bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antigen-Experienced CD4+ T Cells Limit Naïve T-Cell Priming in Response to Therapeutic VaccinationIn vivo
Authors: Schiering Chris , Guarnerio Jlenia , Basso Veronica , Muzio Luca , Mondino Anna 
Published: July 2010

AbstractCD4+ T cells play a central role in protective immunity. In a mouse tumor model, we previously found that tumor growth elicits natural CD4+ T-cell responses, but impedes therapeutic vaccination. We show here that inhibition of vaccine-mediated naïve T-cell priming is due to the presence of a minor but distinct population of tumor-reactive CD4+ T cells. These cells are generated in the tumor draining lymph nodes (LN), are capable of systemic redistribution, and act to limit the representation of antigen-bearing MHC II+ antigen-presenting cells (APC) in contralateral LNs or when transferred to tumor-free mice. Surgical tumor resection, which lowers the representation of tumor primed CD4+ T cells, restored to some extent vaccine-induced CD4+ T-cell activation. Likewise, vaccination with artificial APCs (latex beads) or higher numbers of dendritic cells allowed comparable CD4+ T-cell priming in tumor-free and tumor-bearing mice. Together, our results emphasize the ability of antigen-experienced CD4+ T lymphocytes to interfere with therapeutic vaccination and highlight the need for alternative strategies able to surmount limitations imposed by ongoing immune responses. Cancer Res; 70(15); 6161–70. ©2010 AACR.
A Microfluidic Platform for Systems Pathology: Multiparameter Single-Cell Signaling Measurements of Clinical Brain Tumor Specimens
Authors: Sun Jing , Masterman-Smith Michael D. , Graham Nicholas A. , Jiao Jing , Mottahedeh Jack , Laks Dan R. , Ohashi Minori , DeJesus Jason , Kamei Ken-ichiro , Lee Ki-Bum , Wang Hao , Yu Zeta T.F. , Lu Yi-Tsung , Hou Shuang , Li Keyu , Liu Max , Zhang Nangang , Wang Shutao , Angenieux Brigitte , Panosyan Eduard , Samuels Eric R. , Park Jun , Williams Dirk , Konkankit Vera , Nathanson David , van Dam R. Michael , Phelps Michael E. , Wu Hong , Liau Linda M. , Mischel Paul S. , Lazareff Jorge A. , Kornblum Harley I. , Yong William H. , Graeber Thomas G. , Tseng Hsian-Rong 
Published: July 2010

Abstract
The clinical practice of oncology is being transformed by molecular diagnostics that will enable predictive and personalized medicine. Current technologies for quantitation of the cancer proteome are either qualitative (e.g., immunohistochemistry) or require large sample sizes (e.g., flow cytometry). Here, we report a microfluidic platform—microfluidic image cytometry (MIC)—capable of quantitative, single-cell proteomic analysis of multiple signaling molecules using only 1,000 to 2,800 cells. Using cultured cell lines, we show simultaneous measurement of four critical signaling proteins (EGFR, PTEN, phospho-Akt, and phospho-S6) within the oncogenic phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. To show the clinical application of the MIC platform to solid tumors, we analyzed a panel of 19 human brain tumor biopsies, including glioblastomas. Our MIC measurements were validated by clinical immunohistochemistry and confirmed the striking intertumoral and intratumoral heterogeneity characteristic of glioblastoma. To interpret the multiparameter, single-cell MIC measurements, we adapted bioinformatic methods including self-organizing maps that stratify patients into clusters that predict tumor progression and patient survival. Together with bioinformatic analysis, the MIC platform represents a robust, enabling in vitro molecular diagnostic technology for systems pathology analysis and personalized medicine. Cancer Res; 70(15); 6128–38. ©2010 AACR.
Joint Loss of PAX2 and PTEN Expression in Endometrial Precancers and Cancer
Authors: Monte Nicolas M. , Webster Kaitlyn A. , Neuberg Donna , Dressler Gregory R. , Mutter George L. 
Published: July 2010

Abstract
Latent endometrial carcinoma precancers are normal-appearing endometrial glands with sporadic loss of tumor suppressor gene function such as PTEN. Progression to carcinoma is inefficient and requires additional genetic damage that creates a histologic precursor lesion called endometrial intraepithelial neoplasia (EIN). In this study, we examined loss of PAX2 expression, a gene required for embryonic uterine development, during endometrial carcinogenesis. Normal proliferative, EIN, and malignant (endometrial adenocarcinoma) endometrial tissues were immunostained for PTEN and PAX2. Proliferative samples with loss of protein in at least one gland were scored as latent precancers. EIN and cancer lesions were scored by the majority pattern. Overall prevalence and topography of joint PAX2-PTEN expression loss was examined. The prevalence of PAX2 protein loss in the sequence of normal to precancer to cancer was 36%, 71%, and 77%, respectively, and for PTEN, it was 49%, 44%, and 68%, respectively. The normal endometrial prevalence of PAX2- or PTEN-deficient latent precancers was unaffected by biopsy indication, but increased significantly with age. Coincident loss of PAX2 and PTEN expression in an individual normal endometrium was seen in 21% of patients, but usually involved different glands. Coincident loss was more common in precancers (31%) and carcinoma (55%), in which case, both markers were protein null in an overlapping clonal distribution. PAX2 and PTEN protein loss occurs independently and accumulates with increasing age in latent precancers of normal premenopausal endometrium. Loss of function of both genes in an overlapping distribution characterizes the clinical emergence of a premalignant lesion which is carried forward to carcinoma. Cancer Res; 70(15); 6225–32. ©2010 AACR.
Circadian Rhythm of Transferrin Receptor 1 Gene Expression Controlled by c-Myc in Colon Cancer–Bearing Mice
Authors: Okazaki Fumiyasu , Matsunaga Naoya , Okazaki Hiroyuki , Utoguchi Naoki , Suzuki Ryo , Maruyama Kazuo , Koyanagi Satoru , Ohdo Shigehiro 
Published: July 2010

Abstract
The abundance of cell surface levels of transferrin receptor 1 (TfR1), which regulates the uptake of iron-bound transferring, correlates with the rate of cell proliferation. Because TfR1 expression is higher in cancer cells than in normal cells, it offers a target for cancer therapy. In this study, we found that the expression of TfR1 in mouse colon cancer cells was affected by the circadian organization of the molecular clock. The core circadian oscillator is composed of an autoregulatory transcription-translation feedback loop, in which CLOCK and BMAL1 are positive regulators and the Period (Per), Cryptochrome (Cry), and Dec genes act as negative regulators. TfR1 in colon cancer–bearing mice exhibited a 24-hour rhythm in mRNA and protein levels. Luciferase reporter analysis and chromatin immunoprecipitation experiments suggested that the clock-controlled gene c-MYC rhythmically activated the transcription of the TfR1 gene. Platinum incorporation into tumor DNA and the antitumor efficacy of transferrin-conjugated liposome-delivered oxaliplatin could be enhanced by drug administration at times when TfR1 expression increased. Our findings suggest that the 24-hour rhythm of TfR1 expression may form an important aspect of strategies for TfR1-targeted cancer therapy. Cancer Res; 70(15); 6238–46. ©2010 AACR.
Inhibition of ADP Ribosylation Prevents and Cures Helicobacter-Induced Gastric Preneoplasia
Authors: Toller Isabella M. , Altmeyer Matthias , Kohler Esther , Hottiger Michael O. , Müller Anne 
Published: July 2010

Abstract
Gastric adenocarcinoma develops as a consequence of chronic inflammation of the stomach lining that is caused by persistent infection with the bacterium Helicobacter pylori. Gastric carcinogenesis progresses through a sequence of preneoplastic lesions that manifest histologically as atrophic gastritis, intestinal metaplasia, and dysplasia. We show here in several preclinical models of Helicobacter-induced atrophic gastritis, epithelial hyperplasia, and metaplasia that the inhibition of ADP ribosylation by the small-molecule inhibitor PJ34 not only prevents the formation of gastric cancer precursor lesions, but also efficiently reverses preexisting lesions. PJ34 exerts its chemopreventive and therapeutic effects by impairing Helicobacter-specific T-cell priming and TH1 polarization in the gut-draining mesenteric lymph nodes. The subsequent infiltration of pathogenic T cells into the gastric mucosa and the ensuing gastric T cell–driven immunopathology are prevented efficiently by PJ34. Our data indicate that PJ34 directly suppresses T-cell effector functions by blocking the IFN-γ production of mesenteric lymph node T cells ex vivo. Upon exposure to PJ34, purified T cells failed to synthesize ADP-ribose polymers and to activate the transcription of genes encoding IFN-γ, interleukin 2, and the interleukin 2 receptor α chain in response to stimuli such as CD3/CD28 cross-linking or phorbol 12-myristate 13-acetate/ionomycin. The immunosuppressive and chemoprotective effects of PJ34 therefore result from impaired T-cell activation and TH1 polarization, and lead to the protection from preneoplastic gastric immunopathology. In conclusion, ADP-ribosylating enzymes constitute novel targets for the treatment of Helicobacter-associated gastric lesions predisposing infected individuals to gastric cancer and may also hold promise for the treatment of other T cell–driven chronic inflammatory conditions and autoimmune pathologies. Cancer Res; 70(14); 5912–22. ©2010 AACR.
Advances in Targeting Src in the Treatment of Breast Cancer and Other Solid Malignancies
Authors: Mayer Erica L. , Krop Ian E. 
Published: July 2010

AbstractSrc, a membrane-associated nonreceptor tyrosine kinase, plays a crucial role in the coordination and facilitation of cell-signaling pathways controlling a wide range of cellular functions, including growth, survival, invasion, adhesion, and migration. Deregulation and increased activity of Src has been observed in multiple human malignancies, prompting the development of specific inhibitors of Src. In preclinical studies, Src inhibitors show antitumor effects in multiple solid tumor types. Recently completed early-phase trials using the inhibitors dasatinib and bosutinib have suggested modest activity as monotherapy in breast and prostate cancer, with potentially greater activity in combination regimens. Given the interaction between Src and the estrogen receptor, ongoing trials are exploring combinations with endocrine therapy. The relationship between Src and the vascular endothelial growth factor receptor also justifies investigation of combinations with angiogenesis inhibitors. Future trials will continue to explore the contribution of Src inhibition with both chemotherapy and targeted agents. Clin Cancer Res; 16(14); 3526–32. ©2010 AACR.
Preclinical and Clinical Estimates of the Basal Apoptotic Rate of a Cancer Predict the Amount of Apoptosis Induced by Subsequent Proapoptotic Stimuli
Authors: Zhang Lian , Kavanagh Brian D. , Thorburn Andrew M. , Camidge D. Ross 
Published: July 2010

Abstract
Purpose: We hypothesized that the basal apoptotic rate (BAR) of a cancer would predict sensitivity to subsequent proapoptotic stimuli. To explore this, preclinical and clinical BAR assays were developed measuring cumulative apoptotic events through ELISAs for soluble caspase-cleaved cytokeratin 18 (M30) normalized to either cell number increase or total tumor volume, respectively.
Experimental Design: The BARs of A549, HCC44, and SW1573 non–small cell lung carcinoma cell lines were measured following different pro/antiapoptotic manipulations. In isogenic wild-type and stable knockdown (KD) series, pretreatment BARs were correlated with response to proapoptotic stimuli and compared with established apoptosis assays. Pretreatment and posttreatment serum was available from stereotactic body radiation therapy patients.
Results: Caspase inhibition and p53 KDs reduced the BAR, whereas serum deprivation, XIAP, or Bcl2 KDs increased the BAR. The nontreated BAR rank ordering of the XIAP series recapitulated that with terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling and caspase-3/7 activity assays, and predicted each line's sensitivity to TRAIL or irradiation. Terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling, however, underestimated basal apoptosis during increased apoptotic stress, and caspase-3/7 activity detected minimal death in the media. P53 KDs with lower nontreated BARs were less sensitive to TRAIL and cisplatinum than wild-type. Stereotactic body radiation therapy increased serum M30 values, and the pretreatment clinical BAR strongly correlated with fold change in M30 on treatment (r = 0.93).
Conclusions: M30-based BAR assays reflect apoptosis accurately and are more amenable to clinical application than existing apoptosis assays. The pretreatment BAR correlates with cell and/or tumor sensitivity to extrinsic and intrinsic apoptotic pathway stimulation. Prospective clinical exploration is warranted. Clin Cancer Res; 16(17); 4478–89. ©2010 AACR.
Role of synectin in lymphatic development in zebrafish and frogs
Authors: Hermans Karlien , Claes Filip , Vandevelde Wouter , Zheng Wei , Geudens Ilse , Orsenigo Fabrizio , De Smet Frederik , Gjini Evisa , Anthonis Kristof , Ren Bin , Kerjaschki Dontcho , Autiero Monica , Ny Annelii , Simons Michael , Dewerchin Mieke , Schulte-Merker Stefan , Dejana Elisabetta , Alitalo Kari , Carmeliet Peter 
Published: July 2010

AbstractThe molecular basis of lymphangiogenesis remains incompletely characterized. Here, we document a novel role for the PDZ domain-containing scaffold protein synectin in lymphangiogenesis using genetic studies in zebrafish and tadpoles. In zebrafish, the thoracic duct arises from parachordal lymphangioblast cells, which in turn derive from secondary lymphangiogenic sprouts from the posterior cardinal vein. Morpholino knockdown of synectin in zebrafish impaired formation of the thoracic duct, due to selective defects in lymphangiogenic but not angiogenic sprouting. Synectin genetically interacted with Vegfr3 and neuropilin-2a in regulating lymphangiogenesis. Silencing of synectin in tadpoles caused lymphatic defects due to an underdevelopment and impaired migration of Prox-1+ lymphatic endothelial cells. Molecular analysis further revealed that synectin regulated Sox18-induced expression of Prox-1 and vascular endothelial growth factor C–induced migration of lymphatic endothelial cells in vitro. These findings reveal a novel role for synectin in lymphatic development.
Novel biomarkers predict liver fibrosis in hepatitis C patients: alpha 2 macroglobulin, vitamin D binding protein and apolipoprotein AI
Authors: Ho Ai-Sheng , Cheng Chun-Chia , Lee Shui-Cheng , Liu Meng-Lun , Lee Jing-Ying , Wang Wen-Ming , Wang Chia-Chi 
Published: July 2010

Abstract

Background
The gold standard of assessing liver fibrosis is liver biopsy, which is invasive and not without risk. Therefore, searching for noninvasive serologic biomarkers for liver fibrosis is an importantly clinical issue.

Methods
A total of 16 healthy volunteers and 45 patients with chronic hepatitis C virus (HCV) were enrolled (F0: n = 16, F1: n = 7, F2: n = 17, F3: n = 8 and F4: n = 13, according to the METAVIR classification). Three serum samples of each fibrotic stage were analyzed by two-dimension difference gel electrophoresis (2D-DIGE). The differential proteins were identified by the cooperation of MALDI-TOF/TOF and MASCOT; then western blotting and Bio-Plex Suspension Array were used to quantify the protein levels.

Results
Three prominent candidate biomarkers were identified: alpha 2 macroglobulin (A2M) is up regulated; vitamin D binding protein (VDBP) and apolipoprotein AI (ApoAI) are down regulated. The serum concentration of A2M was significantly different among normal, mild (F1/F2) and advanced fibrosis (F3/F4) (p < 0.01). The protein levels of VDBP and ApoAI were significantly higher in normal/mild fibrosis, when compared to those in advanced fibrosis (both p < 0.01).

Conclusions
This study not only reveals three putative biomarkers of liver fibrosis (A2M, VDBP and ApoAI) but also proves the differential expressions of those markers in different stages of fibrosis. We expect that combination of these novel biomarkers could be applied clinically to predict the stage of liver fibrosis without the need of liver biopsy.
Peripheral blood T Regulatory cell counts may not predict transplant rejection
Authors: Huang Yuchuan , Shan Juan , Zhang Chuntao , Zhang Jie , Feng Li , Li Shengfu , Li Youping 
Published: July 2010

Abstract

Background
Recent evidence shows that allograft survival rates show a positive correlation with the number of circulating T regulatory cells (Tregs). This study investigated both the number and the cytokine profiles exhibited by Foxp3+ Tregs in blood, spleen and lymph nodes of Lewis rat recipients of BN rat cardiac allografts after a single-dose of Rapamycin (RAPA).

Results
Rats were divided into three groups: control group (containing healthy control and acute rejection group), and recipients treated with a single dose of RAPA on either Day 1 (1D group)or Day 3 (3D group) post-transplant. We analyzed the number of Foxp3+Tregs and the expression of Foxp3 and cytokines in the peripheral blood and the peripheral lymphoid tissues. No difference was found in the numbers of circulating Foxp3+ Tregs between these three groups. RAPA administration significantly increased Foxp3 expression in peripheral lymphoid tissues after a single dose of RAPA on Day 3 post-transplant. Foxp3+Tregs inhibited the activity of effector T cells (Teff) via the secretion of TGF-β1.

Conclusion
The number of Tregs in the recipient's blood may not be a good predictor of transplant rejection. Foxp3+Tregs inhibit the activity of Teff cells mainly in the peripheral lymphoid tissues.
Breakdown of resistance to grapevine downy mildew upon limited deployment of a resistant variety
Authors: Peressotti Elisa , Wiedemann-Merdinoglu Sabine , Delmotte François , Bellin Diana , Di Gaspero Gabriele , Testolin Raffaele , Merdinoglu Didier , Mestre Pere 
Published: July 2010

Abstract

Background
Natural disease resistance is a cost-effective and environmentally friendly way of controlling plant disease. Breeding programmes need to make sure that the resistance deployed is effective and durable. Grapevine downy mildew, caused by the Oomycete Plasmopara viticola, affects viticulture and it is controlled with pesticides. Downy mildew resistant grapevine varieties are a promising strategy to control the disease, but their use is currently restricted to very limited acreages. The arising of resistance-breaking isolates under such restricted deployment of resistant varieties would provide valuable information to design breeding strategies for the deployment of resistance genes over large acreages whilst reducing the risks of the resistance being defeated. The observation of heavy downy mildew symptoms on a plant of the resistant variety Bianca, whose resistance is conferred by a major gene, provided us with a putative example of emergence of a resistance-breaking isolate in the interaction between grapevine and P. viticola.

Results
In this paper we describe the emergence of a P. viticola isolate (isolate SL) that specifically overcomes Rpv3, the major resistance gene carried by Bianca at chromosome 18. We show that isolate SL has the same behaviour as two P. viticola isolates avirulent on Bianca (isolates SC and SU) when inoculated on susceptible plants or on resistant plants carrying resistances derived from other sources, suggesting there is no fitness cost associated to the virulence. Molecular analysis shows that all three isolates are genetically closely related.

Conclusions
Our results are the first description of a resistance-breaking isolate in the grapevine/P. viticola interaction, and show that, despite the reduced genetic variability of P. viticola in Europe compared to its basin of origin and the restricted use of natural resistance in European viticulture, resistance-breaking isolates overcoming monogenic resistances may arise even in cases where deployment of the resistant varieties is limited to small acreages. Our findings represent a warning call for the use of resistant varieties and an incentive to design breeding programmes aiming to optimize durability of the resistances.
Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells
Authors: Zhang Yu , Huang Qing , Cheng Jung-Chien , Nishi Yoshihiro , Yanase Toshihiko , Huang He-Feng , Leung Peter CK 
Published: July 2010

AbstractBackgroundHomeobox (HOX) genes encode transcription factors, which regulate cell proliferation, differentiation, adhesion, and migration. The deregulation of HOX genes is frequently associated with human reproductive system disorders. However, knowledge regarding the role of HOX genes in human granulosa cells is limited.MethodsTo determine the role of HOXA7 in the regulation and associated mechanisms of cell proliferation in human granulosa cells, HOXA7 and epidermal growth factor receptor (EGFR) expressions were examined in primary granulosa cells (hGCs), an immortalized human granulosa cell line, SVOG, and a granulosa tumor cell line, KGN, by real-time PCR and Western blotting. To manipulate the expression of HOXA7, the HOXA7 specific siRNA was used to knockdown HOXA7 in KGN. Conversely, HOXA7 was overexpressed in SVOG by transfection with the pcDNA3.1-HOAX7 vector. Cell proliferation was measured by the MTT assay.ResultsOur results show that HOXA7 and EGFR were overexpressed in KGN cells compared to hGCs and SVOG cells. Knockdown of HOXA7 in KGN cells significantly decreased cell proliferation and EGFR expression. Overexpression of HOXA7 in SVOG cells significantly promoted cell growth and EGFR expression. Moreover, the EGF-induced KGN proliferation was abrogated, and the activation of downstream signaling was diminished when HOXA7 was knocked down. Overexpression of HOXA7 in SVOG cells had an opposite effect.ConclusionsOur present study reveals a novel mechanistic role for HOXA7 in modulating granulosa cell proliferation via the regulation of EGFR. This finding contributes to the knowledge of the pro-proliferation effect of HOXA7 in granulosa cell growth and differentiation.