bluuebunny/crossref_metadata_2025_split huggingface dataset:
A subset of head and neck squamous cell carcinomas exhibits integration of HPV 16/18 DNA and overexpression of p16INK4A and p53 in the absence of mutations in p53 exons 5–8
Authors: Hafkamp Harriet C. , Speel Ernst J.M. , Haesevoets Annick , Bot Fredrik J. , Dinjens Winand N.M. , Ramaekers Frans C.S. , Hopman Anton H.N. , Manni Johannes J. 
Published: September 2003

AbstractBesides well‐known risk factors such as tobacco use and alcohol consumption, oncogenic human papillomavirus (HPV) infection also has recently been suggested to promote head and neck tumorigenesis. HPV is known to cause cancer by inactivation of cell cycle regulators p53 and pRb via expression of viral oncoproteins E6 and E7. This indicates that p53 mutations are not a prerequisite in HPV‐induced tumor development. However, discrepancy exists with respect to the frequency of head and neck squamous cell carcinomas (HNSCC) harboring DNA of oncogenic HPV and the fraction of these tumors showing p53 mutations. In our study, we examined the frequency of HNSCC demonstrating HPV 16/18 integration as identified by fluorescence in situ hybridization (FISH) and investigated their p53 (mutation) status by immunohistochemistry and single‐strand conformation polymorphism (SSCP) analysis of exons 5–8. Paraffin‐embedded, archival biopsy material from 27 premalignant mucosal lesions and 47 cases of HNSCC were analyzed. Ten of the 47 (21%) HNSCC unequivocally exhibited HPV 16 integration, including 8 of 12 (67%) tonsillar carcinomas. This is supported by the immunohistochemical detection of p16INK4A overexpression in all 10 HPV‐positive tumors. Although FISH is considered to be less sensitive than PCR‐based methods for HPV detection, our data clearly demonstrate clonal association of HPV with these tumors, as illustrated by the presence of integrated HPV 16 in both the primary tumor and their metastases in 2 patients. In contrast, HPV 16/18 DNA could not be detected in the premalignant lesions. In 30 of 47 (64%), HNSCC accumulation of p53 was observed, including 8 of the 10 HPV‐positive carcinomas. However, in none of the latter cases could mutations in exons 5–8 be identified, except for a polymorphism in codon 213 of exon 6 in one patient. Evaluation of clinical data revealed a significant inverse relation between tobacco use with or without alcohol consumption, and HPV positivity of the tumors. © 2003 Wiley‐Liss, Inc.
Aberrant methylation of the cyclin D2 promoter in primary small cell, nonsmall cell lung and breast cancers
Authors: Virmani Arvind , Rathi Asha , Heda Shashank , Sugio Kenji , Lewis Cheryl , Tonk Vijay , Takahashi Takashi , Roth Jack A. , Minna John D. , Euhus David M. , Gazdar Adi F. 
Published: September 2003

AbstractDNA methylation alteration of several genes contributes to human tumorigenesis. Cyclin D2, a member of the D‐type cyclins, is implicated in cell cycle regulation and malignant transformation. In our study, we examined the methylation status of the cyclin D2 promoter in small cell lung cancer (SCLC), nonsmall cell lung cancer (NSCLC), breast tumors and tumor cell lines. We observed that aberrant methylation of cyclin D2 was present in 32 of 56 (57%) SCLC cell lines, 7 of 32 (22%) SCLC tumor tissues; 25 of 61 (47%) NSCLC cell lines, 19 of 48 (40%) NSCLC tumor tissues; 18 of 30 (60%) breast tumor cell lines and 19 of 63 (30%) breast tumor tissues. Methylation was more frequent in the tumor cell lines compared to the primary breast and SCLC tumors (p = 0.007 and p = 0.001, respectively). Methylation was rare in the control tissue samples; 0 of 12 peripheral blood lymphocytes; 0 of 12 buccal epithelial cells; 0 of 18 nonmalignant lung tissues and 3 of 28 (11%) nonmalignant breast tissues. Promoter methylation correlated with loss of transcript by reverse transcription PCR (RT‐PCR) in 9 of 11 (6 lung, 5 breast) tumor cell lines tested. Two cell lines that were not methylated also lacked expression, suggesting that other mechanisms of inactivation may be involved. Expression was restored by treatment with the demethylating agent, 5 aza 2′ deoxycytidine, in all 9 methylated cell lines. Our results confirm earlier reports in breast cancer and indicate that aberrant methylation of cyclin D2 may contribute to the pathogenesis of the 2 major types of lung cancers. © 2003 Wiley‐Liss, Inc.
Whole bladder wall photodynamic therapy of transitional cell carcinoma rat bladder tumors using intravesically administered hypericin
Authors: Kamuhabwa Appolinary A.R. , Roskams Tania , D'Hallewin Marie‐Ange , Baert Luc , Van Poppel Hein , de Witte Peter A.M. 
Published: September 2003

AbstractWhole‐bladder wall photodynamic therapy (PDT) is a promising treatment for carcinoma in situ (CIS) and diffuse premalignant changes of the bladder. After the results of our clinical studies showing that intravesical hypericin selectively accumulates in superficial bladder tumors, we investigated the hypericin‐PDT efficacy in an AY‐27 orthotopic transitional cell carcinoma rat bladder tumor model. After the instillation of hypericin (30 μM, 2 hr) in the bladder, tumors were irradiated (25–50 mW/cm 6–48 J/cm2) using 595 nm laser light. Data demonstrate that light doses of 12–48 J/cm2 resulted in selective PDT‐induced urothelial tumor damage without damaging detrusor musculature. Histological assessment of bladder sections 2 days after PDT showed tumor destruction, with tumor cells shrinking and detaching from the bladder wall. There were tumor regrowth 1–3 weeks after treatment. The in vivo/in vitro clonogenic assay results revealed up to 98% of tumor cell kill by hypericin PDT. In conclusion, hypericin PDT can be used to safely induce a selective urothelial tumor damage without damaging detrusor musculature, when optimum hypericin concentration and light fluences are used. A small percentage (2–5%) of tumor cells that survive the photodynamic treatment resulting in tumor regrowth after a prolonged period of time is likely due to oxygen depletion during light irradiation. © 2003 Wiley‐Liss, Inc.
Site‐specific human breast cancer (MDA‐MB‐231) metastases in nude rats: Model characterisation and in vivo effects of ibandronate on tumour growth
Authors: Neudert Marcus , Fischer Christian , Krempien Burkhard , Bauss Frieder , Seibel Markus J. 
Published: September 2003

AbstractAnimal models are important tools to study the development of bone metastases and to evaluate strategies for their prevention and treatment. We here describe a new model in which tumour inoculation is achieved by injection of cancer cells into the femoral artery. This approach results in the development of multiple osteolytic lesions in the distal femora and proximal tibiae within 18 days after inoculation, with a success rate of 95–100% and no additional comorbidity. In untreated animals, osteolyses expanded continuously at a growth rate of 4.7–8.2 mm2/4 days, causing extensive destruction of resident bone structures by the tumour, significant loss of tibial bone density and a transient rise in urinary bone resorption markers. Continuous daily treatment with ibandronate (10 μg/kg) inhibited further growth of fully established metastases and reduced the mean osteolytic growth rate to 0.03 mm2/4 days. In lesions <6 mm bisphosphonate treatment resulted in a negative growth rate (−0.33 to −0.81 mm2/4 days). When ibandronate was started 3 days prior to tumour cell inoculation, the development of osteolytic lesions was substantially reduced (take rate only 17%) and bone density and structure were mostly preserved. We conclude that the intra‐arterial approach used in this new model of metastatic bone disease results in site‐specific osteolytic lesions with high take rates, steady tumour growth and no additional morbidity. While serial bone marker assessments did not prove useful to monitor osteolytic growth, our studies provide in vivo evidence that ibandronate treatment induces tumour remission by reversal of tumour growth. © 2003 Wiley‐Liss, Inc.
Overexpression of histone deacetylase HDAC1 modulates breast cancer progression by negative regulation of estrogen receptor α
Authors: Kawai Hideki , Li Huchun , Avraham Shalom , Jiang Shuxian , Avraham Hava Karsenty 
Published: September 2003

AbstractThe interaction between 17β‐estradiol and estrogen receptor alpha (ER‐α) plays an important role in breast carcinogenesis and breast cancer treatment. ER‐α is a critical growth regulatory gene in breast cancer and its expression level is tightly linked to the prognosis and treatment outcomes of breast cancer patients. Loss of ER‐α expression in breast epithelial cells is critical for breast cancer progression. The underlying molecular mechanisms for this loss, however, are poorly defined. Histone deacetylases (HDACs) are implicated in the alteration of chromatin assembly and tumorigenesis. We show that histone deacetylase 1 (HDAC1) interacts with ER‐α in vitro and in vivo and suppresses ER‐α transcription activity. The interaction of HDAC1 with ER‐α was mediated by the AF‐2 and DBD domains of ER‐α. We observed an endogenous interaction of HDAC1 with ER‐α in breast cancer cells, which was decreased in the presence of estrogen. Interestingly, overexpression of HDAC1 in stable transfected MCF‐7 clones induced loss of ER‐α and significantly increased cell proliferation and colony formation, as compared to the control MCF‐7 cells, whereas treatment of stable MCF‐7 clones with the HDAC specific inhibitor trichostatin A (TSA) induced re‐expression of ER‐α mRNA and protein. Our findings strongly suggest that HDAC1 affects breast cancer progression by promoting cellular proliferation in association with a reduction in both ER‐α protein expression and transcriptional activity. Thus, HDAC1 may be a potential target for therapeutic intervention in the treatment of a subset of ER‐negative breast cancers. © 2003 Wiley‐Liss, Inc.
Centrosomal aberrations in primary invasive breast cancer are associated with nodal status and hormone receptor expression
Authors: Schneeweiss Andreas , Sinn Hans‐Peter , Ehemann Volker , Khbeis Tanja , Neben Kai , Krause Ulf , Ho Anthony D. , Bastert Gunther , Krämer Alwin 
Published: September 2003

AbstractOur purpose was to assess the presence of centrosomal aberrations as measured by immunohistochemistry in primary invasive breast cancer and their association with established and proposed prognostic factors. Tissue sections of 103 primary invasive breast cancers were examined using centrosome‐specific antibodies to pericentrin and γ‐tubulin. At least 3 different tumor regions per case were examined to determine maximum centrosomal aberration levels, which represent the proportion of cells with abnormal centrosomes in the region with the highest percentage of cells with centrosomal aberrations. The χ2 test was performed to evaluate the association of maximum centrosomal aberration levels with patient age; tumor size; nodal status; nuclear grade; hormone receptor and Her2/neu expression; proportion of Ki67‐, p53‐ and Bcl‐2‐positive tumor cells; DNA index; S‐phase fraction; and proliferation index. With pericentrin immunohistochemistry, maximum centrosomal aberration levels >35% were detectable in 92 of the 103 breast carcinomas (89%). We found a highly significant correlation of maximum centrosomal aberration levels above 35% with axillary nodal tumor involvement (p < 0.0001) and the absence of hormone receptors (p < 0.0001). In addition, there was a borderline significant relationship with age <50 years (p = 0.050) and Her2/neu overexpression (p = 0.050). Among node‐negative patients, maximum centrosomal aberration levels >35% were also associated with an increased DNA index (p = 0.006). In a subset of patients, additional staining of centrosomes with a monoclonal anti‐γ‐tubulin antibody essentially confirmed these results. In primary invasive breast cancer, centrosomal aberrations are associated with those factors predicting a more aggressive course of disease. This might indicate a fundamental role of centrosomal dysfunction in disease evolution, possibly as a result of chromosome missegregation during mitosis. © 2003 Wiley‐Liss, Inc.
The synthetic retinoid adapalene inhibits proliferation and induces apoptosis in colorectal cancer cells in vitro
Authors: Ocker Matthias , Herold Christoph , Ganslmayer Marion , Hahn Eckhart G. , Schuppan Detlef 
Published: September 2003

AbstractChemotherapy of advanced stages of colorectal carcinoma is unsatisfactory. Retinoids inhibit cell growth and induce apoptosis in a variety of human malignancies. We compared the effect of the synthetic retinoid adapalene (ADA) and 9‐cis‐retinoic acid (CRA) on carcinoma cell lines in vitro. Colon carcinoma cell lines CC‐531, HT‐29 and LOVO as well as human foreskin fibroblasts were exposed to different concentrations of ADA and CRA for 3–72 hr. Proliferation was assessed by BrdU incorporation and apoptosis by FACS analysis. Breakdown of ΔΨm was determined by JC‐1 staining and activity of caspases 3 and 8, by a colorimetric assay. Quantitative Western blots were performed to detect changes in bax, bcl‐2 and caspase‐3. Both retinoic derivatives suppressed DNA synthesis and induced apoptosis in all tested cell lines time‐ and dose‐dependently. While the natural retinoid CRA showed moderate antiproliferative and proapoptotic effects only at the highest concentration (10–4 M), the synthetic retinoic ADA was significantly more effective, showing remarkable effects even at 10–5 M. ADA and CRA disrupt ΔΨm and induce caspase‐3 activity in responsive tumor cells. Quantitative Western blots showed a shift of the bax:bcl‐2 ratio toward proapoptotic bax in ADA‐treated cells. Our results clearly indicate the superiority of ADA compared to CRA. Therefore, we suggest that ADA may be far more suitable as an adjunctive therapeutic agent for treatment of colon cancer in vivo. © 2003 Wiley‐Liss, Inc.
Selective suppression of monocyte chemoattractant protein‐1 expression by human papillomavirus E6 and E7 oncoproteins in human cervical epithelial and epidermal cells
Authors: Kleine‐Lowinski Kerstin , Rheinwald James G. , Fichorova Raina N. , Anderson Deborah J. , Basile John , Münger Karl , Daly Christine M. , Rösl Frank , Rollins Barrett J. 
Published: September 2003

AbstractInfection of cervical keratinocytes by high‐risk HPV is involved in the etiology of cervical carcinoma. Since viral products are immunogenic, development of cancer may require suppression of immune responses directed against infected epithelial cells. Many markers of host immune effector responses decrease as cervical intraepithelial neoplasia progresses. Among these is epithelial cell expression of the chemokine MCP‐1, though the mechanism for its suppression is unclear. Here, we show that the E6 and E7 viral oncogenes from high‐risk HPV, individually and together, suppress MCP‐1 expression in primary epithelial cells derived from the female genital tract. This is not a consequence of global suppression of chemokine expression since other chemokines, including IP‐10, IL‐8 and RANTES, were less affected. Furthermore, 4 of 6 HPV‐positive cervical carcinoma cell lines did not express MCP‐1. Our data indicate that suppression of MCP‐1 expression is part of the program of high‐risk HPV E6/E7‐induced transformation of primary epithelial cells. These observations are consistent with a model in which MCP‐1 expression by infected keratinocytes, which would stimulate an immune attack on HPV‐transformed cells, is suppressed for invasive cervical cancer to appear. © 2003 Wiley‐Liss, Inc.
Air pollution and lung cancer mortality in the vicinity of a nonferrous metal smelter in Sweden
Authors: Bessö Anna , Nyberg Fredrik , Pershagen Göran 
Published: September 2003

AbstractTo evaluate the importance of exposure to ambient air pollution for lung cancer risk, we conducted a case‐control study in the vicinity of a nonferrous metal smelter. The smelter started operations in 1930 and had very high emissions during the early decades, particularly of arsenic and SO2. Among subjects deceased 1961–1990 in the municipality where the smelter is located and who had not worked at the smelter, 209 male and 107 female lung cancer cases were identified and matched by sex and year of birth to 518 and 209 controls, respectively. Information on smoking habits, occupations and residences was collected by questionnaire to next‐of‐kin and from registry data. Living close to the smelter was associated with a relative risk (RR) for lung cancer of 1.38 [95% confidence interval (CI) 0.89–2.14] among men, adjusted for smoking and occupational exposures. No clear difference in risk was detected for men deceased 1961–1979 compared to men deceased 1980–1990 (RR point estimates 1.42 and 1.29, respectively). There appeared to be an increased risk especially for men exposed in the beginning of the operations (RR = 1.51, 95% CI 0.90–2.54), in particular combined with exposure duration shorter than 20 years (RR = 2.52, 95% CI 0.89–7.11). For women, however, no overall increased risk for lung cancer was observed. Although not significant, our findings thus indicated an increased risk of lung cancer among men living close to the nonferrous smelter. This increase appeared to concern primarily men exposed during the early years of operations, when emissions were very high. © 2003 Wiley‐Liss, Inc.
ERK inhibitor PD98059 enhances docetaxel‐induced apoptosis of androgen‐independent human prostate cancer cells
Authors: Zelivianski Stanislav , Spellman Matthew , Kellerman Mark , Kakitelashvilli Vladimir , Zhou Xia‐Wei , Lugo Esmeralda , Lee Ming‐Shyue , Taylor Rodney , Davis Thomas L. , Hauke Ralph , Lin Ming‐Fong 
Published: September 2003

AbstractAnticancer drugs docetaxel and vinorelbine suppress cell growth by altering microtubule assembly and activating the proapoptotic signal pathway. Vinorelbine and docetaxel have been approved for treating several advanced cancers. However, their efficacy in the management of advanced hormone‐refractory prostate cancer remains to be clarified. Microtubule damage by some anticancer drugs can activate the ERK survival pathway, which conversely compromises chemotherapeutic efficacy. We analyzed the effect of ERK inhibitors PD98059 and U0126 on vinorelbine‐ and docetaxel‐induced cell growth suppression of androgen‐independent prostate cancer cells. In androgen‐independent C‐81 LNCaP cells, inhibition of ERK by PD98059, but not U0126, plus docetaxel resulted in enhanced growth suppression by an additional 20% compared to the sum of each agent alone (p < 0.02). The combination treatment of docetaxel plus PD98059 also increased cellular apoptosis, which was in part due to the inactivation of Bcl‐2 by increasing phosphorylated Bcl‐2 by more than 6‐fold and Bax expression by 3‐fold over each agent alone. At these dosages, docetaxel alone caused only marginal phosphorylation of Bcl‐2 (10%). Docetaxel plus U0126 had only 20% added effect on Bcl‐2 phosphorylation compared to docetaxel alone. Nevertheless, both U0126 and PD98059 exhibited an enhanced effect on docetaxel‐induced growth suppression in PC‐3 cells. No enhanced effect was observed for vinorelbine plus PD98059 or U0126. Thus, the combination therapy of docetaxel plus PD98059 may represent a new anticancer strategy, requiring lower drug dosages compared to docetaxel monotherapy. This may lower the cytotoxicity and enhance tumor suppression in vivo. This finding of a combination effect could be of potential clinical importance in treating hormone‐refractory prostate cancer. © 2003 Wiley‐Liss, Inc.
Long‐term cancer pain management in morphine pre‐treated and opioid naive patients with transdermal fentanyl
Authors: Mystakidou Kyriaki , Tsilika Eleni , Parpa Efi , Kouloulias Vassilios , Kouvaris Ioannis , Georgaki Stavroula , Vlahos Lambros 
Published: September 2003

AbstractThere is emerging data supporting the use of TTS‐F (transdermal therapeutic system‐fentanyl) in opioid naive patients. Our study examines the safety and efficacy of TTS‐F in the long‐term control of cancer pain in opioid naive patients and those transferring from oral morphine. Pain was assessed in 589 patients (Group A: 268 opioid naive, Group B: 321 transferring from morphine) using a Visual Analogue Scale (VAS; 0–10), based on selected questions from the Greek Brief Pain Inventory (GBPI). Overall treatment satisfaction was assessed on a 4‐point scale. Quality of Life (QOL) and ECOG (0–4) status were also recorded. These were assessed in relation to TTS‐F dose, pain type (neuropathic, combined, nociceptive), concomitant use of anti‐inflammatory drugs and other demographic data. Of 589 patients, 59 (10%) withdrew as a result of inadequate pain satisfaction or for other reasons. There were no discontinuations due to side effects; no Grade 3–4 events occurred. A total of 530 continued on‐study, 211 patients died during study period and 295 departed; all (506; 89%) were satisfied with their pain relief. Analysis of patients at baseline, 28 days, 6 and 12 month time points (n = 153 Group A; n = 214 Group B) with respect to QOL and pain measures indicated a statistically significant (p < 0.001) improvement in all measures across time independent of pain type, or any other patient characteristic(s). In patients with intolerable pain, transfer to TTS‐F offers an efficient and safe long‐term analgesic option. TTS‐F offers durable long‐term maintenance of pain relief with acceptable side effects in opioid naive patients. In general, TTS‐F as a first line analgesic approach for carefully selected and monitored patients experiencing moderate to severe cancer pain should be considered. © 2003 Wiley‐Liss, Inc.
High frequency of activated K‐ras codon 15 mutant in colorectal carcinomas from Taiwanese patients
Authors: Wang Jaw‐Yuan , Hsieh Jan‐Sing , Chen Fang‐Ming , Yeh Ching‐Sheng , Alexandersen Ketil , Huang Tsung‐Jen , Chen David c.p. , Lin Shiu‐Ru 
Published: September 2003

AbstractColorectal carcinogenesis is regarded as a multistep process resulting from accumulation of genetic alterations, including activation of protooncogenes and inactivation of tumor suppressor genes via signal transduction trigger the stage‐wise progression to malignancy. The reported incidence of K‐ras mutation detected in general tissue samples ranges from 21–60% in primary colorectal cancers (CRC). To assess the prevalence and spectrum of K‐ras mutations in Taiwanese patients with CRC, we analyzed 65 CRC patients by polymerase chain reaction‐single strand conformation polymorphism analysis, followed by direct sequencing. K‐ras mutations were detected in 43.1% (28 of 65) of the tumors. The mutational hot spots were located at codons 12, 13, 15 and 20, especially with the highest frequency at codon 15. To understand whether the codon 15 mutations in CRC were associated with activation of K‐ras oncogene and the alterations of its biocharacteristics, mutant K‐ras genes were cloned from tumor tissues and then inserted into expression vector pBKCMV to construct the prokaryotic expression plasmid pK15MCMV. Mutant K‐ras genes were expressed at high levels in E. coli and the mutant K‐ras proteins were shown to be functional with respect to their well‐known specific, high‐affinity, GDP/GTP binding. The purified K‐ras protein from E. coli was then measured for its intrinsic GTPase activity and the extrinsic GTPase activity in the presence of GTPase‐activating protein for ras. We found that the extrinsic GTPase activity of the codon 15 mutant K‐ras proteins (p21K‐ras15M) in the presence of GAP is much lower than that of the wild‐type K‐ras protein (p21 BN), whereas the intrinsic GTPase activity is nearly the same as that of the wild‐type K‐ras protein. The results indicated that mutation at the codon 15 of K‐ras gene indeed decreased GTPase activity in CRC, however, its association with tumorigenesis of CRC needs be clarified by further studies. © 2003 Wiley‐Liss, Inc.