bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toughness and Oblique Metalcutting
Authors: Atkins A. G. 
Published: July 2006

AbstractThe implications of whether new surfaces in cutting are formed just by plastic flow past the tool or by some fracturelike separation process involving significant surface work, are discussed. Oblique metalcutting is investigated using the ideas contained in a new algebraic model for the orthogonal machining of metals (Atkins, A. G., 2003, “Modeling Metalcutting Using Modern Ductile Fracture Mechanics: Quantitative Explanations for Some Longstanding Problems,” Int. J. Mech. Sci., 45, pp. 373–396) in which significant surface work (ductile fracture toughnesses) is incorporated. The model is able to predict explicit material-dependent primary shear plane angles ϕ and provides explanations for a variety of well-known effects in cutting, such as the reduction of ϕ at small uncut chip thicknesses; the quasilinear plots of cutting force versus depth of cut; the existence of a positive force intercept in such plots; why, in the size-effect regime of machining, anomalously high values of yield stress are determined; and why finite element method simulations of cutting have to employ a “separation criterion” at the tool tip. Predictions from the new analysis for oblique cutting (including an investigation of Stabler’s rule for the relation between the chip flow velocity angle ηC and the angle of blade inclination i) compare consistently and favorably with experimental results.
Histological processing variability in the determination of lateral resection margins in rectal cancer
Authors: Eid I , El-Muhtaseb M S , Mukherjee R , Renwick R , Gardiner D S , Macdonald A 
Published: July 2006

Background:Involvement of the lateral resection margin (LRM) has been shown to be a reliable predictor of local recurrence of rectal cancer. Accurate determination of the LRM status is crucial in selecting patients for postoperative radiotherapy. However, variability in processing factors may affect the measurement of the LRM.Aim:To investigate how formalin fixation and laboratory processing affects the measurement of the LRM.Methods:For this study, rectal cancer specimens (n = 9) were fixed in formalin for 4 days and then sectioned transversally, and one half of the specimen was sent for processing. The effacing tumours were placed back in formalin for another 3 days. At day 7, the effacing tumour block (mirror image) was sent for processing. The longest and the shortest perpendicular resection margins for each of the day 4 and day 7 specimens were measured. In a second experiment, control tissue (colon; n = 40), length 10 (0.05) mm, was also processed from a normal sigmoid colon.Specimens were retained in formalin for 24 h (n = 12), 48 h (n = 12), 72 h (n = 9) and 96 h (n = 7). The degree of tissue shrinkage was then recorded. Variations in the recorded LRM and length of colonic tissue are presented as a median (interquartile range) and data were compared using analysis of variance.Results:In the cases of rectal cancer, the variation in measured LRM between day 4 and day 7 specimens was 3.2 (1.5–5) mm. In 30 of the 37 comparisons, the day 7 LRM increased in length, whereas in the remaining 7 it decreased. In the second experiment, control tissue of the original length 10 (0.05) mm increased in length to 10.9 (8.9–13.0) mm, p<0.01.Conclusion:These results suggest that the fixation period/laboratory processes result in measurable differences in the reported LRM. This degree of variation has implications for the reliable reporting of the LRM, predicting local recurrence rates and planning subsequent adjuvant radiotherapy.
Spontaneous renal haemorrhage in the peritoneal cavity
Authors: Abdellaoui A , Al-Daraji W , Natarajan V , Sandilands D 
Published: July 2006

Abstract
A 49 year old woman was admitted to hospital after a sudden onset of severe back pain. Twelve hours later, the haemoglobin had decreased to 5.9 and became unstable. She underwent emergency laparotomy that showed intraperitoneal bleeding, secondary to spontaneous kidney rupture. The patient was given a nephrectomy. Histological examination showed an angiomyolipoma as the cause of the bleeding. To the knowledge of the authors, only five previous cases of spontaneous renal bleeding into the peritoneal cavity have been reported in English literature.
Myeloma associated amyloidosis presenting as subacute liver failure
Authors: Cross T J S , Wendon J A , Quaglia A , Salisbury J R , Heneghan M A , Harrison P M 
Published: July 2006

Abstract
Multiple myeloma related amyloidosis is rare and its presentation with subacute liver failure (SALF) has not been reported. A case is described of a 46 year old woman presenting with a six week history of nausea, abdominal pain, and jaundice. Routine tests failed to establish a cause. Computed tomography showed a small volume liver consistent with SALF. Emergency liver transplantation was not undertaken because of the suspicion of underlying malignancy. At necropsy, liver biopsy showed amyloid deposition and bone marrow biopsy showed multiple myeloma. Thus, amyloidosis should be added to the list of potential causes of SALF.
Insulin-Like Growth Factor-I Receptor Expression Regulates Neuroblastoma Metastasis to Bone
Authors: van Golen Cynthia M. , Schwab Tracy S. , Kim Bhumsoo , Soules Mary E. , Su Oh Sang , Fung Kevin , van Golen Kenneth L. , Feldman Eva L. 
Published: July 2006

Abstract
Neuroblastoma is a pediatric tumor that preferentially metastasizes to bone. Patients with bone metastases have a mortality rate &gt;93%, indicating a need for novel treatment targets. Our laboratory has shown that type I insulin-like growth factor receptor (IGF-IR) expression and activation regulate neuroblastoma cell proliferation, motility, invasion, and survival, and that expression of the IGF-IR correlates with neuroblastoma tumorigenicity. Bone expresses large amounts of IGF ligands, and the IGF system is required for normal bone physiology. The current study addresses the role of the IGF system in neuroblastoma metastasis to bone. Upon reaching the bone marrow through the circulation, neuroblastoma cells must dock at the bone marrow endothelium, extravasate into the bone microenvironment, and destroy bone tissue to allow for tumor growth. This report examines the effects of high IGF-IR expression on neuroblastoma cell interaction with bone. The current data show that neuroblastoma cells with high IGF-IR expression, either endogenously or through transfection, adhere to human bone marrow endothelial cells and subsequently migrate toward both IGF-I and human bone stromal cells. High IGF-IR–expressing neuroblastoma cells adhere tightly to bone stromal cells, flatten, and extend processes. When neuroblastoma cells are injected directly into the tibiae of mice, those cells with increased IGF-IR form both osteolytic lesions within the tibiae and secondary tumors within other sites. These results support the hypothesis that IGF-IR expression in neuroblastoma cells increases tumor cell interaction with the bone microenvironment, resulting in greater formation of metastases.(Cancer Res 2006; 66(13): 6570-8)
DDX3, a DEAD Box RNA Helicase with Tumor Growth–Suppressive Property and Transcriptional Regulation Activity of the p21waf1/cip1 Promoter, Is a Candidate Tumor Suppressor
Authors: Chao Chi-Hong , Chen Chun-Ming , Cheng Pei-Lin , Shih Jing-Wen , Tsou Ann-Ping , Wu Lee Yan-Hwa 
Published: July 2006

Abstract
DDX3 is a DEAD box RNA helicase with diverse biological functions. Using colony formation assay, our results revealed that DDX3 inhibited the colony formation ability of various tumor cells, and this inhibition might be due to a reduced growth rate caused by DDX3. Additionally, we identified p21waf1/cip1, a cyclin-dependent kinase inhibitor, as a target gene of DDX3, and the up-regulation of p21waf1/cip1 expression accounted for the colony-suppressing activity of DDX3. Moreover, DDX3 exerted its transactivation function on p21waf1/cip1 promoter through an ATPase-dependent but helicase-independent mechanism, and the four Sp1 sites located within the −123 to −63 region, relative to the transcription start site of p21waf1/cip1 promoter, were essential for the response to DDX3. Furthermore, DDX3 interacted and cooperated with Sp1 to up-regulate the promoter activity of p21waf1/cip1. To determine the relevance of DDX3 in clinical cancers, the expression profile of DDX3 in various tumors was also examined. A declined expression of DDX3 mRNA and protein was found in ∼58% to 73% of hepatoma specimens, which led to the reduction of p21waf1/cip1 expression in a manner independent of p53 status. Additionally, an alteration of subcellular localization from nuclei to cytoplasm was also observed in &gt;70% of cutaneous squamous cell carcinoma samples. Because DDX3 exhibits tumor suppressor functions, such as a growth-suppressive property and transcriptional activation of the p21waf1/cip1 promoter, and is inactivated through down-regulation of gene expression or alteration of subcellular localization in tumor cells, all these features together suggest that DDX3 might be a candidate tumor suppressor. (Cancer Res 2006; 66(13): 6579-88)
Activation of Mammalian Target of Rapamycin Signaling Pathway Contributes to Tumor Cell Survival in Anaplastic Lymphoma Kinase–Positive Anaplastic Large Cell Lymphoma
Authors: Vega Francisco , Medeiros L. Jeffrey , Leventaki Vasiliki , Atwell Coralyn , Cho-Vega Jeong Hee , Tian Ling , Claret Francois-Xavier , Rassidakis George Z. 
Published: July 2006

Abstract
Anaplastic lymphoma kinase (ALK)–positive anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in aberrant expression of chimeric nucleophosmin-ALK. Previously, nucleophosmin-ALK has been shown to activate phosphatidylinositol 3-kinase (PI3K) and its downstream effector, the serine/threonine kinase AKT. In this study, we hypothesized that the mammalian target of rapamycin (mTOR) pathway, which functions downstream of AKT, mediates the oncogenic effects of activated PI3K/AKT in ALK+ ALCL. Here, we provide evidence that mTOR signaling phosphoproteins, including mTOR, eukaryotic initiation factor 4E–binding protein-1, p70S6K, and ribosomal protein S6, are highly phosphorylated in ALK+ ALCL cell lines and tumors. We also show that AKT activation contributes to mTOR phosphorylation, at least in part, as forced expression of constitutively active AKT by myristoylated AKT adenovirus results in increased phosphorylation of mTOR and its downstream effectors. Conversely, inhibition of AKT expression or activity results in decreased mTOR phosphorylation. In addition, pharmacologic inhibition of PI3K/AKT down-regulates the activation of the mTOR signaling pathway. We also show that inhibition of mTOR with rapamycin, as well as silencing mTOR gene product expression using mTOR-specific small interfering RNA, decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis in ALK+ ALCL cells. Cell cycle arrest was associated with modulation of G1-S-phase regulators, including the cyclin-dependent kinase inhibitors p21waf1 and p27kip1. Apoptosis following inhibition of mTOR expression or function was associated with down-regulation of antiapoptotic proteins, including c-FLIP, MCL-1, and BCL-2. These findings suggest that the mTOR pathway contributes to nucleophosmin-ALK/PI3K/AKT-mediated tumorigenesis and that inhibition of mTOR represents a potential therapeutic strategy in ALK+ ALCL. (Cancer Res 2006; 66(13): 6589-97)
MYC Can Induce DNA Breaks In vivo and In vitro Independent of Reactive Oxygen Species
Authors: Ray Suma , Atkuri Kondala R. , Deb-Basu Debabrita , Adler Adam S. , Chang Howard Y. , Herzenberg Leonore A. , Felsher Dean W. 
Published: July 2006

Abstract
MYC overexpression is thought to initiate tumorigenesis by inducing cellular proliferation and growth and to be restrained from causing tumorigenesis by inducing cell cycle arrest, cellular senescence, and/or apoptosis. Here we show that MYC can induce DNA breaks both in vitro and in vivo independent of increased production of reactive oxygen species (ROS). We provide an insight into the specific circumstances under which MYC generates ROS in vitro and propose a possible mechanism. We found that MYC induces DNA double-strand breaks (DSBs) independent of ROS production in murine lymphocytes in vivo as well as in normal human foreskin fibroblasts (NHFs) in vitro in normal (10%) serum, as measured by γH2AX staining. However, NHFs cultured in vitro in low serum (0.05%) and/or ambient oxygen saturation resulted in ROS-associated oxidative damage and DNA single-strand breaks (SSBs), as measured by Ape-1 staining. In NHFs cultured in low versus normal serum, MYC induced increased expression of CYP2C9, a gene product well known to be associated with ROS production. Specific inhibition of CYP2C9 by small interfering RNA was shown to partially inhibit MYC-induced ROS production. Hence, MYC overexpression can induce ROS and SSBs under some conditions, but generally induces widespread DSBs in vivo and in vitro independent of ROS production. (Cancer Res 2006; 66(13): 6598-605)
Hair Cycle–Dependent Basal Cell Carcinoma Tumorigenesis in Ptc1neo67/+ Mice Exposed to Radiation
Authors: Mancuso Mariateresa , Leonardi Simona , Tanori Mirella , Pasquali Emanuela , Pierdomenico Maria , Rebessi Simonetta , Di Majo Vincenzo , Covelli Vincenzo , Pazzaglia Simonetta , Saran Anna 
Published: July 2006

Abstract
We examined the effects of hair cycle phase on basal cell carcinoma (BCC) tumorigenesis induced by radiation in mice lacking one Patched allele (Ptc1neo67/+). Our results show that Ptc1neo67/+ mouse skin irradiated in early anagen is highly susceptible to tumor induction, as a 3.2-fold incidence of visible BCC-like tumors was observed in anagen-irradiated compared with telogen-irradiated mice. Microscopic nodular BCC-like tumors were also enhanced by irradiation during active hair-follicle growth phases. Interestingly, histologic examination of the tumors revealed a qualitative difference in BCC tumorigenesis depending on hair growth phase at the time of exposure. In fact, in addition to typical BCC-like tumors, we observed development of a distinct basal cell tumor subtype characterized by anti–cytokeratin 14 and anti–smooth muscle actin reactivity. These tumors showed relatively short latency and rapid growth and were strictly dependent on age at irradiation, as they occurred only in mice irradiated in early anagen phase. Examination of anatomic and immunohistochemical relationships revealed a close relation of these tumors with the follicular outer root sheath of anagen skin. In contrast, there are strong indications for the derivation of typical, smooth muscle actin–negative BCC-like tumors from cell progenitors of interfollicular epidermis. These results underscore the role of follicular bulge stem cells and their progeny with high self-renewal capacity in the formation of basal cell tumors and contribute to clarify the relationship between target cell and tumor phenotype in BCC tumorigenesis induced by radiation. (Cancer Res 2006; 66(13): 6606-14)
Genetic Background Controls Tumor Development in Pten-Deficient Mice
Authors: Freeman Dan , Lesche Ralf , Kertesz Nathalie , Wang Shungyou , Li Gang , Gao Jing , Groszer Matthias , Martinez-Diaz Hilda , Rozengurt Nora , Thomas George , Liu Xin , Wu Hong 
Published: July 2006

Abstract
PTEN is one of the most frequently mutated tumor suppressor genes in human cancers. Germ line mutations of PTEN have been detected in three rare autosomal-dominant disorders. However, identical mutations in the PTEN gene may lead to different symptoms that have traditionally been described as different disorders, such as Cowden disease, Lhermitte-Duclos disease, and Bannayan-Zonana syndromes. This lack of genotype-phenotype correlation prompted us to directly test the possible effects of genetic background or modifier genes on PTEN-controlled tumorigenesis using genetically engineered mouse models. In this study, we generated two animal models in which either exon 5 (PtenΔ5) or promoter to exon 3 (Pten−) of the murine Pten gene were deleted and compared phenotypes associated with individual mutations on two genetic backgrounds. We found that the onset and spectrum of tumor formation depend significantly on the genetic background but less on the type of mutation generated. Our results suggest that PTEN plays a critical role in cancer development, and genetic background may influence the onset, the spectrum, and the progression of tumorigenesis caused by Pten mutation. (Cancer Res 2006; 66(13): 6492-6)
TP53 and KRAS2 Mutations in Plasma DNA of Healthy Subjects and Subsequent Cancer Occurrence: A Prospective Study
Authors: Gormally Emmanuelle , Vineis Paolo , Matullo Giuseppe , Veglia Fabrizio , Caboux Elodie , Le Roux Emilie , Peluso Marco , Garte Seymour , Guarrera Simonetta , Munnia Armelle , Airoldi Luisa , Autrup Herman , Malaveille Christian , Dunning Alison , Overvad Kim , Tjønneland Anne , Lund Eiliv , Clavel-Chapelon Françoise , Boeing Heiner , Trichopoulou Antonia , Palli Domenico , Krogh Vittorio , Tumino Rosario , Panico Salvatore , Bueno-de-Mesquita H. Bas , Peeters Petra H. , Pera Guillem , Martinez Carmen , Dorronsoro Miren , Barricarte Aurelio , Navarro Carmen , Quirós José Ramón , Hallmans Göran , Day Nicholas E. , Key Timothy J. , Saracci Rodolfo , Kaaks Rudolf , Riboli Elio , Hainaut Pierre 
Published: July 2006

Abstract
In cancer patients, plasma often contains mutant DNA released by cancer cells. We have assessed the significance of plasma DNA mutations for subsequent cancer development in healthy subjects in a large longitudinal prospective study. The European Prospective Investigation into Cancer and Nutrition study was analyzed with a nested case-control design. Cases were nonsmokers or ex-smokers for &gt;10 years and newly diagnosed with lung, bladder, or upper aerodigestive tract cancers or leukemia accrued after a median follow-up of 6.3 years. Controls were matched 2:1 for follow-up, age, sex, area of recruitment, and smoking status. KRAS2 mutations were detected by mutant-enriched PCR and sequencing (n = 1,098). TP53 mutations were detected by denaturing high-performance liquid chromatography, temporal temperature gradient electrophoresis, and sequencing (n = 550). KRAS2 or TP53 mutations were detected in 13 of 1,098 (1.2%) and 20 of 550 (3.6%) subjects, respectively, 16 of whom developed cancer on average after 18.3 months of follow-up. Among 137 subjects who developed bladder cancer, 5 had KRAS2 mutations [odds ratio (OR), 4.25; 95% confidence interval (95% CI), 1.27-14.15] and 7 had TP53 mutations (OR, 1.81; 95% CI, 0.66-4.97). There was a nonsignificant trend for association between TP53 mutations and bulky adducts in lymphocyte DNA (OR, 2.78; 95% CI, 0.64-12.17). This is the first report of TP53 or KRAS2 mutations in the plasma of healthy subjects in a prospective study, suggesting that KRAS2 mutation is detectable ahead of bladder cancer diagnosis. TP53 mutation may be associated with environmental exposures. These observations have implications for monitoring early steps of carcinogenesis. (Cancer Res 2006; 66(13): 6871-6)
Coexpression of NRASQ61R and BRAFV600E in Human Melanoma Cells Activates Senescence and Increases Susceptibility to Cell-Mediated Cytotoxicity
Authors: Petti Carlotta , Molla Alessandra , Vegetti Claudia , Ferrone Soldano , Anichini Andrea , Sensi Marialuisa 
Published: July 2006

AbstractActivating mutations in BRAF and NRAS oncogenes in human melanomas are mutually exclusive. This finding has suggested an epistatic relationship but is consistent even with synthetic lethality. To evaluate the latter possibility, a mutated NRASQ61R oncogene was expressed, under a constitutive or a doxycycline-regulated promoter, in a metastatic melanoma clone (clone 21) harboring an activated BRAFV600E oncogene. After the first 10 to 12 in vitro passages, the constitutive NRASQ61R transfectant displayed progressive accumulation in G0-G1 phase of the cell cycle and stained for the senescence-associated β-galactosidase activity (SA-β-Gal). Inducible expression of NRASQ61R, by the Tet-Off system, in clone 21 cells (21NRAS61ON) led to overactivation of the RAS/RAF/mitogen-activated protein kinase signaling pathway and, after the 10th in vitro passage, led to promotion of senescence. This was documented by reduced proliferation, flattened cell morphology, reduced growth in Matrigel, positive staining for SA-β-Gal, and expression of AMP-activated protein kinase and of the cell cycle inhibitor p21waf1/Cip1. These effects were detected neither in 21 cells with silenced NRASQ61R (21NRAS61OFF) nor in cells transfected with an inducible wild-type NRAS gene (21NRASWTON). In addition, when compared with parental 21 cells, or with 21NRAS61OFF, 21NRAS61ON and constitutive NRASQ61R transfectants cells showed increased susceptibility to cytotoxicity by both HLA class I antigen–restricted and nonspecific T cells and up-regulation of several MHC class I antigen processing machinery components. These results suggest a relationship of synthetic lethality between NRAS and BRAF oncogenes, leading to selection against “double-mutant” cells. (Cancer Res 2006; 66(13): 6503-11)
GM2 Expression in Renal Cell Carcinoma: Potential Role in Tumor-Induced T-Cell Dysfunction
Authors: Biswas Kaushik , Richmond Amy , Rayman Patricia , Biswas Soumika , Thornton Mark , Sa Gaurisankar , Das Tanya , Zhang Renliang , Chahlavi Ali , Tannenbaum Charles S. , Novick Andrew , Bukowski Ronald , Finke James H. 
Published: July 2006

AbstractMultiple mechanisms have been proposed to account for immune escape by tumors. Although gangliosides have long been known to suppress T-cell immunity, few studies have examined the effect of human tumor-derived gangliosides on immune responses. Here, we show that gangliosides isolated from renal cell carcinoma (RCC) cell lines and clear cell tumor tissue can induce apoptosis in peripheral blood T cells. The RCC tissue-derived gangliosides also suppressed IFN-γ and, in many cases, interleukin-4 production by CD4+ T cells at concentrations (1 ng/mL-100 pg/mL) well below those that induce any detectable T-cell death (4-20 μg/mL). Additional findings show that GM2 expressed by RCC plays a significant role in promoting T-cell dysfunction. This is supported by the demonstration that all RCC cell lines examined (n = 5) expressed GM2 as did the majority of tumors (15 of 18) derived from patients with clear cell RCC. Furthermore, an antibody specific for GM2 (DMF10.167.4) partially blocked (50-60%) T-cell apoptosis induced by coculturing lymphocytes with RCC cell lines or with RCC tissue-derived gangliosides. DMF10.167.4 also partially blocked the suppression of IFN-γ production induced by RCC tissue-derived gangliosides, suggesting that GM2 plays a role in down-regulating cytokine production by CD4+ T cells. (Cancer Res 2006; 66(13): 6816-25)