bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of radionecrosis on cognitive dysfunction in patients after radiotherapy for nasopharyngeal carcinoma
Authors: Cheung Mei‐Chun , Chan Agnes S. , Law Stephen C. , Chan John H. , Tse Vincent K.
Published: April 2003

BACKGROUND

Cognitive dysfunction is common in patients who develop radionecrosis after receiving radiotherapy for nasopharyngeal carcinoma (NPC). However, the impact of the location and volume of radionecrosis on cognitive dysfunction remains unclear. The authors found a significant association between the severity of cognitive impairment and the volume of radionecrosis; in turn, the volume of radionecrosis was affected by patient age at time radiotherapy was completed.

METHODS

Fifty patients with NPC who received radiotherapy were evaluated by a battery of neuropsychologic tests of cognitive function. The brain lesion volume was quantified, and the lesion locations were identified by standardized brain templates. The results of the neuropsychologic tests were correlated with lesion volume. Gender, education, age at the completion of radiotherapy, brain volume, total dose, and fractional dose were evaluated as risk factors for lesion volume.

RESULTS

Lesion volume was correlated significantly with the severity of cognitive deficits. Larger left‐hemisphere lesions were correlated with lower verbal memory (from P < 0.001 to P = 0.008) and language abilities (from P = 0.001 to P = 0.018), whereas larger right‐hemisphere lesions were associated with worse visual memory (from P = 0.009 to P = 0.039). Finally, patients who received radiotherapy at a younger age had smaller lesion volumes (P < 0.001).

CONCLUSIONS

The volume and location of radionecrosis had an influential impact on the pattern of cognitive impairment found in patients with NPC, and patient age at the time radiotherapy was completed appeared to affect the volume of radionecrosis found after radiotherapy. Cancer 2003;97:2019–26. © 2003 American Cancer Society.

DOI 10.1002/cncr.11295
Phase II study of SU5416—a small‐molecule, vascular endothelial growth factor tyrosine‐kinase receptor inhibitor—in patients with refractory myeloproliferative diseases
Authors: Giles Francis J. , Cooper Maureen A. , Silverman Lewis , Karp Judith E. , Lancet Jeffrey E. , Zangari Maurizio , Shami Paul J. , Khan Khuda D. , Hannah Alison L. , Cherrington Julie M. , Thomas Deborah A. , Garcia‐Manero Guillermo , Albitar Maher , Kantarjian Hagop M. , Stopeck Alison T.
Published: April 2003

BACKGROUND

Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are of adverse prognostic significance in patients with myeloproliferative disorders (MPD), including agnogenic myeloid metaplasia (AMM), chronic myeloid leukemia in blastic phase (CML‐BP), and chronic myelomonocytic leukemia (CMML). VEGF is a soluble, circulating, angiogenic molecule that acts through receptor tyrosine kinases (RTK), including VEGF receptor 2 (VEGFR‐2). SU5416 is a small‐molecule RTK inhibitor (RTKI) that targets VEGFR‐2, c‐kit, and fms‐related tyrosine kinase Flk2.

METHODS

Adult patients with advanced CMML, AMM, CML‐BP, or other BCR‐ABL negative MPD were entered on a multicenter, Phase II study.

RESULTS

Thirty‐two patients (19 patients with BCR‐ABL negative MPD, 6 patients with CMML, 4 patients with CML‐BP, and 3 patients with AMM) with a median age of 66 years (range, 29–85 years) received SU5416 145 mg/m2 twice weekly intravenously for a median of three 4‐week cycles (maximum, 12 cycles). Drug‐related Grade 3–4 toxicities included acute abdominal pain (13%), bone pain (9%), infusion‐related dyspnea (9%) or headache (6%), fatigue (6%), diarrhea (3%), and catheter site reactions (3%). Eleven patients (34%) did not receive a second cycle of therapy (6 patients had progressive disease, 3 because of adverse events; 2 patients withdrew due to lack of response). One patient with AMM achieved a partial response. Eight patients received more than 6 months of therapy.

CONCLUSIONS

SU5416 had minimal clinical activity in patients with MPD. Long‐term administration of a twice‐weekly, hyperosmolar, intravenous solution containing polyoxyl 35 castor oil was difficult. More tolerable RTKI may be worthy of further investigation in patients with MPD. Cancer 2003;97:1920–8. © 2003 American Cancer Society.

DOI 10.1002/cncr.11315
IARC Handbooks of Cancer Prevention
Authors: Feig Stephen A.
Published: April 2003

DOI 10.1002/cncr.11334
Attributable and absolute risk of lung cancer death by smoking status: Findings from the Japan collaborative cohort study
Authors: Ando Masahiko , Wakai Kenji , Seki Nao , Tamakoshi Akiko , Suzuki Koji , Ito Yoshinori , Nishino Yoshikazu , Kondo Takaaki , Watanabe Yoshiyuki , Ozasa Kotaro , Ohno Yoshiyuki ,   JACC Study Group
Published: April 2003

Estimating the proportion of lung cancer deaths that can be avoided is important in assessing the potential impact of antismoking efforts on the reduction of lung cancer deaths. We calculated the population attributable risk (PAR) and absolute risk of lung cancer death according to smoking status based on the Japan Collaborative Cohort (JACC) Study. The analytic cohort included 45,010 males and 55,724 females aged 40–79 years. Cox proportional hazards model was used to determine age‐adjusted relative risks and PAR according to smoking status. We also computed lung cancer mortality according to age and smoking status. In males, 52.2% and 14.8% of lung cancer deaths were attributable to current and former cigarette smoking, respectively. In females, the corresponding figures were 11.8% and 2.8%. Among current male smokers, the relative risk was strongly correlated with the intensity and duration of cigarette smoking. In contrast, the PAR was associated with an intermediate level of smoking except for the years of smoking: the largest PARs were observed in those with 20–29 cigarettes per day, 40–59 pack‐years and 20–22 years old at starting smoking. Absolute risks were estimated to increase with age and duration of smoking and not to decrease even after cessation. These findings suggest that avoidable lung cancer deaths are primarily among light to moderate smokers who are considered amenable to population‐based antismoking strategies. For all current smokers, immediate cessation is encouraged because it offers the only realistic way to avoid a substantial increase in lung cancer mortality brought about by further continuation of smoking. © 2003 Wiley‐Liss, Inc.
Ki‐67 index enhances the prognostic accuracy of the urothelial superficial bladder carcinoma risk group classification
Authors: Santos Lúcio , Amaro Teresina , Costa Céu , Pereira Sofia , Bento Maria José , Lopes Paula , Oliveira Jorge , Criado Begoña , Lopes Carlos
Published: April 2003

Approximately 80% of bladder tumors are urothelial superficial papillary carcinomas (USPC). Despite a generally good prognosis, these tumors have a strong propensity to recur and about 1/3 of them compared to disease progression. Histological assessment of these superficial tumors is not sufficiently discriminator in predicting prognosis; therefore, we decided to evaluate the prognostic significance of p53 and Ki‐67 immunoexpression in low‐grade (GI‐II) USPC in order to predict the potential outcome of these tumors. P53 and Ki‐67 immunoexpression were studied in function of recurrence‐free and progression‐free survival in 159 primary superficial bladder tumors. A prognostic risk model based on grade, stage and multifocality was also evaluated. P53 accumulation was significantly related to tumor progression (p=0.006). High Ki‐67 index (≥18%) and multifocality were significantly related to recurrence (both p=0.0001) and progression‐free survival (both p=0.0001) and were independent prognostic factors in the multivariate analysis. The prognostic risk model based on grade, stage and multifocality was not an efficient discriminator of outcome. Adding the Ki‐67 index into the risk model, single pTa/T1‐GI Ki‐67 positive tumors, usually classified as low risk, were reclassified as of intermediate risk. After this reclassification, the risk group model identified a subgroup of pTa/T1‐G1 with a high risk of recurrence and progression. Ki‐67 index is a reliable prognostic marker in urothelial superficial bladder carcinoma and, when included into a risk profile classification of the low‐grade USPC, the accuracy of the prognostic discrimination is enhanced. © 2003 Wiley‐Liss, Inc.
Hypermethylation of the tumor suppressor gene RASSFIA and frequent concomitant loss of heterozygosity at 3p21 in cervical cancers
Authors: Yu Mei Y. , Tong Joanna H.M. , Chan Paul K.S. , Lee Tin L. , Chan Michael W.Y. , Chan Anthony W.H. , Lo Kwok W. , To Kai F.
Published: April 2003

Loss of heterozygosity (LOH) at chromosome 3p21 is frequent in cervical cancers. The candidate tumor suppressor gene, RASSF1A located at 3p21.3, is found to be inactivated in several major human cancers, implicating its significance in carcinogenesis. We aimed to investigate the status of RASSF1A in cervical cancers. The mutation and methylation status of RASSF1A were analysed in 4 cervical cancer cell lines, 50 primary cervical cancers including 33 squamous cell carcinoma (SCC), 17 adenocarcinoma (AC) and 11 normal controls. The primary cancer samples were also detected for LOH at 3p21 and human papillomavirus (HPV). Hypermethylation of RASSF1A was detected in 30% of SCC, 12% of AC and in 1 of the 4 cancer cell lines but was absent in all normal cases. Methylation of the cancer cell line was associated with loss of gene expression, which was restored by demethylation. About 67% (8 of 12) of hypermethylated primary cancers showed concomitant LOH at 3p21. No somatic mutation was found in all primary cancer samples or cell lines but 2 cases showed germline polymorphism at codon 133. Oncogenic HPV DNAs were found in most cancer samples. No correlation was detected between RASSF1A‐hypermethylation or LOH at 3p21 and age of patient, HPV genotype, tumor grade and stage. Hypermethylation of RASSF1A occurs in a subset of cervical cancers, among which concomitant LOH at 3p21 is common. The results supported that RASSF1A may be one of the cervical cancer‐related tumor suppressor genes located at 3p21 regions. © 2003 Wiley‐Liss, Inc.
Differences in T‐cell immunity toward tumor‐associated antigens in colorectal cancer and breast cancer patients
Authors: Nagorsen Dirk , Scheibenbogen Carmen , Schaller Gerhard , Leigh Binta , Schmittel Alexander , Letsch Anne , Thiel Eckhard , Keilholz Ulrich
Published: April 2003

There is increasing evidence that tumors elicit specific T‐cell responses in a substantial proportion of patients. Recently, we have shown that in patients with colorectal cancer specific T cells against the tumor‐associated antigens (TAA) Ep‐CAM, her‐2/neu or CEA can be detected in peripheral blood using IFNγ‐ELISPOT assay. In our study, we have analyzed T‐cell responses against HLA‐A*0201‐restricted epitopes of these TAA in peripheral blood of patients with breast cancer and colorectal cancer. Surprisingly, a complete absence of ex vivo T‐cell responses against these TAA was found in 20 patients with breast cancer. In contrast, specific T cells were detectable in 12 of 49 patients with colorectal cancer against at least 1 of these TAA, confirming our previous results. T‐cell responses against influenza‐derived peptides were similar in both malignancies. The results of our study indicate a difference either of tumor immunogenicity or of the migratory pattern of tumor‐specific T cells between breast cancer and colorectal cancer patients. The findings reported here have implications for the development of antigen‐specific T‐cell therapies. © 2003 Wiley‐Liss, Inc.
Atopic disease and childhood acute lymphoblastic leukemia
Authors: Schüz Joachim , Morgan Gareth , Böhler Eva , Kaatsch Peter , Michaelis Jörg
Published: April 2003

Our objective was to test the hypothesis that the risk of childhood leukemia is associated with allergies or a family history of allergy. We used a German population‐based case‐control study with self‐reported information on allergies of the children and their first‐degree relatives. Our study included a total of 1,130 cases of acute lymphoblastic leukemia (ALL), 164 cases of acute myeloid leukemia (AML) and 2,957 controls. A major finding of our study is that hay fever, neurodermatitis and contact eczema are underrepresented within the group of children with ALL, with respective odds ratios (OR) of 0.45 (95% confidence interval [CI] 0.31–0.66) for hay fever, of 0.49 (CI 0.34–0.71) for neurodermatitis and of 0.62 (CI 0.39–0.99) for eczema, respectively. Atopic diseases, comprising hay fever, neurodermatitis and asthma, are much stronger related with a reduced risk of ALL than other allergies (OR 0.52, CI 0.40–0.67 vs. OR 0.89, CI 0.66–1.21). The strongest association is seen with an atopy in the index child; however, ALL risk is also reduced if one of the parents or a sibling had an atopic disease. No such consistent pattern is seen for AML. Our data suggest that atopy or a family history of atopy are associated with a reduced risk of childhood ALL. Recall bias remains a concern, but sensitivity analysis provided some evidence that the protective effect is unlikely to be attributable to this bias in its entirety. © 2003 Wiley‐Liss, Inc.
Targeting of cells expressing wild‐type EGFR and type‐III mutant EGFR (EGFRvIII) by anti‐EGFR MAb ICR62: A two‐pronged attack for tumour therapy
Authors: Modjtahedi Helmout , Moscatello David K. , Box Gary , Green Margaret , Shotton Christine , Lamb David J. , Reynolds Lesley J. , Wong Albert J. , Dean Christopher , Thomas Hilary , Eccles Suzanne
Published: April 2003

With a view to their use in cancer therapy, we have produced rat monoclonal antibodies (MAbs) directed against 5 distinct epitopes (A–E) on the external domain of the wild‐type human EGF receptor (EGFR). Here, we have investigated the relative binding and anti‐tumour activity of our anti‐EGFR MAbs against HC2 20d2/c cells, which have been engineered to overexpress the type‐III mutated form of the human EGFR (EGFRvIII). We found that anti‐EGFR MAbs that are the most effective antagonists of EGFR ligands (e.g., ICR16, ICR62 and ICR80) also bind to cells that overexpress the EGFRvIII. Although these antibodies are potent inhibitors of the growth of cells which express wild‐type EGFR, they did not directly inhibit the growth in vitro of EGFRvIII expressing HC2 20d2/c cells, or the constitutive tyrosine kinase activity of this receptor. However, in the presence of human peripheral blood mononuclear cells (PBMC), the rat IgG2b MAb ICR62 induced strong antibody‐dependent cell‐mediated cytotoxicity (ADCC) against HC2 20d2/c cells in culture. Interestingly, MAb ICR62 also inhibited very effectively experimental lung metastases of HC2 20d2/c cells in athymic nude mice. Our results suggest that anti‐EGFR MAb ICR62, which binds to the EGFRvIII, may have potential in the treatment of tumors which overexpress the EGFRvIII via immunological mechanisms such as ADCC. Since tumours that are EGFRvIII positive may also overexpress the wild‐type EGFR, the use of anti‐EGFR MAbs that target both wild‐type and mutant receptors may have advantages over those that target only1form. © 2003 Wiley‐Liss, Inc.
Immunization with tumor‐derived ER chaperone grp170 elicits tumor‐specific CD8+ T‐cell responses and reduces pulmonary metastatic disease
Authors: Wang Xiang‐Yang , Kazim Latif , Repasky Elizabeth A. , Subjeck John R.
Published: April 2003

Glucose‐regulated protein (grp) 170 is a molecular chaperone localized in endoplasmic reticulum (ER), which has been demonstrated to interact with the peptides translocated by transporter associated with antigen presentation (TAP). In our study, we have evaluated the therapeutic efficacy of tumor‐derived grp170 against the highly metastatic and poorly immunogenic murine melanoma B16F10. Immunization of mice with grp170 preparations from autologous tumor significantly delayed progression of the primary cancer and reduced established pulmonary metastases, which was associated with the prolonged survival of metastases‐bearing mice. However, grp170 from normal liver or antigenically distinct tumor failed to exhibit therapeutic effect. In addition, tumor‐derived grp170 elicited a potent cytotoxic T‐lymphocyte response specific for B16F10 tumor, which correlates with in vivo protective effects. Adoptive transfer of splenocytes obtained from B16F10‐grp170‐primed animals remarkably suppressed pulmonary metastases. Depletion of either CD4+ or CD8+ T cells in priming phase significantly abrogated the tumor immunity induced by the B16F10‐grp170. However, the vaccine activity was intact when CD4+, not CD8+, T cells were depleted in effector phase. It suggests that CD4+ T helper cells play an important role in the generation of effective antitumor response, whereas CD8+ T cells are predominantly involved in direct killing of tumor cells. These observations have strong clinical implications for using tumor‐derived grp170 as a therapeutic vaccine against metastatic diseases. © 2003 Wiley‐Liss, Inc.
Altered tumor vessel maturation and proliferation in placenta growth factor‐producing tumors: Potential relationship to post‐therapy tumor angiogenesis and recurrence
Authors: Taylor Alice P. , Rodriguez Marisol , Adams Kelly , Goldenberg David M. , Blumenthal Rosalyn D.
Published: April 2003

Cells in human tumor xenografts express similar levels of angiogenic growth factors before treatment. After radioimmunotherapy (RAIT) surviving tumor cells upregulate angiogenic growth factors, including placenta growth factor (PlGF), in a tumor‐specific pattern. To determine the role of post‐treatment PlGF expression on blood vessel recovery, tumor xenografts were assayed for post‐RAIT vessel density (CD34+), proliferation (PCNA+) and maturity (SMA+ pericytes/mural cells). To further analyze the role of PlGF in blood vessel formation, PlGF‐containing Matrigel implants were also assessed in a similar manner. The xenografts producing post‐treatment PlGF increased CD34+ microvessel density 2‐ to 4‐fold over untreated controls (p < 0.05) within 3 weeks of RAIT treatment. The proportion of mature microvessels (SMA+) decreased. Pericyte coverage and density of microvessels remained stable in the tumor that expressed neither PlGF nor VEGF after treatment. Hemoglobin content of PlGF‐containing Matrigel implants was 5.7‐fold that of anti‐PlGF/anti‐VEGF treated controls (Day 6, p < 0.03). The vessel density in PlGF‐implants averaged 36.8 ± 10.6/mm compared to 4.9 ± 6.5/mm2 in controls (p < 0.001). Vessels of PlGF‐implants were lined by vWF+ cells, which were mostly flt‐1+. These findings point to a role for PlGF in rapid restoration of tumor blood supply after treatment and thus, to enhanced likelihood of tumor regrowth. Likewise, the cells of primary human tumors that upregulate PlGF after treatment may be more likely to survive and form recurring tumors. Prevention of this angiogenic response to treatment may require administration of anti‐angiogenic therapy during, rather than after, treatment. © 2003 Wiley‐Liss, Inc.
Von Hippel‐Lindau gene alterations in sporadic benign and malignant pheochromocytomas
Authors: Dannenberg Hilde , De Krijger Ronald R. , van der Harst Erwin , Abbou Mustaffa , IJzendoorn Ynske , Komminoth Paul , Dinjens Winand N.M.
Published: April 2003

The Von Hippel‐Lindau (VHL) gene product has a wide spectrum of tissue‐specific functions, and specific germline mutations are associated with clinical phenotypes in VHL disease. In particular, missense mutations are correlated with the susceptibility to pheochromocytomas. An association between VHL aberrations and prognosis has been suggested in renal clear cell carcinoma but has not been studied in pheochromocytomas. We studied the frequency and spectrum of VHL alterations in apparently sporadic pheochromocytomas in relation to the clinical behavior in 72 patients, including 48 patients with clinically benign and 24 patients with malignant pheochromocytomas. Single‐strand conformation polymorphism (SSCP) analysis followed by DNA sequencing, loss of heterozygosity analysis of the VHL locus and immunohistochemistry for VHL protein expression were used to investigate somatic VHL gene alterations. In 2 patients, 1 with a malignant tumor, germline mutations were identified in the stop codon. Tumor‐specific intragenic VHL mutations and accompanying loss of heterozygosity were identified in 2 (4.3%) of 47 sporadic benign pheochromocytomas compared to 4 (17.4%) of 23 malignant tumors (p = 0.064). Only one of these mutations has been previously described, in a renal clear cell carcinoma. Expression of the VHL protein was observed in all pheochromocytomas. No distinction in the nature of VHL alterations between benign and malignant pheochromocytomas and no correlation with histopathologic or clinical features was observed. We report novel VHL mutations in sporadic pheochromocytomas, which are slightly correlated with malignancy. VHL mutations may have some impact on the malignant transformation of pheochromocytomas. © 2003 Wiley‐Liss, Inc.
TP53, p14ARF, p16INK4a and H‐ras gene molecular analysis in intestinal‐type adenocarcinoma of the nasal cavity and paranasal sinuses
Authors: Perrone Federica , Oggionni Maria , Birindelli Sarah , Suardi Simona , Tabano Silvia , Romano Roberta , Moiraghi Maria Luisa , Bimbi Gabriella , Quattrone Pasquale , Cantu Giulio , Pierotti Marco A. , Licitra Lisa , Pilotti Silvana
Published: April 2003

Intestinal‐type adenocarcinoma (ITAC) of the nasal cavity and paranasal sinuses is an uncommon tumor associated with occupational exposure to dusts of different origin. Few investigations addressed molecular alterations in ITAC mainly focused on TP53, K‐ras and H‐ras gene mutations. The occurrence of TP53, p14ARF and p16INK4a deregulation and H‐ras mutations was investigated in 21 consecutive and untreated ITACs cases, 17 with known professional exposure. No H‐ras mutations were found. In patients with known exposure, cumulative evidence of TP53 or p14ARF alterations accounted for 88% and the evidence of p16INK4a alterations for 65%, respectively. TP53 mutations were present in 44% of the ITACs, consisted of G:C→A:T transitions in 86%, and involved the CpG dinucleotides in 50% of the cases. LOH at the locus 17p13 and an uncommon high rate of p53 stabilization were detected in 58% and 59% of the cases, respectively. p14ARFand p16INK4a promoter methylation accounted for 80% and 67% respectively, and LOH at the locus 9p21 occurred in 45% of the cases. Interestingly, all dust‐exposed tumors with p16INK4a alterations shared TP53 or p14ARF deregulation. The present results show a close association of this occupational tumor with TP53, p14ARF and p16INK4a gene deregulation. Given the important role that these genes play in cell growth control and apoptosis, the knowledge of ITAC genetic profile may be helpful in selecting more tailored treatments. © 2003 Wiley‐Liss, Inc.
Overexpression of CCR7 mRNA in nonsmall cell lung cancer: Correlation with lymph node metastasis
Authors: Takanami Iwao
Published: April 2003

Tumor cell migration into the lymph nodes is an important aspect of cancer, yet little is known about the processes involved. CCR7 has been shown to play an important role in tumor cell migration and lymph node metastasis. The aim of our study was to evaluate the expression of CCR7 in nonsmall cell lung cancers (NSCLCs). We investigated CCR7 expression in 71 patients with NSCLC who underwent curative tumor resection by means of reverse transcription‐polymerase chain reaction (RT‐PCR) and immunohistochemistry. CCR7 mRNA was expressed in 45 cases (63.3%). The CCR7 mRNA expression was significantly associated with lymph node metastasis, stage, lymphatic invasion, CCR7 protein and CXCR4 protein (p = 0.0001 for lymph node metastasis; p < 0.0001 for stage; p = 0.0454 for lymphatic invasion; p < 0.0001 for CCR7 protein; p = 0.0013 for CXCR4 protein). Twenty‐six (57.8%) of 45 cases with CCR7 mRNA expression in their cancer tissues were node‐positive, whereas only 3 (11.5%) of 26 cases without CCR7 mRNA expression were node‐positive. Furthermore, expression of CCR7 mRNA was shown to be an independent predictor of lymph node metastasis by multivariate analysis (p = 0.0117). Our study demonstrates that CCR7 might be related to the development of lymph node metastasis in NSCLC. The expression of CCR7 mRNA could open up a new window for the diagnostic staging and treatment of NSCLC. © 2003 Wiley‐Liss, Inc.
Persistence of xenogenized vaccine cells in vivo
Authors: Graf Nicolas , Adam Christian , Mocikat Ralph
Published: April 2003

Trioma cell vaccination is a potent new immunotherapeutic strategy for the treatment of B cell neoplasias. It is based on the specific redirection of tumor antigens against surface receptors on professional antigen‐presenting cells (APC) that internalize antigens and present immunogenic peptides to T‐lymphocytes. Tumor cells are converted to trioma cells by fusion with xenogeneic hybridomas expressing an anti‐APC specificity. The trioma cell is a polyvalent vaccine that contains potentially all lymphoma‐derived antigens. Apart from the expression of the APC‐binding arm by the trioma cell, another requirement for successful tumor protection is the xenogeneic moiety of the trioma cells. We show that, despite their xenogenicity, trioma cells persist for extended periods in vaccinated animals. Trioma cells could be identified in spleens as long as about 12 weeks post vaccination. By using a suicide gene approach, trioma cells could partly be eliminated from immunized mice, whereby the antitumor effect was partly abrogated. We argue that not all trioma cells are immediately lysed in vivo and that the cell cycle of the remaining cells is arrested after having undergone few divisions. Trioma cells surviving in vivo may be instrumental for efficient induction of tumor immunity. © 2003 Wiley‐Liss, Inc.
Expression of hypoxia‐inducible factor‐1α is associated with tumor vascularization in human colorectal carcinoma
Authors: Kuwai Toshio , Kitadai Yasuhiko , Tanaka Shinji , Onogawa Seiji , Matsutani Norimasa , Kaio Eijiro , Ito Masanori , Chayama Kazuaki
Published: April 2003

HIF‐1 is reported to transactivate expression of VEGF, which is an important angiogenic factor. To determine whether HIF‐1α plays a role in angiogenesis through its regulation of VEGF, we examined expression of HIF‐1α and its relation to clinicopathologic features, VEGF expression and prognosis of patients with colorectal carcinoma. Expression of HIF‐1α and VEGF was examined in 4 colorectal carcinoma cell lines (COLO320DM, COLO201, DLD‐1, WiDr) and 149 colorectal carcinoma tissues (10 fresh specimens, 139 archival, paraffin‐embedded specimens). HIF‐1α protein levels were increased by hypoxia in 3 of 4 colorectal carcinoma cell lines (COLO201, DLD‐1, WiDr), and VEGF mRNA levels were also increased by hypoxia in the same cell lines. In 8 of 10 patients with colorectal cancer, expression of HIF‐1α and VEGF was increased in tumor tissues compared to corresponding normal mucosa. Of 139 archival specimens of colorectal carcinoma, 81 (58.3%) expressed HIF‐1α protein at a high level. HIF‐1α expression was correlated with tumor invasion, tumor stage, lymphatic invasion, venous invasion and liver metastasis. Moreover, HIF‐1α expression was correlated significantly with VEGF expression and microvessel density. Although there was a tendency for poorer prognosis in patients with high HIF‐1α‐expressing tumors, this correlation was not statistically significant. These findings suggest that HIF‐1α may play a role in angiogenesis and tumor progression via regulation of VEGF in human colorectal carcinoma. © 2003 Wiley‐Liss, Inc.
Children, family and cancer survival in Norway
Authors: Kravdal Øystein
Published: April 2003

Models for all‐cause mortality among 45,000 men and women with cancer in 12 different sites were estimated, using register and census data for complete Norwegian birth cohorts. This observed‐survival method appeared to be an adequate approach. The results support the idea that women who were pregnant shortly before a breast cancer diagnosis may have a poorer prognosis than others. In principle, such an effect may also reflect that these women have a young child during the follow‐up period and are burdened by that. However, this social explanation can hardly be very important, given the absence of a corresponding significant effect in men and for other cancer sites in women. Breast cancer is different from other malignancies also with respect to the effect of parenthood more generally, regardless of the timing of the pregnancies. On the whole, male and female cancer patients with children experience lower mortality than the childless, though without a special advantage associated with adult children. This suggests a social effect, perhaps operating through a link between parenthood, lifestyle and general health. No parity effect was seen for breast cancer, however, which may signal that the social effect is set off against an adverse physiologic effect of motherhood for this particular cancer. Among men, both marriage and parenthood were associated with a good prognosis. Married male cancer patients with children had mortality one‐third lower than that among the childless and never‐married. Women who had never married did not have the same disadvantage. © 2003 Wiley‐Liss, Inc.
Frequent downregulation of DMBT1 and galectin‐3 in epithelial skin cancer
Authors: Mollenhauer Jan , Deichmann Martin , Helmke Burkhard , Müller Hanna , Kollender Gaby , Holmskov Uffe , Ligtenberg Toon , Krebs Inge , Wiemann Stefan , Bantel‐Schaal Ursula , Madsen Jens , Bikker Floris , Klauck Sabine M. , Otto Herwart F. , Moldenhauer Gerd , Poustka Annemarie
Published: April 2003

DMBT1 and galectin‐3 are potential interacting proteins with presumably complex roles in tumorigenesis. While at present a variety of mechanisms are discussed for DMBT1 and its participation in cancer, galectin‐3 is commonly known to exert tumor‐promoting effects. However, in vitro studies in a rodent system have suggested that DMBT1/galectin‐3 interaction in the ECM triggers epithelial differentiation, which would point to tumor‐suppressive properties. To improve the understanding of DMBT1/galectin‐3 action in cancer, we carried out studies in skin cancer of different origins. Mutational analyses of DMBT1 identified a missense mutation in 1 of 13 melanoma cell lines. It led to an exchange of an evolutionary conserved proline residue for serine and located within the second CUB domain of DMBT1. Immunohistochemical analyses demonstrated absence of DMBT1/galectin‐3 expression from melanocytes but induction of DMBT1 expression in 1 of 8 nevi and 1 of 11 melanomas and of galectin‐3 expression in 3 of 8 nevi and 4 of 8 melanomas. These data suggest that DMBT1 and galectin‐3 are unlikely to act as classical tumor suppressors in melanomas. DMBT1 and galectin‐3 appear to be secreted to the ECM by epithelial cells within the epidermis and the hair follicle. Compared to the flanking normal epidermis, skin tumors of epithelial origin frequently displayed downregulation of DMBT1 (18 of 19 cases) and galectin‐3 (12 of 12 cases). Thus, loss of DMBT1/galectin‐3 expression may play a role in the genesis of epithelial skin cancer. This would support the view that galectin‐3 can exert tumor‐suppressive effects in certain scenarios, and DMBT1/galectin‐3‐mediated differentiation represents a candidate mechanism for this effect. © 2003 Wiley‐Liss, Inc.
A robust method for determining 1H–15N long‐range correlations: 15N optimized CIGAR‐HMBC experiments
Authors: Kline Mike , Cheatham Steve
Published: April 2003

An examination of a variety of common nitrogen‐containing systems was undertaken to optimize parameters for observation of 1H–15N long‐range correlations. Because of the diversity of coupling constants encountered with 1H–15N correlations, a modified accordion‐based sequence was used to provide the best results. Optimization of the values for the accordion delay revealed that a range between 3 and 10 Hz provided the best compromise between detection of weak correlations and loss of signal to T2 processes. Multiple bond correlations were readily detected for each class of compound with the exception of anilines. Correlations within heterocyclic systems revealed some general patterns. In general, stronger correlations were observed from protons to ‘pyrrole‐like’ nitrogens than to the ‘pyridine‐type’ nitrogens of imidazoles and pyrazoles. Very long‐range (four‐ and five‐bond) correlations were routinely observed between methyl groups and the nitrogens of aromatic heterocycles. Copyright © 2003 John Wiley & Sons, Ltd.
NMR study of fumarprotocetraric acid, a complex lichen depsidone derivative from Cladonia furcata
Authors: Su Bao‐Ning , Cuendet Muriel , Nikolic Dejan , Kristinsson Hördur , Ingólfsdóttir Kristín , van Breemen Richard B. , Fong Harry H. S. , Pezzuto John M. , Kinghorn A. Douglas
Published: April 2003

A lichen depsidone derivative, fumarprotocetraric acid, was obtained as the major constituent of Cladonia furcata (Huds.) Schrad. collected in Iceland. In the 1H NMR spectrum (in DMSO‐d6) of this compound, the trans double bond proton signals of the fumaryl unit appeared as overlapping singlets. To confirm the presence of a trans double bond in the molecule, fumarprotocetraric acid was treated with triethylamine. The 1H NMR spectrum of the resultant triethylamine salt displayed a pair of clear doublets with coupling constants of 15.7 Hz, which are characteristic of a trans double bond. Unambiguous 1H and 13C NMR spectral data for both fumarprotocetraric acid and its triethylamine salt were assigned for the first time based on the interpretation of their 2D NMR (HMQC, HMBC and NOESY) spectra. Copyright © 2003 John Wiley & Sons, Ltd.
Multinuclear magnetic resonance study of chiral mesoionic oxa‐ and thiatriazole and tetrazole derivatives: adducts with dirhodium complexes and chiral recognition
Authors: Jaźwiński Jaroslaw , Rozwadowski Zbigniew , Magiera Damian , Duddeck Helmut
Published: April 2003

Mesoionic compounds 1–8 were synthesized and their 1H, 13C, 14N, 15N and 17O NMR spectra recorded in the absence and presence of the chiral dirhodium complex Rh*. It is shown that the enantiomers of the mesoionic compounds could be differentiated satisfactorily (‘dirhodium method’). Copyright © 2003 John Wiley & Sons, Ltd.
Structural investigations of three triazines: solution‐state NMR studies of internal rotation and structural information from solid‐state NMR, plus a full structure determination from powder x‐ray diffraction in one case
Authors: Birkett Helen E. , Cherryman Julian C. , Chippendale A. Margaret , Evans John S. O. , Harris Robin K. , James Mark , King Ian J. , McPherson Graham J.
Published: April 2003

Three model 2,4,6‐tris(amino)‐1,3,5‐triazines, structurally related to a dyestuff molecule previously studied by NMR, were synthesized in order to enable the effects of rotamer exchange on the NMR spectra to be investigated in more detail. Two of the compounds are novel. Internal rotation of the triazine ring substituents was studied by variable‐temperature solution‐state 1H, 13C and 15N NMR spectroscopy. All the expected rotamers were detected for each molecule. Rotamer exchange rates varied from slow to fast over the temperature range −40 to 90 °C, as observed for the dyestuff molecule itself. Solid‐state 13C and 15N NMR provided information about the structures of the solid molecules. A full crystal structure determination from high‐resolution powder x‐ray diffraction was achieved for one of the molecules using simulated annealing techniques. Ab initio MO and 15N NMR chemical shift calculations, based on energy‐minimized structures derived from the x‐ray structure determination, enabled the effect of intermolecular hydrogen bonding on the 15N NMR chemical shifts to be studied. The results compared favourably with the experimental solid‐state 15N NMR shifts. Copyright © 2003 John Wiley & Sons, Ltd.
Computer‐assisted structure elucidation of natural products with limited 2D NMR data: application of the StrucEluc system
Authors: Blinov Kirill A. , Carlson Dean , Elyashberg Mikhail E. , Martin Gary E. , Martirosian Eduard R. , Molodtsov Sergey , Williams Antony J.
Published: April 2003

This paper considers the strategy of the StrucEluc expert system application for structure elucidation of new natural products when there is a lack of connectivity information that is characteristic of proton‐deficient molecules. It is shown that in this case, a database search for fragments using a 13C NMR spectrum as input allows an investigator to fill gaps in the recorded data. Algorithms and programs have been developed that allow fragments found in the library and/or proposed by the user to be embedded in the molecular connectivities diagrams built on the basis of 2D NMR data analysis. We demonstrate the structure determination of three alkaloids from the cryptolepine series using the principles of construction and application of a user fragment library. The approach described appears to be the most efficient means of structure elucidation for natural products with 2D NMR spectra characterized by sparse responses. Copyright © 2003 John Wiley & Sons, Ltd.
DFT/FPT studies of the structural dependencies of long‐range 1H,1H coupling over four bonds 4J(H,H′) in propanic and allylic systems
Authors: Barfield Michael
Published: April 2003

A study is presented of the structural dependencies for scalar J‐coupling across four bonds in propanic and allylic systems. Density functional theory (DFT) and finite perturbation theory (FPT) were used to obtain the Fermi contact (FC) contributions to 1H,1H coupling. Interproton couplings 4J(H,H′) in propane were obtained as functions of the dihedral angles φ1 and φ3, which are measured about the C(1)—C(2) and C(2)—C(3) bonds, respectively, and on the C(1)—C(2)—C(3) internal angle θ2. A four‐term trigonometric expression reproduces the dependence on φ1 and φ3 with a standard deviation of 0.1 Hz. The molecular structures for a series of bicycloalkanes were fully optimized and DFT/FPT results for 4J(H,H′) are in good agreement with the available experimental data. However, in non‐W arrangements of bicyclic systems the propane trigonometric expression for 4J(H,H′) often gives signs opposite to those observed. It is now clear the conformational dependence of coupling constants in propane is not, in general, applicable to bicyclic systems. The DFT/FPT propane‐based results for coupling involving a methyl group (H—C—C—CH3) are in better conformity with the experimental data. The DFT/FPT results for cisoid and transoid allylic coupling 4J(H,H′) in propene were obtained as functions of the dihedral angle φ measured about the C(2)—C(3) bond. Trigonometric expressions with three terms reproduce the calculated propene results with standard deviations 0.1 Hz. The molecular structures for a series of bicycloalkenes were fully optimized and DFT/FPT results for cisoid and transoid coupling are in fairly good agreement with the available experimental data. In contrast to the propanic coupling, the trigonometric expressions for propenic coupling constants are generally applicable to conformational analyses in bicycloalkenes. Copyright © 2003 John Wiley & Sons, Ltd.
13C and 23Na solid‐state NMR spectra of organosodium compounds
Authors: Jost Steffen , Günther Harald
Published: April 2003

For three organosodium complexes, namely triphenylmethylsodium(tmeda) (1), fluorenylsodium(pmdta) (2) and fluorenylsodium(tmeda) (3), 13C and 23Na solid‐state FT‐NMR spectra have been measured for the first time. They were analysed in terms of chemical shifts, δ(13C) and δ(23Na), and 23Na quadrupole coupling constants, χ(23Na). It is shown that the NMR parameters are sensitive to the structural features of the complexes and correlate well with the contact ion‐pair structures of 1–3. 23Na resonances are shielded by ring current effects of the aromatic ligands. Copyright © 2003 John Wiley & Sons, Ltd.
Relative stereochemical determination of β‐hydroxycarbonyl compounds (aldol products) utilizing the J‐based configuration analysis method
Authors: Williamson R. Thomas , Marquez Brian L. , Sosa Ana Carolina Barrios , Koehn Frank E.
Published: April 2003

β‐Hydroxycarbonyl moieties (aldol products) are common features in a variety of molecular structures. Whether this structural motif is synthetically prepared or incorporated into a natural product, the determination of the anti or syn (threo and erythro, respectively) relationship between the α and β centers using previously reported NMR methods has, up to this point, been unreliable. Here, we report a method to determine the relative configuration of aldol products through the combined use of 3JHH homonuclear and, nJCH long‐range heteronuclear coupling constants in tandem with dipolar couplings in a manner related to the previously described J‐based configuration analysis method. Copyright © 2003 John Wiley & Sons, Ltd.
Poly(1‐butene)/clay nanocomposites: Preparation and properties
Authors: Wanjale Santosh D. , Jog J. P.
Published: April 2003

The preparation and properties of poly(1‐butene) (PB)/clay nanocomposites are described for the first time. Nanocomposites were prepared with the melt‐intercalation technique, using organically modified clay. The X‐ray diffraction patterns portrayed well‐defined diffraction peaks at higher d‐spacing than pristine clay, confirming the intercalation of polymer in silicate layers. Because PB exhibits time‐dependent polymorphism, the effect of clay on the phase transformation of PB was examined with thermal analysis. The phase transformation from a metastable tetragonal form to a stable hexagonal form was enhanced because of incorporation of layered silicates in the polymer matrix. The nanocomposites exhibited about a 40–140% increase in storage modulus depending on the clay content and significantly lower coefficient of thermal expansion. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 1014–1021, 2003
Miscibility level and mechanical characterization of blends of two liquid‐crystalline polymers based on p‐hydroxybenzoic acid
Authors: García M. , Eguiazábal J. I. , Nazábal J.
Published: April 2003

Injection‐molded blends composed of two liquid‐crystalline polymers (LCPs) based on 60/40 p‐hydroxybenzoic acid/ethylene terephthalate (R3) and 73/27 p‐hydroxybenzoic acid/2,6‐hydroxynaphthoic acid (VA) copolymers, respectively, were obtained across the whole composition range. The two amorphous phases of the blends contained only slight amounts of the minority component, and the occurrence of some chemical reaction, mainly at high VA contents, was detected by Fourier transform infrared. Synergisms in the modulus of elasticity and in the tensile strength were seen in most of the blend compositions. The largest synergism was in the 50/50 R3/VA blend, which showed a modulus of elasticity 26% higher than that of either of the two components and a 17% positive deviation in the tensile strength with respect to the rule of mixtures. The different orientation of the LCPs in the blends explains the differences in the mechanical behavior. However, contrary to previous works on LCP blends and despite the almost complete immiscibility, the observed negative volume of mixing appears to be the main parameter that determines the synergistic mechanical behavior. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 1022–1032, 2003
Epoxy resin/poly(ϵ‐caprolactone) blends cured with 2,2‐bis[4‐(4‐aminophenoxy)phenyl]propane. I. Miscibility and crystallization kinetics
Authors: Zheng Sixun , Zheng Haifeng , Guo Qipeng
Published: April 2003

Crystalline thermosetting blends composed of 2,2′‐bis[4‐(4‐aminophenoxy)phenyl]propane (BAPP)‐cured epoxy resin (ER) and poly(ϵ‐caprolactone) (PCL) were prepared via the in situ curing reaction of epoxy monomers in the presence of PCL, which started from initially homogeneous mixtures of diglycidyl ether of bisphenol A (DGEBA), BAPP, and PCL. The miscibility of the blends after and before the curing reaction was established with differential scanning calorimetry and dynamic mechanical analysis. Single and composition‐dependent glass‐transition temperatures (Tg's) were observed in the entire blend composition after and before the crosslinking reaction. The experimental Tg's were in good agreement with the prediction by the Fox and Gordon–Taylor equations. The curing reaction caused a considerable increase in the overall crystallization rate and dramatically influenced the mechanism of nucleation and the growth of the PCL crystals. The equilibrium melting point depression was observed for the blends. An analysis of the kinetic data according to the Hoffman–Lauritzen crystallization kinetic theory showed that with an increasing amorphous content, the surface energy of the extremity surfaces increased dramatically for DGEBA/PCL blends but decreased for ER/PCL blends. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 1085–1098, 2003
Epoxy resin/poly(ϵ‐caprolactone) blends cured with 2,2‐bis[4‐(4‐aminophenoxy)phenyl]propane. II. Studies by Fourier transform infrared and carbon‐13 cross‐polarization/magic‐angle spinning nuclear magnetic resonance spectroscopy
Authors: Zheng Sixun , Guo Qipeng , Chan Chi‐Ming
Published: April 2003

Crystalline thermosetting blends composed of 2,2′‐bis[4‐(4‐aminophenoxy)phenyl]propane‐crosslinked epoxy resin (ER) and poly(ϵ‐caprolactone) (PCL) were investigated by means of Fourier transform infrared (FTIR) spectroscopy and high‐resolution solid‐state NMR spectroscopy. FTIR investigations indicated that there were specific intermolecular interactions between ER and PCL and that the intermolecular hydrogen‐bonding interactions were weaker than the self‐association in pure epoxy. The intermolecular hydrogen bonding was considered to be the driving force for the miscibility of the thermosetting blends. For the examination of the miscibility of the thermosetting blends at the molecular level, high‐resolution solid‐state 13C cross‐polarity/magic‐angle spinning (CP‐MAS) NMR spectroscopy was employed. The line width of 13C CP‐MAS spectra decreased with increasing PCL contents, and the chemical shift of the carbonyl carbon resonance of PCL shifted to a low field with an increasing epoxy content in the blends. The proton spin–lattice relaxation experiments in the laboratory frame showed that all the blends possessed identical, composition‐dependent relaxation times (i.e., the proton spin–lattice relaxation times in the laboratory frame), suggesting that the thermosetting blends were homogeneous on the scale of 20–30 nm in terms of the spin‐diffusion mechanism, and this was in a good agreement with the results of differential scanning calorimetry and dynamic mechanical analysis. For the examination of the miscibility of the blends at the molecular level, the behavior of the proton lattice relaxation in the rotating frame was investigated. The homogeneity of the thermosetting blends at the molecular level was quite dependent on the blend composition. The PCL‐lean ER/PCL blends (e.g., 70/30) displayed a single homogeneous amorphous phase, and the molecular chains were intimately mixed on the segmental scale. The PCL‐rich blends displayed biexponential decay in experiments concerning the proton spin–lattice relaxation times in the rotating frame, which was ascribed to amorphous and crystalline phases. In the amorphous region, the molecular chains of epoxy and PCL were intimately mixed at the molecular level. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 1099–1111, 2003