bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of Nuclear Factor κB
In vivo
Selectively Protects the Murine Small Intestine against Ionizing Radiation-Induced Damage
Authors: Wang Yong , Meng Aimin , Lang Hainan , Brown Stephen A. , Konopa Jennifer L. , Kindy Mark S. , Schmiedt Richard A. , Thompson John S. , Zhou Daohong 
Published: September 2005

Abstract
Exposure of mice to total body irradiation induces nuclear factor κB (NFκB) activation in a tissue-specific manner. In addition to the spleen, lymph nodes, and bone marrow, the tissues that exhibit NFκB activation now include the newly identified site of the intestinal epithelial cells. NFκB activated by total body irradiation mainly consists of NFκB p50/RelA heterodimers, and genetically targeted disruption of the NFκB p50 gene in mice significantly decreased the activation. By comparing tissue damage and lethality in wild-type and NFκB p50 knockout (p50−/−) mice after they were exposed to increasing doses of total body irradiation, we additionally examined the role of NFκB activation in total body irradiation-induced tissue damage. The results show that p50−/− mice are more sensitive to total body irradiation-induced lethality than wild-type mice (LD50/Day 7: wild-type = 13.12 Gy versus p50−/− = 7.75 Gy and LD50/Day 30: wild-type = 9.31 Gy versus p50−/− = 7.81 Gy). The increased radiosensitivity of p50−/− mice was associated with an elevated level of apoptosis in intestinal epithelial cells and decreased survival of the small intestinal crypts compared with wild-type mice (P &lt; 0.01). In addition, RelA/TNFR1-deficient (RelA/TNFR1−/−) mice also exhibited a significant increase in intestinal epithelial cell apoptosis after they were exposed to total body irradiation as compared with TNFR1-deficient (TNFR1−/−) mice (P &lt; 0.01). In contrast, no significant increase in total body irradiation-induced apoptosis or tissue injury was observed in bone marrow cells, spleen lymphocytes, and the liver, heart, lung, and kidney of p50−/− mice in comparison with wild-type mice. These findings indicate that activation of NFκB selectively protects the small intestine against ionizing radiation-induced damage.
The Gap Junction Protein Connexin32 Is a Mouse Lung Tumor Suppressor
Authors: King Timothy J. , Lampe Paul D. 
Published: September 2005

Abstract
Although loss of connexin expression and/or gap junction intercellular communication correlates with decreased growth control and increased neoplastic potential, there is limited evidence directly linking gap junction intercellular communication function with tumor suppression in situ. Here, we show for the first time that a gap junction protein, connexin32 (Cx32), acts as a lung tumor suppressor in a mouse model. Cx32-deficient nontumorous lung tissue exhibited an increased proliferative index (P &lt; 0.001), and, after exposure to the carcinogen diethylnitrosamine, Cx32-deficient mice exhibited a highly statistically significant (P &lt; 0.001) increase in bronchioloalveolar lung tumor incidence (28 of 45, 62%) and a 45% increase in average multiplicity compared with wild-type mice (7 of 29, 24%). Tumors from Cx32-deficient mice also showed increased activation of mitogen-activated protein kinase (P &lt; 0.001) compared with wild-type tumors, implicating this signaling pathway in Cx32/gap junction intercellular communication-associated lung tumorigenesis.
Dendritic Cells Pulsed with an Anti-Idiotype Antibody Mimicking Carcinoembryonic Antigen (CEA) Can Reverse Immunological Tolerance to CEA and Induce Antitumor Immunity in CEA Transgenic Mice
Authors: Saha Asim , Chatterjee Sunil K. , Foon Kenneth A. , Primus F. James , Sreedharan Sunil , Mohanty Kartik , Bhattacharya-Chatterjee Malaya 
Published: September 2005

AbstractIn this report, we have studied the immunogenicity of the nominal antigen, carcinoembryonic antigen (CEA), and that of an anti-idiotype antibody, 3H1, which mimics CEA and can be used as a surrogate for CEA. We have demonstrated that immunization of CEA transgenic mice with bone marrow-derived mature dendritic cells (DC) loaded with anti-idiotype 3H1 or CEA could reverse CEA unresponsiveness and result in the induction of CEA-specific immune responses and the rejection of CEA-transfected MC-38 colon carcinoma cells, C15. Immunized mice splenocytes proliferated in an antigen-specific manner by a mechanism dependent on the functions of CD4, MHC II, B7–2, CD40, CD28, and CD25. However, immune splenic lymphocytes isolated from 3H1-DC-vaccinated mice when stimulated in vitro with 3H1 or CEA secreted significantly higher levels of Th1 cytokines than did CEA-DC vaccinated mice. DC vaccination also induced antigen-specific effector CD8+ T cells capable of expressing interluekin-2, IFN-γ, and tumor necrosis factor (TNF)-α and displayed cytotoxic activity against C15 cells in an MHC class I-restricted manner. 3H1-DC vaccination resulted in augmented CTL responses and the elevated expression of CD69, CD25, and CD28 on CD8+ CTLs. The immune responses developed in 3H1-DC-immunized mice resulted in rejection of C15 tumor cells in nearly 100% of experimental mice, whereas only 40% of experimental mice immunized with CEA-DC were protected from C15 tumor growth. These findings suggest that under the experimental conditions used, 3H1-DC vaccination was better than CEA-DC vaccination in breaking immune tolerance to CEA and inducing protective antitumor immune responses in this murine model transgenic for human CEA.
CC Chemokine Ligand 25 Enhances Resistance to Apoptosis in CD4+ T Cells from Patients with T-Cell Lineage Acute and Chronic Lymphocytic Leukemia by Means of Livin Activation
Authors: Qiuping Zhang , Jei Xiong , Youxin Jin , Wei Ju , Chun Liu , Jin Wang , Qun Wu , Yan Liu , Chunsong Hu , Mingzhen Yang , Qingping Gao , Kejian Zhang , Zhimin Sun , Qun Li , Junyan Liu , Jinquan Tan 
Published: September 2005

AbstractWe investigated CD4 and CD8 double-positive thymocytes, CD4+ T cells from typical patients with T-cell lineage acute lymphocytic leukemia (T-ALL) and T cell lineage chronic lymphocytic leukemia (T-CLL), and MOLT4 T cells in terms of CC chemokine ligand 25 (CCL25) functions of induction of resistance to tumor necrosis factor α (TNF-α)–mediated apoptosis. We found that CCL25 selectively enhanced resistance to TNF-α–mediated apoptosis in T-ALL and T-CLL CD4+ T cells as well as in MOLT4 T cells, but CD4 and CD8 double-positive thymocytes did not. One member protein of the inhibitor of apoptosis protein (IAP) family, Livin, was selectively expressed in the malignant cells at higher levels, particularly in T-ALL CD4+ T cells, in comparison with the expression in CD4 and CD8 double-positive thymocytes. After stimulation with CCL25 and apoptotic induction with TNF-α, the expression levels of Livin in these malignant cells were significantly increased. CCL25/thymus-expressed chemokine (TECK), by means of CC chemokine receptor 9 (CCR9) ligation, selectively activated Livin to enhance resistance to TNF-α–mediated apoptosis in c-jun-NH2-kinase 1 (JNK1) kinase-dependent manner. These findings suggested differential functions of CCR9/CCL25 in distinct types of cells. CD4 and CD8 double-positive thymocytes used CCR9/CCL25 for migration, homing, development, maturation, selection, cell homeostasis, whereas malignant cells, particularly T-ALL CD4+ T cells, used CCR9/CCL25 for infiltration, resistance to apoptosis, and inappropriate proliferation.
Acetylcholinesterase Plays a Pivotal Role in Apoptosome Formation
Authors: Park Sang Eun , Kim Nam Deuk , Yoo Young Hyun 
Published: September 2005

Abstract
Although a recent study (Zhang et al. Cell Death Differ 2002; 9; 790–800) presented that acetylcholinesterase (AChE) might be an important common component in leading to various types of apoptosis, the molecular mechanism, by which AChE functions, had remained elusive before that study. We explored the role of AChE in apoptosis by silencing the AChE gene. Silencing of the AChE gene abolished the expression of AChE and prevented caspase-9 activation, decrease of cell viability, nuclear condensation and poly(adenosine diphosphate-ribose) polymerase cleavage but not mitochondrial events. Importantly, silencing of the AChE gene blocked the interaction between apoptotic protease-activating factor-1 and cytochrome c. Here we propose that AChE plays a pivotal role in the formation of apoptosome.
Functional
STK15
Phe31Ile Polymorphism Is Associated with the Occurrence and Advanced Disease Status of Esophageal Squamous Cell Carcinoma
Authors: Miao Xiaoping , Sun Tong , Wang Yonggang , Zhang Xuemei , Tan Wen , Lin Dongxin 
Published: September 2005

Abstract
STK15/BTAK/Aurora-A involved in regulating centrosomes and chromosome segregation is amplified and overexpressed in human cancers. A T91A polymorphism in STK15 causes Phe31Ile substitution, and the 31Ile variant has been shown to be preferentially amplified and associated with degree of aneuploidy in human tumors. We genotyped 656 patients with esophageal squamous cell carcinoma (ESCC) and 656 controls for the polymorphism to examine the hypothesis that the STK15 variation may affect individual susceptibility to the occurrence and aggression of ESCC. It was found that the Ile/Ile genotype was significantly associated with increased risk of ESCC occurrence [odds ratio (OR) = 1.97, 95% confidence interval (CI) = 1.36–2.85] compared with the Phe/Phe genotype. The 31Ile allele frequency significantly increased as ESCC stage increased (trend test, P = 0.006). Patients with the Ile/Ile genotype had an increased risk for invasive disease (stage II-IV; OR = 2.13, 95% CI = 1.04–4.39) or metastatic disease (stage III and IV; OR = 2.31, 95% CI = 1.06–5.05) compared with those with the Phe/Phe genotype. A positive correlation between the Ile/Ile genotype and high ESCC grade was also observed. Our results demonstrate for the first time that the STK15 polymorphism is a genetic susceptibility factor for the occurrence and aggression of ESCC.
Kaposi’s Sarcoma-Associated Herpesvirus Induction of Chromosome Instability in Primary Human Endothelial Cells
Authors: Pan Hongyi , Zhou Fuchun , Gao Shou-Jiang 
Published: September 2005

Abstract
Chromosome instability contributes to the multistep oncogenesis of cancer cells. Kaposi’s sarcoma (KS), an angiogenic vascular spindle cancer of endothelial cells, displays stage advancement with lesions at early stage being hyperproliferative, whereas lesions at late stage are clonal or multiclonal and can exhibit a neoplastic nature and chromosome instability. Although infection with KS-associated herpesvirus (KSHV) has been associated with the initiation and promotion of KS, the mechanism of KS neoplastic transformation remains unclear. We show that KSHV infection of primary human umbilical vein endothelial cells induces abnormal mitotic spindles and centrosome duplication. As a result, KSHV-infected cells manifest chromosome instability, including chromosomal misalignments and laggings, mitotic bridges, and formation of micronuclei and multinucleation. Our results indicate that KSHV infection could predispose cells to malignant transformation through induction of genomic instability and contributes to the development of KS.
Nitric Oxide Confers Therapeutic Activity to Dendritic Cells in a Mouse Model of Melanoma
Authors: Perrotta Cristiana , Falcone Sestina , Capobianco Annalisa , Camporeale Annalisa , Sciorati Clara , Palma Clara De , Pisconti Addolorata , Rovere-Querini Patrizia , Bellone Matteo , Manfredi Angelo A. , Clementi Emilio 
Published: September 2005

AbstractSusceptibility of dendritic cells (DCs) to tumor-induced apoptosis reduces their efficacy in cancer therapy. Here we show that delivery within exponentially growing B16 melanomas of DCs treated ex vivo with nitric oxide (NO), released by the NO donor (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO), significantly reduced tumor growth, with cure of 37% of animals. DETA-NO-treated DCs became resistant to tumor-induced apoptosis because DETA-NO prevented tumor-induced changes in the expression of Bcl-2, Bax, and Bcl-xL; activation of caspase-9; and a reduction in the mitochondrial membrane potential. DETA-NO also increased DC cytotoxic activity against tumor cells and DC ability to trigger T-lymphocyte proliferation. All of the effects of DETA-NO were mediated through cGMP generation. NO and NO-generating drugs may therefore be used to increase the anticancer efficacy of DCs.
Augmenting Chemosensitivity of Malignant Melanoma Tumors via Proteasome Inhibition
Authors: Amiri Katayoun I. , Horton Linda W. , LaFleur Bonnie J. , Sosman Jeffrey A. , Richmond Ann 
Published: September 2005

Abstract
Melanoma poses a great challenge to patients, oncologists, and biologists because of its nearly universal resistance to chemotherapy. Many studies have shown that nuclear factor κB is constitutively activated in melanoma, thereby promoting the proliferation of melanoma cells by inhibiting the apoptotic responses to chemotherapy. Nuclear factor κB activity is regulated by phosphorylation and subsequent degradation of inhibitor of nuclear factor κB by the ubiquitin-proteasome pathway. In this study, we show that the novel proteasome inhibitor, bortezomib, inhibited the growth of melanoma cells in vitro at a concentration range of 0.1–10 nm and in combination with the chemotherapeutic agent temozolomide, the inhibitory effect on melanoma cell growth was even more prominent. Data from a murine model showed reduced tumor growth when bortezomib was administered to human melanoma tumors. Strikingly, animals receiving bortezomib in combination with temozolomide achieved complete remission of palpable tumors after only 30 days of therapy, lasting &gt;200 days. Our data indicate strongly that bortezomib in combination with chemotherapeutic agents should be studied additionally for the treatment of melanoma.
Synergistic Suppression of Microtubule Dynamics by Discodermolide and Paclitaxel in Non-Small Cell Lung Carcinoma Cells
Authors: Honore Stéphane , Kamath Kathy , Braguer Diane , Horwitz Susan Band , Wilson Leslie , Briand Claudette , Jordan Mary Ann 
Published: September 2005

Abstract
Discodermolide is a new microtubule-targeted antimitotic drug in Phase I clinical trials that, like paclitaxel, stabilizes microtubule dynamics and enhances microtubule polymer mass in vitro and in cells. Despite their apparently similar binding sites on microtubules, discodermolide acts synergistically with paclitaxel to inhibit proliferation of A549 human lung cancer cells (L. Martello et al., Clin. Cancer Res., 6: 1978–1987, 2000). To understand their synergy, we examined the effects of the two drugs singly and in combination in A549 cells and found that, surprisingly, their antiproliferative synergy is related to their ability to synergistically inhibit microtubule dynamic instability and mitosis. The combination of discodermolide and paclitaxel at their antiproliferative IC50s (7 nm for discodermolide and 2 nm for paclitaxel) altered all of the parameters of dynamic instability synergistically except the time-based rescue frequency. For example, together the drugs inhibited overall microtubule dynamicity by 71%, but each drug individually inhibited dynamicity by only 24%, giving a combination index (CI) of 0.23. Discodermolide and paclitaxel also synergistically blocked cell cycle progression at G2-M (41, 9.6, and 16% for both drugs together, for discodermolide alone, and for paclitaxel alone, respectively; CI = 0.59), and they synergistically enhanced apoptosis (CI = 0.85). Microtubules are unique receptors for drugs. The results suggest that ligands that bind to large numbers of binding sites on an individual microtubule can interact in a poorly understood manner to synergistically suppress microtubule dynamic instability and inhibit both mitosis and cell proliferation, with important consequences for combination clinical therapy with microtubule-targeted drugs.
Epidermal Growth Factor Receptor Regulates Aberrant Expression of Insulin-Like Growth Factor-Binding Protein 3
Authors: Takaoka Munenori , Harada Hideki , Andl Claudia D. , Oyama Kenji , Naomoto Yoshio , Dempsey Kelly L. , Klein-Szanto Andres J. , El-Deiry Wafik S. , Grimberg Adda , Nakagawa Hiroshi 
Published: September 2005

Abstract
Epidermal growth factor receptor (EGFR) is frequently overexpressed in esophageal carcinoma and its precursor lesions. To gain insights into how EGFR overexpression affects cellular functions in primary human esophageal cells, we performed gene expression profiling and identified insulin-like growth factor-binding protein (IGFBP)-3 as the most up-regulated gene. IGFBP-3 regulates cell proliferation through both insulin-like growth factor-dependent and independent mechanisms. We found that IGFBP-3 mRNA and protein expression was increased in EGFR-overexpressing primary and immortalized human esophageal cells. IGFBP-3 was also up-regulated in EGFR-overexpressing cells in organotypic culture and in EGFR transgenic mice. Furthermore, IGFBP-3 mRNA was overexpressed in 80% of primary esophageal squamous cell carcinomas and 60% of primary esophageal adenocarcinomas. Concomitant up-regulation of EGFR and IGFBP-3 was observed in 60% of primary esophageal squamous cell carcinomas. Immunohistochemistry revealed cytoplasmic localization of IGFBP-3 in the preponderance of preneoplastic and neoplastic esophageal lesions. IGFBP-3 was also overexpressed in esophageal cancer cell lines at both mRNA (60%) and protein (40%) levels. IGFBP-3 secreted by cancer cells was capable of binding to insulin-like growth factor I. Functionally, epidermal growth factor appeared to regulate IGFBP-3 expression in esophageal cancer cell lines. Finally, suppression of IGFBP-3 by small interfering RNA augmented cell proliferation, suggesting that IGFBP-3 may inhibit tumor cell proliferation as a negative feedback mechanism. In aggregate, we have identified for the first time that IGFBP-3 is an aberrantly regulated gene through the EGFR signaling pathway and it may modulate EGFR effects during carcinogenesis.
Functional Correlation of Trophinin Expression with the Malignancy of Testicular Germ Cell Tumor
Authors: Hatakeyama Shingo , Ohyama Chikara , Minagawa Shingo , Inoue Takamitsu , Kakinuma Hideaki , Kyan Atsushi , Arai Yoichi , Suga Tomoaki , Nakayama Jun , Kato Tetsuro , Habuchi Tomonori , Fukuda Michiko N. 
Published: September 2005

Abstract
Trophinin is a membrane protein that is potentially involved in human embryo implantation by mediating homophillic cell adhesion between trophoblastic cells and endometrial cells. Trophinin expression by maternal cells may be induced by the embryo that secretes human chorionic gonadotropin (hCG). Because the process of tumor metastasis resembles that of trophoblast invasion and proliferation during embryo implantation, we hypothesized that testicular cancers that synthesize hCG express trophinin thus becoming aggressive trophoblast-like cells. We screened paraffin-embedded orchiectomy specimens of 158 patients with testicular germ cell tumor by immunohistochemistry using antitrophinin antibody. This screening identified trophinin-positive specimens with the frequencies 39 of 91 (43%) in stage I, 14 of 24 (58%) in stage II, and 41 of 43 (95%) in stage III (P &lt; 0.001). Thus, trophinin expression positively correlates with clinical stage. Remarkably, trophinin was found in all of the cases (33 of 33) with lung metastasis. The levels of serum hCG-β were significantly higher in the patients with trophinin-positive tumors than those with trophinin-negative tumors (P = 0.004). To determine whether trophinin promotes aggressiveness of the cell, trophinin-negative human seminona cell line JKT-1 was stably transfected with a mammalian expression vector containing trophinin cDNA. In vitro assays revealed that trophinin-expressing JKT-1-Tro cells are more invasive than JKT-1-mock cells, whereas there are no differences between JKT-1-Tro and JKT-1-mock in their proliferation activity. Upon orthotopic inoculation to athymic nude mice, JKT-1-Tro cells exhibited i.p. metastases in all of the mice (n = 5), whereas JKT-1-mock produced no metastases (n = 5). These results suggest strongly that trophinin enhances invasiveness of the cells and promotes metastasis of testicular germ cell tumor.
Highly Successful Therapeutic Vaccinations Combining Dendritic Cells and Tumor Cells Secreting Granulocyte Macrophage Colony-stimulating Factor
Authors: Driessens Gregory , Hamdane Malika , Cool Vincent , Velu Thierry , Bruyns Catherine 
Published: September 2005

Abstract
In an attempt to induce potent immune antitumor activities, we investigated, within the rat 9L gliosarcoma model, distal therapeutic vaccinations associating three therapies: dendritic cell vaccination, intratumoral granulocyte macrophage colony-stimulating factor (GM-CSF) gene transfer, and tumor apoptosis induction. Vaccines of dendritic cells coinjected with processed GM-CSF secreting 9L cells induced systemic responses, resulting in the complete regression of distant preimplanted 9L tumor masses in, with the best strategy, 94% of male rats. All of the cured rats developed a long-term resistance to a rechallenge with parental cells. The curative responses were correlated with the detection of elevated specific cytotoxic activities and a CD4+, CD8+ T cell-, and natural killer (NK) cell-mediated IFN-γ production. The survival rate of the rat seemed more directly linked to the amount of GM-CSF secreted by the transduced tumor cells, which in turn depended on the toxicity of the apoptosis-inducing treatment, than to the level of apoptosis induced. Unexpectedly, alive GM-CSF secreting 9L cells became apoptotic when injected in vivo. Thus we documented the positive role of apoptosis in the induction of therapeutic antitumor responses by comparing, at equal GM-CSF exogenous supply, the effects of dendritic cells coinjected with apoptotic or necrotic 9L cells. The data showed the superior therapeutic efficiency of combined vaccines containing apoptotic tumor cells. In conclusion, vaccinations with dendritic cells associated with apoptotic tumor cells secreting GM-CSF show a very high therapeutic potency that should show promise for the treatment of human cancer.
P-Cadherin Is Up-Regulated by the Antiestrogen ICI 182,780 and Promotes Invasion of Human Breast Cancer Cells
Authors: Paredes Joana , Stove Christophe , Stove Veronique , Milanezi Fernanda , Van Marck Veerle , Derycke Lara , Mareel Marc , Bracke Marc , Schmitt Fernando 
Published: September 2005

Abstract
P-cadherin expression in breast carcinomas has been associated with tumors of high histologic grade and lacking estrogen receptor-α, suggesting a link between these proteins. In the MCF-7/AZ breast cancer cell line, blocking estrogen receptor-α signaling with the antiestrogen ICI 182,780 induced an increase of P-cadherin, which coincided with induction of in vitro invasion. Retroviral transduction of MCF-7/AZ cells, as well as HEK 293T cells, showed the proinvasive activity of P-cadherin, which requires the juxtamembrane domain of its cytoplasmic tail. This study establishes a direct link between P-cadherin expression and the lack of estrogen receptor-α signaling in breast cancer cells and suggests a role for P-cadherin in invasion, through its interaction with proteins bound to the juxtamembrane domain.