bluuebunny/crossref_metadata_2025 huggingface dataset:
RETRACTED: Enhanced susceptibility of oral squamous cell carcinoma cell lines to FAS‐mediated apoptosis by cisplatin and 5‐fluorouracil
Authors: Iwase Masayasu , Watanabe Hitoshi , Kondo Gen , Ohashi Masaru , Nagumo Masao
Published: July 2003

Our study was conducted to investigate whether anticancer drugs, cisplatin (CDDP) and/or 5‐fluorouracil (5‐FU), can modulate Fas‐mediated apoptosis in oral squamous cell carcinoma (OSCC) cell lines. When OSCC cell lines, NA and HSC‐4, were treated with CDDP and/or 5‐FU, Fas and its mRNA expression on the plasma membrane were enhanced. An increase in caspase‐3 and ‐8 activities was then observed by the addition of agonistic anti‐Fas antibody, CH‐11. Apoptosis of OSCC cells treated with anticancer drugs were significantly enhanced by CH‐11, whereas untreated cells were nearly resistant to apoptosis. Moreover, the combination of CDDP and 5‐FU resulted in an increasing susceptibility to apoptosis. Caspase‐3 and ‐8 inhibitors, but not caspase‐9 inhibitor, reduced Fas‐mediated apoptosis enhanced by the anticancer drugs. Furthermore, OSCC cells treated with anticancer drugs exhibited decreased cellular FADD‐like interleukin 1‐converting enzyme‐inhibitory protein (c‐FLIP) levels, whereas neither the Fas‐associated death domain‐containing protein (FADD) nor procaspase‐8 changed the expression. Moreover, antisense oligonucleotide to c‐FLIP confirmed that down‐regulation of c‐FLIP induced sensitization to Fas‐mediated apoptosis. These results suggest that CDDP and 5‐FU may enhance the susceptibility to Fas‐mediated apoptosis through down‐regulation of c‐FLIP. From these findings, a new potential strategy may be developed to improve the efficacy of anticancer drugs. © 2003 Wiley‐Liss, Inc.
Antihistamine use and breast cancer risk
Authors: Nadalin Victoria , Cotterchio Michelle , Kreiger Nancy
Published: July 2003

Antihistamines are structurally similar to DPPE, a tamoxifen derivative known to promote tumor growth, and to antidepressants. Animal experiments have linked certain antihistamines and antidepressants with enhanced tumor growth in mice. The few epidemiologic studies examining antihistamine use have not indicated an increased risk. In light of suggestive animal data, structural similarities between antihistamines and DPPE, the widespread use of antihistamines, and the lack of epidemiologic investigation into their use and breast cancer risk, it is important to examine this issue. Female cases aged 25–74 years, diagnosed 1996 to 1998, were identified through the Ontario Cancer Registry. Controls were a random, age‐matched sample of women. Cases (n=3,133) and controls (n=3,062) completed a mailed questionnaire that included questions about antihistamines used regularly (undefined), type and duration. Age‐adjusted odds ratio (OR) estimates and 95% confidence intervals (CIs) were obtained using logistic regression. Antihistamine users were at no increased risk for breast cancer (OR=0.93, 95% CI: 0.81, 1.06), and no trend in risk was observed for age starting or duration of use. Antihistamine users were at no increased risk. No confounding or effect modification was identified in multivariate modeling. Our findings do not support the hypothesis that women who use antihistamines are at a greater breast cancer risk than those who do not. © 2003 Wiley‐Liss, Inc.
Histogenesis of hepatoid adenocarcinoma of the stomach:Molecular evidence of identical origin with coexistent tubular adenocarcinoma
Authors: Akiyama Sunao , Tamura Gen , Endoh Yasushi , Fukushima Norimasa , Ichihara Yukihiro , Aizawa Kikuo , Kawata Sumio , Motoyama Teiichi
Published: July 2003

Hepatoid adenocarcinoma of the stomach is a highly malignant neoplasm. Most gastric hepatoid adenocarcinomas coexist with tubular adenocarcinoma. However, the relationship between hepatoid adenocarcinoma and tubular adenocarcinoma is still unclear. In the present study, the characteristics of the coexistent tubular adenocarcinomas were determined by examining their profiles of mucin production. Subsequently, molecular pathological techniques were applied to determine the clonality of 15 mixed hepatoid and tubular adenocarcinomas of the stomach. Mucin analysis suggested that the coexistent tubular adenocarcinomas with hepatoid adenocarcinoma were of the intestinal type. The patterns of chromosome X inactivation were identical between the hepatoid adenocarcinoma component and tubular adenocarcinoma component in all of 3 informative female cases. Mutations in the p53 gene were found in 5 cases. The sequences were identical within both tumor components in all 5 cases. Microsatellite analysis indicated more than 3 common patterns of loss of heterozygosity in 8 cases. These observations strongly suggested that hepatoid adenocarcinomas were of identical origin to coexistent tubular adenocarcinomas. © 2003 Wiley‐Liss, Inc.
In vitro and in vivo biologic evaluation of long‐circulating biodegradable drug carriers loaded with the pure antiestrogen RU 58668
Authors: Ameller Thibault , Marsaud Véronique , Legrand Philippe , Gref Ruxandra , Renoir Jack‐Michel
Published: July 2003

We have developed a parenteral delivery system for the administration of the highly promising pure antiestrogen RU 58668 (RU). Two types of nanoparticles (NP) made of biodegradable copolymers and coated with polyethylene‐glycol (PEG) chains were prepared: nanospheres (NS) (diameter, ∼110 nm) and nanocapsules (NC) with an oily core (diameter, ∼250 nm). The amount of RU incorporated into NS and NC was ∼33 vs. ∼5 μg RU/mg of polymer, respectively. Coating with PEG chains prolonged the antiestrogenic potency of RU, as shown by a prolonged antiuterotrophic activity of encapsulated RU into PEG‐poly(D,L lactic acid) (PLA) NS, as compared to that of conventional nonpegylated NS. In mice bearing MCF‐7 estrogen‐dependent tumors, free RU injected at 4.3 mg/kg/week by i.v. route slightly decreased the estradiol‐promoted (0.5 mg/kg/week) tumor growth while RU‐loaded PEG‐PLA NS injected at the same dose strongly reduced it. Analysis of cell cycle parameters in tumors treated with RU indicated that RU‐loaded PEG‐PLA NS injected at 4.3 mg/kg/week in MCF‐7 tumors decreased cyclin D1 and cyclin E simultaneously, and increased p27. The antitumoral activity of RU encapsulated within pegylated NC was stronger than that of RU entrapped with pegylated NS loaded at an equivalent dose. Indeed, the former decreased the tumor size in nude mice transplanted with the estrogen receptor‐positive but estrogen‐independent MCF‐7/Ras breast cancer cells at a concentration 2.5 times lower than that of the latter (0.4 mg/kg/week compared to 1 mg/kg/week). Empty PEG‐PLA NS and NC were devoid of antiuterotrophic and antitumoral activities. Altogether, these results suggest that the incorporation of the pure antiestrogen RU into long‐circulating NP could represent a novel antiestrogen drug delivery system for the parenteral route. © 2003 Wiley‐Liss, Inc.
Natural killer cell cytolytic activity is necessary for in vivo antitumor activity of the dipeptide L‐glutamyl‐L‐tryptophan
Authors: Smith D. Lynne , Cai Jie , Zhu SuTao , Wei Wen , Fukumoto Jon , Sharma Sanjai , Masood Rizwan , Gill Parkash S.
Published: July 2003

A dipeptide, L‐glutamyl L‐tryptophan (L‐glu‐L‐trp), was identified in a screen for immunomodulators in the soluble fraction of the thymus. L‐glu‐L‐trp inhibits tumor growth in mice without showing direct cellular toxicity in a variety of human tumor cell lines. L‐glu‐L‐trp antitumor activity in vivo requires the presence of natural killer (NK) cells. Defective trafficking of cytoplasmic granules caused by the Lyst mutation also resulted in loss of antitumor activity of the dipeptide. The effect of L‐glu‐L‐trp on tumor growth in mice with targeted gene mutations demonstrated the absolute requirement for perforin for antitumor activity. The requirement of 2 major modulators of NK cell activity, gamma interferon (IFNγ) and interleukin (IL)‐12, were also tested. L‐glu‐L‐trp had full antitumor activity in IFNγ knockout mice, but had significantly diminished activity in IL‐12 knockout mice. These data show that L‐glu‐L‐trp antitumor activity in mice is dependent on cytolytic cell activity of NK or NKT cells. L‐glu‐L‐trp in vivo regulates NK cell function independent of IFNγ but partly dependent on IL‐12. © 2003 Wiley‐Liss, Inc.
Invasion of melanoma cells into dermal connective tissue in vitro: Evidence for an important role of cysteine proteases
Authors: Dennhöfer Ralf , Kurschat Peter , Zigrino Paola , Klose Anke , Bosserhoff Anja , van Muijen Goos , Krieg Thomas , Mauch Cornelia , Hunzelmann Nicolas
Published: July 2003

Invasion of melanoma cells into the dermal connective tissue is a major characteristic in the complex process of metastasis. Proteases play an important role in tumor cell invasion as these enzymes are able to degrade most components of the extracellular matrix (ECM), and thus enable cells to penetrate interstitial connective tissues and basement membranes. We developed an improved culture model that allows the detailed study of melanoma cell invasion in vitro. In this model, high (BLM) or low (530) invasive melanoma cells were seeded on the dermal side of dead deepidermized dermis (DDD) and cultured for 14 days at the air/liquid interface. The high invasive cells invaded the tissue, leading to dermal tumor formation, whereas the low invasive cells did not. Analysis of the enzymatic activity of gelatinases by in situ gelatin zymography at neutral pH revealed proteolysis only in those composites cultured with high invasive melanoma cells. Interestingly, in situ zymograms performed at more acidic conditions, favoring the activity of cysteine proteases, exhibited markedly enhanced and widespread gelatinolysis compared to neutral pH. Cysteine protease inhibitors (E‐64 and leupeptin) significantly reduced invasion of melanoma cells into these composites. These results indicate an important role of cysteine proteases for tumor invasion. © 2003 Wiley‐Liss, Inc.
Antitumor and antimetastatic activities of Angelica keiskei roots, part 1: Isolation of an active substance, xanthoangelol
Authors: Kimura Yoshiyuki , Baba Kimiye
Published: July 2003

The roots of Angelica keiskei Koizumi have traditionally been used as a health food, with diuretic, laxative, analeptic and galactagogic effects. It has been thought that the roots and leaves of A. keiskei have preventive effects against coronary heart disease, hypertension and cancer. In the present study, we examined the antitumor and antimetastatic activities of various fractions isolated from a 50% ethanol extract of A. keiskei roots. The ethyl acetate‐soluble fraction of the 50% ethanol extract inhibited tumor growth in LLC‐bearing mice at a daily dose of 100 mg/kg prolonged survival time and inhibited metastasis to the lung after surgical removal of primary tumors. Two active substances were isolated from fractions 1 and 2: compound 1 was identified as xanthoangelol based on the data of the 1H‐ and 13C‐NMR spectra. Xanthoangelol inhibited tumor growth in LLC‐bearing mice as well as lung metastasis and prolonged survival time in carcinectomized mice at a daily dose of 50 mg per kg. Furthermore, xanthoangelol (50 or 100 mg per kg daily) inhibited liver metastasis and the growth of metastasized tumor cells in the livers of mice with intrasplenically implanted LLC. Xanthoangelol inhibited DNA synthesis in LLC cells at concentrations of 10 and 100 μM, but it had no effect on DNA synthesis in HUVECs or on the adherence of LLC cells to HUVECs. Xanthoangelol inhibited tumor‐induced neovascularization (in vivo) at doses of 10 and 20 mg per kg, and it inhibited the Matrigel‐induced formation of capillary‐like tubes by HUVECs at concentrations of 1–100 μM. Furthermore, xanthoangelol inhibited the binding of VEGF to HUVECs at concentrations of 1–100 μM. These results indicate that the antitumor and/or antimetastatic activities of xanthoangelol may be due to inhibition of DNA synthesis in LLC cells and of tumor‐induced neovascularization through inhibition of the formation of capillary‐like tubes by vascular endothelial cells and inhibition of the binding of VEGF to vascular endothelial cells. © 2003 Wiley‐Liss, Inc.
Bidi smoking and oral cancer: A meta‐analysis
Authors: Rahman Mahbubur , Sakamoto Junichi , Fukui Tsuguya
Published: July 2003

Several epidemiological studies suggest that bidi smoking increases the risk of oral cancer. No systematic review, however, has been reported to examine how consistent the evidence is across the studies. We undertook a meta‐analysis of epidemiological studies investigating the relationship between bidi smoking and oral cancer. Primary studies were identified through a computerized literature search of Medline. Articles abstracted were all epidemiological studies published as original articles in English during 1966–2002 that included quantitative information on bidi smoking and oral cancer. Summary odds ratios (OR) were calculated based on random effects model. A total of 12 case‐control studies used for this meta‐analysis provided the summary estimates of OR of bidi smoking for oral cancer compared to that of non‐smokers. An increased risk of oral cancer was found for bidi smokers compared to never smokers (OR = 3.1, 95% confidence interval [CI] 2.0–5.0) whereas no significant pattern of risk was found for cigarette smokers (OR = 1.1, 95% CI = 0.7–1.8). There was substantial heterogeneity in the pooled OR estimate. Our results clearly indicate that bidi smokers are at increased risk of oral cancer. It is important that this information be incorporated into smoking prevention and cessation efforts, particularly among the urban poor and rural mass in South Asian countries where bidi smoking is widely prevalent. © 2003 Wiley‐Liss, Inc.
Identification of tumor‐associated antigens by screening phage‐displayed human cDNA libraries with sera from tumor patients
Authors: Minenkova Olga , Pucci Andrea , Pavoni Emiliano , De Tomassi Amedeo , Fortugno Paola , Gargano Nicola , Cianfriglia Maurizio , Barca Stefano , De Placido Sabino , Martignetti Angelo , Felici Franco , Cortese Riccardo , Monaci Paolo
Published: July 2003

Screening cDNA libraries from solid human tumors with sera of autologous patients (SEREX) has proven to be a powerful approach to identifying tumor antigens recognized by the humoral arm of the immune system. In many cases, application of this methodology has led to the discovery of novel tumor antigens as unknown gene products. We tried to improve the potency of the SEREX approach by combining it with phage‐display technology. We designed a new lambda vector to express protein fragments as N‐terminal fusions to the D capsid protein and generated high‐complexity cDNA libraries from human breast carcinoma cell lines and solid tumors. Screening these phage‐displayed libraries required limited amounts of sera from patients and efficiently identified several tumor antigens specifically reacting with sera from breast cancer patients. © 2003 Wiley‐Liss, Inc.
Rapid onset of nucleolar disintegration preceding cell cycle arrest in roscovitine‐induced apoptosis of human MCF‐7 breast cancer cells
Authors: Wojciechowski Jacek , Horky Marcel , Gueorguieva Marieta , Węsierska‐Gądek Józefa
Published: July 2003

The aim of our study was to explore the antiproliferative and pro‐apoptotic action of roscovitine (ROSC) on human breast cancer MCF‐7 cells. We examined the effect of ROSC on cell proliferation, cell cycle progression, nucleolar morphology, posttranslational modifications of histones as well as on induction of apoptosis. The effects of ROSC on the argyrophilic nucleolar organizer regions (AgNORs) and nucleolar RNA of MCF‐7 cells were marked: ROSC treatment changed the pattern of AgNORs in a time‐dependent manner. The disintegration of nucleoli manifested by increasing number of nucleolar fragments already began at 6 hr posttreatment. This was accompanied by a redistribution of the nucleolin from the nucleolus beginning after 6 hr and preceded a decrease of histone acetylation and phosphorylation. Inhibition of DNA synthesis and accumulation of G2/M‐arrested cells starting 6 hr posttreatment coincided with a strong increase of the p53 level and with an appearance of a few cells committed to undergo apoptosis. However, all these changes preceded the main wave of apoptosis, which occurred after 24 hr ROSC treatment as assessed by determination of the frequency of Annexin binding, activation of caspases as well as of DNA fragmentation. Onset of PARP‐1 cleavage detected by immunoblotting and by immunohistochemistry 6 hr or 9 hr posttreatment, respectively, preceded for a few hours the DNA fragmentation detected in situ by TUNEL assay. Reconstitution of MCF‐7 cells with caspase‐3 did not change the kinetics of ROSC‐induced apoptosis. Our results show that disintegration of nucleoli is an early marker of ROSC‐induced changes. Cell cycle arrest precedes the main wave of apoptosis. © 2003 Wiley‐Liss, Inc.
Immunocytochemical analysis of the circadian clock protein in mouse hepatocytes
Authors: Malatesta Manuela , Baldelli Beatrice , Marcheggiani Francesco , Gazzanelli Giancarlo
Published: July 2003

Many biochemical, physiological, and behavioral processes in organisms ranging from prokaryotes to humans exhibit circadian rhythms, defined as cyclic oscillations of about 24 hours. The mechanism of the cellular circadian clock relies on interlocking positive and negative transcriptional/translational feedback loops based on the regulated expression of several genes. Clock is one of these genes and its transcript, CLOCK protein, is a transcription factor belonging to the bHLH‐PAS family. In mammals the clock gene is expressed in several tissues, including the liver. In the present study, we analyzed by means of quali‐quantitative immunoelectron microscopy the fine intracellular distribution of the CLOCK protein in mouse hepatocytes during the daily cycle. We demonstrated that CLOCK protein is mostly located in the cell nucleus, where it accumulates on perichromatin fibrils, representing the in situ form of nascent pre‐mRNA, while condensed chromatin and nucleoli contain lower amounts of protein. Moreover, we found that CLOCK protein shows circadian oscillations in these nuclear compartments, peaking in late afternoon. At this time the hepatic transcriptional rate reaches the maximal level, thus suggesting an important role of CLOCK protein in the regulation of liver gene expression. Microsc. Res. Tech. 61:414–418, 2003. © 2003 Wiley‐Liss, Inc.
Managing for competitiveness: a proposed model for managerial focus
Authors: Connor Tom
Published: July 2003

The word competitiveness is used extensively in management discourse concerning national economic performance, international economic performance comparisons and at the level of the firm.

It is a word of elusive meaning. Indeed, it is used in so many different ways that there must be serious doubt that the word has any concrete meaning at all. This is regrettable because it could make a valuable contribution to our thinking about economic policy and the management of business.

This paper considers the concept of competitiveness at the level of the business unit and proposes an interpretation, which will be of value to practising managers in their efforts to improve the economic performance of their businesses.

Copyright © 2003 John Wiley & Sons, Ltd.
Why bother to be better? strategically stagnant personal current accounts
Authors: Martin Stephen , Mainelli Michael
Published: July 2003

Banks are keen to supply current accounts because apart from direct income, they are more successful in selling a wide range of their financial services to customers who possess a current account.

The UK market for current accounts appears to exhibit little customer movement and is dominated by 4 out of at least 140 suppliers, despite variable levels of service.

Using Prospect Theory, attempts are made to explain why this market is so stagnant and to suggest how suppliers could be more successful at promoting change.

Results suggest that changing the initial perceptions of customers will have more impact than trying to induce customers to change suppliers by promoting the benefits of an alternative bank.

Copyright © 2003 John Wiley & Sons, Ltd.
c‐erbB‐4/HER4: friend or foe?
Authors: Gullick William J
Published: July 2003

The c‐erbB‐4 receptor has ligand stimulated tyrosine kinase activity but reports differ as to whether it induces cell division or differentiation. There is also controversy regarding its role in breast cancer, with some reports associating overexpression with short survival and others with longer life. Copyright © 2003 John Wiley & Sons, Ltd.
Impaired hepatic granuloma formation in mice deficient in C–C chemokine receptor 2
Authors: Jinnouchi Katsunori , Terasaki Yasuhiro , Fujiyama Shigetoshi , Tomita Kimio , Kuziel William A , Maeda Nobuyo , Takahashi Kiyoshi , Takeya Motohiro
Published: July 2003

Granulomas are characterized histologically by a nodular collection of macrophages with occasional admixture of epithelioid cells, multinucleate giant cells, and other immunocompetent cells. Chemokines are considered to play an important role in the recruitment of these constituent cells of granulomas. The present study has examined the effect of a deficiency of C–C chemokine receptor‐2 (CCR2) on hepatic granuloma formation induced by a single injection of Zymosan A. In CCR2+/+ mice, the number and the size of granulomas gradually increased until they reached peak values at 10 days after the injection. In contrast, both the number and the size of granulomas were smaller in CCR2−/− mice than in CCR2+/+ mice from days 5 to 21. They showed low peaks at day 5, after which the number and the size of the granulomas gradually decreased. Immunohistochemical analysis of the constituent granuloma cells using cell type‐specific monoclonal antibodies revealed rapid accumulation of blood monocytes, with subsequent differentiation to macrophages, in CCR2+/+ mice during days 2–10. This process was greatly impaired in CCR2−/− mice and granulomas remained small. At all time points, the percentage of polymorphonuclear cells in granulomas was higher in CCR2−/− mice than in CCR2+/+ mice. Interestingly, multinucleate giant cells were frequently observed in granulomas in CCR2−/− mice, whereas they rarely appeared in CCR2+/+ mice. Profiles of liver cytokine RNA levels as well as serum cytokine levels revealed reduced expression of the Th1 cytokine IFN‐γ in CCR2−/− mice. These data clearly indicate that signalling through CCR2 has many effects on the normal growth and development of hepatic granulomas. Copyright © 2003 John Wiley & Sons, Ltd.
In vivo and in vitro models demonstrate a role for caveolin‐1 in the pathogenesis of ischaemic acute renal failure
Authors: Mahmoudi Mitra , Willgoss Desley , Cuttle Leila , Yang Tao , Pat Betty , Winterford Clay , Endre Zoltan , Johnson David W , Gobé Glenda C
Published: July 2003

Caveolae and their proteins, the caveolins, transport macromolecules; compartmentalize signalling molecules; and are involved in various repair processes. There is little information regarding their role in the pathogenesis of significant renal syndromes such as acute renal failure (ARF). In this study, an in vivo rat model of 30 min bilateral renal ischaemia followed by reperfusion times from 4 h to 1 week was used to map the temporal and spatial association between caveolin‐1 and tubular epithelial damage (desquamation, apoptosis, necrosis). An in vitro model of ischaemic ARF was also studied, where cultured renal tubular epithelial cells or arterial endothelial cells were subjected to injury initiators modelled on ischaemia–reperfusion (hypoxia, serum deprivation, free radical damage or hypoxia–hyperoxia). Expression of caveolin proteins was investigated using immunohistochemistry, immunoelectron microscopy, and immunoblots of whole cell, membrane or cytosol protein extracts. In vivo, healthy kidney had abundant caveolin‐1 in vascular endothelial cells and also some expression in membrane surfaces of distal tubular epithelium. In the kidneys of ARF animals, punctate cytoplasmic localization of caveolin‐1 was identified, with high intensity expression in injured proximal tubules that were losing basement membrane adhesion or were apoptotic, 24 h to 4 days after ischaemia–reperfusion. Western immunoblots indicated a marked increase in caveolin‐1 expression in the cortex where some proximal tubular injury was located. In vitro, the main treatment‐induced change in both cell types was translocation of caveolin‐1 from the original plasma membrane site into membrane‐associated sites in the cytoplasm. Overall, expression levels did not alter for whole cell extracts and the protein remained membrane‐bound, as indicated by cell fractionation analyses. Caveolin‐1 was also found to localize intensely within apoptotic cells. The results are indicative of a role for caveolin‐1 in ARF‐induced renal injury. Whether it functions for cell repair or death remains to be elucidated. Copyright © 2003 John Wiley & Sons, Ltd.
Retracted: Autonomous histopathological regression of primary tumours associated with specific immune responses to cancer antigens
Authors: Saleh Farid H , Crotty Kerry A , Hersey Peter , Menzies Scott W , Rahman Wassim
Published: July 2003

This article has been retracted. See retraction notice [DOI: 10.1002/path.2082]

Spontaneous histopathological regression of cancer has been reported. The involvement of the immune system in such regression has been advocated, leading to the theory of immunological surveillance against cancer. A prediction of this theory is that common tumour antigens can be recognized upon repeated exposure by cell‐mediated immunity, which leads to tumour regression and the subsequent appearance of tumour antigen‐loss variants. However, no direct evidence has been provided in non‐viral‐induced experimental animal models of primary malignancy or in human primary cancer. This study examined two groups of melanoma patients where histopathological regression of the primary tumour was observed. Many of the 23 patients with multiple (≥3) primary melanomas showed significant regression of their last melanoma (median 33%, mean 40) compared with matched melanomas from patients with a single primary melanoma (median 0%, mean 12) (p = 0.0080), or compared with their first primary melanoma (p = 0.0013). Regression was consistent with an ‘immunization effect’ seen in murine tumour transplantation studies, where inoculation with ≥3 asynchronous tumours induces transplantation rejection on subsequent challenge. A significant decrease in the expression of the melanoma common tumour antigen MART‐1 in the last primary tumour from multiple melanoma patients (median 8%, mean 24) versus matched single melanoma patients (median 79%, mean 68) (p = 0.0041) and in the last versus first tumour in multiple primary patients was found (p = 0.0083). Metastases from 17 patients whose primary skin melanomas had completely regressed (occult primary melanoma) also showed significant MART‐1 loss (median 0%, mean 11) compared with matched metastases from patients with non‐regressing primary melanoma (median 51%, mean 50) (p = 0.0013). MART‐1 antigen‐loss variants observed in the multiple primary and occult primary patients correlated with the presence of peripheral blood MART‐1‐specific cytotoxic T lymphocytes (CTLs) (p = 0.03). No similar effects were observed with two other melanoma antigens, gp100 and CD63. Thus, in two groups of human melanoma patients, evidence is provided for histopathological tumour regression associated with cancer immune surveillance. Copyright © 2003 John Wiley & Sons, Ltd.
Histological evidence of testicular dysgenesis in contralateral biopsies from 218 patients with testicular germ cell cancer
Authors: Hoei‐Hansen Christina E , Holm Mette , Rajpert‐De Meyts Ewa , Skakkebaek Niels E
Published: July 2003

This study was prompted by a hypothesis that testicular germ cell cancer may be aetiologically linked to other male reproductive abnormalities as a part of the so‐called ‘testicular dysgenesis syndrome’ (TDS). To corroborate the hypothesis of a common association of germ cell cancer with testicular dysgenesis, microscopic dysgenetic features were quantified in contralateral testicular biopsies in patients with a testicular germ cell tumour. Two hundred and eighty consecutive contralateral testicular biopsies from Danish patients with testicular cancer diagnosed in 1998–2001 were evaluated retrospectively. Two hundred and eighteen specimens were subsequently included in this study, after 63 patients who did not meet inclusion criteria had to be excluded. The presence of carcinoma in situ (which is believed to originate from transformed gonocytes) was detected in 8.7% of biopsies. The incidence of other dysgenetic features was immature tubules with undifferentiated Sertoli cells, 4.6%; microcalcifications (microliths), 6.0%; and the presence of a Sertoli‐cell‐only pattern in at least a few tubules, 13.8%. The cumulative incidence of one or more signs of testicular dysgenesis was 25.2%. In a few patients, areas with immature and morphologically distorted tubules were also noted. Spermatogenesis was qualitatively normal in 51.4%, whereas 11.5% had very poor or absent spermatogenesis. It is concluded that microscopic testicular dysgenesis is a frequent feature in contralateral biopsies from patients presenting with testicular germ cell neoplasms of the adolescent and young type. The findings therefore support the hypothesis that this cancer is part of a testicular dysgenesis syndrome. The presence of contralateral carcinoma in situ was higher in the present study than previously reported. Copyright © 2003 John Wiley & Sons, Ltd.
The basement membrane matrix in malignancy
Authors: Engbring Jean A , Kleinman Hynda K
Published: July 2003

Cancer is the second most common cause of death among Americans, although for several age groups it ranks first. Most of these deaths are not due to the primary tumour but rather to tumour cell metastases to distant organs. There are many steps that lead to metastasis, all of which are being studied with the goal of preventing these fatalities. Normally, cells attach to the extracellular matrix to maintain tissue integrity. During cancer progression, cells become more motile and acquire invasive qualities. Tumour cells move along blood and lymph vessels or invade into them to travel to distant sites. Then, the tumour cells must attach to the vessel wall, extravasate from the vessel, invade the new tissue, proliferate, and form a secondary tumour. Angiogenesis, the formation of new blood vessels, is critical to survival of these cells at the new site and is also important for primary tumour growth and spread. Tumour cell metastasis is a complex cascade of sequential steps, each of which is not yet fully understood. Progress has been made in identifying several key activators, one of which is the extracellular matrix. A major tumour promoter is the glycoprotein laminin, which is predominantly found in the extracellular matrix produced by endothelial and epithelial cells. This review will follow the metastatic process with particular attention to the effect of laminin on tumour cells. Copyright © 2003 John Wiley & Sons, Ltd.
Integrins in regulation of tissue development and function
Authors: Danen Erik HJ , Sonnenberg Arnoud
Published: July 2003

An erratum for this article has been published in Journal of Pathology; 201(4): 632–641.

Cell adhesion is indispensable for embryonic development and for proper tissue function. In metazoans, integrins are the major adhesion receptors that connect cells to components of the extracellular matrix. Integrins are implicated in assembly of extracellular matrices, cell adhesion and migration on extracellular matrices, and in vertebrates (in which the integrin family has expanded) they can also mediate cell–cell adhesion. Furthermore, integrin‐mediated adhesion can modulate many different signal transduction cascades and support cell survival, proliferation, and influence the expression of differentiation‐related genes. In this review we briefly explain how integrins can affect so many different aspects of cell behavior and discuss evidence for roles of integrins in tissue development, function, and disease. Copyright © 2003 John Wiley & Sons, Ltd.
ECM homeostasis in renal diseases: a genomic approach
Authors: Eikmans M , Baelde JJ , de Heer E , Bruijn JA
Published: July 2003

Chronic renal disease is in general histologically accompanied by a vast amount of scar tissue, ie glomerulosclerosis and interstitial fibrosis. Scarring results from excessive accumulation of extracellular matrix (ECM) components, a process driven by a plethora of cytokines and growth factors. Studies in experimental renal disease which target these regulators using gene therapy limit or prevent the development of scarring. This review focuses specifically on the role of transforming growth factor‐beta, platelet‐derived growth factor, connective tissue growth factor, hepatocyte growth factor, and epidermal growth factor. The results obtained in animal models hold promise for molecular intervention strategies in human renal disease. Microarray technology allows large‐scale gene expression profiling in kidney tissue to identify common molecular pathways in a step towards discovery of new drug targets. Molecular techniques are expected to be used for diagnostic and prognostic purposes in nephrological practice to supplement renal biopsy. Several studies already show that molecular techniques might be of use in routine diagnostic practice. Improvement of diagnosis and prediction of outcome in renal patients might lead to more efficient and earlier therapeutic intervention. Copyright © 2003 John Wiley & Sons, Ltd.
Microvascular basement membranes in diabetes mellitus
Authors: Tsilibary Effie C
Published: July 2003

The alterations in the microvascular system of diabetes mellitus patients are responsible for the most devastating complications of this widespread disease. In the kidney, the microangiopathy leads to thickening of the glomerular capillary basement membrane but also to the expansion of the mesangial matrix and thickening of the tubular basement membrane. Several mechanisms are implicated in the pathogenesis of diabetic renal microangiopathy. These include increased synthesis of type IV collagen following hyperglycaemia‐induced alteration of the pattern of podocyte–integrin expression, decreased expression of matrix metalloproteinases (MMP‐2 and 3), and increased expression of tissue inhibitor of metalloproteinase (TIMP). An altered morphology of podocytes accompanies these basement membrane alterations. Other factors which may contribute to renal matrix accumulation include vascular endothelial growth factor (VEGF), since treatment with anti‐VEGF antibodies attenuates glomerular basement membrane thickening, platelet‐derived growth factor (PDGF) (B chain) and its receptor, which appear to be highly expressed in mesangial and visceral epithelial cells and might play a role in the development of diabetic nephropathy. Also oxygen radicals/oxidative stress may play a role in matrix accumulation in diabetic nephropathy as aminoguanidine, an inhibitor of the formation of advanced glycation end‐products but with antioxidant properties, attenuates diabetic nephropathy. Retinal diabetic microangiopathy follows much the same principles, be it that microvascular proliferation is a distinctive element in the retina. Nephropathy and retinopathy occur frequently but not always together, indicating that in their multifactorial pathogenesis much remains to be clarified. Copyright © 2003 John Wiley & Sons, Ltd.
Electrospray ionization mass spectrometry coupled to liquid chromatography for detection of cisplatin and its hydrated complexes
Authors: Cui Meng , Mester Zoltán
Published: July 2003

Electrospray ionization mass spectrometry (ESI‐MS) coupled to liquid chromatography (LC) has been applied to investigate cisplatin and its hydrated complexes. Three hydrolysis products were identified following incubation of cisplatin in aqueous solution: monohydrated species, dihydrated species and the hydroxo‐bridged dimer, each of which exhibited characteristic mass spectrometric behavior. The technique was employed to investigate the time‐ and pH‐dependent hydrolysis of cisplatin in aqueous solution. The results have demonstrated that LC/ESI‐MS is a powerful technique for the analysis of Pt(II) complexes and for monitoring their hydrolysis reactions. Copyright © 2003 Crown in the right of Canada. Published by John Wiley & Sons, Ltd.
Reversed‐phase ion‐pairing liquid chromatography/ion trap mass spectrometry for the analysis of negatively charged, derivatized glycans
Authors: Gennaro Lynn A. , Harvey David J. , Vouros Paul
Published: July 2003

The significant complexity, similar polarity and lack of ionizable sites make the analysis of glycans an analytical challenge. These compounds are often derivatized and separated by normal‐phase high‐performance liquid chromatography (HPLC) or capillary electrophoresis (CE) followed by UV or fluorescence detection. Due to widespread use of reversed‐phase chromatography coupled to electrospray mass spectrometry as an analytical tool, our laboratory has developed this methodology for the analysis of glycans derivatized with a negatively charged tag, 8‐aminonaphthalene‐1,3,6‐trisulfonic acid (ANTS). It is possible to exploit the ability of this negatively charged tag to interact with a mobile phase ion‐pairing reagent, allowing retention on a reversed‐phase C18 column for subsequent on‐line UV or MS analysis. ANTS‐derivatized samples, including a maltooligosaccharide ladder and glycans released from bovine ribonuclease B, bovine fetuin, and chicken ovalbumin, were analyzed using this method. In addition to reversed‐phase retention, ribonuclease B and ovalbumin derivatives displayed highly desirable isomeric separation. With the use of mass spectrometric detection for glycan identity, this allowed relative quantitation of individual components. Copyright © 2003 John Wiley & Sons, Ltd.
Proton transfer reaction ion trap mass spectrometer
Authors: Prazeller Peter , Palmer Peter T. , Boscaini Elena , Jobson Tom , Alexander Michael
Published: July 2003

Proton transfer reaction mass spectrometry is a relatively new field that has attracted a great deal of interest in the last few years. This technique uses H3O+ as a chemical ionization (CI) reagent to measure volatile organic compounds (VOCs) in the parts per billion by volume (ppbv) to parts per trillion by volume (pptv) range. Mass spectra acquired with a proton transfer reaction mass spectrometer (PTR‐MS) are simple because proton transfer chemical ionization is ‘soft’ and results in little or no fragmentation. Unfortunately, peak identification can still be difficult due to isobaric interferences. A possible solution to this problem is to couple the PTR drift tube to an ion trap mass spectrometer (ITMS). The use of an ITMS is appealing because of its ability to perform MS/MS and possibly distinguish between isomers and other isobars. Additionally, the ITMS duty cycle is much higher than that of a linear quadrupole so faster data acquisition rates are possible that will allow for detection of multiple compounds. Here we present the first results from a proton transfer reaction ion trap mass spectrometer (PTR‐ITMS). The aim of this study was to investigate ion injection and storage efficiency of a simple prototype instrument in order to estimate possible detection limits of a second‐generation instrument. Using this prototype a detection limit of 100 ppbv was demonstrated. Modifications are suggested that will enable further reduction in detection limits to the low‐ppbv to high‐pptv range. Furthermore, the applicability of MS/MS in differentiating between isobaric species was determined. MS/MS spectra of the isobaric compounds methyl vinyl ketone (MVK) and methacrolein (MACR) are presented and show fragments of different mass making differentiation possible, even when a mixture of both species is present in the same sample. However, MS/MS spectra of acetone and propanal produce fragments with the same molecular masses but with different intensity ratios. This allows quantitative distinction only if one species is predominant. Fragmentation mechanisms are proposed to explain the results. Copyright © 2003 John Wiley & Sons, Ltd.
A rapid and sensitive liquid chromatography/tandem mass spectrometry method for determination of docetaxel in human plasma
Authors: Wang L. Z. , Goh B. C. , Grigg M. E. , Lee S. C. , Khoo Y. M. , Lee H. S.
Published: July 2003

A novel, rapid and sensitive isocratic liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed for quantification of docetaxel in human plasma with paclitaxel as internal standard. The high sensitivity and specificity of MS/MS detection enabled the use of a small volume of plasma (0.05 mL) and a simple liquid‐liquid extraction procedure. Furthermore, a very short run‐time (3 min) fulfilled the need for monitoring plasma levels of docetaxel from large‐scale clinical studies. The calibration curve for docetaxel was linear over the range 5–1000 ng/mL with coefficients of correlation >0.999 using only 0.05 mL plasma. The intra‐ and inter‐day precisions (CV) of analysis were <7%, and accuracy ranged from 96 to 110%. The applicability of the method was demonstrated in a pharmacokinetic study of a 1‐h infusion of docetaxel with dosages of 75 mg/m2. Possible conjugated metabolites of docetaxel were not detected in patients' samples. Copyright © 2003 John Wiley & Sons, Ltd.
Urine drug testing for opioids, cocaine, and metabolites by direct injection liquid chromatography/tandem mass spectrometry
Authors: Dams Riet , Murphy Constance M. , Lambert Willy E. , Huestis Marilyn A.
Published: July 2003

A sensitive and specific liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the simultaneous quantification of opioids, cocaine, and metabolites in urine was developed and validated. A 10‐μL aliquot of urine was injected directly onto the LC/MS/MS system. The lack of sample preparation substantially reduced total analysis time. Separation was performed by reversed‐phase chromatography with gradient elution for all analytes in 26 min. Atmospheric pressure chemical ionization (APCI) was a rugged and efficient ionization technique for basic drugs. Identification and quantification was based on selected reaction monitoring (SRM). Calibration, with deuterated internal standards, was performed by linear regression analysis (weighting factor 1/x). Limits of quantitation (LOQ) were established between 10–100 ng/mL and linearity was obtained up to a maximum of 10 000 ng/mL with an average correlation coefficient (R2) > 0.99. Analytical validation criteria for specificity, precision, accuracy, dilution integrity, matrix effect, and stability were fulfilled. The method proved to be simple and time efficient, and was applicable for illicit drug use monitoring and methadone treatment compliance in clinical research projects at the National Institute on Drug Abuse (NIDA). Published in 2003 by John Wiley & Sons, Ltd.
Making Claims for Power: A New Agenda in Dalit Politics of Uttar Pradesh, 1946-48
Authors: Rawat Ramnarayan S.
Published: July 2003

‘. . . [T]he awakened untouchable today is repeatedly asking them [the Congress] if they could not remove the ‘social evil’ of their own creation without political power, how do they expect us [the untouchables] to liberate ourselves without political power’. (Shastri, Poona Pact. 1946, p. 24)

‘This is 1946, not 1932’. (Shastri, Poona Pact. 1946, p.76)

Shankaranand Shastri's statements help us locate two related propositions that came to constitute Dalit politics in Uttar Pradesh in the 1940s. The first proposition deals with claims made by Dalits to acquire political power—specifically in the form of adequate representation in the provincial legislative assemblies and in the Constituent Assembly. They demanded positive discrimination in the form of reservations within legislative and executive institutions. Safeguards for Dalits, it was argued, should be incorporated into the proposed constitution for Indian citizens. The second proposition concerns achhut identity, through which Dalits hoped to reconstitute their polity in UP. The Scheduled Castes Federation (SCF) and even a section of Congress Harijans staked a claim for achhut identity to distinguish their difference from ‘other communities.’ Dalit writings increasingly depicted the Poona Pact as a great betrayal by the Congress and the British. From their experience of the two general elections of 1937 and 1946, they argued that the electoral mechanism worked out under the aegis of the Poona Pact was structured against the Dalits.
Banten Rebellion, 1750-1752: Factors behind the Mass Participation
Authors: Ota Atsushi
Published: July 2003

The Banten Rebellion of 1750 has been described in two recent standard accounts in totally different ways. M. C.
Ricklefs emphasizes the political conflicts between the ruler and the elite in court circles as a principal cause of the
uprising, while J. Kathirithamby-Wells views this event as a consequence of the economic exploitation of an
oppressed people. Why has this same event been depicted so differently?
Commissioning care services for older people in England: the view from care managers, users and carers
Authors: WARE TRICIA , MATOSEVIC TIHANA , HARDY BRIAN , KNAPP MARTIN , KENDALL JEREMY , FORDER JULIEN
Published: July 2003

One of the key objectives of the community care reforms of 1990 in the United Kingdom was the development of a flourishing independent sector alongside good quality public services. The aims of the reforms were to increase the available range of options, widen consumer choice and promote independence. The purpose of the study reported here was to examine – from the perspective of older service users, their carers and care managers – experiences at the operational level of arranging, delivering and receiving care services. The findings are based on data gathered in seven local authorities including reviews of case files, policy documents and face-to-face, in-depth interviews with 55 users, 37 carers and 28 care managers. There is evidence of a pronounced emphasis on procedure-based systems of care management. Potentially this has two significant consequences. First, the fostering of personal relationships may be subordinated to the organisation of short-term tasks and thereby may threaten patterns of trust and accountability. Second, the associated fragmentation of the assessment and care management process which in turn can lead to discontinuities of care for users and their carers. The paper concludes that there is still some way to go before care managers as micro-commissioners have sufficient and reliable information or available service capacity to match providers' capabilities with users' and carers' needs.
Care-giver network transformations: the need for an integrated perspective
Authors: CARPENTIER NORMAND , DUCHARME FRANCINE
Published: July 2003

This paper reviews recent research on care-giver networks and the concepts and approach that they apply, with particular reference to the support networks of the primary care-givers of older people with Alzheimer's disease. It makes the case for an integrated approach to the explanation of the various combinations of formal and informal support that are found. It argues that more attention needs to be given to transformations in care-giver networks over time, and that this will require more development of both theoretical perspectives and analytical tools. The stages of a care-giver's commitment towards an elderly relative are examined, to understand the associations between changes in the ailing person's needs, the structure of the support network and the primary care-giver's roles. This approach makes useful contributions to the understanding of the development, maintenance and dissolution of supportive ties. Following the work of Pescosolido (1991), we propose an integrated perspective that combines the ‘care-giver career’ approach and the methods of ‘social network’ analysis.