ying Bei; Tickoo, Satish K; Reuter, Victor E; Cheng, Emily H; Sander, Chris; Hsieh, James J

    2016-01-11

    Dysregulated metabolism is a hallmark of cancer, manifested through alterations in metabolites. We performed metabolomic profiling on 138 matched clear cell renal cell carcinoma (ccRCC)/normal tissue pairs and found that ccRCC is characterized by broad shifts in central carbon metabolism, one-carbon metabolism, and antioxidant response. Tumor progression and metastasis were associated with metabolite increases in glutathione and cysteine/methionine metabolism pathways. We develop an analytic pipeline and visualization tool (metabolograms) to bridge the gap between TCGA transcriptomic profiling and our metabolomic data, which enables us to assemble an integrated pathway-level metabolic atlas and to demonstrate discordance between transcriptome and metabolome. Lastly, expression profiling was performed on a high-glutathione cluster, which corresponds to a poor-survival subgroup in the ccRCC TCGA cohort. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Clear cell sarcoma: A case mimicking primary cutaneous malignant melanoma

    Directory of Open Access Journals (Sweden)

    Rodriguez-Martin M

    2009-01-01

    Full Text Available Clear cell sarcoma (CCS is a recently described variant of sarcoma characterized by prominent clear cells showing features similar to clear cell melanoma. This neoplasm was first described by Dr. Franz M. Erzinger. Primary CCS usually arises in deeper soft tissues, in association with fascia, tendons, or aponeuroses. Characteristic translocation t(12;22 (q13;q12 has been considered pathognomonic for CCS. Prognosis is related to tumor size. An early recognition and initial radical surgery is the key to a favourable outcome. We present a patient with an unusual neoplasm that resembled malignant melanoma.

  9. Mines and human casualties: a robotics approach toward mine clearing

    Science.gov (United States)

    Ghaffari, Masoud; Manthena, Dinesh; Ghaffari, Alireza; Hall, Ernest L.

    2004-10-01

    An estimated 100 million landmines which have been planted in more than 60 countries kill or maim thousands of civilians every year. Millions of people live in the vast dangerous areas and are not able to access to basic human services because of landmines" threats. This problem has affected many third world countries and poor nations which are not able to afford high cost solutions. This paper tries to present some experiences with the land mine victims and solutions for the mine clearing. It studies current situation of this crisis as well as state of the art robotics technology for the mine clearing. It also introduces a survey robot which is suitable for the mine clearing applications. The results show that in addition to technical aspects, this problem has many socio-economic issues. The significance of this study is to persuade robotics researchers toward this topic and to peruse the technical and humanitarian facets of this issue.

  10. Does clear cell carcinoma of stomach exist? Clinicopathological and prognostic significance of clear cell changes in gastric adenocarcinomas.

    Science.gov (United States)

    Kim, Joo-Yeon; Park, Do Youn; Kim, Gwang Ha; Jeon, Tae-Yong; Lauwers, Gregory Y

    2014-07-01

    In contrast to clear cell carcinomas developing in other organs (e.g. ovary and uterus), gastric adenocarcinomas with clear cell features are not well characterized. We evaluated a series of 762 gastric adenocarcinomas for the presence of clear cell changes; and investigated the nature of the changes using several histochemical and immunohistochemical markers, their association with various clinicopathological features, and their prognostic significance. Clear cell changes were observed in 8.5% (n = 65) of gastric cancers. Cases with clear cell changes (GCC) were associated significantly with older age, intestinal type histology, body/fundic location, greater depth of invasion, lymph node metastases and lymphovascular invasion. An increasing proportion of clear cell changes indicated a worsening prognosis, and was identified as an independent marker of poor prognosis using the Cox proportional hazard model (hazard ratio, 0.462; P = 0.003). Of 62 GCCs subjected to special staining, 35 cases (55.6%) displayed cytoplasmic accumulation of glycogen, while 21 (33.3%) contained mucin. GCCs showing glycogen accumulation expressed AFP, glypican-3 and CD10 more commonly than those with mucin, which commonly expressed Muc5AC and Muc6. Clear cell gastric adenocarcinoma is a unique subgroup of gastric cancer which, although heterogeneous, has a poor prognosis. © 2014 John Wiley & Sons Ltd.

  11. Gene expression profile of renal cell carcinoma clear cell type

    Directory of Open Access Journals (Sweden)

    Marcos F. Dall’Oglio

    2010-08-01

    Full Text Available PURPOSE: The determination of prognosis in patients with renal cell carcinoma (RCC is based, classically, on stage and histopathological aspects. The metastatic disease develops in one third of patients after surgery, even in localized tumors. There are few options for treating those patients, and even the new target designed drugs have shown low rates of success in controlling disease progression. Few studies used high throughput genomic analysis in renal cell carcinoma for determination of prognosis. This study is focused on the identification of gene expression signatures in tissues of low-risk, high-risk and metastatic RCC clear cell type (RCC-CCT. MATERIALS AND METHODS: We analyzed the expression of approximately 55,000 distinct transcripts using the Whole Genome microarray platform hybridized with RNA extracted from 19 patients submitted to surgery to treat RCC-CCT with different clinical outcomes. They were divided into three groups (1 low risk, characterized by pT1, Fuhrman grade 1 or 2, no microvascular invasion RCC; (2 high risk, pT2-3, Fuhrman grade 3 or 4 with, necrosis and microvascular invasion present and (3 metastatic RCC-CCT. Normal renal tissue was used as control. RESULTS: After comparison of differentially expressed genes among low-risk, high-risk and metastatic groups, we identified a group of common genes characterizing metastatic disease. Among them Interleukin-8 and Heat shock protein 70 were over-expressed in metastasis and validated by real-time polymerase chain reaction. CONCLUSION: These findings can be used as a starting point to generate molecular markers of RCC-CCT as well as a target for the development of innovative therapies.

  12. Clear cell colitis: A form of microscopic colitis in children

    Institute of Scientific and Technical Information of China (English)

    Jan J(o)zefczuk; Bogdan Marian Wozniewicz

    2008-01-01

    AIM: To describe a new clinical and pathological subtype of microscopic colitis in children.METHODS: A selected group of children with abdominal pain, constipation and/or diarrhoea showing discrete or no macroscopic abnormalities on endoscopy was described.RESULTS: Multiple biopsies of colon showed large mononuclear clear cells in lamina propria of mucous membrane provided that good quality histological sections were performed and observed under a higher magnification. Otherwise, they could be misinterpreted as artefacts. Their presence in routine histology might suggest a systemic storage disease (Whipple's disease), and neuronal intestine dysplasia.Using immunohistochemical staining and electron microscopy we confirmed their origin from CD68 positive mononuclear macrophages.CONCLUSION: The presence of large clear cells is a constant microscopic feature. Failure of transient large bowel stationary macrophages plays a role in the pathogenesis of this benign microscopic clear cell colitis,sometimes coexisting with allergy.

  13. The utility of using immunohistochemistry in the differentiation of metastatic, cutaneous clear cell renal cell carcinoma and clear cell hidradenoma.

    Science.gov (United States)

    Velez, Moises J; Thomas, Courtney L; Stratton, Jason; Bergfeld, Wilma; Weaver, Joshua

    2017-04-04

    Clear cell hidradenoma and cutaneous clear cell renal cell carcinoma (CCRCC) overlap morphologically. The distinction may be difficult in a patient with a history of CCRCC, presenting with a cutaneous nodule, potentially leading to an erroneous diagnosis. We investigated the usefulness of napsin A and paired box gene 8 (PAX-8) with previously studied markers epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), vimentin and cluster of differentiation marker 10 (CD10) in differentiating CCRCC from hidradenoma. We evaluated hidradenomas and cutaneous CCRCCs for immunohistochemical expression of napsin A, PAX-8, EMA, CEA, vimentin and CD10. PAX-8 was expressed in all CCRCCs (8/8) while negative in hidradenomas. Napsin A was negative in both hidradenomas (0/12) and CCRCCs (0/10). EMA showed membranous reactivity in 11 of 12 hidradenomas and 8 of 10 CCRCCs; and highlighted ductal epithelium in 1 of 12 hidradenomas and cystic areas in 4 of 10 CCRCCs. CD10 showed ductal expression in 3 of 12 hidradenomas and membranous staining in 8 of 9 CCRCCs. CEA highlighted ductal epithelium in 11 of 12 hidradenomas while absent in CCRCCs (0/10). Vimentin highlighted neoplastic cells in 8 of 8 CCRCCs and failed to stain the hidradenomas (0/12). A conservative immunohistochemical panel including PAX-8, vimentin and CEA allow for easy distinction of CCRCC from hidradenoma, whereas napsin A added no additional value. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Treatment results and prognostic factors of clear cell ovarian carcinomas and ovarian carcinomas with clear cell component

    Directory of Open Access Journals (Sweden)

    M. D. Ahmedova

    2012-01-01

    Full Text Available The most important prognostic factors for clear cell carcinoma (CCC are clinical and morphological signs and clinical stage of the disease. Analyses of 5-year survival in patients with I stage of CCC is 69 %, in II stage – 55 %, in III stage – 14 % and in IV stage – 4 % patients. We analyzed distant results of treatment of 71 patients with CCC and of 25 patients with mixed malignant ovaries neoplasm with obligatory clear cell component taking into consideration main clinical and morphological sings of disease. On the base of performed reseal we revealed that morphological structure of the tumors and stage of the disease exerted heist influence on the exponent of survival of the patients with clear CCC ovaries neoplasm. Besides, there is a correlation between exponent of patients’ survival and radicalized of surgery, character of tumor growth, differentiation degree, cell anaplasia and mitotic activity of tumor cells.

  15. Clear cell odontogenic carcinoma of maxilla: A diagnostic challenge

    Directory of Open Access Journals (Sweden)

    Fouzia Siraj

    2016-01-01

    Full Text Available Clear cell odontogenic carcinoma (CCOC is a rare odontogenic tumor which occurs mostly in the mandible. It is primarily seen in fifth to seventh decades with a female predilection. We report a case of CCOC in the maxillary arch of a 66-year-old woman. Morphologic examination along with histochemical and immunohistochemical markers led to the establishment of the diagnosis. It is important to diagnose this entity and differentiate it from other clear cell tumors in the head and neck region as it is a locally aggressive tumor with a propensity for regional, nodal, and distant metastasis.

  16. Clear cell ovarian cancer and endometriosis: is there a relationship?

    Directory of Open Access Journals (Sweden)

    Maria Szubert

    2016-07-01

    Full Text Available Introduction: Ovarian clear cell carcinoma is a rare type of ovarian cancer. In recent years, issues of the common genetic origin of endometriosis and ovarian clear cell carcinoma have been raised. Aim of this study was to evaluate the prevalence of this type of cancer, risk factors, prognosis and its potential aetiological association with endometriosis. Material and methods: In a retrospective study, we analysed histopathological data of patients operated in the First Department of Gynaecology and Obstetrics (MU, Lodz due to ovarian cancer in 2004-2014. Among the 394 patients operated on for ovarian cancer, clear cell carcinoma was found in 0.02% (9/394. Menstrual history, parity, comorbidities, data from physical examination, operational protocols and histopathological diagnoses were analysed. Follow-up was obtained from 77.8% of patients. Statistical analysis was performed using Microsoft Excel 2013. Results: The mean age of patients at diagnosis was 57.6 years; the BMI in the study group was 27.2; the majority of patients were multiparous (77.8%. Clear cell carcinoma was detected mostly at stage Ia (n = 4. The concentration of Ca125 in the study group had an average of 142.75 U/ml and a median of 69.3 U/ml. The coexistence of endometriosis could not be clinically or histologically confirmed amongst our patients. The most common comorbidity in the study group was hypertension. Conclusions : In our clinical material, ovarian clear cell carcinoma is a rare histopathological specimen with a prognostic value comparable to that of serous ovarian cancer. Due to the rarity of this histopathological subtype, proving a cause-and-effect relationship between it and endometriosis can only be elucidated through statistical studies of the entire population.

  17. Clear cell sarcoma of the kidney: A case report

    Directory of Open Access Journals (Sweden)

    Dipanwita Nag

    2014-01-01

    Full Text Available Clear cell sarcoma of the kidney is a rare malignant neoplasm of childhood, known for its aggressiveness, its tendency for recurrence, and to metastasize to bone. We report the observation of 8-month-old child presenting with a large abdominal mass. Clinically, it was diagnosed as Wilm′s tumor, and left nephrectomy was done. Grossly, 10 cm × 8 cm × 3.5 cm globular, white, encapsulated, smooth mass uniformly involving the whole kidney was noted. Histologically, the tumor was diagnosed as clear cell sarcoma with renal vein showing presence of tumor embolus in lumen. The tumor was given stage-II (NWTS-5 protocol. Immunohistochemistry showed vimentin positive and cytokeratin negative tumor cells. The child is currently undergoing chemotherapy and has not yet shown any sign of bony metastasis.

  18. Cerebellar clear cell ependymoma in a 10 year old girl

    Energy Technology Data Exchange (ETDEWEB)

    Thinzar Aye Nyein; Moon, Ah Rim; Hwang, Sun Chul; Hong, Hyun Sook; Lee, A Leum; Chang, Kee Hyun; Kim, Hee Kyung; Chin, Su Sie [Soonchunhyang University Bucheon Hospital, Bucheon (Korea, Republic of); Park, Ji Sang [Soonchunhyang University Gumi Hospital, Gumi (Korea, Republic of)

    2016-01-15

    Clear cell ependymoma (CCE) is a histological rare variant (1–5%) of ependymoma, which is distinguished from other histological subtypes by the presence of fusiform cells arrayed radially around small blood vessels. These alleged perivascular pseudorosettes are significant characteristic features of ependymomas. About 95% of infratentorial ependymomas are found in the fourth ventricle and the remainder occurs as cerebellopontine angle lesions. In previous reports, the cerebellum is found to be a rare location for ependymoma. In this study we report one case of CCE originating from the cerebellar hemisphere, showing unusual morphology on 3T MRI.

  19. Clear cell variant of diffuse large B-cell lymphoma: a case report

    Directory of Open Access Journals (Sweden)

    Sahatciu-Meka Vjollca

    2011-05-01

    Full Text Available Abstract Introduction Diffuse large B-cell lymphoma is a diffuse proliferation of large neoplastic B lymphoid cells with a nuclear size equal to or exceeding the normal macrophage nuclei. We report a case of a clear cell variant of diffuse large B-cell lymphoma involving a lymph node in the neck, which was clinically suspected of being metastatic carcinoma. Case presentation A 39-year-old Caucasian ethnic Albanian man from Kosovo presented with a rapidly enlarging lymph node in his neck, but he also disclosed B symptoms and fatigue. A cytological aspirate of the lymph node revealed pleomorphic features. Our patient underwent a cervical lymph node biopsy (large excision. The mass was homogeneously fish-flesh, pale white tissue replacing almost the whole structure of the lymph node. The lymph node biopsy showed a partial alveolar growth pattern, which raised clinical suspicion that it was an epithelial neoplasm. With regard to morphological and phenotypic features, we discovered large nodules in diffuse areas, comprising large cells with slightly irregular nuclei and clear cytoplasm admixed with a few mononuclear cells. In these areas, there was high mitotic activity, and in some areas there were macrophages with tangible bodies. Staining for cytokeratins was negative. These areas had the following phenotypes: cluster designation marker 20 (CD20 positive, B-cell lymphoma (Bcl-2-positive, Bcl-6-, CD5-, CD3-, CD21+ (in alveolar patterns, prostate-specific antigen-negative, human melanoma black marker 45-negative, melanoma marker-negative, cytokeratin-7-negative and multiple myeloma marker 1-positive in about 30% of cells, and exhibited a high proliferation index marker (Ki-67, 80%. Conclusion According to the immunohistochemical findings, we concluded that this patient has a clear cell variant of diffuse large B-cell lymphoma of activated cell type, post-germinal center cell origin. Our patient is undergoing R-CHOP chemotherapy treatment.

  20. A giant benign clear cell hidradenoma on the anterior trunk

    Directory of Open Access Journals (Sweden)

    Damlanur Sakiz

    2011-10-01

    Full Text Available Clear cell hidroadenoma (CCA is a uncommon variant of bening cutaneous adnexial tumors. These tumors are clinically asymptomatic, solitary dermal nodules. they occur most frequently on the scalp, face, abdomen and the extremities. Growth is slow and malignant change is rare. 45- year-old woman presented us with a nodule with a central ulceration and a minimal hemoragic discharge on her anterior abdomen wall which had begun 4 years ago as a small nodular asymptomatic lesion. On dermatological examination there was a 6.5x4x5 cm non-tender, soft reddish purple nodule with lobular appearence and ulceration. In the laboratory investigations, all the hematologic and biochemical tests were normal. A CT scan demonstrated a cyctic tumor with lobulated countour with contrast enhancement. The lesion excised totally. In histopathological examination the tumor was composed of biphasic  smaller dark polygonal cells and larger clera cells and coarse nuclear chromatine. There were duct like structures. Immunohistochemical investigation was done for the suspicion of malignancy. Cytoplasm of clear cells and duct like structures showed PAS positive and d-Pas resistant staining. There was a positive reactivity to epithelial membrane antigen and carcinoembrionic antigen. The mitotic index in Ki 67 examination was low. All these findings confirmed the diagnosis of bening CCA. 

  1. Acanthosis Nigricans associated with clear-cell renal cell carcinoma

    Science.gov (United States)

    Narvaez, Margarita Rosa Aveiga; Reis, Paola Vasconcellos Soares; Gomes, Augusto Cesar Marins; Paraskevopoulos, Daniela Kallíope de Sá; Santana, Frederico; Fugita, Oscar Eduardo Hidetoshi

    2016-01-01

    Acanthosis nigricans (AN), an entity recognized since the 19th century, is a dermatopathy associated with insulin-resistant conditions, endocrinopathies, drugs, chromosome abnormalities and neoplasia. The latter, also known as malignant AN, is mostly related to abdominal neoplasms. Malignant AN occurs frequently among elderly patients. In these cases, the onset is subtle, and spreading involves the flexural regions of the body, particularly the axillae, palms, soles, and mucosa. Gastric adenocarcinoma is the most frequent associated neoplasia, but many others have been reported. Renal cell carcinoma (RCC), although already reported, is rarely associated with malignant AN. The authors report the case of a woman who was being treated for depression but presented a long-standing and marked weight loss, followed by darkening of the neck and the axillary regions. Physical examination disclosed a tumoral mass in the left flank and symmetrical, pigmented, velvety, verrucous plaques on both axillae, which is classical for AN. The diagnostic work-up disclosed a huge renal mass, which was resected and further diagnosed as a RCC. The post-operative period was uneventful and the skin alteration was evanescent at the first follow-up consultation. The authors call attention to the association of AN with RCC. PMID:27284539

  2. Primary abdominal wall clear cell carcinoma arising from incisional endometriosis

    Institute of Scientific and Technical Information of China (English)

    Burcu Gundogdu; Isin Ureyen; Gunsu Kimyon; Hakan Turan; Nurettin Boran; Gokhan Tulunay; Dilek Bulbul; Taner Turan; M Faruk Kose

    2013-01-01

    A 49 year-old patient with the complaint of a mass located in the caesarean scar was admitted. There was a fixed mass 30í30 mm in diameter with regular contour located at the right corner of the pfannenstiel incision. Computed tomography revealed a (40í50í50) mm solid mass lesion with margins that cannot be distinguished from the uterus, bladder and small intestines and a heterogeneous mass lesion (50í45í55) mm in diameter, located in the right side of the anterior abdominal wall. Cytoreductive surgery including total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed. Final pathology was clear cell carcinoma. Clear cell carcinoma arising from an extraovarian endometriotic focus was diagnosed and the patient received 6 cycles paclitaxel-carboplatin chemotherapy as adjuvant treatment. The patient who was lost to follow-up applied to our clinic 2 years after surgery with a recurrent mass in the left inguinal region. After 3 cycles of chemotherapy, the patient's tumoral mass in the left inguinal region was excised. The result of the pathology was carcinoma metastasis. It is decided that the following treatment of the patient should be palliative radiation therapy. The patient who underwent palliative radiation therapy died of disease after 4 months of the second operation.

  3. Clear Cell Adenocarcinoma of the Urethra: Review of the Literature

    Directory of Open Access Journals (Sweden)

    Anthony Kodzo-Grey Venyo

    2015-01-01

    Full Text Available Background. Clear cell adenocarcinoma of the urethra (CCAU is extremely rare and a number of clinicians may be unfamiliar with its diagnosis and biological behaviour. Aims. To review the literature on CCAU. Methods. Various internet databases were used. Results/Literature Review. (i CCAU occurs in adults and in women in the great majority of cases. (ii It has a particular association with urethral diverticulum, which has been present in 56% of the patients; is indistinguishable from clear cell adenocarcinoma of the female genital tract but is not associated with endometriosis; and probably does not arise by malignant transformation of nephrogenic adenoma. (iii It is usually, readily distinguished from nephrogenic adenoma because of greater cytological a-typicality and mitotic activity and does not stain for prostate-specific antigen or prostatic acid phosphatase. (iv It has been treated by anterior exenteration in women and cystoprostatectomy in men and at times by radiotherapy; chemotherapy has rarely been given. (v CCAU is aggressive with low 5-year survival rates. (vi There is no consensus opinion of treatment options that would improve the prognosis. Conclusions. Few cases of CCAU have been reported. Urologists, gynaecologists, pathologists, and oncologists should report cases of CCAU they encounter and enter them into a multicentric trial to determine the best treatment options that would improve the prognosis.

  4. Genetic characteristics of the non-clear cell renal cancer

    Directory of Open Access Journals (Sweden)

    D. S. Mikhaylenko

    2016-01-01

    Full Text Available Renal cancer (RC is one of the most frequent diseases in oncological urology; the most common form of RC is the clear cell carcinoma. However, percentage of less-studied non-clear cell RC (nccRC reaches up to 25 % of cases suggesting further studying, improvement of diagnosis and treatment of these tumors. The key events of carcinogenesis are genetic alterations including chromosomal aberrations and point mutations in proto-oncogenes and tumor suppressor genes. This review describes cytogenetic aberrations in the context of nccRC diversity according to the current ISUP classification. Translocation variants of nccRC (MiT-RC were characterized separately as particular cases of the chromosome rearrangements involving MiT gene family (TFE3, TFEB, MITF. In addition, the main nccRC hereditary forms caused by germinal mutations in the genes FLCN, FH, and MET, as well as recent studies of sporadic tumors with using the next generation sequencing techniques were reviewed. These experiments were designed to search for somatic mutations throughout the tumor genome or exom and revealed the different mutational profiles of I/II papillary RC subtypes, chromophobe carcinoma versus oncocytoma. The review may be informative for oncologists, urologists, geneticists and specialists in related sciences. 

  5. MUTATIONS IN THE VHL GENE FRIOM POTASSIUM BROMATE-INDUCED RAT CLEAR CELL RENAL TUMORS

    Science.gov (United States)

    Potassium bromate (KBrO3) is a rat renal carcinogen and a major drinking water disinfection by-product in water disinfected with ozone. Clear cell renal tumors, the most common form of human renal epithelial neoplasm, are rare in animals but are inducible by KBrO3 in F344 rats. ...

  6. Renal Clear Cell Sarcoma - Anaplastic Variant: A Rare Entity.

    Science.gov (United States)

    Walke, Vaishali Atmaram; Shende, Nitin Y; Kumbhalkar, D T

    2017-01-01

    Clear Cell Sarcoma of Kidney (CCSK) is known for its morphologic diversity, aggressive behaviour, tendency to recur and metastasis to bone. Amongst the various morphologic subtypes, anaplastic CCSK is associated with worse prognosis. Here, we report a case of this rare variant of CCSK. A five-year-old boy presented with history of lump and pain in abdomen since one week. The Computed Tomography (CT) scan revealed a large mass occupying the middle and inferior pole of right kidney. The clinical impression was Wilms tumour. Nephrectomy specimen was received and the diagnosis of CCSK anaplastic variant was offered only after excluding the differentials and after performing ancillary tests such as Immunohistochemistry (IHC). Thus, this case emphasizes the diagnostic challenges on morphology and the essential role of IHC in arriving at a definitive diagnosis, because failure to do so may deprive the child from optimal treatment.

  7. Clear Cell Adenocarcinoma Arising from Abdominal Wall Endometriosis

    Directory of Open Access Journals (Sweden)

    Thouraya Achach

    2008-01-01

    Full Text Available Endometriosis is a frequent benign disorder. Malignancy arising in extraovarian endometriosis is a rare event. A 49-year-old woman is presented with a large painful abdominal wall mass. She underwent a myomectomy, 20 years before, for uterus leiomyoma. Computed tomography suggested that this was a desmoid tumor and she underwent surgery. Histological examination showed a clear cell adenocarcinoma associated with endometriosis foci. Pelvic ultrasound, computed tomography, and endometrial curettage did not show any malignancy or endometriosis in the uterus and ovaries. Adjuvant chemotherapy was recommended, but the patient was lost to follow up. Six months later, she returned with a recurrence of the abdominal wall mass. She was given chemotherapy and then she was reoperated.

  8. Clear cell chondrosarcoma mimicking chondroblastoma in a skeletally immature patient

    Energy Technology Data Exchange (ETDEWEB)

    Cannon, Christopher P. [Department of Orthopaedic Surgery, Madigan Army Medical Center, Ft. Lewis, WA (United States); Nelson, Scott D. [Department of Pathology and Laboratory Medicine, University of California, Los Angeles School of Medicine, CA (United States); Seeger, Leanne L. [Department of Radiological Sciences, University of California, CA (United States); Eckardt, Jeffrey J. [Department of Orthopaedic Surgery, University of California, Los Angeles School of Medicine, CA (United States)

    2002-06-01

    We report the case of a clear cell chondrosarcoma (CCCS) occurring in the femoral head of a 14-year-old skeletally immature boy. Radiographic examination revealed a well-defined, osteolytic lesion in the epiphysis of the femoral head. Given the patient's age and the radiographic appearance of the lesion, chondroblastoma was high on the differential diagnosis. A frozen section was performed at the time of open biopsy was felt to be consistent with either chondroblastoma or CCCS. CCCS in a skeletally immature patient was felt to be unlikely, so curettage and bone grafting was performed. Final pathology review, however, confirmed the diagnosis of CCCS. The patient was taken back to surgery 4 weeks later for a wide resection and hemiarthroplasty. (orig.)

  9. Hemosiderotic clear-cell acanthoma: A pigmented mimicker

    Directory of Open Access Journals (Sweden)

    Leonardo Bugatti

    2011-01-01

    Full Text Available The authors report on a case of a 65-year-old man with pigmented clear-cell acanthoma located on the right thigh. Dermoscopy disclosed a peculiar picture consisting of diffuse black pigmentation with a superficial greyish veil in the central portion, dotted-to-globular dark red-black structures mainly located at the periphery with a homogenous regular reticular arrangement; peripheral translucid desquamation. Dermoscopic features are correlated with the histology, where hemosiderin deposits present in a sheet-like arrangement in the perivascular papillary dermis and in a band-like disposition in the reticular dermis at the base of the lesion can account for the pigmented picture. The lesion arose on a trauma-prone skin site; thus the authors believe that traumatic irritation may be responsible for the clinical and dermoscopic pictures, giving rise to a reaction similar in a way to the Auspitz′s sign provocated by trauma for psoriasis. Red blood cells extravasation from extremely superficialized capillaries may have led to hemosiderin deposition in the papillary and the reticular dermis.

  10. Renal cell carcinoma with areas mimicking renal angiomyoadenomatous tumor/clear cell papillary renal cell carcinoma.

    Science.gov (United States)

    Petersson, Fredrik; Grossmann, Petr; Hora, Milan; Sperga, Maris; Montiel, Delia Perez; Martinek, Petr; Gutierrez, Maria Evelyn Cortes; Bulimbasic, Stela; Michal, Michal; Branzovsky, Jindrich; Hes, Ondrej

    2013-07-01

    We present a cohort of 8 renal carcinomas that displayed a variable (5%-95% extent) light microscopic appearance of renal angiomyoadenomatous tumor/clear cell papillary renal cell carcinoma (RAT/CCPRCC) without fulfilling the criteria for these tumors. All but 1 case predominantly (75%-95% extent) showed histopathologic features of conventional clear cell renal cell carcinoma. In 5 of 7 cases with mostly conventional clear renal cell carcinoma (CRCC) morphology, a diagnosis of CRCC was supported by the molecular genetic findings (presence of von Hippel-Lindau tumor suppressor [VHL] mutation and/or VHL promoter methylation and/or loss of heterozygosity [LOH] for 3p). Of the other 2 cases with predominantly characteristic CRCC morphology, 1 tumor did not reveal any VHL mutation, VHL promoter methylation, or LOH for 3p, and both chromosomes 7 and 17 were disomic, whereas the other tumor displayed polysomy for chromosomes 7 and 17 and no VHL mutation, VHL promoter methylation, or LOH for 3p. One tumor was composed primarily (95%) of distinctly RAT/CCPRCC-like morphology, and this tumor harbored a VHL mutation and displayed polysomy for chromosomes 7 and 17. Of the 5 cases with both histomorphologic features and molecular genetic findings of CRCC, we detected significant immunoreactivity for α-methylacyl-CoA racemase in 2 cases and strong diffuse immunopositivity for cytokeratin 7 in 3 cases. Despite the combination of positivity for α-methylacyl-CoA racemase and cytokeratin 7 in 2 cases, there was nothing to suggest of the possibility of a conventional papillary renal cell carcinoma with a predominance of clear cells.

  11. Clear cell papillary renal cell carcinoma: micro-RNA expression profiling and comparison with clear cell renal cell carcinoma and papillary renal cell carcinoma.

    Science.gov (United States)

    Munari, Enrico; Marchionni, Luigi; Chitre, Apurva; Hayashi, Masamichi; Martignoni, Guido; Brunelli, Matteo; Gobbo, Stefano; Argani, Pedram; Allaf, Mohamad; Hoque, Mohammad O; Netto, George J

    2014-06-01

    Clear cell papillary renal cell carcinoma (CCPRCC) is a low-grade renal neoplasm with morphological characteristics mimicking both clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). However, despite some overlapping features, their morphological, immunohistochemical, and molecular profiles are distinct. Micro-RNAs (miRNAs) are small noncoding RNAs that play a crucial role in regulating gene expression and are involved in various biological processes, including cancer development. To better understand the biology of this tumor, we aimed to analyze the miRNA expression profile of a set of CCPRCC using microarray and quantitative reverse transcription-polymerase chain reaction. A total of 15 cases diagnosed as CCPRCC were used in this study. Among the most differentially expressed miRNA in CCPRCC, we found miR-210, miR-122, miR-34a, miR-21, miR-34b*, and miR-489 to be up-regulated, whereas miR-4284, miR-1202, miR-135a, miR-1973, and miR-204 were down-regulated compared with normal renal parenchyma. To identify consensus of differentially regulated miRNA between CCPRCC, CCRCC, and PRCC, we additionally determined differential miRNA expression using 2 publically available microarray data sets from the NCBI Gene Expression Omnibus database (GSE41282 and GSE3798). This comparison revealed that the miRNA expression profile of CCPRCC shows some overlapping characteristics between CCRCC and PRCC. Moreover, CCPRCC lacks dysregulation of important miRNAs typically associated with aggressive behavior. In summary, we describe the miRNA expression profile of a relatively infrequent type of renal cancer. Our results may help in understanding the molecular underpinning of this newly recognized entity. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Renal cell carcinoma: evolving approaches to advanced non-clear cell carcinoma

    Directory of Open Access Journals (Sweden)

    Ronald M. Bukowski

    2011-12-01

    Full Text Available The treatment of metastatic renal cell carcinoma (RCC has changed dramatically with the introduction of targeted therapies including sunitinib, sorafenib, and temsirolimus. Because patients with conventional clear cell histology account for 75- 80% of all patients with RCC, there has been little accumulated evidence on the treatment of patients with non-clear cell histologies. Most clinical trials have excluded them from enrolment, except for randomized studies investigating temsirolimus. Many retrospective studies on the use of all three of these targeted therapies in patients with non-clear cell histology have demonstrated response rates ranging from 3.7%–16%. Although response rates may not be as high compared to patients with clear cell histologies, targeted therapy does provide a clinically meaningful response.

  13. Renal cell carcinoma: evolving approaches to advanced non-clear cell carcinoma

    Directory of Open Access Journals (Sweden)

    Daniel Y.C. Heng

    2011-12-01

    Full Text Available The treatment of metastatic renal cell carcinoma (RCC has changed dramatically with the introduction of targeted therapies including sunitinib, sorafenib, and temsirolimus. Because patients with conventional clear cell histology account for 75- 80% of all patients with RCC, there has been little accumulated evidence on the treatment of patients with non-clear cell histologies. Most clinical trials have excluded them from enrolment, except for randomized studies investigating temsirolimus. Many retrospective studies on the use of all three of these targeted therapies in patients with non-clear cell histology have demonstrated response rates ranging from 3.7%–16%. Although response rates may not be as high compared to patients with clear cell histologies, targeted therapy does provide a clinically meaningful response.

  14. Transglutaminase 2 Expression and Its Prognostic Significance in Clear Cell Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Min Jee Park

    2015-01-01

    Full Text Available Background: A few recent studies have demonstrated a possible role of transglutaminase 2 (TG2 in tumorigenesis or progression of renal cell carcinoma (RCC. The aim of this study was to examine TG2 expression and its clinicopathologic significance in a large number of human clear cell RCCs (CCRCCs. Methods: We analyzed 638 CCRCC patients who underwent partial or radical nephrectomy between 1995 and 2005. The expression of TG2 was determined by immunohistochemistry and categorized into four groups, according to staining intensity: negative (0, mild (1+, moderate (2+, and strong (3+. Results: TG2 staining intensity was negative in 8.5% of CCRCC (n=54, 1+ in 32.6% (n=208, 2+ in 50.5% (n=322, and 3+ in 8.5% (n=54. Strong TG2 expression was correlated with high Fuhrman nuclear grade (p=.011, high T category (p=.049, metastasis (p=.043 and male sex (p<.001 but not with N category.The survival analysis showed a significant association between strong TG2 expression and worse overall and cancer-specific survival (p=.027 and p=.010, respectively. On multivariate analysis, strong TG2 expression was a marginally significant prognostic indicator for Fuhrman nuclear grade and TNM staging (p=.054. Conclusions: Our study is the first to demonstrate the clinicopathologic significance of TG2 expression in a large number of human CCRCC samples. Strong TG2 expression was associated with high nuclear grade and poor prognosis.

  15. A Link between mir-100 and FRAP1/mTOR in Clear Cell Ovarian Cancer

    Science.gov (United States)

    Nagaraja, Ankur K.; Creighton, Chad J.; Yu, Zhifeng; Zhu, Huifeng; Gunaratne, Preethi H.; Reid, Jeffrey G.; Olokpa, Emuejevoke; Itamochi, Hiroaki; Ueno, Naoto T.; Hawkins, Shannon M.; Anderson, Matthew L.; Matzuk, Martin M.

    2010-01-01

    MicroRNAs (miRNAs) are small noncoding RNAs that direct gene regulation through translational repression and degradation of complementary mRNA. Although miRNAs have been implicated as oncogenes and tumor suppressors in a variety of human cancers, functional roles for individual miRNAs have not been described in clear cell ovarian carcinoma, an aggressive and chemoresistant subtype of ovarian cancer. We performed deep sequencing to comprehensively profile miRNA expression in 10 human clear cell ovarian cancer cell lines compared with normal ovarian surface epithelial cultures and discovered 54 miRNAs that were aberrantly expressed. Because of the critical roles of the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin (mTOR) pathway in clear cell ovarian cancer, we focused on mir-100, a putative tumor suppressor that was the most down-regulated miRNA in our cancer cell lines, and its up-regulated target, FRAP1/mTOR. Overexpression of mir-100 inhibited mTOR signaling and enhanced sensitivity to the rapamycin analog RAD001 (everolimus), confirming the key relationship between mir-100 and the mTOR pathway. Furthermore, overexpression of the putative tumor suppressor mir-22 repressed the EVI1 oncogene, which is known to suppress apoptosis by stimulating phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1 signaling. In addition to these specific effects, reversing the expression of mir-22 and the putative oncogene mir-182 had widespread effects on target and nontarget gene populations that ultimately caused a global shift in the cancer gene signature toward a more normal state. Our experiments have revealed strong candidate miRNAs and their target genes that may contribute to the pathogenesis of clear cell ovarian cancer, thereby highlighting alternative therapeutic strategies for the treatment of this deadly cancer. PMID:20081105

  16. Clear cell variant of calcifying epithelial odontogenic tumor of maxilla: Report of a rare case.

    Science.gov (United States)

    Badrashetty, Dinesh; Rangaswamy, Shruthi; Belgode, Niranjan

    2013-09-01

    The calcifying epithelial odontogenic tumor (CEOT) is a rare benign tumor of the jaws. Pindborg's tumor having clear cells is extremely rare. Twelve central lesions have been reported of which only three cases have occurred in maxilla. Clear cell variant is a distinct entity, has more aggressive biological behavior and higher chances of recurrence. Hence it is important that presence of clear cells be included in histopathological diagnosis. Here we present a rare case of clear cell CEOT having aggressive behavior.

  17. Clear cell variant of intraosseous mucoepidermoid carcinoma: Report of a rare entity

    Directory of Open Access Journals (Sweden)

    Sujatha Varma

    2012-01-01

    Full Text Available Intraosseous mucoepidermoid carcinoma of jaw bones is a rare lesion. Abundance of clear cells in an intraosseous mucoepidermoid carcinoma may complicate its histopathologic diagnosis. It becomes extremely important to distinguish this lesion from other clear cell lesions of jaw region. Here, we report a case of clear cell variant of intraosseous mucoepidermoid carcinoma in the mandible.

  18. Clear-cell variant of calcifying epithelial odontogenic tumor (Pindborg tumor) in the mandible

    Institute of Scientific and Technical Information of China (English)

    Ching-Yi Chen; Chung-Wei Wu; Wen-Chen Wang; Li-Min Lin; Yuk-Kwan Chen

    2013-01-01

    We present an uncommon case (female patient aged 59 years) of the clear-cell variant of calcifying epithelial odontogenic tumor (CEOT) (also known as Pindborg tumor) in the mandible. The clinical characteristics and probable origins of the clear tumor cells of previously reported cases of clear-cell variant of intraosseous CEOT are also summarized and discussed.

  19. Gluconeogenesis and amino acids metabolism in ovarian clear cell carcinoma

    OpenAIRE

    2013-01-01

    Dissertação de mestrado, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2013 Tumor cells may exhibit different metabolic profiles compared to normal tissues from which they are derived. Those observations gave rise to the new concept that tumorigenesis requires metabolic alterations to sustain cell proliferation. Several studies reveal that increased cell proliferation is accompanied by increased glucose consumption. In OCCC, a typical morphol...

  20. Selective cytotoxicity of indirect nonequilibrium atmospheric pressure plasma against ovarian clear-cell carcinoma.

    Science.gov (United States)

    Utsumi, Fumi; Kajiyama, Hiroaki; Nakamura, Kae; Tanaka, Hiromasa; Hori, Masaru; Kikkawa, Fumitaka

    2014-01-01

    Ovarian clear cell carcinoma (CCC) is a histological type of epithelial ovarian cancer that is less responsive to chemotherapy and associated with a poorer prognosis than serous and endometrioid carcinoma. Non-thermal atmospheric pressure plasma which produces reactive species has recently led to an explosion of research in plasma medicine. Plasma treatment can be applied to cancer treatment to induce apoptosis and tumor growth arrest. Furthermore, recent studies have shown that a medium exposed to plasma also has an anti-proliferative effect against cancer in the absence of direct exposure to plasma. In this study, we confirmed whether this indirect plasma has an anti-tumor effect against CCC, and investigated whether this efficacy is selective for cancer cells. Non-thermal atmospheric pressure plasma induced apoptosis in CCC cells, while human peritoneal mesothelial cells remained viable. Non-thermal atmospheric pressure plasma exhibits selective cytotoxicity against CCC cells which are resistant to chemotherapy.

  1. Carcinomas of ovary and lung with clear cell features: can immunohistochemistry help in differential diagnosis?

    Science.gov (United States)

    Howell, Nicole R; Zheng, Wenxin; Cheng, Liang; Tornos, Carmen; Kane, Philip; Pearl, Michael; Chalas, Eva; Liang, Sharon X

    2007-04-01

    Metastatic lung carcinomas with clear cell morphology can be confused with primary ovarian clear cell carcinomas. We performed immunohistochemical stains in 14 cases of non-small cell lung carcinomas with clear cell features and 14 cases of ovarian clear cell carcinomas using a panel of markers, including thyroid transcription factor 1 (TTF-1), carcinoembryonic antigen (CEA), Wilms tumor gene 1, octamer-binding transcription factor 4 (OCT-4), cancer antigen 125 (CA-125), estrogen receptor, and progesterone receptor. Among non-small cell lung carcinomas with clear cell features, 87.5% of adenocarcinomas (or 50% overall frequency in lung carcinomas) were positive for TTF-1, whereas none of the ovarian clear cell carcinomas were positive (P = 0.002). All 14 ovarian clear cell carcinomas stained for CA-125 as compared with 1 non-small cell lung carcinoma (P < 0.001). On the other hand, 85% of non-small cell lung carcinomas stained for CEA, whereas none of the ovarian clear cell carcinomas did (P < 0.001). Interestingly, 4 ovarian clear cell carcinomas (28%) showed positive staining for the germ cell marker OCT-4. Either lung or ovarian carcinomas stained for Wilms tumor gene 1, estrogen receptor, or progesterone receptor very infrequently; and the difference between the 2 groups was not statistically significant. Our results suggest that an immunohistochemical panel consisting of TTF-1, CEA, CA-125, and OCT-4 is helpful in distinguishing most pulmonary and ovarian carcinomas with clear cell features.

  2. Diagnostic utility of hepatocyte nuclear factor 1-beta immunoreactivity in endometrial carcinomas: lack of specificity for endometrial clear cell carcinoma.

    Science.gov (United States)

    Fadare, Oluwole; Liang, Sharon X

    2012-12-01

    Hepatocyte nuclear factor 1-beta (HNF1β) has recently emerged as a relatively sensitive and specific marker for ovarian clear cell carcinoma. The purpose of this study is to assess the diagnostic utility of this marker for endometrial clear cell carcinoma. Immunohistochemical analysis was performed on 75 endometrial tissues using a goat polyclonal antibody raised against a peptide mapping at the C-terminus of human HNF1β protein. The 75 cases included 15 clear cell carcinomas, 20 endometrioid carcinomas, 15 endometrial serous carcinomas/uterine papillary serous carcinomas, 20 cases of normal endometrium, 2 cases of clear cell metaplasia, and 3 cases of Arias Stella reaction. Staining interpretations were based on a semiquantitative scoring system, a 0 to 12+ continuous numerical scale that was derived by multiplying the extent of staining (0 to 4+ scale) by the intensity of staining (0 to 3+ scale) for each case. HNF1β expression was found to be present in a wide spectrum of tissues. Twenty-seven (54%) of the 50 carcinomas displayed at least focal nuclear HNF1β expression, including 11 (73%) of 15, 9 (60%) of 15, and 7 (35%) of 20 clear cell, serous, and endometrioid carcinomas, respectively. The average nuclear staining scores for clear cell carcinomas, endometrioid carcinomas, and serous carcinomas were 5.2, 1.4, and 4.1, respectively. Clear cell carcinomas and endometrioid carcinomas displayed statistically significant differences regarding their nuclear staining scores (P = 0.0027), but clear cell carcinomas and endometrial serous carcinomas did not (P = 0.45). The calculated sensitivity of any nuclear HNF1β expression in classifying a carcinoma as being of the clear cell histotype was 73%, whereas the specificity was 54%. Nineteen of 20 normal endometrium samples displayed at least focal nuclear expression of HNF1β, and this expression was often diffuse. The 5 cases of benign histologic mimics of clear cell carcinomas (Arias Stella reaction and clear

  3. Alteration of ASIC1 expression in clear cell renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Li Y

    2015-08-01

    Full Text Available Yan Li,1 Guoxiong Xu,2 Kai Huang,1 Jun Wang,3 Jihong Zhang,2 Jikai Liu,1 Zhanyu Wang,1 Gang Chen1 1Department of Urology, 2Central Laboratory, Jinshan Hospital, Fudan University, 3Department of Urology, Shanghai First People’s Hospital, Medical College of Shanghai Jiao Tong University, Shanghai, People’s Republic of China Background: Acidic extracellular pH is a major feature of tumor tissue. Acid-sensing ion channels (ASICs represent an H+-gated subgroup of the degenerin/epithelial Na+ channel family and are activated by acidic microenvironment. Little is known about the expression and clinical significance of ASICs in solid tumors. The purpose of this study was to examine the expression of ASIC1 in human clear cell renal cell carcinoma (CCRCC and to determine if the expression of ASIC1 is associated with clinicopathological features.Methods: The expression of ASIC1 in CCRCC tissues at the mRNA and protein levels was determined by real-time quantitative polymerase chain reaction and Western blot analysis, respectively. A tissue microarray was used to assess the expression of ASIC1 protein in tumor tissue and matched adjacent normal tissues from 75 patients with CCRCC.Results: ASIC1 expression was detected in normal renal and CCRCC samples. The expressions of ASIC1 protein and mRNA were significantly decreased in the CCRCC tissues compared with matched normal renal tissues (P<0.05. The staining density measurement showed that the expression of ASIC1 was significantly decreased in stage I (P=0.037, stage II (P=0.026, and stage III (P=0.026, grades I–II CCRCC (P=0.004, and CCRCC from male patients (P=0.00002. However, no significant difference was observed for ASIC1 expression between CCRCC and normal tissue in patients with stage IV CCRCC (P=0.236, patients with grades III–IV CCRCC (P=0.314, and female patients (P=0.095. Spearman correlations demonstrated that ASIC1 expression did not correlate to tumor stage (correlation coefficient [CC

  4. Glycogen-rich clear cell carcinoma of the breast

    DEFF Research Database (Denmark)

    Sørensen, Flemming Brandt; Paulsen, S M

    1987-01-01

    cells were stained by antisera to carcinoembryonic antigen, keratin and epithelial membrane antigen, but not by antisera to alpha-lactalbumin, desmin or vimentin. Ultrastructurally, the epithelial derivation of the tumour was confirmed. Only a few intracytoplasmic lumina were demonstrated. The tumour...

  5. Overexpression of G6PD Represents a Potential Prognostic Factor in Clear Cell Renal Cell Carcinoma

    Science.gov (United States)

    Zhang, Qiao; Yi, Xiaojia; Yang, Zhe; Han, Qiaoqiao; Di, Xuesong; Chen, Fufei; Wang, Yanling; Yi, Zihan; Kuang, Yingmin; Zhu, Yuechun

    2017-01-01

    Glucose-6-phosphate dehydrogenase (G6PD) participates in glucose metabolism and it acts as the rate-limiting enzyme of the pentose phosphate pathway (PPP). Recently, G6PD dysregulation has been found in a variety of human cancers. Through analyzing published data in The Cancer Genome Atlas (TCGA), our pilot study indicated that G6PD mRNA expression was significantly higher in advanced Fuhrman grade in clear cell renal cell carcinoma (ccRCC). These clues promoted us to further evaluate the expression profile of G6PD and its prognostic impact in patients with ccRCC. In this study, G6PD expression levels were analyzed in 149 human ccRCC and normal tissues using immunohistochemistry. The results showed that compared with that in the normal renal samples, G6PD was found highly expressed in 51.0% of ccRCC (p<0.05). High expression of G6PD was significantly correlated to tumor extent, lymph node metastasis, Fuhrman grade, and TNM stage of ccRCC (all p<0.05). Moreover, positive G6PD expression was associated with poorer overall survival in ccRCC (p<0.001). In Cox regression analyses, high expression of G6PD also could be an independent prognostic factor for overall survival in ccRCC (p=0.007). This study suggests that overexpression of G6PD is associated with advanced disease status and therefore may become an important prognosticator for poor outcomes in ccRCC, as well as a potential therapeutic target for developing effective treatment modalities. PMID:28367246

  6. A Study of Varlilumab (Anti-CD27) and Sunitinib in Patients With Metastatic Clear Cell Renal Cell Carcinoma

    Science.gov (United States)

    2016-09-15

    Carcinoma, Renal Cell; Kidney Diseases; Kidney Neoplasms; Urogenital Neoplasms; Urologic Diseases; Urologic Neoplasms; Neoplasms; Neoplasms by Histologic Type; Clear-cell Metastatic Renal Cell Carcinoma

  7. Vaginal clear cell carcinoma in a Japanese Black cow

    OpenAIRE

    Michishita, Masaki; HORI, Makito; NAKAHIRA, Rei; Takahashi, Kimimasa

    2016-01-01

    During artificial insemination of an 18-year-old female Japanese Black cow, a mass that was of a hen’s egg size was found in the vagina. On necropsy, the firm mass, measuring approximately 3.5 × 3.5 × 3.0 cm, was located at the superior region of the vagina. The cut surface of the mass was gray-white in color with occasional necrotic or hemorrhagic areas. Histologically, the mass was composed of tumor cells arranged in solid nests of various sizes with an occasional tubular structure separate...

  8. Cell cycle progression score predicts metastatic progression of clear cell renal cell carcinoma after resection.

    Science.gov (United States)

    Askeland, Eric J; Chehval, Vincent A; Askeland, Ryan W; Fosso, Placede G; Sangale, Zaina; Xu, Nafei; Rajamani, Saradha; Stone, Steven; Brown, James A

    2015-01-01

    The outcome of surgically resected, apparently localized, clear cell renal carcinoma (ccRCC) is uncertain. To evaluate if cell cycle progression (CCP) gene expression can predict future metastasis. Pathologic T2a-T3b tumors at University of Iowa were reviewed. Patients with known or suspected metastasis, lymph node involvement or who received neoadjuvant or adjuvant radiation, chemotherapy or immunotherapy were excluded. Case and control cohorts were defined as those who did or did not develop metastatic disease within 5 years. Measured levels of 31 cell cycle genes and 15 control genes from the tumor were calculated as a CCP score. Additionally, gene expression data for a separate ccRCC cohort was downloaded from The Cancer Genome Atlas (TCGA). Univariate analysis of 26 cases and 38 controls revealed that the CCP score predicted progression to metastasis (OR 2.65, p = 0.0091). In multivariate logistic regression modeling, CCP expression remained a significant independent predictor for progression (p = 0.026). The CCP score was also significantly associated with distant metastasis in the TCGA renal cancer cohort in both univariate (p = 1.0 × 10-9) and multivariate (p = 5.6 × 10-3) analysis. The CCP score has prognostic value in predicting metastatic progression after resection of organ-confined ccRCC.

  9. Clear cell variant of squamous cell carcinoma of skin: A report of a case

    Directory of Open Access Journals (Sweden)

    Ahmed Oluwatoyin Lawal

    2013-01-01

    Full Text Available Clear cell squamous cell carcinoma (SCC is a rare variant of SCC of skin in which ultraviolet radiation has been suggested as possible etiology. This case is that of a 62-year-old male concrete block maker/bricklayer who presented with a 6 months history of a non-healing ulcer on the left side of his face. Histology showed features of malignant epithelial neoplasm composed of islands of large oval to polyhedral malignant squamous cells with eosinophilic to amphophilic cytoplasm and vesicular nuclei and there were areas showing clear cell differentiation and isolated areas of keratin pearl formation. The lesion was also negative for periodic acid schiff, mucicarmine, and alcian blue stains but was strongly positive for AE1/AE3 (immuno-stain. This case showed an aggressive and bizarre clinical presentation but more report of cases are needed to have a better characterization of the clinical presentation and prognosis of this variant of SCC.

  10. Clear cell variant of squamous cell carcinoma of skin: A report of a case.

    Science.gov (United States)

    Lawal, Ahmed Oluwatoyin; Adisa, Akinyele Olumuyiwa; Olajide, Mofoluwaso A; Olusanya, Adeola Adenike

    2013-01-01

    Clear cell squamous cell carcinoma (SCC) is a rare variant of SCC of skin in which ultraviolet radiation has been suggested as possible etiology. This case is that of a 62-year-old male concrete block maker/bricklayer who presented with a 6 months history of a non-healing ulcer on the left side of his face. Histology showed features of malignant epithelial neoplasm composed of islands of large oval to polyhedral malignant squamous cells with eosinophilic to amphophilic cytoplasm and vesicular nuclei and there were areas showing clear cell differentiation and isolated areas of keratin pearl formation. The lesion was also negative for periodic acid schiff, mucicarmine, and alcian blue stains but was strongly positive for AE1/AE3 (immuno-stain). This case showed an aggressive and bizarre clinical presentation but more report of cases are needed to have a better characterization of the clinical presentation and prognosis of this variant of SCC.

  11. Water Clear Cell Adenoma of the Parathyroid Gland: A Forgotten Cause of Primary Hyperparathyroidism.

    Science.gov (United States)

    El Hussein, Siba; Poppiti, Robert

    2017-08-01

    Water clear cell adenoma of the parathyroid gland is a rare neoplasm composed of large clear cells with foamy cytoplasm and mild nuclear pleomorphism, compressing the residual nonneoplastic parathyroid tissue. The differential diagnosis includes a variety of neoplasms with clear cell features. In this article, we provide an overview of the entity with a historical perspective, in order to help pathologists in distinguishing it from other neoplasms in their daily practice.

  12. Clear cell variant of calcifying epithelial odontogenic tumor of maxilla: Report of a rare case

    Directory of Open Access Journals (Sweden)

    Dinesh Badrashetty

    2013-01-01

    Full Text Available The calcifying epithelial odontogenic tumor (CEOT is a rare benign tumor of the jaws. Pindborg′s tumor having clear cells is extremely rare. Twelve central lesions have been reported of which only three cases have occurred in maxilla. Clear cell variant is a distinct entity, has more aggressive biological behavior and higher chances of recurrence. Hence it is important that presence of clear cells be included in histopathological diagnosis. Here we present a rare case of clear cell CEOT having aggressive behavior.

  13. Clear cell myoepithelial carcinoma of salivary glands showing EWSR1 rearrangement: molecular analysis of 94 salivary gland carcinomas with prominent clear cell component.

    Science.gov (United States)

    Skálová, Alena; Weinreb, Ilan; Hyrcza, Martin; Simpson, Roderick H W; Laco, Jan; Agaimy, Abbas; Vazmitel, Marina; Majewska, Hanna; Vanecek, Tomas; Talarčik, Peter; Manajlovic, Spomenka; Losito, Simona N; Šteiner, Petr; Klimkova, Adela; Michal, Michal

    2015-03-01

    This study examines the presence of the EWSR1 rearrangement in a variety of clear cell salivary gland carcinomas with myoepithelial differentiation. A total of 94 salivary gland carcinomas with a prominent clear cell component included 51 cases of clear cell myoepithelial carcinomas de novo (CCMC), 21 cases of CCMCs ex pleomorphic adenoma (CCMCexPA), 11 cases of epithelial-myoepithelial carcinoma (EMC), 6 cases of EMC with solid clear cell overgrowth, and 5 cases of hyalinizing clear cell carcinoma of minor salivary glands. In addition, 10 cases of myoepithelial carcinomas devoid of clear cell change and 12 cases of benign myoepithelioma were included as well. All the tumors in this spectrum were reviewed, reclassified, and tested by fluorescence in situ hybridization (FISH) for the EWSR1 rearrangement using the Probe Vysis EWSR1 Break Apart FISH Probe Kit. The EWSR1 rearrangement was detected in 20 of 51 (39%) cases of CCMC, in 5 of 21 (24%) cases of CCMCexPA, in 1 of 11 (9%) cases of EMC, and in 4 of 5 (80%) cases of hyalinizing clear cell carcinoma. The 25 EWSR1-rearranged CCMCs and CCMCexPAs shared similar histomorphology. They were arranged in nodules composed of compact nests of large polyhedral cells with abundant clear cytoplasm. Necrosis, areas of squamous metaplasia, and hyalinization were frequent features. Immunohistochemically, the tumors expressed p63 (96%), cytokeratin CK14 (96%), and S100 protein (88%). MIB1 index varied from 10% to 100%, with most cases in the 20% to 40% range. Clinical follow-up information was available in 21 cases (84%) and ranged from 3 months to 15 years (mean 5.2 y); 4 patients were lost to follow-up. Ten patients are alive with no evidence of recurrent or metastatic disease in the follow-up period from 3 months to 15 years (mean 5 y), 3 patients are alive with recurrent and metastatic disease, and 8 died of disseminated cancer 9 months to 16 years after diagnosis (mean 6 y). Lymph node metastasis appeared in 5 patients

  14. Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib.

    Science.gov (United States)

    Miller, Rowan E; Brough, Rachel; Bajrami, Ilirjana; Williamson, Chris T; McDade, Simon; Campbell, James; Kigozi, Asha; Rafiq, Rumana; Pemberton, Helen; Natrajan, Rachel; Joel, Josephine; Astley, Holly; Mahoney, Claire; Moore, Jonathan D; Torrance, Chris; Gordan, John D; Webber, James T; Levin, Rebecca S; Shokat, Kevan M; Bandyopadhyay, Sourav; Lord, Christopher J; Ashworth, Alan

    2016-07-01

    New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G1-S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1A-mutant OCCC. Mol Cancer Ther; 15(7); 1472-84. ©2016 AACR.

  15. Systematic Evaluation of the Prognostic Impact and Intratumour Heterogeneity of Clear Cell Renal Cell Carcinoma Biomarkers

    DEFF Research Database (Denmark)

    Gulati, Sakshi; Martinez, Pierre; Joshi, Tejal;

    2014-01-01

    BackgroundCandidate biomarkers have been identified for clear cell renal cell carcinoma (ccRCC) patients, but most have not been validated. ObjectiveTo validate published ccRCC prognostic biomarkers in an independent patient cohort and to assess intratumour heterogeneity (ITH) of the most promising...... markers to guide biomarker optimisation. Design, setting, and participantsCancer-specific survival (CSS) for each of 28 identified genetic or transcriptomic biomarkers was assessed in 350 ccRCC patients. ITH was interrogated in a multiregion biopsy data set of 10 ccRCCs. Outcome measurements...... of published biomarkers to predict the survival of patients with clear cell kidney cancer in an independent patient cohort. Only one molecular test adds prognostic information to routine clinical assessments. This marker showed good and poor prognosis results within most individual cancers. Future biomarkers...

  16. Identification of novel therapeutic targets in microdissected clear cell ovarian cancers.

    Directory of Open Access Journals (Sweden)

    Michael P Stany

    Full Text Available Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients.

  17. Clear Cell Sarcoma of Gluteal Region Malignant Melanoma of Soft Parts

    Directory of Open Access Journals (Sweden)

    Haren V. Oza

    2013-04-01

    Full Text Available Clear cell sarcoma (CCS is described as variant of sarcoma characterized by prominent clear cells showing features similar to malignant melanoma of soft parts. This neoplasm was first described by Dr. Franz m. Enzinger. Primary CCS usually arises in deeper soft tissues, in association with fascia, tendons, or aponeuroses. Clear cell sarcoma (CCS is a rare malignant tumor with a propensity for slow progressive invasion. It is a tumor derived from Melanoblast like cell. They occur most commonly in the extremities, with a predilection for young females. Clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts and conventional malignant melanoma may demonstrate significant morphologic overlap at the light microscopic and ultra structural level. The tumor is very rare and can pose clinical challenges in early diagnosis. This case report demonstrates an unusual site of occurrence for clear cell sarcoma. [Natl J Med Res 2013; 3(2.000: 193-195

  18. Inhibition of IGF-1-Mediated Cellular Migration and Invasion by Migracin A in Ovarian Clear Cell Carcinoma Cells.

    Directory of Open Access Journals (Sweden)

    Tamami Ukaji

    Full Text Available Previously we isolated migracin A from a Streptomyces culture filtrate as an inhibitor of cancer cell migration. In the present research, we found that migracin A inhibited migration and invasion of ovarian clear cell carcinoma ES-2 cells. In the course of our mechanistic study, migracin A was shown to enhance vasohibin-1 expression in an angiogenesis array. We also confirmed that it increased the mRNA expression of this protein. Moreover, overexpression of vasohibin-1 lowered the migration but not the invasion of ES-2 cells. Then, we looked for another target protein employing a motility array, and found that migracin A lowered the IGF-1 expression. Knockdown of IGF-1 by siRNA decreased the migration and invasion of ES-2 cells. Migracin A also decreased Akt phosphorylation involved in the downstream signaling. Crosstalk analysis indicated that overexpression of vasohibin-1 decreased the IGF-1 expression. On the other hand, it showed no direct anticancer activity in terms of the ES-2 growth in agar. Migracin A inhibited the migration and IGF-1 expression in not only ES-2 but also another ovarian clear cell carcinoma JHOC-5 cells. In addition, it also inhibited capillary tube formation of human umbilical vein endothelial cells. Since its cytotoxicity is very low, migracin A may be a candidate for an anti-metastasis agent not exhibiting prominent toxicity.

  19. A novel grading system for clear cell renal cell carcinoma incorporating tumor necrosis.

    Science.gov (United States)

    Delahunt, Brett; McKenney, Jesse K; Lohse, Christine M; Leibovich, Bradley C; Thompson, Robert Houston; Boorjian, Stephen A; Cheville, John C

    2013-03-01

    Grading of renal cell carcinoma (RCC) has prognostic significance, and there is recent consensus by the International Society of Urological Pathology (ISUP) that for clear cell and papillary RCC, grading should primarily be based on nucleolar prominence. Microscopic tumor necrosis also predicts outcome independent of tumor grading. This study was undertaken to assess whether the incorporation of microscopic tumor necrosis into the ISUP grading system provides survival information superior to ISUP grading alone. Data on 3017 patients treated surgically for clear cell RCC, 556 for papillary RCC, and 180 for chromophobe RCC were retrieved from the Mayo Clinic Registry. Median follow-up periods were 8.9, 9.7, and 8.5 years, respectively. Four proposed grades were defined: grade 1: ISUP grade 1+ISUP grade 2 without necrosis; grade 2: ISUP grade 2 with necrosis+ISUP grade 3 without necrosis; grade 3: ISUP grade 3 with necrosis+ISUP grade 4 without necrosis; grade 4: ISUP grade 4 with necrosis or sarcomatoid/rhabdoid tumors. There was a significant difference in survival between each of the grades for clear cell RCC, and the concordance index was superior to that of ISUP grading. The proposed grading system also outperformed the ISUP grading system when cases were stratified according to the TNM stage. Similar results were not obtained for papillary RCC or chromophobe RCC. We conclude that grading for clear cell RCC should be based on nucleolar prominence and necrosis, that ISUP grading should be used for papillary RCC, and that chromophobe RCC should not be graded.

  20. Clear cell adenocarcinoma of the colon: A case report and review of literature

    Institute of Scientific and Technical Information of China (English)

    Koichi Soga; Ken-Ichi Mukaisho; Takanori Hattori; Hideyuki Konishi; Natsuko Tatsumi; Chika Konishi; Keimei Nakano; Naold Wakabayashi; Shoji Mitsufuji; Keisho Kataoka; Takeshi Okanoue

    2008-01-01

    A primary clear cell adenocarcinoma of the colon is arare oncologic entity.We herein report a case of such atumor of the sigmoid colon in a 71-year-old woman whowas successfully treated by an endoscopic polypecLomy in our hospital.We also reviewed the published reports regarding cases of primary clear cell tumors in the colon.

  1. Apoptotic Cells Are Cleared by Directional Migration and elmo1-Dependent Macrophage Engulfment

    NARCIS (Netherlands)

    van Ham, Tjakko J.; Kokel, David; Peterson, Randall T.

    2012-01-01

    Apoptotic cell death is essential for development and tissue homeostasis [1, 2]. Failure to clear apoptotic cells can ultimately cause inflammation and autoimmunity [3, 4]. Apoptosis has primarily been studied by staining of fixed tissue sections, and a clear understanding of the behavior of apoptot

  2. Clear-Cell Adenocarcinoma of Vesical Origin: A Case Study of Metastatic Disease Treated with Chemotherapy

    Directory of Open Access Journals (Sweden)

    Carolina Pena Álvarez

    2010-01-01

    Full Text Available Vesical clear cell adenocarcinoma is an uncommon tumour. The description of nearly all published cases focuses on histological issues, providing few clinical particulars and limited followup. The treatment choice is resection. No publications have been found regarding systemic treatments for advanced disease. We present a case of metastatic clear cell adenocarcinoma of the bladder treated with chemotherapy.

  3. Succinate Dehydrogenase B (SDHB): A New Prognostic Biomarker in Clear Cell Renal Cell Carcinoma

    Science.gov (United States)

    Cornejo, Kristine M.; Lu, Min; Yang, Ping; Wu, Shulin; Cai, Chao; Zhong, Wei-de; Olumi, Aria; Young, Robert H.; Wu, Chin-Lee

    2015-01-01

    Succinate dehydrogenase B (SDHB) is a mitochondrial enzyme complex subunit. Loss of SDHB protein expression has been found to correlate with SDHx gene mutations. Little is known about its expression in subtypes of renal cell carcinoma (RCC), and whether it’s a prognostic indicator. Four-hundred-fifty renal epithelial neoplasms were analyzed for SDHB, comprising of clear cell RCC (CCRCC) (n=240), papillary RCC (PRCC) (n=84), chromophobe RCC (ChRCC) (n=49), renal oncocytoma (RO) (n=47), clear cell papillary RCC (CCPRCC) (n=19) and von Hippel Lindau (VHL)- associated CCPRCC-like tumors (n=11). SDHB expression was graded based upon staining intensity using a 4-tiered system (0–3+), in which 3+ was strongest and complete absence was 0. Neoplasms were further categorized based upon staining extent into SDHB-weak (1–2+) and strong (3+). SDHB was strongly preserved in 131/240 (55%) CCRCCs, 84/84 (100%) PRCCs, 49/49 (100%) ChRCCs, 1/19 (5%) CCPRCC, 5/11 (45%) VHL-associated CCPRCC-like tumors and 47/47 (100%) ROs. The remaining 109 CCRCCs (45%), 18 CCPRCCs and 6 VHL-associated CCPRCC-like tumors had weak but preserved SDHB. SDHB expression in CCRCCs with high International Society of Urological Pathology (ISUP) nucleolar grade (G3-G4) correlated significantly with survival (log rank P=0.0004). SDHB is variably expressed in RCCs with clear cell morphology and strongly preserved in most other neoplasms. Therefore, weak staining, particularly in clear neoplasms, should not be misinterpreted as negative. Finally, SDHB expression in CCRCCs with high nucleolar grade (G3-G4) is significantly associated with survival, indicating it may be both a diagnostic and prognostic marker in RCC. PMID:25827535

  4. Chronic lymphocytic lymphoma and concomitant renal cell carcinoma (Clear Cell Type: Review of the literature

    Directory of Open Access Journals (Sweden)

    Burak Uz

    2016-01-01

    Full Text Available In the present report, a 73 years-old male patient who developed clear cell type renal cell carcinoma (RCC 5 years after the diagnosis of chronic lymphocytic lymphoma (CLL and plausible explanations for this association were discussed by the authors. The incidence of CLL and RCC occurring in the same patient is higher than that expected in the general population. Various explicative hypotheses of this concurrence include treatment-related development of a second malignancy, immunomodulatory mechanisms, viral aetiology, cytokine (interleukin 6 release from a tumor, and common genetic mutations. Further investigations are warranted.

  5. Clear cell renal cell carcinoma: Validation of WHO/ISUP grading.

    Science.gov (United States)

    Dagher, Julien; Delahunt, Brett; Rioux-Leclercq, Nathalie; Egevad, Lars; Srigley, John R; Coughlin, Geoffrey; Dunglinson, Nigel; Gianduzzo, Troy; Kua, Boon; Malone, Greg; Martin, Ben; Preston, John; Pokorny, Morgan; Wood, Simon; Yaxley, John; Samaratunga, Hemamali

    2017-07-18

    In 2012, the International Society of Urological Pathology (ISUP) introduced a novel grading system for clear cell and papillary renal cell carcinoma (RCC) based upon increasing nucleolar prominence in grades 1 to 3, with the presence of extreme nuclear pleomorphism and/or tumour giant cells and/or sarcomatoid and/or rhabdoid differentiation as criteria for grade 4. This system is now incorporated in the latest World Health Organization renal tumour classification, being designated WHO/ISUP grading. This study was undertaken to compare WHO/ISUP and Fuhrman grading and to validate WHO/ISUP grading as a prognostic parameter in a series of clear cell RCC. Analysis of 681 cases of clear cell RCC showed that 144 tumours could not be assigned a Fuhrman grade on the basis of ambiguous grading features. The application of WHO/ISUP grading resulted in a general down-grading of cases when compared with Fuhrman grading. In a sub-group of 376 cases, for which outcome data were available, 9.3% were WHO/ISUP grade 1, 50.0% were grade 2, 24.2% grade 3 and 16.5% grade 4, while the distribution of Fuhrman grades was 0.4% grade 1, 48.7% grade 2, 29.4% grade 3 and 21.5% grade 4. There were no recurrence/metastases amongst patients with WHO/ISUP grade 1 tumours and there was a significant difference in outcome for WHO/ISUP grades 2, 3 and 4. For Fuhrman grading the cancer-free survival was not significantly different for grade 2 and grade 3 tumours. On multivariate analysis WHO/ISUP grade and pT staging category were found to retain prognostic significance. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  6. Clear cell odontogenic carcinoma: case report with immunohistochemical findings adding support to the challenging diagnosis

    OpenAIRE

    XAVIER, FLÁVIA CALÓ AQUINO; Rodini, Camila Oliveira; Ramalho,Luciana Maria Pedreira; Sarmento,Viviane Almeida; Nunes, Fabio Daumas

    2008-01-01

    Acesso restrito: Texto completo. p. 403-410 Clear cell odontogenic carcinoma (CCOC) is a rare odontogenic tumor associated with aggressive clinical behavior, metastasis, and low survival. We report a case of CCOC affecting the mandible of a 39-year-old man. The tumor presented a biphasic pattern composed of clear cell nests intermingled with eosinophilic cells and separated by collagenous stroma. Immunoreactivity to cytokeratin (CK), specifically AE1/AE3 and CK 8, 14, 18, and 19 was fou...

  7. Expression of insulin-like growth factor family genes in clear cell renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Ryszard Braczkowski

    2016-06-01

    Full Text Available Aim of the study : Despite significant progress in the pathology of clear cell renal cell carcinoma (ccRCC, diagnostic and predictive factors of major importance have not been discovered. Some hopes are associated with insulin-like growth factors. The aim of the study was to compare the expression of genes for insulin-like growth factor family in tumours and in tissue of kidneys without cancer. Material and methods : Fifty-two patients years with clear cell renal cell cancer were qualified to the study group; patients nephrectomised because of hydronephrosis were included in the control group. Expression of genes were evaluated by RT-PCR. Results : Expression of IGFR-1 gene in tumour accounts for about 60% of cases. The incidence is higher than in corresponding adjacent non-cancerous kidney tissues and higher (but with no statistical significance than in kidney without cancer. Expression of IGFR-2 gene in tumours has not been established. The incidence of the expression in corresponding adjacent non-cancerous kidney tissues is small. Expression of this gene has been present in all specimens from kidneys without cancer. Expression of IGFBP-3 gene ascertained in all (except four cases of ccRCC and in the majority of clippings from adjacent tissue. It was not found in kidneys from the control group. IGF-1, IGF-2, and IGFR-1 mRNA copy numbers in ccRCC were higher than in the material from the control group

  8. A Case of Hyalinizing Clear Cell Carcinoma, So-Called Clear Cell Carcinoma, Not Otherwise Specified, of the Minor Salivary Glands of the Buccal Mucosa

    Directory of Open Access Journals (Sweden)

    Takahiro Yamanishi

    2015-01-01

    Full Text Available Hyalinizing clear cell carcinoma (HCCC, so-called clear cell carcinoma, not otherwise specified (CCC (NOS, of the salivary glands is a rare and low-grade malignant tumor. We report a case of HCCC so-called CCC (NOS (referred to as HCCC of the minor salivary gland of the buccal mucosa. A 52-year-old woman had presented with a gradually growing and indolent mass in the right buccal mucosa for about two years. The first biopsy histopathologically suggested the possibility of malignancy derived from the minor salivary glands. A month later, she visited our hospital. The tumor measured approximately 1.5 cm in diameter and was elastic hard, smooth, and well movable. Image examinations demonstrated internal homogeneity of the lesion, which had a smooth margin, in the right buccal mucosa. Complete tumor resection followed by covering with a polyglycolic acid sheet and fibrin glue spray was performed without surgical flap reconstruction. Histopathological findings revealed proliferating tumor cells with clear cytoplasm surrounded by hyalinizing stroma in the submucosal minor salivary glands. Immunohistochemical stains revealed these tumor cells to be positive for epithelial cell markers but negative for myoepithelial ones. These findings confirmed the diagnosis of HCCC. Good wound healing and no evidence of local recurrence and metastasis have been shown since surgery.

  9. Clear Cell Adenocarcinoma of the Renal Pelvis in a Male Patient

    Directory of Open Access Journals (Sweden)

    Sarawut Kongkarnka

    2013-01-01

    Full Text Available Carcinoma of the renal pelvis is an uncommon renal neoplasm. Clear cell adenocarcinoma in the urinary tract is rare and has a histomorphology resembling that of the female genital tract. We herein present a case of clear cell adenocarcinoma of the renal pelvis, which is the first example in a male patient to our knowledge. A 54-year-old man presented with right flank pain. The tumor was associated with renal stones and hydronephrosis and invaded into the peripelvic fat tissue with regional lymph node metastasis. The patient died of metastatic disease six months postoperatively. Histologically, the tumor showed complex papillary architecture lined with clear and hobnail cells. Clear cell adenocarcinoma of the renal pelvis may pose a diagnostic challenge on histological grounds, particularly in the distinction from renal cell carcinoma. The immunohistochemical stains could help confirm the diagnosis. Due to its rarity, an effective treatment regimen remains to be determined.

  10. Clear cell adenocarcinoma of a female urethra: A case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Amel Trabelsi

    2009-01-01

    Full Text Available Context : Clear cell adenocarcinoma of the urethra is an extremely rare tumour. Its histogenetic derivation remains controversial. Case report : We report a new case of clear cell adenocarcinoma of the proximal urethra in a 56-year-old woman who presented with grossly hematuria. Urethral cystoscopy revealed a tumour protruding from the posterior urethral wall at the bladder neck. Treatment consisted of urethrocystectomy with pelvic lymph node dissection. Histologically, the neoplasm consisted of clear cell adenocarcinoma of the urethra. Conclusion : It appears that female urethral adenocarcinoma has more than one tissue of origin.

  11. Clear-cell melanocytic lesions with balloon-cell and sebocyte-like melanocytes: a unifying concept.

    Science.gov (United States)

    Kazlouskaya, Viktoryia; Guo, Ying; Maia-Cohen, Sandra; Mones, Joan

    2014-05-01

    Melanocytes may assume unique shapes and sizes but rarely have clear cytoplasm. We studied 28 melanocytic lesions that contained clear-cell melanocytes of the balloon-cell and sebocyte-like types. Clear-cell melanocytes were found more commonly in females (64%) than in males (36%), with predominance in females younger than 50 years (79%) and predominance in males older than 50 years (67%). They were distributed evenly throughout the body but were not found on acral sites. Clear-cell melanocytes were most prevalent in congenital nevi (18 or 72%) but were also found in 5 Clark nevi, 2 Meischer nevi, 1 Unna nevus, 1 atypical intra-epidermal proliferation, and 1 melanoma. The clear cells were distributed diffusely in 86% of the lesions and focally in 14%. The overall percentage of clear-cell melanocytes was 56%. The percentage of balloon cells was 57% and sebocyte-like melanocytes 32%. Clear cells with morphologic features of both balloon cells and sebocyte-like melanocytes, that is, intermediate cells, were present in all lesions with an overall percentage of 12%. The presence of melanocytes of both the balloon-cell and sebocyte-like types and the finding of clear-cell melanocytes with intermediate features in all lesions lends support to the theory that balloon-cell and sebocyte-like melanocytes may represent morphologic expressions of the same alteration in melanogenesis.

  12. A case of clear cell meningioma with tyrosine-rich crystals.

    Science.gov (United States)

    Schollenberg, Erica; Easton, Alexander S

    2013-08-01

    We present a case of clear cell meningioma with unusual clinical and pathologic features. The patient was a 54-year-old man who underwent laminectomy and durotomy for an intradural tumor in the lumbar spinal canal. Sections showed a predominance of dense collagenous tissue with irregularly shaped and irregularly sized magenta-colored extracellular deposits. On electron microscopy, these deposits were osmiophilic and "petaloid." The final diagnosis of clear cell meningioma rested on relatively inconspicuous intervening nests of glycogen-containing clear cells that were positive for epithelial membrane antigen. The unusual extracellular deposits seen in this case have previously been characterized as tyrosine-rich crystals of the type most commonly seen in salivary gland tumors. Recognition of this tumor as a clear cell meningioma, despite misleading clinical features and initially challenging histologic findings, is not only a matter of diagnostic accuracy but also imparts important prognostic information.

  13. Clear-cell chondrosarcoma of the maxilla Report of a case

    NARCIS (Netherlands)

    Slootweg, P.J.

    1980-01-01

    Clear-cell chondrosarcoma is a variant of chondrosarcoma which is characterized by a typical histomorphology and a very slow rate of growth. A case is presented in which the tumor was located in the maxilla.

  14. A unique presentation of a renal clear cell carcinoma with atypical metastases

    Directory of Open Access Journals (Sweden)

    F. Staderini

    2015-01-01

    Conclusion: Recent series highlight surgery as a key-point in the management of advanced renal clear cell carcinoma. Our case demonstrates the validity of a surgical strategy supported by a multidisciplinary approach.

  15. Chondroblastoma and clear cell chondrosarcoma: radiological and MRI characteristics with histopathological correlation

    Energy Technology Data Exchange (ETDEWEB)

    Kaim, Achim H.; Huegli, Rolf [Institute of Diagnostic Radiology, University Hospital Basle (Switzerland); Bonel, Harald M. [Institute of Clinical Radiology, University Hospital, Munich-Grosshadern (Germany); Jundt, Gernot [Institute of Pathology, University Hospital Basle (Switzerland)

    2002-02-01

    Objective: To analyze and compare the radiological and magnetic resonance imaging (MRI) appearances of chondroblastoma and clear cell chondrosarcoma with histopathological correlation. Design and patients: Twelve patients with histologically proven chondroblastoma and of another four patients with clear cell chondrosarcoma were investigated by radiographs and MRI (T1-, T2-weighted sequences, intravenous gadolinium application). Additionally, the clinical and radiologic data of seven cases of clear cell chondrosarcoma without available MRI were considered. The localization, calcification of tumor matrix, periosteal reaction, cortical bone and patterns of bone destruction were analyzed according to the Lodwick radiological grading system (LRGS). The signal intensity on T1- and T2-weighted sequences, characteristics of contrast enhancement, associated bone marrow edema, soft tissue reaction and joint involvement were evaluated. Histopathological specimens were available in all cases. Results: The age of patients with chondroblastoma (range 15-59 years, mean 22.3 years) was lower than that of those with clear cell chondrosarcoma (range 19-61 years, mean 36.6 years), and the lesions were smaller in the chondroblastoma group (range 1-4 cm, mean 2.3 cm) than in patients with clear cell chondrosarcoma (range 3-7.5 cm, mean 5.2 cm). The chondroblastomas were more confined to the epiphysis (10/12) than the clear cell chondrosarcomas. All chondroblastomas and clear cell chondrosarcomas except one were classified as grade 1A or 1B according to the LRGS; one clear cell chondrosarcoma was judged as grade 2. Signal intensity of the tumors on MRI was very heterogeneous in both groups. High signal intensity on T2-weighted MR images in chondroblastoma mostly corresponded to areas with aneurysmal bone cyst components and in clear cell chondrosarcoma to islands of hyaline cartilage. Contrast enhancement occurred in all tumors and tended to be more intense with clear cell

  16. Solar cell process development in the European integrated project CrystalClear

    Energy Technology Data Exchange (ETDEWEB)

    Beaucarne, G.; John, J.; Choulat, P.; Ma, Y. [IMEC vzw, Kapeldreef 75, B-3001 Leuven (Belgium); Russel, R. [BP Solar Espana, Madrid (Spain); Romijn, I.; Weeber, A. [ECN Solar Energy, PO Box 1, NL 1755 ZG Petten (Netherlands); Hofmann, M.; Preu, R. [Fraunhofer Institute for Solar Energy Systems ISE, Heidenhofstr. 2, 79110 Freiburg (Germany); Slaoui, A. [InESS, Strassbourg (France); Le Quang, N.; Nichiporuk, O. [Photowatt Technologies, Bourgoin-Jallieu (France); Del Caoizo, C; Pan, A. [Polytechnical University of Madrid, Madrid (Spain); Solheim, H.; Evju, J. [REC Scancell, Sandvika (Norway); Nagel, H.; Horzel, J. [SCHOTT Solar, Alzenau (Germany); Bitnar, B.; Heemeier, M.; Weber, T. [SolarWorld, Freiberg/Sachsen (Germany); Raabe, B.; Haverkamp, H.; Struempel, C.; Junge, J.; Riegel, S.; Seren, S.; Hahn, G. [University of Konstanz, Department of Physics, P.O.Box X916, 78457 Konstanz (Germany)

    2008-10-15

    CrystalClear is a large integrated project funded by the European Commission that aims to drastically reduce the cost of crystalline Si PV modules, down to 1 Euro/Wp. Among the different subprojects, the one dealing with the development of advanced solar cells is relatively large (with 11 partners out of the 15 Crystal Clear partners taking part) and has a crucial role. The goal of the subproject is to develop cell design concepts and manufacturing processes that would enable a reduction in the order of 40% of the cell processing costs per Wp. In this paper, we give an overview of all the development work that has taken place in the CrystalClear solar cells subproject so far. World class results have been achieved, particularly on high efficiency cells on Si ribbons, and on industrial-type solar cells on very thin (120 {mu}m thick) substrates.

  17. Expression of CIDE proteins in clear cell renal cell carcinoma and their prognostic significance.

    Science.gov (United States)

    Yu, Ming; Wang, Hui; Zhao, Jun; Yuan, Yuan; Wang, Chao; Li, Jing; Zhang, Lijun; Zhang, Liying; Li, Qing; Ye, Jing

    2013-06-01

    Clear cell renal cell carcinoma (ccRCC) is the major and aggressive subtype of renal cell carcinoma. It is known to derive its histologic appearance from accumulation of abundant lipids and glycogens. The cell death-inducing DFF45-like effector (CIDE) family has been characterized as the lipid droplet proteins involved in the metabolism of lipid storage droplets. The purpose of this study was to evaluate the expression of CIDE proteins in ccRCC cells and to investigate their prognostic significance. We examined consecutive patients with sporadic ccRCC, who underwent nephrectomy, to measure their mRNA and protein expression of CIDE proteins. We found that Cidec and ADRP expression were significantly up-regulated in ccRCC, compared with normal kidney tissues. Cideb was down-regulated. We also found that Cideb was expressed more in low-grade ccRCC than in high-grade tumors. To further clarify the relationship between Cideb expression and patient prognosis, we evaluated 57 ccRCC patients followed up for 120 months. Reduced ccRCC Cideb expression was associated with a higher Fuhrman nuclear grade. Patients with high Cideb expression had better overall survival rate than those with low expression (p < 0.05). Cideb expression was an independent predictor of survival (p = 0.001). Although the biologic function of Cideb in ccRCC remains unknown, the expression level of Cideb might be a novel predictor of prognosis in ccRCC.

  18. The autophagoproteasome a novel cell clearing organelle in baseline and stimulated conditions

    Directory of Open Access Journals (Sweden)

    Paola Lenzi

    2016-07-01

    Full Text Available Protein clearing pathways named autophagy (ATG and ubiquitin proteasome (UP control homeostasis within eukaryotic cells, while their dysfunction produces neurodegeneration. These pathways are viewed as distinct biochemical cascades occurring within specific cytosolic compartments owing pathway-specific enzymatic activity.Recent data strongly challenged the concept of two morphologically distinct and functionally segregated compartments. In fact, preliminary evidence suggests the convergence of these pathways to form a novel organelle named autophagoproteasome. This is characterized in the present study by using a cell line where, mTOR activity is upregulated and autophagy is suppressed. This was reversed dose-dependently by administering the mTOR inhibitor rapamycin. Thus, we could study autophagoproteasomes when autophagy was either suppressed or stimulated. The occurrence of autophagoproteasome was shown also in non-human cell lines. Ultrastructural morphometry, based on the stochiometric binding of immunogold particles allowed the quantitative evaluation of ATG and UP component within autophagoproteasomes. The number of autophagoproteasomes increases following mTOR inhibition. Similarly, mTOR inhibition produces overexpression of both LC3 and P20S particles. This is confirmed by the fact that the ratio of free vs autophagosome-bound LC3 is similar to that measured for P20S, both in baseline conditions and following mTOR inhibition. Remarkably, within autophagoproteasomes there is a slight prevalence of ATG compared with UP components for low rapamycin doses, whereas for higher rapamycin doses UP increases more than ATG. While LC3 is widely present within cytosol, UP is strongly polarized within autophagoproteasomes. These fine details were evident at electron microscopy but could not be deciphered by using confocal microscopy. Despite its morphological novelty autophagoproteasomes appear the natural site where clearing pathways (once believed

  19. The Autophagoproteasome a Novel Cell Clearing Organelle in Baseline and Stimulated Conditions.

    Science.gov (United States)

    Lenzi, Paola; Lazzeri, Gloria; Biagioni, Francesca; Busceti, Carla L; Gambardella, Stefano; Salvetti, Alessandra; Fornai, Francesco

    2016-01-01

    Protein clearing pathways named autophagy (ATG) and ubiquitin proteasome (UP) control homeostasis within eukaryotic cells, while their dysfunction produces neurodegeneration. These pathways are viewed as distinct biochemical cascades occurring within specific cytosolic compartments owing pathway-specific enzymatic activity. Recent data strongly challenged the concept of two morphologically distinct and functionally segregated compartments. In fact, preliminary evidence suggests the convergence of these pathways to form a novel organelle named autophagoproteasome. This is characterized in the present study by using a cell line where, mTOR activity is upregulated and autophagy is suppressed. This was reversed dose-dependently by administering the mTOR inhibitor rapamycin. Thus, we could study autophagoproteasomes when autophagy was either suppressed or stimulated. The occurrence of autophagoproteasome was shown also in non-human cell lines. Ultrastructural morphometry, based on the stochiometric binding of immunogold particles allowed the quantitative evaluation of ATG and UP component within autophagoproteasomes. The number of autophagoproteasomes increases following mTOR inhibition. Similarly, mTOR inhibition produces overexpression of both LC3 and P20S particles. This is confirmed by the fact that the ratio of free vs. autophagosome-bound LC3 is similar to that measured for P20S, both in baseline conditions and following mTOR inhibition. Remarkably, within autophagoproteasomes there is a slight prevalence of ATG compared with UP components for low rapamycin doses, whereas for higher rapamycin doses UP increases more than ATG. While LC3 is widely present within cytosol, UP is strongly polarized within autophagoproteasomes. These fine details were evident at electron microscopy but could not be deciphered by using confocal microscopy. Despite its morphological novelty autophagoproteasomes appear in the natural site where clearing pathways (once believed to be

  20. The Autophagoproteasome a Novel Cell Clearing Organelle in Baseline and Stimulated Conditions

    Science.gov (United States)

    Lenzi, Paola; Lazzeri, Gloria; Biagioni, Francesca; Busceti, Carla L.; Gambardella, Stefano; Salvetti, Alessandra; Fornai, Francesco

    2016-01-01

    Protein clearing pathways named autophagy (ATG) and ubiquitin proteasome (UP) control homeostasis within eukaryotic cells, while their dysfunction produces neurodegeneration. These pathways are viewed as distinct biochemical cascades occurring within specific cytosolic compartments owing pathway-specific enzymatic activity. Recent data strongly challenged the concept of two morphologically distinct and functionally segregated compartments. In fact, preliminary evidence suggests the convergence of these pathways to form a novel organelle named autophagoproteasome. This is characterized in the present study by using a cell line where, mTOR activity is upregulated and autophagy is suppressed. This was reversed dose-dependently by administering the mTOR inhibitor rapamycin. Thus, we could study autophagoproteasomes when autophagy was either suppressed or stimulated. The occurrence of autophagoproteasome was shown also in non-human cell lines. Ultrastructural morphometry, based on the stochiometric binding of immunogold particles allowed the quantitative evaluation of ATG and UP component within autophagoproteasomes. The number of autophagoproteasomes increases following mTOR inhibition. Similarly, mTOR inhibition produces overexpression of both LC3 and P20S particles. This is confirmed by the fact that the ratio of free vs. autophagosome-bound LC3 is similar to that measured for P20S, both in baseline conditions and following mTOR inhibition. Remarkably, within autophagoproteasomes there is a slight prevalence of ATG compared with UP components for low rapamycin doses, whereas for higher rapamycin doses UP increases more than ATG. While LC3 is widely present within cytosol, UP is strongly polarized within autophagoproteasomes. These fine details were evident at electron microscopy but could not be deciphered by using confocal microscopy. Despite its morphological novelty autophagoproteasomes appear in the natural site where clearing pathways (once believed to be

  1. Composite renal cell carcinoma with clear cell renal cell carcinomatous and carcinoid tumoral elements: a first case report.

    Science.gov (United States)

    Bressenot, A; Delaunay, C; Gauchotte, G; Oliver, A; Boudrant, G; Montagne, K

    2010-02-01

    Renal endocrine tumours are extremely rare, and carcinoid tumoral elements in renal cell carcinoma have never been reported. This is the first report of a composite renal cell carcinoma containing a clear cell renal cell carcinoma associated with carcinoid tumoral elements, in a patient with synchronous metastatic disease. In the absence of specific radiological and clinical manifestations, typical morphological features as well as an immunostaining profile of neuroendocrine differentiation were identified by microscopy. Secondary nodal and liver localisations were characterised by carcinoid elements only. Despite antiangiogenic therapy, liver metastasis progressed, suggesting that adjuvant therapy cannot be based on the presence of the clear cell renal cell carcinoma component. In this context, extensive tissue sampling is recommended to reveal the endocrine component that is the most aggressive element of such a composite carcinoma.

  2. Clear Cells of Toker in the Developing Anogenital Region of Male and Female Fetuses

    NARCIS (Netherlands)

    van der Putte, Sebastian C. J.

    2011-01-01

    The clear cells of Toker are a mysterious population of intra-epidermal glandular cells. They were originally described in nipples, but were recently observed in the vulva as well. It was hypothesized that intra-epidermal embryonic remnants or underlying glands were a potential source. The embryolog

  3. Gender Specific Mutation Incidence and Survival Associations in Clear Cell Renal Cell Carcinoma (CCRCC.

    Directory of Open Access Journals (Sweden)

    Christopher J Ricketts

    Full Text Available Renal cell carcinoma (RCC is diagnosed in >200,000 individuals worldwide each year, accounting for ~2% of all cancers, but the spread of this disease amongst genders is distinctly uneven. In the U.S. the male:female incidence ratio is approximately 2:1. A potential hypothesis is mutation spectra may differ between tumors dependent upon the gender of the patient, such as mutations of X chromosome encoded genes being more prevalent in male-derived tumors. Combined analysis of three recent large-scale clear cell renal cell carcinoma (CCRCC mutation sequencing projects identified a significantly increased mutation frequency of PBRM1 and the X chromosome encoded KDM5C in tumors from male patients and BAP1 in tumors from female patients. Mutation of BAP1 had previously been significantly associated with poorer overall survival; however, when stratified by gender, mutation of BAP1 only significantly affected overall survival in female patients. Mutation of chromatin remodeling genes alters gene regulation, but the overall effect of these alterations may also be modified by the presence of other gender specific factors. Thus, the combination of gender and mutation of a specific gene, such as BAP1, may have implications not only for prognosis but also for understanding the role of chromatin remodeling gene mutations in kidney cancer progression.

  4. Imaging Nuclear Morphology and Organization in Cleared Plant Tissues Treated with Cell Cycle Inhibitors.

    Science.gov (United States)

    de Souza Junior, José Dijair Antonino; de Sa, Maria Fatima Grossi; Engler, Gilbert; Engler, Janice de Almeida

    2016-01-01

    Synchronization of root cells through chemical treatment can generate a large number of cells blocked in specific cell cycle phases. In plants, this approach can be employed for cell suspension cultures and plant seedlings. To identify plant cells in the course of the cell cycle, especially during mitosis in meristematic tissues, chemical inhibitors can be used to block cell cycle progression. Herein, we present a simplified and easy-to-apply protocol to visualize mitotic figures, nuclei morphology, and organization in whole Arabidopsis root apexes. The procedure is based on tissue clearing, and fluorescent staining of nuclear DNA with DAPI. The protocol allows carrying out bulk analysis of nuclei and cell cycle phases in root cells and will be valuable to investigate mutants like overexpressing lines of genes disturbing the plant cell cycle.

  5. Primary clear cell carcinoma of parotid gland: Case report and review of literature.

    Science.gov (United States)

    Rodríguez, Marta Saldaña; Reija, Maria Fe García; Rodilla, Irene González

    2013-01-01

    Clear cell carcinoma (CCC) is a rare low-grade carcinoma that represents only 1% to 2% of all salivary glands tumors. The finding of a clear cell tumor in a parotid gland involves the necessity of differential diagnosis between primary clear cell parotid tumors and metastases, mainly from kidney. The biological behavior is not very aggressive and development, which is very slow, is usually asymptomatic and indeed, the tumor often reaches considerable dimensions before being diagnosed. The treatment of choice is the surgical excision. There are rare cases of local recurrence and distant metastases. The aim of this article is to report a primary CCC in the parotid gland that microscopically closely resembled a metastatic CCC of renal origin, making microscopic differentiation difficult.

  6. [Intra-spinal clear cell meningioma. Case report and literature review].

    Science.gov (United States)

    Tuñón-Pitalúa, M C; Molina-Olier, O; Alcalá-Cerra, G; Niño-Hernández, L M; Lozano-Tangua, C F

    2011-02-01

    Clear cell meningioma is a rare variety of meningiomas, occurring frequently at the cerebellopontine angle and spinal canal. A case of a female patient 28 years of age with a complete cauda equina syndrome was described. Magnetic resonance imaging of lumbo-sacral spine revealed a mass lesion occupying the spinal canal from L3 to S1. Subtotal resection was performed and pathological pathological examination revealed a clear cell meningioma. Radiotherapy was indicated, however, it was delayed because we discovered that the patient was pregnant. The recurrence was clinically evident at seven months and a new surgical resection previous complementary radiotherapy was necessary. A systematic review of literature was performed, exposing the behavior of clear cell meningioma in the spinal canal.

  7. Addressing metabolic heterogeneity in clear cell renal cell carcinoma with quantitative Dixon MRI

    Science.gov (United States)

    Zhang, Yue; Udayakumar, Durga; Cai, Ling; Hu, Zeping; Kapur, Payal; Kho, Eun-Young; Pavía-Jiménez, Andrea; Fulkerson, Michael; de Leon, Alberto Diaz; Yuan, Qing; Dimitrov, Ivan E.; Ye, Jin; Mitsche, Matthew A.; Kim, Hyeonwoo; McDonald, Jeffrey G.; Madhuranthakam, Ananth J.; Dwivedi, Durgesh K.; Lenkinski, Robert E.; Cadeddu, Jeffrey A.; Margulis, Vitaly; Brugarolas, James; DeBerardinis, Ralph J.

    2017-01-01

    BACKGROUND. Dysregulated lipid and glucose metabolism in clear cell renal cell carcinoma (ccRCC) has been implicated in disease progression, and whole tumor tissue–based assessment of these changes is challenged by the tumor heterogeneity. We studied a noninvasive quantitative MRI method that predicts metabolic alterations in the whole tumor. METHODS. We applied Dixon-based MRI for in vivo quantification of lipid accumulation (fat fraction [FF]) in targeted regions of interest of 45 primary ccRCCs and correlated these MRI measures to mass spectrometry–based lipidomics and metabolomics of anatomically colocalized tissue samples isolated from the same tumor after surgery. RESULTS. In vivo tumor FF showed statistically significant (P quantitative Dixon-based MRI as a biomarker of reprogrammed lipid metabolism in ccRCC, which may serve as a predictor of tumor aggressiveness before surgical intervention. FUNDING. NIH R01CA154475 (YZ, MF, PK, IP), NIH P50CA196516 (IP, JB, RJD, JAC, PK), Welch Foundation I-1832 (JY), and NIH P01HL020948 (JGM). PMID:28768909

  8. Screening disrupted molecular functions and pathways associated with clear cell renal cell carcinoma using Gibbs sampling.

    Science.gov (United States)

    Nan, Ning; Chen, Qi; Wang, Yu; Zhai, Xu; Yang, Chuan-Ce; Cao, Bin; Chong, Tie

    2017-10-01

    To explore the disturbed molecular functions and pathways in clear cell renal cell carcinoma (ccRCC) using Gibbs sampling. Gene expression data of ccRCC samples and adjacent non-tumor renal tissues were recruited from public available database. Then, molecular functions of expression changed genes in ccRCC were classed to Gene Ontology (GO) project, and these molecular functions were converted into Markov chains. Markov chain Monte Carlo (MCMC) algorithm was implemented to perform posterior inference and identify probability distributions of molecular functions in Gibbs sampling. Differentially expressed molecular functions were selected under posterior value more than 0.95, and genes with the appeared times in differentially expressed molecular functions ≥5 were defined as pivotal genes. Functional analysis was employed to explore the pathways of pivotal genes and their strongly co-regulated genes. In this work, we obtained 396 molecular functions, and 13 of them were differentially expressed. Oxidoreductase activity showed the highest posterior value. Gene composition analysis identified 79 pivotal genes, and survival analysis indicated that these pivotal genes could be used as a strong independent predictor of poor prognosis in patients with ccRCC. Pathway analysis identified one pivotal pathway - oxidative phosphorylation. We identified the differentially expressed molecular functions and pivotal pathway in ccRCC using Gibbs sampling. The results could be considered as potential signatures for early detection and therapy of ccRCC. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Variation in genomic landscape of clear cell renal cell carcinoma across Europe.

    Science.gov (United States)

    Scelo, Ghislaine; Riazalhosseini, Yasser; Greger, Liliana; Letourneau, Louis; Gonzàlez-Porta, Mar; Wozniak, Magdalena B; Bourgey, Mathieu; Harnden, Patricia; Egevad, Lars; Jackson, Sharon M; Karimzadeh, Mehran; Arseneault, Madeleine; Lepage, Pierre; How-Kit, Alexandre; Daunay, Antoine; Renault, Victor; Blanché, Hélène; Tubacher, Emmanuel; Sehmoun, Jeremy; Viksna, Juris; Celms, Edgars; Opmanis, Martins; Zarins, Andris; Vasudev, Naveen S; Seywright, Morag; Abedi-Ardekani, Behnoush; Carreira, Christine; Selby, Peter J; Cartledge, Jon J; Byrnes, Graham; Zavadil, Jiri; Su, Jing; Holcatova, Ivana; Brisuda, Antonin; Zaridze, David; Moukeria, Anush; Foretova, Lenka; Navratilova, Marie; Mates, Dana; Jinga, Viorel; Artemov, Artem; Nedoluzhko, Artem; Mazur, Alexander; Rastorguev, Sergey; Boulygina, Eugenia; Heath, Simon; Gut, Marta; Bihoreau, Marie-Therese; Lechner, Doris; Foglio, Mario; Gut, Ivo G; Skryabin, Konstantin; Prokhortchouk, Egor; Cambon-Thomsen, Anne; Rung, Johan; Bourque, Guillaume; Brennan, Paul; Tost, Jörg; Banks, Rosamonde E; Brazma, Alvis; Lathrop, G Mark

    2014-10-29

    The incidence of renal cell carcinoma (RCC) is increasing worldwide, and its prevalence is particularly high in some parts of Central Europe. Here we undertake whole-genome and transcriptome sequencing of clear cell RCC (ccRCC), the most common form of the disease, in patients from four different European countries with contrasting disease incidence to explore the underlying genomic architecture of RCC. Our findings support previous reports on frequent aberrations in the epigenetic machinery and PI3K/mTOR signalling, and uncover novel pathways and genes affected by recurrent mutations and abnormal transcriptome patterns including focal adhesion, components of extracellular matrix (ECM) and genes encoding FAT cadherins. Furthermore, a large majority of patients from Romania have an unexpected high frequency of A:T>T:A transversions, consistent with exposure to aristolochic acid (AA). These results show that the processes underlying ccRCC tumorigenesis may vary in different populations and suggest that AA may be an important ccRCC carcinogen in Romania, a finding with major public health implications.

  10. Primary clear cell ductal adenocarcinoma of the pancreas: A case report and clinicopathologic literature review

    Directory of Open Access Journals (Sweden)

    Yashpal Modi

    2014-01-01

    Full Text Available We present a very rare, interesting case of a carcinoma of the pancreas with predominantly abundant clear cell morphology. According to the WHO classification, primary clear cell carcinoma of the pancreas is classified as a rare "miscellaneous" carcinoma. The tumor was observed in the distal body and tail of the pancreas of a 74-year-old woman. The histopathology of tumor cells showed well-defined cell membranes, clear cytoplasm, and prominent cell boundaries. Immunohistochemical (IHC staining showed positive reactions to antibodies against vimentin, cytokeratin 7 (CK-7, mucicarmine (MUC-1, periodic acid-Schiff (PAS, periodic acid-Schiff with diastase (PASD, carcinoembryonic antigen (CEA, and Carbohydrate Antigen 19-9 (CA 19-9. On the other hand, IHC staining was negative for alpha-fetoprotein (AFP, cytokeratin 20 (CK-20, HMB45, chromogranin, and synaptophysin. The patient was subsequently diagnosed with a primary solid-type pancreatic clear cell carcinoma with hepatic metastasis. Herein, we report this rare case and include a review of the current literature of this tumor.

  11. CD 9 and vimentin distinguish clear cell from chromophobe renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Ljunberg Börje

    2009-11-01

    Full Text Available Abstract Background Clear cell renal cell carcinoma (ccRCC and chromophobe renal cell carcinoma (chRCC can usually be distinguished by histologic characteristics. Occasionally, diagnosis proves challenging and diagnostic difficulty will likely increase as needle biopsies of renal lesions become more common. Methods To identify markers that aid in differentiating ccRCC from chRCC, we used gene expression profiles to identify candidate markers that correlate with histology. 39 antisera and antibodies, including 35 for transcripts identified from gene expression profiling, were evaluated. Promising markers were tested on a tissue microarray (TMA containing 428 renal neoplasms. Strength of staining of each core on the TMA was formally scored and the distribution of staining across different types of renal neoplasms was analyzed. Results Based on results from initial immunohistochemical staining of multitissue titer arrays, 23 of the antisera and antibodies were selected for staining of the TMA. For 7 of these markers, strength of staining of each core on the TMA was formally scored. Vimentin (positive in ccRCC and CD9 (positive in chRCC best distinguished ccRCC from chRCC. The combination of vimentin negativity and CD9 positivity was found to distinguish chRCC from ccRCC with a sensitivity of 100.0% and a specificity of 95.2%. Conclusion Based on gene expression analysis, we identify CD9 and vimentin as candidate markers for distinguishing between ccRCC and chRCC. In difficult cases and particularly when the amount of diagnostic tissue is limited, vimentin and CD9 staining could serve as a useful adjunct in the differential diagnosis of ccRCC and chRCC.

  12. An association between overexpression of DNA methyltransferase 3B4 and clear cell renal cell carcinoma.

    Science.gov (United States)

    Liu, You; Sun, Liantao; Fong, Peter; Yang, Jie; Zhang, Zhuxia; Yin, Shuihui; Jiang, Shuyuan; Liu, Xiaolei; Ju, Hongge; Huang, Lihua; Bai, Jing; Gong, Kerui; Yan, Shaochun; Zhang, Chunyang; Shao, Guo

    2017-02-01

    It is well known that abnormal DNA methylations occur frequently in kidney cancer. However, it remains unclear exactly which types of DNA methyltransferases (DNMT) contribute to the pathologies of kidney cancers. In order to determine the functions of DNA methyltransferase in kidney tumorigenesis on the molecular level, we examined the mRNA expression levels of DNMT1, DNMT3A, DNMT3B, and DNMT3B variants in renal cell carcinoma tissue. Both mRNA and protein levels of DNMT3B4, a splice variant of DNMT3B, were increased in renal cell carcinoma tissue compared with adjacent control tissues. Additionally, Alu elements and long interspersed nuclear elements (LINE-1) were hypomethylated in renal cell carcinoma tissue. Meanwhile, methylation of the promoter for RASSF1A, a tumor suppressor gene, was moderately increased in renal cell carcinoma tissue, while RASSF1A expression was decreased. Thus, our data suggest that the overexpression of DNMT3B4 may play an important role in human kidney tumorigenesis through chromosomal instability and methylation of RASSF1A.

  13. Integrative bioinformatics links HNF1B with clear cell carcinoma and tumor-associated thrombosis.

    Directory of Open Access Journals (Sweden)

    Justin Cuff

    Full Text Available Clear cell carcinoma (CCC is a histologically distinct carcinoma subtype that arises in several organ systems and is marked by cytoplasmic clearing, attributed to abundant intracellular glycogen. Previously, transcription factor hepatocyte nuclear factor 1-beta (HNF1B was identified as a biomarker of ovarian CCC. Here, we set out to explore more broadly the relation between HNF1B and carcinomas with clear cell histology. HNF1B expression, evaluated by immunohistochemistry, was significantly associated with clear cell histology across diverse gynecologic and renal carcinomas (P<0.001, as was hypomethylation of the HNF1B promoter (P<0.001. From microarray analysis, an empirically-derived HNF1B signature was significantly enriched for computationally-predicted targets (with HNF1 binding sites (P<0.03, as well as genes associated with glycogen metabolism, including glucose-6-phophatase, and strikingly the blood clotting cascade, including fibrinogen, prothrombin and factor XIII. Enrichment of the clotting cascade was also evident in microarray data from ovarian CCC versus other histotypes (P<0.01, and HNF1B-associated prothrombin expression was verified by immunohistochemistry (P = 0.015. Finally, among gynecologic carcinomas with cytoplasmic clearing, HNF1B immunostaining was linked to a 3.0-fold increased risk of clinically-significant venous thrombosis (P = 0.043, and with a 2.3-fold increased risk (P = 0.011 in a combined gynecologic and renal carcinoma cohort. Our results define HNF1B as a broad marker of clear cell phenotype, and support a mechanistic link to glycogen accumulation and thrombosis, possibly reflecting (for gynecologic CCC derivation from secretory endometrium. Our findings also implicate a novel mechanism of tumor-associated thrombosis (a major cause of cancer mortality, based on the direct production of clotting factors by cancer cells.

  14. Clear cell myoepithelioma of palate with emphasis on clinical and histological differential diagnosis.

    Science.gov (United States)

    Nair, Bindu J; Vivek, Velayudhannair; Sivakumar, Trivandrum T; Joseph, Anna P; Varun, Babyamma Raghavanpillai; Mony, Vinod

    2014-03-27

    Myoepitheliomas account for less than 1% of all salivary gland tumors and mostly occur in the parotid gland and palate. A 58-year old male patient reported to the Outpatient Department of PMS College of Dental Science and Research (Kerala, India) with a slow growing painless swelling on the palate for 4 years. Pleomorphic adenoma, basal cell adenoma, myoepithelioma, cyst adenoma, lipoma, neurofibroma, neurilemmoma and leiomyoma were considered. Histopathology revealed a thinly encapsulated tumor composed mainly of sheets of clear cells mixed with cells having eosinophilic cytoplasm. Histopathological differential diagnosis included pleomorphic adenoma, oncocytoma, oncocytic hyperplasia, sebaceous adenoma, malignant salivary gland neoplasms and metastatic lesions from kidney and thyroid. Myoepitheliomas mostly occur in the parotid gland and palatal region and various histological types of myoepithelioma are described. Myoepitheliomas of the palate are rare with clear cell variant even rarer.

  15. Prognostic value of plasma and urine glycosaminoglycan scores in clear cell renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Francesco Gatto

    2016-11-01

    Full Text Available The prognosis of metastatic clear cell renal cell carcinoma (ccRCC vastly improved since the introduction of antiangiogenic targeted therapy. However, it is still unclear which biological processes underlie ccRCC aggressiveness and affect prognosis. Here, we checked whether a recently discovered systems biomarker based on plasmatic or urinary measurements of glycosaminoglycans aggregated into diagnostic scores correlated with ccRCC prognosis.Thirty-one patients with a diagnosis of ccRCC (23 metastatic were prospectively enrolled and their urine and plasma biomarker scores were correlated to progression-free survival (PFS and overall survival (OS as either a dichotomous (Low vs. High or a continuous variable in a multivariate survival analysis.The survival difference between High vs. Low-scored patients was significant in the case of urine scores (2-year PFS rate = 53.3% vs. 100%, p = 310-4 and 2-year OS rate = 73.3% vs. 100%, p = 0.0078 and in the case of OS for plasma scores (2-year PFS rate = 60% vs. 84%, p = 0.0591 and 2-year OS rate = 66.7% vs. 90%, p = 0.0206. In multivariate analysis, the urine biomarker score was an independent predictor of PFS (HR: 4.62, 95% CI: 1.66 to 12.83, p = 0.003 and OS (HR: 10.13, 95% CI: 1.80 to 57.04, p = 0.009.This is the first report on an association between plasma or urine GAG scores and the prognosis of ccRCC patients. Prospective trials validating the prognostic and predictive role of this novel systems biomarker are warranted.

  16. Single nucleotide polymorphisms in the Wilms' tumour gene 1 in clear cell renal cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Xingru Li

    Full Text Available The Wilms' tumour gene 1 (WT1 single nucleotide polymorphism (SNP rs16754 has recently been described as an independent prognostic factor in acute myeloid leukaemia (AML patients. It is of great interest to test whether WT1 SNPs can be used as a molecular marker in other cancer types in order to improve risk and treatment stratification. We performed sequencing analysis on all 10 exons of the WT1 gene in a total of 182 patients with clear cell renal cell carcinoma (ccRCC. Six different SNPs were identified, in descending order for minor allele frequency: rs2234582, rs16754, rs1799925, rs5030315, rs2234583, and rs2234581. At least one minor allele for WT1 SNP was identified in 61% of ccRCC patients. In the entire study population, only 6% carried two copies of the minor allele. The genotypes of WT1 SNPs in 78 tumour-free kidney tissue specimens were found to be in 95% concordance with corresponding tumour samples. No correlation was observed between WT1 SNP genotypes and RNA expression level. WT1 SNP genotypes did not associate with clinical and pathological characteristics. We found favourable outcomes associated with the homozygous minor allele for WT1 SNP. However, SNP genotypes did not show to be of prognostic significance when comparing wild-type versus homozygous or heterozygous for the minor allele in the entire cohort. None of the previously reported WT1 mutations in AML was found in the present study. A novel WT1 missense mutation was identified in only one patient. Our data suggest that common WT1 mutations are not involved in ccRCC. Due to too few cases harbouring the homozygous minor allele, the prognostic impact needs to be verified in larger study populations.

  17. A case report of the clear cell variant of gallbladder carcinoma

    Directory of Open Access Journals (Sweden)

    Ravi Maharaj

    2017-01-01

    Conclusion: In these cases, clinical case management should be personalized for increased survival with the possible incorporation of next generation sequencing approaches to guide therapeutic algorithms. We discuss this exceedingly rare case of the clear cell variant of gallbladder carcinoma in detail, highlighting some of the diagnostic, and clinical challenges.

  18. Clear Cell Carcinoma of the Breast: A Rare Breast Cancer Subtype - Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Vilma Ratti

    2015-11-01

    Full Text Available Background: Glycogen-rich clear cell breast carcinoma is a rare histological breast cancer subtype. Its prognosis may vary depending on specific clinical and pathological characteristics such as low grade, strong positivity of estrogen receptor (ER expression and early diagnosis. Case Presentation: We present the case of a 53-year-old woman with a bleeding 10-cm-diameter mass in the left breast. The histological examination showed a poorly differentiated tumor with malignant cells characterized by abundant clear cytoplasm. The diagnosis of clear cell carcinoma was based on the histological characteristics of the tumor, and a nonmammary origin was initially ruled out. The tumor was triple negative [i.e. ER, progesterone receptor (PR and HER2 negative]. Four months after the initial locoregional treatment, the patient developed lung and distant lymph node metastases. Conclusions: Glycogen-rich clear cell carcinoma of the breast is a rare tumor. Early diagnosis, absence of lymph node metastases and ER/PR positivity are associated with a better prognosis, as in other common breast cancer subtypes.

  19. TCF21 hypermethylation in genetically quiescent clear cell sarcoma of the kidney

    NARCIS (Netherlands)

    Gooskens, Saskia L.; Gadd, Samantha; Guidry Auvil, Jaime M.; Gerhard, Daniela S.; Khan, Javed; Patidar, Rajesh; Meerzaman, Daoud; Chen, Qing Rong; Hsu, Chih Hao; Yan, Chunhua; Nguyen, Cu; Hu, Ying; Mullighan, Charles G.; Ma, Jing; Jennings, Lawrence J.; de Krijger, Ronald R.; van den Heuvel-Eibrink, Marry M.; Smith, Malcolm A.; Ross, Nicole; Gastier-Foster, Julie M.; Perlman, Elizabeth J.

    2015-01-01

    Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood tumor whose molecular pathogenesis remains poorly understood. We analyzed a discovery set of 13 CCSKs for changes in chromosome copy number, mutations, rearrangements, global gene expression and global DNA methylation. No recurrent segmenta

  20. CD163-positive cancer cells are potentially associated with high malignant potential in clear cell renal cell carcinoma.

    Science.gov (United States)

    Ma, Chaoya; Horlad, Hasita; Ohnishi, Koji; Nakagawa, Takenobu; Yamada, Sohsuke; Kitada, Shohei; Motoshima, Takanobu; Kamba, Tomomi; Nakayama, Toshiyuki; Fujimoto, Naohiro; Takeya, Motohiro; Komohara, Yoshihiro

    2017-07-07

    CD163 is preferentially expressed by monocyte/macrophages; however, recent studies using immunohistochemistry (IHC) have reported that some cancer cells also express CD163. In the present IHC study, we investigated CD163 staining of cancer cells and macrophages in clear cell renal cell carcinoma (ccRCC) tissues and determined the relationship between cancer cell CD163 expression and clinical prognosis in patients with ccRCC. IHC for CD163 was performed in ccRCC tissues from 103 patients. CD163-positive cancer cells were detected in 35% of the patients (36/103); however, the positive signals on cancer cells were significantly lower than those on macrophages. CD163-positive cancer cells were preferentially detected in patients with high T classification, and females, and were significantly associated with shortened progression-free survival and a lower overall survival ratio. Notably, a high intensity of CD163-positive macrophage infiltration was detected in the CD163-positive cancer cell-high tumor areas. Although CD163 mRNA was detected in cultured macrophages, no CD163 mRNA was detected in two cultured RCC cell lines. The detailed mechanism by which a positive signal is detected on cancer cells has not been clarified. Detection of the CD163 antigen on cancer cells might be a useful marker for evaluating the clinical course of patients with ccRCC.

  1. High expression of HMGA2 predicts poor survival in patients with clear cell renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Na N

    2016-11-01

    Full Text Available Ning Na,1,* Tujie Si,2,* Zhengyu Huang,1,* Bin Miao,1 Liangqing Hong,1 Heng Li,1 Jiang Qiu,2 Jianguang Qiu3 1Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, 2Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, 3Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: High-mobility group AT-hook 2 (HMGA2 is involved in a wide spectrum of biological processes and is upregulated in several tumors, but its role in renal carcinoma remains unclear. The aim of this study was to examine the expression of HMGA2 and its relationship to the overall survival (OS of patients with non-metastatic clear cell renal cell carcinoma (ccRCC following surgery. The expression of HMGA2 was evaluated retrospectively by immunohistochemistry (IHC in 162 patients with ccRCC who underwent nephrectomy in 2003 and 2004. An IHC analysis revealed that HMGA2 was expressed in the nuclei of tumor cells in 146 (90.1% patients with ccRCC. The level of HMGA2 was positively correlated with tumor size, lymph node metastasis, and Fuhrman Grade. A Kaplan–Meier analysis with log-rank test found that patients with high HMGA2 expression had a poor outcome and that patients with low HMGA2 expression had better survival. Cox regression analysis showed that HMGA2 expression could serve as an independent prognostic factor for ccRCC patients. The efficacy of the following prognostic models was improved when HMGA2 expression was added: tumor node metastasis stage, UCLA Integrated Scoring System, Mayo Clinic stage, size, grade, and necrosis score. In summary, this study showed that HMGA2 expression is an independent prognostic factor for OS in patients with ccRCC. HMGA2 was found to be a valuable biomarker for ccRCC progression. Keywords: renal carcinoma, high-mobility group protein A

  2. EGFR kinase-dependent and kinase-independent roles in clear cell renal cell carcinoma.

    Science.gov (United States)

    Cossu-Rocca, Paolo; Muroni, Maria R; Sanges, Francesca; Sotgiu, Giovanni; Asunis, Anna; Tanca, Luciana; Onnis, Daniela; Pira, Giovanna; Manca, Alessandra; Dore, Simone; Uras, Maria G; Ena, Sara; De Miglio, Maria R

    2016-01-01

    Epidermal growth factor receptor (EGFR) is associated with progression of many epithelial malignancies and represents a significant therapeutic target. Although clear cell renal cell carcinoma (CCRCC) has been widely investigated for EGFR molecular alterations, genetic evidences of EGFR gene activating mutations and/or gene amplification have been rarely confirmed in the literature. Therefore, until now EGFR-targeted therapies in clinical trials have been demonstrated unsuccessful. New evidence has been given about the interactions between EGFR and the sodium glucose co-transporter-1 (SGLT1) in maintaining the glucose basal intracellular level to favour cancer cell growth and survival; thus a new functional role may be attributed to EGFR, regardless of its kinase activity. To define the role of EGFR in CCRCC an extensive investigation of genetic changes and functional kinase activities was performed in a series of tumors by analyzing the EGFR mutational status and expression profile, together with the protein expression of downstream signaling pathways members. Furthermore, we investigated the co-expression of EGFR and SGLT1 proteins and their relationships with clinic-pathological features in CCRCC. EGFR protein expression was identified in 98.4% of CCRCC. Furthermore, it was described for the first time that SGLT1 is overexpressed in CCRCC (80.9%), and that co-expression with EGFR is appreciable in 79.4% of the tumours. Moreover, the activation of downstream EGFR pathways was found in about 79.4% of SGLT1-positive CCRCCs. The mutational status analysis of EGFR failed to demonstrate mutations on exons 18 to 24 and the presence of EGFR-variantIII (EGFRvIII) in all CCRCCs analyzed. FISH analysis revealed absence of EGFR amplification, and high polysomy of chromosome 7. Finally, the EGFR gene expression profile showed gene overexpression in 38.2% of CCRCCs. Our study contributes to define the complexity of EGFR role in CCRCC, identifying its bivalent kinase

  3. Validation of the histologic grading for ovarian clear cell adenocarcinoma: a retrospective multi-institutional study by the Japan Clear Cell Carcinoma Study Group.

    Science.gov (United States)

    Yamamoto, Sohei; Kasajima, Atsuko; Takano, Masashi; Yaegashi, Nobuo; Fujiwara, Hiroyuki; Kuzuya, Kazuo; Kigawa, Junzo; Tsuda, Hiroshi; Kurachi, Hirohisa; Kikuchi, Yoshihiro; Sugiyama, Toru; Tsuda, Hitoshi; Moriya, Takuya

    2011-03-01

    Pathologic slides from 150 patients with clear cell adenocarcinoma from the collaborating institutions were reviewed independently by 2 pathologists, and each tumor was graded histologically using the Shimizu-Silverberg and International Federation of Gynecology and Obstetrics (FIGO) grading systems. For the Shimizu-Silverberg grading system, 3 parameters-architectural pattern, nuclear pleomorphism, and mitotic activity-were assessed and scored as 1 to 3. When the summed scores of these parameters were 3 to 5, 6 to 7, and 8 to 9, grades 1, 2, and 3 were assigned, respectively. The FIGO grade was based on the ratio of glandular/papillary growth versus solid growth: grade 1, less than 5% solid tumor; grade 2, 5% to 50% solid tumor; grade 3, greater than 50% solid tumor. Interobserver agreement levels for assignment of both gradings were fair (κ=0.32 and 0.24, respectively). After consensus had been acquired, 82 (55%), 56 (37%), and 12 (8%) tumors were classified as grades 1, 2, and 3 by the Shimizu-Silverberg grading system, and 88 (59%), 38 (25%), and 24 (16%) were classified as grades 1, 2, and 3 by the FIGO grading system, respectively. Survival analyses indicated that patients with grade 3 tumors, as defined by both the grading systems, tended to have a poor outcome, but any differences between them were not statistically significant. Multivariate analysis showed that only the presence of residual tumor after initial surgery was an independent prognostic factor for overall survival. These results suggest that the 2 tested grading systems have limited value for the prognostication of patients with clear cell adenocarcinoma, and that a more effective grading system for this tumor may be required.

  4. Orai1 and STIM1 are critical for cell migration and proliferation of clear cell renal cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ji-Hee [Department of Physiology, Yonsei University Wonju College of Medicine, Wonju (Korea, Republic of); Lkhagvadorj, Sayamaa; Lee, Mi-Ra [Department of Pathology, Yonsei University Wonju College of Medicine, Wonju (Korea, Republic of); Hwang, Kyu-Hee [Department of Physiology, Yonsei University Wonju College of Medicine, Wonju (Korea, Republic of); Chung, Hyun Chul; Jung, Jae Hung [Department of Urology, Yonsei University Wonju College of Medicine, Wonju (Korea, Republic of); Cha, Seung-Kuy, E-mail: skcha@yonsei.ac.kr [Department of Physiology, Yonsei University Wonju College of Medicine, Wonju (Korea, Republic of); Institute of Lifestyle Medicine, and Nuclear Receptor Research Consortium, Yonsei University Wonju College of Medicine, Wonju (Korea, Republic of); Eom, Minseob, E-mail: eomm@yonsei.ac.kr [Department of Pathology, Yonsei University Wonju College of Medicine, Wonju (Korea, Republic of)

    2014-05-23

    Highlights: • Orai1 channel is highly expressed in clear cell renal cell carcinoma (ccRCC) tissues. • Orai1 and STIM1 constitute a native store-operated Ca{sup 2+} entry in ccRCC cells. • Orai1 and STIM1 promote cell migration and proliferation of ccRCC cells. - Abstract: The intracellular Ca{sup 2+} regulation has been implicated in tumorigenesis and tumor progression. Notably, store-operated Ca{sup 2+} entry (SOCE) is a major Ca{sup 2+} entry mechanism in non-excitable cells, being involved in cell proliferation and migration in several types of cancer. However, the expression and biological role of SOCE have not been investigated in clear cell renal cell carcinoma (ccRCC). Here, we demonstrate that Orai1 and STIM1, not Orai3, are crucial components of SOCE in the progression of ccRCC. The expression levels of Orai1 in tumor tissues were significantly higher than those in the adjacent normal parenchymal tissues. In addition, native SOCE was blunted by inhibiting SOCE or by silencing Orai1 and STIM1. Pharmacological blockade or knockdown of Orai1 or STIM1 also significantly inhibited RCC cell migration and proliferative capability. Taken together, Orai1 is highly expressed in ccRCC tissues illuminating that Orai1-mediated SOCE may play an important role in ccRCC development. Indeed, Orai1 and STIM1 constitute a native SOCE pathway in ccRCC by promoting cell proliferation and migration.

  5. Clear cell renal cell carcinoma with hemangioblastoma-like features: A recently described pattern with unusual immunohistochemical profile

    Directory of Open Access Journals (Sweden)

    Sankalp Sancheti

    2015-01-01

    Full Text Available The diagnosis of clear cell renal cell carcinoma may sometimes pose challenges because of the presence of uncharacteristic morphology, varied immunophenotypic patterns and due to lack of molecular or genetic determinants. More often, the morphological variations can be easily overlooked in routine practice and a more common diagnosis is usually put forward. Solid, acinar and alveolar are the common patterns described in the literature. We report a recently described pattern of clear cell renal cell carcinoma which has hemangioblastoma-like morphology and an unusual immunoprofile. In our case, the tumor showed a diffuse hemangioblastoma-like pattern and diffuse positivity for Alpha-inhibin on immunohistochemistry. A thorough literature search, extensive sampling and an expanded immunohistochemistry panel revealed a clear cell renal cell carcinoma component. Presence of renal vein thrombosis and focal necrosis were other helpful features in discerning the malignant nature of tumor.

  6. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma

    DEFF Research Database (Denmark)

    Guo, Guangwu; Gui, Yaoting; Gao, Shengjie;

    2012-01-01

    We sequenced whole exomes of ten clear cell renal cell carcinomas (ccRCCs) and performed a screen of similar to 1,100 genes in 88 additional ccRCCs, from which we discovered 12 previously unidentified genes mutated at elevated frequencies in ccRCC. Notably, we detected frequent mutations in the u......We sequenced whole exomes of ten clear cell renal cell carcinomas (ccRCCs) and performed a screen of similar to 1,100 genes in 88 additional ccRCCs, from which we discovered 12 previously unidentified genes mutated at elevated frequencies in ccRCC. Notably, we detected frequent mutations...

  7. Clear cell sarcoma (malignant melanoma of soft parts) and sentinel lymph node biopsy.

    Science.gov (United States)

    Picciotto, Franco; Zaccagna, Alessandro; Derosa, Giovanni; Pisacane, Alberto; Puiatti, Paolo; Colombo, Enrico; Dardano, Fabrizio; Ottinetti, Antonio

    2005-01-01

    Clear cell sarcoma of the tendons and aponeuroses is an aggressive, rare soft tissue tumour that occurs predominantly in the extremities of young adults. Although it appears to be histogenetically related to melanoma, its clinical behaviour resembles soft tissue sarcoma. Prognosis is reported to be poor due to the great propensity of regional and distant metastases. The risk of metastases to regional lymph nodes is very high. We describe a case of clear cell sarcoma of the hand and evaluate the feasibility of the sentinel lymph node biopsy (SLNB) technique in this kind of tumour. Up to now, there are no reports that describe the use of SLNB in clear cell sarcoma. The SLNB technique was carried out with success and the sentinel lymphnode was easily identified. Histological examination of the lymphnode allowed identification of metastatic cells and thus provide for radical lymphadenectomy. We maintain that SLNB can be successfully used for this type of tumour although this result should be evaluated and confirmed by larger case studies.

  8. Multiparametric magnetic resonance imaging for the differentiation of low and high grade clear cell renal carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Cornelis, F.; Tricaud, E.; Lasserre, A.S.; Petitpierre, F.; Le Bras, Y.; Bouzgarrou, M.; Grenier, N. [Pellegrin Hospital, Department of Radiology, Bordeaux (France); Bernhard, J.C. [Pellegrin Hospital, Department of Urology, Bordeaux (France); Yacoub, M. [Pellegrin Hospital, Department of Pathology, Bordeaux (France); Ravaud, A. [Saint-Andre Hospital, Department of Oncology, Bordeaux (France)

    2015-01-15

    To retrospectively evaluate the ability of magnetic resonance (MR) imaging to differentiate low from high Fuhrman grade renal cell carcinoma (RCC). MR images from 80 consecutive pathologically proven RCC (57 clear cell, 16 papillary and 7 chromophobe) were evaluated. Double-echo chemical shift, dynamic contrast-enhanced T1- and T2-weighted images and apparent diffusion coefficient (ADC) maps were reviewed independently. Signal intensity index (SII), tumour-to-spleen SI ratio (TSR), ADC ratio, wash-in (WiI) and wash-out indices (WoI) between different phases were calculated and compared to pathological grade and size. The Fuhrman scoring system was used. Low grade (score ≤2) and high grade (score ≥3) tumours were compared using univariate and multivariate analyses. No associations between grade and imaging factors were found for papillary and chromophobe RCCs. For clear cell RCCs, there was a significant association between the grade and parenchymal WiI (WiI2) (P = 0.02) or ADCr (P = 0.03). A significant association between tumour grade and size (P = 0.01), WiI2 (P = 0.02) and ADCr (P = 0.05) remained in multivariate analysis. Multiparametric MRI can be used to accurately differentiate low Fuhrman grade clear cell RCC from high grade. High Fuhrman grade (≥3) RCCs were larger, had lower parenchymal wash-in indices and lower ADC ratios than low grade. (orig.)

  9. MicroRNA Expression Profiling in Clear Cell Renal Cell Carcinoma: Identification and Functional Validation of Key miRNAs.

    Directory of Open Access Journals (Sweden)

    Haowei He

    Full Text Available This study aims to profile dysregulated microRNA (miRNA expression in clear cell renal cell carcinoma (ccRCC and to identify key regulatory miRNAs in ccRCC.miRNA expression profiles in nine pairs of ccRCC tumor samples at three different stages and the adjacent, non-tumorous tissues were investigated using miRNA arrays. Eleven miRNAs were identified to be commonly dysregulated, including three up-regulated (miR-487a, miR-491-3p and miR-452 and eight down-regulated (miR-125b, miR-142-3p, miR-199a-5p, miR-22, miR-299-3p, miR-29a, miR-429, and miR-532-5p in tumor tissues as compared with adjacent normal tissues. The 11 miRNAs and their predicted target genes were analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG pathway enrichment analysis, and three key miRNAs (miR-199a-5p, miR-22 and miR-429 were identified by microRNA-gene network analysis. Dysregulation of the three key miRNAs were further validated in another cohort of 15 ccRCC samples, and the human kidney carcinoma cell line 786-O, as compared with five normal kidney samples. Further investigation showed that over-expression of miR-199a-5p significantly inhibited the invasion ability of 786-O cells. Luciferase reporter assays indicated that miR-199a-5p regulated expression of TGFBR1 and JunB by directly interacting with their 3' untranslated regions. Transfection of miR-199a-5p successfully suppressed expression of TGFBR1 and JunB in the human embryonic kidney 293T cells, further confirming the direct regulation of miR-199a-5p on these two genes.This study identified 11 commonly dysregulated miRNAs in ccRCC, three of which (miR-199a-5p, miR-22 and miR-429 may represent key miRNAs involved in the pathogenesis of ccRCC. Further studies suggested that miR-199a-5p plays an important role in inhibition of cell invasion of ccRCC cells by suppressing expression of TGFBR1 and JunB.

  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. Stage-dependent prognostic impact of molecular signatures in clear cell renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Weber T

    2014-05-01

    Full Text Available Thomas Weber,1,2 Matthias Meinhardt,3 Stefan Zastrow,1 Andreas Wienke,4 Kati Erdmann,1 Jörg Hofmann,1 Susanne Fuessel,1 Manfred P Wirth11Department of Urology, Technische Universität Dresden, Dresden, Germany; 2Department of Oncology and Hematology, Martin-Luther-University Halle-Wittenberg, Halle (Saale, Germany; 3Institute of Pathology, Technische Universität Dresden, Dresden, Germany; 4Institute of Medical Epidemiology, Biostatistics, and Informatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale, GermanyPurpose: To enhance prognostic information of protein biomarkers for clear cell renal cell carcinomas (ccRCCs, we analyzed them within prognostic groups of ccRCC harboring different tumor characteristics of this clinically and molecularly heterogeneous tumor entity.Methods: Tissue microarrays from 145 patients with primary ccRCC were immunohistochemically analyzed for VHL (von Hippel-Lindau tumor suppressor, Ki67 (marker of proliferation 1, p53 (tumor protein p53, p21 (cyclin-dependent kinase inhibitor 1A, survivin (baculoviral IAP repeat containing 5, and UEA-1 (ulex europaeus agglutinin I to assess microvessel-density.Results: When analyzing all patients, nuclear staining of Ki67 (hazard ratio [HR] 1.08, 95% confidence interval [CI] 1.04–1.12 and nuclear survivin (nS; HR 1.04, 95% CI 1.01–1.08 were significantly associated with disease-specific survival (DSS. In the cohort of patients with advanced localized or metastasized ccRCC, high staining of Ki67, p53 and nS predicted shorter DSS (Ki67: HR 1.07, 95% CI 1.02–1.11; p53: HR 1.05, 95% CI 1.01–1.09; nS: HR 1.08, 95% CI 1.02–1.14. In organ-confined ccRCC, patients with high p21-staining had a longer DSS (HR 0.96, 95% CI 0.92–0.99. In a multivariate model with stepwise backward elimination, tumor size and p21-staining showed a significant association with DSS in patients with "organ-confined" ccRCCs. The p21-staining increased the concordance index of tumor size from

  12. Hand-Assisted Laparoscopic Hepatectomy for Primary Clear Cell Hepatocellular Carcinoma of the Liver

    Directory of Open Access Journals (Sweden)

    Kazutoshi Kida

    2012-05-01

    Full Text Available We report a case of primary clear cell hepatocellular carcinoma of the liver (PCCCL for which we performed hand-assisted laparoscopic hepatectomy. A 71-year-old female with hepatitis C infection and diabetes mellitus was admitted to our department for a hepatic tumor with gallstone. Abdominal computed tomography revealed a tumor 25 mm in diameter on the surface in segment 5 of the liver. The imaging results suggested small hepatocellular carcinoma located on the surface in segment 5 of the liver, and we performed laparoscopic surgery aiming at a minimally invasive procedure. We performed laparoscopic cholecystectomy and hand-assisted laparoscopic hepatectomy. Histopathological findings showed moderately differentiated hepatocellular carcinoma, and as the proportion of clear cells was 75%, the tumor was diagnosed as PCCCL. This is the first report of hand-assisted laparoscopic hepatectomy for PCCCL. Laparoscopic hepatectomy is a useful minimally invasive surgical procedure when the tumor is located on the surface of the liver.

  13. Primary Clear Cell Adenocarcinoma of a Urethral Diverticulum Treated with Multidisciplinary Robotic Anterior Pelvic Exenteration

    Directory of Open Access Journals (Sweden)

    Dane Scantling

    2013-01-01

    Full Text Available Primary urethral carcinoma is extremely rare and is marked by a variety of clinical symptoms. Primary carcinoma of a urethral diverticulum is still rarer and clear cell adenocarcinoma of the urethra is particularly uncommon (Swartz et al., 2006. Such infrequency has led to inadequate management guidance in the literature for a disease that is often late in presentation and carries substantial morbidity and mortality. This treatable but grave disease deserves definitive curative treatment. We present the first published instance in which it was treated with robotic anterior exenteration. In our case, a 47-year-old female was referred to the urology service for investigation of recurring urinary tract infections. During the workup, the patient was found to have an advanced clear cell urethral adenocarcinoma originating in a urethral diverticulum. We discuss the natural history of this condition, its consequences, and the first instance of its treatment using robotic anterior pelvic exenteration.

  14. Spinal clear cell meningioma in a 3-year-old: a case report.

    Science.gov (United States)

    Balogun, James A; Halliday, William; Bouffet, Eric; Kulkarni, Abhaya V

    2013-01-01

    Clear cell meningioma (CCM) is an aggressive meningioma variant with a tendency to early recurrence posing a challenge to its treatment. Although spinal meningiomas are uncommon in children, this rare entity has been described as the most common variant of spinal meningiomas in the pediatric age group. We present the case of a 3-year-old with a confirmed lumbar spine CCM and discuss the problems encountered in the management of this disease.

  15. Opposite prognostic roles of HIF1β and HIF2β expressions in bone metastatic clear cell renal cell cancer

    DEFF Research Database (Denmark)

    Szendroi, Attila; Szász, A. Marcell; Kardos, Magdolna

    2016-01-01

    BACKGROUND: Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1β/HIF2β and their selected target genes in primary tumors and corresponding bone metastases. RESULTS: Expression of HIF2β was lower in mRCC both at mRNA...

  16. Notch Pathway Is Activated via Genetic and Epigenetic Alterations and Is a Therapeutic Target in Clear Cell Renal Cancer.

    Science.gov (United States)

    Bhagat, Tushar D; Zou, Yiyu; Huang, Shizheng; Park, Jihwan; Palmer, Matthew B; Hu, Caroline; Li, Weijuan; Shenoy, Niraj; Giricz, Orsolya; Choudhary, Gaurav; Yu, Yiting; Ko, Yi-An; Izquierdo, María C; Park, Ae Seo Deok; Vallumsetla, Nishanth; Laurence, Remi; Lopez, Robert; Suzuki, Masako; Pullman, James; Kaner, Justin; Gartrell, Benjamin; Hakimi, A Ari; Greally, John M; Patel, Bharvin; Benhadji, Karim; Pradhan, Kith; Verma, Amit; Susztak, Katalin

    2017-01-20

    Clear cell renal cell carcinoma (CCRCC) is an incurable malignancy in advanced stages and needs newer therapeutic targets. Transcriptomic analysis of CCRCCs and matched microdissected renal tubular controls revealed overexpression of NOTCH ligands and receptors in tumor tissues. Examination of the TCGA RNA-seq data set also revealed widespread activation of NOTCH pathway in a large cohort of CCRCC samples. Samples with NOTCH pathway activation were also clinically distinct and were associated with better overall survival. Parallel DNA methylation and copy number analysis demonstrated that both genetic and epigenetic alterations led to NOTCH pathway activation in CCRCC. NOTCH ligand JAGGED1 was overexpressed and associated with loss of CpG methylation of H3K4me1-associated enhancer regions. JAGGED2 was also overexpressed and associated with gene amplification in distinct CCRCC samples. Transgenic expression of intracellular NOTCH1 in mice with tubule-specific deletion of VHL led to dysplastic hyperproliferation of tubular epithelial cells, confirming the procarcinogenic role of NOTCH in vivo Alteration of cell cycle pathways was seen in murine renal tubular cells with NOTCH overexpression, and molecular similarity to human tumors was observed, demonstrating that human CCRCC recapitulates features and gene expression changes observed in mice with transgenic overexpression of the Notch intracellular domain. Treatment with the γ-secretase inhibitor LY3039478 led to inhibition of CCRCC cells in vitro and in vivo In summary, these data reveal the mechanistic basis of NOTCH pathway activation in CCRCC and demonstrate this pathway to a potential therapeutic target.

  17. A clear cell adenocarcinoma of the gallbladder with hepatoid differentiation: case report and review of literature

    Directory of Open Access Journals (Sweden)

    Zhang C

    2016-09-01

    Full Text Available Chengsheng Zhang,1,2 Wei Zhang,1,2 Dianbin Mu,1 Xuetao Shi,1 Lei Zhao1,2 1Department of Hepatobiliary Surgery, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Science, 2School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China Abstract: An 80-year-old male was referred to our department for a gallbladder mass. He denied any history of alcohol consumption or cholecystitis and smoking. Hepatitis B surface antigen test and antihepatitis C antibody test were found to be negative. Serum carbohydrate antigen 19-9 (CA19-9 and carcinoembryonic antigen were elevated (CA19-9 was 59.92 U/mL and carcinoembryonic antigen was 12.64 ng/mL, whereas alpha-fetoprotein was below the normal limit (2.46 ng/mL. Computed tomography scan revealed a solid mass with measurements of 4.6×5.6×7.1 cm, which nearly filled the whole gallbladder space. Radical cholecystectomy, including segments IV B and V of the liver and lymphadenectomy, was performed. The neoplasm in gallbladder was completely resected, and the patient obtained a negative margin. Histological and immunohistochemical profile suggested a clear cell adenocarcinoma of the gallbladder with hepatoid differentiation. After reviewing the literature, we reported that this case is the first identified case of cell adenocarcinoma of the gallbladder with extensive hepatoid differentiation. However, clinical features of clear cell adenocarcinoma with hepatoid differentiation remain unclear due to the extremely rare incidence. There was no indication of adjuvant chemotherapy and no literature has been reported on the application of chemotherapy. This case showed a promising clinical outcome after curative resection, which indicated that surgical treatment could be potentially considered for suitable patients. Keywords: gallbladder, clear cell adenocarcinoma, hepatoid differentiation 

  18. External validation of TNM-C score in three community hospital cohorts for clear cell renal cell carcinoma.

    Science.gov (United States)

    Nakayama, Takayuki; Saito, Kazutaka; Ishioka, Junichiro; Kawano, Keizo; Morimoto, Shinji; Matsuoka, Yoh; Okuno, Tetsuo; Moriyama, Shingo; Takeshita, Hideki; Noro, Akira; Fujii, Yasuhisa; Kihara, Kazunori

    2014-02-01

    To assess the general applicability of TNM-C scoring, which consists of TNM classification and preoperative C-reactive protein concentration, the predictive ability of the TNM-C score was externally validated for patients with clear cell renal cell carcinoma (ccRCC) at three community hospitals. Seven hundred patients underwent radical or partial nephrectomy after being diagnosed with RCC. Out of the 700 patients, 518 with clear cell carcinoma served as the current study cohort. The predictive ability of the TMN-C score for cancer-specific survival (CSS) was estimated using Harrell's concordance index (c-index). The c-index of the TNM-C score was 0.85 in the entire data set. CSS rates were clearly stratified according to the scoring model (pTNM-C score alone (without pathological details) has a high predictive ability for the prognosis of ccRCC patients, it is generally applicable for use in community hospitals.

  19. A Protective Role for Androgen Receptor in Clear Cell Renal Cell Carcinoma Based on Mining TCGA Data.

    Directory of Open Access Journals (Sweden)

    Hongjuan Zhao

    Full Text Available Androgen receptor (AR is expressed in normal murine and human kidneys of both genders, but its physiologic role is uncertain. Several studies showed loss of AR in renal cell carcinoma (RCC in conjunction with increasing clinical stage and pathological grade, but others found that higher AR expression correlated with worse outcomes. Limited functional studies with renal cell lines suggested tumor-promoting activity of AR. In this study, we queried transcriptomic, proteomic, epigenetic and survival data from The Cancer Genome Atlas (TCGA to evaluate AR expression and its association with overall survival in three subtypes of RCC (clear cell [ccRCC], papillary [pRCC], and chromophobe [chRCC]. We found that although there was no significant difference in AR mRNA expression in ccRCC of males vs. females, AR protein expression in ccRCC was significantly higher in male compared to female patients. More importantly, higher expression of AR at both transcript and protein levels was associated with improved overall survival in both genders with ccRCC, but did not predict survival of either gender with pRCC or chRCC. Genes whose transcript levels were associated with AR mRNA levels significantly overlapped between ccRCC and pRCC, but not with chRCC, suggesting a similar transcriptional program mediated by AR in ccRCC and pRCC. Ingenuity pathway analysis also identified overlapping pathways and upstream regulators enriched in AR-associated genes in ccRCC and pRCC. Hypermethylation of CpG sites located in the promoter and first exon of AR was associated with loss of AR expression and poor overall survival. Our findings support a tumor suppressor role for AR in both genders that might be exploited to decrease the incidence or progression of ccRCC.

  20. Serial Pancreas, Liver and Duodenal Metastasis from Renal Clear Cell Cancer: a Case Report

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    @@ Case Report In August 2004, a 76-year-old patient was referred to our hospital for progressive loss of appetite, accompanied with mild upper abdominal distention, pain, hiccups and dyspepsia over a recent 3 months period. Reviewing his disease history showed that 16 months before admission (April 2003), he was diagnosed with a recurring left renal clear cell cancer (immunohistochemical staining of tumor cells were positive for CK and Vim, but negative for SMA, HMB-45 and HHF-35, Fig. 1) 10 years after a nephrectomy due to a right renal cancer. At that time, he was treated with photodynamic therapy followed by bio-immunotherapy(interleukine-2 plus lymphokine-activated killer cells). Follow-up by an abdominal CT scan every 3 months showed significant regression of the left renal carcinoma.

  1. Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium.

    Science.gov (United States)

    Maltez, Vivien I; Tubbs, Alan L; Cook, Kevin D; Aachoui, Youssef; Falcone, E Liana; Holland, Steven M; Whitmire, Jason K; Miao, Edward A

    2015-11-17

    Defective neutrophils in patients with chronic granulomatous disease (CGD) cause susceptibility to extracellular and intracellular infections. Microbes must first be ejected from intracellular niches to expose them to neutrophil attack, so we hypothesized that inflammasomes detect certain CGD pathogens upstream of neutrophil killing. Here, we identified one such ubiquitous environmental bacterium, Chromobacterium violaceum, whose extreme virulence was fully counteracted by the NLRC4 inflammasome. Caspase-1 protected via two parallel pathways that eliminated intracellular replication niches. Pyroptosis was the primary bacterial clearance mechanism in the spleen, but both pyroptosis and interleukin-18 (IL-18)-driven natural killer (NK) cell responses were required for liver defense. NK cells cleared hepatocyte replication niches via perforin-dependent cytotoxicity, whereas interferon-γ was not required. These insights suggested a therapeutic approach: exogenous IL-18 restored perforin-dependent cytotoxicity during infection by the inflammasome-evasive bacterium Listeria monocytogenes. Therefore, inflammasomes can trigger complementary programmed cell death mechanisms, directing sterilizing immunity against intracellular bacterial pathogens.

  2. Clear cell adenocarcinoma of the ulterine cervix in a 15 year old girl: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Seung Joon; Kim, Jee Eun; KIm, Hyung Sik; Choi, Hye Young [Dept. of Radiology, Gachon University Gil Hospital, Incheon (Korea, Republic of)

    2013-10-15

    Cervical cancer is rare in the pediatric population. In cases of cervical cancer, adenocarcinoma is predominantly reported. Clear cell adenocarcinoma (CCAC) of the uterine cervix is a very rare tumor and accounts for only 4% of all adenocarcinomas of the uterine cervix. Risk factors and pathogenesis of this disease are not exactly revealed. The intrauterine exposure to diethylstilbestrol (DES) and associated non-steroidal estrogen during pregnancy before 18 weeks is the only known risk factor. This study reports the imaging finding of primary uterine cervical tumor in a 15-year-old girl, who was finally diagnosed with CCAC, with no maternal history of DES exposure in utero.

  3. The clinical and imaging features of clear cell meningioma in ten cases

    Directory of Open Access Journals (Sweden)

    ZHAO Guang-zuo

    2012-10-01

    Full Text Available Objective To investigate the clinical features and imaging findings of intracranial clear cell meningioma. Methods The clinical data were reviewed, including presentation, imaging and prognosis of 10 patients suffered from intracranial clear cell meningioma for 2 months-7 years and underwent surgical treatment. The patients included five males and five females with the age from nine to sixty-two years old (mean 35.43. The tumors were located at cerebellopontine angle (CPA zone (n = 5, parietal lobe (n = 1, tuberculum sella (n = 1, jugular foramen (n = 1, tentorium of cerebellum (n = 1 or lateral cerebral ventricle (n = 1. The initial symptoms included headache (n = 4, gait disturbance (n = 2, hearing loss (n = 2, vision loss (n = 1 and bucking (n = 1 which were associated with the mass locations. Results CT (n = 8 and MRI (n = 10 of 10 patients were retrospectively reviewed. CT findings of the lesions presented with hyperdensity (n = 6, isodensity (n = 1, or isodensity with hyperdensity (n = 1. MRI T1WI showed isointensity (n = 4, hypointensity with isointensity (n = 4 or hyperintensity (n = 2, whereas T2WI isointensity with hyperintensity (n = 7, presented hypointensity (n = 1, isointensity (n = 1, or hyperintensity (n = 1. On gadolinium-enhanced T1WI, moderate enhancement was seen in 8 lesions and marked enhancement was seen in 2 lesions. In initial CT scanning peritumoral edema was found in 7 cases, dural tail sign in 5 cases, cysts in 7 cases, calcification in 3 cases, periosteal proliferation in 1 case and bone destruction in 5 cases. Seven patients underwent complete resection and 3 underwent subtotal resection. Follow-up period was 11-120 months. Recurrence occurred in 5 patients. The mean recurrence time was 55.62 months. Conclusion Clear cell meningioma is a rare meningioma and often occurs in young persons without significant difference in sex. The CPA zone is the most affected area. The prognosis is closely related to the extent of

  4. Skull Base Clear Cell Carcinoma, Metastasis of Renal Primary Tumor: A Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Ilson Sepúlveda

    2013-08-01

    Full Text Available We report on a patient who presented with cranial nerve VI bilateral paresis, absence of pharyngeal reflex, dysarthria, right tongue deviation, and right facial paralysis. Imaging studies showed an expansive process in the cranial base with clivus and petrous apex osteolysis. A biopsy confirmed the presence of clear cell adenocarcinoma and suspicion of renal tumor metastases. Abdominal imaging studies revealed a mass in the right kidney. Consequently, radiotherapy was performed, and the patient was enrolled in a palliative care and pain control program.

  5. Clear-cell carcinoma of the lung metastatic to the hamate: a case report.

    Science.gov (United States)

    Nissenbaum, M; Kutz, J E; Lister, G D

    1978-01-01

    Metastatic lesions of the hand are uncommon. A report of a solitary metastasis to the hamate seems not to have appeared previously in the literature. A 46-year-old factory worker presented a rare tumor, clear-cell carcinom of the lung, metastasizing to an unusual location, the hamate. The symptoms simulated sympathetic dystrophy and diagnosis was delayed because of the late appearance of radiographic changes over 6 months after symptoms first appeared. Early bone scanning in patients with chronic pain may provide useful information prior to the appearance of X-ray changes.

  6. [Clear-cell sarcoma of the kidney: about a paediatric case].

    Science.gov (United States)

    Namaoui, R Y; Castex, M P; Vial, J; Galinier, P; Rubie, H; Laprie Mazieres, A; Le Mandat, A; Brousset, P; Delsol-Tahou, M

    2010-06-01

    Clear-cell sarcoma of the kidney (CCSK) is a rare malignant tumor of childhood, known for its aggressiveness, its tendency to recurrence and to metastasis to bone. We report an observation of a child of 48 months carrying a large abdominal mass. The diagnosis of the SCCR was made on biopsy, since imaging remained uncertain as to the renal origin of the mass. Indeed, our observation underlines the difficulty of its diagnosis. Excepting the morphological aspect, there is no criterion for its recognition. Its prognosis has been improved by the new treatments.

  7. Infrared Signatures of Bacillus Bacteria: Clear IR Distinctions Between Sporulated and Vegetative Cells with Chemical Assighments

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, Timothy J.; Williams, Stephen D.; Valentine, Nancy B.; Su, Yin-Fong; Kreuzer-Martin, Helen W.; Wahl, Karen L.; Forrester, Joel B.

    2009-05-04

    This paper highlights the distinctions between the infrared (IR) absorption spectra of vegetative versus sporulated Bacillus bacteria. It is observed that there are unique signatures clearly associated with either the sporulated or the vegetative state, and that vegetative cells (and associated debris) can contribute to the spore spectra. A distinct feature at ~1739 cm-1 appears to be unique to vegetative cell spectra, and can also be used as an indicator of vegetative cells or cell debris in the spore spectra. The data indicate the band is caused by a phospholipid carbonyl bond and are consistent with, but do not prove it to be, either phosphatidyl ethanolamine (PE) or phosphatidyl glycerol (PG), the two major classes of phospholipids found in vegetative cells of Bacillus species. The endospore spectra show characteristic peaks at 1441, 1277, and 1015 cm-1 along with a distinct quartet of peaks at 766, 725, 701, and 659 cm-1. These are clearly associated with calcium dipicolinate trihydrate, CaDP•3H2O. We emphasize that the spore peaks, especially the quartet, arise from the calcium dipicolinate trihydrate and not from dipicolinic acid or other dipicolinate hydrate salts. The CaDP•3H2O vibrational peaks and the effects of hydration were studied using quantum chemistry in the PQS software package. The quartet is associated with many motions including contributions from the Ca2+ counterion and hydration waters including Ca-O-H bends, H2O-Ca-O torsions and O-C-O bends. The 1441 and 1015 cm-1 modes are planar pyridine modes with the 1441 mode primarily a ring C-N stretch and the 1015 mode primarily a ring C-C stretch.

  8. Infrared signatures of Bacillus bacteria: Clear IR distinctions between sporulated and vegetative cells with chemical assignments

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, Timothy J.; Williams, Stephen D.; Valentine, Nancy B.; Su, Yin-Fong; Kreuzer-Martin, Helen W.; Wahl, Karen L.; Forrester, Joel B.

    2009-05-08

    This paper highlights the distinctions between the infrared (IR) absorption spectra of vegetative versus sporulated Bacillus bacteria. It is observed that there are unique signatures clearly associated with either the sporulated or the vegetative state, and that vegetative cells (and associated debris) can contribute to the spore spectra. A distinct feature at ~1739 cm-1 appears to be unique to vegetative cell spectra, and can also be used as an indicator of vegetative cells or cell debris in the spore spectra. The data indicate the band is caused by a phospholipid carbonyl bond and are consistent with, but do not prove it to be, either phosphatidyl ethanolamine (PE) or phosphatidyl glycerol (PG), the two major classes of phospholipids found in vegetative cells of Bacillus species. The endospore spectra show characteristic peaks at 1441, 1277, and 1015 cm-1 along with a distinct quartet of peaks at 766, 725, 701, and 659 cm-1. These are clearly associated with calcium dipicolinate trihydrate, CaDP•3H2O. We emphasize that the spore peaks, especially the quartet, arise from the calcium dipicolinate trihydrate and not from dipicolinic acid or other dipicolinate hydrate salts. The CaDP•3H2O vibrational peaks and the effects of hydration were studied using quantum chemistry in the PQS software package. The quartet is associated with many motions including contributions from the Ca2+ counterion and hydration waters including Ca-O-H bends, H2O-Ca-O torsions and O-C-O bends. The 1441 and 1015 cm-1 modes are planar pyridine modes with the 1441 mode primarily a ring C-N stretch and the 1015 mode primarily a ring C-C stretch.

  9. Gene set enrichment analysis and ingenuity pathway analysis of metastatic clear cell renal cell carcinoma cell line.

    Science.gov (United States)

    Khan, Mohammed I; Dębski, Konrad J; Dabrowski, Michał; Czarnecka, Anna M; Szczylik, Cezary

    2016-08-01

    In recent years, genome-wide RNA expression analysis has become a routine tool that offers a great opportunity to study and understand the key role of genes that contribute to carcinogenesis. Various microarray platforms and statistical approaches can be used to identify genes that might serve as prognostic biomarkers and be developed as antitumor therapies in the future. Metastatic renal cell carcinoma (mRCC) is a serious, life-threatening disease, and there are few treatment options for patients. In this study, we performed one-color microarray gene expression (4×44K) analysis of the mRCC cell line Caki-1 and the healthy kidney cell line ASE-5063. A total of 1,921 genes were differentially expressed in the Caki-1 cell line (1,023 upregulated and 898 downregulated). Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) approaches were used to analyze the differential-expression data. The objective of this research was to identify complex biological changes that occur during metastatic development using Caki-1 as a model mRCC cell line. Our data suggest that there are multiple deregulated pathways associated with metastatic clear cell renal cell carcinoma (mccRCC), including integrin-linked kinase (ILK) signaling, leukocyte extravasation signaling, IGF-I signaling, CXCR4 signaling, and phosphoinositol 3-kinase/AKT/mammalian target of rapamycin signaling. The IPA upstream analysis predicted top transcriptional regulators that are either activated or inhibited, such as estrogen receptors, TP53, KDM5B, SPDEF, and CDKN1A. The GSEA approach was used to further confirm enriched pathway data following IPA.

  10. p75 neurotrophin receptor and pro-BDNF promote cell survival and migration in clear cell renal cell carcinoma

    Science.gov (United States)

    Sánchez-Prieto, Ricardo; Saada, Sofiane; Naves, Thomas; Guillaudeau, Angélique; Perraud, Aurélie; Sindou, Philippe; Lacroix, Aurélie; Descazeaud, Aurélien; Lalloué, Fabrice; Jauberteau, Marie-Odile

    2016-01-01

    p75NTR, a member of TNF receptor family, is the low affinity receptor common to several mature neurotrophins and the high affinity receptor for pro-neurotrophins. Brain-Derived Neurotrophic Factor (BDNF), a member of neurotrophin family has been described to play an important role in development and progression of several cancers, through its binding to a high affinity tyrosine kinase receptor B (TrkB) and/or p75NTR. However, the functions of these two receptors in renal cell carcinoma (RCC) have never been investigated. An overexpression of p75NTR, pro-BDNF, and to a lesser extent for TrkB and sortilin, was detected by immunohistochemistry in a cohort of 83 clear cell RCC tumors. p75NTR, mainly expressed in tumor tissues, was significantly associated with higher Fuhrman grade in multivariate analysis. In two derived-RCC lines, 786-O and ACHN cells, we demonstrated that pro-BDNF induced cell survival and migration, through p75NTR as provided by p75NTR RNA silencing or blocking anti-p75NTR antibody. This mechanism is independent of TrkB activation as demonstrated by k252a, a tyrosine kinase inhibitor for Trk neurotrophin receptors. Taken together, these data highlight for the first time an important role for p75NTR in renal cancer and indicate a putative novel target therapy in RCC. PMID:27120782

  11. Metastatic clear cell carcinoma of the kidney: therapeutic role of bevacizumab.

    Science.gov (United States)

    Bukowski, Ronald M

    2010-03-26

    The biology and pathogenesis of clear cell carcinoma of the kidney has been extensively investgated, and the role of von Hipple-Landau gene inactivation and tumor associated angiogenesis is now recognized. Development of vascular endothelial growth factor inhibitors and phase 3 clinical trials utilizing this class of agents has produced a new treatment paradigm for patients with metastatic renal cell carcinoma (RCC). One of the active regimens identified is the combination of bevacizumab and interferon-α. Recently published reports provided evidence of the clinical and biologic activity of this therapy. The current manuscript reviews the background and rationale for the activity of bevacizumab in RCC, and results from recent clinical trials with this agent alone or in combination with targeted agents or cytokines. The role of this therapy in contrast to other targeted agents is reviewed, and the potential utility as well as questions raised by recent studies are discussed.

  12. Clear cell chondrosarcoma calcaneum - a case report and review of literature.

    Science.gov (United States)

    Nagmani, Singh; Rakesh, John; Aditya, Aggarwal; Sandeep, Patel; Arjun, R H H; Debasis, Gochhait

    2015-03-01

    Chondrosarcoma is the second most common primary bone malignancy accounting for 20-25% of all bone sarcomas. However chondrosarcoma of the foot is rare with just a handful of cases being described. Among the subtypes clear cell variant is the rarest and has never been documented in the foot. We present a rare case of clear cell chondrosarcoma of the calcaneum with multiple metastases that was treated at our institute. The patient was a 62-year old male who presented to us with pain and mass in the left hindfoot with difficulty in walking for 2 years and a discharging ulcer over the lateral aspect for 4 months. Radiography showed aggressive, destructive, lytic lesion in the calcaneum with cortical breach and soft tissue invasion. Bone scan and PET-CT revealed multiple bony metastases and lung metastasis. After initial biopsy, patient underwent below knee amputation and has been in remission since the last 18 months. Given the rarity of this tumor in the calcaneum, this report highlights the importance to consider the possibility of this tumor in the calcaneum as an early diagnosis; complete metastatic workup and expeditious management can thus significantly improve prognosis.

  13. Pediatric intracranial clear cell meningioma associated with a germline mutation of SMARCE1: a novel case.

    Science.gov (United States)

    Raffalli-Ebezant, Helen; Rutherford, Scott A; Stivaros, Stavros; Kelsey, Anna; Smith, Miriam; Evans, D Gareth; Kilday, John-Paul

    2015-03-01

    Intracranial clear cell meningioma (CCM) represents a rare and potentially more aggressive subgroup of meningioma that is observed more frequently in children and adolescents. Despite its characterization as a histological entity, there is little evidence identifying tumorigenic etiologies. Recently, a novel mutation in SMARCE1, encoding a subunit of the SWI/SNF chromatin remodeling complex, was identified in a cohort of spinal CCMs. To date, no intracranial CCM has been subjected to analysis. We report the case of an isolated intracranial CCM in a 14-year-old girl. Gross total resection was achieved following a two-stage approach with no evidence of tumor recurrence 8 months following presentation. Exon sequencing identified a germline mutation in SMARCE1, which was also present in tumor DNA. Extensive literature review confirmed our study is the first to seek and report a genetic anomaly for childhood intracranial CCMs outside of the NF2 gene locus, and the first to make an association between a germline SMARCE1 mutation and childhood intracranial CCMs. Together with the previous description of SMARCE1 mutations in spinal CCMs, our report suggests that SMARCE1 aberrations may be implicated in establishing a clear cell histology irrespective of meningioma location. We would advocate that, where feasible, genetic sequencing is performed on future new cases of childhood neuraxial CCMs and includes interrogation of the SMARCE1 gene.

  14. Case report 423: Clear-cell sarcoma plantar aspect of right foot

    Energy Technology Data Exchange (ETDEWEB)

    Sartoris, D.J.; Resnick, D.; Haghighi, P.

    1987-06-01

    The case is presented of a 65-year-old woman who developed a painful swelling of the plantar aspect of the right foot over a 3-year period. Conventional roentgenograms of the foot showed a large, soft tissue mass on the plantar aspect, with some suggestion of erosion of the adjacent metatarsals. CT studies, however, failed to confirm the presence of any bony abnormalities. At the time of the initial presentation, a biopsy was performed and approximately 3 months later the patient was treated definitely with wide excision of the mass. Histological sections showed the presence of a clear-cell sarcoma - an uncommon lesion mainly confined to the lower extremities and originating either in tendons or aponeurosis. The differential diagnosis, radiologically and clinically was described, and similarly, the differential diagnosis pathologically was also considered. The clinical, pathological and radiological aspects of clear-cell sarcoma of tendon sheath or aponeurosis were discussed in depth and the treatment and prognosis were considered. The authors stress that the importance of the case from a diagnostic imaging perspective lies in the successful use of CT in defining such a soft tissue neoplasm. The ability of CT to determine the extent of involvement of soft tissue and bone by such a lesion is important. Cross-sectional techniques, including magnetic resonance as well as CT, must be the procedure of choice in the definitive diagnosis and treatment of such lesions.

  15. Hepatocellular Carcinoma with Foamy Histiocyte-Like Appearance: A Deceptively Clear Cell Carcinoma Appearing Variant

    Directory of Open Access Journals (Sweden)

    Takuji Noro

    2010-08-01

    Full Text Available Hepatocellular carcinoma (HCC shows many pathological features, and it varies architecturally and cytologically. There have been many reports and discussions of the morphological features of HCC. A 63-year-old man was found to have a solitary tumor in liver segment 7 that was diagnosed as HCC. A partial resection of liver segment 7 was performed. Microscopically, the tumor lesion showed a moderately differentiated HCC. There was also a lesion with foamy histiocyte-like cells corresponding to the white lesion in the face of the cut tumor. Immunohistochemical staining showed that they were negative for CD68, S-100, vimentin, and HMB-45. The cytoplasm itself was negative on periodic acid Schiff (PAS and Sudan staining. Without immunohistological analysis, it is difficult to distinguish this HCC variant from clear cell carcinoma or metastases of renal cell carcinoma. It is important to recognize this type as a specific cytological variant of HCC that requires confirmation by immunohistochemistry. This report describes the case of a patient with a morphologically distinctive pattern of HCC with prominent cell cytoplasm that had a foamy histiocyte-like appearance. To the best of our knowledge, this is the first report of this HCC variant.

  16. Reasoning about embryos, cloning and stem cells: let's get more clear and distinct.

    Science.gov (United States)

    Parker, Malcolm

    2003-01-01

    Plural democratic societies encourage and require the tolerance of disparate views. However, in relation to contentious areas like assisted reproductive technologies and destructive embryo research, tolerance is strained by the normative force of our fundamental beliefs about the moral status of early human forms. Yet in the continuing debates, spokespersons for different positions often do not concede all the implications of their arguments, may sidestep the real moral issues, and can fail to be clear about the foundations on which their arguments and policy advice ultimately rely. Guidelines and statutes can be rendered incoherent by the desire to balance and satisfy opposing values, rather than honestly reflecting the primary values they espouse. I call for greater clarity and honesty as these issues continue to be debated. An uncritical adherence to pluralism will encourage strategic obfuscation, but citizens of democracies need to be clearly informed about all the premises of opposing positions. Decisions about ethically and legally acceptable reproductive technologies ultimately depend on support for one metaphysical grounding at the expense of another. This should be acknowledged, as should its implications for policy.

  17. Clear & Simple

    Science.gov (United States)

    ... Cultural Respect Language Access Talking to Your Doctor Research Underway Plain Language Clear & Simple What is Clear & Simple? Clear & Simple ... schedule? A: Pretesting need not be an elaborate, time-consuming research project and depends on: How quickly you work, ...

  18. ERK5/BMK1 Is a Novel Target of the Tumor Suppressor VHL: Implication in Clear Cell Renal Carcinoma12

    Science.gov (United States)

    Arias-González, Laura; Moreno-Gimeno, Inmaculada; del Campo, Antonio Rubio; Serrano-Oviedo, Leticia; Valero, María Llanos; Esparís-Ogando, Azucena; de la Cruz-Morcillo, Miguel Ángel; Melgar-Rojas, Pedro; García-Cano, Jesús; Cimas, Francisco José; Hidalgo, María José Ruiz; Prado, Alfonso; Callejas-Valera, Juan Luis; Nam-Cha, Syong Hyun; Giménez-Bachs, José Miguel; Salinas-Sánchez, Antonio S; Pandiella, Atanasio; del Peso, Luis; Sánchez-Prieto, Ricardo

    2013-01-01

    Extracellular signal-regulated kinase 5 (ERK5), also known as big mitogen-activated protein kinase (MAPK) 1, is implicated in a wide range of biologic processes, which include proliferation or vascularization. Here, we show that ERK5 is degraded through the ubiquitin-proteasome system, in a process mediated by the tumor suppressor von Hippel-Lindau (VHL) gene, through a prolyl hydroxylation-dependent mechanism. Our conclusions derive from transient transfection assays in Cos7 cells, as well as the study of endogenous ERK5 in different experimental systems such as MCF7, HMEC, or Caki-2 cell lines. In fact, the specific knockdown of ERK5 in pVHL-negative cell lines promotes a decrease in proliferation and migration, supporting the role of this MAPK in cellular transformation. Furthermore, in a short series of fresh samples from human clear cell renal cell carcinoma, high levels of ERK5 correlate with more aggressive and metastatic stages of the disease. Therefore, our results provide new biochemical data suggesting that ERK5 is a novel target of the tumor suppressor VHL, opening a new field of research on the role of ERK5 in renal carcinomas. PMID:23730213

  19. ERK5/BMK1 Is a Novel Target of the Tumor Suppressor VHL: Implication in Clear Cell Renal Carcinoma

    Directory of Open Access Journals (Sweden)

    Laura Arias-González

    2013-06-01

    Full Text Available Extracellular signal-regulated kinase 5 (ERK5, also known as big mitogen-activated protein kinase (MAPK 1, is implicated in a wide range of biologic processes, which include proliferation or vascularization. Here, we show that ERK5 is degraded through the ubiquitin-proteasome system, in a process mediated by the tumor suppressor von Hippel-Lindau (VHL gene, through a prolyl hydroxylation-dependent mechanism. Our conclusions derive from transient transfection assays in Cos7 cells, as well as the study of endogenous ERK5 in different experimental systems such as MCF7, HMEC, or Caki-2 cell lines. In fact, the specific knockdown of ERK5 in pVHL-negative cell lines promotes a decrease in proliferation and migration, supporting the role of this MAPK in cellular transformation. Furthermore, in a short series of fresh samples from human clear cell renal cell carcinoma, high levels of ERK5 correlate with more aggressive and metastatic stages of the disease. Therefore, our results provide new biochemical data suggesting that ERK5 is a novel target of the tumor suppressor VHL, opening a new field of research on the role of ERK5 in renal carcinomas.

  20. Metastatic clear cell carcinoma of the kidney: therapeutic role of bevacizumab

    Directory of Open Access Journals (Sweden)

    Ronald M Bukowski

    2010-03-01

    Full Text Available Ronald M BukowskiCleveland Clinic Taussig Cancer Center, CCF Lerner College of Medicine of CWRU Cleveland, OH, USAAbstract: The biology and pathogenesis of clear cell carcinoma of the kidney has been extensively investgated, and the role of von Hipple-Landau gene inactivation and tumor associated angiogenesis is now recognized. Development of vascular endothelial growth factor inhibitors and phase 3 clinical trials utilizing this class of agents has produced a new treatment paradigm for patients with metastatic renal cell carcinoma (RCC. One of the active regimens identified is the combination of bevacizumab and interferon-α. Recently published reports provided evidence of the clinical and biologic activity of this therapy. The current manuscript reviews the background and rationale for the activity of bevacizumab in RCC, and results from recent clinical trials with this agent alone or in combination with targeted agents or cytokines. The role of this therapy in contrast to other targeted agents is reviewed, and the potential utility as well as questions raised by recent studies are discussed.Keywords: metastatic renal cell carcinoma, bevacizumab, interferon-α

  1. Ultrasound guided electrochemotherapy for the treatment of a clear cell thymoma in a cat

    Science.gov (United States)

    Spugnini, Enrico Pierluigi; Menicagli, Francesco; Pettorali, Michela; Baldi, Alfonso

    2017-01-01

    A twelve-year-old male castrated domestic shorthair cat was presented for rapidly progressing respiratory distress. The cat was depressed, tachypneic and moderately responsive. Ultrasonography showed a mediastinal mass associated with a significant pleural effusion that needed tapping every five to seven days. Ultrasound guided biopsy yielded a diagnosis of clear cell thymoma upon histopathology. After complete staging procedures, the owner elected to treat the cat with electrochemotherapy (ECT) using systemic bleomycin. Two sessions of ultrasound guided ECT were performed at two week intervals with trains of biphasic electric pulses applied using needle electrodes until complete coverage of the area was achieved. The treatment was well tolerated and resulted in partial remission (PR). Additional sessions were performed on a monthly basis. The cat is still in PR after fourteen months. ECT resulted in improved local control and should be considered among the available adjuvant treatments in pets carrying visceral tumors. PMID:28331834

  2. Unusual Ultrasound Presentation of Testicular Metastasis from Renal Clear Cell Carcinoma

    Science.gov (United States)

    Dell’Atti, Lucio

    2016-01-01

    Testicular metastases from renal clear cell carcinoma (RCC) are extremely uncommon. To the best of our knowledge, only 32 cases have been reported in the literature. We report a rare case of testicular metastasis from RCC. A 69-year-old patient presented with discomfort and pain in his left testis. He had undergone laparoscopic left radical nephrectomy at another institution. Scrotal ultrasonography revealed a non-palpable lesion at the upper pole of the left testis with hypoechoic aspect, highly suspicious for malignancy. We performed a left inguinal orchiectomy. The testicular lesion was diagnosed as a metastasis from RCC. After orchiectomy, a computed tomography of the chest and abdomen revealed no other metastatic lesions. The patient remains free of clinical recurrence after 20 months without adjuvant therapy.

  3. Metastasis of renal clear-cell carcinoma to the oral mucosa, an atypical location.

    Science.gov (United States)

    Maestre-Rodríguez, Oscar; González-García, Raúl; Mateo-Arias, Jesús; Moreno-García, Carlos; Serrano-Gil, Herminia; Villanueva-Alcojol, Laura; Campos-de-Orellana, Ana Ma; Monje-Gil, Florencio

    2009-11-01

    The majority of cases of metastatic tumors involve the mandible and some the maxilla but they are considerably less common in intraoral soft tissues. In addition, the primary tumor is known in the majority of cases; although in one-third of such cases, metastasis is the first clinical manifestation. The most common primary tumors metastasizing to the mouth are lung carcinoma in men and breast carcinoma in women. An oral metastasis implies a serious prognosis, as in the majority of patients there is multiple organ involvement at the time of diagnosis. We present the case of a 52-year old patient with renal pathology who came to the emergency room due to a rapidly increasing gingival tumor. With the provisional clinical diagnosis of a pyogenic granuloma,the tumor was excised. Subsequent anatomopathological analysis revealed a tumor metastasis compatible with clear-cell carcinoma, and its renal origin was confirmed by means of immunohistochemical techniques.

  4. Vaginal brachytherapy for early stage uterine papillary serous and clear cell endometrial cancer.

    Science.gov (United States)

    Townamchai, Kanokpis; Berkowitz, Ross; Bhagwat, Mandar; Damato, Antonio L; Friesen, Scott; Lee, Larissa J; Matulonis, Ursula; O'Farrell, Desmond; Viswanathan, Akila N

    2013-04-01

    To report clinical outcomes following adjuvant high-dose-rate (HDR) vaginal brachytherapy (VB) for early-stage uterine papillary serous (UPSC) and clear cell (CC) endometrial cancer. A retrospective study of Stage I and II papillary serous and clear cell endometrial cancer treated with post-operative HDR VB between October 2005 and May 2012 was performed. A total of 37 patients were identified, 26 with UPSC, 9 with CC and 2 with mixed UPSC/CC. After total hysterectomy and bilateral salpingo-oophorectomy, VB was administered without external-beam radiation with a dose of 24 Gy in 6 fractions prescribed to the vaginal surface. Chemotherapy was given to 30 patients (75%). The median follow up time was 24.8 months (range, 2.0 to 71.5 months). Four patients relapsed, 2 with UPSC and 2 with CC. The initial site of relapse was concurrent vagina, pelvic/para-aortic nodes and abdominal wall (1), pelvic/para-aortic nodes (1) and para-aortic nodes alone (2). The 2-year vaginal-control rate was 96.8%. The pelvic-control rate including vaginal and nodal relapse was 93.5%. The 2-year disease-free and overall survival rates were 89.3% and 100%, respectively. HDR VB as the sole adjuvant treatment modality for early-stage UPSC/CC is associated with a low rate of vaginal relapse and excellent survival outcomes. This novel low-dose regimen for VB is safe and effective. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Clear-cell variant urothelial carcinoma of the bladder: a case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Hossein Tezval

    2012-10-01

    Full Text Available Clear cell variants of transitional cell carcinomas (TCC of the bladder are extremely rare tumors. Only 6 cases have been reported until now. We report of a 67 year old man who presented with fast growing tumor disease. While initial diagnosis showed localized bladder tumor, final histopathology revealed pT4, G3, L1 urothelial carcinoma with clear cell differentiation. No more than 14 weeks after initial diagnosis the patient died from multi-organ failure after unsuccessful salvage laparotomy which showed massive tumor burden within the pelvis and peritoneal carcinosis. This case demonstrated an extremely fast tumor growth. Therefore, patients with clear cell urothelial carcinoma should be treated vigorously and without time delay. We present a case of clear cell variant of TCC which exhibited an extremely aggressive behavior. To our knowledge this is the fifth report of this rare disease.

  6. Clear cell carcinoma of the uterine cervix: clinical characteristics and feasibility of fertility-preserving treatment

    Directory of Open Access Journals (Sweden)

    Jiang X

    2014-01-01

    Full Text Available Xiang Jiang, Ying Jin, Yan Li, Hui-Fang Huang, Ming Wu, Keng Shen, Ling-Ya Pan Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China Abstract: The objective of this retrospective study was to analyze the clinical characteristics and prognosis of clear cell adenocarcinoma (CCA in the post-diethylstilbestrol (DES era and to evaluate the feasibility of fertility-preserving treatment. The records of 32 patients with CCAs who were treated at Peking Union Medical College Hospital from August 1986 to June 2012 were retrospectively reviewed. Three of the patients had undergone fertility-preserving treatment. The incidence of CCA among cervical adenocarcinomas was 15.2%. The median age was 38 years: 11 patients (34.4% were diagnosed before 30 years of age and two (6.3% after 70 years of age. Ten patients (31.2% were nulliparous. No patient had been exposed to DES. Twenty-nine patients (90.6% presented with obvious symptoms, and the cervix appeared abnormal in 26 patients (81.3%. Cervical Papanicolaou (Pap tests were abnormal in all four patients in whom they were performed (three had high-grade squamous intraepithelial lesions and one had atypical squamous cells of undetermined significance. The distribution by stage was 56.3% stage I, 34.4% stage II, 6.3% stage III, and 3.1% stage IV. Treatments mainly included surgery for patients with stage I to IIA CCA and radiochemotherapy for patients with advanced CCA. The overall 5-year progression-free survival was 72.2%. Patients with stage I to IIA CCA had better 5-year progression-free survival than did patients with stage IIB to IV CCA (81.5% versus 40.0%, P=0.003. The three patients who had undergone fertility-preserving treatment had no recurrences. CCA may also affect adolescents and children without prior DES exposure, who are often misdiagnosed as having functional uterine

  7. Gene expression-based biomarkers for discriminating early and late stage of clear cell renal cancer

    Science.gov (United States)

    Bhalla, Sherry; Chaudhary, Kumardeep; Kumar, Ritesh; Sehgal, Manika; Kaur, Harpreet; Sharma, Suresh; Raghava, Gajendra P. S.

    2017-01-01

    In this study, an attempt has been made to identify expression-based gene biomarkers that can discriminate early and late stage of clear cell renal cell carcinoma (ccRCC) patients. We have analyzed the gene expression of 523 samples to identify genes that are differentially expressed in the early and late stage of ccRCC. First, a threshold-based method has been developed, which attained a maximum accuracy of 71.12% with ROC 0.67 using single gene NR3C2. To improve the performance of threshold-based method, we combined two or more genes and achieved maximum accuracy of 70.19% with ROC of 0.74 using eight genes on the validation dataset. These eight genes include four underexpressed (NR3C2, ENAM, DNASE1L3, FRMPD2) and four overexpressed (PLEKHA9, MAP6D1, SMPD4, C11orf73) genes in the late stage of ccRCC. Second, models were developed using state-of-art techniques and achieved maximum accuracy of 72.64% and 0.81 ROC using 64 genes on validation dataset. Similar accuracy was obtained on 38 genes selected from subset of genes, involved in cancer hallmark biological processes. Our analysis further implied a need to develop gender-specific models for stage classification. A web server, CancerCSP, has been developed to predict stage of ccRCC using gene expression data derived from RNAseq experiments. PMID:28349958

  8. Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary

    OpenAIRE

    Ryoko Takahashi; Seiji Mabuchi; Mahiru Kawano; Tomoyuki Sasano; Yuri Matsumoto; Hiromasa Kuroda; Katsumi Kozasa; Kae Hashimoto; Kenjiro Sawada; Tadashi Kimura

    2016-01-01

    Objective The objective of this study was to evaluate the antitumor effects of lurbinectedin as a single agent or in combination with existing anticancer agents for clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histological subtype. Methods Using human ovarian CCC cell lines, the antitumor effects of lurbinectedin, SN-38, doxorubicin, cisplatin, and paclitaxel as single agents were assessed using the MTS assay. Then, the antitumor effects of comb...

  9. Autocrine stimulation of clear-cell renal carcinoma cell migration in hypoxia via HIF-independent suppression of thrombospondin-1

    Science.gov (United States)

    Bienes-Martínez, Raquel; Ordóñez, Angel; Feijoo-Cuaresma, Mónica; Corral-Escariz, María; Mateo, Gloria; Stenina, Olga; Jiménez, Benilde; Calzada, María J.

    2012-01-01

    Thrombospondin-1 is a matricellular protein with potent antitumour activities, the levels of which determine the fate of many different tumours, including renal carcinomas. However, the factors that regulate this protein remain unclear. In renal carcinomas, hypoxic conditions enhance the expression of angiogenic factors that help adapt tumour cells to their hostile environment. Therefore, we hypothesized that anti-angiogenic factors should correspondingly be dampened. Indeed, we found that hypoxia decreased the thrombospondin-1 protein in several clear cell renal carcinoma cell lines (ccRCC), although no transcriptional regulation was observed. Furthermore, we proved that hypoxia stimulates multiple signals that independently contribute to diminish thrombospondin-1 in ccRCC, which include a decrease in the activity of oxygen-dependent prolylhydroxylases (PHDs) and activation of the PI3K/Akt signalling pathway. In addition, thrombospondin-1 regulation in hypoxia proved to be important for ccRCC cell migration and invasion. PMID:23145312

  10. Synchronous clear cell renal cell carcinoma and multilocular cystic renal cell neoplasia of low malignant potential: A clinico-pathologic and molecular study.

    Science.gov (United States)

    Raspollini, Maria Rosaria; Castiglione, Francesca; Cheng, Liang; Montironi, Rodolfo; Lopez-Beltran, Antonio

    2016-05-01

    We report a rare case of synchronous clear cell renal cell carcinoma and multilocular cystic renal cell neoplasia of low malignant potential in the same kidney. The tumors were seen incidentally in a 45-year-old man. Pathologic study revealed that the former tumor was nucleolar grade 2, and the multilocular cystic renal cell neoplasia of low malignant potential was nucleolar grade 1. At immunohistochemistry, the clear cells in both tumors were positive for CD10 and CA IX. Interestingly, these uncommon synchronous tumors showed a different KRAS/NRAS mutation analysis that was characterized by KRAS mutation at codon p.G12C in the clear cell renal cell carcinoma, while this mutation was not present in the case of multilocular cystic renal cell neoplasia of low malignant potential. NRAS mutation was not seen in any of the tumors.

  11. A case of clear cell adenocarcinoma arising from the urethral diverticulum: Utility of urinary cytology and immunohistochemistry

    Directory of Open Access Journals (Sweden)

    Shin-ichi Nakatsuka

    2012-01-01

    Full Text Available Carcinomas rarely arise from the urethral diverticulum. In this report, we present a case of clear cell adenocarcinoma arising from the urethral diverticulum. A 42-year-old woman complained of bloody discharge and lower back pain. Imaging studies showed a tumor involving the region surrounding the urethra and cystourethroscopy showed papillary and villous tumors in the urethral diverticula. Cytology of the urine sediment showed papillary or spherical clusters of atypical cells, some of which had clear abundant cytoplasm and formed mirror ball-like clusters, suggesting adenocarcinoma. Although histological diagnosis was indeterminate by biopsy and transurethral resection (TUR because of absence of stromal invasion, surgically resected specimen via cysturethrectomy revealed that the tumor was clear cell carcinoma. Urinary cytological findings and immunohistochemical analysis for CD15, Ki-67, and p53 might be useful for accurate diagnosis of clear cell adenocarcinoma that arises from the urethral diverticulum when sufficient materials are not available by biopsy and TUR.

  12. Identifying mRNA targets of microRNA dysregulated in cancer: with application to clear cell Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Liou Louis S

    2010-04-01

    Full Text Available Abstract Background MicroRNA regulate mRNA levels in a tissue specific way, either by inducing degradation of the transcript or by inhibiting translation or transcription. Putative mRNA targets of microRNA identified from seed sequence matches are available in many databases. However, such matches have a high false positive rate and cannot identify tissue specificity of regulation. Results We describe a simple method to identify direct mRNA targets of microRNA dysregulated in cancers from expression level measurements in patient matched tumor/normal samples. The word "direct" is used here in a strict sense to: a represent mRNA which have an exact seed sequence match to the microRNA in their 3'UTR, b the seed sequence match is strictly conserved across mouse, human, rat and dog genomes, c the mRNA and microRNA expression levels can distinguish tumor from normal with high significance and d the microRNA/mRNA expression levels are strongly and significantly anti-correlated in tumor and/or normal samples. We apply and validate the method using clear cell Renal Cell Carcinoma (ccRCC and matched normal kidney samples, limiting our analysis to mRNA targets which undergo degradation of the mRNA transcript because of a perfect seed sequence match. Dysregulated microRNA and mRNA are first identified by comparing their expression levels in tumor vs normal samples. Putative dysregulated microRNA/mRNA pairs are identified from these using seed sequence matches, requiring that the seed sequence be conserved in human/dog/rat/mouse genomes. These are further pruned by requiring a strong anti-correlation signature in tumor and/or normal samples. The method revealed many new regulations in ccRCC. For instance, loss of miR-149, miR-200c and mir-141 causes gain of function of oncogenes (KCNMA1, LOX, VEGFA and SEMA6A respectively and increased levels of miR-142-3p, miR-185, mir-34a, miR-224, miR-21 cause loss of function of tumor suppressors LRRC2, PTPN13, SFRP1

  13. Early Diagnosis of Clear Cell Kidney Cancer via VHL/HIF Pathway Regulated-Circulating microRNA

    Science.gov (United States)

    2016-05-01

    Award Number: W81XWH-11-1-0715 TITLE: Early Diagnosis of Clear Cell Kidney Cancer via VHL/HIF Pathway -Regulated Circulating microRNA PRINCIPAL...TITLE AND SUBTITLE Sa. CONTRACT NUMBER Early Diagnosis of Clear Cell Kidney Cancer via VHL/HIF Pathway - Regulated Circulating microRNA Sb. GRANT NUMBER...panel of diagnostic miRNAs that are measurable in serum and will be able to identify kidney cancer in its earliest stages. We hypothesized that serum

  14. Clear-cell meningioma; CT and MR imaging findings in two cases involving the spinal canal and cerebellopontine angle

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Ki Bong; Lim, Myung Kwan; Kim, Hyung Jin; Suh, Chang Hae; Park, Hyung Chun; Kim, Eun Young; Han, Hye Seung [Inha University Hospital College of Medicine, Incheon (Korea, Republic of)

    2002-06-01

    Clear-cell meningioma is a rare subtype of meningioma which occurs at a younger age and has a higher recurrence rate than other subtypes. We report two cases of clear-cell meningioma, one in the thoracolumbar spinal canal and the other in the cerebellopontine angle. Though the CT and MR imaging findings were not different from those of ordinary meningioma, after surgical removal the condition recurred repeatedly in the patient with spinal canal involvement.

  15. Clear-Cell Meningioma: CT and MR Imaging Findings in Two Cases Involving the Spinal Canal and Cerebellopontine Angle

    Science.gov (United States)

    Yu, Ki Bong; Kim, Hyung Jin; Suh, Chang Hae; Park, Hyung Chun; Kim, Eun Young; Han, Hye Seung

    2002-01-01

    Clear-cell meningioma is a rare subtype of meningioma which occurs at a younger age and has a higher recurrence rate than other subtypes. We report two cases of clear-cell meningioma, one in the thoracolumbar spinal canal and the other in the cerebellopontine angle. Though the CT and MR imaging findings were not different from those of ordinary meningioma, after surgical removal the condition recurred repeatedly in the patient with spinal canal involvement. PMID:12087202

  16. Clear Cell Sarcoma (Malignant Melanoma of Soft Parts: A Clinicopathologic Study of 52 Cases

    Directory of Open Access Journals (Sweden)

    O. Hocar

    2012-01-01

    Full Text Available Clear cell sarcomas are aggressive, rare soft tissue tumors and their classification among melanoma or sarcoma is still undetermined due to their clinical, pathologic, and molecular properties found in both types of tumors. This is a retrospective study of 52 patients with CCS seen between April 1979 and April 2005 in two institutions. The EWS-ATF-1 fusion transcript was studied in 31 patients and an activating mutation of the BRAF or NRAS gene was researched in 22 patients. 30 men and 22 women, with a mean age of 33 were studied. Forty-three tumors (82.69% were located in the extremities, specially the foot (19 tumors. Median initial tumor size was 4.8 cm (1 to 15 cm. Necrosis involving more than 50% of the tumor cells was found in 14 cases (26.92%. High mitotic rate (>10 was found in 25 cases (48.07%. The EWS/ATF-1 translocation was found in 28 (53.84% of 31 patients studied, and mutation of BRAF or NRAS was found in only 2 of 22 patients analyzed cases (3.84%. Among the tumor-associated parameters, only tumor size (>4 cm emerged as a significant prognostic factor. Forty-nine patients had a localized disease at diagnosis (94.23% and underwent surgical resection immediately (90% or after neoadjuvant chemotherapy (CT (10%. Various CT regimens were used in 37 patients (71.15% with no significant efficacy. The 5- and 10-year OS rates were 59% and 41%, respectively. Tumor size was the only emerging prognosis factor in our series. Complete surgical resection remains the optimal treatment for this aggressive chemoresistant tumor.

  17. Clear genetic distinctiveness between human- and pig-derived Trichuris based on analyses of mitochondrial datasets

    DEFF Research Database (Denmark)

    Liu, Guo-Hua; Gasser, Robin B.; Su, Ang;

    2012-01-01

    The whipworm, Trichuris trichiura, causes trichuriasis in ~600 million people worldwide, mainly in developing countries. Whipworms also infect other animal hosts, including pigs (T. suis), dogs (T. vulpis) and non-human primates, and cause disease in these hosts, which is similar to trichuriasis...... of humans. Although Trichuris species are considered to be host specific, there has been considerable controversy, over the years, as to whether T. trichiura and T. suis are the same or distinct species. Here, we characterised the entire mitochondrial genomes of human-derived Trichuris and pig...... for nuclear ribosomal DNA. Using molecular analytical tools, employing genetic markers defined herein, future work should conduct large-scale studies to establish whether T. trichiura is found in pigs and T. suis in humans in endemic regions....

  18. [The changes in complete blood count in patients treated with sunitinib malate for metastatic clear cell renal cell carcinoma].

    Science.gov (United States)

    Kucharz, Jakub; Michałowska-Kaczmarczyk, Anna; Streb, Joanna; Kuzniewski, Marek; Herman, Roman M; Krzemieniecki, Krzysztof

    2013-01-01

    Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies. For stage I - III RCC surgery is the primary treatment. Systemic therapy is used in the patients with disseminated disease (stage IV). Sunitinib malate is commonly used in the patients with clear cell renal cell carcinoma (ccRCC) rated as 'low' or 'intermediate' risk according to the Motzer scale. Treatment with sunitinib malate is associated with myelotoxicity. To assess its clinical significance we conducted a pilot study in a group of 10 patients. We noticed a gradual decrease in the mean haemoglobin level during subsequent treatment cycles. Alternations in the platelet count were of no clinical significance. Episodes of the neutropenia were noticed in the study group. In some patients neutrophil count decreased to the level that put them at risk of the infectious complications.

  19. Metabolomic profile of glycolysis and the pentose phosphate pathway identifies the central role of glucose-6-phosphate dehydrogenase in clear cell-renal cell carcinoma.

    Science.gov (United States)

    Lucarelli, Giuseppe; Galleggiante, Vanessa; Rutigliano, Monica; Sanguedolce, Francesca; Cagiano, Simona; Bufo, Pantaleo; Lastilla, Gaetano; Maiorano, Eugenio; Ribatti, Domenico; Giglio, Andrea; Serino, Grazia; Vavallo, Antonio; Bettocchi, Carlo; Selvaggi, Francesco Paolo; Battaglia, Michele; Ditonno, Pasquale

    2015-05-30

    The analysis of cancer metabolome has shown that proliferating tumor cells require a large quantities of different nutrients in order to support their high rate of proliferation. In this study we analyzed the metabolic profile of glycolysis and the pentose phosphate pathway (PPP) in human clear cell-renal cell carcinoma (ccRCC) and evaluate the role of these pathways in sustaining cell proliferation, maintenance of NADPH levels, and production of reactive oxygen species (ROS). Metabolomic analysis showed a clear signature of increased glucose uptake and utilization in ccRCC tumor samples. Elevated levels of glucose-6-phosphate dehydrogenase (G6PDH) in association with higher levels of PPP-derived metabolites, suggested a prominent role of this pathway in RCC-associated metabolic alterations. G6PDH inhibition, caused a significant decrease in cancer cell survival, a decrease in NADPH levels, and an increased production of ROS, suggesting that the PPP plays an important role in the regulation of ccRCC redox homeostasis. Patients with high levels of glycolytic enzymes had reduced progression-free and cancer-specific survivals as compared to subjects with low levels. Our data suggest that oncogenic signaling pathways may promote ccRCC through rerouting the sugar metabolism. Blocking the flux through this pathway may serve as a novel therapeutic target.

  20. Annexin A4 is involved in proliferation, chemo-resistance and migration and invasion in ovarian clear cell adenocarcinoma cells.

    Directory of Open Access Journals (Sweden)

    Tae Mogami

    Full Text Available Ovarian clear cell adenocarcinoma (CCC is the second most common subtype of ovarian cancer after high-grade serous adenocarcinomas. CCC tends to develop resistance to the standard platinum-based chemotherapy, and has a poor prognosis when diagnosed in advanced stages. The ANXA4 gene, along with its product, a Ca(++-binding annexin A4 (ANXA4 protein, has been identified as the CCC signature gene. We reported two subtypes of ANXA4 with different isoelectric points (IEPs that are upregulated in CCC cell lines. Although several in vitro investigations have shown ANXA4 to be involved in cancer cell proliferation, chemoresistance, and migration, these studies were generally based on its overexpression in cells other than CCC. To elucidate the function of the ANXA4 in CCC cells, we established CCC cell lines whose ANXA4 expressions are stably knocked down. Two parental cells were used: OVTOKO contains almost exclusively an acidic subtype of ANXA4, and OVISE contains predominantly a basic subtype but also a detectable acidic subtype. ANXA4 knockdown (KO resulted in significant growth retardation and greater sensitivity to carboplatin in OVTOKO cells. ANXA4-KO caused significant loss of migration and invasion capability in OVISE cells, but this effect was not seen in OVTOKO cells. We failed to find the cause of the different IEPs of ANXA4, but confirmed that the two subtypes are found in clinical CCC samples in ratios that vary by patient. Further investigation to clarify the mechanism that produces the subtypes is needed to clarify the function of ANXA4 in CCC, and might allow stratification and improved treatment strategies for patients with CCC.

  1. Annexin A4 is involved in proliferation, chemo-resistance and migration and invasion in ovarian clear cell adenocarcinoma cells.

    Science.gov (United States)

    Mogami, Tae; Yokota, Naho; Asai-Sato, Mikiko; Yamada, Roppei; Koizume, Shiro; Sakuma, Yuji; Yoshihara, Mitsuyo; Nakamura, Yoshiyasu; Takano, Yasuo; Hirahara, Fumiki; Miyagi, Yohei; Miyagi, Etsuko

    2013-01-01

    Ovarian clear cell adenocarcinoma (CCC) is the second most common subtype of ovarian cancer after high-grade serous adenocarcinomas. CCC tends to develop resistance to the standard platinum-based chemotherapy, and has a poor prognosis when diagnosed in advanced stages. The ANXA4 gene, along with its product, a Ca(++)-binding annexin A4 (ANXA4) protein, has been identified as the CCC signature gene. We reported two subtypes of ANXA4 with different isoelectric points (IEPs) that are upregulated in CCC cell lines. Although several in vitro investigations have shown ANXA4 to be involved in cancer cell proliferation, chemoresistance, and migration, these studies were generally based on its overexpression in cells other than CCC. To elucidate the function of the ANXA4 in CCC cells, we established CCC cell lines whose ANXA4 expressions are stably knocked down. Two parental cells were used: OVTOKO contains almost exclusively an acidic subtype of ANXA4, and OVISE contains predominantly a basic subtype but also a detectable acidic subtype. ANXA4 knockdown (KO) resulted in significant growth retardation and greater sensitivity to carboplatin in OVTOKO cells. ANXA4-KO caused significant loss of migration and invasion capability in OVISE cells, but this effect was not seen in OVTOKO cells. We failed to find the cause of the different IEPs of ANXA4, but confirmed that the two subtypes are found in clinical CCC samples in ratios that vary by patient. Further investigation to clarify the mechanism that produces the subtypes is needed to clarify the function of ANXA4 in CCC, and might allow stratification and improved treatment strategies for patients with CCC.

  2. Clear genetic distinctiveness between human- and pig-derived Trichuris based on analyses of mitochondrial datasets.

    Science.gov (United States)

    Liu, Guo-Hua; Gasser, Robin B; Su, Ang; Nejsum, Peter; Peng, Lifei; Lin, Rui-Qing; Li, Ming-Wei; Xu, Min-Jun; Zhu, Xing-Quan

    2012-01-01

    The whipworm, Trichuris trichiura, causes trichuriasis in ∼600 million people worldwide, mainly in developing countries. Whipworms also infect other animal hosts, including pigs (T. suis), dogs (T. vulpis) and non-human primates, and cause disease in these hosts, which is similar to trichuriasis of humans. Although Trichuris species are considered to be host specific, there has been considerable controversy, over the years, as to whether T. trichiura and T. suis are the same or distinct species. Here, we characterised the entire mitochondrial genomes of human-derived Trichuris and pig-derived Trichuris, compared them and then tested the hypothesis that the parasites from these two host species are genetically distinct in a phylogenetic analysis of the sequence data. Taken together, the findings support the proposal that T. trichiura and T. suis are separate species, consistent with previous data for nuclear ribosomal DNA. Using molecular analytical tools, employing genetic markers defined herein, future work should conduct large-scale studies to establish whether T. trichiura is found in pigs and T. suis in humans in endemic regions.

  3. Clear genetic distinctiveness between human- and pig-derived Trichuris based on analyses of mitochondrial datasets.

    Directory of Open Access Journals (Sweden)

    Guo-Hua Liu

    Full Text Available The whipworm, Trichuris trichiura, causes trichuriasis in ∼600 million people worldwide, mainly in developing countries. Whipworms also infect other animal hosts, including pigs (T. suis, dogs (T. vulpis and non-human primates, and cause disease in these hosts, which is similar to trichuriasis of humans. Although Trichuris species are considered to be host specific, there has been considerable controversy, over the years, as to whether T. trichiura and T. suis are the same or distinct species. Here, we characterised the entire mitochondrial genomes of human-derived Trichuris and pig-derived Trichuris, compared them and then tested the hypothesis that the parasites from these two host species are genetically distinct in a phylogenetic analysis of the sequence data. Taken together, the findings support the proposal that T. trichiura and T. suis are separate species, consistent with previous data for nuclear ribosomal DNA. Using molecular analytical tools, employing genetic markers defined herein, future work should conduct large-scale studies to establish whether T. trichiura is found in pigs and T. suis in humans in endemic regions.

  4. Survival of women with clear cell and papillary serous endometrial cancer after adjuvant radiotherapy.

    Science.gov (United States)

    Foerster, Robert; Kluck, Robert; Rief, Harald; Rieken, Stefan; Debus, Juergen; Lindel, Katja

    2014-06-18

    Type II (papillary serous and clear cell) endometrial carcinoma (EC) is a rare subgroup and is considered to have an unfavorable prognosis. The purpose of this retrospective analysis was to elucidate the meaning of adjuvant radiotherapy (RT) for clinical outcome and to define prognostic factors in these patients (pts). From 2004-2012 forty-two pts with type II EC underwent surgery followed by adjuvant RT at our department. Median age was 72 years. The majority were early stage carcinomas (FIGO I n = 27 [64.3%], FIGO II n = 4 [9.5%], FIGO III n = 11 [26.2%]. Seven pts (16.7%) received adjuvant chemotherapy (ChT). Pts were treated with external beam radiotherapy (EBRT) and brachytherapy (IVB) boost. Five-year local recurrence free survival (LRFS), distant metastases free survival (DMFS) and overall survival (OS) were 85.4%, 78%, and 64.5% respectively. LRFS was better with lower pT stage, without lymphangiosis (L0), without haemangiosis (V0) and negative resection margins (R0). DMFS was prolonged in lymph node negatives (N0), L0, V0 and R0. OS was improved in younger pts, N0, L0, V0 and after lymphadenectomy (LNE). Multivariate analysis revealed haemangiosis (V1) as the only independent prognostic factor for OS (p = .014) and DMFS (p = .008). For LRFS pT stage remained as an independent prognostic factor (p = .028). Adjuvant RT with EBRT/IVB ensures adequate local control in type II EC, but control rates remain lower than in type I EC. A benefit of additional adjuvant ChT could not be demonstrated and a general omission of EBRT cannot be recommended at this point. Lymphovascular infiltration and pT stage might be the best predictive factors for a benefit from combined local and systemic treatment.

  5. Human mesenchymal stem cells

    DEFF Research Database (Denmark)

    Abdallah, Basem; Kassem, Moustapha

    2008-01-01

    Mesenchymal stem cells (MSC) are a group of clonogenic cells present among the bone marrow stroma and capable of multilineage differentiation into mesoderm-type cells such as osteoblasts, adipocytes and chondrocytes. Due to their ease of isolation and their differentiation potential, MSC are being...... introduced into clinical medicine in variety of applications and through different ways of administration. Here, we discuss approaches for isolation, characterization and directing differentiation of human mesenchymal stem cells (hMSC). An update of the current clinical use of the cells is also provided....

  6. RNA Sequencing Reveals Upregulation of RUNX1-RUNX1T1 Gene Signatures in Clear Cell Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Zuquan Xiong

    2014-01-01

    Full Text Available In the past few years, therapies targeted at the von Hippel-Lindau (VHL and hypoxia-inducible factor (HIF pathways, such as sunitinib and sorafenib, have been developed to treat clear cell renal cell carcinoma (ccRCC. However, the majority of patients will eventually show resistance to antiangiogenesis therapies. The purpose of our study was to identify novel pathways that could be potentially used as targets for new therapies. Whole transcriptome sequencing (RNA-Seq was conducted on eight matched tumor and adjacent normal tissue samples. A novel RUNX1-RUNX1T1 pathway was identified which was upregulated in ccRCC through gene set enrichment analysis (GSEA. We also confirmed the findings based on previously published gene expression microarray data. Our data shows that upregulated of the RUNX1-RUNX1T1 gene set maybe an important factor contributing to the etiology of ccRCC.

  7. Context-dependent role for chromatin remodeling component PBRM1/BAF180 in clear cell renal cell carcinoma

    Science.gov (United States)

    Murakami, A; Wang, L; Kalhorn, S; Schraml, P; Rathmell, W K; Tan, A C; Nemenoff, R; Stenmark, K; Jiang, B-H; Reyland, M E; Heasley, L; Hu, C-J

    2017-01-01

    A subset of clear cell renal cell carcinoma (ccRCC) tumors exhibit a HIF1A gene mutation, yielding two ccRCC tumor types, H1H2 type expressing both HIF1α and HIF2α, and H2 type expressing HIF2α, but not functional HIF1α protein. However, it is unclear how the H1H2 type ccRCC tumors escape HIF1's tumor-suppressive activity. The polybromo-1 (PBRM1) gene coding for the BAF180 protein, a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, is inactivated in 40% ccRCCs, the function and mechanism of BAF180 mutation is unknown. Our previous study indicates that BAF180-containing SWI/SNF chromatin remodeling complex is a co-activator for transcription factor HIF to induce HIF target genes. Thus, our questions are if BAF180 is involved in HIF-mediated hypoxia response and if PBRM1/BAF180 mutation has any association with the HIF1A retention in H1H2 type ccRCC. We report here that BAF180 is mutated in H1H2 ccRCC cell lines and tumors, and BAF180 re-expression in H1H2 ccRCC cell lines reduced cell proliferation/survival, indicating that BAF180 has tumor-suppressive role in these cells. However, BAF180 is expressed in HIF1-deficient H2 ccRCC cell lines and tumors, and BAF180 knockdown in H2 type ccRCC cell lines reduced cell proliferation/survival, indicating that BAF180 has tumor-promoting activity in these cells. In addition, our data show that BAF180 functions as co-activator for HIF1- and HIF2-mediated transcriptional response, and BAF180's tumor-suppressive and -promoting activity in ccRCC cell lines depends on co-expression of HIF1 and HIF2, respectively. Thus, our studies reveal that BAF180 function in ccRCC is context dependent, and that mutation of PBRM1/BAF180 serves as an alternative strategy for ccRCC tumors to reduce HIF1 tumor-suppressive activity in H1H2 ccRCC tumors. Our studies define distinct functional subgroups of ccRCCs based on expression of BAF180, and suggest that BAF180 inhibition may be a novel therapeutic

  8. PAI-1 expression and its regulation by promoter 4G/5G polymorphism in clear cell renal cell carcinoma.

    Science.gov (United States)

    Choi, Jung-Woo; Lee, Ju-Han; Park, Hong Seok; Kim, Young-Sik

    2011-10-01

    To characterise patients with high plasminogen activator inhibitor-1 (PAI-1) expression as oral PAI-1 antagonists are currently in preclinical trials, and to determine whether the PAI-1 promoter 4G/5G polymorphism regulates PAI-1 expression in clear cell renal cell carcinoma (CCRCC). PAI-1 expression was examined by immunohistochemistry in 69 CCRCC specimens. In addition, the promoter 4G/5G polymorphism was investigated by both allele-specific PCR and direct DNA sequencing. PAI-1 was overexpressed in 25/69 (36.2%) patients with CCRCC. PAI-1 staining was intense in tumour cells with a high Fuhrman nuclear grade and in spindle-shaped tumour cells. PAI-1 expression was significantly associated with older age at diagnosis (p=0.027), high nuclear grade (p4G/4G, 43.5% (30/69) 4G/5G and 31.9% (22/69) 5G/5G. The homozygous 4G/4G or 5G/5G group showed a tendency for a high nuclear grade (p=0.05) but the 4G/5G polymorphism was not related to other prognostic parameters. PAI-1 expression was poorly correlated with its promoter 4G/5G polymorphism (Spearman ρ=0.088). CCRCC with high PAI-1 expression is characterised by older age, high nuclear grade, advanced stage, distant metastasis and/or shortened disease-free survival. PAI-1 expression is not affected by the promoter 4G/5G polymorphism.

  9. Clearing the air: a review of the effects of particulate matter air pollution on human health.

    Science.gov (United States)

    Anderson, Jonathan O; Thundiyil, Josef G; Stolbach, Andrew

    2012-06-01

    The World Health Organization estimates that particulate matter (PM) air pollution contributes to approximately 800,000 premature deaths each year, ranking it the 13th leading cause of mortality worldwide. However, many studies show that the relationship is deeper and far more complicated than originally thought. PM is a portion of air pollution that is made up of extremely small particles and liquid droplets containing acids, organic chemicals, metals, and soil or dust particles. PM is categorized by size and continues to be the fraction of air pollution that is most reliably associated with human disease. PM is thought to contribute to cardiovascular and cerebrovascular disease by the mechanisms of systemic inflammation, direct and indirect coagulation activation, and direct translocation into systemic circulation. The data demonstrating PM's effect on the cardiovascular system are strong. Populations subjected to long-term exposure to PM have a significantly higher cardiovascular incident and mortality rate. Short-term acute exposures subtly increase the rate of cardiovascular events within days of a pollution spike. The data are not as strong for PM's effects on cerebrovascular disease, though some data and similar mechanisms suggest a lesser result with smaller amplitude. Respiratory diseases are also exacerbated by exposure to PM. PM causes respiratory morbidity and mortality by creating oxidative stress and inflammation that leads to pulmonary anatomic and physiologic remodeling. The literature shows PM causes worsening respiratory symptoms, more frequent medication use, decreased lung function, recurrent health care utilization, and increased mortality. PM exposure has been shown to have a small but significant adverse effect on cardiovascular, respiratory, and to a lesser extent, cerebrovascular disease. These consistent results are shown by multiple studies with varying populations, protocols, and regions. The data demonstrate a dose

  10. Contrast-enhanced ultrasound for detection and diagnosis of renal clear cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    DONG Xiao-qiu; SHEN Yi; XU Li-wei; XU Chun-mei; BI Wei; WANG Xiao-min

    2009-01-01

    Background Renal clear cell carcinoma (RCCC) is the most common malignant renal tumor. It is highly malignant,does not cause clinical symptoms in its eady stages, and cannot be diagnosed using conventional ultrasound. This study was aimed to investigate the contrast-enhanced ultrasound (CEUS) mode and characteristics of the time-intensity curve for RCCC and its pathological basis.Methods Forty-two patients with pathologically diagnosed RCCC underwent CEUS examination before surgery. The patients' kidneys were visualized after injection of contrast agents using the Technos MPX DU8. We analyzed the CEUS mode, time-intensity curve, and pathological findings.Results The detection rate of RCCC with conventional ultrasound was about 71%, while the rate using CEUS was 100%. Larger tumors (33 cases) showed non-uniform enhancement with defective filling. CEUS modes were divided into 4 types: type Ⅰ, "quick in and out" (26.19%, 11/42); type Ⅱ, "quick in and slow out" (40.48%, 17/42); type Ⅲ, "Simultaneous in and out" (16.67%, 7/42); and type Ⅳ "slow in and out" (16.67%, 7/42). All types had a close correlation to the pathological basis. "Time-intensity curve of CEUS consisted of 3 phases, the perfusion phase, regression phase, and lag phase. Cases of types Ⅰ and Ⅲ only had a perfusion and regression phase, those of type Ⅱ and Ⅳ had a perfusion phase,regression phase, and lag phase. Quantitative analysis of the time-intensity curve showed that the time-to-peak (TTP) of the lesions was shorter than that of normal renal parenchyma (P <0.0001), the mean value of the up slope rate of the absolute value of lesions was higher than that of the ipsilateral normal renal parenchyma (P <0.0001), and that the mean value of descent slope rate of the absolute value of lesions was lower than that of the ipsilateral normal renal parenchyma (P <0.0001).Conclusions CEUS is useful in detecting small vessels in tumors. Although there are several different CEUS modes,type

  11. Primary clear cell carcinoma in the liver:CT and MRI findings

    Institute of Scientific and Technical Information of China (English)

    Qing-Yu Liu; Hai-Gang Li; Ming Gao; Xiao-Feng Lin; Yong Li; Jian-Yu Chen

    2011-01-01

    AIM:To retrospectively analyze the computed tomography (CT) and magnetic resonance imaging (MRI) appearances of primary clear cell carcinoma of the liver (PCCCL) and compare the imaging appearances of PCCCL and common type hepatocellular carcinoma (CHCC) to determine whether any differences exist between the two groups.METHODS:Twenty cases with pathologically proven PCCCL and 127 cases with CHCC in the Second Affiliated Hospital of Sun Yat-sen University were included in this study.CT or MRI images from these patients were retrospectively analyzed.The following imaging findings were reviewed:the presence of liver cirrhosis,tumor size,the enhancement pattern on dynamic contrast scanning,the presence of pseudo capsules,tumor rupture,portal vein thrombosis and lymph node metastasis.RESULTS:Both PCCCL and CHCC were prone to occur in patients with liver cirrhosis,the association rate of liver cirrhosis was 80.0% and 78.7%,respectively (P > 0.05).The mean sizes of PCCCL and CHCC tumors were (7.28 ± 4.25) cm and (6.96 ± 3.98) cm,respectively.Small HCCs were found in 25.0% (5/20) of PCCCL and 19.7% (25/127) of CHCC cases.No significant differences in mean size and ratio of small HCCs were found between the two groups (P = 0.658 and 0.803,respectively).Compared with CHCC patients,PCCCL patients were more prone to form pseudo capsules (49.6% vs 75.0%,P = 0.034).Tumor rupture,typical HCC enhancement patterns and portal vein tumor thrombosis were detected in 15.0% (3/20),72.2% (13/18) and 20.0% (4/20) of patients with PCCCL and 3.1% (4/127),83.6% (97/116) and 17.3% (22/127) of patients with CHCC,respectively.There were no significant differences between the two groups (all P > 0.05).No patients with PCCCL and 2.4% (3/127) of patients with CHCC showed signs of lymph node metastasis (P > 0.05).CONCLUSION:The imaging characteristics of PCCCL are similar to those of CHCC and could be useful for differentiating these from other liver tumors (such as hemangioma and hepatic

  12. Urinary KIM-1 and AQP-1 in patients with clear renal cell carcinoma: Potential noninvasive biomarkers

    Directory of Open Access Journals (Sweden)

    Mijušković Mirjana

    2016-01-01

    Full Text Available Background/Aim. Kidney injury molecule-1 (KIM-1 and aquaporin-1 (AQP-1 are potential early urinary biomarkers of clear renal cell carcinoma (cRCC. The aim of this study was to ascertain relationship between the urine concentrations KIM-1 and AQP-1 with tumor size, grade, pT stage and type of operation (radical or partial nephrectomy in patients with cRCC. Methods. Urinary concentrations of urinary KIM-1 (uKIM-1 and urinary AQP-1 (uAQP-1 were determined by commercially available ELISA kits. The analysis included 40 patients undergoing partial or radical nephrectomy for cRCC and 40 age- and sex-matched healthy adult volunteers. Results. The median preoperative concentrations of KIM-1 in the cRCC group [0.724 ± 1.120 ng/mg urinary creatinine (Ucr] were significantly greater compared with controls (healthy volunteers (0.210 ± 0.082 ng/mgUcr (p = 0.0227. Postoperatively, uKIM-1 concentration decreased significantly to control values (0.177 ± 0.099 ng/mgUcr vs 0.210 ± 0.082 ng/mgUcr, respectively. The size, grade and stage of tumor were correlated positively with preoperative uKIM-1 concentrations. Contrary to these results, concentrations of uAQP-1 in the cRCC group were significantly lower (0.111 ± 0.092 ng/mgUcr compared with the control group (0.202 ± 0.078 ng/mgUcr (p = 0.0014. Postoperatively, the concentrations of uAQP-1 increased progressively up to control values, approximately. We find no significant correlation between preoperative uAQP-1 concentrations and tumor size, grade and stage. Conclusion. uKIM-1 was found to be a reliable diagnostic marker of cRCC, based on its significantly increased values before and decreased values after the nephrectomy. [Projekat Ministarstva nauke Republike Srbije, br. III41018

  13. Expression and Prognostic Significance of EP300, TP53 and BAX in Clear Cell Renal Cell Carcinoma.

    Science.gov (United States)

    Godlewski, Janusz; Krazinski, Bartlomiej E; Kowalczyk, Anna E; Kiewisz, Jolanta; Kiezun, Jacek; Kwiatkowski, Przemyslaw; Sliwińska-Jewsiewicka, Agnieszka; Wierzbicki, Piotr W; Kmieć, Zbigniew

    2017-06-01

    Histone acetyltransferase E1A-binding protein p300 (EP300), tumor protein p53 (TP53) and B-cell lymphoma-2-associated X protein (BAX) contribute to the regulation of the cell cycle and apoptosis, cellular processes that are often impaired in cancer cells. The aim of this study was to determine the expression levels of EP300, TP53 and BAX genes and their respective proteins in clear cell renal cell carcinoma (ccRCC) and evaluate the value of these factors as prognostic factors. EP300, TP53 and BAX expression at the transcript and protein levels were determined by quantitative polymerase-chain reaction (QPCR) and immunohistochemistry (IHC) in paired tumor and kidney specimens from 31 patients with ccRCC. Levels of EP300, TP53 and BAX transcripts were found increased in tumor tissues. Immunoreactivity for TP53 was elevated in cancer cells when compared to unchanged kidney, while EP300 and BAX immunoexpression in ccRCC did not differ from that of normal renal tissue. Immunoreactivity for TP53 was positively associated with larger tumor size. In contrast, stronger BAX immunoexpression correlated with smaller tumor diameters. The average immunoreactivity for BAX was higher in localized, kidney-confined tumor than in advanced/recurrent tumors. None of the analyzed transcripts or proteins correlated with the overall survival of patients. Although TP53 and BAX immunoreactivity levels were associated with some clinicopathological parameters of the patients, the expression of EP300, TP53 and BAX did not reveal any prognostic significance in ccRCC. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  14. Clear retainer

    Directory of Open Access Journals (Sweden)

    Priyakorn Chaimongkol

    2017-01-01

    Full Text Available A clear retainer is a removable retainer that is popular in the present day. Compared with conventional fixed and removable orthodontic retainers, it is a more esthetic, comfortable, and inexpensive appliance. Although several studies have been published about clear retainers, it could be difficult to interpret the results because of the variety of study designs, sample sizes, and research methods. This article is intended to compile the content from previous studies and discuss advantages, disadvantages, fabrication, insertion, and adjustment. Moreover, the effectiveness in maintaining dental position, occlusion, retention protocols, thickness, and survival rate of clear retainers is discussed.

  15. Downregulation of dystroglycan glycosyltransferases LARGE2 and ISPD associate with increased mortality in clear cell renal cell carcinoma.

    Science.gov (United States)

    Miller, Michael R; Ma, Deqin; Schappet, James; Breheny, Patrick; Mott, Sarah L; Bannick, Nadine; Askeland, Eric; Brown, James; Henry, Michael D

    2015-07-30

    Dystroglycan (DG) is a cell-surface laminin receptor that links the cytoskeleton to the extracellular matrix in a variety of epithelial tissues. Its function as a matrix receptor requires extensive glycosylation of its extracellular subunit αDG, which involves at least 13 distinct genes. Prior work has shown loss of αDG glycosylation in an assortment of carcinomas, including clear cell renal cell carcinoma (ccRCC) though the cause (s) and functional consequences of this loss are still unclear. Using The Cancer Genome Atlas (TCGA) database, we analyzed the DG glycosylation pathway to identify changes in mRNA expression and correlation with clinical outcomes. We validated our findings with a cohort of 65 patients treated with radical nephrectomy by analyzing DG glycosylation via immunohistochemistry and gene expression via qRT-PCR. Analysis of TCGA database revealed frequent dysregulation of a subset of DG glycosyltransferases. Most notably, there was a frequent, significant downregulation of GYLTL1B (LARGE2) and ISPD. DG glycosylation is frequently impaired in ccRCC patient samples and most strongly associates with downregulation of GYLTL1B. Reduced levels of GYLTL1B and ISPD mRNA associated with increased patient mortality and are the likely cause of αDG hypoglycosylation in ccRCC.

  16. A Synchronous Pancreatic Metastasis from Renal Clear Cell Carcinoma, with Unusual CT Characteristics, Completely Regressed after Therapy with Sunitinib

    Directory of Open Access Journals (Sweden)

    Salvatore Lauro

    2014-01-01

    Full Text Available We present a case report of a 75-years-old woman affected by renal clear cell carcinoma with a synchronous pancreatic metastasis and a metachronous lung metastasis. This case has two peculiarities. First the pancreatic metastasis was treated just with medical therapy, that is, Sunitinib, instead of the surgical therapy that is mostly considered. Secondly, the pancreatic lesion showed different characteristics on the computed tomography scan compared to the usual pancreatic metastases from renal clear cell carcinoma. The pancreatic metastasis totally regressed after medical treatment and nowadays, four years after the diagnosis, the patient is disease-free.

  17. Differentiation of Renal Oncocytoma and Renal Clear Cell Carcinoma Using Relative CT Enhancement Ratio

    Directory of Open Access Journals (Sweden)

    An Ren

    2015-01-01

    Full Text Available Background: The difference between renal oncocytomas (RO and renal clear cell carcinomas (RCCs presents the greatest diagnostic challenge. The aim of this study was to retrospectively determine if RO and RCCs could be differentiated on computed tomography (CT images on the basis of their enhancement patterns with a new enhancement correcting method. Methods: Forty-six patients with a solitary renal mass who underwent total or partial nephrectomy were included in this study. Fourteen of those were RO and 32 were RCCs. All patients were examined with contrast-enhanced CT. The pattern and degree of enhancement were evaluated. We selected the area that demonstrated the greatest degree of enhancement of the renal lesion in the corticomedullary nephrographic and excretory phase images. Regions of interest (ROI were also placed in adjacent normal renal cortex for normalization. We used the values of the normal renal cortex that were measured at the same time as divisors. The ratios of lesion-to-renal cortex enhancement were calculated for all three phases. The Student′s t-test and Pearson′s Chi-square test were used for statistical analyses. Results: All RCCs masses showed contrast that appeared to be better enhanced than RO on all contrast-enhanced phases of CT imaging, but there was no significant difference in absolute attenuation values between these two diseases (P > 0.05. The ratio of lesion-to-cortex attenuation in the corticomedullary phase showed significantly different values between RO and RCCs. The degree of contrast enhancement in RCCs was equal to or greater than that of the normal renal cortex, but it was less than that of the normal cortex in RO in the corticomedullary phase. The ratio of lesion-to-cortex attenuation in the corticomedullary phase was higher than the cut off value of 1.0 in most RCCs (84%, 27/32 and lower than 1.0 in most RO (93%, 13/14 (P < 0.05. In the nephrographic phase, the ratio of lesion-to-cortex attenuation

  18. Primary clear cell renal carcinoma cells display minimal mitochondrial respiratory capacity resulting in pronounced sensitivity to glycolytic inhibition by 3-Bromopyruvate.

    Science.gov (United States)

    Nilsson, H; Lindgren, D; Mandahl Forsberg, A; Mulder, H; Axelson, H; Johansson, M E

    2015-01-08

    Changes of cellular metabolism are an integral property of the malignant potential of most cancer cells. Already in the 1930s, Otto Warburg observed that tumor cells preferably utilize glycolysis and lactate fermentation for energy production, rather than the mitochondrial oxidative phosphorylation dominating in normal cells, a phenomenon today known as the Warburg effect. Even though many tumor types display a high degree of aerobic glycolysis, they still retain the activity of other energy-producing metabolic pathways. One exception seems to be the clear cell variant of renal cell carcinoma, ccRCC, where the activity of most other pathways than that of glycolysis has been shown to be reduced. This makes ccRCC a promising candidate for the use of glycolytic inhibitors in treatment of the disease. However, few studies have so far addressed this issue. In this report, we show a strikingly reduced mitochondrial respiratory capacity of primary human ccRCC cells, resulting in enhanced sensitivity to glycolytic inhibition by 3-Bromopyruvate (3BrPA). This effect was largely absent in established ccRCC cell lines, a finding that highlights the importance of using biologically relevant models in the search for new candidate cancer therapies. 3BrPA markedly reduced ATP production in primary ccRCC cells, followed by cell death. Our data suggest that glycolytic inhibitors such as 3BrPA, that has been shown to be well tolerated in vivo, should be further analyzed for the possible development of selective treatment strategies for patients with ccRCC.

  19. MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors

    Directory of Open Access Journals (Sweden)

    Brian Shuch

    2015-01-01

    Full Text Available Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available. Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P=0.1. MET expression weakly correlated between primary and matched metastatic sites (R=0.5 and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P=0.39. Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents.

  20. Evaluation of CD45 protein expression and transcript in canine small clear cell/T zone lymphoma.

    Directory of Open Access Journals (Sweden)

    Marzia Cozzi

    2015-07-01

    Full Text Available Canine small clear cell lymphoma is a peculiar lymphoma entity with T-zone histopathological pattern andindolent clinical course. From an immunophenotypic point of view the main feature is the lack of CD45 staining by flow-cytometry (FC, which accounts for >95% of cases. Underlying mechanisms have never been investigated.Aim of this work was to evaluate CD45 protein and mRNA expression in small clear cell lymphoma.Lymph nodes of 18 cases and 11 controls, with either reactive hyperplasia or CD45-positive high grade T-cell lymphoma, were investigated. FC was performed on lymph node fine needle aspiration and CD45 median fluorescence intensity (MFI was then evaluated on small clear cells and normal residual T-lymphocytes. CD45 surface expression was also evaluated by immunohistochemical reaction on paraffin wax-embedded lymph node sections.Quantitative real-time RT-PCR was performed on cases and controls. Total RNA was isolated from cell suspension in RNA later. The generated CD45cDNA was amplified and ΔΔCt method was used for the relative mRNA quantification.CD45-MFI in neoplastic cells was <1% compared to normal residual T-lymphocytes in the same sample. Cells were also negative for CD45 stain on histopathological preparations. RT-PCR showed a significantly lower amount of CD45 transcript in neoplastic samples compared to controls, likely due to the residual population.Results showed the lack of CD45 surface antigen and the virtually absence of CD45-mRNA in small clear cell lymphoma. We hypothesize a possible genomic/epigenomic aberration; further studies are in progress to investigate the pathogenesis of this aberrancy and the possible linkage to lymphomagenesis.

  1. Differential expression of microRNA501-5p affects the aggressiveness of clear cell renal carcinoma

    Directory of Open Access Journals (Sweden)

    Alessandra Mangolini

    2014-01-01

    Full Text Available Renal cell carcinoma is a common neoplasia of the adult kidney that accounts for about 3% of adult malignancies. Clear cell renal carcinoma is the most frequent subtype of kidney cancer and 20–40% of patients develop metastases. The absence of appropriate biomarkers complicates diagnosis and prognosis of this disease. In this regard, small noncoding RNAs (microRNAs, which are mutated in several neoplastic diseases including kidney carcinoma, may be optimal candidates as biomarkers for diagnosis and prognosis of this kind of cancer. Here we show that patients with clear cell kidney carcinoma that express low levels of miR501-5p exhibited a good prognosis compared with patients with unchanged or high levels of this microRNA. Consistently, in kidney carcinoma cells the downregulation of miR501-5p induced an increased caspase-3 activity, p53 expression as well as decreased mTOR activation, leading to stimulation of the apoptotic pathway. Conversely, miR501-5p upregulation enhanced the activity of mTOR and promoted both cell proliferation and survival. These biological processes occurred through p53 inactivation by proteasome degradation in a mechanism involving MDM2-mediated p53 ubiquitination. Our results support a role for miR501-5p in balancing apoptosis and cell survival in clear cell renal carcinoma. In particular, the downregulation of microRNA501-5p promotes a good prognosis, while its upregulation contributes to a poor prognosis, in particular, if associated with p53 and MDM2 overexpression and mTOR activation. Thus, the expression of miR501-5p is a possible biomarker for the prognosis of clear cell renal carcinoma.

  2. Regulation of V-ATPase recycling via a RhoA- and ROCKII-dependent pathway in epididymal clear cells.

    Science.gov (United States)

    Shum, Winnie Waichi; Da Silva, Nicolas; Belleannée, Clémence; McKee, Mary; Brown, Dennis; Breton, Sylvie

    2011-07-01

    Luminal acidification in the epididymis is critical for sperm maturation and storage. Clear cells express the vacuolar H(+)-ATPase (V-ATPase) in their apical membrane and are major contributors to proton secretion. We showed that this process is regulated via recycling of V-ATPase-containing vesicles. We now report that RhoA and its effector ROCKII are enriched in rat epididymal clear cells. In addition, cortical F-actin was detected beneath the apical membrane and along the lateral membrane of "resting" clear cells using a pan-actin antibody or phalloidin-TRITC. In vivo luminal perfusion of the cauda epididymal tubule with the ROCK inhibitors Y27632 (10-30 μM) and HA1077 (30 μM) or with the cell-permeable Rho inhibitor Clostridium botulinum C3 transferase (3.75 μg/ml) induced the apical membrane accumulation of V-ATPase and extension of V-ATPase-labeled microvilli in clear cells. However, these newly formed microvilli were devoid of ROCKII. In addition, Y27632 (30 μM) or HA1077 (30 μM) decreased the ratio of F-actin to G-actin detected by Western blot analysis in epididymal epithelial cells, and Y27632 also decreased the ratio of F-actin to G-actin in clear cells isolated by fluorescence activated cell sorting from B1-enhanced green fluorescence protein (EGFP) transgenic mice. These results provide evidence that depolymerization of the cortical actin cytoskeleton via inhibition of RhoA or its effector ROCKII favors the recruitment of V-ATPase from the cytosolic compartment into the apical membrane in clear cells. In addition, our data suggest that the RhoA-ROCKII pathway is not locally involved in the elongation of apical microvilli. We propose that inhibition of RhoA-ROCKII might be part of the intracellular signaling cascade that is triggered upon agonist-induced apical membrane V-ATPase accumulation.

  3. SNOW CLEARING

    CERN Multimedia

    Groupe de Transport/Transport Group

    1999-01-01

    In order to facilitate snow-clearing operations, which commence at 4.30 every morning, drivers of CERN vehicles are kindly requested to group their cars together in the car parks. This will greatly help us in our work. Thank you for your co-operation.Transport Group / ST-HMTel. 72202

  4. Canine small clear cell/T-zone lymphoma: clinical presentation and outcome in a retrospective case series.

    Science.gov (United States)

    Martini, V; Marconato, L; Poggi, A; Riondato, F; Aresu, L; Cozzi, M; Comazzi, S

    2016-08-01

    Published studies, taken together, suggest the existence of a single canine lymphoma entity, with a small clear cell appearance by cytological evaluation, a histopathological T-zone pattern and an aberrant CD45-negative T-cell phenotype, mostly characterized by long-term survival. We describe clinical presentation and outcome in a retrospective case series of canine small clear cell/T-zone lymphoma. Despite the reported predisposition of Golden retriever, this breed was not represented in our case series. Most dogs presented with stage V disease, whereas only few had clinical signs or peripheral cytopenias. Blood was almost always more infiltrated than bone marrow. Median survival confirmed the favourable prognosis described in literature, but a few dogs died within a short time. Also, a subgroup of dogs developed second malignancies, eventually leading to death. We did not investigate possible prognostic factors because of the wide variety in treatments, and further studies are needed to identify high-risk animals.

  5. Profiling microRNA from nephrectomy and biopsy specimens: predictors of progression and survival in clear cell renal cell carcinoma.

    Science.gov (United States)

    Kowalik, Casey G; Palmer, Drew A; Sullivan, Travis B; Teebagy, Patrick A; Dugan, John M; Libertino, John A; Burks, Eric J; Canes, David; Rieger-Christ, Kimberly M

    2017-09-01

    To identify microRNA (miRNA) characteristic of metastatic clear cell renal cell carcinoma (ccRCC) and those indicative of cancer-specific survival (CSS) in nephrectomy and biopsy specimens. We also sought to determine if a miRNA panel could differentiate benign from ccRCC tissue. RNA was isolated from nephrectomy and kidney biopsy specimens (n = 156 and n = 46, respectively). Samples were grouped: benign, non-progressive, and progressive ccRCC. MiRNAs were profiled by microarray and validated by quantitative reverse transcription-polymerase chain reaction. Biomarker signatures were developed to predict cancer status in nephrectomy and biopsy specimens. CSS was examined using Kaplan-Meier and Cox proportional hazards analyses. Microarray analysis revealed 20 differentially expressed miRNAs comparing non-progressive with progressive tumours. A biomarker signature validated in nephrectomy specimens had a sensitivity of 86.7% and a specificity of 92.9% for differentiating benign and ccRCC specimens. A second signature differentiated non-progressive vs progressive ccRCC with a sensitivity of 93.8% and a specificity of 83.3%. These biomarkers also discriminated cancer status in biopsy specimens. Levels of miR-10a-5p, -10b-5p, and -223-3p were associated with CSS. This study identified miRNAs differentially expressed in ccRCC samples; as well as those correlating with CSS. Biomarkers identified in this study have the potential to identify patients who are likely to have progressive ccRCC, and although preliminary, these results may aid in differentiating aggressive and indolent ccRCC based on biopsy specimens. © 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.

  6. Differing von Hippel Lindau genotype in paired primary and metastatic tumors in patients with clear cell renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Susan A.J. Vaziri

    2012-05-01

    Full Text Available In sporadic clear cell renal cell carcinoma (CCRCC, the von Hippel Lindau (VHL gene is inactivated by mutation or methylation in the majority of primary (P tumors. Due to differing effects of wild-type (WT and mutant (MT VHL gene on downstream signaling pathways regulating angiogenesis, VHL gene status could impact clinical outcome. In CCRCC, comparative genomic hybridization (CGH analysis studies have reported genetic differences between paired P and metastatic (M tumors. We thus sequenced the VHL gene in paired tumor specimens from 10 patients to determine a possible clonal relationship between the P tumor and M lesion(s in patients with CCRCC. Using paraffin embedded specimens, genomic DNA from microdissected samples (>80% tumor of paired P tumor and M lesions from all 10 patients, as well as in normal tissue from 6 of these cases, was analyzed. The DNA was used for PCR-based amplification of each of the 3 exons of the VHL gene. Sequences derived from amplified samples were compared to the wild-type VHL gene sequence (GeneBank Accession No. AF010238. Methylation status of the VHL gene was determined using VHL methylation-specific PCR primers after DNA bisulfite modification. In 4/10 (40% patients the VHL gene status differed between the P tumor and the M lesion. As expected, when the VHL gene was mutated in both the P tumor and M lesion, the mutation was identical. Further, while the VHL genotype differed between the primary tumor in different kidneys or multiple metastatic lesions in the same patient, the VHL germline genotype in the normal adjacent tissue was always wild-type irrespective of the VHL gene status in the P tumor. These results demonstrate for the first time that the VHL gene status can be different between paired primary and metastatic tissue in patients with CCRCC.

  7. VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma.

    Science.gov (United States)

    Lessi, Francesca; Mazzanti, Chiara Maria; Tomei, Sara; Di Cristofano, Claudio; Minervini, Andrea; Menicagli, Michele; Apollo, Alessandro; Masieri, Lorenzo; Collecchi, Paola; Minervini, Riccardo; Carini, Marco; Bevilacqua, Generoso

    2014-03-01

    Von Hipple-Lindau gene (VHL) inactivation represents the most frequent abnormality in clear cell renal cell carcinoma (ccRCC). Hypoxia-inducible factor-1α (HIF-1α) expression is regulated by O2 level. In normal O2 conditions, VHL binds HIF-1α and allows HIF-1α proteasomal degradation. A single-nucleotide polymorphism (SNP) has been found located in the oxygen-dependent degradation domain at codon 582 (C1772T, rs11549465, Pro582Ser). In hypoxia, VHL/HIF-1α interaction is abolished and HIF-1α activates target genes in the nucleus. This study analyzes the impact of genetic alterations and protein expression of VHL and the C1772T SNP of HIF-1α gene (HIF-1α) on prognosis in early-stage ccRCC (pT1a, pT1b, and pT2). Mutational analysis of the entire VHL sequence and the genotyping of HIF-1α C1772T SNP were performed together with VHL promoter methylation analysis and loss of heterozygosis (LOH) analysis at (3p25) locus. Data obtained were correlated with VHL and HIF-1α protein expression and with tumor-specific survival (TSS). VHL mutations, methylation status, and LOH were detected in 51, 11, and 12% of cases, respectively. Our results support the association between biallelic alterations and/or VHL silencing with a worse TSS. Moreover, we found a significant association between the HIF-1α C1772C genotype and a worse TSS. The same association was found when testing the presence of HIF-1α protein in the nucleus. Our results highlight the role of VHL/HIF-1α pathway in RCC and support the molecular heterogeneity of early-stage ccRCC. More important, we show the involvement of HIF-1α C1772T SNP in ccRCC progression.

  8. CLINICAL VALUE OF THE MARKERS OF PROLIFERATION AND APOPTOSIS IN PATIENTS WITH CLEAR CELL RENAL CELL CARCINOMA

    Directory of Open Access Journals (Sweden)

    N. A. Gorban

    2014-07-01

    Full Text Available Renal cell carcinoma (RCC is a heterogeneous disease in which the patients survive for months to years. At the present time the prognostic models have no sufficient information or exact prognostic value. Cell proliferation and apoptosis play a key role in cell cycle regulation; and impairment in these processes is commonly detected in different human tumors. The investigation enrolled 76 patients (49 men, 27 women aged 32 to 73 years (mean age 56 ± 7.6 years diagnosed with RCC. The follow-up was 8 to 116 months (mean 36.5 months. All the patients underwent nephrectomy; antibodies against р53, Bcl-2, and Ki-67 were investigated by immunohistochemistry. The expression of p53 and none or reduced expression of Bcl-2 are poor prognostic factors and associated with the metastatic potential of a tumor and with low relapse-free survival. High Ki-67 levels are a risk factor for metastases. A combination of p53 expression and high proliferative activity reflects the aggressive potential of a tumor and suggests the high risk of metastases just at the disease diagnosis and early tumor dissemination. 

  9. Introduction: characterization and functions of human T regulatory cells.

    Science.gov (United States)

    Romagnani, Sergio

    2005-06-01

    The field of human T regulatory (Treg) cells is a rapidly progressing, but still confused field of immunology. The effects of dendritic cell (DC) manipulation in Treg generation and the main features of human "natural" Treg cells, as well as of different populations of adaptive Treg subsets, are still partially unclear. However, it is clear that Treg cells play an important role in human diseases, such as autoimmune disorders, allergy, HIV infection, tumors and graft-versus-host disease.

  10. Renal cell tumors with clear cell histology and intact VHL and chromosome 3p: a histological review of tumors from the Cancer Genome Atlas database.

    Science.gov (United States)

    Favazza, Laura; Chitale, Dhananjay A; Barod, Ravi; Rogers, Craig G; Kalyana-Sundaram, Shanker; Palanisamy, Nallasivam; Gupta, Nilesh S; Williamson, Sean R

    2017-07-21

    Clear cell renal cell carcinoma is by far the most common form of kidney cancer; however, a number of histologically similar tumors are now recognized and considered distinct entities. The Cancer Genome Atlas published data set was queried (http://cbioportal.org) for clear cell renal cell carcinoma tumors lacking VHL gene mutation and chromosome 3p loss, for which whole-slide images were reviewed. Of the 418 tumors in the published Cancer Genome Atlas clear cell renal cell carcinoma database, 387 had VHL mutation, copy number loss for chromosome 3p, or both (93%). Of the remaining, 27/31 had whole-slide images for review. One had 3p loss based on karyotype but not sequencing, and three demonstrated VHL promoter hypermethylation. Nine could be reclassified as distinct or emerging entities: translocation renal cell carcinoma (n=3), TCEB1 mutant renal cell carcinoma (n=3), papillary renal cell carcinoma (n=2), and clear cell papillary renal cell carcinoma (n=1). Of the remaining, 6 had other clear cell renal cell carcinoma-associated gene alterations (PBRM1, SMARCA4, BAP1, SETD2), leaving 11 specimens, including 2 high-grade or sarcomatoid renal cell carcinomas and 2 with prominent fibromuscular stroma (not TCEB1 mutant). One of the remaining tumors exhibited gain of chromosome 7 but lacked histological features of papillary renal cell carcinoma. Two tumors previously reported to harbor TFE3 gene fusions also exhibited VHL mutation, chromosome 3p loss, and morphology indistinguishable from clear cell renal cell carcinoma, the significance of which is uncertain. In summary, almost all clear cell renal cell carcinomas harbor VHL mutation, 3p copy number loss, or both. Of tumors with clear cell histology that lack these alterations, a subset can now be reclassified as other entities. Further study will determine whether additional entities exist, based on distinct genetic pathways that may have implications for treatment.Modern Pathology advance online publication, 21

  11. Cell encoding recombinant human erythropoietin

    Energy Technology Data Exchange (ETDEWEB)

    Beck, A.K.; Withy, R.M.; Zabrecky, J.R.; Masiello, N.C.

    1990-09-04

    This patent describes a C127 cell transformed with a recombinant DNA vector. It comprises: a DNA sequence encoding human erythropoietin, the transformed cell being capable of producing N-linked and O-linked glycosylated human erythropoietin.

  12. Hemangioblastoma and renal clear cell carcinoma distinguished by means of the AgNOR method.

    Science.gov (United States)

    Crocker, J; Carey, M P; Allcock, R

    1990-04-01

    In view of the difficulty encountered in distinguishing between 2 degrees renal cell carcinoma (RCC) and hemangioblastoma (HBl) in the central nervous system, the AgNOR technique has been applied empirically to a series of 16 specimens of HBl, 5 primary RCC, and 6 specimens of secondary RCC in the CNS. To avoid tautology, the nature of these was confirmed by immunostaining for epithelial membrane antigen (EMA) and factor VIII-related antigen (FVII RAg). It was found that mean nuclear AgNOR counts in the stromal and endothelial cells of HBl exceeded significantly the counts in the tumor and endothelial cells of RCC, with no overlap in values. It is suggested that the AgNOR method is a useful adjunct in achieving the differential diagnosis of HBl and RCC in the nervous system.

  13. Analyses of Potential Predictive Markers and Response to Targeted Therapy in Patients with Advanced Clear-cell Renal Cell Carcinoma

    Institute of Scientific and Technical Information of China (English)

    Yan Song; Jing Huang; Ling Shan; Hong-Tu Zhang

    2015-01-01

    Background:Vascular endothelial growth factor-targeted agents are standard treatments in advanced clear-cell renal cell carcinoma (ccRCC),but biomarkers of activity are lacking.The aim of this study was to investigate the association of Von Hippel-Lindau (VHL) gene status,vascular endothelial growth factor receptor (VEGFR) or stem cell factor receptor (KIT) expression,and their relationships with characteristics and clinical outcome of advanced ccRCC.Methods:A total of 59 patients who received targeted treatment with sunitinib or pazopanib were evaluated for determination at Cancer Hospital and Institute,Chinese Academy of Medical Sciences between January 2010 and November 2012.Paraffin-embedded tumor samples were collected and status of the VHL gene and expression of VEGFR and KIT were determined by VHL sequence analysis and immunohistochemistry.Clinical-pathological features were collected and efficacy such as response rate and Median progression-free survival (PFS) and ovcrall survival (OS) were calculated and then compared based on expression status.The Chi-square test,the KaplanMeier method,and the Lon-rank test were used for statistical analyses.Results:Of 59 patients,objective responses were observed in 28 patients (47.5%).The median PFS was 13.8 months and median OS was 39.9 months.There was an improved PFS in patients with the following clinical features:Male gender,number of metastatic sites 2 or less,VEGFR-2 positive or KIT positive.Eleven patients (18.6%) had evidence of VHL mutation,with an objective response rate of 45.5%,which showed no difference with patients with no VHL mutation (47.9%).VHL mutation status did not correlate with either overall response rate (P =0.938) or PFS (P =0.277).The PFS was 17.6 months and 22.2 months in VEGFR-2 positive patients and KIT positive patients,respectively,which was significantly longer than that of VEGFR-2 or KIT negative patients (P =0.026 and P =0.043).Conclusion:VHL mutation status could not predict

  14. Analyses of Potential Predictive Markers and Response to Targeted Therapy in Patients with Advanced Clear-cell Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Yan Song

    2015-01-01

    Full Text Available Background: Vascular endothelial growth factor-targeted agents are standard treatments in advanced clear-cell renal cell carcinoma (ccRCC, but biomarkers of activity are lacking. The aim of this study was to investigate the association of Von Hippel-Lindau (VHL gene status, vascular endothelial growth factor receptor (VEGFR or stem cell factor receptor (KIT expression, and their relationships with characteristics and clinical outcome of advanced ccRCC. Methods: A total of 59 patients who received targeted treatment with sunitinib or pazopanib were evaluated for determination at Cancer Hospital and Institute, Chinese Academy of Medical Sciences between January 2010 and November 2012. Paraffin-embedded tumor samples were collected and status of the VHL gene and expression of VEGFR and KIT were determined by VHL sequence analysis and immunohistochemistry. Clinical-pathological features were collected and efficacy such as response rate and Median progression-free survival (PFS and overall survival (OS were calculated and then compared based on expression status. The Chi-square test, the Kaplan-Meier method, and the Lon-rank test were used for statistical analyses. Results: Of 59 patients, objective responses were observed in 28 patients (47.5%. The median PFS was 13.8 months and median OS was 39.9 months. There was an improved PFS in patients with the following clinical features: Male gender, number of metastatic sites 2 or less, VEGFR-2 positive or KIT positive. Eleven patients (18.6% had evidence of VHL mutation, with an objective response rate of 45.5%, which showed no difference with patients with no VHL mutation (47.9%. VHL mutation status did not correlate with either overall response rate (P = 0.938 or PFS (P = 0.277. The PFS was 17.6 months and 22.2 months in VEGFR-2 positive patients and KIT positive patients, respectively, which was significantly longer than that of VEGFR-2 or KIT negative patients (P = 0.026 and P = 0.043. Conclusion

  15. Imaging and cell count in cleared intact cochlea in the Mongolian gerbil using laser scanning confocal microscopy.

    Science.gov (United States)

    Risoud, M; Sircoglou, J; Dedieu, G; Tardivel, M; Vincent, C; Bonne, N-X

    2017-09-01

    To draw up a clearing protocol for Mongolian gerbil cochlea, and to assess the feasibility of quantifying and analyzing 3D cell architecture in the transparent cochleae. Freshly dissected inner ears were prepared on a 13-day protocol: fixation, microdissection, post-fixation, decalcification, pretreatment (signal enhancement, permeabilization and blocking), fluorescent labeling (indirect immunolabeling and direct labeling), dehydration, clearing in Spalteholz solution (MSBB: methyl salicylate and benzyl benzoate) and mounting. Image acquisition used laser scanning confocal microscopy. ImageJ software was used to measure the length of the organ of Corti thus available for analysis and to count inner and outer hair cells. Four cochleas underwent imaging. 3D reconstruction enabled organ of Corti length to be measured, at a mean 1269±346μm. Mean inner and outer hair-cell count per organ of Corti length was 142±44 and 400±122, respectively. Cochlear clearing by MSBB was feasible in Mongolian gerbils and provided high-resolution immunofluorescence-labeled inner-ear images. To our knowledge, this was the first application of the technique in this species. Cell count could thus be performed along the organ of Corti length without traumatic dissection. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  16. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

    Science.gov (United States)

    Hampras, Shalaka S.; Sucheston-Campbell, Lara E.; Cannioto, Rikki; Chang-Claude, Jenny; Modugno, Francesmary; Dörk, Thilo; Hillemanns, Peter; Preus, Leah; Knutson, Keith L.; Wallace, Paul K.; Hong, Chi-Chen; Friel, Grace; Davis, Warren; Nesline, Mary; Pearce, Celeste L.; Kelemen, Linda E.; Goodman, Marc T.; Bandera, Elisa V.; Terry, Kathryn L.; Schoof, Nils; Eng, Kevin H.; Clay, Alyssa; Singh, Prashant K.; Joseph, Janine M.; Aben, Katja K.H.; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bean, Yukie; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Cook, Linda S.; Cramer, Daniel W.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Despierre, Evelyn; Dicks, Ed; Doherty, Jennifer A.; du Bois, Andreas; Dürst, Matthias; Easton, Doug; Eccles, Diana; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Gronwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hogdall, Claus; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Klapdor, Rüdiger; Kolomeyevskaya, Nonna; Krakstad, Camilla; Kjaer, Susanne K.; Kruszka, Bridget; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashikant; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Liu, Song; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valeria; McLaughlin, John R.; McNeish, Ian; Menon, Usha; Moes-Sosnowska, Joanna; Narod, Steven A.; Nedergaard, Lotte; Nevanlinna, Heli; Nickels, Stefan; Olson, Sara H.; Orlow, Irene; Weber, Rachel Palmieri; Paul, James; Pejovic, Tanja; Pelttari, Liisa M.; Perkins, Barbara; Permuth-Wey, Jenny; Pike, Malcolm C.; Plisiecka-Halasa, Joanna; Poole, Elizabeth M.; Risch, Harvey A.; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schernhammer, Eva; Schmitt, Kristina; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Tangen, Ingvild L.; Teo, Soo-Hwang; Thompson, Pamela J.; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S.; Tyrer, Jonathan; van Altena, Anna M.; Vergote, Ignace; Vierkant, Robert A.; Walsh, Christine; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wu, Anna H.; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Gayther, Simon A.; Ramus, Susan J.; Sellers, Thomas A.; Schildkraut, Joellen M.; Phelan, Catherine M.; Berchuck, Andrew; Chenevix-Trench, Georgia; Cunningham, Julie M.; Pharoah, Paul P.; Ness, Roberta B.; Odunsi, Kunle; Goode, Ellen L.; Moysich, Kirsten B.

    2016-01-01

    Background Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with (p = 0.001) and clear cell EOC. Gene associations with histotypes at< 0.05 included:(p = 0.005 and = 0.008, serous and high-grade serous, respectively), (p = 0.035, endometrioid and mucinous), (p = 0.03, mucinous), (p = 0.022, clear cell), (p = 0.021 endometrioid) and (p = 0.017 and = 0.025, endometrioid and mucinous, respectively). Conclusions Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients. PMID:27533245

  17. Clear Cell Atypical Fibroxanthoma: Clinicopathological Study of 6 Cases and Review of the Literature With Special Emphasis on the Differential Diagnosis.

    Science.gov (United States)

    Tardío, Juan C; Pinedo, Fernando; Aramburu, José Antonio; Martínez-González, Miguel Á; Arias, Dolores; Khedaoui, Radia; Suárez-Massa, Dolores; Santonja, Carlos

    2016-08-01

    Atypical fibroxanthoma (AFX) is an uncommon dermal-based neoplasm arising on the sun-damaged skin of elderly people. Clear cell AFX is a rare variant with only 12 cases reported until the present date, all of them as case reports, except for 1 small series of 3 cases. The authors report 6 new cases and review the literature with special emphasis on the differential diagnosis. The clear cell variant represents 5% of AFX from their files. Histopathologically, it consists of sheets of epithelioid, pleomorphic cells, intermixed with a varying number of giant multinucleated and spindle cells, the latter arranged in a fascicular pattern. All cell types predominantly exhibit a clear, microvacuolated cytoplasm with well-demarcated cell borders. The clinical and immunohistochemical features of this variant are similar to those of the classic type. Clear cell AFX must be differentiated from other cutaneous clear cell neoplasms, some of them with an aggressive clinical behavior, including clear cell melanoma, primary cutaneous and metastatic clear cell carcinomas, clear cell sarcoma, pleomorphic liposarcoma, tumor of perivascular epithelioid cells, and distinctive dermal clear cell mesenchymal neoplasm. The clinical presentation and immunohistochemical profile play a key role in the differential diagnosis.

  18. Proteotranscriptomic Analysis Reveals Stage Specific Changes in the Molecular Landscape of Clear-Cell Renal Cell Carcinoma.

    Directory of Open Access Journals (Sweden)

    Benjamin A Neely

    Full Text Available Renal cell carcinoma comprises 2 to 3% of malignancies in adults with the most prevalent subtype being clear-cell RCC (ccRCC. This type of cancer is well characterized at the genomic and transcriptomic level and is associated with a loss of VHL that results in stabilization of HIF1. The current study focused on evaluating ccRCC stage dependent changes at the proteome level to provide insight into the molecular pathogenesis of ccRCC progression. To accomplish this, label-free proteomics was used to characterize matched tumor and normal-adjacent tissues from 84 patients with stage I to IV ccRCC. Using pooled samples 1551 proteins were identified, of which 290 were differentially abundant, while 783 proteins were identified using individual samples, with 344 being differentially abundant. These 344 differentially abundant proteins were enriched in metabolic pathways and further examination revealed metabolic dysfunction consistent with the Warburg effect. Additionally, the protein data indicated activation of ESRRA and ESRRG, and HIF1A, as well as inhibition of FOXA1, MAPK1 and WISP2. A subset analysis of complementary gene expression array data on 47 pairs of these same tissues indicated similar upstream changes, such as increased HIF1A activation with stage, though ESRRA and ESRRG activation and FOXA1 inhibition were not predicted from the transcriptomic data. The activation of ESRRA and ESRRG implied that HIF2A may also be activated during later stages of ccRCC, which was confirmed in the transcriptional analysis. This combined analysis highlights the importance of HIF1A and HIF2A in developing the ccRCC molecular phenotype as well as the potential involvement of ESRRA and ESRRG in driving these changes. In addition, cofilin-1, profilin-1, nicotinamide N-methyltransferase, and fructose-bisphosphate aldolase A were identified as candidate markers of late stage ccRCC. Utilization of data collected from heterogeneous biological domains strengthened

  19. Proteotranscriptomic Analysis Reveals Stage Specific Changes in the Molecular Landscape of Clear-Cell Renal Cell Carcinoma.

    Science.gov (United States)

    Neely, Benjamin A; Wilkins, Christopher E; Marlow, Laura A; Malyarenko, Dariya; Kim, Yunee; Ignatchenko, Alexandr; Sasinowska, Heather; Sasinowski, Maciek; Nyalwidhe, Julius O; Kislinger, Thomas; Copland, John A; Drake, Richard R

    2016-01-01

    Renal cell carcinoma comprises 2 to 3% of malignancies in adults with the most prevalent subtype being clear-cell RCC (ccRCC). This type of cancer is well characterized at the genomic and transcriptomic level and is associated with a loss of VHL that results in stabilization of HIF1. The current study focused on evaluating ccRCC stage dependent changes at the proteome level to provide insight into the molecular pathogenesis of ccRCC progression. To accomplish this, label-free proteomics was used to characterize matched tumor and normal-adjacent tissues from 84 patients with stage I to IV ccRCC. Using pooled samples 1551 proteins were identified, of which 290 were differentially abundant, while 783 proteins were identified using individual samples, with 344 being differentially abundant. These 344 differentially abundant proteins were enriched in metabolic pathways and further examination revealed metabolic dysfunction consistent with the Warburg effect. Additionally, the protein data indicated activation of ESRRA and ESRRG, and HIF1A, as well as inhibition of FOXA1, MAPK1 and WISP2. A subset analysis of complementary gene expression array data on 47 pairs of these same tissues indicated similar upstream changes, such as increased HIF1A activation with stage, though ESRRA and ESRRG activation and FOXA1 inhibition were not predicted from the transcriptomic data. The activation of ESRRA and ESRRG implied that HIF2A may also be activated during later stages of ccRCC, which was confirmed in the transcriptional analysis. This combined analysis highlights the importance of HIF1A and HIF2A in developing the ccRCC molecular phenotype as well as the potential involvement of ESRRA and ESRRG in driving these changes. In addition, cofilin-1, profilin-1, nicotinamide N-methyltransferase, and fructose-bisphosphate aldolase A were identified as candidate markers of late stage ccRCC. Utilization of data collected from heterogeneous biological domains strengthened the findings from

  20. Stratification of clear cell renal cell carcinoma (ccRCC) genomes by gene-directed copy number alteration (CNA) analysis.

    Science.gov (United States)

    Thiesen, H-J; Steinbeck, F; Maruschke, M; Koczan, D; Ziems, B; Hakenberg, O W

    2017-01-01

    Tumorigenic processes are understood to be driven by epi-/genetic and genomic alterations from single point mutations to chromosomal alterations such as insertions and deletions of nucleotides up to gains and losses of large chromosomal fragments including products of chromosomal rearrangements e.g. fusion genes and proteins. Overall comparisons of copy number alterations (CNAs) presented in 48 clear cell renal cell carcinoma (ccRCC) genomes resulted in ratios of gene losses versus gene gains between 26 ccRCC Fuhrman malignancy grades G1 (ratio 1.25) and 20 G3 (ratio 0.58). Gene losses and gains of 15762 CNA genes were mapped to 795 chromosomal cytoband loci including 280 KEGG pathways. CNAs were classified according to their contribution to Fuhrman tumour gradings G1 and G3. Gene gains and losses turned out to be highly structured processes in ccRCC genomes enabling the subclassification and stratification of ccRCC tumours in a genome-wide manner. CNAs of ccRCC seem to start with common tumour related gene losses flanked by CNAs specifying Fuhrman grade G1 losses and CNA gains favouring grade G3 tumours. The appearance of recurrent CNA signatures implies the presence of causal mechanisms most likely implicated in the pathogenesis and disease-outcome of ccRCC tumours distinguishing lower from higher malignant tumours. The diagnostic quality of initial 201 genes (108 genes supporting G1 and 93 genes G3 phenotypes) has been successfully validated on published Swiss data (GSE19949) leading to a restricted CNA gene set of 171 CNA genes of which 85 genes favour Fuhrman grade G1 and 86 genes Fuhrman grade G3. Regarding these gene sets overall survival decreased with the number of G3 related gene losses plus G3 related gene gains. CNA gene sets presented define an entry to a gene-directed and pathway-related functional understanding of ongoing copy number alterations within and between individual ccRCC tumours leading to CNA genes of prognostic and predictive value.

  1. Analysis and interpretation of transcriptomic data obtained from extended Warburg effect genes in patients with clear cell renal cell carcinoma

    Science.gov (United States)

    Sanders, Edward; Diehl, Svenja

    2015-01-01

    Background Many cancers adopt a metabolism that is characterized by the well-known Warburg effect (aerobic glycolysis). Recently, numerous attempts have been made to treat cancer by targeting one or more gene products involved in this pathway without notable success. This work outlines a transcriptomic approach to identify genes that are highly perturbed in clear cell renal cell carcinoma (CCRCC). Methods We developed a model of the extended Warburg effect and outlined the model using Cytoscape. Following this, gene expression fold changes (FCs) for tumor and adjacent normal tissue from patients with CCRCC (GSE6344) were mapped on to the network. Gene expression values with FCs of greater than two were considered as potential targets for treatment of CCRCC. Results The Cytoscape network includes glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP), the TCA cycle, the serine/glycine pathway, and partial glutaminolysis and fatty acid synthesis pathways. Gene expression FCs for nine of the 10 CCRCC patients in the GSE6344 data set were consistent with a shift to aerobic glycolysis. Genes involved in glycolysis and the synthesis and transport of lactate were over-expressed, as was the gene that codes for the kinase that inhibits the conversion of pyruvate to acetyl-CoA. Interestingly, genes that code for unique proteins involved in gluconeogenesis were strongly under-expressed as was also the case for the serine/glycine pathway. These latter two results suggest that the role attributed to the M2 isoform of pyruvate kinase (PKM2), frequently the principal isoform of PK present in cancer: i.e. causing a buildup of glucose metabolites that are shunted into branch pathways for synthesis of key biomolecules, may not be operative in CCRCC. The fact that there was no increase in the expression FC of any gene in the PPP is consistent with this hypothesis. Literature protein data generally support the transcriptomic findings. Conclusions A number of key genes have

  2. Mural nodules of clear cell carcinoma in a mucinous borderline tumor of the ovary: a case report.

    Science.gov (United States)

    Allende, Daniela S; Drake, Richard D; Chen, Longwen

    2010-04-13

    Mural nodules of ovarian mucinous borderline tumors are rare. In this study, we report a case of mural nodules of clear cell carcinoma in an intestinal type mucinous borderline tumor of the ovary. The patient was a 54-years-old woman presented with back and pelvic pain for 3 months. A right-sided multiloculated ovarian mass approximately 20 cm was identified on the CT scan. CA-125 was moderately elevated. She underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and bilateral pelvic and para-aortic lymphadenectomy. Grossly, the right ovarian mass showed a multiloculated cystic mass with mucinous fluid. There were papillations in the internal surface and two mural nodules were seen. Microscopic examination revealed that the cystic mass was an intestinal type borderline mucinous tumor. The mural nodules showed a classic histology of clear cell carcinoma with tubulocystic and papillary growth patterns. This is an extremely rare case of mural nodules of clear cell carcinoma arising in a mucinous borderline tumor.

  3. Case of clear-cell hepatocellular carcinoma that developed in the normal liver of a middle-aged woman

    Institute of Scientific and Technical Information of China (English)

    Atsushi Takahashi; Hiromasa Ohira; Hironobu Saito; Yukiko Kanno; Kazumichi Abe; Junko Yokokawa; Atsushi Irisawa; Akira Kenjo; Takuro Saito; Mitsukazu Gotoh

    2008-01-01

    A 36-year-old woman was admitted to our department for close examination of a liver tumor that was found during a medical checkup. Abdominal US, CT and MRI showed a tumor in segment 7 (S7) of the liver. Although imaging suggested hepatocellular carcinoma, laboratory tests showed no abnormality in liver function, hepatitis virus markers were negative, and tumor markers including protein induced by vitamin K absence or antagonist Ⅱ (PIVKA-Ⅱ), a-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA)were all within normal ranges. Upon aspiration biopsy of the liver, the histopathological diagnosis was moderately differentiated hepatocellular carcinoma. Therefore, right hepatectomy was performed. Although a part of the tumor was necrotic, about 60% of the viable part showed a clear-cell variant. Consequently, it was diagnosed as clear-cell hepatocellular carcinoma. It was noted that the background liver tissue was normal. This case is worthy of reporting because development of clear-cell hepatocellular carcinoma in the normal liver of a middle-aged woman is rarely seen.

  4. Adenocarcinoma of the rete testis with prominent papillary structure and clear neoplastic cells: Morphologic and immunohistochemical findings and differential diagnosis

    Directory of Open Access Journals (Sweden)

    Pei-Wen Huang

    2015-01-01

    Full Text Available Adenocarcinoma of the rete testis is rare, and its etiology is unknown. The definite diagnosis merely depends on the exclusion of other tumors and histological features. We first describe a 38-year-old man with a carcinoma arising in the rete testis. The tumor was characterized by clear neoplastic cells and branching papillary growth. Focal stromal invasion and transition of normal rete epithelium to neoplastic cells were seen. The neoplastic cells were positive for epithelial membrane antigen, Ber-Ep4, vimentin, renal cell carcinoma marker, and CD10, while negative for Wilms′ tumor 1, thyroid transcription factor-1, estrogen receptor, prostate specific antigen, placental alkaline phosphate, CD117, and alpha-1-fetoprotein. According to the above features, we diagnosed this tumor as adenocarcinoma of the rete testis. To our best knowledge, this is the first reported case of adenocarcinoma of the rete testis with prominently papillary structure and clear neoplastic cells. The rarity of adenocarcinoma of the rete testis and the unique features in our case cause diagnostic pitfalls. A complete clinicopathological study and thorough differential diagnosis are crucial for the correct result.

  5. Renal clear cell carcinoma metastasis to salivary glands - a series of 9 cases: clinico-pathological study.

    Science.gov (United States)

    Majewska, H; Skálová, A; Radecka, K; Stodulski, D; Hyrcza, M; Stankiewicz, C; Biernat, W

    2016-03-01

    Metastatic tumors involving salivary glands arising from the non-head and neck area are very rare. Renal cell carcinoma (RCC) is known for its high propensity for metastasis to unusual localizations. RCC metastasis to the maxillofacial area is an uncommon event (16%), but metastasis to salivary glands is extremely rare. We report a series of 9 such cases retrieved from two institutions. The group included 6 females and 3 males. The age at diagnosis ranged from 60 to 97 years (mean 72.6 years). The tumors involved the parotid gland in 7 cases, and the submandibular and small salivary gland of the oral cavity in 1 case each. The size of tumors ranged from 0.4 to 5 cm. Total parotidectomy with selective neck dissection was performed in 4 cases, while superficial parotidectomy was performed in 1 case and simple resection in 3 cases. Histologically, all the tumors were clear cell renal cell carcinomas, and therefore the differential diagnosis mainly included clear cell variants of salivary gland carcinomas. The parotid gland was the initial manifestation of renal malignancy in 4 of the cases, while in the remaining 5 cases a history of RCC had been known. The salivary gland involvement developed from 11 months to 13 years after the time of diagnosis of the primary tumor. In 2 cases it was the first site of dissemination. Pathologists need to maintain a high index of suspicion for the possibility of metastasis when confronted with oncocytic or clear cell neoplasms developing in salivary glands. RCC, although rare, should be included in this differential diagnosis.

  6. Nuclear EGFR characterize still controlled proliferation retained in better differentiated clear cell RCC.

    Science.gov (United States)

    Ahel, J; Dordevic, G; Markic, D; Mozetic, V; Spanjol, J; Grahovac, B; Stifter, S

    2015-08-01

    Renal cell carcinoma (RCC) is the most common solid kidney tumor representing 2-3% of all cancers, with the highest frequency occurring in Western countries. There was a worldwide and European annual increase in incidence of approximately 2% although incidence has been stabilized in last few years. One third of the patients already have metastases in the time of the diagnosis with poor prognosis because RCC are radio and chemoresistant. The prognostic value of EGFR over-expression in RCC is a controversial issue that could be explained by different histological types of study tumors and non-standardized criteria for evaluation of expression. Recent evidences points to a new mode of EGFR signaling pathway in which activated EGFR undergoes nuclear translocalization and then, as transcription factor, mediates gene expression and other cellular events required for highly proliferating activities. According to our observations, the membranous expression of EGFR associates with high nuclear grade and poor differentiated tumors. On the other hand, nuclear EGFR expression was high in low nuclear graded and well differentiated tumors with good prognosis. We hypothesize that this mode of EGFR signaling characterizes still controlled proliferation retained in well differentiated RCC with Furhman nuclear grade I or II.

  7. Clear cell adenocarcinoma of the colon is a unique morphological variant of intestinal carcinoma: Case report with molecular analysis

    Institute of Scientific and Technical Information of China (English)

    Marta Barisella; Andrea Lampis; Federica Perrone; Antonino Carbone

    2008-01-01

    Here we report a new case of clear cell adenocarcinoma (CCA) of the colon in a 54-year-old Caucasian man. Despite of the previous reported cases, the lesion was located in the right colon and was not associated with the conventional adenoma. We performed immunohistochemical and molecular analyses in order to explore whether the CCA had the molecular features generally associated with conventional colorectal carcinoma. The immunohistochemical and molecular analyses showed that the different morphology of CCA does not reflect a distinct biological entity but only an unusual morphological variant of intestinal carcinoma.

  8. Demographic Clinical and Prognostic Factors of Primary Ovarian Adenocarcinomas of Serous and Clear Cell Histology-A Comparative Study

    DEFF Research Database (Denmark)

    Schnack, Tine H; Høgdall, Estrid; Nedergaard, Lotte;

    2016-01-01

    OBJECTIVE: To compare clinical demographic and prognostic factors as well as overall survival in a nationwide cohort of patients diagnosed with ovarian clear cell carcinoma (oCCC) and high grade ovarian serous adenocarcinoma (oSAC) during 2005 to 2013. MATERIALS AND METHODS: Population...... poorer among oCCC than oSAC cases in analyses restricted to stages III and IV (odds ratio, 1.87; 95% confidence interval, 1.35-2.61), whereas no difference between early stage oCCC and oSAC was observed. CONCLUSIONS: The study confirms that demographic features and risk factors differ between oCCC and o...

  9. Integrative genome-wide gene expression profiling of clear cell renal cell carcinoma in Czech Republic and in the United States.

    Directory of Open Access Journals (Sweden)

    Magdalena B Wozniak

    Full Text Available Gene expression microarray and next generation sequencing efforts on conventional, clear cell renal cell carcinoma (ccRCC have been mostly performed in North American and Western European populations, while the highest incidence rates are found in Central/Eastern Europe. We conducted whole-genome expression profiling on 101 pairs of ccRCC tumours and adjacent non-tumour renal tissue from Czech patients recruited within the "K2 Study", using the Illumina HumanHT-12 v4 Expression BeadChips to explore the molecular variations underlying the biological and clinical heterogeneity of this cancer. Differential expression analysis identified 1650 significant probes (fold change ≥2 and false discovery rate <0.05 mapping to 630 up- and 720 down-regulated unique genes. We performed similar statistical analysis on the RNA sequencing data of 65 ccRCC cases from the Cancer Genome Atlas (TCGA project and identified 60% (402 of the downregulated and 74% (469 of the upregulated genes found in the K2 series. The biological characterization of the significantly deregulated genes demonstrated involvement of downregulated genes in metabolic and catabolic processes, excretion, oxidation reduction, ion transport and response to chemical stimulus, while simultaneously upregulated genes were associated with immune and inflammatory responses, response to hypoxia, stress, wounding, vasculature development and cell activation. Furthermore, genome-wide DNA methylation analysis of 317 TCGA ccRCC/adjacent non-tumour renal tissue pairs indicated that deregulation of approximately 7% of genes could be explained by epigenetic changes. Finally, survival analysis conducted on 89 K2 and 464 TCGA cases identified 8 genes associated with differential prognostic outcomes. In conclusion, a large proportion of ccRCC molecular characteristics were common to the two populations and several may have clinical implications when validated further through large clinical cohorts.

  10. CLOSTRIDIUM SPORE ATTACHMENT TO HUMAN CELLS

    Energy Technology Data Exchange (ETDEWEB)

    PANESSA-WARREN,B.; TORTORA,G.; WARREN,J.

    1997-08-10

    This paper uses high resolution scanning electron microscopy (SEM) with a LaB6 gun and the newest commercial field emission guns, to obtain high magnification images of intact clostridial spores throughout the activation/germination/outgrowth process. By high resolution SEM, the clostridial exosporial membrane can be seen to produce numerous delicate projections (following activation), that extend from the exosporial surface to a nutritive substrate (agar), or cell surface when anaerobically incubated in the presence of human cells (embryonic fibroblasts and colon carcinoma cells). Magnifications of 20,000 to 200,000Xs at accelerating voltages low enough to minimize or eliminate specimen damage (1--5 kV) have permitted the entire surface of C.sporogenes and C.difficile endospores to be examined during all stages of germination. The relationships between the spore and the agar or human cell surface were also clearly visible.

  11. Keap1/Nrf2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma.

    Science.gov (United States)

    Fabrizio, Federico Pio; Costantini, Manuela; Copetti, Massimiliano; la Torre, Annamaria; Sparaneo, Angelo; Fontana, Andrea; Poeta, Luana; Gallucci, Michele; Sentinelli, Steno; Graziano, Paolo; Parente, Paola; Pompeo, Vincenzo; De Salvo, Laura; Simone, Giuseppe; Papalia, Rocco; Picardo, Francesco; Balsamo, Teresa; Flammia, Gerardo Paolo; Trombetta, Domenico; Pantalone, Angela; Kok, Klaas; Paranita, Ferronika; Muscarella, Lucia Anna; Fazio, Vito Michele

    2017-01-04

    The Keap1/Nrf2 pathway is a master regulator of the cellular redox state through the induction of several antioxidant defence genes implicated in chemotherapeutic drugs resistance of tumor cells. An increasing body of evidence supports a key role for Keap1/Nrf2 pathway in kidney diseases and renal cell carcinoma (RCC), but data concerning the molecular basis and the clinical effect of its deregulation remain incomplete.Here we present a molecular profiling of the KEAP1 and NFE2L2 genes in five different Renal Cell Carcinoma histotypes by analysing 89 tumor/normal paired tissues (clear cell Renal Carcinoma, ccRCCs; Oncocytomas; Papillary Renal Cell Carcinoma Type 1, PRCC1; Papillary Renal Cell Carcinoma Type 2, PRCC2; and Chromophobe Cell Carcinoma).A tumor-specific DNA methylation of the KEAP1 gene promoter region was found as a specific feature of the ccRCC subtype (18/37, 48.6%) and a direct correlation with mRNA levels was confirmed by in vitro 5-azacytidine treatment. Analysis of an independent data set of 481 ccRCC and 265 PRCC tumors corroborates our results and multivariate analysis reveals a significant correlation among ccRCCs epigenetic KEAP1 silencing and staging, grading and overall survival.Our molecular results show for the the first time the epigenetic silencing of KEAP1 promoter as the leading mechanism for modulation of KEAP1 expression in ccRCCs and corroborate the driver role of Keap1/Nrf2 axis deregulation with potential new function as independent epigenetic prognostic marker in renal cell carcinoma.

  12. Genome engineering in human cells.

    Science.gov (United States)

    Song, Minjung; Kim, Young-Hoon; Kim, Jin-Soo; Kim, Hyongbum

    2014-01-01

    Genome editing in human cells is of great value in research, medicine, and biotechnology. Programmable nucleases including zinc-finger nucleases, transcription activator-like effector nucleases, and RNA-guided engineered nucleases recognize a specific target sequence and make a double-strand break at that site, which can result in gene disruption, gene insertion, gene correction, or chromosomal rearrangements. The target sequence complexities of these programmable nucleases are higher than 3.2 mega base pairs, the size of the haploid human genome. Here, we briefly introduce the structure of the human genome and the characteristics of each programmable nuclease, and review their applications in human cells including pluripotent stem cells. In addition, we discuss various delivery methods for nucleases, programmable nickases, and enrichment of gene-edited human cells, all of which facilitate efficient and precise genome editing in human cells.

  13. Inhibition of endogenous hydrogen sulfide production in clear-cell renal cell carcinoma cell lines and xenografts restricts their growth, survival and angiogenic potential.

    Science.gov (United States)

    Sonke, Eric; Verrydt, Megan; Postenka, Carl O; Pardhan, Siddika; Willie, Chantalle J; Mazzola, Clarisse R; Hammers, Matthew D; Pluth, Michael D; Lobb, Ian; Power, Nicholas E; Chambers, Ann F; Leong, Hon S; Sener, Alp

    2015-09-15

    Clear cell renal cell carcinoma (ccRCC) is characterized by Von Hippel-Lindau (VHL)-deficiency, resulting in pseudohypoxic, angiogenic and glycolytic tumours. Hydrogen sulfide (H2S) is an endogenously-produced gasotransmitter that accumulates under hypoxia and has been shown to be pro-angiogenic and cytoprotective in cancer. It was hypothesized that H2S levels are elevated in VHL-deficient ccRCC, contributing to survival, metabolism and angiogenesis. Using the H2S-specific probe MeRhoAz, it was found that H2S levels were higher in VHL-deficient ccRCC cell lines compared to cells with wild-type VHL. Inhibition of H2S-producing enzymes could reduce the proliferation, metabolism and survival of ccRCC cell lines, as determined by live-cell imaging, XTT/ATP assay, and flow cytometry respectively. Using the chorioallantoic membrane angiogenesis model, it was found that systemic inhibition of endogenous H2S production was able to decrease vascularization of VHL-deficient ccRCC xenografts. Endogenous H2S production is an attractive new target in ccRCC due to its involvement in multiple aspects of disease.

  14. Optical clearing at cellular level

    Science.gov (United States)

    Kinnunen, Matti; Bykov, Alexander V.; Tuorila, Juho; Haapalainen, Tomi; Karmenyan, Artashes V.; Tuchin, Valery V.

    2014-07-01

    Strong light scattering in tissues and blood reduces the usability of many optical techniques. By reducing scattering, optical clearing enables deeper light penetration and improves resolution in several optical imaging applications. We demonstrate the usage of optical tweezers and elastic light scattering to study optical clearing [one of the major mechanisms-matching of refractive indices (RIs)] at the single particle and cell level. We used polystyrene spheres and human red blood cells (RBCs) as samples and glycerol or glucose water solutions as clearing agents. Optical tweezers kept single microspheres and RBCs in place during the measurement of light scattering patterns. The results show that optical clearing reduces the scattering cross section and increases g. Glucose also decreased light scattering from a RBC. Optical clearing affected the anisotropy factor g of 23.25-μm polystyrene spheres, increasing it by 0.5% for an RI change of 2.2% (20% glycerol) and 0.3% for an RI change of 1.1% (13% glucose).

  15. Spectra from 2.5-15 {mu}m of tissue phantom materials, optical clearing agents and ex vivo human skin: implications for depth profiling of human skin

    Energy Technology Data Exchange (ETDEWEB)

    Viator, John A [Beckman Laser Institute, University of California, 1002 Health Sciences Road East, Irvine, CA (United States); Choi, Bernard [Beckman Laser Institute, University of California, 1002 Health Sciences Road East, Irvine, CA (United States); Peavy, George M [Beckman Laser Institute, University of California, 1002 Health Sciences Road East, Irvine, CA (United States); Kimel, Sol [Beckman Laser Institute, University of California, 1002 Health Sciences Road East, Irvine, CA (United States); Nelson, J Stuart [Beckman Laser Institute, University of California, 1002 Health Sciences Road East, Irvine, CA (United States)

    2003-01-21

    Infrared measurements have been used to profile or image biological tissue, including human skin. Usually, analysis of such measurements has assumed that infrared absorption is due to water and collagen. Such an assumption may be reasonable for soft tissue, but introduction of exogenous agents into skin or the measurement of tissue phantoms has raised the question of their infrared absorption spectrum. We used Fourier transform infrared spectroscopy in attenuated total reflection mode to measure the infrared absorption spectra, in the range of 2-15 {mu}m, of water, polyacrylamide, Intralipid, collagen gels, four hyperosmotic clearing agents (glycerol, 1,3-butylene glycol, trimethylolpropane, Topicare{sup TM}), and ex vivo human stratum corneum and dermis. The absorption spectra of the phantom materials were similar to that of water, although additional structure was noted in the range of 6-10 {mu}m. The absorption spectra of the clearing agents were more complex, with molecular absorption bands dominating between 6 and 12 {mu}m. Dermis was similar to water, with collagen structure evident in the 6-10 {mu}m range. Stratum corneum had a significantly lower absorption than dermis due to a lower content of water. These results suggest that the assumption of water-dominated absorption in the 2.5-6 {mu}m range is valid. At longer wavelengths, clearing agent absorption spectra differ significantly from the water spectrum. This spectral information can be used in pulsed photothermal radiometry or utilized in the interpretation of reconstructions in which a constant {mu}{sub ir} is used. In such cases, overestimating {mu}{sub ir} will underestimate chromophore depth and vice versa, although the effect is dependent on actual chromophore depth. (note)

  16. C3H Male Mice with Severe Combined Immunodeficiency Cannot Clear a Urethral Infection with a Human Serovar of Chlamydia trachomatis▿

    Science.gov (United States)

    Pal, Sukumar; Sarcon, Annahita K.; de la Maza, Luis M.

    2009-01-01

    The pathogenesis of an infection of the male genitourinary tract of mice with a human serovar of Chlamydia trachomatis has not been characterized. To establish a new model, we inoculated C3H/HeN (H-2k) mice in the meatus urethra with C. trachomatis serovar D. To determine the 50% infectious dose (ID50), male mice were inoculated with doses ranging from 102 to 106 inclusion-forming units (IFU). The mice were euthanized 10 days post infection (p.i.), and the urethra, bladder, epididimydes, and testes were cultured for Chlamydia. Positive cultures were obtained from the urethra, urinary bladder, and epididimydes, and the ID50 was determined to be 5 × 104 IFU/mouse. Subsequently, to characterize the course of the infection, wild-type (WT) and C3H animals with severe combined immunodeficiency (SCID animals) were inoculated with 106 IFU/mouse (20 times the ID50). In the WT mice, the infection peaked in the second week, and by 42 days p.i., it was cleared. In contrast, most of the SCID mice continued to have positive cultures at 60 days p.i. C. trachomatis-specific antibodies were first detected in WT animals' sera at 21 days p.i. and increased until 42 days p.i. The immunoglobulin G2a (IgG2a) titers were 32-fold higher than those of IgG1, indicative of a Th1-biased immune response. A lymphoproliferative assay using splenocytes showed a significant cell-mediated immune response in the WT mice. As expected, no humoral or cell-mediated immune responses were observed in the SCID animals. In conclusion, inoculation of WT male mice in the meatus urethra with a human serovar of C. trachomatis resulted in a limited infection mainly localized to the lower genitourinary tract. On the other hand, SCID animals could not clear the infection, suggesting that in male mice, the adaptive immune response is necessary to control an infection with a C. trachomatis human serovar. PMID:19805533

  17. Met is the most frequently amplified gene in endometriosis-associated ovarian clear cell adenocarcinoma and correlates with worsened prognosis.

    Directory of Open Access Journals (Sweden)

    Yoriko Yamashita

    Full Text Available Clear cell adenocarcinoma of the ovary (OCC is a chemo-resistant tumor with a relatively poor prognosis and is frequently associated with endometriosis. Although it is assumed that oxidative stress plays some role in the malignant transformation of this tumor, the characteristic molecular events leading to carcinogenesis remain unknown. In this study, an array-based comparative genomic hybridization (CGH analysis revealed Met gene amplification in 4/13 OCC primary tumors and 2/8 OCC cell lines. Amplification of the AKT2 gene, which is a downstream component of the Met/PI3K signaling pathway, was also observed in 5/21 samples by array-based CGH analysis. In one patient, both the Met and AKT2 genes were amplified. These findings were confirmed using fluorescence in situ hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemistry. In total, 73 OCC cases were evaluated using real-time quantitative PCR; 37.0% demonstrated Met gene amplification (>4 copies, and 8.2% had AKT2 amplification. Furthermore, stage 1 and 2 patients with Met gene amplification had significantly worse survival than patients without Met gene amplification (p<0.05. Met knockdown by shRNA resulted in reduced viability of OCC cells with Met amplification due to increased apoptosis and cellular senescence, suggesting that the Met signaling pathway plays an important role in OCC carcinogenesis. Thus, we believe that targeted inhibition of the Met pathway may be a promising treatment for OCC.

  18. An integrated computational approach can classify VHL missense mutations according to risk of clear cell Renal carcinoma

    OpenAIRE

    Gossage, Lucy; Pires, Douglas E.V.; Olivera-Nappa, Álvaro; Asenjo,Juan A.; Bycroft, Mark; Blundell, Tom L.; Eisen, Tim

    2014-01-01

    This is the final published version, also available from the publisher website at at: http://hmg.oxfordjournals.org/content/early/2014/06/26/hmg.ddu321.long Mutations in the von Hippel‐Lindau (VHL) gene are pathogenic in VHL disease, congenital  polycythaemia and clear cell renal carcinoma. pVHL forms a ternary complex with Elongin C  and Elongin B, critical for pVHL stability and function, which interacts with Cullin‐2 and  RING‐box protein 1 to target Hypoxia‐inducible factor fo...

  19. Clear Cell Cancer of the Uterine Corpus: The Association of Clinicopathologic Parameters and Treatment on Disease Progression

    Directory of Open Access Journals (Sweden)

    Joyce Varughese

    2011-01-01

    Full Text Available This paper presents a single-institution experience regarding the clinicopathologic features and treatment strategies used in uterine clear cell cancer (UCC, a rare, aggressive histologic subtype of uterine cancer with poor prognosis and discusses parameters associated with progression-free survival (PFS and overall survival (OS. A retrospective chart review was performed on all patients (=80 diagnosed with UCC and treated between 1994 and 2009 at a single academic institution. Data on demographics, FIGO stage, treatment regimens, and recurrences were collected. Patients with early-stage UCC had an excellent survival regardless of adjuvant therapy. Advanced-stage patients had a worse survival. Vaginal apex brachytherapy was associated with an increased OS (=0.02 but not PFS (=0.10. The use of platinum-based chemotherapy in combination with vaginal apex brachytherapy did not significantly improve survival. Innovative therapies still need to be identified for this uncommon uterine cancer.

  20. Individual Bromodomains of Polybromo-1 Contribute to Chromatin Association and Tumor Suppression in Clear Cell Renal Carcinoma.

    Science.gov (United States)

    Porter, Elizabeth G; Dykhuizen, Emily C

    2017-02-17

    The architecture of chromatin is governed, in part, by ATP-dependent chromatin remodelers. These multiprotein complexes contain targeting domains that recognize post-translational marks on histones. One such targeting domain is the bromodomain (BD), which recognizes acetyl-lysines and recruits proteins to sites of acetylation across the genome. Polybromo1 (PBRM1), a subunit of the Polybromo-associated BRG1- or hBRM-associated factors (PBAF) chromatin remodeler, contains six tandem BDs and is frequently mutated in clear cell renal cell carcinoma (ccRCC). Mutations in the PBRM1 gene often lead to the loss of protein expression; however, missense mutations in PBRM1 have been identified and tend to cluster in the BDs, particularly BD2 and BD4, suggesting that individual BDs are critical for PBRM1 function. To study the role of these six BDs, we inactivated each of the six BDs of PBRM1 and re-expressed these mutants in Caki2 cells (ccRCC cells with the loss of function mutation in PBRM1). Four of the six BDs abrogated PBRM1 tumor suppressor function, gene regulation, and chromatin affinity with the degree of importance correlating strongly to the rate of missense mutations in patients. Furthermore, we identified BD2 as the most critical for PBRM1 and confirmed BD2-mediated association to histone H3 peptides acetylated at lysine 14 (H3K14Ac), validating the importance of this specific acetylation mark for PBRM1 binding. From these data, we conclude that four of the BDs act together to target PBRM1 to sites on chromatin; when a single BD is mutated, PBRM1 no longer controls gene expression properly, leading to increased cell proliferation.

  1. MOLECULAR GENETIC DISORDERS IN THE VHL GENE AND METHYLATION OF SOME SUPPRESSOR GENES IN SPORADIC CLEAR-CELL RENAL CARCINOMAS

    Directory of Open Access Journals (Sweden)

    D. S. Mikhailenko

    2014-07-01

    Full Text Available Renal carcinoma (RC is one of ten most common malignancies in adults and an urgent problem of modern oncology. The purpose of the study was to make a molecular genetic analysis of a number of suppressor genes in RC, which was aimed at searching for and characterizing the potential markers of the disease. Two hundred and nine RC samples were examined, of them there were 192 clear-cell carcinomas. VHL gene mutations were detected by single-strand conformation polymorphism and sequence analyses while the methylation of suppressor genes was by the methylation-sensitive polymerase chain reaction. Somatic VHL mutations were determined in 35.4% of cases of clear-cell RC (CCRC. VHL gene disorders were found in 53.7% of patients with Stage 1, which counts in favor of VHL inactivation in early-stage CCRC. The methylation of the VHL, RASSF1, FHIT, and CDH1 genes was identified in 12, 56, 58.4, and 46.4% of primary tumors, respectively; that of at least one gene was in 84.1% of the samples. The hypermethylation of the RASSF1 gene was associated with late stages (p = 0.015 and the presence of metastases (p = 0.036; that of the CDH1 gene was related to the progression, invasion, and dissemination of primary tumors (p = 0.009, 0.039, and 0.002, respectively. The findings show it possible to use an analysis of abnormalities in the VHL gene and the methylation of the RASSF1 and CDH1 genes to develop a system of molecular genetic markers of RC.

  2. Nuclear factor XIIIa staining (clone AC-1A1 mouse monoclonal) is a sensitive and specific marker to discriminate sebaceous proliferations from other cutaneous clear cell neoplasms.

    Science.gov (United States)

    Uhlenhake, Elizabeth E; Clark, Lindsey N; Smoller, Bruce R; Shalin, Sara C; Gardner, Jerad M

    2016-08-01

    Sebaceous carcinoma is a rare but serious malignancy that may be difficult to diagnose when poorly differentiated. Other epithelial tumors with clear cell change may mimic sebaceous carcinoma. Few useful or specific immunohistochemical markers for sebaceous differentiation are available. Nuclear staining with factor XIIIa (clone AC-1A1) was recently found to be a highly sensitive marker of sebaceous differentiation. We evaluated nuclear factor XIIIa (AC-1A1) staining in sebaceous neoplasms vs. other cutaneous clear cell tumors. We stained 27 sebaceous proliferations: sebaceous hyperplasia (7), sebaceous adenoma (8), sebaceoma (5), sebaceous carcinoma (7). We also stained 67 tumors with clear cell change: basal cell carcinoma (8), squamous cell carcinoma (8), hidradenoma (7), desmoplastic trichilemmoma (2), trichilemmoma (10), trichilemmal carcinoma (3), clear cell acanthoma (9), atypical fibroxanthoma (1), syringoma (8), trichoepithelioma (1), metastatic renal cell carcinoma (2), and nevi with balloon cell change (8). Nuclear factor XIIIa (AC-1A1) staining was present in 100% of sebaceous proliferations; 96% displayed strong staining. Non-sebaceous clear cell tumors were negative or only weakly positive with factor XIIIa (AC-1A1) in 95.5%; only 4.5% showed strong staining. This suggests that strong nuclear factor XIIIa (AC-1A1) staining is a sensitive and specific marker of sebaceous neoplasms vs. other clear cell tumors.

  3. Nuclear localization of the CK2α-subunit correlates with poor prognosis in Clear Cell Renal Cell Carcinoma

    DEFF Research Database (Denmark)

    Rabjerg, Maj; Guerra, Barbara; Oliván-Viguera, Aida

    2017-01-01

    Protein kinase CK2a, one of the two catalytic isoforms of the protein kinase CK2 has been shown to contribute to tumor development, tumor proliferation and suppression of apoptosis in various malignancies. We conducted this study to investigate CK2 expression in different subtypes of Renal Cell C...

  4. The additional utility of apparent diffusion coefficient values of clear-cell renal cell carcinoma for predicting metastasis during clinical staging

    Science.gov (United States)

    Yoshizako, Takeshi; Hisatoshi, Araki; Mori, Hiroshi; Tamaki, Yukihisa; Ishikawa, Noriyoshi; Kitagaki, Hajime

    2017-01-01

    Background The apparent diffusion coefficient (ADC) value is known to be an indicator of tumor activity. The ADC value of high-grade clear-cell renal cell carcinoma (RCC) is significantly lower than that of low-grade clear-cell RCC. Purpose To investigate the utility of ADC values of clear-cell RCC by comparing ADC values between groups with T1a RCC (tumor size ≤ 4 cm) without metastasis and the group with metastasis. Material and Methods A retrospective review was performed on 51 patients with 51 RCCs who underwent 1.5 T magnetic resonance imaging (MRI) for evaluating a renal mass confirmed pathologically to be clear-cell RCC between January 2010 and August 2014. We compared ADC values between group A (T1a RCC without metastasis, T1aN0M0) and group B (RCC with metastasis) using the Mann–Whitney U test. Results The patients were divided into group A (n = 30; tumor size: median, 24.5 mm; range, 8–40 mm; ADC value [×10−3 mm2/s]: median, 1.71; range, 1.23–2.24) and group B (n = 21; tumor size: median, 87.5 mm; range, 18–150 mm; ADC value [×10−3 mm2/s]: median, 1.35; range, 0.91–1.94). The ADC value differed significantly between the two groups. The area under the receiver operating characteristic curve was 0.869. Using the optimum cutoff value (1.552 × 10−3 mm2/s), ADC had a sensitivity of 80.0% and specificity of 81.0%. Conclusion There was a statistically significant difference in the ADC between group A (T1a clear-cell RCC without distant metastasis) and group B (advanced clear-cell RCC with lymph node metastasis or distant metastasis). PMID:28210496

  5. Classification models for clear cell renal carcinoma stage progression, based on tumor RNAseq expression trained supervised machine learning algorithms.

    Science.gov (United States)

    Jagga, Zeenia; Gupta, Dinesh

    2014-01-01

    Clear-cell Renal Cell Carcinoma (ccRCC) is the most- prevalent, chemotherapy resistant and lethal adult kidney cancer. There is a need for novel diagnostic and prognostic biomarkers for ccRCC, due to its heterogeneous molecular profiles and asymptomatic early stage. This study aims to develop classification models to distinguish early stage and late stage of ccRCC based on gene expression profiles. We employed supervised learning algorithms- J48, Random Forest, SMO and Naïve Bayes; with enriched model learning by fast correlation based feature selection to develop classification models trained on sequencing based gene expression data of RNAseq experiments, obtained from The Cancer Genome Atlas. Different models developed in the study were evaluated on the basis of 10 fold cross validations and independent dataset testing. Random Forest based prediction model performed best amongst the models developed in the study, with a sensitivity of 89%, accuracy of 77% and area under Receivers Operating Curve of 0.8. We anticipate that the prioritized subset of 62 genes and prediction models developed in this study will aid experimental oncologists to expedite understanding of the molecular mechanisms of stage progression and discovery of prognostic factors for ccRCC tumors.

  6. Chromosome 3p loss of heterozygosity is associated with a unique metabolic network in clear cell renal carcinoma

    Science.gov (United States)

    Gatto, Francesco; Nookaew, Intawat; Nielsen, Jens

    2014-01-01

    Several common oncogenic pathways have been implicated in the emergence of renowned metabolic features in cancer, which in turn are deemed essential for cancer proliferation and survival. However, the extent to which different cancers coordinate their metabolism to meet these requirements is largely unexplored. Here we show that even in the heterogeneity of metabolic regulation a distinct signature encompassed most cancers. On the other hand, clear cell renal cell carcinoma (ccRCC) strongly deviated in terms of metabolic gene expression changes, showing widespread down-regulation. We observed a metabolic shift that associates differential regulation of enzymes in one-carbon metabolism with high tumor stage and poor clinical outcome. A significant yet limited set of metabolic genes that explained the partial divergence of ccRCC metabolism correlated with loss of von Hippel-Lindau tumor suppressor (VHL) and a potential activation of signal transducer and activator of transcription 1. Further network-dependent analyses revealed unique defects in nucleotide, one-carbon, and glycerophospholipid metabolism at the transcript and protein level, which contrasts findings in other tumors. Notably, this behavior is recapitulated by recurrent loss of heterozygosity in multiple metabolic genes adjacent to VHL. This study therefore shows how loss of heterozygosity, hallmarked by VHL deletion in ccRCC, may uniquely shape tumor metabolism. PMID:24550497

  7. mTOR is a Promising Therapeutic Target Both in Cisplatin-Sensitive and Cisplatin-Resistant Clear Cell Carcinoma of the Ovary

    Science.gov (United States)

    Mabuchi, Seiji; Kawase, Chiaki; Altomare, Deborah A.; Morishige, Kenichirou; Sawada, Kenjiro; Hayashi, Masami; Tsujimoto, Masahiko; Yamoto, Mareo; Klein-Szanto, Andres J.; Schilder, Russell J.; Ohmichi, Masahide; Testa, Joseph R.; Kimura, Tadashi

    2009-01-01

    Translational Relevance Clear cell carcinoma (CCC) of the ovary is a distinctive subtype of epithelial ovarian cancer associated with a poorer sensitivity to platinum-based chemotherapy and a worse prognosis than the more common serous adenocarcinoma (SAC). To improve survival, the development of new treatment strategies that target CCC more effectively is necessary. Our results show that mTOR is more frequently activated in CCCs than in SACs. Our data have relevance for the design of future clinical studies of first-line treatment for patients with CCC of the ovary. Moreover, the finding of increased expression of phospho-mTOR and greater sensitivity to RAD001 in cisplatin-resistant CCC cells than in cisplatin-sensitive cells suggests a novel treatment option for patients with recurrent disease after cisplatin-based first-line chemotherapy. Purpose mTOR (mammalian target of rapamycin) plays a central role in cell proliferation and is regarded as a promising target in cancer therapy including for ovarian cancer. This study aims to examine the role of mTOR as a therapeutic target in clear cell carcinoma (CCC) of the ovary which is regarded as aggressive, chemo-resistant histological subtype. Experimental Design Using tissue microarrays of 98 primary ovarian cancers (52 clear cell carcinomas and 46 serous adenocarcinomas), the expression of phospho-mTOR was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTOR inhibition by RAD001 (everolimus) was examined using 2 pairs of cisplatin-sensitive parental (RMG1 and KOC7C) and cisplatin-resistant human CCC cell lines (RMG1-CR and KOC7C-CR) both in vitro and in vivo. Results Immunohistochemical analysis demonstrated mTOR was more frequently activated in CCCs than in serous adenocarcinomas (86.6% vs 50%). Treatment with RAD001 markedly inhibited the growth of both RMG1 and KOC7C cells both in vitro and in vivo. Increased expression of phospho-mTOR was observed in cisplatin-resistant RMG1-CR and KOC7C

  8. Diffusion inside living human cells

    DEFF Research Database (Denmark)

    Leijnse, N.; Jeon, J. -H.; Loft, Steffen

    2012-01-01

    Naturally occurring lipid granules diffuse in the cytoplasm and can be used as tracers to map out the viscoelastic landscape inside living cells. Using optical trapping and single particle tracking we found that lipid granules exhibit anomalous diffusion inside human umbilical vein endothelial...... cells. For these cells the exact diffusional pattern of a particular granule depends on the physiological state of the cell and on the localization of the granule within the cytoplasm. Granules located close to the actin rich periphery of the cell move less than those located towards to the center...... of the cell or within the nucleus. Also, granules in cells which are stressed by intense laser illumination or which have attached to a surface for a long period of time move in a more restricted fashion than those within healthy cells. For granules diffusing in healthy cells, in regions away from the cell...

  9. Nonbacterial thrombotic endocarditis with embolic cerebral vascular accidents in a patient with advanced, recurrent clear cell carcinoma of the ovary: A case report.

    Science.gov (United States)

    Liang, Lusha W; Perez, Alexander R; Cangemi, Nicholas A; Young, Robert J; Makker, Vicky

    2016-04-01

    •Nonbacterial thrombotic endocarditis can occur in ovarian clear cell carcinoma.•We report on NBTE-associated embolic cerebrovascular infarcts in advanced OCCC.•Further NBTE-associated embolic events can be prevented with anticoagulant therapy.

  10. 18-F fluorodeoxyglucose uptake in positron emission tomography as a pathological grade predictor for renal clear cell carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Noda, Yoshifumi; Goshima, Satoshi; Kondo, Hiroshi; Watanabe, Haruo; Kawada, Hiroshi; Kawai, Nobuyuki; Tanahashi, Yukichi [Gifu University Hospital, Department of Radiology, Gifu (Japan); Kanematsu, Masayuki [Gifu University Hospital, Department of Radiology, Gifu (Japan); Gifu University Hospital, Department of Radiology Services, Gifu (Japan); Suzui, Natsuko [Gifu University Hospital, Department of Pathology, Gifu (Japan); Hirose, Yoshinobu [Osaka Medical College, Department of Pathology, Osaka (Japan); Matsunaga, Kengo [Kizawa Memorial Hospital, Department of Pathology, Minokamo (Japan); Nishibori, Hironori [Kizawa Memorial Hospital, Department of Radiology, Minokamo (Japan); Bae, Kyongtae T. [University of Pittsburgh Medical Center, Department of Radiology, Pittsburgh, PA (United States)

    2015-10-15

    To evaluate the usefulness of Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18-F FDG-PET/CT) in the prediction of Fuhrman pathological grades of renal clear cell carcinoma (cRCC). This retrospective study was approved by our institutional review board, and written informed consent was waived. Thirty-one patients with pathologically proven cRCC underwent 18-F FDG-PET/CT for tumour staging. Maximum standardized uptake value of cRCC (tumour SUV{sub max}) and mean SUV of the liver and spleen (liver and spleen SUV{sub mean}) were measured by two independent observers. Tumour SUV{sub max}, tumour-to-liver SUV ratio, and tumour-to-spleen SUV ratio were correlated with the pathological grades. Logistic analysis demonstrated that only the tumour-to-liver SUV ratio was a significant parameter for differentiating high-grade (Fuhrman grades 3 and 4) tumours from low-grade (Fuhrman grades 1 and 2) tumours (P = 0.007 and 0.010 for observers 1 and 2, respectively). Sensitivity, specificity, and positive and negative predictive values for detecting tumours of Fuhrman grades 3 and 4 were 64, 100, 100, and 77 %, respectively, for observer 1, and 79, 88, 85, and 83 %, respectively, for observer 2. The tumour-to-liver SUV ratio with 18-F FDG-PET/CT appeared to be a valuable imaging biomarker in the prediction of high-grade cRCC. (orig.)

  11. Integrative genome-wide analysis of the determinants of RNA splicing in kidney renal clear cell carcinoma.

    Science.gov (United States)

    Lehmann, Kjong-Van; Kahles, André; Kandoth, Cyriac; Lee, William; Schultz, Nikolaus; Stegle, Oliver; Rätsch, Gunnar

    2015-01-01

    We present a genome-wide analysis of splicing patterns of 282 kidney renal clear cell carcinoma patients in which we integrate data from whole-exome sequencing of tumor and normal samples, RNA-seq and copy number variation. We proposed a scoring mechanism to compare splicing patterns in tumor samples to normal samples in order to rank and detect tumor-specific isoforms that have a potential for new biomarkers. We identified a subset of genes that show introns only observable in tumor but not in normal samples, ENCODE and GEUVADIS samples. In order to improve our understanding of the underlying genetic mechanisms of splicing variation we performed a large-scale association analysis to find links between somatic or germline variants with alternative splicing events. We identified 915 cis- and trans-splicing quantitative trait loci (sQTL) associated with changes in splicing patterns. Some of these sQTL have previously been associated with being susceptibility loci for cancer and other diseases. Our analysis also allowed us to identify the function of several COSMIC variants showing significant association with changes in alternative splicing. This demonstrates the potential significance of variants affecting alternative splicing events and yields insights into the mechanisms related to an array of disease phenotypes.

  12. Increased Nicotinamide Phosphoribosyltransferase and Cystathionine-β-Synthase in Renal Oncocytomas, Renal Urothelial Carcinoma, and Renal Clear Cell Carcinoma.

    Science.gov (United States)

    Shackelford, Rodney E; Abdulsattar, Jehan; Wei, Eric X; Cotelingam, James; Coppola, Domenico; Herrera, Guillermo A

    2017-07-01

    Renal oncocytomas (ROs), and clear cell (RCC) and urothelial carcinomas (UC), are common renal neoplasms. Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step of NAD(+) synthesis and its expression is increased in several tumors. Nampt concomitantly regulates hydrogen sulfide (H2S)-synthesizing enzyme levels, including cystathionine-β-synthase (CBS). We used tissue microarrays to examine Nampt and the H2S-synthesizing enzyme CBS protein levels in benign kidney, RCC, UC and ROs. Compared to benign kidney, all three neoplasms showed increased Nampt and CBS protein levels, with the levels increasing in RCC at higher Fuhrman grades. H2S is known to ameliorate chronic renal failure but, as yet, no role for H2S in renal neoplasia has been demonstrated. Here, we showed, for the first time, that Nampt, CBS and, likely, H2S likely play a role in malignant and benign neoplastic renal disease. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  13. Human stromal (mesenchymal) stem cells

    DEFF Research Database (Denmark)

    Aldahmash, Abdullah; Zaher, Walid; Al-Nbaheen, May

    2012-01-01

    Human stromal (mesenchymal) stem cells (hMSC) represent a group of non-hematopoietic stem cells present in the bone marrow stroma and the stroma of other organs including subcutaneous adipose tissue, placenta, and muscles. They exhibit the characteristics of somatic stem cells of self-renewal and......Human stromal (mesenchymal) stem cells (hMSC) represent a group of non-hematopoietic stem cells present in the bone marrow stroma and the stroma of other organs including subcutaneous adipose tissue, placenta, and muscles. They exhibit the characteristics of somatic stem cells of self...... of clinical applications, e.g., non-healing bone fractures and defects and also non-skeletal degenerative diseases like heart failure. Currently, the numbers of clinical trials that employ MSC are increasing. However, several biological and biotechnological challenges need to be overcome to benefit from...

  14. Evaluation of the efficiency of combination palliative treatment in patients with metastatic clear-cell renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    P. S. Borisov

    2015-01-01

    Full Text Available Background. Experience with combination treatment, i.e. systemic therapy in combination with palliative surgery, in the treatment of metastatic kidney cancer is very rarely described in world literature.Objective: to evaluate the efficiency of combination treatment in combination with palliative cytoreductive surgery and targeted therapy and to define optimal indications for combination treatment.Subjects and methods. Data on 47 patients with metastatic renal cell carcinoma (mRCC who received systemic (targeted therapy in combination or after incomplete cytoreduction (iCR were analyzed in this retrospective study. The proportion of men and women was 72.3 % and 27.7 %, respectively; their ratio was 2.6:1. All the patients (100% underwent surgical treatment as nephrectomy or kidney resection for primary tumor. In the patients who had received radical treatment in different periods, the median relapse-free survival was 25.3 (0-187 months; the mean follow-up duration in the study was 33.2 (27.4–39.0 months. Out of the histological characteristics of a primary tumor, its Fuhrman grade was studied. Prior to initiation of mRCC therapy, Memorial Sloan Kettering Cancer Center (MSKCC prognosis groups were assessed; the patients were divided into good (n = 9 (19.1 %, interim (n = 28 (59.6 %, and bad (n = 10 (21.3 % prognosis groups. Their total somatic status was separately rated using the ECOG scale: 0, (n = 10 (21.3%, 1 (n = 24 (51.1 %, and 2, (n = 13 (27.6 %. The sites of metastases were as follows: the lung (n = 29, bones (n = 18, adrenals (n = 11, recurrence in the removed kidney bed (n = 10, and liver (n = 10. Multiple organ involvements were detected in 22 (46.8 % patients. There were more than 5 metastases in one organ in 18 (40.0 % patients and only 15 (33.3 % were found to have a single focus in one organ. Whether iCR might be used as a separate line treatment was studied. A comparative analysis was made between 2 groups of

  15. Preclinical Investigations of PM01183 (Lurbinectedin as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary.

    Directory of Open Access Journals (Sweden)

    Ryoko Takahashi

    Full Text Available The objective of this study was to evaluate the antitumor effects of lurbinectedin as a single agent or in combination with existing anticancer agents for clear cell carcinoma (CCC of the ovary, which is regarded as an aggressive, chemoresistant, histological subtype.Using human ovarian CCC cell lines, the antitumor effects of lurbinectedin, SN-38, doxorubicin, cisplatin, and paclitaxel as single agents were assessed using the MTS assay. Then, the antitumor effects of combination therapies involving lurbinectedin and 1 of the other 4 agents were evaluated using isobologram analysis to examine whether these combinations displayed synergistic effects. The antitumor activity of each treatment was also examined using cisplatin-resistant and paclitaxel-resistant CCC sublines. Finally, we determined the effects of mTORC1 inhibition on the antitumor activity of lurbinectedin-based chemotherapy.Lurbinectedin exhibited significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. An examination of mouse CCC cell xenografts revealed that lurbinectedin significantly inhibits tumor growth. Among the tested combinations, lurbinectedin plus SN-38 resulted in a significant synergistic effect. This combination also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Everolimus significantly enhanced the antitumor activity of lurbinectedin-based chemotherapies.Lurbinectedin, a new agent that targets active transcription, exhibits antitumor activity in CCC when used as a single agent and has synergistic antitumor effects when combined with irinotecan. Our results indicate that lurbinectedin is a promising agent for treating ovarian CCC, both as a first-line treatment and as a salvage treatment for recurrent lesions that develop after platinum-based or paclitaxel treatment.

  16. Lung Clear “Sugar” Cell Tumor and Jak V617f Positive Essential Thrombocythemia: A simple Coıncıdence?

    Directory of Open Access Journals (Sweden)

    Volkan Yazak

    2013-04-01

    Full Text Available The primary clear cell tumor of the lung is an extremely rare benign tumor, which is called “sugar tumor”, because of the large content of glycogen. Here we are presenting essential thrombocythemia and lung clear cell tumor which was not reported before to the best of our knowledge. A 44 years old woman admitted to the clinic with complaint of lassitude lasting for 2 months. In her physical examination the spleen was 3 cm palpable from the costa arch In laboratory findings number of platelet was 1014000 mm³. A 3.5 cm in diameter pulmonary nodule is detected in right upper lobe in the graphy of the lungs. Subsequently  computed tomography  (CT of thorax was carried out. Due to the benign features in the display of  the detected nodule, a total excision with curative and diagnostic intentions was performed. Microscopically the tumor were composed of nests of rounded or oval cells with distinct cell borders and optically clear cytoplasm. The nuclei were small. Immunohistochemically the tumor cells expressed HMB-45, NSE and focal S100 antigen. It was diagnosed as clear  “sugar” cell tumor. In conclusion, in lung clear cell tumor, it is important to make evaluation in terms of myeloproliferative disease in adults whose thrombocytosis continue after the treatment.

  17. Eruptive dermal clear cell desmo-plastic mesenchymal tumors with perivascular myoid differentiation in a young boy. A clinical, histopathologic, immunohistochemical and electron microscopy study of 17 lesions.

    Science.gov (United States)

    Tomasini, Carlo; Metze, Dieter; Osella-Abate, Simona; Novelli, Mauro; Kutzner, Heinz

    2014-02-01

    Clear cell tumors of the skin are observed in a wide variety of benign and malignant conditions with different histogenesis, sharing the presence of cells with abundant clear cytoplasm. Herein, we report the clinicopathologic features of a healthy young patient affected by asymptomatic, eruptive and disseminated, benign clear cell dermal tumors since early infancy. Neither family history nor genetic testing and counseling provided further useful information. The lesions were mostly confined to the face and lower left extremity with pink teleangiectatic papules and small nodules. Over a 4-year period, a total of 16 different cutaneous lesions were biopsied and histopathologic and immunohistochemical studies carried out; an additional lesion was also removed for electron microscopy examination. Histopathology evidenced multiple perivascular growths of spindle to oval and round cells intermingled with clear/granular cells throughout the dermis, with prominent desmoplasia and numerous capillary-like vessels with focal hemangiopericytoma-like features. Immunohistochemical neoplastic cells were uniformly positive for h-caldesmon and focally smooth muscle α-actin and CD13 indicating myoid differentiation whereas the consistent diffuse cytoplasmic staining for lysosome antigen, such as CD68PG-M1 and NKI/C3 along with the ultrastructural findings supported the view of a lysosome-mediated apoptotic process. The differential diagnosis with other clear cell cutaneous neoplasms is discussed.

  18. c-Myc modulates glucose metabolism via regulation of miR-184/PKM2 pathway in clear-cell renal cell carcinoma.

    Science.gov (United States)

    Huang, Jiwei; Kong, Wen; Zhang, Jin; Chen, Yonghui; Xue, Wei; Liu, Dongming; Huang, Yiran

    2016-10-01

    Renal cell carcinoma (RCC) is one of the most malignant tumors worldwide. Among all subtypes of RCC, clear-cell RCC (ccRCC) is the most common and aggressive one. The difficulty in overcoming resistance of traditional treatment is a threat for ccRCC therapies. Therefore, to understand the mechanism that underlies ccRCC progression is critical for new drug development. In the present study, we identified that miR-184 could be downregulated by c-Myc, which is different from the standard opinion that c-Myc is a target of miR-184. Overexpression of pre-miR-184 changed the metabolic and proliferation features of ccRCC cells by reducing cell glucose consumption, lactate production and cell proliferation. Further analysis by computer bioinformatics revealed that PKM2 is a target of miR-184. Both PKM2 mRNA and protein were significantly affected by addition of miR-184. Importantly, the PKM2 expression level was indeed increased in ccRCC samples, which is totally reverse compared to the decreased miR-184 expression level. Interestingly, we found that when PKM2 was knocked down in ccRCC cells, the rapid proliferation, high glucose consumption and high lactate production were all clearly inhibited, which indicates metabolic reprogramming and cancer progression blocking the in ccRCC cells. Our findings shed new light on ccRCC molecular study and provide a new and solid basis for developing ccRCC therapy.

  19. Radiogenomics of clear cell renal cell carcinoma: preliminary findings of The Cancer Genome Atlas-Renal Cell Carcinoma (TCGA-RCC) Imaging Research Group.

    Science.gov (United States)

    Shinagare, Atul B; Vikram, Raghu; Jaffe, Carl; Akin, Oguz; Kirby, Justin; Huang, Erich; Freymann, John; Sainani, Nisha I; Sadow, Cheryl A; Bathala, Tharakeswara K; Rubin, Daniel L; Oto, Aytekin; Heller, Matthew T; Surabhi, Venkateswar R; Katabathina, Venkat; Silverman, Stuart G

    2015-08-01

    To investigate associations between imaging features and mutational status of clear cell renal cell carcinoma (ccRCC). This multi-institutional, multi-reader study included 103 patients (77 men; median age 59 years, range 34-79) with ccRCC examined with CT in 81 patients, MRI in 19, and both CT and MRI in three; images were downloaded from The Cancer Imaging Archive, an NCI-funded project for genome-mapping and analyses. Imaging features [size (mm), margin (well-defined or ill-defined), composition (solid or cystic), necrosis (for solid tumors: 0%, 1%-33%, 34%-66% or >66%), growth pattern (endophytic, <50% exophytic, or ≥50% exophytic), and calcification (present, absent, or indeterminate)] were reviewed independently by three readers blinded to mutational data. The association of imaging features with mutational status (VHL, BAP1, PBRM1, SETD2, KDM5C, and MUC4) was assessed. Median tumor size was 49 mm (range 14-162 mm), 73 (71%) tumors had well-defined margins, 98 (95%) tumors were solid, 95 (92%) showed presence of necrosis, 46 (45%) had ≥50% exophytic component, and 18 (19.8%) had calcification. VHL (n = 52) and PBRM1 (n = 24) were the most common mutations. BAP1 mutation was associated with ill-defined margin and presence of calcification (p = 0.02 and 0.002, respectively, Pearson's χ (2) test); MUC4 mutation was associated with an exophytic growth pattern (p = 0.002, Mann-Whitney U test). BAP1 mutation was associated with ill-defined tumor margins and presence of calcification; MUC4 mutation was associated with exophytic growth. Given the known prognostic implications of BAP1 and MUC4 mutations, these results support using radiogenomics to aid in prognostication and management.

  20. The Role of Vaginal Brachytherapy in the Treatment of Surgical Stage I Papillary Serous or Clear Cell Endometrial Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Barney, Brandon M., E-mail: barney.brandon@mayo.edu [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Petersen, Ivy A. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Mariani, Andrea; Dowdy, Sean C.; Bakkum-Gamez, Jamie N. [Division of Gynecologic Surgery, Mayo Clinic, Rochester, Minnesota (United States); Haddock, Michael G. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States)

    2013-01-01

    Objectives: The optimal adjuvant therapy for International Federation of Gynecology and Obstetrics (FIGO) stage I papillary serous (UPSC) or clear cell (CC) endometrial cancer is unknown. We report on the largest single-institution experience using adjuvant high-dose-rate vaginal brachytherapy (VBT) for surgically staged women with FIGO stage I UPSC or CC endometrial cancer. Methods and Materials: From 1998-2011, 103 women with FIGO 2009 stage I UPSC (n=74), CC (n=21), or mixed UPSC/CC (n=8) endometrial cancer underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy followed by adjuvant high-dose-rate VBT. Nearly all patients (n=98, 95%) also underwent extended lymph node dissection of pelvic and paraortic lymph nodes. All VBT was performed with a vaginal cylinder, treating to a dose of 2100 cGy in 3 fractions. Thirty-five patients (34%) also received adjuvant chemotherapy. Results: At a median follow-up time of 36 months (range, 1-146 months), 2 patients had experienced vaginal recurrence, and the 5-year Kaplan Meier estimate of vaginal recurrence was 3%. The rates of isolated pelvic recurrence, locoregional recurrence (vaginal + pelvic), and extrapelvic recurrence (including intraabdominal) were similarly low, with 5-year Kaplan-Meier estimates of 4%, 7%, and 10%, respectively. The estimated 5-year overall survival was 84%. On univariate analysis, delivery of chemotherapy did not affect recurrence or survival. Conclusions: VBT is effective at preventing vaginal relapse in women with surgical stage I UPSC or CC endometrial cancer. In this cohort of patients who underwent comprehensive surgical staging, the risk of isolated pelvic or extrapelvic relapse was low, implying that more extensive adjuvant radiation therapy is likely unnecessary.

  1. Difference of the Nuclear Green Light Intensity between Papillary Carcinoma Cells Showing Clear Nuclei and Non-neoplastic Follicular Epithelia in Papillary Thyroid Carcinoma

    Science.gov (United States)

    Lee, Hyekyung; Baek, Tae Hwa; Park, Meeja; Lee, Seung Yun; Son, Hyun Jin; Kang, Dong Wook; Kim, Joo Heon; Kim, Soo Young

    2016-01-01

    Background There is subjective disagreement regarding nuclear clearing in papillary thyroid carcinoma. In this study, using digital instruments, we were able to quantify many ambiguous pathologic features and use numeric data to express our findings. Methods We examined 30 papillary thyroid carcinomas. For each case, we selected representative cancer cells showing clear nuclei and surrounding non-neoplastic follicular epithelial cells and evaluated objective values of green light intensity (GLI) for quantitative analysis of nuclear clearing in papillary thyroid carcinoma. Results From 16,274 GLI values from 600 cancer cell nuclei and 13,752 GLI values from 596 non-neoplastic follicular epithelial nuclei, we found a high correlation of 94.9% between GLI and clear nuclei. GLI between the cancer group showing clear nuclei and non-neoplastic follicular epithelia was statistically significant. The overall average level of GLI in the cancer group was over two times higher than the non-neoplastic group despite a wide range of GLI. On a polygonal line graph, there was a fluctuating unique difference between both the cancer and non-neoplastic groups in each patient, which was comparable to the microscopic findings. Conclusions Nuclear GLI could be a useful factor for discriminating between carcinoma cells showing clear nuclei and non-neoplastic follicular epithelia in papillary thyroid carcinoma. PMID:27550048

  2. Rotating cell culture systems for human cell culture: human trophoblast cells as a model.

    Science.gov (United States)

    Zwezdaryk, Kevin J; Warner, Jessica A; Machado, Heather L; Morris, Cindy A; Höner zu Bentrup, Kerstin

    2012-01-18

    -grown cells are able to respond to chemical and molecular gradients in three dimensions (i.e. at their apical, basal, and lateral surfaces) because they are cultured on the surface of porous microcarrier beads. When grown as two-dimensional monolayers on impermeable surfaces like plastic, cells are deprived of this important communication at their basal surface. Consequently, the spatial constraints imposed by the environment profoundly affect how cells sense and decode signals from the surrounding microenvironment, thus implying an important role for the 3-D milieu. We have used the RCCS to engineer biologically meaningful 3-D models of various human epithelial tissues. Indeed, many previous reports have demonstrated that cells cultured in the RCCS can assume physiologically relevant phenotypes that have not been possible with other models. In summary, culture in the RCCS represents an easy, reproducible, high-throughput platform that provides large numbers of differentiated cells that are amenable to a variety of experimental manipulations. In the following protocol, using EVTs as an example, we clearly describe the steps required to three-dimensionally culture adherent cells in the RCCS.

  3. Human embryonic stem cells handbook

    Directory of Open Access Journals (Sweden)

    Carlo Alberto Redi

    2013-03-01

    Full Text Available After the Nobel prize in physiology or medicine was awarded jointly to Sir John Gurdon and Shinya Yamanaka for the discovery that mature cells can be reprogrammed to become pluripotent it became imperative to write down the review for a book entirely devoted to human embryonic stem cells (hES, those cells that are a urgent need for researchers, those cells that rekindle the ethical debates and finally, last but not least, those cells whose study paved the way to obtain induced pluripotent stem cells by the OSKC’s Yamanaka method (the OSKC acronim refers, for those not familiar with the topic, to the four stemness genes used to transfect somatic fibroblasts: Oct4, Sox2, Klf4 and c-Myc....

  4. Identification of a candidate stem cell in human gallbladder.

    Science.gov (United States)

    Manohar, Rohan; Li, Yaming; Fohrer, Helene; Guzik, Lynda; Stolz, Donna Beer; Chandran, Uma R; LaFramboise, William A; Lagasse, Eric

    2015-05-01

    There are currently no reports of identification of stem cells in human gallbladder. The differences between human gallbladder and intrahepatic bile duct (IHBD) cells have also not been explored. The goals of this study were to evaluate if human fetal gallbladder contains a candidate stem cell population and if fetal gallbladder cells are distinct from fetal IHBD cells. We found that EpCAM+CD44+CD13+ cells represent the cell population most enriched for clonal self-renewal from primary gallbladder. Primary EpCAM+CD44+CD13+ cells gave rise to EpCAM+CD44+CD13+ and EpCAM+CD44+CD13- cells in vitro, and gallbladder cells expanded in vitro exhibited short-term engraftment in vivo. Last, we found that CD13, CD227, CD66, CD26 and CD49b were differentially expressed between gallbladder and IHBD cells cultured in vitro indicating clear phenotypic differences between the two cell populations. Microarray analyses of expanded cultures confirmed that both cell types have unique transcriptional profiles with predicted functional differences in lipid, carbohydrate, nucleic acid and drug metabolism. In conclusion, we have isolated a distinct clonogenic population of epithelial cells from primary human fetal gallbladder with stem cell characteristics and found it to be unique compared to IHBD cells.

  5. Combined cell surface carbonic anhydrase 9 and CD147 antigens enable high-efficiency capture of circulating tumor cells in clear cell renal cell carcinoma patients.

    Science.gov (United States)

    Liu, Shijie; Tian, Zuhong; Zhang, Lei; Hou, Shuang; Hu, Sijun; Wu, Junshen; Jing, Yuming; Sun, Huimin; Yu, Fei; Zhao, Libo; Wang, Ruoxiang; Tseng, Hsian-Rong; Zhau, Haiyen E; Chung, Leland W K; Wu, Kaichun; Wang, Hao; Wu, Jason Boyang; Nie, Yongzhan; Shao, Chen

    2016-09-13

    Circulating tumor cells (CTCs) have emerged as promising tools for noninvasive cancer detection and prognosis. Most conventional approaches for capturing CTCs use an EpCAM-based enrichment strategy, which does not work well in cancers that show low or no expression of EpCAM, such as renal cell carcinoma (RCC). In this study, we developed a new set of cell surface markers including CA9 and CD147 as alternative CTC-capture antigens specifically designed for RCC patients. We showed that the expression of both CA9 and CD147 was prevalent in a RCC patient cohort (n=70) by immunohistochemical analysis, with both molecules in combination covering 97.1% of cases. The NanoVelcro platform combined with CA9-/CD147-capture antibodies demonstrated significantly higher efficiency for capturing both CTC-mimicking renal cancer cells and RCC CTCs in peripheral blood, compared to the conventional EpCAM-based method. Using immunofluorescence cytological validation at the single-cell level, we were able to identify bona fide CTCs in RCC patient blood following the well-accepted criteria in our CTC-capture system. We further demonstrated a significant association of CTC numbers as well as the CTC expression status of Vimentin, a mesenchymal marker, with disease progression, including pathologic features and clinical staging. These results provide new insights into developing novel, effective targets/approaches for capturing CTCs, making CTCs a valuable tool for improved cancer detection, prognosis and treatment in RCC.

  6. Involvement of Chromatin Remodeling Genes and the Rho GTPases RhoB and CDC42 in Ovarian Clear Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Nicolai Skovbjerg Arildsen

    2017-05-01

    Full Text Available ObjectiveOvarian clear cell carcinomas (OCCCs constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyond ARID1A, which is reportedly mutated in 30–50% of OCCCs. We aimed to further characterize OCCCs by combined global transcriptional profiling and targeted deep sequencing of a panel of well-established cancer genes. Increased knowledge of OCCC-specific genetic aberrations may help in guiding development of targeted treatments and ultimately improve patient outcome.MethodsGene expression profiling of formalin-fixed, paraffin-embedded (FFPE tissue from a cohort of the major ovarian cancer subtypes (cohort 1; n = 67 was performed using whole-genome cDNA-mediated Annealing, Selection, extension and Ligation (WG-DASL bead arrays, followed by pathway, gene module score, and gene ontology analyses, respectively. A second FFPE cohort of 10 primary OCCCs was analyzed by targeted DNA sequencing of a panel of 60 cancer-related genes (cohort 2. Non-synonymous and non-sense variants affecting single-nucleotide variations and insertions or deletions were further analyzed. A tissue microarray of 43 OCCCs (cohort 3 was used for validation by immunohistochemistry and chromogenic in situ hybridization.ResultsGene expression analyses revealed a distinct OCCC profile compared to other histological subtypes, with, e.g., ERBB2, TFAP2A, and genes related to cytoskeletal actin regulation being overexpressed in OCCC. ERBB2 was, however, not overexpressed on the protein level and ERBB2 amplification was rare in the validation cohort. Targeted deep sequencing revealed non-synonymous variants or insertions/deletions in 11/60 cancer-related genes. Genes involved in chromatin remodeling, including ARID1A, SPOP, and KMT2D were frequently mutated across OCCC tumors.ConclusionOCCCs appear

  7. Postoperative renormalization of C-reactive protein with adjuvant lienal polypeptide and its association with tumour recurrence in T1 clear cell renal cell carcinoma.

    Science.gov (United States)

    Guo, Yijun; Hu, Qingfeng; Sun, Chuanyu; Gu, Bin; Xu, Ke; Xia, Guowei

    2016-06-01

    To evaluate the effect of pre- and postoperative C-reactive protein (CRP) levels on tumour recurrence following curative nephrectomy in patients with stage T1 clear cell renal cell carcinoma (CCRCC). Patients with stage T1 CCRCC were recruited. CRP was quantified 3 days before and 4 weeks after surgery. Patients were followed-up for clinical outcome every 3 months. A subset of patients received lienal polypeptide as adjuvant treatment. Patients with elevated preoperative CRP levels (≥8.2 mg/l; n = 61) had higher grade tumours, were more likely to require radical nephrectomy and were more likely to experience recurrence than those with normal CRP levels. Non-normalization of elevated preoperative CRP was associated with tumour recurrence, but elevated CRP was not an independent risk factor of tumour recurrence. Postoperative renormalization of elevated CRP is associated with decreased risk of recurrence in CCRCC. © The Author(s) 2016.

  8. VHL missense mutations in the p53 binding domain show different effects on p53 signaling and HIFα degradation in clear cell renal cell carcinoma.

    Science.gov (United States)

    Razafinjatovo, Caroline Fanja; Stiehl, Daniel; Deininger, Eva; Rechsteiner, Markus; Moch, Holger; Schraml, Peter

    2017-02-07

    Clear cell Renal Cell Carcinoma (ccRCC) formation is connected to functional loss of the von Hippel-Lindau (VHL) gene. Recent data identified its gene product, pVHL, as a multifunctional adaptor protein which interacts with HIFα subunits but also with the tumor suppressor p53. p53 is hardly expressed and rarely mutated in most ccRCC. We showed that low and absent p53 expression correlated with the severity of VHL mutations in 262 analyzed ccRCC tissues. In contrast to nonsense and frameshift mutations which abrogate virtually all pVHL functions, missense mutations may rather influence one or few functions. Therefore, we focused on four VHL missense mutations, which affect the overlapping pVHL binding sites of p53 and Elongin C, by investigating their impact on HIFα degradation, p53 expression and signaling, as well as on cellular behavior using ccRCC cell lines and tissues. TP53 mRNA and its effector targets p21, Bax and Noxa, were altered both in engineered cell lines and in tumor tissues which carried the same missense mutations. Two of these mutations were not able to degrade HIFα whereas the remaining two mutations led to HIFα downregulation, suggesting the latter are p53 binding site-specific. The selected VHL missense mutations further enhanced tumor cell survival, but had no effects on cell proliferation. Whereas Sunitinib was able to efficiently reduce cell proliferation, Camptothecin was additionally able to increase apoptotic activity of the tumor cells. It is concluded that systematic characterization of the VHL mutation status may help optimizing targeted therapy for patients with metastatic ccRCC.

  9. Exploring the miRNA-mRNA Regulatory Network in Clear Cell Renal Cell Carcinomas by Next-Generation Sequencing Expression Profiles

    Directory of Open Access Journals (Sweden)

    Sören Müller

    2014-01-01

    Full Text Available Altered microRNA (miRNA expression is a hallmark of many cancer types. The combined analysis of miRNA and messenger RNA (mRNA expression profiles is crucial to identifying links between deregulated miRNAs and oncogenic pathways. Therefore, we investigated the small non-coding (snc transcriptomes of nine clear cell renal cell carcinomas (ccRCCs and adjacent normal tissues for alterations in miRNA expression using a publicly available small RNA-Sequencing (sRNA-Seq raw-dataset. We constructed a network of deregulated miRNAs and a set of differentially expressed genes publicly available from an independent study to in silico determine miRNAs that contribute to clear cell renal cell carcinogenesis. From a total of 1,672 sncRNAs, 61 were differentially expressed across all ccRCC tissue samples. Several with known implications in ccRCC development, like the upregulated miR-21-5p, miR-142-5p, as well as the downregulated miR-106a-5p, miR-135a-5p, or miR-206. Additionally, novel promising candidates like miR-3065, which i.a. targets NRP2 and FLT1, were detected in this study. Interaction network analysis revealed pivotal roles for miR-106a-5p, whose loss might contribute to the upregulation of 49 target mRNAs, miR-135a-5p (32 targets, miR-206 (28 targets, miR-363-3p (22 targets, and miR-216b (13 targets. Among these targets are the angiogenesis, metastasis, and motility promoting oncogenes c-MET, VEGFA, NRP2, and FLT1, the latter two coding for VEGFA receptors.

  10. Prognostic significance of lymphocyte-to-monocyte ratio and CRP in patients with nonmetastatic clear cell renal cell carcinoma: a retrospective multicenter analysis

    Directory of Open Access Journals (Sweden)

    Xia WK

    2016-05-01

    Full Text Available Wen-Kai Xia, Xia Wu, Tang-Hong Yu, Yu Wu, Xia-Juan Yao, Hong Hu Department of Nephrology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu, People’s Republic of China Background: Inflammation has been reported to be involved in carcinogenesis and cancer progression. This study was designed to explore the prognostic significance of lymphocyte-to-monocyte ratio (LMR and serum C-reactive protein (CRP in nonmetastatic clear cell renal cell carcinoma (ccRCC patients after treatment.Methods: The retrospective study consisted of 985 patients with ccRCC who had undergone nephrectomy from 2005 to 2010 at multiple centers. The patients were divided into four groups using a quartile of LMR or CRP, and their associations with clinical characteristics and outcome were systematically estimated.Results: Both low LMR and high CRP significantly diminished overall survival (OS and metastasis-free survival (MFS in patients with ccRCC. Further investigation indicated that LMR and CRP were independent prognostic factors of both OS and MFS. Integration of LMR and CRP into a predictive model, including significant variables in multivariate analysis, established a nomogram to predict accurately the 3- and 5-year survival for nonmetastatic patients with ccRCC.Conclusion: LMR and CRP represent independent prognostic factors of OS and MFS for patients with ccRCC. Incorporation of LMR and CRP into the traditional TNM staging system may improve their predictive performance. Keywords: C-reactive protein, lymphocyte-to-monocyte ratio, clear cell renal cell carcinoma, survival, nomogram

  11. Validation of Gene Expression Signatures to Identify Low-risk Clear-cell Renal Cell Carcinoma Patients at Higher Risk for Disease-related Death.

    Science.gov (United States)

    Parasramka, Mansi; Serie, Daniel J; Asmann, Yan W; Eckel-Passow, Jeanette E; Castle, Erik P; Stanton, Melissa L; Leibovich, Brad C; Thompson, Robert Houston; Thompson, E Aubrey; Parker, Alexander S; Ho, Thai H; Joseph, Richard W

    2016-12-15

    Approximately 5-10% of patients with "low-risk" clear cell renal cell carcinoma (ccRCC), as stratified by externally validated clinicopathologic prognostic algorithms, eventually have disease relapse and die. Improving prognostic algorithms for these low-risk patients could help to provide improved individualized surveillance recommendations. To identify genes that are differentially expressed in patients with low-risk ccRCC who did and did not die of their disease. Using the Mayo Clinic Renal Registry, we identified formalin-fixed paraffin-embedded samples from patients with low-risk ccRCC, as defined by Mayo Clinic stage, size, grade, and necrosis score of 0-3. We conducted a nested case-control study between patients who did (cases) and did not (controls) have ccRCC relapse and death, using two independent sets (discovery and validation). We performed RNA sequencing of all samples in the discovery set to identify differentially expressed genes. In the independent validation set, we assessed the top 50 expressed genes using the nCounter Analysis System (NanoString Technologies, Seattle, WA, USA). In the discovery set of 24 cases and 24 controls, 92 genes were differentially expressed with pidentify patients with low-risk ccRCC who die of their disease. This finding provides an opportunity to help guide improved surveillance in patients with low-risk ccRCC. In the current study we identified RNA signatures from low-risk clear cell renal cell carcinoma patients who died from this disease. Improving prognostic algorithms for these low-risk patients could help to provide improved individualized surveillance recommendations. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  12. Bilateral synchronous high-grade serous carcinoma and clear cell carcinoma in right and left ovaries with immunohistochemical confirmation: An exceptional finding

    Directory of Open Access Journals (Sweden)

    Agarwal Preeti

    2014-01-01

    Full Text Available Synchronous epithelial or mixed epithelial and germ cells tumors in the same ovary is a recognized event, however, having two different surface epithelial tumors in contra lateral ovaries is a rare occurrence; prognosis and pathogenesis of which is still not clear. We came across similar finding in a 60-year-old female with different types of surface epithelial neoplasm in right and left ovaries at the same time; both of which were malignant. Clinicoradiologically only the left ovary revealed tumor, right ovary was atrophic. To our surprise, left ovary revealed high grade serous carcinoma and the right ovary displayed clear cell carcinoma. We performed immunohistochemistry to rule out the possibility of clear cell variant of serous papillary carcinoma. On literature search, we found; only single case with synchronous presentation of two different surface epithelial ovarian tumors in the same patient, both of which were benign.

  13. Low expression of phosphatase and tensin homolog in clear-cell renal cell carcinoma contributes to chemoresistance through activating the Akt/HDM2 signaling pathway

    Science.gov (United States)

    CHEN, JUN; ZHU, HE; ZHANG, YAN; CUI, MAN-HUA; HAN, LI-YING; JIA, ZHAN-HUI; WANG, LING; TENG, HONG; MIAO, LI-NING

    2015-01-01

    Clear-cell renal cell carcinoma (CCRCC) is the most frequent primary malignancy in the adult kidney. Most patients with advanced CCRCC have poor prognosis as CCRCC remains resistant to chemotherapy. The present study explored the possible mechanism underlying CCRCC resistance to chemotherapy and found that loss of PTEN in CCRCC may be involved. Knockdown of PTEN in the CCRCC cell line ACHN blocked etoposide-induced apoptosis and etoposide-impaired cell proliferation was also inhibited. It has been demonstrated that most chemotherapy drugs exert their anti-cancer effects via p53-mediated apoptosis, and in accordance, with this, the present study showed that treatment with etoposide significantly increased p53 levels. Silencing of PTEN in ACHN inhibited the Akt/HDM2 signaling cascade and depressed p53 expression, and the interaction between HDM2 and p53 was also enhanced. This was further verified in CCRCC tissue specimens from patients The results of the present study suggested that loss of PTEN, which deactivated Akt/HDM2 signaling followed by degradation of p53, may contribute to the development of etoposide resistance in CCRCC. PMID:25954860

  14. Xp11 translocation renal cell carcinoma morphologically mimicking clear cell-papillary renal cell carcinoma in an adult patient: report of a case expanding the morphologic spectrum of Xp11 translocation renal cell carcinomas.

    Science.gov (United States)

    Parihar, Asmita; Tickoo, Satish K; Kumar, Sunil; Arora, Vinod Kumar

    2015-05-01

    Xp11 translocation renal cell carcinoma (RCC) is a relatively rare tumor mainly affecting children and adolescents. It shows significant morphological overlap with the 2 most common adult renal tumors, which are the clear cell (conventional) RCC and papillary RCC. We describe case of a young adult female who presented with right flank pain and abdominal mass. Radiological investigations showed features suggestive of renal cell carcinoma in the right kidney. Histopathological findings while suggestive of Xp11 carcinoma, showed significant overlap with the recently described entity clear cell papillary RCC. TFE3 immunohistochemistry confirmed the tumor to be Xp11 translocation RCC. The patient had an aggressive course with lymph node metastasis. In this report, we discuss differential diagnosis and the diagnostic challenges of Xp11 translocation RCC in adults.

  15. Tumor Necrosis Adds Prognostically Significant Information to Grade in Clear Cell Renal Cell Carcinoma: A Study of 842 Consecutive Cases From a Single Institution.

    Science.gov (United States)

    Khor, Li-Yan; Dhakal, Hari P; Jia, Xuefei; Reynolds, Jordan P; McKenney, Jesse K; Rini, Brian I; Magi-Galluzzi, Cristina; Przybycin, Christopher G

    2016-09-01

    Tumor necrosis has been shown to be an independent predictor of adverse outcome in renal cell carcinoma. A modification of the International Society of Urological Pathology (ISUP) grading system for renal cell carcinomas has recently been proposed, which incorporates the presence of tumor necrosis into grade. The investigators proposing this system found that necrosis added significant prognostic information to ISUP grade. We attempted to describe our experience with the effect of tumor necrosis in relationship to nuclear grade by reviewing the slides from a large consecutive series of localized clear cell renal cell carcinomas from our institution and obtaining long-term clinical follow-up information (overall survival). Of the 842 clear cell renal cell carcinomas reviewed, 265 (31.5%) were ISUP grade 1 or 2, 437 (51.9%) were ISUP grade 3, and 140 (16.6%) were ISUP grade 4. Tumor necrosis was present in 177 (21%) cases. Five hundred and forty-seven (64.9%) cases were stage pT1, 83 (9.9%) were stage pT2, 193 (22.9%) were stage pT3a, and 19 (2.3%) were pT3b or higher. Median follow-up was 73.2 months (range 0.12 to 273.6), and 310 (36.8%) patients died. On univariable analysis, there was no significant difference in outcome for tumors of ISUP grades 1 to 3. After adjustment for age, tumor stage, and tumor size, ISUP grade 4 and necrosis were significant predictors of overall survival on multivariable analysis. When the recently proposed modified grading system incorporating tumor necrosis was applied to our data, there was no significant difference in overall survival between patients with modified grade 1 tumors and those with modified grade 2 tumors (P=0.31); however, there was a statistically significant difference between patients with modified grade 1 or 2 tumors and those with modified grade 3 tumors (P=0.04),and a substantial difference in outcome between those with modified grade 3 and modified grade 4 tumors (PISUP grade could be further prognostically

  16. Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke.

    Science.gov (United States)

    Ishida, Masaru; Mikami, Shuji; Shinojima, Toshiaki; Kosaka, Takeo; Mizuno, Ryuichi; Kikuchi, Eiji; Miyajima, Akira; Okada, Yasunori; Oya, Mototsugu

    2015-07-15

    Although exposure to environmental pollutants is one of the risk factors for renal cell carcinoma (RCC), its relationship with carcinogenesis and the progression of RCC remains unknown. The present study was designed to elucidate the role of the aryl hydrocarbon receptor (AhR), a major mediator of carcinogenesis caused by environmental pollutants, in the progression of RCC. The expression of AhR was investigated in 120 patients with RCC using immunohistochemistry, and its relationship with clinicopathological parameters and prognoses was statistically analyzed. RCC cell lines were exposed to indirubin or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), AhR ligands, to activate the AhR pathway, or were transfected with small interfering RNA (siRNA) for AhR. The expression of the AhR target genes CYP1A1 and CYP1B1, matrix metalloproteinases (MMPs), and invasion through Matrigel(TM) were then examined. AhR was predominantly expressed in the nuclei of high-grade clear cell RCC (ccRCC) and tumor-infiltrating lymphocytes (TILs), and its expression levels in cancer cells and TILs correlated with the pathological tumor stage and histological grade. A multivariate Cox analysis revealed that the strong expression of AhR in cancer cells was a significant and independent predictor of disease-specific survival. AhR ligands up-regulated the expression of AhR and CYPs and promoted invasion by up-regulating MMPs. Furthermore, siRNA for AhR down-regulated CYPs, and inhibited cancer cell invasion together with the down-regulation of MMPs. These results suggest that AhR regulates the invasion of ccRCC and may be involved in tumor immunity. Therefore, inhibiting the activation of AhR may represent a potentially attractive therapeutic target for ccRCC patients.

  17. Analysis of Pathological Diagnosis of Renal Clear Cell Carcinoma%肾脏透明细胞癌的病理诊断分析

    Institute of Scientific and Technical Information of China (English)

    杜晓敏

    2015-01-01

    Objective To investigate the pathological diagnosis of renal clear cell carcinoma. Methods The 163 patients were re-garded as research subjects, which pathological diagnosis of renal clear cell carcinoma in Pathology from 2011 January to 2014 June, and the pathological data were retrospectively analyzed. Results In 163 patients, renal clear cell carcinoma grade I 56 cases, accounting for 34.4%, renal cell carcinoma 43 cases, accounting for 26.4%, clear cell renal III 35 cases, accounting for 21.5%, re-nal clear cell carcinoma grade IV 29 cases, accounting for 17.7%. Under microscope, tumor cells larger, circular or polygonal, abundant cytoplasm, transparent, full of interstitial capillaries and sinuses. Conclusion The pathological diagnosis was observed under microscope in tissue structure and cell lesion characteristics and disease diagnosis made, Renal clear cell carcinoma is the most common malignant tumor, renal cell carcinoma with good prognosis, early pathological diagnosis analysis, can greatly improve the quality of life of the patients.%目的:探讨肾脏透明细胞癌的病理诊断分析。方法整群选取2011年1月-2014年6月在该病理科进行肾脏透明细胞癌的病理诊断的163例患者作为研究对象,并对其病理资料进行回顾性分析。结果163例患者中,肾透明细胞癌玉级56例,占34.4%,肾透明细胞癌Ⅱ级43例,占26.4%,肾透明细胞芋级35例,占21.5%,肾透明细胞癌Ⅳ级29例,占17.7%。镜下可见肿瘤细胞体积较大,圆形或多边形,胞质丰富,透明状,间质富有毛细血管和血窦。结论病理诊断是在镜下观察组织结构和细胞病变特征而做出的疾病诊断,肾脏透明细胞癌是肾癌中最常见的恶性肿瘤,预后较好,及早进行病理诊断分析,可以大大的提高患者的生活质量。

  18. Human fetal mesenchymal stem cells.

    Science.gov (United States)

    O'Donoghue, Keelin; Chan, Jerry

    2006-09-01

    Stem cells have been isolated at all stages of development from the early developing embryo to the post-reproductive adult organism. However, the fetal environment is unique as it is the only time in ontogeny that there is migration of stem cells in large numbers into different organ compartments. While fetal neural and haemopoietic stem cells (HSC) have been well characterised, only recently have mesenchymal stem cells from the human fetus been isolated and evaluated. Our group have characterised in human fetal blood, liver and bone marrow a population of non-haemopoietic, non-endothelial cells with an immunophenotype similar to adult bone marrow-derived mesenchymal stem cells (MSC). These cells, human fetal mesenchymal stem cells (hfMSC), are true multipotent stem cells with greater self-renewal and differentiation capacity than their adult counterparts. They circulate in first trimester fetal blood and have been found to traffic into the maternal circulation, engrafting in bone marrow, where they remain microchimeric for decades after pregnancy. Though fetal microchimerism has been implicated in the pathogenesis of autoimmune disease, the biological role of hfMSC microchimerism is unknown. Potential downstream applications of hfMSC include their use as a target cell for non-invasive pre-natal diagnosis from maternal blood, and for fetal cellular and gene therapy. Using hfMSC in fetal therapy offers the theoretical advantages of avoidance of immune rejection, increased engraftment, and treatment before disease pathology sets in. Aside from allogeneic hfMSC in utero transplantation, the use of autologous hfMSC has been brought a step forward with the development of early blood sampling techniques, efficient viral transduction and clonal expansion. Work is ongoing to determine hfMSC fate post-transplantation in murine models of genetic disease. In this review we will examine what is known about hfMSC biology, as well as discussing areas for future research. The

  19. Emergency Pancreatoduodenectomy with Preservation of Gastroduodenal Artery for Massive Gastrointestinal Bleeding due to Duodenal Metastasis by Clear Cell Renal Cell Carcinoma in a Patient with Celiac Artery Stenosis

    Directory of Open Access Journals (Sweden)

    Kyriakos Neofytou

    2014-01-01

    Full Text Available Duodenal metastasis from renal cell carcinoma is rare, and even rarer is a massive gastrointestinal bleeding from such tumours. Coeliac occlusive disease, although rarely symptomatic, can lead to ischaemic changes with anastomotic dehiscence and leaks when a patient undergoes pancreatoduodenectomy. A 41-year-old man with known metastasis to the adrenal glands and the second part of the duodenum close to the ampulla of Vater from clear cell renal cell carcinoma was admitted to our department due to massive gastrointestinal bleeding from the duodenal metastasis. Endoscopic control of the bleed was not possible, while the bleeding vessel embolization was able to control the haemorrhage only temporarily. An angiography during the embolization demonstrated the presence of stenosis of the coeliac artery and also hypertrophic inferior pancreaticoduodenal arteries supplying the proper hepatic artery via the gastroduodenal artery (GDA. The patient underwent emergency pancreatoduodenectomy with preservation of the gastroduodenal artery. The patient had an uneventful recovery and did not experience further bleeding. Also the blood flow to the liver was compromised as shown by the normal liver function tests (LFTs postoperatively. To the best of our knowledge, this is the first report of a preservation of the GDA during an emergency pancreatoduodenectomy.

  20. Effects of HIF-1 and HIF2 on Growth and Metabolism of Clear-Cell Renal Cell Carcinoma 786-0 Xenografts

    Directory of Open Access Journals (Sweden)

    Swethajit Biswas

    2010-01-01

    Full Text Available In cultured clear-cell renal carcinoma (CCRCC 786-0 cells transfected with HIF1 (HIF-1+, HIF-2 (HIF-2+, or empty vector (EV, no significant differences were observed in the growth rates in vitro, but when grown in vivo as xenografts HIF-2 significantly increased, and HIF-1 significantly decreased growth rates, compared to EV tumors. Factors associated with proliferation were increased and factors associated with cell death were decreased in HIF-2+ tumors. Metabolite profiles showed higher glucose and lower lactate and alanine levels in the HIF-2+ tumors whilst immunostaining demonstrated higher pyruvate dehydrogenase and lower pyruvate dehydrogenase kinase 1, compared to control tumors. Taken together, these results suggest that overexpression of HIF-2 in CCRCC 786-0 tumors regulated growth both by maintaining a low level of glycolysis and by allowing more mitochondrial metabolism and tolerance to ROS induced DNA damage. The growth profiles observed may be mediated by adaptive changes to a more oxidative phenotype.

  1. Screening for potential targets for therapy in mesenchymal, clear cell, and dedifferentiated chondrosarcoma reveals Bcl-2 family members and TGFβ as potential targets

    DEFF Research Database (Denmark)

    van Oosterwijk, Jolieke G; Meijer, Danielle; van Ruler, Maayke A J H

    2013-01-01

    The mesenchymal, clear cell, and dedifferentiated chondrosarcoma subtypes are extremely rare, together constituting 10% to 15% of all chondrosarcomas. Their poor prognosis and lack of efficacious treatment emphasizes the need to elucidate the pathways playing a pivotal role in these tumors. We co...

  2. Differentiated human stem cells resemble fetal, not adult, β cells.

    Science.gov (United States)

    Hrvatin, Sinisa; O'Donnell, Charles W; Deng, Francis; Millman, Jeffrey R; Pagliuca, Felicia Walton; DiIorio, Philip; Rezania, Alireza; Gifford, David K; Melton, Douglas A

    2014-02-25

    Human pluripotent stem cells (hPSCs) have the potential to generate any human cell type, and one widely recognized goal is to make pancreatic β cells. To this end, comparisons between differentiated cell types produced in vitro and their in vivo counterparts are essential to validate hPSC-derived cells. Genome-wide transcriptional analysis of sorted insulin-expressing (INS(+)) cells derived from three independent hPSC lines, human fetal pancreata, and adult human islets points to two major conclusions: (i) Different hPSC lines produce highly similar INS(+) cells and (ii) hPSC-derived INS(+) (hPSC-INS(+)) cells more closely resemble human fetal β cells than adult β cells. This study provides a direct comparison of transcriptional programs between pure hPSC-INS(+) cells and true β cells and provides a catalog of genes whose manipulation may convert hPSC-INS(+) cells into functional β cells.

  3. IV measurements of mc-Si solar cells. Comparison of results from institute and industry partners within the EU CrystalClear project

    Energy Technology Data Exchange (ETDEWEB)

    Hahn, G.; Herguth, A.; Helfricht, A. [University of Konstanz, Department of Physics, Jacob-Burckhardt-Str. 29, 78464 Konstanz (Germany); Hofmann, M; Warta, W. [Fraunhofer Institute for Solar Energy Systems ISE, Heidenhofstr. 2, 79110 Freiburg (Germany); Van der Borg, N.J.C.M.; Weeber, A.W. [ECN Solar Energy, PO Box 1, NL 1755 ZG Petten (Netherlands); John, J.; Beaucarne, G. [IMEC, Kapeldreef 75, B-3001 Leuven (Belgium); Bagus, S.; Nagel, H. [SCHOTT Solar GmbH, Carl-Zeiss-Strasse 4, 63755 Alzenau (Germany); Le Quang, N.; Nichiporuk, O. [Photowatt International S.A.S. 33, Rue St. Honore 38300 Bourgoin Jallieu (France); Vincueria, I. [BP Solar Espana SAU, P.I. Tres Cantos Zona Oeste, s/n 28760, Madrid (Spain); Brochs, M. [REC Scancell, 8512 Narvik (Norway)

    2008-10-15

    Determination of solar cell parameters by illuminated IV measurement is a standard characterisation technique used by many partners active in photovoltaics. The aim of this work is to carry out a cross check of different measurement set-ups used by different research partners of the EU CrystalClear project using industrial type multicrystalline Si solar cells. In a first round robin a significant spread of all cell parameters (Voc, jsc, FF and efficiency) could be observed. After distribution of sister cells to selected cells calibrated at ISE CalLab, a second round robin was carried out. The spread in FF and jsc could be significantly reduced. Repeatability tests showed that by using a photo diode fluctuations of light intensity can be minimised and variations in jsc can be decreased down to 0.2 mA/cm{sup 2}. Remaining systematic errors are control of cell temperature, contacting geometry, and use of appropriate reference cells.

  4. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

    DEFF Research Database (Denmark)

    Hampras, Shalaka S; Sucheston-Campbell, Lara E; Cannioto, Rikki

    2016-01-01

    BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases a...

  5. Arecoline is cytotoxic for human endothelial cells.

    Science.gov (United States)

    Ullah, Mafaz; Cox, Stephen; Kelly, Elizabeth; Boadle, Ross; Zoellner, Hans

    2014-11-01

    Oral submucous fibrosis is a pre-malignant fibrotic condition caused by areca nut use and involves reduced mucosal vascularity. Arecoline is the principal areca nut alkaloid and is cytotoxic for epithelium and fibroblasts. Endothelial cell cycle arrest is reported on exposure to arecoline, as is cytotoxicity for endothelial-lung carcinoma hybrid cells. We here describe cytotoxicity for primary human endothelial cultures from seven separate donors. Human umbilical vein endothelial cells were exposed to increasing concentrations of arecoline and examined by: phase-contrast microscopy, haemocytometer counts, transmission electron microscopy, lactate dehydrogenase release and the methyl-thiazol-tetrazolium assay. Vacuolation and detachment of endothelium were observed at and above arecoline concentrations of 333 μg/ml or more. Ultrastructural features of cellular stress were seen after 24-h treatment with 111 μg/ml arecoline and included reduced ribosomal studding of endoplasmic reticulum, increased autophagolysosomal structures, increased vacuolation and reduced mitochondrial cristae with slight swelling. Similar changes were seen at 4 h with arecoline at 333 μg/ml or above, but with more severe mitochondrial changes including increased electron density of mitochondrial matrix and greater cristal swelling, while by 24 h, these cells were frankly necrotic. Haemocytometer counts were paralleled by both lactate dehydrogenase release and the methyl-thiazol-tetrazolium assays. Arecoline is cytotoxic via necrosis for endothelium, while biochemical assays indicate no appreciable cellular leakage before death and detachment, as well as no clear effect on mitochondrial function in viable cells. Arecoline toxicity may thus contribute to reduced vascularity in oral submucous fibrosis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Extracellular protonation modulates cell-cell interaction mechanics and tissue invasion in human melanoma cells

    Science.gov (United States)

    Hofschröer, Verena; Koch, Kevin Alexander; Ludwig, Florian Timo; Friedl, Peter; Oberleithner, Hans; Stock, Christian; Schwab, Albrecht

    2017-01-01

    Detachment of cells from the primary tumour precedes metastatic progression by facilitating cell release into the tissue. Solid tumours exhibit altered pH homeostasis with extracellular acidification. In human melanoma, the Na+/H+ exchanger NHE1 is an important modifier of the tumour nanoenvironment. Here we tested the modulation of cell-cell-adhesion by extracellular pH and NHE1. MV3 tumour spheroids embedded in a collagen matrix unravelled the efficacy of cell-cell contact loosening and 3D emigration into an environment mimicking physiological confinement. Adhesive interaction strength between individual MV3 cells was quantified using atomic force microscopy and validated by multicellular aggregation assays. Extracellular acidification from pHe7.4 to 6.4 decreases cell migration and invasion but increases single cell detachment from the spheroids. Acidification and NHE1 overexpression both reduce cell-cell adhesion strength, indicated by reduced maximum pulling forces and adhesion energies. Multicellular aggregation and spheroid formation are strongly impaired under acidification or NHE1 overexpression. We show a clear dependence of melanoma cell-cell adhesion on pHe and NHE1 as a modulator. These effects are opposite to cell-matrix interactions that are strengthened by protons extruded via NHE1. We conclude that these opposite effects of NHE1 act synergistically during the metastatic cascade. PMID:28205573

  7. Altered metabolic pathways in clear cell renal cell carcinoma: A meta-analysis and validation study focused on the deregulated genes and their associated networks.

    Science.gov (United States)

    Zaravinos, Apostolos; Pieri, Myrtani; Mourmouras, Nikos; Anastasiadou, Natassa; Zouvani, Ioanna; Delakas, Dimitris; Deltas, Constantinos

    2014-01-01

    Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cell carcinoma (RCC). It is one of the most therapy-resistant carcinomas, responding very poorly or not at all to radiotherapy, hormonal therapy and chemotherapy. A more comprehensive understanding of the deregulated pathways in ccRCC can lead to the development of new therapies and prognostic markers. We performed a meta- analysis of 5 publicly available gene expression datasets and identified a list of co- deregulated genes, for which we performed extensive bioinformatic analysis coupled with experimental validation on the mRNA level. Gene ontology enrichment showed that many proteins are involved in response to hypoxia/oxygen levels and positive regulation of the VEGFR signaling pathway. KEGG analysis revealed that metabolic pathways are mostly altered in ccRCC. Similarly, Ingenuity Pathway Analysis showed that the antigen presentation, inositol metabolism, pentose phosphate, glycolysis/gluconeogenesis and fructose/mannose metabolism pathways are altered in the disease. Cellular growth, proliferation and carbohydrate metabolism, were among the top molecular and cellular functions of the co-deregulated genes. qRT-PCR validated the deregulated expression of several genes in Caki-2 and ACHN cell lines and in a cohort of ccRCC tissues. NNMT and NR3C1 increased expression was evident in ccRCC biopsies from patients using immunohistochemistry. ROC curves evaluated the diagnostic performance of the top deregulated genes in each dataset. We show that metabolic pathways are mostly deregulated in ccRCC and we highlight those being most responsible in its formation. We suggest that these genes are candidate predictive markers of the disease.

  8. High-level expression of Notch1 increased the risk of metastasis in T1 stage clear cell renal cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Qing Ai

    Full Text Available BACKGROUND: Although metastasis of clear cell renal cell carcinoma (ccRCC is basically observed in late stage tumors, T1 stage metastasis of ccRCC can also be found with no definite molecular cause resulting inappropriate selection of surgery method and poor prognosis. Notch signaling is a conserved, widely expressed signal pathway that mediates various cellular processes in normal development and tumorigenesis. This study aims to explore the potential role and mechanism of Notch signaling in the metastasis of T1 stage ccRCC. METHODOLOGY/PRINCIPAL FINDINGS: The expression of Notch1 and Jagged1 were analyzed in tumor tissues and matched normal adjacent tissues obtained from 51 ccRCC patients. Compared to non-tumor tissues, Notch1 and Jagged1 expression was significantly elevated both in mRNA and protein levels in tumors. Tissue samples of localized and metastatic tumors were divided into three groups based on their tumor stages and the relative mRNA expression of Notch1 and Jagged1 were analyzed. Compared to localized tumors, Notch1 expression was significantly elevated in metastatic tumors in T1 stage while Jagged1 expression was not statistically different between localized and metastatic tumors of all stages. The average size of metastatic tumors was significantly larger than localized tumors in T1 stage ccRCC and the elevated expression of Notch1 was significantly positive correlated with the tumor diameter. The functional significance of Notch signaling was studied by transfection of 786-O, Caki-1 and HKC cell lines with full-length expression plasmids of Notch1 and Jagged1. Compared to the corresponding controls, all cell lines demonstrated significant promotion in cell proliferation and migration while cell cycle remained unaffected. CONCLUSIONS/SIGNIFICANCE: High-level expression of Notch signaling increased the risk of metastasis in T1 stage ccRCC by stimulating the proliferation and migration of tumor cells, which may be helpful for the

  9. Clear cell adenocarcinoma of the cervix in second generation young women who are without maternal exposure to diethylstilbestrol: A case report

    Directory of Open Access Journals (Sweden)

    Tanitra Tantitamit

    2017-05-01

    Full Text Available Clear cell adenocarcinoma of the cervix (CCAC is a rare type of gynecological cancer. The risk factors and pathogenesis have yet to be clearly determined. This is a case report of a 19-year-old woman, who was never exposed to DES from her mother, who had gone for an examination for vaginal bleeding. A polypoid mass measured at 3 cm presenting in her cervix was discovered. Histological diagnosis following cervical biopsy proved the tumor to be a clear cell carcinoma. The patient was then referred to our hospital. A loop electrosurgical excision procedure (LEEP was done and the pathological diagnosis was confirmed for clear cell carcinoma with a positive endocervical margin. Radical hysterectomy, pelvic lymphadenectomy and incidental appendectomy were achieved without any complications. The microscopic findings had revealed no residual tumor. The patient did not require adjuvant treatment. No sign of recurrence has been detected throughout 6 months of follow-up. We have performed the literature review on the clinical presentation, pathogenesis, pathology, diagnosis, treatment, and prognosis of this unusual tumor.

  10. Carbonic anhydrase IX as a specific biomarker for clear cell renal cell carcinoma: comparative study of Western blot and immunohistochemistry and implications for diagnosis.

    Science.gov (United States)

    Giménez-Bachs, José M; Salinas-Sánchez, Antonio S; Serrano-Oviedo, Leticia; Nam-Cha, Syong H; Rubio-Del Campo, Antonio; Sánchez-Prieto, Ricardo

    2012-10-01

    This study aimed to evaluate the usefulness of carbonic anhydrase IX (CA-IX) expression in clear cell renal cell carcinoma (CCRCC) using two different techniques to detect protein expression. An experimental, cross-sectional, analytical study was conducted to analyse proteins in renal tumour and healthy tissue specimens from 38 consecutive patients who underwent nephrectomy for renal cancer. CA-IX protein expression was measured by immunohistochemistry and Western blot analysis and quantified. Statistical analysis was performed with the positive and negative specific agreements and kappa coefficient. The sensitivity and specificity of both techniques were assessed. Statistical tests were conducted to analyse the association between CA-IX expression quantitation and normal prognosis factors (TNM stage and Fuhrman nuclear grade), only in CCRCC. The mean patient age was 65 years, 78.9% of patients were men and 57.9% of tumours were CCRCC. CA-IX protein expression was positive in 63.2% of tumours by immunohistochemistry and in 60.5% by Western blot. Both techniques detected CA-IX expression only in CCRCC and unclassifiable tumours. High concordance indices were observed for CCRCC diagnosis. Western blot and immunohistochemistry had a sensitivity of 95.5% and 100%, respectively; the specificity was 100% in both techniques. CA-IX expression quantitation did not correlate with tumour stage or Fuhrman nuclear grade. Immunochemistry and Western blot techniques can be used to detect abnormal CA-IX protein expression in CCRCC and to support morphology-based diagnostic techniques.

  11. Triphasic and epithelioid minimal fat renal angiomyolipoma and clear cell renal cell carcinoma: qualitative and quantitative CEUS characteristics and distinguishing features.

    Science.gov (United States)

    Lu, Qing; Li, Cui-xian; Huang, Bei-jian; Xue, Li-yun; Wang, Wen-ping

    2015-02-01

    To determine the contrast-enhanced ultrasonography (CEUS) characteristics of minimal fat renal angiomyolipoma (AML) (triphasic and epithelioid) and compare them to each other and to clear cell renal cell carcinoma (ccRCC) to explore their differential diagnostic clue. Qualitative and quantitative CEUS analyses were retrospectively conducted for epithelioid renal AMLs (EAMLs) (n = 15), triphasic minimal fat AMLs (TAMLs) (n = 25), and ccRCCs (n = 113). Enhancement patterns and features with CEUS were qualitatively evaluated. As for the quantitative parameters, rise times (RT), time to peak (TTP), and tumor-to-cortex enhancement ratio (TOC ratio) were compared among these renal tumor histotypes. No significant differences were detected on conventional ultrasound in the three histotypes of renal tumor. On qualitative CEUS analysis, centripetal enhancement in cortical phase (73.3% in EAMLs, 84.0% in TAMLs vs. 18.6% in ccRCCs, p quantitative analysis, RT and TTP were much shorter in ccRCCs than those in EAMLs and TAMLs. However, all these qualitative and quantitative characteristics made no significant difference between EAMLs and TAMLs. In the differential diagnosis of EAMLs from TAMLs, pseudocapsule sign was valuable (40.0% in EAMLs vs. 0.0% in TAMLs, p 97.34% as the criteria to differentiate ccRCCs and EAMLs from TAMLs, the sensitivity and specificity were 80.0% and 87.5%, respectively. Qualitative and quantitative CEUS analyses are helpful in the differential diagnosis of ccRCCs, EAMLs, and TAMLs.

  12. Paraneoplastic hormones: parathyroid hormone-related protein (PTHrP) and erythropoietin (EPO) are related to vascular endothelial growth factor (VEGF) expression in clear cell renal cell carcinoma.

    Science.gov (United States)

    Feng, Chen-chen; Ding, Guan-xiong; Song, Ning-hong; Li, Xuan; Wu, Zhong; Jiang, Hao-wen; Ding, Qiang

    2013-12-01

    To investigate the correlation between parathyroid hormone-related protein (PTHrP), erythropoietin (EPO), and vascular endothelial growth factor (VEGF) expression in clear cell renal cell carcinoma (ccRCC). Immunohistochemical studies on PTHrP, EPO and VEGF were performed in 249 patients with ccRCC. Serum calcium level and haematocrit were analyzed. The expression of the factors and clinicopathological parameters were studied statistically for possible correlations. The incidence for hypercalcaemia and polycythaemia were 15.3% and 2.0% respectively. Expression of PTHrP, EPO, and VEGF were respectively related to advanced stage (P PTHrP was not related to tumour grade. Expressions of EPO and VEGF were correlated to tumour grade significantly. All factors were expressed higher in hypercalcaemic patients. PTHrP, EPO, and VEGF were positively correlated with each other in non-hypercalcaemic patients yet not in hypercalcaemic ones. PTHrP and EPO are related to VEGF expression and to the progression of ccRCC. This finding offers us new insight on the behaviour of ccRCC and offers possible targets in RCC treatment.

  13. Preparation of pancreatic β-cells from human iPS cells with small molecules.

    Science.gov (United States)

    Hosoya, Masaki

    2012-01-01

    Human induced pluripotent stem (iPS) cells obtained from patients are expected to be a useful source for cell transplantation therapy, because many patients (including those with type 1 diabetes and severe type 2 diabetes) are on waiting lists for transplantation for a long time due to the shortage of donors. At present, many concerns related to clinical application of human iPS cells have been raised, but rapid development of methods for the establishment, culture, and standardization of iPS cells will lead autologous cell therapy to be realistic sooner or later. However, establishment of a method for preparing some of desired cell types is still challenging. Regarding pancreatic β-cells, there have been many reports about differentiation of these cells from human embryonic stem (ES)/iPS cells, but a protocol for clinical application has still not been established. Since there is clear proof that cell transplantation therapy is effective for diabetes based on the results of clinical islet transplantation, pancreatic β-cells prepared from human iPS cells are considered likely to be effective for reducing the burden on patients. In this article, the current status of procedures for preparing pancreatic β-cells from human ES/iPS cells, including effective use of small molecules, is summarized, and some of the problems that still need to be overcome are discussed.

  14. A Clear Cell Renal Cell Carcinoma Inhibiting the Response to Intravitreal Antivascular Endothelial Growth Factor Therapy in Wet Age-Related Macular Disease

    Directory of Open Access Journals (Sweden)

    Manuel S. Falcão

    2012-12-01

    Full Text Available Purpose: Wet age-related macular degeneration (AMD is an ocular disorder that can be successfully treated with intravitreal antivascular endothelial growth factor (VEGF therapy. We report a case of incomplete response to intravitreal therapy associated with a clear cell renal cell carcinoma (ccRCC. Methods: A 72-year-old male with wet AMD responded poorly to intravitreal bevacizumab and ranibizumab injections. The removal of a ccRCC led to the spontaneous stabilization of the choroidal neovascular lesion. The renal carcinoma was examined for Von Hippel-Lindau (VHL gene alterations. Immunohistochemical profiling of the hypoxia-inducible factor (HIF pathway addressing the marker HIF-1α and its downstream targets VEGF, glucose transporter 1 and carbonic anhydrase IX was performed. Results: Genotyping of the ccRCC revealed the presence of a truncating VHL mutation (p.E134fs*25. Immunohistochemistry displayed HIF pathway target activation and VEGF expression in the ccRCC tumour cells. Following tumour removal, the neovascular lesion remained stable for 6 months without any further anti-VEGF therapy. Conclusion: The somatic VHL mutation correlates with persistent high levels of HIF-1α pathway targets and VEGF expression in the ccRCC. We postulate that this increased VEGF in the tumour and subsequently in the plasma levels could have caused the incomplete response to intravitreal anti-VEGF therapy. Stabilization of the wet AMD following tumour removal indicates that the angiogenic secreting tumour (ccRCC abrogates the response to VEGF inhibitor therapy. Thus, in cases of poor response to intravitreal anti-VEGF therapy, systemic evaluation including plasma levels of VEGF and/or systemic screening for VEGF-producing tumours should be considered.

  15. A Clear Cell Renal Cell Carcinoma Inhibiting the Response to Intravitreal Antivascular Endothelial Growth Factor Therapy in Wet Age-Related Macular Disease

    Science.gov (United States)

    Falcão, Manuel S.; Vinagre, João; Soares, Paula; Lopes, José Manuel; Brandão, Elisete; Carneiro, Ângela M.

    2012-01-01

    Purpose Wet age-related macular degeneration (AMD) is an ocular disorder that can be successfully treated with intravitreal antivascular endothelial growth factor (VEGF) therapy. We report a case of incomplete response to intravitreal therapy associated with a clear cell renal cell carcinoma (ccRCC). Methods A 72-year-old male with wet AMD responded poorly to intravitreal bevacizumab and ranibizumab injections. The removal of a ccRCC led to the spontaneous stabilization of the choroidal neovascular lesion. The renal carcinoma was examined for Von Hippel-Lindau (VHL) gene alterations. Immunohistochemical profiling of the hypoxia-inducible factor (HIF) pathway addressing the marker HIF-1α and its downstream targets VEGF, glucose transporter 1 and carbonic anhydrase IX was performed. Results Genotyping of the ccRCC revealed the presence of a truncating VHL mutation (p.E134fs*25). Immunohistochemistry displayed HIF pathway target activation and VEGF expression in the ccRCC tumour cells. Following tumour removal, the neovascular lesion remained stable for 6 months without any further anti-VEGF therapy. Conclusion The somatic VHL mutation correlates with persistent high levels of HIF-1α pathway targets and VEGF expression in the ccRCC. We postulate that this increased VEGF in the tumour and subsequently in the plasma levels could have caused the incomplete response to intravitreal anti-VEGF therapy. Stabilization of the wet AMD following tumour removal indicates that the angiogenic secreting tumour (ccRCC) abrogates the response to VEGF inhibitor therapy. Thus, in cases of poor response to intravitreal anti-VEGF therapy, systemic evaluation including plasma levels of VEGF and/or systemic screening for VEGF-producing tumours should be considered. PMID:23341823

  16. The potency of human testicular stem cells

    NARCIS (Netherlands)

    Chikhovskaya, J.V.

    2013-01-01

    In this thesis, we evaluate the stem cell state of cells present in primary human testicular cell cultures as well as their origin and relation to germ or somatic lineages within testicular tissue. We conclude that human testis-derived embryonic stem cell-like (htES-like) colonies arising in primary

  17. Influence of Exposure to Chronic Persistent Low-Dose Ionizing Radiation on the Tumor Biology of Clear-Cell Renal-Cell Carcinoma. An Immunohistochemical and Morphometric Study of Angiogenesis and Vascular Related Factors.

    Science.gov (United States)

    Ruiz-Saurí, Amparo; Valencia-Villa, Gerardo; Romanenko, Alina; Pérez, Jesús; García, Raúl; García, Heydi; Benavent, José; Sancho-Tello, María; Carda, Carmen; Llombart-Bosch, Antonio

    2016-10-01

    Increased angiogenesis is related to boosted growth and malignancy in carcinomas. "Chronic Persistent Low-Dose Ionizing Radiation" (CPLDIR) exposure increases incidence and aggressive behavior of clear-cell renal-cell carcinoma (CCRCC). The aim was to study the biology of angiogenesis, including microvessel density (MVD), in human clear-cell renal-cell carcinomas (CCRCC) originating from a radio-contaminated geographical area (Ukraine) and to compare with similar tumors diagnosed in non-contaminated regions of Europe (Spain, Valencia) and Latin America (Colombia, Barranquilla). MVD was comparatively examined in 124 patients diagnosed with CCRCC from three geographical areas by means of digital micro-imaging and computerized analysis. Additionally, 50 adult normal kidneys were used for controls (autopsy kidneys from Valencia and Barranquilla). Furthermore, an immunohistochemical study of several vascular related growth factors was undertaken using a similar methodology. MVD as well as VEFG are the most discriminating factors associated with an aggressive behavior of CCRCC. Their expression increased in proportion to the level of exposure to chronic low-dose ionizing radiation in Ukrainian patients in the 25 years since the Chernobyl accident substantiated by comparison with the two control groups of renal carcinomas present in non-irradiated areas (Spain and Colombia). No major biological differences relating to angiogenesis appear to exist between the CCRCC diagnosed in two distant geographical areas of the world. HIF-1α expression was similar in all groups, with no statistical significance. Present findings demonstrate the existence of a significant relationship between MVD and VEGF in CCRCC: an increased expression of VEGF is associated with a high level of angiogenesis.

  18. Antibody-Independent Function of Human B Cells Contributes to Antifungal T Cell Responses.

    Science.gov (United States)

    Li, Rui; Rezk, Ayman; Li, Hulun; Gommerman, Jennifer L; Prat, Alexandre; Bar-Or, Amit

    2017-03-08

    Fungal infections (e.g., Candida albicans) can manifest as serious medical illnesses, especially in the elderly and immune-compromised hosts. T cells are important for Candida control. Whether and how B cells are involved in antifungal immunity has been less clear. Although patients with agammaglobulinemia exhibit normal antifungal immunity, increased fungal infections are reported following B cell-depleting therapy, together pointing to Ab-independent roles of B cells in controlling such infections. To test how human B cells may contribute to fungal-associated human T cell responses, we developed a novel Ag-specific human T cell/B cell in vitro coculture system and found that human B cells could induce C. albicans-associated, MHC class II-restricted responses of naive T cells. Activated B cells significantly enhanced C. albicans-mediated Th1 and Th17 T cell responses, which were both strongly induced by CD80/CD86 costimulation. IL-6(+)GM-CSF(+) B cells were the major responding B cell subpopulation to C. albicans and provided efficient costimulatory signals to the T cells. In vivo B cell depletion in humans resulted in reduced C. albicans-associated T responses. Of note, the decreased Th17, but not Th1, responses could be reversed by soluble factors from B cells prior to depletion, in an IL-6-dependent manner. Taken together, our results implicate an Ab-independent cytokine-defined B cell role in human antifungal T cell responses. These findings may be particularly relevant given the prospects of chronic B cell depletion therapy use in lymphoma and autoimmune disease, as patients age and are exposed to serial combination therapies.

  19. Stem cell differentiation and human liver disease

    Institute of Scientific and Technical Information of China (English)

    Wen-Li Zhou; Claire N Medine; Liang Zhu; David C Hay

    2012-01-01

    Human stem cells are scalable cell populations capable of cellular differentiation.This makes them a very attractive in vitro cellular resource and in theory provides unlimited amounts of primary cells.Such an approach has the potential to improve our understanding of human biology and treating disease.In the future it may be possible to deploy novel stem cell-based approaches to treat human liver diseases.In recent years,efficient hepatic differentiation from human stem cells has been achieved by several research groups including our own.In this review we provide an overview of the field and discuss the future potential and limitations of stem cell technology.

  20. Comparative effectiveness of adrenal sparing radical nephrectomy and non-adrenal sparing radical nephrectomy in clear cell renal cell carcinoma: Observational study of survival outcomes

    Science.gov (United States)

    Nason, Gregory J.; Walsh, Leon G.; Redmond, Ciaran E.; Kelly, Niall P.; McGuire, Barry B.; Sharma, Vidit; Kelly, Michael E.; Galvin, David J.; Mulvin, David W.; Lennon, Gerald M.; Quinlan, David M.; Flood, Hugh D.; Giri, Subhasis K.

    2015-01-01

    Introduction: We compare the survival outcomes of patients with clear cell renal cell carcinoma (RCC) treated with adrenal sparing radical nephrectomy (ASRN) and non-adrenal sparing radical nephrectomy (NASRN). Methods: We conducted an observational study based on a composite patient population from two university teaching hospitals who underwent RN for RCC between January 2000 and December 2012. Only patients with pathologically confirmed RCC were included. We excluded patients undergoing cytoreductive nephrectomy, with loco-regional lymph node involvement. In total, 579 patients (ASRN = 380 and NASRN = 199) met our study criteria. Patients were categorized by risk groups (all stage, early stage and locally advanced RCC). Overall survival (OS) and cancer-specific survival (CSS) were analyzed for risk groups. Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards regression. Results: The median follow-up was 41 months (range: 12–157). There were significant benefits in OS (ASRN 79.5% vs. NASRN 63.3%; p = 0.001) and CSS (84.3% vs. 74.9%; p = 0.001), with any differences favouring ASRN in all stage. On multivariate analysis, there was a trend towards worse OS (hazard ratio [HR] 1.759, 95% confidence interval [CI] 0.943–2.309, p = 0.089) and CSS (HR 1.797, 95% CI 0.967–3.337, p = 0.064) in patients with NASRN (although not statistically significant). Of these patients, only 11 (1.9%) had adrenal involvement. Conclusions: The inherent limitations in our study include the impracticality of conducting a prospective randomized trial in this scenario. Our observational study with a 13-year follow-up suggests ASRN leads to better survival than NASRN. ASRN should be considered the gold standard in treating patients with RCC, unless it is contraindicated. PMID:26425218

  1. Application of the revised Tumour Node Metastasis (TNM) staging system of clear cell renal cell carcinoma in eastern China: advantages and limitations

    Institute of Scientific and Technical Information of China (English)

    Chao Qin; Li-Jiang Sun; Li Cui; Qiang Cao; Jian Zhu; Pu Li; Gui-Ming Zhang

    2013-01-01

    This study was designed to evaluate whether the revised 2010 Tumour Node Metastasis (TNM) staging system could lead to a more accurate prediction of the prognosis of renal cell carcinoma (RCC) patients.A total of 1216 patients who had undergone radical nephrectomy or partial nephrectomy for RCC from 2003 to 2011 were enrolled.All of the patients had pathologically confirmed clear cell RCC (ccRCC).All cases were staged by both the 2002 and 2010 TNM staging systems after pathological review,and survival data were collected.Univariate and multivariate Cox regression models were used to evaluate cancer-specific survival (CSS) and progression-free survival (PFS) after surgery.Continuous variables,such as age and tumour diameter,were calculated as mean values and standard deviations (s.d.) or as median values.Survival was calculated by the Kaplan-Meier method,and the log-rank test assessed differences between groups.Statistically significant differences in CSS and PFS were noted among patients in T3 subgroups using the new 2010 staging system.Therefore,the revised 2010 TNM staging system can lead to a more accurate prediction of the prognosis of ccRCC patients.However,when using the revised 2010 staging system,we found that more than 92% of patients (288/313) with T3 tumours were staged in the T3a subgroup,and their survival data were not significantly different from those of patients with T2b tumours.In addition,T2 subclassification failed to independently predict survival in RCC patients.

  2. Assessment of survival of patients with metastatic clear cell renal cell carcinoma after radical cytoreductive nephrectomy versus no surgery: a SEER analysis

    Directory of Open Access Journals (Sweden)

    Wen-Jun Xiao

    2015-04-01

    Full Text Available Purposes To examine the factors related to the choice of cytoreductive nephrectomy (CN for patients with metastatic clear cell renal cell carcinoma (mCCRCC, and compare the population-based survival rates of patients treated with or without surgery in the modern targeted therapy era. Materials and Methods From 2006 to 2009, patients with mCCRCC were identified from SEER database. The factors that affected patients to be submitted to CN were examined and propensity scores for each patient were calculated. Then patients were matched based upon propensity scores. Univariable and multivariable cox regression models were used to compare survival rates of patients treated with or without surgery. Finally, sensitivity analysis for the cox model on a hazard ratio scale was performed. Results Age, race, tumor size, T stage and N stage were associated with nephrectomy univariablely. After the match based upon propensity scores, the 1-, 2-, and 3-year cancer-specific survival rate estimates were 45.1%, 27.9%, and 21.7% for the no-surgery group vs 70.6%, 52.2%, and 41.7% for the surgery group, respectively (hazard ratio 0.42, 95%CI: 0.35-0.52, log-rank P<0.001. In multivariable Cox proportional hazard regression model, race, T stage, N stage and median household income were significantly associated with survival. Sensitivity analysis on a hazard ratio scale indicated that the hazard ratio might be above 1.00 only when the unknown factor had an opposite effect on survival which was 3-fold than CN. Conclusion The results of our study showed that CN significantly improves the survival of patients with metastatic CCRCC even in the targeted therapy era.

  3. Combined GSTM1-Null, GSTT1-Active, GSTA1 Low-Activity and GSTP1-Variant Genotype Is Associated with Increased Risk of Clear Cell Renal Cell Carcinoma.

    Science.gov (United States)

    Coric, Vesna M; Simic, Tatjana P; Pekmezovic, Tatjana D; Basta-Jovanovic, Gordana M; Savic Radojevic, Ana R; Radojevic-Skodric, Sanja M; Matic, Marija G; Dragicevic, Dejan P; Radic, Tanja M; Bogdanovic, Ljiljana M; Dzamic, Zoran M; Pljesa-Ercegovac, Marija S

    2016-01-01

    The aim of this study was to evaluate specific glutathione S-transferase (GST) gene variants as determinants of risk in patients with clear cell renal cell carcinoma (cRCC), independently or simultaneously with established RCC risk factors, as well as to discern whether phenotype changes reflect genotype-associated risk. GSTA1, GSTM1, GSTP1 and GSTT1 genotypes were determined in 199 cRCC patients and 274 matched controls. Benzo(a)pyrene diolepoxide (BPDE)-DNA adducts were determined in DNA samples obtained from cRCC patients by ELISA method. Significant association between GST genotype and risk of cRCC development was found for the GSTM1-null and GSTP1-variant genotype (p = 0.02 and pnull, GSTT1-active, GSTA1-low activity and GSTP1-variant genotype, exhibiting 9.32-fold elevated cRCC risk compared to the reference genotype combination (p = 0.04). Significant association between GST genotype and cRCC risk in smokers was found only for the GSTP1 genotype, while GSTM1-null/GSTP1-variant/GSTA1 low-activity genotype combination was present in 94% of smokers with cRCC, increasing the risk of cRCC up to 7.57 (p = 0.02). Furthermore, cRCC smokers with GSTM1-null genotype had significantly higher concentration of BPDE-DNA adducts in comparison with GSTM1-active cRCC smokers (p = 0.05). GSTM1, GSTT1, GSTA1 and GSTP1 polymorphisms might be associated with the risk of cRCC, with special emphasis on GSTM1-null and GSTP1-variant genotypes. Combined GSTM1-null, GSTT1-active, GSTA1 low activity and GSTP1-variant genotypes might be considered as "risk-carrying genotype combination" in cRCC.

  4. ERK5/BMK1 is a novel target of the tumor suppressor VHL: Implication in clear cell renal carcinoma

    OpenAIRE

    Arias-González, Laura; Moreno-Gimeno, Inmaculada; del Campo, Antonio Rubio; Leticia, Serrano-Oviedo; Valero, María Llanos; Esparís-Ogando, Azucena; de la Cruz-Morcillo, Miguel Ángel; Melgar-Rojas, Pedro; García-Cano, Jesús; Cimas, Francisco José; Hidalgo, María José Ruiz; Prado, Alfonso; Callejas-Valera, Juan Luis; Nam-Cha, Syong Hyun; Giménez-Bachs, José Miguel

    2013-01-01

    Extracellular signal-regulated kinase 5 (ERK5), also known as big mitogen-activated protein kinase (MAPK) 1, is implicated in a wide range of biologic processes, which include proliferation or vascularization. Here, we show that ERK5 is degraded through the ubiquitin-proteasome system, in a process mediated by the tumor suppressor von Hippel-Lindau (VHL) gene, through a prolyl hydroxylation-dependent mechanism. Our conclusions derive from transient transfection assays in Cos7 cells, as well a...

  5. ERK5/BMK1 Is a Novel Target of the Tumor Suppressor VHL: Implication in Clear Cell Renal Carcinoma12

    OpenAIRE

    Arias-González, Laura; Moreno-Gimeno, Inmaculada; del Campo, Antonio Rubio; Serrano-Oviedo, Leticia; Valero, María Llanos; Esparís-Ogando, Azucena; de la Cruz-Morcillo, Miguel Ángel; Melgar-Rojas, Pedro; García-Cano, Jesús; Cimas, Francisco José; Hidalgo, María José Ruiz; Prado, Alfonso; Callejas-Valera, Juan Luis; Nam-Cha, Syong Hyun; Giménez-Bachs, José Miguel

    2013-01-01

    Extracellular signal-regulated kinase 5 (ERK5), also known as big mitogen-activated protein kinase (MAPK) 1, is implicated in a wide range of biologic processes, which include proliferation or vascularization. Here, we show that ERK5 is degraded through the ubiquitin-proteasome system, in a process mediated by the tumor suppressor von Hippel-Lindau (VHL) gene, through a prolyl hydroxylation-dependent mechanism. Our conclusions derive from transient transfection assays in Cos7 cells, as well a...

  6. The human airway epithelial basal cell transcriptome.

    Directory of Open Access Journals (Sweden)

    Neil R Hackett

    Full Text Available BACKGROUND: The human airway epithelium consists of 4 major cell types: ciliated, secretory, columnar and basal cells. During natural turnover and in response to injury, the airway basal cells function as stem/progenitor cells for the other airway cell types. The objective of this study is to better understand human airway epithelial basal cell biology by defining the gene expression signature of this cell population. METHODOLOGY/PRINCIPAL FINDINGS: Bronchial brushing was used to obtain airway epithelium from healthy nonsmokers. Microarrays were used to assess the transcriptome of basal cells purified from the airway epithelium in comparison to the transcriptome of the differentiated airway epithelium. This analysis identified the "human airway basal cell signature" as 1,161 unique genes with >5-fold higher expression level in basal cells compared to differentiated epithelium. The basal cell signature was suppressed when the basal cells differentiated into a ciliated airway epithelium in vitro. The basal cell signature displayed overlap with genes expressed in basal-like cells from other human tissues and with that of murine airway basal cells. Consistent with self-modulation as well as signaling to other airway cell types, the human airway basal cell signature was characterized by genes encoding extracellular matrix components, growth factors and growth factor receptors, including genes related to the EGF and VEGF pathways. Interestingly, while the basal cell signature overlaps that of basal-like cells of other organs, the human airway basal cell signature has features not previously associated with this cell type, including a unique pattern of genes encoding extracellular matrix components, G protein-coupled receptors, neuroactive ligands and receptors, and ion channels. CONCLUSION/SIGNIFICANCE: The human airway epithelial basal cell signature identified in the present study provides novel insights into the molecular phenotype and biology of

  7. Effects of Clear Kefir on Biomolecular Aspects of Glycemic Status of Type 2 Diabetes Mellitus (T2DM Patients in Bandung, West Java [Study on Human Blood Glucose, c Peptide and Insulin

    Directory of Open Access Journals (Sweden)

    Judiono J

    2014-08-01

    Full Text Available Background: Diabetes Mellitus (DM triggers an excessive reaction of free-radicals. It increases reactive oxygen species and reduces antioxidants status as well as the β cell damage. Clear kefir was used for DM therapies, however it limited biomolecular exploration of its bioactive roles. Research aimed to investigate the effects of clear kefir on the biomolecular nature of the glycemic status of T2DM in Bandung. Methods: The randomized pretest-posttest control group was conducted by 106 T2DM patients. Research was done in several hospitals in Bandung and Cimahi, West Java from 2012–2013. Samples were divided randomly into three groups: (1 T2DM with HbA1c 7 fed standard diet and supplemented 200 ml/day by clear kefir, (3 T2DM with HbA1c was fed a standard diet as a control group. Dose response was obtained from a preeliminary vivo study, and then converted to human dosage by year 2011. Intervention was effectively done for 30 days. HbA1c was measured by HPLC. Fasting blood glucose (FBG and Postprandial blood glucose levels (PBG were measured by enzymes levels. C Peptide and insulin were measured by Elisa. Data was analyzed by a statictics programme by significance p<0,05. Study was approved by ethic committee. Results : HbA1c was significantly reduced in delta level (p<0.01 and FBG (p<0.015 among kefir groups. PBG was not significantly reduced among groups. C-Peptide was significantly increased in delta level, except in control group (p<0.014. Insulin was reduced significantly, except in control group (p<0.003. Conclusions : Supplementation of clear kefir reduced blood glucose levels (HbA1c, FBG, PBG and increased c-peptide. Clear kefir’s biomolecular mechanisms and chemistry characterization is a challenge for future studies.

  8. Does the Loss of ARID1A (BAF-250a Expression in Endometrial Clear Cell Carcinomas Have Any Clinicopathologic Significance? A Pilot Assessment

    Directory of Open Access Journals (Sweden)

    Oluwole Fadare, Idris L. Renshaw, Sharon X. Liang

    2012-01-01

    Full Text Available SWI/SNF chromatin-modification complexes use the energy of ATP hydrolysis to remodel nucleosomes and to affect transcription and several cellular processes. Accordingly, their loss of function has been associated with malignant transformation. ARID1A (the expression of whose product, BAF250a, a key complex component, is lost when mutated has recently been identified as a tumor suppressor gene that is mutated in 46-57% of ovarian clear cell carcinoma (CCC. The purposes of this study are to assess the frequency of loss of BAF250a expression in endometrial CCC and whether this loss has any discernable clinicopathologic implications. 34 endometrial carcinomas with a CCC component (including 22 pure CCC, 8 mixed carcinomas with a 10% CCC component, and 4 carcinosarcomas with a CCC epithelial component, were evaluated by immunohistochemistry using a monoclonal antibody directed against the human BAF250a protein. 5 (22.7% of the 22 pure CCC were entirely BAF250a negative, whereas the remainder showed diffuse immunoreactivity. None of 4 carcinosarcomas and only 1 (12.5% of the 8 mixed carcinomas were BAF250a negative. There was no discernable relationship between BAF250a immunoreactivity status and tumor architectural patterns (solid, papillary or tubulocystic areas or cell type (flat, hobnail or polygonal. Of the 22 patients with pure CCC, 14, 2, 3, and 3 were International Federation of Gynecology and Obstetrics stages 1, II, III and IV respectively. Interestingly, all 5 BAF250a negative cases were late stage [stages III or IV] as compared with 1 of 17 BAF250a positive cases (p=0.0002. Thus, 83% (5/6 of all late stage cases were BAF250a [-], as compared with 0 (0% of the 16 early stage (I or II cases (p=.0002. BAF250a negative and positive cases did not show any statistically significant difference regarding patient age and frequency of lymphovascular invasion or myometrial invasion. As may be anticipated from the concentration of late stage cases in

  9. “人之性恶明矣”--荀子人性论的四重视界%“It Is Clear That Human Nature Is Evil”:The Four Perspectives of Tsunzi’s Theory of Human Nature

    Institute of Scientific and Technical Information of China (English)

    魏义霞

    2015-01-01

    “人之性恶明矣”是《荀子·性恶》篇的主题。“人之性恶明矣”不仅使荀子在人性论上主张性恶一目了然,而且透射出荀子对人性有别于孟子等人的思考。由此,荀学风采、儒家神韵、先秦特质和中国印记便构成了“人之性恶明矣”的四重视界。%“It is clear that human nature is evil”is the theme of Human Nature Is Evil by Tsunzi. It not only makes Tsunzi’s idea of human nature clear that human nature is evil but also shows his thinking of human nature which is different from that of Mencius’. Based on this, Tsunzi’s learning style, Confucian fascinating expressiveness, Pre-qin characteristics and Chinese impressiveness have formed the four perspectives of the idea of“it is clear that human nature is evil”.

  10. Boron neutron capture therapy for clear cell sarcoma (CCS): Biodistribution study of p-borono-L-phenylalanine in CCS-bearing animal models

    Energy Technology Data Exchange (ETDEWEB)

    Andoh, T. [Laboratory of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences and Cooperative Research Center of Life Sciences, Kobe Gakuin University, Kobe 650-8586 (Japan); Fujimoto, T. [Department of Orthopaedic Surgery, Hyogo Cancer Center, Akashi 673-0021 (Japan); Sudo, T. [Section of Translational Research, Hyogo Cancer Center, Akashi 673-0021 (Japan); Fujita, I.; Imabori, M. [Department of Orthopaedic Surgery, Hyogo Cancer Center, Akashi 673-0021 (Japan); Moritake, H. [Department of Pediatrics, Miyazaki University, Kiyotake 889-1692 (Japan); Sugimoto, T. [Department of Pediatrics, Saiseikai Shigaken Hospital, Ritto 520-3046 (Japan); Sakuma, Y. [Department of Pathology, Hyogo Cancer Center, Akashi 673-0021 (Japan); Takeuchi, T. [Department of Pathology, Kochi University, Nangoku 783-8505 (Japan); Kawabata, S. [Department of Neurosurgery, Osaka Medical College, Osaka 569-8686 (Japan); Kirihata, M. [Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai 599-8531 (Japan); Akisue, T. [Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017 (Japan); Yayama, K. [Laboratory of Cardiovascular Pharmacology, Faculty of Pharmaceutical Sciences and Cooperative Research Center of Life Sciences, Kobe Gakuin University, Kobe 650-8586 (Japan); Kurosaka, M. [Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017 (Japan); Miyatake, S. [Department of Neurosurgery, Osaka Medical College, Osaka 569-8686 (Japan); Fukumori, Y. [Laboratory of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences and Cooperative Research Center of Life Sciences, Kobe Gakuin University, Kobe 650-8586 (Japan); Ichikawa, H., E-mail: ichikawa@pharm.kobegakuin.ac.jp [Laboratory of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences and Cooperative Research Center of Life Sciences, Kobe Gakuin University, Kobe 650-8586 (Japan)

    2011-12-15

    Clear cell sarcoma (CCS) is a rare melanocytic malignant tumor with a poor prognosis. Our previous study demonstrated that in vitro cultured CCS cells have the ability to highly uptake L-BPA and thus boron neutron capture therapy could be a new option for CCS treatment. This paper proved that a remarkably high accumulation of {sup 10}B (45-74 ppm) in tumor was obtained even in a CCS-bearing animal with a well-controlled biodistribution followed by intravenous administration of L-BPA-fructose complex (500 mg BPA/kg).

  11. Continuous production of erythropoietin by an established human renal carcinoma cell line: development of the cell line

    Energy Technology Data Exchange (ETDEWEB)

    Sherwood, J.B.; Shouval, D.

    1986-01-01

    Establishment of a stable, transformed human renal carcinoma cell line that produces erythropoietin in vitro and has maintained this function continuously since 1981 and for > 150 passages in monolayer culture was accomplished by transplantation of human renal clear cell carcinoma tissue from a patient with erythrocytosis into an immunosuppressed athymic mouse. In addition to its immunocrossreactivity with native human urinary erythropoietin, the tumor erythropoietin demonstrates biological activity in the in vitro mouse erythroid colony-forming unit assay and in tumor-bearing nude mice. The cloned renal carcinoma cell line has an abnormal human karyotype and has ultrastructural features characteristic of human renal clear cell carcinoma. This cell line provides a reproducible model system for the production of an erythropoietin-like material and for the study of its synthesis and secretion.

  12. Endocannabinoids and Human Sperm Cells

    Directory of Open Access Journals (Sweden)

    Giovanna Zolese

    2010-10-01

    Full Text Available N-acylethanolamides (NAEs are naturally occurring signaling lipids consisting of amides and esters of long-chain polyunsaturated fatty acids. Usually they are present in a very small amounts in many mammalian tissues and cells, including human reproductive tracts and fluids. Recently, the presence of N-arachidonoylethanolamide (anandamide, AEA, the most characterised member of endocannabinoids, and its congeners palmitoylethanolamide (PEA and oleylethanolamide (OEA in seminal plasma, oviductal fluid, and follicular fluids was demonstrated. AEA has been shown to bind not only type-1 (CB1 and type-2 (CB2 cannabinoid receptors, but also type-1 vanilloid receptor (TRPV1, while PEA and OEA are inactive with respect to classical cannabinoid CB1 and CB2 but activate TRPV1 or peroxisome proliferator activate receptors (PPARs. This review concerns the most recent experimental data on PEA and OEA, endocannabinoid-like molecules which appear to exert their action exclusively on sperm cells with altered features, such as membrane characteristics and kinematic parameters. Their beneficial effects on these cells could suggest a possible pharmacological use of PEA and OEA on patients affected by some forms of idiopathic infertility.

  13. Human Stem Cell Derived Cardiomyocytes: An Alternative ...

    Science.gov (United States)

    Chemical spills and associated deaths in the US has increased 2.6-fold and 16-fold from 1983 to 2012, respectfully. In addition, the number of chemicals to which humans are exposed to in the environment has increased almost 10-fold from 2001 to 2013 within the US. Internationally, a WHO report on the global composite impact of chemicals on health reported that 16% of the total burden of cardiovascular disease was attributed to environmental chemical exposure with 2.5 million deaths per year. Clearly, the cardiovascular system, at all its various developmental and life stages, represents a critical target organ system that can be adversely affected by existing and emerging chemicals (e.g., engineered nanomaterials) in a variety of environmental media. The ability to assess chemical cardiac risk and safety is critically needed but extremely challenging due to the number and categories of chemicals in commerce, as indicated. This presentation\\session will evaluate the use of adult human stem cell derived cardiomyocytes, and existing platforms, as an alternative model to evaluate environmental chemical cardiac toxicity as well as provide key information for the development of predictive adverse outcomes pathways associated with environmental chemical exposures. (This abstract does not represent EPA policy) Rapid and translatable chemical safety screening models for cardiotoxicity current status for informing regulatory decisions, a workshop sponsored by the Society

  14. Tumor-specific hypermethylation of epigenetic biomarkers, including SFRP1, predicts for poorer survival in patients from the TCGA Kidney Renal Clear Cell Carcinoma (KIRC project.

    Directory of Open Access Journals (Sweden)

    Christopher J Ricketts

    Full Text Available The recent publication of the TCGA Kidney Renal Clear Cell Carcinoma (KIRC project has provided an immense wealth and breadth of data providing an invaluable tool for confirmation and expansion upon previous observations in a large data set containing multiple data types including DNA methylation, somatic mutation, and clinical information. In clear cell renal cell carcinoma (CCRCC many genes have been demonstrated to be epigenetically inactivated by promoter hypermethylated and in a small number of cases to be associated with clinical outcome. This study created two cohorts based on the Illumina BeadChip array used to confirm the frequency of tumor-specific hypermethylation of these published hypermethylated genes, assess the impact of somatic mutation or chromosomal loss and provide the most comprehensive assessment to date of the association of this hypermethylation with patient survival. Hypermethylation of the Fibrillin 2 (FBN2 gene was the most consistent epigenetic biomarker for CCRCC across both cohorts in 40.2% or 52.5% of tumors respectively. Hypermethylation of the secreted frizzled-related protein 1 (SFRP1 gene and the basonuclin 1 (BNC1 gene were both statistically associated with poorer survival in both cohorts (SFRP1 - p = <0.0001 or 0.0010 and BNC1 - p = <0.0001 or 0.0380 and represented better independent markers of survival than tumor stage, grade or dimension in one cohort and tumor stage or dimension in the other cohort. Loss of the SFRP1 protein can potentially activate the WNT pathway and this analysis highlighted hypermethylation of several other WNT pathway regulating genes and demonstrated a poorer survival outcome for patients with somatic mutation of these genes. The success of demethylating drugs in hematological malignances and the current trials in solid tumors suggest that the identification of clinically relevant hypermethylated genes combined with therapeutic advances may improve the effectiveness and

  15. Human regulatory B cells control the TFH cell response.

    Science.gov (United States)

    Achour, Achouak; Simon, Quentin; Mohr, Audrey; Séité, Jean-François; Youinou, Pierre; Bendaoud, Boutahar; Ghedira, Ibtissem; Pers, Jacques-Olivier; Jamin, Christophe

    2017-07-01

    Follicular helper T (TFH) cells support terminal B-cell differentiation. Human regulatory B (Breg) cells modulate cellular responses, but their control of TFH cell-dependent humoral immune responses is unknown. We sought to assess the role of Breg cells on TFH cell development and function. Human T cells were polyclonally stimulated in the presence of IL-12 and IL-21 to generate TFH cells. They were cocultured with B cells to induce their terminal differentiation. Breg cells were included in these cultures, and their effects were evaluated by using flow cytometry and ELISA. B-cell lymphoma 6, IL-21, inducible costimulator, CXCR5, and programmed cell death protein 1 (PD-1) expressions increased on stimulated human T cells, characterizing TFH cell maturation. In cocultures they differentiated B cells into CD138(+) plasma and IgD(-)CD27(+) memory cells and triggered immunoglobulin secretions. Breg cells obtained by Toll-like receptor 9 and CD40 activation of B cells prevented TFH cell development. Added to TFH cell and B-cell cocultures, they inhibited B-cell differentiation, impeded immunoglobulin secretions, and expanded Foxp3(+)CXCR5(+)PD-1(+) follicular regulatory T cells. Breg cells modulated IL-21 receptor expressions on TFH cells and B cells, and their suppressive activities involved CD40, CD80, CD86, and intercellular adhesion molecule interactions and required production of IL-10 and TGF-β. Human Breg cells control TFH cell maturation, expand follicular regulatory T cells, and inhibit the TFH cell-mediated antibody secretion. These novel observations demonstrate a role for the Breg cell in germinal center reactions and suggest that deficient activities might impair the TFH cell-dependent control of humoral immunity and might lead to the development of aberrant autoimmune responses. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  16. Prolyl hydroxylase 2 dependent and Von-Hippel-Lindau independent degradation of Hypoxia-inducible factor 1 and 2 alpha by selenium in clear cell renal cell carcinoma leads to tumor growth inhibition

    Directory of Open Access Journals (Sweden)

    Chintala Sreenivasulu

    2012-07-01

    Full Text Available Abstract Background Clear cell renal cell carcinoma (ccRCC accounts for more than 80% of the cases of renal cell carcinoma. In ccRCC deactivation of Von-Hippel-Lindau (VHL gene contributes to the constitutive expression of hypoxia inducible factors 1 and 2 alpha (HIF-α, transcriptional regulators of several genes involved in tumor angiogenesis, glycolysis and drug resistance. We have demonstrated inhibition of HIF-1α by Se-Methylselenocysteine (MSC via stabilization of prolyl hydroxylases 2 and 3 (PHDs and a significant therapeutic synergy when combined with chemotherapy. This study was initiated to investigate the expression of PHDs, HIF-α, and VEGF-A in selected solid cancers, the mechanism of HIF-α inhibition by MSC, and to document antitumor activity of MSC against human ccRCC xenografts. Methods Tissue microarrays of primary human cancer specimens (ccRCC, head & neck and colon were utilized to determine the incidence of PHD2/3, HIF-α, and VEGF-A by immunohistochemical methods. To investigate the mechanism(s of HIF-α inhibition by MSC, VHL mutated ccRCC cells RC2 (HIF-1α positive, 786–0 (HIF-2α positive and VHL wild type head & neck cancer cells FaDu (HIF-1α were utilized. PHD2 and VHL gene specific siRNA knockdown and inhibitors of PHD2 and proteasome were used to determine their role in the degradation of HIF-1α by MSC. Results We have demonstrated that ccRCC cells express low incidence of PHD2 (32%, undetectable PHD3, high incidence of HIF-α (92%, and low incidence of VEGF-A compared to head & neck and colon cancers. This laboratory was the first to identify MSC as a highly effective inhibitor of constitutively expressed HIF-α in ccRCC tumors. MSC did not inhibit HIF-1α protein synthesis, but facilitated its degradation. The use of gene knockdown and specific inhibitors confirmed that the inhibition of HIF-1α was PHD2 and proteasome dependent and VHL independent. The effects of MSC treatment on HIF-α were associated with

  17. Transcriptome Sequencing (RNAseq) Enables Utilization of Formalin-Fixed, Paraffin-Embedded Biopsies with Clear Cell Renal Cell Carcinoma for Exploration of Disease Biology and Biomarker Development.

    Science.gov (United States)

    Eikrem, Oystein; Beisland, Christian; Hjelle, Karin; Flatberg, Arnar; Scherer, Andreas; Landolt, Lea; Skogstrand, Trude; Leh, Sabine; Beisvag, Vidar; Marti, Hans-Peter

    2016-01-01

    Formalin-fixed, paraffin-embedded (FFPE) tissues are an underused resource for molecular analyses. This proof of concept study aimed to compare RNAseq results from FFPE biopsies with the corresponding RNAlater® (Qiagen, Germany) stored samples from clear cell renal cell carcinoma (ccRCC) patients to investigate feasibility of RNAseq in archival tissue. From each of 16 patients undergoing partial or full nephrectomy, four core biopsies, such as two specimens with ccRCC and two specimens of adjacent normal tissue, were obtained with a 16g needle. One normal and one ccRCC tissue specimen per patient was stored either in FFPE or RNAlater®. RNA sequencing libraries were generated applying the new Illumina TruSeq® Access library preparation protocol. Comparative analysis was done using voom/Limma R-package. The analysis of the FFPE and RNAlater® datasets yielded similar numbers of detected genes, differentially expressed transcripts and affected pathways. The FFPE and RNAlater datasets shared 80% (n = 1106) differentially expressed genes. The average expression and the log2 fold changes of these transcripts correlated with R2 = 0.97, and R2 = 0.96, respectively. Among transcripts with the highest fold changes in both datasets were carbonic anhydrase 9 (CA9), neuronal pentraxin-2 (NPTX2) and uromodulin (UMOD) that were confirmed by immunohistochemistry. IPA revealed the presence of gene signatures of cancer and nephrotoxicity, renal damage and immune response. To simulate the feasibility of clinical biomarker studies with FFPE samples, a classifier model was developed for the FFPE dataset: expression data for CA9 alone had an accuracy, specificity and sensitivity of 94%, respectively, and achieved similar performance in the RNAlater dataset. Transforming growth factor-ß1 (TGFB1)-regulated genes, epithelial to mesenchymal transition (EMT) and NOTCH signaling cascade may support novel therapeutic strategies. In conclusion, in this proof of concept study, RNAseq data

  18. BAP1 is overexpressed in black compared with white patients with Mx-M1 clear cell renal cell carcinoma: A report from the cancer genome atlas.

    Science.gov (United States)

    Paulucci, David J; Sfakianos, John P; Yadav, Shalini Singh; Badani, Ketan K

    2016-06-01

    Incidence of renal cell carcinoma (RCC) is higher in Black patients with disease-specific and overall survival being lower compared with White patients even though renal tumors among Black patients are more likely to be localized. These disparities have been attributed to higher rates of obesity and hypertension, lower rates of nephrectomy, and a lack of access to quality health care. With scant genomic evidence to account for these disparities, the present study sought to compare BAP1 expression between Black and White patients with clear cell RCC (ccRCC); a gene that inhibits tumor progression when overexpressed and results in poor clinical outcomes when silenced. The cancer genome atlas dataset was used to identify 58 (9.9%) Black and 529 (90.9%) White patients with ccRCC with an initial pathologic diagnosis from 1998 to 2013. BAP1 expression was compared using a Mann-Whitney U test. The association between BAP1 expression and pathologic stage, American Joint Committee on Cancer (AJCC) stage, and Fuhrman grade was assessed for the overall cohort and stratified by race. The association between BAP1 expression and overall survival was assessed using Cox proportion hazards models adjusting for Fuhrman grade, pathologic stage, and the presence of pathologic metastases for the overall cohort and stratified by race. The level of BAP1 expression was significantly higher in Black vs. White patients with ccRCC (10.5 vs. 10.3; P<.001). For the overall cohort, increasing BAP1 expression was associated with decreasing pathologic stage (β =-0.25, P = .004) and decreasing AJCC stage (β =-0.029, P = .006). For Black patients, increasing BAP1 expression was associated with decreasing AJCC stage (β =-0.79, P = .016), decreasing Fuhrman grade (β =-0.55, P = .011), and a decreased risk of pathologic metastases (odds ratio [OR] = 0.83, P = .038). For White patients, increasing BAP1 expression was associated with decreasing pathologic stage (β =-0.20, P = .026). BAP1 is

  19. Tumor biology of non-metastatic stages of clear cell renal cell carcinoma; overexpression of stearoyl desaturase-1, EPO/EPO-R system and hypoxia-related proteins.

    Science.gov (United States)

    Stoyanoff, Tania Romina; Rodríguez, Juan Pablo; Todaro, Juan Santiago; Espada, Joaquín Diego; Colavita, Juan Pablo Melana; Brandan, Nora Cristina; Torres, Adriana Mónica; Aguirre, María Victoria

    2016-10-01

    Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinomas. There is great interest to know the molecular basis of the tumor biology of ccRCC that might contribute to a better understanding of the aggressive biological behavior of this cancer and to identify early biomarkers of disease. This study describes the relationship among proliferation, survival, and apoptosis with the expression of key molecules related to tumoral hypoxia (hypoxia-inducible factor (HIF)-1α, erythropoietin (EPO), vascular endothelial growth factor (VEGF)), their receptors (EPO-R, VEGFR-2), and stearoyl desaturase-1 (SCD-1) in early stages of ccRCC. Tissue samples were obtained at the Urology Unit of the J.R. Vidal Hospital (Corrientes, Argentina), from patients who underwent radical nephrectomy for renal cancer between 2011 and 2014. Four experimental groups according to pathological stage and nuclear grade were organized: T1G1 (n = 6), T2G1 (n = 4), T1G2 (n = 7), and T2G2 (n = 7). The expression of HIF-1α, EPO, EPO-R, VEGF, VEGFR-2, Bcl-xL, and SCD-1 were evaluated by immunohistochemistry, Western blotting, and/or RT-PCR. Apoptosis was assessed by the TUNEL in situ assay, and tumor proliferation was determined by Ki-67 immunohistochemistry. Data revealed that HIF-1α, EPO, EPO-R, VEGF, and VEGF-R2 were overexpressed in most samples. The T1G1 group showed the highest EPO levels, approximately 200 % compared with distal renal tissue. Bcl-xL overexpression was concomitant with the enhancement of proliferative indexes. SCD-1 expression increased with the tumor size and nuclear grade. Moreover, the direct correlations observed between SCD-1/HIF-1α and SCD-1/Ki-67 increments suggest a link among these molecules, which would determine tumor progression in early stages of ccRCC. Our results demonstrate the relationship among proliferation, survival, and apoptosis with the expression of key molecules related to tumoral hypoxia (HIF-1α, EPO, VEGF), their

  20. Transcriptome Sequencing (RNAseq Enables Utilization of Formalin-Fixed, Paraffin-Embedded Biopsies with Clear Cell Renal Cell Carcinoma for Exploration of Disease Biology and Biomarker Development.

    Directory of Open Access Journals (Sweden)

    Oystein Eikrem

    Full Text Available Formalin-fixed, paraffin-embedded (FFPE tissues are an underused resource for molecular analyses. This proof of concept study aimed to compare RNAseq results from FFPE biopsies with the corresponding RNAlater® (Qiagen, Germany stored samples from clear cell renal cell carcinoma (ccRCC patients to investigate feasibility of RNAseq in archival tissue. From each of 16 patients undergoing partial or full nephrectomy, four core biopsies, such as two specimens with ccRCC and two specimens of adjacent normal tissue, were obtained with a 16g needle. One normal and one ccRCC tissue specimen per patient was stored either in FFPE or RNAlater®. RNA sequencing libraries were generated applying the new Illumina TruSeq® Access library preparation protocol. Comparative analysis was done using voom/Limma R-package. The analysis of the FFPE and RNAlater® datasets yielded similar numbers of detected genes, differentially expressed transcripts and affected pathways. The FFPE and RNAlater datasets shared 80% (n = 1106 differentially expressed genes. The average expression and the log2 fold changes of these transcripts correlated with R2 = 0.97, and R2 = 0.96, respectively. Among transcripts with the highest fold changes in both datasets were carbonic anhydrase 9 (CA9, neuronal pentraxin-2 (NPTX2 and uromodulin (UMOD that were confirmed by immunohistochemistry. IPA revealed the presence of gene signatures of cancer and nephrotoxicity, renal damage and immune response. To simulate the feasibility of clinical biomarker studies with FFPE samples, a classifier model was developed for the FFPE dataset: expression data for CA9 alone had an accuracy, specificity and sensitivity of 94%, respectively, and achieved similar performance in the RNAlater dataset. Transforming growth factor-ß1 (TGFB1-regulated genes, epithelial to mesenchymal transition (EMT and NOTCH signaling cascade may support novel therapeutic strategies. In conclusion, in this proof of concept study

  1. Effect of ambient light on monoclonal antibody product quality during small-scale mammalian cell culture process in clear glass bioreactors.

    Science.gov (United States)

    Mallaney, Mary; Wang, Szu-Han; Sreedhara, Alavattam

    2014-01-01

    During a small-scale cell culture process producing a monoclonal antibody, a larger than expected difference was observed in the charge variants profile of the harvested cell culture fluid (HCCF) between the 2 L and larger scales (e.g., 400 L and 12 kL). Small-scale studies performed at the 2 L scale consistently showed an increase in acidic species when compared with the material made at larger scale. Since the 2 L bioreactors were made of clear transparent glass while the larger scale reactors are made of stainless steel, the effect of ambient laboratory light on cell culture process in 2 L bioreactors as well as handling the HCCF was carefully evaluated. Photoreactions in the 2 L glass bioreactors including light mediated increase in acidic variants in HCCF and formulation buffers were identified and carefully analyzed. While the acidic variants comprised of a mixture of sialylated, reduced disulfide, crosslinked (nonreducible), glycated, and deamidated forms, an increase in the nonreducible forms, deamidation and Met oxidation was predominantly observed under light stress. The monoclonal antibody produced in glass bioreactors that were protected from light behaved similar to the one produced in the larger scale. Our data clearly indicate that care should be taken when glass bioreactors are used in cell culture studies during monoclonal antibody production.

  2. Satellite cells in human skeletal muscle plasticity.

    Science.gov (United States)

    Snijders, Tim; Nederveen, Joshua P; McKay, Bryon R; Joanisse, Sophie; Verdijk, Lex B; van Loon, Luc J C; Parise, Gianni

    2015-01-01

    Skeletal muscle satellite cells are considered to play a crucial role in muscle fiber maintenance, repair and remodeling. Our knowledge of the role of satellite cells in muscle fiber adaptation has traditionally relied on in vitro cell and in vivo animal models. Over the past decade, a genuine effort has been made to translate these results to humans under physiological conditions. Findings from in vivo human studies suggest that satellite cells play a key role in skeletal muscle fiber repair/remodeling in response to exercise. Mounting evidence indicates that aging has a profound impact on the regulation of satellite cells in human skeletal muscle. Yet, the precise role of satellite cells in the development of muscle fiber atrophy with age remains unresolved. This review seeks to integrate recent results from in vivo human studies on satellite cell function in muscle fiber repair/remodeling in the wider context of satellite cell biology whose literature is largely based on animal and cell models.

  3. IMMUNORESPONSES OF HUMANIZED SCID MICE TO HUMAN LUNG CANCER CELLS

    Institute of Scientific and Technical Information of China (English)

    陈力真; 王树蕙; 张云; 王世真

    1996-01-01

    HuPBL-SCID mice were used to explore how they would response to human ttmoor cells of 801/MLC.Living 801/MLC cells appeared to be fetal to the the mice due to the production of human TNF. The huP-BL-SCID rniee did not generate any noticeable amotmt of specific human immunoglobttlin either by single immunization with living 801/MLC cells or by repeated immunization with irradiated 801/MLC cells. Our preliminary experiments with huPBL-SCID mice showed that such chimeras would he a very useful models for tumor immunological researches.

  4. Search for naive human pluripotent stem cells

    Institute of Scientific and Technical Information of China (English)

    Simone Aparecida Siqueira Fonseca; Roberta Montero Costas; Lygia Veiga Pereira

    2015-01-01

    Normal mouse pluripotent stem cells were originallyderived from the inner cell mass (ICM) of blastocystsand shown to be the in vitro equivalent of those preimplantationembryonic cells, and thus were calledembryonic stem cells (ESCs). More than a decade later,pluripotent cells were isolated from the ICM of humanblastocysts. Despite being called human ESCs, thesecells differ significantly from mouse ESCs, includingdifferent morphology and mechanisms of control ofpluripotency, suggesting distinct embryonic originsof ESCs from the two species. Subsequently, mousepluripotent stem cells were established from the ICMderivedepiblast of post-implantation embryos. Thesemouse epiblast stem cells (EpiSCs) are morphologicaland epigenetically more similar to human ESCs. Thisraised the question of whether cells from the humanICM are in a more advanced differentiation stage thantheir murine counterpart, or whether the availableculture conditions were not adequate to maintain thosehuman cells in their in vivo state, leading to a transitioninto EpiSC-like cells in vitro . More recently, novel cultureconditions allowed the conversion of human ESCs intomouse ESC-like cells called naive (or ground state)human ESCs, and the derivation of naive human ESCsfrom blastocysts. Here we will review the characteristicsof each type of pluripotent stem cells, how (andwhether) these relate to different stages of embryonicdevelopment, and discuss the potential implications ofnaive human ESCs in research and therapy.

  5. Endothelial cells derived from human embryonic stem cells

    Science.gov (United States)

    Levenberg, Shulamit; Golub, Justin S.; Amit, Michal; Itskovitz-Eldor, Joseph; Langer, Robert

    2002-04-01

    Human embryonic stem cells have the potential to differentiate into various cell types and, thus, may be useful as a source of cells for transplantation or tissue engineering. We describe here the differentiation steps of human embryonic stem cells into endothelial cells forming vascular-like structures. The human embryonic-derived endothelial cells were isolated by using platelet endothelial cell-adhesion molecule-1 (PECAM1) antibodies, their behavior was characterized in vitro and in vivo, and their potential in tissue engineering was examined. We show that the isolated embryonic PECAM1+ cells, grown in culture, display characteristics similar to vessel endothelium. The cells express endothelial cell markers in a pattern similar to human umbilical vein endothelial cells, their junctions are correctly organized, and they have high metabolism of acetylated low-density lipoprotein. In addition, the cells are able to differentiate and form tube-like structures when cultured on matrigel. In vivo, when transplanted into SCID mice, the cells appeared to form microvessels containing mouse blood cells. With further studies, these cells could provide a source of human endothelial cells that could be beneficial for potential applications such as engineering new blood vessels, endothelial cell transplantation into the heart for myocardial regeneration, and induction of angiogenesis for treatment of regional ischemia.

  6. Induced pluripotent stem cell lines derived from human somatic cells.

    Science.gov (United States)

    Yu, Junying; Vodyanik, Maxim A; Smuga-Otto, Kim; Antosiewicz-Bourget, Jessica; Frane, Jennifer L; Tian, Shulan; Nie, Jeff; Jonsdottir, Gudrun A; Ruotti, Victor; Stewart, Ron; Slukvin, Igor I; Thomson, James A

    2007-12-21

    Somatic cell nuclear transfer allows trans-acting factors present in the mammalian oocyte to reprogram somatic cell nuclei to an undifferentiated state. We show that four factors (OCT4, SOX2, NANOG, and LIN28) are sufficient to reprogram human somatic cells to pluripotent stem cells that exhibit the essential characteristics of embryonic stem (ES) cells. These induced pluripotent human stem cells have normal karyotypes, express telomerase activity, express cell surface markers and genes that characterize human ES cells, and maintain the developmental potential to differentiate into advanced derivatives of all three primary germ layers. Such induced pluripotent human cell lines should be useful in the production of new disease models and in drug development, as well as for applications in transplantation medicine, once technical limitations (for example, mutation through viral integration) are eliminated.

  7. Clear cell carcinoma derived from an endometriosis focus in a scar after a caesarean section--a case report and literature review.

    Science.gov (United States)

    Dobrosz, Zuzanna; Paleń, Piotr; Stojko, Rafał; Właszczuk, Paweł; Niesłuchowska-Hoxha, Anna; Piechuta-Kośmider, Ilona

    2014-10-01

    Endometriosis is defined as the occurrence of endometrial glands and endometrial stromal cells outside their typical localization within the uterus. Malignant transformation of endometriosis foci in a scar after a caesarean section (cc) is very rare--until 2013 (in a span of 40 years), about 40 such cases have been described. In our article, we describe a case of a 42-year-old woman with a tumour localized in a scar after a caesarean section. The tumour was diagnosed as clear cell carcinoma derived from an endometriosis focus. The long time interval--17 years in average (from 3 to 39 years) between the surgery (cesarean section in most cases) and the tumor diagnosis is characteristic. In the case we describe, the patient was diagnosed 16 years after the endometriosis focus in the scar had arised. Even though endometriosis is a benign lesion, it has many features distinctive for invasive carcinoma; it may itself undergo a malignant transformation as well as increase the risk of endometrial carcinoma or clear cell ovarian carcinoma. Maybe in future, more exhaustive studies will allow establishing a therapeutic protocol in patients with extra-ovarian malignant transformation of endometriosis foci.

  8. Evaluation of BPA uptake in clear cell sarcoma (CCS) in vitro and development of an in vivo model of CCS for BNCT studies

    Energy Technology Data Exchange (ETDEWEB)

    Fujimoto, T., E-mail: fujitaku@hp.pref.hyogo.jp [Department of Orthopaedic Surgery, Hyogo Cancer Center, Akashi 673-0021 (Japan); Andoh, T. [Faculty of Pharmaceutical Sciences and Cooperative Research Center of Life Sciences, Kobe Gakuin University, Kobe 650-8586 (Japan); Sudo, T. [Section of Translational Research, Hyogo Cancer Center, Akashi 673-0021 (Japan); Fujita, I.; Imabori, M. [Department of Orthopaedic Surgery, Hyogo Cancer Center, Akashi 673-0021 (Japan); Moritake, H. [Division of Pediatrics, University of Miyazaki, Miyazaki 889-1692 (Japan); Sugimoto, T. [Department of Pediatrics, Saiseikai Shigaken Hospital, Ritto 520-3046 (Japan); Sakuma, Y. [Department of Pathology, Hyogo Cancer Center, Akashi 673-0021 (Japan); Takeuchi, T. [Department of Pathology, Kochi Medical School, Nangoku 783-8505 (Japan); Sonobe, H. [Department of Pathology, Chugoku Central Hospital, Fukuyama 720-0001 (Japan); Epstein, Alan L. [Department of Pathology, Keck School of Medicine,University of Southern California, Los Angeles,CA 90033 (United States); Akisue, T. [Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017 (Japan); Kirihata, M. [Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai 599-8531 (Japan); Kurosaka, M. [Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017 (Japan); Fukumori, Y.; Ichikawa, H. [Faculty of Pharmaceutical Sciences and Cooperative Research Center of Life Sciences, Kobe Gakuin University, Kobe 650-8586 (Japan)

    2011-12-15

    Clear cell sarcoma (CCS), a rare malignant tumor with a predilection for young adults, is of poor prognosis. Recently however, boron neutron capture therapy (BNCT) with the use of p-borono-L-phenylalanine (BPA) for malignant melanoma has provided good results. CCS also produces melanin; therefore, the uptake of BPA is the key to the application of BNCT to CCS. We describe, for the first time, the high accumulation of boron in CCS and the CCS tumor-bearing animal model generated for BNCT studies.

  9. A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK)

    OpenAIRE

    Powles, T; J. Brown; Larkin, J.; Jones, R.; Ralph, C.; Hawkins, R; Chowdhury, S.; Boleti, E.; Bhal, A.; Fife, K.; Webb, A; Crabb, S.; Geldart, T; Hill, R; Dunlop, J.

    2016-01-01

    Background Preclinical work suggests SRC proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear-cell renal cancer (mRCC). This hypothesis was tested in this trial using the SRC inhibitor saracatinib and the VEGF inhibitor cediranib.\\ud \\ud Patients and methods Patients with disease progression after ≥1 VEGF-targeted therapy were eligible to participate in this double-blind, randomized (1:1) phase II study. The st...

  10. Renal-cell carcinomas in end-stage kidneys: a clinicopathological study with emphasis on clear-cell papillary renal-cell carcinoma and acquired cystic kidney disease-associated carcinoma.

    Science.gov (United States)

    Bhatnagar, Ramneesh; Alexiev, Borislav A

    2012-02-01

    Clear-cell papillary renal-cell carcinoma (CCPC) and acquired cystic kidney disease-associated carcinoma (ACDAC) are neoplasms with distinct morphological characteristics that behave less aggressively than conventional renal-cell carcinomas. End-stage kidney specimens from 61 patients (47 males and 14 females) with 109 renal-cell carcinomas were selected. Papillary renal-cell carcinoma was the most common malignancy (61/109, 56%), followed by CCPC (20/109, 18%). The CCPC showed a papillary or tubular/solid architecture, clear cytoplasm, low nuclear grade, and a distinct immunohistochemical profile (RCC-, vimentin+, CK7+, p504S-). ACDAC displayed a variety of architectural patterns, eosinophilic cytoplasm, high nuclear grade, intratumoral calcium oxalate deposits, and an immunohistochemical profile similar to type 2 papillary renal-cell carcinoma (RCC+, vimentin+, CK7-/+, p504S+). Less than 5% (3/69) of pathologically staged renal-cell carcinomas in end-stage kidneys presented with lymphogenous and/or hematogenous metastases.

  11. Trophoblast lineage cells derived from human induced pluripotent stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ying, E-mail: ying.chen@hc.msu.edu [Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, 333 Bostwick NE, Grand Rapids, MI 49503 (United States); Wang, Kai; Chandramouli, Gadisetti V.R. [Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, 333 Bostwick NE, Grand Rapids, MI 49503 (United States); Knott, Jason G. [Developmental Epigenetics Laboratory, Department of Animal Science, Michigan State University (United States); Leach, Richard, E-mail: Richard.leach@hc.msu.edu [Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, 333 Bostwick NE, Grand Rapids, MI 49503 (United States); Department of Obstetrics, Gynecology and Women’s Health, Spectrum Health Medical Group (United States)

    2013-07-12

    Highlights: •Epithelial-like phenotype of trophoblast lineage cells derived from human iPS cells. •Trophoblast lineage cells derived from human iPS cells exhibit trophoblast function. •Trophoblasts from iPS cells provides a proof-of-concept in regenerative medicine. -- Abstract: Background: During implantation, the blastocyst trophectoderm attaches to the endometrial epithelium and continues to differentiate into all trophoblast subtypes, which are the major components of a placenta. Aberrant trophoblast proliferation and differentiation are associated with placental diseases. However, due to ethical and practical issues, there is almost no available cell or tissue source to study the molecular mechanism of human trophoblast differentiation, which further becomes a barrier to the study of the pathogenesis of trophoblast-associated diseases of pregnancy. In this study, our goal was to generate a proof-of-concept model for deriving trophoblast lineage cells from induced pluripotency stem (iPS) cells from human fibroblasts. In future studies the generation of trophoblast lineage cells from iPS cells established from patient’s placenta will be extremely useful for studying the pathogenesis of individual trophoblast-associated diseases and for drug testing. Methods and results: Combining iPS cell technology with BMP4 induction, we derived trophoblast lineage cells from human iPS cells. The gene expression profile of these trophoblast lineage cells was distinct from fibroblasts and iPS cells. These cells expressed markers of human trophoblasts. Furthermore, when these cells were differentiated they exhibited invasive capacity and placental hormone secretive capacity, suggesting extravillous trophoblasts and syncytiotrophoblasts. Conclusion: Trophoblast lineage cells can be successfully derived from human iPS cells, which provide a proof-of-concept tool to recapitulate pathogenesis of patient placental trophoblasts in vitro.

  12. Whole-body and Whole-Organ Clearing and Imaging Techniques with Single-Cell Resolution: Toward Organism-Level Systems Biology in Mammals.

    Science.gov (United States)

    Susaki, Etsuo A; Ueda, Hiroki R

    2016-01-21

    Organism-level systems biology aims to identify, analyze, control and design cellular circuits in organisms. Many experimental and computational approaches have been developed over the years to allow us to conduct these studies. Some of the most powerful methods are based on using optical imaging in combination with fluorescent labeling, and for those one of the long-standing stumbling blocks has been tissue opacity. Recently, the solutions to this problem have started to emerge based on whole-body and whole-organ clearing techniques that employ innovative tissue-clearing chemistry. Here, we review these advancements and discuss how combining new clearing techniques with high-performing fluorescent proteins or small molecule tags, rapid volume imaging and efficient image informatics is resulting in comprehensive and quantitative organ-wide, single-cell resolution experimental data. These technologies are starting to yield information on connectivity and dynamics in cellular circuits at unprecedented resolution, and bring us closer to system-level understanding of physiology and diseases of complex mammalian systems.

  13. Consciousness CLEARS the mind.

    Science.gov (United States)

    Grossberg, Stephen

    2007-11-01

    A full understanding of consciousness requires that we identify the brain processes from which conscious experiences emerge. What are these processes, and what is their utility in supporting successful adaptive behaviors? Adaptive Resonance Theory (ART) predicted a functional link between processes of Consciousness, Learning, Expectation, Attention, Resonance and Synchrony (CLEARS), including the prediction that "all conscious states are resonant states". This connection clarifies how brain dynamics enable a behaving individual to autonomously adapt in real time to a rapidly changing world. The present article reviews theoretical considerations that predicted these functional links, how they work, and some of the rapidly growing body of behavioral and brain data that have provided support for these predictions. The article also summarizes ART models that predict functional roles for identified cells in laminar thalamocortical circuits, including the six layered neocortical circuits and their interactions with specific primary and higher-order specific thalamic nuclei and nonspecific nuclei. These predictions include explanations of how slow perceptual learning can occur without conscious awareness, and why oscillation frequencies in the lower layers of neocortex are sometimes slower beta oscillations, rather than the higher-frequency gamma oscillations that occur more frequently in superficial cortical layers. ART traces these properties to the existence of intracortical feedback loops, and to reset mechanisms whereby thalamocortical mismatches use circuits such as the one from specific thalamic nuclei to nonspecific thalamic nuclei and then to layer 4 of neocortical areas via layers 1-to-5-to-6-to-4.

  14. Regulation of VH replacement by B cell receptor-mediated signaling in human immature B cells.

    Science.gov (United States)

    Liu, Jing; Lange, Miles D; Hong, Sang Yong; Xie, Wanqin; Xu, Kerui; Huang, Lin; Yu, Yangsheng; Ehrhardt, Götz R A; Zemlin, Michael; Burrows, Peter D; Su, Kaihong; Carter, Robert H; Zhang, Zhixin

    2013-06-01

    VH replacement provides a unique RAG-mediated recombination mechanism to edit nonfunctional IgH genes or IgH genes encoding self-reactive BCRs and contributes to the diversification of Ab repertoire in the mouse and human. Currently, it is not clear how VH replacement is regulated during early B lineage cell development. In this article, we show that cross-linking BCRs induces VH replacement in human EU12 μHC(+) cells and in the newly emigrated immature B cells purified from peripheral blood of healthy donors or tonsillar samples. BCR signaling-induced VH replacement is dependent on the activation of Syk and Src kinases but is inhibited by CD19 costimulation, presumably through activation of the PI3K pathway. These results show that VH replacement is regulated by BCR-mediated signaling in human immature B cells, which can be modulated by physiological and pharmacological treatments.

  15. Human Neural Cell-Based Biosensor

    Science.gov (United States)

    2013-05-28

    including incubation with factors such as SHH ) and proceed to Human Neural Progenitor Cells Dopaminergic Differentiation β-III Tubulin/TH...exposure in human embryonic stem cells. J Recept Signal Transduct Res. 2011 Jun;31(3):206-13. Gerwe BA, Angel PM, West FD, Hasneen K, Young A

  16. Multiple chromophobe and clear cell renal cancer in a patient affected by Birt-Hogg-Dubè syndrome: a case report.

    Science.gov (United States)

    Castellucci, Roberto; Marchioni, Michele; Valenti, Sergio; Sortino, Giuseppe; Borgonovo, Giulio; Pesenti, Nicola; Vismara, Alberto C A; Circo, Maria C; Sessa, Barbara; Micheli, Emanuele; Lembo, Antonino

    2017-04-28

    Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant characterized by the presence of fibrofolliculomas and/or trichodiscomas, pulmonary cysts, spontaneous pneumothorax, and renal tumors. The syndrome is linked to mutations in the FLCN gene, which is preferentially expressed in the skin, kidney, and lung. The aim of our paper is to describe a case of multiple bilateral renal cancer in a patient affected by BHDS. Patient subjected to enucleoresection seven kidney tumors discovered right after ultrasound performed for other reasons. Definitive histologic examination were as follows: multifocal type chromophobe renal cell carcinoma and clear cell. After 1 month, the patient was readmitted for spontaneous pneumothorax. After about a year, the patient was again subjected to resection of multiple renal tumors left. Histological examination proved that it was multifocal renal cell carcinoma, clear cell varieties. The genome analysis highlighted positive for mutation c. 1379_1380 of FLCN gene, BHDS gene. Currently, the patient is under close follow-up. After 1 year, the chest computed tomography (CT) confirmed the presence of minute air bubbles scattered on both sides. Instead, the abdominal CT was positive for a small round lesion 6 mm exophytic. The BHDS is a rare syndrome whose management is extremely complex both in terms of oncological and functional. Kidney tumors associated with BHDS usually have a favorable clinical course. Present evidence suggests a close follow-up of the carriers of the genetic mutation patients whether or not they have expressed the lesions of disease given the high rate of recurrence of renal lesions.

  17. Cortical network from human embryonic stem cells

    OpenAIRE

    2010-01-01

    Abstract The connection of embryonic stem cell technology and developmental biology provides valuable tools to decipher the mechanisms underlying human brain development and diseases, especially among neuronal populations, that are not readily available in primary cultures. It is obviously the case of neurons forming the human cerebral cortex. In the images that are presented, the neurons were generated in vitro from human embryonic stem cells via forebrain-like progenitors. Maintained in cul...

  18. Importance of 3-D radiant flux densities for outdoor human thermal comfort on clear-sky summer days in Freiburg, Southwest Germany

    Directory of Open Access Journals (Sweden)

    Hyunjung Lee

    2014-09-01

    Full Text Available This study concerns the role of short- and long-wave radiant flux densities from different directions in complex urban settings for human thermal comfort on clear-sky summer days. The aims of the investigation are to quantify the importance of the sky view factor as an urban design-dependent variable for the 3-D radiant flux densities absorbed by the standardized human-biometeorological reference person and to analyze the varying impact of the absorbed 3-D short- and long-wave radiant flux densities on the mean radiant temperature (Tmrt$T_{\\text{mrt}}$, near-surface air temperature (Ta$T_{\\text{a}}$ and physiologically equivalent temperature (PET.The results obtained by measuring campaigns and numerical simulations point to the different importance of the absorbed 3-D radiant flux densities for human thermal comfort characterized by Ta$T_{\\text{a}}$, Tmrt$T_{\\text{mrt}}$ and PET. The magnitude of Tmrt$T_{\\text{mrt}}$ is mainly determined by the total of the absorbed 3-D long-wave radiant flux densities. However, the fluctuations of Tmrt$T_{\\text{mrt}}$ are mainly governed by the total of the absorbed 3-D short-wave radiant flux densities. Their variance can be well explained by the variance of the sky view factor related to the southern part of the upper half space. Taking account of the different impact of the 3-D radiant flux densities, Tmrt$T_{\\text{mrt}}$ can be quite well estimated by a multiple regression using the total of the absorbed 3-D short-wave radiant flux densities and the absorbed long-wave radiant flux density from the lower half space as independent variables. PET can be well estimated by a multiple regression showing Tmrt$T_{\\text{mrt}}$ and Ta$T_{\\text{a}}$ as independent variables. On a hot summer day, the increase of the albedo of vertical building walls within a simple E-W oriented street canyon leads to a decrease of the surface temperature of the S-facing wall, but to an increase of Tmrt$T_{\\text{mrt}}$ and PET

  19. Arsenic trioxide inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells.

    Science.gov (United States)

    Wang, Hongtao; Gao, Peng; Zheng, Jie

    2014-09-05

    Arsenic trioxide (As2O3) has shown therapeutic effects in some leukemias and solid cancers. However, the molecular mechanisms of its anticancer efficacy have not been clearly elucidated, particularly in solid cancers. Our previous data showed that As2O3 induced apoptosis of human papillomavirus (HPV) 16 DNA-immortalized human cervical epithelial cells and cervical cancer cells and inhibited the expression of HPV oncogenes in these cells. In the present study, we systemically examined the effects of As2O3 on five human cervical cancer cell lines and explored the possible molecular mechanisms. MTT assay showed that HPV-negative C33A cells were more sensitive to growth inhibition induced by As2O3 than HPV-positive cervical cancer cells, and HPV 18-positive HeLa and C4-I cells were more sensitive to As2O3 than HPV 16-positive CaSki and SiHa cells. After As2O3 treatment, both mRNA and protein levels of HPV E6 and E7 obviously decreased in all HPV positive cell lines. In contrast, p53 and Rb protein levels increased in all tested cell lines. Transcription factor AP-1 protein expression decreased significantly in HeLa, CaSki and C33A cells with ELISA method. These results suggest that As2O3 is a potential anticancer drug for cervical cancer.

  20. Kisspeptin and GPR54 immunoreactivity in a cohort of 518 patients defines favourable prognosis and clear cell subtype in ovarian carcinoma

    Directory of Open Access Journals (Sweden)

    Mehl Erika

    2007-11-01

    Full Text Available Abstract Background Kisspeptins and their G-protein coupled receptor, GPR54 are required for GnRH release and have been associated with anti-metastatic tumour cell behaviour in model systems. The latter might suggest that their overexpression would be associated with a better prognosis in cancer. However, kisspeptin/GPR54 interactions (autocrine, paracrine, and/or endocrine could also impact tumour behaviour in a negative manner. Here, for the first time, we associate the immunoreactivity of the kisspeptin/GPR54 ligand-receptor pair with favourable prognosis in a large cohort of ovarian carcinomas. Methods Immunohistochemical analysis for kisspeptin and GPR54 was performed on a tissue microarray (TMA consisting of 518 early stage ovarian carcinomas, all with linked clinical outcome data. The TMA was scored using a staining intensity scale of 0 (negative, +1 (mild-moderate, and +2 (strong. Strong staining cases were considered either kisspeptin or GPR54 positive and designated as 1, while all other cases were considered negative and designated 0. All statistical analysis was conducted using two-sided tests and a p value equal to or less than 0.05 was considered significant. Results Kisspeptin and GPR54 immunoreactive cases show a favourable prognosis in univariable disease specific survival (p = 0.0023, p = 0.0092, as well as in overall survival (p = 0.0006, p = 0.0002. Furthermore, kisspeptin is an independent marker for favourable prognosis as determined by multivariable disease specific (p = 0.0046 and overall survival analysis (p = 0.0170, while GPR54 is an independent marker for overall survival only (p = 0.0303. Both kisspeptin positive and GPR54 positive cases are strongly associated with the ovarian carcinoma clear cell subtype (p Conclusion Kisspeptin and GPR54 immunoreactivity are significantly associated with favourable prognosis in both disease specific and overall survival, as well as being significantly associated with the clear

  1. Human renal medullary interstitial cells and analgesic nephropathy.

    Science.gov (United States)

    Whiting, P H; Tisocki, K; Hawksworth, G M

    1999-01-01

    The aim of this study was to investigate the effects of known papillotoxins using cultures of human renal interstital medullary cells (hRMIC). The culture of hMIC was based on the primary culture of human renal medullary explants, selective detachment of interstitial cells and selective overgrowth of these cells in a serum-rich medium after dilution cloning. The homogeneous population of cells obtained exhibited the characteristic morphological and functional characteristics of Type I interstitial cells, viz. stellate-shaped cells demonstrating numerous lipid droplets, abundant endoplasmic reticulum and mitochondria, fine filaments underlying the cell membrane and the production of extracellular matrix. Cytotoxicity studies using hMIC and known papillotoxins clearly demonstrated a reduction in cell viability that varied with bath exposure time and type of agent tested. While only phenylbutazone and mefenamic acid produced significant cytotoxicity after a 24 h incubation period, cell viability assessed using the MTT assay was only profoundly reduced by aspirin and paracetamol following sub-chronic exposure for 7 days. The rank order of cytotoxicity observed in hMIC was phenylbutazone > mefenamic acid > aspirin > paracetamol. The results demonstrate the potential of hMIC for investigating and defining the early cellular events in the pathogenesis of analgesic nephropathy.

  2. Human hematopoietic cell culture, transduction, and analyses

    DEFF Research Database (Denmark)

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

    2008-01-01

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

  3. Human embryonic stem cells derived by somatic cell nuclear transfer.

    Science.gov (United States)

    Tachibana, Masahito; Amato, Paula; Sparman, Michelle; Gutierrez, Nuria Marti; Tippner-Hedges, Rebecca; Ma, Hong; Kang, Eunju; Fulati, Alimujiang; Lee, Hyo-Sang; Sritanaudomchai, Hathaitip; Masterson, Keith; Larson, Janine; Eaton, Deborah; Sadler-Fredd, Karen; Battaglia, David; Lee, David; Wu, Diana; Jensen, Jeffrey; Patton, Phillip; Gokhale, Sumita; Stouffer, Richard L; Wolf, Don; Mitalipov, Shoukhrat

    2013-06-06

    Reprogramming somatic cells into pluripotent embryonic stem cells (ESCs) by somatic cell nuclear transfer (SCNT) has been envisioned as an approach for generating patient-matched nuclear transfer (NT)-ESCs for studies of disease mechanisms and for developing specific therapies. Past attempts to produce human NT-ESCs have failed secondary to early embryonic arrest of SCNT embryos. Here, we identified premature exit from meiosis in human oocytes and suboptimal activation as key factors that are responsible for these outcomes. Optimized SCNT approaches designed to circumvent these limitations allowed derivation of human NT-ESCs. When applied to premium quality human oocytes, NT-ESC lines were derived from as few as two oocytes. NT-ESCs displayed normal diploid karyotypes and inherited their nuclear genome exclusively from parental somatic cells. Gene expression and differentiation profiles in human NT-ESCs were similar to embryo-derived ESCs, suggesting efficient reprogramming of somatic cells to a pluripotent state.

  4. Defining the nature of human pluripotent stem cell progeny

    Institute of Scientific and Technical Information of China (English)

    Michaela Patterson; David N Chan; Iris Ha; Dana Case; Yongyan Cui; Ben Van Handel; Hanna KA Mikkola; William E Lowry

    2012-01-01

    While it is clear that human pluripotent stem cells (hPSCs) can differentiate to generate a panoply of various cell types,it is unknown how closely in vitro development mirrors that which occurs in vivo.To determine whether human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) make equivalent progeny,and whether either makes cells that are analogous to tissue-derived cells,we performed comprehensive transcriptome profiling of purified PSC derivatives and their tissue-derived counterparts.Expression profiling demonstrated that hESCs and hiPSCs make nearly identical progeny for the neural,hepatic,and mesenchymal lineages,and an absence of re-expression from exogenous reprogramming factors in hiPSC progeny.However,when compared to a tissuederived counterpart,the progeny of both hESCs and hiPSCs maintained expression of a subset of genes normally associated with early mammalian development,regardless of the type of cell generated.While pluripotent genes (OCT4,SOX2,REX1,and NANOG) appeared to be silenced immediately upon differentiation from hPSCs,genes normally unique to early embryos (LIN28A,LIN28B,DPPA4,and others) were not fully silenced in hPSC derivatives.These data and evidence from expression patterns in early human fetal tissue (3-16 weeks of development) suggest that the differentiated progeny of hPSCs are reflective of very early human development (< 6 weeks).These findings provide support for the idea that hPSCs can serve as useful in vitro models of early human development,but also raise important issues for disease modeling and the clinical application of hPSC derivatives.

  5. Human Neuroepithelial Cells Express NMDA Receptors

    Directory of Open Access Journals (Sweden)

    Cappell B

    2003-11-01

    Full Text Available Abstract L-glutamate, an excitatory neurotransmitter, binds to both ionotropic and metabotropic glutamate receptors. In certain parts of the brain the BBB contains two normally impermeable barriers: 1 cerebral endothelial barrier and 2 cerebral epithelial barrier. Human cerebral endothelial cells express NMDA receptors; however, to date, human cerebral epithelial cells (neuroepithelial cells have not been shown to express NMDA receptor message or protein. In this study, human hypothalamic sections were examined for NMDA receptors (NMDAR expression via immunohistochemistry and murine neuroepithelial cell line (V1 were examined for NMDAR via RT-PCR and Western analysis. We found that human cerebral epithelium express protein and cultured mouse neuroepithelial cells express both mRNA and protein for the NMDA receptor. These findings may have important consequences for neuroepithelial responses during excitotoxicity and in disease.

  6. Antitumor activity and induction of TP53-dependent apoptosis toward ovarian clear cell adenocarcinoma by the dual PI3K/mTOR inhibitor DS-7423.

    Science.gov (United States)

    Kashiyama, Tomoko; Oda, Katsutoshi; Ikeda, Yuji; Shiose, Yoshinobu; Hirota, Yasuhide; Inaba, Kanako; Makii, Chinami; Kurikawa, Reiko; Miyasaka, Aki; Koso, Takahiro; Fukuda, Tomohiko; Tanikawa, Michihiro; Shoji, Keiko; Sone, Kenbun; Arimoto, Takahide; Wada-Hiraike, Osamu; Kawana, Kei; Nakagawa, Shunsuke; Matsuda, Koichi; McCormick, Frank; Aburatani, Hiroyuki; Yano, Tetsu; Osuga, Yutaka; Fujii, Tomoyuki

    2014-01-01

    DS-7423, a novel, small-molecule dual inhibitor of phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR), is currently in phase I clinical trials for solid tumors. Although DS-7423 potently inhibits PI3Kα (IC50 = 15.6 nM) and mTOR (IC50 = 34.9 nM), it also inhibits other isoforms of class I PI3K (IC50 values: PI3Kβ = 1,143 nM; PI3Kγ = 249 nM; PI3Kδ = 262 nM). The PI3K/mTOR pathway is frequently activated in ovarian clear cell adenocarcinomas (OCCA) through various mutations that activate PI3K-AKT signaling. Here, we describe the anti-tumor effect of DS-7423 on a panel of nine OCCA cell lines. IC50 values for DS-7423 were DS-7423 suppressed the tumor growth of OCCA in a dose-dependent manner. Flow cytometry analysis revealed a decrease in S-phase cell populations in all the cell lines and an increase in sub-G1 cell populations following treatment with DS-7423 in six of the nine OCCA cell lines tested. DS-7423-mediated apoptosis was induced more effectively in the six cell lines without TP53 mutations than in the three cell lines with TP53 mutations. Concomitantly with the decreased phosphorylation level of MDM2 (mouse double minute 2 homolog), the level of phosphorylation of TP53 at Ser46 was increased by DS-7423 in the six cell lines with wild-type TP53, with induction of genes that mediate TP53-dependent apoptosis, including p53AIP1 and PUMA at 39 nM or higher doses. Our data suggest that the dual PI3K/mTOR inhibitor DS-7423 may constitute a promising molecular targeted therapy for OCCA, and that its antitumor effect might be partly obtained by induction of TP53-dependent apoptosis in TP53 wild-type OCCAs.

  7. Effect of Deep Space Radiation on Human Hematopoietic Cells

    Science.gov (United States)

    Kalota, Anna; Bennett, Paula; Swider, Cezary R.; Sutherland, Betsy M.; Gewirtz, Alan M.

    Astronaut flight crews on long-term missions in deep space will be exposed to a unique radiation environment as a result of exposure to galactic cosmic rays (GCR) and solar particle events (SPE). This environment consists predominantly of high energy protons, helium and high charge, high energy (HZE) atomic nuclei from iron predominantly, but all other elements as well. The effect of such particles, alone, or in combination, on human hematopoietic stem and progenitor cells (HSPC) has not been well studied but is clearly of interest since blood forming cells are known to be sensitive to radiation, and irreversible damage to these cells could quickly compromise a mission due to loss of marrow function. To better understand the effects of GCR and SPE on human stem/progenitor cell function, we have exposed partially purified CD34+ normal human marrow cells to protons, radioactive Fe, and Ti, alone, and in combination at varying doses up to 70cGy, and down to 1, 2, and 4 particle hits per nucleus. We then examined the effects of these radiations on HSPC function, as assessed by the ability to form CFU-GEMM, and LTCIC colonies in semi-solid culture medium. At the highest doses (50 and 70cGy), all radiation types tested significantly diminished the ability of CD34+ cells to form such colonies. The number of CFU-GEMM in irradiated samples was 70-90

  8. Human stem cells as a model for cardiac differentiation and disease

    NARCIS (Netherlands)

    Beqqali, A.; van Eldik, W.; Mummery, C.L.; Passier, R.

    2009-01-01

    Studies on identification, derivation and characterization of human stem cells in the last decade have led to high expectations in the field of regenerative medicine. Although it is clear that for successful stem cell-based therapy several obstacles have to be overcome, other opportunities lay ahead

  9. Measurement of human embryonic stem cell in the growing cycle

    Science.gov (United States)

    Li, X.; Zhao, L.; Oh, Steve K. W.; Chong, W. K.; Ong, J. K.; Chen, Allen K.; Choo, Andre B. H.

    2008-09-01

    A measurement and imaging system has been developed for in-line continuous measurement of live, unmodified, human embryonic stem cells (hESC). The measurement will not affect cell growth, structure, sterility and suitability for clinical use. The stem cell imaging system (SCIS) can be used to support the optimization of automated stem cell growth for invitro study and for high-volume bio-manufacture. This paper present the experimental and analysis for the optimization of system parameters. A non-linear lighting is developed to obtain a clear images. The individual cluster can be traced from day one to day two. The whole system is calibrated with measurement microscope and haemacytometer. The measurement accuracy is better than 90%.

  10. Cell Cycle Progression of Human Cells Cultured in Rotating Bioreactor

    Science.gov (United States)

    Parks, Kelsey

    2009-01-01

    Space flight has been shown to alter the astronauts immune systems. Because immune performance is complex and reflects the influence of multiple organ systems within the host, scientists sought to understand the potential impact of microgravity alone on the cellular mechanisms critical to immunity. Lymphocytes and their differentiated immature form, lymphoblasts, play an important and integral role in the body's defense system. T cells, one of the three major types of lymphocytes, play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and natural killer cells by the presence of a special receptor on their cell surface called T cell receptors. Reported studies have shown that spaceflight can affect the expression of cell surface markers. Cell surface markers play an important role in the ability of cells to interact and to pass signals between different cells of the same phenotype and cells of different phenotypes. Recent evidence suggests that cell-cycle regulators are essential for T-cell function. To trigger an effective immune response, lymphocytes must proliferate. The objective of this project is to investigate the changes in growth of human cells cultured in rotating bioreactors and to measure the growth rate and the cell cycle distribution for different human cell types. Human lymphocytes and lymphoblasts will be cultured in a bioreactor to simulate aspects of microgravity. The bioreactor is a cylindrical culture vessel that incorporates the aspects of clinostatic rotation of a solid fluid body around a horizontal axis at a constant speed, and compensates gravity by rotation and places cells within the fluid body into a sustained free-fall. Cell cycle progression and cell proliferation of the lymphocytes will be measured for a number of days. In addition, RNA from the cells will be isolated for expression of genes related in cell cycle regulations.

  11. Cell Cycle Progression of Human Cells Cultured in Rotating Bioreactor

    Science.gov (United States)

    Parks, Kelsey

    2009-01-01

    Space flight has been shown to alter the astronauts immune systems. Because immune performance is complex and reflects the influence of multiple organ systems within the host, scientists sought to understand the potential impact of microgravity alone on the cellular mechanisms critical to immunity. Lymphocytes and their differentiated immature form, lymphoblasts, play an important and integral role in the body's defense system. T cells, one of the three major types of lymphocytes, play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and natural killer cells by the presence of a special receptor on their cell surface called T cell receptors. Reported studies have shown that spaceflight can affect the expression of cell surface markers. Cell surface markers play an important role in the ability of cells to interact and to pass signals between different cells of the same phenotype and cells of different phenotypes. Recent evidence suggests that cell-cycle regulators are essential for T-cell function. To trigger an effective immune response, lymphocytes must proliferate. The objective of this project is to investigate the changes in growth of human cells cultured in rotating bioreactors and to measure the growth rate and the cell cycle distribution for different human cell types. Human lymphocytes and lymphoblasts will be cultured in a bioreactor to simulate aspects of microgravity. The bioreactor is a cylindrical culture vessel that incorporates the aspects of clinostatic rotation of a solid fluid body around a horizontal axis at a constant speed, and compensates gravity by rotation and places cells within the fluid body into a sustained free-fall. Cell cycle progression and cell proliferation of the lymphocytes will be measured for a number of days. In addition, RNA from the cells will be isolated for expression of genes related in cell cycle regulations.

  12. Derivation of naive human embryonic stem cells.

    Science.gov (United States)

    Ware, Carol B; Nelson, Angelique M; Mecham, Brigham; Hesson, Jennifer; Zhou, Wenyu; Jonlin, Erica C; Jimenez-Caliani, Antonio J; Deng, Xinxian; Cavanaugh, Christopher; Cook, Savannah; Tesar, Paul J; Okada, Jeffrey; Margaretha, Lilyana; Sperber, Henrik; Choi, Michael; Blau, C Anthony; Treuting, Piper M; Hawkins, R David; Cirulli, Vincenzo; Ruohola-Baker, Hannele

    2014-03-25

    The naïve pluripotent state has been shown in mice to lead to broad and more robust developmental potential relative to primed mouse epiblast cells. The human naïve ES cell state has eluded derivation without the use of transgenes, and forced expression of OCT4, KLF4, and KLF2 allows maintenance of human cells in a naïve state [Hanna J, et al. (2010) Proc Natl Acad Sci USA 107(20):9222-9227]. We describe two routes to generate nontransgenic naïve human ES cells (hESCs). The first is by reverse toggling of preexisting primed hESC lines by preculture in the histone deacetylase inhibitors butyrate and suberoylanilide hydroxamic acid, followed by culture in MEK/ERK and GSK3 inhibitors (2i) with FGF2. The second route is by direct derivation from a human embryo in 2i with FGF2. We show that human naïve cells meet mouse criteria for the naïve state by growth characteristics, antibody labeling profile, gene expression, X-inactivation profile, mitochondrial morphology, microRNA profile and development in the context of teratomas. hESCs can exist in a naïve state without the need for transgenes. Direct derivation is an elusive, but attainable, process, leading to cells at the earliest stage of in vitro pluripotency described for humans. Reverse toggling of primed cells to naïve is efficient and reproducible.

  13. Regulatory T Cells in Human Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Dong-Jun Peng

    2012-01-01

    Full Text Available Multiple layers of suppressive components including regulatory T (TReg cells, suppressive antigen-presenting cells, and inhibitory cytokines form suppressive networks in the ovarian cancer microenvironment. It has been demonstrated that as a major suppressive element, TReg cells infiltrate tumor, interact with several types of immune cells, and mediate immune suppression through different molecular and cellular mechanisms. In this paper, we focus on human ovarian cancer and will discuss the nature of TReg cells including their subsets, trafficking, expansion, and function. We will briefly review the development of manipulation of TReg cells in preclinical and clinical settings.

  14. Generation of pancreatic islet cells from human embryonic stem cells

    Institute of Scientific and Technical Information of China (English)

    ZHANG DongHui; JIANG Wei; SHI Yan; DENG HongKui

    2009-01-01

    Efficiently obtaining functional pancreaUc islet cells derived from human embryonic stem (hES) cells not only provides great potential to solve the shortage of islets sources for type I diabetes cell therapy,but also benefits the study of the development of the human pancreas and diabetes pathology. In 2001,hES cells were reported to have the capacity to generate insulin-producing cells by spontaneous differentiation in vitro. Since then, many strategies (such as overexpression of key transcription factors,delivery of key proteins for pancreatic development, co-transplantation of differentiated hES cells along with fetal pancreas, stepwise differentiation by mimicking in vivo pancreatic development) have been employed in order to induce the differentiation of pancreatic islet cells from hES cells. Moreover, patient-specific induced pluripotent stem (iPS) cells can be generated by reprogramming somatic cells.iPS cells have characteristics similar to those of ES cells and offer a new cell source for type I diabetes cell therapy that reduces the risk of immunologic rejection. In this review, we summarize the recent progress made in the differentiation of hES and iPS cells into functional pancreatic islet cells and discuss the challenges for their future study.

  15. Generation of pancreatic islet cells from human embryonic stem cells

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Efficiently obtaining functional pancreatic islet cells derived from human embryonic stem(hES) cells not only provides great potential to solve the shortage of islets sources for type I diabetes cell therapy,but also benefits the study of the development of the human pancreas and diabetes pathology.In 2001,hES cells were reported to have the capacity to generate insulin-producing cells by spontaneous differentiation in vitro.Since then,many strategies(such as overexpression of key transcription factors,delivery of key proteins for pancreatic development,co-transplantation of differentiated hES cells along with fetal pancreas,stepwise differentiation by mimicking in vivo pancreatic development) have been employed in order to induce the differentiation of pancreatic islet cells from hES cells.Moreover,patient-specific induced pluripotent stem(iPS) cells can be generated by reprogramming somatic cells.iPS cells have characteristics similar to those of ES cells and offer a new cell source for type I diabetes cell therapy that reduces the risk of immunologic rejection.In this review,we summarize the recent progress made in the differentiation of hES and iPS cells into functional pancreatic islet cells and discuss the challenges for their future study.

  16. Plasma membrane proteomics of human embryonic stem cells and human embryonal carcinoma cells.

    NARCIS (Netherlands)

    Dormeyer, W.; van Hoof, D.; Braam, S.R.; Heck, A.J.R.; Mummery, C.L.; Krijgsveld, J.

    2008-01-01

    Human embryonic stem cells (hESCs) are of immense interest in regenerative medicine as they can self-renew indefinitely and can give rise to any adult cell type. Human embryonal carcinoma cells (hECCs) are the malignant counterparts of hESCs found in testis tumors. hESCs that have acquired chromosom

  17. Derivation of Human Skin Fibroblast Lines for Feeder Cells of Human Embryonic Stem Cells.

    Science.gov (United States)

    Unger, Christian; Felldin, Ulrika; Rodin, Sergey; Nordenskjöld, Agneta; Dilber, Sirac; Hovatta, Outi

    2016-02-03

    After the first derivations of human embryonic stem cell (hESC) lines on fetal mouse feeder cell layers, the idea of using human cells instead of mouse cells as feeder cells soon arose. Mouse cells bear a risk of microbial contamination, and nonhuman immunogenic proteins are absorbed from the feeders to hESCs. Human skin fibroblasts can be effectively used as feeder cells for hESCs. The same primary cell line, which can be safely used for up to 15 passages after stock preparations, can be expanded and used for large numbers of hESC derivations and cultures. These cells are relatively easy to handle and maintain. No animal facilities or animal work is needed. Here, we describe the derivation, culture, and cryopreservation procedures for research-grade human skin fibroblast lines. We also describe how to make feeder layers for hESCs using these fibroblasts.

  18. Mesenchymal stem cell like (MSCl) cells generated from human embryonic stem cells support pluripotent cell growth

    Energy Technology Data Exchange (ETDEWEB)

    Varga, Nora [Membrane Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest (Hungary); Vereb, Zoltan; Rajnavoelgyi, Eva [Department of Immunology, Medical and Health Science Centre, University of Debrecen, Debrecen (Hungary); Nemet, Katalin; Uher, Ferenc; Sarkadi, Balazs [Membrane Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest (Hungary); Apati, Agota, E-mail: apati@kkk.org.hu [Membrane Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest (Hungary)

    2011-10-28

    Highlights: Black-Right-Pointing-Pointer MSC like cells were derived from hESC by a simple and reproducible method. Black-Right-Pointing-Pointer Differentiation and immunosuppressive features of MSCl cells were similar to bmMSC. Black-Right-Pointing-Pointer MSCl cells as feeder cells support the undifferentiated growth of hESC. -- Abstract: Mesenchymal stem cell like (MSCl) cells were generated from human embryonic stem cells (hESC) through embryoid body formation, and isolated by adherence to plastic surface. MSCl cell lines could be propagated without changes in morphological or functional characteristics for more than 15 passages. These cells, as well as their fluorescent protein expressing stable derivatives, efficiently supported the growth of undifferentiated human embryonic stem cells as feeder cells. The MSCl cells did not express the embryonic (Oct4, Nanog, ABCG2, PODXL, or SSEA4), or hematopoietic (CD34, CD45, CD14, CD133, HLA-DR) stem cell markers, while were positive for the characteristic cell surface markers of MSCs (CD44, CD73, CD90, CD105). MSCl cells could be differentiated toward osteogenic, chondrogenic or adipogenic directions and exhibited significant inhibition of mitogen-activated lymphocyte proliferation, and thus presented immunosuppressive features. We suggest that cultured MSCl cells can properly model human MSCs and be applied as efficient feeders in hESC cultures.

  19. Collision tumor of the kidney composed of clear cell carcinoma and collecting duct carcinoma:report of a case with unusual morphology and clinical follow-up

    Institute of Scientific and Technical Information of China (English)

    Rhonda Burch-Smith; Nizar M Tannir; Erika Resetkova; Pheroze Tamboli; Priya Rao

    2014-01-01

    We report the case of a 67-year-old female who presented with a large renal mass. Gross examination of the nephrectomy specimen demonstrated a 6-cm renal mass that invaded into the renal sinus and perinephric fat. Histologic examination revealed two distinct tumor types. The first type was a conventional (clear cell) renal cell carcinoma that was of low nuclear grade and comprised the minority of the overall tumor. The second type was a high-grade collecting duct carcinoma with glandular/tubular differentiation and composed the majority of the tumor. Immunohistochemical studies demonstrated distinctive patterns of the two tumor types, thus confirming two distinct lineages. Five months postoperatively, the patient developed metastasis to the lungs and right hilar lymph node region. A fine needle aspiration of a lung nodule demonstrated a metastatic, poorly differentiated carcinoma, similar to the colecting duct carcinoma component in the kidney. Colision tumors of the kidney are rare with fewer than 10 cases reported in the literature. Our report further expands the spectrum of this rare phenomenon.

  20. Characterization of human PGD blastocysts with unbalanced chromosomal translocations and human embryonic stem cell line derivation?

    Science.gov (United States)

    Frydman, N; Féraud, O; Bas, C; Amit, M; Frydman, R; Bennaceur-Griscelli, A; Tachdjian, G

    2009-01-01

    Novel embryonic stem cell lines derived from embryos carrying structural chromosomal abnormalities obtained after preimplantation genetic diagnosis (PGD) are of interest to study in terms of the influence of abnormalities on further development. A total of 22 unbalanced blastocysts obtained after PGD were analysed for structural chromosomal defects. Morphological description and chromosomal status of these blastocysts was established and they were used to derive human embryonic stem cell (ESC) lines. An outgrowth of cells was observed for six blastocysts (6/22; 27%). For two blastocysts, the exact morphology was unknown since they were at early stage, and for four blastocysts, the inner cell mass was clearly visible. Fifteen blastocysts carried an unbalanced chromosomal defect linked to a reciprocal translocation, resulting in a positive outgrowth of cells for five blastocysts. One human ESC line was obtained from a blastocyst carrying a partial chromosome-21 monosomy and a partial chromosome-1 trisomy. Six blastocysts carried an unbalanced chromosomal defect linked to a Robertsonian translocation, and one showed a positive outgrowth of cells. One blastocyst carried an unbalanced chromosomal defect linked to an insertion and no outgrowth was observed. The efficiency of deriving human ESC lines with constitutional chromosomal disorders was low and probably depends on the initial morphological aspect of the blastocysts and/or the type of the chromosomal disorders.

  1. Integrated microRNA and mRNA Signature Associated with the Transition from the Locally Confined to the Metastasized Clear Cell Renal Cell Carcinoma Exemplified by miR-146-5p.

    Directory of Open Access Journals (Sweden)

    Zofia Wotschofsky

    Full Text Available MicroRNAs (miRNAs regulate gene expression by interfering translation or stability of target transcripts. This interplay between miRNA and their mRNA has been proposed as an important process in cancer development and progression. We have investigated molecular networks impacted by predicted mRNA targets of differentially expressed miRNAs in patients with clear cell renal cell carcinoma (ccRCC diagnosed with or without metastasis.miRNA and mRNA microarray expression profiles derived from primary ccRCC from patients with (16 samples or without diagnosed metastasis (22 samples were used to identify anti-correlated miRNA-mRNA interaction in ccRCC. For this purpose, Ingenuity pathway analysis microRNA Target Filter, which enables prioritization of experimentally validated and predicted mRNA targets was used. By applying an expression pairing tool, the analysis was focused on targets exhibiting altered expression in our analysis, finding miRNAs and their target genes with opposite or same expression. The resulting identified interactions were revalidated by RT-qPCR in another cohort of ccRCC patients. A selection of the predicted miRNA-mRNA interactions was tested by functional analyses using miRNA knockdown and overexpression experiments in renal cancer cell lines.Among the significantly differentially expressed miRNAs, we have identified three miRNAs (miR-146a-5p, miR-128a-3p, and miR-17-5p that were upregulated in primary tumors from patients without metastasis and downregulated in primary tumors from patients with metastasis. We have further identified mRNA targets, which expression were inversely correlated to these 3 miRNAs, and have been previously experimentally demonstrated in cancer setting in humans. Specifically, we showed that CXCL8/IL8, UHRF1, MCM10, and CDKN3 were downregulated and targeted by miR-146a-5p. The interaction between miR-146a-5p and their targets CXCL8 and UHRF1 was validated in cell culture experiments.We identified novel

  2. Effect of microemulsions on cell viability of human dermal fibroblasts

    Science.gov (United States)

    Li, Juyi; Mironava, Tatsiana; Simon, Marcia; Rafailovich, Miriam; Garti, Nissim

    Microemulsions are optically clear, thermostable and isotropic mixture consisting of water, oil and surfactants. Their advantages of ease preparation, spontaneous formation, long-term stability and enhanced solubility of bioactive materials make them great potentials as vehicles in food and pharmaceutical applications. In this study, comparative in vitro cytotoxicity tests were performed to select a best formulation of microemulsion with the least toxicity for human dermal fibroblasts. Three different kinds of oils and six different kinds of surfactants were used to form microemulsions by different ratios. The effect of oil type and surfactant type as well as their proportions on cell proliferation and viability were tested.

  3. Snow-clearing operations

    CERN Multimedia

    EN Department

    2010-01-01

    To facilitate snow clearing operations, which commence at 4.30 in the morning, all drivers of CERN cars are kindly requested to park them together in groups. This will help us greatly assist us in our work. Thank-you for your help. Transport Group / EN-HE Tel. 72202

  4. One cases report:adult clear cell sarcoma of kidney%成人肾透明细胞肉瘤1例病例报道

    Institute of Scientific and Technical Information of China (English)

    江冬梅; 王凤玮

    2015-01-01

    Clear cell sarcoma of kidney(CCSK) is a rare and malignant sarcoma, whose the origin of organization is not clear,and most reports indicated the patients is children,but not adults.The sarcoma has hard prognosis and poor sur-vival rate.CCSK is similar to other renal malignant tumors very much in clinical and histological aspects,therefore,the differential diagnosis with other renal malignant tumor is very important.Now we report a case of an adult female pa-tients who was already diagnosed with CCSK of the kidney,and state the discrimination with CCSK of kidney and Wilms’tumor.%肾透明细胞肉瘤(CCSK)是一种组织来源尚未十分清楚的罕见软组织恶性肿瘤,该病多见于儿童,成人患者罕见。成人CCSK预后极差,生存期短。 CCSK临床表现和组织形态学与多种肾恶性肿瘤相似,误诊率较高,在患者预后和治疗方面,CCSK与其他肾恶性肿瘤差别较大,因此,CCSK与其他肾恶性肿瘤的鉴别诊断对于CCSK的确诊至关重要。本文报道我院1例已确诊为CCSK的成年女性患者,简要阐述该疾病与肾透明细胞癌、肾母细胞瘤的鉴别。

  5. In Vitro Brucella suis Infection Prevents the Programmed Cell Death of Human Monocytic Cells

    Science.gov (United States)

    Gross, Antoine; Terraza, Annie; Ouahrani-Bettache, Safia; Liautard, Jean-Pierre; Dornand, Jacques

    2000-01-01

    During the complex interaction between an infectious agent and a host organism, the pathogen can interfere with the host cell's programmed death to its own benefit. Induction or prevention of host cell apoptosis appears to be a critical step for determining the infection outcome. Members of the gram-negative bacterial genus Brucella are intracellular pathogens which preferentially invade monocytic cells and develop within these cells. We investigated the effect of Brucella suis infection on apoptosis of human monocytic phagocytes. The present study provides evidence that Brucella infection inhibited spontaneously occurring apoptosis in human monocytes. Prevention of monocyte apoptosis was not mediated by Brucella lipopolysaccharide and required bacterial survival within infected cells. Both invaded and noninvaded cells were protected, indicating that soluble mediators released during infection were involved in the phenomenon. Analysis of Brucella-infected monocytes revealed specific overexpression of the A1 gene, a member of the bcl-2 family implicated in the survival of hematopoietic cells. Brucella infection also rendered macrophage-like cells resistant to Fas ligand- or gamma interferon-induced apoptosis, suggesting that Brucella infection protected host cells from several cytotoxic processes occurring at different steps of the immune response. The present data clearly show that Brucella suis modulated the monocyte/macrophage's apoptotic response to the advantage of the pathogen, thus preventing host cell elimination. This might represent a strategy for Brucella development in infected hosts. PMID:10603407

  6. Human tumour antigens defined by cytotoxicity and proliferative responses of cultured lymphoid cells

    Science.gov (United States)

    Vose, Brent M.; Bonnard, Guy D.

    1982-03-01

    The long-term goal of many laboratories has been to develop cellular reagents having specific reactivity against human tumour cells. Such immune cells should prove useful for defining the antigenicity of human malignancies and may have important therapeutic potential, as has been clearly shown in some animal models1. Here we describe methods of initiating continued lymphocyte cultures (CLC) having specific anti-tumour reactivity using conditioned media containing interleukin-2 (IL-2).

  7. Stem cells in the human breast

    DEFF Research Database (Denmark)

    Petersen, Ole William; Polyak, Kornelia

    2010-01-01

    The origins of the epithelial cells participating in the development, tissue homeostasis, and cancer of the human breast are poorly understood. However, emerging evidence suggests a role for adult tissue-specific stem cells in these processes. In a hierarchical manner, these generate the two main...

  8. Human hair genealogies and stem cell latency

    Directory of Open Access Journals (Sweden)

    Tavaré Simon

    2006-02-01

    Full Text Available Abstract Background Stem cells divide to reproduce themselves and produce differentiated progeny. A fundamental problem in human biology has been the inability to measure how often stem cells divide. Although it is impossible to observe every division directly, one method for counting divisions is to count replication errors; the greater the number of divisions, the greater the numbers of errors. Stem cells with more divisions should produce progeny with more replication errors. Methods To test this approach, epigenetic errors (methylation in CpG-rich molecular clocks were measured from human hairs. Hairs exhibit growth and replacement cycles and "new" hairs physically reappear even on "old" heads. Errors may accumulate in long-lived stem cells, or in their differentiated progeny that are eventually shed. Results Average hair errors increased until two years of age, and then were constant despite decades of replacement, consistent with new hairs arising from infrequently dividing bulge stem cells. Errors were significantly more frequent in longer hairs, consistent with long-lived but eventually shed mitotic follicle cells. Conclusion Constant average hair methylation regardless of age contrasts with the age-related methylation observed in human intestine, suggesting that error accumulation and therefore stem cell latency differs among tissues. Epigenetic molecular clocks imply similar mitotic ages for hairs on young and old human heads, consistent with a restart with each new hair, and with genealogies surreptitiously written within somatic cell genomes.

  9. Human neutrophils facilitate tumor cell transendothelial migration.

    LENUS (Irish Health Repository)

    Wu, Q D

    2012-02-03

    Tumor cell extravasation plays a key role in tumor metastasis. However, the precise mechanisms by which tumor cells migrate through normal vascular endothelium remain unclear. In this study, using an in vitro transendothelial migration model, we show that human polymorphonuclear neutrophils (PMN) assist the human breast tumor cell line MDA-MB-231 to cross the endothelial barrier. We found that tumor-conditioned medium (TCM) downregulated PMN cytocidal function, delayed PMN apoptosis, and concomitantly upregulated PMN adhesion molecule expression. These PMN treated with TCM attached to tumor cells and facilitated tumor cell migration through different endothelial monolayers. In contrast, MDA-MB-231 cells alone did not transmigrate. FACScan analysis revealed that these tumor cells expressed high levels of intercellular adhesion molecule-1 (ICAM-1) but did not express CD11a, CD11b, or CD18. Blockage of CD11b and CD18 on PMN and of ICAM-1 on MDA-MB-231 cells significantly attenuated TCM-treated, PMN-mediated tumor cell migration. These tumor cells still possessed the ability to proliferate after PMN-assisted transmigration. These results indicate that TCM-treated PMN may serve as a carrier to assist tumor cell transendothelial migration and suggest that tumor cells can exploit PMN and alter their function to facilitate their extravasation.

  10. Efficient induction of cross-presentating human B cell by transduction with human adenovirus type 7 vector.

    Science.gov (United States)

    Peng, Ying; Lai, Meimei; Lou, Yunyan; Liu, Yanqing; Wang, Huiyan; Zheng, Xiaoqun

    2016-01-01

    Although human autologous B cells represent a promising alternative to dendritic cells (DCs) for easy large-scale preparation, the naive human B cells are always poor at antigen presentation. The safe and effective usage record of human adenovirus type 7 (HAdV7) live vaccines makes it attractive as a promising vaccine vector candidate. To investigate whether HAdV7 vector could be used to induce the human B cells cross-presentation, in the present study, we constructed the E3-defective recombinant HAdV7 vector encoding green fluorescent protein (GFP) and carcinoembryonic antigen (CEA). We demonstrated that naive human B cells can efficiently be transduced, and that the MAPKs/NF-κB pathway can be activated by recombinant HAdV7. We proved that cytokine TNF-α, IL-6 and IL-10, surface molecule MHC class I and the CD86, antigen-processing machinery (APM) compounds ERp57, TAP-1, and TAP-2. were upregulated in HAdV7 transduced human B cells. We also found that CEA-specific IFNγ expression, degranulation, and in vitro and ex vivo cytotoxicities are induced in autologous CD8(+) T cells presensitized by HAd7CEA modified human B cells. Meanwhile, our evidences clearly show that Toll-like receptors 9 (TLR9) antagonist IRS 869 significantly eliminated most of the HAdV7 initiated B cell activation and CD8(+) T cells response, supporting the role and contribution of TLR9 signaling in HAdV7 induced human B cell cross-presentation. Besides a better understanding of the interactions between recombinant HAdV7 and human naive B cells, to our knowledge, the present study provides the first evidence to support the use of HAdV7-modified B cells as a vehicle for vaccines and immunotherapy.

  11. Global gene expression profiling of a mouse model of ovarian clear cell carcinoma caused by ARID1A and PIK3CA mutations implicates a role for inflammatory cytokine signaling

    Directory of Open Access Journals (Sweden)

    Ronald L. Chandler

    2015-09-01

    Full Text Available Ovarian clear-cell carcinoma (OCCC is an aggressive form of epithelial ovarian cancer (EOC. OCCC represents 5–25% of all EOC incidences and is the second leading cause of death from ovarian cancer (Glasspool and McNeish, 2013 [1]. A recent publication by Chandler et al. reported the first mouse model of OCCC that resembles human OCCC both genetically and histologically by inducing a localized deletion of ARID1A and the expression of the PIK3CAH1047R substitution mutation (Chandler et al., 2015 [2]. We utilized Affymetrix Mouse Gene 2.1 ST arrays for the global gene expression profiling of mouse primary OCCC tumor samples and animal-matched normal ovaries to identify cancer-dependent gene expression. We describe the approach used to generate the differentially expressed genes from the publicly available data deposited at the Gene Expression Omnibus (GEO database under the accession number GSE57380. These data were used in cross-species comparisons to publically available human OCCC gene expression data and allowed the identification of coordinately regulated genes in both mouse and human OCCC and supportive of a role for inflammatory cytokine signaling in OCCC pathogenesis (Chandler et al., 2015 [2].

  12. INTERACTIONS BETWEEN THE HUMAN GASTRIC CARCINOMA CELL AND THE HUMAN VASCULAR ENDOTHELIAL CELL

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective To definite the interactions between the human gastric carcinoma cell and the human vascular endothelial cell during the establishment and maintenance of the tumor vascular system and the tumor hematogenous metastasis.Methods We prepared the conditioned mediums of each cell so as to study the effect of the conditioned medium on itself or others by MTT colorimetry. The comprehensive effect of interactions between two cells was determined by stratified transfilter co-culture or direct contact co-culture.Results The conditioned medium of human gastric carcinoma cell can stimulate the proliferation of the human vascular endothelial cell, but the CM of HVEC can inhibit the growth of HGCC. Both kinds of cells can inhibit the growth of itself. The ultimate comprehensive effect of the interactions between two kinds of cells was increase of total cell numbers.Conclusion There exist the complicated interactions between the human gastric carcinoma cell and the human vascular endothelial cell during the tumor angiogenesis and the tumor hematogenous metastasis. The ultimate comprehensive effect of the interactions is increase of total cells numbers and tumor volume.

  13. Directed Differentiation of Human Pluripotent Stem Cells to Microglia

    Directory of Open Access Journals (Sweden)

    Panagiotis Douvaras

    2017-06-01

    Full Text Available Microglia, the immune cells of the brain, are crucial to proper development and maintenance of the CNS, and their involvement in numerous neurological disorders is increasingly being recognized. To improve our understanding of human microglial biology, we devised a chemically defined protocol to generate human microglia from pluripotent stem cells. Myeloid progenitors expressing CD14/CX3CR1 were generated within 30 days of differentiation from both embryonic and induced pluripotent stem cells (iPSCs. Further differentiation of the progenitors resulted in ramified microglia with highly motile processes, expressing typical microglial markers. Analyses of gene expression and cytokine release showed close similarities between iPSC-derived (iPSC-MG and human primary microglia as well as clear distinctions from macrophages. iPSC-MG were able to phagocytose and responded to ADP by producing intracellular Ca2+ transients, whereas macrophages lacked such response. The differentiation protocol was highly reproducible across several pluripotent stem cell lines.

  14. Human CD14 mediates recognition and phagocytosis of apoptotic cells.

    Science.gov (United States)

    Devitt, A; Moffatt, O D; Raykundalia, C; Capra, J D; Simmons, D L; Gregory, C D

    1998-04-02

    Cells undergoing programmed cell death (apoptosis) are cleared rapidly in vivo by phagocytes without inducing inflammation. Here we show that the glycosylphosphatidylinositol-linked plasma-membrane glycoprotein CD14 on the surface of human macrophages is important for the recognition and clearance of apoptotic cells. CD14 can also act as a receptor that binds bacterial lipopolysaccharide (LPS), triggering inflammatory responses. Overstimulation of CD14 by LPS can cause the often fatal toxic-shock syndrome. Here we show that apoptotic cells interact with CD14, triggering phagocytosis of the apoptotic cells. This interaction depends on a region of CD14 that is identical to, or at least closely associated with, a region known to bind LPS. However, apoptotic cells, unlike LPS, do not provoke the release of pro-inflammatory cytokines from macrophages. These results indicate that clearance of apoptotic cells is mediated by a receptor whose interactions with 'non-self' components (LPS) and 'self' components (apoptotic cells) produce distinct macrophage responses.

  15. Fibronectin production by human mammary cells

    Energy Technology Data Exchange (ETDEWEB)

    Stampfer, M.R. (Univ. of California, Berkeley); Vlodavsky, I.; Smith, H.S.; Ford, R.; Becker, F.F.; Riggs, J.

    1981-01-01

    Human mammary cells were examined for the presence of the high-molecular-weight surface glycoprotein fibronectin. Early passage mammary epithelial cell and fibroblast cultures from both carcinomas and normal tissues were tested for the presence of cell-associated fibronectin by immunofluorescence microscopy and for the synthesis and secretion of fibronectin by specific immunoprecipitation of metabolically labeled protein. In vivo frozen sections of primary carcinomas and normal tissues were tested for the localization of fibronectin by immunofluorescence microscopy. In contrast to the extensive fibrillar networks of fibronectin found in the fibroblast cultures, the epithelial cell cultures from both tissue sources displayed a pattern of cell-associated fibronectin characterizd by powdery, punctate staining. However, the cultured epithelial cells, as well as the fibroblasts, secreted large quantities of fibronectin into the medium. Putative myoepithelial cells also displayed extensive fibrillar networks of fibronectin. The difference in cell-associated fibronectin distribution between the epithelial cells and the fibroblasts and putative myoepithelial cells provided a simple means of quantitating stromal and myoepithelial cell contamination of the mammary epithelial cells in culture. In vivo, normal tissues showed fibronectin primarily localized in the basement membrane surrounding the epithelial cells and in the stroma. Most primary carcinomas displayed powdery, punctate staining on the epithelial cells in addition to the fibronectin present in the surrounding stroma.

  16. The herpes virus Fc receptor gE-gI mediates antibody bipolar bridging to clear viral antigens from the cell surface.

    Science.gov (United States)

    Ndjamen, Blaise; Farley, Alexander H; Lee, Terri; Fraser, Scott E; Bjorkman, Pamela J

    2014-03-01

    The Herpes Simplex Virus 1 (HSV-1) glycoprotein gE-gI is a transmembrane Fc receptor found on the surface of infected cells and virions that binds human immunoglobulin G (hIgG). gE-gI can also participate in antibody bipolar bridging (ABB), a process by which the antigen-binding fragments (Fabs) of the IgG bind a viral antigen while the Fc binds to gE-gI. IgG Fc binds gE-gI at basic, but not acidic, pH, suggesting that IgG bound at extracellular pH by cell surface gE-gI would dissociate and be degraded in acidic endosomes/lysosomes if endocytosed. The fate of viral antigens associated with gE-gI-bound IgG had been unknown: they could remain at the cell surface or be endocytosed with IgG. Here, we developed an in vitro model system for ABB and investigated the trafficking of ABB complexes using 4-D confocal fluorescence imaging of ABB complexes with transferrin or epidermal growth factor, well-characterized intracellular trafficking markers. Our data showed that cells expressing gE-gI and the viral antigen HSV-1 gD endocytosed anti-gD IgG and gD in a gE-gI-dependent process, resulting in lysosomal localization. These results suggest that gE-gI can mediate clearance of infected cell surfaces of anti-viral host IgG and viral antigens to evade IgG-mediated responses, representing a general mechanism for viral Fc receptors in immune evasion and viral pathogenesis.

  17. The herpes virus Fc receptor gE-gI mediates antibody bipolar bridging to clear viral antigens from the cell surface.

    Directory of Open Access Journals (Sweden)

    Blaise Ndjamen

    2014-03-01

    Full Text Available The Herpes Simplex Virus 1 (HSV-1 glycoprotein gE-gI is a transmembrane Fc receptor found on the surface of infected cells and virions that binds human immunoglobulin G (hIgG. gE-gI can also participate in antibody bipolar bridging (ABB, a process by which the antigen-binding fragments (Fabs of the IgG bind a viral antigen while the Fc binds to gE-gI. IgG Fc binds gE-gI at basic, but not acidic, pH, suggesting that IgG bound at extracellular pH by cell surface gE-gI would dissociate and be degraded in acidic endosomes/lysosomes if endocytosed. The fate of viral antigens associated with gE-gI-bound IgG had been unknown: they could remain at the cell surface or be endocytosed with IgG. Here, we developed an in vitro model system for ABB and investigated the trafficking of ABB complexes using 4-D confocal fluorescence imaging of ABB complexes with transferrin or epidermal growth factor, well-characterized intracellular trafficking markers. Our data showed that cells expressing gE-gI and the viral antigen HSV-1 gD endocytosed anti-gD IgG and gD in a gE-gI-dependent process, resulting in lysosomal localization. These results suggest that gE-gI can mediate clearance of infected cell surfaces of anti-viral host IgG and viral antigens to evade IgG-mediated responses, representing a general mechanism for viral Fc receptors in immune evasion and viral pathogenesis.

  18. Epithelial cells as alternative human biomatrices for comet assay

    Directory of Open Access Journals (Sweden)

    Emilio eRojas

    2014-11-01

    Full Text Available The comet assay is a valuable experimental tool aimed at mapping DNA damage in human cells in vivo for environmental and occupational monitoring, as well as for therapeutic purposes, such as storage prior to transplant, during tissue engineering, and in experimental ex vivo assays. Furthermore, due to its great versatility, the comet assay allows to explore the use of alternative cell types to assess DNA damage, such as epithelial cells. Epithelial cells, as specialized components of many organs, have the potential to serve as biomatrices that can be used to evaluate genotoxicity and may also serve as early effect biomarkers. Furthermore, 80% of solid cancers are of epithelial origin, which points to the importance of studying DNA damage in these tissues. Indeed, studies including comet assay in epithelial cells have either clear clinical applications (lens and corneal epithelial cells or examine genotoxicity within human biomonitoring and in vitro studies. We here review improvements in determining DNA damage using the comet assay by employing lens, corneal, tear duct, buccal, and nasal epithelial cells. For some of these tissues invasive sampling procedures are needed. Desquamated epithelial cells must be obtained and dissociated prior to examination using the comet assay, and such procedures may induce varying amounts of DNA damage. Buccal epithelial cells require lysis enriched with proteinase K to obtain free nucleosomes.Over a thirty year period, the comet assay in epithelial cells has been litlle employed, however its use indicates that it could be an extraordinary tool not only for risk assessment, but also for diagnosis, prognosis of treatments and diseases.

  19. Laser printing of skin cells and human stem cells.

    Science.gov (United States)

    Koch, Lothar; Kuhn, Stefanie; Sorg, Heiko; Gruene, Martin; Schlie, Sabrina; Gaebel, Ralf; Polchow, Bianca; Reimers, Kerstin; Stoelting, Stephanie; Ma, Nan; Vogt, Peter M; Steinhoff, Gustav; Chichkov, Boris

    2010-10-01

    Laser printing based on laser-induced forward transfer (LIFT) is a new biofabrication technique for the arrangement of biological materials or living cells in well-defined patterns. In the current study, skin cell lines (fibroblasts/keratinocytes) and human mesenchymal stem cells (hMSC) were chosen for laser printing experiments due to their high potential in regeneration of human skin and new application possibilities of stem cell therapy. To evaluate the influence of LIFT on the cells, their survival rate, their proliferation and apoptotic activity, and the DNA damages and modifications of their cell surface markers were assessed and statistically evaluated over several days. The cells survived the transfer procedure with a rate of 98%  +/- 1% standard error of the mean (skin cells) and 90%  +/- 10% (hMSC), respectively. All used cell types maintain their ability to proliferate after LIFT. Further, skin cells and hMSC did not show an increase of apoptosis or DNA fragmentation. In addition, the hMSC keep their phenotype as proven by fluorescence activated cell sorting (FACS) analysis. This study demonstrates LIFT as a suitable technique for unharmed computer-controlled positioning of different cell types and a promising tool for future applications in the ex vivo generation of tissue replacements.

  20. Comprehensive assessment of the expression of the SWI/SNF complex defines two distinct prognostic subtypes of ovarian clear cell carcinoma.

    Science.gov (United States)

    Abou-Taleb, Hisham; Yamaguchi, Ken; Matsumura, Noriomi; Murakami, Ryusuke; Nakai, Hidekatsu; Higasa, Koichiro; Amano, Yasuaki; Abiko, Kaoru; Yoshioka, Yumiko; Hamanishi, Junzo; Koshiyama, Masafumi; Baba, Tsukasa; Yamada, Ryo; Matsuda, Fumihiko; Konishi, Ikuo; Mandai, Masaki

    2016-08-23

    Somatic mutations in the ARID1A tumor-suppressor gene have been frequently identified in ovarian clear cell carcinoma (CCC) cases. BAF250a encoded by ARID1A is a member of the SWI/SNF complex, but the expression and mutation status of other SWI/SNF subunits have not been explored. The current study aimed to elucidate the biological and clinical significance of the SWI/SNF complex subunits, by assessing the expression and mutation status of SWI/SNF subunits, and distinct genomic aberrations associated with their expression. Of 82 CCC specimens, 38 samples presented no BAF250a expression, and 50 samples exhibited the loss of at least one subunit of the SWI/SNF complex. Cases which lack at least one SWI/SNF complex component exhibited significantly more advanced stages, faster growth and stronger nuclear atypia compared with SWI/SNF-positive samples (pcomplex subunit exhibited significantly shorter overall and progression-free survivals (pcomplex serves as an independent prognostic factor (pcomplex subunits demonstrated aggressive behaviors and poor prognosis, whereas the CCCs with positive expression for all SWI/SNF components presented more copy number alterations and a favorable prognosis.

  1. Human spleen and red blood cells

    Science.gov (United States)

    Pivkin, Igor; Peng, Zhangli; Karniadakis, George; Buffet, Pierre; Dao, Ming

    2016-11-01

    Spleen plays multiple roles in the human body. Among them is removal of old and altered red blood cells (RBCs), which is done by filtering cells through the endothelial slits, small micron-sized openings. There is currently no experimental technique available that allows us to observe RBC passage through the slits. It was previously noticed that people without a spleen have less deformable red blood cells, indicating that the spleen may play a role in defining the size and shape of red blood cells. We used detailed RBC model implemented within the Dissipative Particle Dynamics (DPD) simulation framework to study the filter function of the spleen. Our results demonstrate that spleen indeed plays major role in defining the size and shape of the healthy human red blood cells.

  2. Ultrastructure of human neural stem/progenitor cells and neurospheres

    Institute of Scientific and Technical Information of China (English)

    Yaodong Zhao; Tianyi Zhang; Qiang Huang; Aidong Wang; Jun Dong; Qing Lan; Zhenghong Qin

    2009-01-01

    BACKGROUND: Biological and morphological characteristics of neural stern/progenitor cells (NSPCs) have been widely investigated.OBJECTIVE: To explore the ultrastructure of human embryo-derived NSPCs and neurospheres cultivated in vitro using electron microscopy.DESIGN, TIME AND SETTING: A cell biology experiment was performed at the Brain Tumor Laboratory of Soochow University, and Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University between August 2007 and April 2008.MATERIALS: Human fetal brain tissue was obtained from an 8-week-old aborted fetus; serum-free Dulbecco's modified Eagle's medium/F12 culture medium was provided by Gibco, USA; scanning electron microscope was provided by Hitachi instruments, Japan; transmission electron microscope was provided by JEOL, Japan.METHODS: NSPCs were isolated from human fetal brain tissue and cultivated in serum-free Dulbecco's modified Eagle's medium/F12 culture medium. Cells were passaged every 5-7 days. After three passages, NSPCs were harvested and used for ultrastructural examination.MAIN OUTCOME MEASURES: Ultrastructural examination of human NSPCs and adjacent cells in neurospheres.RESULTS: Individual NSPCs were visible as spherical morphologies with rough surfaces under scanning electron microscope. Generally, they had large nuclei and little cytoplasm. Nuclei were frequently globular with large amounts of euchromatin and a small quantity of heterochromatin, and most NSPCs had only one nucleolus. The Golgi apparatus and endoplasmic reticulum were underdeveloped; however, autophagosomes were clearly visible. The neurospheres were made up of NSPCs and non-fixiform material inside. Between adjacent cells and at the cytoplasmic surface of apposed plasma membranes, there were vesicle-like structures. Some membrane boundaries with high permeabilities were observed between some contiguous NSPCs in neurospheres, possibly attributable to plasmalemmal fusion between adjacent cells.CONCLUSION: A large number

  3. Extracellular calcium sensing receptor in human pancreatic cells

    Science.gov (United States)

    Rácz, G Z; Kittel, Á; Riccardi, D; Case, R M; Elliott, A C; Varga, G

    2002-01-01

    Background and aims: The extracellular calcium sensing receptor (CaR) plays a key role in the calcium homeostatic system and is therefore widely expressed in tissues involved in calcium metabolism. However, the CaR has also been identified in other tissues where its role is less clear. We have investigated the presence of the CaR in the human pancreas. Methods: Messenger RNA for the CaR was detected by reverse transcription-polymerase chain reaction and the protein was localised by immunostaining. CaR function was assayed in Capan-1 cells by measuring intracellular calcium and [3H] thymidine incorporation. Results: The receptor was highly expressed in human pancreatic ducts. It was also expressed in exocrine acinar cells, in islets of Langerhans, and in intrapancreatic nerves and blood vessels. The CaR was expressed in both normal and neoplastic human tissue samples but was detected in only one of five ductal adenocarcinoma cells lines examined. Experiments on the CaR expressing adenocarcinoma cell line Capan-1 showed that the CaR was functional and was linked to mobilisation of intracellular calcium. Stimulation of the CaR reduced Capan-1 cell proliferation. Conclusions: We propose that the CaR may play multiple functional roles in the human pancreas. In particular, the CaR on the duct luminal membrane may monitor and regulate the Ca2+ concentration in pancreatic juice by triggering ductal electrolyte and fluid secretion. This could help to prevent precipitation of calcium salts in the duct lumen. The CaR may also help to regulate the proliferation of pancreatic ductal cells. PMID:12377811

  4. Autophagy in human embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Thien Tra

    Full Text Available Autophagy (macroautophagy is a degradative process that involves the sequestration of cytosolic material including organelles into double membrane vesicles termed autophagosomes for delivery to the lysosome. Autophagy is essential for preimplantation development of mouse embryos and cavitation of embryoid bodies. The precise roles of autophagy during early human embryonic development, remain however largely uncharacterized. Since human embryonic stem cells constitute a unique model system to study early human embryogenesis we investigated the occurrence of autophagy in human embryonic stem cells. We have, using lentiviral transduction, established multiple human embryonic stem cell lines that stably express GFP-LC3, a fluorescent marker for the autophagosome. Each cell line displays both a normal karyotype and pluripotency as indicated by the presence of cell types representative of the three germlayers in derived teratomas. GFP expression and labelling of autophagosomes is retained after differentiation. Baseline levels of autophagy detected in cultured undifferentiated hESC were increased or decreased in the presence of rapamycin and wortmannin, respectively. Interestingly, autophagy was upregulated in hESCs induced to undergo differentiation by treatment with type I TGF-beta receptor inhibitor SB431542 or removal of MEF secreted maintenance factors. In conclusion we have established hESCs capable of reporting macroautophagy and identify a novel link between autophagy and early differentiation events in hESC.

  5. The use of automated quantitative analysis to evaluate epithelial-to-mesenchymal transition associated proteins in clear cell renal cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Fiach C O'Mahony

    Full Text Available BACKGROUND: Epithelial-to-mesenchymal transition (EMT has recently been implicated in the initiation and progression of renal cell carcinoma (RCC. Some mRNA gene expression studies have suggested a link between the EMT phenotype and poorer clinical outcome from RCC. This study evaluated expression of EMT-associated proteins in RCC using in situ automated quantitative analysis immunofluorescence (AQUA and compared expression levels with clinical outcome. METHODS/PRINCIPAL FINDINGS: Unsupervised hierarchical cluster analysis of pre-existing RCC gene expression array data (GSE16449 from 36 patients revealed the presence of an EMT transcriptional signature in RCC [E-cadherin high/SLUG low/SNAIL low]. As automated immunofluorescence technology is dependent on accurate definition of the tumour cells in which measurements take place is critical, extensive optimisation was carried out resulting in a novel pan-cadherin based tumour mask that distinguishes renal cancer cells from stromal components. 61 patients with ccRCC and clinical follow-up were subsequently assessed for expression of EMT-associated proteins (WT1, SNAIL, SLUG, E-cadherin and phospho-β-catenin on tissue microarrays. Using Kaplan-Meier analysis both SLUG (p = 0.029 and SNAIL (p = 0.024 (log rank Mantel-Cox were significantly associated with prolonged progression free survival (PFS. Using Cox regression univariate and multivariate analysis none of the biomarkers were significantly correlated with outcome. 14 of the 61 patients expressed the gene expression analysis predicted EMT-protein signature [E-cadherin high/SLUG low/SNAIL low], which was not found to be associated to PFS when measured at the protein level. A combination of high expression of SNAIL and low stage was able to stratify patients with greater significance (p = 0.001 then either variable alone (high SNAIL p = 0.024, low stage p = 0.029. CONCLUSIONS: AQUA has been shown to have the potential to

  6. Receptors for advanced glycation end products (RAGE) is associated with microvessel density and is a prognostic biomarker for clear cell renal cell carcinoma.

    Science.gov (United States)

    Guo, Yong; Xia, Peng; Zheng, Jian-Jian; Sun, Xian-Bin; Pan, Xiao-Dong; Zhang, Xing; Wu, Cun-Zao

    2015-07-01

    The receptor for advanced glycation end products (RAGE) is involved in a variety of biological processes, including tumorigenisis. Previous studies have demonstrated that RAGE regulates the neo-angiogenesis related downstream molecule - vascular endothelial growth factor receptor 2 (VEGFR-2). Here, we investigated the potential relationship between RAGE, VEGFR-2 and angiogenesis in 80 renal cell carcinoma (RCC) patients. Real-time quantitative PCR and ELISA analysis were used to explore the RAGE and VEGFR-2 gene expression levels and the protein of VEGFR-2 expression. Meanwhile, angiogenesis was detected by the semi-quantification of endothelial cell marker CD34 combined with caldesmon, which was detected by microvessel density (MVD) technique and immunohistochemistry. Tumors were classified as low or high RAGE-expressing using the median as the cut-off. Immunofluorescence staining for RAGE protein was performed as well. Additionally, the median gene expression levels of VEGFR-2 in the tumors were significantly lower expressing low levels of RAGE expression, 0.34 (95% CI, 0.28-0.39) compared to the expressing high levels of RAGE expression, 0.45 (95% CI, 0.29-0.61), (P=0.03). The median MVD was significantly lower in the tumors expressing low levels of RAGE, 6.5 (95% CI, 6.21-7.43), compared to the expressing high levels, 7.9 (95% CI, 6.25-8.93), (PRAGE expression are associated with high VEGFR-2 mRNA/protein levels and a higher density of microvessels; conversely, Kaplan-Meier survival analysis suggests that a significant correlation of elevated RAGE expression with decreased overall survival and metastasis-free survival. Our results establish that RAGE was identified as a potential prognostic biomarker for disease prognosis of RCC. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  7. Human embryonic stem cells for neuronal repair.

    Science.gov (United States)

    Ben-Hur, Tamir

    2006-02-01

    Human embryonic stem cells may serve as a potentially endeless source of transplantable cells to treat various neurologic disorders. Accumulating data have shown the therapeutic value of various neural precursor cell types in experimental models of neurologic diseases. Tailoring cell therapy for specific disorders requires the generation of cells that are committed to specific neural lineages. To this end, protocols were recently developed for the derivation of dopaminergic neurons, spinal motor neurons and oligodendrocytes from hESC. These protocols recapitulate normal development in culture conditions. However, a novel concept emerging from these studies is that the beneficial effect of transplanted stem cells is not only via cell replacement in damaged host tissue, but also by trophic and protective effects, as well as by an immunomodulatory effect that down-regulates detrimental brain inflammation.

  8. The art of thinking clearly

    CERN Document Server

    Dobelli, Rolf

    2013-01-01

    The Art of Thinking Clearly by world-class thinker and entrepreneur Rolf Dobelli is an eye-opening look at human psychology and reasoning — essential reading for anyone who wants to avoid “cognitive errors” and make better choices in all aspects of their lives. Have you ever: Invested time in something that, with hindsight, just wasn’t worth it? Or continued doing something you knew was bad for you? These are examples of cognitive biases, simple errors we all make in our day-to-day thinking. But by knowing what they are and how to spot them, we can avoid them and make better decisions. Simple, clear, and always surprising, this indispensable book will change the way you think and transform your decision-making—work, at home, every day. It reveals, in 99 short chapters, the most common errors of judgment, and how to avoid them.

  9. Novel agents inhibit human leukemic cells

    Institute of Scientific and Technical Information of China (English)

    Wei-ping YU; Juan LI

    2012-01-01

    Ouabain (OUA) and pyrithione zinc (PZ) have been proved as the potential drugs for treating acute myeloid leukemia (AML).Selected from a screening among 1040 Food and Drug Administration-approved pharmacological agents,both drugs showability to induce apoptosis of the culturing AML cells,exhibiting the poisoning effect on the cells.Studies also reveal the efficiency of the drugs in inhibiting the growth of human AML cells injected into the mice lacking of immunity and killing primary AML cells from the peripheral blood of AML patients[1].

  10. Clearing the Big Smog

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Beijing is trying to clean up its sky with a new standard for vehicle emissions From March 1,Beijing has imple- mented a new stricter vehicle emission standard that could lead to cleaner air,but also force thousands of cars off the road. StandardⅣ,the latest in a series of measures aimed at clearing the per- sistent smog,will match the current standard of the European Union. All the new light petro vehicles that are on sale in the Beijing market shall

  11. Immunohistochemical distinction of renal cell carcinoma from other carcinomas with clear-cell histomorphology: utility of CD10 and CA-125 in addition to PAX-2, PAX-8, RCCma, and adipophilin.

    Science.gov (United States)

    Mentrikoski, Mark J; Wendroth, Scott M; Wick, Mark R

    2014-10-01

    Clear-cell renal cell carcinoma (CC-RCC) is the most common primary kidney malignancy, yet this morphology is not unique to renal primary tumors, as clear-cell variants of numerous nonrenal carcinomas of varying lineages exist. Therefore, because of CC-RCC's ability to metastasize to nearly any anatomic location, ancillary studies such as immunohistochemistry are often needed to establish the diagnosis. Despite CD10 and renal cell carcinoma monoclonal antibody (RCCma) being touted as sensitive and specific markers, some have suggested that more recent stains including PAX-2, PAX-8, or adipophilin (ADP) are more robust markers of CC-RCC. In this study, 26 cases of CC-RCC, and 51 nonrenal carcinomas with clear-cell histomorphology (CCM) were stained with CD10, RCCma, PAX-2, PAX-8, and ADP. CA-125 was also included to help distinguish CC-RCC from Müllerian clear-cell carcinomas, due the known expression of PAX-2 and PAX-8 in both these entities. RCCma highlighted 77% of CC-RCC and 27% of the CCM group, whereas CD10 was positive in 85% and 25%, respectively. ADP highlighted all CC-RCC and 45% of CCMs. PAX-2 was positive in 81% of CC-RCC and 24% of CCM, whereas PAX-8 stained 100% of CC-RCC and 39% of CCM. Müllerian-derived tumors (clear-cell carcinomas of the ovary, vagina, and cervix) were positive with PAX-2 and PAX-8 in 69% and 100% of cases, respectively. No cases of CC-RCC stained with CA-125, whereas 88% of the Müllerian-derived tumors were positive. In summary, although new markers such as PAX-2 and PAX-8 tend to be more sensitive markers of CC-RCC, they lose specificity when Müllerian tumors are included. Inclusion of a classic renal marker such as CD10 or RCCma in the immunohistochemical panel, as well as CA-125 obviates this difficulty.

  12. Plaque assay for human coronavirus NL63 using human colon carcinoma cells

    Directory of Open Access Journals (Sweden)

    Drosten Christian

    2008-11-01

    Full Text Available Abstract Background Coronaviruses cause a broad range of diseases in animals and humans. Human coronavirus (hCoV NL63 is associated with up to 10% of common colds. Viral plaque assays enable the characterization of virus infectivity and allow for purifying virus stock solutions. They are essential for drug screening. Hitherto used cell cultures for hCoV-NL63 show low levels of virus replication and weak and diffuse cytopathogenic effects. It has not yet been possible to establish practicable plaque assays for this important human pathogen. Results 12 different cell cultures were tested for susceptibility to hCoV-NL63 infection. Human colon carcinoma cells (CaCo-2 replicated virus more than 100 fold more efficiently than commonly used African green monkey kidney cells (LLC-MK2. CaCo-2 cells showed cytopathogenic effects 4 days post infection. Avicel, agarose and carboxymethyl-cellulose overlays proved suitable for plaque assays. Best results were achieved with Avicel, which produced large and clear plaques from the 4th day of infection. The utility of plaque assays with agrose overlay was demonstrated for purifying virus, thereby increasing viral infectivity by 1 log 10 PFU/mL. Conclusion CaCo-2 cells support hCoV-NL63 better than LLC-MK2 cells and enable cytopathogenic plaque assays. Avicel overlay is favourable for plaque quantification, and agarose overlay is preferred for plaque purification. HCoV-NL63 virus stock of increased infectivity will be beneficial in antiviral screening, animal modelling of disease, and other experimental tasks.

  13. In vivo liver regeneration potential of human induced pluripotent stem cells from diverse origins.

    Science.gov (United States)

    Liu, Hua; Kim, Yonghak; Sharkis, Saul; Marchionni, Luigi; Jang, Yoon-Young

    2011-05-11

    Human induced pluripotent stem cells (iPSCs) are a potential source of hepatocytes for liver transplantation to treat end-stage liver disease. In vitro differentiation of human iPSCs into hepatic cells has been achieved using a multistage differentiation protocol, but whether these cells are functional and capable of engrafting and regenerating diseased liver tissue is not clear. We show that human iPSC-derived hepatic cells at various differentiation stages can engraft the liver in a mouse transplantation model. Using the same differentiation and transplantation protocols, we also assessed the ability of human iPSCs derived from each of the three developmental germ layer tissues (that is, ectoderm, mesoderm, and endoderm) to regenerate mouse liver. These iPSC lines, with similar but distinct global DNA methylation patterns, differentiated into multistage hepatic cells with an efficiency similar to that of human embryonic stem cells. Human hepatic cells at various differentiation stages derived from iPSC lines of different origins successfully repopulated the liver tissue of mice with liver cirrhosis. They also secreted human-specific liver proteins into mouse blood at concentrations comparable to that of proteins secreted by human primary hepatocytes. Our results demonstrate the engraftment and liver regenerative capabilities of human iPSC-derived multistage hepatic cells in vivo and suggest that human iPSCs of distinct origins and regardless of their parental epigenetic memory can efficiently differentiate along the hepatic lineage.

  14. Multidisciplinary management of clear-cell renal cell carcinoma in Africa and the Middle East: current practice and recommendations for improvement

    Directory of Open Access Journals (Sweden)

    Zekri J

    2015-07-01

    Full Text Available Jamal Zekri,1 Lydia M Dreosti,2 Marwan Ghosn,3 Emad Hamada,4 Mohamed Jaloudi,5 Ola Khorshid,6 Blaha Larbaoui7 1College of Medicine, King Faisal Specialist Hospital and Research Centre, Alfaisal University, Jeddah, Saudi Arabia; 2Department of Medical Oncology, University of Pretoria, Pretoria, South Africa; 3Faculty of Medicine Hematology, Oncology Department, Saint Joseph University, Beirut, Lebanon; 4Faculty of Medicine, Cairo University, Kasr Alainy, Cairo, Egypt; 5Oncology Hematology Department, Tawam Hospital, Al Ain, Abu Dhabi, United Arab Emirates; 6National Cancer Institute, Cairo University, Kasr El Ainy, Cairo, Egypt; 7Oncology Service, Université Djillali Liabés, Sidi Bel Abbés, Algeria Abstract: The management of renal cell carcinoma (RCC has evolved considerably in recent years. This report represents the consensus of 22 relevant medical specialists from Africa and the Middle East region engaged in the management of RCC. Partial or radical nephrectomy is the standard of care for most patients with localized RCC. It is essential that patients are followed up appropriately after surgery to enable local and distant relapses to be identified and treated promptly. The treatment of advanced/metastatic disease has changed dramatically with the introduction of targeted therapies. Follow-up of these patients enables therapy optimization and assessment of response to treatment. There was universal agreement on the importance of management of RCC by a multidisciplinary team supported by a multidisciplinary tumor board. Barriers hindering this approach were identified. These included lack of awareness of the benefits of multidisciplinary team role, poor communication among relevant disciplines, time constraints, and specifics of private practice. Other challenges include shortage of expert specialists as urologists and oncologists and lack of local management guidelines in some countries. Solutions were proposed and discussed. Medical

  15. 3 CFR - Guidelines for Human Stem Cell Research

    Science.gov (United States)

    2010-01-01

    ... 3 The President 1 2010-01-01 2010-01-01 false Guidelines for Human Stem Cell Research Presidential Documents Other Presidential Documents Memorandum of July 30, 2009 Guidelines for Human Stem Cell Research..., scientifically worthy human stem cell research, including human embryonic stem cell research, to the extent...

  16. Myristoylation profiling in human cells and zebrafish

    Directory of Open Access Journals (Sweden)

    Malgorzata Broncel

    2015-09-01

    Full Text Available Human cells (HEK 293, HeLa, MCF-7 and zebrafish embryos were metabolically tagged with an alkynyl myristic acid probe, lysed with an SDS buffer and tagged proteomes ligated to multifunctional capture reagents via copper-catalyzed alkyne azide cycloaddition (CuAAC. This allowed for affinity enrichment and high-confidence identification, by delivering direct MS/MS evidence for the modification site, of 87 and 61 co-translationally myristoylated proteins in human cells and zebrafish, respectively. The data have been deposited to ProteomeXchange Consortium (Vizcaíno et al., 2014 Nat. Biotechnol., 32, 223–6 (PXD001863 and PXD001876 and are described in detail in Multifunctional reagents for quantitative proteome-wide analysis of protein modification in human cells and dynamic protein lipidation during vertebrate development׳ by Broncel et al., Angew. Chem. Int. Ed.

  17. Establishment of Human Neural Progenitor Cells from Human Induced Pluripotent Stem Cells with Diverse Tissue Origins

    Science.gov (United States)

    Fukusumi, Hayato; Shofuda, Tomoko; Bamba, Yohei; Yamamoto, Atsuyo; Kanematsu, Daisuke; Handa, Yukako; Okita, Keisuke; Nakamura, Masaya; Yamanaka, Shinya; Okano, Hideyuki; Kanemura, Yonehiro

    2016-01-01

    Human neural progenitor cells (hNPCs) have previously been generated from limited numbers of human induced pluripotent stem cell (hiPSC) clones. Here, 21 hiPSC clones derived from human dermal fibroblasts, cord blood cells, and peripheral blood mononuclear cells were differentiated using two neural induction methods, an embryoid body (EB) formation-based method and an EB formation method using dual SMAD inhibitors (dSMADi). Our results showed that expandable hNPCs could be generated from hiPSC clones with diverse somatic tissue origins. The established hNPCs exhibited a mid/hindbrain-type neural identity and uniform expression of neural progenitor genes. PMID:27212953

  18. Establishment of Human Neural Progenitor Cells from Human Induced Pluripotent Stem Cells with Diverse Tissue Origins.

    Science.gov (United States)

    Fukusumi, Hayato; Shofuda, Tomoko; Bamba, Yohei; Yamamoto, Atsuyo; Kanematsu, Daisuke; Handa, Yukako; Okita, Keisuke; Nakamura, Masaya; Yamanaka, Shinya; Okano, Hideyuki; Kanemura, Yonehiro

    2016-01-01

    Human neural progenitor cells (hNPCs) have previously been generated from limited numbers of human induced pluripotent stem cell (hiPSC) clones. Here, 21 hiPSC clones derived from human dermal fibroblasts, cord blood cells, and peripheral blood mononuclear cells were differentiated using two neural induction methods, an embryoid body (EB) formation-based method and an EB formation method using dual SMAD inhibitors (dSMADi). Our results showed that expandable hNPCs could be generated from hiPSC clones with diverse somatic tissue origins. The established hNPCs exhibited a mid/hindbrain-type neural identity and uniform expression of neural progenitor genes.

  19. Multidisciplinary management of clear-cell renal cell carcinoma in Africa and the Middle East: current practice and recommendations for improvement.

    Science.gov (United States)

    Zekri, Jamal; Dreosti, Lydia M; Ghosn, Marwan; Hamada, Emad; Jaloudi, Mohamed; Khorshid, Ola; Larbaoui, Blaha

    2015-01-01

    The management of renal cell carcinoma (RCC) has evolved considerably in recent years. This report represents the consensus of 22 relevant medical specialists from Africa and the Middle East region engaged in the management of RCC. Partial or radical nephrectomy is the standard of care for most patients with localized RCC. It is essential that patients are followed up appropriately after surgery to enable local and distant relapses to be identified and treated promptly. The treatment of advanced/metastatic disease has changed dramatically with the introduction of targeted therapies. Follow-up of these patients enables therapy optimization and assessment of response to treatment. There was universal agreement on the importance of management of RCC by a multidisciplinary team supported by a multidisciplinary tumor board. Barriers hindering this approach were identified. These included lack of awareness of the benefits of multidisciplinary team role, poor communication among relevant disciplines, time constraints, and specifics of private practice. Other challenges include shortage of expert specialists as urologists and oncologists and lack of local management guidelines in some countries. Solutions were proposed and discussed. Medical educational initiatives and awareness activities were highlighted as keys to encouraging cooperation between specialties to improve patients' outcome. Establishing combined genitourinary cancer clinics and formal referral systems should encourage a culture of effective communication. Joining forces with professionals in peripheral areas and the private sector is likely to help standardize care. Sustained action will be required to ensure that all patients with RCC in the region benefit from up-to-date care.

  20. Osthole inhibits proliferation of human breast cancer cells by inducing cell cycle arrest and apoptosis

    Institute of Scientific and Technical Information of China (English)

    Lintao Wang; Yanyan Peng; Kaikai Shi; Haixiao Wang; Jianlei Lu; Yanli Li; Changyan Ma

    2015-01-01

    Recent studies have revealed that osthole,an active constituent isolated from the fruit of Cnidium monnieri (L.) Cusson,a traditional Chinese medicine,possesses anticancer activity.However,its effect on breast cancer cells so far has not been elucidated clearly.In the present study,we evaluated the effects of osthole on the proliferation,cell cycle and apoptosis of human breast cancer cells MDA-MB 435.We demonstrated that osthole is effective in inhibiting the proliferation of MDA-MB 435 cells,The mitochondrion-mediated apoptotic pathway was involved in apoptosis induced by osthole,as indicated by activation of caspase-9 and caspase-3 followed by PARP degradation.The mechanism underlying its effect on the induction of G1 phase arrest was due to the up-regulation of p53 and p21 and down-regulation of Cdk2 and cyclin D1 expression.Were observed taken together,these findings suggest that the anticancer efficacy of osthole is mediated via induction of cell cycle arrest and apoptosis in human breast cancer cells and osthole may be a potential chemotherapeutic agent against human breast cancer.

  1. Efficient derivation and genetic modifications of human pluripotent stem cells on engineered human feeder cell lines.

    Science.gov (United States)

    Zou, Chunlin; Chou, Bin-Kuan; Dowey, Sarah N; Tsang, Kitman; Huang, Xiaosong; Liu, Cyndi F; Smith, Cory; Yen, Jonathan; Mali, Prashant; Zhang, Yu Alex; Cheng, Linzhao; Ye, Zhaohui

    2012-08-10

    Derivation of pluripotent stem cells (iPSCs) induced from somatic cell types and the subsequent genetic modifications of disease-specific or patient-specific iPSCs are crucial steps in their applications for disease modeling as well as future cell and gene therapies. Conventional procedures of these processes require co-culture with primary mouse embryonic fibroblasts (MEFs) to support self-renewal and clonal growth of human iPSCs as well as embryonic stem cells (ESCs). However, the variability of MEF quality affects the efficiencies of all these steps. Furthermore, animal sourced feeders may hinder the clinical applications of human stem cells. In order to overcome these hurdles, we established immortalized human feeder cell lines by stably expressing human telomerase reverse transcriptase, Wnt3a, and drug resistance genes in adult mesenchymal stem cells. Here, we show that these immortalized human feeders support efficient derivation of virus-free, integration-free human iPSCs and long-term expansion of human iPSCs and ESCs. Moreover, the drug-resistance feature of these feeders also supports nonviral gene transfer and expression at a high efficiency, mediated by piggyBac DNA transposition. Importantly, these human feeders exhibit superior ability over MEFs in supporting homologous recombination-mediated gene targeting in human iPSCs, allowing us to efficiently target a transgene into the AAVS1 safe harbor locus in recently derived integration-free iPSCs. Our results have great implications in disease modeling and translational applications of human iPSCs, as these engineered human cell lines provide a more efficient tool for genetic modifications and a safer alternative for supporting self-renewal of human iPSCs and ESCs.

  2. Regulatory B cells and tolerance in transplantation: from animal models to human.

    Directory of Open Access Journals (Sweden)

    Melanie eChesneau

    2013-12-01

    Full Text Available Until recently, the role of B cells in transplantation was thought to be restricted to producing antibodies that have been clearly shown to be deleterious in the long term, but, in fact, B cells are also able to produce cytokine and to present antigen. Their role as regulatory cells in various pathological situations has also been highlighted, and their role in transplantation is beginning to emerge in animal, and also in human, models. This review summarizes the different studies in animals and humans that suggest a B-cell regulatory role in the transplant tolerance mechanisms.

  3. [Human pluripotent stem cell and neural differentiation].

    Science.gov (United States)

    Wataya, Takafumi; Muguruma, Keiko; Sasai, Yoshiki

    2008-10-01

    Recovery of lost brain function is an important issue in medical studies because neurons of the central nervous system (CNS) have poor potential for regeneration. Since few CNS diseases can be treated completely by medicines, regenerative therapy by using stem cells should be studied as a new type of therapeutic intervention. The efficacy of cell replacement therapy in Parkinson's disease has been well investigated. Several studies on fetal tissue transplantation have revealed that quantity and purity of transplanted cells are necessary for recovery of symptoms. SFEB (Serum-free floating culture of embryoid body-like aggregates) method is capable of inducing multi-potential CNS progenitors that can be steered to differentiate into region-specific tissues. On the basis of the existing knowledge of embryology, we have succeeded in the generating of various types of neurons such as telencephalic, cerebeller (Purkinje and granule cells), retinal (photoreceptor cells) and hypothalamic neurons. Application of this culture method to human ES (hES) cells is necessary for clinical purpose: however, poor survival of hES cells in SFEB culture might limit the possibility of using these cells for future medical applications. We found that a selective Rho-associated kinase (ROCK) inhibitor, Y-27632, markedly diminished the dissociation-induced apoptosis of hES cells and enabled the cells to form aggregates in SFEB culture. For both mouse and human ES cells, SFEB culture is a favorable method that can generate large amounts of region-specific neurons. However, stem cell-based therapy continues to face several obstacles. It is important that researchers in the basic sciences and clinical medicine should discuss these problems together to overcome both scientific and ethical issues related to stem cells.

  4. T-cell response in human leishmaniasis

    DEFF Research Database (Denmark)

    Kharazmi, A; Kemp, K; Ismail, A

    1999-01-01

    In the present communication we provide evidence for the existence of a Th1/Th2 dichotomy in the T-cell response to Leishmania antigens in human leishmaniasis. Our data suggest that the pattern of IL-4 and IFN-gamma response is polarised in these patients. Lymphocytes from individuals recovered......+. Furthermore, IL-10 plays an important role in the development of post kala azar dermal leishmaniasis (PKDL) from VL. The balance between the parasitic-specific T-cell response plays an important regulatory role in determining the outcome of Leishmania infections in humans....

  5. Characterization of human pluripotent stem cells.

    Science.gov (United States)

    Gokhale, Paul J; Andrews, Peter W

    2013-12-18

    Human pluripotent stem cells (PSCs), whether embryonic stem cells or induced PSCs, offer enormous opportunities for regenerative medicine and other biomedical applications once we have developed the ability to harness their capacity for extensive differentiation. Central to this is our ability to identify and characterize such PSCs, but this is fraught with potential difficulties that arise from a tension between functional definitions of pluripotency and the more convenient use of 'markers', a problem exacerbated by ethical issues, our lack of knowledge of early human embryonic development, and differences from the mouse paradigm.

  6. Human pluripotent stem cells in contemporary medicine

    Directory of Open Access Journals (Sweden)

    S. A. Rodin

    2015-01-01

    Full Text Available Human pluripotent stem cells (hPSCs are capable of indefinite proliferation and can be differentiated into any cell type of the human body. Therefore, they are a promising source of cells for treatment of numerous degenerative diseases and injuries. Pluripotent stem cells are also associated with a number of ethical, safety and technological issues. In this review, we describe various types of hPSCs, safety issues that concern all or some types of hPSCs and methods of clinical-grade hPSC line development. Also, we discuss current and past clinical trials involving hPSCs, their outcomes and future perspectives of hPSC-based therapy. 

  7. Copper entry into human cells: progress and unanswered questions.

    Science.gov (United States)

    Maryon, Edward B; Molloy, Shannon A; Zimnicka, Adriana M; Kaplan, Jack H

    2007-06-01

    In this brief review we summarize what is known about the role of hCTR1 in mediating the entry of copper into human cells. There is a body of information that clearly identifies this protein as being a major source (though not the only source) of copper entry into human cells, and thus a crucial element of copper homeostasis. However, much remains that is poorly understood and key aspects of the physiological roles of hCTR1 and its regulation are only superficially appreciated. The particular characteristics of a transport process that in vivo involves the binding, transmembrane transport and release of a substrate that is not present in a free form in the intracellular or extracellular compartments poses particular challenges that are not encountered in the transport of more familiar physiologically important metal cations. Thus much of what we have learned about the more commonly encountered transported ions provides an inadequate model for studies of copper homeostasis. In this article we review progress made and identify the major questions that need to be resolved before an adequate description is attained of how copper entry into human cells is mediated and regulated by hCTR1.

  8. Cell pattern in adult human corneal endothelium.

    Directory of Open Access Journals (Sweden)

    Carlos H Wörner

    Full Text Available A review of the current data on the cell density of normal adult human endothelial cells was carried out in order to establish some common parameters appearing in the different considered populations. From the analysis of cell growth patterns, it is inferred that the cell aging rate is similar for each of the different considered populations. Also, the morphology, the cell distribution and the tendency to hexagonallity are studied. The results are consistent with the hypothesis that this phenomenon is analogous with cell behavior in other structures such as dry foams and grains in polycrystalline materials. Therefore, its driving force may be controlled by the surface tension and the mobility of the boundaries.

  9. Merkel cell distribution in the human eyelid

    Directory of Open Access Journals (Sweden)

    C.A. May

    2013-10-01

    Full Text Available Although Merkel cell carcinoma of the eye lid is reported frequently in the literature, only limited information exists about the distribution of Merkel cells in this tissue. Therefore, serial sections of 18 human cadaver eye lids (donors ages ranging between 63 and 97 years were stained for cytokeratin 20 in various planes. The overall appearance of Merkel cells in these samples was low and mainly located in the outer root layer of the cilia hair follicles. Merkel cells were more frequent in the middle, and almost not detectable at the nasal and temporal edges. The localization is in accordance with that of Merkel cell carcinoma, but concerning the scarce appearance within this adulthood group, a specific physiological role of these cells in the eye lid is difficult to establish.

  10. Natural killer cells in human autoimmune disorders

    Science.gov (United States)

    2013-01-01

    Natural killer (NK) cells are innate lymphocytes that play a critical role in early host defense against viruses. Through their cytolytic capacity and generation of cytokines and chemokines, NK cells modulate the activity of other components of the innate and adaptive immune systems and have been implicated in the initiation or maintenance of autoimmune responses. This review focuses on recent research elucidating a potential immunoregulatory role for NK cells in T-cell and B-cell-mediated autoimmune disorders in humans, with a particular focus on multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematous. A better understanding of the contributions of NK cells to the development of autoimmunity may lead to novel therapeutic targets in these diseases. PMID:23856014

  11. Human Colon Cancer Cells Cultivated in Space

    Science.gov (United States)

    1995-01-01

    Within five days, bioreactor cultivated human colon cancer cells (shown) grown in Microgravity on the STS-70 mission in 1995, had grown 30 times the volume of the control specimens on Earth. The samples grown in space had a higher level of cellular organization and specialization. Because they more closely resemble tumors found in the body, microgravity grown cell cultures are ideal for research purposes.

  12. Adjuvant Chemotherapy and Vaginal Vault Brachytherapy With or Without Pelvic Radiotherapy for Stage 1 Papillary Serous or Clear Cell Endometrial Cancer.

    Science.gov (United States)

    Tétreault-Laflamme, Audrey; Nguyen-Huynh, Thu Van; Carrier, Jean-François; Samouëlian, Vanessa; Sauthier, Philippe; Beauchemin, Marie-Claude; Barkati, Maroie

    2016-02-01

    The aim of this study was to assess and compare adjuvant chemotherapy followed by either high-dose-rate vaginal vault brachytherapy (VBT) alone or combined with pelvic external beam radiotherapy (EBRT) for International Federation of Gynaecology and Obstetrics stage 1 serous or clear cell (CC) endometrial cancer. Between 2006 and 2012, 84 women with stage 1 serous or CC endometrial cancer were evaluated postoperatively for adjuvant treatment at our hospital. More than 80% of patients had pelvic lymphadenectomy. Patients declining or not completing adjuvant treatments were excluded. Twenty-five women received 4 to 6 cycles of carboplatin/paclitaxel followed by EBRT and VBT. Thirty-two women received 6 cycles of carboplatin/paclitaxel followed by VBT. Locoregional control and toxicities were assessed during follow-up. The 3-year disease-free survival and overall survival rates for the VBT group compared with the EBRT + VBT group were 88% versus 84%, P = 0.6, and 100% versus 94%, P = 0.6, respectively. Only 1 patient in the EBRT + VBT group developed a distant recurrence. One patient had grade 3 toxicity (chronic gastrointestinal [GI] toxicity) in the EBRT + VBT group. Acute grade 1-to-2 GI and grade 1 genitourinary (GU) toxicities were less frequent in the VBT group compared with the EBRT + VBT group (P = 0.008 and P = 0.019, respectively). Late GI and GU toxicities were comparable. Grade 1 vaginal toxicity was similar in both groups. No acute or late grade 2 GU or vaginal toxicities were reported. According to this study, VBT alone seems to be as effective as EBRT and VBT for stage 1 serous and CC endometrial cancer treated with surgery and adjuvant chemotherapy. Furthermore, less acute GI and GU toxicities were seen in the VBT group.

  13. Von Hippel-Lindau (VHL inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors.

    Directory of Open Access Journals (Sweden)

    Lee E Moore

    2011-10-01

    Full Text Available Renal tumor heterogeneity studies have utilized the von Hippel-Lindau VHL gene to classify disease into molecularly defined subtypes to examine associations with etiologic risk factors and prognosis. The aim of this study was to provide a comprehensive analysis of VHL inactivation in clear cell renal tumors (ccRCC and to evaluate relationships between VHL inactivation subgroups with renal cancer risk factors and VHL germline single nucleotide polymorphisms (SNPs. VHL genetic and epigenetic inactivation was examined among 507 sporadic RCC/470 ccRCC cases using endonuclease scanning and using bisulfite treatment and Sanger sequencing across 11 CpG sites within the VHL promoter. Case-only multivariate analyses were conducted to identify associations between alteration subtypes and risk factors. VHL inactivation, either through sequence alterations or promoter methylation in tumor DNA, was observed among 86.6% of ccRCC cases. Germline VHL SNPs and a haplotype were associated with promoter hypermethylation in tumor tissue (OR = 6.10; 95% CI: 2.28-16.35, p = 3.76E-4, p-global = 8E-5. Risk of having genetic VHL inactivation was inversely associated with smoking due to a higher proportion of wild-type ccRCC tumors [former: OR = 0.70 (0.20-1.31 and current: OR = 0.56 (0.32-0.99; P-trend = 0.04]. Alteration prevalence did not differ by histopathologic characteristics or occupational exposure to trichloroethylene. ccRCC cases with particular VHL germline polymorphisms were more likely to have VHL inactivation through promoter hypermethylation than through sequence alterations in tumor DNA, suggesting that the presence of these SNPs may represent an example of facilitated epigenetic variation (an inherited propensity towards epigenetic variation in renal tissue. A proportion of tumors from current smokers lacked VHL alterations and may represent a biologically distinct clinical entity from inactivated cases.

  14. Quercetin Inhibits Cell Migration and Invasion in Human Osteosarcoma Cells

    Directory of Open Access Journals (Sweden)

    Haifeng Lan

    2017-09-01

    Full Text Available Background/Aims: Osteosarcoma is a malignant tumor associated with high mortality; however, no effective therapies for the disease have been developed. Several studies have focused on elucidating the pathogenesis of osteosarcoma and have aimed to develop novel therapies for the disease. Quercetin is a vital dietary flavonoid that has been shown to have a variety of anticancer effects, as it induces cell cycle arrest, apoptosis, and differentiation and is involved in cell adhesion, metastasis and angiogenesis. Herein, we aimed to investigate the effects of quercetin on osteosarcoma migration and invasion in vitro and in vivo and to explore the molecular mechanisms underlying its effects on osteosarcoma migration and invasion. Methods: Cell viability, cell cycle activity and cell apoptosis were measured using CCK-8 assay and flow cytometry, and cell migration and invasion were evaluated by wound healing and transwell assays, respectively. The mRNA and protein expression levels of several proteins of interest were assessed by real-time quantitative PCR and western blotting, respectively. Moreover, a nude mouse model of human osteosarcoma lung metastasis was established to assess the anti-metastatic effects of quercetin in vivo. Results: We noted no significant differences in cell cycle activity and apoptosis between HOS and MG63 cells and control cells. Treatment with quercetin significantly attenuated cell migration and invasion in HOS and MG63 cells compared with treatment with control medium. Moreover HIF-1α, VEGF, MMP2, and MMP9 mRNA and protein expression levels were significantly downregulated in HOS cells treated with quercetin compared with HOS cells treated with controls. Additionally, treatment with quercetin attenuated metastatic lung tumor formation and growth in the nude mouse model of osteosarcoma compared with treatment with controls. Conclusion: Our findings regarding the inhibitory effects of quercetin on cell migration and

  15. Human Mammary Luminal Epithelial Cells Contain Progenitors to Myoepithelial Cells

    Energy Technology Data Exchange (ETDEWEB)

    Pechoux, Christine; Gudjonsson, Thorarinn; Ronnov-Jessen, Lone; Bissell, Mina J; Petersen, Ole

    1999-02-01

    The origin of the epithelial and myoepithelial cells in the human breast has not been delineated. In this study we have addressed whether luminal epithelial cells and myoepithelial cells are vertically connected, i.e., whether one is the precursor for the other. We used a primary culture assay allowing preservation of basic phenotypic traits of luminal epithelial and myoepithelial cells in culture. The two cell types were then separated immunomagnetically using antibodies directed against lineage-specific cell surface antigens into at best 100% purity. The cellular identity was ascertained by cytochemistry, immunoblotting, and 2-D gel electrophoresis. Luminal epithelial cells were identified by strong expression of cytokeratins 18 and 19 while myoepithelial cells were recognized by expression of vimentin and {alpha}-smooth muscle actin. We used a previously devised culture medium (CDM4) that allows vigorous expansion of proliferative myoepithelial cells and also devised a medium (CDM6) that allowed sufficient expansion of differentiated luminal epithelial cells based on addition of hepatocyte growth factor/scatter factor. The two different culture media supported each lineage for at least five passages without signs of interconversion. We used parallel cultures where we switched culture media, thus testing the ability of each lineage to convert to the other. Whereas the myoepithelial lineage showed no signs of interconversion, a subset of luminal epithelial cells, gradually, but distinctly, converted to myoepithelial cells. We propose that in the mature human breast, it is the luminal epithelial cell compartment that gives rise to myoepithelial cells rather than the other way around.

  16. Genetic Manipulation of Human Embryonic Stem Cells.

    Science.gov (United States)

    Eiges, Rachel

    2016-01-01

    One of the great advantages of embryonic stem (ES) cells over other cell types is their accessibility to genetic manipulation. They can easily undergo genetic modifications while remaining pluripotent, and can be selectively propagated, allowing the clonal expansion of genetically altered cells in culture. Since the first isolation of ES cells in mice, many effective techniques have been developed for gene delivery and manipulation of ES cells. These include transfection, electroporation, and infection protocols, as well as different approaches for inserting, deleting, or changing the expression of genes. These methods proved to be extremely useful in mouse ES cells, for monitoring and directing differentiation, discovering unknown genes, and studying their function, and are now being extensively implemented in human ES cells (HESCs). This chapter describes the different approaches and methodologies that have been applied for the genetic manipulation of HESCs and their applications. Detailed protocols for generating clones of genetically modified HESCs by transfection, electroporation, and infection will be described, with special emphasis on the important technical details that are required for this purpose. All protocols are equally effective in human-induced pluripotent stem (iPS) cells.

  17. In vitro cytokine profiles and viability of different human cells treated with whole cell lysate of Mycobacterium avium subsp. paratuberculosis

    Directory of Open Access Journals (Sweden)

    Rani Pittu

    2012-09-01

    Full Text Available Abstract Mycobacterium avium subsp. paratuberculosis (MAP is a zoonotic pathogen, a very slow growing bacterium which is difficult to isolate and passage in conventional laboratory culture. Although its association with Johne’s disease or paratuberculosis of cattle is well established, it has been only putatively linked to Crohn’s disease in humans. Further, MAP has been recently suggested to be a trigger for other autoimmune diseases such as type-1 diabetes mellitus (T1DM. Recently, some studies have indicated that exposure to MAP is associated with elevated levels of antibodies against MAP lysate although the exact mechanism and significance of the same remains unclear. Further, the cytokine profiles relevant in MAP associated diseases of humans and their exact role in the pathophysiology are not clearly known. We performed in vitro cytokine analyses after exposing different cultured human cells to the whole cell lysate of MAP and found that MAP lysate induces secretion of cytokines IL-1β, IL-6, IL-8, IL-10 and TNF-α by human peripheral blood mononuclear cells (PBMCs. Also, it induces secretion of IL-8 by cultured human stomach adenocarcinoma cells (AGS and PANC-1(human pancreatic carcinoma cell line cells. We also found that MAP lysate induced cytotoxicity in PANC-1cells. Collectively, these results provide a much needed base-line data set of cytokines broadly signifying a MAP induced cellular response by human cells.

  18. Enriched retinal ganglion cells derived from human embryonic stem cells

    Science.gov (United States)

    Gill, Katherine P.; Hung, Sandy S. C.; Sharov, Alexei; Lo, Camden Y.; Needham, Karina; Lidgerwood, Grace E.; Jackson, Stacey; Crombie, Duncan E.; Nayagam, Bryony A.; Cook, Anthony L.; Hewitt, Alex W.; Pébay, Alice; Wong, Raymond C. B.

    2016-01-01

    Optic neuropathies are characterised by a loss of retinal ganglion cells (RGCs) that lead to vision impairment. Development of cell therapy requires a better understanding of the signals that direct stem cells into RGCs. Human embryonic stem cells (hESCs) represent an unlimited cellular source for generation of human RGCs in vitro. In this study, we present a 45-day protocol that utilises magnetic activated cell sorting to generate enriched population of RGCs via stepwise retinal differentiation using hESCs. We performed an extensive characterization of these stem cell-derived RGCs by examining the gene and protein expressions of a panel of neural/RGC markers. Furthermore, whole transcriptome analysis demonstrated similarity of the hESC-derived RGCs to human adult RGCs. The enriched hESC-RGCs possess long axons, functional electrophysiological profiles and axonal transport of mitochondria, suggestive of maturity. In summary, this RGC differentiation protocol can generate an enriched population of functional RGCs from hESCs, allowing future studies on disease modeling of optic neuropathies and development of cell therapies. PMID:27506453

  19. Human ES cells: starting culture from frozen cells.

    Science.gov (United States)

    Trish, Erin; Dimos, John; Eggan, Kevin

    2006-11-09

    Here we demonstrate how our lab begins a HuES human embryonic stem cell line culture from a frozen stock. First, a one to two day old ten cm plate of approximately one (to two) million irradiated mouse embryonic fibroblast feeder cells is rinsed with HuES media to remove residual serum and cell debris, and then HuES media added and left to equilibrate in the cell culture incubator. A frozen vial of cells from long term liquid nitrogen storage or a -80 C freezer is sourced and quickly submerged in a 37 C water bath for quick thawing. Cells in freezing media are then removed from the vial and placed in a large volume of HuES media. The large volume of HuES media facilitates removal of excess serum and DMSO, which can cause HuES human embryonic stem cells to differentiate. Cells are gently spun out of suspension, and then re-suspended in a small volume of fresh HuES media that is then used to seed the MEF plate. It is considered important to seed the MEF plate by gently adding the HuES cells in a drop wise fashion to evenly disperse them throughout the plate. The newly established HuES culture plate is returned to the incubator for 48 hrs before media is replaced, then is fed every 24 hours thereafter.

  20. Sodium Valproate Induces Cell Senescence in Human Hepatocarcinoma Cells

    Directory of Open Access Journals (Sweden)

    Hong-Mei An

    2013-12-01

    Full Text Available Hepatocarcinogenesis is associated with epigenetic changes, including histone deacetylases (HDACs. Epigenetic modulation by HDAC inhibition is a potentially valuable approach for hepatocellular carcinoma treatment. In present study, we evaluated the anticancer effects of sodium valproate (SVP, a known HDAC inhibitor, in human hepatocarcinoma cells. The results showed SVP inhibited the proliferation of Bel-7402 cells in a dose-dependent manner. Low dose SVP treatment caused a large and flat morphology change, positive SA-β-gal staining, and G0/G1 phase cell cycle arrest in human hepatocarcinoma cells. Low dose SVP treatment also increased acetylation of histone H3 and H4 on p21 promoter, accompanied by up-regulation of p21 and down-regulation of RB phosphorylation. These observations suggested that a low dose of SVP could induce cell senescence in hepatocarcinoma cells, which might correlate with hyperacetylation of histone H3 and H4, up-regulation of p21, and inhibition of RB phosphorylation. Since the effective concentration inducing cell senescence in hepatocarcinoma cells is clinically available, whether a clinical dose of SVP could induce cell senescence in clinical hepatocarcinoma is worthy of further study.

  1. Characterization of the interaction between human respiratory syncytial virus and the cell cycle in continuous cell culture and primary human airway epithelial cells.

    Science.gov (United States)

    Wu, Weining; Munday, Diane C; Howell, Gareth; Platt, Gareth; Barr, John N; Hiscox, Julian A

    2011-10-01

    Viruses can modify conditions inside cells to make them more favorable for replication and progeny virus production. One way of doing this is through manipulation of the cell cycle, a process that describes the ordered growth and division of cells. Analysis of model cell lines, such as A549 cells and primary airway epithelial cells, infected with human respiratory syncytial virus (HRSV) has shown alteration of the cell cycle during infection, although the signaling events were not clearly understood. In this study, targeted transcriptomic analysis of HRSV-infected primary airway epithelial cells revealed alterations in the abundances of many mRNAs encoding cell cycle-regulatory molecules, including decreases in the D-type cyclins and corresponding cyclin-dependent kinases (CDK4 and CDK6 [CDK4/6]). These alterations were reflected in changes in protein abundance and/or relocalization in HRSV-infected cells; taken together, they were predicted to result in G(0)/G(1) phase arrest. In contrast, there was no change in the abundances of D-type cyclins in A549 cells infected with HRSV. However, the abundance of the G(1)/S phase progression inhibitor p21(WAF1/CIP1) was increased over that in mock-treated cells, and this, again, was predicted to result in G(0)/G(1) phase arrest. The G(0)/G(1) phase arrest in both HRSV-infected primary cells and A549 cells was confirmed using dual-label flow cytometry that accurately measured the different stages of the cell cycle. Comparison of progeny virus production in primary and A549 cells enriched in G(0)/G(1) using a specific CDK4/6 kinase inhibitor with asynchronously replicating cells indicated that this phase of the cell cycle was more efficient for virus production.

  2. Human embryonic stem cell lines model experimental human cytomegalovirus latency.

    Science.gov (United States)

    Penkert, Rhiannon R; Kalejta, Robert F

    2013-05-28

    Herpesviruses are highly successful pathogens that persist for the lifetime of their hosts primarily because of their ability to establish and maintain latent infections from which the virus is capable of productively reactivating. Human cytomegalovirus (HCMV), a betaherpesvirus, establishes latency in CD34(+) hematopoietic progenitor cells during natural infections in the body. Experimental infection of CD34(+) cells ex vivo has demonstrated that expression of the viral gene products that drive productive infection is silenced by an intrinsic immune defense mediated by Daxx and histone deacetylases through heterochromatinization of the viral genome during the establishment of latency. Additional mechanistic details about the establishment, let alone maintenance and reactivation, of HCMV latency remain scarce. This is partly due to the technical challenges of CD34(+) cell culture, most notably, the difficulty in preventing spontaneous differentiation that drives reactivation and renders them permissive for productive infection. Here we demonstrate that HCMV can establish, maintain, and reactivate in vitro from experimental latency in cultures of human embryonic stem cells (ESCs), for which spurious differentiation can be prevented or controlled. Furthermore, we show that known molecular aspects of HCMV latency are faithfully recapitulated in these cells. In total, we present ESCs as a novel, tractable model for studies of HCMV latency.

  3. Urea and thiourea modified polypropyleneimine dendrimers clear intracellular α-synuclein aggregates in a human cell line

    DEFF Research Database (Denmark)

    Laumann, Kristoffer; Boas, Ulrik; Larsen, Hjalte Martin;

    2015-01-01

    Synucleinopathies are neurodegenerative pathologies in which disease progression is closely correlated to brain accumulation of insoluble α-synuclein, a small protein abundantly expressed in neural tissue. Here, two types of modified polypropyleneimine (PPI) dendrimers having either urea or methy......Synucleinopathies are neurodegenerative pathologies in which disease progression is closely correlated to brain accumulation of insoluble α-synuclein, a small protein abundantly expressed in neural tissue. Here, two types of modified polypropyleneimine (PPI) dendrimers having either urea...

  4. Necdin modulates proliferative cell survival of human cells in response to radiation-induced genotoxic stress

    Directory of Open Access Journals (Sweden)

    Lafontaine Julie

    2012-06-01

    Full Text Available Abstract Background The finite replicative lifespan of cells, termed cellular senescence, has been proposed as a protective mechanism against the proliferation of oncogenically damaged cells, that fuel cancer. This concept is further supported by the induction of premature senescence, a process which is activated when an oncogene is expressed in normal primary cells as well as following intense genotoxic stresses. Thus, deregulation of genes that control this process, like the tumor suppressor p53, may contribute to promoting cancer by allowing cells to bypass senescence. A better understanding of the genes that contribute to the establishment of senescence is therefore warranted. Necdin interacts with p53 and is also a p53 target gene, although the importance of Necdin in the p53 response is not clearly understood. Methods In this study, we first investigated Necdin protein expression during replicative senescence and premature senescence induced by gamma irradiation and by the overexpression of oncogenic RasV12. Gain and loss of function experiments were used to evaluate the contribution of Necdin during the senescence process. Results Necdin expression declined during replicative aging of IMR90 primary human fibroblasts or following induction of premature senescence. Decrease in Necdin expression seemed to be a consequence of the establishment of senescence since the depletion of Necdin in human cells did not induce a senescence-like growth arrest nor a flat morphology or SA-β-galactosidase activity normally associated with senescence. Similarly, overexpression of Necdin did not affect the life span of IMR90 cells. However, we demonstrate that in normal human cells, Necdin expression mimicked the effect of p53 inactivation by increasing radioresistance. Conclusion This result suggests that Necdin potentially attenuate p53 signaling in response to genotoxic stress in human cells and supports similar results describing an inhibitory function

  5. [Immune system evolution. (From cells to humans)].

    Science.gov (United States)

    Belek, A S

    1992-01-01

    The great variety of cells and molecules observed in the mammalian immune system can be explained by stepwise acquisition of them during phylogeny. Self/nonself discrimination and cell-mediated immunity have been present since the early stages of evolution. Although some inducible antimicrobial molecules have been demonstrated in invertebrates, immunoglobulins appear in vertebrates. T and B cell diversity, development of the lymphoid organs, MHC molecules, complement and cytokines are the characteristics that appear through the evolution of vertebrates. Further knowledge that will be obtained from phylogenetic studies will improve our understanding of the immune system of human.

  6. Centre for human development, stem cells & regeneration.

    Science.gov (United States)

    Oreffo, Richard O C

    2014-01-01

    The Centre for Human Development, Stem Cells and Regeneration (CHDSCR) was founded in 2004 as a cross-disciplinary research and translational program within the Faculty of Medicine at the University of Southampton. The Centre undertakes fundamental research into early development and stem cells together with applied translational research for patient benefit. The Centre has vibrant and thriving multidisciplinary research programs that harness the translational strength of the Faculty together with an innovative Stem Cell PhD program, outstanding clinical infrastructure and enterprise to deliver on this vision.

  7. Biobanking human embryonic stem cell lines

    DEFF Research Database (Denmark)

    Holm, Søren

    2016-01-01

    Stem cell banks curating and distributing human embryonic stem cells have been established in a number of countries and by a number of private institutions. This paper identifies and critically discusses a number of arguments that are used to justify the importance of such banks in policy...... are curiously absent from the particular stem cell banking policy discourse. This to some extent artificially isolates this discourse from the broader discussions about the flows of reproductive materials and tissues in modern society, and such isolation may lead to the interests of important actors being...

  8. Advances in human B cell phenotypic profiling

    Directory of Open Access Journals (Sweden)

    Denise A Kaminski

    2012-10-01

    Full Text Available To advance our understanding and treatment of disease, research immunologists have been called-upon to place more centralized emphasis on impactful human studies. Such endeavors will inevitably require large-scale study execution and data management regulation (Big Biology, necessitating standardized and reliable metrics of immune status and function. A well-known example setting this large-scale effort in-motion is identifying correlations between eventual disease outcome and T lymphocyte phenotype in large HIV-patient cohorts using multiparameter flow cytometry. However, infection, immunodeficiency, and autoimmunity are also characterized by correlative and functional contributions of B lymphocytes, which to-date have received much less attention in the human Big Biology enterprise. Here, we review progress in human B cell phenotyping, analysis, and bioinformatics tools that constitute valuable resources for the B cell research community to effectively join in this effort.

  9. Human plasma cells express granzyme B.

    Science.gov (United States)

    Xu, Wei; Narayanan, Priya; Kang, Ning; Clayton, Sandra; Ohne, Yoichiro; Shi, Peiqing; Herve, Marie-Cecile; Balderas, Robert; Picard, Capucine; Casanova, Jean-Laurent; Gorvel, Jean-Pierre; Oh, Sangkon; Pascual, Virginia; Banchereau, Jacques

    2014-01-01

    While studying the plasma cell (PC) compartment in human tonsils, we identified that immunoglobulin kappa or lambda chain-expressing PCs are the main cells expressing granzyme B (GrzB). In vitro studies revealed that activated B cells differentiated into GrzB-expressing PCs when co-cultured with macrophages and follicular helper T cells. This effect could be reproduced on combined stimulation of IL-15 (produced by macrophages) and IL-21 (produced by T follicular helper cells) in a STAT3-dependent manner. Whereas IL-21 triggers the transcription of mRNA of GrzB, IL-15 synergizes the translation of GrzB proteins. The precise role of GrzB in PC biology remains to be understood and studies in mice will not help as their PCs do not express GrzB.

  10. Human CD56bright NK Cells

    DEFF Research Database (Denmark)

    Michel, Tatiana; Poli, Aurélie; Cuapio, Angelica

    2016-01-01

    Human NK cells can be subdivided into various subsets based on the relative expression of CD16 and CD56. In particular, CD56(bright)CD16(-/dim) NK cells are the focus of interest. They are considered efficient cytokine producers endowed with immunoregulatory properties, but they can also become...... cytotoxic upon appropriate activation. These cells were shown to play a role in different disease states, such as cancer, autoimmunity, neuroinflammation, and infection. Although their phenotype and functional properties are well known and have been extensively studied, their lineage relationship with other...... NK cell subsets is not fully defined, nor is their precise hematopoietic origin. In this article, we summarize recent studies about CD56(bright) NK cells in health and disease and briefly discuss the current controversies surrounding them....

  11. Human embryonic stem cells: preclinical perspectives

    Directory of Open Access Journals (Sweden)

    Sarda Kanchan

    2008-01-01

    Full Text Available Abstract Human embryonic stem cells (hESCs have been extensively discussed in public and scientific communities for their potential in treating diseases and injuries. However, not much has been achieved in turning them into safe therapeutic agents. The hurdles in transforming hESCs to therapies start right with the way these cells are derived and maintained in the laboratory, and goes up-to clinical complications related to need for patient specific cell lines, gender specific aspects, age of the cells, and several post transplantation uncertainties. The different types of cells derived through directed differentiation of hESC and used successfully in animal disease and injury models are described briefly. This review gives a brief outlook on the present and the future of hESC based therapies, and talks about the technological advances required for a safe transition from laboratory to clinic.

  12. Stem cell factor and c-Kit in human primordial germ cells and fetal ovaries

    DEFF Research Database (Denmark)

    Høyer, Poul Erik; Byskov, Anne Grete; Møllgård, Kjeld

    2005-01-01

    Prenatal ovary (human), Primordial germ cells, Folliculogenesis, c-Kit, Stem cell factor, immunohistochemistry......Prenatal ovary (human), Primordial germ cells, Folliculogenesis, c-Kit, Stem cell factor, immunohistochemistry...

  13. Arsenic trioxide inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Hongtao [Department of Pathology, School of Medicine, Southeast University, Nanjing 210009 (China); Gao, Peng [Department of Internal Medicine, University of Iowa, Iowa City, IA 52242 (United States); Zheng, Jie, E-mail: jiezheng54@126.com [Department of Pathology, School of Medicine, Southeast University, Nanjing 210009 (China)

    2014-09-05

    Highlights: • As{sub 2}O{sub 3} inhibits growth of cervical cancer cells and expression of HPV oncogenes in these cells. • HPV-negative cervical cancer cells are more sensitive to As{sub 2}O{sub 3} than HPV-positive cervical cancer cells. • HPV-18 positive cervical cancer cells are more sensitive to As{sub 2}O{sub 3} than HPV-16 positive cancer cells. • Down-regulation of HPV oncogenes by As{sub 2}O{sub 3} is partially due to the diminished AP-1 binding. - Abstract: Arsenic trioxide (As{sub 2}O{sub 3}) has shown therapeutic effects in some leukemias and solid cancers. However, the molecular mechanisms of its anticancer efficacy have not been clearly elucidated, particularly in solid cancers. Our previous data showed that As{sub 2}O{sub 3} induced apoptosis of human papillomavirus (HPV) 16 DNA-immortalized human cervical epithelial cells and cervical cancer cells and inhibited the expression of HPV oncogenes in these cells. In the present study, we systemically examined the effects of As{sub 2}O{sub 3} on five human cervical cancer cell lines and explored the possible molecular mechanisms. MTT assay showed that HPV-negative C33A cells were more sensitive to growth inhibition induced by As{sub 2}O{sub 3} than HPV-positive cervical cancer cells, and HPV 18-positive HeLa and C4-I cells were more sensitive to As{sub 2}O{sub 3} than HPV 16-positive CaSki and SiHa cells. After As{sub 2}O{sub 3} treatment, both mRNA and protein levels of HPV E6 and E7 obviously decreased in all HPV positive cell lines. In contrast, p53 and Rb protein levels increased in all tested cell lines. Transcription factor AP-1 protein expression decreased significantly in HeLa, CaSki and C33A cells with ELISA method. These results suggest that As{sub 2}O{sub 3} is a potential anticancer drug for cervical cancer.

  14. An overview of botanical clearing technique.

    Science.gov (United States)

    Gardner, R O

    1975-03-01

    Clearing techniques are outlined with reference to their action on the chemical constituents of plant tissue. The most general technique would include pretreatment with solvents, dissolution of protoplasm, dissolution of other substances, bleaching, infiltration with a dense fluid, and staining. Extensive chemical changes go on during these steps and may prevent satisfactory clearing, an important example being the discoloration of phenolic compounds. Rational design of clearing methods for the chemically distinct cell types and tissue seems a likely future development.

  15. Differences in the microrheology of human embryonic stem cells and human induced pluripotent stem cells.

    Science.gov (United States)

    Daniels, Brian R; Hale, Christopher M; Khatau, Shyam B; Kusuma, Sravanti; Dobrowsky, Terrence M; Gerecht, Sharon; Wirtz, Denis

    2010-12-01

    Embryonic and adult fibroblasts can be returned to pluripotency by the expression of reprogramming genes. Multiple lines of evidence suggest that these human induced pluripotent stem (hiPS) cells and human embryonic stem (hES) cells are behaviorally, karyotypically, and morphologically similar. Here we sought to determine whether the physical properties of hiPS cells, including their micromechanical properties, are different from those of hES cells. To this end, we use the method of particle tracking microrheology to compare the viscoelastic properties of the cytoplasm of hES cells, hiPS cells, and the terminally differentiated parental human fibroblasts from which our hiPS cells are derived. Our results indicate that although the cytoplasm of parental fibroblasts is both viscous and elastic, the cytoplasm of hiPS cells does not exhibit any measurable elasticity and is purely viscous over a wide range of timescales. The viscous phenotype of hiPS cells is recapitulated in parental cells with disassembled actin filament network. The cytoplasm of hES cells is predominantly viscous but contains subcellular regions that are also elastic. This study supports the hypothesis that intracellular elasticity correlates with the degree of cellular differentiation and reveals significant differences in the mechanical properties of hiPS cells and hES cells. Because mechanical stimuli have been shown to mediate the precise fate of differentiating stem cells, our results support the concept that stem cell "softness" is a key feature of force-mediated differentiation of stem cells and suggest there may be subtle functional differences between force-mediated differentiation of hiPS cells and hES cells.

  16. Clinical features of clear cell meningioma: a retrospective study of 36 cases among 10,529 patients in a single institution.

    Science.gov (United States)

    Li, Peng; Yang, Zhijun; Wang, Zhenmin; Zhou, Qiangyi; Li, Shiwei; Wang, Xingchao; Wang, Bo; Zhao, Fu; Liu, Pinan

    2016-01-01

    Clear cell meningioma (CCM) is a rare subtype of meningioma. We present the largest series of 36 CCMs and evaluate several prognostic factors of patient's clinical outcome. Thirty-six patients with pathologically confirmed CCM among a total of 10,529 meningioma patients were retrospectively reviewed. CCM constituted 0.3 % of the intracranial meningiomas and 1.4 % of the intraspinal meningiomas. The male-to-female ratio (36 vs 64 %) for CCMs was similar to that for total meningiomas (28 vs 72 %) patients (chi-squared test, p = 0.3). The mean age at diagnosis of CCM patients (29.3 ± 18.4 years) was significantly younger than that of total meningiomas (49.8 ± 11.9 years) patients (t-test, p = 0). During the follow-up, 15 patients (42 %) suffered from tumor recurrence. The recurrence time ranged from 10 months to 12 years, with a median time of 29 months. Kaplan-Meier survival analysis showed that patients after total resection (Simpson grades I and II) had significantly longer progression-free survival (PFS) time than those after subtotal resection (Simpson grades III and IV) (log-rank test, p = 0.006). However, age (≤20 years or >20 years, p = 0.9), gender (p = 0.3), postoperative radiotherapy (p = 0.4), progesterone receptor staining (positivity or negativity, p = 0.2), and Ki-67 index (≤5 % or >5 %, p = 0.4) did not have significant effects on patients' PFS time. The proportion of CCM in spinal meningiomas is likely to be much larger than that in intracranial meningiomas. CCMs should be resected totally when possible to decrease the risk of recurrence or prolong patient's PFS time.

  17. The prognostic value of pretreatment CA-125 levels and CA-125 normalization in ovarian clear cell carcinoma: a two-academic-institute study

    Science.gov (United States)

    Bai, Huimin; Sha, Guisha; Xiao, Meizhu; Gao, Huiqiao; Cao, Dongyan; Yang, Jiaxin; Chen, Jie; Wang, Yue; Zhang, Zhenyu; Shen, Keng

    2016-01-01

    Objectives The present study investigated the clinical implications of pretreatment carbohydrate antigen 125 (CA-125) levels and CA-125 normalization in patients with ovarian clear cell carcinoma (CCC), and it provides useful information for the improvement of monitoring strategies for this lethal disease. Methods The medical records of patients with ovarian CCC who had undergone primary staging surgery or cytoreductive surgery followed by systemic chemotherapy were retrospectively reviewed. A range of clinico-pathological parameters were collected and examined. Results A total of 375 women were included in the analysis. FIGO stage (p < 0.001) was identified as the only significant prognostic factor for relapse. Residual tumor and advanced stage (p = 0.001 and p < 0.001, respectively) were identified as independent adverse factors for survival. The potential risk factors associated with elevated pretreatment CA-125 levels included advanced-stage disease, positive residual tumors and negative endometriosis (p < 0.001, p = 0.001 and p <0.001, respectively). Pretreatment CA-125 levels were not associated with relapse-free survival (RFS) or overall survival (OS) (p = 0.060 and p = 0.176, respectively). CA-125 normalization after chemotherapy exhibited a positive linear correlation with advanced stage (r = 0.97, p = 0.001) and residual tumor (r = 0.81, p = 0.027) and a negative relationship with 5-year RFS (r = −0.97, p = 0.002) and 5-year OS (r = −0.97, p= 0.001). Patients with CA-125 levels that normalized before cycle 2 of chemotherapy had a similar prognosis as patients whose CA-125 levels normalized prior to chemotherapy (RFS: p = 0.327; OS: p = 0.654). By contrast, patients with CA-125 levels that normalized after cycle 2 of chemotherapy or never normalized were significantly more likely to experience disease progression. Conclusions Pretreatment CA-125 levels are not very useful for predicting clinical outcome. CA-125 levels following treatment are a valid

  18. Generation of mature hematopoietic cells from human pluripotent stem cells.

    Science.gov (United States)

    Togarrati, Padma Priya; Suknuntha, Kran

    2012-06-01

    A number of malignant and non-malignant hematological disorders are associated with the abnormal production of mature blood cells or primitive hematopoietic precursors. Their capacity for continuous self-renewal without loss of pluripotency and the ability to differentiate into adult cell types from all three primitive germ layers make human embryonic stem cells and induced pluripotent stem cells (hiPSCs) attractive complementary cell sources for large-scale production of transfusable mature blood cell components in cell replacement therapies. The generation of patient-specific hematopoietic stem/precursor cells from iPSCs by the regulated manipulation of various factors involved in reprograming to ensure complete pluripotency, and developing innovative differentiation strategies for generating unlimited supply of clinically safe, transplantable, HLA-matched cells from hiPSCs to outnumber the inadequate source of hematopoietic stem cells obtained from cord blood, bone marrow and peripheral blood, would have a major impact on the field of regenerative and personalized medicine leading to translation of these results from bench to bedside.

  19. Human colostral cells. I. Separation and characterization.

    Science.gov (United States)

    Crago, S S; Prince, S J; Pretlow, T G; McGhee, J R; Mestecky, J

    1979-12-01

    Analyses of the cells present in human colostrum obtained from fifty-four healthy donors during the first four days of lactation revealed that there were 3.3 x 10(6) (range 1.1 x 10(5)--1.2 x 10(7)) cells per ml of colostrum. Based on histochemical examinations, it was found that this population consisted of 30--47% macrophages, 40--60% polymorphonuclear leucocytes, 5.2--8.9% lymphocytes, and 1.3--2.8% colostral corpuscles; epithelial cells were rarely encountered. The identity of various cell types was confirmed by Wright's stain and by a series of histochemical techniques which disclosed the presence of non-specific esterase, peroxidase, and lipids. For further characterization, the different types of cells were separated by various methods, such as Ficoll-Hypaque density centrifugation, isokinetic centrifugation on a linear Ficoll gradient, adherence to glass or plastic, and phagocytosis of carbonyl iron. Immunohistochemical staining with FITC- and/or TRITC-labelled reagents to IgA, IgM, IgG, K- and lambda-chains, secretory component, lactoferrin, and alpha-lactalbumin were applied to unseparated as well as separated colostral cells. Polymorphonuclear leucocytes (staining for peroxidase) as well as macrophages and colostral corpuscles (staining for non-specific esterase) exhibited numerous intracellular vesicles that contained lipids as well as various combinations of milk proteins. Lymphoid cells did not stain with any of these reagents and plasma cells were not detected among the colostral cells. Individual phagocytic cells contained immunoglobulins of the IgA and IgM classes, both K and lambda light chains, secretory component, lactoferrin, and alpha-lactalbumin. The coincidental appearance of these proteins in single, phagocytic cells but not in lymphoid cells indicate that the cells acquired these proteins by ingestion from the environment. Markers commonly used for the identification of B lymphocytes (surface immunoglobulins) and T lymphocytes (receptors

  20. Laminin-511 expression is associated with the functionality of feeder cells in human embryonic stem cell culture.

    Science.gov (United States)

    Hongisto, Heidi; Vuoristo, Sanna; Mikhailova, Alexandra; Suuronen, Riitta; Virtanen, Ismo; Otonkoski, Timo; Skottman, Heli

    2012-01-01

    Fibroblast feeder cells play an important role in supporting the derivation and long term culture of undifferentiated, pluripotent human embryonic stem cells (hESCs). The feeder cells secrete various growth factors and extracellular matrix (ECM) proteins into extracellular milieu. However, the roles of the feeder cell-secreted factors are largely unclear. Animal feeder cells and use of animal serum also make current feeder cell culture conditions unsuitable for derivation of clinical grade hESCs. We established xeno-free feeder cell lines using human serum (HS) and studied their function in hESC culture. While human foreskin fibroblast (hFF) feeder cells were clearly hESC supportive, none of the established xeno-free human dermal fibroblast (hDF) feeder cells were able to maintain undifferentiated hESC growth. The two fibroblast types were compared for their ECM protein synthesis, integrin receptor expression profiles and key growth factor secretion. We show that hESC supportive feeder cells produce laminin-511 and express laminin-binding integrins α3ß1, α6ß1 and α7ß1. These results indicate specific laminin isoforms and integrins in maintenance of hESC pluripotency in feeder-dependent cultures. In addition, several genes with a known or possible role for hESC pluripotency were differentially expressed in distinct feeder cells. Copyright © 2011 Elsevier B.V. All rights reserved.

  1. 21 CFR 864.2280 - Cultured animal and human cells.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cultured animal and human cells. 864.2280 Section... (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Cell And Tissue Culture Products § 864.2280 Cultured animal and human cells. (a) Identification. Cultured animal and human cells are in vitro...

  2. DNA repair responses in human skin cells

    Energy Technology Data Exchange (ETDEWEB)

    Hanawalt, P.C.; Liu, S.C.; Parsons, C.S.

    1981-07-01

    Sunlight and some environmental chemical agents produce lesions in the DNA of human skin cells that if unrepaired may interfere with normal functioning of these cells. The most serious outcome of such interactions may be malignancy. It is therefore important to develop an understanding of mechanisms by which the lesions may be repaired or tolerated without deleterious consequences. Our models for the molecular processing of damaged DNA have been derived largely from the study of bacterial systems. Some similarities but significant differences are revealed when human cell responses are tested against these models. It is also of importance to learn DNA repair responses of epidermal keratinocytes for comparison with the more extensive studies that have been carried out with dermal fibroblasts. Our experimental results thus far indicate similarities for the excision-repair of ultraviolet-induced pyrimidine dimers in human keratinocytes and fibroblasts. Both the monoadducts and the interstrand crosslinks produced in DNA by photoactivated 8-methoxypsoralen (PUVA) can be repaired in normal human fibroblasts but not in those from xeroderma pigmentosum patients. The monoadducts, like pyrimidine dimers, are probably the more mutagenic/carcinogenic lesions while the crosslinks are less easily repaired and probably result in more effective blocking of DNA function. It is suggested that a split-dose protocol that maximizes the production of crosslinks while minimizing the yield of monoadducts may be more effective and potentially less carcinogenic than the single ultraviolet exposure regimen in PUVA therapy for psoriasis.

  3. Impairment of cell cycle progression by aflatoxin B1 in human cell lines.

    Science.gov (United States)

    Ricordy, R; Gensabella, G; Cacci, E; Augusti-Tocco, G

    2002-05-01

    Aflatoxin B1 is a mycotoxin produced by Aspergillus flavus and Aspergillus parasiticum, which may be present as a food contaminant. It is known to cause acute toxic effects and act as a carcinogenic agent. The carcinogenic action has been related to its ability to form unstable adducts with DNA, which represent possible mutagenic sites. On the other hand, the primary cellular target responsible for its toxic action has not yet been clearly identified. Previous data suggested a possible correlation between cell proliferation and responsiveness to aflatoxin toxicity. These observations led us to investigate the effect of the toxin on cell cycle progression of three human cell lines (HepG2, SK-N-MC and SK-N-SH derived from liver and nervous tissue tumours); they were shown to display different responses to toxin exposure and have different growth kinetics. We performed analysis of the cell cycle, DNA synthesis and expression of p21 and p53 in the presence and absence of the toxin in all cell lines exposed. The results of cell cycle cytofluorometric analysis show significant alterations of cell cycle progression as a result of toxin treatment. In all cell lines exposure to a 24 h toxin treatment causes a dose-dependent accumulation in S phase, however, the ability to recover from impairment to traverse S phase varies in the cell lines under study. SK-N-MC cells appear more prone to resume DNA synthesis when the toxin is removed, while the other two cell lines maintain a significant inhibition of DNA synthesis, as indicated by cytofluorimetry and [(3)H]dTR incorporation. The level of p53 and p21 expression in the three cell lines was examined by western blot analysis and significant differences were detected. The ready resumption of DNA synthesis displayed by SK-N-MC cells could possibly be related to the absence of p53 control of cell cycle progression.

  4. Human T Cell Memory: A Dynamic View

    Directory of Open Access Journals (Sweden)

    Derek C. Macallan

    2017-02-01

    Full Text Available Long-term T cell-mediated protection depends upon the formation of a pool of memory cells to protect against future pathogen challenge. In this review we argue that looking at T cell memory from a dynamic viewpoint can help in understanding how memory populations are maintained following pathogen exposure or vaccination. For example, a dynamic view resolves the apparent paradox between the relatively short lifespans of individual memory cells and very long-lived immunological memory by focussing on the persistence of clonal populations, rather than individual cells. Clonal survival is achieved by balancing proliferation, death and differentiation rates within and between identifiable phenotypic pools; such pools correspond broadly to sequential stages in the linear differentiation pathway. Each pool has its own characteristic kinetics, but only when considered as a population; single cells exhibit considerable heterogeneity. In humans, we tend to concentrate on circulating cells, but memory T cells in non-lymphoid tissues and bone marrow are increasingly recognised as critical for immune defence; their kinetics, however, remain largely unexplored. Considering vaccination from this viewpoint shifts the focus from the size of the primary response to the survival of the clone and enables identification of critical system pinch-points and opportunities to improve vaccine efficacy.

  5. Biological impact of human embryonic stem cells.

    Science.gov (United States)

    Martín, Miguel; Menéndez, Pablo

    2012-01-01

    Research on human embryonic stem cells (hESCs) and induced pluripotent (iPS) stem cells is currently a field of great potential in biomedicine. These cells represent a highly valuable tool for developmental biology studies, disease models, and drug screening and toxicity. The ultimate goal of hESCs and iPS cell research is the treatment of diseases or disorders for which there is currently no treatment or existing therapies are only partially effective. Despite the disproportionate short-term hopes generated, which are putting too much pressure on scientists, the international scientific community is making rapid progress in understanding hESCs and iPS cells. Nonetheless, great efforts have to be made to provide an answer to still quite basic questions concerning their biology. Moreover, translation to clinical applications in cell replacement therapy requires prior solution to ethical barriers. The recent development of iPS cells has provided a strong alternative to overcome ethical issues concerning hESCs. However, an in-depth characterization of their genetic and epigenetic features, as well as their differentiation potential still remains to be undertaken. This chapter will describe, precisely, what the critical issues are, where scientific and ethical barriers stand, and how we are to overcome them. Only then, we shall finally discover whether hESCs and iPS cells will allow building reproducible disease models, and whether they really are a safe tool, with great potential for regenerative medicine.

  6. Human fetal liver stromal cells expressing erythropoietin promote hematopoietic development from human embryonic stem cells.

    Science.gov (United States)

    Yang, Chao; Ji, Lei; Yue, Wen; Shi, Shuang-Shuang; Wang, Ruo-Yong; Li, Yan-Hua; Xie, Xiao-Yan; Xi, Jia-Fei; He, Li-Juan; Nan, Xue; Pei, Xue-Tao

    2012-02-01

    Blood cells transfusion and hematopoietic stem cells (HSCs) transplantation are important methods for cell therapy. They are widely used in the treatment of incurable hematological disorder, infectious diseases, genetic diseases, and immunologic deficiency. However, their availability is limited by quantity, capacity of proliferation and the risk of blood transfusion complications. Recently, human embryonic stem cells (hESCs) have been shown to be an alternative resource for the generation of hematopoietic cells. In the current study, we describe a novel method for the efficient production of hematopoietic cells from hESCs. The stable human fetal liver stromal cell lines (hFLSCs) expressing erythropoietin (EPO) were established using the lentiviral system. We observed that the supernatant from the EPO transfected hFLSCs could induce the hESCs differentiation into hematopoietic cells, especially erythroid cells. They not only expressed fetal and embryonic globins but also expressed the adult-globin chain on further maturation. In addition, these hESCs-derived erythroid cells possess oxygen-transporting capacity, which indicated hESCs could generate terminally mature progenies. This should be useful for ultimately developing an animal-free culture system to generate large numbers of erythroid cells from hESCs and provide an experimental model to study early human erythropoiesis.

  7. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling.

    Science.gov (United States)

    Eyerich, Stefanie; Eyerich, Kilian; Pennino, Davide; Carbone, Teresa; Nasorri, Francesca; Pallotta, Sabatino; Cianfarani, Francesca; Odorisio, Teresa; Traidl-Hoffmann, Claudia; Behrendt, Heidrun; Durham, Stephen R; Schmidt-Weber, Carsten B; Cavani, Andrea

    2009-12-01

    Th subsets are defined according to their production of lineage-indicating cytokines and functions. In this study, we have identified a subset of human Th cells that infiltrates the epidermis in individuals with inflammatory skin disorders and is characterized by the secretion of IL-22 and TNF-alpha, but not IFN-gamma, IL-4, or IL-17. In analogy to the Th17 subset, cells with this cytokine profile have been named the Th22 subset. Th22 clones derived from patients with psoriasis were stable in culture and exhibited a transcriptome profile clearly separate from those of Th1, Th2, and Th17 cells; it included genes encoding proteins involved in tissue remodeling, such as FGFs, and chemokines involved in angiogenesis and fibrosis. Primary human keratinocytes exposed to Th22 supernatants expressed a transcriptome response profile that included genes involved in innate immune pathways and the induction and modulation of adaptive immunity. These proinflammatory Th22 responses were synergistically dependent on IL-22 and TNF-alpha. Furthermore, Th22 supernatants enhanced wound healing in an in vitro injury model, which was exclusively dependent on IL-22. In conclusion, the human Th22 subset may represent a separate T cell subset with a distinct identity with respect to gene expression and function, present within the epidermal layer in inflammatory skin diseases. Future strategies directed against the Th22 subset may be of value in chronic inflammatory skin disorders.

  8. Cell phoney: human cloning after Quintavalle.

    Science.gov (United States)

    Morgan, Derek; Ford, Mary

    2004-12-01

    Reproductive cloning has thrown up new scientific possibilities, ethical conundrums, and legal challenges. An initial question, considered by the English courts in 2003, was whether the technique presently available, that of cell nucleus replacement, falls outside the provisions of the Human Fertilisation and Embryology Act 1990. If it does, the creation and use, including use in research protocols, of human embryos would be unregulated, disclosing a need to consider remedial legislation. The resolution by the courts of this legal question dramatically engages them in a resolution of fundamental ethical dilemmas, and discloses the possibilities and limitation of negotiating science policy through the processes of litigation.

  9. Expression of oxidative stress proteins in the clear-cell renal cell carcinoma%肾透明细胞癌中氧化应激蛋白的表达

    Institute of Scientific and Technical Information of China (English)

    田美娟; 李雨遥; 罗长琴; 吕美玲; 杨谨

    2012-01-01

    [目的]探讨人肾透明细胞癌细胞株RLC-310与人正常肾近曲小管上皮细胞株HK-2,肾癌及其癌旁组织中氧化应激蛋白表达的差异.[方法]体外培养RLC-310和HK-2,采用PF-2D蛋白分级分离系统分离细胞总蛋白,选取差异蛋白组分进行毛细管LC-ESI-MS/MS分析,结合蛋白质数据库检索对差异蛋白进行鉴定,并对代表性氧化应激差异蛋白采用免疫组织化学方法进行验证.[结果]两个细胞株经串联质谱分析共鉴定出12个氧化应激差异表达蛋白,分别是peroxiredoxin-1( PRX-1)、peroxiredoxin-6( PRX-6)、superoxide dismutase [ Cu-Zn] SOD1、glutathione peroxidase 1、catalase、glutathione synthetase、glutathione S-transferase Pi(GSTPi)、thioredoxin、热休克蛋白10( heat shock protein,HSP10)、HSP 60、HSP 70和HSP 90.其中PRX-6、HSP 60、GSTPi三种代表性差异蛋白在人肾透明细胞癌细胞株RLC-310和人正常肾近曲小管上皮细胞株HK-2中均有表达,前者的表达水平较后者显著升高(P<0.05),这三种蛋白在肾癌组织中表达也较癌旁组织显著升高(P<0.05).[结论]人肾透明细胞癌中存在抗氧化应激蛋白的差异表达,这些氧化应激蛋白的异常表达在阻止肾癌细胞氧化损伤中起一定作用.%AIM: To investigate the expression of the oxidative stress proteins in human clear-cell renal cell carcinoma (CROC) cell line (RLC-310) and normal renal proximal tubule epithelial cell line (HK-2), the CRCC and the corresponding normal renal tissues. METHODS; RLC-310 and HK-2 cells were cultured in vitro. Total proteins of the two cell lines were separated by PF-2D protein fractiona-fon system. The differentially expressed proteins of the two cell lines were analyzed using capillary LOESI-MS/MS and identified using the protein database. The representative differential oxidative stress proteins were verified by immuno-histochemistry in the CRCC and corresponding normal renal tissues. RESULTS; Twelve

  10. Activation of human natural killer cells by the soluble form of cellular prion protein

    Energy Technology Data Exchange (ETDEWEB)

    Seong, Yeon-Jae [Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon (Korea, Republic of); Hafis Clinic, Seoul (Korea, Republic of); Sung, Pil Soo; Jang, Young-Soon; Choi, Young Joon [Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon (Korea, Republic of); Park, Bum-Chan [Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Park, Su-Hyung [Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, KAIST, Daejeon (Korea, Republic of); Park, Young Woo [Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Shin, Eui-Cheol, E-mail: ecshin@kaist.ac.kr [Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon (Korea, Republic of)

    2015-08-21

    Cellular prion protein (PrP{sup C}) is widely expressed in various cell types, including cells of the immune system. However, the specific roles of PrP{sup C} in the immune system have not been clearly elucidated. In the present study, we investigated the effects of a soluble form of recombinant PrP{sup C} protein on human natural killer (NK) cells. Recombinant soluble PrP{sup C} protein was generated by fusion of human PrP{sup C} with the Fc portion of human IgG{sub 1} (PrP{sup C}-Fc). PrP{sup C}-Fc binds to the surface of human NK cells, particularly to CD56{sup dim} NK cells. PrP{sup C}-Fc induced the production of cytokines and chemokines and the degranulation of granzyme B from NK cells. In addition, PrP{sup C}-Fc facilitated the IL-15-induced proliferation of NK cells. PrP{sup C}-Fc induced phosphorylation of ERK-1/2 and JNK in NK cells, and inhibitors of the ERK or the JNK pathways abrogated PrP{sup C}-Fc-induced cytokine production in NK cells. In conclusion, the soluble form of recombinant PrP{sup C}-Fc protein activates human NK cells via the ERK and JNK signaling pathways. - Highlights: • Recombinant soluble PrP{sup C} (PrP{sup C}-Fc) was generated by fusion of human PrP{sup C} with IgG1 Fc portion. • PrP{sup C}-Fc protein induces the production of cytokines and degranulation from human NK cells. • PrP{sup C}-Fc protein enhances the IL-15-induced proliferation of human NK cells. • PrP{sup C}-Fc protein activates human NK cells via the ERK and JNK signaling pathways.

  11. Effects of active bufadienolide compounds on human cancer cells and CD4+CD25+Foxp3+ regulatory T cells in mitogen-activated human peripheral blood mononuclear cells.

    Science.gov (United States)

    Yuan, Bo; He, Jing; Kisoh, Keishi; Hayashi, Hideki; Tanaka, Sachiko; Si, Nan; Zhao, Hai-Yu; Hirano, Toshihiko; Bian, Baolin; Takagi, Norio

    2016-09-01

    The growth inhibitory effects of bufadienolide compounds were investigated in two intractable cancer cells, a human glioblastoma cell line U-87 and a pancreatic cancer cell line SW1990. Among four bufadienolide compounds, a dose-dependent cytotoxicity was observed in these cancer cells after treatment with gamabufotalin and arenobufagin. The IC50 values of the two compounds were 3-5 times higher in normal peripheral blood mononuclear cells (PBMCs) than these values for both cancer cell lines. However, similar phenomena were not observed for two other bufadienolide compounds, telocinobufagin and bufalin. These results thus suggest that gamabufotalin and arenobufagin possess selective cytotoxic activity against tumor cells rather than normal cells. Moreover, a clear dose-dependent lactate dehydrogenase (LDH) release, a well-known hallmark of necrosis, was observed in both cancer cells treated with gamabufotalin, suggesting that gamabufotalin-mediated cell death is predominantly associated with a necrosis-like phenotype. Of most importance, treatment with as little as 8 ng/ml of gamabufotalin, even an almost non-toxic concentration to PBMCs, efficiently downregulated the percentages of CD4+CD25+Foxp3+ regulator T (Treg) cells in mitogen-activated PBMCs. Given that Treg cells play a critical role in tumor immunotolerance by suppressing antitumor immunity, these results suggest that gamabufotalin may serve as a promising candidate, as an adjuvant therapeutic agent by manipulating Treg cells to enhance the efficacy of conventional anticancer drugs and lessen their side-effects. These findings provide insights into the clinical application of gamabufotalin for cancer patients with glioblastoma/pancreatic cancer based on its cytocidal effect against tumor cells as well as its depletion of Treg cells.

  12. Lymphoid Cell-Glioma Cell Interaction Enhances Cell Coat Production by Human Gliomas: Novel Suppressor Mechanism

    Science.gov (United States)

    Dick, Steven J.; Macchi, Beatrice; Papazoglou, Savvas; Oldfield, Edward H.; Kornblith, Paul L.; Smith, Barry H.; Gately, Maurice K.

    1983-05-01

    Certain human glioma lines produce mucopolysaccharide coats that impair the generation of cytolytic lymphocytes in response to these lines in vitro. Coat production is substantially enhanced by the interaction of glioma cells with a macromolecular factor released by human peripheral blood mononuclear cells in culture. This interaction thus constitutes an unusual mechanism by which inflammatory cells may nonspecifically suppress the cellular immune response to at least one class of solid tumors in humans.

  13. Human induced pluripotent stem cell-derived models to investigate human cytomegalovirus infection in neural cells.

    Directory of Open Access Journals (Sweden)

    Leonardo D'Aiuto

    Full Text Available Human cytomegalovirus (HCMV infection is one of the leading prenatal causes of congenital mental retardation and deformities world-wide. Access to cultured human neuronal lineages, necessary to understand the species specific pathogenic effects of HCMV, has been limited by difficulties in sustaining primary human neuronal cultures. Human induced pluripotent stem (iPS cells now provide an opportunity for such research. We derived iPS cells from human adult fibroblasts and induced neural lineages to investigate their susceptibility to infection with HCMV strain Ad169. Analysis of iPS cells, iPS-derived neural stem cells (NSCs, neural progenitor cells (NPCs and neurons suggests that (i iPS cells are not permissive to HCMV infection, i.e., they do not permit a full viral replication cycle; (ii Neural stem cells have impaired differentiation when infected by HCMV; (iii NPCs are fully permissive for HCMV infection; altered expression of genes related to neural metabolism or neuronal differentiation is also observed; (iv most iPS-derived neurons are not permissive to HCMV infection; and (v infected neurons have impaired calcium influx in response to glutamate.

  14. Human somatic cell nuclear transfer and cloning.

    Science.gov (United States)

    2012-10-01

    This document presents arguments that conclude that it is unethical to use somatic cell nuclear transfer (SCNT) for infertility treatment due to concerns about safety; the unknown impact of SCNT on children, families, and society; and the availability of other ethically acceptable means of assisted reproduction. This document replaces the ASRM Ethics Committee report titled, "Human somatic cell nuclear transfer (cloning)," last published in Fertil Steril 2000;74:873-6. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  15. Dopamine receptor repertoire of human granulosa cells

    Directory of Open Access Journals (Sweden)

    Kunz Lars

    2007-10-01

    Full Text Available Abstract Background High levels of dopamine (DA were described in human ovary and recently evidence for DA receptors in granulosa and luteal cells has been provided, as well. However, neither the full repertoire of ovarian receptors for DA, nor their specific role, is established. Human granulosa cells (GCs derived from women undergoing in vitro fertilization (IVF are an adequate model for endocrine cells of the follicle and the corpus luteum and were therefore employed in an attempt to decipher their DA receptor repertoire and functionality. Methods Cells were obtained from patients undergoing IVF and examined using cDNA-array, RT-PCR, Western blotting and immunocytochemistry. In addition, calcium measurements (with FLUO-4 were employed. Expression of two DA receptors was also examined by in-situ hybridization in rat ovary. Effects of DA on cell viability and cell volume were studied by using an ATP assay and an electronic cell counter system. Results We found members of the two DA receptor families (D1- and D2 -like associated with different signaling pathways in human GCs, namely D1 (as expected and D5 (both are Gs coupled and linked to cAMP increase and D2, D4 (Gi/Gq coupled and linked to IP3/DAG. D3 was not found. The presence of the trophic hormone hCG (10 IU/ml in the culture medium for several days did not alter mRNA (semiquantitative RT-PCR or protein levels (immunocytochemistry/Western blotting of D1,2,4,5 DA receptors. Expression of prototype receptors for the two families, D1 and D2, was furthermore shown in rat granulosa and luteal cells by in situ hybridization. Among the DA receptors found in human GCs, D2 expression was marked both at mRNA and protein levels and it was therefore further studied. Results of additional RT-PCR and Western blots showed two splice variants (D2L, D2S. Irrespective of these variants, D2 proved to be functional, as DA raised intracellular calcium levels. This calcium mobilizing effect of DA was observed

  16. TALEN-Induced Translocations in Human Cells.

    Science.gov (United States)

    Piganeau, Marion; Renouf, Benjamin; Ghezraoui, Hind; Brunet, Erika

    2016-01-01

    Induction of chromosomal translocations in human cells is of a great interest to study tumorigenesis and genome instability. Here, we explain in detail a method to induce translocations using the transcription activator-like effector nucleases (TALENs). We describe how to detect translocation formation by PCR, calculate translocation frequency by 96-well PCR screen, and analyze breakpoint junctions. When inducing cancer translocations, it is also possible to detect the fusion gene by FISH analysis or western blot.

  17. The core regulatory network in human cells.

    Science.gov (United States)

    Kim, Man-Sun; Kim, Dongsan; Kang, Nam Sook; Kim, Jeong-Rae

    2017-03-04

    In order to discover the common characteristics of various cell types in the human body, many researches have been conducted to find the set of genes commonly expressed in various cell types and tissues. However, the functional characteristics of a cell is determined by the complex regulatory relationships among the genes rather than by expressed genes themselves. Therefore, it is more important to identify and analyze a core regulatory network where all regulatory relationship between genes are active across all cell types to uncover the common features of various cell types. Here, based on hundreds of tissue-specific gene regulatory networks constructed by recent genome-wide experimental data, we constructed the core regulatory network. Interestingly, we found that the core regulatory network is organized by simple cascade and has few complex regulations such as feedback or feed-forward loops. Moreover, we discovered that the regulatory links from genes in the core regulatory network to genes in the peripheral regulatory network are much more abundant than the reverse direction links. These results suggest that the core regulatory network locates at the top of regulatory network and plays a role as a 'hub' in terms of information flow, and the information that is common to all cells can be modified to achieve the tissue-specific characteristics through various types of feedback and feed-forward loops in the peripheral regulatory networks. We also found that the genes in the core regulatory network are evolutionary conserved,