bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment of patients with progressive unresectable metastatic melanoma with a heterologous polyvalent melanoma whole cell vaccine
Authors: Vilella Ramon , Benitez Daniel , Milà Jordi , Vilalta Antoni , Rull Ramon , Cuellar Francisco , Conill Carles , Vidal‐Sicart Sergi , Costa Josep , Yachi Eva , Palou Josep , Malvehy Josep , Puig Susana , Marti Rosa , Mellado Begoña , Castel Teresa 
Published: July 2003

AbstractUnresectable metastatic melanoma has no elective treatment. Neither chemotherapy, intravenous IL‐2 nor biochemotherapy clearly improves the overall survival. Recent assays with therapeutic vaccines have been recently yielded promising results. Here, we describe the application, clinical tolerance and antitumoural activity of a heterologous polyvalent melanoma whole cell vaccine in patients with metastatic melanoma. Twenty‐eight AJCC stage III/IV melanoma patients with progressive unresectable metastatic disease were treated with our heterologous polyvalent melanoma whole cell vaccine between July 1, 1998 and July 1, 2002. All patients had already been unsuccessfully treated with high doses of IFN‐α2 and/or polychemotherapy and/or biochemotherapy and/or perfusion of extremities, or could not receive other treatments due to their age or underlying illness. Twenty‐three were assessable. The vaccine was constituted by 10 melanoma cell lines, derived from primary, lymph node and metastatic melanomas. Prior to intradermal inoculation, the cells were irradiated and mixed with BCG, and 50% were treated with DNFB. After a median follow‐up of 19 months, 26% of patients responded: 3 CR (18, 16+, and 26+ months), 2 PR (8 and 22 months) and 1 MR (36+ months). The median survival of the whole group was 20.2 months. None of the 28 patients initially included in the study presented significant toxicity. This vaccination program had specific antitumoural activity in advanced metastatic melanoma patients and was well tolerated. The clinical responses and the median survival of our group of patients, together with the low toxicity of our polyvalent vaccine, suggest that this approach could be applied to earlier metastatic melanoma patients. © 2003 Wiley‐Liss, Inc.
Influence of drug‐induced apoptotic death on processing and presentation of tumor antigens by dendritic cells
Authors: Buttiglieri Stefano , Galetto Alessandra , Forno Sarah , De Andrea Marco , Matera Lina 
Published: July 2003

AbstractHere we have studied the effects of apoptotic cell death induced by chemotherapic agents on tumor phagocytosis by dendritic cells (DC) and presentation of the relevant antigen to T lymphocytes. Annexin‐V‐FITC (Ann‐V) and propidium iodide (PI) staining was used to assess early apoptotic (Ann‐V+/PI−) vs. late apoptotic/secondary necrotic (Ann‐V+/PI+) death after a 24 hr observation of untreated and drug‐treated gastric carcinoma cells. After treatments, the HLA‐A*0201+ tumor cell line KATO III was exposed for 24 hr to allogeneic, HLA‐related GM‐CSF, IL‐4‐driven immature (i) DC. Tumor‐loaded iDC were tested for IL‐12 release in an ELISA assay, incubated with the DC‐maturating factor TNF‐α and used as stimulators for autologous T lymphocytes. Generation of antitumor T response against KATO cells was evaluated in an anti‐MHC class I MAb‐blocked Interferon‐γ ELISPOT assay. After treatment with Cis‐platin (cis), all dying cells were in early apoptosis, whereas secondary necrosis was the prevalent death pattern observed after epirubicin (epi) and doxorubicin (doxo). Doxo and epi increased tumor expression of heat shock protein (hsp) 70 and uptake of tumor cell components by DC, whereas cis treatment had no effect on hsp70 and was associated with poor tumor uptake by DC. Significant upmodulation of IL‐12 was observed by DC that had taken up the doxo‐ and epi‐treated tumors (p< 0.005 and p< 0.01, respectively). Increased IFN‐γ release was also observed after stimulation of T lymphocytes with DC loaded with doxo‐ and epi‐treated (p< 0.02 and p< 0.005, respectively) but not with cis‐treated DC. These data show that the products of early apoptosis cannot efficiently cross‐activate MHC class I‐restricted anti‐tumor lymphocytes even in the presence of DC maturating factors, whereas secondary necrosis is associated with robust T cell response. © 2003 Wiley‐Liss, Inc.
Polymorphisms in the CYP1A1 gene are associated with prostate cancer risk
Authors: Chang Bao‐li , Zheng Siqun L. , Isaacs Sarah D. , Turner Aubrey , Hawkins Gregory A. , Wiley Kathy E. , Bleecker Eugene R. , Walsh Patrick C. , Meyers Deborah A. , Isaacs William B. , Xu Jianfeng 
Published: July 2003

AbstractCYP1A1 is likely to play an important role in the etiology of CaP through its function in activating environmental procarcinogens and catalyzing the oxidative metabolites of estrogens. To test the hypothesis that genetic polymorphisms in the CYP1A1 gene may be associated with the risk for CaP, we compared the allele, genotype and haplotype frequencies of 3 SNPs (3801T>C, 2455A>G and 2453C>A) of CYP1A1 among 159 HPC probands, 245 sporadic CaP cases and 222 unaffected men. Two SNPs (3801T>C and 2455A>G) were each individually associated with CaP risk when the allele and genotype frequencies were compared between CaP patients and unaffected controls. Furthermore, a combined SNP analysis using a haplotype approach revealed an even stronger association in Caucasians. Specifically, 4 major haplotypes (T‐A‐C, C‐A‐C, C‐G‐C and T‐A‐A) accounted for 99.8% of all observed haplotypes. These 4 haplotypes correspond to the previously described nomenclature (CYP1A1*1A, CYP1A1*2A, CYP1A1*2B and CYP1A1*4). The frequencies of these 4 haplotypes were significantly different among CaP patients and controls. The haplotype T‐A‐C (CYP1A1*1A) was significantly associated with increased risk for CaP, and the haplotype C‐A‐C (CYP1A1*2A) was significantly associated with decreased risk for CaP. These findings suggest that genetic polymorphisms in CYP1A1 may modify the risk for CaP. © 2003 Wiley‐Liss, Inc.
Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C, hepatitis B and alcoholic liver cirrhosis
Authors: Edamoto Yoshihiro , Hara Akira , Biernat Wojciech , Terracciano Luigi , Cathomas Gieri , Riehle Hans‐Martin , Matsuda Masanori , Fujii Hideki , Scoazec Jean‐Yves , Ohgaki Hiroko 
Published: July 2003

AbstractMajor etiologic factors associated with human hepatocellular carcinomas (HCCs) include infection with hepatitis C (HCV) and hepatitis B virus (HBV), excess alcohol intake and aflatoxin B1 exposure. While the G→T p53 mutation at codon 249 has been identified as a genetic hallmark of HCC caused by aflatoxin B1, the genetic profile associated with other etiologic factors appears to be less distinctive. In our study, we screened HCCs resulting from HCV infection (51 cases), HBV infection (26 cases) or excess alcohol intake (23 cases) for alterations in genes involved in the RB1 pathway (p16INK4a, p15INK4b, RB1, CDK4 and cyclin D1), the p53 pathway (p53, p14ARF and MDM2) and the Wnt pathway (β‐catenin, APC). Alterations of the RB1 pathway, mainly p16INK4a methylation, loss of RB1 expression and cyclin D1 amplification, were most common (69–100% of cases). There was a significant correlation between loss of RB1 expression and RB1 methylation. All 24 HCCs with RB1 promoter methylation lacked RB1 expression, while none of the 67 cases with RB1 expression exhibited RB1 methylation (p < 0.0001), suggesting that promoter methylation is a major mechanism of loss of RB1 expression in HCCs. Alterations of the p53 pathway consisted mostly of p53 mutations or p14ARF promoter methylation (20–48%). Mutations of the p53 gene were found at a similar frequency (13–15%) in all etiologic groups, without any consistent base change or hot spot. Mutations of β‐catenin were found in 13–31% of cases, while no APC mutations were detected in any of the HCCs analyzed. With the exception of only 3 of 39 cases (8%), cyclin D1 amplification and β‐catenin mutations were mutually exclusive, supporting the view that cyclin D1 is a target of the Wnt signaling pathway. Overall, the RB1, p53 and Wnt pathways were commonly affected in HCCs of different etiology, probably reflecting common pathogenetic mechanisms, i.e., chronic liver injury and cirrhosis, but tumors associated with alcoholism had more frequent alterations in the RB1 and p53 pathways than those caused by HCV infection. © 2003 Wiley‐Liss, Inc.
Expression of Concern: The retinoblastoma protein interacts with Bag‐1 in human colonic adenoma and carcinoma derived cell lines
Authors: Arhel Nathalie J. , Packham Graham , Townsend Paul A. , Collard Tracey J. , H‐Zadeh Akram M. , Sharp Adam , Cutress Ramsey I. , Malik Karim , Hague Angela , Paraskeva Chris , Williams Ann C. 
Published: July 2003

AbstractAlthough the retinoblastoma susceptibility gene RB1 is inactivated in a wide range of human tumours, overexpression in colonic carcinomas has been linked to the antiapoptotic function of the protein. In the current study we show that the Retinoblastoma susceptibility protein (Rb) protein interacts with Bag‐1, an apoptotic regulator, in human colonic adenoma‐ and carcinoma‐derived cell lines. Coimmunoprecipitation demonstrated that endogenous Rb and Bag‐1 interact in both adenoma‐ and carcinoma‐derived cell lines. The specificity of the interaction was demonstrated by expression of human Papillomavirus E7 oncoprotein, an inhibitor of Rb protein interactions, which disrupted the Rb/Bag‐1 complex. We report that Bag‐1 is predominantly localised in the nucleus of colorectal adenoma‐ and carcinoma‐derived epithelial cells. Disruption of the Rb/Bag‐1 complex through expression of E7 changes the subcellular distribution of Bag‐1, decreasing nuclear localised Bag‐1. Our work establishes that the Rb protein interacts with the Bag‐1 apoptotic regulator protein, and introduces a novel function for Rb, involving modulation of the subcellular localisation of Bag‐1 in human colonic epithelial cells. © 2003 Wiley‐Liss, Inc.
Green tea and risk of breast cancer in Asian Americans
Authors: Wu Anna H. , Yu Mimi C. , Tseng Chiu‐Chen , Hankin Jean , Pike Malcolm C. 
Published: July 2003

AbstractThere is substantial in vitro and in vivo evidence implicating tea polyphenols as chemopreventive agents against various cancers. However, epidemiologic data obtained from mainly Western populations are not supportive of a protective role of tea, mainly black tea, in the etiology of breast cancer. Much less is known about the relationship between green tea and breast cancer risk. During 1995–1998, we conducted a population‐based, case‐control study of breast cancer among Chinese, Japanese and Filipino women in Los Angeles County and successfully interviewed 501 breast cancer patients and 594 control subjects. Detailed information on menstrual and reproductive factors; dietary habits, including intake of black and green tea; and other lifestyle factors was collected. Risk of breast cancer was not related to black tea consumption. In contrast, green tea drinkers showed a significantly reduced risk of breast cancer, and this was maintained after adjusting for age, specific Asian ethnicity, birthplace, age at menarche, parity, menopausal status, use of menopausal hormones, body size and intake of total calories and black tea. Compared to women who did not drink green tea regularly (i.e., less than once a month), there was a significant trend of decreasing risk with increasing amount of green tea intake, adjusted odds ratios being 1.00, 0.71 (95% confidence interval [CI] 0.51–0.99) and 0.53 (95% CI 0.35–0.78), respectively, in association with no, 0–85.7 and >85.7 ml of green tea per day. The significant inverse association between risk of breast cancer and green tea intake remained after further adjustment for other potential confounders, including smoking; alcohol, coffee and black tea intake; family history of breast cancer; physical activity; and intake of soy and dark green vegetables. While both green tea and soy intake had significant, independent protective effects on breast cancer risk, the benefit of green tea was primarily observed among subjects who were low soy consumers. Similarly, the protective effect of soy was primarily observed among subjects who were nondrinkers of green tea. In summary, our results point to an important role of both green tea and soy intake in relation to breast cancer risk in Asian‐American women. © 2003 Wiley‐Liss, Inc.
Expression profiling reveals that methylation of TIMP3 is involved in uveal melanoma development
Authors: van der Velden Pieter A. , Zuidervaart Wieke , Hurks Monique H.M.H. , Pavey Sandra , Ksander Bruce R. , Krijgsman Elise , Frants Rune R. , Tensen Cornelis P. , Willemze Rein , Jager Martine J. , Gruis Nelleke A. 
Published: July 2003

AbstractUveal melanoma is associated with a high tumor‐related mortality due to the propensity to develop metastases. The mechanisms that are responsible for malignant dissemination are largely unknown and need to be explored to facilitate diagnosis and treatment of metastases. To identify molecules involved in dissemination, we used cell lines derived from a primary uveal melanoma and 2 liver metastases from the same patient as a model for tumor progression. Using a microarray representing 1,176 genes, we identified 63 differentially expressed genes. Forty genes showed a higher expression and 23 showed a lower expression in the primary cell line compared to the metastasis cell lines. These genes are involved in processes like angiogenesis, apoptosis, macrophage stimulation, and extracellular matrix regulation. In contrast, the 2 liver metastasis cell lines produced nearly identical expression profiles. Demethylation of the primary melanoma cell line by 5‐aza‐2′deoxycytidine treatment revealed that 19 genes were suppressed by hypermethylation. An important finding was the 5‐fold decreased expression of TIMP3 in the metastatic cell lines, a molecule involved in extracellular matrix degradation. We demonstrate in the cell lines that TIMP3 expression is regulated by methylation. These observations were confirmed in primary uveal melanoma and suggests a role for TIMP3 in uveal melanoma development. © 2003 Wiley‐Liss, Inc.
Obesity and hormone‐dependent tumors: Cohort and co‐twin control studies based on the Swedish Twin Registry
Authors: Jonsson Fredrik , Wolk Alicja , Pedersen Nancy L. , Lichtenstein Paul , Terry Paul , Ahlbom Anders , Feychting Maria 
Published: July 2003

AbstractObesity increases the risk of certain cancer types, e.g., cancer of the endometrium, colon and gallbladder. For some other cancer forms, e.g., prostate cancer, the association is less clear. We examined the association between body mass index (BMI) and hormone‐dependent tumors, utilizing a cohort of 21,884 Swedish twins born during 1886–1925. Information about BMI at different ages and potential confounding factors was collected prospectively. The Swedish Cancer Registry was used to identify cases of cancer in the prostate (n = 666), breast (n = 607), corpus uteri (n = 150) and ovary (n = 118) during 1969–1997. The material was analyzed as a traditional cohort and with co‐twin control analyses that allow for control of genetic influences. Obesity (BMI ≥30 kg/m2) at baseline was positively associated with cancer in the corpus uteri [relative risk (RR) = 3.03, 95% confidence interval (CI) 1.82–5.03], as was BMI at age 25, independently of BMI at baseline. Increased risk was also found for breast cancer but only in older women (≥70 years). Overweight at age 25 was associated with decreased risk of breast cancer (RR = 0.51, 95% CI 0.33–0.78). No association was found for prostate cancer. We conclude that age is an important effect modifier of cancer risk associated with obesity and that obesity and overweight in young adult life may affect cancer risk also later in life. © 2003 Wiley‐Liss, Inc.
Nitric oxide‐mediated promotion of mammary tumour cell migration requires sequential activation of nitric oxide synthase, guanylate cyclase and mitogen‐activated protein kinase
Authors: Jadeski Lorraine C. , Chakraborty Chandan , Lala Peeyush K. 
Published: July 2003

AbstractUsing clonal derivatives of spontaneous mammary tumours in C3H/HeJ mice, we had earlier shown that tumour‐derived nitric oxide (NO), resulting from endothelial type (e) NO synthase (NOS) expression by tumour cells, promoted tumour growth and metastasis by multiple mechanisms: stimulation of tumour cell invasiveness, migration and angiogenesis. Our present study examined the signaling mechanisms underlying NO‐mediated promotion of tumour cell migration in a highly metastatic and high eNOS‐expressing C3H/HeJ mammary tumour cell line, C3L5. C3L5 cell migration was reduced in the presence of NG‐nitro‐L‐arginine methyl ester (L‐NAME, NOS inhibitor) in a concentration‐dependent manner and restored in the additional presence of excess L‐arginine (NOS substrate), confirming a migration‐promoting role of endogenous NO. Migratory capacity of C3L5 cells was reduced after treatment with the guanylate cyclase (GC) inhibitor 1‐H‐[1,2,4]oxadiaxolo[4,3‐a]quinolalin‐1‐one (ODQ) and restored in the additional presence of 8‐bromoguanosine 3′5′‐cyclic monophosphate (8‐Br cGMP, cGMP analogue), demonstrating a pivotal role for GC in C3L5 cell migration. Mitogen‐activated protein kinase kinase (MAPKK; MEK) inhibitor, UO126, blocked migration, demonstrating MEK involvement in C3L5 cell migration. Furthermore, both ODQ and UO126 blocked migration‐restoring effects of L‐arginine in L‐NAME‐treated cells, indicating that GC and MAPK pathways are required for endogenous NO‐mediated migratory responses. Similarly, L‐NAME reduced and additional treatment with excess L‐arginine or sodium nitroprusside (SNP, NO donor) stimulated phosphorylation of extracellular signal‐regulated kinases (ERK1/2), demonstrating a role for endogenous and exogenous NO in ERK1/2 activation. ODQ inhibited ERK1/2 activation, whereas 8‐Br cGMP stimulated ERK1/2 phosphorylation in L‐NAME‐treated cells, indicating that cGMP is a downstream effector of NOS for ERK1/2 activation. Finally, both ODQ and UO126 blocked the capacity of L‐arginine to restore ERK1/2 phosphorylation in L‐NAME‐treated cells, demonstrating that GC and MEK are both required for endogenous NO‐mediated MAPK activation. Together, these results indicate sequential activation of NOS, GC and MAPK pathways in mediating signals for C3L5 cell migration, an essential step in invasion and metastasis. Since NOS activity is positively associated with human breast cancer progression, the present results are relevant for development of therapeutic modalities for this disease. © 2003 Wiley‐Liss, Inc.
Prevalence of BRCA1 and BRCA2 germline mutations in young breast cancer patients: A population‐based study
Authors: de Sanjosé Silvia , Léoné Mélanie , Bérez Victoria , Izquierdo Angel , Font Rebeca , Brunet Joan M. , Louat Thierry , Vilardell Loreto , Borras Joan , Viladiu Pau , Bosch F. Xavier , Lenoir Gilbert M. , Sinilnikova Olga M. 
Published: July 2003

AbstractOur aim was to estimate the prevalence of mutations in the BRCA1 and BRCA2 genes among unselected incident cases of breast cancer in young women. We identified 158 incident breast cancer cases diagnosed before age 46 years in predefined geographic areas in Girona and Tarragona, Spain, during 1995–1997. Of these, 136 (86%) provided information on family history of cancer and were screened for BRCA1 and BRCA2 mutations. Nine of the 136 (6.6%) were found to carry BRCA deleterious mutations (MUT) (1 BRCA1 and 8 BRCA2), and 20 were detected with rare BRCA variants of unknown significance (UV). Both MUT and US BRCA alterations were more frequent in younger patients: 7 (11.6%) MUT and 12 (19.3%) UV carriers were found in the group of 62 patients younger than 40 years, whereas 2 (2.7%) MUT and 9 (12%) US carriers were identified in the group of 74 patients aged 40–45. Family history of breast and ovarian cancers suggestive of hereditary condition (at least 2 first‐ or second‐degree relatives affected with breast cancer or at least 1 relative affected with ovarian cancer or early‐onset breast cancer) was absent for 5 of 9 MUT carriers. This suggests that BRCA screening policies based on family history of cancer would miss a considerable proportion of BRCA mutations. Mutations in the BRCA1 and BRCA2 genes explain at least 10% of breast cancer cases diagnosed before age 40 years. The contribution of these genes to early‐onset breast cancer is likely to be even higher given that certain UV cases might be disease‐associated. © 2003 Wiley‐Liss, Inc.
Detection of micrometastatic breast cancer by means of real time quantitative RT‐PCR and immunostaining in perioperative blood samples and sentinel nodes
Authors: Schröder Carolien P. , Ruiters Marcel H.J. , de Jong Steven , Tiebosch Anton T.M.G. , Wesseling Jelle , Veenstra Rense , de Vries Jaap , Hoekstra Harold J , de Leij Lou F.M.H. , de Vries Elisabeth G.E. 
Published: July 2003

AbstractThe aim of our study was to detect micrometastatic breast cancer by epithelial glycoprotein‐2 (EGP‐2) and cytokeratin 19 (CK19), using immunostaining and real time quantitative reverse transcriptase‐polymerase chain reaction (qRT‐PCR). Fifty‐eight breast cancer patients, 52 primary tumors, 75 sentinel nodes (SN) and 149 peripheral blood (PB) samples (from before, during and 4 days after operation) were examined. Immunostaining was performed with antibodies directed against EGP‐2 and CK19. Detection limits were one Michigan Cancer Foundation‐7 (MCF‐7) breast cancer cell line cell/2.106 leukocytes (immunostaining) and one MCF‐7 cell/106 leukocytes qRT‐PCR. Control noncancer lymph nodes (n = 10) showed nonspecific CK19 staining, but were qRT‐PCR negative; control healthy volunteer PB (n = 11) was always negative. Primary tumor samples, all positive with immunostaining, showed a wide variation of EGP‐2 (>104 fold) and CK19 mRNA expression (>103 fold). SN (n = 19) from 16 patients were tumor‐positive with routine haematoxylin‐eosin (H&E) and/or immunostaining. SN tumor presence was positively correlated to qRT‐PCR expression, but 3 tumor‐positive SN were false negative with qRT‐PCR. Three SN were qRT‐PCR positive, while tumor negative with H&E and/or immunostaining. No immunostaining positive PB was observed, but 19 patients (33%) had one or more qRT‐PCR positive PB samples. We concluded that primary tumors have varying expressions of EGP‐2 and CK19 mRNA. Both markers can be used in qRT‐PCR to obtain adequate sensitivity for single tumor cell detection. In SN, immunostaining appears more sensitive/specific than H&E or qRT‐PCR for tumor detection. No immunostaining positivity was found in PB, while 33% of patients had qRT‐PCR positive PB. The clinical value of these findings will have to be clarified. © 2003 Wiley‐Liss, Inc.
Development of the vomeronasal receptor epithelium and the accessory olfactory bulb in sheep
Authors: Salazar Ignacio , Lombardero Matilde , Alemañ Nuria , Sánchez Quinteiro Pablo 
Published: July 2003

AbstractThe morphological development of the vomeronasal organ (VNO) and accessory olfactory bulb (AOB) of the sheep from anlage to birth were studied by classical and histochemical methods using embryos and fetuses obtained from an abattoir with ages estimated from crown‐to‐rump length. Both VNO and AOB developed in a biologically logical sequence and completed their morphological development around day 98, at entry into the last third of the gestation period. A lectin with specificity for oligomeric N‐acetylglucosamine labeled the sensory epithelium of the VNO, the vomeronasal nerves, and the nervous and glomerular layers of the AOB before birth. These results suggest that the vomeronasal system, which is well developed and functional in adult sheep, may be able to function at or even before birth in these animals (whereas in rodents, for example, this is precluded by the AOB not completing its development until after birth). Microsc. Res. Tech. 61:438–447, 2003. © 2003 Wiley‐Liss, Inc.