bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loh and mutation analysis of CDKN2 in primary human ovarian cancers
Authors: Campbell Ian G. , Beynon Gareth , Davis Michael , Englefield Pat 
Published: February 2007

AbstractThe CDKN2 gene encodes a cell cycle regulatory protein and is located on chromosome 9p21, a region deleted in a wide variety of primary tumours. While mutations in the CDKN2 gene itself are frequently observed in tumour cell lines, they are less common in primary tumours. We have investigated the role of the CDKN2 gene in ovarian cancer by analysis for allelic loss of 9p21 and single‐strand conformational polymorphism analysis of exons 1 and 2 of CDKN2 in 67 primary ovarian tumours. Loss of heterozygosity on 9p21 was frequently observed (24/50 informative tumours) and was common in early‐stage tumours, suggesting that it is an early event in ovarian tumorigenesis. Homozygous deletion of the CDKN2 gene was detected in only 1 tumour. No somatic or germline mutations were observed in CDKN2, though a codon 140 polymorphism was detected in 2 cases. This suggests that CDKN2 is not involved in ovarian tumorigenesis and that another gene(s) may be the target of the frequent 9p allelic losses observed.
CDKN2 in HPV‐positive and HPV‐negative cervical‐carcinoma cell lines
Authors: Kelley Michael J. , Otterson Gregory A. , Kaye Frederic J. , Popescu Nicholas C. , Johnson Bruce E. , Dipaolo Joseph A. 
Published: February 2007

AbstractHuman cervical cancers frequently contain retinoblastoma protein (Rb) that is inactivated by binding with human papilloma virus (HPV) E7 protein or through mutation. The CDKN2 gene encodes p 16INK4 which inhibits cdk4‐cyclin D phosphorylation of Rb, preventing the G1‐S transition. To determine whether abnormalities of CDKN2 occur in cervical‐cancer cells, 11 cervical cell lines, including 8 HPV‐positive cell lines, 2 HPV‐negative cell lines containing mutant Rb, and one tumorigenic cell line derived from normal cervical cells following transfection with HPV‐16 and v‐H‐ras (CX16‐2HR), were analyzed. No cell line had a homozygous deletion of exon 1 or 2 of CDKN2, and only one cell line, CX16‐2HR, had an altered DNA sequence, which represents a common polymorphism at codon 148. To exclude the possibility of other subtle inactivating mutations, immunoblot analysis of protein lysates was performed using a polyclonal anti‐p 16INK4 rabbit anti‐serum. Abundant levels of normal‐sized pl6INK4 were observed in all cell samples. Thus, no alterations of CDKN2 were detected in these cervical cell lines. These results confirm that mutational inactivation of p 16INK4 is a rare event in tumor samples with compromised Rb activity.
Development of new ricin A‐chain immunotoxins with potent anti‐tumor effects against human hodgkin cells in vitro and disseminated Hodgkin tumors in scid mice using high‐affinity monoclonal antibodies directed against the CD30 antigen
Authors: Schneix Roland , Linnartz Christoph , Katouzi Ali A. , Schon Gisela , Bohlen Heribert , Horn‐Lohrens Ottmar , Parwaresch Reza M. , Lange Hans , Diehl Volker , Lemke Hilmar , Engert Andreas 
Published: February 2007

AbstractThe lymphocyte activation marker CD30 has been shown to be an excellent target for the immunotherapy of human Hodgkin's lymphoma. In order to develop new potent immunotoxins (ITs) against CD30, we chemically linked 6 recently described monoclonal antibodies (MAbs) via SMPT to deglycosylated ricin A‐chain (dgA). Cross‐blocking experiments demonstrated that these MAbs, termed Ki‐2 to Ki‐7, recognize 3 different clusters on the CD30 antigen: Ki‐2, Ki‐4, Ki‐5 and Ki‐7 recognize cluster A; Ki‐6 recognizes cluster B; Ki‐3 binds to cluster C. Staining of 29 sections of normal human organs revealed no major cross‐reactivity of any MAbs tested. Binding to the CD30 antigen on LS40Cy Hodgkin cells was assessed by flow cytometry, and demonstrated high affinities for Ki‐2, Ki‐3 and Ki‐4. The concentration giving 50% of the mean fluorescence intensity (MFI50) was 0.58 μg/ml to 0.78 μg/ml. MAbs Ki‐5, Ki‐6, and Ki‐7 bound much more weakly. The staining intensity of the MAbs correlated with the cytotoxicity of the corresponding ITs. Ki‐2.dgA, Ki‐3.dgA and Ki‐4.dgA inhibited the protein synthesis of L540Cy cells by 50% at concentrations (IC50) of 3.5 × 10−l0 M to 4.0 × 10−11 M. The most effective IT, Ki‐4.dgA, is 5‐fold more potent than previously reported CD30 ricin A‐chain ITs. Ki‐4.dgA was subsequently used for the treatment of disseminated human Hodgkin's lymphoma in a SCID mouse model. The mean survival time (MST) of lymphoma‐bearing SCID mice was extended from 42 days in untreated controls to more than 132 days when Ki‐4.dgA was applied one day after tumor challenge. Ki‐4.dgA is a new potent IT suitable for further evaluation against Hodgkin's lymphoma in man.
Endogenous D‐factor activity partially mediates the toxic but not the therapeutic effects of tumor necrosis factor
Authors: Block Mark I. , Fraker Douglas L. , Strassmann Gideon , Billingsley Kevin G. , Arnold W. Scott , Perlis Cliff , Alexander H. Richard 
Published: February 2007

AbstractWe have earlier shown that passive immunization against differentiation‐inducing factor/leukemia‐inhibitory factor (D factor) activity improves the survival of endotoxemic mice, suggesting that D factor may contribute to the systemic toxicity associated with tumor necrosis factor (TNF). In the current experiments, TNF induced D‐factor gene expression in various tissues of non‐tumor‐bearing female C57B1/6 mice. Passive immunization against D‐factor significantly improved survival after a lethal TNF challenge in both non‐tumor‐bearing (p2 < 0.02) and tumor‐bearing mice (p2 < 0.01). In mice bearing 10‐days.c. MCA 105 sarcomas, D‐factor antibody alone had no effect on tumor growth as compared with control IgG. Tumor regression and regrowth in mice treated i.v. with TNF was not affected by pre‐treatment with D‐factor antibody, as compared with pre‐treatment with IgG. However, TNF‐treatment‐related mortality was abrogated by pre‐treatment with D‐factor antibody (0% vs. 36% for IgG‐pre‐treated controls). These results indicate that endogenous D‐factor activity contributes to the toxicity but not to the anti‐tumor effects of TNF therapy. With renewed interest in the use of TNF for the treatment of patients with cancer, improved understanding of the role of D factor in mediating the effects of TNF may have important clinical benefits.
Cell‐cycle‐dependent invasion in vitro by rat ascites hepatoma cells
Authors: Iwasaki Teruo , Shinkai Kiyoko , Mukai Mutsuko , Yoshioka Kiyoko , Fujii Yoshitaka , Nakahara Kazuya , Matsuda Hikaru , Akedo Hitoshi 
Published: February 2007

AbstractThe relationship between cell cycle and experimental metastasis of tumor cells in vivo has been investigated, but it remains to be elucidated which step of metastasis, or whether tumor‐cell invasion in particular, depends on cell cycle. We previously reported an in vitro cell‐monolayer invasion (transcellular migration) assay system, in which the invasive capacity of tumor cells is measured by counting tumor cells penetrating beneath a cultured mesothelial cell monolayer after tumor‐cell seeding. Using our invasion assay system, the relationship between invasive capacity and cell‐cycle distribution of MMI cells, a highly invasive clone of rat ascites hepatoma AH130, was investigated. Invasive capacity of aphidicolin‐ or hydroxyurea‐synchronized tumor cells enriched in G1/S—early S‐phase cells was about 2 to 6 times higher than that of asynchronous cells. According to time‐course experiments to examine the relationship between invasive capacity and the size of fraction of cells in each phase after release from an aphidicolin or a nocodazole block, it was suggested that MMI cells are most invasive in G1/S‐S phase. Phagokinetic assay using colloidal gold particles showed that one possible reason for the enhanced invasiveness might be the increased cell motility in such phases, as suggested by the in vitro invasion assay.
Cocktails of ricin a‐chain immunotoxins against different antigens on hodgkin and sternberg‐reed cells have superior anti‐tumor effects against H‐RS cells in vitro and solid Hodgkin tumors in mice
Authors: Engert Andreas , Gottstein Claudia , Bohlen Heribert , Winkler Ute , Schön Gisela , Manske Oliver , Schnell Roland , Diehl Volker , Thorpe Philip 
Published: February 2007

AbstractThree ricin A‐chain immunotoxins (ITs) recognizing different antigens on Hodgkin‐Reed/Sternberg (H‐RS) cells were evaluated for their anti‐tumor effects when used in combination as “cocktails”. These ITs, BB10.dgA (CD2S), HRS3.dgA (CD30), and IRac.dgA (70 kDa), strongly inhibited the growth of L540Cy H‐RS cells in vitro. The protein synthesis of this cell line was reduced more efficiently by the combination of 2 of these ITs than by BB10.dgA, HRS3.dgA or IRac.dgA alone. A cocktail of all 3 ITs was most effective in vitro. This was at least in part due to the non‐homogeneous distribution of CD25, CD30 or IRac on the L540Cy H‐RS target cells and to the fact that sub‐populations deficient in one antigen nevertheless expressed appreciable levels of the other target antigens. IT cocktails were also superior as anti‐tumor agents in nude mice with solid L540Cy tumors. Ninety percent of mice treated with cocktails containing 2 or 3 ITs had continuous complete remissions (CCR), as compared with only 40% of mice treated with the same dose of a single IT. Analysis of 7 L540Cy sub‐lines re‐established ex vivo from mice that relapsed after having achieved complete remission (CR) after therapy with a single IT showed that the surviving tumor cells were antigen‐deficient variants which were resistant to the original IT, but which could be killed by ITs directed against other target antigens. Thus, IT cocktails give superior results against human H‐RS cells, both in vitro and in vivo.
Lung carcinoma and malignant mesothelioma in patients exposed to thorotrast: Incidence, histology and p53 status
Authors: Andersson Michael , Wallin Håkan , Jönsson Marzieh , Nielsen Lise L. , Visfeldt Jakob , Vyberg Mogens , Bennett William P. , De Benedetti Virna M. G. , Travis Lois B. , Storm Hans H. 
Published: February 2007

AbstractIn a previous registry‐based survey of 999 patients injected with α‐emitting 232ThO2 (Thorotrast), we identified elevated risks for lung carcinoma and malignant mesothelioma. Since injected Thorotrast is retained lifelong mostly in liver, spleen and lymph nodes, the mesothelial surfaces of these organs are constantly irradiated. Thorotrast‐administered patients also perpetually exhale 220Rn, a 232Th‐daughter. Study of Thorotrast‐exposed patients may, therefore, provide data with regard to carcinogenicity of radon exposure, a current public health concern, as well as the pathogenesis of malignant mesothelioma. The incidence and histologic types of lung carcinoma and malignant mesothelioma within the cohort were examined by review of available histopathologic material and medical records. Further, mutations of the p53 gene were analyzed whenever possible as it has previously been suggested that radon‐associated lung carcinomas exhibit specific mutational patterns. The cumulative risk for lung carcinoma reached 11.0% based on 20 confirmed cases. Nine were small cell lung cancer (SCLC), whereas the expected frequency was 18%. The risk for malignant mesothelioma reached 2.5% based on 7 cases. The actuarial risk of malignant mesothelioma for patients given more than 20 ml Thorotrast was 7.8% compared to 1.4% for patients administered smaller amounts. Seven lung carcinomas and 5 malignant mesotheliomas were analyzed for p53 mutations; only 1 (in a lung adenocarcinoma) was detected. A possible association between Thorotrast and SCLC is suggested. In addition, a possible dose‐response gradient exists for Thorotrast and malignant mesothelioma.
No preferential loss of one parental allele of chromosome 17p13.3 in childhood medulloblastoma
Authors: Scheurlen Wolfram G. , Krauss Jürgen , Kühl Joachim 
Published: February 2007

AbstractMedulloblastomas are the most frequent malignant tumors of the central nervous system in childhood. Loss of heterozygosity of the telomeric part of chromosome 17p has been described frequently in these tumors, suggesting a possible second tumor‐suppressor gene in this region apart from the p53 gene. Using restriction‐fragment‐length polymorphism and microsatellite polymorphism analysis, we screened 16 medulloblastomas for 17p 13.3 deletions and compared the DNA patterns of patients' tumors and normal tissues with those of one or both parents. Loss of heterozygosity of chromosome 17p 13.3 could be detected in 6 out of 16 tumors (37.5%). In 4 of these 6 tumors the maternal allele was deleted, in 2 tumors the paternal allele. Although the number of tumors investigated is limited, we find no evidence that genomic imprinting of the chromosomal region most frequently deleted in medulloblastoma plays a role in tumorigenesis.
Expression of MAGE genes in primary and metastatic cutaneous melanoma
Authors: Brasseur Francis , Rimoldi Donata , Liénard Danielle , Lethé Bernard , Carrel Stefan , Arienti Flavio , Suter Ludwig , Vanwijck Romain , Bourlond André , Humblet Yves , Vacca Angelo , Conese Marina , Lahaye Thierry , Degiovanni Gérard , Deraemaecker Rika , Beauduin Marc , Sastre Xavier , Salamon Emile , Dréno Brigitte , Jäger Elke , Knuth Alex , Chevreau Christine , Suciu Stefan , Lachapelle Jean‐Marie , Pouillart Pierre , Parmiani Giorgio , Lejeune Ferdy , Cerottini Jean‐Charles , Boon Thierry , Marchand Marie 
Published: February 2007

AbstractHuman genes MAGE‐1 and MAGE‐3 code for antigens that are recognized on melanoma cells by autologous cytolytic T lymphocytes. These antigens may constitute useful targets for specific anti‐tumor immunization of cancer patients, since genes MAGE‐1 and MAGE‐3 are expressed in a number of tumors of different histological types, but are not expressed in normal adult tissues other than testis. This also applies to genes MAGE‐2 and MAGE‐4, which are closely related to MAGE‐1 and MAGE‐2. We have analyzed the expression of these 4 MAGE genes in cutaneous melanoma. Sixteen of 100 primary tumors vs. 69 (48%) of 145 metastases from individual patients expressed MAGE‐1. Similar differences in the frequency of gene expression between primary and metastatic tumor samples were observed for MAGE‐2, MAGE‐2, and MAGE‐4.MAGE expression in primary tumors was correlated with tumor thickness: there was a significantly increased frequency in the expression of MAGE‐1, ‐2 and ‐3 in tumors of greater thickness. Benign and dysplastic nevi, as well as in situ melanomas, did not express any of the 4 MAGE genes.
Radioimmunotherapy of prostatic adenocarcinomas: Effects of 131I‐labelled E4 antibodies on cells at different depth in DU 145 spheroids
Authors: Essand Magnus , Grönvik Christina , Hartman Torbjörn , Carlsson Jörgen 
Published: February 2007

AbstractSpheroids of the human prostatic adenocarcinoma cell line DU 145 were used to study experimental radioimmunotherapy. Spheroids were incubated with the 131l‐labelled monoclonal E4 antibody until the radionuclide immunoconjugate had bound the 5 to 6 outermost cell layers of the spheroids. A set of 50 spheroids were exposed, either immediately or 48 hr after antibody incubation and washings, to a dilute trypsin solution with the aim of stripping off cells from the spheroid surface. Stripped cells were collected in fractions corresponding to defined spherical shells. Cells were subsequently plated for clonogenic growth. The technique of automated sequential trypsinization of spheroids followed by a clonogenic survival assay permits studies on therapeutic efficacy for radionuclide immunoconjugates on cells from different layers of spheroids. In addition, the absorbed doses throughout a spheroid were calculated. The binding and retention kinetics of the radionuclide immunoconjugate and the excess of 131l‐E4 in the culture medium during incubation are factors that were all accounted for in the calculations. If the calculated absorbed doses were inserted into the linear‐quadratic survival model and the low dose rate was taken into account, survival values were well in accordance with the experimentally obtained values. The results demonstrate that the 131I‐labelled E4 antibody is capable of sterilizing cultured tumour cells that have bound the radionuclide immunoconjugate and, by means of radiation “cross‐fire”, those cells located in close proximity.
c‐jun expression and growth stimulation in human ovarian carcinoma cell lines following exposure to cytokines
Authors: Spinner Daniel M. , Brandstetter Thomas , Kiechle‐Schwarz Marion , Du Bois Andreas , Angel Peter , Bauknecht Thomas 
Published: February 2007

AbstractWe evaluated the effects of recombinant human G‐CSF, rhGM‐CSF, rhM‐CSF and rhIL‐1α on proliferation and regulation of c‐jun gene expression in 4 human ovarian‐carcinoma (HOC) cell lines, NIH:OVCAR‐3, SK‐OV‐3, HEY and BG‐I, and in one primary ovarian tumor in vitro. The cytokines were administered in concentrations of 0.1 U/ml to 1000 U/ml. Cell growth was measured by crystal‐violet‐ and thiazolyl‐blue(MTT)‐based cell counts, c‐jun transcripts were measured by the solution hybridization/RNAse protection assay. RhM‐CSF and rhGM‐CSF showed no growth stimulation of any of the 5 cell lines tested. Results from exposure to rhG‐CSF were different. The cell lines NIH:OVCAR‐3, SK‐OV‐3, BG‐I and the primary ovarian tumor showed no proliferative response. A 2‐ to 3‐fold increase in proliferation was observed in the HEY HOC cell line. rhIL‐lα led to growth stimulation in the BG‐I cell line, but showed an inhibitory effect in the NIH:OVCAR‐3 cells. No effects of rhIL‐1α were observed in the remaining 2 cell lines nor in the primary ovarian tumor. Growth stimulation was accompanied by an increase in c‐jun expression in the HEY cell line, and the BG‐I cell line. No alterations in c‐jun expression were observed in the remaining 3 cell lines. Our results indicate that rhG‐CSF or rhIL‐1α influence cell proliferation in 2 out of 5 human ovarian‐tumor cell lines, accompanied by an increase in c‐jun expression.
Effects of organic and inorganic selenium compounds on rat mammary tumor cells
Authors: Ronai Ze'Ev , Tillotson Joanne K. , Traganos Frank , Darzynkiewicz Z. , Conaway C. Clifford , Upadhyaya Parmod , El‐Bayoumy Karam 
Published: February 2007

AbstractTo explore cellular effects of potent organoselenium chemo‐preventive agents we have used a rat mammary tumor cell line. We demonstrate that 1,4‐phenylenebis(methylene) selenocyanate (p‐XSC) at a dose of 5 μM is a more potent inhibitor of DNA, RNA and protein synthesis as well as of mitochondrial transmembrane potential than its chemopreventive counterparts benzyl selenocyanate (BSC) and sodium selenite. These differences were also reflected in reduced growth rate by 24 and 48 hr. Cell‐cycle and cell‐morphology analysis revealed that higher doses of p‐XSC (10 μM) caused DNA fragmentation which was accompanied with partial loss of nuclear stainability, whereas BSC caused a noticeable change in cell‐cycle distribution and extensive micronucleation. Overall, our results point to cellular targets of selenium compounds which may mediate their chemopreventive activities in mammary tissues.
Multiple APC messenger RNA isoforms encoding exon 15 short open reading frames are expressed in the context of a novel exon 10A‐derived sequence
Authors: Sulekova Zora , Reina‐Sanchez Julio , Ballhausen Wolfgang G. 
Published: February 2007

AbstractIntragenic splice mechanisms affecting the coding exons 8 to 15 of the human adenomatous polyposis coli (APC) gene have been analyzed. Three mechanisms within this gene area were found to contribute to mRNA heterogeneity: (i) facultative expression of exon 9‐encoded sequences; (ii) in‐frame insertion of a 54‐nucleotide sequence encoded by a novel exon located 1.6 kb down‐stream from exon 10, provisionally designated APC exon 10A; (iii) skipping of exon 14, resulting in a novel exon 13/15 connection. Interestingly the latter event provided the mRNA with a novel open reading frame, which was terminated after 19 codons of exon 15‐derived sequences. Combinatorial joining of these segments yielded 7 different transcripts in addition to an mRNA species resulting from an exon 10/15 connection, as determined by cloning and sequence analysis. RT‐PCR expression analyses were carried out to demonstrate that this complexity of splice variants is indeed synthesized in cell lines derived from various tissues. Furthermore, in accordance with our findings at the transcript level, we provide Western blot analyses demonstrating that moderate steady‐state levels of genuine APC‐specific low m.w. polypeptide chains exist. These APC “light chains”, however, are not identical with polypeptide chains, which have been reported to accompany apoptosis and necrosis, since the molecules described here are definitively co‐expressed with p300apc at the transcript and protein levels.
Toombak dipping and cancer of the oral cavity in the Sudan: A case‐control study
Authors: Idris A. M. , Ahmed H. M. , Malik M. O. A. 
Published: February 2007

AbstractTo investigate the possible causal association between squamous‐cell carcinomas of the oral cavity and use of toombak, we retrospectively compared the history of use of this substance in 375 patients with squamous‐cell carcinomas of the lip, buccal cavity and floor of mouth, and 271 patients with squamous carcinomas of the tongue, palate and maxillary sinus, with 204 patients exhibiting non‐squamous oral and non‐oral malignant neoplasms and 2,820 individuals who had no malignancy, selected from the general population. The study revealed that the high prevalence of oral cancer in the Sudan is largely due to chronic use of toombak. The adjusted ORs associated with toombak dipping for the first case group, cancer of the lip, buccal cavity and floor of mouth in comparison with the hospital and population control groups, were 7.3 and 3.9 (95% confidence limits, 4.3–12.4 and 2.9–5.3) respectively and among long‐term users the adjusted ORs were 11.0 and 4.3 (95% confidence limits, 4.8–25.1 and 2.9–6.3) respectively. The elevated risk found when investigating intra‐oral cancers of sites in direct contact with toombak quid compared to those with little or no contact, confirms the hypothesis that direct contact with tissues is an important factor in tobacco carcinogenesis in the mouth. The increased risk associated with the use of toombak is of particular concern in view of its wide consumption in the Sudan.
Dietary fiber and risk of benign proliferative epithelial disorders of the breast
Authors: Baghurst Peter A. , Rohan Thomas E. 
Published: February 2007

AbstractFollowing a recent finding, from a case‐control study in Adelaide, South Australia, of a reduced risk of breast cancer among women consuming diets rich in fiber, the fiber densities in the diets of 354 women with incident benign proliferative epithelial disorders of the breast (BPED) were compared with the fiber densities of the diets of 354 matched community controls and with those of 189 unmatched controls having breast conditions for which there was no evidence of BPED at biopsy. Fiber intakes were estimated by means of a self‐administered quantitative food‐frequency questionnaire, and the risk of BPED was estimated for each quintile of fiber density (grams of fiber/megajoule of total energy intake) relative to an arbitrarily assigned risk of one for the lowest quintile. For women with the highest dietary fiber densities the estimated risk was 0.64 (95% Cl 0.34, 1.19) when cases were compared with community controls, and 0.45 (95% Cl 0.24, 0.82) when cases were compared with biopsy‐negative controls. Similar trends in risk were observed for the intakes of other major fiber components, the association being stronger when the comparison was made with biopsy‐negative as opposed to community controls. If these findings can be substantiated, they may open the way to dietary intervention strategies for reducing the incidence of breast cancer.