bluuebunny/crossref_metadata_2025 huggingface dataset:
Alanine aminotransferase isoenzymes: Molecular cloning and quantitative analysis of tissue expression in rats and serum elevation in liver toxicity #
Authors: Yang Rong-Ze , Park Soohyun , Reagan William J. , Goldstein Rick , Zhong Shao , Lawton Michael , Rajamohan Francis , Qian Kun , Liu Li , Gong Da-Wei
Published: September 2008

The elevation of serum alanine aminotransferase (ALT) is regarded as an indicator of liver damage based on the presumption that ALT protein is specifically and abundantly expressed in the liver. However, ALT elevation is also observed in non–liver injury conditions (for example, muscle injury) and in apparently healthy people. Conversely, serum ALT activity is normal in many patients with confirmed liver diseases (for example, cirrhosis and hepatitis C infection). To improve the diagnostic value of the ALT assay and to understand the molecular basis for serum ALT changes in various pathophysiological conditions, we have cloned rat ALT isoenzyme ALT1 and ALT2 complementary DNAs (cDNAs), examined their tissue expressions at the messenger RNA and protein levels, and determined ALT1 and ALT 2 serum levels in response to liver damage in rodents. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis shows that ALT1 messenger RNA is widely distributed and mainly expressed in intestine, liver, fat tissues, colon, muscle, and heart, in the order of high to low expression level, whereas ALT2 gene expression is more restricted, mainly in liver, muscle, brain, and white adipose tissue. The tissue distribution pattern of ALT1 and ALT2 proteins largely agrees with their messenger RNA expression. Interestingly, hepatic ALT2 protein is approximately four times higher in male rats than in female rats. In addition, ALT isoenzymes distribute differentially at the subcellular level in that ALT1 is a cytoplasmic protein and ALT2 a mitochondrial protein, supporting bioinformatic prediction of mitochondrial localization of ALT2. Conclusion: Using animal models of hepatoxicity induced by carbon tetrachloride and acetaminophen, we found that both serum ALT1 and ALT2 protein levels were significantly elevated and correlated with ALT activity, providing, for the first time, the molecular basis for the elevated total serum ALT activity. (Hepatology 2008.)
γ‐Cyclodextrin as Inhibitor of the Precipitation Reaction between Berberine and Glycyrrhizin in Decoctions of Natural Medicines: Interaction Studies of Cyclodextrins with Glycyrrhizin and Glycyrrhetic Acid by 1H‐NMR Spectroscopy and Molecular‐Dynamics Calculation
Authors: Kamigauchi Miyoko , Kawanishi Kazuko , Sugiura Makiko , Ohishi Hirofumi , Ishida Toshimasa
Published: September 2008

To prevent the precipitation reaction between glycyrrhizin (1) and berberine (3) in the decoctions of Glycyrrhiza/Coptis rhizome or Glycyrrhiza/Phellodendron bark, the presence of cyclodextrin (CD) in the mixture was proven to be effective. The preventing effect decreased in the order γ‐CD>β‐CD, and no effect was observed for α‐CD. On the other hand, the extraction degree of 1 from the natural medicine Glycyrrhia was considerably increased in the presence of γ‐CD, γ‐CD being much more effective than α‐ or β‐CD. Thus, the blocking effect of CD on the precipitate formation between 1 and 3 is suggested to be primarily dependent on the stability of the inclusion complex of the CD with 1. To establish the structure of such a preferred inclusion complex, the interactions of 1 with β‐ and γ‐CDs were investigated by 1H‐NMR spectroscopy and molecular‐dynamics (MD) calculations. The 1H‐NMR measurements showed that the increase in solubility of 1 in H2O is dependent on the degree of its inclusion into the CD, which depends on the molecular size of the CD. The MD calculations suggested that the H‐bond interactions are sufficiently strong to form a stable [1/γ‐CD] complex, in which the lipophilic rings C, D, and E of 1 are fully inserted into the molecular cavity of γ‐CD, thus forming a kind of structure covered by a hydrophilic molecular capsule, while such an interaction mode is impossible for α‐ or β‐CD.
Triterpene Saponins from the Leaves of Ilex pernyi
Authors: Xie Guang‐Bo , Zheng Jiao , Tu Peng‐Fei , Liu Guo‐Qing
Published: September 2008

Eight new triterpene saponins, ilexpernosides C–J (1–8, resp.), and eight known triterpene saponins were isolated from the 70% EtOH extract of the leaves of Ilex pernyi. The structures of the new compounds were elucidated by spectroscopic data and chemical degradation.
Synthesis and Structures of Two Isomeric 4‐Diazo‐2,3,4,5‐tetrahydrofuran‐3‐ones
Authors: Malashikhin Sergey A. , Linden Anthony , Heimgartner Heinz , Rodina Ludmila L. , Nikolaev Valerij A.
Published: September 2008

The two regioisomeric 4‐diazo‐2,3,4,5‐tetrahydrofuran‐3‐ones 6 and 7 were prepared via the common intermediate 2,3,4,5‐tetrahydro‐2,2‐dimethyl‐5,5‐diphenylfuran‐3‐one (8). Diazo transfer with 2,4,6‐triisopropylbenzenesulfonyl azide yielded 6, whereas 7 was obtained via oxidation of the monohydrazone 12, which was prepared selectively from tetrahydrofuran‐3,4‐dione 11. The crystal structures of 6 and 7 have been established by X‐ray crystallography.
Oligonucleotide Analogues with Integrated Bases and Backbone
Authors: Ritter Anne , Bernet Bruno , Vasella Andrea
Published: September 2008

The thiomethylene‐linked U*[s]U(*) dimers 9–14 were synthesized by substitution of the 6‐[(mesyloxy)methyl]uridine 6 by the thiolate derived from the uridine‐5′‐thioacetates 7 and 8 followed by O‐deprotection. Similarly, the thiomethylene‐linked A*[s]A(*) dimers 9–14 were obtained from the 8‐(bromomethyl)adenosine 15 and the adenosine‐5′‐thioacetates 16 and 17. The concentration dependence of both HN(3) of the U*[s]U(*) dimers 9–14 evidences the formation of linear and cyclic duplexes, and of linear higher associates, C(8 or 6)CH2OH and/or C(5′/II)OH groups favouring the formation of cyclic duplexes. The concentration dependence of the chemical shift for both H2NC(6) of the A*[s]A(*) dimers 18–23 evidences the formation of mainly linear associates. The heteroassociation of U*[s]U(*) to A*[s]A(*) dimers is stronger than the homoassociation of U*[s]U(*) dimers, as evidenced by diluting equimolar mixtures of 11/20 and 13/22. A 1 : 1 stoichiometry of the heteroassociation is evidenced by a Job's plot for 11/20, and by mole ratio plots for 9/18, 10/19, 12/21, 13/22, and 14/23.
Chemical Constituents from the Bark of Garcinia xanthochymus and Their 1,1‐Diphenyl‐2‐picrylhydrazyl (DPPH) Radical‐Scavenging Activities
Authors: Zhong Fang‐Fang , Chen Yu , Yang Guang‐Zhong
Published: September 2008

A new bis‐xanthone (xanthone=9H‐xanthen‐9‐one), named bigarcinenone A (1) which is the first example of a bis‐xanthone with the xanthone–xanthone linkage between an aromatic C‐atom and a C5 side chain from a guttiferae plant, a new phloroglucinol (=benzene‐1,3,5‐triol) derivative, named garcinenone F (2), together with seven known xanthones were isolated from the bark of Garcinia xanthochymus. Their structures were elucidated by spectroscopic methods, especially 2D‐NMR techniques. Bigarcinenone A (1) exhibited potent antioxidant activity in the 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) radical‐scavenging test with a IC50 value of 9.2 μM, compared to the positive control, the well‐known antioxidant butylated hydroxytoluene (BHT) with a IC50 of 20 μM (Table 3).
Synthesis and Cytotoxicity Studies of New (Dimethylamino)‐Functionalised and 7‐Azaindole‐Substituted ‘Titanocene’ Anticancer Agents (7‐Azaindole=1H‐Pyrrolo[2,3‐b]pyridine)
Authors: Hogan Megan , Cotter Juliet , Claffey James , Gleeson Brendan , Wallis Denise , O'Shea Donal , Tacke Matthias
Published: September 2008

From the carbolithiation of 1‐(cyclopenta‐2,4‐dien‐1‐ylidene)‐N,N‐dimethylmethanamine (=6‐(dimethylamino)fulvene; 3) and different lithiated azaindoles 2 (1‐methyl‐7‐azaindol‐2‐yl, 1‐[(diethylamino)methyl]‐7‐azaindol‐2‐yl, and 1‐(methoxymethyl)‐7‐azaindol‐2‐yl), the corresponding lithium cyclopentadienide intermediates 4a–4c were formed (7‐azaindole=1H‐pyrrolo[2,3‐b]pyridine). The latter underwent a transmetallation reaction with TiCl4 resulting in the (dimethylamino)‐functionalised ‘titanocenes’ 5a–5c. When the ‘titanocenes’ 5a–5c were tested against LLC‐PK cells, the IC50 values obtained were of 8.8, 12, and 87 μM, respectively. The most cytotoxic ‘titanocene’, 5a, with an IC50 value of 8.8 μM is nearly as cytotoxic as cis‐platin, which showed an IC50 value of 3.3 μM when tested on the epithelial pig kidney LLC‐PK cell line, and ca. 200 times better than ‘titanocene dichloride’ itself.
Quetiapine augmentation in depressed patients with partial response to antidepressants
Authors: Olver James S , Ignatiadis Sophie , Maruff Paul , Burrows Graham D , Norman Trevor R
Published: September 2008

Objective

Clinical trials suggest between 30–50% of depressed patients have an inadequate outcome to antidepressant pharmacotherapy. Among the approaches to improve outcome has been augmentation with antipsychotic medications. We aim to investigate the efficacy and tolerability of augmentation with quetiapine in depressed patients with a partial response to antidepressants.

Methods

Patients with a Major Depressive Disorder (DSMIV) who had partial/no response to a stable dose of an Selective Serotonin Reuptake Inhibitors (SSRI)/SNRI were recruited. All patients received add‐on quetiapine (200–600 mg nocte) in a 6‐week trial. Outcome measures (HAMD, MADRS) were assessed at screening, baseline, weeks 1, 2, 4 and 6. Extrapyramidal symptoms (EPSEs) were assessed at baseline, weeks 2, 4 and 6. A neuropsychological battery of tests was administered at baseline, weeks 3 and 6.

Results

Nineteen patients entered the trial and 18 completed the trial per protocol. We report a rapid improvement in depression ratings over 6 weeks (p < 0.0005) and remission rates of 67% at week 1 and 94% at week 6. There was no evidence of EPSE and no worsening (and some improvement) of cognition.

Conclusion

This suggests clinical benefits of quetiapine augmentation of SSRI/SNRI antidepressants with no worsening, and possible improvements in cognition. Copyright © 2008 John Wiley & Sons, Ltd.
Promoter methylation of p16 associated with Helicobacter pylori infection in precancerous gastric lesions: A population‐based study
Authors: Dong Cai‐Xuan , Deng Da‐Jun , Pan Kai‐Feng , Zhang Lian , Zhang Yang , Zhou Jing , You Wei‐Cheng
Published: September 2008

To investigate the relationship between p16 methylation and Helicobacter pylori infection in precancerous gastric lesions, a population‐based study was conducted in Linqu County, a high‐risk area of gastric cancer in China. Methylation status of p16 was evaluated by methylation‐specific polymerase chain reaction in 920 subjects with precancerous gastric lesions. H. pylori status was determined by 13C‐urea breath test and the density of H. pylori in biopsy specimens used for detecting methylation status was assessed by the modified Giemsa stain. The frequency of p16 methylation was significantly higher in subjects with H. pylori positive than those with H. pylori negative in each category of gastric lesion (p < 0.001, respectively). Compared with H. pylori negative, the odds ratios (ORs) of p16 methylation were markedly elevated in subjects with H. pylori positive for superficial gastritis (OR, 9.45; 95% confidence interval [CI]: 2.94–30.41), chronic atrophic gastritis (OR, 15.92; 95%CI: 7.60–33.36), intestinal metaplasia (OR, 4.46; 95%CI: 2.44–8.13), indefinite dysplasia (OR, 3.67; 95%CI: 1.90–7.10), and dysplasia (OR, 2.48; 95%CI: 1.02–5.99). Moreover, the frequencies of p16 methylation increased steadily with the severity of H. pylori density in gastric mucosa. Compared with H. pylori negative, the OR of p16 methylation was 1.02–16.13 times higher in subjects with mild H. pylori infection, and 2.69–38.73 times higher in those with moderate/severe infection, respectively. Our findings indicate that p16 methylation was significantly associated with H. pylori infection in precancerous gastric lesions, suggesting that H. pylori infection could potently induce methylation of p16 CpG island. © 2008 Wiley‐Liss, Inc.
Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inhibitor FK228 through AIF translocation
Authors: Watanabe Motonobu , Adachi Souichi , Matsubara Hiroshi , Imai Tsuyoshi , Yui Yoshihiro , Mizushima Yasuhiro , Hiraumi Yoshimi , Watanabe Ken‐ichiro , Kamitsuji Yuri , Toyokuni Shin‐ya , Hosoi Hajime , Sugimoto Toru , Toguchida Junya , Nakahata Tatsutoshi
Published: September 2008

Malignant rhabdoid tumors (MRT) exhibit a very poor prognosis because of their resistance to chemotherapeutic agents and new therapies are needed for the treatment of this cancer. Here, we show that the histone deacetylase (HDAC) inhibitor FK228 (depsipeptide) has an antitumor effect on MRT cells both in vitro and in vivo. FK228 is a unique cyclic peptide and is among the most potent inhibitors of both Class I and Class II HDACs. FK228 inhibited proliferation and induced apoptosis in all MRT cell lines tested. Preincubation with the pancaspase inhibitor zVAD‐fmk did not completely rescue FK228‐induced cell death, although it did inhibit apoptosis. Transmission electron microscopy (TEM) showed that FK228 could stimulate MRT cells to undergo apoptosis, necrosis or autophagy. FK228 converted unconjugated microtubule‐associated protein light chain 3 (LC3‐I) to conjugated light chain 3 (LC3‐II) and induced localization of LC3 to autophagosomes. Apoptosis inducing factor (AIF), which plays a role in caspase‐independent cell death, translocated to the nucleus in response to FK228 treatment. Moreover, small interfering RNA (siRNA) targeting of AIF prevented the morphological changes associated with autophagy and redistribution of LC3 to autophagosomes. Disrupting autophagy with chloroquine treatment enhanced FK228‐induced cell death. In vivo, FK228 caused a reduction in tumor size and induced autophagy in tumor tissues. Using immunoelectron microscopy, we confirmed AIF translocation into the nucleus of FK228‐induced autophagic cells in vivo. Thus, FK228 is a novel candidate for an antitumor agent for MRT cells. © 2008 Wiley‐Liss, Inc.
Radiation‐induced HIF‐1α cell survival pathway is inhibited by soy isoflavones in prostate cancer cells
Authors: Singh‐Gupta Vinita , Zhang Hao , Banerjee Sanjeev , Kong Dejuan , Raffoul Julian J. , Sarkar Fazlul H. , Hillman Gilda G.
Published: September 2008

We previously showed that treatment of prostate cancer cells with soy isoflavones and radiation resulted in greater cell killing in vitro, and caused downregulation of NF‐κB and APE1/Ref‐1. APE1/Ref‐1 functions as a redox activator of transcription factors, including NF‐κB and HIF‐1α. These molecules are upregulated by radiation and implicated in radioresistance of cancer cells. We extended our studies to investigate the role of HIF‐1α survival pathway and its upstream Src and STAT3 molecules in isoflavones and radiation interaction. Radiation induced phosphorylation of Src and STAT3 leading to induction of HIF‐1α. Genistein, daidzein or a mixture of soy isoflavones did not activate this pathway. These data were observed both in PC‐3 (AR‐) and C4‐2B (AR+) androgen‐independent cell lines. Pretreatment with isoflavones inhibited Src/STAT3/HIF‐1α activation by radiation and nuclear translocation of HIF‐1α. These findings correlated with decreased expression of APE1/Ref‐1 and DNA binding activity of HIF‐1α and NF‐κB. In APE1/Ref‐1 cDNA transfected cells, radiation caused a greater increase in HIF‐1α and NF‐κB activities but this effect was inhibited by pretreatment with soy prior to radiation. Transfection experiments indicate that APE1/Ref‐1 inhibition by isoflavones impairs the radiation‐induced transcription activity of NF‐κB and HIF‐1α. This mechanism could result in the inhibition of genes essential for tumor growth and angiogenesis, as demonstrated by inhibition of VEGF production and HUVECs tube formation. Our novel findings suggest that the increased responsiveness to radiation mediated by soy isoflavones could be due to pleiotropic effects of isoflavones blocking cell survival pathways induced by radiation including Src/STAT3/HIF‐1α, APE1/Ref‐1 and NF‐κB. © 2008 Wiley‐Liss, Inc.
The gene expression signature of genomic instability in breast cancer is an independent predictor of clinical outcome
Authors: Habermann Jens K. , Doering Jana , Hautaniemi Sampsa , Roblick Uwe J. , Bündgen Nana K. , Nicorici Daniel , Kronenwett Ulrike , Rathnagiriswaran Shruti , Mettu Rama K. R. , Ma Yan , Krüger Stefan , Bruch Hans‐Peter , Auer Gert , Guo Nancy L. , Ried Thomas
Published: September 2008

Recently, expression profiling of breast carcinomas has revealed gene signatures that predict clinical outcome, and discerned prognostically relevant breast cancer subtypes. Measurement of the degree of genomic instability provides a very similar stratification of prognostic groups. We therefore hypothesized that these features are linked. We used gene expression profiling of 48 breast cancer specimens that profoundly differed in their degree of genomic instability and identified a set of 12 genes that defines the 2 groups. The biological and prognostic significance of this gene set was established through survival prediction in published datasets from patients with breast cancer. Of note, the gene expression signatures that define specific prognostic subtypes in other breast cancer datasets, such as luminal A and B, basal, normal‐like, and ERBB2+, and prognostic signatures including MammaPrint® and Oncotype DX, predicted genomic instability in our samples. This remarkable congruence suggests a biological interdependence of poor‐prognosis gene signatures, breast cancer subtypes, genomic instability, and clinical outcome. © 2008 Wiley‐Liss, Inc.
Functional significance of VEGFR‐2 on ovarian cancer cells
Authors: Spannuth Whitney A. , Nick Alpa M. , Jennings Nicholas B. , Armaiz‐Pena Guillermo N. , Mangala Lingegowda S. , Danes Christopher G. , Lin Yvonne G. , Merritt William M. , Thaker Premal H. , Kamat Aparna A. , Han Liz Y. , Tonra James R. , Coleman Robert L. , Ellis Lee M. , Sood Anil K.
Published: September 2008

Vascular endothelial growth factor receptor (VEGFR) has recently been discovered on ovarian cancer cells, but its functional significance is unknown and is the focus of this study. By protein analysis, A2780‐par and HeyA8 ovarian cancer cell lines expressed VEGFR‐1 and HeyA8 A2774, and SKOV3ip1 expressed VEGFR‐2. By in situ hybridization (ISH), 85% of human ovarian cancer specimens showed moderate to high VEGFR‐2 expression, whereas only 15% showed moderate to high VEGFR‐1 expression. By immunofluorescence, little or no VEGFR‐2 was detected in normal ovarian surface epithelial cells, whereas expression was detected in 75% of invasive ovarian cancer specimens. To differentiate between the effects of tumor versus host expression of VEGFR, nude mice were injected with SKOV3ip1 cells and treated with either human VEGFR‐2 specific antibody (1121B), murine VEGFR‐2 specific antibody (DC101) or the combination. Treatment with 1121B reduced SKOV3ip1 cell migration by 68% (p < 0.01) and invasion by 72% (p < 0.01), but exposure to VEGFR‐1 antibody had no effect. Treatment with 1121B effectively blocked VEGF‐induced phosphorylation of p130Cas. In vivo treatment with either DC101 or 1121B significantly reduced tumor growth alone and in combination in the SKOV3ip1 and A2774 models. Decreased tumor burden after treatment with DC101 or 1121B correlated with increased tumor cell apoptosis, decreased proliferative index, and decreased microvessel density. These effects were significantly greater in the combination group (p < 0.001). We show functionally active VEGFR‐2 is present on most ovarian cancer cells. The observed anti‐tumor activity of VEGF‐targeted therapies may be mediated by both anti‐angiogenic and direct anti‐tumor effects. © 2008 Wiley‐Liss, Inc.
Antigenicity of clones of mouse prostate cells transformed in vitro
Authors: Embleton M. J. , Heidelberger Charles
Published: September 2008

New cell‐surface antigens were detected on nineteen of twenty‐four malignant lines of 3‐methylcholanthrene (MCA)‐ or MCA‐epoxide‐transformed cells derived from cloned C3H mouse prostate cells. Exhaustive cross‐tests between lines derived from single control clones showed that in all but two lines these antigens were individually distinct and did not cross‐react. Eight spontaneously transformed cell lines were also examined but only two of these were antigenic. The remaining six lines appeared to be non‐immunogenic in syngeneic mice, although cell surface alloantigens were detectable. Non‐transformed cells were not immunogenic in syngeneic hosts, whether or not they had been treated with MCA.
The short‐term effects of 4‐nitroquinoline 1‐oxide on the immune response in mice
Authors: Phillips Jennifer M.
Published: September 2008

The short‐term effects of the carcinogen 4‐Nitroquinoline 1‐oxide (NQO) on the number of plaque‐forming spleen cells (PFC) after immunization with sheep erythrocytes have been tested in (C57BL × IF) mice. The number of PFC was reduced in the NQO‐treated mice and this reduction was greater with higher doses of carcinogen. The times of appearance of the peaks of the 19S and 7S antibody response do not appear to be altered. Two non‐carcinogenic analogues of NQO, chloroquinoline‐N‐oxide (CQO) and nitropyridine N‐oxide (NPO) had no such immunodepressive effect. NQO had its maximum immunosuppressive effect when administered two days after the antigen, at the time of maximum division of the antibody‐producing cells. Reconstitution experiments suggest that the rapidly dividing bone‐marrow cells are most affected by NQO and there is no evidence that the thymus cells are affected. Correspondingly, no depression of cell‐mediated immunity by NQO was found, either in rejection time of skin allografts or of the graft‐versus‐host reaction.

These findings are discussed in relation to suggestions that immune depression by chemical carcinogens is of aetiological significance.
Polyps of the colon and rectum in cali, Colombia
Authors: Correa Pelayo , Duque Edgar , Cuello Carlos , Haenszel William
Published: September 2008

A systematic search for polyps was carried out in 1,499 autopsy specimens of large intestine from Cali, Colombia, a low‐incidence area for colo‐rectal carcinoma. No cases of carcinoma were found in the series studied. The prevalence of each of the main types of polyps, namely adenomatous, hyperplastic and retention, is described. Retention polyps tend to disappear with age. Hyperplastic polyps appear around the 4th decade of life, are often multiple, are mostly found in the sigmoid and rectum and their prevalence does not increase appreciably with age; these findings are interpreted as added evidence against an association between hyperplastic polyps and carcinoma of the colon and rectum. Adenomatous polyps increase in prevalence with age and are more often multiple and in males tend to be concentrated in the sigmoid; tentative comparisons of Cali data with findings from countries at high risk for colo‐rectal cancer suggest a statistical association between prevalence of adenomas and incidence of carcinoma of the colon and an even stronger association between colon cancer and atypical cellular changes in adenomas. It is suggested that populations at high risk to colon cancer are probably characterized by an increased prevalence of adenomatous polyps, particularly in the sigmoid colon of males, and display a larger proportion of multiple polyps and atypical cellular changes.
Facilitation of polyoma tumor growth in rats by blocking sera and tumor eluate
Authors: Bansal S. C. , Hargreaves R. , Sjögren H. O.
Published: September 2008

It has been shown previously that sera of tumor‐bearing individuals are capable of blocking specifically the lymphocyte cytotoxicity in vitro against the tumor cells in question. The present investigation demonstrates that blocking material, in the form of sera of rats carrying progressively growing polyoma tumors and low pH eluates of polyoma tumor tissue inoculated into polyoma isografted rats, cause an enhanced tumor growth. Corresponding serum from rats carrying an MCA‐induced sarcoma and eluate from such tumor tissue had no significant enhancing effect. The administered blocking activity was detectable in the sera of the recipients for 3 days after inoculation. No delay or decrease in the level of cell‐mediated anti‐tumor immunity could be detected by in vitro tests for lymphocyte cytotoxicity against polyoma tumor cells. This indicates that the mechanism of the facilitated tumor growth in vitro is akin to a central or an efferent type of enhancement.
Studies on the reversal of the selective antitumour effect of the aziridinyl derivative cb 1954 by 4‐amino‐5‐imidazolecarboxamide
Authors: Connors T. A. , Mandel H. G. , Melzack D. H.
Published: September 2008

The selective toxicity of CB 1954 (5‐aziridinyl‐2,4‐dinitrobenzamide) for Walker tumour cells, previously shown in the whole animal and in an in vitro/in vivo system, has been confirmed in an in vitro system In each case its actions on the Walker tumour were reversed by 4‐amino‐5‐imidazolecarboxamide, the ribotide of which is a purine precursor, provided it was given before or soon after the CB 1954. Other purines also produced this reversal, while pyrimidines and several other compounds did not. This evidence suggested that CB 1954, in addition to its alkylating properties, had features of a purine antimetabolite. However, anthranilamide was also very effective in protecting against CB 1954, suggesting that reversal could be achieved by compounds structurally related to CB 1954 which competed with it for some receptor site.
Persistence of rous sarcoma virus in transformed non‐permissive cells: mechanism of virus induction by association with permissive cells in the absence of sendai virus
Authors: Vigier Philippe
Published: September 2008

Virus induction by association of non‐permissive cells transformed by Rous sarcoma virus (RSV) and permissive chicken cells in the absence of Sendai virus has been studied with two clones of BHK21 hamster fibroblasts transformed respectively by Schmidt‐Ruppin strain RSV (clone RS2) and Bryan strain RSV (clone RB12), and with sub‐clones derived from these clones after many divisions. The main results have been the following: (1) All the transformed non‐permissive (TNP) cells presumably carry at least one complete viral genome since RSV could be recovered from all the subclones tested. (2) The first infective centers which appear in mixed cultures are presumably heterokaryons formed by spontaneous fusion of single TNP cells with chicken cells; and Rous cells (transformed chicken cells) which appear later on, arise by secondary infection of chicken cells. (3) The incidence of appearance of infective centers is low and can vary considerably depending on subclones in the case of RS2 cells. In the most highly inducible subclones, it never exceeds one center per 103 RS2 cells and it can be much less in other subclones. (4) No induction was observed with two RS2 subclones from which RSV was nevertheless recovered after Sendai virus‐mediated cell fusion. (5) In the case of one of these subclones, even heterokaryon formation was inefficient in removing the block of virus production in the TNP cells. (6) No induction was obtained by any other method than cell association and no subviral determinant able to give rise to virus in CE cells was recovered from TNP cells.

The reasons for non‐permissiveness and the mechanism of induction are discussed.
Pancreatic cancer, blood glucose and beverage consumption
Authors: Hiatt Robert A. , Klatsky Arthur L. , Armstrong Mary Anne
Published: September 2008

We studied the incidence of pancreatic cancer in 122,894 men and women who had previously reported amount and frequency of coffee, tea, and alcohol consumption; reporting was done at a multi‐phasic health check‐up (MHC) taken while subjects were members of a large prepaid health plan. We also tested the hypothesis that a pre‐clinical effect of pancreatic cancer on glucose homeostasis leads to mild hyperglycemia and a generally increased thirst. If true, this could partially explain the increased consumption of beverages (particularly coffee) reported in association with pancreatic cancer in some case‐control studies. However, in the 49 pancreatic cancer cases diagnosed during 6 years of follow‐up, we found no evidence of increased risk associated with coffee, tea, or alcoholic beverages. We also found no evidence to support the increased‐thirst hypothesis when we examined the 19 cases diagnosed within 12 months of having MHC. We did confirm a significantly increased risk among cigarette smokers (relative risk, 2.5; 95% confidence interval, 1.3‐4.7) which was progressive with increasing levels of cigarette use. In addition, risk of pancreatic cancer was greater for persons previously under treatment for diabetes mellitus (relative risk, 4.5; 95% confidence interval, 1.2‐16.7). Our results add to the growing body of evidence against a causal role of coffee in pancreatic cancer.
Plasminogen activator expression and steroid hormone receptors in female breast cancer: A multifactorial study
Authors: Pacheco Mercia M. , Brentani M. Mitzi , Franco Eduardo L. , Fontelles Jose A. , Chamone Dalton F. , Marques Lourdes A.
Published: September 2008

In order to evaluate the relationship of plasminogen activator (PA) activity to the expression of estrogen (ER) and progesterone (PR) receptors, we assayed primary tumor specimens from 121 cases of female breast cancer. Other clinical and histopathological variables were also investigated with respect to their possible association with PA activity in the samples. Statistical correlations were examined by stratified analysis techniques and by multiple regression methods. PA activity was higher in tumors which were ER +PR+ than in those exhibiting other subsets of joint receptor expression, a finding which was particularly predominant in tumors from post‐menopausal women. Of the other variables examined, only disease stage, nodal status and vascular infiltration presented marginal positive statistical associations with PA activity, although this was not confirmed by multivariate analysis. The latter technique showed that the presence of PR was sufficient to explain the variation in PA levels. However, ER emerged as the sole significantly explanatory factor when ER+PR− patients were removed from analysis. Both PR and age (negatively) were independent contributory factors for PA activity in the analysts of post‐menopausal women. None of the variables examined emerged as being significantly associated with PA when data from pre‐menopausal patients were used. These findings indicate that PA activity in breast tumor samples is statistically associated with the expression of functional estradiol receptors, although to a lesser extent than PR.
Site‐specific linkage of methotrexate to monoclonal antibodies using an intermediate carrier
Authors: Shih Lisa Beewen , Sharkey Robert M. , Primus F. James , Goldenberg David M.
Published: September 2008

The site‐specific conjugation of methotrexate, 4‐amino‐N10‐methylpteroylglutamic acid, to a monoclonal anti‐carcinoembryonic antigen (CEA) antibody, using an intermediate aminodextran carrier system, resulted in a ratio of 30‐50 molecules of MTX per molecule of immunoglobulin. The immunoreactivity of the conjugate was analyzed using flow cytometry or a competitive binding assay, which showed that the conjugate has significant retention of the antigen‐binding activity. The pharmacokinetic behavior of the immunoconjugate in BALB/c mice and tumor localization in hamsters indicated that the conjugate remained in the circulation with higher concentration than free antibody, and could recognize the tumor as efficiently as the unconjugated antibody. The high degree of drug incorporation with retained immunoreactivity makes this method preferable to direct antibody conjugation.
Tumor cells are protected from NK‐cell‐mediated lysis by adhesion to endothelial cells
Authors: Kaminski Marek , Auerbach Robert
Published: September 2008

We have examined the effect of various cell monolayers on the ability of mouse spleen cells to lyse tumor cell targets (natural cytotoxicity reaction). Natural killer (NK) cell activity was reduced by as much as 75% depending on the cell substrate, with the greatest protection afforded by endotheiial cells. Cell adhesion to the underlying cell monolayer was directly correlated with the degree of protection from lysis. Since it has previously been shown that tumor cells manifest selective adhesion to endothelial cells from those organs to which they are likely to metastasize, the experiments suggest a means by which natural surveillance mechanisms might be circumvented during the metastatic process.
Serial transplantation of an HTLV‐I‐transformed hamster lymphoid cell line into hamsters
Authors: Ecuchi T. , Kubonishi I. , Daikata M. , Yano S. , Imamura J. , Ohtsuki Y. , Miyoshi I.
Published: September 2008

A hamster lymphoid cell line, HCT‐2, transformed by human T‐ceM leukemia virus type I (HTLV‐I) was serially transplanted for 9 passages in newborn hamsters. A total of 34 newborn hamsters inoculated intraperitoneally (i.p.) with 0.2‐2 × 107 HCT‐2 cells developed fatal lymphomas with dissemination to various organs within 5‐10 days. The growth of i.p. inoculated HCT‐2 cells was found to be dependent on the age of recipients: all 21 suckling hamsters inoculated when aged 5‐10 days succumbed to disseminated lymphomas within 6‐7 days, while 4 of 12 older hamsters inoculated at the age of 15‐25 days developed less extensive disease with signs of tumor regression. To investigate the effect of immunosuppression on host resistance, 3 adult hamsters treated with anti‐thymocyte serum were inoculated i.v. with 2‐4 × 107 HCT‐2 cells; all 3 developed fatal leukemias in 5‐7 days. Irrespective of whether HCT‐2 cells were inoculated into newborn, suckling, or adult hamsters, histopathological findings were similar, with frequent involvement of liver, spleen, lungs, kidneys, lymph nodes, blood, and bone marrow. Cells harvested from tumors and peripheral blood of some tumor‐bearing hamsters could be readily recultured as cell lines. Chromosome analysis and Southern blot hybridization showed that tumors were caused by growth of HCT‐2 cells.
Transformation of rat 3Y1 cells by human papillomavirus type‐18 DNA
Authors: Watanabe Sumie , Yoshiike Kunito
Published: September 2008

Rat 3Y1 cell cultures transfected with human papiilomavirus type‐18(HPV 18) DNA produced foci of morphologically transformed cells capable of anchorage‐independent growth. Analyses of the transformed cell clones obtained after transfection with EcoRI‐cleaved linear HPV IS DNA showed that, although the viral DNAs integrated in the cell DNA had rearrangements (probably around the sites of integration), they appeared to retain the putative transcriptional control region and the downstream area containing E6E7 open reading frames (ORF) intact, and to be transcription ally active. The expression plasmids constructed from an 5V40‐derived expression vector (pSV2‐0) and HPV 18 DNA fragments containing either E6 or E7 ORF intact were examined for their transforming capacity. HPV IB E7 ORF was found to encode a transforming gene for rat 3Y1 cells.
Differential expression of hla antigen of HLA anigens on human B‐cell lines of normal and malignant origin: A consequence of immune surveillance or a phenotypic vestige of the progenitor cells?
Authors: Torsteinsdottir Sigurbjörg , Brautbar Chaim , Klein George , Klein Eva , Masucci Maria G.
Published: September 2008

Pairs of BL‐derived cell lines and in vitro EBV‐transformed LCLs, derived from the same patient, were compared for the expression of MHC class‐l antigenic determinants as shown both by monoclonal antibody (MAb) binding and by sensitivity to HLA‐specific CTL clones. BL lines expressed all polymorphic determinants tested at a lower level than the corresponding LCLs, as indicated by the binding of the MAbs AUF 5.13 (anti‐HLA A3,AII), GS 142.1 (anti‐HLA Al), GS 114.1 (anti‐HLA A24), GSP 35.1 (anti‐HLA A2.A28), GSP 55.1 (anti‐HLA A25.A32), TER MA32 (anti‐HLA A32), GSP 145.2 (anti‐HLA B27), B27 M.I (anti‐HLA B27,B7) and GSP 8.1 (anti‐HLA B8). The difference was most pronounced for HLA All and least for B27,AI and B8 with intermediate differences for the other specificities. The BL lines were also less sensitive to lysis by HLA‐specific CTL clones directed to the same and to additional antigens. The polymorphic determinants detected by the AUF 5.13 and GSP 35.1. MAbs were expressed at a lower level in resting T and B cells compared to mitogen‐ and EBV‐induced blasts. An analogous change in the expression of polymorphic determinants was observed in EBV‐converted sublines of originally EBV‐negative BLs that have become more “LCL‐like” after conversion. The appearance of B‐cell activation markers was paralleled by the up‐regulation of both the serologically defined and the CTL‐target epitopes. The findings suggest that the low expression of HLA determinants on the BL cells is a phenotypic vestige of the normal BL precursor.
Screening for breast cancer in pre‐menopausal women. Who should decide?
Authors: Berrino Franco , Bouchardy Christine , Sasco Annie J.
Published: September 2008

The recent UICC meeting on breast cancer screening in pre‐menopausal women showed that experts disagree: some would recommend that screening begin at age 40, others would postpone it until after age 50 (Eckhardt et al., 1994). There is full consensus that screening at ages 40 to 49 may detect a substantial fraction of breast‐cancer cases before their clinical manifestation, but the trials carried out have not indicated a significant reduction in subsequent mortality. As stated in the report of the UICC meeting, “this issue is too large for it to remain only the concern of experts.” In our opinion, women should be provided with full information to enable them to decide themselves what is better for them. This means that the available scientific evidence both on benefits and on risks should be made quantitatively explicit. As recently reviewed by Hurley and Kaldor (1992), potential benefits include saved lives, increased use of conservative therapies, and reassurance of women without pre‐clinical cancer; risks include radiationinduced breast cancer, unnecessary investigations for false positives, useless early diagnosis and treatment, diagnosis and treatment of lesions not requiring treatment (over‐diagnosis), false reassurance, and psychological and social morbidity such as anxiety and the stigmatization of women with positive diagnosis. © 1995 Wiley‐Liss, Inc.
Cancer risk following primary hemochromatosis: A population‐based cohort study in Denmark
Authors: Hsing Ann W. , McLaughlin Joseph K. , Olsen Jorgcn H. , Mellemkjar Lenc , Wacholder Sholom , Fraumeni Joseph F.
Published: September 2008

A population‐based cohort of 120 Danish men, discharged with a hospital diagnosis of primary hemochromatosis from 1977 to 1989, was followed up to 1989 for subsequent cancer risk. Nineteen subjects (including 6 with primary liver cancers) were excluded from the analysis, either because they died within the same month of hemochromatosis diagnosis or because they had cancer prior to diagnosis of hemochromatosis. Among the 101 remaining subjects, 4 primary liver cancers occurred one year or more after the diagnosis of hemochromatosis, far surpassing the expected number based on incidence rates from the Danish population (standardized incidence ratio 92.9, 95% confidence interval 25.0 to 237.9). The excess of liver cancer was associated with cirrhosis and included cholangiocarcinoma as well as hepatocellular carcinoma. Significantly elevated risks were also observed for non‐hepatic cancers (13 cases; SIR 3.5, 95% CI 1.9 to 6.0), notably esophageal cancer (2 cases; SIR 42.9, 95% CI 4.8 to 154.9) and skin melanoma (2 cases; SIR 27.8, 95% CI 3.1 to 100.3). The results of this population‐based study are in accordance with the hypothesis that patients with primary hemochromatosis have a substantial risk of primary liver cancer. Further studies of hemochromatosis may be useful in clarifying the relation of non‐hepatic malignancies to body iron stores in the general population. © 1995 Wiley‐Liss, Inc.
Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop
Authors: Guha Abhijit , Dashner Kathleen , Mc Black Peter L. , Wagner John A. , Stiles Charles D.
Published: September 2008

Established cell lines derived from human malignant astrocytomas typically express a combination of platelet‐derived growth factor (PDGF) and PDGF receptor which could form an autocrine loop. In this study, we screened for the essential components of a PDGF autocrine loop in fresh surgical isolates of human astrocytomas, using in situ hybridization and immunohis‐tochemical techniques. Eight malignant astrocytomas (6 glioblastomas and 2 anaplastic astrocytomas), 5 low‐grade astrocytomas and 4 non‐neoplastic glial specimens (mesial temporal sclerosis) were evaluated. Malignant astrocytomas, and to a lesser extent low‐grade astrocytomas, expressed more PDGF‐A and PDGF‐B than non‐neoplastic glia. PDGF‐α‐receptor expression was elevated both in malignant and in iow‐grade astrocytomas. These data support the argument that PDGF autocrine loops contribute to the unregulated growth of human astrocytomas. Expression of PDGF and PDGF receptor in low‐grade astrocytomas suggests that activation of PDGF autocrine loops may be an early event in the pathogenesis of malignant astrocytomas. © 1995 Wiley‐Liss, Inc.
International renal‐cell cancer study. I. Tobacco use
Authors: McLaughlin Joseph K. , Lindblad Per , Mellemgaard Anders , McCredie Margaret , Mandel Jack S. , Schlehofer Brigitte , Pommer Wolfgang , Adami Hans‐Olov
Published: September 2008

The relationship between renal‐cell cancer (RCC) and tobacco use was investigated in an international, multicenter, population‐based case‐control stud/. Coordinated studies were conducted in Australia, Denmark, Germany, Sweden and the United States using a shared protocol and questionnaire. A total of 1,732 cases (1,050 men, 682 women) and 2,309 controls (1,429 men, 880 women) were interviewed for the study. No association was observed between risk and use of cigars, pipes or smokeless tobacco. A statistically significant association was observed for cigarette smoking, with current smokers having a 40% increase in risk [relative risk (RR) = 1.4, 95% confidence interval (CI) 1.2–1.7]. Risk increased with intensity (number of cigarettes) and duration (years smoked). Among current smokers the RR for pack‐years rose from I.I (95% CI 0.8–1.5) for <15.9 pack years to 2.0 (95% CI 1.6–2.7) for >42 pack years (p for trend < 0.001). Long‐term quitters (> 15 years) experienced a reduction in risk of about 15–25% relative to current smokers. Those who started smoking late (>24 years of age) had about two‐thirds the risk of those who started young (< 12 years of age). Overall, the findings of this pooled analysis confirm that cigarette smoking is a causal factor in the etiology of RCC. © 1995 Wiley‐Liss, Inc.
IFN‐α1 gene transfection completely abolishes the tumorigenicity of murine B16 melanoma cells in allogeneic DBA/2 mice and decreases their tumorigenicity in syngeneic C57BL/6 mice
Authors: Kaido Thomas , Bandu Marie‐Thérèse , Maury Chantal , Ferrantini Maria , Belardelli Filippo , Gresser Ion
Published: September 2008

The murine B16 melanoma (H‐2b) was transfected with a retroviral vector containing the mouse IFN‐α1 gene. IFN‐α1‐transfected cells produced IFN‐α in vitro and exhibited an altered phenotype characterized by a decreased rate of multiplication, enhanced expression of H‐2 antigens, an antiviral state to VSV, and decreased pigmentation. Control and IFN‐α1‐transfected cells were tested for their ability to grow in syngeneic (H‐2b) CS7B1/6 and allogeneic (H‐2d) DBA/2 mice. IFN‐α1producing B16 clones were less tumorigenic after s.c, i.p., and i.v. routes of injection than IFN‐non‐producer BI6 clones in syngeneic CS7B1/6 mice. IFN‐α1‐producing B16 cells were, however, totally rejected by allogeneic DBA/2 mice regardless of the routes and inocula tested, while control B16 cells grew in and killed DBA/2 mice. The total rejection of IFN‐α1‐transfected B16 cells in allogeneic mice appeared to be dependent on T cells as these cells grew in DBA/2 nude mice. Incubation of IFN‐α‐producing clones with anti‐mouse IFN‐α/β prior to injection into C57BI/6 mice did not enhance their tumorigenicity. Likewise, injection of C57BI/6 and DBA/2 mice with antibody to IFN‐α/β did not enhance the tumorigenicity of IFN‐α1‐transfected cells. C57B1/6 mice immunized with irradiated IFN‐α1 cells were only slightly protected against a subsequent challenge with parental B16 cells. In contrast, DBA/2 mice immunized with irradiated IFN‐α1 cells exhibited tumor‐specific, long‐lasting immunity to subsequent challenge with parental B16 cells. © 1995 Wiley‐Liss, Inc.
Loss of chromosome 3p arm differentiating tumorigenic from non‐tumorigenic cells derived from the same SV40‐transformed human mammary epithelial cells
Authors: Lebeau Jérocme , Gerbault‐Seureau Michèle , Lemieux Nicole , Apiou Francloise , Calvo Fabien , Berthon Philippe , Goubin Gerard , Dutrillaux Bernard
Published: September 2008

After immortalization of human normal mammary epithelial cells by replication‐defective SV40 genome integration, 2 cultures were developed independently. Both had the same integration site, in band 9q21, but rapidly diverged karyotypically. After a few passages, one, designated SC2T2, exhibited near‐diploid (a) and the other, designated SL2T2, near‐tetraploid (b) karyotypes. The simplest formulas were 44, X, ‐X, der(3;22) (q10;q10), der(4)t(4;9)(q34;q12), +8, +9, add(13)(pl), der(19) t(8; 19)(q21;p 13.3), add(22)(p 1) for karyotype (a) and 93, XXXX, add(1)(q12), add(11)(q13), +20 for karyotype (b). A number of alterations were further acquired with passages. Both cell cultures were tumorigenic, but their efficiency of grafting in nude mice largely differed: it was low for SL2T2 and high for SC2T2 cultures. All cultures of the xenografted tumors, obtained from either SL2T2 or SC2T2, exhibited the same clonal anomalies as those characterizing karyotype (a). It was concluded that only cells with karyotype (a) were tumorigenic, and that the difference in the tumorigenic potential of cultures SC2T2 and SL2T2 was related to their richness in cells with this karyotype. The comparison of the various karyotypes, together with data obtained in other cell types transformed by SV40, suggests that the acquisition of tumorigenicity in S2T2 mammary epithelial cells may be related to the loss of chromosome 3p arm. © 1995 Wiley‐Liss, Inc.