bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional Variants in Cell Death Pathway Genes and Risk of Pancreatic Cancer
Authors: Yang Ming , Sun Tong , Wang Li , Yu Dianke , Zhang Xuemei , Miao Xiaoping , Liu Junniao , Zhao Dan , Li Hui , Tan Wen , Lin Dongxin 
Published: May 2008

AbstractPurpose: Fas-Fas ligand (FasL)–mediated death pathway is important in the life and death of immune cells and, therefore, influences immune surveillance of carcinogenesis. This study examined the association between functional variants of Fas (−1377G→A and −670A→G), FasL (−844T→C), and caspase-8 (CASP8) six-nucleotide deletion polymorphism (−652 6N ins→del) and risk of pancreatic cancer.Experimental Design: Genotypes were determined in 397 cases with pancreatic cancer and 907 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression, and all statistical tests were two sided.Results: We found a significant decrease in risk of pancreatic cancer associated with FasL and CASP8 but not Fas polymorphisms. Compared with noncarriers, the ORs of developing pancreatic cancer for FasL −844CT and TT carriers were 0.73 (95% CI, 0.57-0.94) and 0.35 (95% CI, 0.19-0.63), and for CASP8 −652 6N ins/del and del/del carriers were 0.65 (95% CI, 0.50-0.85) and 0.56 (95% CI, 0.33-0.98), respectively. Gene-gene interaction between the FasL and CASP8 variants further reduced the cancer risk in a multiplicative manner (OR for the presence of both FasL −844TT and CASP8 −652 6N del/del genotype, 0.10; 95% CI, 0.01-0.75). On the other hand, a multiplicative joint effect between the FasL −844CC or CASP8 −652 6N ins/ins genotype and smoking or diabetes mellitus in intensifying risk of pancreatic cancer was also evident.Conclusions: These results suggest that genetic variations in the death pathway genes FasL and CASP8 are involved in susceptibility to developing pancreatic cancer.
Combi-targeting concept: an optimized single-molecule dual-targeting model for the treatment of chronic myelogenous leukemia
Authors: Katsoulas Athanasia , Rachid Zakaria , McNamee James P. , Williams Christopher , Jean-Claude Bertrand J. 
Published: May 2008

AbstractBlockade of Bcr-Abl by the inhibitor Imatinib has proven efficacious in the therapy of chronic myelogenous leukemia (CML). However resistance to the drug emerges at the advanced phases of the disease. Therefore, novel therapy models remained to be designed. We have developed a novel dual targeted agent termed “combi-molecule” designed to not only block Bcr-Abl but also damage DNA. ZRF1, the first optimized prototype of the approach, was “programmed” to degrade into another inhibitor ZRF0 plus a methyl diazonium species. It was ∼2-fold stronger Abl tyrosine kinase inhibitor than Imatinib and a more potent DNA-damaging agent than Temodal. In the p53 wild-type Mo7p210 cells, the potency of ZRF1 was ∼1,000-fold superior to that of the equieffective combinations of Imatinib plus Temodal. More importantly, its superior potency over Imatinib was more pronounced in Bcr-Abl-positive cells coexpressing wild-type p53. Studies to rationalize these results showed that, through its Bcr-Abl inhibitory function, it down-regulated p53. However, sufficient level of the latter protein was available for transactivating p21 and Bax, which are required for cell cycle arrest and apoptosis. The results suggest that, in p53 wild-type cells, apoptosis is induced not only through Bcr-Abl inhibition but also through the p53-controlled DNA-damaging pathway, leading to an additive effect that translates into enhanced cell death. The study conclusively showed that p53 is a major determinant for the cytotoxic advantages of the novel combi-molecular approach in CML, a disease in which 70% to 85% of all the cases express wild-type p53. [Mol Cancer Ther 2008;7(5):1033–43]
Inhibition of mitochondrial metabolism by methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate induces apoptotic or autophagic cell death in chronic myeloid leukemia cells
Authors: Samudio Ismael , Kurinna Svitlana , Ruvolo Peter , Korchin Borys , Kantarjian Hagop , Beran Miloslav , Dunner Kenneth , Kondo Seiji , Andreeff Michael , Konopleva Marina 
Published: May 2008

Abstract
The initial success of the first synthetic bcr-abl kinase inhibitor imatinib has been dampened by the emergence of imatinib-resistant disease in blast crisis chronic myeloid leukemia. Here, we report that the novel triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate (CDDO-Me) potently induced cytotoxicity in imatinib-resistant KBM5 cells expressing the T315I mutation of bcr-abl (24-h EC50, 540 nmol/L). In long-term culture, CDDO-Me abrogated the growth of human parental KBM5 and KBM5-STI cells with 96-h IC50 of 205 and 221 nmol/L, respectively. In addition, CDDO-Me rapidly decreased the viability of murine lymphoid Ba/F3 cells expressing wild-type p210 as well as the imatinib-resistant E255K and T315I mutations of bcr-abl. The low-dose effects of CDDO-Me are associated with inhibition of mitochondrial oxygen consumption, whereas the cytotoxic effects appear to be mediated by a rapid and selective depletion of mitochondrial glutathione that accompanies the increased generation of reactive oxygen species and mitochondrial dysfunction. Interestingly, the mitochondriotoxic effects of CDDO-Me are followed by the rapid autophagocytosis of intracellular organelles or the externalization of phosphatidylserine in different cell types. We conclude that alterations in mitochondrial function by CDDO-Me can result in autophagy or apoptosis of chronic myeloid leukemia cells regardless of the mutational status of bcr-abl. CDDO-Me is in clinical trials and shows signs of clinical activity, with minimal side effects and complete lack of cardiotoxicity. Studies in leukemias are in preparation. [Mol Cancer Ther 2008;7(5):1130–9]
Human papillomavirus type 16 L1E7 chimeric capsomeres have prophylactic and therapeutic efficacy against papillomavirus in mice
Authors: Bian Tao , Wang Yue , Lu Zhenhua , Ye Zhenmei , Zhao Li , Ren Jiao , Zhang Hui , Ruan Li , Tian Houwen 
Published: May 2008

Abstract
Genital human papillomavirus (HPV) infection is the primary cause of cervical cancer in women. Although the HPV recombinant L1 protein was recently licensed as an available vaccine, it has numerous shortcomings. New vaccination strategies should be considered. To enable the design of a prophylactic and therapeutic low-cost vaccine candidate, chimeric HPV16 L1ΔC34E7N1-60 capsomeres were produced in Escherichia coli. The immune characteristics and potential prophylactic and therapeutic effects of these capsomeres were examined in C57BL/6 mice. Following protein purification and renaturation, the majority of the recombinant chimeric proteins (L1ΔC34E7N1-60) assembled into capsomeres. These capsomeres were able to induce conformational and neutralizing antibodies against HPV virus-like particles and trigger cell-mediated specific immune responses against the L1 and E7 peptides. In vivo tumor challenge assays showed that mice immunized with the capsomeres were protected against a challenge with both C3 and TC-1 tumor cells. Furthermore, in vivo tumor rejection assays showed that capsomeres have therapeutic efficacy in mice following inoculation with C3 and TC-1 tumor cells. Chimeric capsomeres are capable of preventing and eliminating HPV16 infection. Therefore, our study has provided an economical vaccine candidate. [Mol Cancer Ther 2008;7(5):1329–35]
Pharmacologic retinoid signaling and physiologic retinoic acid receptor signaling inhibit basal cell carcinoma tumorigenesis
Authors: So Po-Lin , Fujimoto Michele A. , Epstein Ervin H. 
Published: May 2008

AbstractBasal cell carcinoma (BCC) is the most common human cancer. Patients with basal cell nevus syndrome (Gorlin syndrome) are highly susceptible to developing many BCCs as a result of a constitutive inactivating mutation in one allele of PATCHED 1, which encodes a tumor suppressor that is a major inhibitor of Hedgehog signaling. Dysregulated Hedgehog signaling is a common feature of both hereditary and sporadic BCCs. Recently, we showed remarkable anti-BCC chemopreventive efficacy of tazarotene, a retinoid with retinoic acid receptor (RAR) β/γ specificity, in Ptch1+/- mice when treatment was commenced before carcinogenic insults. In this study, we assessed whether the effect of tazarotene against BCC carcinogenesis is sustained after its withdrawal and whether tazarotene is effective against preexisting microscopic BCC lesions. We found that BCCs did not reappear for at least 5 months after topical drug treatment was stopped and that already developed, microscopic BCCs were susceptible to tazarotene inhibition. In vitro, tazarotene inhibited a murine BCC keratinocyte cell line, ASZ001, suggesting that its effect in vivo is by direct action on the actual tumor cells. Down-regulation of Gli1, a target gene of Hedgehog signaling and up-regulation of CRABPII, a target gene of retinoid signaling, were observed with tazarotene treatment. Finally, we investigated the effects of topical applications of other retinoid-related compounds on BCC tumorigenesis in vivo. Tazarotene was the most effective of the preparations studied, and its effect most likely was mediated by RARγ activation. Furthermore, inhibition of basal RAR signaling in the skin promoted BCC carcinogenesis, suggesting that endogenous RAR signaling restrains BCC growth. [Mol Cancer Ther 2008;7(5):1275–84]
Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells
Authors: D'Alise Anna Morena , Amabile Giovanni , Iovino Mariangela , Di Giorgio Francesco Paolo , Bartiromo Marta , Sessa Fabio , Villa Fabrizio , Musacchio Andrea , Cortese Riccardo 
Published: May 2008

Abstract
The demonstration that the small synthetic molecule reversine [2-(4-morpholinoanilino)-N6-cyclohexyladenine] promotes the dedifferentiation of committed cells into multipotent progenitor-type cells has raised hopes on the exploitation of this small chemical tool for the generation of stem cells. Here, we show that reversine causes a failure in cytokinesis and induces polyploidization. These effects of reversine are due to the inhibition of Aurora A and B, two related kinases that are implicated in several aspects of mitosis and that are frequently amplified and overexpressed in human tumors. Reversine inhibits the phosphorylation of histone H3, a direct downstream target of Aurora kinases. Similarly to the Aurora kinase inhibitor VX-680, which has recently entered phase II clinical trials for cancer treatment, reversine inhibited colony formation of leukemic cells from patients with acute myeloid leukemia but was significantly less toxic than VX-680 on cells from healthy donors. The crystal structure of the reversine-Aurora B kinase complex shows that reversine is a novel class of ATP-competitive Aurora kinase inhibitors. Thus, although our studies raise serious doubts on the application of reversine in regenerative medicine, they support the paradigm that reversine might be a useful agent in cancer chemotherapy. [Mol Cancer Ther 2008;7(5):1140–9]
Akt-mediated eminent expression of c-FLIP and Mcl-1 confers acquired resistance to TRAIL-induced cytotoxicity to lung cancer cells
Authors: Wang Xia , Chen Wenshu , Zeng Weihua , Bai Lang , Tesfaigzi Yohannes , Belinsky Steven A. , Lin Yong 
Published: May 2008

Abstract
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a potential anticancer agent due to its selectivity in killing transformed cells. However, TRAIL can also stimulate the proliferation and metastasis of TRAIL-resistant cancer cells. Thus, acquired TRAIL resistance during TRAIL therapy would shift the patient's treatment from beneficial to detrimental. In this study, we focused on the acquired TRAIL resistance mechanism and showed that the elevated expression of the antiapoptotic factor cellular FLICE-like inhibitory protein (c-FLIP) and the prosurvival Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) underlie the main mechanism of this type of TRAIL resistance in lung cancer cells. Chronic exposure to TRAIL resulted in lung cancer cell resistance to TRAIL-induced cytotoxicity, and this resistance was associated with the increase in the cellular levels of c-FLIPL and Mcl-1L. Overexpresssion of c-FLIPL suppressed recruitment of caspase-8 to the death-inducing signaling complex, whereas increased Mcl-1L expression blunted the mitochondrial apoptosis pathway. The elevation of c-FLIPL and Mcl-1L expression was due to Akt-mediated stabilization of these proteins in TRAIL-resistant cells. Importantly, suppressing c-FLIPL and Mcl-1L expression by RNA interference collectively alleviated acquired TRAIL resistance. Taken together, these results identify c-FLIPL and Mcl-1L as the major determinants of acquired TRAIL resistance and could be molecular targets for improving the therapeutic value of TRAIL against lung cancer. [Mol Cancer Ther 2008;7(5):1156–63]
Requirement of hypoxia-inducible factor-1α down-regulation in mediating the antitumor activity of the anti–epidermal growth factor receptor monoclonal antibody cetuximab
Authors: Li Xinqun , Lu Yang , Liang Ke , Pan Tianhong , Mendelsohn John , Fan Zhen 
Published: May 2008

Abstract
We tested our novel hypothesis that down-regulation of hypoxia-inducible factor-1α (HIF-1α), the regulated subunit of HIF-1 transcription factor that controls gene expression involved in key functional properties of cancer cells (including metabolism, survival, proliferation, invasion, angiogenesis, and metastasis), contributes to a major antitumor mechanism of cetuximab, an approved therapeutic monoclonal antibody that blocks activation of the epidermal growth factor receptor. We showed that cetuximab treatment down-regulates HIF-1α levels by inhibiting synthesis of HIF-1α rather than by enhancing degradation of the protein. Inhibition of HIF-1α protein synthesis was dependent on effective inhibition of the phosphoinositide-3 kinase (PI3K)/Akt pathway by cetuximab, because the inhibition was prevented in cells transfected with a constitutively active PI3K or a constitutively active Akt but not in cells with a constitutively active MEK. Overexpression of HIF-1α conferred cellular resistance to cetuximab-induced apoptosis and inhibition of vascular endothelial growth factor production in sensitive cancer cell models, and expression knockdown of HIF-1α by RNA interference substantially restored cellular sensitivity to the cetuximab-mediated antitumor activities in experimental resistant cell models created by transfection of an oncogenic Ras gene (G12V) or by concurrent treatment of the cells with insulin-like growth factor-I. In summary, our data show that cetuximab decreases HIF-1α protein synthesis through inhibition of a PI3K-dependent pathway and that an effective down-regulation of HIF-1α is required for maximal therapeutic effects of cetuximab in cancer cells. [Mol Cancer Ther 2008;7(5):1207–17]
Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors
Authors: Johansson Gunnar , Mahller Yonatan Y. , Collins Margaret H. , Kim Mi-Ok , Nobukuni Takahiro , Perentesis John , Cripe Timothy P. , Lane Heidi A. , Kozma Sara C. , Thomas George , Ratner Nancy 
Published: May 2008

Abstract
Malignant peripheral nerve sheath tumors (MPNST) are chemoresistant sarcomas with poor 5-year survival that arise in patients with neurofibromatosis type 1 (NF1) or sporadically. We tested three drugs for single and combinatorial effects on collected MPNST cell lines and in MPNST xenografts. The mammalian target of rapamycin complex 1 inhibitor RAD001 (Everolimus) decreased growth 19% to 60% after 4 days of treatment in NF1 and sporadic-derived MPNST cell lines. Treatment of subcutaneous sporadic MPNST cell xenografts with RAD001 significantly, but transiently, delayed tumor growth, and decreased vessel permeability within xenografts. RAD001 combined with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib caused additional inhibitory effects on growth and apoptosis in vitro, and a small but significant additional inhibitory effect on MPNST growth in vivo that were larger than the effects of RAD001 with doxorubicin. RAD001 plus erlotinib, in vitro and in vivo, reduced phosphorylation of AKT and total AKT levels, possibly accounting for their additive effect. The results support the consideration of RAD001 therapy in NF1 patient and sporadic MPNST. The preclinical tests described allow rapid screening strata for drugs that block MPNST growth, prior to tests in more complex models, and should be useful to identify drugs that synergize with RAD001. [Mol Cancer Ther 2008;7(5):1237–45]
Proteasome inhibitor PS-341 (VELCADE) induces stabilization of the TRAIL receptor DR5 mRNA through the 3′-untranslated region
Authors: Kandasamy Karthikeyan , Kraft Andrew S. 
Published: May 2008

Abstract
Addition of proteasome inhibitor PS-341 (VELCADE, bortezomib) to prostate cancer cells enhances cell death mediated by tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). PS-341 sensitizes prostate cancer cells to TRAIL-induced apoptosis by increasing TRAIL receptors (DR5), inhibiting protein degradation, and elevating DR5 mRNA. Investigations into how PS-341 regulates the stability of DR5 mRNA revealed that PS-341 increased DR5 mRNA by extending its half-life from 4 to 10 h. The 2.5-kb 3′-untranslated region of the DR5 gene stabilized a heterologous gene in LNCaP human prostate cancer cells, suggesting the importance of this mRNA sequence. In contrast, human prostate cancer cell lines PC-3 and DU145 do not show this stabilization, suggesting cell specificity. PS-341 treatment of LNCaP cells increases the level of specific cytoplasmic mRNA-binding proteins, including AUF-1 isoforms, hnRNP C1/C2, and HuR proteins. In UV cross-linking experiments, after PS-341 treatment, the HuR protein markedly increases binding to specific sequences in the DR5 3′-untranslated region. In LNCaP cells treated with PS-341, small interfering RNA–mediated knockdown of HuR markedly decreases the half-life of DR5 mRNA, indicating that HuR is essential for mRNA stabilization. HuR protein is ubiquitinated, suggesting that PS-341 increases this protein by preventing its degradation. These experiments implicate modulation of mRNA stability as a novel mechanism by which proteasome inhibitors function, sensitizing cancer cells to antineoplastic agents. [Mol Cancer Ther 2008;7(5):1091–100]
The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis
Authors: Liby Karen , Black Candice C. , Royce Darlene B. , Williams Charlotte R. , Risingsong Renee , Yore Mark M. , Liu Xi , Honda Tadashi , Gribble Gordon W. , Lamph William W. , Sporn Thomas A. , Dmitrovsky Ethan , Sporn Michael B. 
Published: May 2008

AbstractFemale A/J mice injected with the carcinogen vinyl carbamate develop atypical adenomatous hyperplasias in lungs 4 weeks after injection with the carcinogen. The number and severity of tumors then increase over time, making these mice a useful model for evaluating potential chemopreventive agents. The rexinoid LG100268 (LG268), a selective ligand for the retinoid X receptor, and the methyl amide of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) both significantly reduced the number, size, and severity of the histopathology of lung tumors in female A/J mice when fed in diet for 14 to 20 weeks. The total tumor burden was 85% to 87% lower in mice fed LG268 and CDDO-MA than in controls, and the percentage of high-grade tumors decreased from 59% in the controls to 25% or 30% with CDDO-MA and LG268. Erlotinib, which is used to treat lung cancer patients and is an inhibitor of the epidermal growth factor receptor, was less effective in this model. Immunohistochemical staining of geminin, a marker of cell cycle progression, was higher in lung sections from control mice than in mice treated with LG268. Because rexinoids and triterpenoids signal through different biological pathways, they should be tested in combination for the prevention of lung cancer. [Mol Cancer Ther 2008;7(5):1251–7]
Cytotoxicity of the matrix metalloproteinase–activated anthrax lethal toxin is dependent on gelatinase expression and B-RAF status in human melanoma cells
Authors: Alfano Randall W. , Leppla Stephen H. , Liu Shihui , Bugge Thomas H. , Herlyn Meenhard , Smalley Keiran S. , Bromberg-White Jennifer L. , Duesbery Nicholas S. , Frankel Arthur E. 
Published: May 2008

Abstract
Anthrax lethal toxin (LeTx) shows potent mitogen-activated protein kinase pathway inhibition and apoptosis in melanoma cells that harbor the activating V600E B-RAF mutation. LeTx is composed of two proteins, protective antigen and lethal factor. Uptake of the toxin into cells is dependent on proteolytic activation of protective antigen by the ubiquitously expressed furin or furin-like proteases. To circumvent nonspecific LeTx activation, a substrate preferably cleaved by gelatinases was substituted for the furin LeTx activation site. Here, we have shown that the toxicity of this matrix metalloproteinase (MMP)–activated LeTx is dependent on host cell surface MMP-2 and MMP-9 activity as well as the presence of the activating V600E B-RAF mutation, making this toxin dual specific. This additional layer of tumor cell specificity would potentially decrease systemic toxicity from the reduction of nonspecific toxin activation while retaining antitumor efficacy in patients with V600E B-RAF melanomas. Moreover, our results indicate that cell surface-associated gelatinase expression can be used to predict sensitivity among V600E B-RAF melanomas. This finding will aid in the better selection of patients that will potentially respond to MMP-activated LeTx therapy. [Mol Cancer Ther 2008;7(5):1218–26]
Breaking Up the Family: Divorce in Egyptian Law and Practice
Authors: Bernard-Maugiron Nathalie , Dupret Baudouin 
Published: May 2008

AbstractIf the legal status of women wishing to end an unhappy marriage has undoubtedly improved through the codification process of personal status law in Egypt in the twentieth century, it still remains very unequal in comparison to the privileges enjoyed by men in that field. Moreover, the practical effects of these legal reforms can be questioned. This chapter will study marriage breakups in Egypt through both legal and sociological approaches. Legal texts governing family law will first be examined to expose the different ways marriage can be broken up and how the reforms were legitimated by reference to sharî'a principles. Then the various obstacles that impede the effective implementation of these reforms will be exposed, to stress that the study of law should capture the language of law in action and not only of law in books.