bluuebunny/crossref_metadata_2025_split huggingface dataset:
How to manage falls in community dwelling older adults: a review of the evidence
Authors: McKay Claire , Anderson Kathryn E 
Published: April 2010

Abstract
Recurrent falls in older people are one of the leading causes of hospital admission. There is evidence available for identifying many of those at risk and in whom prevention strategies should be targeted. This review discusses the evidence behind the guidelines and highlights the potential benefits for older people. The key features of prevention include multidisciplinary assessment, by experienced individuals, followed by targeted multifactorial interventions. The impact depends on individual factors such as cognitive impairment and on the setting in which they are used. Screening is feasible but cost implications and benefits are unclear, as are the benefits in terms of injury and fracture prevention. It is known that some of the strongest interventions include individually tailored exercise programmes in cognitively intact individuals. When combined with multifactorial risk reduction programmes this approach can reduce falls risk by approximately 30%.
In situ Vaccination Combined with Androgen Ablation and Regulatory T-Cell Depletion Reduces Castration-Resistant Tumor Burden in Prostate-Specific Pten Knockout Mice
Authors: Akins Elizabeth J. , Moore Miranda L. , Tang Shuai , Willingham Mark C. , Tooze Janet A. , Dubey Purnima 
Published: April 2010

Abstract
There is no effective treatment for prostate cancer arising after androgen ablation. Previous studies have analyzed the short-term effects of androgen ablation on the immune system and suggest an abatement of immune suppression by hormone removal. Because castration-resistant disease can arise years after treatment, it is crucial to determine the duration of immune potentiation by castration. Because immunotherapeutic efficacy is determined by the balance of immune cell subsets and their location within the tumor, we assessed the acute and chronic effect of androgen ablation on the localization of T-cell subsets within castration-resistant murine prostate cancer. We observed a transient increase in CD4+ and CD8+ T-cell numbers at the residual tumor after androgen ablation. More than 2 months later, regulatory T cells (Treg) were increasingly found within prostate epithelium, whereas CTLs, which were evenly distributed before androgen ablation, became sequestered within stroma. Anti-CD25 antibody administration along with castration enhanced CTL access to cancerous glands but did not increase effector function. Intraprostatic injection of LIGHT-expressing tumor cells increased the proportion of CD8+ T cells with functional capacity within the cancerous gland. In addition, Treg depletion within the tumor was enhanced. Together, these manipulations significantly reduced castration-resistant tumor burden. Thus, our results indicate that immune modulations, which prevent Treg accumulation and augment effector cell infiltration of prostatic epithelium, may be effective in reducing tumor burden or preventing tumor recurrence after androgen ablation therapy. Cancer Res; 70(9); 3473–82. ©2010 AACR.
Hypoxia Induces Trimethylated H3 Lysine 4 by Inhibition of JARID1A Demethylase
Authors: Zhou Xue , Sun Hong , Chen Haobin , Zavadil Jiri , Kluz Thomas , Arita Adriana , Costa Max 
Published: April 2010

Abstract
Histone H3 lysine 4 (H3K4) trimethylation (H3K4me3) at the promoter region of genes has been linked to transcriptional activation. In the present study, we found that hypoxia (1% oxygen) increased H3K4me3 in both normal human bronchial epithelial Beas-2B cells and human lung carcinoma A549 cells. The increase of H3K4me3 from hypoxia was likely caused by the inhibition of H3K4 demethylating activity, as hypoxia still increased H3K4me3 in methionine-deficient medium. Furthermore, an in vitro histone demethylation assay showed that 1% oxygen decreased the activity of H3K4 demethylases in Beas-2B nuclear extracts because ambient oxygen tensions were required for the demethylation reaction to proceed. Hypoxia only minimally increased H3K4me3 in the BEAS-2B cells with knockdown of JARID1A, which is the major histone H3K4 demethylase in this cell line. However, the mRNA and protein levels of JARID1A were not affected by hypoxia. GeneChip and pathway analysis in JARID1A knockdown Beas-2B cells revealed that JARID1A regulates the expression of hundreds of genes involved in different cellular functions, including tumorigenesis. Knocking down of JARID1A increased H3K4me3 at the promoters of HMOX1 and DAF genes. Thus, these results indicate that hypoxia might target JARID1A activity, which in turn increases H3K4me3 at both the global and gene-specific levels, leading to the altered programs of gene expression and tumor progression. Cancer Res; 70(10); 4214–21. ©2010 AACR.
Anti–Vascular Endothelial Growth Factor Therapies as a Novel Therapeutic Approach to Treating Neurofibromatosis-Related Tumors
Authors: Wong Hon Kit , Lahdenranta Johanna , Kamoun Walid S. , Chan Annie W. , McClatchey Andrea I. , Plotkin Scott R. , Jain Rakesh K. , di Tomaso Emmanuelle 
Published: April 2010

Abstract
Patients with bilateral vestibular schwannomas associated with neurofibromatosis type 2 (NF2) experience significant morbidity such as complete hearing loss. We have recently shown that treatment with bevacizumab provided tumor stabilization and hearing recovery in a subset of NF2 patients with progressive disease. In the current study, we used two animal models to identify the mechanism of action of anti–vascular endothelial growth factor (VEGF) therapy in schwannomas. The human HEI193 and murine Nf2−/− cell lines were implanted between the pia and arachnoid meninges as well as in the sciatic nerve to mimic central and peripheral schwannomas. Mice were treated with bevacizumab (10 mg/kg/wk i.v.) or vandetanib (50 mg/kg/d orally) to block the VEGF pathway. Using intravital and confocal microscopy, together with whole-body imaging, we measured tumor growth delay, survival rate, as well as blood vessel structure and function at regular intervals. In both models, tumor vessel diameter, length/surface area density, and permeability were significantly reduced after treatment. After 2 weeks of treatment, necrosis in HEI193 tumors and apoptosis in Nf2−/− tumors were significantly increased, and the tumor growth rate decreased by an average of 50%. The survival of mice bearing intracranial schwannomas was extended by at least 50%. This study shows that anti-VEGF therapy normalizes the vasculature of schwannoma xenografts in nude mice and successfully controls the tumor growth, probably by reestablishing a natural balance between VEGF and semaphorin 3 signaling. Cancer Res; 70(9); 3483–93. ©2010 AACR.
The Tumor-Suppressive Function of Connexin43 in Keratinocytes Is Mediated in Part via Interaction with Caveolin-1
Authors: Langlois Stéphanie , Cowan Kyle N. , Shao Qing , Cowan Bryce J. , Laird Dale W. 
Published: April 2010

Abstract
Connexin43 (Cx43) is known to have tumor-suppressive effects, but the underlying mechanisms are still poorly understood. In keratinocytes, we previously showed that the COOH-terminal domain of Cx43 directly interacts with the tumor suppressor Cav-1. We now show that rat epidermal keratinocytes (REK) that are reduced in Cx43 present features of epithelial-to-mesenchymal transition and are more invasive than their control counterparts, whereas overexpression of Cx43 inhibited the 12-O-tetradecanoyl-phorbol-13-acetate (TPA)– and epidermal growth factor (EGF)–induced invasive properties. Carbenoxolone did not alter the inhibitory effect of Cx43 against TPA- and EGF-induced cell invasion, indicating the involvement of a gap junctional intercellular communication–independent mechanism. Interestingly, the association of Cx43 with Cav-1 was found to be reduced after TPA and EGF treatment. Accordingly, the colocalization of Cx43 with Cav-1 was diminished in cells from a human epidermal squamous cell carcinoma, as well as in sections from human keratinocyte tumors, suggesting that Cx43/Cav-1 interaction plays a protective role against keratinocyte transformation. As opposed to cells that overexpress Cx43-GFP, invasion could be induced in rat epidermal keratinocytes that overexpressed a GFP-tagged truncated mutant of Cx43 (Δ244-GFP) that we previously showed not to interact with Cav-1, as well as in cells that overexpressed Cx43-GFP but were reduced in Cav-1. Our data show that Cx43 possesses tumor-suppressive properties in keratinocytes and provide the first evidence that the Cx43/Cav-1 interaction is altered in keratinocyte transformation processes, as well as in human keratinocyte tumors, and that this association might play a role in Cx43-mediated tumor suppression. Cancer Res; 70(10); 4222–32. ©2010 AACR.
Molecular Target Class Is Predictive of In vitro Response Profile
Authors: Greshock Joel , Bachman Kurtis E. , Degenhardt Yan Y. , Jing Junping , Wen Yuan H. , Eastman Stephen , McNeil Elizabeth , Moy Christopher , Wegrzyn Ronald , Auger Kurt , Hardwicke Mary Ann , Wooster Richard 
Published: April 2010

Abstract
Preclinical cellular response profiling of tumor models has become a cornerstone in the development of novel cancer therapeutics. As efforts to predict clinical efficacy using cohorts of in vitro tumor models have been successful, expansive panels of tumor-derived cell lines can recapitulate an “all comers” efficacy trial, thereby identifying which tumors are most likely to benefit from treatment. The response profile of a therapy is most often studied in isolation; however, drug treatment effect patterns in tumor models across a diverse panel of compounds can help determine the value of unique molecular target classes in specific tumor cohorts. To this end, a panel of 19 compounds was evaluated against a diverse group of cancer cell lines (n = 311). The primary oncogenic targets were a key determinant of concentration-dependent proliferation response, as a total of five of six, four of four, and five of five phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, insulin-like growth factor-I receptor (IGF-IR), and mitotic inhibitors, respectively, clustered with others of that common target class. In addition, molecular target class was correlated with increased responsiveness in certain histologies. A cohort of PI3K/AKT/mTOR inhibitors was more efficacious in breast cancers compared with other tumor types, whereas IGF-IR inhibitors more selectively inhibited growth in colon cancer lines. Finally, specific phenotypes play an important role in cellular response profiles. For example, luminal breast cancer cells (nine of nine; 100%) segregated from basal cells (six of seven; 86%). The convergence of a common cellular response profile for different molecules targeting the same oncogenic pathway substantiates a rational clinical path for patient populations most likely to benefit from treatment. Cancer Res; 70(9); 3677–86. ©2010 AACR.
FOXC1 Is a Potential Prognostic Biomarker with Functional Significance in Basal-like Breast Cancer
Authors: Ray Partha S. , Wang Jinhua , Qu Ying , Sim Myung-Shin , Shamonki Jaime , Bagaria Sanjay P. , Ye Xing , Liu Bingya , Elashoff David , Hoon Dave S. , Walter Michael A. , Martens John W. , Richardson Andrea L. , Giuliano Armando E. , Cui Xiaojiang 
Published: April 2010

Abstract
Gene expression signatures for a basal-like breast cancer (BLBC) subtype have been associated with poor clinical outcomes, but a molecular basis for this disease remains unclear. Here, we report overexpression of the transcription factor FOXC1 as a consistent feature of BLBC compared with other molecular subtypes of breast cancer. Elevated FOXC1 expression predicted poor overall survival in BLBC (P = 0.0001), independently of other clinicopathologic prognostic factors including lymph node status, along with a higher incidence of brain metastasis (P = 0.02) and a shorter brain metastasis–free survival in lymph node–negative patients (P &lt; 0.0001). Ectopic overexpression of FOXC1 in breast cancer cells increased cell proliferation, migration, and invasion, whereas shRNA-mediated FOXC1 knockdown yielded opposite effects. Our findings identify FOXC1 as a theranostic biomarker that is specific for BLBC, offering not only a potential prognostic candidate but also a potential molecular therapeutic target in this breast cancer subtype. Cancer Res; 70(10); 3870–6. ©2010 AACR.
Attenuation of Tumor Growth by Formation of Antiproliferative Glycosaminoglycans Correlates with Low Acetylation of Histone H3
Authors: Nilsson Ulrika , Johnsson Richard , Fransson Lars-Åke , Ellervik Ulf , Mani Katrin 
Published: April 2010

Abstract
Glycosaminoglycan (GAG) chains anchored to core proteins form proteoglycans, widely distributed cell-surface macromolecules with multiple functions, such as regulation of growth factor and cytokine signaling, cell-cell interactions, and uptake of biomolecules. The biosynthesis of GAG can be manipulated by xylosides attached to various hydrophobic groups, and we have earlier reported that a naphthoxyloside, 2-(6-hydroxynaphthyl) β-d-xylopyranoside (XylNapOH), which serves as a primer for GAG synthesis, reduces tumor load up to 97% in vivo, despite lower efficiency in vitro. Here we show, using radiolabeled xylosides and coculture experiments, that XylNapOH-treated bladder and breast carcinoma cells secrete antiproliferative GAG chains that are taken up by both normal and cancer cells and transported to the cell nuclei where they induce an antiproliferative effect, accompanied by apoptosis. We also show that XylNapOH treatment lowers the level of histone H3 acetylation selectively in bladder and breast carcinoma cells without affecting expression of histone H3. However, XylNapOH-primed GAG chains from normal cells are not internalized and do not cause growth retardation. Using in vitro and in vivo C6 glioma cell and tumor models, we show that XylNapOH is much more effective in vivo than in vitro. We propose that, in vivo, the antiproliferative XylNapOH-primed GAG chains produced by tumor cells inhibit tumor growth in an autocrine fashion by formation of antiproliferative GAG chains on the xyloside prodrug, whereas no antiproliferative GAG chains are produced by surrounding normal cells. This is a novel mechanism for targeting tumor cells, making these xylosides promising drug candidates for antitumor therapy. Cancer Res; 70(9); 3771–9. ©2010 AACR.
Tumor-Initiated Inflammation Overrides Protective Adaptive Immunity in an Induced Melanoma Model in Mice
Authors: Soudja Saïdi M. , Wehbe Maria , Mas Amandine , Chasson Lionel , de Tenbossche Céline Powis , Huijbers Ivo , Van den Eynde Benoît , Schmitt-Verhulst Anne-Marie 
Published: April 2010

Abstract
We studied the effect of the immune system on two differentially aggressive melanomas developing in mice on conditional deletion of the INK4A/ARF tumor suppressor gene, with concomitant expression of oncogene H-RasG12V and a natural cancer-germline tumor antigen (TA). “Slow progressor” melanomas contained no activated T lymphocytes (TL). In contrast, “aggressive” melanomas were infiltrated by activated TLs lacking effector molecules and expressing high levels of PD-1, indicating an exhausted phenotype. Aggressive melanomas were also infiltrated by immature myeloid cells (IMC). Infiltration was associated with local inflammation and systemic Th2/Th17-oriented chronic inflammation that seemed to impair further activation of TLs, as tumor-specific T cells adoptively transferred into mice bearing aggressive melanomas were poorly activated and failed to infiltrate the melanoma. This immunosuppression also led to the incapacity of these mice to reject inoculated TA-positive tumors, in contrast to slow-progressing melanoma-bearing mice, which were responsive. To test the role of adaptive immunity in tumor progression, we induced melanomas in immunodeficient RagKO compound mice. These mice developed aggressive but not slow-progressing melanomas at a higher frequency and with a shorter latency than immunocompetent mice. Immunodeficient mice also developed abnormal inflammation and infiltration of IMCs in a manner similar to immunocompetent mice, indicating that this phenotype was not dependent on adaptive immunity. Therefore, tumor-intrinsic factors distinguishing the two melanoma types control the initiation of inflammation, which was independent of adaptive immunity. The latter delayed development of aggressive melanomas but was overridden by inflammation. Cancer Res; 70(9); 3515–25. ©2010 AACR.
More Modifiers Move on DNA Damage
Authors: Morris Joanna R. 
Published: April 2010

Abstract
In mammalian cells the accumulation of repair proteins to double-strand breaks is a phosphorylation- and ubiquitylation-regulated process. Some of the genes that encode the kinases and ubiquitin ligases in this pathway are cancer predisposition genes, most prominently the breast cancer predisposition gene BRCA1, which encodes a ubiquitin ligase. How BRCA1 ligase activity was regulated following DNA damage was poorly understood. In this review I summarize new data that show a third post-translational modification, by the small ubiquitin like modifier SUMO, is part of the same cascade, enabling and activating DNA damage-regulated processes, including the BRCA1 ligase activity. Cancer Res; 70(10); 3861–3. ©2010 AACR.
A Phase Ib Study of AMG 102 in Combination with Bevacizumab or Motesanib in Patients with Advanced Solid Tumors
Authors: Rosen Peter J. , Sweeney Christopher J. , Park Dorothy J. , Beaupre Darrin M. , Deng Hongjie , Leitch Ian M. , Shubhakar Poornima , Zhu Min , Oliner Kelly S. , Anderson Abraham , Yee Lorrin K. 
Published: April 2010

Abstract
Purpose: This phase Ib study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 102, a fully human monoclonal antibody against hepatocyte growth factor/scatter factor (HGF/SF), in combination with bevacizumab or motesanib in patients with advanced solid tumors.
Experimental Design: Patients with treatment-refractory advanced solid tumors were sequentially enrolled into four cohorts (3, 10, or 20 mg/kg AMG 102 plus 10 mg/kg bevacizumab i.v. every 2 weeks, or 3 mg/kg AMG 102 i.v. every 2 weeks plus 75 mg motesanib orally once daily).
Results: Fourteen patients were enrolled and received AMG 102. The combination of AMG 102 with bevacizumab (n = 12) seemed to have acceptable toxicity. The number of patients (n = 2) who received AMG 102 plus motesanib was insufficient to adequately assess safety. No dose-limiting toxicities were reported. Enrollment in the motesanib cohort was suspended because of reports of cholecystitis in other motesanib studies. Treatment-emergent adverse events among patients receiving AMG 102 plus bevacizumab were generally mild and included fatigue (75%), nausea (58%), constipation (42%), and peripheral edema (42%). No anti-AMG 102 antibodies were detected. Bevacizumab did not seem to affect AMG 102 pharmacokinetics. Circulating total HGF/SF increased from baseline throughout the study. Eight of 10 evaluable patients had reductions in tumor dimensions, and stable disease at ≥8, ≥16, and ≥24 weeks occurred in 9, 7, and 4 patients, respectively. Progression-free survival ranged from 7.9 to 121.9 weeks.
Conclusions: AMG 102 in combination with bevacizumab was well tolerated. Further evaluation of AMG 102 in combination with antiangiogenic agents is warranted. Clin Cancer Res; 16(9); 2677–87. ©2010 AACR.
New Molecular and Biological Mechanism of Antitumor Activities of KW-2478, a Novel Nonansamycin Heat Shock Protein 90 Inhibitor, in Multiple Myeloma Cells
Authors: Nakashima Takayuki , Ishii Toshihiko , Tagaya Hisashi , Seike Toshihiro , Nakagawa Hiroshi , Kanda Yutaka , Akinaga Shiro , Soga Shiro , Shiotsu Yukimasa 
Published: April 2010

Abstract
Purpose: The heat shock protein 90 (Hsp90) plays an important role in chaperoning oncogenic client proteins in multiple myeloma (MM) cells, and several Hsp90 inhibitors have shown antitumor activities both in vitro and in vivo. However the precise mechanism of action of Hsp90 inhibitor in MM has not been fully elucidated.
Experimental Design: We evaluated the antitumor activities of KW-2478, a nonansamycin Hsp90 inhibitor, in MM cells with various chromosomal translocations of immunoglobulin heavy chain (IgH) loci both in vitro and in vivo.
Results: Our studies revealed that exposure of KW-2478 to MM cells resulted in growth inhibition and apoptosis, which were associated with degradation of well-known client proteins as well as a decrease in IgH translocation products (FGFR3, c-Maf, and cyclin D1), and FGFR3 was shown to be a new client protein of Hsp90 chaperon complex. In addition, KW-2478 depleted the Hsp90 client Cdk9, a transcriptional kinase, and the phosphorylated 4E-BP1, a translational inhibitor. Both inhibitory effects of KW-2478 on such transcriptional and translational pathways were shown to reduce c-Maf and cyclin D1 expression. In NCI-H929 s.c. inoculated model, KW-2478 showed a significant suppression of tumor growth and induced the degradation of client proteins in tumors. Furthermore, in a novel orthotopic MM model of i.v. inoculated OPM-2/green fluorescent protein, KW-2478 showed a significant reduction of both serum M protein and MM tumor burden in the bone marrow.
Conclusions: These results suggest that targeting such diverse pathways by KW-2478 could be a promising strategy for the treatment of MM with various cytogenetic abnormalities. Clin Cancer Res; 16(10); 2792–802. ©2010 AACR.
Gene Expression Signature in Urine for Diagnosing and Assessing Aggressiveness of Bladder Urothelial Carcinoma
Authors: Mengual Lourdes , Burset Moisès , Ribal María José , Ars Elisabet , Marín-Aguilera Mercedes , Fernández Manuel , Ingelmo-Torres Mercedes , Villavicencio Humberto , Alcaraz Antonio 
Published: April 2010

Abstract
Purpose: To develop an accurate and noninvasive method for bladder cancer diagnosis and prediction of disease aggressiveness based on the gene expression patterns of urine samples.
Experimental Design: Gene expression patterns of 341 urine samples from bladder urothelial cell carcinoma (UCC) patients and 235 controls were analyzed via TaqMan Arrays. In a first phase of the study, three consecutive gene selection steps were done to identify a gene set expression signature to detect and stratify UCC in urine. Subsequently, those genes more informative for UCC diagnosis and prediction of tumor aggressiveness were combined to obtain a classification system of bladder cancer samples. In a second phase, the obtained gene set signature was evaluated in a routine clinical scenario analyzing only voided urine samples.
Results: We have identified a 12+2 gene expression signature for UCC diagnosis and prediction of tumor aggressiveness on urine samples. Overall, this gene set panel had 98% sensitivity (SN) and 99% specificity (SP) in discriminating between UCC and control samples and 79% SN and 92% SP in predicting tumor aggressiveness. The translation of the model to the clinically applicable format corroborates that the 12+2 gene set panel described maintains a high accuracy for UCC diagnosis (SN = 89% and SP = 95%) and tumor aggressiveness prediction (SN = 79% and SP = 91%) in voided urine samples.
Conclusions: The 12+2 gene expression signature described in urine is able to identify patients suffering from UCC and predict tumor aggressiveness. We show that a panel of molecular markers may improve the schedule for diagnosis and follow-up in UCC patients. Clin Cancer Res; 16(9); 2624–33. ©2010 AACR.