Intraductal Glycogen-Rich Clear Cell Carcinoma of the Breast: A Rare Presentation and Review of the Literature

PubMed Central

Salemis, Nikolaos S.

2012-01-01

Background Glycogen-rich clear cell carcinoma of the breast is a rare histological subtype of breast cancer, accounting for 0.9–2.8% of all breast cancer cases. Fewer than 100 cases have been reported in the literature. Most of these tumors are invasive carcinomas. The intraductal glycogen-rich clear cell carcinoma is a very rare occurrence. Case Report Herein is described a case of a pure intraductal glycogen-rich clear cell carcinoma of the breast in a 42-year-old premenopausal woman. A literature review has also been carried out. Mammography was inconclusive due to the presence of dense breast tissue, but magnetic resonance imaging (MRI) showed several nodular lesions measuring 7 × 6 cm in diameter and involving the upper aspect of the right breast suggestive of multifocal malignancy. A modified radical mastectomy was performed. The patient started hormonal therapy with tamoxifen and is currently well 16 months after surgery. Conclusion A pure intraductal glycogen-rich clear cell carcinoma of the breast is a very rare occurrence. The case presented here exhibited uncommon MRI features, whereas the tumor size is one of the largest reported in the literature. Mammography may be inconclusive in the presence of dense breast tissue, but MRI is of great importance in the preoperative evaluation of the patient. PMID:23904836

PT2385 for the Treatment of Von Hippel-Lindau Disease-Associated Clear Cell Renal Cell Carcinoma

ClinicalTrials.gov

2017-08-23

VHL Gene Mutation; VHL; VHL Syndrome; VHL Gene Inactivation; Von Hippel; Von Hippel-Lindau Disease; Von Hippel's Disease; Von Hippel-Lindau Syndrome, Modifiers of; Clear Cell Renal Cell Carcinoma; Clear Cell RCC; ccRCC

Combined Papillated Bowen Disease and Clear Cell Atypical Fibroxanthoma

PubMed Central

Suárez-Vilela, Dimas; Izquierdo-García, Francisco; Domínguez-Iglesias, Francisco; Méndez-Álvarez, Jose Ramón

2010-01-01

We describe a case of papillated Bowen disease (PBD), associated with a clear cell atypical fibroxanthoma (CCAFXA). The epidermal lesion showed a bowenoid papillomatous growth pattern with histologic features suggestive of infection by human papilloma virus (HPV). In the dermis a neoplasm made up by spindled or polygonal cells with wide clear cytoplasm and moderate nuclear pleomorphism was found. Immunohistochemical characteristics of these two lesions were clearly different. The atypical cells of the intraepidermal proliferation were positive for AE1-AE3 anticytokeratin antibody, EMA, p16, p53 and p63. The dermal tumor was positive for vimentin, CD10, CD68, CD99, alpha-1-antitrypsin and c-kit. Histological features and immunohistochemical profile of the dermal tumor corresponded to a CCAFXA, a very uncommon neoplasm of which only 10 cases have been reported. In situ hybridization for numerous types of HPVs was negative in both lesions. PMID:21103191

High Occurrence of Non-Clear Cell Renal Cell Carcinoma in Oman.

PubMed

Venniyoor, Ajit; Essam, Abdul Monem; Ramadhan, Fatma; Keswani, Heeranand; Mehdi, Itrat; Bahrani, Bassim Al

2016-01-01

It is conventionally accepted that renal cell carcinoma (RCC) occurs in older patients and the clear cell type is the most common histology. However, ethnic variations exist and this study was carried out to determine the epidemiological pattern of RCC in Oman. Ninety RCC patients who presented to a tertiary care center in the Sultanate of Oman from 2010 to 2014 were studied. The main findings were that the median age of presentation was low, more patients presented with localized stage, and there was a higher incidence of non-clear (especially papillary) histology. Data from other Gulf countries and possible reasons for the different profile are discussed.

Ependymal tumors with oligodendroglioma like clear cells: Experience from a tertiary care hospital in Pakistan

PubMed Central

Hashmi, Fauzan Alam; Khan, Muhammad Faheem; Khan, Saad Akhtar; Waqas, Muhammad; Bari, Muhammad Ehsan; Ahmed, Arsalan

2015-01-01

Background: Ependymal tumors with oligodendroglioma like clear cells have never been reported from Pakistan. We aimed to see the features and outcomes of this rare entity. Methods: It was retrospective cohort conducted at the Department of Neurosurgery, Aga Khan University from 2003 to 2013. The medical records and radiology of patients with proven histopathology were reviewed. Analysis was done on SPSS 20. Results: Eleven cases of ependymal tumors with clear cells were found, which equated to 1.5% of the total tumor burden in 11 years. The median age was 49 years. Most common presenting symptom was headache 54.5%. Out of 11 patients, 9 patients had a supratentorial tumor. Magnetic resonance imaging showed hypointense signals on T1 and hyperintense signals on T2-weighted images in all cases. Contrast enhancement was found in 9 patients (77.8%), necrosis and hemorrhage was found in 4 (36%) and 3 (27%) patients, respectively. Immunohistochemistry showed glial fibrillary acidic protein and epithelial membrane antigen positivity in all cases. Ki-67 showed high proliferative index in 6 patients. According to the World Health Organization grading of ependymal tumors, 2 patients had Grade II tumors, and 9 patients had Grade III tumors with clear cells. Gross total resection was achieved in 6 (54.5%) and subtotal resection in 5 patients (45.4%). Recurrence was observed in 9 patients. Six patients died of the disease. Median progression-free survival and overall survival was 8 months and 10 months, respectively. Conclusion: Ependymal tumors with clear cells presented more commonly in Grade III lesions and were more aggressive in behavior with poorer outcome compared to similar studies. PMID:26664928

Differentiation of low- and high-grade clear cell renal cell carcinoma: Tumor size versus CT perfusion parameters.

PubMed

Chen, Chao; Kang, Qinqin; Xu, Bing; Guo, Hairuo; Wei, Qiang; Wang, Tiegong; Ye, Hui; Wu, Xinhuai

To compare the utility of tumor size and CT perfusion parameters for differentiation of low- and high-grade clear cell renal cell carcinoma (RCC). Tumor size, Equivalent blood volume (Equiv BV), permeability surface-area product (PS), blood flow (BF), and Fuhrman pathological grading of clear cell RCC were retrospectively analyzed. High-grade clear cell RCC had significantly higher tumor size and lower PS than low grade. Tumor size positively correlated with Fuhrman grade, but PS negatively did. Tumor size and PS were significantly independent indexes for differentiating high-grade from low-grade clear cell RCC. Copyright © 2017 Elsevier Inc. All rights reserved.

Clear cell trichoblastoma: a clinicopathological and ultrastructural study of two cases.

PubMed

Kazakov, Dmitry V; Mentzel, Thomas; Erlandson, Robert A; Mukensnabl, Petr; Michal, Michal

2006-06-01

Clear cell change in basal cell carcinomas is a well-recognized phenomenon, but is obviously rare in trichoblastomas. We present two cases of clear cell trichoblastoma in which clear cell change was very much prominent, and the results of an ultrastructural study intended to explore the basis of that feature. Both our patients were women, aged 56 and 77 years, who presented with solitary, slowly growing nodules that measured 3 to 5 cm in largest dimension and were located on the scalp and the flexor aspect of the lower arm. Microscopically, the tumors in both cases were symmetric, non-ulcerated, and composed of variably sized and shaped (cribriform, racemiform, strands, cords, nodules) aggregations of monomorphous basaloid epithelial cells that were associated with a specific trichogenic stroma. Common to both tumors was clear cell cytoplasm evident in the majority of the epithelial cells in one case and almost in the entire epithelial cell population in the other. In most epithelial aggregations the epithelial cells with clear cytoplasm often appeared columnar and were arranged in a palisade along a recognizable basal membrane, thus indicative of outer sheath differentiation at the bulb. There were other signs of follicular differentiation. Ultrastructurally, variably sized clusters of uniform small basaloid epithelial cells were separated from the stroma by a thin discontinuous basement membrane. In addition to the usual organelles, the cytoplasm contained fairly conspicuous tonofilaments and variably sized vacuoles devoid of a limiting membrane, located between the palisaded nuclei and the outer cell membrane. The majority of vacuoles were empty, although clumps of a finely granular substance were occasionally evident. No distinct lipid droplets or glycogen particles were identified. The basaloid cells were joined by scattered small desmosomes. These findings were consistent with trichilemmal differentiation at the bulb.

Parametric imaging of clear cell and papillary renal cell carcinoma using contrast-enhanced ultrasound (CEUS).

PubMed

Rübenthaler, J; Reimann, R; Hristova, P; Staehler, M; Reiser, M; Clevert, D A

2015-10-16

The aim of this study was to analyse clear cell and papillary renal cell carcinoma (RCC) examined with contrast-enhanced ultrasound (CEUS) and a second generation blood pool agent (SonoVue®, Bracco, Milan, Italy) before clinical intervention. A total of 41 patients with histologically proven subtypes of RCC were examined. 29 patients had a clear cell RCC and 12 patients showed a papillary RCC. Average size in the clear cell RCC group was 6.07 cm and 1.88 cm in the papillary RCC group. An experienced radiologist examined all patients with CEUS. The following parameters were analysed: maximum signal intensity (PEAK), time elapsed until PEAK is reached (MTT), local blood flow (RBF), area under the time intensity curve (AUC) and the signal intensity (SI) during the course of time. For both groups all comparisons were made based on healthy renal parenchyma. In the clear cell RCC significant differences (significance level p < 0.05) between cancerous tissue and the healthy renal parenchyma were noticed in all four parameters. The clear cell RCC showed a significant reduced blood volume. It reached the PEAK reading relatively rapidly and its signal intensity was always lower than that of the healthy renal parenchyma. In the arterial phase retarded absorption of the contrast agent was observed, followed by fast washing out of the contrast agent bubbles.In the papillary RCC group, significant findings as to PEAK and RBF as well as a slightly significant difference as to AUC were recorded. The papillary RCC had a lower blood supply and reached its PEAK reading later. Its signal intensity was also reduced. The signal intensity of papillary NCC was significantly lower compared with clear cell RCC; absorption and washing out of the contrast agent was delayed. CEUS seems to be an useful additional method to clinically differentiate between clear cell and papillary RCC. In daily clinical use, patients with contraindication for other imaging methods, especially the

Primary mucoepidermoid carcinoma of the lung with prominent clear cells

PubMed Central

Fink, David D.; Lomas, Angela M.; Roden, Anja C.; Shah, Prashant C.

2017-01-01

Mucoepidermoid carcinoma of the lung is a rare malignancy of salivary gland-type origin. We report a case of a 21-year-old man with a right mainstem bronchus mass composed predominantly of clear cells. This case represents a rare primary pulmonary low-grade mucoepidermoid carcinoma positive for MAML2 rearrangement by fluorescence in situ hybridization with a prominent clear cell component. PMID:28670072

Single-cell genetic analysis validates cytopathological identification of circulating cancer cells in patients with clear cell renal cell carcinoma.

PubMed

Broncy, Lucile; Njima, Basma Ben; Méjean, Arnaud; Béroud, Christophe; Romdhane, Khaled Ben; Ilie, Marius; Hofman, Veronique; Muret, Jane; Hofman, Paul; Bouhamed, Habiba Chaabouni; Paterlini-Bréchot, And Patrizia

2018-04-13

Circulating Rare Cells (CRC) are non-haematological cells circulating in blood. They include Circulating Cancer Cells (CCC) and cells with uncertain malignant features (CRC-UMF) according to cytomorphology. Clear cell renal cell carcinomas frequently bear a mutated Von Hippel-Lindau (VHL) gene. To match blind genetic analysis of CRC and tumor samples with CRC cytopathological diagnosis. 29/30 patients harboured CRC (20 harboured CCC, 29 CRC-UMF) and 25/29 patients carried VHL mutations in their tumour. 205 single CRC (64 CCC, 141 CRC-UMF) provided genetic data. 57/57 CCC and 104/125 CRC-UMF from the 25 patients with VHL-mutated tumor carried the same VHL mutation detected in the tumor. Seven CCC and 16 CRC-UMF did not carry VHL mutations but were found in patients with wild-type VHL tumor tissue. All the CCC and 83,2% (104/125) of the CRC-UMF were found to carry the same VHL mutation identified in the corresponding tumorous tissue, validating cytopathological identification of CCC in patients with clear cell renal cell carcinoma. The blood of 30 patients with clear cell renal cell carcinoma was treated by ISET ® for CRC isolation, cytopathology and single-cell VHL mutations analysis, performed blindly and compared to VHL mutations of corresponding tumor tissues and leukocytes.

Imprint cytology of clear cell sarcoma-like tumor of the gastrointestinal tract in the small intestine: A case report.

PubMed

Kato, Takashi; Ichihara, Shin; Gotoda, Hiroko; Muraoka, Shunji; Kubo, Terufumi; Sugita, Shintaro; Hasegawa, Tadashi

2017-12-01

Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLGT) is an extremely rare malignant neoplasm in the digestive tract. Its cytomorphologic features have never previously been reported. Here, we describe a case of CCSLGT, including its cytologic examination findings. A 47-year-old woman presented with a mass in the small intestine, which was resected and sent for imprint cytology. Imprint smears revealed tumor cells with light eosinophilic or clear cytoplasm in a necrotic background. Many of the tumor cells were arranged in a perivascular growth with a pseudopapillary formation, and there were some non-neoplastic osteoclast-like giant cells. Histological examination revealed solid nests and a pseudopapillary pattern of the tumor cells with clear or pale eosinophilic cytoplasm and large nuclei with small nucleoli. Immunohistochemistry showed positive for vimentin, S-100, and SOX-10, and negative for SMA, c-KIT, cytokeratin, HMB-45, and MelanA. The EWSR1 gene split signal was detected by reverse transcriptase fluorescence in situ hybridization, and EWSR1-CREB1 gene fusion was indicated by reverse transcriptase polymerase chain reaction analysis. From these findings, we diagnosed the tumor as CCSLGT. To best of our knowledge, this is the first description of the imprint cytology features of CCSLGT. © 2017 Wiley Periodicals, Inc.

The Presence of Vascular Mimicry Predicts High Risk of Clear Cell Renal Cell Carcinoma after Radical Nephrectomy.

PubMed

Zhou, Lin; Chang, Yuan; Xu, Le; Liu, Zheng; Fu, Qiang; Yang, Yuanfeng; Lin, Zongming; Xu, Jiejie

2016-08-01

Vascular mimicry is a type of tumor cell plasticity. The aim of this study was to determine the prognostic value of vascular mimicry in patients with clear cell renal cell carcinoma. We performed a retrospective cohort study in 387 patients with clear cell renal cell carcinoma who underwent radical nephrectomy at Zhongshan Hospital, Fudan University between 2008 and 2009. Pathological features, baseline patient characteristics and followup data were recorded. Vascular mimicry in clear cell renal cell carcinoma tissue was identified by CD31-periodic acid-Schiff double staining. Univariate and multivariate Cox regression models were used to analyze the impact of prognostic factors on recurrence-free survival. The concordance index and the Akaike information criterion were used to assess the predictive accuracy and sufficiency of different models. Positive vascular mimicry staining occurred in 25 of 387 clear cell renal cell carcinoma cases (6.5%) and it was associated with an increased risk of recurrence (log-rank p <0.001). Incorporating vascular mimicry into pT stage, Fuhrman grade and Leibovich score helped refine individual risk stratification. Moreover, vascular mimicry was identified as an independent prognostic factor (p = 0.001). It was entered into a nomogram together with pT stage, Fuhrman grade, tumor size and necrosis. In the primary cohort the Harrell concordance index for the established nomogram to predict recurrence-free survival was slightly higher than that of the Leibovich model (0.850 vs. 0.823), which failed to reach statistical significance (p = 0.158). Vascular mimicry could be a potential prognosticator for recurrence-free survival in patients with clear cell renal cell carcinoma after radical nephrectomy. Further external validation and functional analysis should be pursued to assess its potential prognostic and therapeutic values for clear cell renal cell carcinoma. Copyright © 2016 American Urological Association Education and Research

Primary non-clear-cell adenocarcinoma of the vagina in a diethylstilbestrol exposed woman.

PubMed

Patel, Samit A; Sunde, Jan

2014-04-01

A 54-year-old woman with a history of in-utero diethylstilbestrol (DES) exposure, who had a prior hysterectomy for symptomatic leiomyomata and dysmenorrhea, presented for vaginal bleeding. Vaginal biopsies showed a non-clear-cell adenocarcinoma, and the patient was subsequently treated with radiation therapy. We present a case of primary vaginal non-clear-cell adenocarcinoma in a patient with in-utero DES exposure. Continued monitoring of older DES-exposed women for vaginal lesions is warranted because of reported cases of non-clear-cell adenocarcinoma and persistent risk of clear cell adenocarcinoma. Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.

Metastatic clear-cell hidradenocarcinoma of the vulva.

PubMed

Messing, M J; Richardson, M S; Smith, M T; King, L; Gallup, D G

1993-02-01

Clear-cell hidradenocarcinoma is a malignant tumor of sweat gland origin. It is most often found on the trunk, head, and extremities. This case report describes a rare occurrence of this tumor on the vulva of a young woman. The discovery of metastatic disease reflects the potentially aggressive nature of this tumor.

Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy.

PubMed

Martínez-Sáez, Olga; Gajate Borau, Pablo; Alonso-Gordoa, Teresa; Molina-Cerrillo, Javier; Grande, Enrique

2017-03-01

The loss of the Von Hippel-Lindau tumor suppressor (VHL) is a key oncogenic event in the vast majority of patients with clear cell renal cell carcinoma (ccRCC). With the loss of the VHL protein (pVHL) function, the hypoxia inducible factor α (HIF-α) accumulates inside the tumor cell and dimerizes with HIF-β. The HIF-α/HIF-β complex transcriptionally activates hundreds of genes promoting the adaptation to hypoxia that is implicated in tumor development. There is growing evidence showing that HIF-2α subunit has a central role in ccRCC over HIF-1α. Thus, efforts have been made to specifically target this pathway. PT2385 and PT2399 are first-in-class, orally available, small molecule inhibitors of HIF-2 that selectively disrupt the heterodimerization of HIF-2α with HIF-1β. Preclinical and clinical data indicate that these new molecules are effective in blocking cancer cell growth, proliferation, and tumor angiogenesis characteristic in ccRCC. Treatment with HIF-2α specific antagonists, either alone or in combination with immunotherapy or other antiangiogenic agents have the potential to transform the therapeutic landscape in this tumor in the future. Herein, we summarize the molecular background behind the use of HIF-2α inhibitors in ccRCC and give an overview of the development of new agents in this setting. Copyright © 2017 Elsevier B.V. All rights reserved.

Water-clear cell adenoma of the parathyroid. A case report with immunohistochemistry and electron microscopy.

PubMed

Grenko, R T; Anderson, K M; Kauffman, G; Abt, A B

1995-11-01

We report a water-clear cell adenoma of the parathyroid gland, a lesion which to our knowledge has not been described previously. Like its rare but well-described hyperplastic counterpart, water-clear cell hyperplasia, this adenoma is composed of cells with abundant foamy-to-granular cytoplasm and mild nuclear pleomorphism. The cells form glandular structures and cell nests separated by fine fibrovascular septae. The tumor cells stain positively with anti-parathyroid hormone and show characteristic glassy and flocculate material by electron microscopy. Unlike water-clear cell hyperplasia, water-clear cell adenoma is a solitary lesion that compresses the residual nonneoplastic parathyroid gland.

Establishment and characterization of clear cell renal cell carcinoma cell lines with different metastatic potential from Chinese patients.

PubMed

Tan, Xiaojie; He, Songqin; Han, Yifang; Yu, Yongwei; Xiao, Jianru; Xu, Danfeng; Wang, Guoping; Du, Yan; Chang, Wenjun; Yin, Jianhua; Su, Tong; Hou, Jianguo; Cao, Guangwen

2013-02-26

Clear cell renal cell carcinoma (ccRCC) cell lines with distinct metastatic potential are essential to study the mechanism of ccRCC metastasis. However, none of them originated from Chinese. Primary cell cultures were performed using a primary tumor of a 49-year-old male ccRCC patient and a metastatic tumor of a 62-year-old male patient who had received nephrectomy to excise primary ccRCC 10 years ago. Cell growth, microstructure, cytogenetics, cytometry, expression of metastasis-associated molecules, tumorigenesis and metastasis were subsequently characterized. Two successive cell lines named NRCC from the primary ccRCC and MRCC from the metastatic ccRCC were established, respectively. Compared to NRCC, MRCC exhibited stronger anchorage-independent growth and invasion potentials and contained more glycogen granules in the cytoplasm. Gains of chromosomes and some translocations were the major chromosomal aberrations in both cell strains. CD24 expression was more frequent in MRCC than in NRCC and the same was true for CD56. The transcriptional levels of TNFα, IL-6, VEGF, HIF2α, MMP2, and RhoC were significantly higher in MRCC than in NRCC. Cytosolic IκBα protein was more degraded in MRCC than in NRCC following TNFα treatment. Both cell lines had strong tumorigenicity in athymic nude mice. However, MRCC had strong potential in generating metastasis to lung and hemorrhagic ascites than NRCC following orthotopic transplantations. Cancer cells isolated from metastatic ccRCC have more malignant and metastatic potential than those from the primary tumor from the patients who shared the similar race background. Establishment of MRCC and NRCC may provide suitable models with which to investigate molecular mechanisms of ccRCC metastasis.

Serum microRNAs in clear cell carcinoma of the ovary.

PubMed

Chao, Angel; Lai, Chyong-Huey; Chen, Hua-Chien; Lin, Chiao-Yun; Tsai, Chia-Lung; Tang, Yun-Hsin; Huang, Huei-Jean; Lin, Chen-Tao; Chen, Min-Yu; Huang, Kuang-Gen; Chou, Hung-Hsueh; Chang, Ting-Chang; Chen, Shu-Jen; Wang, Tzu-Hao

2014-12-01

To identify candidate microRNAs (miRNAs) in the serum of patients with clear cell carcinomas in monitoring disease progression. The sera of patients with diagnosed ovarian clear cell carcinoma were collected from 2009 to 2012. Real-time quantitative polymerase chain reaction (PCR) analysis for 270 miRNAs was performed. To offset the potential extraction bias, an equal amount of Caenorhabditis elegans cel-miR-238 was added to each serum specimen before miRNA isolation. miRNA expression was analyzed using the ΔCt method, with cel-miR-238 as controls. Twenty-one patients with clear cell carcinoma were included. In the discovery phase on four pairs of pre- and postoperative sera, 18 differentially expressed miRNAs were selected from 270 miRNAs. In the validation phase on an independent set of 11 pairs of pre- and postoperative sera, 4 miRNAs (hsa-miR-130a, hsa-miR-138, hsa-miR-187, and hsa-miR-202) were confirmed to be higher in the preoperative sera. In the application phase, hsa-miR-130a remained consistent with the different time points in seven of the 10 patients during clinical follow-up periods. More importantly, in three patients, hsa-miR-130a levels were elevated in early disease recurrences before CA125 was found to be elevated. Hsa-miR-130a may be a useful serum biomarker for detecting recurrence of ovarian clear cell cancer, and warrants further studies. Copyright © 2014. Published by Elsevier B.V.

A giant benign clear cell hidradenoma on the anterior trunk.

PubMed

Demirci, Gulsen Tukenmez; Atis, Guldehan; Altunay, Ilknur Kivanç; Sakiz, Damlanur

2011-10-05

Clear cell hidradenoma (CCH) is an uncommon variant of benign cutaneous adnexal tumors. These tumors are clinically asymptomatic, solitary dermal nodules. They occur most frequently on the scalp, face abdomen and extremities. Growth is slow and malignant change is rare. 45-year-old woman presented with a nodule which had begun 4 years ago as a small nodular asymptomatic lesion and had a central ulceration and a minimal hemorrhagic discharge on her anterior abdomen wall. On dermatologic examination there was a 6.5×5×4 cm non-tender, soft reddish purple nodule, with lobular appearance and ulceration. In the laboratory investigations, all hematologic and biochemical tests were normal. A computed tomography (CT) scan demonstrated a cystic tumor with lobulated contour with contrast enhancement. The lesion was excised totally. In histopathological examination, the tumor was composed of biphasic smaller dark polygonal cells and larger clear cells and coarse nuclear chromatine. There were duct like structures. Immunohistochemical investigation was done for the suspicion of malignancy. Cytoplasm of clear cells and of duct like structures showed PAS-positive and d-PAS resistant staining. There was a positive reaction to epithelial membrane antigen and carcinoembryonic antigen. The mitotic index in Ki 67 examination was low. All these findings confirmed the diagnosis of benign CCH.

A giant benign clear cell hidradenoma on the anterior trunk

PubMed Central

Demirci, Gulsen Tukenmez; Atis, Guldehan; Altunay, Ilknur Kivanç; Sakiz, Damlanur

2011-01-01

Clear cell hidradenoma (CCH) is an uncommon variant of benign cutaneous adnexal tumors. These tumors are clinically asymptomatic, solitary dermal nodules. They occur most frequently on the scalp, face abdomen and extremities. Growth is slow and malignant change is rare. 45-year-old woman presented with a nodule which had begun 4 years ago as a small nodular asymptomatic lesion and had a central ulceration and a minimal hemorrhagic discharge on her anterior abdomen wall. On dermatologic examination there was a 6.5×5×4 cm non-tender, soft reddish purple nodule, with lobular appearance and ulceration. In the laboratory investigations, all hematologic and biochemical tests were normal. A computed tomography (CT) scan demonstrated a cystic tumor with lobulated contour with contrast enhancement. The lesion was excised totally. In histopathological examination, the tumor was composed of biphasic smaller dark polygonal cells and larger clear cells and coarse nuclear chromatine. There were duct like structures. Immunohistochemical investigation was done for the suspicion of malignancy. Cytoplasm of clear cells and of duct like structures showed PAS-positive and d-PAS resistant staining. There was a positive reaction to epithelial membrane antigen and carcinoembryonic antigen. The mitotic index in Ki 67 examination was low. All these findings confirmed the diagnosis of benign CCH. PMID:25386297

Lack of effective systemic therapy for recurrent clear cell carcinoma of the ovary.

PubMed

Crotzer, David R; Sun, Charlotte C; Coleman, Robert L; Wolf, Judith K; Levenback, Charles F; Gershenson, David M

2007-05-01

Clear cell carcinoma of the ovary is an aggressive tumor characterized by relative chemoresistance and a poor prognosis. The purpose of this study was to review our experience with recurrent clear cell carcinoma of the ovary to evaluate its responsiveness to systemic cytotoxic and hormonal agents. All patients diagnosed with clear cell carcinoma of the ovary seen at our institution between 1990 and 2002 were identified and their medical records reviewed. Eligibility criteria were: 1) primary diagnosis of clear cell carcinoma of the ovary, 2) measurable recurrent disease, 3) treatment of recurrent disease with 1 or more systemic regimens, and 4) adequate clinical information. End points were clinical response, progression-free survival, and overall survival. Fifty-one patients treated for recurrent clear cell carcinoma were identified. The patients received a total of 105 regimens (344 cycles of therapy). Among patients with platinum-sensitive disease (n=22 regimens), 2 patients (9%) had partial responses to retreatment with carboplatin plus paclitaxel, and 4 (18%) had stable disease. Among patients with platinum-resistant disease (n=83 regimens), only 1 patient (1%) had a partial response - to gemcitabine - and 1 patient had stable disease in response to 2 different regimens-paclitaxel and gemcitabine. The median progression-free survival was 8 months, and the median overall survival was 18 months. Our findings suggest that recurrent clear cell carcinoma of the ovary is particularly chemoresistant. A continued search for more active, targeted agents is warranted.

An unusual cause of hypercalcemic crisis: Water-clear cell double parathyroid adenoma.

PubMed

Yazar, Fatih Mehmet; Karaağaç, Mustafa; İşler, Ali; Bülbüloğlu, Ertan; Ezberci, Fikret

2017-01-01

To evaluate the clinical characteristics of a patient operated for water-clear cell adenoma and to discuss these in the light of relevant literature. PubMed and Google Scholar were searched to identify articles related to water-clear cell adenoma using the following keywords: parathyroid tissue, parathyroid gland, parathyroid cells, parathyroid adenoma, parathyroid hyperplasia, water-clear-cell, and water clear cell. The search included case reports, review articles, and original articles that had been published between January 1990 and November 2014 without any restrictions on language. All articles that contained information on the study population and treatment related data were identified and retrieved. In addition, an evaluation was of a case of a 47-year-old male patient with PHC who was treated at our clinic was conducted. A total of 19 patients, including our new case, (age range: 18 to 81 years, mean±SD: 57.47±16.31 years) were included in the analysis. Eleven patients were female. Information about adenoma location was available from studies involving 17 patients and they indicated the following distribution of locations: left inferior (n=10), right superior (n=4). When preoperative imaging methods were examined, a false negative result was given by ultrasonography in 28.5% of patients and only 57.1% were positive on scintigraphy. Concomitant thyroid papillary carcinoma was determined in 1 patient. The mean tissue dimensions were 3.47±1.73 cm (range, 0.8-6.8 cm). Water-clear cell adenoma, which shows similar clinical characteristics to other parathyroid adenomas, is an uncommon cause of hyperparathyroidism.

Clear cell variant of follicular thyroid carcinoma with normal thyroid-stimulating hormone value: a case report

PubMed Central

2014-01-01

Introduction Clear cell carcinomas of the thyroid gland with normal thyroid-stimulating hormone value are very rare, but clear cell changes are described in most reported cases of thyroidal lesions. Case presentation In this report, we describe the case of a 50-year-old Caucasian woman with a normal thyroid-stimulating hormone level who underwent surgery to treat a multi-nodular goiter. The pathology was a clear cell variant of follicular thyroid carcinoma. The tumor was 1cm in diameter and consisted of pure clear cells. Conclusion Clear cell variants of follicular thyroid carcinoma are rarely seen, especially it is misdiagnosed with metastatic renal cell carcinoma. In this report, we describe the case of a patient with a clear cell variant of follicular thyroid carcinoma with an interesting pathology. PMID:24884725

Validation of a Postoperative Nomogram Predicting Recurrence in Patients with Conventional Clear Cell Renal Cell Carcinoma.

PubMed

Lee, Byron H; Feifer, Andrew; Feuerstein, Michael A; Benfante, Nicole E; Kou, Lei; Yu, Changhong; Kattan, Michael W; Russo, Paul

2018-01-01

Clear cell renal cell carcinoma (RCC) continues to be the most commonly diagnosed subtype and is associated with more aggressive behavior than papillary and chromophobe RCC. Predicting disease recurrence after surgical extirpation is important for counseling and targeting those at high risk for adjuvant therapy clinical trials. To validate a postoperative nomogram predicting 5-yr recurrence-free probability (RFP) for clinically localized clear cell RCC. We identified all patients who underwent nephrectomy for clinically localized clear cell RCC from 1990 to 2009 at Memorial Sloan Kettering Cancer Center. After excluding patients with bilateral renal masses, familial RCC syndromes, and T3c or T4 tumors due to the limited number, 1642 participants were available for analysis. Partial or radical nephrectomy. Disease recurrence was defined as any new tumor after nephrectomy or kidney cancer-specific mortality, whichever occurred first. A postoperative nomogram was used to calculate the predicted 5-yr RFP, and these values were compared with the actual 5-yr RFP. Nomogram performance was evaluated by concordance index and calibration plot. Median follow-up was 39 mo (interquartile range: 14-79 mo), and disease recurrence was observed in 50 patients. The nomogram concordance index was 0.81. The calibration curve showed that the nomogram underestimated the actual 5-yr RFP. We updated the nomogram by including the entire patient population, which maintained performance and significantly improved calibration. The updated clear cell RCC postoperative nomogram performed well in the combined cohort. Underestimation of actual 5-yr RFP by the original nomogram may be due to increased surgeon experience and other unknown variables. We updated a valuable prediction tool used for assessing the disease recurrence probability after nephrectomy for clear cell renal cell carcinoma. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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

PubMed Central

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

Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse transcriptase promoter mutation.

PubMed

Huang, Hsien-Neng; Chiang, Ying-Cheng; Cheng, Wen-Fang; Chen, Chi-An; Lin, Ming-Chieh; Kuo, Kuan-Ting

2015-02-01

Recently, mutations of telomerase reverse transcriptase (TERT) promoter were found in several types of cancer. A few reports demonstrate TERT promoter mutations in ovarian clear cell carcinomas but endometrial clear cell carcinoma has not been studied. The aims of this study were to compare differences of molecular alterations and clinical factors, and identify their prognostic impact in endometrial and ovarian clear cell carcinomas. We evaluated mutations of the TERT promoter and PIK3CA, expression of ARID1A, and other clinicopathological factors in 56 ovarian and 14 endometrial clear cell carcinomas. We found that TERT promoter mutations were present in 21% (3/14) of endometrial clear cell carcinomas and 16% (9/56) of ovarian clear cell carcinomas. Compared with ovarian clear cell carcinomas, endometrial clear cell carcinomas showed older mean patient age (P<0.001), preserved ARID1A immunoreactivity (P=0.017) and infrequent PIK3CA mutation (P=0.025). In ovarian clear cell carcinomas, TERT promoter mutations were correlated with patient age >45 (P=0.045) and preserved ARID1A expression (P=0.003). In cases of endometrial clear cell carcinoma, TERT promoter mutations were not statistically associated with any other clinicopathological factors. In ovarian clear cell carcinoma patients with early FIGO stage (stages I and II), TERT promoter mutation was an independent prognostic factor and correlated with a shorter disease-free survival and overall survival (P=0.015 and 0.009, respectively). In recurrent ovarian clear cell carcinoma patients with early FIGO stage, TERT promoter mutations were associated with early relapse within 6 months (P=0.018). We concluded that TERT promoter mutations were present in endometrial and ovarian clear cell carcinomas. Distinct molecular alteration patterns in endometrial and ovarian clear cell carcinomas implied different processes of tumorigenesis in these morphologically similar tumors. In ovarian clear cell carcinoma of early FIGO

Clear cell carcinoma of the ovary mimicking struma ovarii and carcinoid tumor.

PubMed

Alduaij, Ahmad; Quddus, M Ruhul

2011-04-01

Clear cell carcinomas are considered as high-grade tumor often with poor prognosis. We describe 2 cases of clear cell carcinomas of the ovary mimicking benign or less aggressive tumors encountered in the female genital track. The first case is mimicking a benign monodermal teratoma, the so-called struma ovarii, and the second mimicking a carcinoid tumor. Copyright © 2011 Elsevier Inc. All rights reserved.

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

PubMed

Maharaj, Ravi; Cave, Christo; Sarran, Kevin; Bascombe, Nigel; Dan, Dilip; Greaves, Wesley; Warner, Wayne A

2017-01-01

Clear cell gallbladder carcinoma accounts for less than 1% of all gallbladder malignancies and demonstrates its unique histopathological characteristics in patients with no prior medical illness or familial predisposition. Here we present a case of a 56-year-old female, with no prior medical conditions presented with a 2-month history of upper abdominal pain. Routine hematological and biochemical tests were unremarkable. An abdominal ultrasound revealed the presence of a gallbladder calculi, and a fundic mass while magnetic resonance cholangiopancreatography revealed a 8.0cm×3.5cm gallbladder mass. Computed tomography imaging excluded any distant haematogenous metastases. An open cholecystectomy with lymphadenectomy was proceeded by staging laparoscopy. Upon pathologic investigation, the morphologic and immunophenotypic features supported a diagnosis of clear cell variant of gallbladder carcinoma. Pathological prognostications for primary clear cell gall bladder carcinomas are not well defined due to the rarity of cases and possible misidentification as secondary metastases. Foci of adenocarcinoma within the tumor along with immunohistochemical staining probes can be informative in consideration of differential diagnosis. 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. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

“String of pearls pattern”: report of three cases of non clear-cell acanthoma*

PubMed Central

Espinosa, Ana Elena Domínguez; Akay, Bengu Nisa; González-Ramírez, Roger Adrian

2017-01-01

The coiled and dotted vessels in a serpiginous arrangement or “string of pearls” is considered a classical vascular pattern associated with clear cell acanthoma. We present three cases of epidermal tumors different from clear cell acanthoma that have the same “string of pearls” vascular pattern. Even though most authors keep considering the “string of pearls” vascular pattern an almost pathognomonic sign of clear-cell acanthoma, the cases presented here suggest that some other epidermal tumors can also show this pattern. PMID:29267474

Primary paranasal sinus hyalinizing clear cell carcinoma: a case report.

PubMed

AlAli, Batool M; Alyousef, Mohammed J; Kamel, Ahmad Salah; Al Hamad, Mohammad A; Al-Bar, Mohammad H; Algowiez, Roaa M

2017-09-25

Hyalinizing clear cell carcinoma (HCCC) is a rare low-grade tumour of salivary glands that was first described as a distinct entity in 1994 by Milchgrub et al. EWSR1-ATF1 fusion was found to be specific for this tumour. The majority of the reported cases of HCCC arise from minor salivary glands within the oral cavity. Primary HCCC of the paranasal sinus is extremely uncommon. To our knowledge, only three cases have been reported in the English literature. Herein, we present a case of HCCC of the posterior ethmoid/maxillary sinus. A 63-year-old lady who presented with a long history of epistaxis. CT scan revealed a destructive mass in the left ethmoid/posterior maxillary sinus extending to the nasal cavity. Surgical excision was done and microscopic evaluation showed a tumour composed mainly of nests of clear epithelial cells separated by fibrocellular and hyalinized septa with extensive bone destruction. The tumour cells expressed CK5/6, EMA and p63 immunohistochemically but were negative for S100 protein, PAX-8, RCC and CK7. Sinonasal renal cell-like adenocarcinomas, myoepithelial carcinoma and metastatic renal cell carcinoma were excluded by radiological and immunohistochemical studies. Fluorescence in situ hybridization analysis revealed an EWSR1 gene rearrangement. Postoperative radiation was administrated and the patient did not show recurrence or distant metastasis 4 months after the surgery. Head and neck region have many tumours that demonstrate clear cell changes on histology. Thus, the differential diagnosis for HCCC is wide. Awareness of this rare entity and the possibility of it is arising in unusual location is necessary. EWSR1-AFT1 fusion, a consistent finding in HCCC, can be used to confirm the diagnosis.

Ovarian clear cell carcinoma--bad endometriosis or bad endometrium?

PubMed

Gounaris, Ioannis; Charnock-Jones, D Stephen; Brenton, James D

2011-10-01

It has become increasingly clear that the four main histological subtypes of epithelial ovarian cancer (EOC), high-grade serous, endometrioid, clear cell and mucinous, are entities with different epidemiologies, clinical presentations, responses to treatment, and ultimate outcomes. In fact, for all intents and purposes, they can be considered different diseases, their only common denominator being that they frequently involve the ovary and pelvic organs. However, clinical practice has not caught up with these insights and the treatment of EOC is that of a single disease entity. In part, this is because we lack detailed knowledge of the molecular mechanisms driving the pathogenesis of each disease, which is vital in order to develop therapeutic approaches against common driver events. In the last few years, mutations in ARID1A and PIK3CA have been described in a substantial fraction of cases of ovarian clear cell carcinoma, yet the paper by Yamamoto et al in this issue of The Journal of Pathology reveals that PIK3CA mutations can be detected in precursor endometriosis tissues. These and other recent observations underscore the importance of investigating whether mutations in the eutopic endometrium actually predispose to endometriosis and eventually to malignancy. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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

PubMed

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.

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

PubMed Central

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. PMID:23798840

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

PubMed Central

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 < 0.0001) positive correlation with histologic fat content (Spearman correlation coefficient, ρ = 0.79), spectrometric triglycerides (ρ = 0.56) and cholesterol (ρ = 0.47); it showed negative correlation with free fatty acids (ρ = –0.44) and phospholipids (ρ = –0.65). We observed both inter- and intratumoral heterogeneity in lipid accumulation within the same tumor grade, whereas most aggressive tumors (International Society of Urological Pathology [ISUP] grade 4) exhibited reduced lipid accumulation. Cellular metabolites in tumors were altered compared with adjacent renal parenchyma. CONCLUSION. Our results support the use of noninvasive 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

On-chip clearing of arrays of 3-D cell cultures and micro-tissues.

PubMed

Grist, S M; Nasseri, S S; Poon, T; Roskelley, C; Cheung, K C

2016-07-01

Three-dimensional (3-D) cell cultures are beneficial models for mimicking the complexities of in vivo tissues, especially in tumour studies where transport limitations can complicate response to cancer drugs. 3-D optical microscopy techniques are less involved than traditional embedding and sectioning, but are impeded by optical scattering properties of the tissues. Confocal and even two-photon microscopy limit sample imaging to approximately 100-200 μm depth, which is insufficient to image hypoxic spheroid cores. Optical clearing methods have permitted high-depth imaging of tissues without physical sectioning, but they are difficult to implement for smaller 3-D cultures due to sample loss in solution exchange. In this work, we demonstrate a microfluidic platform for high-throughput on-chip optical clearing of breast cancer spheroids using the SeeDB, Clear(T2), and ScaleSQ clearing methods. Although all three methods are able to effectively clear the spheroids, we find that SeeDB and ScaleSQ more effectively clear the sample than Clear(T2); however, SeeDB induces green autofluorescence while ScaleS causes sample expansion. Our unique on-chip implementation permits clearing arrays of 3-D cultures using perfusion while monitoring the 3-D cultures throughout the process, enabling visualization of the clearing endpoint as well as monitoring of transient changes that could induce image artefacts. Our microfluidic device is compatible with on-chip 3-D cell culture, permitting the use of on-chip clearing at the endpoint after monitoring the same spheroids during their culture. This on-chip method has the potential to improve readout from 3-D cultures, facilitating their use in cell-based assays for high-content drug screening and other applications.

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

ClinicalTrials.gov

2017-11-10

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

Urinary collecting system invasion is associated with poor survival in patients with clear-cell renal cell carcinoma.

PubMed

Bailey, George C; Boorjian, Stephen A; Ziegelmann, Matthew J; Westerman, Mary E; Lohse, Christine M; Leibovich, Bradley C; Cheville, John C; Thompson, R Houston

2017-04-01

To evaluate the prognostic significance of urinary collecting system invasion (UCSI) in a large series of patients with clear-cell renal cell carcinoma (RCC). Patients with clear-cell RCC treated with nephrectomy between 2001 and 2010 were reviewed from a prospectively maintained registry. One urological pathologist re-reviewed all slides. Cancer-specific survival was estimated using the Kaplan-Meier method, and associations of UCSI with death from RCC were evaluated using Cox models. Of the 859 patients with clear-cell RCC, 58 (6.8%) had UCSI. At last follow-up, 310 patients had died from RCC at a median of 1.8 years after surgery. The median follow-up for patients alive at last follow-up was 8.2 years. The estimated cancer-specific survival at 10 years after surgery for patients with UCSI was 17%, compared with 60% for patients without UCSI (P < 0.001). In a multivariable model, UCSI remained independently associated with an increased risk of death from RCC (hazard ratio 1.5; P = 0.018). Further, among patients with pT3 RCC, those with USCI had survival outcomes similar to those of patients with pT4 RCC. Collecting system invasion is associated with poor prognosis among patients with clear-cell RCC. If validated, consideration should be given to including UCSI in future staging systems. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

Malignant melanocytic neoplasm of pancreas with liver metastasis: Is it malignant melanoma or clear cell sarcoma?

PubMed

Kodiatte, Thomas Alex; George, Sam Varghese; Chacko, Raju Titus; Ramakrishna, Banumathi

2017-01-01

Malignant melanocytic neoplasm, usually seen in soft tissues, is rare in a visceral location and presents as a diagnostic dilemma. We present a case of pancreatic malignant melanocytic neoplasm with liver metastasis. A 58-year-old man presented with left upper abdominal swelling and loss of appetite. Imaging revealed a large mass arising from the pancreatic tail, and this was diagnosed as malignant neoplasm with melanocytic differentiation on biopsy with the possible differentials of malignant melanoma, clear cell sarcoma (CCS), and perivascular epithelioid cell neoplasm. The patient underwent distal pancreatectomy and splenectomy for the same. Follow-up imaging 6 months later showed a metastatic liver lesion, for which he also underwent a liver resection. BRAF mutational analysis was found to be negative. Both CCS and malignant melanoma have similar morphological features and melanocytic differentiation, but each harbors a distinct genetic background. Differentiation of both has diagnostic and therapeutic implications.

Clear cell hidradenocarcinoma developing in pacemaker pocket.

PubMed

Reyes, Cesar V

2008-11-01

An octagenerian woman developed clear cell hidradenocarcinoma, a rare neoplasm of eccrine sweat gland origin, 4 years following pacemaker implantation in her right lateral chest. The tumor immunohistochemically mimicked a metastatic lobular breast carcinoma, for example, strongly positive estrogen, weakly positive progesterone, and weakly reactive mammoglobin. A complete surgical excision of the tumor was complemented with ipsilateral dissection of involved adjacent axillary lymph nodes. Recommended irradiation was refused by the patient. Retrospective 3-year mammogram review, 2-year postsurgery follow-up, and complete postmortem evaluation failed to prove a primary breast malignancy or other metastatic lesion elsewhere.

Hyalinizing clear cell carcinoma of the nasopharynx operated by trans-oral and trans-palatal approach.

PubMed

Nakashima, T; Yasumatsu, R; Yamauchi, M; Toh, S; Nakano, T; Yamamoto, H; Komune, S

2015-03-01

Hyalinizing clear cell carcinoma is a rare minor salivary gland neoplasm. The treatment of choice is surgical resection with or without post-operative radiotherapy. This tumour often demonstrates a good prognosis. We report a case of hyalinizing clear cell carcinoma arising in the nasopharynx. A 27-year-old female presented with progressive hearing disturbance and tinnitus. On examination, an expansile mass was observed in her nasopharynx. Biopsy was performed and the pathology results returned as clear cell carcinoma. Surgical resection was performed trans-orally accompanied by trans-palatal approach. She has no recurrence during more than two years of follow up.

Cells in 3D-reconstitutued eccrine sweat gland cell spheroids differentiate into gross cystic disease fluid protein 15-expressing dark secretory cells and carbonic anhydrase II-expressing clear secretory cells.

PubMed

Li, Haihong; Chen, Liyun; Zhang, Mingjun; Zhang, Bingna

2017-07-01

Secretory coils of eccrine sweat glands are composed of myoepithelial cells, dark secretory cells and clear secretory cells. The two types of cells play important roles in sweat secretion. In our previous study, we demonstrated that the 3D-reconstituted eccrine sweat gland cell spheroids differentiate into secretory coil-like structures. However, whether the secretory coil-like structures further differentiate into dark secretory cells and clear secretory cells were is still unknown. In this study, we detected the differentiation of clear and dark secretory cells in the 3D-reconstituted eccrine sweat gland cell spheroids using the dark secretory cell-specific marker, GCDFP-15, and clear secretory cell-specific marker, CAII by immunofluorescence staining. Results showed that there were both GCDFP-15- and CAII-expressing cells in 12-week-old 3D spheroids, similar to native eccrine sweat glands, indicating that the spheroids possess a cellular structure capable of sweat secretion. We conclude that the 12-week 3D spheroids may have secretory capability. Copyright © 2017 Elsevier GmbH. All rights reserved.

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

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

Kim, Ji-Hee; Lkhagvadorj, Sayamaa; Lee, Mi-Ra

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 renalmore » 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.« less

[64Cu]XYIMSR-06: A dual-motif CAIX ligand for PET imaging of clear cell renal cell carcinoma.

PubMed

Minn, Il; Koo, Soo Min; Lee, Hye Soo; Brummet, Mary; Rowe, Steven P; Gorin, Michael A; Sysa-Shah, Polina; Lewis, William D; Ahn, Hye-Hyun; Wang, Yuchuan; Banerjee, Sangeeta Ray; Mease, Ronnie C; Nimmagadda, Sridhar; Allaf, Mohamad E; Pomper, Martin G; Yang, Xing

2016-08-30

Carbonic anhydrase IX (CAIX) is a cell surface enzyme that is over-expressed in approximately 95% of cases of clear cell renal cell carcinoma (ccRCC), the most common renal cancer. We synthesized and performed in vitro and in vivo evaluation of a dual-motif ligand, [64Cu]XYIMSR-06, for imaging CAIX expression on ccRCC tumors using positron emission tomography (PET). [64Cu]XYIMSR-06 was generated in yields of 51.0 ± 4.5% (n=5) and specific activities of 4.1 - 8.9 GBq/μmol (110-240 Ci/mmol). Tumor was visualized on PET images by 1 h post-injection with high tumor-to-background levels (>100 tumor-to-blood and -muscle) achieved within 24 h. Biodistribution studies demonstrated a maximum tumor uptake of 19.3% injected dose per gram of radioactivity at 4 h. Tumor-to-blood, -muscle and -kidney ratios were 129.6 ± 18.8, 84.3 ± 21.0 and 2.1 ± 0.3, respectively, at 8 h post-injection. At 24 h a tumor-to-kidney ratio of 7.1 ± 2.5 was achieved. These results indicate pharmacokinetics superior to those of previously reported imaging agents binding to CAIX. [64Cu]XYIMSR-06 is a new low-molecular-weight PET ligand targeting CAIX, which can image localized and metastatic ccRCC.

Immunohistochemical characterization of prototypical endometrial clear cell carcinoma--diagnostic utility of HNF-1β and oestrogen receptor.

PubMed

Hoang, Lien N; Han, Guangming; McConechy, Melissa; Lau, Sherman; Chow, Christine; Gilks, C Blake; Huntsman, David G; Köbel, Martin; Lee, Cheng-Han

2014-03-01

The great majority of ovarian clear cell carcinomas have a hepatocyte nuclear factor 1 homeobox B (HNF-1β)-positive and oestrogen receptor (ER)-negative immunoprofile. However, the pattern of HNF-1β and ER immunostaining in clear cell carcinomas of the endometrium and the usefulness of this panel in distinguishing clear cell carcinoma from other histological types of endometrial carcinoma have yet to be well defined. We examined the immunostaining patterns of HNF-1β, ER and p53 in 15 morphologically classic pure endometrial clear cell carcinomas, and compared these patterns with 15 endometrioid and 15 serous carcinomas of the endometrium. We observed the presence of diffuse (>70%) moderate to strong nuclear HNF-1β staining and negative ER staining in 14 of 15 clear cell carcinomas, with the remaining case showing both diffuse strong nuclear HNF-1β staining and focal ER staining. In comparison, only one of 15 serous carcinomas and none of 15 endometrioid carcinomas showed a combination of diffuse moderate to strong HNF-1β nuclear staining and negative ER staining. Aberrant p53 immunostaining was observed in five of 15 (33%) clear cell carcinomas. Overall, our findings demonstrate that, similarly to the situation for the ovary, a diagnostic panel of HNF-1β and ER may be considered for separating clear cell carcinoma from endometrioid and serous carcinoma of the endometrium. © 2013 John Wiley & Sons Ltd.

Comparison of Utility of Histogram Apparent Diffusion Coefficient and R2* for Differentiation of Low-Grade From High-Grade Clear Cell Renal Cell Carcinoma.

PubMed

Zhang, Yu-Dong; Wu, Chen-Jiang; Wang, Qing; Zhang, Jing; Wang, Xiao-Ning; Liu, Xi-Sheng; Shi, Hai-Bin

2015-08-01

The purpose of this study was to compare histogram analysis of apparent diffusion coefficient (ADC) and R2* for differentiating low-grade from high-grade clear cell renal cell carcinoma (RCC). Forty-six patients with pathologically confirmed clear cell RCC underwent preoperative BOLD and DWI MRI of the kidneys. ADCs based on the entire tumor volume were calculated with b value combinations of 0 and 800 s/mm(2). ROI-based R2* was calculated with eight TE combinations of 6.7-22.8 milliseconds. Histogram analysis of tumor ADCs and R2* values was performed to obtain mean; median; width; and fifth, 10th, 90th, and 95th percentiles and histogram inhomogeneity, kurtosis, and skewness for all lesions. Thirty-three low-grade and 13 high-grade clear cell RCCs were found at pathologic examination. The TNM classification and tumor volume of clear cell RCC significantly correlated with histogram ADC and R2* (ρ = -0.317 to 0.506; p < 0.05). High-grade clear cell RCC had significantly lower mean, median, and 10th percentile ADCs but higher inhomogeneity and median R2* than low-grade clear cell RCC (all p < 0.05). Compared with other histogram ADC and R2* indexes, 10th percentile ADC had the highest accuracy (91.3%) in discriminating low- from high-grade clear cell RCC. R2* in discriminating hemorrhage was achieved with a threshold of 68.95 Hz. At this threshold, high-grade clear cell RCC had a significantly higher prevalence of intratumor hemorrhage (high-grade, 76.9%; low-grade, 45.4%; p < 0.05) and larger hemorrhagic area than low-grade clear cell RCC (high-grade, 34.9% ± 31.6%; low-grade, 8.9 ± 16.8%; p < 0.05). A close relation was found between MRI indexes and pathologic findings. Histogram analysis of ADC and R2* allows differentiation of low- from high-grade clear cell RCC with high accuracy.

COMPREHENSIVE MOLECULAR CHARACTERIZATION OF CLEAR CELL RENAL CELL CARCINOMA

PubMed Central

2013-01-01

Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (e.g. VHL) and the maintenance of chromatin states (e.g. PBRM1). We surveyed more than 400 tumors using different genomic platforms and identified 19 significantly mutated genes. The PI3K/Akt pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodeling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving down-regulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, up-regulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 and GRB10. Remodeling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumor stage and severity and offers new views on the opportunities for disease treatment. PMID:23792563

Germ cell tumour growth patterns originating from clear cell carcinomas of the ovary and endometrium: a comparative immunohistochemical study favouring their origin from somatic stem cells.

PubMed

Nogales, Francisco F; Prat, Jaime; Schuldt, Maolly; Cruz-Viruel, Nelly; Kaur, Baljeet; D'Angelo, Emanuela; Matias-Guiu, Xavier; Vidal, August; McCluggage, W Glenn; Oosterhuis, J Wolter

2018-03-01

To report a series of 11 ovarian and one endometrial neoplasm in elderly patients with mixed clear cell tumour and germ cell tumour (GCT) components, to compare their immunohistochemical profiles and demonstrate a putative stem cell population. The clear cell tumours included 11 clear cell carcinomas (CCC) and one borderline clear cell tumour, while the GCT always included glandular yolk sac tumour (YST). In four cases, there were also foci of teratoma with immature neuroepithelial and endodermal tissues and undifferentiated areas showing true embryoids. To distinguish between the clear cell and YST components, the following antibodies were used: HNF1-β, napsin-A, cytokeratin 7 (CK7), PAX8, EMA, AFP, SALL4, villin, glypican-3 (GPC-3), GATA3, HepPar-1, OCT4, CDX2, CD30 and SOX2. HNF1-β, CK7, EMA and GPC-3 were often expressed in both components. Other markers had higher specificity for each cellular lineage; napsin-A and PAX8 were expressed only in CCC, while SALL4, villin, AFP and HepPar-1 were positive in the glandular YST component but negative in the clear cell component. OCT4 expression occurred in six of 10 cases and consistently in teratoma (four of four). There is considerable immunophenotypical overlap between the two components in these mixed neoplasms, and a panel of markers should be used to facilitate the distinction. We propose that OCT4-expressing somatic cancer cells differentiate into GCT and represent spontaneously induced pluripotent stem cells, possibly conditioned by age-related epigenetic factors. These neoplasms have features of prepubertal type GCT showing lack of 12p gain, preponderance of YST and coexistence with immature neuroectoderm. However, there may also be undifferentiated stem cell areas with embryoid bodies, of the type seen in postpubertal testicular GCT, but lacking a complete embryonal carcinoma immunophenotype. © 2017 John Wiley & Sons Ltd.

Alpha-fetoprotein-producing ovarian clear cell adenocarcinoma with fetal gut differentiation: a rare case report and literature review.

PubMed

Chao, Wei-Ting; Liu, Chia-Hao; Lai, Chiung-Ru; Chen, Yi-Jen; Chuang, Chi-Mu; Wang, Peng-Hui

2018-06-22

Alpha-fetoprotein (AFP) is a useful tumor marker for ovarian germ cell tumors, particularly yolk sac tumor (YST). It is valuable for both diagnosis and further follow-up. Epithelial ovarian carcinoma (EOC) rarely secretes AFP, especially for clear cell type and in the postmenopausal women. Based on the limited knowledge about AFP-producing clear cell type EOC, a case and literature review on this topic is extensively reviewed. We report a 55-year-old postmenopausal woman experienced vaginal spotting for one month, and serum level of AFP was 60,721 ng/ml initially. Histological examination was clear cell type EOC. Tumor cells revealed strong immunoreactivity for glypican-3 (GPC3) and AFP and weak for hepatocyte nuclear factor-1 beta (HNF-1 beta), but negative for CD30, making the diagnosis of AFP-producing clear cell type EOC with fetal gut differentiation in focal areas, FIGO (International Federation of Gynecology and Obstetrics) IIIc. Although the patient underwent an intensive treatment, including optimal debulking surgery and multi-agent chemotherapy, the patient died of disease. To provide a better understanding of clinical and molecular characteristics of the AFP-producing clear cell type EOC, we conducted a systematic literature review. A total of three papers described the AFP-producing clear cell type EOC are available. The overall survival rate of these cases, including the current case is 50%. Although immunohistochemical examination is not always needed in routine for the diagnosis of clear cell type EOC, to distinguish from other tumors, especially germ cell tumors, or to provide the better way to monitor therapeutic response or to evaluate the disease status, immunostaining, including GPC3, HNF-1 beta, CD30, cytokeratin 7 or 20, and AFP is taken into account. Due to rarity, the appropriate chemotherapy regimen and the biological behavior of AFP-producing clear cell type EOC are still unclear.

Role of chromosome 3p12-p21 tumour suppressor genes in clear cell renal cell carcinoma: analysis of VHL dependent and VHL independent pathways of tumorigenesis.

PubMed

Martinez, A; Fullwood, P; Kondo, K; Kishida, T; Yao, M; Maher, E R; Latif, F

2000-06-01

Chromosome 3p deletions and loss of heterozygosity (LOH) for 3p markers are features of clear cell renal cell carcinoma but are rare in non-clear cell renal cell carcinoma. The VHL tumour suppressor gene, which maps to 3p25, is a major gatekeeper gene for clear cell renal cell carcinoma and is inactivated in most sporadic cases of this disease. However, it has been suggested that inactivation of other 3p tumour suppressor genes might be crucial for clear cell renal cell carcinoma tumorigenesis, with inactivation (VHL negative) and without inactivation (VHL positive) of the VHL tumour suppressor gene. This study set out to investigate the role of non-VHL tumour suppressor genes in VHL negative and VHL positive clear cell renal cell carcinoma. Eighty two clear cell renal cell carcinomas of known VHL inactivation status were analysed for LOH at polymorphic loci within the candidate crucial regions for chromosome 3p tumour suppressor genes (3p25, LCTSGR1 at 3p21.3, LCTSGR2 at 3p12 and at 3p14.2). Chromosome 3p12-p21 LOH was frequent both in VHL negative and VHL positive clear cell renal cell carcinoma. However, although the frequency of 3p25 LOH in VHL negative clear cell renal cell carcinoma was similar to that at 3p12-p21, VHL positive tumours demonstrated significantly less LOH at 3p25 than at 3p12-p21. Although there was evidence of LOH for clear cell renal cell carcinoma tumour suppressor genes at 3p21, 3p14.2, and 3p12, both in VHL negative and VHL positive tumours, the major clear cell renal cell carcinoma LOH region mapped to 3p21.3, close to the lung cancer tumour suppressor gene region 1 (LCTSGR1). There was no association between tumour VHL status and tumour grade and stage. These findings further indicate that VHL inactivation is not sufficient to initiate clear cell renal cell carcinoma and that loss of a gatekeeper 3p21 tumour suppressor gene is a crucial event for renal cell carcinoma development in both VHL negative and VHL positive clear cell renal

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

PubMed

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

2017-11-01

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.

Comparative Studies of the Proteome, Glycoproteome, and N-Glycome of Clear Cell Renal Cell Carcinoma Plasma before and after Curative Nephrectomy

PubMed Central

2015-01-01

Clear cell renal cell carcinoma is the most prevalent of all reported kidney cancer cases, and currently there are no markers for early diagnosis. This has stimulated great research interest recently because early detection of the disease can significantly improve the low survival rate. Combining the proteome, glycoproteome, and N-glycome data from clear cell renal cell carcinoma plasma has the potential of identifying candidate markers for early diagnosis and prognosis and/or to monitor disease recurrence. Here, we report on the utilization of a multi-dimensional fractionation approach (12P-M-LAC) and LC–MS/MS to comprehensively investigate clear cell renal cell carcinoma plasma collected before (disease) and after (non-disease) curative nephrectomy (n = 40). Proteins detected in the subproteomes were investigated via label-free quantification. Protein abundance analysis revealed a number of low-level proteins with significant differential expression levels in disease samples, including HSPG2, CD146, ECM1, SELL, SYNE1, and VCAM1. Importantly, we observed a strong correlation between differentially expressed proteins and clinical status of the patient. Investigation of the glycoproteome returned 13 candidate glycoproteins with significant differential M-LAC column binding. Qualitative analysis indicated that 62% of selected candidate glycoproteins showed higher levels (upregulation) in M-LAC bound fraction of disease samples. This observation was further confirmed by released N-glycans data in which 53% of identified N-glycans were present at different levels in plasma in the disease vs non-disease samples. This striking result demonstrates the potential for significant protein glycosylation alterations in clear cell renal cell carcinoma cancer plasma. With future validation in a larger cohort, information derived from this study may lead to the development of clear cell renal cell carcinoma candidate biomarkers. PMID:25184692

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

PubMed

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

Clear cell adenocarcinoma of the ovary associated with in utero diethylstilbestrol exposure: case report and clinical overview.

PubMed

Dasanu, Constantin A; Herzog, Thomas J

2009-01-01

Clear cell adenocarcinoma of the vagina and cervix were previously shown to be tumors occurring in female offspring exposed prenatally to diethylstilbestrol. This report describes the first clinical case of clear cell adenocarcinoma of the ovary linked to early diethylstilbestrol exposure in utero. A 45-year-old woman presented with a self-discovered lump in the lower abdominal quadrant. She underwent surgery and staging that revealed clear cell adenocarcinoma confined to the left ovary. Foci of high-grade squamous neoplastic proliferation, inflammation, and a paratubal cyst were also present on the pathology specimen. Medical records established unequivocally that the patient's mother received diethylstilbestrol therapy throughout the pregnancy. Our case is consistent with clear cell adenocarcinoma, probably related to diethylstilbestrol exposure in utero. It reinforces the need for continued vigilance in individuals prenatally exposed to this drug.

Abnormalities at chromosome region 3p12-14 characterize clear cell renal carcinoma.

PubMed

Carroll, P R; Murty, V V; Reuter, V; Jhanwar, S; Fair, W R; Whitmore, W F; Chaganti, R S

1987-06-01

In an effort to determine whether or not any characteristic chromosomal abnormalities exist in renal cancer, cytogenetic findings were correlated with tumor histology in nine cases of renal adenocarcinoma. Metaphase preparations adequate for analysis were obtained from cultures harvested between day 3 and day 21. Model chromosome number was diploid in three cases, hypodiploid in three, and hyperdiploid in the remaining three. One clear cell adenocarcinoma failed to reveal any chromosomal abnormality. Two tumors, a tubular/papillary carcinoma and an acinar/papillary carcinoma, showed the clonal abnormalities del(1)(p2l),+2,+7,+8,+12,+13,+16,+17,-21 and t(2;10)(q14-21;q26),+7q,+11q,-18, respectively. Interestingly, five of six clear cell tumors studied had clonal abnormalities affecting the short arm of chromosome #3 in the 3p12-21 region, and in the remaining case, of 15 karyotyped metaphases suitable for interpretation, one showed a deletion in 3p. These data indicate that clear cell carcinoma of the kidney may be associated with a nonrandom chromosomal abnormality involving the 3p12-14 region.

Clear cell hidradenocarcinoma of the eyelid: a case report with a review of the literature.

PubMed

Singh, Gurcharan; Narasimha, Aparna; Kumar, Harendra; Datti, Narendra

2013-04-01

Clear cell hidradenocarcinomas are extremely rare neoplasms, with very few well-documented cases reported in the literature. The most common sites are the head and neck regions. These tumors are histologically malignant but are not always aggressive. They are known for recurrence and may metastasize widely. Treatment is wide local resection. We report on a case of clear cell hidradenocarcinoma occurring over the eyelid together with a review of the literature.

Role of chromosome 3p12–p21 tumour suppressor genes in clear cell renal cell carcinoma: analysis of VHL dependent and VHL independent pathways of tumorigenesis

PubMed Central

Martinez, A; Fullwood, P; Kondo, K; Kishida, T; Yao, M; Maher, E R; Latif, F

2000-01-01

Aims—Chromosome 3p deletions and loss of heterozygosity (LOH) for 3p markers are features of clear cell renal cell carcinoma but are rare in non-clear cell renal cell carcinoma. The VHL tumour suppressor gene, which maps to 3p25, is a major gatekeeper gene for clear cell renal cell carcinoma and is inactivated in most sporadic cases of this disease. However, it has been suggested that inactivation of other 3p tumour suppressor genes might be crucial for clear cell renal cell carcinoma tumorigenesis, with inactivation (VHL negative) and without inactivation (VHL positive) of the VHL tumour suppressor gene. This study set out to investigate the role of non-VHL tumour suppressor genes in VHL negative and VHL positive clear cell renal cell carcinoma. Methods—Eighty two clear cell renal cell carcinomas of known VHL inactivation status were analysed for LOH at polymorphic loci within the candidate crucial regions for chromosome 3p tumour suppressor genes (3p25, LCTSGR1 at 3p21.3, LCTSGR2 at 3p12 and at 3p14.2). Results—Chromosome 3p12–p21 LOH was frequent both in VHL negative and VHL positive clear cell renal cell carcinoma. However, although the frequency of 3p25 LOH in VHL negative clear cell renal cell carcinoma was similar to that at 3p12–p21, VHL positive tumours demonstrated significantly less LOH at 3p25 than at 3p12–p21. Although there was evidence of LOH for clear cell renal cell carcinoma tumour suppressor genes at 3p21, 3p14.2, and 3p12, both in VHL negative and VHL positive tumours, the major clear cell renal cell carcinoma LOH region mapped to 3p21.3, close to the lung cancer tumour suppressor gene region 1 (LCTSGR1). There was no association between tumour VHL status and tumour grade and stage. Conclusions—These findings further indicate that VHL inactivation is not sufficient to initiate clear cell renal cell carcinoma and that loss of a gatekeeper 3p21 tumour suppressor gene is a crucial event for renal cell carcinoma development in both VHL

Meta-analysis of Clear Cell Renal Cell Carcinoma Gene Expression Defines a Variant Subgroup and Identifies Gender Influences on Tumor Biology

PubMed Central

Brannon, A. Rose; Haake, Scott M.; Hacker, Kathryn E.; Pruthi, Raj S.; Wallen, Eric M.; Nielsen, Matthew E.; Rathmell, W. Kimryn

2011-01-01

Background Clear cell renal cell carcinoma (ccRCC) displays molecular and histologic heterogeneity. Previously described subsets of this disease, ccA and ccB, were defined based on multigene expression profiles, but it is unclear whether these subgroupings reflect the full spectrum of disease or how these molecular subtypes relate to histologic descriptions or gender. Objective Determine whether additional subtypes of ccRCC exist and whether these subtypes are related to von Hippel-Lindau (VHL) inactivation, hypoxia-inducible factor (HIF) 1 and 2 expression, tumor histology, or gender. Design, setting, and participants Six large, publicly available ccRCC gene expression databases were identified that cumulatively provided data for 480 tumors for meta-analysis via meta-array compilation. Measurements Unsupervised consensus clustering was performed on the meta-arrays. Tumors were examined for the relationship of multigene-defined consensus subtypes and expression signatures of VHL mutation and HIF status, tumor histology, and gender. Results and limitations Two dominant subsets of ccRCC were observed. However, a minor third cluster was revealed that correlated strongly with a wild type (WT) VHL expression profile and indications of variant histologies. When variant histologies were removed, ccA tumors naturally divided by gender. This technique is limited by the potential for persistent batch effect, tumor sampling bias, and restrictions of annotated information. Conclusions The ccA and ccB subsets of ccRCC are robust in meta-analysis among histologically conventional ccRCC tumors. A third group of tumors was identified that may represent a new variant of ccRCC. Within definitively clear cell tumors, gender may delineate tumors in such a way that it could have implications regarding current treatments and future drug development. PMID:22030119

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

DTIC Science & Technology

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

The Effect of Anatomical Location of Lymph Node Metastases on Cancer Specific Survival in Patients with Clear Cell Renal Cell Carcinoma

PubMed Central

Nini, Alessandro; Larcher, Alessandro; Cianflone, Francesco; Trevisani, Francesco; Terrone, Carlo; Volpe, Alessandro; Regis, Federica; Briganti, Alberto; Salonia, Andrea; Montorsi, Francesco; Bertini, Roberto; Capitanio, Umberto

2018-01-01

Background Positive nodal status (pN1) is an independent predictor of survival in renal cell carcinoma (RCC) patients. However, no study to date has tested whether the location of lymph node (LN) metastases does affect oncologic outcomes in a population submitted to radical nephrectomy (RN) and extended lymph node dissection (eLND). Objective To describe nodal disease dissemination in clear cell RCC (ccRCC) patients and to assess the effect of the anatomical sites and the number of nodal areas affected on cancer specific mortality (CSM). Design, setting and partecipants The study included 415 patients who underwent RN and eLND, defined as the removal of hilar, side-specific (pre/paraaortic or pre/paracaval) and interaortocaval LNs for ccRCC, at two institutions. Outcome measurement and statistical analysis Descriptive statistics were used to depict nodal dissemination in pN1 patients, stratified according to nodal site and number of involved areas. Multivariable Cox regression analyses and Kaplan-Meier curves were used to explore the relationship between pN1 disease features and survival outcomes. Results and limitations Median number of removed LN was 14 (IQR 9–19); 23% of patients were pN1. Among patients with one involved nodal site, 54 and 26% of patients were positive only in side-specific and interaortocaval station, respectively. The most frequent nodal site was the interaortocaval and side-specific one, for right and left ccRCC, respectively. Interaortocaval nodal positivity (HR 2.3, CI 95%: 1.3–3.9, p < 0.01) represented an independent predictor of CSM. Conclusions When ccRCC patient harbour nodal disease, its spreading can occur at any nodal station without involving the others. The presence of interoartocaval positive nodes does affect oncologic outcomes. Patient summary Lymph node invasion in patients with clear cell renal cell carcinoma is not following a fixed anatomical pattern. An extended lymph node dissection, during treatment for primary

Clear Cell Carcinoma of the Penis: An HPV-related Variant of Squamous Cell Carcinoma: A Report of 3 Cases.

PubMed

Sanchez, Diego F; Rodriguez, Ingrid M; Piris, Adriano; Cañete, Sofía; Lezcano, Cecilia; Velazquez, Elsa F; Fernandez-Nestosa, Maria J; Mendez-Pena, Javier E; Hoang, Mai P; Cubilla, Antonio L

2016-07-01

Penile clear cell carcinoma originating in skin adnexal glands has been previously reported. Here, we present 3 morphologically distinctive penile tumors with prominent clear cell features originating not in the penile skin but in the mucosal tissues of the glans surface squamous epithelium. Clinical and pathologic features were evaluated. Immunohistochemical stains were GATA3 and p16. Human papilloma virus (HPV) detection by in situ hybridization was performed in 3 cases, and whole-tissue section-polymerase chain reaction was performed in 1 case. Patients' ages were 52, 88, and 95 years. Tumors were large and involved the glans and coronal sulcus in all cases. Microscopically, nonkeratinizing clear cells predominated. Growth was in solid nests with comedo-like or geographic necrosis. Focal areas of invasive warty or basaloid carcinomas showing in addition warty or basaloid penile intraepithelial neoplasia were present in 2 cases. There was invasion of corpora cavernosa, lymphatic vessels, veins, and perineural spaces in all cases. p16 was positive, and GATA3 stain was negative in the 3 cases. HPV was detected in 3 cases by in situ hybridization and in 1 case by polymerase chain reaction. Differential diagnoses included other HPV-related penile carcinomas, skin adnexal tumors, and metastatic renal cell carcinoma. Features that support primary penile carcinoma were tumor location, concomitant warty and/or basaloid penile intraepithelial neoplasia, and HPV positivity. Clinical groin metastases were present in all cases, pathologically confirmed in 1. Two patients died from tumor dissemination at 9 and 12 months after penectomy. Clear cell carcinoma, another morphologic variant related to HPV, originates in the penile mucosal surface and is probably related to warty carcinomas.

Epigenetic determinants of ovarian clear cell carcinoma biology

PubMed Central

Yamaguchi, Ken; Huang, Zhiqing; Matsumura, Noriomi; Mandai, Masaki; Okamoto, Takako; Baba, Tsukasa; Konishi, Ikuo; Berchuck, Andrew; Murphy, Susan K.

2015-01-01

Targeted approaches have revealed frequent epigenetic alterations in ovarian cancer, but the scope and relation of these changes to histologic subtype of disease is unclear. Genome-wide methylation and expression data for 14 clear cell carcinoma (CCC), 32 non-CCC, and 4 corresponding normal cell lines were generated to determine how methylation profiles differ between cells of different histological derivations of ovarian cancer. Consensus clustering showed that CCC is epigenetically distinct. Inverse relationships between expression and methylation in CCC were identified, suggesting functional regulation by methylation, and included 22 hypomethylated (UM) genes and 276 hypermethylated (HM) genes. Categorical and pathway analyses indicated that the CCC-specific UM genes were involved in response to stress and many contain hepatocyte nuclear factor (HNF) 1 binding sites, while the CCC-specific HM genes included members of the estrogen receptor alpha (ERalpha) network and genes involved in tumor development. We independently validated the methylation status of 17 of these pathway-specific genes, and confirmed increased expression of HNF1 network genes and repression of ERalpha pathway genes in CCC cell lines and primary cancer tissues relative to non-CCC specimens. Treatment of three CCC cell lines with the demethylating agent Decitabine significantly induced expression for all five genes analyzed. Coordinate changes in pathway expression were confirmed using two primary ovarian cancer datasets (p<0.0001 for both). Our results suggest that methylation regulates specific pathways and biological functions in CCC, with hypomethylation influencing the characteristic biology of the disease while hypermethylation contributes to the carcinogenic process. PMID:24382740

Cancer stem-like cells of ovarian clear cell carcinoma are enriched in the ALDH-high population associated with an accelerated scavenging system in reactive oxygen species.

PubMed

Mizuno, T; Suzuki, N; Makino, H; Furui, T; Morii, E; Aoki, H; Kunisada, T; Yano, M; Kuji, S; Hirashima, Y; Arakawa, A; Nishio, S; Ushijima, K; Ito, K; Itani, Y; Morishige, K

2015-05-01

In ovarian cancer cases, recurrence after chemotherapy is frequently observed, suggesting the involvement of ovarian cancer stem-like cells (CSCs). The chemoresistance of ovarian clear cell carcinomas is particularly strong in comparison to other epithelial ovarian cancer subtypes. We investigated the relationship between a CSC marker, aldehyde dehydrogenase 1 (ALDH1), and clinical prognosis using ovarian clear cell carcinoma tissue samples. Furthermore, we investigated the antioxidant mechanism by which CSCs maintain a lower reactive oxygen species (ROS) level, which provides protection from chemotherapeutic agents. Immunohistochemical staining was performed to examine the CSC markers (CD133, CD44, ALDH1) using ovarian clear cell carcinoma tissue samples (n=81). Clear cell carcinoma cell lines (KOC-7C, OVTOKO) are separated into the ALDH-high and ALDH-low populations by ALDEFLUOR assay and fluorescence-activated cell sorting (FACS). We compared the intracellular ROS level, mRNA level of the antioxidant enzymes and Nrf2 expression of the two populations. High ALDH1 expression levels are related to advanced stage in clear cell carcinoma cases. ALDH1 expression significantly reduced progression free survival. Other markers are not related to clinical stage and prognosis. ALDH-high cells contained a lower ROS level than ALDH-low cells. Antioxidant enzymes were upregulated in ALDH-high cells. ALDH-high cells showed increased expression of Nrf2, a key transcriptional factor of the antioxidant system. ALDH-positive CSCs might have increased Nrf2-induced antioxidant scavengers, which lower ROS level relevant to chemoresistance in ovarian clear cell carcinoma. Copyright © 2014 Elsevier Inc. All rights reserved.

Pathological significance and prognostic roles of densities of CD57+ cells, CD68+ cells, and mast cells, and their ratios in clear cell renal cell carcinoma.

PubMed

Nakanishi, Hiromi; Miyata, Yasuyoshi; Mochizuki, Yasushi; Yasuda, Takuji; Nakamura, Yuichiro; Araki, Kyohei; Sagara, Yuji; Matsuo, Tomohiro; Ohba, Kojiro; Sakai, Hideki

2018-05-19

The immune system is closely associated with malignant behavior in renal cell carcinoma (RCC). Therefore, understanding the pathological roles of immune cells in tumor stroma is essential to discuss the pathological characteristics of RCC. In this study, the clinical significance of densities of CD57+ cells, CD68+ cells, and mast cells, and their ratios were investigated in patients with clear cell RCC. The densities of CD57+, CD68+, and mast cells were evaluated by immunohistochemical techniques in 179 patients. Proliferation index (PI), apoptotic index (AI), and microvessel density (MVD) were evaluated by using anti-Ki-67, anti-cleaved caspase-3, and anti-CD31 antibodies, respectively. The density of CD57+ cell was negatively correlated with grade, pT stage, and metastasis, although densities of CD68+ cell and mast cell were positively correlated. Ratios of CD68+ cell/CD57+ cell and mast cell/CD57+ cell were significantly correlated with grade, pT stage, and metastasis. Survival analyses showed that the CD68+ cell/CD57+ cell ratio was a significant predictor for cause-specific survival by multi-variate analyses (hazard ratio=1.41, 95% confidential interval=1.03-1.93, P=.031), and was significantly correlated with PI, AI, and MVD (r=.47; P <. 001, r=-.31, P<.001, and r=.40, P<.001, respectively). In conclusion, CD57+ cell, CD68+ cell, and mast cell played important roles in malignancy in clear cell RCC. The CD68+ cell/CD57+ cell ratio was strongly correlated with pathological features and prognosis in these patients because this ratio reflected the status of cancer cell proliferation, apoptosis, and angiogenesis. Copyright © 2018. Published by Elsevier Inc.

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

PubMed Central

Mangolini, Alessandra; Bonon, Anna; Volinia, Stefano; Lanza, Giovanni; Gambari, Roberto; Pinton, Paolo; Russo, Gian Rosario; del Senno, Laura; Dell’Atti, Lucio; Aguiari, Gianluca

2014-01-01

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. PMID:25426415

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

PubMed

Ukaji, Tamami; Lin, Yinzhi; Banno, Kouji; Okada, Shoshiro; Umezawa, Kazuo

2015-01-01

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.

Angiomyolipoma with Minimal Fat: Can It Be Differentiated from Clear Cell Renal Cell Carcinoma by Using Standard MR Techniques?

PubMed Central

Hindman, Nicole; Ngo, Long; Genega, Elizabeth M.; Melamed, Jonathan; Wei, Jesse; Braza, Julia M.; Rofsky, Neil M.

2012-01-01

Purpose: To retrospectively assess whether magnetic resonance (MR) imaging with opposed-phase and in-phase gradient-echo (GRE) sequences and MR feature analysis can differentiate angiomyolipomas (AMLs) that contain minimal fat from clear cell renal cell carcinomas (RCCs), with particular emphasis on small (<3-cm) masses. Materials and Methods: Institutional review board approval and a waiver of informed consent were obtained for this HIPAA-compliant study. MR images from 108 pathologically proved renal masses (88 clear cell RCCs and 20 minimal fat AMLs from 64 men and 44 women) at two academic institutions were evaluated. The signal intensity (SI) of each renal mass and spleen on opposed-phase and in-phase GRE images was used to calculate an SI index and tumor-to-spleen SI ratio. Two radiologists who were blinded to the pathologic results independently assessed the subjective presence of intravoxel fat (ie, decreased SI on opposed-phase images compared with that on in-phase images), SI on T1-weighted and T2-weighted images, cystic degeneration, necrosis, hemorrhage, retroperitoneal collaterals, and renal vein thrombosis. Results were analyzed by using the Wilcoxon rank sum test, two-tailed Fisher exact test, and multivariate logistic regression analysis for all renal masses and for small masses. A P value of less than .05 was considered to indicate a statistically significant difference. Results: There were no differences between minimal fat AMLs and clear cell RCCs for the SI index (8.05% ± 14.46 vs 14.99% ± 19.9; P = .146) or tumor-to-spleen ratio (−8.96% ± 16.6 and −15.8% ± 22.4; P = .227) when all masses or small masses were analyzed. Diagnostic accuracy (area under receiver operating characteristic curve) for the SI index and tumor-to-spleen ratio was 0.59. Intratumoral necrosis and larger size were predictive of clear cell RCC (P < .001) for all lesions, whereas low SI (relative to renal parenchyma SI) on T2-weighted images, smaller size, and female

Genomics and epigenomics of clear cell renal cell carcinoma: recent developments and potential applications.

PubMed

Rydzanicz, Małgorzata; Wrzesiński, Tomasz; Bluyssen, Hans A R; Wesoły, Joanna

2013-12-01

Majority of clear cell renal cell carcinomas (ccRCCs) are diagnosed in the advanced metastatic stage resulting in dramatic decrease of patient survival. Thereby, early detection and monitoring of the disease may improve prognosis and treatment results. Recent technological advances enable the identification of genetic events associated with ccRCC and reveal significant molecular heterogeneity of ccRCC tumors. This review summarizes recent findings in ccRCC genomics and epigenomics derived from chromosomal aberrations, DNA sequencing and methylation, mRNA, miRNA expression profiling experiments. We provide a molecular insight into ccRCC pathology and recapitulate possible clinical applications of genomic alterations as predictive and prognostic biomarkers. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Radionuclide and Fluorescence Imaging of Clear Cell Renal Cell Carcinoma Using Dual Labeled Anti-Carbonic Anhydrase IX Antibody G250.

PubMed

Muselaers, Constantijn H J; Rijpkema, Mark; Bos, Desirée L; Langenhuijsen, Johan F; Oyen, Wim J G; Mulders, Peter F A; Oosterwijk, Egbert; Boerman, Otto C

2015-08-01

Tumor targeted optical imaging using antibodies labeled with near infrared fluorophores is a sensitive imaging modality that might be used during surgery to assure complete removal of malignant tissue. We evaluated the feasibility of dual modality imaging and image guided surgery with the dual labeled anti-carbonic anhydrase IX antibody preparation (111)In-DTPA-G250-IRDye800CW in mice with intraperitoneal clear cell renal cell carcinoma. BALB/c nu/nu mice with intraperitoneal SK-RC-52 lesions received 10 μg DTPA-G250-IRDye800CW labeled with 15 MBq (111)In or 10 μg of the dual labeled irrelevant control antibody NUH-82 (20 mice each). To evaluate when tumors could be detected, 4 mice per group were imaged weekly during 5 weeks with single photon emission computerized tomography/computerized tomography and the fluorescence imaging followed by ex vivo biodistribution studies. As early as 1 week after tumor cell inoculation single photon emission computerized tomography and fluorescence images showed clear delineation of intraperitoneal clear cell renal cell carcinoma with good concordance between single photon emission computerized tomography/computerized tomography and fluorescence images. The high and specific accumulation of the dual labeled antibody conjugate in tumors was confirmed in the biodistribution studies. Maximum tumor uptake was observed 1 week after inoculation (mean ± SD 58.5% ± 18.7% vs 5.6% ± 2.3% injected dose per gm for DTPA-G250-IRDye800CW vs NUH-82, respectively). High tumor uptake was also observed at other time points. This study demonstrates the feasibility of dual modality imaging with dual labeled antibody (111)In-DTPA-G250-IRDye800CW in a clear cell renal cell carcinoma model. Results indicate that preoperative and intraoperative detection of carbonic anhydrase IX expressing tumors, positive resection margins and metastasis might be feasible with this approach. Copyright © 2015 American Urological Association Education and Research

[Clear cells cervical adenocarcinoma in a girl no exposed to dietiletilbestrol].

PubMed

Romero-Durán, Elizabeth; Chávez-Bravo, Neyda Cecilia; García-Rodríguez, Antonio Severo

2012-01-01

the clear cell adenocarcinoma (CCA) in cervix is a rare disease. It represents only 2 to 7 % of whole adecocarcinomas of cervix. Its histological pattern seems identical to their counterparts elsewhere in the female genital tract, including the vagina, endometrial and ovary. The CCA is constituted by cells with a clear cytoplasm in tack that are arranged in a solid pattern, tubu-locystic, papillary, or mixed. an eleven year old girl with sporadic and intermittent transvaginal bleeding, and who felt in severe anemia due to hiperpolimenorrea treated with athinyl estradiol deso-gestrel was attended. She had not history of exposition in utero to diethyletilbestrol. Hysteroscopy showed an ectocervical exophytic lesion in a barrel of 7 × 3 × 3 cm, located predominantly in the posterior lip. A frozen section of the lesion was reported as a poorly differentiated malignant tumor compatible with cervical carcinoma. She underwent to simple trachelectomy. diagnostic difficulty was the age of the patient and the lack exposition in utero to DES, the differential diagnosis included the age group tumors and rhabdomyosarcoma botryoides and extragonadal endodermic origen with papillary and reticular pattern. Another was a metastatic CCA.

PET/CT imaging of clear cell renal cell carcinoma with 124I labeled chimeric antibody

PubMed Central

Bahnson, Eamonn E.; Murrey, Douglas A.; Mojzisik, Cathy M.; Hall, Nathan C.; Martinez-Suarez, Humberto J.; Knopp, Michael V.; Martin, Edward W.; Povoski, Stephen P.; Bahnson, Robert R.

2009-01-01

Clear cell renal cell carcinoma (ccRCC) presents problems for urologists in diagnosis, treatment selection, intraoperative surgical margin analysis, and long term monitoring. In this paper we describe the development of a radiolabeled antibody specific to ccRCC (124I-cG250) and its potential to help urologists manage each of these problems. We believe 124I-cG250, in conjunction with perioperative Positron emission tomography/computed tomography imaging and intraoperative handheld gamma probe use, has the potential to diagnose ccRCC, aid in determining a proper course of treatment (operative or otherwise), confirm complete resection of malignant tissue in real time, and monitor patients post-operatively. PMID:21789055

Expression of EphA2 protein is positively associated with age, tumor size and Fuhrman nuclear grade in clear cell renal cell carcinomas.

PubMed

Wang, Longxin; Hu, Haibing; Tian, Feng; Zhou, Wenquan; Zhou, Shuigen; Wang, Jiandong

2015-01-01

The receptor tyrosine kinase of EphA2 has been shown frequently overexpressed in various types of human carcinomas, which implicated that it plays important roles in carcinogenesis. Although EphA2 protein expression has been investigated in many types of human carcinomas, the relationship between the expression of EphA2 protein in clear cell renal cell carcinoma was not well documented. In the present study, using specific anit-EphA2 polyclonal antibody and immunohistochemistry, we evaluated EphA2 protein expression levels in clear cell RCC specimens surgically resected from 90 patients. Our results shows that EphA2 protein was positively expressed in all normal renal tubes of 90 samples (100%, 3+), which was expressed at low levels in renal cortex but high levels in the collecting ducts of the renal medulla and papilla. EphA2 was negatively or weakly expressed in 30 out of 90 samples (33.3%, 0/1+), moderately expressed in 24 samples (26.7%, 2+) and strongly expressed in 36 samples (40%, 3+). Expression of EphA2 was positively associated with age (P=0.029), tumor diameters (P<0.001) and Fuhrman nuclear grade (P<0.001). Our results indicate that EphA2 variably expressed in clear cell renal cell carcinomas. High expression of EphA2 was more often found in big size and high nuclear grade tumors, which indicated EphA2 protein may be used as a new marker for the prognosis of clear cell renal cell carcinoma.

Intraductal glycogen-rich clear cell carcinoma of the breast: a rare presentation and review of the literature.

PubMed

Salemis, Nikolaos S

2012-08-01

Glycogen-rich clear cell carcinoma of the breast is a rare histological subtype of breast cancer, accounting for 0.9-2.8% of all breast cancer cases. Fewer than 100 cases have been reported in the literature. Most of these tumors are invasive carcinomas. The intraductal glycogen-rich clear cell carcinoma is a very rare occurrence. Herein is described a case of a pure intraductal glycogen-rich clear cell carcinoma of the breast in a 42-year-old premenopausal woman. A literature review has also been carried out. Mammography was inconclusive due to the presence of dense breast tissue, but magnetic resonance imaging (MRI) showed several nodular lesions measuring 7 × 6 cm in diameter and involving the upper aspect of the right breast suggestive of multifocal malignancy. A modified radical mastectomy was performed. The patient started hormonal therapy with tamoxifen and is currently well 16 months after surgery. A pure intraductal glycogen-rich clear cell carcinoma of the breast is a very rare occurrence. The case presented here exhibited uncommon MRI features, whereas the tumor size is one of the largest reported in the literature. Mammography may be inconclusive in the presence of dense breast tissue, but MRI is of great importance in the preoperative evaluation of the patient.

Complexity of tumor vasculature in clear cell renal cell carcinoma.

PubMed

Qian, Chao-Nan; Huang, Dan; Wondergem, Bill; Teh, Bin Tean

2009-05-15

Clear cell renal cell carcinoma (CCRCC) is a highly vascularized cancer resistant to conventional chemotherapy and radiotherapy. Antiangiogenic therapy has achieved some effectiveness against this unique malignancy. The complexity of the tumor vasculature in CCRCC has led to differences in correlating tumor microvessel density with patient prognosis. The authors' recent findings demonstrated that there were at least 2 major categories of tumor vessels in CCRCC-namely, undifferentiated and differentiated-correlating with patient prognosis in contrasting ways, with higher undifferentiated vessel density indicating poorer prognosis, and higher differentiated vessel density correlating with better prognosis. Furthermore, the presence of pericytes supporting the differentiated vessels varied in CCRCC. The distributions of pericyte coverage and differentiated vessels in CCRCC were uneven. The tumor margin had a higher pericyte coverage rate for differentiated vessels than did the inner tumor area. The uneven distributions of pericyte coverage and differentiated vessels in CCRCC prompted the authors to revisit the mechanism of tumor central necrosis, which was also known to be a prognostic indicator for CCRCC. The discrepancy of prognostic correlation between protein and messenger RNA levels of vascular endothelial growth factor in CCRCC was discussed. The complexity of the tumor vasculature in CCRCC also led the authors to begin to re-evaluate the therapeutic effects of antiangiogenic agents for each type of tumor vessel, which will in turn significantly broaden understanding of tumor angiogenesis and improve therapeutic effect. (c) 2009 American Cancer Society.

Metastatic clear cell eccrine hidradenocarcinoma of the vulva: survival after primary surgical resection.

PubMed

Massad, L S; Bitterman, P; Clarke-Pearson, D L

1996-05-01

A case of clear cell eccrine hidradenocarcinoma of the vulva metastatic to regional lymph nodes with long survival after surgical resection is presented. Like the only other case reported to date, this suggests that surgical therapy alone may be adequate, even when metastasis is present.

Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.

PubMed

Miao, Diana; Margolis, Claire A; Gao, Wenhua; Voss, Martin H; Li, Wei; Martini, Dylan J; Norton, Craig; Bossé, Dominick; Wankowicz, Stephanie M; Cullen, Dana; Horak, Christine; Wind-Rotolo, Megan; Tracy, Adam; Giannakis, Marios; Hodi, Frank Stephen; Drake, Charles G; Ball, Mark W; Allaf, Mohamad E; Snyder, Alexandra; Hellmann, Matthew D; Ho, Thai; Motzer, Robert J; Signoretti, Sabina; Kaelin, William G; Choueiri, Toni K; Van Allen, Eliezer M

2018-02-16

Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene ( P = 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies ( P = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and PBRM1 -deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Oncology Gold Standard™ practical consensus recommendations 2016 for treatment of advanced clear cell renal cell carcinoma.

PubMed

Batra, U; Parikh, P M; Prabhash, K; Tongaonkar, H B; Chibber, P; Dabkara, D; Deshmukh, C; Ghadyalpatil, N; Hingmire, S; Joshi, A; Raghunath, S K; Rajappa, S; Rajendranath, R; Rawal, S K; Singh, Manisha; Singh, R; Somashekhar, S P; Sood, R

2016-01-01

The Oncology Gold Standard (OGS) Expert Group on renal cell carcinoma (RCC) developed the consensus statement to provide community oncologists practical guidelines on the management of advanced clear cell (cc) RCC using published evidence, practical experience of experts in real life management, and results of a nationwide survey involving 144 health-care professionals. Six broad question categories containing 33 unique questions cover major situations in the routine management of RCC. This document serves as a ready guide for the standard of care to optimize outcome. The table of "Take Home Messages" at the end is a convenient tool for busy practitioners.

Increased expression of CD44 is associated with more aggressive behavior in clear cell renal cell carcinoma.

PubMed

Zanjani, Leili Saeednejad; Madjd, Zahra; Abolhasani, Maryam; Rasti, Arezoo; Fodstad, Oystein; Andersson, Yvonne; Asgari, Mojgan

2018-01-01

Although CD44 has been suggested as a prognostic marker in renal cell carcinoma (RCC), the prognostic significance of this marker in three main subtypes of RCC is still unclear. Thus, the present study was conducted to evaluate the expression and prognostic significance of CD44 as a cancer stem cell marker in different histological subtypes of RCC. Methodology & results: CD44 expression was evaluated in 206 well-defined renal tumor samples using immunohistochemistry on tissue microarrays. Higher CD44 expression was associated with more aggressive behavior, tumor progression and worse prognosis in clear cell RCC (ccRCC) but not in papillary and chromophobe RCC subtypes. Cancer stem cell marker CD44 may be a promising target for cancer treatment only in ccRCC.

A four-gene signature predicts survival in clear-cell renal-cell carcinoma.

PubMed

Dai, Jun; Lu, Yuchao; Wang, Jinyu; Yang, Lili; Han, Yingyan; Wang, Ying; Yan, Dan; Ruan, Qiurong; Wang, Shaogang

2016-12-13

Clear-cell renal-cell carcinoma (ccRCC) is the most common pathological subtype of renal cell carcinoma (RCC), accounting for about 80% of RCC. In order to find potential prognostic biomarkers in ccRCC, we presented a four-gene signature to evaluate the prognosis of ccRCC. SurvExpress and immunohistochemical (IHC) staining of tissue microarrays were used to analyze the association between the four genes and the prognosis of ccRCC. Data from TCGA dataset revealed a prognostic prompt function of the four genes (PTEN, PIK3C2A, ITPA and BCL3). Further discovery suggested that the four-gene signature predicted survival better than any of the four genes alone. Moreover, IHC staining demonstrated a consistent result with TCGA, indicating that the signature was an independent prognostic factor of survival in ccRCC. Univariate and multivariate Cox proportional hazard regression analysis were conducted to verify the association of clinicopathological variables and the four genes' expression levels with survival. The results further testified that the risk (four-gene signature) was an independent prognostic factors of both Overall Survival (OS) and Disease-free Survival (DFS) (P<0.05). In conclusion, the four-gene signature was correlated with the survival of ccRCC, and therefore, may help to provide significant clinical implications for predicting the prognosis of patients.

Development of background-free tame fluorescent probes for intracellular live cell imaging

PubMed Central

Alamudi, Samira Husen; Satapathy, Rudrakanta; Kim, Jihyo; Su, Dongdong; Ren, Haiyan; Das, Rajkumar; Hu, Lingna; Alvarado-Martínez, Enrique; Lee, Jung Yeol; Hoppmann, Christian; Peña-Cabrera, Eduardo; Ha, Hyung-Ho; Park, Hee-Sung; Wang, Lei; Chang, Young-Tae

2016-01-01

Fluorescence labelling of an intracellular biomolecule in native living cells is a powerful strategy to achieve in-depth understanding of the biomolecule's roles and functions. Besides being nontoxic and specific, desirable labelling probes should be highly cell permeable without nonspecific interactions with other cellular components to warrant high signal-to-noise ratio. While it is critical, rational design for such probes is tricky. Here we report the first predictive model for cell permeable background-free probe development through optimized lipophilicity, water solubility and charged van der Waals surface area. The model was developed by utilizing high-throughput screening in combination with cheminformatics. We demonstrate its reliability by developing CO-1 and AzG-1, a cyclooctyne- and azide-containing BODIPY probe, respectively, which specifically label intracellular target organelles and engineered proteins with minimum background. The results provide an efficient strategy for development of background-free probes, referred to as ‘tame' probes, and novel tools for live cell intracellular imaging. PMID:27321135

Thyroid metastasis as initial presentation of clear cell renal carcinoma

PubMed Central

Ramírez-Plaza, César Pablo; Domínguez-López, Marta Elena; Blanco-Reina, Francisco

2015-01-01

Introduction Metastatic tumors account for 1.4–2.5% of thyroid malignancies. About 25–30% of patients with clear cell renal carcinoma (CCRC) have distant metastasis at the time of diagnosis, being the thyroid gland a rare localization [5%]. Presentation of the case A 62-year woman who underwent a cervical ultrasonography and a PAAF biopsy reporting atypical follicular proliferation with a few intranuclear vacuoles “suggestive” of thyroid papillary cancer in the context of a multinodular goiter was reported. A total thyroidectomy was performed and the histology of a clear cell renal carcinoma (CCRC) was described in four nodules of the thyroid gland. A CT scan was performed and a renal giant right tumor was found. The patient underwent an eventful radical right nephrectomy and the diagnosis of CCRC was confirmed. Discussion Thyroid metastasis (TM) from CCRC are usually apparent in a metachronic context during the follow-up of a treated primary (even many years after) but may sometimes be present at the same time than the primary renal tumor. Our case is exceptional because the TM was the first evidence of the CCRC, which was subsequently diagnosed and treated. Conclusion The possibility of finding of an incidental metastatic tumor in the thyroid gland from a previous unknown and non-diganosed primary (as CCRC in our case was) is rare and account only for less than 1% of malignancies. Nonetheless, the thyroid gland is a frequent site of metastasis and the presence of “de novo” thyroid nodules in oncologic patients must be always considered and studied. PMID:25827295

The genetic landscape of endometrial clear cell carcinomas.

PubMed

DeLair, Deborah F; Burke, Kathleen A; Selenica, Pier; Lim, Raymond S; Scott, Sasinya N; Middha, Sumit; Mohanty, Abhinita S; Cheng, Donavan T; Berger, Michael F; Soslow, Robert A; Weigelt, Britta

2017-10-01

Clear cell carcinoma of the endometrium is a rare type of endometrial cancer that is generally associated with an aggressive clinical behaviour. Here, we sought to define the repertoire of somatic genetic alterations in endometrial clear cell carcinomas (ECCs), and whether ECCs could be classified into the molecular subtypes described for endometrial endometrioid and serous carcinomas. We performed a rigorous histopathological review, immunohistochemical analysis and massively parallel sequencing targeting 300 cancer-related genes of 32 pure ECCs. Eleven (34%), seven (22%) and six (19%) ECCs showed abnormal expression patterns for p53, ARID1A, and at least one DNA mismatch repair (MMR) protein, respectively. Targeted sequencing data were obtained from 30 of the 32 ECCs included in this study, and these revealed that two ECCs (7%) were ultramutated and harboured mutations affecting the exonuclease domain of POLE. In POLE wild-type ECCs, TP53 (46%), PIK3CA (36%), PPP2R1A (36%), FBXW7 (25%), ARID1A (21%), PIK3R1 (18%) and SPOP (18%) were the genes most commonly affected by mutations; 18% and 11% harboured CCNE1 and ERBB2 amplifications, respectively, and 11% showed DAXX homozygous deletions. ECCs less frequently harboured mutations affecting CTNNB1 and PTEN but more frequently harboured PPP2R1A and TP53 mutations than non-POLE endometrioid carcinomas from The Cancer Genome Atlas (TCGA). Compared to endometrial serous carcinomas (TCGA), ECCs less frequently harboured TP53 mutations. When a surrogate model for the molecular-based TCGA classification was used, all molecular subtypes previously identified in endometrial endometrioid and serous carcinomas were present in the ECCs studied, including POLE, MMR-deficient, copy-number high (serous-like)/p53 abnormal, and copy-number low (endometrioid)/p53 wild-type, which were significantly associated with disease-free survival in univariate analysis. These findings demonstrate that ECCs constitute a histologically and

Clear cell renal cell carcinoma: validation of World Health Organization/International Society of Urological Pathology grading.

PubMed

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

2017-12-01

In 2012, the International Society of Urological Pathology (ISUP) introduced a novel grading system for clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma. This system is incorporated into 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 ccRCC 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 374 cases, for which outcome data were available, 9.3% were WHO/ISUP grade 1, 50.3% were grade 2, 24.1% grade 3 and 16.3% 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. The study demonstrates that FG cannot be applied in >20% of cases of ccRCC and the WHO/ISUP provides superior prognostic information. © 2017 John Wiley & Sons Ltd.

Oncology Gold Standard™ practical consensus recommendations 2016 for treatment of advanced clear cell renal cell carcinoma

PubMed Central

Batra, U; Parikh, PM; Prabhash, K; Tongaonkar, HB; Chibber, P; Dabkara, D; Deshmukh, C; Ghadyalpatil, N; Hingmire, S; Joshi, A; Raghunath, SK; Rajappa, S; Rajendranath, R; Rawal, SK; Singh, Manisha; Singh, R; Somashekhar, SP; Sood, R

2016-01-01

The Oncology Gold Standard (OGS) Expert Group on renal cell carcinoma (RCC) developed the consensus statement to provide community oncologists practical guidelines on the management of advanced clear cell (cc) RCC using published evidence, practical experience of experts in real life management, and results of a nationwide survey involving 144 health-care professionals. Six broad question categories containing 33 unique questions cover major situations in the routine management of RCC. This document serves as a ready guide for the standard of care to optimize outcome. The table of “Take Home Messages” at the end is a convenient tool for busy practitioners. PMID:28032079

HDAC 1 and 6 modulate cell invasion and migration in clear cell renal cell carcinoma.

PubMed

Ramakrishnan, Swathi; Ku, ShengYu; Ciamporcero, Eric; Miles, Kiersten Marie; Attwood, Kris; Chintala, Sreenivasulu; Shen, Li; Ellis, Leigh; Sotomayor, Paula; Swetzig, Wendy; Huang, Ray; Conroy, Dylan; Orillion, Ashley; Das, Gokul; Pili, Roberto

2016-08-09

Class I histone deacetylases (HDACs) have been reported to be overexpressed in clear cell renal cell carcinoma (ccRCC), whereas the expression of class II HDACs is unknown. Four isogenic cell lines C2/C2VHL and 786-O/786-OVHL with differential VHL expression are used in our studies. Cobalt chloride is used to mimic hypoxia in vitro. HIF-2α knockdowns in C2 and 786-O cells is used to evaluate the effect on HDAC 1 expression and activity. Invasion and migration assays are used to investigate the role of HDAC 1 and HDAC 6 expression in ccRCC cells. Comparisons are made between experimental groups using the paired T-test, the two-sample Student's T-test or one-way ANOVA, as appropriate. ccRCC and the TCGA dataset are used to observe the clinical correlation between HDAC 1 and HDAC 6 overexpression and overall and progression free survival. Our analysis of tumor and matched non-tumor tissues from radical nephrectomies showed overexpression of class I and II HDACs (HDAC6 only in a subset of patients). In vitro, both HDAC1 and HDAC6 over-expression increased cell invasion and motility, respectively, in ccRCC cells. HDAC1 regulated invasiveness by increasing matrix metalloproteinase (MMP) expression. Furthermore, hypoxia stimulation in VHL-reconstituted cell lines increased HIF isoforms and HDAC1 expression. Presence of hypoxia response elements in the HDAC1 promoter along with chromatin immunoprecipitation data suggests that HIF-2α is a transcriptional regulator of HDAC1 gene. Conversely, HDAC6 and estrogen receptor alpha (ERα) were co-localized in cytoplasm of ccRCC cells and HDAC6 enhanced cell motility by decreasing acetylated α-tubulin expression, and this biological effect was attenuated by either biochemical or pharmacological inhibition. Finally, analysis of human ccRCC specimens revealed positive correlation between HIF isoforms and HDAC. HDAC1 mRNA upregulation was associated with worse overall survival in the TCGA dataset. Taking together, these results

Debulking Surgery for Clear Cell Carcinoma of the Ovary - A Case Report and Literature Review.

PubMed

Bacalbasa, Nicolae; Balescu, Irina; Filipescu, Alexandru

2017-10-01

Ovarian clear cell carcinoma represents a distinct histopathological subtype of epithelial ovarian cancer, with poor outcomes, especially in cases diagnosed in advanced stages of disease. However, even in these cases, it seems that the most effective treatment remains debulking surgery to no residual disease. We present the case of a 56-year-old patient diagnosed with a large pelvic mass invading the rectosigmoidal colon, and ileal loop who was successfully submitted to cytoreductive surgery to no residual disease. The histopathological studies demonstrated the presence of a well-differentiated clear cell ovarian carcinoma of the ovary. At 1-year follow-up there is no evidence of residual disease. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

An intraventricular clear cell meningioma revealed by an inflammatory syndrome in a male adult: a case report.

PubMed

Cassereau, J; Lavigne, C; Michalak-Provost, S; Ghali, A; Dubas, F; Fournier, H D

2008-07-01

Intraventricular meningiomas are infrequent intracranial tumors. Clinical symptoms are mainly due to an increased intracranial pressure or a direct pressure on the surrounding brain structures. Inflammatory syndrome was described in some patients with chordoid meningiomas. Here we report a case of right intraventricular clear cell meningioma in a 50-year-old man who presented with fever, headache, and inflammatory syndrome. Clinical and biological normalization was rapidly obtained after tumor removal. Immunohistochemical examination showed tumor cells and lymphocytes positivity for the pyrogenic cytokine interleukin-6, with a same intensity. To our knowledge, this is the first case described in the literature concerning an adult man with an intraventricular clear cell meningioma associated with a systemic inflammatory syndrome.

ClearedLeavesDB: an online database of cleared plant leaf images

PubMed Central

2014-01-01

Background Leaf vein networks are critical to both the structure and function of leaves. A growing body of recent work has linked leaf vein network structure to the physiology, ecology and evolution of land plants. In the process, multiple institutions and individual researchers have assembled collections of cleared leaf specimens in which vascular bundles (veins) are rendered visible. In an effort to facilitate analysis and digitally preserve these specimens, high-resolution images are usually created, either of entire leaves or of magnified leaf subsections. In a few cases, collections of digital images of cleared leaves are available for use online. However, these collections do not share a common platform nor is there a means to digitally archive cleared leaf images held by individual researchers (in addition to those held by institutions). Hence, there is a growing need for a digital archive that enables online viewing, sharing and disseminating of cleared leaf image collections held by both institutions and individual researchers. Description The Cleared Leaf Image Database (ClearedLeavesDB), is an online web-based resource for a community of researchers to contribute, access and share cleared leaf images. ClearedLeavesDB leverages resources of large-scale, curated collections while enabling the aggregation of small-scale collections within the same online platform. ClearedLeavesDB is built on Drupal, an open source content management platform. It allows plant biologists to store leaf images online with corresponding meta-data, share image collections with a user community and discuss images and collections via a common forum. We provide tools to upload processed images and results to the database via a web services client application that can be downloaded from the database. Conclusions We developed ClearedLeavesDB, a database focusing on cleared leaf images that combines interactions between users and data via an intuitive web interface. The web interface

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

PubMed Central

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

Clear cell papillary renal cell carcinoma: a chromosomal microarray analysis of two cases using a novel Molecular Inversion Probe (MIP) technology.

PubMed

Alexiev, Borislav A; Zou, Ying S

2014-12-01

Chromosomal microarray analysis using novel Molecular Inversion Probe (MIP) technology demonstrated 2,570 kb copy neutral LOH of 10q11.22 in two clear cell papillary renal cell carcinomas. In addition, one of the tumors had a big 29,784 kb deletion of 13q11-q14.2. There were two variants of unknown significance, a 2,509 kb gain of Xp22.33 and a 257 kb homozygous deletion of 8p11.22. The somatic mutation panel containing 74 mutations in nine genes did not reveal any mutations. Besides identification of submicroscopic duplications or deletions, SNP microarrays can reveal abnormal allelic imbalances including LOH and copy neutral LOH, which cannot be recognized by chromosome, FISH, and non-SNP microarray arrays. To the best of our knowledge, this is the first study demonstrating copy neutral LOH of 10q11.22 in clear cell papillary renal cell carcinomas using the new MIP SNP OncoScan FFPE Assay Kit on formalin-fixed paraffin-embedded tumor samples. Copyright © 2014 Elsevier GmbH. All rights reserved.

Different Angiogenic Potential in Low and High Grade Sporadic Clear Cell Renal Cell Carcinoma Is Not Related to Alterations in the von Hippel–Lindau Gene

PubMed Central

Baldewijns, Marcella M.; van Vlodrop, Iris J. H.; Smits, Kim M.; Vermeulen, Peter B.; Van den Eynden, Gert G.; Schot, Fiona; Roskams, Tania; van Poppel, Hein; van Engeland, Manon; de Bruïne, Adriaan P.

2009-01-01

Background: von Hippel–Lindau (VHL) inactivation is common in sporadic clear cell renal cell carcinomas (ccRCC). pVHL is part of the ubiquitin ligase complex that targets the alpha subunits of hypoxia-inducible transcription factor (HIF) for degradation under well-oxygenated conditions. In the absence of wild-type pVHL, as observed in VHL patients and most sporadic ccRCCs, constitutive upregulation of HIF results in transcriptional activation of angiogenesis-related genes, such as VEGF. Differences in angiogenic activity within the group of ccRCCs were reported and strong genotype-phenotype correlations were found in patients with VHL disease, raising a question about the importance of VHL inactivation status in angiogenic behaviour and tumour progression. Methods: To address this question, we investigated the influence of VHL mutation (direct sequencing)/hypermethylation (methylation-specific PCR) on angiogenesis/tumour parameters (immunohistochemistry) in 150 patients with sporadic ccRCC. Results: We found no significant association between VHL mutation or methylation and angiogenesis/tumour parameters. Conclusions: These data indicate that tumour progression and angiogenesis are not directly influenced by VHL alterations and that additional genetic/epigenetic events should be considered to explain the diverse angiogenic and proliferative behaviour during tumour progression. PMID:19759417

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

PubMed

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

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

PubMed Central

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

Comprehensive Exploration of Novel Chimeric Transcripts in Clear Cell Renal Cell Carcinomas Using Whole Transcriptome Analysis

PubMed Central

Gotoh, Masahiro; Ichikawa, Hitoshi; Arai, Eri; Chiku, Suenori; Sakamoto, Hiromi; Fujimoto, Hiroyuki; Hiramoto, Masaki; Nammo, Takao; Yasuda, Kazuki; Yoshida, Teruhiko; Kanai, Yae

2014-01-01

The aim of this study was to clarify the participation of expression of chimeric transcripts in renal carcinogenesis. Whole transcriptome analysis (RNA sequencing) and exploration of candidate chimeric transcripts using the deFuse program were performed on 68 specimens of cancerous tissue (T) and 11 specimens of non-cancerous renal cortex tissue (N) obtained from 68 patients with clear cell renal cell carcinomas (RCCs) in an initial cohort. As positive controls, two RCCs associated with Xp11.2 translocation were analyzed. After verification by reverse transcription (RT)-PCR and Sanger sequencing, 26 novel chimeric transcripts were identified in 17 (25%) of the 68 clear cell RCCs. Genomic breakpoints were determined in five of the chimeric transcripts. Quantitative RT-PCR analysis revealed that the mRNA expression levels for the MMACHC, PTER, EPC2, ATXN7, FHIT, KIFAP3, CPEB1, MINPP1, TEX264, FAM107A, UPF3A, CDC16, MCCC1, CPSF3, and ASAP2 genes, being partner genes involved in the chimeric transcripts in the initial cohort, were significantly reduced in 26 T samples relative to the corresponding 26 N samples in the second cohort. Moreover, the mRNA expression levels for the above partner genes in T samples were significantly correlated with tumor aggressiveness and poorer patient outcome, indicating that reduced expression of these genes may participate in malignant progression of RCCs. As is the case when their levels of expression are reduced, these partner genes also may not fully function when involved in chimeric transcripts. These data suggest that generation of chimeric transcripts may participate in renal carcinogenesis by inducing dysfunction of tumor-related genes. PMID:25230976

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

EPA Science Inventory

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. ...

Reduced background autofluorescence for cell imaging using nanodiamonds and lanthanide chelates.

PubMed

Cordina, Nicole M; Sayyadi, Nima; Parker, Lindsay M; Everest-Dass, Arun; Brown, Louise J; Packer, Nicolle H

2018-03-14

Bio-imaging is a key technique in tracking and monitoring important biological processes and fundamental biomolecular interactions, however the interference of background autofluorescence with targeted fluorophores is problematic for many bio-imaging applications. This study reports on two novel methods for reducing interference with cellular autofluorescence for bio-imaging. The first method uses fluorescent nanodiamonds (FNDs), containing nitrogen vacancy centers. FNDs emit at near-infrared wavelengths typically higher than most cellular autofluorescence; and when appropriately functionalized, can be used for background-free imaging of targeted biomolecules. The second method uses europium-chelating tags with long fluorescence lifetimes. These europium-chelating tags enhance background-free imaging due to the short fluorescent lifetimes of cellular autofluorescence. In this study, we used both methods to target E-selectin, a transmembrane glycoprotein that is activated by inflammation, to demonstrate background-free fluorescent staining in fixed endothelial cells. Our findings indicate that both FND and Europium based staining can improve fluorescent bio-imaging capabilities by reducing competition with cellular autofluorescence. 30 nm nanodiamonds coated with the E-selectin antibody was found to enable the most sensitive detective of E-selectin in inflamed cells, with a 40-fold increase in intensity detected.

Establishment of a novel clear cell sarcoma cell line (Hewga-CCS), and investigation of the antitumor effects of pazopanib on Hewga-CCS

PubMed Central

2014-01-01

Background Clear cell sarcoma (CCS) is a therapeutically unresolved, aggressive, soft tissue sarcoma (STS) that predominantly affects young adults. This sarcoma is defined by t(12;22)(q13;q12) translocation, which leads to the fusion of Ewing sarcoma gene (EWS) to activating transcription factor 1 (ATF1) gene, producing a chimeric EWS-ATF1 fusion gene. We established a novel CCS cell line called Hewga-CCS and developed an orthotopic tumor xenograft model to enable comprehensive bench-side investigation for intensive basic and preclinical research in CCS with a paucity of experimental cell lines. Methods Hewga-CCS was derived from skin metastatic lesions of a CCS developed in a 34-year-old female. The karyotype and chimeric transcript were analyzed. Xenografts were established and characterized by morphology and immunohistochemical reactivity. Subsequently, the antitumor effects of pazopanib, a recently approved, novel, multitargeted, tyrosine kinase inhibitor (TKI) used for the treatment of advanced soft tissue sarcoma, on Hewga-CCS were assessed in vitro and in vivo. Results Hewga-CCS harbored the type 2 EWS-ATF1 transcript. Xenografts morphologically mimicked the primary tumor and expressed S-100 protein and antigens associated with melanin synthesis (Melan-A, HMB45). Pazopanib suppressed the growth of Hewga-CCS both in vivo and in vitro. A phospho-receptor tyrosine kinase array revealed phosphorylation of c-MET, but not of VEGFR, in Hewga-CCS. Subsequent experiments showed that pazopanib exerted antitumor effects through the inhibition of HGF/c-MET signaling. Conclusions CCS is a rare, devastating disease, and our established CCS cell line and xenograft model may be a useful tool for further in-depth investigation and understanding of the drug-sensitivity mechanism. PMID:24946937

Epigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma

PubMed Central

Mehdi, Ali; Riazalhosseini, Yasser

2017-01-01

Clear cell renal cell carcinoma (ccRCC), the most common form of Kidney cancer, is characterized by frequent mutations of the von Hippel-Lindau (VHL) tumor suppressor gene in ~85% of sporadic cases. Loss of pVHL function affects multiple cellular processes, among which the activation of hypoxia inducible factor (HIF) pathway is the best-known function. Constitutive activation of HIF signaling in turn activates hundreds of genes involved in numerous oncogenic pathways, which contribute to the development or progression of ccRCC. Although VHL mutations are considered as drivers of ccRCC, they are not sufficient to cause the disease. Recent genome-wide sequencing studies of ccRCC have revealed that mutations of genes coding for epigenome modifiers and chromatin remodelers, including PBRM1, SETD2 and BAP1, are the most common somatic genetic abnormalities after VHL mutations in these tumors. Moreover, recent research has shed light on the extent of abnormal epigenome alterations in ccRCC tumors, including aberrant DNA methylation patterns, abnormal histone modifications and deregulated expression of non-coding RNAs. In this review, we discuss the epigenetic modifiers that are commonly mutated in ccRCC, and our growing knowledge of the cellular processes that are impacted by them. Furthermore, we explore new avenues for developing therapeutic approaches based on our knowledge of epigenome aberrations of ccRCC. PMID:28812986

Epigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma.

PubMed

Mehdi, Ali; Riazalhosseini, Yasser

2017-08-16

Clear cell renal cell carcinoma (ccRCC), the most common form of Kidney cancer, is characterized by frequent mutations of the von Hippel-Lindau ( VHL ) tumor suppressor gene in ~85% of sporadic cases. Loss of pVHL function affects multiple cellular processes, among which the activation of hypoxia inducible factor (HIF) pathway is the best-known function. Constitutive activation of HIF signaling in turn activates hundreds of genes involved in numerous oncogenic pathways, which contribute to the development or progression of ccRCC. Although VHL mutations are considered as drivers of ccRCC, they are not sufficient to cause the disease. Recent genome-wide sequencing studies of ccRCC have revealed that mutations of genes coding for epigenome modifiers and chromatin remodelers, including PBRM1 , SETD2 and BAP1 , are the most common somatic genetic abnormalities after VHL mutations in these tumors. Moreover, recent research has shed light on the extent of abnormal epigenome alterations in ccRCC tumors, including aberrant DNA methylation patterns, abnormal histone modifications and deregulated expression of non-coding RNAs. In this review, we discuss the epigenetic modifiers that are commonly mutated in ccRCC, and our growing knowledge of the cellular processes that are impacted by them. Furthermore, we explore new avenues for developing therapeutic approaches based on our knowledge of epigenome aberrations of ccRCC.

Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing

PubMed Central

Varela, Ignacio; Fisher, Rosalie; McGranahan, Nicholas; Matthews, Nicholas; Santos, Claudio R; Martinez, Pierre; Phillimore, Benjamin; Begum, Sharmin; Rabinowitz, Adam; Spencer-Dene, Bradley; Gulati, Sakshi; Bates, Paul A; Stamp, Gordon; Pickering, Lisa; Gore, Martin; Nicol, David L; Hazell, Steven; Futreal, P Andrew; Stewart, Aengus; Swanton, Charles

2015-01-01

Clear cell renal carcinomas (ccRCCs) can display intratumor heterogeneity (ITH). We applied multiregion exome sequencing (M-seq) to resolve the genetic architecture and evolutionary histories of ten ccRCCs. Ultra-deep sequencing identified ITH in all cases. We found that 73–75% of identified ccRCC driver aberrations were subclonal, confounding estimates of driver mutation prevalence. ITH increased with the number of biopsies analyzed, without evidence of saturation in most tumors. Chromosome 3p loss and VHL aberrations were the only ubiquitous events. The proportion of C>T transitions at CpG sites increased during tumor progression. M-seq permits the temporal resolution of ccRCC evolution and refines mutational signatures occurring during tumor development. PMID:24487277

Low enhancement on multiphase contrast-enhanced CT images: an independent predictor of the presence of high tumor grade of clear cell renal cell carcinoma.

PubMed

Zhu, Ye-Hua; Wang, Xun; Zhang, Jin; Chen, Yong-Hui; Kong, Wen; Huang, Yi-Ran

2014-09-01

The purpose of this study was to assess the relation between tumor enhancement on multiphase contrast-enhanced CT images and Fuhrman grade of clear cell renal cell carcinoma. A single-institution retrospective review was conducted on the records of 255 patients who underwent radical or partial nephrectomy and received a histologic diagnosis of clear cell renal cell carcinoma. Two radiologists recorded the radiographic features of each patient, including the attenuation value of the lesion, lesion size, calcification within the lesion, cystic versus solid appearance, and margin regularity. Parameters representing the extent of tumor enhancement were defined and calculated. The association between tumor enhancement and Fuhrman grade was analyzed, and multivariate analysis was performed to find independent predictors of high tumor grade. Significant differences existed in tumor enhancement among different Fuhrman grades (p < 0.001). High-grade tumors had significantly lower enhancement (p < 0.001). The enhancement parameter had a sensitivity of 0.84 and specificity of 0.93 in prediction of high tumor grade. In the multivariate analysis, more advanced age, irregular margin, and low tumor enhancement were the three independent predictors of high tumor grade. Tumor enhancement of clear cell renal cell carcinoma on multiphase contrast-enhanced CT images is associated with Fuhrman grade. Low tumor enhancement in the corticomedullary phase is an independent predictor of high tumor grade. This system may be helpful in clinical decision making about the care of patients treated by nonsurgical approaches.

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

PubMed

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.

Renal Clear Cell Sarcoma - Anaplastic Variant: A Rare Entity

PubMed Central

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. PMID:28273978

VEGF is a Promising Therapeutic Target for the Treatment of Clear Cell Carcinoma of the Ovary

PubMed Central

Mabuchi, Seiji; Kawase, Chiaki; Altomare, Deborah A.; Morishige, Kenichirou; Hayashi, Masami; Sawada, Kenjiro; Ito, Kimihiko; Terai, Yoshito; Nishio, Yukihiro; Klein-Szanto, Andres J.; Burger, Robert A.; Ohmichi, Masahide; Testa, Joseph R.; Kimura, Tadashi

2010-01-01

This study examined the role of VEGF as a therapeutic target in clear cell carcinoma (CCC) of the ovary, which has been regarded as a chemoresistant histological subtype. Immunohistochemical analysis using tissue microarrays of 98 primary ovarian cancers revealed that VEGF was strongly expressed both in early stage and advanced stage CCC of the ovary. In early stage CCCs, patients who had tumors with high levels of VEGF had significantly shorter survival than those with low levels of VEGF. In vitro experiments revealed that VEGF expression was significantly higher in cisplatin-refractory human clear cell carcinoma cells (RMG1-CR and KOC7C-CR), compared to the respective parental cells (RMG1 and KOC7C) in the presence of cisplatin. In vivo treatment with bevacizumab markedly inhibited the growth of both parental CCC cells-derived (RMG1 and KOC7C) and cisplatin-refractory CCC cells-derived (RMG1-CR and KOC7C-CR) tumors as a result of inhibition of tumor angiogenesis. The results of the current study indicate that VEGF is frequently expressed and can be a promising therapeutic target in the management of CCC. Bevacizumab may be efficacious not only as a first-line treatment but also as a second-line treatment of recurrent disease in patients previously treated with cisplatin. PMID:20663925

Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation.

PubMed

Kapur, Payal; Peña-Llopis, Samuel; Christie, Alana; Zhrebker, Leah; Pavía-Jiménez, Andrea; Rathmell, W Kimryn; Xie, Xian-Jin; Brugarolas, James

2013-02-01

Clear-cell renal-cell carcinomas display divergent clinical behaviours. However, the molecular genetic events driving these behaviours are unknown. We discovered that BAP1 is mutated in about 15% of clear-cell renal-cell carcinoma, and that BAP1 and PBRM1 mutations are largely mutually exclusive. The aim of this study was to investigate the clinicopathological significance of these molecular subtypes and to determine whether patients with BAP1-mutant and PBRM1-mutant tumours had different overall survival. In this retrospective analysis, we assessed 145 patients with primary clear-cell renal-cell carcinoma and defined PBRM1 and BAP1 mutation status from the University of Texas Southwestern Medical Center (UTSW), TX, USA, between 1998 and 2011. We classified patients into those with BAP1-mutant tumours and those with tumours exclusively mutated for PBRM1 (PBRM1-mutant). We used a second independent cohort (n=327) from The Cancer Genome Atlas (TCGA) for validation. In both cohorts, more than 80% of patients had localised or locoregional disease at presentation. Overall both cohorts were similar, although the TCGA had more patients with metastatic and higher-grade disease, and more TCGA patients presented before molecularly targeted therapies became available. The median overall survival in the UTSW cohort was significantly shorter for patients with BAP1-mutant tumours (4·6 years; 95% CI 2·1-7·2), than for patients with PBRM1-mutant tumours (10·6 years; 9·8-11·5), corresponding to a HR of 2·7 (95% CI 0·99-7·6, p=0·044). Median overall survival in the TCGA cohort was 1·9 years (95% CI 0·6-3·3) for patients with BAP1-mutant tumours and 5·4 years (4·0-6·8) for those with PBRM1-mutant tumours. A HR similar to the UTSW cohort was noted in the TCGA cohort (2·8; 95% CI 1·4-5·9; p=0·004). Patients with mutations in both BAP1 and PBRM1, although a minority (three in UTSW cohort and four in TCGA cohort), had the worst overall survival (median 2·1 years, 95

Impact of Adjuvant External-Beam Radiation Therapy in Early-Stage Uterine Papillary Serous and Clear Cell Carcinoma

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

Kim, Anne, E-mail: akim2@health-quest.org; Schreiber, David; Rineer, Justin

2011-11-15

Purpose: Adjuvant radiation therapy (RT) in early-stage high- to intermediate-risk endometrioid adenocarcinoma is well established and has been shown to improve locoregional control. Its role in the management of early-stage clear cell carcinoma and uterine papillary serous carcinoma (UPSC) remains controversial. Methods and Materials: Using the Surveillance Epidemiology and End Results database, we identified women with American Joint Committee on Cancer Stage Sixth Edition. Stage IA-IIB clear cell carcinoma or UPSC who underwent hysterectomy with or without adjuvant RT between 1988 and 2003. We used Kaplan-Meier and Cox regression analysis to compare overall survival (OS) for all patients. Results: Wemore » identified 1,333 women of whom 451 had clear cell carcinoma and 882 had UPSC. Of those patients, 775 underwent surgery alone and 558 received adjuvant RT as well. For Stages I-IIB disease, the median OS with surgery alone was 106 months, vs. 151 months with adjuvant RT (p = 0.006). On subgroup analysis, we saw the benefit from adjuvant RT only in Stage IB-C patients. For Stage IB disease, patients undergoing surgery alone had a median OS of 117 months, vs. median survival not reached with the addition of RT (p = 0.006). For Stage IC disease, surgery alone had a median OS of 35 months vs. 120 months with RT (p = 0.001). Although the apparent benefit of RT diminished when measured via multivariate analysis, the impact of RT on survival did show a trend toward significance (hazard ration 0.808, confidence interval 95% 0.651-1.002, p = 0.052) Conclusion: In FIGO Stage IB-C papillary serous and clear cell uterine carcinoma, adjuvant RT seems to play an important role in improving survival.« less

A three-dimensional single-cell-resolution whole-brain atlas using CUBIC-X expansion microscopy and tissue clearing.

PubMed

Murakami, Tatsuya C; Mano, Tomoyuki; Saikawa, Shu; Horiguchi, Shuhei A; Shigeta, Daichi; Baba, Kousuke; Sekiya, Hiroshi; Shimizu, Yoshihiro; Tanaka, Kenji F; Kiyonari, Hiroshi; Iino, Masamitsu; Mochizuki, Hideki; Tainaka, Kazuki; Ueda, Hiroki R

2018-04-01

A three-dimensional single-cell-resolution mammalian brain atlas will accelerate systems-level identification and analysis of cellular circuits underlying various brain functions. However, its construction requires efficient subcellular-resolution imaging throughout the entire brain. To address this challenge, we developed a fluorescent-protein-compatible, whole-organ clearing and homogeneous expansion protocol based on an aqueous chemical solution (CUBIC-X). The expanded, well-cleared brain enabled us to construct a point-based mouse brain atlas with single-cell annotation (CUBIC-Atlas). CUBIC-Atlas reflects inhomogeneous whole-brain development, revealing a significant decrease in the cerebral visual and somatosensory cortical areas during postnatal development. Probabilistic activity mapping of pharmacologically stimulated Arc-dVenus reporter mouse brains onto CUBIC-Atlas revealed the existence of distinct functional structures in the hippocampal dentate gyrus. CUBIC-Atlas is shareable by an open-source web-based viewer, providing a new platform for whole-brain cell profiling.

Downregulation of HSP60 disrupts mitochondrial proteostasis to promote tumorigenesis and progression in clear cell renal cell carcinoma

PubMed Central

Tang, Haiping; Chen, Yuling; Liu, Xiaohui; Wang, Shiyu; Lv, Yang; Wu, Di; Wang, Qingtao; Luo, Minkui; Deng, Haiteng

2016-01-01

In the present study, we demonstrate that HSP60 is unequivocally downregulated in clear cell renal cell carcinoma (ccRCC) tissues compared to pericarcinous tissues. Overexpression of HSP60 in ccRCC cancer cells suppresses cell growth. HSP60 knockdown increases cell growth and proliferation in both cell culture and nude mice xenografts, and drives cells to undergo epithelial to mesenchymal transition (EMT). Our results propose that HSP60 silencing disrupts the integrity of the respiratory complex I and triggers the excessive ROS production, which promotes tumor progression in the following aspects: (1) ROS activates the AMPK pathway that promotes acquisition of the Warburg phenotype in HSP60-KN cells; (2) ROS generated by HSP60 knockdown or by rotenone inhibition drives cells to undergo EMT; and (3) the high level of ROS may also fragment the Fe-S clusters that up regulates ADHFe1 expression and the 2-hydroxygluterate (2-HG) production leading to changes in DNA methylation. These results suggest that the high level of ROS is needed for tumorigenesis and progression in tumors with the low HSP60 expression and HSP60 is a potential diagnostic biomarker as well as a therapeutic target in ccRCC. PMID:27246978

Clear cell hidradenocarcinoma of the ear helix: report of primary ear helix adnexal carcinoma with regional lymph node metastasis.

PubMed

Bae, Tae Hui; Kang, Shin Hyuk; Kim, Han Koo; Kim, Woo Seob; Kim, Mi Kyung

2014-07-01

Clear cell hidradenocarcinoma is a rare tumor of eccrine sweat gland origin that has a predilection for the head and neck. It has an indolent growth pattern and a higher incidence of regional and distant metastases. Metastasizing adnexal carcinomas are rare; thus, currently there is no uniform treatment guideline. We report a case of an 89-year-old female patient with clear cell hidradenocarcinoma manifesting in the right ear helix that metastasized to the right parotid gland who was treated by wide local excision and radiation therapy.

The Association Between PD-L1 Expression and the Clinical Outcomes to Vascular Endothelial Growth Factor-Targeted Therapy in Patients With Metastatic Clear Cell Renal Cell Carcinoma

PubMed Central

Shin, Su-Jin; Jeon, Yoon Kyung; Cho, Yong Mee; Lee, Jae-Lyun; Chung, Doo Hyun; Park, Ji Young

2015-01-01

Background. Vascular endothelial growth factor pathway (VEGF)-tyrosine kinase inhibitors (TKIs) are used as the first-line treatment for patients with metastatic clear cell renal cell carcinoma (mCCRCC). Recently, programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) blockade emerged as promising therapy for renal cell carcinoma. However, the expression pattern and prognostic implication of programmed death-ligands (PD-Ls) in mCCRCC patients receiving VEGF-TKI remain unclear. Patients and Methods. PD-L1 and PD-L2 expression in tumor cells and the quantities of PD-1+ tumor-infiltrating lymphocytes were immunohistochemically evaluated in 91 mCCRCC patients treated with VEGF-TKI, and their associations with VEGF-TKI responsiveness and clinical outcome were analyzed. Results. PD-L1 immunopositivity was observed in 17.6% and significantly associated with a high International Society of Urological Pathology grade (p = .031) and sarcomatoid features (p = .014). PD-L2 immunopositivity was observed in 39.6% and was not associated with any of the assessed clinicopathological variables. PD-L1-positive cases showed poor VEGF-TKI responsiveness (p = .012) compared with PD-L1-negative cases. In univariate survival analysis, PD-L1 immunopositivity was significantly associated with shorter overall survival (OS) (p = .037) and progression-free survival (PFS) (p = .043). Multivariate survival analysis revealed that PD-L1 expression was independently associated with poor OS (p = .038) and PFS (p = .013) in addition to tumor necrosis (p = .006; p = .029, respectively) and Memorial Sloan Kettering Cancer Center score (p = .018; p = .032, respectively). PD-L2 expression was neither associated with VEGF-TKI responsiveness nor patients’ outcome. Conclusion. PD-L1 expression was significantly related to lack of VEGF-TKI responsiveness and independently associated with shorter survival in mCCRCC patients after VEGF-TKI treatment. PD-L1 may have a predictive and prognostic value

Clear cell hidradenocarcinoma--a case report with unusual in situ malignant changes.

PubMed

Al-Irhayim, B

1984-05-01

Clear cell hidradenocarcinoma is a rare tumour, the histogenesis of which has been much debated in the past. However, it is now considered a tumour of sweat gland origin. Presented herewith is a report of a case with unusual histological features of in situ malignant changes within sweat glands. These changes very closely simulate lobular cancerisation of the breast. On reviewing the English literature on the histopathology of sweat gland tumours, we have not found similar histological findings. These histological findings provide supportive evidence of the sweat gland origin of these tumours.

Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

PubMed Central

Kawahara, Naoki; Ogawa, Kenji; Nagayasu, Mika; Kimura, Mai; Sasaki, Yoshikazu; Kobayashi, Hiroshi

2017-01-01

Inhibitors of poly(ADP-ribose) polymerase (PARP) are new types of personalized treatment of relapsed platinum-sensitive ovarian cancer harboring BRCA1/2 mutations. Ovarian clear cell cancer (CCC), a subset of ovarian cancer, often appears as low-stage disease with a higher incidence among Japanese. Advanced CCC is highly aggressive with poor patient outcome. The aim of the present study was to determine the potential synthetic lethality gene pairs for PARP inhibitions in patients with CCC through virtual and biological screenings as well as clinical studies. We conducted a literature review for putative PARP sensitivity genes that are associated with the CCC pathophysiology. Previous studies identified a variety of putative target genes from several pathways associated with DNA damage repair, chromatin remodeling complex, PI3K-AKT-mTOR signaling, Notch signaling, cell cycle checkpoint signaling, BRCA-associated complex and Fanconi's anemia susceptibility genes that could be used as biomarkers or therapeutic targets for PARP inhibition. BRCA1/2, ATM, ATR, BARD1, CCNE1, CHEK1, CKS1B, DNMT1, ERBB2, FGFR2, MRE11A, MYC, NOTCH1 and PTEN were considered as candidate genes for synthetic lethality gene partners for PARP interactions. When considering the biological background underlying PARP inhibition, we hypothesized that PARP inhibitors would be a novel synthetic lethal therapeutic approach for CCC tumors harboring homologous recombination deficiency and activating oncogene mutations. The results showed that the majority of CCC tumors appear to have indicators of DNA repair dysfunction similar to those in BRCA-mutation carriers, suggesting the possible utility of PARP inhibitors in a subset of CCC. PMID:29109859

Circulating aldosterone induces the apical accumulation of the proton pumping V-ATPase and increases proton secretion in clear cells in the caput epididymis.

PubMed

Roy, Jeremy W; Hill, Eric; Ruan, Ye Chun; Vedovelli, Luca; Păunescu, Teodor G; Brown, Dennis; Breton, Sylvie

2013-08-15

Clear cells express the vacuolar proton-pumping H(+)-ATPase (V-ATPase) and acidify the lumen of the epididymis, a process that is essential for male fertility. The renin-angiotensin-aldosterone system (RAAS) regulates fluid and electrolyte balance in the epididymis, and a previous study showed binding of aldosterone exclusively to epididymal clear cells (Hinton BT, Keefer DA. Steroid Biochem 23: 231-233, 1985). We examined here the role of aldosterone in the regulation of V-ATPase in the epididymis. RT-PCR showed expression of the mineralocorticoid receptor [MR; nuclear receptor subfamily 3, group C member 2 (NR3C2)] and 11-β-dehydrogenase isozyme 2 (HSD11β2) mRNAs specifically in clear cells, isolated by fluorescence-activated cell sorting from B1-enhanced green fluorescent protein (EGFP) mice. Tail vein injection of adult rats with aldosterone, 1,2-dioctanoyl-sn-glycerol (DOG), or 8-(4-chlorophenylthio)-cAMP (cpt-cAMP) induced V-ATPase apical membrane accumulation and extension of V-ATPase-labeled microvilli in clear cells in the caput epididymis but not in the cauda. V-ATPase activity was measured in EGFP-expressing clear cells using the intracellular pH (pHi)-sensing dye seminaphthorhodafluor-5F-5-(and 6)-carboxylic acid, acetoxymethyl ester acetate (SNARF-5F). Aldosterone induced a rapid increase in the rate of Na(+)- and bicarbonate-independent pHi recovery following an NH4Cl-induced acid load in clear cells isolated from the caput but not the cauda. This effect was abolished by concanamycin A, spironolactone, and chelerythrine but not myristoylated-protein kinase inhibitor (mPKI) or mifepristone. Thus aldosterone increases V-ATPase-dependent proton secretion in clear cells in the caput epididymis via MR/NR3C2 and PKC activation. This study, therefore, identifies aldosterone as an active member of the RAAS for the regulation of luminal acidification in the proximal epididymis.

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

PubMed Central

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

Algorithms in the First-Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma--Analysis Using Diagnostic Nodes.

PubMed

Rothermundt, Christian; Bailey, Alexandra; Cerbone, Linda; Eisen, Tim; Escudier, Bernard; Gillessen, Silke; Grünwald, Viktor; Larkin, James; McDermott, David; Oldenburg, Jan; Porta, Camillo; Rini, Brian; Schmidinger, Manuela; Sternberg, Cora; Putora, Paul M

2015-09-01

With the advent of targeted therapies, many treatment options in the first-line setting of metastatic clear cell renal cell carcinoma (mccRCC) have emerged. Guidelines and randomized trial reports usually do not elucidate the decision criteria for the different treatment options. In order to extract the decision criteria for the optimal therapy for patients, we performed an analysis of treatment algorithms from experts in the field. Treatment algorithms for the treatment of mccRCC from experts of 11 institutions were obtained, and decision trees were deduced. Treatment options were identified and a list of unified decision criteria determined. The final decision trees were analyzed with a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees. The most common treatment recommendations were determined, and areas of discordance were identified. The analysis revealed heterogeneity in most clinical scenarios. The recommendations selected for first-line treatment of mccRCC included sunitinib, pazopanib, temsirolimus, interferon-α combined with bevacizumab, high-dose interleukin-2, sorafenib, axitinib, everolimus, and best supportive care. The criteria relevant for treatment decisions were performance status, Memorial Sloan Kettering Cancer Center risk group, only or mainly lung metastases, cardiac insufficiency, hepatic insufficiency, age, and "zugzwang" (composite of multiple, related criteria). In the present study, we used diagnostic nodes to compare treatment algorithms in the first-line treatment of mccRCC. The results illustrate the heterogeneity of the decision criteria and treatment strategies for mccRCC and how available data are interpreted and implemented differently among experts. The data provided in the present report should not be considered to serve as treatment recommendations for the management of treatment-naïve patients with multiple metastases from metastatic clear cell renal cell carcinoma outside

CLEAR: Communications Link Expert Assistance Resource

NASA Technical Reports Server (NTRS)

Hull, Larry G.; Hughes, Peter M.

1987-01-01

Communications Link Expert Assistance Resource (CLEAR) is a real time, fault diagnosis expert system for the Cosmic Background Explorer (COBE) Mission Operations Room (MOR). The CLEAR expert system is an operational prototype which assists the MOR operator/analyst by isolating and diagnosing faults in the spacecraft communication link with the Tracking and Data Relay Satellite (TDRS) during periods of realtime data acquisition. The mission domain, user requirements, hardware configuration, expert system concept, tool selection, development approach, and system design were discussed. Development approach and system implementation are emphasized. Also discussed are system architecture, tool selection, operation, and future plans.

Optical clearing of the pancreas for visualization of mature β-cells and vessels in mice.

PubMed

Nishimura, Wataru; Sakaue-Sawano, Asako; Takahashi, Satoru; Miyawaki, Atsushi; Yasuda, Kazuki; Noda, Yasuko

2018-05-04

Glucose metabolism is regulated by insulin, which is produced from β-cells in the pancreas. Because insulin is secreted into vessels in response to blood glucose, vascular structures of the pancreas, especially the relationship between vessels and β-cells, are important for physiological and pathological glucose metabolism. Here, we developed a system to visualize vessels surrounding mature β-cells expressing transcription factor MafA in a three-dimensional manner. Optical clearing of the pancreas prevented light scattering of fluorescence driven by the bacterial artificial chromosome (BAC)-mafA promoter in β-cells. Reconstruction of confocal images demonstrated mature β-cells and the glomerular-like structures of β-cell vasculatures labeled with DyLight 488-conjugated lectin in normal mice as well as in low-dose streptozotocin-injected diabetes model mice with reduced β-cell mass. This technological innovation of organ imaging can be used to investigate morphological changes in vascular structures during transplantation, regeneration and diabetes development.

Two rare entities in the same palate lesion: hyalinizing-type clear cell carcinoma and necrotizing sialometaplasia.

PubMed

Arpaci, Rabia Bozdoğan; Kara, Tuba; Porgali, Canan; Serinsoz, Ebru; Polat, Ayse; Vayisoglu, Yusuf; Ozcan, Cengiz

2014-05-01

Hyalinizing clear cell carcinoma is a low-grade malignant epithelial neoplasm of the salivary glands. The tumor has epithelial cells and lacks myoepithelial cells. Necrotizing sialometaplasia is a benign, self-limiting lesion of the salivary glands. The clinical and histologic features mimic those of mucoepidermoid carcinoma or squamous cell carcinoma. The importance of these entities are the rarity of both of them and their potential to be misdiagnosed as other lesions. Pathologists and clinicians should be aware of these entities to prevent misdiagnosis. This is the first clinical report of 2 rare and consecutive different entities of the same location on the hard palate to our knowledge.

[Non-metastatic clear cell renal cancer: dependence of the tumour stage on clinico-anatomic and morphologic factors; prognostic value of macro- and karyometric characteristics].

PubMed

Iurin, A G

2010-01-01

Non-metastatic clear-cell renal cancer: dependence of the tumour stage on clinico-anatomic and morphologic factors; prognostic value of macro- and karyometric characteristics Sankt Peterburg Pathology Bureau, Sankt Peterburg It was shown based on multivariate regression analysis that pT1a3bN0MO stages of non-metastatic clear-cell renal cancer significantly correlate not only with the tumor size and invasion into the fatty tissue and/or renal vein but also with the invasion into the renal capsule and with the mean maximum diameter and mean nucleus area of tumor cells. There was no correlation of clear-cell renal cancer stages with tumor proliferative activity, gene p53 mutation, oncosuppressor gene PTEN expression, fraction of tumour clear-cell component, and such clinical characteristics as patients' sex, age, and body mass index. Taking into account statistically significant differences between the patients' survival rates, the regression equations developed in this work may be used for the prediction of disease outcome.

Percutaneous Cryoablation of Solitary, Sporadic Renal Cell Carcinoma: Outcome Analysis Based on Clear-Cell versus Papillary Subtypes.

PubMed

Haddad, Mustafa M; Schmit, Grant D; Kurup, A Nicholas; Schmitz, John J; Boorjian, Stephen A; Geske, Jennifer; Thompson, R Houston; Callstrom, Matthew R; Atwell, Thomas D

2018-06-07

To evaluate treatment outcomes with percutaneous cryoablation (PCA) based on renal cell carcinoma (RCC) histology. Patients treated with PCA for a solitary, sporadic stage T1a RCC from 2003 to 2016 were identified from a single institution's renal ablation registry. Patients with multiple tumors, history of RCC, or genetic syndromes associated with RCC (n = 60); no specific RCC subtype determined from core biopsy (n = 66); RCC subtype other than clear-cell or papillary (n = 7); or less than 3 mo of follow-up imaging (n = 5) were excluded. In total, 173 patients met study inclusion criteria. Oncologic outcomes, clinical outcomes, and complications were evaluated based on tumor subtype. Of the 173 patients who underwent PCA for a stage T1a RCC, 130 (75%) had clear-cell RCC (ccRCC) and 43 (25%) had papillary RCC (pRCC). Median tumor size was 2.9 cm (range, 1.3-4.0 cm). Technically successful cryoablation was achieved in all 173 patients. Local tumor recurrence developed in 6 patients with ccRCC (4.6%), new renal tumors developed in 1 patient (0.8%), and metastatic RCC developed in 1 patient (0.8%) who also had local tumor recurrence. No patients with pRCC showed local tumor recurrence, new renal tumors, or metastatic disease. The 5-year disease-free survival rate in patients with ccRCC was 88%, compared with 100% in patients with pRCC (P = .48). Nine patients (5.2%), all with ccRCC, experienced major complications (P = .11). Percutaneous ablation is a viable treatment option for patients with clinical stage T1a pRCC and ccRCC. Percutaneous ablation may be a very favorable treatment strategy particularly for pRCC. Copyright © 2018 SIR. Published by Elsevier Inc. All rights reserved.

Clear cell odontogenic carcinoma: report of 7 new cases and systematic review of the current knowledge.

PubMed

Loyola, Adriano Mota; Cardoso, Sergio Vitorino; de Faria, Paulo Rogério; Servato, João Paulo Silva; Barbosa de Paulo, Luiz Fernando; Eisenberg, Ana Lúcia Amaral; Dias, Fernando Luiz; Gomes, Carolina Cavalieri; Gomez, Ricardo Santiago

2015-10-01

The goal of this study is to describe 7 cases of clear cell odontogenic carcinoma among a Brazilian population and compare these data with a systematic review of the English-language literature. Descriptive statististics were used to compare the clinicopathologic data gathered retrospectively with those compiled from a review. Tumor sections were immunostained for Ki-67, p16, p53, and cytokeratins (CKs) 7, 8, 14, 18, and 19. Log-rank tests were performed for survival analysis. Most cases occurred in the posterior mandible (5/7, 71.4%), and recurrence was diagnosed in all treated patients. Metastatic disease occurred in 2 patients (28.6%). Tumors were focally positive for CKs 7, 8, 14, and 18 and diffusely positive for CK19, p53, and p16. The mean number of Ki-67-positive cells was 35.2 cells/high-power field. Our systematic review provided evidence that tumor size (P = .046), histologic pattern (P = .034), regional metastasis (P = .001), distant metastasis (P = .001), and local recurrence (P = .05) were of significant prognostic value. This study has contributed to improved characterization of clear cell odontogenic carcinoma, which is an aggressive odontogenic malignant neoplasm diagnosed mainly in the posterior mandible of middle-aged women and typically at an advanced stage. Radical surgical procedures remain the gold standard treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of perineoplasm perinephric adipose tissues on migration of clear cell renal cell carcinoma cells: a potential role of WNT signaling.

PubMed

Zi, Xiaolin; Lusch, Achim; Blair, Christopher A; Okhunov, Zhamshid; Yokoyama, Noriko N; Liu, Shuman; Baker, Molly; Huynh, Victor; Landman, Jaime

2016-08-16

To investigate the cellular and molecular interactions between clear-cell renal cell carcinoma (ccRCC) and perinephric adipose tissue (PAT), perineoplasm PAT, PAT away from the neoplasm, renal sinus and subcutaneous adipose tissues were collected at the time of renal surgery for renal masses and conditioned medium (CM) was generated from 62 patients. Perineoplasm PAT CMs from 44 out of 62 (about 71%) of patients with ccRCC or benign renal diseases (e.g. oncocytomas, angiomyolipomas, multicystic kidney, interstitial fibrosis, etc.) enhanced the migration of CaKi-2 cells. Perineoplasm PAT CMs from ccRCC significantly increased migration of ACHN and CaKi-2 cells by ~8.2 and ~2.4 folds, respectively, relative to those from benign renal diseases, whereas there is no significant difference in migration between ccRCC and benign renal diseases in CMs collected from culturing PAT away from neoplasm, renal sinus and subcutaneous adipose tissues. High Fuhrman Grade was associated with increased migration of Caki-2 cells by perineoplasm PAT CMs. Perineoplasm PATs from pT3 RCCs overexpressed multiple WNTs and their CMs exhibited higher WNT/ß-catenin activity and increased the migration of Caki-2 cells compared to CMs from benign neoplasms. Addition of secreted WNT inhibitory factor-1 recombinant protein into perineoplasm PAT CMs completely blocked the cell migration. These results indicate that WNT related factors from perineoplasm PAT may promote progression of local ccRCC to locally advanced (pT3) disease by increasing ccRCC cell mobility.

Second-line treatment for metastatic clear cell renal cell cancer: experts' consensus algorithms.

PubMed

Rothermundt, C; von Rappard, J; Eisen, T; Escudier, B; Grünwald, V; Larkin, J; McDermott, D; Oldenburg, J; Porta, C; Rini, B; Schmidinger, M; Sternberg, C N; Putora, P M

2017-04-01

Second-line systemic treatment options for metastatic clear cell renal cell cancer (mccRCC) are diverse and treatment strategies are variable among experts. Our aim was to investigate the approach for the second-line treatment after first-line therapy with a tyrosine kinase inhibitor (TKI). Recently two phase III trials have demonstrated a potential role for nivolumab (NIV) and cabozantinib (CAB) in this setting. We aimed to estimate the impact of these trials on clinical decision making. Eleven international experts were asked to provide their treatment strategies for second-line systemic therapy for mccRCC in the current setting and once NIV and CAB will be approved and available. The treatment strategies were analyzed with the objective consensus approach. The analysis of the decision trees revealed everolimus (EVE), axitinib (AXI), NIV and TKI switch (sTKI) as therapeutic options after first-line TKI therapy in the current situation and mostly NIV and CAB in the future setting. The most commonly used criteria for treatment decisions were duration of response, TKI tolerance and zugzwang a composite of several related criteria. In contrast to the first-line setting, recommendations for second-line systemic treatment of mccRCC among experts were not as heterogeneous. The agents mostly used after disease progression on a first-line TKI included: EVE, AXI, NIV and sTKI. In the future setting of NIV and CAB availability, NIV was the most commonly chosen drug, whereas several experts identified situations where CAB would be preferred.

Piwi-interacting RNAs as novel prognostic markers in clear cell renal cell carcinomas.

PubMed

Busch, Jonas; Ralla, Bernhard; Jung, Monika; Wotschofsky, Zofia; Trujillo-Arribas, Elena; Schwabe, Philipp; Kilic, Ergin; Fendler, Annika; Jung, Klaus

2015-06-14

Piwi-interacting RNAs (piRNAs) are small RNAs of 27-30 nucleotides mapping to transposons or clustering in repeat genomic regions. Preliminary studies suggest an important role in cancerogenesis. This study is the first one investigating their prognostic impact in clear cell renal cell cancer (ccRCC) patients. Three piRNAs (piR-30924, piR-57125, and piR-38756) selected on the basis of initial piRNA microarray analyses were determined using RT-qPCR in non-metastatic (n = 76) and metastatic (n = 30) ccRCC tissue at the time of nephrectomy in comparison to normal renal tissue (n = 77) and tissue from distant ccRCC metastases (n = 13). Primary clinical end points were recurrence-free and overall survival. piR-57125 showed lower expression in metastatic than in non-metastatic tumors, whereas the expression of piR-30924 and piR-38756 increased in metastatic tumors. The higher expression of piR-30924 and piR-38756 as well as the lower expression of piR-57125 in metastatic primary tumors were significantly associated with tumor recurrence and overall survival. Multivariate Cox regression analyses revealed both piR-30924 and piR-57125 as independent prognostic predictors. This impact was even more pronounced in non-metastatic patients. This study demonstrates that the expression levels of these piRNAs in primary non-metastatic and metastatic ccRCC tissue can serve as potential prognostic biomarkers in combination with clinicopathological factors.

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

PubMed

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

2016-10-25

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. 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. 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 TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). 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.

CO2 Efflux from Cleared Mangrove Peat

PubMed Central

Lovelock, Catherine E.; Ruess, Roger W.; Feller, Ilka C.

2011-01-01

Background CO2 emissions from cleared mangrove areas may be substantial, increasing the costs of continued losses of these ecosystems, particularly in mangroves that have highly organic soils. Methodology/Principal Findings We measured CO2 efflux from mangrove soils that had been cleared for up to 20 years on the islands of Twin Cays, Belize. We also disturbed these cleared peat soils to assess what disturbance of soils after clearing may have on CO2 efflux. CO2 efflux from soils declines from time of clearing from ∼10 600 tonnes km−2 year−1 in the first year to 3000 tonnes km2 year−1 after 20 years since clearing. Disturbing peat leads to short term increases in CO2 efflux (27 umol m−2 s−1), but this had returned to baseline levels within 2 days. Conclusions/Significance Deforesting mangroves that grow on peat soils results in CO2 emissions that are comparable to rates estimated for peat collapse in other tropical ecosystems. Preventing deforestation presents an opportunity for countries to benefit from carbon payments for preservation of threatened carbon stocks. PMID:21738628

Outcomes of fertility-sparing surgery among young women with FIGO stage I clear cell carcinoma of the ovary.

PubMed

Park, Jeong-Yeol; Suh, Dae-Shik; Kim, Jong-Hyeok; Kim, Yong-Man; Kim, Young-Tak; Nam, Joo-Hyun

2016-07-01

To evaluate the outcome of fertility-sparing surgery among young women with early-stage clear cell carcinoma of the ovary. In a retrospective study, data were reviewed for patients aged 45years or younger who had FIGO stage I clear cell carcinoma of the ovary and had attended one institution in South Korea between December 1999 and December 2009. Outcomes were compared between women undergoing fertility-sparing surgery, defined as preservation of the uterus and at least one adnexa, and those undergoing radical surgery. Overall, 47 patients were included (22 underwent fertility-sparing surgery, 25 radical surgery). After a median follow-up of 72months (range 8-175), 5 (23%) patients who underwent fertility-sparing surgery and 5 (20%) in the radical surgery group had recurrent disease (P=0.820). The mean time to recurrence was 19months after fertility-sparing surgery versus 20months after radical surgery (P=0.935). The anatomical location of recurrence did not differ. There was no difference in 5-year disease-free survival (77% vs 84%; P=0.849) or 5-year overall survival (91% vs 88%; P=0.480). Fertility-sparing surgery was found to be a safe alternative for young women with FIGO stage I clear cell carcinoma of the ovary who wish to preserve fertility. Copyright © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Targeted mutation analysis of endometrial clear cell carcinoma.

PubMed

Hoang, Lien N; McConechy, Melissa K; Meng, Bo; McIntyre, John B; Ewanowich, Carol; Gilks, Cyril Blake; Huntsman, David G; Köbel, Martin; Lee, Cheng-Han

2015-04-01

Endometrial clear cell carcinomas (CCC) constitute fewer than 5% of all carcinomas of the endometrium. Currently, little is known regarding the genetic basis of endometrial CCC. We performed genomic and immunohistochemical analyses on 14 rigorously reviewed pure endometrial CCC. The genomic analysis consisted of sequencing the coding regions of 26 genes implicated previously in endometrial carcinoma. Twelve of 14 tumours displayed a prototypical CCC immunophenotype [napsin A+, hepatocyte nuclear factor-1β (HNF1β(+) ) and oestrogen receptor(-) ] and all showed intact mismatch repair protein expression. We detected mutations in 11 of 14 tumours, and there was a predominance of mutations involving genes that are mutated more frequently in endometrial serous carcinomas than in endometrioid carcinomas. Two tumours displayed a prototypical serous carcinoma mutation profile (concurrent TP53 and PPP2R1A mutations, without PTEN, CTNNB1 or ARID1A mutation). No mutations in PTEN, CTNNB1 or POLE were identified. The overall mutation profile of this cohort of endometrial CCC appears to be more serous-like than endometrioid-like, with a minor subset in the TP53-mutated CCC showing serous carcinoma profile. These findings provide new insights into the molecular features of morphologically prototypical endometrial CCC, and underscore the need for further investigations into the oncogenesis of endometrial CCC. © 2014 John Wiley & Sons Ltd.

Diagnosis and treatment of clear cell hidradenocarcinoma of the scalp.

PubMed

Shu, Kai; Xiao, Qungen; Büchele, Fabian; Zhang, Suojun; Jiang, Wei; Lei, Ting

2012-12-01

Clear cell hidradenocarcinoma (CCH) is an exceedingly rare and highly malignant tumor of the eccrine sweat glands. Its treatment is extremely difficult due to the characteristically aggressive clinical course including repeated local recurrence and uncontrollable distal metastasis coming along with a very poor prognosis. Most published case studies recommend a wide surgical excision followed by adjuvant conservative therapy, which is generally considered to be the standard treatment. Two cases of nodular CCH of the scalp either presenting as a singular primary lesion or at an already metastatic stage were analyzed retrospectively. Wide local excision of the tumor couldn't prevent the primary carcinoma from recurring and metastasizing. Both cases received various therapies but the results were unsatisfactory. Although most authors have recommended that early wide surgical excision of the tumor is a feasible therapeutic measurement, our results raise doubts on the efficacy of this treatment strategy. As alternative approaches (i.e. chemotherapy, radiotherapy) are similarly controversial, further studies and a wide exchange of clinical experiences are crucial.

The Clinical Activity of PD-1/PD-L1 inhibitors in Metastatic Non-Clear Cell Renal Cell Carcinoma.

PubMed

McKay, Rana R; Bossé, Dominick; Xie, Wanling; Wankowicz, Stephanie A M; Flaifel, Abdallah; Brandao, Raphael; Lalani, Aly-Khan; Martini, Dylan J; Wei, Xiao X; Braun, David A; Van Allen, Eliezer M; Castellano, Daniel; de Velasco, Guillermo; Wells, J Connor; Heng, Daniel Y C; Fay, Andre P; Schutz, Fabio A; Hsu, JoAnn; Pal, Sumanta Kumar; Lee, Jae-Lyun; Hsieh, James; Harshman, Lauren C; Signoretti, Sabina; Motzer, Robert J; Feldman, Darren R; Choueiri, Toni K

2018-05-10

Programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors have shown activity in metastatic clear cell renal cell carcinoma (ccRCC). Data on the activity of these agents in patients with non-clear cell RCC (nccRCC) or patients with sarcomatoid/rhabdoid differentiation is limited. In this multicenter analysis, we explored the efficacy of PD-1/PD-L1 inhibitors in patients with nccRCC or sarcomatoid/rhabdoid differentiation. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate. Secondary endpoints include time-to-treatment failure (TTF), overall survival (OS), and biomarker correlates. Forty-three patients were included: papillary (n = 14; 33%), chromophobe (n = 10; 23%), unclassified (n = 9; 21%), translocation (n = 3; 7%), and ccRCC with sarcomatoid differentiation (n = 7, 16%). Of those 43 patients, 11 patients (26%) had sarcomatoid and/or rhabdoid differentiation (n = 7 with ccRCC; n = 4 nccRCC). Overall, eight patients (19%) objectively responded, including four patients (13%) who received PD-1/PD-L1 monotherapy. Responses were observed in patients with ccRCC with sarcomatoid and/or rhabdoid differentiation (n = 3/7, 43%), translocation RCC (n = 1/3, 33%), and papillary RCC (n = 4/14, 29%). The median TTF was 4.0 months (95% confidence interval (CI) 2.8, 5.5) and median OS was 12.9 months (95% CI 7.4, not reached). No specific genomic alteration was associated with clinical benefit. Modest antitumor activity for PD-1/PD-L1 blocking agents was observed in some patients with nccRCC. Further prospective studies are warranted to investigate the efficacy of PD-1/PD-L1 blockade in this heterogeneous patient population. Copyright ©2018, American Association for Cancer Research.

Tyrosine Kinase Signaling in Clear Cell and Papillary Renal Cell Carcinoma Revealed by Mass Spectrometry-Based Phosphotyrosine Proteomics

PubMed Central

Haake, Scott M.; Li, Jiannong; Bai, Yun; Kinose, Fumi; Fang, Bin; Welsh, Eric; Zent, Roy; Dhillon, Jasreman; Pow-Sang, Julio; Chen, Yian Ann; Koomen, John; Rathmell, W. Kimryn; Fishman, Mayer; Haura, Eric B.

2016-01-01

Purpose Targeted therapies in renal cell carcinoma (RCC) are limited by acquired resistance. Novel therapeutic targets are needed to combat resistance and, ideally, target the unique biology of RCC subtypes. Experimental Design Tyrosine kinases provide critical oncogenic signaling and their inhibition has significantly impacted cancer care. In order to describe a landscape of tyrosine kinase activity in RCC that could inform novel therapeutic strategies, we performed a mass spectrometry-based system-wide survey of tyrosine phosphorylation in 10 RCC cell lines as well as 15 clear cell and 15 papillary RCC human tumors. To prioritize identified tyrosine kinases for further analysis, a 63 tyrosine kinase inhibitor (TKI) drug screen was performed. Results Among the cell lines, 28 unique tyrosine phosphosites were identified across 19 kinases and phosphatases including EGFR, MET, JAK2, and FAK in nearly all samples. Multiple FAK TKIs decreased cell viability by at least 50% and inhibited RCC cell line adhesion, invasion, and proliferation. Among the tumors, 49 unique tyrosine phosphosites were identified across 44 kinases and phosphatases. FAK pY576/7 was found in all tumors and many cell lines, while DDR1 pY792/6 was preferentially enriched in the papillary RCC tumors. Both tyrosine kinases are capable of transmitting signals from the extracellular matrix and emerged as novel RCC therapeutic targets. Conclusions Tyrosine kinase profiling informs novel therapeutic strategies in RCC and highlights the unique biology amongst kidney cancer subtypes. PMID:27220961

The Analysis of Cell Cycle-related Proteins in Ovarian Clear Cell Carcinoma Versus High-grade Serous Carcinoma.

PubMed

Hazama, Yukiko; Moriya, Takuya; Sugihara, Mika; Sano, Rikiya; Shiota, Mitsuru; Nakamura, Takafumi; Shimoya, Koichiro

2017-10-10

In Japan, the frequency of ovarian clear cell carcinoma (CCC) is twice as high as that in the United States and Europe. Often, patient prognosis of CCC is poor because of chemoresistance. Here, we focus on the cell cycle, which is one of the mechanisms of chemoresistance. To detect the informative markers and improve the strategy of chemotherapy for CCC, we performed immunochemical staining of cell cycle-related proteins in ovarian malignant tumors. We detected that each of the 29 samples of CCC and high-grade serous carcinoma (HGSC) were necessary to reveal the significant differences in immunostaining and prognosis. We performed the immunostaining analysis using the antibodies of cell cycle-related proteins such as Ki-67, Cdt1, MCM7, and geminin. The positive rate of Cdt1 in the CCC group was significantly higher than that in the HGSC group (P<0.0001). However, the positive rate of geminin in the HGSC group was significantly higher than that in the CCC group (P<0.0001). The overall survival of CCC patients with high labeling index of Cdt1 was significantly worse than that of CCC patients with low labeling index of Cdt1 (P=0.004). The study results suggested that the cancer cells of CCC and HGSC exist in the G1 phase and S, G2, and M phases, respectively. The differences in cell cycle of CCC might be one of the reasons for chemotherapy resistance. Further investigations are necessary to reveal the usefulness of Cdt1 as a biomarker in CCC.

Evaluation of programmed cell death protein 1 (PD-1) expression as a prognostic biomarker in patients with clear cell renal cell carcinoma.

PubMed

Kim, Kyu Seo; Sekar, Rishi R; Patil, Dattatraya; Dimarco, Michelle A; Kissick, Haydn T; Bilen, Mehmet A; Osunkoya, Adeboye O; Master, Viraj A

2018-01-01

Programmed cell death protein 1 (PD-1) immune checkpoint inhibitors have shown activity in patients with advanced renal cell carcinoma (RCC). However, the role of PD-1 expression in tumor-infiltrating lymphocytes (TILs) as a biomarker for poor outcome is not clear. In this study, we evaluated the prognostic value of TIL PD-1 expression in patients with clear cell RCC (ccRCC). 82 patients who underwent nephrectomy for localized or metastatic ccRCC and followed up for at least four years were searched from our database and retrospectively enrolled. Their fixed primary tumor specimens were stained with anti-PD-1 (NAT105). The specimens were classified as negative or positive for PD-1 expression, and the positive specimens were further scored in 10% increments. 37 (45.12%) patients were negative (<1% stained), 26 (31.71%) patients were low (<10 and 10%), and 19 (23.17%) patients were high (20-50%) for PD-1 expression. The prognostic value of TIL PD-1 expression was evaluated by univariate Cox proportional hazards regression on overall and recurrence-free survivals. Higher TIL PD-1 expression was not associated with increased risk of death (P = 0.336) or with increased risk of recurrence (P = 0.572). Higher primary tumor stage was associated with increased risk of recurrence (P = 0.003), and higher Fuhrman nuclear grade was associated with increased risk of death (P <0.001) and with increased risk of recurrence (P <0.001). Our study shows that TIL PD-1 expression by immunohistochemistry (IHC) does not correlate with poor clinical outcome in patients with ccRCC and is inferior to established prognosticating tools.

Boron neutron capture therapy as new treatment for clear cell sarcoma: trial on different animal model.

PubMed

Andoh, Tooru; Fujimoto, Takuya; Sudo, Tamotsu; Suzuki, Minoru; Sakurai, Yoshinori; Sakuma, Toshiko; Moritake, Hiroshi; Sugimoto, Tohru; Takeuchi, Tamotsu; Sonobe, Hiroshi; Epstein, Alan L; Fukumori, Yoshinobu; Ono, Koji; Ichikawa, Hideki

2014-06-01

Clear cell sarcoma (CCS) is a rare malignant tumor with a poor prognosis. In our previous study, the tumor disappeared under boron neutron capture therapy (BNCT) on subcutaneously-transplanted CCS-bearing animals. In the present study, the tumor disappeared under this therapy on model mice intramuscularly implanted with three different human CCS cells. BNCT led to the suppression of tumor-growth in each of the different model mice, suggesting its potentiality as an alternative to, or integrative option for, the treatment of CCS. Copyright © 2013 Elsevier Ltd. All rights reserved.

Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background

PubMed Central

Cook, Matthew S.; Munger, Steven C.; Nadeau, Joseph H.; Capel, Blanche

2011-01-01

Human germ cell tumors show a strong sensitivity to genetic background similar to Dnd1Ter/Ter mutant mice, where testicular teratomas arise only on the 129/SvJ genetic background. The introduction of the Bax mutation onto mixed background Dnd1Ter/Ter mutants, where teratomas do not typically develop, resulted in a high incidence of teratomas. However, when Dnd1Ter/Ter; Bax–/– double mutants were backcrossed to C57BL/6J, no tumors arose. Dnd1Ter/Ter germ cells show a strong downregulation of male differentiation genes including Nanos2. In susceptible strains, where teratomas initiate around E15.5-E17.5, many mutant germ cells fail to enter mitotic arrest in G0 and do not downregulate the pluripotency markers NANOG, SOX2 and OCT4. We show that DND1 directly binds a group of transcripts that encode negative regulators of the cell cycle, including p27Kip1 and p21Cip1. P27Kip1 and P21Cip1 protein are both significantly decreased in Dnd1Ter/Ter germ cells on all strain backgrounds tested, strongly suggesting that DND1 regulates mitotic arrest in male germ cells through translational regulation of cell cycle genes. Nonetheless, in C57BL/6J mutants, germ cells arrest prior to M-phase of the cell cycle and downregulate NANOG, SOX2 and OCT4. Consistent with their ability to rescue cell cycle arrest, C57BL/6J germ cells overexpress negative regulators of the cell cycle relative to 129/SvJ. This work suggests that reprogramming of pluripotency in germ cells and prevention of tumor formation requires cell cycle arrest, and that differences in the balance of cell cycle regulators between 129/SvJ and C57BL/6 might underlie differences in tumor susceptibility. PMID:21115610

The two glycolytic markers GLUT1 and MCT1 correlate with tumor grade and survival in clear-cell renal cell carcinoma

PubMed Central

Dadone, Bérengère; Durand, Matthieu; Borchiellini, Delphine; Amiel, Jean; Pouyssegur, Jacques; Rioux-Leclercq, Nathalie; Pages, Gilles; Burel-Vandenbos, Fanny; Mazure, Nathalie M.

2018-01-01

Background Clear-cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Although ccRCC is characterized by common recurrent genetic abnormalities, including inactivation of the von Hippel-Lindau (vhl) tumor suppressor gene resulting in stabilization of hypoxia-inducible factors (HIFs), the tumor aggressiveness and outcome of ccRCC is variable. New biomarkers are thus required to improve ccRCC diagnosis, prognosis and therapeutic options. This work aims to investigate the expression of HIF and proteins involved in metabolism and pH regulation. Their correlation to histoprognostic parameters and survival was analyzed. Methods ccRCC of 45 patients were analyzed. HIF-1α, HIF-2α, HAF, GLUT1, MCT1, MCT4, CAIX and CAXII expression was assessed by immunohistochemistry in a semi-quantitative and qualitative manner. The GLUT1, MCT1, MCT4, CAIX and CAXII mRNA levels were analyzed in an independent cohort of 43 patients. Results A significant correlation was observed between increased GLUT1, MCT1, CAXII protein expression and a high Fuhrman grade in ccRCC patients. Moreover, while HIF-1α, HIF-2α and HAF expression was heterogenous within tumors, we observed and confirmed that HIF-2α co-localized with HAF. We confirmed, in an independent cohort, that GLUT1, MCT1 and CAXII mRNA levels correlated with the Fuhrman grade. Moreover, we demonstrated that the high mRNA level of both MCT1 and GLUT1 correlated with poor prognosis. Conclusions This study demonstrates for the first time a link between the aggressiveness of high- Fuhrman grade ccRCC and metabolic reprogramming. It also confirms the role of HIF-2α and HAF in tumor invasiveness. Finally, these results demonstrate that MCT1 and GLUT1 are strong prognostic markers and promising therapeutic targets. PMID:29481555

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

PubMed Central

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

2016-01-01

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. PMID:26068241

Global isoform-specific transcript alterations and deregulated networks in clear cell renal cell carcinoma

PubMed Central

Hamilton, Michael J.; Girke, Thomas; Martinez, Ernest

2018-01-01

Extensive genome-wide analyses of deregulated gene expression have now been performed for many types of cancer. However, most studies have focused on deregulation at the gene-level, which may overlook the alterations of specific transcripts for a given gene. Clear cell renal cell carcinoma (ccRCC) is one of the best-characterized and most pervasive renal cancers, and ccRCCs are well-documented to have aberrant RNA processing. In the present study, we examine the extent of aberrant isoform-specific RNA expression by reporting a comprehensive transcript-level analysis, using the new kallisto-sleuth-RATs pipeline, investigating coding and non-coding differential transcript expression in ccRCC. We analyzed 50 ccRCC tumors and their matched normal samples from The Cancer Genome Altas datasets. We identified 7,339 differentially expressed transcripts and 94 genes exhibiting differential transcript isoform usage in ccRCC. Additionally, transcript-level coexpression network analyses identified vasculature development and the tricarboxylic acid cycle as the most significantly deregulated networks correlating with ccRCC progression. These analyses uncovered several uncharacterized transcripts, including lncRNAs FGD5-AS1 and AL035661.1, as potential regulators of the tricarboxylic acid cycle associated with ccRCC progression. As ccRCC still presents treatment challenges, our results provide a new resource of potential therapeutics targets and highlight the importance of exploring alternative methodologies in transcriptome-wide studies.

Renal Cell Carcinoma, Unclassified with Medullary Phenotype and Synchronous Renal Clear Cell Carcinoma Present in a Patient with No Sickle Cell Trait/Disease: Diagnostic and Therapeutic Challenges.

PubMed

Lai, Jenny Z; Lai, H Henry; Cao, Dengfeng

2018-06-01

Renal medullary carcinoma (RMC) is an aggressive high-grade renal cell carcinoma (RCC) associated almost exclusively with sickle cell trait or sickle cell disease. However, RCC with RMC features has rarely been reported in patients with no sickle cell trait or disease. Renal cell carcinoma unclassified with medullary phenotype (RCCU-MP) is a newly-coined term used by an international panel of experts to describe renal cell carcinoma showing morphologic and immunohistochemical features of renal medullary carcinoma in patients without sickle cell trait/disease. So far, only one study in the English literature has described five such cases. Here, we report a case with unique clinical and pathological features in a 76-year-old male patient without sickle cell trait. The patient had a history of colon cancer with liver and lung metastases and was found to have a new renal mass in his right kidney during the follow up. A right nephrectomy was performed and showed two separate masses (tumor 1 and tumor 2). Tumor 1 had histologic features of RMC and the tumor cells were positive for CK7, Pax8, and OCT4 and showed loss of nuclear INI1 expression. Tumor 1 was diagnosed as RCCU-MP (6.3 cm, pT3aNx, WHO/ISUP nuclear grade 3). Tumor 2 showed features of clear cell type of RCC (0.6 cm, pT1aNx, WHO/ISUP grade 2) with intact nuclear INI1 expression. Three-months post-nephrectomy, the patient developed lung metastasis of RCCU-MP. To the best of our knowledge, this was the first documented case with synchronous RCCU-MP and clear cell RCC presenting in a patient without sickle cell trait. Careful histologic assessment with a panel of immunohistochemical biomarkers was helpful to render a correct diagnosis for early aggressive treatment. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Genetic backgrounds and redox conditions influence morphological characteristics and cell differentiation of osteoclasts in mice.

PubMed

Narahara, Shun; Matsushima, Haruna; Sakai, Eiko; Fukuma, Yutaka; Nishishita, Kazuhisa; Okamoto, Kuniaki; Tsukuba, Takayuki

2012-04-01

Osteoclasts (OCLs) are multinucleated giant cells and are formed by the fusion of mononuclear progenitors of monocyte/macrophage lineage. It is known that macrophages derived from different genetic backgrounds exhibit quite distinct characteristics of immune responses. However, it is unknown whether OCLs from different genetic backgrounds show distinct characteristics. In this study, we showed that bone-marrow macrophages (BMMs) derived from C57BL/6, BALB/c and ddY mice exhibited considerably distinct morphological characteristics and cell differentiation into OCLs. The differentiation of BMMs into OCLs was comparatively quicker in the C57BL/6 and ddY mice, while that of BALB/c mice was rather slow. Morphologically, ddY OCLs showed a giant cell with a round shape, C57BL/6 OCLs were of a moderate size with many protrusions and BALB/c OCLs had the smallest size with fewer nuclei. The intracellular signaling of differentiation and expression levels of marker proteins of OCLs were different in the respective strains. Treatment of BMMs from the three different strains with the reducing agent N-acetylcysteine (NAC) or with the oxidation agent hydrogen peroxide (H(2)O(2)) induced changes in the shape and sizes of the cells and caused distinct patterns of cell differentiation and survival. Thus, genetic backgrounds and redox conditions regulate the morphological characteristics and cell differentiation of OCLs.

TCF21 hypermethylation in genetically quiescent clear cell sarcoma of the kidney | Office of Cancer Genomics

Cancer.gov

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 segmental chromosomal copy number changes or somatic variants (single nucleotide or small insertion/deletion) were identified.

VX680/MK-0457, a potent and selective Aurora kinase inhibitor, targets both tumor and endothelial cells in clear cell renal cell carcinoma

PubMed Central

Li, Yan; Zhang, Zhong-Fa; Chen, Jindong; Huang, Dan; Ding, Yan; Tan, Min-Han; Qian, Chao-Nan; Resau, James H; Kim, Hyung; Teh, Bin Tean

2010-01-01

Aurora kinases are key regulators of cell mitosis and have been implicated in the process of tumorigenesis. In recent years, the Aurora kinases have attracted much interest as promising targets for cancer treatment. Here we report on the roles of Aurora A and Aurora B kinases in clear cell renal cell carcinoma (ccRCC). Using genomewide expression array analysis of 174 patient samples of ccRCC, we found that expression levels of Aurora A and B were significantly elevated in ccRCC compared to normal kidney samples. High expression levels of Aurora A and Aurora B were significantly associated with advanced tumor stage and poor patient survival. Inhibition of Aurora kinase activity with the drug VX680 (also referred to as MK-0457) inhibited ccRCC cell growth in vitro and led to ccRCC cell accumulation in the G2/M phase and apoptosis. Growth of ccRCC xenograft tumors was also inhibited by VX680 treatment, accompanied by a reduction of tumor microvessel density. Analysis of endothelial cell lines demonstrated that VX680 inhibits endothelial cell growth with effects similar to that seen in ccRCC cells. Our findings suggest that VX680 inhibits the growth of ccRCC tumors by targeting the proliferation of both ccRCC tumor cells and tumor-associated endothelial cells. Aurora kinases and their downstream cell cycle proteins have an important role in ccRCC and may be potent prognostic markers and therapy targets for this disease. PMID:20589168

Clear cell sarcoma: the Roswell Park experience.

PubMed

Finley, J W; Hanypsiak, B; McGrath, B; Kraybill, W; Gibbs, J F

2001-05-01

Clear cell sarcoma of the tendons and aponeuroses (CCSTA) is an aggressive, rare soft-tissue tumor with approximately 300 reported cases. Although it appears to be histogenetically related to melanoma, its clinical behavior resembles soft tissue sarcoma with a propensity for lymph node metastases. We report our experience at a tertiary cancer center. Eight cases of CCSTA evaluated at Roswell Park Cancer Institute between 1970 and 1998 were reviewed retrospectively. Patient data analyzed included patient age, gender, anatomic location, size of tumor, development of local, regional and distant recurrence, and patient status at last follow up. Six of eight patients were alive at 2 years, while three of seven patients were alive at 5 years. Of the patients alive with no evidence of recurrence, two had tumors of less than 2 cm, and the remaining patient had incomplete information regarding tumor size. Five patients recurred within 2 years of definitive surgical management. Four had tumors > 5 cm. All five patients progressed to metastatic disease at a median follow up of 20 months (range 1-108 months) following definitive surgical management and all eventually died of their disease at a median of 3 months (range 0-24 months) from presentation with metastatic disease. Four of five patients with lesions > 5 cm received adjuvant chemotherapy with intent to cure, but all eventually died of disease at 4, 22, 34, and 41 months from initial presentation. CCSTA is an aggressive tumor of the soft tissues. Early recognition and management are associated with an excellent long-term prognosis. Tumors greater than 5 cm warrant aggressive surgical management and treatment, and are at high risk of the development of distant disease. Aggressive multiagent chemotherapy appeared to have no impact on outcome. Other adjuvant therapeutic options including immunotherapy should be investigated. Copyright 2001 Wiley-Liss, Inc.

Forkhead-box series expression network is associated with outcome of clear-cell renal cell carcinoma.

PubMed

Jia, Zhongwei; Wan, Fangning; Zhu, Yao; Shi, Guohai; Zhang, Hailiang; Dai, Bo; Ye, Dingwei

2018-06-01

Previous studies have demonstrated that several members of the Forkhead-box (FOX) family of genes are associated with tumor progression and metastasis. The objective of the current study was to screen candidate FOX family genes identified from analysis of molecular networks in clear cell renal cell carcinoma (ccRCC). The expression of FOX family genes as well as FOX family-associated genes was examined, and Kaplan-Meier survival analysis was performed in The Cancer Genome Atlas (TCGA) cohort (n=525). Patient characteristics, including sex, age, tumor diameter, laterality, tumor-node-metastasis, tumor grade, stage, white blood cell count, platelet count, the levels of hemoglobin, overall survival (OS) and disease-free survival (DFS), were collected for univariate and multivariate Cox proportional hazards ratio analyses. A total of seven candidate FOX family genes were selected from the TCGA database subsequent to univariate and multivariate Cox proportional hazards ratio analyses. FOXA1, FOXA2, FOXD1, FOXD4L2, FOXK2 and FOXL1 were associated with poor OS time, while FOXA1, FOXA2, FOXD1 and FOXK2 were associated with poor DFS time (P<0.05). FOXN2 was associated with favorable outcomes for overall and disease-free survival (P<0.05). In the gene cluster network analysis, the expression of FOX family-associated genes, including nuclear receptor coactivator ( NCOA ) 1 , NADH-ubiquinone oxidoreductase flavoprotein 3 ( NDUFV3 ), phosphatidylserine decarboxylase ( PISD ) and pyruvate kinase liver and red blood cell ( PKLR ), were independent prognostic factors for OS in patients with ccRCC. Results of the present study revealed that the expression of FOX family genes, including FOXA1, FOXA2, FOXD1, FOXD4L2, FOXK2 and FOXL1 , and FOX family-associated genes, including NCOA1, NDUFV3, PISD and PKLR , are independent prognostic factors for patients with ccRCC.

Tyrosine Kinase Signaling in Clear Cell and Papillary Renal Cell Carcinoma Revealed by Mass Spectrometry-Based Phosphotyrosine Proteomics.

PubMed

Haake, Scott M; Li, Jiannong; Bai, Yun; Kinose, Fumi; Fang, Bin; Welsh, Eric A; Zent, Roy; Dhillon, Jasreman; Pow-Sang, Julio M; Chen, Y Ann; Koomen, John M; Rathmell, W Kimryn; Fishman, Mayer; Haura, Eric B

2016-11-15

Targeted therapies in renal cell carcinoma (RCC) are limited by acquired resistance. Novel therapeutic targets are needed to combat resistance and, ideally, target the unique biology of RCC subtypes. Tyrosine kinases provide critical oncogenic signaling and their inhibition has significantly impacted cancer care. To describe a landscape of tyrosine kinase activity in RCC that could inform novel therapeutic strategies, we performed a mass spectrometry-based system-wide survey of tyrosine phosphorylation in 10 RCC cell lines as well as 15 clear cell and 15 papillary RCC human tumors. To prioritize identified tyrosine kinases for further analysis, a 63 tyrosine kinase inhibitor (TKI) drug screen was performed. Among the cell lines, 28 unique tyrosine phosphosites were identified across 19 kinases and phosphatases including EGFR, MET, JAK2, and FAK in nearly all samples. Multiple FAK TKIs decreased cell viability by at least 50% and inhibited RCC cell line adhesion, invasion, and proliferation. Among the tumors, 49 unique tyrosine phosphosites were identified across 44 kinases and phosphatases. FAK pY576/7 was found in all tumors and many cell lines, whereas DDR1 pY792/6 was preferentially enriched in the papillary RCC tumors. Both tyrosine kinases are capable of transmitting signals from the extracellular matrix and emerged as novel RCC therapeutic targets. Tyrosine kinase profiling informs novel therapeutic strategies in RCC and highlights the unique biology among kidney cancer subtypes. Clin Cancer Res; 22(22); 5605-16. ©2016 AACR. ©2016 American Association for Cancer Research.

A CpG-methylation-based assay to predict survival in clear cell renal cell carcinoma

PubMed Central

Wei, Jin-Huan; Haddad, Ahmed; Wu, Kai-Jie; Zhao, Hong-Wei; Kapur, Payal; Zhang, Zhi-Ling; Zhao, Liang-Yun; Chen, Zhen-Hua; Zhou, Yun-Yun; Zhou, Jian-Cheng; Wang, Bin; Yu, Yan-Hong; Cai, Mu-Yan; Xie, Dan; Liao, Bing; Li, Cai-Xia; Li, Pei-Xing; Wang, Zong-Ren; Zhou, Fang-Jian; Shi, Lei; Liu, Qing-Zuo; Gao, Zhen-Li; He, Da-Lin; Chen, Wei; Hsieh, Jer-Tsong; Li, Quan-Zhen; Margulis, Vitaly; Luo, Jun-Hang

2015-01-01

Clear cell renal cell carcinomas (ccRCCs) display divergent clinical behaviours. Molecular markers might improve risk stratification of ccRCC. Here we use, based on genome-wide CpG methylation profiling, a LASSO model to develop a five-CpG-based assay for ccRCC prognosis that can be used with formalin-fixed paraffin-embedded specimens. The five-CpG-based classifier was validated in three independent sets from China, United States and the Cancer Genome Atlas data set. The classifier predicts the overall survival of ccRCC patients (hazard ratio=2.96−4.82; P=3.9 × 10−6−2.2 × 10−9), independent of standard clinical prognostic factors. The five-CpG-based classifier successfully categorizes patients into high-risk and low-risk groups, with significant differences of clinical outcome in respective clinical stages and individual ‘stage, size, grade and necrosis' scores. Moreover, methylation at the five CpGs correlates with expression of five genes: PITX1, FOXE3, TWF2, EHBP1L1 and RIN1. Our five-CpG-based classifier is a practical and reliable prognostic tool for ccRCC that can add prognostic value to the staging system. PMID:26515236

Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas.

PubMed

Arai, Eri; Gotoh, Masahiro; Tian, Ying; Sakamoto, Hiromi; Ono, Masaya; Matsuda, Akio; Takahashi, Yoriko; Miyata, Sayaka; Totsuka, Hirohiko; Chiku, Suenori; Komiyama, Motokiyo; Fujimoto, Hiroyuki; Matsumoto, Kenji; Yamada, Tesshi; Yoshida, Teruhiko; Kanai, Yae

2015-12-01

CpG-island methylator phenotype (CIMP)-positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP-positive renal carcinogenesis. Genome (whole-exome and copy number), transcriptome and proteome (two-dimensional image converted analysis of liquid chromatography-mass spectrometry) analyses were performed using tissue specimens of 87 CIMP-negative and 14 CIMP-positive clear cell RCCs and corresponding specimens of non-cancerous renal cortex. Genes encoding microtubule-associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non-synonymous single-nucleotide mutations and insertions/deletions) in CIMP-positive RCCs, whereas CIMP-negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP-positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the "The metaphase checkpoint (p = 1.427 × 10(-6))," "Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 × 10(-6))" and "Spindle assembly and chromosome separation (p = 9.260 × 10(-6))" pathways. Quantitative RT-PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP-positive than in CIMP-negative RCCs. All CIMP-positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP-positive renal carcinogenesis, and that AURKA and AURKB may be potential therapeutic targets in more aggressive CIMP-positive RCCs. �

Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas

PubMed Central

Arai, Eri; Gotoh, Masahiro; Tian, Ying; Sakamoto, Hiromi; Ono, Masaya; Matsuda, Akio; Takahashi, Yoriko; Miyata, Sayaka; Totsuka, Hirohiko; Chiku, Suenori; Komiyama, Motokiyo; Fujimoto, Hiroyuki; Matsumoto, Kenji; Yamada, Tesshi; Yoshida, Teruhiko

2015-01-01

CpG‐island methylator phenotype (CIMP)‐positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP‐positive renal carcinogenesis. Genome (whole‐exome and copy number), transcriptome and proteome (two‐dimensional image converted analysis of liquid chromatography‐mass spectrometry) analyses were performed using tissue specimens of 87 CIMP‐negative and 14 CIMP‐positive clear cell RCCs and corresponding specimens of non‐cancerous renal cortex. Genes encoding microtubule‐associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non‐synonymous single‐nucleotide mutations and insertions/deletions) in CIMP‐positive RCCs, whereas CIMP‐negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP‐positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the “The metaphase checkpoint (p = 1.427 × 10−6),” “Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 × 10−6)” and “Spindle assembly and chromosome separation (p = 9.260 × 10−6)” pathways. Quantitative RT‐PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP‐positive than in CIMP‐negative RCCs. All CIMP‐positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP‐positive renal carcinogenesis, and that AURKA and AURKB may be potential

SAP modulates B cell functions in a genetic background-dependent manner.

PubMed

Detre, Cynthia; Yigit, Burcu; Keszei, Marton; Castro, Wilson; Magelky, Erica M; Terhorst, Cox

2013-06-01

Mutations affecting the SLAM-associated protein (SAP) are responsible for the X-linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and dysgammaglobulinemia. It is well accepted that insufficient help by SAP-/- CD4+ T cells, in particular during the germinal center reaction, is a component of dysgammaglobulinemia in XLP patients and SAP-/- animals. It is however not well understood whether in XLP patients and SAP-/- mice B cell functions are affected, even though B cells themselves do not express SAP. Here we report that B cell intrinsic responses to haptenated protein antigens are impaired in SAP-/- mice and in Rag-/- mice into which B cells derived from SAP-/- mice together with wt CD4+ T cells had been transferred. This impaired B cells functions are in part depending on the genetic background of the SAP-/- mouse, which affects B cell homeostasis. Surprisingly, stimulation with an agonistic anti-CD40 causes strong in vivo and in vitro B cell responses in SAP-/- mice. Taken together, the data demonstrate that genetic factors play an important role in the SAP-related B cell functions. The finding that anti-CD40 can in part restore impaired B cell responses in SAP-/- mice, suggests potentially novel therapeutic interventions in subsets of XLP patients. Copyright © 2013 Elsevier B.V. All rights reserved.

77 FR 37803 - Customer Clearing Documentation, Timing of Acceptance for Clearing, and Clearing Member Risk...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-25

... COMMODITY FUTURES TRADING COMMISSION 17 CFR Part 38 RIN 3038-0092, -0094 Customer Clearing Documentation, Timing of Acceptance for Clearing, and Clearing Member Risk Management; Core Principles and Other... for Clearing, and Clearing Member Risk Management, and Core Principles and Other Requirements for...

Delta-like ligand 4: A predictor of poor prognosis in clear cell renal cell carcinoma

PubMed Central

WANG, WEI; YU, YI; WANG, YA; LI, XIAOMING; BAO, JUNSHENG; WU, GONGJIN; CHANG, HONG; SHI, TINGKAI; YUE, ZHONGJIN

2014-01-01

Delta-like ligand 4 (Dll4)-Notch signaling is important in tumor angiogenesis; however, the prognostic value of D114 detection in patients with clear cell renal cell carcinoma (CCRCC) remains unclear. The present study aimed to determine whether the presence of high Dll4 expression levels was correlated with poor prognosis in CCRCC following curative resection. The D114 expression levels in four paired samples of CCRCC tissues and adjacent normal renal tissues were assayed by western blotting. Surgical specimens comprised 121 CCRCC tissue samples and 65 normal renal tissue samples, obtained from patients with CCRCC. The specimens were immunohistochemically assessed to determine Dll4 and vascular endothelial growth factor receptor 2 (VEGFR-2) expression levels. The prognostic significance of Dll4 expression levels was evaluated by the Kaplan-Meier method and Cox regression analysis. The correlation between Dll4 expression levels and VEGFR-2 expression levels, tumor stage, tumor grade and metastasis, was examined by χ2 test and multivariate logistic regression. As determined by the western blotting results, Dll4 protein expression levels were significantly increased in CCRCC tissues compared with those in adjacent non-cancerous tissues. From the analysis of the surgical specimens, 53 (43.8%) CCRCC patients exhibited immunohistochemically high Dll4 expression levels and 68 (56.2%) patients exhibited low Dll4 expression levels. The survival curves revealed that the patients with high Dll4 expression levels had significantly shorter survival times than the patients with low Dll4 expression levels (P<0.001). Multivariate survival analysis demonstrated that the presence of high Dll4 expression levels was independently associated with reduced overall survival and progression-free survival times (P=0.021 and 0.034, respectively). A positive correlation was also identified between Dll4 and VEGFR-2 expression levels (P=0.001). In conclusion, the results show that the

Altered levels of acid, basic, and neutral peptidase activity and expression in human clear cell renal cell carcinoma.

PubMed

Varona, Adolfo; Blanco, Lorena; López, José I; Gil, Javier; Agirregoitia, Ekaitz; Irazusta, Jon; Larrinaga, Gorka

2007-02-01

Peptides play important roles in cell regulation and signaling in many tissues and are regulated by peptidases, most of which are highly expressed in the kidney. Several peptide convertases have a function in different tumor stages, and some have been clearly characterized as diagnostic and prognostic markers for solid tumors, including renal cancer; however, little is known about their in vivo role in kidney tumors. The present study compares the activity of a range of peptidases in human tumor samples and nontumor tissue obtained from clear cell renal cell carcinoma (CCRCC) patients. To cover the complete spectrum and subcellular distribution of peptide-converting activity, acid, neutral, basic, and omega activities were selected. CCRCC displays a selective and restricted pattern of peptidase activities. Puromycin-sensitive aminopeptidase activity in the tumor increases [tumor (t) = 10,775 vs. nontumor (n) = 7,635 units of peptidase (UP)/mg protein; P < 0.05], whereas aminopeptidase N decreases (t = 6,664 vs. n = 33,381 UP/mg protein; P < 0.001). Aminopeptidase B activity of the particulate fraction in tumors decreases (t = 2,399 vs. n = 13,536 UP/mg protein; P < 0.001) compared with nontumor tissues, and aspartyl-aminopeptidase activity decreases significantly in CCRCC (t = 137 vs. n = 223 UP/mg protein; P < 0.05). Soluble and particulate pyroglutamyl peptidase I activities, aminopeptidase A activity, and soluble aminopeptidase B activity do not vary in renal cancer. The relative expression for the aforementioned peptidases, assayed using quantitative RT-PCR, increases in CCRCC for aminopeptidases B (1.5-fold) and A (19-fold), aspartyl-aminopeptidase (3.9-fold), puromycin-sensitive aminopeptidase (2.5-fold), and pyroglutamyl peptidase I (7.6-fold). Only aminopeptidase N expression decreases in tumors (1.3-fold). This peptidase activity profile in the neoplastic kidney suggests a specific role for the studied convertases and the possible involvement of an

Fluorescence lifetime correlation spectroscopy for precise concentration detection in vivo by background subtraction

NASA Astrophysics Data System (ADS)

Gärtner, Maria; Mütze, Jörg; Ohrt, Thomas; Schwille, Petra

2009-07-01

In vivo studies of single molecule dynamics by means of Fluorescence correlation spectroscopy can suffer from high background. Fluorescence lifetime correlation spectroscopy provides a tool to distinguish between signal and unwanted contributions via lifetime separation. By studying the motion of the RNA-induced silencing complex (RISC) within two compartments of a human cell, the nucleus and the cytoplasm, we observed clear differences in concentration as well as mobility of the protein complex between those two locations. Especially in the nucleus, where the fluorescence signal is very weak, a correction for background is crucial to provide reliable results of the particle number. Utilizing the fluorescent lifetime of the different contributions, we show that it is possible to distinguish between the fluorescent signal and the autofluorescent background in vivo in a single measurement.

High Expression of KCa3.1 in Patients with Clear Cell Renal Carcinoma Predicts High Metastatic Risk and Poor Survival

PubMed Central

Rabjerg, Maj; Oliván-Viguera, Aida; Hansen, Lars Koch; Jensen, Line; Sevelsted-Møller, Linda; Walter, Steen; Jensen, Boye L.; Marcussen, Niels; Köhler, Ralf

2015-01-01

Background Ca2+-activated K+ channels have been implicated in cancer cell growth, metastasis, and tumor angiogenesis. Here we hypothesized that high mRNA and protein expression of the intermediate-conductance Ca2+-activated K+ channel, KCa3.1, is a molecular marker of clear cell Renal Cell Carcinoma (ccRCC) and metastatic potential and survival. Methodology/Principal Findings We analyzed channel expression by qRT-PCR, immunohistochemistry, and patch-clamp in ccRCC and benign oncocytoma specimens, in primary ccRCC and oncocytoma cell lines, as well as in two ccRCC cell lines (Caki-1 and Caki-2). CcRCC specimens contained 12-fold higher mRNA levels of KCa3.1 than oncocytoma specimens. The large-conductance channel, KCa1.1, was 3-fold more highly expressed in ccRCC than in oncocytoma. KCa3.1 mRNA expression in ccRCC was 2-fold higher than in the healthy cortex of the same kidney. Disease specific survival trended towards reduction in the subgroup of high-KCa3.1-expressing tumors (p<0.08 vs. low-KCa3.1-expressing tumors). Progression-free survival (time to metastasis/recurrence) was reduced significantly in the subgroup of high-KCa3.1-expressing tumors (p<0.02, vs. low-KCa3.1-expressing tumors). Immunohistochemistry revealed high protein expression of KCa3.1 in tumor vessels of ccRCC and oncocytoma and in a subset of ccRCC cells. Oncocytoma cells were devoid of KCa3.1 protein. In a primary ccRCC cell line and Caki-1/2-ccRCC cells, we found KCa3.1-protein as well as TRAM-34-sensitive KCa3.1-currents in a subset of cells. Furthermore, Caki-1/2-ccRCC cells displayed functional Paxilline-sensitive KCa1.1 currents. Neither KCa3.1 nor KCa1.1 were found in a primary oncocytoma cell line. Yet KCa-blockers, like TRAM-34 (KCa3.1) and Paxilline (KCa1.1), had no appreciable effects on Caki-1 proliferation in-vitro. Conclusions/Significance Our study demonstrated expression of KCa3.1 in ccRCC but not in benign oncocytoma. Moreover, high KCa3.1-mRNA expression levels were indicative

Proteomic approach toward molecular backgrounds of drug resistance of osteosarcoma cells in spheroid culture system.

PubMed

Arai, Kazuya; Sakamoto, Ruriko; Kubota, Daisuke; Kondo, Tadashi

2013-08-01

Chemoresistance is one of the most critical prognostic factors in osteosarcoma, and elucidation of the molecular backgrounds of chemoresistance may lead to better clinical outcomes. Spheroid cells resemble in vivo cells and are considered an in vitro model for the drug discovery. We found that spheroid cells displayed more chemoresistance than conventional monolayer cells across 11 osteosarcoma cell lines. To investigate the molecular mechanisms underlying the resistance to chemotherapy, we examined the proteomic differences between the monolayer and spheroid cells by 2D-DIGE. Of the 4762 protein species observed, we further investigated 435 species with annotated mass spectra in the public proteome database, Genome Medicine Database of Japan Proteomics. Among the 435 protein species, we found that 17 species exhibited expression level differences when the cells formed spheroids in more than five cell lines and four species out of these 17 were associated with spheroid-formation associated resistance to doxorubicin. We confirmed the upregulation of cathepsin D in spheroid cells by western blotting. Cathepsin D has been implicated in chemoresistance of various malignancies but has not previously been implemented in osteosarcoma. Our study suggested that the spheroid system may be a useful tool to reveal the molecular backgrounds of chemoresistance in osteosarcoma. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Concurrent primaries of vaginal clear cell adenocarcinoma and endometrial adenocarcinoma in a 39-year old woman with in utero diethylstilbestrol exposure.

PubMed

Keller, C; Nanda, R; Shannon, R L; Amit, A; Kaplan, A L

2001-01-01

Diethylstilbestrol (DES) was used widely in the late 1940s in an attempt to prevent adverse pregnancy outcomes. In 1971 the US Food and Drug Administration proscribed its use for pregnancy support secondary to its association with clear cell adenocarcinoma of the vagina. Several studies in animal models demonstrated an association with endometrial cancer among offspring following in utero DES exposure. To date, there is only one case report of endometrial cancer in women exposed to DES in utero. We present the first case, to our knowledge, of a woman exposed to DES in utero who presented with double primaries of clear cell cancer of the vagina concomitant with endometrial cancer.

Clear cell carcinoma of the ovary: molecular insights and future therapeutic perspectives

PubMed Central

2016-01-01

Clear cell carcinoma (CCC) of the ovary is known to show poorer sensitivity to chemotherapeutic agents and to be associated with a worse prognosis than the more common serous adenocarcinoma or endometrioid adenocarcinoma. To improve the survival of patients with ovarian CCC, the deeper understanding of the mechanism of CCC carcinogenesis as well as the efforts to develop novel treatment strategies in the setting of both front-line treatment and salvage treatment for recurrent disease are needed. In this presentation, we first summarize the mechanism responsible for carcinogenesis. Then, we highlight the promising therapeutic targets in ovarian CCC and provide information on the novel agents which inhibit these molecular targets. Moreover, we discuss on the cytotoxic anti-cancer agents that can be best combined with targeted agents in the treatment of ovarian CCC. PMID:27029752

MicroRNA-187, down-regulated in clear cell renal cell carcinoma and associated with lower survival, inhibits cell growth and migration though targeting B7-H3

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

Zhao, Jun; Lei, Ting; Xu, Congjie

2013-08-23

Highlights: •miR-187 is down-regulated in clear cell renal cell carcinoma (ccRCC). •Down-regulation of miR-187 is associated with poor outcomes in patients with ccRCC. •miR-187 inhibits cell growth and migration though targeting B7-H3 in ccRCC. -- Abstract: Aberrantly expressed microRNAs (miRNAs) are frequently associated with the aggressive malignant behavior of human cancers, including clear cell renal cell carcinoma (ccRCC). Based on the preliminary deep sequencing data, we hypothesized that miR-187 may play an important role in ccRCC development. In this study, we found that miR-187 was down-regulated in both tumor tissue and plasma of ccRCC patients. Lower miR-187 expression levels weremore » associated with higher tumor grade and stage. All patients with high miR-187 expression survived 5 years, while with low miR-187 expression, only 42% survived. Suppressed in vitro proliferation, inhibited in vivo tumor growth, and decreased motility were observed in cells treated with the miR-187 expression vector. Further studies showed that B7 homolog 3 (B7-H3) is a direct target of miR-187. Over-expression of miR-187 decreased B7-H3 mRNA level and repressed B7-H3-3′-UTR reporter activity. Knockdown of B7-H3 using siRNA resulted in similar phenotype changes as that observed for overexpression of miR-187. Our data suggest that miR-187 is emerging as a novel player in the disease state of ccRCC. miR-187 plays a tumor suppressor role in ccRCC.« less

The Effect of Anatomical Location of Lymph Node Metastases on Cancer Specific Survival in Patients with Clear Cell Renal Cell Carcinoma.

PubMed

Nini, Alessandro; Larcher, Alessandro; Cianflone, Francesco; Trevisani, Francesco; Terrone, Carlo; Volpe, Alessandro; Regis, Federica; Briganti, Alberto; Salonia, Andrea; Montorsi, Francesco; Bertini, Roberto; Capitanio, Umberto

2018-01-01

Positive nodal status (pN1) is an independent predictor of survival in renal cell carcinoma (RCC) patients. However, no study to date has tested whether the location of lymph node (LN) metastases does affect oncologic outcomes in a population submitted to radical nephrectomy (RN) and extended lymph node dissection (eLND). To describe nodal disease dissemination in clear cell RCC (ccRCC) patients and to assess the effect of the anatomical sites and the number of nodal areas affected on cancer specific mortality (CSM). The study included 415 patients who underwent RN and eLND, defined as the removal of hilar, side-specific (pre/paraaortic or pre/paracaval) and interaortocaval LNs for ccRCC, at two institutions. Descriptive statistics were used to depict nodal dissemination in pN1 patients, stratified according to nodal site and number of involved areas. Multivariable Cox regression analyses and Kaplan-Meier curves were used to explore the relationship between pN1 disease features and survival outcomes. Median number of removed LN was 14 (IQR 9-19); 23% of patients were pN1. Among patients with one involved nodal site, 54 and 26% of patients were positive only in side-specific and interaortocaval station, respectively. The most frequent nodal site was the interaortocaval and side-specific one, for right and left ccRCC, respectively. Interaortocaval nodal positivity (HR 2.3, CI 95%: 1.3-3.9, p < 0.01) represented an independent predictor of CSM. When ccRCC patient harbour nodal disease, its spreading can occur at any nodal station without involving the others. The presence of interoartocaval positive nodes does affect oncologic outcomes. Lymph node invasion in patients with clear cell renal cell carcinoma is not following a fixed anatomical pattern. An extended lymph node dissection, during treatment for primary kidney tumour, would aid patient risk stratification and multimodality upfront treatment.

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

PubMed

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

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

PubMed Central

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

[Clear cell carcinoma of the ovary simulating a yolk sac tumor].

PubMed

Bahri, Ibticem; Boudawara, Tahya; Khabir, Abdelmajid; Beyrouti, Mohamed Issam; Frikha, Mounir; Jlidi, Rachid

2003-04-01

Clear cell carcinoma (CCC) of the ovary is uncommon. In young patients, this tumor may simulate a yolk sac tumor. In this case, the morphologic distinction between these tumors is often difficult but the immunohistochemical staining for CA125 and alpha foeto protein (AFP) and the response to chemotherapy are particularly helpful to resolve this problem of differential diagnosis. We report a case of a 17 year old patient who was operated for a tumor of the right ovary. The diagnosis of a yolk sac tumor was first suggested. However, because of the non response to chemotherapy, a second laparotomy was performed; the definitive pathologic examination concluded to the diagnosis of a CCC of the ovary. The young age and the immunohistochemical staining for AFP are unusual and misleading features for a CCC. Our objective about this particular case is to discuss the anatomoclinical aspects of the CCC of the ovary and to prove the role of immunohistochemistry in the differential diagnosis.

The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma.

PubMed

Miess, Heike; Dankworth, Beatrice; Gouw, Arvin M; Rosenfeldt, Mathias; Schmitz, Werner; Jiang, Ming; Saunders, Becky; Howell, Michael; Downward, Julian; Felsher, Dean W; Peck, Barrie; Schulze, Almut

2018-06-05

Metabolic reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Here we investigated metabolic dependencies in a panel of ccRCC cell lines using nutrient depletion, functional RNAi screening and inhibitor treatment. We found that ccRCC cells are highly sensitive to the depletion of glutamine or cystine, two amino acids required for glutathione (GSH) synthesis. Moreover, silencing of enzymes of the GSH biosynthesis pathway or glutathione peroxidases, which depend on GSH for the removal of cellular hydroperoxides, selectively reduced viability of ccRCC cells but did not affect the growth of non-malignant renal epithelial cells. Inhibition of GSH synthesis triggered ferroptosis, an iron-dependent form of cell death associated with enhanced lipid peroxidation. VHL is a major tumour suppressor in ccRCC and loss of VHL leads to stabilisation of hypoxia inducible factors HIF-1α and HIF-2α. Restoration of functional VHL via exogenous expression of pVHL reverted ccRCC cells to an oxidative metabolism and rendered them insensitive to the induction of ferroptosis. VHL reconstituted cells also exhibited reduced lipid storage and higher expression of genes associated with oxidiative phosphorylation and fatty acid metabolism. Importantly, inhibition of β-oxidation or mitochondrial ATP-synthesis restored ferroptosis sensitivity in VHL reconstituted cells. We also found that inhibition of GSH synthesis blocked tumour growth in a MYC-dependent mouse model of renal cancer. Together, our data suggest that reduced fatty acid metabolism due to inhibition of β-oxidation renders renal cancer cells highly dependent on the GSH/GPX pathway to prevent lipid peroxidation and ferroptotic cell death.

Reducing WBC background in cancer cell separation products by negative acoustic contrast particle immuno-acoustophoresis.

PubMed

Cushing, Kevin; Undvall, Eva; Ceder, Yvonne; Lilja, Hans; Laurell, Thomas

2018-02-13

Cancer cells display acoustic properties enabling acoustophoretic separation from white blood cells (WBCs) with 2-3 log suppression of the WBC background. However, a subset of WBCs has overlapping acoustic properties with cancer cells, which is why label-free acoustophoretic cancer cell isolation needs additional purification prior to analysis. This paper reports for the first time a proof of concept for continuous flow acoustophoretic negative selection of WBCs from cancer cells using negative acoustic contrast elastomeric particles (EPs) activated with CD45-antibodies that specifically bind to WBCs. The EP/WBC complexes align at the acoustic pressure anti-nodes along the channel walls while unbound cancer cells focus to the pressure node in the channel center, enabling continuous flow based depletion of WBC background in a cancer cell product. The method does not provide a single process solution for the CTC separation challenge, but provides an elegant part to a multi-step process by further reducing the WBC background in cancer cell separation products derived from an initial step of label-free acoustophoresis. We report the recorded performance of the negative selection immuno-acoustophoretic WBC depletion and cancer cell recovery. To eliminate the negative impact of the separation due to the known problems of aggregation of negative acoustic contrast particles along the sidewalls of the acoustophoresis channel and to enable continuous separation of EP/WBC complexes from cancer cells, a new acoustic actuation method has been implemented where the ultrasound frequency is scanned (1.991MHz ± 100 kHz, scan rate 200 kHz ms -1 ). Using this frequency scanning strategy EP/WBC complexes were acoustophoretically separated from mixtures of WBCs spiked with breast and prostate cancer cells (DU145 and MCF-7). An 86-fold (MCF-7) and 52-fold (DU145) reduction of WBCs in the cancer cell fractions were recorded with separation efficiencies of 98.6% (MCF-7) and 99

A Whole Brain Staining, Embedding, and Clearing Pipeline for Adult Zebrafish to Visualize Cell Proliferation and Morphology in 3-Dimensions.

PubMed

Lindsey, Benjamin W; Douek, Alon M; Loosli, Felix; Kaslin, Jan

2017-01-01

The field of macro-imaging has grown considerably with the appearance of innovative clearing methods and confocal microscopes with lasers capable of penetrating increasing tissue depths. The ability to visualize and model the growth of whole organs as they develop from birth, or with manipulation, disease or injury, provides new ways of thinking about development, tissue-wide signaling, and cell-to-cell interactions. The zebrafish ( Danio rerio ) has ascended from a predominantly developmental model to a leading adult model of tissue regeneration. The unmatched neurogenic and regenerative capacity of the mature central nervous system, in particular, has received much attention, however tools to interrogate the adult brain are sparse. At present there exists no straightforward methods of visualizing changes in the whole adult brain in 3-dimensions (3-D) to examine systemic patterns of cell proliferation or cell populations of interest under physiological, injury, or diseased conditions. The method presented here is the first of its kind to offer an efficient step-by-step pipeline from intraperitoneal injections of the proliferative marker, 5-ethynyl-2'-deoxyuridine (EdU), to whole brain labeling, to a final embedded and cleared brain sample suitable for 3-D imaging using optical projection tomography (OPT). Moreover, this method allows potential for imaging GFP-reporter lines and cell-specific antibodies in the presence or absence of EdU. The small size of the adult zebrafish brain, the highly consistent degree of EdU labeling, and the use of basic clearing agents, benzyl benzoate, and benzyl alcohol, makes this method highly tractable for most laboratories interested in understanding the vertebrate central nervous system in health and disease. Post-processing of OPT-imaged adult zebrafish brains injected with EdU illustrate that proliferative patterns in EdU can readily be observed and analyzed using IMARIS and/or FIJI/IMAGEJ software. This protocol will be a

A Whole Brain Staining, Embedding, and Clearing Pipeline for Adult Zebrafish to Visualize Cell Proliferation and Morphology in 3-Dimensions

PubMed Central

Lindsey, Benjamin W.; Douek, Alon M.; Loosli, Felix; Kaslin, Jan

2018-01-01

The field of macro-imaging has grown considerably with the appearance of innovative clearing methods and confocal microscopes with lasers capable of penetrating increasing tissue depths. The ability to visualize and model the growth of whole organs as they develop from birth, or with manipulation, disease or injury, provides new ways of thinking about development, tissue-wide signaling, and cell-to-cell interactions. The zebrafish (Danio rerio) has ascended from a predominantly developmental model to a leading adult model of tissue regeneration. The unmatched neurogenic and regenerative capacity of the mature central nervous system, in particular, has received much attention, however tools to interrogate the adult brain are sparse. At present there exists no straightforward methods of visualizing changes in the whole adult brain in 3-dimensions (3-D) to examine systemic patterns of cell proliferation or cell populations of interest under physiological, injury, or diseased conditions. The method presented here is the first of its kind to offer an efficient step-by-step pipeline from intraperitoneal injections of the proliferative marker, 5-ethynyl-2′-deoxyuridine (EdU), to whole brain labeling, to a final embedded and cleared brain sample suitable for 3-D imaging using optical projection tomography (OPT). Moreover, this method allows potential for imaging GFP-reporter lines and cell-specific antibodies in the presence or absence of EdU. The small size of the adult zebrafish brain, the highly consistent degree of EdU labeling, and the use of basic clearing agents, benzyl benzoate, and benzyl alcohol, makes this method highly tractable for most laboratories interested in understanding the vertebrate central nervous system in health and disease. Post-processing of OPT-imaged adult zebrafish brains injected with EdU illustrate that proliferative patterns in EdU can readily be observed and analyzed using IMARIS and/or FIJI/IMAGEJ software. This protocol will be a

Metabolic Modulation of Clear-cell Renal Cell Carcinoma with Dichloroacetate, an Inhibitor of Pyruvate Dehydrogenase Kinase.

PubMed

Kinnaird, Adam; Dromparis, Peter; Saleme, Bruno; Gurtu, Vikram; Watson, Kristalee; Paulin, Roxane; Zervopoulos, Sotirios; Stenson, Trevor; Sutendra, Gopinath; Pink, Desmond B; Carmine-Simmen, Katia; Moore, Ronald; Lewis, John D; Michelakis, Evangelos D

2016-04-01

Clear-cell renal cell carcinoma (ccRCC) exhibits suppressed mitochondrial function and preferential use of glycolysis even in normoxia, promoting proliferation and suppressing apoptosis. ccRCC resistance to therapy is driven by constitutive hypoxia-inducible factor (HIF) expression due to genetic loss of von Hippel-Lindau factor. In addition to promoting angiogenesis, HIF suppresses mitochondrial function by inducing pyruvate dehydrogenase kinase (PDK), a gatekeeping enzyme for mitochondrial glucose oxidation. To reverse mitochondrial suppression of ccRCC using the PDK inhibitor dichloroacetate (DCA). Radical nephrectomy specimens from patients with ccRCC were assessed for PDK expression. The 786-O ccRCC line and two animal models (chicken in ovo and murine xenografts) were used for mechanistic studies. Mitochondrial function, proliferation, apoptosis, HIF transcriptional activity, angiogenesis, and tumor size were measured in vitro and in vivo. Independent-sample t-tests and analysis of variance were used for statistical analyses. PDK was elevated in 786-O cells and in ccRCC compared to normal kidney tissue from the same patient. DCA reactivated mitochondrial function (increased respiration, Krebs cycle metabolites such as α-ketoglutarate [cofactor of factor inhibiting HIF], and mitochondrial reactive oxygen species), increased p53 activity and apoptosis, and decreased proliferation in 786-O cells. DCA reduced HIF transcriptional activity in an FIH-dependent manner, inhibiting angiogenesis in vitro. DCA reduced tumor size and angiogenesis in vivo in both animal models. DCA can reverse the mitochondrial suppression of ccRCC and decrease HIF transcriptional activity, bypassing its constitutive expression. Its previous clinical use in humans makes it an attractive candidate for translation to ccRCC patients. We show that an energy-boosting drug decreases tumor growth and tumor blood vessels in animals carrying human kidney cancer cells. This generic drug has been

Cytoplasmic expression of CD133 stemness marker is associated with tumor aggressiveness in clear cell renal cell carcinoma.

PubMed

Saeednejad Zanjani, Leili; Madjd, Zahra; Abolhasani, Maryam; Andersson, Yvonne; Rasti, Arezoo; Shariftabrizi, Ahmad; Asgari, Mojgan

2017-10-01

Prominin-1 (CD133) is one of the most commonly used markers for cancer stem cells (CSCs), which are characterized by their ability for self-renewal and tumorigenicity. However, the clinical and prognostic significance of CSCs in renal cell carcinoma (RCC) remains unclear. The aim of this study was to investigate the expression patterns and prognostic significance of the cancer stem cell marker CD133 in different histological subtypes of RCC. CD133 expression was evaluated using immunohistochemistry in 193 well-defined renal tumor samples on tissue microarrays, including 136 (70.5%) clear cell renal cell carcinomas (CCRCCs), 26 (13.5%) papillary RCCs, and 31 (16.1%) chromophobe RCCs. The association between CD133 expression and clinicopathological features as well as the survival outcomes was determined. There was a statistically significant difference between CD133 expression among the different RCC subtypes. In CCRCC, higher cytoplasmic expression of CD133 was significantly associated with increase in grade, stage, microvascular invasion (MVI) and lymph node invasion (LNI), while no association was found with the membranous expression. Moreover, on multivariate analysis, TNM stage and nuclear grade were independent prognostic factors for overall survival (OS) in cytoplasmic expression. We showed that higher cytoplasmic CD133 expression was associated with more aggressive tumor behavior and more advanced disease in CCRCC but not in the other examined subtypes. Our results demonstrated that higher cytoplasmic CD133 expression is clinically significant in CCRCC and is associated with increased tumor aggressiveness and is useful for predicting cancer progression. Copyright © 2017 Elsevier Inc. All rights reserved.

Pancreatic mixed serous neuroendocrine neoplasm with clear cells leading to diagnosis of von Hippel Lindau disease.

PubMed

Kakkar, Aanchal; Sharma, Mehar C; Yadav, Rajni; Panwar, Rajesh; Mathur, Sandeep R; Iyer, Venkateswaran K; Sahni, Peush

2016-08-01

Mixed serous neuroendocrine neoplasms are extremely rare tumors that are usually seen in female patients and are often associated with von Hippel Lindau (VHL) disease. We describe the case of a 38-year-old male who presented with complaints of anorexia, weight loss, and abdominal pain. CT abdomen showed a mass in the head of the pancreas, multiple small nodules in the body of pancreas, and bilateral adrenal masses. Fine needle aspiration cytology (FNAC) from the mass showed features of a neuroendocrine tumor, with many of the cells demonstrating abundant clear cytoplasm. Histopathological examination of the pancreaticoduodenectomy specimen showed a mixed serous neuroendocrine neoplasm with two components viz. serous cystadenoma and neuroendocrine tumor (NET) World Health Organization (WHO) grade 2. In addition, he was diagnosed to have bilateral pheochromocytomas and a paraganglioma. The synchronicity of these tumors suggested the possibility of VHL disease. Thus, identification of a NET with clear cells or of a mixed serous neuroendocrine neoplasm should raise suspicion of VHL disease. In a mixed tumor, FNAC may identify only one of the two components. Thorough processing of all pancreatic serous tumors for pathological examination is recommended, as NET may occur as a small nodule within the serous cystadenoma. Copyright © 2016 Elsevier GmbH. All rights reserved.

Lynch Syndrome-Related Clear Cell Carcinoma of the Cervix: A Case Report.

PubMed

Nakamura, Kohei; Nakayama, Kentaro; Minamoto, Toshiko; Ishibashi, Tomoka; Ohnishi, Kaori; Yamashita, Hitomi; Ono, Ruriko; Sasamori, Hiroki; Razia, Sultana; Hossain, Mohammad Mahmud; Kamrunnahar, Shanta; Ishikawa, Masako; Ishikawa, Noriyoshi; Kyo, Satoru

2018-03-25

Lynch syndrome, a hereditary cancer syndrome, occurs because of germline mutations in at least one of four DNA mismatch repair genes (MutL Homolog 1 ( MLH1 ), MutS Homolog 2 ( MSH2 ), MutS Homolog 6 ( MSH6 ), and PMS1 Homolog 2 ( PMS2 )). The disorder is associated with colorectal, endometrial, and other epithelial malignancies, but not cervical cancer. We report a woman with Lynch syndrome with synchronous cervical cancer. This is the first report of Lynch syndrome-related clear cell carcinoma of the cervix, which indicates the possibility of an association between cervical cancer and Lynch syndrome. Suitable genetic tests are required to determine whether common genetics can account for synchronous or subsequent malignancies in Lynch syndrome patients and their families. Such knowledge will also enhance our understanding of the genetic mechanisms governing the development of apparently unrelated cancers.

Schwann cells use TAM receptor-mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury.

PubMed

Brosius Lutz, Amanda; Chung, Won-Suk; Sloan, Steven A; Carson, Glenn A; Zhou, Lu; Lovelett, Emilie; Posada, Sean; Zuchero, J Bradley; Barres, Ben A

2017-09-19

Ineffective myelin debris clearance is a major factor contributing to the poor regenerative ability of the central nervous system. In stark contrast, rapid clearance of myelin debris from the injured peripheral nervous system (PNS) is one of the keys to this system's remarkable regenerative capacity, but the molecular mechanisms driving PNS myelin clearance are incompletely understood. We set out to discover new pathways of PNS myelin clearance to identify novel strategies for activating myelin clearance in the injured central nervous system, where myelin debris is not cleared efficiently. Here we show that Schwann cells, the myelinating glia of the PNS, collaborate with hematogenous macrophages to clear myelin debris using TAM (Tyro3, Axl, Mer) receptor-mediated phagocytosis as well as autophagy. In a mouse model of PNS nerve crush injury, Schwann cells up-regulate TAM phagocytic receptors Axl and Mertk following PNS injury, and Schwann cells lacking both of these phagocytic receptors exhibit significantly impaired myelin phagocytosis both in vitro and in vivo. Autophagy-deficient Schwann cells also display reductions in myelin clearance after mouse nerve crush injury, as has been recently shown following nerve transection. These findings add a mechanism, Axl/Mertk-mediated myelin clearance, to the repertoire of cellular machinery used to clear myelin in the injured PNS. Given recent evidence that astrocytes express Axl and Mertk and have previously unrecognized phagocytic potential, this pathway may be a promising avenue for activating myelin clearance after CNS injury.

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

PubMed Central

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

Clinical impact of targeted therapies in patients with metastatic clear-cell renal cell carcinoma

PubMed Central

Nerich, Virginie; Hugues, Marion; Paillard, Marie Justine; Borowski, Laëtitia; Nai, Thierry; Stein, Ulrich; Nguyen Tan Hon, Thierry; Montcuquet, Philippe; Maurina, Tristan; Mouillet, Guillaume; Kleinclauss, François; Pivot, Xavier; Limat, Samuel; Thiery-Vuillemin, Antoine

2014-01-01

Introduction The aim of this retrospective clinical study was to assess, in the context of the recent evolution of systemic therapies, the potential effect of targeted therapies on overall survival (OS) of patients with metastatic clear-cell renal cell carcinoma (mccRCC) in daily practice. Patients and methods All consecutive patients with histologically confirmed mccRCC who received systemic therapy between January 2000 and December 2010 in two oncology treatment centers in our Franche-Comté region in eastern France were included in the analysis. The primary end point was OS. The analysis of prognostic factors was performed using a two-step approach: univariate then multivariate analysis with a stepwise Cox proportional hazards regression model. Results For the entire cohort of 111 patients, the median OS was 17 months (95% confidence interval [CI]; 13–22 months) and the two-year OS was 39%. Three prognostic factors were independent predictors of long survival: prior nephrectomy (hazard ratio =0.38 [0.22–0.64], P<0.0001); systemic therapy by targeted therapy (hazard ratio =0.50 [0.31–0.80], P=0.005); and lack of liver metastasis (hazard ratio =0.43 [0.22–0.82], P=0.002). Median OS was 21 months [14–29 months] for patients who received at least one targeted therapy compared with 12 months [7–15 months] for patients who were treated only by immunotherapy agents (P=0.003). Conclusion Our results suggest that targeted therapies are associated with improved OS in comparison with cytokines, which is in line with other publications. PMID:24600236

Demographic, Clinical, and Prognostic Factors of Ovarian Clear Cell Adenocarcinomas According to Endometriosis Status.

PubMed

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

2017-11-01

Women with endometriosis carry an increased risk for ovarian clear cell adenocarcinomas (CCCs). Clear cell adenocarcinoma may develop from endometriosis lesions. Few studies have compared clinical and prognostic factors and overall survival in patients diagnosed as having CCC according to endometriosis status. Population-based prospectively collected data on CCC with coexisting pelvic (including ovarian; n = 80) and ovarian (n = 46) endometriosis or without endometriosis (n = 95) were obtained through the Danish Gynecological Cancer Database. χ Test, independent-samples t test, logistic regression, Kaplan-Meier test, and Cox regression were used. Statistical tests were 2 sided. P values less than 0.05 were considered statistically significant. Patients with CCC and pelvic or ovarian endometriosis were significantly younger than CCC patients without endometriosis, and a higher proportion of them were nulliparous (28% and 31% vs 17% (P = 0.07 and P = 0.09). Accordingly, a significantly higher proportion of women without endometriosis had given birth to more than 1 child. Interestingly, a significantly higher proportion of patients with ovarian endometriosis had pure CCCs (97.8% vs 82.1%; P = 0.001) as compared with patients without endometriosis. Overall survival was poorer among CCC patients with concomitant ovarian endometriosis (hazard ratio, 2.56 [95% confidence interval, 1.29-5.02], in the multivariate analysis. Age at CCC diagnosis and parity as well as histology differ between CCC patients with and without concomitant endometriosis. Furthermore, CCC patients with concomitant ovarian endometriosis have a poorer prognosis compared with endometriosis-negative CCC patients. These differences warrant further research to determine whether CCCs with and without concomitant endometriosis develop through distinct pathogenic pathways.

Lynch Syndrome-Related Clear Cell Carcinoma of the Cervix: A Case Report

PubMed Central

Nakamura, Kohei; Nakayama, Kentaro; Minamoto, Toshiko; Ishibashi, Tomoka; Ohnishi, Kaori; Yamashita, Hitomi; Ono, Ruriko; Sasamori, Hiroki; Razia, Sultana; Hossain, Mohammad Mahmud; Kamrunnahar, Shanta; Ishikawa, Masako; Ishikawa, Noriyoshi; Kyo, Satoru

2018-01-01

Lynch syndrome, a hereditary cancer syndrome, occurs because of germline mutations in at least one of four DNA mismatch repair genes (MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and PMS1 Homolog 2 (PMS2)). The disorder is associated with colorectal, endometrial, and other epithelial malignancies, but not cervical cancer. We report a woman with Lynch syndrome with synchronous cervical cancer. This is the first report of Lynch syndrome-related clear cell carcinoma of the cervix, which indicates the possibility of an association between cervical cancer and Lynch syndrome. Suitable genetic tests are required to determine whether common genetics can account for synchronous or subsequent malignancies in Lynch syndrome patients and their families. Such knowledge will also enhance our understanding of the genetic mechanisms governing the development of apparently unrelated cancers. PMID:29587389

The Coordinated Actions of TIM-3 on Cancer and Myeloid Cells in the Regulation of Tumorigenicity and Clinical Prognosis in Clear Cell Renal Cell Carcinomas.

PubMed

Komohara, Yoshihiro; Morita, Tomoko; Annan, Dorcas A; Horlad, Hasita; Ohnishi, Koji; Yamada, Sohsuke; Nakayama, Toshiyuki; Kitada, Shohei; Suzu, Shinya; Kinoshita, Ichiro; Dosaka-Akita, Hirotoshi; Akashi, Koichi; Takeya, Motohiro; Jinushi, Masahisa

2015-09-01

Clear cell renal cell carcinoma (ccRCC) is one of most common cancers in urogenital organs. Although recent experimental and clinical studies have shown the immunogenic properties of ccRCC as illustrated by the clinical sensitivities to various immunotherapies, the detailed immunoregulatory machineries governing the tumorigenicity of human ccRCC remain largely obscure. In this study, we demonstrated the clinical significance and functional relevance of T-cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) expressed on tumor cells and myeloid cells in patients with ccRCC. TIM-3 expression was detected on cancer cells and CD204(+) tumor-associated macrophages (TAM), and higher expression level of TIM-3 was positively correlated with shorter progression-free survival (PFS) in patients with ccRCC. We found that TIM-3 expression was detected on a large number of tumors, and there was significant correlation between an increased number of TAMs and high expression level of TIM-3 in patients with ccRCC. Furthermore, TIM-3 rendered RCC cells with the ability to induce resistance to sunitinib and mTOR inhibitors, the standard regimen for patients with ccRCC, as well as stem cell activities. TIM-3 expression was induced on CD14(+) monocytes upon long-term stimulation with RCC cells, and TIM-3-expressing myeloid cells play a critical role in augmenting tumorigenic activities of TIM-3-negative RCC cells. More importantly, treatment with anti-TIM-3 mAb suppressed its tumorigenic effects in in vitro and in vivo settings. These findings indicate the coordinated action of TIM-3 in cancer cells and in myeloid cells regulates the tumorigenicity of human RCC. ©2015 American Association for Cancer Research.

Renal cell carcinoma in children and young adults: analysis of clinicopathological, immunohistochemical and molecular characteristics with an emphasis on the spectrum of Xp11.2 translocation-associated and unusual clear cell subtypes.

PubMed

Wu, A; Kunju, L P; Cheng, L; Shah, R B

2008-11-01

Recent studies suggest that paediatric renal cell carcinoma (RCC) may represent a distinct group of tumours; however, its biological behaviour and classification remain poorly understood. The aim was to analyse 13 RCCs from patients < or =23 years of age to determine their clinicopathological, immunohistochemical and molecular characteristics. The histological spectrum included: Xp11.2 translocation-associated (6/13 patients, 46%), clear cell (5/13 patients, 38%), papillary (1/13 patients) and unclassified (1/13 patients) types. The Xp11.2 translocation-associated RCCs had a wide morphological spectrum, with high nuclear grade cells with abundant cytoplasm ranging from clear to granular and architecture ranging from solid to papillary. These tumours lacked cytokeratin expression and were confirmed by nuclear reactivity for TFE3 protein. Most of these translocation-associated tumours presented at high stage and had an unfavourable outcome. Three clear cell RCCs had unusual features that have not been previously characterized, including solid and cystic architecture, cells with abundant eosinophilic cytoplasm yet low nuclear grade and focal cytoplasmic inclusions, resembling oncocytoma. Deletion of subtelomeric 3p25 was observed in two of these RCCs. Xp11.2 translocation-associated RCC represents a predominant and aggressive subtype in the paediatric age group. Increased awareness of this subtype is important due to its heterogeneous morphology.

Background fluorescence estimation and vesicle segmentation in live cell imaging with conditional random fields.

PubMed

Pécot, Thierry; Bouthemy, Patrick; Boulanger, Jérôme; Chessel, Anatole; Bardin, Sabine; Salamero, Jean; Kervrann, Charles

2015-02-01

Image analysis applied to fluorescence live cell microscopy has become a key tool in molecular biology since it enables to characterize biological processes in space and time at the subcellular level. In fluorescence microscopy imaging, the moving tagged structures of interest, such as vesicles, appear as bright spots over a static or nonstatic background. In this paper, we consider the problem of vesicle segmentation and time-varying background estimation at the cellular scale. The main idea is to formulate the joint segmentation-estimation problem in the general conditional random field framework. Furthermore, segmentation of vesicles and background estimation are alternatively performed by energy minimization using a min cut-max flow algorithm. The proposed approach relies on a detection measure computed from intensity contrasts between neighboring blocks in fluorescence microscopy images. This approach permits analysis of either 2D + time or 3D + time data. We demonstrate the performance of the so-called C-CRAFT through an experimental comparison with the state-of-the-art methods in fluorescence video-microscopy. We also use this method to characterize the spatial and temporal distribution of Rab6 transport carriers at the cell periphery for two different specific adhesion geometries.

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

PubMed Central

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

2015-01-01

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. PMID:25569102

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

PubMed

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.

A low-background piston-cylinder-type hybrid high pressure cell for muon-spin rotation/relaxation experiments

NASA Astrophysics Data System (ADS)

Shermadini, Z.; Khasanov, R.; Elender, M.; Simutis, G.; Guguchia, Z.; Kamenev, K. V.; Amato, A.

2017-10-01

A low background double-wall piston-cylinder-type pressure cell is developed at the Paul Scherrer Institute. The cell is made from BERYLCO-25 (beryllium copper) and MP35N nonmagnetic alloys with the design and dimensions which are specifically adapted to muon-spin rotation/relaxation (μSR) measurements. The mechanical design and performance of the pressure cell are evaluated using finite-element analysis (FEA). By including the measured stress-strain characteristics of the materials into the finite-element model, the cell dimensions are optimized with the aim to reach the highest possible pressure while maintaining the sample space large (6 mm in diameter and 12 mm high). The presented unconventional design of the double-wall piston-cylinder pressure cell with a harder outer MP35N sleeve and a softer inner CuBe cylinder enables pressures of up to 2.6 GPa to be reached at ambient temperature, corresponding to 2.2 GPa at low temperatures without any irreversible damage to the pressure cell. The nature of the muon stopping distribution, mainly in the sample and in the CuBe cylinder, results in a low-background μSR signal.

TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma

PubMed Central

Hall, Daniel P.; Cost, Nicholas G.; Hegde, Shailaja; Kellner, Emily; Mikhaylova, Olga; Stratton, Yiwen; Ehmer, Birgit; Abplanalp, William A.; Pandey, Raghav; Biesiada, Jacek; Harteneck, Christian; Plas, David R.; Meller, Jarek; Czyzyk-Krzeska, Maria F.

2014-01-01

Summary Autophagy promotes tumor growth by generating nutrients from the degradation of intracellular structures. Here we establish, using shRNAs, a dominant negative mutant, and a pharmacologic inhibitor, mefenamic acid (MFA), that the Transient Receptor Potential Melastatin 3 (TRPM3) channel promotes growth of clear cell renal cell carcinoma (ccRCC) and stimulates MAP1LC3A (LC3A) and MAP1LC3B (LC3B) autophagy. Increased expression of TRPM3 in RCC leads to Ca2+ influx, activation of CAMKK2, AMPK, and ULK1, and phagophore formation. In addition, TRPM3 Ca2+ and Zn2+ fluxes inhibit miR-214 which directly targets LC3A and LC3B. The von Hippel-Lindau tumor suppressor (VHL) represses TRPM3 through miR-204 directly and indirectly through another miR-204 target, Caveolin 1 (CAV1). PMID:25517751

The effect of adjuvant radiation on survival in early stage clear cell ovarian carcinoma.

PubMed

Hogen, Liat; Thomas, Gillian; Bernardini, Marcus; Bassiouny, Dina; Brar, Harinder; Gien, Lilian T; Rosen, Barry; Le, Lisa; Vicus, Danielle

2016-11-01

To assess the impact of adjuvant radiotherapy (RT) on survival in patients with stage I and II ovarian clear cell carcinoma (OCCC). Data collection and analysis of stage I and II OCCC patients treated at two tertiary centers in Toronto, between 1995 and 2014, was performed. Descriptive statistics and Kaplan-Meier survival probability estimates were completed. The log-rank test was used to compare survival curves. 163 patients were eligible. 44 (27%) patients were treated with adjuvant RT: 37 of them received adjuvant chemotherapy (CT), and 7 had RT only. In the no-RT group, there were 119 patients: 83 patients received adjuvant CT and 36 had no adjuvant treatment. The 10year progression free survival (PFS) was 65% for patients treated with RT, and 59% no-RT patients. There were a total of 41 (25%) recurrences in the cohort: 12 (27.2%) patients in RT group and 29 (24.3%) in the no-RT group. On multivariable analysis, adjuvant RT was not significantly associated with an increased PFS (0.85 (0.44-1.63) p=0.63) or overall survival (OS) (0.84 (0.39-1.82) p=0.66). In the subset of 59 patients defined as high-risk: stage IC with positive cytology and/or surface involvement and stage II: RT was not found to be associated with a better PFS (HR 1.18 (95% CI: 0.55-2.54) or O S(HR 1.04 (95% CI: 0.40-2.69)). Adjuvant RT was not found to be associated with a survival benefit in patients with stage I and II ovarian clear cell carcinoma or in a high risk subset of patients including stage IC cytology positive/surface involvement and stage II patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Multidisciplinary treatment of brain metastases derived from clear cell renal cancer incorporating stereotactic radiosurgery.

PubMed

Samlowski, Wolfram E; Majer, Martin; Boucher, Kenneth M; Shrieve, Annabelle F; Dechet, Christopher; Jensen, Randy L; Shrieve, Dennis C

2008-11-01

Brain metastases are a frequent complication in patients with metastatic clear cell renal cancer. Survival after whole-brain radiotherapy (WBRT) is disappointing. A retrospective analysis of multimodality treatment was performed in patients who had received linear accelerator (LINAC)-based stereotactic radiosurgery (SRS). Thirty-two patients underwent SRS-based treatment for 71 metastatic foci between 2000 and 2006. All patients had a Karnofsky performance status >or=70 and all 32 patients had extracranial metastatic disease (Radiation Therapy Oncology Group recursive partitioning analysis [RPA] Class 2). Survival was calculated from the time of diagnosis of brain metastases. The minimum potential follow-up was 1 year after SRS. Univariate and multivariate analysis of potential prognostic factors affecting survival was performed. Twenty-six patients required only 1 SRS treatment (84%) to achieve central nervous system (CNS) control, whereas 5 patients received 2 to 3 treatments (16%). The median survival of renal cancer patients from the diagnosis of brain metastases was 10.1 months (95% confidence interval, 6.4-14.8 months). One-year and 3-year survival rates were 43% and 16%, respectively. The addition of surgery or WBRT did not appear to prolong survival. Immunotherapy after control of brain metastases with SRS appeared to result in significantly improved survival. Survival was also found to be strongly influenced by prognostic stratification of metastatic disease using Motzer or modified risk criteria. The results of the current study demonstrated that SRS-based treatment of patients with up to 5 brain metastases from clear cell renal cancer is feasible and results in excellent CNS control. Survival beyond 3 years from the time of diagnosis of brain metastases was achievable in 16% of patients and was associated with the use of systemic immunotherapy with interleukin-2 and interferon but not antiangiogenic agents.

Modulation of estrogenic action in clear cell carcinoma of the ovary (Review)

PubMed Central

TANASE, YASUHITO; YAMADA, YOSHIHIKO; SHIGETOMI, HIROSHI; KAJIHARA, HIROTAKA; OONOGI, AKIRA; YOSHIZAWA, YORIKO; FURUKAWA, NAOTO; HARUTA, SHOJI; YOSHIDA, SHOZO; SADO, TOSHIYUKI; OI, HIDEKAZU; KOBAYASHI, HIROSHI

2012-01-01

Two histologic types, clear cell carcinoma (CCC) and endometrioid adenocarcinoma (EAC), are the common histology in ovarian cancer patients who have associated endometriosis. However, both tumor types have distinct clinicopathological characteristics and molecular phenotypes. EAC is predominantly positive for estrogen receptor (ER), but CCC specifically exhibits lower ER expression. This study reviews the current understanding of the role of the ER information in the pathogenesis of CCC, as well as the English language literature for biochemical studies on ER expression and estrogenic action in CCC. The iron-mediated oxidative stress occurs due to repeated hemorrhage in endometriosis, then this compound oxidatively modifies genomic DNA and, subsequently, ER depletion may be observed. There are a number of factors that interfere with ER expression and estrogen activity, which include DNA methylation of the promoter region, histone deacetylation, heme and iron binding, chromatin remodeling and ubiquitin ligase activity. Loss of estrogen function may be a turning point in CCC progression and aggressiveness. PMID:22969838

Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma.

PubMed

Itamochi, Hiroaki; Oishi, Tetsuro; Oumi, Nao; Takeuchi, Satoshi; Yoshihara, Kosuke; Mikami, Mikio; Yaegashi, Nobuo; Terao, Yasuhisa; Takehara, Kazuhiro; Ushijima, Kimio; Watari, Hidemichi; Aoki, Daisuke; Kimura, Tadashi; Nakamura, Toshiaki; Yokoyama, Yoshihito; Kigawa, Junzo; Sugiyama, Toru

2017-08-22

Ovarian clear cell carcinoma (OCCC) is mostly resistant to standard chemotherapy that results in poor patient survival. To understand the genetic background of these tumours, we performed whole-genome sequencing of OCCC tumours. Tumour tissue samples and matched blood samples were obtained from 55 Japanese women diagnosed with OCCC. Whole-genome sequencing was performed using the Illumina HiSeq platform according to standard protocols. Alterations to the switch/sucrose non-fermentable (SWI/SNF) subunit, the phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway, and the receptor tyrosine kinase (RTK)/Ras signalling pathway were found in 51%, 42%, and 29% of OCCC tumours, respectively. The 3-year overall survival (OS) rate for patients with an activated PI3K/Akt signalling pathway was significantly higher than that for those with inactive pathway (91 vs 40%, hazard ratio 0.24 (95% confidence interval (CI) 0.10-0.56), P=0.0010). Similarly, the OS was significantly higher in patients with the activated RTK/Ras signalling pathway than in those with the inactive pathway (91 vs 53%, hazard ratio 0.35 (95% CI 0.13-0.94), P=0.0373). Multivariable analysis revealed that activation of the PI3K/Akt and RTK/Ras signalling pathways was an independent prognostic factor for patients with OCCC. The PI3K/Akt and RTK/Ras signalling pathways may be potential prognostic biomarkers for OCCC patients. Furthermore, our whole-genome sequencing data highlight important pathways for molecular and biological characterisations and potential therapeutic targeting in OCCC.

POTASSIUM BROMATE-INDUCED RAT CLEAR CELL RENAL TUMOR IS INDEPENDENT OF CODING REGION MUTATIONS IN THE VON HIPPEL- LINDAU GENE

EPA Science Inventory

Potassium bromate (KBr03) is a rat renal carcinogen and a major drinking water disinfection by-product from ozonization. While KBr03 is a human nephro- and neuro-toxicant, its carcinogenicity in humans is unknown. Clear cell renal tumors, the common form of human renal carcinomas...

Optical clearing of articular cartilage: a comparison of clearing agents

NASA Astrophysics Data System (ADS)

Bykov, Alexander; Hautala, Tapio; Kinnunen, Matti; Popov, Alexey; Karhula, Sakari; Saarakkala, Simo; Nieminen, Miika T.; Tuchin, Valery

2015-07-01

Optical clearing technique was applied to the problem of OCT imaging of articular cartilage and subchondral bone. We show that optical clearing significantly enhances visualization of articular cartilage and cartilage-bone interface. The effect of different clearing agents was analyzed. For the clearing, iohexol solution and propylene glycol (PG) were used. Clearing was performed in vitro at room temperature by immersion method. Cylindrical osteochondral samples (d=4.8mm) were drilled from bovine lateral femur and stored in phosphate-buffered saline at -20°C until clearing. Monitoring of clearing process was performed using high-speed spectral-domain OCT system providing axial resolution of 5.8μm at 930nm. Total duration of experiment was 90-100min to ensure saturation of clearing. We have shown that iohexol solution and PG are capable to optically clear articular cartilage enabling reliable characterization of cartilagebone interface with OCT. Being a low osmolarity agent, iohexol provides minimal changes to the thickness of cartilage sample. Clearing saturation time for the cartilage sample with the thickness of 0.9 mm measured with OCT is of 50 min. However, less than 15 min is enough to reliably detect the rear cartilage boundary. Alternatively, PG significantly (60%) reduces the cartilage thickness enabling better visualization of subchondral bone. It was observed that PG has higher clearing rate. The clearing saturation time is of 30 min, however less than 5 min is enough to detect cartilage-bone interface. We conclude that iohexol solution is superior for OCT imaging of cartilage and cartilage-bone interface, while PG suits better for subhondral bone visualization.

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

PubMed

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. © 2014 American Institute of Chemical Engineers.

Background ELF magnetic fields in incubators: a factor of importance in cell culture work.

PubMed

Mild, Kjell Hansson; Wilén, Jonna; Mattsson, Mats-Olof; Simko, Myrtill

2009-07-01

Extremely low frequency (ELF) magnetic fields in cell culture incubators have been measured. Values of the order of tens of muT were found which is in sharp contrast to the values found in our normal environment (0.05-0.1microT). There are numerous examples of biological effects found after exposure to MF at these levels, such as changes in gene expression, blocked cell differentiation, inhibition of the effect of tamoxifen, effects on chick embryo development, etc. We therefore recommend that people working with cell culture incubators check for the background magnetic field and take this into account in performing their experiments, since this could be an unrecognised factor of importance contributing to the variability in the results from work with cell cultures.

Clear-Sky Narrowband Albedo Datasets Derived from Modis Data

NASA Astrophysics Data System (ADS)

Chen, Y.; Minnis, P.; Sun-Mack, S.; Arduini, R. F.; Hong, G.

2013-12-01

Satellite remote sensing of clouds requires an accurate estimate of the clear-sky radiances for a given scene to detect clouds and aerosols and to retrieve their microphysical properties. Knowing the spatial and angular variability of clear-sky albedo is essential for predicting the clear-sky radiance at solar wavelengths. The Clouds and the Earth's Radiant Energy System (CERES) Project uses the near-infrared (NIR; 1.24, 1.6 or 2.13 μm) and visible (VIS; 0.63 μm) channels available on the Terra and Aqua Moderate Resolution Imaging Spectroradiometers (MODIS) to help identify clouds and retrieve their properties. Generally, clear-sky albedo for a given surface type is determined for conditions when the vegetation is either thriving or dormant and free of snow. The clear-sky albedos are derived using a radiative transfer parameterization of the impact of the atmosphere, including aerosols, on the observed reflectances. This paper presents the method of generating monthly clear-sky overhead albedo maps for both snow-free and snow-covered surfaces of these channels using one year of MODIS (Moderate Resolution Imaging Spectroradiometer) CERES products. Maps of 1.24 and 1.6 μm are being used as the background to help retrieve cloud properties (e.g., effective particle size, optical depth) in CERES cloud retrievals in both snow-free and snow-covered conditions.

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

PubMed Central

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

Outcome of papillary versus clear cell renal cell carcinoma varies significantly in non-metastatic disease

PubMed Central

Edelmann, Dominic; Benner, Axel; Zigeuner, Richard; Borgmann, Hendrik; Wolff, Ingmar; Krabbe, Laura M.; Musquera, Mireia; Dell’Oglio, Paolo; Capitanio, Umberto; Klatte, Tobias; Cindolo, Luca; May, Matthias; Brookman-May, Sabine D.

2017-01-01

Renal cell carcinoma (RCC) comprises a heterogenous group of tumors. Traditionally, papillary RCC (pRCC) is associated with a favorable outcome compared to clear cell RCC (ccRCC), while other series report equivalent or worse prognosis. In this paper we comparatively evaluate outcome of pRCC versus ccRCC in two large multi-institutional databases (cohort study), including distribution of pRCC subtypes 1 and 2. Retrospective data of 1,943 surgically treated pRCC patients from 17 European/ North American centers between 1984–2015 were compared to 5,600 ccRCC patients from a database comprising 11 European/ North American centers (1984–2011). Median follow-up was 64.6 months. Differences between pRCC, subtypes, and ccRCC were compared with t-tests, Chi^2-tests, and exact Fisher tests. Cancer-specific mortality was analyzed with cumulative incidence curves and Cox cause-specific hazard models. The robustness of our results was examined with sensitivity analyses. We present that cancer-specific mortality rates and variables as stage, lymph node, and distant metastasis differ significantly between groups. Furthermore, we demonstrate that patients with non-metastatic pRCC had a significantly better cancer-specific mortality (HR 0.76, p = 0.007), when compared to ccRCC. Additionally, pRCC type 2 versus ccRCC exhibited no difference in cancer-specific mortality (HR 0.9, p = 0.722), whereas pRCC type 1 versus ccRCC displayed a risk of death reduced by 69% (p = 0.044). Taken together, outcome of pRCC versus ccRCC varies significantly in non-metastatic disease. Furthermore, pRCC type 2 exhibited no difference in cancer-specific mortality, whereas pRCC type 1 displayed a significantly reduced risk of death. Consequently, there is urgent need to respect histopathological entities and their subtypes, when assigning follow-up or targeted therapy to RCC patients. PMID:28934212

AFM feature definition for neural cells on nanofibrillar tissue scaffolds.

PubMed

Tiryaki, Volkan M; Khan, Adeel A; Ayres, Virginia M

2012-01-01

A diagnostic approach is developed and implemented that provides clear feature definition in atomic force microscopy (AFM) images of neural cells on nanofibrillar tissue scaffolds. Because the cellular edges and processes are on the same order as the background nanofibers, this imaging situation presents a feature definition problem. The diagnostic approach is based on analysis of discrete Fourier transforms of standard AFM section measurements. The diagnostic conclusion that the combination of dynamic range enhancement with low-frequency component suppression enhances feature definition is shown to be correct and to lead to clear-featured images that could change previously held assumptions about the cell-cell interactions present. Clear feature definition of cells on scaffolds extends the usefulness of AFM imaging for use in regenerative medicine. © Wiley Periodicals, Inc.

Clear cell adenocarcinoma of cervix in 1-year-old girl without in utero exposure to diethylstilbestrol: an uncommon tumour at an uncommon age and site.

PubMed

Arora, Aditi; Rastogi, Anurag; Neyaz, Azfar; Husain, Nuzhat

2017-03-16

Adenocarcinoma of cervix constitutes about 10-15% cases of carcinoma cervix. Clear cell variant is even a rarer variant of adenocarcinoma. It rarely occurs in the paediatric age group and a known risk factor is in utero exposure to diethylstilbestrol (DES). We report here a case of primary cervical tumour in a 1-year-old girl, which was initially suspected to be an embryonal rhabdomyosarcoma botryoides. Histopathology with immunohistochemical analysis revealed clear cell adenocarcinoma. There was no maternal history of DES intake during pregnancy. We discuss the histopathological characteristics and clinical course of this unusual tumour. 2017 BMJ Publishing Group Ltd.

Deregulation of energetic metabolism in the clear cell renal cell carcinoma: A multiple pathway analysis based on microarray profiling.

PubMed

Soltysova, Andrea; Breza, Jan; Takacova, Martina; Feruszova, Jana; Hudecova, Sona; Novotna, Barbora; Rozborilova, Eva; Pastorekova, Silvia; Kadasi, Ludevit; Krizanova, Olga

2015-07-01

Clear cell renal cell carcinoma (ccRCC) is the most frequent type of kidney cancer. In order to better understand the biology of ccRCC, we accomplished the gene profiling of fresh tissue specimens from 11 patients with the renal tumors (9 ccRCCs, 1 oncocytoma and 1 renal B-lymphoma), in which the tumor-related data were compared to the paired healthy kidney tissues from the same patients. All ccRCCs exhibited a considerably elevated transcription of the gene coding for carbonic anhydrase IX (CAIX). Moreover, the ccRCC tumors consistently displayed increased expression of genes encoding the glycolytic pathway enzymes, e.g. hexokinase II (HK2) and lactate dehydrogenase A (LDHA) and a decreased expression of genes for the mitochondrial electron transport chain components, indicating an overall reprogramming of the energetic metabolism in this tumor type. This appears to be accompanied by altered expression of the genes of the pH regulating machinery, including ion and lactate transporters. Immunohistochemical staining of tumor tissue sections confirmed the increased expression of CAIX, HK2 and LDHA in ccRCC, validating the microarray data and supporting their potential as the energetic metabolism-related biomarkers of the ccRCC.

Single-molecule RNA detection at depth by hybridization chain reaction and tissue hydrogel embedding and clearing.

PubMed

Shah, Sheel; Lubeck, Eric; Schwarzkopf, Maayan; He, Ting-Fang; Greenbaum, Alon; Sohn, Chang Ho; Lignell, Antti; Choi, Harry M T; Gradinaru, Viviana; Pierce, Niles A; Cai, Long

2016-08-01

Accurate and robust detection of mRNA molecules in thick tissue samples can reveal gene expression patterns in single cells within their native environment. Preserving spatial relationships while accessing the transcriptome of selected cells is a crucial feature for advancing many biological areas - from developmental biology to neuroscience. However, because of the high autofluorescence background of many tissue samples, it is difficult to detect single-molecule fluorescence in situ hybridization (smFISH) signals robustly in opaque thick samples. Here, we draw on principles from the emerging discipline of dynamic nucleic acid nanotechnology to develop a robust method for multi-color, multi-RNA imaging in deep tissues using single-molecule hybridization chain reaction (smHCR). Using this approach, single transcripts can be imaged using epifluorescence, confocal or selective plane illumination microscopy (SPIM) depending on the imaging depth required. We show that smHCR has high sensitivity in detecting mRNAs in cell culture and whole-mount zebrafish embryos, and that combined with SPIM and PACT (passive CLARITY technique) tissue hydrogel embedding and clearing, smHCR can detect single mRNAs deep within thick (0.5 mm) brain slices. By simultaneously achieving ∼20-fold signal amplification and diffraction-limited spatial resolution, smHCR offers a robust and versatile approach for detecting single mRNAs in situ, including in thick tissues where high background undermines the performance of unamplified smFISH. © 2016. Published by The Company of Biologists Ltd.

Clinical Significance of Tissue Factor Pathway Inhibitor 2, a Serum Biomarker Candidate for Ovarian Clear Cell Carcinoma

PubMed Central

Arakawa, Noriaki; Kobayashi, Hiroshi; Yonemoto, Naohiro; Masuishi, Yusuke; Ino, Yoko; Shigetomi, Hiroshi; Furukawa, Naoto; Ohtake, Norihisa; Miyagi, Yohei; Hirahara, Fumiki; Hirano, Hisashi; Miyagi, Etsuko

2016-01-01

Background There is currently no reliable serum biomarker for ovarian clear cell carcinoma (CCC), a highly lethal histological subtype of epithelial ovarian cancer (EOC). Previously, using a proteome-based approach, we identified tissue factor pathway inhibitor 2 (TFPI2) as a candidate serum biomarker for CCC. In this study, we sought to evaluate the clinical diagnostic performance of TFPI2 in preoperative prediction of CCC. Methods Serum TFPI2 levels were measured in serum samples from a retrospective training set consisting of patients with benign and borderline ovarian tumors, EOC subtypes, and uterine diseases. Via receiver operating characteristic (ROC) analyses, we compared the diagnostic performance of TFPI2 with that of CA125 in discrimination of patients with ovarian CCC from other patient groups. The observed diagnostic performances were examined in a prospective validation set. Results The 268-patient training set included 29 patients with ovarian CCC. Unlike CA125, which was also elevated in patients with endometriosis and several EOC subtypes, serum TFPI2 levels were specifically elevated only in ovarian CCC patients, consistent with the mRNA expression pattern in tumor tissues. The area under the ROC curve (AUC) of serum TFPI2 was obviously higher than that of CA125 for discrimination of CCC from other ovarian diseases (AUC = 0.891 versus 0.595). Applying a cut-off value of 280 pg/mL, TFPI2 could distinguish early-stage (FIGO I and II) CCC from endometriosis with 72.2% sensitivity, 93.3% specificity, and 88.8% accuracy. Similar results were confirmed in an independent 156-patient prospective validation set. Conclusions TFPI2 is a useful serum biomarker for preoperative clinical diagnosis of CCC. PMID:27798689

Efficient generation of patient-matched malignant and normal primary cell cultures from clear cell renal cell carcinoma patients: clinically relevant models for research and personalized medicine.

PubMed

Lobo, Nazleen C; Gedye, Craig; Apostoli, Anthony J; Brown, Kevin R; Paterson, Joshua; Stickle, Natalie; Robinette, Michael; Fleshner, Neil; Hamilton, Robert J; Kulkarni, Girish; Zlotta, Alexandre; Evans, Andrew; Finelli, Antonio; Moffat, Jason; Jewett, Michael A S; Ailles, Laurie

2016-07-16

Patients with clear cell renal cell carcinoma (ccRCC) have few therapeutic options, as ccRCC is unresponsive to chemotherapy and is highly resistant to radiation. Recently targeted therapies have extended progression-free survival, but responses are variable and no significant overall survival benefit has been achieved. Commercial ccRCC cell lines are often used as model systems to develop novel therapeutic approaches, but these do not accurately recapitulate primary ccRCC tumors at the genomic and transcriptional levels. Furthermore, ccRCC exhibits significant intertumor genetic heterogeneity, and the limited cell lines available fail to represent this aspect of ccRCC. Our objective was to generate accurate preclinical in vitro models of ccRCC using tumor tissues from ccRCC patients. ccRCC primary single cell suspensions were cultured in fetal bovine serum (FBS)-containing media or defined serum-free media. Established cultures were characterized by genomic verification of mutations present in the primary tumors, expression of renal epithelial markers, and transcriptional profiling. The apparent efficiency of primary cell culture establishment was high in both culture conditions, but genotyping revealed that the majority of cultures contained normal, not cancer cells. ccRCC characteristically shows biallelic loss of the von Hippel Lindau (VHL) gene, leading to accumulation of hypoxia-inducible factor (HIF) and expression of HIF target genes. Purification of cells based on expression of carbonic anhydrase IX (CA9), a cell surface HIF target, followed by culture in FBS enabled establishment of ccRCC cell cultures with an efficiency of >80 %. Culture in serum-free conditions selected for growth of normal renal proximal tubule epithelial cells. Transcriptional profiling of ccRCC and matched normal cell cultures identified up- and down-regulated networks in ccRCC and comparison to The Cancer Genome Atlas confirmed the clinical validity of our cell cultures. The

Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer

PubMed Central

Samartzis, Eleftherios Pierre; Dedes, Ioannis; Lambros, Maryou B; Natrajan, Rachael; Gauthier, Arnaud; Piscuoglio, Salvatore; Töpfer, Chantal; Vukovic, Vesna; Daley, Frances; Weigelt, Britta; Reis-Filho, Jorge S

2017-01-01

Purpose To determine if models of ovarian clear cell carcinomas (OCCCs) harbouring defects in homologous recombination (HR) DNA repair of double strand breaks (DSBs) are sensitive to cisplatin and/or PARP inhibition. Experimental Design The HR status of 12 OCCC cell lines was determined using RAD51/γH2AX foci formation assays. Sensitivity to cisplatin and the PARP inhibitor BMN-673 was correlated with HR status. BRCA1, BRCA2, MRE11 and PTEN loss of expression was investigated as a potential determinant of BMN-673 sensitivity. A tissue microarray containing 50 consecutive primary OCCC was assessed for PTEN expression using immunohistochemistry. Results A subset of OCCC cells displayed reduced RAD51 foci formation in the presence of DNA DSBs, suggestive of HR defects. HR-defective OCCC cells, with the exception of KOC-7c, had higher sensitivity to cisplatin/ BMN-673 than HR-competent OCCC cell lines (Log10 SF50 –9.4 (SD +/− 0.29) vs –8.1 (SD +/− 0.35), mean difference 1.3, p < 0.01). Of the cell lines studied, two, TOV-21G and KOC-7c, showed loss of PTEN expression. In primary OCCCs, loss of PTEN expression was observed in 10% (5/49) of cases. Conclusions A subset of OCCC cells are sensitive to PARP inhibition in vitro, which can be predicted by HR defects as defined by γH2AX/RAD51 foci formation. These results provide a rationale for the testing of HR deficiency and PARP inhibitors as a targeted therapy in a subset of OCCCs. PMID:28002809

Ultrastructural effects of silicone oil on the clear crystalline lens of the human eye.

PubMed

Soliman, Wael; Sharaf, Mohamed; Abdelazeem, Khaled; El-Gamal, Dalia; Nafady, Allam

2018-03-01

To evaluate light and electron microscopic changes of the anterior capsule and its epithelium after clear lens extraction of vitrectomized myopic eyes with silicone oil tamponade. This prospective, controlled, non-randomized, interventional study included 20 anterior lens capsular specimens that were excised during combined clear lens extraction and silicone oil removal from previously vitrectomized highly myopic patients with silicone oil tamponade for previous retinal detachment surgeries. The specimens were examined via light microscopy and electron microscopy and compared with 20 anterior capsule specimens removed during clear lens extraction of non-vitrectomized highly myopic eyes. Light microscopic examination of clear lens anterior capsule specimens of vitrectomized myopic eyes filled with silicone oil showed relatively more flat cells with irregular outline of lens' epithelial cells with wide intercellular spaces, deeply stained nuclei, and multiple intracytoplasmic vacuoles. Scanning electron microscopy revealed collagenous surfaces filled with multiple pits, depressions, and abnormal deposits. Transmission electron microscopy revealed lens epithelial cells with apoptotic changes, many cytoplasmic vacuoles, and filopodia-like protrusions between lens epithelial cells and the capsule. Epithelial proliferation and multilayering were also observed. silicone oil may play a role in the development of apoptotic and histopathological changes in clear lens epithelial cells. Clarity of the lens at the time of silicone oil removal does not indicate an absence of cataractous changes. We found justification of combined clear lens extraction and silicone oil removal or combined phacovitrectomy when silicone oil injection is planned, but further long-term studies with larger patient groups are required.

Evaluation and Assimilation of Cloud Cleared Radiances for AIRS in GEOS-5

NASA Technical Reports Server (NTRS)

Liu, Hui-chun

2008-01-01

The use of clear (cloud-free) channels for AIRS in GEOS-5 had shown positive impact on forecast skills in both hemispheres. However, improvements in forecast skills due to the assimilation of AIRS data are less impressive since the number of assimilated channels from AIRS is much larger than that from other Infrared sounders such as HIRS-3 onboard NOAA 15-17 satellites. This limitation of AIRS radiance data to improve the forecast skill is mainly due to the fact that channels capable of peaking below clouds are not used in the assimilation and yet those have highest vertical resolving capability of AIRS instrument are concentrated in the lower troposphere. On average, the percentage of AIRS footprints completely clear for all channels is less than 10%. The percentage of assimilated AIRS channel radiances however ranges from 100% for channels peaking in the upper stratosphere, above the cloud, to no more that 5% in the lower atmosphere due to cloud contamination. Our current ability to model and predict clouds accurately in global model, and to fully characterize and parameterize optical properties of cloud particles in radiative transfer model are the two major obstacles prohibiting us to use cloudy radiance directly in the assimilation. To further improve forecast skill using AIRS data, we ought to use the channels peaking below the clouds in the troposphere, which can be accomplished by assimilating cloud-cleared radiance. The cloud-cleared radiance data for AIRS used in this study were obtained from optimal cloud clearing procedures developed by researchers at CIMSS of University of Wisconsin at Madison to retrieve clear column radiances for all AIRS channels by collocating multi-band MODIS IR clear radiance observations with the AIRS cloudy radiances on a single footprint basis. Two adjacent AIRS cloudy footprints are used to retrieve one AIRS cloud-cleared radiance spectrum and no background information (first guess) is needed. To assimilate the cloud-cleared

Solitary vertebral metastasis of primary clear cell carcinoma of the liver: a case report and review of literature

PubMed Central

Maharajan, Karthikeyan; Tham, Ivan; Thamboo, Thomas Paulraj; Wong, Alvin; Khan, Irfan Sagir; Kumar, Naresh

2017-01-01

Primary clear cell carcinoma of liver (PCCCL) is an uncommon variant of primary hepatocellular carcinoma. Though the literature describes a better prognosis in relation to the proportion of clear cells in the tumour when compared to the other variants, there is no general consensus in the management due to its rarity and unclear clinicopathological and prognostic factors. There is dearth of evidence with regard to the metastasizing nature of PCCCL and its management. In addition, the management of recurrent spinal tumours both primary and metastatic is not clear as the available evidence is mostly based on case reports. We describe an unusual presentation of PCCCL with solitary spinal metastasis and further complicated by tumour recurrence in a 71-year-old male. Such presentation has never been described before. He presented with low back pain and incomplete neurological deficits involving both lower limbs. On detailed evaluation, he was found to have a solitary metastasis at L3 vertebra secondary to PCCCL. He underwent radical excision of tumour and reconstruction for the solitary metastasis at L3 vertebral body and trans arterial chemo embolisation (TACE) for the hepatic lesion. Pt was asymptomatic until 9 months post operatively when he developed tumour recurrence at L3 vertebra. Patient subsequently underwent 2 stage palliative surgery followed by radiotherapy and chemotherapy. At his latest follow-up (1 year), the patient’s overall general condition has improved with residual neurological deficits in the lower limb. PCCCL is a rare type of hepatocellular carcinoma which can present as “solitary metastasis” to the spine. Although the literature suggests a good prognosis for this histological type, this case did not have a good outcome. In addition to providing information for the management of similar cases in the future, this case report highlights that every patient has to be managed on a case-by-case basis. PMID:28744515

Dynamic Computed Tomographic Features of Adult Renal Cell Carcinoma Associated With Xp11.2 Translocation/TFE3 Gene Fusions: Comparison With Clear Cell Renal Cell Carcinoma.

PubMed

He, Jian; Gan, Weidong; Liu, Song; Zhou, Kefeng; Zhang, Gutian; Guo, Hongqian; Zhu, Bin

2015-01-01

To investigate the dynamic contrast-enhanced computed tomography (CT) characteristics of renal cell carcinoma associated with Xp11.2 translocation and TFE gene fusion (Xp11.2 RCC) by comparison with clear cell renal cell carcinoma (CCRCC). Dynamic contrast-enhanced CT images and clinical and pathological records of 20 adult patients with Xp11.2 RCC confirmed by TFE3 immunohistochemical and fluorescence in situ hybridization assay were retrospectively analyzed and compared with the findings of 21 contemporary CCRCCs. Renal cell carcinoma associated with Xp11.2 translocation and TFE gene fusions often occurred in young (30.6 ± 8.6 years) patients with hematuria (9/20). They presented as well-defined (17/20) cystic-solid (17/20) mass with hemorrhage (8/20) and circular/rim calcifications (6/20). Dynamic contrast-enhanced CT showed heterogeneous moderate prolonged enhancement. A tumor-to-cortex attenuation ratio in corticomedullary phase less than 0.62 gave a sensitivity of 90.0% and a specificity of 92.9% in differentiating Xp11.2 RCC from CCRCC (area under the receiver operating characteristic curve = 0.957, P < 0.001). Computed tomographic characteristics and dynamic contrast-enhanced patterns and index can differentiate Xp11.2 RCC from CCRCC.

Toward an understanding of the pathophysiology of clear cell carcinoma of the ovary (Review)

PubMed Central

UEKURI, CHIHARU; SHIGETOMI, HIROSHI; ONO, SUMIRE; SASAKI, YOSHIKAZU; MATSUURA, MIYUKI; KOBAYASHI, HIROSHI

2013-01-01

Endometriosis-associated ovarian cancers demonstrate substantial morphological and genetic diversity. The transcription factor, hepatocyte nuclear factor (HNF)-1β, may be one of several key genes involved in the identity of ovarian clear cell carcinoma (CCC). The present study reviews a considerably expanded set of HNF-1β-associated genes and proteins that determine the pathophysiology of CCC. The current literature was reviewed by searching MEDLINE/PubMed. Functional interpretations of gene expression profiling in CCC are provided. Several important CCC-related genes overlap with those known to be regulated by the upregulation of HNF-1β expression, along with a lack of estrogen receptor (ER) expression. Furthermore, the genetic expression pattern in CCC resembles that of the Arias-Stella reaction, decidualization and placentation. HNF-1β regulates a subset of progesterone target genes. HNF-1β may also act as a modulator of female reproduction, playing a role in endometrial regeneration, differentiation, decidualization, glycogen synthesis, detoxification, cell cycle regulation, implantation, uterine receptivity and a successful pregnancy. In conclusion, the present study focused on reviewing the aberrant expression of CCC-specific genes and provided an update on the pathological implications and molecular functions of well-characterized CCC-specific genes. PMID:24179489

Tubular epithelial cells in renal clear cell carcinoma express high RIPK1/3 and show increased susceptibility to TNF receptor 1-induced necroptosis

PubMed Central

Al-Lamki, R S; Lu, W; Manalo, P; Wang, J; Warren, A Y; Tolkovsky, A M; Pober, J S; Bradley, J R

2016-01-01

We previously reported that renal clear cell carcinoma cells (RCC) express both tumor necrosis factor receptor (TNFR)-1 and -2, but that, in organ culture, a TNF mutein that only engages TNFR1, but not TNFR2, causes extensive cell death. Some RCC died by apoptosis based on detection of cleaved caspase 3 in a minority TUNEL-positive cells but the mechanism of death in the remaining cells was unexplained. Here, we underpin the mechanism of TNFR1-induced cell death in the majority of TUNEL-positive RCC cells, and show that they die by necroptosis. Malignant cells in high-grade tumors displayed threefold to four fold higher expression of both receptor-interacting protein kinase (RIPK)1 and RIPK3 compared with non-tumor kidney tubular epithelium and low-grade tumors, but expression of both enzymes was induced in lower grade tumors in organ culture in response to TNFR1 stimulation. Furthermore, TNFR1 activation induced significant MLKLSer358 and Drp1Ser616 phosphorylation, physical interactions in RCC between RIPK1-RIPK3 and RIPK3-phospho-MLKLSer358, and coincidence of phospho-MLKLser358 and phospho-Drp1Ser616 at mitochondria in TUNEL-positive RCC. A caspase inhibitor only partially reduced the extent of cell death following TNFR1 engagement in RCC cells, whereas three inhibitors, each targeting a different step in the necroptotic pathway, were much more protective. Combined inhibition of caspases and necroptosis provided additive protection, implying that different subsets of cells respond differently to TNF-α, the majority dying by necroptosis. We conclude that most high-grade RCC cells express increased amounts of RIPK1 and RIPK3 and are poised to undergo necroptosis in response to TNFR1 signaling. PMID:27362805

Osteomalacia-inducing renal clear cell carcinoma uncovered by 99mTc-Hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNIC-TOC) scintigraphy.

PubMed

Jin, Xiaona; Jing, Hongli; Li, Fang; Zhuang, Hongming

2013-11-01

Most osteomalacia-causing tumors are small, benign mesenchymal neoplasms, which are commonly located in the extremities or craniofacial regions. An 18-year-old male patient with suspicion of tumor-induced osteomalacia underwent (99m)Tc-HYNIC-TOC scintigraphy to search potential culprit tumor. The images showed a large activity in the region of the left kidney. The lesion was resected and a clear cell renal cell carcinoma was found. One year after the left nephrectomy, the patient was tumor-free without symptoms of osteomalacia.

Children's Perception of Conversational and Clear American-English Vowels in Noise

ERIC Educational Resources Information Center

Leone, Dorothy; Levy, Erika S.

2015-01-01

Purpose: Much of a child's day is spent listening to speech in the presence of background noise. Although accurate vowel perception is important for listeners' accurate speech perception and comprehension, little is known about children's vowel perception in noise. "Clear speech" is a speech style frequently used by talkers in the…

Highly sensitive low-background fluorescent probes for imaging of nitric oxide in cells and tissues.

PubMed

Zhang, Hui-Xian; Chen, Jian-Bo; Guo, Xiao-Feng; Wang, Hong; Zhang, Hua-Shan

2014-03-18

Small-molecule fluorescent probes in combination with fluorescent microscopy can be a powerful tool to provide real-time detection and high spatiotemporal resolution of transient molecules in cells and bodies. For the design of fluorescent probes for transient molecule imaging, high detection sensitivity is crucial. In this report, two new fluorescent probes, 8-(3,4-diaminophenyl)-4,4-difluoro-4-bora-3a,4a-diaza-di(1,2-dihydro)naphtho[b,g]-s-indacene (DANPBO-H) and 8-(3,4-diaminophenyl)-1,7-dimethyl-4,4-difluoro-4-bora-3a,4a-diaza-di(1,2-dihydro)naphtho[b,g]-s-indacene (DANPBO-M), have been developed for nitric oxide (NO) imaging. The detection sensitivity has been efficiently improved by use of these probes through increasing NO detection signals and decreasing background fluorescence. Fluorescence in the far-red region is enhanced by 400- and 550-fold after reaction with NO is achieved and remains stable for at least 24 h under the irradiation of xenon lamp. Excitation and emission wavelengths longer than 600 nm and excellent intracellular retention of these probes and their NO products create dark background inside and outside cells and tissues. What is more, the excellent intracellular retention of these compounds is obtained by their strong lipophilicity, which is a novel design concept diametrically opposite to the traditional approaches. The high sensitivity and dark background make DANPBO-H and DANPBO-M competitive for NO imaging in cells and tissues. The lipophilicity-based intracellular retention mechanism as a design strategy has great potential in the development of fluorescent probes for bioimaging.

Downregulation of long non-coding RNA ENSG00000241684 is associated with poor prognosis in advanced clear cell renal cell carcinoma.

PubMed

Su, Hengchuan; Wang, Hongkai; Shi, Guohai; Zhang, Hailiang; Sun, Fukang; Ye, Dingwei

2018-06-01

In order to identify potential novel biomarkers of advanced clear cell renal cell carcinoma (ccRCC), we re-evaluated published long non-coding RNA (lncRNA) expression profiling data. The lncRNA expression profiles in ccRCC microarray dataset GSE47352 were analyzed and an independent cohort of 61 clinical samples including 21 advanced and 40 localized ccRCC patients was used to confirm the most statistically significant lncRNAs by real time PCR. Next, the relationships between the selected lncRNAs and ccRCC patients' clinicopathological features were investigated. The effects of LncRNAs on the invasion and proliferation of renal carcinoma cells were also investigated. The PCR results in a cohort of 21 advanced ccRCC and 40 localized ccRCC tissues were used for confirmation of the selected lncRNAs which were statistically most significant. The PCR results showed that the expression of three LncRNA (ENSG00000241684, ENSG00000231721 and NEAT1) were significantly downregulated in advanced ccRCC. Kaplan-Meier analysis revealed that reduced expression of LncRNA ENSG00000241684 and NEAT1 were significantly associated with poor overall survival. The univariate and multivariate Cox regression indicated LncRNA ENSG00000241684 had significant hazard ratios for predicting clinical outcome. LncRNA ENSG00000241684 expression was negatively correlated with pTNM stage. Overexpression of ENSG00000241684 significantly impaired cell proliferation and reduced the invasion ability in 786-O and ACHN cells. lncRNAs are involved in renal carcinogenesis and decreased lncRNA ENSG00000241684 expression may be an independent adverse prognostic factor in advanced ccRCC patients. Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

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

PubMed

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 (p<0.001), advanced clinical stage (p=0.030) and distant metastasis (p=0.009). In survival analyses, PAI-1 expression was correlated with disease-free survival in Kaplan-Meier curves (p=0.015) but was not significant in the Cox hazards model (p=0.527). The frequencies of the promoter polymorphism were 24.6% (17/69) 4G/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.

[Evaluation of signal noise ratio on analysis of clear cell renal cell carcinoma using DWI with multi-b values].

PubMed

Ding, Jiule; Xing, Wei; Chen, Jie; Dai, Yongming; Sun, Jun; Li, Dengfa

2014-01-21

To explore the influence of signal noise ratio (SNR) on analysis of clear cell renal cell carcinoma (CCRCC) using DWI with multi-b values. The images of 17 cases with CCRCC were analyzed, including 17 masses and 9 pure cysts. The signal intensity of the cysts and masses was measured separately on DWI for each b value. The minimal SNR, as the threshold, was recorded when the signal curve manifest as the single exponential line. The SNR of the CCRCC was calculated on DWI for each b value, and compared with the threshold by independent Two-sample t Test. The signal decreased on DWI with increased b factors for both pure cysts and CCRCC. The threshold is 1.29 ± 0.17, and the signal intensity of the cysts on DWI with multi-b values shown as a single exponential line when b ≤ 800 s/mm(2). For the CCRCC, the SNR is similar to the threshold when b = 1 000 s/mm(2) (t = 0.40, P = 0.69), and is lower when b = 1 200 s/mm(2) (t = -2.38, P = 0.03). The SNR should be sufficient for quantitative analysis of DWI, and the maximal b value is 1000 s/mm(2) for CCRCC.

Concurrent primary carcinoid tumor arising within mature teratoma and clear cell renal cell carcinoma in the horseshoe kidney: report of a rare case and review of the literature.

PubMed

Sun, Ke; You, Qihan; Zhao, Ming; Yao, Hongtian; Xiang, Hua; Wang, Lijun

2013-01-01

Primary carcinoid tumor arising in a mature teratoma of the horseshoe kidney is exceptionally rare and only 4 such cases have been reported in the world literature to date. The simultaneous occurrence of different subtypes of renal cell carcinoma (RCC) or RCC coexistence with non-RCC neoplasms from the same kidney is unusual and infrequently reported. Herein we report a case of primary carcinoid tumor arising within mature teratoma, concurrent with a clear cell RCC in the horseshoe kidney of a 37-year-old man. Histologically, both the carcinoid tumor and clear cell RCC demonstrated the characteristic morphology in their classic forms. In addition to the carcinoid tumor, the mature teratoma consisted of variably sized, large cystic spaces lined by cytologically bland mucinous columnar epithelium, pseudostratified columnar epithelium, ciliated epithelium and mature smooth muscle fibers were also identified within the cystic wall. Furthermore, foci of round, small nodules composed of mature prostatic acinus were noted in the teratoma which was confirmed by exhibiting strong immunoreactivity for prostate specific antigen. The present case serves to expand the histologic component that may be encountered in the mature terotoma of the kidney and further broadens the spectrum of primary tumors occurring in the horseshoe kidney.

A BAP1 Mutation-specific MicroRNA Signature Predicts Clinical Outcomes in Clear Cell Renal Cell Carcinoma Patients with Wild-type BAP1

PubMed Central

Ge, Yu-Zheng; Xu, Lu-Wei; Zhou, Chang-Cheng; Lu, Tian-Ze; Yao, Wen-Tao; Wu, Ran; Zhao, You-Cai; Xu, Xiao; Hu, Zhi-Kai; Wang, Min; Yang, Xiao-Bing; Zhou, Liu-Hua; Zhong, Bing; Xu, Zheng; Li, Wen-Cheng; Zhu, Jia-Geng; Jia, Rui-Peng

2017-01-01

Background: Clear cell renal cell carcinoma (ccRCC) is the most prevalent histologic subtype of kidney cancers in adults, which could be divided into two distinct subgroups according to the BRCA1 associated protein-1 (BAP1) mutation status. In the current study, we comprehensively analyzed the genome-wide microRNA (miRNA) expression profiles in ccRCC, with the aim to identify the differentially expressed miRNAs between BAP1 mutant and wild-type tumors, and generate a BAP1 mutation-specific miRNA signature for ccRCC patients with wild-type BAP1. Methods: The BAP1 mutation status and miRNA profiles in BAP1 mutant and wild-type tumors were analyzed. Subsequently, the association of the differentially expressed miRNAs with patient survival was examined, and a BAP1 mutation-specific miRNA signature was generated and examined with Kaplan-Meier survival, univariate and multivariate Cox regression analyses. Finally, the bioinformatics methods were adopted for the target prediction of selected miRNAs and functional annotation analyses. Results: A total of 350 treatment-naïve primary ccRCC patients were selected from The Cancer Genome Atlas project, among which 35 (10.0%) subjects carried mutant BAP1 and had a shorter overall survival (OS) time. Furthermore, 33 miRNAs were found to be differentially expressed between BAP1 mutant and wild-type tumors, among which 11 (miR-149, miR-29b-2, miR-182, miR-183, miR-21, miR-365-2, miR-671, miR-365-1, miR-10b, miR-139, and miR-181a-2) were significantly associated with OS in ccRCC patients with wild-type BAP1. Finally, a BAP1 mutation-specific miRNA signature consisting of 11 miRNAs was generated and validated as an independent prognostic parameter. Conclusions: In summary, our study identified a total of 33 miRNAs differentially expressed between BAP1 mutant and wild-type tumors, and generated a BAP1 mutation-specific miRNA signature including eleven miRNAs, which could serve as a novel prognostic biomarker for ccRCC patients with

PIK3CA and KRAS mutations in cell free circulating DNA are useful markers for monitoring ovarian clear cell carcinoma

PubMed Central

Morikawa, Asuka; Hayashi, Tomoatsu; Shimizu, Naomi; Kobayashi, Mana; Taniue, Kenzui; Takahashi, Akiko; Tachibana, Kota; Saito, Misato; Kawabata, Ayako; Iida, Yasushi; Ueda, Kazu; Saito, Motoaki; Yanaihara, Nozomu; Tanabe, Hiroshi; Yamada, Kyosuke; Takano, Hirokuni; Nureki, Osamu; Okamoto, Aikou; Akiyama, Tetsu

2018-01-01

Ovarian clear cell carcinoma (OCCC) exhibits distinct phenotypes, such as resistance to chemotherapy, poor prognosis and an association with endometriosis. Biomarkers and imaging techniques currently in use are not sufficient for reliable diagnosis of this tumor or prediction of therapeutic response. It has recently been reported that analysis of somatic mutations in cell-free circulating DNA (cfDNA) released from tumor tissues can be useful for tumor diagnosis. In the present study, we attempted to detect mutations in PIK3CA and KRAS in cfDNA from OCCC patients using droplet digital PCR (ddPCR). Here we show that we were able to specifically detect PIK3CA-H1047R and KRAS-G12D in cfDNA from OCCC patients and monitor their response to therapy. Furthermore, we found that by cleaving wild-type PIK3CA using the CRISPR/Cas9 system, we were able to improve the sensitivity of the ddPCR method and detect cfDNA harboring PIK3CA-H1047R. Our results suggest that detection of mutations in cfDNA by ddPCR would be useful for the diagnosis of OCCC, and for predicting its recurrence. PMID:29632642

ClearedLeavesDB: an online database of cleared plant leaf images.

PubMed

Das, Abhiram; Bucksch, Alexander; Price, Charles A; Weitz, Joshua S

2014-03-28

Leaf vein networks are critical to both the structure and function of leaves. A growing body of recent work has linked leaf vein network structure to the physiology, ecology and evolution of land plants. In the process, multiple institutions and individual researchers have assembled collections of cleared leaf specimens in which vascular bundles (veins) are rendered visible. In an effort to facilitate analysis and digitally preserve these specimens, high-resolution images are usually created, either of entire leaves or of magnified leaf subsections. In a few cases, collections of digital images of cleared leaves are available for use online. However, these collections do not share a common platform nor is there a means to digitally archive cleared leaf images held by individual researchers (in addition to those held by institutions). Hence, there is a growing need for a digital archive that enables online viewing, sharing and disseminating of cleared leaf image collections held by both institutions and individual researchers. The Cleared Leaf Image Database (ClearedLeavesDB), is an online web-based resource for a community of researchers to contribute, access and share cleared leaf images. ClearedLeavesDB leverages resources of large-scale, curated collections while enabling the aggregation of small-scale collections within the same online platform. ClearedLeavesDB is built on Drupal, an open source content management platform. It allows plant biologists to store leaf images online with corresponding meta-data, share image collections with a user community and discuss images and collections via a common forum. We provide tools to upload processed images and results to the database via a web services client application that can be downloaded from the database. We developed ClearedLeavesDB, a database focusing on cleared leaf images that combines interactions between users and data via an intuitive web interface. The web interface allows storage of large collections

Risk factor for clear cell renal cell carcinoma in Chinese population: a case-control study.

PubMed

Wang, Guoping; Hou, Jianguo; Ma, Liye; Xie, Jiaxin; Yin, Jianhua; Xu, Danfeng; Chang, Wenjun; Tan, Xiaojie; Su, Tong; Zhang, Hongwei; Cao, Guangwen

2012-04-01

Risk factors for clear cell renal cell carcinoma (ccRCC) differ among populations and remain controversial. We carried out a hospital-based case-control study to examine the effects of health status, lifestyle, and some genetic polymorphisms on ccRCC risk in Chinese subjects. Between 2007 and 2009, 250 newly diagnosed, histologically confirmed ccRCC cases and 299 sex-, age-matched healthy controls provided complete information including consumption of tea and alcohol, smoking, occupational exposure, body mass index (BMI), hypertension, diabetes, and urolithiasis by face-to-face interview in Shanghai. Genetic polymorphisms of cytochrome P450 mono-oxygenase (CYP1A1: 6235T>C, 4889A>G, and 4887C>A), glutathione S-transferase (GSTP1: 342A>G), and N-acetyltransferase (NAT2: 481C>T, 590G>A, and 857G>A) were identified by PCR-RFLP and DNA sequencing. Adjusted odds ratio (AOR) and 95% confidence interval (CI) were derived through multivariate logistic regression. Green tea intake (≥500 ml/d) was inversely associated with ccRCC risk, with an AOR of 0.34 (95% CI 0.21-0.55). BMI (≥25 kg/m(2)), hypertension, and urolithiasis were independently associated with an increased risk of ccRCC, with AOR (95% CI) of 2.10 (1.32-3.34), 2.49 (1.57-3.93), and 3.33 (1.12-9.89), respectively. No association was observed between smoking, alcohol consumption, or occupational exposure with ccRCC risk. The polymorphisms and their interactions with the environmental exposures were mostly not associated with ccRCC risk. BMI (≥25 kg/m(2)), hypertension, and urolithiasis are independently associated with an increased risk, whereas green tea intake (≥500 ml/d) is independently associated with a decreased risk of ccRCC. The polymorphisms of the xenobiotic-metabolizing enzymes are weakly associated with ccRCC risk in Chinese subjects. Copyright © 2011 Elsevier Ltd. All rights reserved.

Lymphovascular invasion in clear cell renal cell carcinoma--association with disease-free and cancer-specific survival.

PubMed

Belsante, Michael; Darwish, Oussama; Youssef, Ramy; Bagrodia, Aditya; Kapur, Payal; Sagalowsky, Arthur I; Lotan, Yair; Margulis, Vitaly

2014-01-01

The objective is to evaluate the effect of lymphovascular invasion (LVI) on disease-free survival (DFS) and cancer-specific survival (CSS) in patients with clinically localized clear cell renal cell carcinoma (ccRCC). Patients with ccRCC who were treated surgically in 1997 to 2010 were identified. Retrospective chart review was performed to identify clinical outcomes. Independent pathologic re-review was performed by a single pathologist to confirm LVI status. Pathologic features were correlated with clinical outcomes using Kaplan-Meier and Cox regression analyses. Four hundred and nineteen patients with nonmetastatic ccRCC comprised the study cohort. Three hundred and thirty-three of these patients had an organ-confined (pT1-2, N any, and M0) disease. LVI was present in 14.3% of all nonmetastatic patients. In all patients with nonmetastatic ccRCC, presence of LVI was correlated with significantly shorter DFS (P <0.001) and CSS (P = 0.001) on Kaplan-Meier analysis. In cases of organ-confined, nonmetastatic ccRCC, presence of LVI was a significant predictor of DFS (hazard ratio = 4.0, P = 0.026) and CSS (hazard ratio = 12.7, P = 0.01) on multivariate analysis. Patients with organ-confined RCC who were LVI positive had similar DFS (P = 0.957) and CSS (P = 0.799) to patients with locally advanced tumors (pT3-pT4, N any, and M0) on Kaplan-Meier analysis. The presence of LVI is an independent predictor of both DFS and CSS in organ-confined, nonmetastatic ccRCC. LVI positivity in patients with otherwise pathologically organ-confined ccRCC confers oncologic outcomes similar to those of patients with locally advanced disease. If confirmed by others, future revisions to the tumor-node-metastasis staging system may incorporate LVI status into the prognostic algorithm of patients with RCC. Copyright © 2014 Elsevier Inc. All rights reserved.

Low Expression of Mucin-4 Predicts Poor Prognosis in Patients With Clear-Cell Renal Cell Carcinoma

PubMed Central

Fu, Hangcheng; Liu, Yidong; Xu, Le; Chang, Yuan; Zhou, Lin; Zhang, Weijuan; Yang, Yuanfeng; Xu, Jiejie

2016-01-01

Abstract Mucin-4 (MUC4), a member of membrane-bound mucins, has been reported to exert a large variety of distinctive roles in tumorigenesis of different cancers. MUC4 is aberrantly expressed in clear-cell renal cell carcinoma (ccRCC) but its prognostic value is still unveiled. This study aims to assess the clinical significance of MUC4 expression in patients with ccRCC. The expression of MUC4 was assessed by immunohistochemistry in 198 patients with ccRCC who underwent nephrectomy retrospectively in 2003 and 2004. Sixty-seven patients died before the last follow-up in the cohort. Kaplan–Meier method with log-rank test was applied to compare survival curves. Univariate and multivariate Cox regression models were applied to evaluate the prognostic value of MUC4 expression in overall survival (OS). The predictive nomogram was constructed based on the independent prognostic factors. The calibration was built to evaluate the predictive accuracy of nomogram. In patients with ccRCC, MUC4 expression, which was determined to be an independent prognostic indicator for OS (hazard ratio [HR] 3.891; P < 0.001), was negatively associated with tumor size (P = 0.036), Fuhrman grade (P = 0.044), and OS (P < 0.001). The prognostic accuracy of TNM stage, UCLA Integrated Scoring System (UISS), and Mayo clinic stage, size, grade, and necrosis score (SSIGN) prognostic models was improved when MUC4 expression was added. The independent prognostic factors, pT stage, distant metastases, Fuhrman grade, sarcomatoid, and MUC4 expression were integrated to establish a predictive nomogram with high predictive accuracy. MUC4 expression is an independent prognostic factor for OS in patients with ccRCC. PMID:27124015

Clear-cell differentiation and lymphatic invasion, but not the revised TNM classification, predict lymph node metastases in pT1 penile cancer: a clinicopathologic study of 76 patients from a low incidence area.

PubMed

Mannweiler, Sebastian; Sygulla, Stephan; Tsybrovskyy, Oleksiy; Razmara, Yas; Pummer, Karl; Regauer, Sigrid

2013-10-01

Prediction of lymph node (LN) metastases in penile invasive cancer relies on clinical features and histologic characteristics of the primary tumor. Correct prediction, however, is difficult, as only 50% patients undergoing lymphadenectomies will have LN metastases. In 2009, the tumor, nodes, metastases (TNM) classification for staging of early penile cancers was revised. We tested the predictive accuracy of the revised TNM classification in a low incidence area for penile carcinoma. The presence of LN metastases in 76 men with pT1 penile cancers was correlated with the 2009 TNM subclassification, which is based on a combined evaluation of tumor grade and lymphatic invasion, but also with individual parameters, such as histologic grade, lymphatic invasion, perineural invasion, invasion depth, growth pattern and human papilloma virus (HPV) status. 76pT1 penile cancers were reclassified into 31pT1a squamous cell carcinomas (SCC) and 45pT1b (41 SCC; 4 clear-cell carcinomas); 12/22 men (55%; 8 SCC, 4 clear-cell carcinomas) undergoing lymphadenectomy for enlarged inguinal lymph nodes had metastases, 54 patients without enlarged LN and lymphadenectomies had no LN metastases during follow-up of median 47 months. Statistically, clear cell differentiation of the primary carcinoma was highly associated with metastases (100% clear-cell carcinomas vs. 11% SCC) and poor survival (50% vs. 5.5%). Among conventional SCC, only lymphatic invasion showed a highly significant association with metastases with 100% specificity. The 2009 TNM classification, tumor grade alone, perineural invasion, growth pattern, invasion depth or HPV status could not predict LN status. Lymphadenectomy for enlarged LN resulted in 100% sensitivity and 42% predictive probability for identifying metastases and a 16% false positive rate. Statistically, survival correlated significantly with clear-cell differentiation and with lymphatic invasion in both clear-cell carcinomas and conventional SCC. Penile clear-cell

Whole-body and Whole-Organ Clearing and Imaging Techniques with Single-Cell Resolution: Toward Organism-Level Systems Biology in Mammals.

PubMed

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. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ba2+- and bupivacaine-sensitive background K+ conductances mediate rapid EPSP attenuation in oligodendrocyte precursor cells

PubMed Central

Chan, Chu-Fang; Kuo, Tzu-Wei; Weng, Ju-Yun; Lin, Yen-Chu; Chen, Ting-Yu; Cheng, Jen-Kun; Lien, Cheng-Chang

2013-01-01

Glutamatergic transmission onto oligodendrocyte precursor cells (OPCs) may regulate OPC proliferation, migration and differentiation. Dendritic integration of excitatory postsynaptic potentials (EPSPs) is critical for neuronal functions, and mechanisms regulating dendritic propagation and summation of EPSPs are well understood. However, little is known about EPSP attenuation and integration in OPCs. We developed realistic OPC models for synaptic integration, based on passive membrane responses of OPCs obtained by simultaneous dual whole-cell patch-pipette recordings. Compared with neurons, OPCs have a very low value of membrane resistivity, which is largely mediated by Ba2+- and bupivacaine-sensitive background K+ conductances. The very low membrane resistivity not only leads to rapid EPSP attenuation along OPC processes but also sharpens EPSPs and narrows the temporal window for EPSP summation. Thus, background K+ conductances regulate synaptic responses and integration in OPCs, thereby affecting activity-dependent neuronal control of OPC development and function. PMID:23940377

Alternative to xylene as a clearing agent in histopathology

PubMed Central

Alwahaibi, Nasar; Aljaradi, Shaima; Alazri, Horiyah

2018-01-01

INTRODUCTION: Clearing is an essential step in processing tissue for light microscopy. Xylene is the clearing agent used most commonly worldwide. Xylene is toxic and therefore a threat to personnel working in histopathology laboratories. We evaluated a safer alternative clearing agent for use in the histopathology laboratory. MATERIALS AND METHODS: We used 230 formalin-fixed, paraffin-embedded tissue blocks from 19 different tissues. Half of the specimens were processed using xylene and half were processed using UltraClear™. Tissues were evaluated for eight parameters: sectioning, nuclear staining, cytoplasmic staining, overall cell morphology, clarity of staining, uniformity of staining, quality of immunohistochemistry (IHC), and cost. RESULTS: Both UltraClear™ and xylene processed sections scored 100% for IHC. Sections processed using UltraClear™ were easy to cut (81.7%) as were xylene processed sections (96.5%). UltraClear™ processed sections showed 67%, 60.9%, 52.2%, 63.5%, and 67% for nuclear staining, cytoplasmic staining, cell morphology, clarity of staining, and uniformity of staining, respectively. UltraClear™ is twice as expensive as xylene. We found that tissues processed using UltraClear™ were easy to cut and worked well for both hematoxylin and eosin and IHC staining. CONCLUSION: UltraClear™ is less toxic, less flammable, friendlier to the environment, and easy to handle, but it is two times expensive than xylene. The findings of this study recommend the use of UltraClear™ solution as a routine clearing agent in histopathology laboratories. However, further studies are required. PMID:29692586

Neoadjuvant sunitinib effectiveness in T4 renal clear cell carcinoma: a case report.

PubMed

Ricciardulli, Stefano; Del Biondo, Dario; Cicero, Calogero; Leo, Genesio; Zeccolini, Guglielmo; Celia, Antonio

2015-01-01

Sunitinib therapy showed an improvement in survival of patients with metastatic renal cell carcinoma. A 51-year-old man, with Eastern Cooperative Oncology Group Score (ECOG) of 0, presented at our Institute in March 2012 for macrohematuria and urinary retention. A computed tomography (CT) scan of the abdomen showed a right renal lesion. The lesion had a diameter of 15 cm and was developing towards the liver, in the absence of cleavage planes between the liver and kidney. A 12 mm finding, suspected as secondary lesion, was detected at the level of the VII hepatic segment. Neoadjuvant chemotherapy with Sunitinib was proposed. The patient underwent a ultrasound-guided biopsy, which confirmed the presence of Clear Cell Carcinoma. The patient began chemotherapy treatment in May 2012 according to the scheme SUNITINIB 50 mg daily for 4 weeks every 6 weeks. After four courses of treatment, according to RECIST criteria for solid tumors, 40% (9 cm vs 15 cm) regression of the primary tumor and 33% (8 mm vs 12 mm) regression of the secondary lesion were observed at a CT scan of the abdomen. In February 2013, Laparoscopic Adrenal-Sparing Radical Nephrectomy was performed. At a follow-up of 3 months, performed with a thorax and abdomen CT scans, there was a complete remission of hepatic secondary lesion and no areas of secondary localization of disease. This case report showed the effectiveness of neoadjuvant chemotherapy with Sunitinib. The use of this chemotherapy agent can change the approach to the management of cRCC.

Long noncoding RNA lung cancer associated transcript 1 promotes proliferation and invasion of clear cell renal cell carcinoma cells by negatively regulating miR-495-3p.

PubMed

Wang, Li-Na; Zhu, Xin-Qing; Song, Xi-Shuang; Xu, Yong

2018-06-22

Recently, long noncoding RNAs have emerged as new gene regulators and prognostic markers in several cancers, including renal cell carcinoma (RCC). Here, we focused on the long noncoding RNA lung cancer associated transcript 1 (LUCAT1) based on clear cell RCC (ccRCC) the cancer genome atlas (TCGA) data. However, whether aberrant expression of LUCAT1 in ccRCC is correlated with malignancy, metastasis or prognosis has not been elucidated. In the current study, we found that the expression of LUCAT1 was upregulated in ccRCC tissues and cancer cell lines. Upregulated LUCAT1 was positively correlated with larger tumor size, advanced tumor-node-metastasis (TNM) stage, higher smoking frequency, nodal metastasis and shorter overall survival in patients with ccRCC. Inhibition of LUCAT1 by small interfering RNA reduced cell proliferation and invasion of ccRCC cells in vitro. In vivo assay showed that the tumor volume and weight were lower in the group of LUCAT1 inhibition than that in the control group. We then found that LUCAT1 directly bound and inhibited the expression of micoRNA-495-3p (miR-495-3p), which subsequently regulated the expression of special adenine-thymine (AT)-rich DNA-binding protein 1 (SATB1). Collectively, LUCAT1 was critical for proliferation and invasion of ccRCC cells by regulating miR-495-3p and SATB1. Our findings indicated that LUCAT1 and miR-495-3p may offer potential novel therapeutic targets of treatment of ccRCC. © 2018 Wiley Periodicals, Inc.

Stiffness of RBC optical confinement affected by optical clearing

NASA Astrophysics Data System (ADS)

Grishin, Oleg V.; Fedosov, Ivan V.; Tuchin, Valery V.

2017-03-01

In vivo optical trapping is a novel applied direction of an optical manipulation, which enables one to noninvasive measurement of mechanical properties of cells and tissues in living animals directly. But an application area of this direction is limited because strong scattering of many biological tissues. An optical clearing enables one to decrease the scattering and therefore increase a depth of light penetration, decrease a distortion of light beam, improve a resolution in imaging applications. Now novel methods had appeared for a measurement an optical clearing degree at a cellular level. But these methods aren't applicable in vivo. In this paper we present novel measurement method of estimate of the optical clearing, which are based on a measurement of optical trap stiffness. Our method may be applicable in vivo.

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

PubMed Central

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

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

PubMed

Andoh, T; Fujimoto, T; Sudo, T; Fujita, I; Imabori, M; Moritake, H; Sugimoto, T; Sakuma, Y; Takeuchi, T; Kawabata, S; Kirihata, M; Akisue, T; Yayama, K; Kurosaka, M; Miyatake, S; Fukumori, Y; Ichikawa, H

2011-12-01

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 (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). Copyright © 2011 Elsevier Ltd. All rights reserved.

High-dose-rate brachytherapy – a novel treatment approach for primary clear cell adenocarcinoma of male urethra

PubMed Central

Lewis, Shirley; Pal, Mahendra; Bakshi, Ganesh; Ghadi, Yogesh G.; Menon, Santosh; Murthy, Vedang

2015-01-01

The incidence of male urethral cancer is rare with age preponderance of 50 to 60 years. The standard management approach is surgery. Here, we present a novel treatment approach for male urethral cancer. Thirty-six year old male, case of primary clear cell adenocarcinoma of urethra who refused surgery, underwent cystoscopic assisted intraluminal HDR brachytherapy. Patient received a dose of 36 Gy in 9 fractions (4 Gy per fraction) followed by a boost of 24 Gy in 6 fractions. At 11 months post treatment, disease is well controlled with no post treatment toxicity so far. Intraluminal brachytherapy seems to be an effective novel treatment for male urethral cancer. PMID:26207115

Potential role of mTORC2 as a therapeutic target in clear cell carcinoma of the ovary.

PubMed

Hisamatsu, Takeshi; Mabuchi, Seiji; Matsumoto, Yuri; Kawano, Mahiru; Sasano, Tomoyuki; Takahashi, Ryoko; Sawada, Kenjiro; Ito, Kimihiko; Kurachi, Hirohisa; Schilder, Russell J; Testa, Joseph R; Kimura, Tadashi

2013-07-01

The goal of this study was to examine the role of mTOR complex 2 (mTORC2) as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histologic subtype. Using tissue microarrays of 98 primary ovarian cancers [52 CCCs and 46 serous adenocarcinomas (SAC)], activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTOR complex 1 (mTORC1) inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR). mTORC2 was more frequently activated in CCCs than in SACs (71.2% vs. 45.7%). Simultaneous inhibition of mTORC1 and mTORC2 by AZD8055 markedly inhibited the proliferation of both RAD001-sensitive and -resistant cells in vitro. Treatment with RAD001 induced mTORC2-mediated AKT activation in RAD001-sensitive CCC cells. Moreover, increased activation of mTORC2-AKT signaling was observed in RAD001-resistant CCC cells compared with the respective parental cells. Inhibition of mTORC2 during RAD001 treatment enhanced the antitumor effect of RAD001 and prevented CCC cells from acquiring resistance to RAD001. In conclusion, mTORC2 is frequently activated, and can be a promising therapeutic target, in ovarian CCCs. Moreover, mTORC2-targeted therapy may be efficacious in a first-line setting as well as for second-line treatment of recurrent disease developing after RAD001-treatment.

Macrophages clear refrigerator storage-damaged red blood cells and subsequently secrete cytokines in vivo, but not in vitro, in a murine model.

PubMed

Wojczyk, Boguslaw S; Kim, Nina; Bandyopadhyay, Sheila; Francis, Richard O; Zimring, James C; Hod, Eldad A; Spitalnik, Steven L

2014-12-01

In mice, refrigerator-stored red blood cells (RBCs) are cleared by extravascular hemolysis and induce cytokine production. To enhance understanding of this phenomenon, we sought to model it in vitro. Ingestion of refrigerator-stored murine RBCs and subsequent cytokine production were studied using J774A.1 mouse macrophage cells and primary murine splenic macrophages. Wild-type and Ccl2-GFP reporter mice were used for RBC clearance in vivo. Although J774A.1 cells and primary macrophages preferentially ingested refrigerator-stored RBCs in vitro, compared to freshly isolated RBCs, neither produced increased cytokines after erythrophagocytosis. In contrast, phagocytosis of refrigerator-stored RBCs in vivo induced increases in circulating monocyte chemoattractant protein-1 (MCP-1) and keratinocyte chemoattractant (KC) and correspondingly increased mRNA levels in mouse spleen and liver. In the spleen, these were predominantly expressed by CD11b+ cells. Using Ccl2-GFP reporter mice, the predominant splenic population responsible for MCP-1 mRNA production was tissue-resident macrophages (i.e., CD45+, CD11b+, F4/80+, Ly6c+, and CD11c(low) cells). J774A.1 cells and primary macrophages selectively ingested refrigerator-stored RBCs by phagocytosis. Although cytokine expression was not enhanced, this approach could be used to identify the relevant receptor-ligand combination(s). In contrast, cytokine levels increased after phagocytosis of refrigerator-stored RBCs in vivo. These were primarily cleared in the liver and spleen, which demonstrated increased MCP-1 and KC mRNA expression. Finally, in mouse spleen, tissue-resident macrophages were predominantly involved in MCP-1 mRNA production. The differences between cytokine production in vitro and in vivo are not yet well understood. © 2014 AABB.

76 FR 41056 - Amendment to Rule Filing Requirements for Dually-Registered Clearing Agencies

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-13

... we receive and intend to respond as necessary or appropriate. I. Introduction A. Background on... successor entity of ICE Trust (``ICE Trust'') will become Registered Clearing Agencies solely for the... rule amendments that, among other things, present novel or complex issues that require additional time...

Cutaneous Clear Cell Sarcoma: a clinicopathologic, immunohistochemical and molecular analysis of 12 cases emphasizing its distinction from dermal melanoma

PubMed Central

Hantschke, Markus; Mentzel, Thomas; Rütten, Arno; Palmedo, Gabriele; Calonje, Eduardo; Lazar, Alexander J.; Kutzner, Heinz

2010-01-01

Clear cell sarcoma (CCS) of tendons and aponeuroses / malignant melanoma of soft parts is a rare tumor and in the majority of cases presents a characteristic reciprocal translocation t(12;22)(q13;q12) that results in fusion of the EWS and ATF1 genes. Although the melanocytic differentiation of CCS is indisputable, its precise lineage remains unclear. Typically, the slowly growing tumor affects the extremities of adolescents or young adults, especially around the ankle and foot. CCS is classically regarded as a deep soft tissue tumor associated with tendons or aponeuroses. This traditional view is put into perspective by the description of primary CCS of the gastrointestinal tract, which may have a variant fusion gene EWSR1-CREB1. We describe 12 cases of cutaneous CCS and discuss the differential diagnoses. These 12 cases share an identical immunohistochemical profile with malignant melanoma (MM) and thus can easily be confused with a dermal variant of spindle cell MM or metastasis of MM. The patients' ages ranged from 6 to 74 years (median: 25 y), and there was a female predominance (10 females, 2 males). Most tumors (n = 9) were located on the extremities, 2 tumors arose on the back, and 1 on the abdomen. The mean tumor size was 0,97 cm (range, 0,4 to 1,7 cm). Six cases showed invasion of the subcutis, the other 6 cases were entirely dermal. Tumor necrosis was evident in 2 cases, melanin pigment in 2 cases, and ulceration in 1 tumor. All cases showed uniform nests and fascicles of pale spindled or slightly epitheloid cells with finely granular eosinophilic or clear cytoplasm. There was fair pleomorphism with plump spindled nuclei and significantly prominent nucleoli. Multinucleated wreath-like tumor giant cells were observed in two-thirds of cases, but were usually present only focally. The dense cellular aggregates were encased by delicate fibrous septa. The stroma showed a sclerotic reticulated pattern. Partly, the nests of spindle cells bordered the epidermis

PKCepsilon overexpression, irrespective of genetic background, sensitizes skin to UVR-induced development of squamous-cell carcinomas.

PubMed

Sand, Jordan M; Aziz, Moammir H; Dreckschmidt, Nancy E; Havighurst, Thomas C; Kim, KyungMann; Oberley, Terry D; Verma, Ajit K

2010-01-01

Chronic exposure to UVR is the major etiologic factor in the development of human skin cancers including squamous-cell carcinoma (SCC). We have previously shown that protein Kinase C epsilon (PKCepsilon) transgenic mice on FVB/N background, which overexpress PKCepsilon protein approximately eightfold over endogenous levels in epidermis, exhibit about threefold more sensitivity than wild-type littermates to UVR-induced development of SCC. To determine whether it is PKCepsilon and not the mouse genetic background that determines susceptibility to UVR carcinogenesis, we cross-bred PKCepsilon FVB/N transgenic mice with SKH-1 hairless mice to generate PKCepsilon-overexpressing SKH-1 hairless mice. To evaluate the susceptibility of PKCepsilon SKH-1 hairless transgenic mice to UVR carcinogenesis, the mice were exposed to UVR (1-2 KJ m(-2)) three times weekly from a bank of six kodacel-filtered FS40 sunlamps. As compared with the wild-type hairless mice, PKCepsilon overexpression in SKH-1 hairless mice decreased the latency (12 weeks), whereas it increased the incidence (twofold) and multiplicity (fourfold) of SCC. The SKH hairless transgenic mice were observed to be as sensitive as FVB/N transgenic mice to UVR-induced development of SCC and expression of proliferative markers (proliferating cell nuclear antigen, signal transducers and activators of transcription 3, and extracellular signal-regulated kinase 1/2). The results indicate that PKCepsilon level dictates susceptibility, irrespective of genetic background, to UVR carcinogenesis.

Biologic Activity of Autologous, Granulocyte-Macrophage Colony Stimulating Factor Secreting Alveolar Soft Parts Sarcoma and Clear Cell Sarcoma Vaccines

PubMed Central

Goldberg, John; Fisher, David E.; Demetri, George D.; Neuberg, Donna; Allsop, Stephen A.; Fonseca, Catia; Nakazaki, Yukoh; Nemer, David; Raut, Chandrajit P.; George, Suzanne; Morgan, Jeffrey A.; Wagner, Andrew J.; Freeman, Gordon J.; Ritz, Jerome; Lezcano, Cecilia; Mihm, Martin; Canning, Christine; Hodi, F. Stephen; Dranoff, Glenn

2015-01-01

Purpose Alveolar soft parts sarcoma (ASPS) and clear cell sarcoma (CCS) are rare mesenchymal malignancies driven by chromosomal translocations that activate members of the microphthalmia transcription factor (MITF) family. However, in contrast to malignant melanoma, little is known about their immunogenicity. To learn more about the host response to ASPS and CCS, we conducted a phase I clinical trial of vaccination with irradiated, autologous sarcoma cells engineered by adenoviral mediated gene transfer to secrete granulocyte-macrophage colony stimulating factor (GM-CSF). Experimental Design Metastatic tumors from ASPS and CCS patients were resected, processed to single cell suspensions, transduced with a replication defective adenoviral vector encoding GM-CSF, and irradiated. Immunizations were administered subcutaneously and intradermally weekly times three and then every other week. Results Vaccines were successfully manufactured for 11 of the 12 enrolled patients. Eleven subjects received from 3 to 13 immunizations. Toxicities were restricted to grade 1–2 skin reactions at inoculation sites. Vaccination elicited local dendritic cell infiltrates and stimulated T cell mediated delayed type-hypersensitivity reactions to irradiated, autologous tumor cells. Antibody responses to tissue-type plasminogen activator (tTPA) and angiopoietins-1/2 were detected. Tumor biopsies showed programmed death-1 (PD-1) positive CD8+ T cells in association with PD ligand-1 (PD-L1) expressing sarcoma cells. No tumor regressions were observed. Conclusions Vaccination with irradiated, GM-CSF secreting autologous sarcoma cell vaccines is feasible, safe, and biologically active. Concurrent targeting of angiogenic cytokines and antagonism of the PD-1 negative regulatory pathway might intensify immune-mediated tumor destruction. PMID:25805798

ClearSee: a rapid optical clearing reagent for whole-plant fluorescence imaging

PubMed Central

Kurihara, Daisuke; Mizuta, Yoko; Sato, Yoshikatsu; Higashiyama, Tetsuya

2015-01-01

Imaging techniques for visualizing and analyzing precise morphology and gene expression patterns are essential for understanding biological processes during development in all organisms. With the aid of chemical screening, we developed a clearing method using chemical solutions, termed ClearSee, for deep imaging of morphology and gene expression in plant tissues. ClearSee rapidly diminishes chlorophyll autofluorescence while maintaining fluorescent protein stability. By adjusting the refractive index mismatch, whole-organ and whole-plant imaging can be performed by both confocal and two-photon excitation microscopy in ClearSee-treated samples. Moreover, ClearSee is applicable to multicolor imaging of fluorescent proteins to allow structural analysis of multiple gene expression. Given that ClearSee is compatible with staining by chemical dyes, the technique is useful for deep imaging in conjunction with genetic markers and for plant species not amenable to transgenic approaches. This method is useful for whole imaging for intact morphology and will help to accelerate the discovery of new phenomena in plant biological research. PMID:26493404

Macrophages clear refrigerator storage-damaged RBCs and subsequently secrete cytokines in vivo, but not in vitro, in a murine model

PubMed Central

Wojczyk, Boguslaw S.; Kim, Nina; Bandyopadhyay, Sheila; Francis, Richard O.; Zimring, James C.; Hod, Eldad A.; Spitalnik, Steven L.

2014-01-01

BACKGROUND In mice, refrigerator-stored red blood cells (RBCs) are cleared by extravascular hemolysis and induce cytokine production. To enhance understanding of this phenomenon, we sought to model it in vitro. STUDY DESIGN AND METHODS Ingestion of refrigerator-stored murine RBCs and subsequent cytokine production were studied using J774A.1 mouse macrophage cells and primary murine splenic macrophages. Wild-type and Ccl2-GFP-reporter mice were used for RBC clearance in vivo. RESULTS Although J774A.1 cells and primary macrophages preferentially ingested refrigerator-stored RBCs in vitro, as compared to freshly-isolated RBCs, neither produced increased cytokines following erythrophagocytosis. In contrast, phagocytosis of refrigerator-stored RBCs in vivo induced increases in circulating monocyte chemoattractant protein-1 (MCP-1) and keratinocyte chemoattractant (KC), and correspondingly increased mRNA levels in mouse spleen and liver. In the spleen, these were predominantly expressed by CD11b+ cells. Using Ccl2-GFP-reporter mice, the predominant splenic population responsible for MCP-1 mRNA production were tissue-resident macrophages (i.e., CD45+, CD11b+, F4/80+, Ly6c+, CD11clow cells). CONCLUSION J774A.1 cells and primary macrophages selectively ingested refrigerator-stored RBCs by phagocytosis. Although cytokine expression was not enhanced, this approach could be used to identify the relevant receptor-ligand combination(s). In contrast, cytokine levels increased following phagocytosis of refrigerator-stored RBCs in vivo. These were primarily cleared in the liver and spleen, which demonstrated increased MCP-1 and KC mRNA expression. Finally, in mouse spleen, tissue-resident macrophages were predominantly involved in MCP-1 mRNA production. The differences between cytokine production in vitro and in vivo are not yet well understood. PMID:25041478

miR-19a correlates with poor prognosis of clear cell renal cell carcinoma patients via promoting cell proliferation and suppressing PTEN/SMAD4 expression.

PubMed

Ma, Qiang; Peng, Zhiqiang; Wang, Lei; Li, Yanming; Wang, Kaizhen; Zheng, Junfang; Liang, Zhiyong; Liu, Tonghua

2016-12-01

MicroRNAs (miRNAs) were reported to be involved in the development of clear cell renal cell carcinoma (ccRCC). However, the study on miRNAs in ccRCC is far from complete. The present study identified miRNAs which could act as potential novel prognostic markers for ccRCC, and analyzed its possible mechanism. We found that miR-19a correlated with poor prognosis of ccRCC patients via promoting cell proliferation and suppressing PTEN/SMAD4 expression. Both the microarray screening result and TCGA KIRC dataset analysis showed that miR-19a was significantly upregulated in ccRCC tissues, and further analysis of TCGA data revealed that the upregulated level of miR-19a was strongly associated with advanced T stage and poor prognosis of ccRCC patients. Consistent with clinical observations, miR-19a overexpression significantly promoted ccRCC cell proliferation in vitro. To further explore the mechanism by which miR-19a correlated with cell proliferation and poor prognosis of ccRCC, we performed gene set enrichment analysis (GSEA) for target genes of miR-19a in ccRCC patients. Result indicated that the key target genes of miR-19a included SMAD4 and PTEN. In ccRCC tissues, expression levels of SMAD4 and PTEN were negatively correlated with expression level of miR-19a, revealing that miR-19a suppressed the expression of SMAD4 and PTEN in ccRCC patients. miR-19a overexpression significantly suppressed the expression of SMAD4 and PTEN in vitro, further verifying that SMAD4 and PTEN were the target genes of miR-19a in ccRCC cells. Our results elucidated the tumor promoting role of miR-19a and established miR-19a as a potential novel prognostic marker for ccRCC.

Positive feedback loop and synergistic effects between hypoxia-inducible factor-2α and stearoyl-CoA desaturase-1 promote tumorigenesis in clear cell renal cell carcinoma.

PubMed

Zhang, Yujian; Wang, Hui; Zhang, Jin; Lv, Jianwei; Huang, Yiran

2013-04-01

Adapting to hypoxic stress is pivotal in tumor progression and determining tumor malignancy. The transcriptional factor hypoxia-inducible factor (HIF) is crucial in modulating tumorous hypoxic responses through altering cell energy metabolism, which includes the modification of glucose and lipid metabolism-associated gene expression. Stearoyl-CoA desaturase-1 (SCD1) is the main isoform of SCDs, the rate-limiting enzymes in the biosynthesis of monounsaturated fatty acids from saturated fatty acids, which is extensively activated in cancer progression. In this study, we found that SCD1 and HIF-2α were overexpressed in human clear cell renal cell carcinoma (ccRCC) tissues and ccRCC cell lines, and were upregulated in the 786-0 ccRCC cell line under hypoxia. Knockdown of SCD1 or HIF-2α impacted the other's expression. Enhancing SCD1 resulted in HIF-2α upregulation, which could be blocked by inhibiting the PI3K/Akt pathway. Deficiency of SCD1 or HIF-2α in 768-0 cells led to apoptosis, less colony formation ability, and decreased cell migration. More obvious effects were observed in 786-0 cells with double SCD1 and HIF-2α knockdown. These results indicate a PI3K/Akt-mediated loop between SCD1 and HIF-2α that mutually enhances their protein levels. Both SCD1 and HIF-2α are critical to promoting tumorigenesis by synergistically acting on maintaining cell survival, triggering cell migration, and enhancing the colony formation ability of cancer cells. © 2013 Japanese Cancer Association.

Positron Emission Tomography/Computed Tomography Identification of Clear Cell Renal Cell Carcinoma: Results From the REDECT Trial

PubMed Central

Divgi, Chaitanya R.; Uzzo, Robert G.; Gatsonis, Constantine; Bartz, Roman; Treutner, Silke; Yu, Jian Qin; Chen, David; Carrasquillo, Jorge A.; Larson, Steven; Bevan, Paul; Russo, Paul

2013-01-01

Purpose A clinical study to characterize renal masses with positron emission tomography/computed tomography (PET/CT) was undertaken. Patients and Methods This was an open-label multicenter study of iodine-124 (124I) -girentuximab PET/CT in patients with renal masses who were scheduled for resection. PET/CT and contrast-enhanced CT (CECT) of the abdomen were performed 2 to 6 days after intravenous 124I-girentuximab administration and before resection of the renal mass(es). Images were interpreted centrally by three blinded readers for each imaging modality. Tumor histology was determined by a blinded central pathologist. The primary end points—average sensitivity and specificity for clear cell renal cell carcinoma (ccRCC)—were compared between the two modalities. Agreement between and within readers was assessed. Results 124I-girentuximab was well tolerated. In all, 195 patients had complete data sets (histopathologic diagnosis and PET/CT and CECT results) available. The average sensitivity was 86.2% (95% CI, 75.3% to 97.1%) for PET/CT and 75.5% (95% CI, 62.6% to 88.4%) for CECT (P = .023). The average specificity was 85.9% (95% CI, 69.4% to 99.9%) for PET/CT and 46.8% (95% CI, 18.8% to 74.7%) for CECT (P = .005). Inter-reader agreement was high (κ range, 0.87 to 0.92 for PET/CT; 0.67 to 0.76 for CECT), as was intrareader agreement (range, 87% to 100% for PET/CT; 73.7% to 91.3% for CECT). Conclusion This study represents (to the best of our knowledge) the first clinical validation of a molecular imaging biomarker for malignancy. 124I-girentuximab PET/CT can accurately and noninvasively identify ccRCC, with potential utility for designing best management approaches for patients with renal masses. PMID:23213092

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

PubMed

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.

Acoustic properties of naturally produced clear speech at normal speaking rates

NASA Astrophysics Data System (ADS)

Krause, Jean C.; Braida, Louis D.

2004-01-01

Sentences spoken ``clearly'' are significantly more intelligible than those spoken ``conversationally'' for hearing-impaired listeners in a variety of backgrounds [Picheny et al., J. Speech Hear. Res. 28, 96-103 (1985); Uchanski et al., ibid. 39, 494-509 (1996); Payton et al., J. Acoust. Soc. Am. 95, 1581-1592 (1994)]. While producing clear speech, however, talkers often reduce their speaking rate significantly [Picheny et al., J. Speech Hear. Res. 29, 434-446 (1986); Uchanski et al., ibid. 39, 494-509 (1996)]. Yet speaking slowly is not solely responsible for the intelligibility benefit of clear speech (over conversational speech), since a recent study [Krause and Braida, J. Acoust. Soc. Am. 112, 2165-2172 (2002)] showed that talkers can produce clear speech at normal rates with training. This finding suggests that clear speech has inherent acoustic properties, independent of rate, that contribute to improved intelligibility. Identifying these acoustic properties could lead to improved signal processing schemes for hearing aids. To gain insight into these acoustical properties, conversational and clear speech produced at normal speaking rates were analyzed at three levels of detail (global, phonological, and phonetic). Although results suggest that talkers may have employed different strategies to achieve clear speech at normal rates, two global-level properties were identified that appear likely to be linked to the improvements in intelligibility provided by clear/normal speech: increased energy in the 1000-3000-Hz range of long-term spectra and increased modulation depth of low frequency modulations of the intensity envelope. Other phonological and phonetic differences associated with clear/normal speech include changes in (1) frequency of stop burst releases, (2) VOT of word-initial voiceless stop consonants, and (3) short-term vowel spectra.

The EPIC-MOS Particle-Induced Background Spectra

NASA Technical Reports Server (NTRS)

Kuntz, K. D.; Sowden, S. L.

2007-01-01

In order to analyse diffuse emission that fills the field of view, one must accurately characterize the instrumental backgrounds. For the XMM-Newton EPIC instrument these backgrounds include a temporally variable "quiescent" component. as well as the strongly variable soft proton contamination. We have characterized the spectral and spatial response of the EPIC detectors to these background components and have developed tools to remove these backgrounds from observations. The "quiescent" component was characterized using a combination of the filter-wheel-closed data and a database of unexposed-region data. The soft proton contamination was characterized by differencing images and spectra taken during flared and flare-free intervals. After application of our modeled backgrounds, the differences between independent observations of the same region of "blank sky" are consistent with the statistical uncertainties except when there is clear spectral evidence of solar wind charge exchange emission. Using a large sample of blank sky data, we show that strong magnetospheric SWCX emission requires elevated solar wind fluxes; observations through the densest part of the magnetosheath are not necessarily strongly contaminated with SWCX emission.

The immune synapse clears and excludes molecules above a size threshold

PubMed Central

Cartwright, Adam N. R.; Griggs, Jeremy; Davis, Daniel M.

2014-01-01

Natural killer cells assess target cell health via interactions at the immune synapse (IS) that facilitates signal integration and directed secretion. Here we test whether the IS also functions as a gasket. Quantitative fluorescence microscopy of nanometer-scale dextrans within synapses formed by various effector-target cell conjugates reveal that molecules are excluded in a size-dependent manner at activating synapses. Dextran sized ≤4 nm move in and out of the IS, but access is significantly reduced (by >50%) for dextran sized 10–13 nm, and dextran ≥32 nm is almost entirely excluded. Depolymerization of F-actin abrogated exclusion. Unexpectedly, larger-sized dextrans are cleared as the IS assembles in a zipper-like manner. Monoclonal antibodies are also excluded from the IS but smaller single-domain antibodies are able to penetrate. Therefore, the IS can clear and exclude molecules above a size threshold, and drugs designed to target synaptic cytokines or cytotoxic proteins must fit these dimensions. PMID:25407222

Immunohistochemical characterization of endometrial carcinomas: endometrioid, serous and clear cell adenocarcinomas in association with genetic analysis.

PubMed

Yasuda, Masanori

2014-12-01

Developments in immunohistochemistry, which are closely linked with the advances in the analyses of genetic abnormalities and their associated molecular disorders as early and late histogenetic events, have contributed greatly to the improvement of pathological diagnostic confirmation and validation. Immunohistochemistry has also generated great benefit to the innovation of therapeutic strategies for various kinds of cancers. In this article, the three representative histological types of corpus cancer, namely, endometrioid adenocarcinoma, serous adenocarcinoma and clear cell adenocarcinoma, will be histologically approached in association with their immunohistochemical profiles as well as genetic disorders. First, the focus will be on 'Conventional/prototypic features,' followed by 'Controversy over conventional histological subclassification,' and subsequently 'Tumorigenesis and re-subclassification'. © 2014 The Author. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.

Cytoplasmic expression of Twist1, an EMT-related transcription factor, is associated with higher grades renal cell carcinomas and worse progression-free survival in clear cell renal cell carcinoma.

PubMed

Rasti, Arezoo; Madjd, Zahra; Abolhasani, Maryam; Mehrazma, Mitra; Janani, Leila; Saeednejad Zanjani, Leili; Asgari, Mojgan

2018-05-01

Twist1 is a key transcription factor, which confers tumor cells with cancer stem cell (CSC)-like characteristics and enhances epithelial-mesenchymal transition in pathological conditions including tumor malignancy and metastasis. This study aimed to evaluate the expression patterns and clinical significance of Twist1 in renal cell carcinoma (RCC). The cytoplasmic and nuclear expression of Twist1 were examined in 252 well-defined renal tumor tissues, including 173 (68.7%) clear cell renal cell carcinomas (ccRCC), 45 (17.9%) papillary renal cell carcinomas (pRCC) and 34 (13.5%) chromophobe renal cell carcinoma, by immunohistochemistry on a tissue microarray. The association between expression of this marker and clinicopathologic parameters and survival outcomes were then analyzed. Twist1 was mainly localized to the cytoplasm of tumor cells (98.8%). Increased cytoplasmic expression of Twist1 was associated with higher grade tumors (P = 0.045), renal vein invasion (P = 0.031) and microvascular invasion (P = 0.044) in RCC. It was positively correlated with higher grade tumors (P = 0.026), shorter progression-free survival time (P = 0.027) in patients with ccRCC, and also with higher stage in pRCC patients (P = 0.036). Significantly higher cytoplasmic expression levels of Twist1 were found in ccRCC and pRCC subtypes, due to their more aggressive tumor behavior. Increased cytoplasmic expression of Twist1 had a critical role in worse prognosis in ccRCC. These findings suggest that cytoplasmic, rather than nuclear expression of Twist1 can be considered as a prognostic and therapeutic marker for targeted therapy of RCC, especially for ccRCC patients.

Chopart's amputation for resection of clear cell sarcoma of the foot: a case report and review of the literature.

PubMed

Berenji, Manijeh; Kwok-Oleksy, Christina; Dang, Binh Nguyen; Trepal, Michael J; Wallack, Marc K

2009-01-01

Clear cell sarcoma (CCS) is a subset of soft tissue sarcoma that occurs mainly in young Caucasians. Although on initial presentation these growths might not appear to be malignant, CCS has a tendency to disseminate to regional lymph nodes and ultimately develop distant metastasis. We report a case of CCS from our institution, discussing the radiological and pathological findings, surgical treatments, and survival prognoses. To our knowledge, this is the first reported case of using a Chopart's amputation technique in the resection of CCS of the foot. 4.

Sunitinib dose escalation overcomes transient resistance in clear cell renal cell carcinoma and is associated with epigenetic modifications.

PubMed

Adelaiye, Remi; Ciamporcero, Eric; Miles, Kiersten Marie; Sotomayor, Paula; Bard, Jonathan; Tsompana, Maria; Conroy, Dylan; Shen, Li; Ramakrishnan, Swathi; Ku, Sheng-Yu; Orillion, Ashley; Prey, Joshua; Fetterly, Gerald; Buck, Michael; Chintala, Sreenivasulu; Bjarnason, Georg A; Pili, Roberto

2015-02-01

Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). Despite sunitinib's clinical efficacy, patients eventually develop drug resistance and disease progression. Herein, we tested the hypothesis whether initial sunitinib resistance may be transient and could be overcome by dose increase. In selected patients initially treated with 50 mg sunitinib and presenting with minimal toxicities, sunitinib dose was escalated to 62.5 mg and/or 75 mg at the time of tumor progression. Mice bearing two different patient-derived ccRCC xenografts (PDX) were treated 5 days per week with a dose-escalation schema (40-60-80 mg/kg sunitinib). Tumor tissues were collected before dose increments for immunohistochemistry analyses and drug levels. Selected intrapatient sunitinib dose escalation was safe and several patients had added progression-free survival. In parallel, our preclinical results showed that PDXs, although initially responsive to sunitinib at 40 mg/kg, eventually developed resistance. When the dose was incrementally increased, again we observed tumor response to sunitinib. A resistant phenotype was associated with transient increase of tumor vasculature despite intratumor sunitinib accumulation at higher dose. In addition, we observed associated changes in the expression of the methyltransferase EZH2 and histone marks at the time of resistance. Furthermore, specific EZH2 inhibition resulted in increased in vitro antitumor effect of sunitinib. Overall, our results suggest that initial sunitinib-induced resistance may be overcome, in part, by increasing the dose, and highlight the potential role of epigenetic changes associated with sunitinib resistance that can represent new targets for therapeutic intervention. ©2014 American Association for Cancer Research.

Word Learning in Clear and Plain Speech in Quiet and Noisy Listening Conditions

ERIC Educational Resources Information Center

Riley, Kristine Marie Grohne

2010-01-01

Previous research demonstrates enhanced speech perception abilities for typically hearing and hearing-impaired listeners when speakers use clear versus plain speech, particularly in the presence of background noise. To date, very few studies have investigated the effects of noise on word learning and no studies have examined the effects of clear…

Optical clearing: impact of optical and dielectric properties of clearing solutions on pulmonary tissue mechanics.

PubMed

Schwenninger, David; Priebe, Hans-Joachim; Schneider, Matthias; Runck, Hanna; Guttmann, Josef

2017-07-01

Optical clearing allows tissue visualization under preservation of organ integrity. Optical clearing of organs with a physiological change in three-dimensional geometry (such as the lung) would additionally allow visualization of macroscopic and microscopic tissue geometry. A prerequisite, however, is the preservation of the native tissue mechanics of the optically cleared lung tissue. We investigated the impact of optical and dielectric properties of clearing solutions on biomechanics and clearing potency in porcine tissue strips of healthy lungs. After fixation, bleaching, and rehydration, four methods of optical clearing were investigated using eight different protocols. The mechanical and optical properties of the cleared lung tissue strips were investigated by uniaxial tensile testing and by analyzing optical transparency and translucency for red, green, and blue light before, during, and after the biochemical optical clearing process. Fresh tissue strips were used as controls. Best balance between efficient clearing and preserved mechanics was found for clearing with a 1:1 mixture of dimethyl sulfoxide (DMSO) and aniline. Our findings show that 1 ) the degree of tissue transparency and translucency correlated with the refractive index of the clearing solution index ( r = 0.976, P = 0.0004; and r = 0.91, P = 0.0046, respectively), 2 ) tissue mechanics were affected by dehydration and the type of clearing solution, and 3 ) tissue biomechanics and geometry correlated with the dielectric constant of the clearing solution ( r = -0.98, P < 0.00001; and r = 0.69, P = 0.013, respectively). We show that the lower the dielectric constant of the clearing solutions, the larger the effect on tissue stiffness. This suggests that the dielectric constant is an important measure in determining the effect of a clearing solution on lung tissue biomechanics. Optimal tissue transparency requires complete tissue dehydration and a refractive index of 1.55 of the clearing solution

17 CFR 39.4 - Procedures for implementing derivatives clearing organization rules and clearing new products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... derivatives clearing organization rules and clearing new products. 39.4 Section 39.4 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION DERIVATIVES CLEARING ORGANIZATIONS § 39.4 Procedures for implementing derivatives clearing organization rules and clearing new products. (a) Request for approval of...

Seeing through Musculoskeletal Tissues: Improving In Situ Imaging of Bone and the Lacunar Canalicular System through Optical Clearing

PubMed Central

Berke, Ian M.; Miola, Joseph P.; David, Michael A.; Smith, Melanie K.; Price, Christopher

2016-01-01

In situ, cells of the musculoskeletal system reside within complex and often interconnected 3-D environments. Key to better understanding how 3-D tissue and cellular environments regulate musculoskeletal physiology, homeostasis, and health is the use of robust methodologies for directly visualizing cell-cell and cell-matrix architecture in situ. However, the use of standard optical imaging techniques is often of limited utility in deep imaging of intact musculoskeletal tissues due to the highly scattering nature of biological tissues. Drawing inspiration from recent developments in the deep-tissue imaging field, we describe the application of immersion based optical clearing techniques, which utilize the principle of refractive index (RI) matching between the clearing/mounting media and tissue under observation, to improve the deep, in situ imaging of musculoskeletal tissues. To date, few optical clearing techniques have been applied specifically to musculoskeletal tissues, and a systematic comparison of the clearing ability of optical clearing agents in musculoskeletal tissues has yet to be fully demonstrated. In this study we tested the ability of eight different aqueous and non-aqueous clearing agents, with RIs ranging from 1.45 to 1.56, to optically clear murine knee joints and cortical bone. We demonstrated and quantified the ability of these optical clearing agents to clear musculoskeletal tissues and improve both macro- and micro-scale imaging of musculoskeletal tissue across several imaging modalities (stereomicroscopy, spectroscopy, and one-, and two-photon confocal microscopy) and investigational techniques (dynamic bone labeling and en bloc tissue staining). Based upon these findings we believe that optical clearing, in combination with advanced imaging techniques, has the potential to complement classical musculoskeletal analysis techniques; opening the door for improved in situ investigation and quantification of musculoskeletal tissues. PMID:26930293

Seeing through Musculoskeletal Tissues: Improving In Situ Imaging of Bone and the Lacunar Canalicular System through Optical Clearing.

PubMed

Berke, Ian M; Miola, Joseph P; David, Michael A; Smith, Melanie K; Price, Christopher

2016-01-01

In situ, cells of the musculoskeletal system reside within complex and often interconnected 3-D environments. Key to better understanding how 3-D tissue and cellular environments regulate musculoskeletal physiology, homeostasis, and health is the use of robust methodologies for directly visualizing cell-cell and cell-matrix architecture in situ. However, the use of standard optical imaging techniques is often of limited utility in deep imaging of intact musculoskeletal tissues due to the highly scattering nature of biological tissues. Drawing inspiration from recent developments in the deep-tissue imaging field, we describe the application of immersion based optical clearing techniques, which utilize the principle of refractive index (RI) matching between the clearing/mounting media and tissue under observation, to improve the deep, in situ imaging of musculoskeletal tissues. To date, few optical clearing techniques have been applied specifically to musculoskeletal tissues, and a systematic comparison of the clearing ability of optical clearing agents in musculoskeletal tissues has yet to be fully demonstrated. In this study we tested the ability of eight different aqueous and non-aqueous clearing agents, with RIs ranging from 1.45 to 1.56, to optically clear murine knee joints and cortical bone. We demonstrated and quantified the ability of these optical clearing agents to clear musculoskeletal tissues and improve both macro- and micro-scale imaging of musculoskeletal tissue across several imaging modalities (stereomicroscopy, spectroscopy, and one-, and two-photon confocal microscopy) and investigational techniques (dynamic bone labeling and en bloc tissue staining). Based upon these findings we believe that optical clearing, in combination with advanced imaging techniques, has the potential to complement classical musculoskeletal analysis techniques; opening the door for improved in situ investigation and quantification of musculoskeletal tissues.

Establishment of a novel clear cell sarcoma cell line (Hewga-CCS), and investigation of the antitumor effects of pazopanib on Hewga-CCS.

PubMed

Outani, Hidetatsu; Tanaka, Takaaki; Wakamatsu, Toru; Imura, Yoshinori; Hamada, Kenichiro; Araki, Nobuhito; Itoh, Kazuyuki; Yoshikawa, Hideki; Naka, Norifumi

2014-06-19

Clear cell sarcoma (CCS) is a therapeutically unresolved, aggressive, soft tissue sarcoma (STS) that predominantly affects young adults. This sarcoma is defined by t(12;22)(q13;q12) translocation, which leads to the fusion of Ewing sarcoma gene (EWS) to activating transcription factor 1 (ATF1) gene, producing a chimeric EWS-ATF1 fusion gene. We established a novel CCS cell line called Hewga-CCS and developed an orthotopic tumor xenograft model to enable comprehensive bench-side investigation for intensive basic and preclinical research in CCS with a paucity of experimental cell lines. Hewga-CCS was derived from skin metastatic lesions of a CCS developed in a 34-year-old female. The karyotype and chimeric transcript were analyzed. Xenografts were established and characterized by morphology and immunohistochemical reactivity. Subsequently, the antitumor effects of pazopanib, a recently approved, novel, multitargeted, tyrosine kinase inhibitor (TKI) used for the treatment of advanced soft tissue sarcoma, on Hewga-CCS were assessed in vitro and in vivo. Hewga-CCS harbored the type 2 EWS-ATF1 transcript. Xenografts morphologically mimicked the primary tumor and expressed S-100 protein and antigens associated with melanin synthesis (Melan-A, HMB45). Pazopanib suppressed the growth of Hewga-CCS both in vivo and in vitro. A phospho-receptor tyrosine kinase array revealed phosphorylation of c-MET, but not of VEGFR, in Hewga-CCS. Subsequent experiments showed that pazopanib exerted antitumor effects through the inhibition of HGF/c-MET signaling. CCS is a rare, devastating disease, and our established CCS cell line and xenograft model may be a useful tool for further in-depth investigation and understanding of the drug-sensitivity mechanism.

76 FR 47529 - Customer Clearing Documentation and Timing of Acceptance for Clearing; Correction

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-05

... COMMODITY FUTURES TRADING COMMISSION 17 CFR Parts 1, 23, and 39 RIN 3038-AD51 Customer Clearing Documentation and Timing of Acceptance for Clearing; Correction AGENCY: Commodity Futures Trading Commission... published in the Federal Register of August 1, 2011, regarding Customer Clearing Documentation and Timing of...

Diabetes and Risk of Renal Cell Carcinoma

PubMed Central

Habib, Samy L; Prihoda, Thomas J; Luna, Maria; Werner, Sherry A

2012-01-01

Background and objectives: There is evidence that the incidence of solid tumors is markedly increased in patients with diabetes mellitus. In the current study, we investigate the association between diabetes and renal cancer. Patients and Methods: A single-center retrospective analysis of 473 patients who underwent nephrectomy for renal cell carcinoma (RCC) was performed. Diabetic RCC patients were screened for age, gender, ethnicity, HgA1C, glucose levels and renal function. Results: Of the 473 cases with RCC, we identified 120 patients (25.4%) with a history of diabetes. The incidence of diabetes in RCC patients was higher in female than male subjects and in Hispanic compared to White and Other ethnic backgrounds. At diagnosis, the majority of diabetic RCC patients were 50-59 years of age. In diabetic RCC cases, clear cell type histology (92.0%), nuclear grade 2 (56.1%) and tumor size range from 1-5 cm (65.7%) were the most common in each category. Conclusion: Our findings indicate that diabetic RCC patients have a predominance of localized, small clear cell RCC. In addition, females with a history of RCC have a higher frequency of diabetes compared to males. This is the first report of clinical and histopathological features of RCC associated with diabetes. PMID:22232697

Clearing the Dead: Apoptotic Cell Sensing, Recognition, Engulfment, and Digestion

PubMed Central

Hochreiter-Hufford, Amelia; Ravichandran, Kodi S.

2013-01-01

Clearance of apoptotic cells is the final stage of programmed cell death. Uncleared corpses can become secondarily necrotic, promoting inflammation and autoimmunity. Remarkably, even in tissues with high cellular turnover, apoptotic cells are rarely seen because of efficient clearance mechanisms in healthy individuals. Recently, significant progress has been made in understanding the steps involved in prompt cell clearance in vivo. These include the sensing of corpses via “find me” signals, the recognition of corpses via “eat me” signals and their cognate receptors, the signaling pathways that regulate cytoskeletal rearrangement necessary for engulfment, and the responses of the phagocyte that keep cell clearance events “immunologically silent.” This study focuses on our understanding of these steps. PMID:23284042

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression.

PubMed

Lalani, Aly-Khan A; Gray, Kathryn P; Albiges, Laurence; Callea, Marcella; Pignon, Jean-Christophe; Pal, Soumitro; Gupta, Mamta; Bhatt, Rupal S; McDermott, David F; Atkins, Michael B; Woude, G F Vande; Harshman, Lauren C; Choueiri, Toni K; Signoretti, Sabina

2017-11-28

In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0-300): intensity of c-Met staining (0-3) x % of positive cells (0-100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.

Integrative Genome-Wide Gene Expression Profiling of Clear Cell Renal Cell Carcinoma in Czech Republic and in the United States

PubMed Central

Wozniak, Magdalena B.; Le Calvez-Kelm, Florence; Abedi-Ardekani, Behnoush; Byrnes, Graham; Durand, Geoffroy; Carreira, Christine; Michelon, Jocelyne; Janout, Vladimir; Holcatova, Ivana; Foretova, Lenka; Brisuda, Antonin; Lesueur, Fabienne; McKay, James; Brennan, Paul; Scelo, Ghislaine

2013-01-01

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. PMID:23526956

Clear cell renal cell carcinoma: a comparative study of histological and chromosomal characteristics between primary tumors and their corresponding metastases.

PubMed

Dagher, Julien; Kammerer-Jacquet, Solène-Florence; Dugay, Frédéric; Beaumont, Marion; Lespagnol, Alexandra; Cornevin, Laurence; Verhoest, Grégory; Bensalah, Karim; Rioux-Leclercq, Nathalie; Belaud-Rotureau, Marc-Antoine

2017-07-01

Clear cell renal cell carcinoma (ccRCC) has a poor prognosis with a 50% risk of metastases. Little is known about the phenotypic and molecular profiles of metastases regarding their corresponding primary tumors. This study aimed to screen phenotypic and genotypic differences between metastases and their corresponding primary tumors. We selected four cases with available frozen material. The histological, immunohistochemical (VEGFA, CD31, SMA, Ki67, p53, PAR-3), FISH (VHL gene), next-generation sequencing (VHL and c-MET genes), multiplex ligation-dependent probe amplification, and array-(comparative genomic hybridization) CGH analyses were realized. Metastases were nodal, hepatic (synchronous), adrenal, and pulmonary (metachronous). High-grade tumor cells were significantly more frequent in metastases (p = 0.019). Metastases and high-grade zones of primary tumors shared similar characteristics compared to low-grade zones: a lower microscopic vascular density (43.5 vs 382.5 vessels/mm 2 ; p = 0.0027), a higher expression of VEGF (73 vs 10%, p = 0.045), Ki67 (37.6 vs 8.3%; p = 0.011), and p53 (54 vs 10.6%; p = 0.081), and a cytoplasmic and membranous PAR-3 staining. Metastases exhibited more chromosomal imbalances than primary tumors in total (18.75 ± 6.8; p = 0.044) with more genomic gains (13.5 ± 7; p = 0.013). The loss of chromosome 9 and gain of Xq were found in both primary tumors and metastases but gains of loci or chromosomes 2p, 3q, 5, 8q, 12, and 20 were only found in metastases. The VHL gene status was similar in each tumor couple. Although metastases and primary tumors share common histological features, this study highlights chromosomal differences specific to metastases which could be involved in ccRCC metastatic evolution.

Knockdown of long non-coding RNA PVT1 induces apoptosis and cell cycle arrest in clear cell renal cell carcinoma through the epidermal growth factor receptor pathway.

PubMed

Li, Weicong; Zheng, Zaosong; Chen, Haicheng; Cai, Yuhong; Xie, Wenlian

2018-05-01

Previous years have witnessed the importance of long non-coding RNAs (lncRNAs) in cancer research. The lncRNA Pvt1 oncogene (non-protein coding) (PVT1) was revealed to be upregulated in various cancer types. The aim of the present study was to investigate the function of PVT1 in clear cell renal cell carcinoma (ccRCC). The expression of PVT1 in ccRCC was analyzed using reverse transcription-quantitative polymerase chain reaction, and it was revealed that PVT1 expression was upregulated in ccRCC tissues compared with that in normal adjacent tissues. Next, PVT1 expression from The Cancer Genome Atlas datasets was validated, and it was also revealed that the high expression of PVT1 was associated with advanced disease stage and a poor prognosis. Furthermore, the knockdown of PVT1 induced apoptosis by increasing the expression of poly ADP ribose polymerase and Bcl-2-associated X protein, and promoted cell cycle arrest at the G1 phase by decreasing the expression of cyclin D1. Study of the mechanism involved indicated that PVT1 promoted the progression of ccRCC partly through activation of the epidermal growth factor receptor pathway. Altogether, the results of the present study suggested that PVT1 serves oncogenic functions and may be a biomarker and therapeutic target in ccRCC.

VHL-regulated miR-204 Suppresses Tumor Growth through Inhibition of LC3B-mediated Autophagy in Renal Clear Cell Carcinoma

PubMed Central

Mikhaylova, Olga; Stratton, Yiwen; Hall, Daniel; Kellner, Emily; Ehmer, Birgit; Drew, Angela F.; Gallo, Catherine A.; Plas, David R.; Biesiada, Jacek; Meller, Jarek; Czyzyk-Krzeska, Maria F.

2012-01-01

Summary The von Hippel-Lindau tumor-suppressor gene (VHL) is lost in most clear cell renal cell carcinomas (ccRCC). Here, using human ccRCC specimens, VHL-deficient cells, and xenograft models, we show that miR-204 is a VHL-regulated tumor suppressor acting by inhibiting macroautophagy, with MAP1LC3B (LC3B) as a direct and functional target. Importantly, higher tumor grade of human ccRCC was correlated with a concomitant decrease in miR-204 and increase in LC3B levels, indicating that LC3B-mediated macroautophagy is necessary for RCC progression. VHL, in addition to inducing endogenous miR-204, triggered the expression of LC3C, an HIF-regulated LC3B paralog, that suppressed tumor growth. These data reveal a function of VHL as a tumor suppressing regulator of autophagic programs. PMID:22516261

Reduced expression of fumarate hydratase in clear cell renal cancer mediates HIF-2α accumulation and promotes migration and invasion.

PubMed

Sudarshan, Sunil; Shanmugasundaram, Karthigayan; Naylor, Susan L; Lin, Shu; Livi, Carolina B; O'Neill, Christine F; Parekh, Dipen J; Yeh, I-Tien; Sun, Lu-Zhe; Block, Karen

2011-01-01

Germline mutations of FH, the gene that encodes for the tricarboxylic acid TCA (TCA) cycle enzyme fumarate hydratase, are associated with an inherited form of cancer referred to as Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). Individuals with HLRCC are predisposed to the development of highly malignant and lethal renal cell carcinoma (RCC). The mechanisms of tumorigenesis proposed have largely focused on the biochemical consequences of loss of FH enzymatic activity. While loss of the tumor suppressor gene von Hippel Lindau (VHL) is thought to be an initiating event for the majority of RCCs, a role for FH in sporadic renal cancer has not been explored. Here we report that FH mRNA and protein expression are reduced in clear cell renal cancer, the most common histologic variant of kidney cancer. Moreover, we demonstrate that reduced FH leads to the accumulation of hypoxia inducible factor- 2α (HIF-2α), a transcription factor known to promote renal carcinogenesis. Finally, we demonstrate that overexpression of FH in renal cancer cells inhibits cellular migration and invasion. These data provide novel insights into the tumor suppressor functions of FH in sporadic kidney cancer.

Effect of whole-body irradiation of mice on the number of background plaque-forming cells

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

Anderson, R.E.; Lefkovits, I.; Soeederberg, A.

1983-08-01

Mice were exposed in whole-body fashion to several doses of radiation and killed at various times thereafter for a determination of the number of background plaque-forming cells (PFCs) as assayed on either sheep erythrocytes or bromelain-treated autologous mouse erythrocytes. Increased numbers of both types of PFC were found in the irradiated groups. These increases were dependent on radiation dose and time after exposure. They did not appear to be caused by a disruption of normal lymphocyte traffic or a switch in immunoglobulin isotype. An increased number of PFCs on bromelain-treated mouse RBCs but not on sheep RBCs were found inmore » irradiated congenitally athymic nude mice. On the basis of this and related observations, background PFCs on bromelain-treated mouse RBCs and on sheep RBCs appear to fall under different forms of homeostatic control.« less

Neutrophil-to-lymphocyte ratio as an independent predictor for survival in patients with localized clear cell renal cell carcinoma after radiofrequency ablation: a propensity score matching analysis.

PubMed

Chang, Xiaofeng; Zhang, Fan; Liu, Tieshi; Wang, Wei; Guo, Hongqian

2017-06-01

To investigate the role of neutrophil-to-lymphocyte ratio as a prognostic indicator in patients with localized clear cell renal cell carcinoma treated with radiofrequency ablation. We retrospectively analyzed data from patients with renal cell carcinoma who underwent radiofrequency ablation from 2006 to 2013. The Kaplan-Meier method was used to generate the survival curves according to different categories of neutrophil-to-lymphocyte ratio. Relationships between preoperative neutrophil-to-lymphocyte ratio or the change of neutrophil-to-lymphocyte ratio and survival were evaluated with multivariable Cox proportional hazards regression analysis. A propensity score matching analysis was carried out to avoid confounding bias. A total of 185 patients were included in present study. When stratified by preoperative neutrophil-to-lymphocyte ratio cutoff value of 2.79, 5-year recurrence-free survival, 5-year disease-free survival, and 5-year overall survival rates of neutrophil-to-lymphocyte ratio <2.79 versus ≥2.79 were 100, 98.5, and 99.2% versus 80.5, 72.6, and 90.6%, respectively (P < 0.001, P < 0.001, P = 0.003). In terms of propensity score matching analysis, 5-year recurrence-free survival, 5-year disease-free survival, and 5-year overall survival rates of neutrophil-to-lymphocyte ratio <2.79 versus ≥2.79 were 100, 97.9, and 100% versus 82.3, 73.4, and 89.4%, respectively (P = 0.003, P = 0.001, P = 0.022). When combining preoperative neutrophil-to-lymphocyte ratio with the change of neutrophil-to-lymphocyte ratio, patients with both preoperative neutrophil-to-lymphocyte ratio ≥2.79 and the change of neutrophil-to-lymphocyte ratio ≥0.40 had the worst disease-free survival. Results of multivariable analysis showed that preoperative neutrophil-to-lymphocyte ratio and the change of neutrophil-to-lymphocyte ratio correlated with cancer relapse remarkably. High preoperative neutrophil-to-lymphocyte ratio and elevated postoperative neutrophil

The Effect of Background Pressure on Electron Acceleration from Ultra-Intense Laser-Matter Interactions

NASA Astrophysics Data System (ADS)

Le, Manh; Ngirmang, Gregory; Orban, Chris; Morrison, John; Chowdhury, Enam; Roquemore, William

2017-10-01

We present two-dimensional particle-in-cell (PIC) simulations that investigate the role of background pressure on the acceleration of electrons from ultra intense laser interaction at normal incidence with liquid density ethylene glycol targets. The interaction was simulated at ten different pressures varying from 7.8 mTorr to 26 Torr. We calculated conversion efficiencies from the simulation results and plotted the efficiencies with respect to the background pressure. The results revealed that the laser to > 100 keV electron conversion efficiency remained flat around 0.35% from 7.8 mTorr to 1.2 Torr and increased exponentially from 1.2 Torr onward to about 1.47% at 26 Torr. Increasing the background pressure clearly has a dramatic effect on the acceleration of electrons from the target. We explain how electrostatic effects, in particular the neutralization of the target by the background plasma, allows electrons to escape more easily and that this effect is strengthened with higher densities. This work could facilitate the design of future experiments in increasing laser to electron conversion efficiency and generating substantial bursts of electrons with relativistic energies. This research is supported by the Air Force Office of Scientific Research under LRIR Project 17RQCOR504 under the management of Dr. Riq Parra and Dr. Jean-Luc Cambier. Support was also provided by the DOD HPCMP Internship Program.

Fast and background-free three-dimensional (3D) live-cell imaging with lanthanide-doped upconverting nanoparticles.

PubMed

Jo, Hong Li; Song, Yo Han; Park, Jinho; Jo, Eun-Jung; Goh, Yeongchang; Shin, Kyujin; Kim, Min-Gon; Lee, Kang Taek

2015-12-14

We report on the development of a three-dimensional (3D) live-cell imaging technique with high spatiotemporal resolution using lanthanide-doped upconverting nanoparticles (UCNPs). It employs the sectioning capability of confocal microscopy except that the two-dimensional (2D) section images are acquired by wide-field epi-fluorescence microscopy. Although epi-fluorescence images are contaminated with the out-of-focus background in general, the near-infrared (NIR) excitation used for the excitation of UCNPs does not generate any autofluorescence, which helps to lower the background. Moreover, the image blurring due to defocusing was naturally eliminated in the image reconstruction process. The 3D images were used to investigate the cellular dynamics such as nuclear uptake and single-particle tracking that require 3D description.

New type IIB backgrounds and aspects of their field theory duals

NASA Astrophysics Data System (ADS)

Caceres, Elena; Macpherson, Niall T.; Núñez, Carlos

2014-08-01

In this paper we study aspects of geometries in Type IIA and Type IIB String theory and elaborate on their field theory dual pairs. The backgrounds are associated with reductions to Type IIA of solutions with G 2 holonomy in eleven dimensions. We classify these backgrounds according to their G-structure, perform a non-Abelian T-duality on them and find new Type IIB configurations presenting dynamical SU(2)-structure. We study some aspects of the associated field theories defined by these new backgrounds. Various technical details are clearly spelled out.

Genomic landscape of ovarian clear cell carcinoma via whole exome sequencing.

PubMed

Kim, Se Ik; Lee, Ji Won; Lee, Maria; Kim, Hee Seung; Chung, Hyun Hoon; Kim, Jae-Weon; Park, Noh Hyun; Song, Yong-Sang; Seo, Jeong-Sun

2018-02-01

To analyze whole exome sequencing (WES) data on ovarian clear cell carcinoma (OCCC) in Korean patients via the technique of next generation sequencing (NGS). Genomic profiles were compared between endometriosis-associated OCCC (EMS-OCCC) and Non-EMS-OCCC. We used serum samples and cancer tissues, stored at the Seoul National University Hospital Human Biobank, that were initially collected from women diagnosed with OCCC between 2012 and 2016. In total, 15 patients were enrolled: 5 with pathologically confirmed EMS-OCCC and 10 with Non-EMS-OCCC. We performed NGS WES on 15 fresh frozen OCCC tissues and matched serum samples, enabling comprehensive genomic characterization of OCCC. OCCC was characterized by complex genomic alterations, with a median of 178 exonic mutations (range, 111-25,798) and a median of 343 somatic copy number variations (range, 43-1,820) per tumor sample. In all, 54 somatic mutations were discovered across 14 genes, including PIK3CA (40%), ARID1A (40%), and KRAS (20%) in the 15 Korean OCCCs. Copy number gains in NTRK1 (33%), MYC (40%), and GNAS (47%) and copy number losses in TET2 (73%), TSC1 (67%), BRCA2 (60%), and SMAD4 (47%) were frequent. The significantly altered pathways were associated with proliferation and survival (including the PI3K/AKT, TP53, and ERBB2 pathways) in 87% of OCCCs and with chromatin remodeling in 47% of OCCCs. No significant differences in frequencies of genetic alterations were detected between EMS-OCCC and Non-EMS-OCCC groups. We successfully characterized the genomic landscape of 15 Korean patients with OCCC. We identified potential therapeutic targets for the treatment of this malignancy. Copyright © 2017. Published by Elsevier Inc.

Spectrally-selective all-inorganic scattering luminophores for solar energy-harvesting clear glass windows.

PubMed

Alghamedi, Ramzy; Vasiliev, Mikhail; Nur-E-Alam, Mohammad; Alameh, Kamal

2014-10-16

All-inorganic visibly-transparent energy-harvesting clear laminated glass windows are the most practical solution to boosting building-integrated photovoltaics (BIPV) energy outputs significantly while reducing cooling- and heating-related energy consumption in buildings. By incorporating luminophore materials into lamination interlayers and using spectrally-selective thin-film coatings in conjunction with CuInSe2 solar cells, most of the visible solar radiation can be transmitted through the glass window with minimum attenuation while ultraviolet (UV) radiation is down-converted and routed together with a significant part of infrared radiation to the edges for collection by solar cells. Experimental results demonstrate a 10 cm × 10 cm vertically-placed energy-harvesting clear glass panel of transparency exceeding 60%, invisible solar energy attenuation greater than 90% and electrical power output near 30 Wp/m(2) mainly generated by infrared (IR) and UV radiations. These results open the way for the realization of large-area visibly-transparent energy-harvesting clear glass windows for BIPV systems.

Hilar fat infiltration: A new prognostic factor in metastatic clear cell renal cell carcinoma with first-line sunitinib treatment.

PubMed

Kammerer-Jacquet, Solène-Florence; Brunot, Angelique; Bensalah, Karim; Campillo-Gimenez, Boris; Lefort, Mathilde; Bayat, Sahar; Ravaud, Alain; Dupuis, Frantz; Yacoub, Mokrane; Verhoest, Gregory; Peyronnet, Benoit; Mathieu, Romain; Lespagnol, Alexandra; Mosser, Jean; Edeline, Julien; Laguerre, Brigitte; Bernhard, Jean-Christophe; Rioux-Leclercq, Nathalie

2017-10-01

The selection of patients with metastatic clear cell renal cell carcinoma (ccRCC) who may benefit from targeted tyrosine kinase inhibitors has been a challenge, even more so now with the advent of new therapies. Hilar fat infiltration (HFI) is a validated prognostic factor in nonmetastatic ccRCC (TNM 2009 staging system) but has never been studied in metastatic patients. We aimed to assess its phenotype and prognostic effect in patients with metastatic ccRCC treated with first-line sunitinib. In a multicentric study, we retrospectively included 90 patients and studied the corresponding ccRCC at the pathological, immunohistochemical, and molecular levels. Patient and tumor characteristics were compared using univariate and multivariate analysis. All the features were then studied by Cox models for prognostic effect. HFI was found in 42 patients (46.7%), who had worse prognosis (Heng criteria) (P = 0.003), liver metastases (P = 0.036), and progressive diseases at first radiological evaluation (P = 0.024). The corresponding ccRCC was associated with poor pathological prognostic factors that are well known in nonmetastatic ccRCC. For these patients, median progression-free survival was 4 months vs. 13 months (P = 0.02), and median overall survival was 14 months vs. 29 months (P = 0.006). In a multivariate Cox model integrating all the variables, only poor prognosis, according to the Heng criteria and HFI, remained independently associated with both progression-free survival and overall survival. HFI was demonstrated for the first time to be an independent poor prognostic factor. Its potential role in predicting resistance to antiangiogenic therapy warrants further investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

Below-Background Ionizing Radiation as an Environmental Cue for Bacteria

DOE PAGES

Castillo, Hugo; Smith, Geoffrey B.

2017-02-14

All organisms on earth grow under the influence of a natural and relatively constant dose of ionizing radiation referred to as background radiation, and so cells have different mechanisms to prevent the accumulation of damage caused by its different components. However, current knowledge of the deleterious effects of radiation on cells is based on the exposure to acute and high or to chronic, above background doses of radiation and therefore is not appropriate to explain the cellular and biochemical mechanisms that cells employ to sense and respond to chronic below-background levels. Studies at below-background radiation doses can provide insight intomore » the biological role of radiation, as suggested by several examples of what appears to be a stress response in cells grown at doses that range from 10 to 79 times lower than background. Here, we discuss some of the technical constraints to shield cells from radiation to below-background levels, as well as different approaches used to detect and measure responses to such unusual environmental conditions. Then, we present data from Shewanella oneidensis and Deinococcus radiodurans experiments that show how two taxonomically distant bacterial species sense and respond to unnaturally low levels of radiation. Finally, in brief, we grew S. oneidensis and D. radiodurans in liquid culture at dose rates of 72.05 (control) and 0.91 (treatment) nGy hr -1 (including radon) for up to 72 h and measured cell density and the expression of stress-related genes. Our results suggest that a stress response is triggered in the absence of normal levels of radiation.« less

Below-Background Ionizing Radiation as an Environmental Cue for Bacteria

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

Castillo, Hugo; Smith, Geoffrey B.

All organisms on earth grow under the influence of a natural and relatively constant dose of ionizing radiation referred to as background radiation, and so cells have different mechanisms to prevent the accumulation of damage caused by its different components. However, current knowledge of the deleterious effects of radiation on cells is based on the exposure to acute and high or to chronic, above background doses of radiation and therefore is not appropriate to explain the cellular and biochemical mechanisms that cells employ to sense and respond to chronic below-background levels. Studies at below-background radiation doses can provide insight intomore » the biological role of radiation, as suggested by several examples of what appears to be a stress response in cells grown at doses that range from 10 to 79 times lower than background. Here, we discuss some of the technical constraints to shield cells from radiation to below-background levels, as well as different approaches used to detect and measure responses to such unusual environmental conditions. Then, we present data from Shewanella oneidensis and Deinococcus radiodurans experiments that show how two taxonomically distant bacterial species sense and respond to unnaturally low levels of radiation. Finally, in brief, we grew S. oneidensis and D. radiodurans in liquid culture at dose rates of 72.05 (control) and 0.91 (treatment) nGy hr -1 (including radon) for up to 72 h and measured cell density and the expression of stress-related genes. Our results suggest that a stress response is triggered in the absence of normal levels of radiation.« less

The EPIC-MOS Particle-Induced Background Spectrum

NASA Technical Reports Server (NTRS)

Kuntz, K. D.; Snowden, S. L.

2006-01-01

We have developed a method for constructing a spectrum of the particle-induced instrumental background of the XMM-Newton EPIC MOS detectors that can be used for observations of the diffuse background and extended sources that fill a significant fraction of the instrument field of view. The strength and spectrum of the particle-induced background, that is, the background due to the interaction of particles with the detector and the detector surroundings, is temporally variable as well as spatially variable over individual chips. Our method uses a combination of the filter-wheel-closed data and a database of unexposed-region data to construct a spectrum of the "quiescent" background. We show that, using this method of background subtraction, the differences between independent observations of the same region of "blank sky" are consistent with the statistical uncertainties except when there is clear evidence of solar wind charge exchange emission. We use the blank sky observations to show that contamination by SWCX emission is a strong function of the solar wind proton flux, and that observations through the flanks of the magnetosheath appear to be contaminated only at much higher solar wind fluxes. We have also developed a spectral model of the residual soft proton flares, which allows their effects to be removed to a substantial degree during spectral fitting.

Spectrally-selective all-inorganic scattering luminophores for solar energy-harvesting clear glass windows

PubMed Central

Alghamedi, Ramzy; Vasiliev, Mikhail; Nur-E-Alam, Mohammad; Alameh, Kamal

2014-01-01

All-inorganic visibly-transparent energy-harvesting clear laminated glass windows are the most practical solution to boosting building-integrated photovoltaics (BIPV) energy outputs significantly while reducing cooling- and heating-related energy consumption in buildings. By incorporating luminophore materials into lamination interlayers and using spectrally-selective thin-film coatings in conjunction with CuInSe2 solar cells, most of the visible solar radiation can be transmitted through the glass window with minimum attenuation while ultraviolet (UV) radiation is down-converted and routed together with a significant part of infrared radiation to the edges for collection by solar cells. Experimental results demonstrate a 10 cm × 10 cm vertically-placed energy-harvesting clear glass panel of transparency exceeding 60%, invisible solar energy attenuation greater than 90% and electrical power output near 30 Wp/m2 mainly generated by infrared (IR) and UV radiations. These results open the way for the realization of large-area visibly-transparent energy-harvesting clear glass windows for BIPV systems. PMID:25321890

MCT4 surpasses the prognostic relevance of the ancillary protein CD147 in clear cell renal cell carcinoma.

PubMed

Fisel, Pascale; Stühler, Viktoria; Bedke, Jens; Winter, Stefan; Rausch, Steffen; Hennenlotter, Jörg; Nies, Anne T; Stenzl, Arnulf; Scharpf, Marcus; Fend, Falko; Kruck, Stephan; Schwab, Matthias; Schaeffeler, Elke

2015-10-13

Cluster of differentiation 147 (CD147/BSG) is a transmembrane glycoprotein mediating oncogenic processes partly through its role as binding partner for monocarboxylate transporter MCT4/SLC16A3. As demonstrated for MCT4, CD147 is proposed to be associated with progression in clear cell renal cell carcinoma (ccRCC). In this study, we evaluated the prognostic relevance of CD147 in comparison to MCT4/SLC16A3 expression and DNA methylation. CD147 protein expression was assessed in two independent ccRCC-cohorts (n = 186, n = 59) by immunohistochemical staining of tissue microarrays and subsequent manual as well as automated software-supported scoring (Tissue Studio, Definien sAG). Epigenetic regulation of CD147 was investigated using RNAseq and DNA methylation data of The Cancer Genome Atlas. These results were validated in our cohort. Relevance of prognostic models for cancer-specific survival, comprising CD147 and MCT4 expression or SLC16A3 DNA methylation, was compared using chi-square statistics. CD147 protein expression generated with Tissue Studio correlated significantly with those from manual scoring (P < 0.0001, rS = 0.85), indicating feasibility of software-based evaluation exemplarily for the membrane protein CD147 in ccRCC. Association of CD147 expression with patient outcome differed between cohorts. DNA methylation in the CD147/BSG promoter was not associated with expression. Comparison of prognostic relevance of CD147/BSG and MCT4/SLC16A3, showed higher significance for MCT4 expression and superior prognostic power for DNA methylation at specific CpG-sites in the SLC16A3 promoter (e.g. CD147 protein: P = 0.7780,Harrell's c-index = 53.7% vs. DNA methylation: P = 0.0076, Harrell's c-index = 80.0%). Prognostic significance of CD147 protein expression could not surpass that of MCT4, especially of SLC16A3 DNA methylation, corroborating the role of MCT4 as prognostic biomarker for ccRCC.

MCT4 surpasses the prognostic relevance of the ancillary protein CD147 in clear cell renal cell carcinoma

PubMed Central

Winter, Stefan; Rausch, Steffen; Hennenlotter, Jörg; Nies, Anne T.; Stenzl, Arnulf; Scharpf, Marcus; Fend, Falko; Kruck, Stephan; Schwab, Matthias; Schaeffeler, Elke

2015-01-01

Cluster of differentiation 147 (CD147/BSG) is a transmembrane glycoprotein mediating oncogenic processes partly through its role as binding partner for monocarboxylate transporter MCT4/SLC16A3. As demonstrated for MCT4, CD147 is proposed to be associated with progression in clear cell renal cell carcinoma (ccRCC). In this study, we evaluated the prognostic relevance of CD147 in comparison to MCT4/SLC16A3 expression and DNA methylation. Methods CD147 protein expression was assessed in two independent ccRCC-cohorts (n = 186, n = 59) by immunohistochemical staining of tissue microarrays and subsequent manual as well as automated software-supported scoring (Tissue Studio, Definien sAG). Epigenetic regulation of CD147 was investigated using RNAseq and DNA methylation data of The Cancer Genome Atlas. These results were validated in our cohort. Relevance of prognostic models for cancer-specific survival, comprising CD147 and MCT4 expression or SLC16A3 DNA methylation, was compared using chi-square statistics. Results CD147 protein expression generated with Tissue Studio correlated significantly with those from manual scoring (P < 0.0001, rS = 0.85), indicating feasibility of software-based evaluation exemplarily for the membrane protein CD147 in ccRCC. Association of CD147 expression with patient outcome differed between cohorts. DNA methylation in the CD147/BSG promoter was not associated with expression. Comparison of prognostic relevance of CD147/BSG and MCT4/SLC16A3, showed higher significance for MCT4 expression and superior prognostic power for DNA methylation at specific CpG-sites in the SLC16A3 promoter (e.g. CD147 protein: P = 0.7780, Harrell's c-index = 53.7% vs. DNA methylation: P = 0.0076, Harrell's c-index = 80.0%). Conclusions Prognostic significance of CD147 protein expression could not surpass that of MCT4, especially of SLC16A3 DNA methylation, corroborating the role of MCT4 as prognostic biomarker for ccRCC. PMID:26384346

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

PubMed Central

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. PMID

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

PubMed

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.

17 CFR 39.7 - Fraud in connection with the clearing of transactions on a derivatives clearing organization.

Code of Federal Regulations, 2011 CFR

2011-04-01

... clearing of transactions on a derivatives clearing organization. 39.7 Section 39.7 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION DERIVATIVES CLEARING ORGANIZATIONS § 39.7 Fraud in connection with the clearing of transactions on a derivatives clearing organization. It shall be unlawful for any...

Eliminate background interference from latent fingerprints using ultraviolet multispectral imaging

NASA Astrophysics Data System (ADS)

Huang, Wei; Xu, Xiaojing; Wang, Guiqiang

2014-02-01

Fingerprints are the most important evidence in crime scene. The technology of developing latent fingerprints is one of the hottest research areas in forensic science. Recently, multispectral imaging which has shown great capability in fingerprints development, questioned document detection and trace evidence examination is used in detecting material evidence. This paper studied how to eliminate background interference from non-porous and porous surface latent fingerprints by rotating filter wheel ultraviolet multispectral imaging. The results approved that background interference could be removed clearly from latent fingerprints by using multispectral imaging in ultraviolet bandwidth.

17 CFR 39.4 - Procedures for implementing derivatives clearing organization rules and clearing new products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Procedures for implementing derivatives clearing organization rules and clearing new products. 39.4 Section 39.4 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION DERIVATIVES CLEARING ORGANIZATIONS § 39.4 Procedures for...

Characterization of ovarian clear cell carcinoma using target drug-based molecular biomarkers: implications for personalized cancer therapy.

PubMed

Li, Mengjiao; Li, Haoran; Liu, Fei; Bi, Rui; Tu, Xiaoyu; Chen, Lihua; Ye, Shuang; Cheng, Xi

2017-02-10

It has long been appreciated that different subtypes (serous, clear cell, endometrioid and mucinous) of epithelial ovarian carcinoma (EOC) have distinct pathogenetic pathways. However, clinical management, especially chemotherapeutic regimens, for EOC patients is not subtype specific. Ovarian clear cell carcinoma (CCC) is a rare histological subtype of EOC, which exhibits high rates of recurrence and low chemosensitivity. We assessed potential therapeutic targets for ovarian CCC patients through analyzing the variation of drug-based molecular biomarkers expression between ovarian CCC and high-grade serous carcinoma (HGSC). Seven candidate drug-based molecular biomarkers, human epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER2), phosphatase and tensin homolog deleted on chromosome ten (PTEN), aurora kinase A (AURKA), breast cancer susceptibility gene 1 (BRCA1), breast cancer susceptibility gene 2 (BRCA2) and programmed death-ligand 1 (PD-L1) were measured in 96 ovarian CCC and 113 HGSC by immunohistochemistry in paraffin embedded tissues. The relationship between these biomarkers and clinicopathological factors were explored. The expression level of four of the seven drug-based molecular biomarkers was markedly different between HGSC and CCC. High expression levels of HER2 and PD-L1 were more commonly observed in CCC patients (12.6% vs 2.7%, 21.1% vs 11.6%, P = 0.006, 0.064, respectively), while loss of BRCA1 and BRCA2 expression were more frequently occurred in HGSC patients (72.6% vs 54.3%, 89.4% vs 79.8%, P = 0.007, 0.054, respectively). Survival analysis showed that five of seven biomarkers had prognostic values but varied between subtypes. Furthermore, EGFR expressed frequently in CCC patients with endometriosis than in HGSC patients (44.4% vs 8.3%, P = 0.049). AURKA and PD-L1 correlated with the resistance to platinum-based chemotherapy in CCC patients (P = 0.043, 0.028, respectively) while no similar

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

PubMed Central

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. PMID:25594006

Age and clear eyes are associated with an increased risk of cutaneous squamous cell carcinomas in vemurafenib-treated melanoma patients.

PubMed

Herms, Florian; Kramkimel, Nora; Regnier-Rosencher, Elodie; Carlotti, Agnès; Chanal, Johan; Boitier, Françoise; Aractingi, Selim; Dupin, Nicolas; Avril, Marie-Françoise

2016-10-01

Cutaneous squamous cell carcinoma (cSCC) is a frequent side-effect of vemurafenib treatment. The main aim of this study was to identify the clinical risk factors associated with the development of cSCC in melanoma patients treated with vemurafenib. We carried out a retrospective study, including 63 consecutive melanoma patients treated with vemurafenib for BRAF-mutant metastatic melanoma in an oncodermatological department. Clinical and follow-up data were collected and analysed, and a comparison of the subgroups who did and did not develop cSCC was performed. A total of 42.9% of patients (n=27) treated with vemurafenib developed one or more cSCC. Patients with cSCC were significantly older (P=0.01). Clear eyes were also associated with a higher risk of developing cSCC (odds ratio=3.50; 95% confidence interval: 1.08-12.43). Three patients developed cSCC more than 1 year after the initiation of treatment (12, 16 and 18 months, respectively). Clinicians should be vigilant in older patients undergoing vemurafenib therapy as well as patients with clear eyes as they seem to be at increased risk of developing cSCC, even late after the initiation of treatment.

77 FR 12896 - Self-Regulatory Organizations; Midwest Clearing Corporation; Order Cancelling Clearing Agency...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-02

... Act provides that in the event any self- regulatory organization is no longer in existence or has... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-66458; File No. 600-9] Self-Regulatory Organizations; Midwest Clearing Corporation; Order Cancelling Clearing Agency Registration February 24, 2012. I...

Plac8-dependent and inducible NO synthase-dependent mechanisms clear Chlamydia muridarum infections from the genital tract.

PubMed

Johnson, Raymond M; Kerr, Micah S; Slaven, James E

2012-02-15

Chlamydia trachomatis urogenital serovars replicate predominantly in genital tract epithelium. This tissue tropism poses a unique challenge for host defense and vaccine development. Studies utilizing the Chlamydia muridarum mouse model have shown that CD4 T cells are critical for clearing genital tract infections. In vitro studies have shown that CD4 T cells terminate infection by upregulating epithelial inducible NO synthase (iNOS) transcription and NO production. However, this mechanism is not critical, as iNOS-deficient mice clear infections normally. We recently showed that a subset of Chlamydia-specific CD4 T cell clones could terminate replication in epithelial cells using an iNOS-independent mechanism requiring T cell degranulation. We advance that work using microarrays to compare iNOS-dependent and iNOS-independent CD4 T cell clones. Plac8 was differentially expressed by clones having the iNOS-independent mechanism. Plac8-deficient mice had delayed clearance of infection, and Plac8-deficient mice treated with the iNOS inhibitor N-monomethyl-l-arginine were largely unable to resolve genital tract infections over 8 wk. These results demonstrate that there are two independent and redundant T cell mechanisms for clearing C. muridarum genital tract infections: one dependent on iNOS, and the other dependent on Plac8. Although T cell subsets are routinely defined by cytokine profiles, there may be important subdivisions by effector function, in this case CD4(Plac8).

Quenched substrates for live-cell labeling of SNAP-tagged fusion proteins with improved fluorescent background.

PubMed

Stöhr, Katharina; Siegberg, Daniel; Ehrhard, Tanja; Lymperopoulos, Konstantinos; Öz, Simin; Schulmeister, Sonja; Pfeifer, Andrea C; Bachmann, Julie; Klingmüller, Ursula; Sourjik, Victor; Herten, Dirk-Peter

2010-10-01

Recent developments in fluorescence microscopy raise the demands for bright and photostable fluorescent tags for specific and background free labeling in living cells. Aside from fluorescent proteins and other tagging methods, labeling of SNAP-tagged proteins has become available thereby increasing the pool of potentially applicable fluorescent dyes for specific labeling of proteins. Here, we report on novel conjugates of benzylguanine (BG) which are quenched in their fluorescence and become highly fluorescent upon labeling of the SNAP-tag, the commercial variant of the human O(6)-alkylguanosyltransferase (hAGT). We identified four conjugates showing a strong increase, i.e., >10-fold, in fluorescence intensity upon labeling of SNAP-tag in vitro. Moreover, we screened a subset of nine BG-dye conjugates in living Escherichia coli and found them all suited for labeling of the SNAP-tag. Here, quenched BG-dye conjugates yield a higher specificity due to reduced contribution from excess conjugate to the fluorescence signal. We further extended the application of these conjugates by labeling a SNAP-tag fusion of the Tar chemoreceptor in live E. coli cells and the eukaryotic transcription factor STAT5b in NIH 3T3 mouse fibroblast cells. Aside from the labeling efficiency and specificity in living cells, we discuss possible mechanisms that might be responsible for the changes in fluorescence emission upon labeling of the SNAP-tag, as well as problems we encountered with nonspecific labeling with certain conjugates in eukaryotic cells.

Hodgkin/Reed-Sternberg cells and Hodgkin's disease in patients with B-cell chronic lymphocytic leukaemia: an immunohistological, molecular and clinical study of four cases suggesting a heterogeneous pathogenetic background.

PubMed

Pescarmona, E; Pignoloni, P; Mauro, F R; Cerretti, R; Anselmo, A P; Mandelli, F; Baroni, C D

2000-08-01

We report the immunohistological, molecular and clinical findings in four patients affected by B-cell chronic lymphocytic leukaemia (CLL) who developed "Richter's syndrome with Hodgkin's disease (HD) features" or "CLL with Hodgkin's transformation", all characterised by the presence of typical Hodgkin/Reed-Sternberg (H/RS) cells in lymph node biopsies. In three cases the nodal involvement by CLL was demonstrated both by the presence of a predominant background of CD5/CD19/CD23+ small lymphocytes and an IgH monoclonal rearrangement revealed by PCR analysis. Conversely, in the remaining case there was neither immunohistological nor molecular evidence of lymph node involvement by CLL. In all four cases H/RS cells were Epstein-Barr virus (EBV) latent membrane protein (LMP-1) positive. These findings suggest that the presence of H/RS cells in the first three patients, who had CLL/HD nodal involvement, might be related to transformation or clonal evolution of CLL cells in H/RS cells, which is in keeping with use of the term "CLL with Hodgkin's transformation". In the fourth case a de novo HD may be postulated, representing a second malignancy presumably not clonally related to CLL. In all cases a key pathogenetic role of EBV is suggested by the expression of LMP-1 in H/RS cells. Our findings indicate that the presence of typical H/RS cells in lymph node biopsies in CLL patients may reflect a heterogeneous pathogenetic background. The different clinico-pathologic settings should be taken into consideration because of their possible implications for patients' treatment and prognosis.

Common regions of deletion in chromosome regions 3p12 and 3p14.2 in primary clear cell renal carcinomas.

PubMed

Lubinski, J; Hadaczek, P; Podolski, J; Toloczko, A; Sikorski, A; McCue, P; Druck, T; Huebner, K

1994-07-15

Nearly all clear cell renal cell carcinomas (RCCs) exhibit loss of alleles on the short arm of chromosome 3. Loss and mutation at the von Hippel-Lindau (VHL) gene at 3p25 probably occurs in most RCCs and, since the VHL gene was recently cloned, data on VHL involvement in RCCs is accumulating. However, the region 3p14-p12, a region that contains the familial RCC-associated t(3;8)(p14.2;q24) chromosome translocation and the small cell lung carcinoma-associated homozygous deletion at 3p13-12, has also been reported to exhibit allele loss in a large fraction of RCCs. In order to focus future studies on potential suppressor genes in the 3p14-p12 region, we have studied allele loss in 30 RCCs with 9 polymorphic simple sequence repeat markers spanning 3p21.1-p12. Partial losses in the 3p21-p12 region were observed, allowing determination of common regions of loss of heterozygosity overlap in 15 RCCs. Results suggested that most RCCs exhibit loss in a region which brackets the t(3;8) familial chromosome translocation at 3p14.2, and some show additional deletions within the U2020 small cell lung carcinoma deletion at 3p12.

Incidence rates and risks of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix: Update after 40-year follow-up.

PubMed

Huo, Dezheng; Anderson, Diane; Palmer, Julie R; Herbst, Arthur L

2017-09-01

Women exposed to diethylstilbestrol (DES) in utero are at increased risk for the development of vaginal and cervical clear cell adenocarcinoma (CCA) at younger age. It is unknown if a second peak will occur in later life, the ages when CCA developed spontaneously in the pre-DES era. The complete epidemiologic curve of CCA has not been reported, yet. We reviewed 720 cases of CCA from the CCA registry at the University of Chicago through 2014. Incidence rates and cumulative risks for CCA were calculated based on white women born in the U.S. from 1948 through 1971. In 420 CCA cases there was documented evidence of prenatal DES exposure. 80% were among those between ages 15 and 31 but some occurred as late as age 55. A small second peak occurred around age 42. The risk of DES-related CCA was highest in the 1951-1956 birth cohort and this birth cohort effect closely correlated with DES prescriptions over time in the U.S. (r=0.98, P=0.005). By age 50, the cumulative risk of CCA was 1 per 750 exposed women. CCA cases without evidence of DES exposure had similar ages, year of diagnosis, and birth cohort patterns as the documented DES-exposed cases, suggesting that some negative cases were exposed. Their inclusion raises the cumulative risk of CCA to 1 per 520. With the largest data available, our results confirmed the association between prenatal DES exposure and clear cell adenocarcinoma. The study also refines the risks of DES-related CCA. Copyright © 2017 Elsevier Inc. All rights reserved.

77 FR 12896 - Self-Regulatory Organizations; Pacific Clearing Corporation; Order Cancelling Clearing Agency...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-02

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-66459; File No. 600-11] Self-Regulatory Organizations; Pacific Clearing Corporation; Order Cancelling Clearing Agency Registration February 24, 2012. I..., 2006), 72 FR 814 (Jan. 8, 2007). Section 19(a)(3) of the Act \\14\\ provides that in the event any self...

Utility of α-methylacyl-coenzyme-A racemase (p504s) immunohistochemistry in distinguishing endometrial clear cell carcinomas from serous and endometrioid carcinomas.

PubMed

Fadare, Oluwole; Parkash, Vinita; Gwin, Katja; Hanley, Krisztina Z; Jarboe, Elke A; Liang, Sharon X; Quick, Charles M; Zheng, Wenxin; Rawish, Kojo R; Hecht, Jonathan L; Desouki, Mohamed M

2013-12-01

The expression of α-methylacyl-coenzyme-A racemase (AMACR) has previously been reported in 75% to 100% of urethral/bladder clear cell carcinomas, tumors that are known to display broad phenotypic overlap with their identically named müllerian counterparts. Herein, we assess the utility of AMACR in distinguishing endometrial clear cell carcinomas (CCCs) from endometrial serous carcinomas (ESCs) and endometrial endometrioid carcinomas (EECs). A total of 111 endometrial carcinomas in a tissue microarray, including 49 CCCs, 13 ESCs, and 49 EECs, were assessed for AMACR immunoreactivity, with results scored semiquantitatively (scores 0, 1+, 2+, 3+ for 0%, 1%-5%, 6%-50%, >50% immunoreactive cells, respectively). Fifty (45%) of the 111 carcinomas were AMACR positive, with the following score distribution: CCC: 0 (n = 12), 1+ (n = 12), 2+ (n = 3), 3+ (n = 22); EEC: 0 (n = 38), 1+ (n = 4), 2+ (n = 4), 3+ (n = 3); ESC: 0 (n = 11), 1+ (n = 1), 2+ (n = 0), 3+ (n = 1). AMACR expression was significantly more frequent in CCC (75%) than in ESC (15%) or EEC (22%); P < .0001. The sensitivity and specificity of AMACR expression in classifying a carcinoma as CCC were 0.75 (95% confidence interval [CI], 0.61-0.86) and 0.79 (95% CI, 0.66-0.88), respectively, with an odds ratio of 11.62 (95% CI, 5-28; P < .001) and an area under the curve of 0.79 (95% CI, 0.68-0.88). These findings indicate that AMACR expression is strongly associated with CCC and displays a relatively robust diagnostic test performance. However, its practical utility may be limited by the focal nature of its expression in 32% of the AMACR-positive CCC cases as well as its expression in 15% to 22% of the non-CCC histotypes. © 2013.

75 FR 27338 - NASDAQ OMX Commodities Clearing-Contract Merchant LLC; NASDAQ OMX Commodities Clearing-Delivery...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-14

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket Nos. ER10-912-000; ER10-913-000; ER10-914-000] NASDAQ OMX Commodities Clearing--Contract Merchant LLC; NASDAQ OMX Commodities Clearing--Delivery LLC; NASDAQ OMX Commodities Clearing--Finance LLC; Notice of Filing May 6, 2010. Take notice that, on May 3, 2010, NASDAQ OMX Commoditie...

A Fluorogenic TMP-tag for High Signal-to-Background Intracellular Live Cell Imaging

PubMed Central

Jing, Chaoran

2013-01-01

Developed to compliment the use of fluorescent proteins in live cell imaging, chemical tags enjoy the benefit of modular incorporation of organic fluorophores, opening the possibility of high photon output and special photophysical properties. However, the theoretical challenge in using chemical tags as opposed to fluorescent proteins for high-resolution imaging is background noise from unbound and/or non-specifically bound ligand-fluorophore. We envisioned we could overcome this limit by engineering fluorogenic trimethoprim-based chemical tags (TMP-tags) in which the fluorophore is quenched until binding with E. coli dihydrofolate reductase (eDHFR) tagged protein displaces the quencher. Thus, we began by building a non-fluorogenic, covalent TMP-tag based on a proximity-induced reaction known to achieve rapid and specific labeling both in vitro and inside of living cells. Here we take the final step and render the covalent TMP-tag fluorogenic. In brief, we designed a trimeric TMP-fluorophore-quencher molecule (TMP-Q-Atto520) with the quencher attached to a leaving group that, upon TMP binding to eDHFR, would be cleaved by a cysteine residue (Cys) installed just outside the binding pocket of eDHFR. We present the in vitro experiments showing that the eDHFR:L28C nucleophile cleaves the TMP-Q-Atto520 rapidly and efficiently, resulting in covalent labeling and remarkable fluorescence enhancement. Most significantly, while only our initial design, TMP-Q-Atto520 achieved the demanding goal of not only labeling highly abundant, localized intracellular proteins, but also less abundant, more dynamic cytoplasmic proteins. These results suggest that fluorogenic TMP-tag can significantly impact highresolution live cell imaging and further establish the potential of proximity-induced reactivity and organic chemistry more broadly as part of the growing toolbox for synthetic biology and cell engineering. PMID:23745575

Micro-Raman spectroscopy of algae: composition analysis and fluorescence background behavior.

PubMed

Huang, Y Y; Beal, C M; Cai, W W; Ruoff, R S; Terentjev, E M

2010-04-01

Preliminary feasibility studies were performed using Stokes Raman scattering for compositional analysis of algae. Two algal species, Chlorella sorokiniana (UTEX #1230) and Neochloris oleoabundans (UTEX #1185), were chosen for this study. Both species were considered to be candidates for biofuel production. Raman signals due to storage lipids (specifically triglycerides) were clearly identified in the nitrogen-starved C. sorokiniana and N. oleoabundans, but not in their healthy counterparts. On the other hand, signals resulting from the carotenoids were found to be present in all of the samples. Composition mapping was conducted in which Raman spectra were acquired from a dense sequence of locations over a small region of interest. The spectra obtained for the mapping images were filtered for the wavelengths of characteristic peaks that correspond to components of interest (i.e., triglyceride or carotenoid). The locations of the components of interest could be identified by the high intensity areas in the composition maps. Finally, the time evolution of fluorescence background was observed while acquiring Raman signals from the algae. The time dependence of fluorescence background is characterized by a general power law decay interrupted by sudden high intensity fluorescence events. The decreasing trend is likely a result of photo-bleaching of cell pigments due to prolonged intense laser exposure, while the sudden high intensity fluorescence events are not understood. (c) 2009 Wiley Periodicals, Inc.

Internal gravity wave-atmospheric wind interaction - A cause of clear air turbulence.

NASA Technical Reports Server (NTRS)

Bekofske, K.; Liu, V. C.

1972-01-01

The interaction between an internal gravity wave (IGW) and a vertical wind shear is discussed as a possible cause in the production of clear air turbulence in the free atmosphere. It is shown that under certain typical condition the interaction of an IGW with a background wind shear near a critical level provides a mechanism for depositing sufficient momentum in certain regions of the atmosphere to significantly increase the local mean wind shear and to lead to the production of turbulence.

Reprogramming of single-cell derived mesenchymal stem cells into hair cell-like cells

PubMed Central

Lin, Zhaoyu; Perez, Philip; Sun, Zhenyu; Liu, Jan-Jan; Shin, June Ho; Hyrc, Krzysztof L.; Samways, Damien; Egan, Terry; Holley, Matthew C.; Bao, Jianxin

2012-01-01

Hypothesis Adult mesenchymal stem cells (MSCs) can be converted into hair cell-like cells by transdetermination. Background Given the fundamental role sensory hair cells play in sound detection and the irreversibility of their loss in mammals, much research has focused on developing methods to generate new hair cells as a means of treating permanent hearing loss. Although MSCs can differentiate into multiple cell lineages, no efficient means of reprogramming them into sensory hair cells exists. Earlier work has shown that the transcription factor Atoh1 is necessary for early development of hair cells, but it is not clear whether Atoh1 can be used to convert MSCs into hair cells. Methods Clonal MSC cell lines were established and reprogrammed into hair cell-like cells by a combination of protein transfer, adenoviral based gene transfer and co-culture with neurons. During transdetermination, inner ear molecular markers were analyzed by RT-PCR, and cell structures were examined by immunocytochemistry. Results Atoh1 overexpression in MSCs failed to convert MSCs into hair cell-like cells, suggesting that the ability of Atoh1 to induce hair cell differentiation is context dependent. Because Atoh1 overexpression successfully transforms VOT-E36 cells into hair cell-like cells, we modified the cell context of MSCs by performing a total protein transfer from VOT-E36 cells prior to overexpressing Atoh1. The modified MSCs were transformed into hair cell-like cells and attracted contacts from spiral ganglion neurons in a co-culture model. Conclusion We established a new procedure, consisting of VOT-E36 protein transfer, Atoh1 overexpression, and co-culture with spiral ganglion neurons, which can transform MSCs into hair cell-like cells. PMID:23111404

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

PubMed Central

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

PBRM1 and VHL expression correlate in human clear cell renal cell carcinoma with differential association with patient's overall survival.

PubMed

Högner, Anica; Krause, Hans; Jandrig, Burkhard; Kasim, Mumtaz; Fuller, Tom Florian; Schostak, Martin; Erbersdobler, Andreas; Patzak, Andreas; Kilic, Ergin

2018-03-01

To identify the clinicopathological association of PBRM1 (Polybromo-1 gene) and VHL (von Hippel-Lindau gene) expression at mRNA and protein levels in clear cell renal cell carcinoma (ccRCC) and its role in tumor progression. Immunohistochemical analysis, Western blotting and qPCR analysis of PBRM1 and VHL were performed on fresh-frozen ccRCC and adjacent normal tissue obtained from 70 patients who underwent radical nephrectomy. In addition, a tissue microarray (TMA) from specimens of 326 ccRCC patients was used to evaluate the effect of loss of PBRM1 and VHL immunohistological expression on clinicopathological features as well as patient survival. In frozen tissue, PBRM1 and VHL mRNA were significantly down-regulated in most ccRCC tumors (77.6%/80.6%). Simultaneous weak PBRM1 and VHL protein expression was observed in 21.4% of frozen tumors. In the TMA samples, weak PBRM1 and VHL immunohistochemical staining was observed in 60.4% of the cases and was correlated (P<0.001). The association of PBRM1 and VHL immunohistochemical expression with clinicopathological parameters depicts a variable picture: predominantly weak PBRM1 and VHL expression were significantly associated with higher Fuhrman grade (P = 0.012 and 0.024, respectively) but only weak VHL expression was associated with a higher pT stage (P = 0.023). PBRM1 expression did not affect the overall survival, whereas weak VHL expression was associated with decreased patient overall survival (P = 0.013). Our data suggest that reduced expression of PBRM1 and VHL is correlated with an increased tumor aggressiveness. Low VHL expression was identified as a risk factor for worse patient overall survival, independently from PBRM1 expression pattern. Copyright © 2018 Elsevier Inc. All rights reserved.

High truncated-O-glycan score predicts adverse clinical outcome in patients with localized clear-cell renal cell carcinoma after surgery.

PubMed

NguyenHoang, SonTung; Liu, Yidong; Xu, Le; Zhou, Lin; Chang, Yuan; Fu, Qiang; Liu, Zheng; Lin, Zongming; Xu, Jiejie

2017-10-03

Truncated O-glycans, including Tn-antigen, sTn-antigen, T-antigen, sT-antigen, are incomplete glycosylated structures and their expression occur frequently in tumor tissue. The study aims to evaluate the abundance of each truncated O-glycans and its clinical significance in postoperative patients with localized clear-cell renal cell carcinoma (ccRCC). We used immunohistochemical testing to analyze the expression of truncated O-glycans in tumor specimens from 401 patients with localized ccRCC. Truncated-O-glycan score was built by integrating the expression level of Tn-, sTn- and sT-antigen. Kaplan-Meier survival and Cox regression analysis were done to compare clinical outcomes in subgroups. Receiver operating characteristic (ROC) was applied to assess the impact of prognostic factors on overall survival (OS) and recurrence-free survival (RFS). The results identified Tn-, sTn-, sT-antigen as independent prognosticators. The OS and RFS were shortened among the 198 (49.4%) patients with high Truncated-O-glycan score than among the 203 (50.6%) patients with low score (hazard ratio for OS, 7.060; 95% confidence interval [CI]: 2.765 to 18.027; p <0.001; for RFS, 4.612; 95% CI: 2.141 to 9.931; p <0.001). There is no difference between low-risk patients and high-risk patients in low score group ( p = 0.987). High-risk patients with low score showed a better prognosis than low-risk patient with high score ( p = 0.029). The Truncated-O-glycan score showed better prognostic value for OS (AUC: 0.739, p = 0.003) and RFS (AUC: 0.719, p = 0.003) than TNM stage. In summary, the high Truncated-O-glycan score could predict adverse clinical outcome in localized ccRCC patients after surgery.

Recent progress in tissue optical clearing

PubMed Central

Zhu, Dan; Larin, Kirill V; Luo, Qingming; Tuchin, Valery V

2013-01-01

Tissue optical clearing technique provides a prospective solution for the application of advanced optical methods in life sciences. This paper gives a review of recent developments in tissue optical clearing techniques. The physical, molecular and physiological mechanisms of tissue optical clearing are overviewed and discussed. Various methods for enhancing penetration of optical-clearing agents into tissue, such as physical methods, chemical-penetration enhancers and combination of physical and chemical methods are introduced. Combining the tissue optical clearing technique with advanced microscopy image or labeling technique, applications for 3D microstructure of whole tissues such as brain and central nervous system with unprecedented resolution are demonstrated. Moreover, the difference in diffusion and/or clearing ability of selected agents in healthy versus pathological tissues can provide a highly sensitive indicator of the tissue health/pathology condition. Finally, recent advances in optical clearing of soft or hard tissue for in vivo imaging and phototherapy are introduced. PMID:24348874

Development and confirmation of potential gene classifiers of human clear cell renal cell carcinoma using next-generation RNA sequencing.

PubMed

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

2016-12-01

A previous study by this group demonstrated the feasibility of RNA sequencing (RNAseq) technology for capturing disease biology of clear cell renal cell carcinoma (ccRCC), and presented initial results for carbonic anhydrase-9 (CA9) and tumor necrosis factor-α-induced protein-6 (TNFAIP6) as possible biomarkers of ccRCC (discovery set) [Eikrem et al. PLoS One 2016;11:e0149743]. To confirm these results, the previous study is expanded, and RNAseq data from additional matched ccRCC and normal renal biopsies are analyzed (confirmation set). Two core biopsies from patients (n = 12) undergoing partial or full nephrectomy were obtained with a 16 g needle. RNA sequencing libraries were generated with the Illumina TruSeq ® Access library preparation protocol. Comparative analysis was done using linear modeling (voom/Limma; R Bioconductor). The formalin-fixed and paraffin-embedded discovery and confirmation data yielded 8957 and 11,047 detected transcripts, respectively. The two data sets shared 1193 of differentially expressed genes with each other. The average expression and the log 2 -fold changes of differentially expressed transcripts in both data sets correlated, with R²   =   .95 and R²   =   .94, respectively. Among transcripts with the highest fold changes were CA9, neuronal pentraxin-2 and uromodulin. Epithelial-mesenchymal transition was highlighted by differential expression of, for example, transforming growth factor-β 1 and delta-like ligand-4. The diagnostic accuracy of CA9 was 100% and 93.9% when using the discovery set as the training set and the confirmation data as the test set, and vice versa, respectively. These data further support TNFAIP6 as a novel biomarker of ccRCC. TNFAIP6 had combined accuracy of 98.5% in the two data sets. This study provides confirmatory data on the potential use of CA9 and TNFAIP6 as biomarkers of ccRCC. Thus, next-generation sequencing expands the clinical application of tissue analyses.

All Clear for New Horizons

NASA Image and Video Library

2015-07-01

This illustration shows some of the final images used to determine that the coast is clear for New Horizons' flight through the Pluto system. These images show the difference between two sets of 48 combined 10-second exposures with New Horizons Long Range Reconnaissance Imager (LORRI) camera, taken at 8:40 UTC and 10:25 UTC on June 26, 2015, from a range of 21.5 million kilometers (approximately 13 million miles) to Pluto. The known small moons, Nix, Hydra, Kerberos and Styx, are visible as adjacent bright and dark pairs of dots, due to their motion in the 105 minutes between the two image sets. The images have been extensively processed to remove the glare and "ghosts" (i.e., lens flare) from Pluto and Charon, and also to remove background stars, though many of the brighter stars are imperfectly removed and appear as irregular bright and dark blobs. These and other similar sets of images demonstrate that there are no previously unknown moons brighter than 15 times fainter than Styx (the faintest known moon) in the region outside of Charon's orbit, or brighter than five times fainter than Styx in the region between Charon's orbit and a few thousand kilometers above Pluto's surface. http://photojournal.jpl.nasa.gov/catalog/PIA19695

Overexpression of FOXO4 induces apoptosis of clear-cell renal carcinoma cells through downregulation of Bim.

PubMed

Wang, Wei; Zhou, Pang-Hu; Hu, Wei

2016-03-01

Forkhead box O4 (FOXO4) has been reported to be a novel tumor suppressor gene in gastrointestinal cancers; however, its role in clear‑cell renal carcinoma cells (ccRCC) has remained largely elusive. The present study assessed the expression levels of FOXO4 in RCC tissues and cells. Furthermore, the effects of vector‑mediated overexpression of FOXO4 on the apoptotic rate of the 786‑0 and Caki‑1 cell lines and the role of Bim in this process were investigated. The results demonstrated that the protein and mRNA expression levels of FOXO4 were decreased in renal cancer tissues and cell lines compared with those in normal tissues and cell lines. FOXO4 overexpression significantly increased the apoptotic rate of ccRCC cells in vitro, along with increased protein expression levels of Bim, cleaved‑caspase 3, B‑cell lymphoma 2 (Bcl‑2)‑associated X protein (Bax) and cytochrome c, as well as a decrease in Bcl‑2 expression. Of note, the apoptotic effects of FOXO4 overexpression in 786‑0 cells were inhibited by small interfering RNA‑mediated knockdown of Bim. The results of the present study indicated that FOXO4 has an inhibitory effect in ccRCC, at least in part through inducing apoptosis via upregulation of Bim in the mitochondria-dependent pathway.

Integrative kinome profiling identifies mTORC1/2 inhibition as treatment strategy in ovarian clear cell carcinoma.

PubMed

Caumanns, Joseph J; Berns, Katrien; Wisman, G Bea A; Fehrmann, Rudolf S N; Tomar, Tushar; Klip, Harry; Meersma, Gert Jan; Hijmans, E Marielle; Gennissen, Annemiek; Duiker, Evelien W; Weening, Desiree; Itamochi, Hiroaki; Kluin, Roelof Jc; Reyners, An K L; Birrer, Michael J; Salvesen, Helga B; Vergote, Ignace; Van Nieuwenhuysen, Els; Brenton, James D; Braicu, Elena I; Kupryjanczyk, Jolanta; Spiewankiewicz, Beata; Mittempergher, Lorenza; Bernards, Rene; van der Zee, Ate G J; de Jong, Steven

2018-04-23

Advanced stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA. In this study, we aimed to identify currently unknown mutated kinases in OCCC patients and test druggability of downstream affected pathways in OCCC models. In a large set of OCCC patients (n=124), the human kinome (518 kinases) and additional cancer related genes were sequenced and copy number alterations were determined. Genetically characterized OCCC cell lines (n=17) and OCCC patient-derived xenografts (n=3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib and the mTORC1/2 inhibitor AZD8055. We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway or the ERBB family of receptor tyrosine kinases and 82% in the DNA repair pathway. Strong p-S6 staining in OCCC patients suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not towards drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient-derived xenograft models. These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. Copyright ©2018, American Association for Cancer Research.

Mercury Geochemistry of Gold Placer Tailings, Sediments, Bedrock, and Waters in the Lower Clear Creek Area, Shasta County, California - Report of Investigations, 2001-2003

USGS Publications Warehouse

Ashley, Roger P.; Rytuba, James J.

2008-01-01

Clear Creek, one of the major tributaries of the upper Sacramento River, drains the eastern Trinity Mountains. Alluvial plain and terrace gravels of lower Clear Creek, at the northwest edge of the Sacramento Valley, contain placer gold that has been mined since the Gold Rush by various methods including hydraulic mining and dredging. In addition, from the 1950s to the 1980s aggregate-mining operations removed gravel from the lower Clear Creek flood plain. Since Clear Creek is an important stream for salmon production, a habitat restoration program is underway to repair damage from mining and improve conditions for spawning. This program includes moving dredge tailings to increase the area of spawning gravel and to fill gravel pits in the flood plain, raising the concern that mercury lost to these tailings in the gold recovery process may be released and become available to biota. The purposes of our study are to identify sources, transport, and dispersal of mercury in the lower Clear Creek area and identify environments in which bioavailable methylmercury is produced. Analytical data acquired include total mercury and methylmercury concentrations in sediments, tailings, and water. Mercury concentrations in bedrock and unmined gravels in and around the mined area are low and are taken to represent background concentrations. Bulk mercury values in placer mining tailings range from near-background in coarse dry materials to more than 40 times background in sands and silts exposed to mercury in sluices. Tailings are entrained in flood-plain sediments and active stream sediments; consequently, mercury concentrations in these materials range from background to about two to three times background. Mercury in sediments and tailings is associated with fine size fractions. The source of most of this mercury is historical gold mining in the Clear Creek watershed. Although methylmercury levels are low in most of these tailings and sediments, flood-plain sediment in shallow

A new organic solvent for use in the clearing of tissues. I. Soft tissue histology.

PubMed

Wishe, H I; Roy, M; Piliero, S J

1980-07-01

Histosol is a non-flammable solvent mixture of synthetic aromatic hydrocarbons with a flash point of 124 degrees F (T.C.C.). It has a lower vapor pressure and evaporation rate than other organic solvents, such as xylene, routinely used as clearing and deparaffinizing agents. Although both xylene and Histosol clear and deparaffinize soft organ tissues effectively in the preparation of permanently mounted stained slides, Histosol appears, in many instances, to be the choice solvent: tissues are easier to section; cell borders and cell surface modifications are most distinct; cytoplasmic eosinophilia is more vivid; and nuclear detail is improved. Of prime importance, Histosol is a safer and more efficient solvent for use in histological and pathological laboratories.

Molecular effective coverage surface area of optical clearing agents for predicting optical clearing potential

NASA Astrophysics Data System (ADS)

Feng, Wei; Ma, Ning; Zhu, Dan

2015-03-01

The improvement of methods for optical clearing agent prediction exerts an important impact on tissue optical clearing technique. The molecular dynamic simulation is one of the most convincing and simplest approaches to predict the optical clearing potential of agents by analyzing the hydrogen bonds, hydrogen bridges and hydrogen bridges type forming between agents and collagen. However, the above analysis methods still suffer from some problem such as analysis of cyclic molecule by reason of molecular conformation. In this study, a molecular effective coverage surface area based on the molecular dynamic simulation was proposed to predict the potential of optical clearing agents. Several typical cyclic molecules, fructose, glucose and chain molecules, sorbitol, xylitol were analyzed by calculating their molecular effective coverage surface area, hydrogen bonds, hydrogen bridges and hydrogen bridges type, respectively. In order to verify this analysis methods, in vitro skin samples optical clearing efficacy were measured after 25 min immersing in the solutions, fructose, glucose, sorbitol and xylitol at concentration of 3.5 M using 1951 USAF resolution test target. The experimental results show accordance with prediction of molecular effective coverage surface area. Further to compare molecular effective coverage surface area with other parameters, it can show that molecular effective coverage surface area has a better performance in predicting OCP of agents.

The CLEAR 2007 Evaluation

DTIC Science & Technology

2007-01-01

early 2007 and culminated with a two-day workshop held in May 2007. CLEAR is an international effort to evaluate systems for the perception of people ...working on technologies to analyze people , their activities, and their interaction. However, common benchmarks for such technologies are usually not... people and institutions worldwide contributed to the success of CLEAR 2007. Again, the organizers were the Interactive Systems Labs of the Universität

High expression of KCa3.1 in patients with clear cell renal carcinoma predicts high metastatic risk and poor survival.

PubMed

Rabjerg, Maj; Oliván-Viguera, Aida; Hansen, Lars Koch; Jensen, Line; Sevelsted-Møller, Linda; Walter, Steen; Jensen, Boye L; Marcussen, Niels; Köhler, Ralf

2015-01-01

Ca2+-activated K+ channels have been implicated in cancer cell growth, metastasis, and tumor angiogenesis. Here we hypothesized that high mRNA and protein expression of the intermediate-conductance Ca2+-activated K+ channel, KCa3.1, is a molecular marker of clear cell Renal Cell Carcinoma (ccRCC) and metastatic potential and survival. We analyzed channel expression by qRT-PCR, immunohistochemistry, and patch-clamp in ccRCC and benign oncocytoma specimens, in primary ccRCC and oncocytoma cell lines, as well as in two ccRCC cell lines (Caki-1 and Caki-2). CcRCC specimens contained 12-fold higher mRNA levels of KCa3.1 than oncocytoma specimens. The large-conductance channel, KCa1.1, was 3-fold more highly expressed in ccRCC than in oncocytoma. KCa3.1 mRNA expression in ccRCC was 2-fold higher than in the healthy cortex of the same kidney. Disease specific survival trended towards reduction in the subgroup of high-KCa3.1-expressing tumors (p<0.08 vs. low-KCa3.1-expressing tumors). Progression-free survival (time to metastasis/recurrence) was reduced significantly in the subgroup of high-KCa3.1-expressing tumors (p<0.02, vs. low-KCa3.1-expressing tumors). Immunohistochemistry revealed high protein expression of KCa3.1 in tumor vessels of ccRCC and oncocytoma and in a subset of ccRCC cells. Oncocytoma cells were devoid of KCa3.1 protein. In a primary ccRCC cell line and Caki-1/2-ccRCC cells, we found KCa3.1-protein as well as TRAM-34-sensitive KCa3.1-currents in a subset of cells. Furthermore, Caki-1/2-ccRCC cells displayed functional Paxilline-sensitive KCa1.1 currents. Neither KCa3.1 nor KCa1.1 were found in a primary oncocytoma cell line. Yet KCa-blockers, like TRAM-34 (KCa3.1) and Paxilline (KCa1.1), had no appreciable effects on Caki-1 proliferation in-vitro. Our study demonstrated expression of KCa3.1 in ccRCC but not in benign oncocytoma. Moreover, high KCa3.1-mRNA expression levels were indicative of low disease specific survival of ccRCC patients, short

Bcl-2 protein expression associated with resistance to apoptosis in clear cell adenocarcinomas of the vagina and cervix expressing wild-type p53.

PubMed

Waggoner, S E; Baunoch, D A; Anderson, S A; Leigh, F; Zagaja, V G

1998-09-01

Clear cell adenocarcinomas (CCAs) of the vagina and cervix are rare tumors that often overexpress wild-type p53. In vitro, expression of protooncogene bcl-2 can block p53-mediated apoptosis. The objective of this study was to determine if bcl-2 is expressed in CCAs and whether this expression is associated with inhibition of apoptosis. Twenty-one paraffin-embedded clear cell adenocarcinomas were immunohistochemically stained for bcl-2 (antibody M 887, Dako, Carpinteria, CA) and DNA fragmentation (ApopTag, Oncor, Gaithersburg, MD), a marker for apoptosis. Fifteen tumors were associated with in utero exposure to diethylstilbestrol (DES). Prior p53 gene analysis had indicated the presence of wild-type p53 in each tumor. Human lymphoid tissue containing bcl-2-expressing lymphocytes and DNase I-exposed CCA tissue sections were used as positive controls for the bcl-2 and apoptosis assays, respectively. Expression of bcl-2 and DNA fragmentation was classified (0 to 3+) according to percentage of positive cells and intensity of staining. Expression of bcl-2 was identified in each CCA examined, and was strongly positive (2+ to 3+) in 18 of 21 samples. Despite the presence of wild-type p53, only 4 of 21 tumors showed evidence of apoptosis as assessed through DNA fragmentation. DNA damage leads to increased intracellular p53 levels. Overexpression of p53 induces apoptosis as a means of protecting organisms from the development of malignancy. CCAs of the vagina and cervix, which contain wild-type p53 genes and often overexpress p53 protein, presumably have evolved mechanisms to avoid p53-induced apoptosis. Our observations are consistent with the hypothesis that overexpression of bcl-2 can inhibit p53-mediated apoptosis and suggest a mechanism by which these rare tumors can arise without mutation of the p53 gene.

Rapidly curable electrically conductive clear coatings

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

Bowman, Mark P.; Anderson, Lawrence G.; Post, Gordon L.

2018-01-16

Rapidly curable electrically conductive clear coatings are applied to substrates. The electrically conductive clear coating includes to clear layer having a resinous binder with ultrafine non-stoichiometric tungsten oxide particles dispersed therein. The clear coating may be rapidly cured by subjecting the coating to infrared radiation that heats the tungsten oxide particles and surrounding resinous binder. Localized heating increases the temperature of the coating to thereby thermally cure the coating, while avoiding unwanted heating of the underlying substrate.

[PM₂.₅ Background Concentration at Different Directions in Beijing in 2013].

PubMed

Li, Yun-ting; Cheng, Niam-liang; Zhang, Da-wei; Sun, Rui-wen; Dong, Xin; Sun, Nai-di; Chen, Chen

2015-12-01

PM₂.₅, background concentration at different directions in 2013 in Beijing was analyzed combining the techniques of mathematical statistics, physical identification and numerical simulation (CMAQ4.7.1) as well as using monitoring data of six PM₂.₅ auto-monitoring sites and five meteorological sites in 2013. Results showed that background concentrations of PM₂.₅ at northwest, northeast, eastern, southeast, southern and southwest boundary sites were between 40.3 and 85.3 µg · m⁻³ in Beijing. From the lowest to the highest, PMPM₂.₅ background concentrations at different sites were: Miyun reservoir, Badaling, Donggaocun, Yufa, Yongledian and Liulihe. Background concentration of PM₂.₅ was the lowest under north wind, then under west wind, and significantly higher under south and east wind. Calculated PM₂.₅ background average concentrations were 6.5-27.9, 22.4-73.4, 67.2-91.7, 40.7-116.1 µg · m⁻³ respectively in different wind directions. Simulated PM₂.₅ background concentration showed a clear north-south gradient distribution and the surrounding area had a notable effect on the spatial distribution of PM₂.₅ background concentration in 2013 in Beijing.

Skin optical clearing potential of disaccharides

NASA Astrophysics Data System (ADS)

Feng, Wei; Shi, Rui; Ma, Ning; Tuchina, Daria K.; Tuchin, Valery V.; Zhu, Dan

2016-08-01

Skin optical clearing can significantly enhance the ability of biomedical optical imaging. Some alcohols and sugars have been selected to be optical clearing agents (OCAs). In this work, we paid attention to the optical clearing potential of disaccharides. Sucrose and maltose were chosen as typical disaccharides to compare with fructose, an excellent monosaccharide-OCA, by using molecular dynamics simulation and an ex vivo experiment. The experimental results indicated that the optical clearing efficacy of skin increases linearly with the concentration for each OCA. Both the theoretical predication and experimental results revealed that the two disaccharides exerted a better optical clearing potential than fructose at the same concentration, and sucrose is optimal. Since maltose has an extremely low saturation concentration, the other two OCAs with saturation concentrations were treated topically on rat skin in vivo, and optical coherence tomography imaging was applied to monitor the optical clearing process. The results demonstrated that sucrose could cause a more significant increase in imaging depth and signal intensity than fructose.

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

PubMed

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.

Evaluation of BPA uptake in clear cell sarcoma (CCS) in vitro and development of an in vivo model of CCS for BNCT studies.

PubMed

Fujimoto, T; Andoh, T; Sudo, T; Fujita, I; Imabori, M; Moritake, H; Sugimoto, T; Sakuma, Y; Takeuchi, T; Sonobe, H; Epstein, Alan L; Akisue, T; Kirihata, M; Kurosaka, M; Fukumori, Y; Ichikawa, H

2011-12-01

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. Copyright © 2011 Elsevier Ltd. All rights reserved.

Boron neutron capture therapy (BNCT) as a new approach for clear cell sarcoma (CCS) treatment: Trial using a lung metastasis model of CCS.

PubMed

Andoh, Tooru; Fujimoto, Takuya; Suzuki, Minoru; Sudo, Tamotsu; Sakurai, Yoshinori; Tanaka, Hiroki; Fujita, Ikuo; Fukase, Naomasa; Moritake, Hiroshi; Sugimoto, Tohru; Sakuma, Toshiko; Sasai, Hiroshi; Kawamoto, Teruya; Kirihata, Mitsunori; Fukumori, Yoshinobu; Akisue, Toshihiro; Ono, Koji; Ichikawa, Hideki

2015-12-01

Clear cell sarcoma (CCS) is a rare malignant tumor with a poor prognosis. In the present study, we established a lung metastasis animal model of CCS and investigated the therapeutic effect of boron neutron capture therapy (BNCT) using p-borono-L-phenylalanine (L-BPA). Biodistribution data revealed tumor-selective accumulation of (10)B. Unlike conventional gamma-ray irradiation, BNCT significantly suppressed tumor growth without damaging normal tissues, suggesting that it may be a potential new therapeutic option to treat CCS lung metastases. Copyright © 2015 Elsevier Ltd. All rights reserved.

Fluorescent-Protein Stabilization and High-Resolution Imaging of Cleared, Intact Mouse Brains

PubMed Central

Schwarz, Martin K.; Scherbarth, Annemarie; Sprengel, Rolf; Engelhardt, Johann; Theer, Patrick; Giese, Guenter

2015-01-01

In order to observe and quantify long-range neuronal connections in intact mouse brain by light microscopy, it is first necessary to clear the brain, thus suppressing refractive-index variations. Here we describe a method that clears the brain and preserves the signal from proteinaceous fluorophores using a pH-adjusted non-aqueous index-matching medium. Successful clearing is enabled through the use of either 1-propanol or tert-butanol during dehydration whilst maintaining a basic pH. We show that high-resolution fluorescence imaging of entire, structurally intact juvenile and adult mouse brains is possible at subcellular resolution, even following many months in clearing solution. We also show that axonal long-range projections that are EGFP-labelled by modified Rabies virus can be imaged throughout the brain using a purpose-built light-sheet fluorescence microscope. To demonstrate the viability of the technique, we determined a detailed map of the monosynaptic projections onto a target cell population in the lateral entorhinal cortex. This example demonstrates that our method permits the quantification of whole-brain connectivity patterns at the subcellular level in the uncut brain. PMID:25993380

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

PubMed Central

Novoa, Eva Maria; Camacho, Noelia; Tor, Anna; Wilkinson, Barrie; Moss, Steven; Marín-García, Patricia; Azcárate, Isabel G.; Bautista, José M.; Mirando, Adam C.; Francklyn, Christopher S.; Varon, Sònia; Royo, Miriam; Cortés, Alfred; Ribas de Pouplana, Lluís

2014-01-01

Malaria remains a major global health problem. Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein translation is a promising pathway to target. Here we explore the potential of the aminoacyl-tRNA synthetase (ARS) family as a source of antimalarial drug targets. First, a battery of known and novel ARS inhibitors was tested against Plasmodium falciparum cultures, and their activities were compared. Borrelidin, a natural inhibitor of threonyl-tRNA synthetase (ThrRS), stands out for its potent antimalarial effect. However, it also inhibits human ThrRS and is highly toxic to human cells. To circumvent this problem, we tested a library of bioengineered and semisynthetic borrelidin analogs for their antimalarial activity and toxicity. We found that some analogs effectively lose their toxicity against human cells while retaining a potent antiparasitic activity both in vitro and in vivo and cleared malaria from Plasmodium yoelii-infected mice, resulting in 100% mice survival rates. Our work identifies borrelidin analogs as potent, selective, and unexplored scaffolds that efficiently clear malaria both in vitro and in vivo. PMID:25489076

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

PubMed Central

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

2014-01-01

Mutations in the von Hippel–Lindau (VHL) gene are pathogenic in VHL disease, congenital polycythaemia and clear cell renal carcinoma (ccRCC). 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 for polyubiquitination and proteasomal degradation. We describe a comprehensive database of missense VHL mutations linked to experimental and clinical data. We use predictions from in silico tools to link the functional effects of missense VHL mutations to phenotype. The risk of ccRCC in VHL disease is linked to the degree of destabilization resulting from missense mutations. An optimized binary classification system (symphony), which integrates predictions from five in silico methods, can predict the risk of ccRCC associated with VHL missense mutations with high sensitivity and specificity. We use symphony to generate predictions for risk of ccRCC for all possible VHL missense mutations and present these predictions, in association with clinical and experimental data, in a publically available, searchable web server. PMID:24969085

The two glycolytic markers GLUT1 and MCT1 correlate with tumor grade and survival in clear-cell renal cell carcinoma.

PubMed

Ambrosetti, Damien; Dufies, Maeva; Dadone, Bérengère; Durand, Matthieu; Borchiellini, Delphine; Amiel, Jean; Pouyssegur, Jacques; Rioux-Leclercq, Nathalie; Pages, Gilles; Burel-Vandenbos, Fanny; Mazure, Nathalie M

2018-01-01

Clear-cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Although ccRCC is characterized by common recurrent genetic abnormalities, including inactivation of the von Hippel-Lindau (vhl) tumor suppressor gene resulting in stabilization of hypoxia-inducible factors (HIFs), the tumor aggressiveness and outcome of ccRCC is variable. New biomarkers are thus required to improve ccRCC diagnosis, prognosis and therapeutic options. This work aims to investigate the expression of HIF and proteins involved in metabolism and pH regulation. Their correlation to histoprognostic parameters and survival was analyzed. ccRCC of 45 patients were analyzed. HIF-1α, HIF-2α, HAF, GLUT1, MCT1, MCT4, CAIX and CAXII expression was assessed by immunohistochemistry in a semi-quantitative and qualitative manner. The GLUT1, MCT1, MCT4, CAIX and CAXII mRNA levels were analyzed in an independent cohort of 43 patients. A significant correlation was observed between increased GLUT1, MCT1, CAXII protein expression and a high Fuhrman grade in ccRCC patients. Moreover, while HIF-1α, HIF-2α and HAF expression was heterogenous within tumors, we observed and confirmed that HIF-2α co-localized with HAF. We confirmed, in an independent cohort, that GLUT1, MCT1 and CAXII mRNA levels correlated with the Fuhrman grade. Moreover, we demonstrated that the high mRNA level of both MCT1 and GLUT1 correlated with poor prognosis. This study demonstrates for the first time a link between the aggressiveness of high- Fuhrman grade ccRCC and metabolic reprogramming. It also confirms the role of HIF-2α and HAF in tumor invasiveness. Finally, these results demonstrate that MCT1 and GLUT1 are strong prognostic markers and promising therapeutic targets.

17 CFR 39.7 - Fraud in connection with the clearing of transactions on a derivatives clearing organization.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Fraud in connection with the clearing of transactions on a derivatives clearing organization. 39.7 Section 39.7 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION DERIVATIVES CLEARING ORGANIZATIONS § 39.7 Fraud in connection...

Olfactory cortical adaptation facilitates detection of odors against background.

PubMed

Kadohisa, Mikiko; Wilson, Donald A

2006-03-01

Detection and discrimination of odors generally, if not always, occurs against an odorous background. On any given inhalation, olfactory receptor neurons will be activated by features of both the target odorant and features of background stimuli. To identify a target odorant against a background therefore, the olfactory system must be capable of grouping a subset of features into an odor object distinct from the background. Our previous work has suggested that rapid homosynaptic depression of afferents to the anterior piriform cortex (aPCX) contributes to both cortical odor adaptation to prolonged stimulation and habituation of simple odor-evoked behaviors. We hypothesize here that this process may also contribute to figure-ground separation of a target odorant from background stimulation. Single-unit recordings were made from both mitral/tufted cells and aPCX neurons in urethan-anesthetized rats and mice. Single-unit responses to odorant stimuli and their binary mixtures were determined. One of the odorants was randomly selected as the background and presented for 50 s. Forty seconds after the onset of the background stimulus, the second target odorant was presented, producing a binary mixture. The results suggest that mitral/tufted cells continue to respond to the background odorant and, when the target odorant is presented, had response magnitudes similar to that evoked by the binary mixture. In contrast, aPCX neurons filter out the background stimulus while maintaining responses to the target stimulus. Thus the aPCX acts as a filter driven most strongly by changing stimuli, providing a potential mechanism for olfactory figure-ground separation and selective reading of olfactory bulb output.

Performance of Cleared Blood Glucose Monitors.

PubMed

Klonoff, David C; Prahalad, Priya

2015-07-01

Cleared blood glucose monitor (BGM) systems do not always perform as accurately for users as they did to become cleared. We performed a literature review of recent publications between 2010 and 2014 that present data about the frequency of inaccurate performance using ISO 15197 2003 and ISO 15197 2013 as target standards. We performed an additional literature review of publications that present data about the clinical and economic risks of inaccurate BGMs for making treatment decisions or calibrating continuous glucose monitors (CGMs). We found 11 publications describing performance of 98 unique BGM systems. 53 of these 98 (54%) systems met ISO 15197 2003 and 31 of the 98 (32%) tested systems met ISO 15197 2013 analytical accuracy standards in all studies in which they were evaluated. Of the tested systems, 33 were identified by us as FDA-cleared. Among these FDA-cleared BGM systems, 24 out of 32 (75%) met ISO 15197 2003 and 15 out of 31 (48.3%) met ISO 15197 2013 in all studies in which they were evaluated. Among the non-FDA-cleared BGM systems, 29 of 65 (45%) met ISO 15197 2003 and 15 out of 65 (23%) met ISO 15197 2013 in all studies in which they were evaluated. It is more likely that an FDA-cleared BGM system, compared to a non-FDA-cleared BGM system, will perform according to ISO 15197 2003 (χ(2) = 6.2, df = 3, P = 0.04) and ISO 15197 2013 (χ(2) = 11.4, df = 3, P = 0.003). We identified 7 articles about clinical risks and 3 articles about economic risks of inaccurate BGMs. We conclude that a significant proportion of cleared BGMs do not perform at the level for which they were cleared or according to international standards of accuracy. Such poor performance leads to adverse clinical and economic consequences. © 2015 Diabetes Technology Society.

GLI2 expression levels in radical nephrectomy specimens as a predictor of disease progression in patients with metastatic clear cell renal cell carcinoma following treatment with sunitinib

PubMed Central

Furukawa, Junya; Miyake, Hideaki; Fujisawa, Masato

2016-01-01

The aim of the present study was to investigate the role of the Hedgehog signaling pathway in the progression of metastatic clear cell renal cell carcinoma (m-ccRCC) as well as the molecular targets of sunitinib, an inhibitor of multiple tyrosine kinases. A total of 39 patients subjected to radical nephrectomy who were diagnosed with m-ccRCC and were subsequently treated with sunitinib were enrolled in the present study. The expression levels of the Hedgehog signaling proteins (GLI1, GLI2, cyclin D1, cyclin E and transforming growth factor-β) and major molecular targets of sunitinib [vascular endothelial growth factor receptor (VEGFR)-1 and −2, and platelet-derived growth factor receptor-α and -β] in primary RCC specimens were assessed by immunohistochemical staining. The expression levels of GLI2, VEGFR-1, VEGFR-2 and pre-treatment C-reactive protein as well as the Memorial Sloan-Kettering Cancer Center risk were identified as significant predictors of progression-free survival (PFS). Of these, only GLI2 expression was independently correlated to PFS according to multivariate analysis. Furthermore, treatment with sunitinib resulted in a marked inhibition of GLI2 expression in the parental human RCC ACHN cell line, but not in ACHN cells with acquired resistance to sunitinib. These findings suggested that GLI2 may be involved in the acquisition of resistance to sunitinib in RCC; thus, it may be useful to consider the expression levels of GLI2 in addition to conventional prognostic parameters when selecting m-ccRCC patients likely to benefit from treatment with sunitinib. PMID:27602218

Association of primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with clear cell renal carcinoma.

PubMed

Gomes, Letícia da Silva; Kulak, Carolina A M; Costa, Tatiana Munhoz da Rocha Lemos; Vasconcelos, Evandro Cezar Guerreiro; Carvalho, Maurício de; Borba, Victoria Zeghbi Cochenski

2015-02-01

Hypercalcemia is found frequently in patients with cancer. Besides the etiology related to the malignancy, other causes should be considered in the differential diagnostic, as primary hyperparathyroidism, granulomatous diseases and the use of thiazide diuretics. We present a case report of a severe hypercalcemia due to a rare association and review the relevant literature. A female patient, 57 years old, sent to the Endocrinology Service of Hospital das Clínicas da Universidade do Paraná (SEMPR) in order to investigate severe hypercalcemia with frequent need of hospitalization. The patient was in chemotherapy treatment for recurrence of clear cell renal cancer. During the investigation she presented high level of parathyroid hormone (PTH) and parathyroid scintigraphy suggestive of hyperplasia/ adenoma of parathyroid, histopathological diagnosis was confirmed after parathyroidectomy. After surgery the patient presented undetectable levels of PTH. However, she continued with progressive increase of serum calcium, with no signs of bone metastases or change in vitamin D metabolism. The investigation showed high levels of PTH-related protein (PTHrP), leading us to the diagnosis of hypercalcemia of malignancy. The patient presented severe hypercalcemia due to the rare association of primary hyperparathyroidism and humoral hypercalcemia of malignancy due to secretion of PTHrP by tumor cells. The presence of isolated primary hyperparathyroidism, as a cause of hypercalcemia in cancer patients, has been described in approximately 5-10% of the patients. However, the association of primary hyperparathyroidism and humoral hypercalcemia of malignancy (which means with concomitant elevation of PTH and PTHrP) is rare, only three cases have been described in the literature.

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

PubMed

Jiang, Xiang; Jin, Ying; Li, Yan; Huang, Hui-Fang; Wu, Ming; Shen, Keng; Pan, Ling-Ya

2014-01-01

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 bleeding. Radiotherapy appears to be effective for local control but to have no effect on distant recurrences. In our study, the prognosis of patients with early-stage CCA, including those who had undergone fertility-preserving treatment, was not inferior to that of patients with

In situ Observations of Magnetosonic Waves Modulated by Background Plasma Density

NASA Astrophysics Data System (ADS)

Yu, X.; Yuan, Z.; Huang, S.; Wang, D.; Funsten, H. O.

2017-12-01

We report in situ observations by the Van Allen Probe mission that magnetosonic (MS) waves are clearly relevant to appear relevant to the background plasma number density. As the satellite moved across dense and tenuous plasma alternatively, MS waves occurred only in lower density region. As the observed protons with 'ring' distributions provide free energy, local linear growth rates are calculated and show that magnetosonic waves can be locally excited in tenuous plasma. With variations of the background plasma density, the temporal variations of local wave growth rates calculated with the observed proton ring distributions, show a remarkable agreement with those of the observed wave amplitude. Therefore, the paper provides a direct proof that background plasma densities can modulate the amplitudes of magnetosonic waves through controlling the wave growth rates.

Current and future background ozone simulations for Mexico using a multi-scale regional climate modeling system

NASA Astrophysics Data System (ADS)

Lamb, B. K.; Gonzalez Abraham, R.; Avise, J. C.; Chung, S. H.; Salathe, E. P.; Zhang, Y.; Guenther, A. B.; Wiedinmyer, C.; Duhl, T.; Streets, D. G.

2013-05-01

Global change will clearly have a significant impact on the environment. Among the concerns for future air quality in North America, intercontinental transport of pollution has become increasingly important. In this study, we examined the effect of projected changes in Asian emissions and emissions from lightning and wildfires to produce ozone background concentrations within Mexico and the continental US. This provides a basis for developing an understanding of North American background levels and how they may change in the future. Meteorological fields were downscaled from the results of the ECHAM5 global climate model using the Weather Research Forecast (WRF) model. Two nested domains were employed, one covering most of the Northern Hemisphere from eastern Asia to North America using 220 km grid cells (semi-hemispheric domain) and one covering the continental US and northern Mexico using 36 km grid cells. Meteorological results from WRF were used to drive the MEGAN biogenic emissions model, the SMOKE emissions processing tool, and the CMAQ chemical transport model to predict ozone concentrations for current (1995-2004) and future (2045-2054) summertime conditions. The MEGAN model was used to calculate biogenic emissions for all simulations. For the semi-hemispheric domain, year 2000 global emissions of gases (ozone precursors) from anthropogenic (outside of North America), natural, and biomass burning sources from the POET and EDGAR emission inventories were used. The global tabulation for black and organic carbon (BC and OC respectively) was obtained from Bond et al. (2004) For the future decade, the current emissions were projected to the year 2050 following the Intergovernmental Panel for Climate Change (IPCC) A1B emission scenario. Anthropogenic emissions from the US, Canada, and Mexico were omitted so that only global background concentrations, and local biogenic, wildfire, and lightning emissions were treated. In this paper, we focus on background ozone

Cleared DoD Employees at Risk - Report 2 A Study of Barriers to Seeking Help

DTIC Science & Technology

2002-01-01

PERSEREC examined the relationship between DoD security policy and federally mandated employee assistance programs ( EAPs ) for civilians and...counseling/referral services for military personnel to identify any barriers for cleared DoD employees to using these programs . The study, based largely on...appendices that provides background information for the interested reader on such topics as the EAP movement, military counseling/referral programs , and DoD personnel security policies and programs .

Vertical velocity structure and geometry of clear air convective elements

NASA Technical Reports Server (NTRS)

Rowland, J. R.; Arnold, A.

1975-01-01

The paper discusses observations of individual convective elements with a high-power narrow-beam scanning radar, an FM-CW radar, and an acoustic sounder, including the determination of the vertical air velocity patterns of convective structures with the FM-CW radar and acoustic sounder. Data are presented which link the observed velocity structure and geometrical patterns to previously proposed models of boundary layer convection. It is shown that the high-power radar provides a clear three-dimensional picture of convective cells and fields over a large area with a resolution of 150 m, where the convective cells are roughly spherical. Analysis of time-height records of the FM-CW radar and acoustic sounder confirms the downdraft-entrainment mechanism of the convective cell. The Doppler return of the acoustic sounder and the insect-trail slopes on FM-CW radar records are independent but redundant methods for obtaining the vertical velocity patterns of convective structures.

3D on-chip microscopy of optically cleared tissue

NASA Astrophysics Data System (ADS)

Zhang, Yibo; Shin, Yoonjung; Sung, Kevin; Yang, Sam; Chen, Harrison; Wang, Hongda; Teng, Da; Rivenson, Yair; Kulkarni, Rajan P.; Ozcan, Aydogan

2018-02-01

Traditional pathology relies on tissue biopsy, micro-sectioning, immunohistochemistry and microscopic imaging, which are relatively expensive and labor-intensive, and therefore are less accessible in resource-limited areas. Low-cost tissue clearing techniques, such as the simplified CLARITY method (SCM), are promising to potentially reduce the cost of disease diagnosis by providing 3D imaging and phenotyping of thicker tissue samples with simpler preparation steps. However, the mainstream imaging approach for cleared tissue, fluorescence microscopy, suffers from high-cost, photobleaching and signal fading. As an alternative approach to fluorescence, here we demonstrate 3D imaging of SCMcleared tissue using on-chip holography, which is based on pixel-super-resolution and multi-height phase recovery algorithms to digitally compute the sample's amplitude and phase images at various z-slices/depths through the sample. The tissue clearing procedures and the lens-free imaging system were jointly optimized to find the best illumination wavelength, tissue thickness, staining solution pH, and the number of hologram heights to maximize the imaged tissue volume, minimize the amount of acquired data, while maintaining a high contrast-to-noise ratio for the imaged cells. After this optimization, we achieved 3D imaging of a 200-μm thick cleared mouse brain tissue over a field-of-view of <20mm2 , and the resulting 3D z-stack agrees well with the images acquired with a scanning lens-based microscope (20× 0.75NA). Moreover, the lens-free microscope achieves an order-of-magnitude better data efficiency compared to its lens-based counterparts for volumetric imaging of samples. The presented low-cost and high-throughput lens-free tissue imaging technique enabled by CLARITY can be used in various biomedical applications in low-resource-settings.

MODIS Collection 6 Clear Sky Restoral (CSR): Filtering Cloud Mast 'Not Clear' Pixels

NASA Technical Reports Server (NTRS)

Meyer, Kerry G.; Platnick, Steven Edward; Wind, Galina; Riedi, Jerome

2014-01-01

Correctly identifying cloudy pixels appropriate for the MOD06 cloud optical and microphysical property retrievals is accomplished in large part using results from the MOD35 1km cloud mask tests (note there are also two 250m subpixel cloud mask tests that can convert the 1km cloudy designations to clear sky). However, because MOD35 is by design clear sky conservative (i.e., it identifies "not clear" pixels), certain situations exist in which pixels identified by MOD35 as "cloudy" are nevertheless likely to be poor retrieval candidates. For instance, near the edge of clouds or within broken cloud fields, a given 1km MODIS field of view (FOV) may in fact only be partially cloudy. This can be problematic for the MOD06 retrievals because in these cases the assumptions of a completely overcast homogenous cloudy FOV and 1-dimensional plane-parallel radiative transfer no longer hold, and subsequent retrievals will be of low confidence. Furthermore, some pixels may be identified by MOD35 as "cloudy" for reasons other than the presence of clouds, such as scenes with thick smoke or lofted dust, and should therefore not be retrieved as clouds. With such situations in mind, a Clear Sky Restoral (CSR) algorithm was introduced in C5 that attempts to identify pixels expected to be poor retrieval candidates. Table 1 provides SDS locations for CSR and partly cloudy (PCL) pixels.

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

PubMed

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.

Levels of Evidence in Cosmetic Surgery: Analysis and Recommendations Using a New CLEAR Classification

PubMed Central

2013-01-01

Background: The Level of Evidence rating was introduced in 2011 to grade the quality of publications. This system evaluates study design but does not assess several other quality indicators. This study introduces a new “Cosmetic Level of Evidence And Recommendation” (CLEAR) classification that includes additional methodological criteria and compares this new classification with the existing system. Methods: All rated publications in the Cosmetic Section of Plastic and Reconstructive Surgery, July 2011 through June 2013, were evaluated. The published Level of Evidence rating (1–5) and criteria relevant to study design and methodology for each study were tabulated. A new CLEAR rating was assigned to each article, including a recommendation grade (A–D). The published Level of Evidence rating (1–5) was compared with the recommendation grade determined using the CLEAR classification. Results: Among the 87 cosmetic articles, 48 studies (55%) were designated as level 4. Three articles were assigned a level 1, but they contained deficiencies sufficient to undermine the conclusions. The correlation between the published Level of Evidence classification (1–5) and CLEAR Grade (A–D) was weak (ρ = 0.11, not significant). Only 41 studies (48%) evaluated consecutive patients or consecutive patients meeting inclusion criteria. Conclusions: The CLEAR classification considers methodological factors in evaluating study reliability. A prospective study among consecutive patients meeting eligibility criteria, with a reported inclusion rate, the use of contemporaneous controls when indicated, and consideration of confounders is a realistic goal. Such measures are likely to improve study quality. PMID:25289261

DNA methylation profile distinguishes clear cell sarcoma of the kidney from other pediatric renal tumors.

PubMed

Ueno, Hitomi; Okita, Hajime; Akimoto, Shingo; Kobayashi, Kenichiro; Nakabayashi, Kazuhiko; Hata, Kenichiro; Fujimoto, Junichiro; Hata, Jun-Ichi; Fukuzawa, Masahiro; Kiyokawa, Nobutaka

2013-01-01

A number of specific, distinct neoplastic entities occur in the pediatric kidney, including Wilms' tumor, clear cell sarcoma of the kidney (CCSK), congenital mesoblastic nephroma (CMN), rhabdoid tumor of the kidney (RTK), and the Ewing's sarcoma family of tumors (ESFT). By employing DNA methylation profiling using Illumina Infinium HumanMethylation27, we analyzed the epigenetic characteristics of the sarcomas including CCSK, RTK, and ESFT in comparison with those of the non-neoplastic kidney (NK), and these tumors exhibited distinct DNA methylation profiles in a tumor-type-specific manner. CCSK is the most frequently hypermethylated, but least frequently hypomethylated, at CpG sites among these sarcomas, and exhibited 490 hypermethylated and 46 hypomethylated CpG sites in compared with NK. We further validated the results by MassARRAY, and revealed that a combination of four genes was sufficient for the DNA methylation profile-based differentiation of these tumors by clustering analysis. Furthermore, THBS1 CpG sites were found to be specifically hypermethylated in CCSK and, thus, the DNA methylation status of these THBS1 sites alone was sufficient for the distinction of CCSK from other pediatric renal tumors, including Wilms' tumor and CMN. Moreover, combined bisulfite restriction analysis could be applied for the detection of hypermethylation of a THBS1 CpG site. Besides the biological significance in the pathogenesis, the DNA methylation profile should be useful for the differential diagnosis of pediatric renal tumors.

Validation of the McClear clear-sky model in desert conditions with three stations in Israel

NASA Astrophysics Data System (ADS)

Lefèvre, Mireille; Wald, Lucien

2016-03-01

The new McClear clear-sky model, a fast model based on a radiative transfer solver, exploits the atmospheric properties provided by the EU-funded Copernicus Atmosphere Monitoring Service (CAMS) to estimate the solar direct and global irradiances received at ground level in cloud-free conditions at any place any time. The work presented here focuses on desert conditions and compares the McClear irradiances to coincident 1 min measurements made in clear-sky conditions at three stations in Israel which are distant from less than 100 km. The bias for global irradiance is comprised between 2 and 32 W m-2, i.e. between 0 and 4 % of the mean observed irradiance (approximately 830 W m-2). The RMSE ranges from 30 to 41 W m-2 (4 %) and the squared correlation coefficient is greater than 0.976. The bias for the direct irradiance at normal incidence (DNI) is comprised between -68 and +13 W m-2, i.e. between -8 and 2 % of the mean observed DNI (approximately 840 W m-2). The RMSE ranges from 53 (7 %) to 83 W m-2 (10 %). The squared correlation coefficient is close to 0.6. The performances are similar for the three sites for the global irradiance and for the DNI to a lesser extent, demonstrating the robustness of the McClear model combined with CAMS products. These results are discussed in the light of those obtained by McClear for other desert areas in Egypt and United Arab Emirates.

Bidirectional clear speech perception benefit for native and high-proficiency non-native talkers and listeners: Intelligibility and accentednessa

PubMed Central

Smiljanić, Rajka; Bradlow, Ann R.

2011-01-01

This study investigated how native language background interacts with speaking style adaptations in determining levels of speech intelligibility. The aim was to explore whether native and high proficiency non-native listeners benefit similarly from native and non-native clear speech adjustments. The sentence-in-noise perception results revealed that fluent non-native listeners gained a large clear speech benefit from native clear speech modifications. Furthermore, proficient non-native talkers in this study implemented conversational-to-clear speaking style modifications in their second language (L2) that resulted in significant intelligibility gain for both native and non-native listeners. The results of the accentedness ratings obtained for native and non-native conversational and clear speech sentences showed that while intelligibility was improved, the presence of foreign accent remained constant in both speaking styles. This suggests that objective intelligibility and subjective accentedness are two independent dimensions of non-native speech. Overall, these results provide strong evidence that greater experience in L2 processing leads to improved intelligibility in both production and perception domains. These results also demonstrated that speaking style adaptations along with less signal distortion can contribute significantly towards successful native and non-native interactions. PMID:22225056

Role of genetic background in induced instability

NASA Technical Reports Server (NTRS)

Kadhim, Munira A.; Nelson, G. A. (Principal Investigator)

2003-01-01

Genomic instability is effectively induced by ionizing radiation. Recently, evidence has accumulated supporting a relationship between genetic background and the radiation-induced genomic instability phenotype. This is possibly due to alterations in proteins responsible for maintenance of genomic integrity or altered oxidative metabolism. Studies in human cell lines, human primary cells, and mouse models have been performed predominantly using high linear energy transfer (LET) radiation, or high doses of low LET radiation. The interplay between genetics, radiation response, and genomic instability has not been fully determined at low doses of low LET radiation. However, recent studies using low doses of low LET radiation suggest that the relationship between genetic background and radiation-induced genomic instability may be more complicated than these same relationships at high LET or high doses of low LET radiation. The complexity of this relationship at low doses of low LET radiation suggests that more of the population may be at risk than previously recognized and may have implications for radiation risk assessment.

17 CFR 22.17 - Policies and procedures governing disbursements of Cleared Swaps Customer Collateral from Cleared...

Code of Federal Regulations, 2014 CFR

2014-04-01

... Section 22.17 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION CLEARED SWAPS § 22... of Cleared Swaps Customer Collateral with the funds of a futures commission merchant, shall not be construed to prevent a futures commission merchant from having a residual financial interest in the funds...

Monte Carlo simulation for background study of geophysical inspection with cosmic-ray muons

NASA Astrophysics Data System (ADS)

Nishiyama, Ryuichi; Taketa, Akimichi; Miyamoto, Seigo; Kasahara, Katsuaki

2016-08-01

Several attempts have been made to obtain a radiographic image inside volcanoes using cosmic-ray muons (muography). Muography is expected to resolve highly heterogeneous density profiles near the surface of volcanoes. However, several prior works have failed to make clear observations due to contamination by background noise. The background contamination leads to an overestimation of the muon flux and consequently a significant underestimation of the density in the target mountains. To investigate the origin of the background noise, we performed a Monte Carlo simulation. The main components of the background noise in muography are found to be low-energy protons, electrons and muons in case of detectors without particle identification and with energy thresholds below 1 GeV. This result was confirmed by comparisons with actual observations of nuclear emulsions. This result will be useful for detector design in future works, and in addition some previous works of muography should be reviewed from the view point of background contamination.

A flat Universe from high-resolution maps of the cosmic microwave background radiation

PubMed

de Bernardis P; Ade; Bock; Bond; Borrill; Boscaleri; Coble; Crill; De Gasperis G; Farese; Ferreira; Ganga; Giacometti; Hivon; Hristov; Iacoangeli; Jaffe; Lange; Martinis; Masi; Mason; Mauskopf; Melchiorri; Miglio; Montroy; Netterfield

2000-04-27

The blackbody radiation left over from the Big Bang has been transformed by the expansion of the Universe into the nearly isotropic 2.73 K cosmic microwave background. Tiny inhomogeneities in the early Universe left their imprint on the microwave background in the form of small anisotropies in its temperature. These anisotropies contain information about basic cosmological parameters, particularly the total energy density and curvature of the Universe. Here we report the first images of resolved structure in the microwave background anisotropies over a significant part of the sky. Maps at four frequencies clearly distinguish the microwave background from foreground emission. We compute the angular power spectrum of the microwave background, and find a peak at Legendre multipole Ipeak = (197 +/- 6), with an amplitude delta T200 = (69 +/- 8) microK. This is consistent with that expected for cold dark matter models in a flat (euclidean) Universe, as favoured by standard inflationary models.

Multicenter Validation of Enhancer of Zeste Homolog 2 Expression as an Independent Prognostic Marker in Localized Clear Cell Renal Cell Carcinoma

PubMed Central

Ho, Thai Huu; Kapur, Payal; Eckel-Passow, Jeanette E.; Christie, Alana; Joseph, Richard W.; Serie, Daniel J.; Cheville, John C.; Thompson, R. Houston; Homayoun, Farrah; Panwar, Vandana; Brugarolas, James; Parker, Alexander S.

2017-01-01

Purpose Enhancer of zeste homolog 2 (EZH2), a chromatin remodeler, is implicated in the pathogenesis of clear cell renal cell carcinoma (ccRCC). However, the effect of EZH2 on outcomes in localized ccRCC is unclear, and molecular biomarkers are not currently integrated into prognostic models or adjuvant therapy trials. Methods We performed Cox regression to evaluate the association of tumor-based EZH2 gene and protein expression with survival in three independent cohorts: a cohort from The Cancer Genome Atlas (n = 532), a cohort from University of Texas Southwestern Medical Center (n = 122), and a cohort from Mayo Clinic (n = 1,338). Analyses were adjusted for the prognostic stage, size, grade, and necrosis (SSIGN) score as well as within low-, intermediate-, and high-risk SSIGN groups. Results Patients in The Cancer Genome Atlas cohort with EZH2-high gene expression were 1.5 times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 2.3; P = .028). Patients in the University of Texas Southwestern Medical Center cohort with EZH2-high protein expression were two times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 4.4; P = .034). Similarly, patients in the Mayo Clinic cohort with EZH2-high protein expression were 1.4 times more likely to experience overall death (95% CI, 1.2 to 1.7; P < .001). Patients in the Mayo Clinic cohort with EZH2-high protein expression were nearly two times more likely to experience RCC-specific death (95% CI, 1.5 to 2.6; P < .001); EZH2 protein expression was particularly prognostic among patients with low-risk SSIGN tumors (HR, 6.1; 95% CI, 3.4 to 11.1; P < .001). Conclusion EZH2 expression accurately predicts risk of RCC death beyond existing clinicopathologic models, particularly in low- and intermediate-risk SSIGN tumors. Further studies are required to incorporate molecular biomarkers into surveillance guidelines and adjuvant clinical trials

Therapeutic PD-L1 and LAG-3 blockade rapidly clears established blood-stage Plasmodium infection

PubMed Central

Butler, Noah S.; Moebius, Jacqueline; Pewe, Lecia L.; Traore, Boubacar; Doumbo, Ogobara K.; Tygrett, Lorraine T.; Waldschmidt, Thomas J.; Crompton, Peter D.; Harty, John T.

2011-01-01

Plasmodium infection of erythrocytes induces clinical malaria. Parasite-specific CD4+ T cells correlate with reduced parasite burdens and severity of human malaria, and are required to control blood-stage infection in mice. However, the characteristics of CD4+ T cells that determine protection or parasite persistence remain unknown. Here we show that P. falciparum infection of humans increased expression of an inhibitory receptor (PD-1) associated with T cell dysfunction. In vivo blockade of PD-L1 and LAG-3 restored CD4+ T cell function, amplified T follicular helper cell and germinal center B cell and plasmablast numbers, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, which can be rescued to enhance parasite control using inhibitory therapies. PMID:22157630

Difference in suitable mechanical properties of three-dimensional, synthetic scaffolds for self-renewing mouse embryonic stem cells of different genetic backgrounds.

PubMed

Lee, Myungook; Ahn, Jong Il; Ahn, Ji Yeon; Yang, Woo Sub; Hubbell, Jeffrey A; Lim, Jeong Mook; Lee, Seung Tae

2017-11-01

We evaluated whether the genetic background of embryonic stem cells (ESCs) affects the properties suitable for three-dimensional (3D) synthetic scaffolds for cell self-renewal. Inbred R1 and hybrid B6D2F1 mouse ESC lines were cultured for 7 days in hydrogel scaffolds with different properties derived from conjugating 7.5, 10, 12.5, or 15% (wt/vol) vinylsulfone-functionalized three-, four-, or eight-arm polyethylene glycol (PEG) with dicysteine-containing crosslinkers with an intervening matrix metalloproteinase-specific cleavage sites. Cell proliferation and expression of self-renewal-related genes and proteins by ESCs cultured in feeder-free or containing 2D culture plate or 3D hydrogel were monitored. As a preliminary experiment, the E14 ESC-customized synthetic 3D microenvironment did not maintain self-renewal of either the R1 or B6D2F1 ESCs. The best R1 cell proliferation (10.04 vs. 0.16-4.39; p < 0.0001) was observed in the four-arm 7.5% PEG-based hydrogels than those with other properties, whereas the F1 ESCs showed better proliferation when they were embedded in the three-arm 10% hydrogels. Self-renewal-related gene and protein expression by ESCs after feeder-free 3D culture was generally maintained compared with the feeder-containing 2D culture, but expression patterns and quantities differed. However, the feeder-free 3D culture yielded better expression than the feeder-free 2D culture. In conclusion, genetic background determined the suitability of hydrogel scaffolds for self-renewal of ESCs, which requires customization for the mechanical properties of each cell line. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2261-2268, 2017. © 2016 Wiley Periodicals, Inc.

Effects of Elevated Pax6 Expression and Genetic Background on Mouse Eye Development

PubMed Central

Chanas, Simon A.; Collinson, J. Martin; Ramaesh, Thaya; Dorà, Natalie; Kleinjan, Dirk A.; Hill, Robert E.; West, John D.

2009-01-01

Purpose To analyze the effects of Pax6 overexpression and its interaction with genetic background on eye development. Methods Histologic features of eyes from hemizygous PAX77+/− transgenic (high Pax6 gene dose) and wild-type mice were compared on different genetic backgrounds. Experimental PAX77+/−↔wild-type and control wild-type↔wild-type chimeras were analyzed to investigate the causes of abnormal eye development in PAX77+/− mice. Results PAX77+/− mice showed an overlapping but distinct spectrum of eye abnormalities to Pax6+/− heterozygotes (low Pax6 dose). Some previously reported PAX77+/− eye abnormalities did not occur on all three genetic backgrounds examined. Several types of eye abnormalities occurred in the experimental PAX77+/−↔wild-type chimeras, and they occurred more frequently in chimeras with higher contributions of PAX77+/− cells. Groups of RPE cells intruded into the optic nerve sheath, indicating that the boundary between the retina and optic nerve may be displaced. Both PAX77+/− and wild-type cells were involved in this ingression and in retinal folds, suggesting that neither effect was cell-autonomous. Cell-autonomous effects included failure of PAX77+/− and wild-type cells to mix normally and overrepresentation of PAX77+/− in the lens epithelium and RPE. Conclusions The extent of PAX77+/− eye abnormalities depended on PAX77+/− genotype, genetic background, and stochastic variation. Chimera analysis identified two types of cell-autonomous effects of the PAX77+/− genotype. Abnormal cell mixing between PAX77+/− and wild-type cells suggests altered expression of cell surface adhesion molecules. Some phenotypic differences between PAX77+/−↔wild-type and Pax6+/−↔wild-type chimeras may reflect differences in the levels of PAX77+/− and Pax6+/− contributions to chimeric lenses. PMID:19387074

Neural and Behavioral Mechanisms of Clear Speech

ERIC Educational Resources Information Center

Luque, Jenna Silver

2017-01-01

Clear speech is a speaking style that has been shown to improve intelligibility in adverse listening conditions, for various listener and talker populations. Clear-speech phonetic enhancements include a slowed speech rate, expanded vowel space, and expanded pitch range. Although clear-speech phonetic enhancements have been demonstrated across a…

COSMIC INFRARED BACKGROUND FLUCTUATIONS AND ZODIACAL LIGHT

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

Arendt, Richard G.; Kashlinsky, A.; Moseley, S. H.

We performed a specific observational test to measure the effect that the zodiacal light can have on measurements of the spatial fluctuations of the near-IR background. Previous estimates of possible fluctuations caused by zodiacal light have often been extrapolated from observations of the thermal emission at longer wavelengths and low angular resolution or from IRAC observations of high-latitude fields where zodiacal light is faint and not strongly varying with time. The new observations analyzed here target the COSMOS field at low ecliptic latitude where the zodiacal light intensity varies by factors of ∼2 over the range of solar elongations atmore » which the field can be observed. We find that the white-noise component of the spatial power spectrum of the background is correlated with the modeled zodiacal light intensity. Roughly half of the measured white noise is correlated with the zodiacal light, but a more detailed interpretation of the white noise is hampered by systematic uncertainties that are evident in the zodiacal light model. At large angular scales (≳100″) where excess power above the white noise is observed, we find no correlation of the power with the modeled intensity of the zodiacal light. This test clearly indicates that the large-scale power in the infrared background is not being caused by the zodiacal light.« less

Cosmic Infrared Background Fluctuations and Zodiacal Light

NASA Astrophysics Data System (ADS)

Arendt, Richard G.; Kashlinsky, A.; Moseley, S. H.; Mather, J.

2016-06-01

We performed a specific observational test to measure the effect that the zodiacal light can have on measurements of the spatial fluctuations of the near-IR background. Previous estimates of possible fluctuations caused by zodiacal light have often been extrapolated from observations of the thermal emission at longer wavelengths and low angular resolution or from IRAC observations of high-latitude fields where zodiacal light is faint and not strongly varying with time. The new observations analyzed here target the COSMOS field at low ecliptic latitude where the zodiacal light intensity varies by factors of ˜2 over the range of solar elongations at which the field can be observed. We find that the white-noise component of the spatial power spectrum of the background is correlated with the modeled zodiacal light intensity. Roughly half of the measured white noise is correlated with the zodiacal light, but a more detailed interpretation of the white noise is hampered by systematic uncertainties that are evident in the zodiacal light model. At large angular scales (≳100″) where excess power above the white noise is observed, we find no correlation of the power with the modeled intensity of the zodiacal light. This test clearly indicates that the large-scale power in the infrared background is not being caused by the zodiacal light.

Long-term survival of patients with mismatch repair protein-deficient, high-stage ovarian clear cell carcinoma.

PubMed

Stewart, Colin J R; Bowtell, David D L; Doherty, Dorota A; Leung, Yee C

2017-01-01

Gynaecological cancer patients with germline mutations appear to have a better prognosis than those with sporadic malignancies. Following the observation of long-term survival in a patient with stage III ovarian clear cell carcinoma (CCC) and possible Lynch syndrome (LS), DNA mismatch repair (MMR) protein immunohistochemistry was performed in a series of high-stage CCC and correlated with patient outcomes. Thirty-two consecutive cases of stage III/IV ovarian CCCs accessioned between 1992 and 2015 were examined. The tumours from two patients (6%), including the index case, showed loss of MSH2/MSH6 expression while MLH1/PMS2 staining was retained. The index patient subsequently developed colonic and rectal carcinomas that were also MSH2/MSH6-deficient, while the second patient had a genetically confirmed germline MSH2 mutation. All other tumours showed retained expression of the four MMR proteins. The two patients with MMR protein-deficient tumours were alive 160 months and 124 months following surgery, whereas the median survival of patients with MMR protein-intact CCCs was 11.8 months (75th and 25th percentiles of 8.1 months and 39.3 months, respectively), with 21 patients deceased due to tumour. Larger studies are required but high-stage, MMR protein-deficient CCCs may have a relatively favourable prognosis. © 2016 John Wiley & Sons Ltd.

Clear cell adenocarcinoma of the tunica vaginalis of the testis with an adjacent uterus-like tissue.

PubMed

Tulunay, Ozden; Gögüş, Cagatay; Baltaci, Sümer; Bulut, Safak

2004-08-01

Testicular and paratesticular neoplasms that resemble the common epithelial type of ovarian tumor are quite rare. Paratesticular clear cell carcinoma is very uncommon in the testis, with no reported cases of a tumor arising from the tunica vaginalis in the literature to our knowledge. The present case shows that it is highly malignant and metastatic. The differential diagnosis of the tumor was made after thorough clinical, pathological and immunohistochemical investigations, from the mesothelioma of the tunica vaginalis, paratesticular serous papillary carcinoma, carcinoma of the rete testis, epididymal adenocarcioma, yolk sac tumor of the testis and metastatic carcinoma. The tumor showed Bcl-2 and Her-2/neu immunoreactivity, but was non-reactive for p53. This tumor, with a uterus-like structure as a paratesticular tumor-like mass, was composed of endometrial-type glands and stroma surrounded by bundles of smooth muscle, and is the third example of this kind of structure in English written literature. The patient, having normal external genitalia and fertility, represents the first reported case of paratesticular malignant differentiation of müllerian-type epithelium in the normal gonadal state. Müllerian-type epithelium located in the vicinity of the testis and/or endometriotic metaplasia of the mesothelium of the tunica vaginalis might be the possible origins for this uterus-like structure, and as a result, for this tumor.

Genetic background effects in Neuroligin-3 mutant mice: Minimal behavioral abnormalities on C57 background.

PubMed

Jaramillo, Thomas C; Escamilla, Christine Ochoa; Liu, Shunan; Peca, Lauren; Birnbaum, Shari G; Powell, Craig M

2018-02-01

Neuroligin-3 (NLGN3) is a postsynaptic cell adhesion protein that interacts with presynaptic ligands including neurexin-1 (NRXN1) [Ichtchenko et al., Journal of Biological Chemistry, 271, 2676-2682, 1996]. Mice harboring a mutation in the NLGN3 gene (NL3R451C) mimicking a mutation found in two brothers with autism spectrum disorder (ASD) were previously generated and behaviorally phenotyped for autism-related behaviors. In these NL3R451C mice generated and tested on a hybrid C57BL6J/129S2/SvPasCrl background, we observed enhanced spatial memory and reduced social interaction [Tabuchi et al., Science, 318, 71-76, 2007]. Curiously, an independently generated second line of mice harboring the same mutation on a C57BL6J background exhibited minimal aberrant behavior, thereby providing apparently discrepant results. To investigate the origin of the discrepancy, we previously replicated the original findings of Tabuchi et al. by studying the same NL3R451C mutation on a pure 129S2/SvPasCrl genetic background. Here we complete the behavioral characterization of the NL3R451C mutation on a pure C57BL6J genetic background to determine if background genetics play a role in the discrepant behavioral outcomes involving NL3R451C mice. NL3R451C mutant mice on a pure C57BL6J background did not display spatial memory enhancements or social interaction deficits. We only observed a decreased startle response and mildly increased locomotor activity in these mice suggesting that background genetics influences behavioral outcomes involving the NL3R451C mutation. Autism Res 2018, 11: 234-244. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Behavioral symptoms of autism can be highly variable, even in cases that involve identical genetic mutations. Previous studies in mice with a mutation of the Neuroligin-3 gene showed enhanced learning and social deficits. We replicated these findings on the same and different genetic backgrounds. In this study, however, the

Intelligibility of clear speech: effect of instruction.

PubMed

Lam, Jennifer; Tjaden, Kris

2013-10-01

The authors investigated how clear speech instructions influence sentence intelligibility. Twelve speakers produced sentences in habitual, clear, hearing impaired, and overenunciate conditions. Stimuli were amplitude normalized and mixed with multitalker babble for orthographic transcription by 40 listeners. The main analysis investigated percentage-correct intelligibility scores as a function of the 4 conditions and speaker sex. Additional analyses included listener response variability, individual speaker trends, and an alternate intelligibility measure: proportion of content words correct. Relative to the habitual condition, the overenunciate condition was associated with the greatest intelligibility benefit, followed by the hearing impaired and clear conditions. Ten speakers followed this trend. The results indicated different patterns of clear speech benefit for male and female speakers. Greater listener variability was observed for speakers with inherently low habitual intelligibility compared to speakers with inherently high habitual intelligibility. Stable proportions of content words were observed across conditions. Clear speech instructions affected the magnitude of the intelligibility benefit. The instruction to overenunciate may be most effective in clear speech training programs. The findings may help explain the range of clear speech intelligibility benefit previously reported. Listener variability analyses suggested the importance of obtaining multiple listener judgments of intelligibility, especially for speakers with inherently low habitual intelligibility.

7 CFR 1773.42 - Clearing accounts.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Clearing accounts. The CPA's workpapers must contain an analysis of all clearing accounts. Based upon the CPA's determination of materiality, an appropriate sample of transactions should be selected for testing. The CPA's workpapers must document that transactions were reviewed for proper allocation between...

Cytological Study of Grade 3 Endometrioid Adenocarcinoma of Endometrial Origin: Cytoarchitecture and Features of Cell Clusters Assessed With Endometrial Brushing Cytology--Focusing on a comparison with endometrioid adenocarcinoma Grade 1, 2.

PubMed

Matsui, Naruaki; Kajiwara, Hiroshi; Morishita, Akihiro; Tsukada, Hitomi; Nakazawa, Kazumi; Miyazawa, Masaki; Mikami, Mikio; Nakamura, Naoya; Sato, Shinkichi

2015-06-20

Aim of study was to clarify the cytological characteristics of grade 3 endometrioid adenocarcinoma of endometrial origin (G3 EA) by endometrial brushing cytology. The subjects were 11 patients in whom G3 EA was diagnosed by review of preoperative cytological specimens obtained at our hospital and related institutions between 2000 and 2010. These patients were investigated with respect to the preoperative cytological diagnosis, background changes, cell cluster patterns, and individual cellular findings. Background changes were classified as inflammatory or tumorous, while cell clusters were classified as overlapping cell cluster, sheet-like cell cluster, clump of high dense gland, papillary, or other cell cluster. Cellular findings were investigated by comparing the incidence of squamous and clear cell metaplasia, the nuclear rounding rate, and the nuclear area with the findings in a control group (35 patients with G1-2 EA). Background changes were classified as inflammatory in 63.6% and necrotic in 36.4%. The cell clusters were classified as overlapping cell cluster in 44.8%, cell cluster in 21.7%, clump of high dense gland in 10.0%, papillary in 4.0%, and other cell cluster in 19.5%. The incidence of squamous and clear cell metaplasia was 27.2% and 18.1%, respectively. The mean nuclear rounding rate was 0.97, and the mean nuclear area was 55.98 µm2. Investigation of the cytoarchitecture of G3 EA with endometrial brushing cytology revealed overlapping cell cluster and tumor cells of a relatively uniform size. These findings suggest that it is necessary to recognize that there are differences between the cytological findings of G3 EA and the usual features of G1-2 EA.

CO2 efflux from cleared mangrove peat.

PubMed

Lovelock, Catherine E; Ruess, Roger W; Feller, Ilka C

2011-01-01

CO(2) emissions from cleared mangrove areas may be substantial, increasing the costs of continued losses of these ecosystems, particularly in mangroves that have highly organic soils. We measured CO(2) efflux from mangrove soils that had been cleared for up to 20 years on the islands of Twin Cays, Belize. We also disturbed these cleared peat soils to assess what disturbance of soils after clearing may have on CO(2) efflux. CO(2) efflux from soils declines from time of clearing from ∼10,600 tonnes km(-2) year(-1) in the first year to 3000 tonnes km(2) year(-1) after 20 years since clearing. Disturbing peat leads to short term increases in CO(2) efflux (27 umol m(-2) s(-1)), but this had returned to baseline levels within 2 days. Deforesting mangroves that grow on peat soils results in CO(2) emissions that are comparable to rates estimated for peat collapse in other tropical ecosystems. Preventing deforestation presents an opportunity for countries to benefit from carbon payments for preservation of threatened carbon stocks.

Clinical outcomes of patients with clear cell and endometrioid ovarian cancer arising from endometriosis.

PubMed

Paik, E Sun; Kim, Tae Joong; Choi, Chel Hun; Kim, Byoung Gie; Bae, Duk Soo; Lee, Jeong Won

2018-03-01

The aim of this investigation is to compare outcomes of patients according to the presence of cancer arising from endometriosis in ovarian clear cell carcinoma (CCC) and endometrioid carcinoma (EC). This study retrospectively investigated 224 CCC and EC patients treated in Samsung Medical Center from 2001 to 2015 to identify cancer arising from endometriosis according to Sampson and Scott criteria. Propensity score matching was performed to compare patients arising from endometriosis to patients without endometriosis (ratio 1:1) according to stage, age, lymph node metastasis (LNM), cancer antigen (CA)-125 level, and residual status after debulking surgery. Forty-five cases arising from endometriosis were compared with 179 cases without endometriosis. CCC and EC arising from endometriosis tended to present with early age (mean, 45.2 vs. 49.2 years; p=0.003), early-stage (stages I and II, 92.7% vs. 62.3%; p<0.001), lower CA-125 level (mean, 307.1 vs. 556.7; p=0.041), higher percentages of no gross residual disease after surgery (87.8% vs.56.8%; p=0.001), and higher percentages of negative LNM (82.9% vs. 59.0%; p=0.008) compared to cases without endometriosis. Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) showed better outcomes for groups with cancer arising from endometriosis (p=0.014 for PFS; and p=0.010 for OS). However, the association with endometriosis was not significant in multivariate analysis. Also, after propensity score matching, survival differences between the 2 groups were not significant. CCC and EC arising from endometriosis are diagnosed at an earlier age and stage. However, cancer arising from endometriosis was not a significant prognostic factor. Copyright © 2018. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology

7 CFR 1773.42 - Clearing accounts.

Code of Federal Regulations, 2011 CFR

2011-01-01

... § 1773.42 Clearing accounts. The CPA's workpapers must contain an analysis of all clearing accounts. Based upon the CPA's determination of materiality, an appropriate sample of transactions should be selected for testing. The CPA's workpapers must document that transactions were reviewed for proper...

7 CFR 1773.42 - Clearing accounts.

Code of Federal Regulations, 2012 CFR

2012-01-01

... § 1773.42 Clearing accounts. The CPA's workpapers must contain an analysis of all clearing accounts. Based upon the CPA's determination of materiality, an appropriate sample of transactions should be selected for testing. The CPA's workpapers must document that transactions were reviewed for proper...

7 CFR 1773.42 - Clearing accounts.

Code of Federal Regulations, 2010 CFR

2010-01-01

... § 1773.42 Clearing accounts. The CPA's workpapers must contain an analysis of all clearing accounts. Based upon the CPA's determination of materiality, an appropriate sample of transactions should be selected for testing. The CPA's workpapers must document that transactions were reviewed for proper...

7 CFR 1773.42 - Clearing accounts.

Code of Federal Regulations, 2013 CFR

2013-01-01

... § 1773.42 Clearing accounts. The CPA's workpapers must contain an analysis of all clearing accounts. Based upon the CPA's determination of materiality, an appropriate sample of transactions should be selected for testing. The CPA's workpapers must document that transactions were reviewed for proper...

17 CFR 20.3 - Clearing organizations.

Code of Federal Regulations, 2014 CFR

2014-04-01

... day; (5) A proprietary or clearing member customer account indicator; (6) The futures equivalent month...; (13) Gross long non-delta-adjusted swaption positions; and (14) Gross short non-delta-adjusted swaption positions. (c) End of reporting day data. For all futures equivalent months, clearing...

17 CFR 20.3 - Clearing organizations.

Code of Federal Regulations, 2012 CFR

2012-04-01

... day; (5) A proprietary or clearing member customer account indicator; (6) The futures equivalent month...; (13) Gross long non-delta-adjusted swaption positions; and (14) Gross short non-delta-adjusted swaption positions. (c) End of reporting day data. For all futures equivalent months, clearing...

Modulated Raman spectroscopy for enhanced identification of bladder tumor cells in urine samples.

PubMed

Canetta, Elisabetta; Mazilu, Michael; De Luca, Anna Chiara; Carruthers, Antonia E; Dholakia, Kishan; Neilson, Sam; Sargeant, Harry; Briscoe, Tina; Herrington, C Simon; Riches, Andrew C

2011-03-01

Standard Raman spectroscopy (SRS) is a noninvasive technique that is used in the biomedical field to discriminate between normal and cancer cells. However, the presence of a strong fluorescence background detracts from the use of SRS in real-time clinical applications. Recently, we have reported a novel modulated Raman spectroscopy (MRS) technique to extract the Raman spectra from the background. In this paper, we present the first application of MRS to the identification of human urothelial cells (SV-HUC-1) and bladder cancer cells (MGH) in urine samples. These results are compared to those obtained by SRS. Classification using the principal component analysis clearly shows that MRS allows discrimination between Raman spectra of SV-HUC-1 and MGH cells with high sensitivity (98%) and specificity (95%). MRS is also used to distinguish between SV-HUC-1 and MGH cells after exposure to urine for up to 6 h. We observe a marked change in the MRS of SV-HUC-1 and MGH cells with time in urine, indicating that the conditions of sample collection will be important for the application of this methodology to clinical urine samples.

Background odour induces adaptation and sensitization of olfactory receptors in the antennae of houseflies.

PubMed

Kelling, F J; Ialenti, F; Den Otter, C J

2002-06-01

The presence of background odour was found to have a small but significant effect on the sensitivity of the antennal olfactory system of houseflies, Musca domestica Linnaeus (Diptera: Muscidae), to new pulses of odour. We show that cross-adaptation and cross-sensitization between a background odour of (+/-)-1-octen-3-ol and pulses of (+/-)-1-octen-3-ol, 2-pentanone and R-(+)-limonene can occur, confirming that olfactory receptor cells are sensitive to different odours. Background odour can increase the responses to low concentration odour pulses and decrease the responses to higher concentration odour pulses. It is suggested that background odour has a larger effect on olfactory receptor cells that respond with a tonic increase of spike frequency, giving information about the level of odour concentration, i.e. the 'static' environment. Cells that respond in a phasic way only provide information on the dynamics of the olfactory environment.

Potential application of Chinese traditional medicine (CTM) as enhancer for tissue optical clearing

NASA Astrophysics Data System (ADS)

Chen, Wei; Jiang, Jingying; Wang, Ruikang K.; Xu, Kexin

2009-02-01

Many biocompatible hyperosmotic agents such as dimethyl sulfoxide(DMSO) have been used as enhancers for tissue optical clearing technique. However, previous investigations showed that DMSO can induce bradycardia, respiratory problems, and alterations in blood pressure. Also, DMSO could potentially alter the chemical structure, and hence the functional properties, of cell membranes. In this talk, Borneol among natural and nontoxic CTMs was introduced as new enhancer for optical clearing of porcine skin tissue since it has been widely used as new penetration promoter in the field of trandermial drug delivery system(TDDS) and been proved to be effective. In the first, the spectral characteristics of borneol was obtained and analyzed by Fourier Transformation Infrared (FTIR) spectrophotometer. And further experimental studies were performed to probe if borneol is capable of optical clearing of porcine skin tissue in vitro with near infrared spectroscopy, double integrating-spheres system and Inverse Adding-Doubling(IAD) algorithm. Spectral results show that light penetration depth into skin tissue got the increase. Meanwhile, absorption coefficient and scattering coefficient of porcine skin treated by borneol got the decrease during the permeation of Borneol. Therefore, Borneol could be potentially used as enhancer for tissue optical clearing to improve non-invasive light-based diagnostic and imaging techniques while practically optical application and clinical safety are under consideration.

Comparison of the prognostic value of pretreatment measurements of systemic inflammatory response in patients undergoing curative resection of clear cell renal cell carcinoma.

PubMed

Lucca, Ilaria; de Martino, Michela; Hofbauer, Sebastian L; Zamani, Nura; Shariat, Shahrokh F; Klatte, Tobias

2015-12-01

Pretreatment measurements of systemic inflammatory response, including the Glasgow prognostic score (GPS), the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), the platelet-to-lymphocyte ratio (PLR) and the prognostic nutritional index (PNI) have been recognized as prognostic factors in clear cell renal cell carcinoma (CCRCC), but there is at present no study that compared these markers. We evaluated the pretreatment GPS, NLR, MLR, PLR and PNI in 430 patients, who underwent surgery for clinically localized CCRCC (pT1-3N0M0). Associations with disease-free survival were assessed with Cox models. Discrimination was measured with the C-index, and a decision curve analysis was used to evaluate the clinical net benefit. On multivariable analyses, all measures of systemic inflammatory response were significant prognostic factors. The increase in discrimination compared with the stage, size, grade and necrosis (SSIGN) score alone was 5.8 % for the GPS, 1.1-1.4 % for the NLR, 2.9-3.4 % for the MLR, 2.0-3.3 % for the PLR and 1.4-3.0 % for the PNI. On the simultaneous multivariable analysis of all candidate measures, the final multivariable model contained the SSIGN score (HR 1.40, P < 0.001), the GPS (HR 2.32, P < 0.001) and the MLR (HR 5.78, P = 0.003) as significant variables. Adding both the GPS and the MLR increased the discrimination of the SSIGN score by 6.2 % and improved the clinical net benefit. In patients with clinically localized CCRCC, the GPS and the MLR appear to be the most relevant prognostic measures of systemic inflammatory response. They may be used as an adjunct for patient counseling, tailoring management and clinical trial design.

3D microfluidic fabrication using a low refractive index polymer for clear microscopic observation at the fluid boundary

NASA Astrophysics Data System (ADS)

Hanada, Y.

2018-02-01

Microfluidic chips known as μ-TAS or LoC have become versatile tools in cell research, since functional biochips are able to streamline dynamic observations of various cells. Glass or polymers are generally used as the substrate due to their high transparency, chemical stability and cost-effectiveness. However, these materials are not well suited to the microscopic observation at the fluid boundary due to the refractive index mismatch between the medium and the biochip material. For this reason, we have developed a method of fabricating three-dimensional (3D) microfluidic chips made of a low refractive index fluoric polymer CYTOP. CYTOP has a refractive index of 1.34, a value that is almost equivalent to that of water. This optical property is very important for clear 3D microscopic observations of cell motion near the solid boundary, due to the minimal mismatch between the refractive index values of the medium and the CYTOP substrate. Therefore, CYTOP microfluidics are expected to allow the generation of clear images of unique cell migratory processes near the microfluidic sidewall. Therefore, we established the fabrication procedure involving the use of femtosecond laser direct writing, followed by wet etching and annealing, to create high-quality 3D microfluidics inside a polymer substrate. A microfluidic chip made in this manner enables us to more clearly observe areas near the fluid surface, compared to the observations possible using conventional microfluidic chips.

Balloon cell nevus of the iris.

PubMed

Morcos, Mohib W; Odashiro, Alexandre; Bazin, Richard; Pereira, Patricia Rusa; O'Meara, Aisling; Burnier, Miguel N

2014-12-01

Balloon cell nevus is a rare histopathological lesion characterized by a predominance of large, vesicular and clear cells, called balloon cells. There is only 1 case of balloon cell nevus of the iris reported in the literature. A 55 year-old man presented a pigmented elevated lesion in the right iris since the age of 12 years old. The lesion had been growing for the past 2 years and excision was performed. Histopathological examination showed a balloon cell nevus composed of clear and vacuolated cells without atypia. A typical spindle cell nevus of the iris was also observed. The differential diagnosis included xanthomatous lesions, brown adipocyte or other adipocytic lesions, clear cell hidradenoma, metastatic clear cell carcinoma of the kidney and clear cell sarcoma. The tumor was positive for Melan A, S100 protein and HMB45. Balloon cell nevus of the iris is rare but should be considered in the differential diagnosis of melanocytic lesions of the iris. Copyright © 2014 Elsevier GmbH. All rights reserved.

Who Clears Probation?

ERIC Educational Resources Information Center

Wisconsin Univ., Stevens Point. Office of Institutional Research.

After the first semester of 1969-70, 413 freshmen who had entered the University of Wisconsin-Stevens Point in the fall were placed on academic probation with grade point ratios (GPR) ranging from 0.75 to 1.59. After 3 semesters, 73 or 17.7% had cleared probation and another 5% were still on probation. The rest had dropped from school or were…

12 CFR 217.133 - Cleared transactions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 12 Banks and Banking 2 2014-01-01 2014-01-01 false Cleared transactions. 217.133 Section 217.133... Measurement Approaches Risk-Weighted Assets for General Credit Risk § 217.133 Cleared transactions. (a... section 133(c)(2); (B) DF = the funded portion of the Board-regulated institution's default fund...

Clear-air lidar dark band

NASA Astrophysics Data System (ADS)

Girolamo, Paolo Di; Scoccione, Andrea; Cacciani, Marco; Summa, Donato; Schween, Jan H.

2018-04-01

This paper illustrates measurements carried out by the Raman lidar BASIL in the frame of HOPE, revealing the presence of a clear-air dark band phenomenon (i.e. the appearance of a minimum in lidar backscatter echoes) in the upper portion of the convective boundary layer. The phenomenon is clearly distinguishable in the lidar backscatter echoes at 1064 nm. This phenomenon is attributed to the presence of lignite aerosol particles advected from the surrounding open pit mines in the vicinity of the measuring site.

Outcomes of Phacoemulsification Using Different Size of Clear Corneal Incision in Eyes with Previous Radial Keratotomy.

PubMed

Zhang, Jing Shang; Liu, Xue; Wang, Jin Da; Xiong, Ying; Li, Jing; Li, Xiao Xia; Zhao, Jing; You, Qi Sheng; Huang, Yao; Tsai, Frank; Baum, Larry; Jhanji, Vishal; Wan, Xiu Hua

2016-01-01

To evaluate visual outcomes and complications after phacoemulsification in eyes with cataract and previous radial keratotomy (RK) cuts using different sizes of clear corneal incisions. The study was a retrospective study. Thirty eyes with cataract and previous RK underwent phacoemulsification and intraocular lens (IOL) implantation. Among them 7 eyes had 8 RK cuts, 13 eyes had 12 RK cuts, and 10 eyes had 16 RK cuts. Phacoemulsification and IOL implantation were performed through a 2.0-3.2 mm clear corneal incision by a single surgeon. In the 8 RK cuts group, 3.2 mm clear corneal incisions were used in 4 eyes, and 3.0 mm clear corneal incisions were used in 3 eyes. In the 12 RK cuts group, 3.2 mm clear corneal incisions were used in 6 eyes, and 2.2 mm clear corneal incisions were used in 7 eyes. In the 16 RK cuts group, 3.2 mm clear corneal incisions were used in 5 eyes, and 2.0 mm clear corneal incisions were used in 5 eyes. Patients were followed up 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, 2 years, and 3 years postoperatively and were examined for the dehiscence of RK cuts during or after the surgery, post-operative best-corrected visual acuity (BCVA), corneal astigmatism, corneal endothelial cell density and complications. Successful phacoemulsification with IOL implantation was performed in all eyes. No wound dehiscence was noted in any eyes with 8 or 12 RK cuts. Wound dehiscence was noted in 2 eyes with 16 RK cuts. The dehiscence of RK cuts was closed successfully by injecting an air bubble with or without viscoelastic agent into the anterior chamber at the end of surgery. During the follow-up, the cuts were well apposed in all eyes, and no new dehiscence of RK cuts was noted. At the last follow-up, mean BCVA (0.2 ± 0.18 logMAR) was better than preoperative BCVA(0.45±0.19 logMAR) (P < 0.001). There was no significant difference between the long-term preoperative and postoperative mean corneal astigmatism (P = 0.3). However, there was a significant

Intracellular ion concentrations and cell volume during cholinergic stimulation of eccrine secretory coil cells

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

Takemura, T.; Sato, F.; Saga, K.

Methacholine (MCh)-induced changes in intracellular concentrations of Na, K, and Cl (( Na)i, (K)i, and (Cl)i, respectively) and in cellular dry mass (a measure of cell shrinkage) were examined in isolated monkey eccrine sweat secretory coils by electron probe X-ray microanalysis using the peripheral standard method. To further confirm the occurrence of cell shrinkage during MCh stimulation, the change in cell volume of dissociated clear and dark cells were directly determined under a light microscope equipped with differential interference contrast (DIC) optics. X-ray microanalysis revealed a biphasic increase in cellular dry mass in clear cells during continuous MCh stimulation; anmore » initial increase of dry mass to 158% (of control) followed by a plateau at 140%, which correspond to the decrease in cell volume of 37 and 29%, respectively. The latter agrees with the MCh-induced cell shrinkage of 29% in dissociated clear cells. The MCh-induced increase in dry mass in myoepithelial cells was less than half that of clear cells. During the steady state of MCh stimulation, both (K+)i and (Cl)i of clear cells decreased by about 45%, whereas (Na)i increased in such a way to maintain the sum of (Na) i + (K)i constant. There was a small (12-15 mM) increase in (Na)i and a decrease in (K)i in myoepithelial cells during stimulation with MCh. Dissociated dark cells failed to significantly shrink during MCh stimulation. The decrease in (Cl)i in the face of constant (Na)i + (K)i suggests the accumulation of unknown anion(s) inside the clear cell during MCh stimulation.« less

Chemical Literature Exercises and Resources (CLEAR).

ERIC Educational Resources Information Center

Hostettler, John D.; And Others

These materials were developed to make the structure and use of the chemical literature clear to chemistry students and to help them become independent and intelligent users of the library. The design of Chemical Literature Exercises and Resources (CLEAR) includes a users' note and five main parts: introduction to chemical literature, chemical…

76 FR 45730 - Customer Clearing Documentation and Timing of Acceptance for Clearing

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-01

... proposing regulations to facilitate customer access to clearing and to bolster risk management through... and execution of customer transactions on a DCM or SEF on terms that have a reasonable relationship to... a reasonable relationship to the best terms available by prohibiting restrictions in customer...

Surgically induced astigmatism after phacoemulsification by temporal clear corneal and superior clear corneal approach: a comparison.

PubMed

Nikose, Archana Sunil; Saha, Dhrubojyoti; Laddha, Pradnya Mukesh; Patil, Mayuri

2018-01-01

Cataract surgery has undergone various advances since it was evolved from ancient couching to the modern phacoemulsification cataract surgery. Surgically induced astigmatism (SIA) remains one of the most common complications. The introduction of sutureless clear corneal incision has gained increasing popularity worldwide because it offers several advantages over the traditional sutured limbal incision and scleral tunnel. A clear corneal incision has the benefit of being bloodless and having an easy approach, but SIA is still a concern. In this study, we evaluated the SIA in clear corneal incisions with temporal approach and superior approach phacoemulsification. Comparisons between the two incisions were done using keratometric readings of preoperative and postoperative refractive status. It was a hospital-based prospective interventional comparative randomized control trial of 261 patients conducted in a rural-based tertiary care center from September 2012 to August 2014. The visual acuity and detailed anterior segment and posterior segment examinations were done and the cataract was graded according to Lens Opacification Classification System II. Patients were divided for phacoemulsification into two groups, group A and group B, who underwent temporal and superior clear corneal approach, respectively. The patients were followed up on day 1, 7, 30, and 90 postoperatively. The parameters recorded were uncorrected visual acuity, best-corrected visual acuity, slit lamp examination, and keratometry. The mean difference of SIA between 30th and 90th day was statistically evaluated using paired t -test, and all the analyses were performed using SPSS 18.0 (SPSS Inc.) software. The mean postoperative SIA in group A was 0.998 D on the 30th day, which reduced to 0.768 D after 90 days, and in group B the SIA after 30 days was 1.651 D, whereas it reduced to 1.293 D after 90 days. Temporal clear corneal incision is evidently better than superior clear corneal incision as far as

RASSF1A protein expression and correlation with clinicopathological parameters in renal cell carcinoma

PubMed Central

Tezval, Hossein; Merseburger, Axel S; Matuschek, Ira; Machtens, Stefan; Kuczyk, Markus A; Serth, Jürgen

2008-01-01

Background Epigenetic silencing of RAS association family 1A (RASSF1A) tumor suppressor gene occurs in various histological subtypes of renal cell carcinoma (RCC) but RASSF1A protein expression in clear cell RCC as well as a possible correlation with clinicopathological parameters of patients has not been analyzed at yet. Methods 318 primary clear cell carcinomas were analyzed using tissue microarray analysis and immunohistochemistry. Survival analysis was carried out for 187 patients considering a follow-up period of 2–240 month. Results Expression of RASSF1A was found to be significantly decreased in tumoral cells when compared to normal tubular epithelial cells. RASSF1A immunopositivity was significantly associated with pT stage, group stage and histological grade of tumors and showed a tendency for impaired survival in Kaplan-Meier analysis. Conclusion While most tumors demonstrate a loss of RASSF1A protein, a subset of tumors was identified to exhibit substantial RASSF1A protein expression and show increased tumor progression. Thus RCC tumorigenesis without depletion of RASSF1A may be associated with an adverse clinical outcome. PMID:18822131

Applications of the low-background gamma spectroscopy to the geographical origin of marine salts and prunes

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

Perrot, F.

The low background gamma spectroscopy has been applied to try to sign the geographical origin of the French atlantic marine salts and of the prunes from Agen. Most of the activity measurements have been done using low background Ge spectrometers located in Bordeaux. Results have shown that a clear signature exists in the case of the French atlantic salts using the 40K, 137Cs and 226Ra isotopes but not in the case of the prunes.

Major Land Clearing Fires, Kalimantan, Borneo, Indonesia

NASA Technical Reports Server (NTRS)

1991-01-01

These many and intense land clearing fires in the Kalimantan region of the island of Borneo, Indonesia (3.5S, 113.5E) are indicative of the many deforestation activities on a worldwide scale. In order to feed and house ever increasing populations, more cleared land is required for agriculture to feed ever increasing populations. More pasture lands are needed for livestock. And, more cleared lands are needed for housing.

Preliminary Application of WCX Magnetic Bead-Based Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry in Analyzing the Urine of Renal Clear Cell Carcinoma.

PubMed

Dong, De-Xin; Ji, Zhi-Gang; Li, Han-Zhong; Yan, Wei-Gang; Zhang, Yu-Shi

2017-12-30

Objective To evaluate the application of weak cation exchange (WCX) magnetic bead-based Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) in detecting differentially expressed proteins in the urine of renal clear cell carcinoma (RCCC) and its value in the early diagnosis of RCCC.Methods Eleven newly diagnosed patients (10 males and 1 female, aged 46-78, mean 63 years) of renal clear cell carcinoma by biopsy and 10 healthy volunteers (all males, aged 25-32, mean 29.7 years) were enrolled in this study. Urine samples of the RCCC patients and healthy controls were collected in the morning. Weak cation exchange (WCX) bead-based MALDI-TOF MS technique was applied in detecting differential protein peaks in the urine of RCCC. ClinProTools2.2 software was utilized to determine the characteristic proteins in the urine of RCCC patients for the predictive model of RCCC. Results The technique identified 160 protein peaks in the urine that were different between RCCC patients and health controls; and among them, there was one peak (molecular weight of 2221.71 Da) with statistical significance (P=0.0304). With genetic algorithms and the support vector machine, we screened out 13 characteristic protein peaks for the predictive model. Conclusions The application of WCX magnetic bead-based MALDI-TOF MS in detecting differentially expressed proteins in urine may have potential value for the early diagnosis of RCCC.