bluuebunny/crossref_metadata_2025 huggingface dataset:
Potent effect of 5‐HPBR, a butanoate derivative of 4‐HPR, on cell growth and apoptosis in cancer cells
Authors: Han Hye‐Sook , Kwon Youn‐Ja , Park Si‐Ho , Kim Eun‐Joo , Rho Young‐Soy , Sin Hong‐Sig , Um Soo‐Jong
Published: January 2004

Fenretinide, 4‐(N‐hydroxyphenyl) retinamide (4‐HPR), has demonstrated anticancer activity associated with a favorable toxicity profile and is now being investigated in several clinical trials. However, its plasma levels in patients have been far lower than the effective concentration required to induce apoptosis (usually 10 μM). This result has led to the synthesis of derivatives with better efficacy. Sodium butyrate's potential as an anticancer agent prompted us to synthesize a butanoate derivative of 4‐HPR, 5‐hydroxyphenyl butanoate retinamide (5‐HPBR) and compare it to the parent compound for antitumor potential in vitro. The cytotoxicity of 5‐HPBR was 2‐ to 6‐fold greater than that of 4‐HPR against cancer cell lines derived from various tissues. In premalignant bronchial cells (BEAS2B), 5‐HPBR exhibited about a 10‐fold stronger cytotoxicity than did 4‐HPR. Normal CHANG liver cells were unaffected by either 4‐HPR or 5‐HPBR. Subsequent assays using DNA fragmentation, DAPI staining, FACS and Western blotting suggested that the potent inhibitory effect of 5‐HPBR is mediated by apoptosis; the exact mechanism appears to differ among cancer cell types. In transcription assays with COS‐1 cells, 5‐HPBR selectively activated RARβ and RARγ but was a weaker ligand for all 3 subtypes of RAR than either all‐trans retinoic acid or 4‐HPR. Overall, these data suggest that 4‐BHPR may be a promising retinoid with enhanced antitumor activity and reduced toxicity. © 2003 Wiley‐Liss, Inc.
Enhancement of chemotherapeutic response of tumor cells by a heme oxygenase inhibitor, pegylated zinc protoporphyrin
Authors: Fang Jun , Sawa Tomohiro , Akaike Takaaki , Greish Khaled , Maeda Hiroshi
Published: January 2004

Heme oxygenase‐1 (HO‐1), an inducible enzyme that catalyzes oxidative degradation of heme to form biliverdin, carbon monoxide and free iron, may protect tumor cells against oxidative stress, thus contributing to rapid tumor growth in vivo. Here, we discuss whether pegylated zinc protoporphyrin (PEG‐ZnPP), a potent HO inhibitor, modulates the chemotherapeutic response of tumor cells to treatment that generates reactive oxygen species (ROS). PEG‐ZnPP is a water‐soluble HO inhibitor that accumulates in tumor tissues after intravenous administration. Cytotoxicity of antitumor agents in vitro was determined by means of MTT and annexin V assays using human colon carcinoma SW480 cells. Mice bearing sarcoma 180 tumors were used as an in vivo model. Pegylated D‐amino acid oxidase (PEG‐DAO), which behaves as an oxidative chemotherapeutic agent by generating toxic oxidants at tumor tissues, was administered with its substrate D‐proline to mice with or without PEG‐ZnPP pretreatment. PEG‐ZnPP‐treated SW480 cells became vulnerable to insults caused by various cytotoxic agents; the 50% lethal doses were reduced by 25%, 39%, 83%, and 61% for hydrogen peroxide, t‐butyl hydroperoxide, camptothecin and doxorubicin, respectively. Cells treated with PEG‐ZnPP plus cytotoxic oxidants exhibited marked production of intracellular ROS, which paralleled the incidence of apoptosis. PEG‐ZnPP pretreatment significantly reduced tumor growth in mice receiving PEG‐DAO/D‐proline compared to no PEG‐ZnPP pretreatment. These findings suggest that HO‐1 may become an attractive target for chemotherapeutic intervention. Further study of the effect of PEG‐ZnPP plus conventional anticancer drugs that generate ROS, such as cisplatin, camptothecin, doxorubicin, mitomycin C and etoposide, is warranted. © 2003 Wiley‐Liss, Inc.
Targeting and amplification of immune killing of tumor cells by pro‐Smac
Authors: Li Rui , Rüttinger Dominik , Urba Walter , Fox Bernard A. , Hu Hong‐Ming
Published: January 2004

Overexpression of inhibitors of apoptosis (IAP) is one potential mechanism for tumor cells to evade immune surveillance. To determine whether immune‐mediated killing of tumor cells can be enhanced by neutralization of IAP proteins, 2 novel eGFP‐Smac fusion proteins (pro‐Smac) were introduced into the poorly immunogenic mouse melanoma cell line, B16BL6‐D5 (D5). Each fusion protein contained Smac and a cleavage site specific for granzyme B (GrB) or caspase 8, thereby targeting the 2 major killing mechanisms of cytotoxic T‐lymphocyte (CTL) and NK cells. Expression of a pro‐Smac fusion protein by D5 tumor cells greatly enhanced the susceptibility to killing by lymphokine‐activated killer (LAK) cells or purified GrB. GrB‐mediated killing was increased to a much greater extent when tumor cells expressed the eGFP‐Smac fusion protein with a GrB cleavage site compared to a caspase 8 cleavage site. In contrast, perforin‐deficient LAK cells, which lack GrB‐mediated cytotoxicity but process normal ligands for death receptors, killed D5 tumor cells expressed pro‐Smac with caspase 8 cleavage site more efficiently. Enhanced killing by GrB was also accompanied by processing of the fusion protein and increased caspase‐3‐like activity. These results indicate that killing of tumor cells can be amplified by targeting cell‐mediated cytotoxic mechanisms via expression of pro‐Smac fusion proteins. © 2003 Wiley‐Liss, Inc.
Risk factors for squamous intraepithelial lesions (SIL) of the cervix among women residing at the US‐Mexico border
Authors: Giuliano Anna R. , Papenfuss Mary , Mendez Brown de Galaz Elena , Feng Janine , Abrahamsen Martha , Denman Catalina , Guernsey de Zapien Jill , Navarro Henze Jose Luis , Garcia Francisco , Hatch Kenneth
Published: January 2004

It is now well established that cervical cancer is caused by oncogenic human papillomavirus (HPV) infections that commonly infect women worldwide. What remains to be understood are the factors that contribute to cervical cancer in the presence of HPV infection. We conducted a case‐control analysis of women recruited at the US‐Mexico border to simultaneously evaluate factors associated with 3 cytologic outcomes: atypical squamous cells of undetermined significance or atypical glandular cells of undetermined significance (ASCUS/AGUS), low grade squamous intraepithelial lesions (LSIL) and high grade squamous intraepithelial lesions (HSIL). A cross‐sectional binational study of 2,059 women ages 15–79 years was conducted between 1997 and 1998. A significant difference in the distribution of cytologic categories by country was observed (3.0% vs. 0.7% HSIL among Mexican vs. US women, respectively). The only factors independently associated with all 3 cytologic outcomes were HPV infection and viral load. A linear increase in risk with increasing viral load was observed for each of the 3 outcome variables, with the strength of this association increasing with cytology abnormality. In addition to HPV infection, parity and Mexico as a country of residence appear to be associated with LSIL and HSIL, respectively. Factors associated with cytologic outcomes in analyses limited to women with HPV infection were similar to results obtained in models where HPV infection was included as a covariate. Future work is needed to evaluate the predictive value of HPV viral load utilizing more specific and quantitative measures. © 2003 Wiley‐Liss, Inc.
DNA polymerase θ is preferentially expressed in lymphoid tissues and upregulated in human cancers
Authors: Kawamura Kiyoko , Bahar Rumana , Seimiya Mika , Chiyo Masako , Wada Akihiko , Okada Seiji , Hatano Masahiko , Tokuhisa Takeshi , Kimura Hideki , Watanabe Satoshi , Honda Ichiro , Sakiyama Shigeru , Tagawa Masatoshi , O‐Wang Jiyang
Published: January 2004

DNA polymerase θ (Pol θ) is a recently identified family A polymerase that contains an intrinsic helicase domain. Drosophila Pol θ mutants are hypersensitive to bifunctional DNA crosslinking agents and exhibit an elevated frequency of spontaneous chromosomal aberrations, suggesting a role for Pol θ in repair of DNA interstrand crosslinks and in the general maintenance of genome stability. To investigate a possible involvement of Pol θ in tumorigenesis, we have examined its expression in various normal and malignant tissues. Paired tumor and adjacent nontumorous tissues from patients with lung (n = 27), stomach (n = 28) and colon (n = 26) cancer, as well as 26 normal human tissues, were examined for Pol θ expression by RT‐PCR, Northern or Western blot analysis. Pol θ was predominantly expressed in primary lymphoid organs including the fetal liver, thymus and bone marrow where lymphocyte progenitors undergo V(D)J rearrangements of their antigen receptor genes. In addition, Pol θ expression was upregulated in germinal center B cells, in which class switch recombination of the immunoglobulin genes occurs. Examination of Pol θ expression in matched cancer specimens revealed that Pol θ was barely detectable in the nontumorous tissues but was upregulated in 17 of 27 (63%) lung, 11 of 28 (39%) stomach and 20 of 26 (77%) colon cancers. Moreover, patients with high levels of Pol θ expression had a significantly poorer clinical outcome compared with those expressing low levels of Pol θ. These results implicate that Pol θ may have a specialized function in lymphocytes and that its overexpression may contribute to tumor progression. © 2003 Wiley‐Liss, Inc.
Obesity and colon cancer: Does leptin provide a link?
Authors: Stattin Pär , Lukanova Annekatrin , Biessy Carine , Söderberg Stefan , Palmqvist Richard , Kaaks Rudolf , Olsson Tommy , Jellum Egil
Published: January 2004

Obesity, a risk factor for colorectal cancer, is associated with elevated serum levels of leptin, the adipocyte‐derived hormone, and insulin. Experimental and epidemiologic studies have indicated a role for insulin in the pathogenesis of colon cancer, and recent experimental studies have suggested a similar role for leptin. In a case‐control study nested in the Janus Biobank, Norway, we measured serum levels of leptin and C‐peptide (a marker of pancreatic insulin secretion) in cryopreserved prediagnostic sera from men (median age, 45 years) who were diagnosed with cancer of the colon (n = 235) or rectum (n = 143) after blood collection (median time, 17 years), and among 378 controls matched for age and date of blood collection. Conditional logistic regression analyses showed an approximately 3‐fold increase in colon cancer risk with increasing concentrations of leptin up to an odds ratio (OR) of 2.72 (95% CI = 1.44–5.12) for top vs. bottom quartile (ptrend = 0.008). The corresponding OR for C‐peptide was 1.81 (95% CI = 0.67–4.86; ptrend = 0.19). The risk estimates remained unchanged after mutual adjustment. No association of hormone levels with rectal cancer risk was found. Reproducibility of hormone measurements assessed by intraclass coefficients (ICCs) for paired samples taken 1 year apart was high for leptin (ICC = 0.82) but lower for C‐peptide (ICC = 0.30). Our results suggest that leptin is a risk factor for colon cancer, and that leptin may provide a link between obesity and colon cancer. Leptin may be directly involved in colon tumorigenesis or it may serve as a sensitive and robust marker of an obesity‐induced adverse endocrine environment. Only weak support for an association of insulin with colon cancer was found. © 2003 Wiley‐Liss, Inc.
Fruits and vegetables and prostate cancer: No association among 1,104 cases in a prospective study of 130,544 men in the European Prospective Investigation into Cancer and Nutrition (EPIC)
Authors: Key Timothy J. , Allen Naomi , Appleby Paul , Overvad Kim , Tjønneland Anne , Miller Anthony , Boeing Heiner , Karalis Dimitrios , Psaltopoulou Theodora , Berrino Franco , Palli Domenico , Panico Salvatore , Tumino Rosario , Vineis Paolo , Bueno‐de‐Mesquita H.B. , Kiemeney Lambertus , Peeters Petra H.M. , Martinez Carmen , Dorronsoro Miren , González Carlos A. , Chirlaque M.D. , Quiros J. Ramon , Ardanaz Eva , Berglund Göran , Egevad Lars , Hallmans Göran , Stattin Pär , Bingham Sheila , Day Nicholas , Gann Peter , Kaaks Rudolf , Ferrari Pietro , Riboli Elio
Published: January 2004

We examined the association between self‐reported consumption of fruits and vegetables and prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Data on food consumption and complete follow‐up for cancer incidence were available for 130,544 men in 7 countries recruited into EPIC between 1993 and 1999. After an average of 4.8 years of follow‐up, there were 1,104 incident cases of prostate cancer. The associations of consumption of total fruits, total vegetables, cruciferous vegetables and combined total fruits and vegetables with prostate cancer risk were examined using Cox regression, stratified for recruitment center and adjusted for height, weight and energy intake. There was a wide range in consumption of fruits and vegetables: mean intakes (g/day) in the bottom and top fifths of the distribution, as estimated from 24‐hr recalls in a subsample of participants, were 53.2 and 410.7 for fruits, 97.1 and 242.1 for vegetables and 169.0 and 633.7 for fruits and vegetables combined. No significant associations between fruit and vegetable consumption and prostate cancer risk were observed. Relative risks (95% confidence intervals) in the top fifth of the distribution of consumption, compared to the bottom fifth, were 1.06 (0.84–1.34) for total fruits, 1.00 (0.81–1.22) for total vegetables and 1.00 (0.79–1.26) for total fruits and vegetables combined; intake of cruciferous vegetables was not associated with risk. These results suggest that total consumption of fruits and vegetables is not associated with the risk for prostate cancer. © 2003 Wiley‐Liss, Inc.
Cyclin E expression in papillary thyroid carcinoma: Relation to staging
Authors: Brzeziński Jan , Migodziński Adam , Gosek Aleksandra , Tazbir Józef , Dedecjus Marek
Published: January 2004

Cyclin E plays a pivotal role in the regulation of G1‐S transition and relates to malignant transformation of the cells. However, the clinical significance of cyclin E expression in patients with papillary thyroid carcinoma (PTC) remains unknown. We examined by immunohistochemistry the expression of cyclin E in 41 resected PTCs in pathologic stages from pT1a to pT4 and analyzed its relation to clinicohistopathologic factors. The positive staining was divided into 3 grades: no expression if less than 10%, expression if 11–50% and overexpression if more than 50% of the nuclei of tumor cells were stained positively. Cylin E expressions were observed in 75.6% of analyzed PTCs but only 60% of papillary microcarcinomas (PMCs) were immunopositive for cyclin E expression. However, cyclin E staining was observed in 90.4% of PTCs in a group with TNM higher than pT1a. The staining index was significantly different between the PMCs and the rest of the cancers investigated (14.91% ± 14.4% vs. 34.03% ± 23.44%, respectively; p < 0.005) and we observed positive relation between the staining index and factor T of staging of PTCs. All the lymph node metastases coexisted with cyclin E expression and most, but not all, of them coexisted with cyclin E overexpression. These findings indicate that cyclin E may play a key role for the oncogenesis and biologic behavior of PTC. If our results are confirmed in a larger study, a high level of cyclin E expression may become a new prognostic marker for PTCs. © 2003 Wiley‐Liss, Inc.
Bcl‐xL inhibits p53‐ but not apoptin‐induced apoptosis in head and neck squamous cell carcinoma cell line
Authors: Schoop Remilio A.L. , Kooistra Klaas , Baatenburg de Jong Robert J. , Noteborn Mathieu H.M.
Published: January 2004

Nonfunctional p53 and especially upregulation of Bcl‐xL result in advanced disease and poor prognosis of patients suffering head and neck squamous cell carcinoma (HNSCC). Aberrancies of Bcl‐xL and/or p53 in HNSCC lead to inability of anticancer drugs to induce apoptosis. Bcl‐xL and/or mutated p53 inhibit the apoptotic process by preventing the mitochondrial release of cytochrome c and/or activation of execution caspases. Here, we report that expression of the avian virus‐derived apoptin protein resulted in induction of apoptosis in the HNSCC‐derived cell line UMSSC‐14B despite the presence of nonfunctional p53. Apoptin activated the execution caspase 3 and induced the release of mitochondrial cytochrome c. Upregulation of Bcl‐xL in UMSCC‐14B cells did not interfere with the apoptin‐induced apoptosis, whereas it clearly negatively affected the p53‐induced one. Bcl‐xL significantly decreased the p53‐induced cytochrome c release, but not the apoptin‐triggered one. Our data demonstrate that apoptin induces apoptosis independent of Bcl‐xL and p53 and may constitute a potential therapeutic agent for treatment of HNSCC. © 2003 Wiley‐Liss, Inc.
Expression profile of genes associated with antimetastatic gene: nm23‐Mediated metastasis inhibition in breast carcinoma cells
Authors: Zhao Hui , Jhanwar‐Uniyal Meena , Datta Prasun K. , Yemul Srishailam , Ho Lap , Khitrov Gregory , Kupershmidt Ilya , Pasinetti Giulio M. , Ray Tarun , Athwal Raghbir S. , Achary Mohanrao P.
Published: January 2004

Metastases of various malignancies have been shown to be inversely related to the abundance of nm23 protein expression. However, the downstream pathways involved in nm23‐mediated suppression of metastasis have not been elucidated. In the present investigation, we used cDNA microarrays to identify novel genes and functional pathways in nm23‐mediated spontaneous breast metastasis. Microarray experiments were performed in a pair of cell lines, namely, C‐100 (only vector transfected; highly metastatic) and H1‐177 (nm23 transfected; low metastatic), derived from human mammary carcinoma cell line MDA‐MB‐435. The cDNA microarray analysis using GeneSpring software revealed significant as well as consistent alterations in the expression (up‐ and downregulation) of 2,158 genes in a total of 18,889 genes between high and low metastatic cells. Some of these genes were grouped into 6 functional categories, namely, invasion and metastasis, apoptosis and senescence, signal transduction molecules and transcription factors, cell cycle and repair, adhesion, and angiogenesis to extrapolate an association between these genes and different functional pathways involved in nm23‐regulated metastasis. The results suggest that nm23 gene plays a major role in metastasis and its mechanism of action of metastasis suppression may involve downregulation of genes associated with cell adhesion, motility (integrins α2, ‐8, ‐9, ‐L and ‐V, collagen type VIII α1, fibronectin 1, catenin, TGF‐β2, FGF7, MMP14 and 16, ErbB2) and possibly certain tumor/metastasis suppressors (2 members of SWI/SNF‐related matrix‐associated proteins 2 and 5 and PTEN). © 2003 Wiley‐Liss, Inc.
Expression of LDL receptor‐related protein 5 (LRP5) as a novel marker for disease progression in high‐grade osteosarcoma
Authors: Hoang Bang H. , Kubo Tadahiko , Healey John H. , Sowers Rebecca , Mazza BethAnne , Yang Rui , Huvos Andrew G. , Meyers Paul A. , Gorlick Richard
Published: January 2004

The Wingless‐type (Wnt) family of proteins and its coreceptor LRP5 have recently been implicated in human skeletal development. Wnt pathway modulates cell fate and cell proliferation during embryonic development and carcinogenesis through activation of receptor‐mediated signaling. Osteosarcoma (OS) is a bone‐forming tumor of mesenchymal origin whose growth control has been linked to autocrine or paracrine stimulation by several growth factor families. We examined 4 OS cell lines for WNT1, WNT4, WNT5A, WNT7A, WNT11, FZD1‐10 and LRP5 expression by reverse transcription polymerase chain reaction (RT‐PCR). In addition, RT‐PCR for LRP5 expression was performed in 44 OS patient samples and the findings were correlated with clinical data. Expression profiling of Wnts and their receptors revealed the presence of several isoforms in OS cell lines. Overall, 22/44 (50%) of OS patient samples showed evidence of LRP5 expression. Presence of LRP5 correlated significantly with tumor metastasis (p = 0.005) and the chondroblastic subtype of OS (p = 0.045). In addition, patients whose tumors were positive for LRP5 showed a trend toward decreased event‐free survival (p = 0.066). No significant association was found between LRP5 expression and age, gender, site of disease, site of metastasis or degree of chemotherapy‐induced tumor necrosis. Sequencing of exon 3 of LRP5 in 10 OS patient‐derived cell cultures showed no activating mutation of LRP5. These results showed that expression of LRP5 is a common event in OS and strongly suggest a role for LRP and Wnt signaling in the pathobiology and progression of this disease. © 2003 Wiley‐Liss, Inc.
Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer
Authors: Ohata Hiroshi , Kitauchi Shintaro , Yoshimura Noriko , Mugitani Kouichi , Iwane Masataka , Nakamura Hideya , Yoshikawa Akiyoshi , Yanaoka Kimihiko , Arii Kenji , Tamai Hideyuki , Shimizu Yasuhito , Takeshita Tatsuya , Mohara Osamu , Ichinose Masao
Published: January 2004

We conducted a longitudinal cohort study to determine the association of Helicobacter pylori infection and the progression of chronic atrophic gastritis (CAG) with gastric cancer. A cohort of 4,655 healthy asymptomatic subjects was followed for a mean period of 7.7 years. H. pylori infection was established by serum specific antibodies and the presence of CAG was confirmed by serum pepsinogen. During the follow‐up period, 45 gastric cancer cases were detected (incidence rate, 126/100,000 person‐years). A univariate analysis after adjustment for age showed that both H. pylori and CAG were significantly associated with gastric cancer. To clarify the interaction between H. pylori and CAG, an analysis stratified by H. pylori‐ and CAG–status was performed. No cancer developed in the H. pylori(−)/CAG(−) group during the study period. This supports the theory that it is quite rare for any type of gastric cancer to develop in an H. pylori‐free healthy stomach. With the progression of H. pylori‐induced gastritis, the risk of gastric cancer increased in a stepwise fashion from CAG‐free gastritis [H. pylori(+)/CAG(−) group] (HR=7.13, 95%CI=0.95‐53.33) to CAG [H. pylori(+)/CAG(+) group] (HR=14.85, 95%CI=1.96–107.7) and finally to severe CAG with extensive intestinal metaplasia [H. pylori(−)/CAG(+) group] (HR=61.85, 95%CI=5.6–682.64) in which loss of H. pylori from the stomach is observed. Therefore, it is probable that H. pylori alone is not directly associated with stomach carcinogenesis. Instead, H. pylori appears to influence stomach carcinogenesis through the development of CAG. The observed positive correlation between the extent of H. pylori‐induced gastritis and the development of cancer was strong, especially for the intestinal type. These results are compelling evidence that severe gastritis with extensive intestinal metaplasia is a major risk factor for gastric cancer, and they confirm the previously described model of stomach carcinogenesis: the gastritis‐metaplasia‐carcinoma sequence. © 2003 Wiley‐Liss, Inc.
Secondhand smoke exposure in adulthood and risk of lung cancer among never smokers: A pooled analysis of two large studies
Authors: Brennan Paul , Buffler Patricia A. , Reynolds Peggy , Wu Anna H. , Wichmann H. Erich , Agudo Antonio , Pershagen Göran , Jöckel Karl‐Heinz , Benhamou Simone , Greenberg Raymond S. , Merletti Franco , Winck Carlos , Fontham Elizabeth T.H. , Kreuzer Michaela , Darby Sarah C. , Forastiere Francesco , Simonato Lorenzo , Boffetta Paolo
Published: January 2004

The interpretation of the evidence linking exposure to secondhand smoke with lung cancer is constrained by the imprecision of risk estimates. The objective of the study was to obtain precise and valid estimates of the risk of lung cancer in never smokers following exposure to secondhand smoke, including adjustment for potential confounders and exposure misclassification. Pooled analysis of data from 2 previously reported large case‐control studies was used. Subjects included 1,263 never smoking lung cancer patients and 2,740 population and hospital controls recruited during 1985–1994 from 5 metropolitan areas in the United States, 11 areas in Germany, Italy, Sweden, United Kingdom, France, Spain and Portugal. Odds ratios (ORs) of lung cancer were calculated for ever exposure and duration of exposure to secondhand smoke from spouse, workplace and social sources. The OR for ever exposure to spousal smoking was 1.18 (95% CI = 1.01–1.37) and for long‐term exposure was 1.23 (95% CI = 1.01–1.51). After exclusion of proxy interviews, the OR for ever exposure from the workplace was 1.16 (95% CI = 0.99–1.36) and for long‐term exposure was 1.27 (95% CI = 1.03–1.57). Similar results were obtained for exposure from social settings and for exposure from combined sources. A dose‐response relationship was present with increasing duration of exposure to secondhand smoke for all 3 sources, with an OR of 1.32 (95% CI = 1.10–1.79) for the long‐term exposure from all sources. There was no evidence of confounding by employment in high‐risk occupations, education or low vegetable intake. Sensitivity analysis for the effects of misclassification (both positive and negative) indicated that the observed risks are likely to underestimate the true risk. Clear dose‐response relationships consistent with a causal association were observed between exposure to secondhand smoke from spousal, workplace and social sources and the development of lung cancer among never smokers. © 2003 Wiley‐Liss, Inc.
Risk of lung cancer and residential radon in China: Pooled results of two studies
Authors: Lubin Jay H. , Wang Zuo Yuan , Boice John D. , Xu Zhao Yi , Blot William J. , De Wang Long , Kleinerman Ruth A.
Published: January 2004

Studies of radon‐exposed underground miners predict that residential radon is the second leading cause of lung cancer mortality; however, case‐control studies of residential radon have not provided unambiguous evidence of an association. Owing to small expected risks from residential radon and uncertainties in dosimetry, large studies or pooling of multiple studies are needed to fully evaluate effects. We pooled data from 2 case‐control studies of residential radon representing 2 large radon studies conducted in China. The studies included 1,050 lung cancer cases and 1,996 controls. In the pooled data, odds ratios (OR) increased significantly with greater radon concentration. Based on a linear model, the OR with 95% confidence intervals (CI) at 100 Becquerel/cubic‐meter (Bq/m3) was 1.33 (1.01,1.36). For subjects resident in the current home for 30 years or more, the OR at 100 Bq/m3 was 1.32 (1.07,1.91). Results across studies were consistent with homogeneity. Estimates of ORs were similar to extrapolations from miner data and consistent with published residential radon studies in North American and Europe, suggesting long‐term radon exposure at concentrations found in many homes increases lung cancer risk. © 2003 Wiley‐Liss, Inc.
Prognosis of dermal lymphatic invasion with or without clinical signs of inflammatory breast cancer
Authors: Gruber Guenther , Ciriolo Michele , Altermatt Hans Joerg , Aebi Stefan , Berclaz Gilles , Greiner Richard H.
Published: January 2004

It is still an open debate whether tumor emboli in dermal lymphatics without inflammatory signs represent a similar bad prognosis like inflammatory breast cancer. We evaluated the prognostic role of dermal lymphatic invasion (DLI) in breast cancer with (DLI + ID) or without (DLI w/o ID) inflammatory disease (ID). From August 1988 to January 2000, 42 patients with DLI were irradiated. Twenty‐five were classified as pT4, 13 out of them as pT4d (inflammatory disease); the 17 remaining patients had 1 T1c, 12 T2 and 4 T3 cancers with DLI. Axillary dissection revealed node‐positive disease in 39/41 patients (median, 9 positive nodes). Thirty‐eight out of 42 patients received adjuvant systemic treatment(s). After a mean follow‐up of 33 months, 22/42 patients (52%) are disease‐free. The actuarial 3‐year disease‐free survival is 50% (DLI w/o ID, 61%; DLI + ID, 31%; p < 0.03); the corresponding overall survival was 69% (DLI w/o ID, 87%; DLI + ID, 37%; p = 0.005). The presence or absence of ID was the only significant parameter for all endpoints in multivariate analyses. Dissemination occurred in 19 (45%), local relapse in 7 (n = 17%) and regional failure in 4 (10%). Nine patients (21%) had contralateral breast cancer/relapse. Despite the same histopathologic presentation, DLI w/o ID offered a significantly better disease‐free survival and overall survival than ID. The finding of dermal lymphatic tumor invasion predicts a high probability for node‐positive disease. © 2003 Wiley‐Liss, Inc.
Vibrational center–ligand couplings in transition metal complexes
Authors: Neugebauer Johannes , Reiher Markus
Published: January 2004

The mode‐tracking principle [J. Chem. Phys. 2003, 118, 1634] for the direct quantum chemical calculation of preselected, characteristic molecular vibrations makes vibrational analyses of very large molecules feasible. This is demonstrated here for the [(Ph3PAu)6C]2+ complex, in which 18 phenyl groups in the ligand sphere are explicitly taken into account. We are aiming at the motion of the endohedral carbon atom, which is in an extraordinary bonding situation because it is surrounded by an octahedral core of gold atoms in this cluster. Secondary effects of the full ligand sphere on the vibrations of the [Au6C] core embedded in [(R3PAu)6C]2+ clusters are investigated. For this purpose, local vibrations of the octahedral core are generated, and their long‐range couplings with the phosphine ligand sphere become visible in the mode‐tracking iterations. The exact normal modes of these characteristic vibrations of the cluster are then obtained after convergence of the mode‐tracking refinement. This protocol allows us to assess the coupling of the outer ligand sphere with the inner core of the cluster in terms of changes of the vibrational frequencies and of the collective motions of the atomic nuclei. The vibrational frequencies of the octahedral [Au6C] core split due to symmetry breaking in the C1‐symmetric [(Ph3PAu)6C]2+ cluster. Our study demonstrates how effects of the periphery of a large molecule on local vibrations can be quantified. Furthermore, we predict the first set of characteristic vibrational frequencies obtained with first‐principles methods for this gold cluster, whose vibrational spectra have not yet been recorded experimentally. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 587–597, 2004
Continuous medium theory for nonequilibrium solvation: I. How to correctly evaluate solvation free energy of nonequilibrium
Authors: Li Xiang‐Yuan , Fu Ke‐Xiang
Published: January 2004

Considering the influences of electrostatic potential Φ upon the change of solute charge distribution δρ and ρ upon the change δΦ at the same time, a more reasonable integral formula of dG = (1/2) ∫V (ρδΦ + Φδρ)dV is used to calculate the change of the electrostatic free energy in charging the solute–solvent system to a nonequilibrium state, instead of the one of dG = ∫V ΦδρdV used before. This modification improves the expressions of electrostatic free energy and solvation free energy, in which no quantity of the intermediate equilibrium state is explicitly involved. Detailed investigation reveals that the solvation free energy of nonequilibrium only contains the interaction energy between the field due to the solute charge in vacuum, and the dielectric polarization at the nonequilibrium state. The solvent reorganization energies of forward and backward electron transfer reactions have been redefined because the derivations lead to a remarkable feature that these quantities are direction‐dependent, unlike the theoretical models developed before. The deductions are given in the electric field‐displacement form. Relevant discussions on the reliability of theoretical models suggested in this work have also been presented © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 500–509, 2004
A practical valence bond method: A configuration interaction method approach with perturbation theoretic facility
Authors: Song Lingchun , Wu Wei , Zhang Qianer , Shaik Sason
Published: January 2004

The previously developed valence bond configuration interaction (VBCI) method (Wu, W.; Song, L.; Cao, Z.; Zhang, Q.; Shaik, S., J. Phys. Chem. A, 2002, 105, 2721) that borrows the general CI philosophy of the MO theory, is further extended in this article, and its methodological features are improved, resulting in three accurate and cost‐effective procedures: (a) the effect of quadruplet excitation is incorporated using the Davidson correction, such that the new procedure reduces size consistency problems, with due improvement in the quality of the computational results. (b) A cost‐effective procedure, named VBCI(D, S), is introduced. It includes doubly excited structures for active electrons and singly excited structures for inactive pairs. The computational results of VBCI(D, S) match those of VBCISD with much less computational effort than VBCISD. (c) Finally, a second‐order perturbation theory is utilized as a means of configuration selection, and lead to considerable reduction of the computational cost, with little or no loss in accuracy. Applications of the new procedures to bond energies and barriers of chemical reactions are presented and discussed. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 472–478, 2004
Accurate and efficient generalized born model based on solvent accessibility: Derivation and application for LogP octanol/water prediction and flexible peptide docking
Authors: Totrov Maxim
Published: January 2004

A novel method for fast and accurate evaluation of the generalized Born radii in macromolecular solvation electrostatics calculations is proposed, based on the solvent accessibility of the first two solvation layers around an atom. The reverse generalized Born radii calculated by the method have correlation coefficient of 98.7% and RMSD of 0.031 Å−1 with the values obtained using a precise but significantly slower numerical boundary element solution. The method is applied to derive an estimate of the free solvation energy difference between octanol and water and to predict LogP octanol–water. A nine‐parameter model is optimized on an 81 compound training set and applied to predict LogPow for an external evaluation set of 19 drug molecules with RMSD of 0.9. The new GB approximation is also tested in Monte Carlo docking simulations of the fully flexible p53 peptide fragment to MDM2. The best energy solution found in the simulations has RMSD of 2.8 Å to the X‐ray structure. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 609–619, 2004
Modified Gaussian‐2 level investigation of the identity ion‐pair SN2 reactions of lithium halide and methyl halide with inversion and retention mechanisms
Authors: Ren Yi , Chu San‐Yan
Published: January 2004

Identity ion‐pair SN2 reactions LiX + CH3X → XCH3 + LiX (X = F, Cl, Br, and I) have been investigated in the gas phase and in solution at the level of the modified Gaussian‐2 theory. Two possible reaction mechanisms, inversion and retention, are discussed. The reaction barriers relative to the complexes for the inversion mechanism [ΔH(inv)] are found to be much higher than the corresponding values for the gas phase anionic SN2 reactions, decreasing in the following order: F (263.6 kJ mol−1) > Cl (203.3 kJ mol−1) > Br (174.7 kJ mol−1) > I (150.7 kJ mol−1). The barrier gaps between the two mechanisms [ΔH (ret) − ΔH (inv)] increase in the order F (−62.7 kJ mol−1) < Cl (4.4 kJ mol−1) < Br (24.9 kJ mol−1) < I (45.1 kJ mol−1). Thus, the retention mechanism is energetically favorable for fluorine and the inversion mechanism is favored for other halogens, in contrast to the anionic SN2 reactions at carbon where the inversion reaction channel is much more favorable for all of the halogens. The stabilization energies for the dipole–dipole complexes CH3X · · · LiX (ΔHcomp) are found to be similar for the entire set of systems with X = F, Cl, Br, and I, ranging from 53.4 kJ mol−1 for I up to 58.9 kJ mol−1 for F. The polarizable continuum model (PCM) has been used to evaluate the direct solvent effects on the energetics of the anionic and ion‐pair SN2 reactions. The energetic profiles are found to be still double‐well shaped for most of the ion‐pair SN2 reactions in the solution, but the potential profile for reaction LiI + CH3I is predicted to be unimodal in the protic solvent. Good correlations between central barriers [ΔH (inv)] with the geometric looseness of the inversion transition state %C—X≠, the dissociation energies of the C—X bond (DC—X) and Li—X bond (DLi—X) are observed, respectively. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 461–467, 2004
Conformational search of peptides and proteins: Monte Carlo minimization with an adaptive bias method applied to the heptapeptide deltorphin
Authors: Ozkan S. Banu , Meirovitch Hagai
Published: January 2004

The energy function of a protein consists of a tremendous number of minima. Locating the global energy minimum (GEM) structure, which corresponds approximately to the native structure, is a severe problem in global optimization. Recently we have proposed a conformational search technique based on the Monte Carlo minimization (MCM) method of Li and Scheraga, where trial dihedral angles are not selected at random within the range [−180°,180°] (as with MCM) but with biased probabilities depending on the increased structure‐energy correlations as the GEM is approached during the search. This method, called the Monte Carlo minimization with an adaptive bias (MCMAB), was applied initially to the pentapeptide Leu‐enkephalin. Here we study its properties further by applying it to the larger peptide with bulky side chains, deltorphin (H‐Tyr‐D‐Met‐Phe‐His‐Leu‐Met‐Asp‐NH2). We find that on average the number of energy minimizations required by MCMAB to locate the GEM for the first time is smaller by a factor of approximately three than the number required by MCM—in accord with results obtained for Leu‐enkephalin. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 565–572, 2004
AGBNP: An analytic implicit solvent model suitable for molecular dynamics simulations and high‐resolution modeling
Authors: Gallicchio Emilio , Levy Ronald M.
Published: January 2004

We have developed an implicit solvent effective potential (AGBNP) that is suitable for molecular dynamics simulations and high‐resolution modeling. It is based on a novel implementation of the pairwise descreening Generalized Born model for the electrostatic component and a new nonpolar hydration free energy estimator. The nonpolar term consists of an estimator for the solute‐solvent van der Waals dispersion energy designed to mimic the continuum solvent solute‐solvent van der Waals interaction energy, in addition to a surface area term corresponding to the work of cavity formation. AGBNP makes use of a new parameter‐free algorithm to calculate the scaling coefficients used in the pairwise descreening scheme to take into account atomic overlaps. The same algorithm is also used to calculate atomic surface areas. We show that excellent agreement is achieved for the GB self‐energies and surface areas in comparison to accurate, but much more expensive, numerical evaluations. The parameter‐free approach used in AGBNP and the sensitivity of the AGBNP model with respect to large and small conformational changes makes the model suitable for high‐resolution modeling of protein loops and receptor sites as well as high‐resolution prediction of the structure and thermodynamics of protein‐ligand complexes. We present illustrative results for these kinds of benchmarks. The model is fully analytical with first derivatives and is computationally efficient. It has been incorporated into the IMPACT molecular simulation program. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 479–499, 2004
Partial rigid‐body dynamics in NPT, NPAT and NPγT ensembles for proteins and membranes
Authors: Ikeguchi Mitsunori
Published: January 2004

A partial rigid‐body method of molecular dynamics simulations for proteins and membranes is presented. In this method, the symplectic integrator for rigid bodies is combined with the equations of motion for the NPT ensemble. The standard NPT ensemble is extended to the membrane‐specific ensembles, the NPAT (constant normal pressure and lateral surface area of membranes and constant temperature) and NPγT (constant normal pressure and lateral surface tension of membranes and constant temperature) ensembles. By more than 30‐ns simulations of aqueous proteins and hydrated lipid bilayers, the results of the partial rigid‐body method demonstrated excellent conservation of total energy and consistent behavior with the traditional constraint method in terms of structural distribution and fluctuation of proteins and lipids. The efficient implementation of the partial rigid‐body method in parallel computation is presented, which is shown to work well in large‐scale molecular dynamics simulations. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 529–541, 2004
Direct ab initio dynamics studies on the hydrogen‐abstraction reactions of OH radicals with HOX (X = F, Cl, and Br)
Authors: Wang Li , Liu Jing‐Yao , Li Ze‐Sheng , Sun Chia‐Chung
Published: January 2004

The hydrogen abstract reactions of OH radicals with HOF (R1), HOCl (R2), and HOBr (R3) have been studied systematically by a dual‐level direct‐dynamics method. The geometries and frequencies of all the stationary points are optimized at the MP2/6‐311+G(2d, 2p) level of theory. A hydrogen‐bonded complex is located at the product channel for the OH + HOBr reaction. To improve the energetics information along the minimum energy path (MEP), single‐point energy calculations are carried out at the CCSD(T)/6‐311++G(3df, 3pd) level of theory. Interpolated single‐point energy (ISPE) method is employed to correct the energy profiles for the three reactions. It is found that neither the barrier heights (ΔE) nor the H—O bond dissociation energies [D(H—O)] exhibit any clear‐cut linear correlations with the halogen electronegative. The decrease of ΔE and D(H—O) for the three reactions are in order of HOF > HOBr > HOCl. Rate constants for each reaction are calculated by canonical variational transition‐state theory (CVT) with a small‐curvature tunneling correction (SCT) within 200–2000 K. The agreement of the rate constants with available experimental values for reactions R2 and R3 at 298 K is good. Our results show that the variational effect is small while the tunneling correction has an important contribution in the calculation of rate constants in the low‐temperature range. Due to the lack of the kinetic data of these reactions, the present theoretical results are expected to be useful and reasonable to estimate the dynamical properties of these reactions over a wide temperature range where no experimental value is available. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 558–564, 2004
An AM1 semiempirical study of host–guest complexation in hemicarcerand complexes
Authors: Liddell Michael J. , Margetic Davor , Mitchell Anthony S. , Warrener Ronald N.
Published: January 2004

Semiempirical AM1 calculations have been carried out on host–guest complexes of model hemicarcerands 1a and 2a. The justification for the choice of the AM1 Hamiltonian was based on a comparison between reported X‐ray data for the smaller tetrabromocavitand 4a and computational results obtained using several different Hamiltonians. The complexation behavior of hemicarcerands 1a and 2a have been compared with experimental results reported by Cram et al. for the related hemicarcerands 1b and 2b. Based on this comparison, a criterion for predicting guest encapsulation was developed, Ecomplexation, which relies on the calculation of AM1 heats of formation for host, guest, and hemicarceplex. If Ecomplexation is lower than 10 kcal/mol, then a guest will be encapsulated, while if it is greater than 30 kcal/mol, a guest will not be encapsulated. The use of constrained‐path AM1 optimizations to determine the energy barriers to guest entry and exit from the host was found to be a useful tool for examining suitable host–guest combinations when the Ecomplexation criteria does not hold. We have computed the barriers to exit of N, N‐dimethylformamide (dmf) and furan from the hemicarcerand 1a, the former has been compared with the experiment and shows excellent agreement. Based on the success of the above computational methods in predicting which host–guest combinations will form stable hemicarceplexes we have synthesized a new target hemicarceplex 1b.furan. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 542–557, 2004
A hydration study of (1→4) and (1→6) linked α‐glucans by comparative 10 ns molecular dynamics simulations and 500‐MHz NMR
Authors: Corzana Francisco , Motawia Mohammed S. , Du Penhoat Catherine Hervé , Perez Serge , Tschampel Sarah M. , Woods Robert J. , Engelsen Søren B.
Published: January 2004

The hydration behavior of two model disaccharides, methyl‐α‐D‐maltoside (1) and methyl‐α‐D‐isomaltoside (2), has been investigated by a comparative 10 ns molecular dynamics study. The detailed hydration of the two disaccharides was described using three force fields especially developed for modeling of carbohydrates in explicit solvent. To validate the theoretical results the two compounds were synthesized and subjected to 500 MHz NMR spectroscopy, including pulsed field gradient diffusion measurements (1: 4.0 · 10−6 cm2 · s−1; 2: 4.2 · 10−6 cm2 · s−1). In short, the older CHARMM‐based force field exhibited a more structured carbohydrate–water interaction leading to better agreement with the diffusional properties of the two compounds, whereas especially the α‐(1→6) linkage and the primary hydroxyl groups were inaccurately modeled. In contrast, the new generation of the CHARMM‐based force field (CSFF) and the most recent version of the AMBER‐based force field (GLYCAM‐2000a) exhibited less structured carbohydrate–water interactions with the result that the diffusional properties of the two disaccharides were underestimated, whereas the simulations of the α‐(1→6) linkage and the primary hydroxyl groups were significantly improved and in excellent agreement with homo‐ and heteronuclear coupling constants. The difference between the two classes of force field (more structured and less structured carbohydrate–water interaction) was underlined by calculation of the isotropic hydration as calculated by radial pair distributions. At one extreme, the radial O…O pair distribution function yielded a peak density of 2.3 times the bulk density in the first hydration shell when using the older CHARMM force field, whereas the maximum density observed in the GLYCAM force field was calculated to be 1.0, at the other extreme. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 573–586, 2004
A computational study of the role of hydrogen bonds in SN1 and E1 reactions
Authors: Yamabe Shinichi , Tsuchida Noriko
Published: January 2004

The reaction between tertiary butyl chloride and water clusters was examined by applying density functional theory calculations. The carbonium ion t‐Bu+ that is normally sandwiched between the water clusters was found to be absent, such that a CO covalent bond was formed in the intermediate (Int1) after heterolysis. An (H2O)4 cluster is able to bridge the front and rear of the central carbon and promotes heterolysis. A correlation between bond interchanges at the central carbon and proton relays is presented. Stereochemical scrambling in the solvolysis products is discussed in terms of this correlation. In addition, an E1 pathway for the elimination product, iso‐butene, is found from Int1. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 598–608, 2004