bluuebunny/crossref_metadata_2025_split huggingface dataset:
CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin
Authors: Küsters‐Vandevelde Heidi V.N. , Van Leeuwen Arjanne , Verdijk Marian A.J. , de Koning Maurits N.C. , Quint Wim G.V. , Melchers Willem J.G. , Ligtenberg Marjolijn J.L. , Blokx Willeke A.M. 
Published: September 2009

AbstractGenetic alterations in metastatic cutaneous squamous cell carcinoma (CSCC) which might serve as prognostic biomarkers are not well investigated. We investigated the mutation status and protein expression of the CDKN2A (INK4a‐ARF) and TP53 genes in metastatic CSCCs and correlated this with clinicopathological variables, HPV presence, and survival data. Sequence analysis was performed on formalin‐fixed and paraffin‐embedded tissue of 35 metastases and their primary tumors, and was correlated with immunohistochemical stainings for p53, p16 and p14. Beta‐PV and alpha‐PV DNA was detected using PCR‐based assays. Kaplan–Meier and Cox regression methods were used for survival assessment. CDKN2A was mutated in 31% of the metastases and their primary tumors, while the TP53 gene was mutated in 51% of the metastases. P53 protein expression was significantly associated with missense type of mutations (p = 0.002). No persistent HPV types were detected. CDKN2A mutations were significantly associated with disease‐specific death (p = 0.001). A significant difference was observed in disease‐specific survival between patients with or without a CDKN2A mutation (p = 0.010), while this was not the case for TP53. At univariate Cox's regression analysis tumor size (p = 0.010), invasion depth (p = 0.030) and CDKN2A mutations (p = 0.040) were significantly related to shorter disease‐specific survival. At multivariate Cox's regression only tumor size had an adverse effect on survival (p = 0.002). In conclusion, our study indicates that the CDKN2A mutation status might be of prognostic value in metastatic CSCCs. In most cases, CDKN2A and TP53 mutations are early genetic events in CSCC tumorigenesis. The possible role of HPV in metastatic CSCC needs further exploration.
Prognostic role of p‐mTOR expression in cancer tissues and metastatic lymph nodes in pT2b gastric cancer
Authors: An Ji Yeong , Kim Kyoung Mee , Choi Min Gew , Noh Jae Hyung , Sohn Tae Sung , Bae Jae Moon , Kim Sung 
Published: September 2009

AbstractDespite the great interest in mammalian target of rapamycin (mTOR) as a potential anticancer therapy target, the prognostic role of mTOR in gastric cancer has not been elucidated. In this study, we investigated mTOR expression in gastric cancer tissues and in metastatic lymph nodes and examined its association with clinical outcome. A total of 290 patients with pT2b gastric cancer were enrolled in this study. Patients were divided into 3 groups according to metastatic lymph node status: Group 1 contained 96 patients without lymph node metastasis, Group 2 contained 102 patients with a few (1–2) metastatic lymph nodes and Group 3 contained 92 patients with extensive (>16) lymph node metastasis. Phosphorylated mTOR expression was determined immunohistochemically using tissue microarrays. p‐mTOR expression was observed in 36.5% of the gastric cancer tissues in Group 1, 39.2% in Group 2 and 60.9% in Group 3. A significant correlation was found between p‐mTOR expression in gastric cancer tissues and in metastatic lymph nodes. The Borrmann type in Group 1, perineural invasion and p‐mTOR expression in metastatic lymph nodes in Group 2 and p‐mTOR expression in metastatic lymph nodes in Group 3 were found to be independent prognostic factors of disease‐free survival. The 5‐year disease free survival rate of Group 2 patients was 84.4% in negative p‐mTOR and 66.1% in positive p‐mTOR expression in metastatic lymph nodes (p = 0.015). The 5‐year disease free survival rate of Group 3 patients was 37.3% in negative p‐mTOR and 14.9% in positive p‐mTOR expression in metastatic lymph nodes (p = 0.037). There was a linear correlation between the rate of tumor recurrence and mTOR expression scores in metastatic lymph nodes. In pT2b gastric cancer, p‐mTOR expression in gastric cancer is associated with the extent of lymph node metastasis, and p‐mTOR expression in metastatic lymph nodes is correlated with poor disease‐free survival. mTOR may harbor significant potential for a prognostic biomarker and therapeutic target for gastric cancer treatment.
The influence of a period of caloric restriction due to the Dutch famine on breast density
Authors: Haars Gerco , van Gils Carla H. , Elias Sjoerd G. , Lokate Mariëtte , van Noord Paul A.H. , Peeters Petra HM 
Published: September 2009

AbstractRecently, we showed that short, intense caloric restriction due to the Dutch famine increased breast cancer risk in women and influenced the hormonal‐ and IGF‐system. These systems may also affect breast density, which is one of the strongest risk factors for breast cancer. We examined the influence of the Dutch famine on breast density, using mammograms of 1,035 women. Breast size, dense and non‐dense tissue and the relative density were measured on a continuous scale. Mean density was compared between three groups of ascending levels of famine‐exposure. Results were adjusted for known determinants of breast density and stratified by age at exposure. There were no overall, significant differences by exposure. In unexposed compared to severely exposed women, means varied from 124 cm2 to 121 cm2 (ptrend = 0.50) for breast size, from 23.4 to 21.8 cm2 (ptrend = 0.48) for amount of dense tissue, from 87.7 to 85.4 cm2 (ptrend = 0.55) for non‐dense tissue and from 22.8 to 22.3% (ptrend = 0.78) for relative density. Only among women who were younger than 10 years during the famine was the amount of non‐dense tissue significantly lower with higher exposure, with 53.1 cm2 for severely exposed compared to 77.8 cm2 (ptrend = 0.03) for unexposed. This group also appeared to have smaller breasts with more absolute and relative density, but not statistically significant. We observed no overall effect on breast density in women severely exposed to a short, intense caloric restriction. However, in women exposed before puberty, the non‐dense area was smaller and density tended to be higher.
Cutaneous type adult T‐cell leukemia/lymphoma is a characteristic subtype and includes erythema/papule and nodule/tumor subgroups
Authors: Miyata Tomoko , Yonekura Kentaro , Utsunomiya Atae , Kanekura Takuro , Nakamura Shigeo , Seto Masao 
Published: September 2009

AbstractWe first analyzed the genomic profile of cutaneous type adult T‐cell leukemia/lymphoma (ATLL) in an attempt to clarify its clinical and biological characteristics. Genomic gains of 1p, 7q and 18q and loss of 13q were frequently detected. Gain of 1p36.33‐32 or loss of 13q33.1‐3 indicated poor prognosis. Among cases with generalized lesions, erythema/papule or nodule/tumor cases showed a distinct genomic profile, indicating that these 2 groups were biologically different and developed via different genetic pathways. Furthermore, cases with generalized nodule/tumor lesions tended to progress to aggressive ATLL.
Microsomal prostaglandin E synthase‐1 inhibition blocks proliferation and enhances apoptosis in oesophageal adenocarcinoma cells without affecting endothelial prostacyclin production
Authors: Beales Ian L.P. , Ogunwobi Olorunseun O. 
Published: September 2009

AbstractProstaglandins are important in the progression of various gastrointestinal cancers including oesophageal adenocarcinoma (OAC). Cyclo‐oxygenase (COX)‐2 inhibitors reduce OAC prostaglandin production but also have potentially detrimental effects on vascular endothelial function by reducing prostacyclin production and increasing the risk of cardiovascular events. We have examined the effects of inhibiting microsomal prostaglandin synthase‐1 (mPGES‐1), the enzyme downstream of COX‐2 in the prostaglandin synthetic cascade. In OAC cells, reduction of mPGES‐1 with RNA interference blocked PGE2 production, inhibited serum‐induced proliferation and enhanced apoptosis in the COX‐2 expressing cell lines (OE33 and FLO) but had no effect in COX‐2 deficient BIC‐1 cells. Three different methods of inhibiting mPGES‐1 (RNA interference, a novel small molecule inhibitor and the endogenous inhibitor 15‐deoxy‐Δ12,14‐PGJ2) also blocked leptin induced mPGES‐1 expression and PGE2 production and abolished the leptin‐induced proliferative and anti‐apoptotic effects in OE33 cells, without affecting COX‐2 expression. The anti‐proliferative effects were equivalent to those produced by COX‐2 inhibitory concentrations of celecoxib and NS‐398. However, unlike the two COX‐2 inhibitors, mPGES‐1 inhibition did not reduce endothelial prostacyclin production. In contrast to the effects of the COX‐2 inhibitor celecoxib, mPGES‐1 inhibition had no effects on Akt kinase activity in OAC cells. We conclude that inhibition of mPGES‐1 has potentially beneficial effects in OAC without the potentially detrimental effects on vascular endothelial prostacyclin synthesis. We have also confirmed that celecoxib has anticancer actions separate from the inhibition of COX‐2. Inhibition of mPGES‐1 may be therapeutically useful in the treatment and prevention of OAC.
Detection of Merkel cell polyomavirus (MCPyV) in Merkel cell carcinoma cell lines: Cell morphology and growth phenotype do not reflect presence of the virus
Authors: Fischer Nicole , Brandner Johanna , Fuchs Franca , Moll Ingrid , Grundhoff Adam 
Published: September 2009

AbstractThe recently discovered human polyomavirus (MCPyV) is frequently found in Merkel cell carcinoma (MCC) tissue and is believed to be causally linked to MCC pathogenesis. While cell lines established from MCC represent a valuable tool to study the contribution of MCPyV to MCC pathogenesis, hitherto only 1 MCPyV‐positive line has been described. We have analyzed 7 MCC cell lines for the presence, integration pattern and copy number of MCPyV. In 5 cell lines, MCPyV specific sequences were detected. In 3 of these lines, multiple copies of viral genomes per cell were detected, and sequencing of PCR amplificates identified distinct mutations predicted to lead to the expression of a truncated large T‐Antigen (LT‐Ag). In 1 cell line, clonal integration of concatamerized viral genomes was confirmed by Southern Blotting. MCC cell lines are conventionally categorized as “classic” or “variant” and further divided into 4 subtypes, based on expression of neuroendocrine markers and morphology. While it has been suggested that the presence of MCPyV might promote a classic phenotype, such a notion is not supported by our data. Instead, we find MCPyV‐positive as well as ‐negative lines of the classic variety, indicating that the distinguishing features are either inherently independent of viral infection or have become so in the course of tumorigenesis and/or cell line establishment. We therefore suggest a novel classification scheme based on MCPyV presence, integration patterns and T‐Ag mutations. The cell lines described here extend the repertoire of available MCPyV‐positive MCC‐lines and should aid in the elucidation of the role of MCPyV in the pathogenesis of MCC.
Molecular characterization of human homologs of yeast MOB1
Authors: Chow Annabelle , Hao Yawei , Yang Xiaolong 
Published: September 2009

AbstractMOB (Mps one binder) was originally identified in yeast as a regulator of mitotic exit and cytokinesis, and was later identified as a tumor suppressor and a component of an emerging Hippo‐LATS tumor suppressor pathway in Drosophila (D). So far, 7 human homologs of yeast MOB (hMOB1A, 1B, 2A, 2B, 2C, 3, 4) have been identified. Although hMOB1A/B has been extensively studied, the biological features of other hMOBs are largely unknown. In addition, while hMOB1 has been reported to interact with and activate LATS (Large tumor suppressor)/Warts tumor suppressor, the functional significance of this is unknown. In this study, we have characterized, for the first time, the cellular and biochemical function of all human MOBs. By examining hMOB mRNAs expression in various human tissues, we found that hMOBs demonstrated different expression patterns. Further biochemical characterization of hMOBs showed that only hMOB1A and hMOB1B interact with both LATS1 and LATS2 in vitro and in vivo. Significantly, we have discovered that overexpression of hMOB1 in human cancer cells activated LATS activity and inhibited cell proliferation or caused apoptosis while hMOB1, targeting the plasma membrane, led to a more significant phenotype. Reciprocally, short‐hairpin (sh) RNA‐mediated suppression of hMOB1 causes increased cell proliferation. Our findings provided evidence that hMOB1A and hMOB1B are 2 LATS‐binding proteins that may function as tumor suppressors in human cancer cells.
Loss of FBXW7, a cell cycle regulating gene, in colorectal cancer: Clinical significance
Authors: Iwatsuki Masaaki , Mimori Koshi , Ishii Hideshi , Yokobori Takehiko , Takatsuno Yasushi , Sato Tetsuya , Toh Hiroyuki , Onoyama Ichiro , Nakayama Keiichi I. , Baba Hideo , Mori Masaki 
Published: September 2009

AbstractThis study focused on a cell cycle regulatory gene, FBXW7, which ubiquitinates c‐Myc and cyclin E and promotes exit from the cell cycle. We determined the expression level of FBXW7 in colorectal cancer (CRC) cases, correlated those values with clinicopathologic features, and characterized the molecular mechanism of reduced expression of FBXW7 in CRC cells in vitro. FBXW7 mRNA and protein expression were evaluated in 93 CRC cases. Using CGH array, the copy number aberrations of the flanking region of FBXW7 were evaluated in another 130 CRC specimens. In vitro analysis of FBXW7 gene silencing in CRC cells was conducted. FBXW7 mRNA expression was significantly lower in tumor tissues than the corresponding normal tissues. The low FBXW7 expression group showed a significantly poorer prognosis than patients in the high expression group. A concordant relationship was observed between the incidence of FBXW7 repression and the genetic alteration. The incidence of genetic alteration was associated with the stage of disease progression. In vitro, FBXW7‐specific siRNA enhanced expression of c‐MYC and cyclin E proteins and up‐regulated cell proliferation. Genetic alterations in tumors led to the loss of FBXW7 expression and increased cell proliferation. FBXW7 expression provides a prognostic factor for patients with CRC.
Significance of Plk1 regulation by miR‐100 in human nasopharyngeal cancer
Authors: Shi Wei , Alajez Nehad M. , Bastianutto Carlo , Hui Angela B.Y. , Mocanu Joseph D. , Ito Emma , Busson Pierre , Lo Kwok‐Wai , Ng Raymond , Waldron John , O'Sullivan Brian , Liu Fei‐Fei 
Published: September 2009

AbstractPolo‐like kinase 1 (Plk1) is a critical regulator of many stages of mitosis; increasing evidence indicates that Plk1 overexpression correlates with poor clinical outcome, yet its mechanism of regulation remains unknown. Hence, a detailed evaluation was undertaken of Plk1 expression in human nasopharyngeal cancer (NPC), the cellular effects of targeting Plk1 using siRNA in combination with ionizing radiation (RT) and potential upstream microRNAs (miRs) that might regulate Plk1 expression. Using immunohistochemistry, Plk1 was observed to be overexpressed in 28 of 40 (70%) primary NPC biopsies, which in turn was associated with a higher likelihood of recurrence (p = 0.018). SiPlk1 significantly inhibited Plk1 mRNA and protein expression, and decreased Cdc25c levels in NPC cell lines. This depletion resulted in cytotoxicity of C666‐1 cells, enhanced by the addition of RT, mediated by G2/M arrest, increased DNA double‐strand breaks, apoptosis, and caspase activation. Immunofluorescence demonstrated that the G2/M arrest was associated with aberrant spindle formation, leading to mitotic arrest. In vivo, transfection of C666‐1 cells and systemic delivery of siPlk1 decreased tumour growth. MicroRNA‐100 (miR‐100) was predicted to target Plk1 mRNA, which was indeed underexpressed in C666‐1 cells, inversely correlating with Plk1 expression. Using luciferase constructs containing the 3′‐UTR of Plk1 sequence, we document that miR‐100 can directly target Plk1. Hence, our data demonstrate for the first time that underexpressed miR‐100 leads to Plk1 overexpression, which in turn contributes to NPC progression. Targeting Plk1 will cause mitotic catastrophe, with significant cytotoxicity both in vitro and in vivo, underscoring the important therapeutic opportunity of Plk1 in NPC.
Enhancement of tumor‐specific T‐cell responses by transcatheter arterial embolization with dendritic cell infusion for hepatocellular carcinoma
Authors: Mizukoshi Eishiro , Nakamoto Yasunari , Arai Kuniaki , Yamashita Tatsuya , Mukaida Naofumi , Matsushima Kouji , Matsui Osamu , Kaneko Shuichi 
Published: September 2009

AbstractTranscatheter arterial embolization (TAE) destroys a tumor by the induction of necrosis and/or apoptosis and causes inflammation with cytokine production, which may favor immune activation and presentation of tumor‐specific antigens. In the current study, we attempted to identify the effect of TAE on tumor‐specific T‐cell responses and the additional effect of dendritic cell (DC) infusion performed during TAE. The prevalence of tumor antigen‐specific T cells was determined by interferon‐γ enzyme‐linked immunospot analysis using alpha‐fetoprotein (AFP) and tumor antigen‐derived peptides in 20 and 13 patients with hepatocellular carcinoma (HCC) who received TAE and TAE with DC infusion, respectively. The increased frequency of AFP‐specific T cells was observed in 6 of 20 patients after TAE. It was observed more frequently in patients with DC infusion than in those with TAE alone. However, tumor recurrence was not completely prevented in patients albeit displayed enhanced immune responses. The evidence that the enhanced immune responses were transient and attenuated within 3 months was provided in time‐course analysis. In conclusion, TAE with DC infusion enhances the tumor‐specific immune responses more effectively than TAE alone. Although the effect is not sufficient to prevent HCC recurrence, these results may contribute to the development of novel immunotherapeutic approach for HCC.
Double impact on p‐glycoprotein by statins enhances doxorubicin cytotoxicity in human neuroblastoma cells
Authors: Sieczkowski Evelyn , Lehner Claudia , Ambros Peter F. , Hohenegger Martin 
Published: September 2009

AbstractThe development of multidrug resistance (MDR) is a major problem during cancer treatment. Drug efflux via ATP‐binding cassette (ABC) transporters is the main mechanism responsible for resistance to chemotherapeutics. We have recently observed that statins enhance susceptibility to doxorubicin‐induced apoptosis in human rhabdomyosarcoma cells, which is now also observed in human SH‐SY5Y neuroblastoma cells. We have therefore investigated the ABC transporter activity to confirm a possible inhibition by statins in SH‐SY5Y cells. Indeed, simvastatin directly inhibited dye transport at equimolar concentrations of the ABC transporter inhibitor, verapamil. Making use of the fluorescence behavior of doxorubicin the accumulation of anthracycline was monitored in real‐time confocal microscopy. The intracellular doxorubicin accumulation was immediately enhanced by statins in SH‐SY5Y cells and also in a MYCN‐amplified neuroblastoma cell line STA‐NB‐10. The heavily glycosylated P‐glycoprotein (ABCB1, P‐gp) transporter appeared as a 180‐and 140‐kDa species. Atorvastatin and simvastatin reduced the 180‐kDa form of P‐gp, but not verapamil. Thereby the fully glycosylated species is shifted to the core glycosylated species (140 kDa), which was only seen at statin exposure times longer than 24 hr. The functional importance of glycosylation of the transporter was highlighted by exogenous application of N‐glycosidase F, which was sufficient to enhance doxorubicin accumulation. Hence, these novel findings of statins' dual impact on P‐gp have clinical implications. The enhanced intracellular accumulation of chemotherapeutics or other ABC transporter substrates in the presence of statins may represent a novel concept to overcome MDR in cancer therapy and improve drug safety.
Mortalin inhibitors sensitize K562 leukemia cells to complement‐dependent cytotoxicity
Authors: Pilzer David , Saar Moran , Koya Keizo , Fishelson Zvi 
Published: September 2009

AbstractMortalin, the mitochondrial hsp70, is a vital constitutively expressed heat shock protein. Its elevated expression has been correlated with malignant transformation and poor cancer prognosis. Cancer cells exhibit increased resistance to complement‐dependent cytotoxicity, partly due to their capacity to eliminate the complement membrane attack complex (MAC) from their cell surface. As we have previously reported, mortalin and the complement membrane attack complexes are released in membrane vesicles from complement attacked cells. As shown here, knock down of mortalin with specific siRNA reduces MAC elimination and enhances cell sensitivity to MAC‐induced cell death. Similar results were obtained with MKT‐077, a cationic rhodacyanine dye that inhibits mortalin. Treatment of human erythroleukemia K562 and colorectal carcinoma HCT116 cells with MKT‐077 sensitizes them to cell death mediated by MAC but not by streptolysin O. Pre‐treatment of cells with MKT‐077 also reduces the extent of MAC‐mortalin vesiculation following a sublytic complement attack. In the presence of MKT‐077, the direct binding of mortalin to complement C9, the major MAC component, is inhibited. The tumor suppressor protein p53 is a known mortalin client protein. The effect of MKT‐077 on complement‐mediated lysis of HCT116 p53+/+ and p53−/− cells was found to be independent on the presence of p53. Our results also demonstrate that recombinant human mortain inhibits complement‐mediated hemolysis of rabbit erythrocytes as well as zinc‐induced C9 polymerization. We conclude that mortalin supports cancer cell resistance to complement‐dependent cytotoxicity and propose consideration of mortalin as a novel target for cancer adjuvant immunotherapy.
Gene‐expression‐based analysis of local and metastatic neuroblastoma variants reveals a set of genes associated with tumor progression in neuroblastoma patients
Authors: Nevo Ido , Oberthuer Andre , Botzer Edry , Sagi‐Assif Orit , Maman Shelly , Pasmanik‐Chor Metsada , Kariv Naam , Fischer Matthias , Yron Ilana , Witz Isaac P. 
Published: September 2009

AbstractMetastasis is the primary cause of mortality in Neuroblastoma (NB) patients, but the metastatic process in NB is poorly understood. Metastsis is a multistep process that requires the coordinated action of many genes. The identification of genes that promote or suppress tumor metastasis can advance our understanding of this process. In the present study, we utilized a human NB xenograft model comprising local and metastatic NB variants, which was recently developed in our laboratory. We set out to identify molecular correlates of NB metastasis and to determine the clinical relevance of these molecules. We first performed genome‐wide expression profiles of metastatic and nonmetastatic NB variants that have an identical genetic background. We found that some of the proteins highly expressed in the metastatic NB variants are localized in the cytoplasm and endoplasmic reticulum. Other proteins are linked to metabolic processes and signaling pathways, thereby supporting the invasive and metastatic state of the cells. Subsequently, we intersected the differentially expressed genes in the human xenografted variants with genes differentially expressed in Stage 1 and Stage 4 primary tumors of NB patients. By using the same gene‐expression platform, molecular correlates associated with metastatic progression in primary NB tumors were identified. The resulting smaller gene set was clinically relevant as it discriminated between high‐ and low‐risk NB patients.