bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Classification and Prognostication of Adrenocortical Tumors by Transcriptome Profiling
Authors: Giordano Thomas J. , Kuick Rork , Else Tobias , Gauger Paul G. , Vinco Michelle , Bauersfeld Juliane , Sanders Donita , Thomas Dafydd G. , Doherty Gerard , Hammer Gary 
Published: January 2009

Abstract
Purpose: Our understanding of adrenocortical carcinoma (ACC) has improved considerably, yet many unanswered questions remain. For instance, can molecular subtypes of ACC be identified? If so, what is their underlying pathogenetic basis and do they possess clinical significance?
Experimental Design: We did a whole genome gene expression study of a large cohort of adrenocortical tissues annotated with clinicopathologic data. Using Affymetrix Human Genome U133 Plus 2.0 oligonucleotide arrays, transcriptional profiles were generated for 10 normal adrenal cortices (NC), 22 adrenocortical adenomas (ACA), and 33 ACCs.
Results: The overall classification of adrenocortical tumors was recapitulated using principal component analysis of the entire data set. The NC and ACA cohorts showed little intragroup variation, whereas the ACC cohort revealed much greater variation in gene expression. A robust list of 2,875 differentially expressed genes in ACC compared with both NC and ACA was generated and used in functional enrichment analysis to find pathways and attributes of biological significance. Cluster analysis of the ACCs revealed two subtypes that reflected tumor proliferation, as measured by mitotic counts and cell cycle genes. Kaplan-Meier analysis of these ACC clusters showed a significant difference in survival (P &lt; 0.020). Multivariate Cox modeling using stage, mitotic rate, and gene expression data as measured by the first principal component for ACC samples showed that gene expression data contains significant independent prognostic information (P &lt; 0.017).
Conclusions: This study lays the foundation for the molecular classification and prognostication of adrenocortical tumors and also provides a rich source of potential diagnostic and prognostic markers.
Invariant Natural Killer T Cells Regulate Breast Cancer Response to Radiation and CTLA-4 Blockade
Authors: Pilones Karsten A. , Kawashima Noriko , Yang Anne Marie , Babb James S. , Formenti Silvia C. , Demaria Sandra 
Published: January 2009

AbstractPurpose: Immunoregulatory and suppressive mechanisms represent major obstacles to the success of immunotherapy in cancer patients. We have shown that the combination of radiotherapy to the primary tumor and CTL-associated protein 4 (CTLA-4) blockade induces antitumor immunity, inhibiting metastases and extending the survival of mice bearing the poorly immunogenic and highly metastatic 4T1 mammary carcinoma. Similarly to patients with metastatic cancer, however, mice were seldom cured. Here we tested the hypothesis that invariant natural killer T (iNKT) cells, a subset with unique regulatory functions, can regulate the response to radiotherapy and CTLA-4 blockade.Experimental Design: The growth of 4T1 primary tumors and lung metastases was compared in wild-type and iNKT cell–deficient (iNKT-/-) mice. Treatment was started on day 13 when the primary tumors were palpable. Mice received radiotherapy to the primary tumor in two doses of 12 Gy in combination or not with 9H10 monoclonal antibody against CTLA-4. Response to treatment was assessed by measuring primary tumor growth delay/regression, survival, and number of lung metastases.Results: The response to radiotherapy plus 9H10 was markedly enhanced in the absence of iNKT cells, with 50% of iNKT-/- versus 0% of wild-type mice showing complete tumor regression, long-term survival, and resistance to a challenge with 4T1 cells. Administration of the iNKT cell activator α-galactosylceramide did not enhance the response of wild-type mice to radiotherapy plus 9H10. Tumor-infiltrating iNKT cells were markedly reduced in wild-type mice treated with radiotherapy plus 9H10.Conclusions: iNKT cells play a major role in regulating the response to treatment with local radiotherapy and CTLA-4 blockade.
A Novel Cancer Therapy by Skin Delivery of Indoleamine 2,3-Dioxygenase siRNA
Authors: Yen Meng-Chi , Lin Chi-Chen , Chen Yi-Ling , Huang Shih-Shien , Yang Huei-Jiun , Chang Chih-Peng , Lei Huan-Yao , Lai Ming-Derg 
Published: January 2009

Abstract
Purpose: Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan, is a negative immune regulatory molecule of dendritic cells. IDO-expressing dendritic cells suppress T cell responses and may be immunosuppressive in vivo. We hypothesized that silencing the IDO expression in skin dendritic cells in vivo could elicit antitumor activity in tumor-draining lymph nodes.
Experimental Design: The efficiency of IDO-specific small interfering RNA (siRNA) was evaluated in vitro and in vivo. The therapeutic effect was evaluated in MBT-2 murine bladder tumor model and CT-26 colon tumor models.
Results: IDO expression was down-regulated in CD11c-positive lymphocytes after IDO siRNA treatment. In vivo skin administration of IDO siRNA inhibited tumor growth and prolonged survival in both tumor models. The number of infiltrated T cells and neutrophils increased at tumor sites, which are correlated with therapeutic efficacy. The T cells may be mainly responsible for the immunologic rejection because the effect was abolished by depletion of CD8-positive T cells. Adoptive transfer of CD11c-positive dendritic cells from vaccinated mice delayed tumor progression. The cancer therapeutic effect was reproducibly observed with another IDO siRNA targeting at different site, suggesting the effect was not due to off-target effect. In a neu-overexpressing MBT-2 tumor model, IDO siRNA enhanced the therapeutic efficacy of Her2/Neu DNA vaccine. Down-regulation of IDO2, an IDO homologue, with siRNA also generated antitumor immunity in vivo.
Conclusions: Antitumor immunity can be effectively elicited by physical delivery of siRNAs targeting immunoregulatory genes in skin dendritic cells in vivo, as shown by IDO and IDO2 in this report.
ABCB8 Mediates Doxorubicin Resistance in Melanoma Cells by Protecting the Mitochondrial Genome
Authors: Elliott Aaron M. , Al-Hajj Muhammad A. 
Published: January 2009

AbstractDespite their initial effectiveness in the treatment of melanoma, chemotherapeutic agents are ultimately futile against this most aggressive form of skin cancer, and patients inevitably succumb to the disease. One of the mechanisms by which residual melanoma cells become chemoresistant is via the decreased efficiency of chemotherapeutics through the action of ATP-binding cassette (ABC) proteins that are variably expressed by the tumor cells. The clinical relevance of the ABC transporters in the context of cancer is paramount. Inhibitors of these transporters have been shown to increase the efficacy of standard therapy in experimental systems. Their clinical application requires better understanding of the role individual transporters play in the mechanism and the development of more specific inhibitors with minimal off target effects. ABC transporters in tumor cells have been shown to confer multidrug resistance in many solid tumors. However, their role in melanomas is far from clear. Here, we prospectively identify ABCB8 as a specific and major player in the chemoresistance of several melanoma cell lines. ABCB8 knockdown with shRNA reduced doxorubicin resistance ∼3- to 4-fold in these cells. Furthermore, we show that this reversal is specific to doxorubicin and not to other commonly used chemotherapeutics. Our results also provide evidence that ABCB8 conferred resistance through the protection of mitochondrial DNA from doxorubicin-induced DNA damage. (Mol Cancer Res 2009;7(1):79–87)
Establishment of a Dog Model for the p53 Family Pathway and Identification of a Novel Isoform of p21 Cyclin-Dependent Kinase Inhibitor
Authors: Zhang Jin , Chen Xiangling , Kent Michael S. , Rodriguez Carlos O. , Chen Xinbin 
Published: January 2009

Abstract
Spontaneous tumors in the dog offer a unique opportunity as models to study human cancer etiology and therapy. p53, the most commonly mutated gene in human cancers, is found to be altered in dog cancers. However, little is known about the role of p53 in dog tumorigenesis. Here, we found that on exposure to DNA damage agents or MDM2 inhibitor nutlin-3, canine p53 is accumulated and capable of inducing its target genes, MDM2 and p21. We also found that on DNA damage, canine p53 is accumulated in the nucleus, followed by MDM2 nuclear translocation and increased 53BP1 foci formation. In addition, we found that canine p63 and p73 are up-regulated by DNA damage agents. Furthermore, colony formation assay showed that canine tumor cells are sensitive to DNA damage agents and nutlin-3 in a p53-dependent manner. Surprisingly, canine p21 is expressed as two isoforms. Thus, we generated multiple canine p21 mutants and found that amino acids 129 to 142 are required, whereas amino acid 139 is one of the key determinants, for the expression of two p21 isoforms. Finally, we showed that although the full-length human p21 cDNA expresses one polypeptide, amino acid 139 seems to play a similar role as that in canine p21 for various migration patterns. Taken together, our results indicate that canine p53 family proteins have biological activities similar to human counterparts. These similarities make the dog an excellent outbred spontaneous tumor model, and the dog can serve as a translation model from benchtop to cage side and then to bedside. (Mol Cancer Res 2009;7(1):67–78)
Fish Oil Inhibits Human Lung Carcinoma Cell Growth by Suppressing Integrin-Linked Kinase
Authors: Han ShouWei , Sun XiaoJuan , Ritzenthaler Jeffrey D. , Roman Jesse 
Published: January 2009

Abstract
We previously showed that synthetic peroxisome proliferator-activated receptor γ (PPARγ) ligands inhibit non–small cell lung carcinoma (NSCLC) cell growth through multiple signaling pathways. Here, we show that dietary compounds, such as fish oil (which contains certain kinds of fatty acids like ω3 and ω6 polyunsaturated fatty acids), also inhibit NSCLC cell growth by affecting PPARγ and by inhibiting the expression of integrin-linked kinase (ILK). Exogenous expression of ILK overcame, whereas silencing ILK enhanced the inhibitory effect of fish oil on cell growth. The inhibitor of p38 mitogen-activated protein kinase, SB239023, abrogated the inhibitory effect of fish oil on ILK expression, whereas the inhibitor of extracellular signal-regulated kinase, PD98059, had no effect. Transient transfection experiments showed that fish oil reduced ILK promoter activity, and this effect was abolished by AP-2α small interfering RNA and SB239023 and by deletion of a specific portion of the ILK gene promoter. Western blot analysis and gel mobility shift assay showed that fish oil significantly induced AP-2α protein expression and AP-2 DNA-binding activity in the ILK gene promoter and that this was dependent on PPARγ activation. Blockade of AP-2α abrogated the effect of fish oil on ILK expression and on cell growth, whereas exogenous expression of AP-2α enhanced cell growth in the setting of fish oil exposure. Taken together, these findings show that fish oil inhibits ILK expression through activation of PPARγ-mediated and p38 mitogen-activated protein kinase–mediated induction of AP-2α. In turn, this leads to inhibition of NSCLC cell proliferation. This study unveils a novel mechanism by which fish oil inhibits human lung cancer cell growth. (Mol Cancer Res 2009;7(1):108–17)
Targeting Mdm2 and Mdmx in Cancer Therapy: Better Living through Medicinal Chemistry?
Authors: Wade Mark , Wahl Geoffrey M. 
Published: January 2009

Abstract
Genomic and proteomic profiling of human tumor samples and tumor-derived cell lines are essential for the realization of personalized therapy in oncology. Identification of the changes required for tumor initiation or maintenance will likely provide new targets for small-molecule and biological therapeutics. For example, inactivation of the p53 tumor suppressor pathway occurs in most human cancers. Although this can be due to frank p53 gene mutation, almost half of all cancers retain the wild-type p53 allele, indicating that the pathway is disabled by other means. Alternate mechanisms include deletion or epigenetic inactivation of the p53-positive regulator arf, methylation of the p53 promoter, or elevated expression of the p53 regulators Mdm2 and Mdmx. This review discusses current models of p53 regulation by Mdm2 and Mdmx and presents the rationale for design of future Mdmx-specific therapeutics based on our knowledge of its structure and biological functions. (Mol Cancer Res 2009;7(1):1–11)
Evaluation of Lipid Profiles and the Use of Omega-3 Essential Fatty Acid in Professional Football Players
Authors: Yates Anthony , Norwig John , Maroon Joseph C. , Bost Jeffrey , Bradley James P. , Duca Mark , Wecht Daniel A. , Grove Ryan , Iso Ariko , Cobb Ingrid , Ross Nathan , Borden Meghan 
Published: January 2009

Background: Recent research showed 82% of 233 retired National Football League players under age 50 had abnormal narrowing and blockages in arteries compared to the general population of the same age. It has been suggested that early screening and intervention in this at-risk population be a priority. Hypothesis: Omega-3 essential fatty acid has been shown to improve cardiovascular lipid risk factors and should improve lipid profiles in professional football players to help reduce their recently shown accelerated risk of developing cardiovascular disease. Methods: A total of 36 active national football players were randomly assigned to 2 groups: the first group (n = 20) was provided fish oil capsules (2200 mg of mixed docosahexaenoic acid and eicosapentaenoic acid and 360 mg of other omega-3s), and the second group (n = 16) served as controls during a 60-day trial. Vertical Auto Profile cholesterol tests directly measuring serum low-density lipoprotein, high-density lipoprotein, and other subfractions were performed. Compliance, side effects, and seafood consumption data were also collected. Baseline, midpoint, and poststudy blood work measured plasma docosahexaenoic acid and eicosapentaenoic acid. Results: Treatment increased high-density lipoprotein (average percent change: +25.96, control +14.16), decreased triglycerides treatment (–8.06, control +43.98), very low-density lipoprotein treatment (–13.98, control +23.18), intermediate density lipoprotein (–27.58, control +12.07), remnant lipoproteins (–23.86, control +8.33), and very low-density lipoprotein-3 (–17.10, control +7.77). An average increase of 106.67% for docosahexaenoic acid and 365.82% for eicosapentaenoic acid compared to control was also shown. Conclusion: Omega-3 supplementation significantly improved the lipid profile of active players randomized to treatment. These results suggest that fish oil supplementation is an effective way to increase eicosapentaenoic acid and docosahexaenoic acid levels in plasma and should be considered as a method to improve modifiable cardiovascular risk lipid factors in professional football players. Clinical Relevance: A prospective study examining the effects of 60 days of a highly purified fish oil supplementation in professional football players.
Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML
Authors: Zhou Jianbiao , Bi Chonglei , Janakakumara Jasinghe V. , Liu Shaw-Cheng , Chng Wee-Joo , Tay Kian-Ghee , Poon Lai-Fong , Xie Zhigang , Palaniyandi Senthilnathan , Yu Hanry , Glaser Keith B. , Albert Daniel H. , Davidsen Steven K. , Chen Chien-Shing 
Published: January 2009

Abstract
To further investigate potential mechanisms of resistance to FLT3 inhibitors, we developed a resistant cell line by long-term culture of MV4-11 cells with ABT-869, designated as MV4-11-R. Gene profiling reveals up-regulation of FLT3LG (FLT3 ligand) and BIRC5 (survivin), but down-regulation of SOCS1, SOCS2, and SOCS3 in MV4-11-R cells. Hypermethylation of these SOCS genes leads to their transcriptional silencing. Survivin is directly regulated by STAT3. Stimulation of the parental MV4-11 cells with FLT3 ligand increases the expression of survivin and phosphorylated protein STAT1, STAT3, STAT5. Targeting survivin by short-hairpin RNA (shRNA) in MV4-11-R cells induces apoptosis and augments ABT-869–mediated cytotoxicity. Overexpression of survivin protects MV4-11 from apoptosis. Subtoxic dose of indirubin derivative (IDR) E804 resensitizes MV4-11-R to ABT-869 treatment by inhibiting STAT signaling activity and abolishing survivin expression. Combining IDR E804 with ABT-869 shows potent in vivo efficacy in the MV4-11-R xenograft model. Taken together, these results demonstrate that enhanced activation of STAT pathways and overexpression of survivin are important mechanisms of resistance to ABT-869, suggesting that the STAT pathways and survivin could be potential targets for reducing resistance developed in patients receiving FLT3 inhibitors.
BCR-mediated uptake of antigen linked to TLR9 ligand stimulates B-cell proliferation and antigen-specific plasma cell formation
Authors: Eckl-Dorna Julia , Batista Facundo D. 
Published: January 2009

AbstractThe activation of Toll-like receptor 9 (TLR9) expressed within B cells is associated with enhanced humoral immunity. However the role of TLR9 in the stimulation of B-cell responses, and more specifically in shaping the outcome of B-cell differentiation, remains unclear. Here, we observed that immunization with the TLR9 agonist CpG linked to protein antigen gave rise to enhanced production of antigen-specific class-switched antibodies in vivo. Unlike dendritic cells, B cells are unable to acquire these conjugates by macropinocytosis and instead depend on uptake through a signaling-competent B-cell receptor (BCR), provided the overall BCR-antigen avidity exceeds a defined threshold. The resultant stimulation of intrinsic TLR9 leads to enhanced antigen-specific B-cell proliferation and differentiation to form extrafollicular plasma cells. Thus, the direct conjugation of antigen and CpG reveals a mechanism that may operate during the initiation of primary immune responses, and may prove useful as a strategy for the design of adjuvants suitable for vaccinations.
The representation of the verb's argument structure as disclosed by fMRI
Authors: Assadollahi Ramin , Meinzer Marcus , Flaisch Tobias , Obleser Jonas , Rockstroh Brigitte 
Published: January 2009

AbstractBackgroundIn the composition of an event the verb's argument structure defines the number of participants and their relationships. Previous studies indicated distinct brain responses depending on how many obligatory arguments a verb takes. The present functional magnetic resonance imaging (fMRI) study served to verify the neural structures involved in the processing of German verbs with one (e.g. "snore") or three (e.g. "gives") argument structure. Within a silent reading design, verbs were presented either in isolation or with a minimal syntactic context ("snore" vs. "Peter snores").ResultsReading of isolated one-argument verbs ("snore") produced stronger BOLD responses than three-argument verbs ("gives") in the inferior temporal fusiform gyrus (BA 37) of the left hemisphere, validating previous magnetoencephalographic findings. When presented in context one-argument verbs ("Peter snores") induced more pronounced activity in the inferior frontal gyrus (IFG) of the left hemisphere than three-argument verbs ("Peter gives").ConclusionIn line with previous studies our results corroborate the left temporal lobe as site of representation and the IFG as site of processing of verbs' argument structure.
Correlation between MMPs and their inhibitors in breast cancer tumor tissue specimens and in cell lines with different metastatic potential
Authors: Figueira Rita CS , Gomes Luciana R , Neto João S , Silva Fabricio C , Silva Ismael DCG , Sogayar Mari C 
Published: January 2009

Abstract

Background
The metastatic disease rather than the primary tumor itself is responsible for death in most solid tumors, including breast cancer. The role of matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs) and Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in the metastatic process has previously been established. However, in all published studies only a limited number of MMPs/MMP inhibitors was analyzed in a limited number of cell lines. Here, we propose a more comprehensive approach by analyzing the expression levels of several MMPs (MMP-2, MMP-9 and MMP-14) and MMP inhibitors (TIMP-1, TIMP-2 and RECK) in different models (five human breast cancer cell lines, 72 primary breast tumors and 30 adjacent normal tissues).

Methods
We analyzed the expression levels of MMP-2, MMP-9 and MMP-14 and their inhibitors (TIMP-1, TIMP-2 and RECK) by quantitative RT-PCR (qRT-PCR) in five human breast cancer cell lines presenting increased invasiveness and metastatic potential, 72 primary breast tumors and 30 adjacent normal tissues. Moreover, the role of cell-extracellular matrix elements interactions in the regulation of expression and activity of MMPs and their inhibitors was analyzed by culturing these cell lines on plastic or on artificial ECM (Matrigel).

Results
The results demonstrated that MMPs mRNA expression levels displayed a positive and statistically significant correlation with the transcriptional expression levels of their inhibitors both in the cell line models and in the tumor tissue samples. Furthermore, the expression of all MMP inhibitors was modulated by cell-Matrigel contact only in highly invasive and metastatic cell lines. The enzyme/inhibitor balance at the transcriptional level significantly favors the enzyme which is more evident in tumor than in adjacent non-tumor tissue samples.

Conclusion
Our results suggest that the expression of MMPs and their inhibitors, at least at the transcriptional level, might be regulated by common factors and signaling pathways. Therefore, the multi-factorial analysis of these molecules could provide new and independent prognostic information contributing to the determination of more adequate therapy strategies for each patient.
A spindle cell carcinoma presenting with osseous metaplasia in the gingiva: a case report with immunohistochemical analysis
Authors: Katase Naoki , Tamamura Ryo , Gunduz Mehmet , Murakami Jun , Asaumi Jun-Ichi , Tsukamoto Goichi , Sasaki Akira , Nagatsuka Hitoshi 
Published: January 2009

Abstract

Background
Spindle cell carcinoma (SpCC) is a rare, high malignant variant of squamous cell carcinoma (SCC), which shows biphasic proliferation of conventional SCC component and malignant spindle shape cells with sarcomatous appearance.

Methods
A case of Spindle cell carcinoma with bone-like calcified materials, occurring at the mandibular molar region of 71-years-old Japanese male patient was presented with gross finding, histological findings and MRI image. To identify the characteristics of the bone-like materials, immunohistochemistry were performed.

Results
Histologically, the cancer cells were composed of spindle cells and epithelial cells which form nests with prominent keratinization. Histological findings showed typical histology of the SpCC, however, as an uncommon finding, spatters of calcified, bone-like materials were observed in between the cancer cells. Immunohistochemistry revealed that cancer cells were positive for cytokeratins and vimentin to a varying degree and negative for Desmin, S-100, Osteopontin, BMP-2 or BMP-4. These findings implied that the calcified materials were formed by metaplasia of the stromal cells.

Discussion
Bone-like materials formation by osseous and/or cartilaginous metaplasia of the stroma in the carcinoma has been reported. However, the detailed mechanism of these metaplasia and affection on the clinical feature, prognosis and therapies are not well established. In summary, we presented an unique case of SpCC, which has not been described in the literature.