bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tetraspanin CD151 Regulates Growth of Mammary Epithelial Cells in Three-Dimensional Extracellular Matrix: Implication for Mammary Ductal CarcinomaIn situ
Authors: Novitskaya Vera , Romanska Hanna , Dawoud Marwa , Jones J. Louise , Berditchevski Fedor 
Published: May 2010

AbstractTetraspanin CD151 is associated with laminin-binding integrins (i.e., α3β1, α6β1, and α6β4) and regulates tumor cell migration and invasion. Here, we examined the role of CD151 in proliferation of mammary epithelial cells using in vitro and in vivo models. Depletion of CD151 suppressed growth of HB2 cells, a nontumorigenic breast epithelial cell line, in three-dimensional (3D) extracellular matrices (ECM) and in Matrigel-based xenografts. Whereas the presence of α3β1 (but not α6 integrins) was necessary to support growth of HB2 cells in 3D ECM, the pro-proliferative activity of CD151 did not require direct interaction with integrins. Furthermore, depletion of CD151 potentiated formation of the internal lumen and partial restoration of polarity when HB2 cells were cultured in 3D ECM. This correlated with a decrease in phosphorylation levels of extracellular signal-regulated kinase 1/2 and cAkt in CD151-negative cells and increase in activation of caspase-3. Accordingly, the number of CD151-positive colonies with internal lumen was increased by ∼5-fold when cells were cultured in the presence of MAP/ERK kinase (U0126) and phosphoinositide 3-kinase (LY29004) inhibitors. To establish the physiologic relevance of pro-proliferative and morphogenetic activities of CD151, we analyzed the expression of this tetraspanin in ductal carcinoma in situ (DCIS), which is characterized by neoplastic proliferation of mammary epithelial cells. Strong homogeneous membrane expression of CD151 was found to be associated with a high grade of DCIS (P = 0.004). Taken together, these results strongly suggest that CD151 complexes play a crucial role in the development of hyperproliferative diseases in the mammary gland. Cancer Res; 70(11); 4698–708. ©2010 AACR.
Similar Nucleotide Excision Repair Capacity in Melanocytes and Melanoma Cells
Authors: Gaddameedhi Shobhan , Kemp Michael G. , Reardon Joyce T. , Shields Janiel M. , Smith-Roe Stephanie L. , Kaufmann William K. , Sancar Aziz 
Published: May 2010

Abstract
Sunlight UV exposure produces DNA photoproducts in skin that are repaired solely by nucleotide excision repair in humans. A significant fraction of melanomas are thought to result from UV-induced DNA damage that escapes repair; however, little evidence is available about the functional capacity of normal human melanocytes, malignant melanoma cells, and metastatic melanoma cells to repair UV-induced photoproducts in DNA. In this study, we measured nucleotide excision repair in both normal melanocytes and a panel of melanoma cell lines. Our results show that in 11 of 12 melanoma cell lines tested, UV photoproduct repair occurred as efficiently as in primary melanocytes. Importantly, repair capacity was not affected by mutation in the N-RAS or B-RAF oncogenes, nor was a difference observed between a highly metastatic melanoma cell line (A375SM) or its parental line (A375P). Lastly, we found that although p53 status contributed to photoproduct removal efficiency, its role did not seem to be mediated by enhanced expression or activity of DNA binding protein DDB2. We concluded that melanoma cells retain capacity for nucleotide excision repair, the loss of which probably does not commonly contribute to melanoma progression. Cancer Res; 70(12); 4922–30. ©2010 AACR.
Selective Depletion of CD4+CD25+Foxp3+ Regulatory T Cells by Low-Dose Cyclophosphamide Is Explained by Reduced Intracellular ATP Levels
Authors: Zhao Jie , Cao Yuchun , Lei Zhang , Yang Zhuoshun , Zhang Biao , Huang Bo 
Published: May 2010

AbstractCD4+CD25+Foxp3+ regulatory T (Treg) cells have been shown to play important roles in mediating cancer development. Although cyclophosphamide (CY) has shown promise as a drug to selectively target Treg cells with low-dose in vivo, the underlying molecular mechanism remains unclear. In this report, we provide evidence that ATP, the energy molecule and signal element, accounts for the selective depletion of Treg cells by low-dose CY. Relative to conventional T cells or other cell types, ATP levels were much lower in Treg cells. This was due to Treg cells that downregulate one microRNA, miR-142-3p, and upregulate ecto-nucleoside triphosphate diphosphohydrolase CD39. The transfection of miR-142-3p or the blockade of CD39 could increase intracellular ATP levels of Treg cells, consequently decreasing the sensitivity of Treg cells to low-dose CY. On the other hand, the transfection of miR-142-3p inhibitor or the addition of soluble CD39 to the cultured CD4+CD25− T cells resulted in the decrease of intracellular ATP levels and increase of sensitivity of conventional T cells to low-dose CY. Furthermore, we found that the low levels of ATP attenuated the synthesis of glutathione, leading to the decrease of CY detoxification, thus increasing the sensitivity of Treg cells to low-dose CY. Therefore, we here identify a molecular pathway through which low-dose CY selectively ablates Treg cells. Our findings also imply that low levels of ATP are probably related to Treg cell function. Cancer Res; 70(12); 4850–8. ©2010 AACR.
ARF Suppresses Tumor Angiogenesis through Translational Control of VEGFA mRNA
Authors: Kawagishi Hiroyuki , Nakamura Hideaki , Maruyama Mitsuo , Mizutani Shuki , Sugimoto Kazushi , Takagi Masatoshi , Sugimoto Masataka 
Published: May 2010

Abstract
Vascular endothelial growth factor A (VEGFA) is a specific mitogen for vascular endothelial cells that plays a critical role in cancer neoangiogenesis. Here, we report that the nucleolar tumor suppressor p19ARF suppresses VEGFA expression, acting at the level of mRNA translation without affecting the transcription of the VEGFA gene. Translational repression of VEGFA mRNA by p19ARF does not require p53, a major target of the ARF tumor suppressor pathway, but instead correlates with binding to nucleophosmin/B23. Maintaining VEGFA expression relies on nucleophosmin/B23, and downregulating this protein by RNAi or p19ARF leads to translational repression of VEGFA. p19ARF inhibits VEGFA-dependent tumor angiogenesis in nude mice. Additionally, p14ARF expression and microvessel density are inversely correlated in human colon carcinomas. Taken together, our results define a mechanism by which the ARF tumor suppressor targets the translational repression of specific oncogenes during neoplastic transformation. Cancer Res; 70(11); 4749–58. ©2010 AACR.
Phase 1 Study of AMG 386, a Selective Angiopoietin 1/2–Neutralizing Peptibody, in Combination with Chemotherapy in Adults with Advanced Solid Tumors
Authors: Mita Alain C. , Takimoto Chris H. , Mita Monica , Tolcher Anthony , Sankhala Kamalesh , Sarantopoulos John , Valdivieso Manuel , Wood Leslie , Rasmussen Erik , Sun Yu-Nien , Zhong Z. Don , Bass Michael B. , Le NgocDiep , LoRusso Patricia 
Published: May 2010

Abstract
Purpose: To evaluate the safety, pharmacokinetics, and antitumor activity of AMG 386, an investigational selective angiopoietin 1/2-neutralizing peptibody, in combination with FOLFOX-4 (F), carboplatin/paclitaxel (C/P), or docetaxel (D), in adult patients with advanced solid tumors.
Experimental Design: Three cohorts of patients (F, n = 6; C/P, n = 8; D, n = 12) received one full cycle of chemotherapy alone during the pretreatment phase, followed by administration of AMG 386 10 mg/kg i.v. weekly in combination with chemotherapy until disease progression or intolerance. Safety and tolerability, tumor response, pharmacokinetic profiles, and biomarkers were assessed.
Results: Twenty-six patients were enrolled; 22 received treatment with AMG 386. No dose-limiting toxicities or grade 3 or 4 adverse events related to AMG 386 were reported. The most common adverse events were diarrhea and hypomagnesemia (n = 3 each). One patient developed grade 2 hypertension and one had grade 1 subconjunctival eye hemorrhage. No neutralizing antibodies to AMG 386 were detected. There were no pharmacokinetic interactions between AMG 386 and F, C/P, or D. One patient receiving AMG 386 plus C/P for bladder cancer refractory to gemcitabine/cisplatin had a complete response at week 8. The remaining best tumor responses were partial response (n = 3, one from each cohort), stable disease ≥8 weeks (n = 13), and progressive disease (n = 1).
Conclusions: Weekly administration of AMG 386 in combination with three common chemotherapy regimens was well tolerated in patients with advanced solid tumors. No pharmacokinetic interactions between AMG 386 and any of the tested chemotherapy regimens were noted. Promising antitumor activity was observed with all three treatment combinations. Clin Cancer Res; 16(11); 3044–56. ©2010 AACR.
Distinct Roles of Cytochrome P450 Reductase in Mitomycin c Redox Cycling and Cytotoxicity
Authors: Wang Yun , Gray Joshua P. , Mishin Vladimir , Heck Diane E. , Laskin Debra L. , Laskin Jeffrey D. 
Published: May 2010

Abstract
Mitomycin c (MMC), a quinone-containing anticancer drug, is known to redox cycle and generate reactive oxygen species. A key enzyme mediating MMC redox cycling is cytochrome P450 reductase, a microsomal NADPH-dependent flavoenzyme. In the present studies, Chinese hamster ovary (CHO) cells overexpressing this enzyme (CHO-OR cells) and corresponding control cells (CHO-WT cells) were used to investigate the role of cytochrome P450 reductase in the actions of MMC. In lysates from both cell types, MMC was found to redox cycle and generate H2O2; this activity was greater in CHO-OR cells (Vmax = 1.2 ± 0.1 nmol H2O2/min/mg protein in CHO-WT cells versus 32.4 ± 3.9 nmol H2O2/min/mg protein in CHO-OR cells). MMC was also more effective in generating superoxide anion and hydroxyl radicals in CHO-OR cells, relative to CHO-WT cells. Despite these differences in MMC redox cycling, MMC-induced cytotoxicity, as measured by growth inhibition, was similar in the two cell types (IC50 = 72 ± 20 nmol/L for CHO-WT and 75 ± 23 nmol/L for CHO-OR cells), as was its ability to induce G2-M and S phase arrest. Additionally, in nine different tumor cell lines, although a strong correlation was observed between MMC-induced H2O2 generation and cytochrome P450 reductase activity, there was no relationship between redox cycling and cytotoxicity. Hypoxia, which stabilizes MMC radicals generated by redox cycling, also had no effect on the sensitivity of tumor cells to MMC-induced cytotoxicity. These data indicate that NADPH cytochrome P450 reductase–mediated MMC redox cycling is not involved in the cytotoxicity of this chemotherapeutic agent. Mol Cancer Ther; 9(6); 1852–63. ©2010 AACR.
Oncogenic Functions of Secreted Frizzled-Related Protein 2 in Human Renal Cancer
Authors: Yamamura Soichiro , Kawakami Kazumori , Hirata Hiroshi , Ueno Koji , Saini Sharanjot , Majid Shahana , Dahiya Rajvir 
Published: May 2010

Abstract
The secreted Frizzled-related proteins (sFRP) are modulators of the Wnt signaling pathway, which is involved in embryonic development and tumor progression. The functions of sFRP2 have not been studied in renal cancer. Transient transfection of sFRP2 promoted cell growth in renal carcinoma cells, whereby the largest effect was observed in A498 cells. To further study the functions of sFRP2 gene in renal carcinoma cells, we established A498 renal cancer cell lines, which stably expressed sFRP2. Stably expressed sFRP2 significantly promoted cell proliferation in vitro and in vivo tumor growth. The stably expressed sFRP2 cells were also found to have reduced UV-induced apoptosis and increased G2 phase of the cell cycle. The phosphorylation level at Ser33/37/Thr41 of β-catenin was lower in the stable sFRP2 cell lines compared with the control cell line. sFRP2 significantly activated T-cell factor/lymphoid enhancer factor transcriptional activity. In the stable sFRP2 cell line, expression of c-Fos, Bcl2, Bcl-w, cyclin B2, and cyclin E2 genes was significantly increased and p53 expression was decreased. This is the first report documenting that sFRP2 activates the canonical Wnt pathway and promotes cell growth by evoking diverse signaling cascades in renal cancer cells. This study may provide better strategies for the management of renal cancer through regulation of sFRP2 pathways. Mol Cancer Ther; 9(6); 1680–7. ©2010 AACR.
Crosstalk of EDA-A2/XEDAR in the p53 Signaling Pathway
Authors: Tanikawa Chizu , Ri Cui , Kumar Vinod , Nakamura Yusuke , Matsuda Koichi 
Published: May 2010

Abstract
We recently identified X-linked ectodermal dysplasia receptor (XEDAR, also known as TNFRSF27 or EDA2R) as a direct p53 target that was frequently downregulated in colorectal cancer tissues due to its epigenetic alterations or through the p53 gene mutations. However, the role of the posttranslational regulation of XEDAR protein in colorectal carcinogenesis was not well clarified thus far. Here, we report that the extracellular NH2 terminus of XEDAR protein was cleaved by a metalloproteinase and released into culture media. The remaining COOH-terminal membrane–anchored fragment was rapidly degraded through the ubiquitin-proteasome pathway. Interestingly, ectopic p53 expression also transactivated an XEDAR ligand, EDA-A2, together with XEDAR. Moreover, EDA-A2 blocked the cleavage of XEDAR and subsequently inhibited cell growth. We also found a missense mutation of the XEDAR gene in NCI-H716 colorectal cancer cells, which caused the translocation of XEDAR protein from cell membrane to cytoplasm. This mutation attenuated the growth-suppressive effect of XEDAR, indicating that membrane localization is critical for physiologic XEDAR function. Thus, our findings clearly revealed the crucial role of EDA-A2/XEDAR interaction in the p53-signaling pathway. Mol Cancer Res; 8(6); 855–63. ©2010 AACR.
The trajectory of palliative care costs over the last 5 months of life: a Canadian longitudinal study
Authors: Dumont Serge , Jacobs Philip , Turcotte Véronique , Anderson Donna , Harel François 
Published: May 2010

Objective: This study aimed to highlight the trajectory of palliative care costs over the last five months of life in five urban centres across Canada. Subjects: The study sample was comprised of 160 terminally ill patients and their main informal caregivers. Research Design: A first interview took place in the patient’s home, and subsequent follow-up interviews were conducted by telephone at two week intervals until the patient’s passing. Measures: Participants were asked to provide information on the goods and services they used related to the patients’ health condition, and on informal caregiving time. Results: The overall costs of care gradually increased from the fifth to the last month of the patients’ life. A large part of this cost increase was attributable to inpatient care. Among outpatient care costs the largest increase was observed for home care. Informal care costs were particularly high over the last 3 months of life. Conclusions: The knowledge gained from this study would be useful to policy makers when developing policies that could help families caring for a terminally ill loved one at home.
Rifaximin therapy for metronidazole-unresponsive Clostridium difficile infection: a prospective pilot trial
Authors: Basu P. Patrick , Dinani Amreen , Rayapudi Krishna , Pacana Tommy , Shah Niraj James , Hampole Hemant , Krishnaswamy N.V. , Mohan Vinod 
Published: May 2010

Background: Clostridium difficile infection (CDI) is a recent epidemic in the United States, particularly in the hospital setting. Oral metronidazole is standard therapy for C. difficile infection, but resistance to metronidazole is becoming a clinical challenge. Methods: We evaluated the efficacy of the nonsystemic oral antibiotic rifaximin for the treatment of metronidazole-resistant C. difficile infection. Twenty-five patients with C. difficile infection were enrolled in the study. All had mild-to-moderate C. difficile infection (5—10 bowel movements a day without sepsis) unresponsive to metronidazole (i.e. stools positive for toxins A and B after oral metronidazole 500 mg three times daily [t.i.d.] for 5 days). After discontinuation of metronidazole, rifaximin 400 mg t.i.d. for 14 days was prescribed. Patients were followed for 56 days and stool was tested for C. difficile using polymerase chain reaction (PCR) to assess the effect of treatment. A negative PCR test result was interpreted as a favorable response to rifaximin. Results: Sixteen of 22 patients (73%) were eligible for study inclusion and completed rifaximin therapy experienced eradication of infection (stool negative for C. difficile) immediately after rifaximin therapy and 56 days post-treatment. Three patients (12%) discontinued therapy because of abdominal distention. Rifaximin was generally well tolerated. Conclusions: In conclusion, rifaximin may be considered for treatment of mild-to-moderate C. difficile infection that is resistant to metronidazole. Larger randomized trials are needed to confirm these positive findings.
Importance of replication in analyzing time-series gene expression data: Corticosteroid dynamics and circadian patterns in rat liver
Authors: Nguyen Tung T , Almon Richard R , DuBois Debra C , Jusko William J , Androulakis Ioannis P 
Published: May 2010

Abstract

Background
Microarray technology is a powerful and widely accepted experimental technique in molecular biology that allows studying genome wide transcriptional responses. However, experimental data usually contain potential sources of uncertainty and thus many experiments are now designed with repeated measurements to better assess such inherent variability. Many computational methods have been proposed to account for the variability in replicates. As yet, there is no model to output expression profiles accounting for replicate information so that a variety of computational models that take the expression profiles as the input data can explore this information without any modification.

Results
We propose a methodology which integrates replicate variability into expression profiles, to generate so-called 'true' expression profiles. The study addresses two issues: (i) develop a statistical model that can estimate 'true' expression profiles which are more robust than the average profile, and (ii) extend our previous micro-clustering which was designed specifically for clustering time-series expression data. The model utilizes a previously proposed error model and the concept of 'relative difference'. The clustering effectiveness is demonstrated through synthetic data where several methods are compared. We subsequently analyze in vivo rat data to elucidate circadian transcriptional dynamics as well as liver-specific corticosteroid induced changes in gene expression.

Conclusions
We have proposed a model which integrates the error information from repeated measurements into the expression profiles. Through numerous synthetic and real time-series data, we demonstrated the ability of the approach to improve the clustering performance and assist in the identification and selection of informative expression motifs.
Some novel intron positions in conserved Drosophila genes are caused by intron sliding or tandem duplication
Authors: Lehmann Jörg , Eisenhardt Carina , Stadler Peter F , Krauss Veiko 
Published: May 2010

Abstract

Background
Positions of spliceosomal introns are often conserved between remotely related genes. Introns that reside in non-conserved positions are either novel or remnants of frequent losses of introns in some evolutionary lineages. A recent gain of such introns is difficult to prove. However, introns verified as novel are needed to evaluate contemporary processes of intron gain.

Results
We identified 25 unambiguous cases of novel intron positions in 31 Drosophila genes that exhibit near intron pairs (NIPs). Here, a NIP consists of an ancient and a novel intron position that are separated by less than 32 nt. Within a single gene, such closely-spaced introns are very unlikely to have coexisted. In most cases, therefore, the ancient intron position must have disappeared in favour of the novel one. A survey for NIPs among 12 Drosophila genomes identifies intron sliding (migration) as one of the more frequent causes of novel intron positions. Other novel introns seem to have been gained by regional tandem duplications of coding sequences containing a proto-splice site.

Conclusions
Recent intron gains sometimes appear to have arisen by duplication of exonic sequences and subsequent intronization of one of the copies. Intron migration and exon duplication together may account for a significant amount of novel intron positions in conserved coding sequences.
Functional and gene network analyses of transcriptional signatures characterizing pre-weaned bovine mammary parenchyma or fat pad uncovered novel inter-tissue signaling networks during development
Authors: Piantoni Paola , Bionaz Massimo , Graugnard Daniel E , Daniels Kristy M , Everts Robin E , Rodriguez-Zas Sandra L , Lewin Harris A , Hurley Hurley L , Akers Michael , Loor Juan J 
Published: May 2010

Abstract

Background
The neonatal bovine mammary fat pad (MFP) surrounding the mammary parenchyma (PAR) is thought to exert proliferative effects on the PAR through secretion of local modulators of growth induced by systemic hormones. We used bioinformatics to characterize transcriptomics differences between PAR and MFP from ~65 d old Holstein heifers. Data were mined to uncover potential crosstalk through the analyses of signaling molecules preferentially expressed in one tissue relative to the other.

Results
Over 9,000 differentially expressed genes (DEG; False discovery rate ≤ 0.05) were found of which 1,478 had a ≥1.5-fold difference between PAR and MFP. Within the DEG highly-expressed in PAR vs. MFP (n = 736) we noted significant enrichment of functions related to cell cycle, structural organization, signaling, and DNA/RNA metabolism. Only actin cytoskeletal signaling was significant among canonical pathways. DEG more highly-expressed in MFP vs. PAR (n = 742) belong to lipid metabolism, signaling, cell movement, and immune-related functions. Canonical pathways associated with metabolism and signaling, particularly immune- and metabolism-related were significantly-enriched. Network analysis uncovered a central role of MYC, TP53, and CTNNB1 in controlling expression of DEG highly-expressed in PAR vs. MFP. Similar analysis suggested a central role for PPARG, KLF2, EGR2, and EPAS1 in regulating expression of more highly-expressed DEG in MFP vs. PAR. Gene network analyses revealed putative inter-tissue crosstalk between cytokines and growth factors preferentially expressed in one tissue (e.g., ANGPTL1, SPP1, IL1B in PAR vs. MFP; ADIPOQ, IL13, FGF2, LEP in MFP vs. PAR) with DEG preferentially expressed in the other tissue, particularly transcription factors or pathways (e.g., MYC, TP53, and actin cytoskeletal signaling in PAR vs. MFP; PPARG and LXR/RXR Signaling in MFP vs. PAR).

Conclusions
Functional analyses underscored a reciprocal influence in determining the biological features of MFP and PAR during neonatal development. This was exemplified by the potential effect that the signaling molecules (cytokines, growth factors) released preferentially (i.e., more highly-expressed) by PAR or MFP could have on molecular functions or signaling pathways enriched in the MFP or PAR. These bidirectional interactions might be required to coordinate mammary tissue development under normal circumstances or in response to nutrition.