bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating endothelial cells as potential diagnostic biomarkers in primary central nervous system vasculitis
Authors: Deb-Chatterji Milani , Gerdes Stefan , Heeren Meike , Lambrecht Jürgen , Worthmann Hans , Goldbecker Annemarie , Tryc Anita Blanka , Lovric Svjetlana , Schulz-Schaeffer Walter , Brandis Almuth , Dengler Reinhard , Weissenborn Karin , Haubitz Marion 
Published: December 2012

ObjectiveHistological evidence is considered the only proof of primary central nervous system vasculitis (PCNSV). However, brain biopsy is often omitted or delayed because of the invasiveness and possible complications of the procedure. Circulating endothelial cells (CEC) were shown to be elevated in patients with active antineutrophil cytoplasmic antibody-associated vasculitis. We hypothesise that CEC are also elevated in patients with active PCNSV and may contribute to the diagnosis.MethodsCEC were assessed in 18 patients, 3 of whom had biopsy-proven PCNSV and 15 clinical, cerebrospinal fluid and imaging data, highly suggestive of PCNSV. In 3 of these 15 patients CEC assessment was performed after initiation of successful immunosuppressive therapy. CEC numbers of all patients were compared to those of 16 healthy volunteers and 123 subjects with cerebrovascular risk factors and/or ischaemic stroke, who had been studied in our group before. CEC were assessed by immunomagnetic isolation from peripheral blood.ResultsIn patients with proven and suspected active PCNSV, CEC were extremely elevated (>400 cells/ml in most of the patients) and significantly higher than in healthy and disease controls (p≤0.01 for each group). CEC significantly decreased with immunosuppressive treatment.ConclusionsFor the first time it is shown that CEC are significantly elevated in patients with active PCNSV in contrast to other pathologies associated with brain infarction and correlate with disease activity. Sensitivity and specificity of the method for diagnosing PCNSV and the use of the method for treatment monitoring should be addressed in future prospective studies with a larger patient group.
A clinicopathological analysis of 26 patients with infection-associated haemophagocytic lymphohistiocytosis and the importance of bone marrow phagocytosis for the early initiation of immunomodulatory treatment
Authors: Nair Velu , Das Satyaranjan , Sharma Ajay , Sharma Sanjeevan , Sharma Prafull , Ray Sougat , Bhattacharya Shilajit 
Published: December 2012

Abstract

Objective
To analyse the clinicopathological presentation, outcome and importance of bone marrow haemophagocytosis in patients with infection-associated haemophagocytic lymphohistiocytosis (IA-HLH) in a tertiary care hospital in Northern India.

Study design
Between January 2007 and December 2009, 26 consecutive patients meeting the diagnostic criteria for IA-HLH, based on the HLH2004 protocol of the Histiocyte Society, were followed up for between 12 and 34 months (median 20 months).

Results
IA-HLH was diagnosed in three of the five patients who died 5–6 weeks after the onset of the illness, whereas diagnosis in the remaining group was made a median of 2 weeks after the onset of the illness. The predominant presenting features were fever (100%), hepatomegaly (69%), splenomegaly (58%) and anaemia (96%). All patients showed &gt;3% haemophagocytosis on bone marrow studies—in four cases after serial aspiration/biopsies. Twenty-one (80.8%) cases were non-fatal and five (19.2%) patients died. The non-fatal cases included eight (38.1%) cases of viral infection, seven (33.3%) bacterial infections, two (9.6%) fungal and four (19.0%) protozoal infections; whereas four (80%) bacterial infections and one (20%) viral infection were associated with the fatal cases. The mean of the nadir blood counts of white blood cells, absolute neutrophil counts and platelets; the mean of all the peak biochemical parameters of liver function tests, lactate dehydrogenase and ferritin and the lowest fibrinogen values before treatment, differed significantly (p&lt;0.05) between the non-fatal and the fatal group, being worse in the latter.

Conclusions
IA-HLH is important because it can obscure the typical clinical features of the underlying primary disease, thus delaying the diagnosis and having a negative effect on the outcome. Although bone marrow haemophagocytosis is not a mandatory diagnostic criterion, we found it to be a useful tool together with biochemical parameters for early recognition of HLH, especially in developing countries lacking molecular and flow laboratories. The severity of pancytopenia and derangement in biochemical markers were significantly higher in the patients who died.
Informal confidential voting interviewing in a sexual risk assessment of men who have sex with men (MSM) and transgenders (hijra) in Bangalore, India
Authors: Phillips Anna Elizabeth , Molitor John , Boily Marie Claude , Lowndes Catherine M , Gurav Kaveri , Blanchard James , Alary Michel 
Published: December 2012

ObjectiveThe accuracy of self-reporting sensitive sexual risk behaviours is highly susceptible to misreporting. Informal confidential voting interviews (ICVIs) may minimise social desirability bias by increasing the privacy of the interview setting. The objective was to investigate determinants of risky behaviour among men who have sex with men (MSM) and ‘hijra’ (transgenders) reported through two interviewing tools: ICVIs and face-to-face interviews (FTFIs).MethodsCluster random sampling was used to recruit MSM in 85 cruising sites in Bangalore, including eight hammams (bath houses) and 77 public locations where MSM and hijra cruise for sex. Individuals were randomly allocated to one of the data collection methods(5 : 2 FTFI : ICVI). Data were analysed using standard regression and a profile regression approach that associates clusters of behaviours with our outcome (FTFI vs ICVI).ResultsA total of 372 MSM and hijra were interviewed for the FTFIs and 153 respondents completed ICVIs. Participants were more likely to report injecting drug use (4% vs 1%; p=0.008) and paying to have sex with a female sex worker (FSW) in the last year (28% vs 8%; p=0.001) in the ICVIs. There were no differences to questions on sociodemographics, sexual debut with another male, non-condom use (12% vs 14%), ever selling sex to men (58% vs 56%), current female partner (26% vs 20%) and non-condom use with a main female partner (17% vs 19%).ConclusionsThe significant differences between interview modes for certain outcomes, such as intravenous drug use and sex with a FSW, demonstrate how certain behaviour is stigmatised among the MSM community. Nevertheless, the lack of effect of the interviewing tool in other outcomes may indicate either less reporting bias in reporting this behaviour or environmental factors such as the interviewers not adequately screening themselves from the respondent or a potential disadvantage of using other MSM as interviewers.
Bringing it home: community survey of HIV risks to primary sex partners of men and women in alcohol-serving establishments in Cape Town, South Africa
Authors: Kalichman Seth C , Pitpitan Eileen , Eaton Lisa , Cain Demetria , Carey Kate B , Carey Michael P , Harel Ofer , Mehlomakhulu Vuyelwa , Simbayi Leickness Chisamu , Mwaba Kelvin 
Published: December 2012

BackgroundConcurrent sexual relationships facilitate the spread of HIV infection, and sex with non-primary partners may pose particularly high risks for HIV transmission to primary partners.ObjectiveWe examined the sexual and alcohol-related risks associated with sex partners outside of primary relationships among South African men and women in informal drinking establishments.MethodsMen (n=4959) and women (n=2367) with primary sex partners residing in a Xhosa-speaking South African township completed anonymous surveys. Logistic regressions tested associations between having outside partners and risks for sexually transmitted infections (STI)/HIV.ResultsForty-four percent of men and 26% women with primary sex partners reported also having outside sex partners in the previous month. Condom use with outside partners was inconsistent for men and women; only 19% of men and 12% of women used condoms consistently with outside sex partners. Multivariable regressions for men and women showed that having outside partners was significantly associated with having been diagnosed with an STI, consuming alcohol in greater frequency and quantity, alcohol use during sex, meeting sex partners in alcohol-serving venues, and higher rates of unprotected sex.ConclusionsHaving outside sex partners was associated with multiple risk factors for HIV infection among South African shebeen patrons. Social and structural interventions that encourage condom use are needed for men and women with outside partners who patronise alcohol-serving venues.
Endocan Is Upregulated on Tumor Vessels in Invasive Bladder Cancer Where It Mediates VEGF-A–Induced Angiogenesis
Authors: Roudnicky Filip , Poyet Cedric , Wild Peter , Krampitz Sarah , Negrini Fabrizia , Huggenberger Reto , Rogler Anja , Stöhr Robert , Hartmann Arndt , Provenzano Maurizio , Otto Vivianne I. , Detmar Michael 
Published: December 2012

Abstract
Tumor-associated blood vessels differ from normal vessels and proteins present only on tumor vessels may serve as biomarkers or targets for antiangiogenic therapy in cancer. Comparing the transcriptional profiles of blood vascular endothelium from human invasive bladder cancer with normal bladder tissue, we found that the endothelial cell-specific molecule endocan (ESM1) was highly elevated on tumor vessels. Endocan was associated with filopodia of angiogenic endothelial tip cells in invasive bladder cancer. Notably, endocan expression on tumor vessels correlated strongly with staging and invasiveness, predicting a shorter recurrence-free survival time in noninvasive bladder cancers. Both endocan and VEGF-A levels were higher in plasma of patients with invasive bladder cancer than healthy individuals. Mechanistic investigations in cultured blood vascular endothelial cells or transgenic mice revealed that endocan expression was stimulated by VEGF-A through the phosphorylation and activation of VEGFR-2, which was required to promote cell migration and tube formation by VEGF-A. Taken together, our findings suggest that disrupting endocan interaction with VEGFR-2 or VEGF-A could offer a novel rational strategy to inhibit tumor angiogenesis. Furthermore, they suggest that endocan might serve as a useful biomarker to monitor disease progression and the efficacy of VEGF-A–targeting therapies in patients with bladder cancer. Cancer Res; 73(3); 1097–106. ©2012 AACR.
STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer
Authors: Peña Cristina , Céspedes María Virtudes , Lindh Maja Bradic , Kiflemariam Sara , Mezheyeuski Artur , Edqvist Per-Henrik , Hägglöf Christina , Birgisson Helgi , Bojmar Linda , Jirström Karin , Sandström Per , Olsson Eleonor , Veerla Srinivas , Gallardo Alberto , Sjöblom Tobias , Chang Andy C.-M. , Reddel Roger R. , Mangues Ramón , Augsten Martin , Östman Arne 
Published: December 2012

Abstract
Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understood. Here, we report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis. Cancer Res; 73(4); 1287–97. ©2012 AACR.
Myeloid-Derived Suppressor Cells Function as Novel Osteoclast Progenitors Enhancing Bone Loss in Breast Cancer
Authors: Sawant Anandi , Deshane Jessy , Jules Joel , Lee Carnella M. , Harris Brittney A. , Feng Xu , Ponnazhagan Selvarangan 
Published: December 2012

Abstract
Enhanced bone destruction is a hallmark of various carcinomas such as breast cancer, where osteolytic bone metastasis is associated with increased morbidity and mortality. Immune cells contribute to osteolysis in cancer growth, but the factors contributing to aggressive bone destruction are not well understood. In this study, we show the importance of myeloid-derived suppressor cells (MDSC) in this process at bone metastatic sites. Because MDSC originate from the same myeloid lineage as macrophages, which are osteoclast precursors, we hypothesized that MDSC may undergo osteoclast differentiation and contribute to enhanced bone destruction and tumor growth. Using an immunocompetent mouse model of breast cancer bone metastasis, we confirmed that MDSC isolated from the tumor-bone microenvironment differentiated into functional osteoclasts both in vitro and in vivo. Mechanistic investigations revealed that nitric oxide signaling was critical for differentiation of MDSC into osteoclasts. Remarkably, osteoclast differentiation did not occur in MDSC isolated from control or tumor-bearing mice that lacked bone metastasis, signifying the essential cross-talk between tumor cells and myeloid progenitors in the bone microenvironment as a requirement for osteoclast differentiation of MDSC. Overall, our results identify a wholly new facet to the multifunctionality of MDSC in driving tumor progression, in this case as a novel osteoclast progenitor that specifically drives bone metastasis during cancer progression. Cancer Res; 73(2); 672–82. ©2012 AACR.
The Noncoding RNA MALAT1 Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells
Authors: Gutschner Tony , Hämmerle Monika , Eißmann Moritz , Hsu Jeff , Kim Youngsoo , Hung Gene , Revenko Alexey , Arun Gayatri , Stentrup Marion , Groß Matthias , Zörnig Martin , MacLeod A. Robert , Spector David L. , Diederichs Sven 
Published: December 2012

Abstract
The long noncoding RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), also known as MALAT-1 or NEAT2 (nuclear-enriched abundant transcript 2), is a highly conserved nuclear noncoding RNA (ncRNA) and a predictive marker for metastasis development in lung cancer. To uncover its functional importance, we developed a MALAT1 knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements using zinc finger nucleases. The achieved 1,000-fold MALAT1 silencing provides a unique loss-of-function model. Proposed mechanisms of action include regulation of splicing or gene expression. In lung cancer, MALAT1 does not alter alternative splicing but actively regulates gene expression including a set of metastasis-associated genes. Consequently, MALAT1-deficient cells are impaired in migration and form fewer tumor nodules in a mouse xenograft. Antisense oligonucleotides (ASO) blocking MALAT1 prevent metastasis formation after tumor implantation. Thus, targeting MALAT1 with ASOs provides a potential therapeutic approach to prevent lung cancer metastasis with this ncRNA serving as both predictive marker and therapeutic target. Finally, regulating gene expression, but not alternative splicing, is the critical function of MALAT1 in lung cancer metastasis. In summary, 10 years after the discovery of the lncRNA MALAT1 as a biomarker for lung cancer metastasis, our loss-of-function model unravels the active function of MALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis. Cancer Res; 73(3); 1180–9. ©2012 AACR.
ΔNp63α-Mediated Activation of Bone Morphogenetic Protein Signaling Governs Stem Cell Activity and Plasticity in Normal and Malignant Mammary Epithelial Cells
Authors: Balboni Amanda L. , Hutchinson Justine A. , DeCastro Andrew J. , Cherukuri Pratima , Liby Karen , Sporn Michael B. , Schwartz Gary N. , Wells Wendy A. , Sempere Lorenzo F. , Yu Paul B. , DiRenzo James 
Published: December 2012

Abstract
Genetic analysis of TP63 indicates that ΔNp63 isoforms are required for preservation of regenerative stasis within diverse epithelial tissues. In squamous carcinomas, TP63 is commonly amplified, and ΔNp63α confers a potent survival advantage. Genome-wide occupancy studies show that ΔNp63 promotes bidirectional target gene regulation by binding more than 5,000 sites throughout the genome; however, the subset of targets mediating discreet activities of TP63 remains unclear. We report that ΔNp63α activates bone morphogenic proteins (BMP) signaling by inducing the expression of BMP7. Immunohistochemical analysis indicates that hyperactivation of BMP signaling is common in human breast cancers, most notably in the basal molecular subtype, as well as in several mouse models of breast cancer. Suppression of BMP signaling in vitro with LDN193189, a small-molecule inhibitor of BMP type I receptor kinases, represses clonogenicity and diminishes the cancer stem cell–enriched ALDH1+ population. Importantly, LDN193189 blocks reconstitution of mixed ALDH1+/ALDH1− cultures indicating that BMP signaling may govern aspects of cellular plasticity within tumor hierarchies. These results show that BMP signaling enables reversion of committed populations to a stem-like state, potentially supporting progression and maintenance of tumorigenesis. Treatment of a mouse model of breast cancer with LDN193189 caused reduced expression of markers associated with epithelial-to-mesenchymal transition (EMT). Furthermore, in vivo limiting dilution analysis assays revealed that LDN193189 treatment suppressed tumor-initiating capacity and increased tumor latency. These studies support a model in which ΔNp63α-mediated activation of BMP signaling governs epithelial cell plasticity, EMT, and tumorigenicity during breast cancer initiation and progression. Cancer Res; 73(2); 1020–30. ©2012 AACR.
Midkine Promotes Neuroblastoma through Notch2 Signaling
Authors: Kishida Satoshi , Mu Ping , Miyakawa Shin , Fujiwara Masatoshi , Abe Tomoyuki , Sakamoto Kazuma , Onishi Akira , Nakamura Yoshikazu , Kadomatsu Kenji 
Published: December 2012

Abstract
Midkine is a heparin-binding growth factor highly expressed in various cancers, including neuroblastoma, the most common extracranial pediatric solid tumor. Prognosis of patients with neuroblastoma in which MYCN is amplified remains particularly poor. In this study, we used a MYCN transgenic model for neuroblastoma in which midkine is highly expressed in precancerous lesions of sympathetic ganglia. Genetic ablation of midkine in this model delayed tumor formation and reduced tumor incidence. Furthermore, an RNA aptamer that specifically bound midkine suppressed the growth of neuroblastoma cells in vitro and in vivo in tumor xenografts. In precancerous lesions, midkine-deficient MYCN transgenic mice exhibited defects in activation of Notch2, a candidate midkine receptor, and expression of the Notch target gene HES1. Similarly, RNA aptamer-treated tumor xenografts also showed attenuation of Notch2-HES1 signaling. Our findings establish a critical role for the midkine-Notch2 signaling axis in neuroblastoma tumorigenesis, which implicates new strategies to treat neuroblastoma. Cancer Res; 73(4); 1318–27. ©2012 AACR.
Opportunities and Challenges for Selected Emerging Technologies in Cancer Epidemiology: Mitochondrial, Epigenomic, Metabolomic, and Telomerase Profiling
Authors: Verma Mukesh , Khoury Muin J. , Ioannidis John P.A. 
Published: December 2012

Abstract
Remarkable progress has been made in the last decade in new methods for biologic measurements using sophisticated technologies that go beyond the established genome, proteome, and gene expression platforms. These methods and technologies create opportunities to enhance cancer epidemiologic studies. In this article, we describe several emerging technologies and evaluate their potential in epidemiologic studies. We review the background, assays, methods, and challenges and offer examples of the use of mitochondrial DNA and copy number assessments, epigenomic profiling (including methylation, histone modification, miRNAs, and chromatin condensation), metabolite profiling (metabolomics), and telomere measurements. We map the volume of literature referring to each one of these measurement tools and the extent to which efforts have been made at knowledge integration (e.g., systematic reviews and meta-analyses). We also clarify strengths and weaknesses of the existing platforms and the range of type of samples that can be tested with each of them. These measurement tools can be used in identifying at-risk populations and providing novel markers of survival and treatment response. Rigorous analytic and validation standards, transparent availability of massive data, and integration in large-scale evidence are essential in fulfilling the potential of these technologies. Cancer Epidemiol Biomarkers Prev; 22(2); 189–200. ©2012 AACR.
Detection of miR-34a Promoter Methylation in Combination with Elevated Expression of c-Met and β-Catenin Predicts Distant Metastasis of Colon Cancer
Authors: Siemens Helge , Neumann Jens , Jackstadt Rene , Mansmann Ulrich , Horst David , Kirchner Thomas , Hermeking Heiko 
Published: December 2012

Abstract
Purpose: Here, we determined whether epigenetic inactivation of miR-34a and miR-34b/c genes may serve as a prognostic marker for distant metastases in colon cancer.
Experimental Design: Using a case–control study design of 94 primary colon cancer samples with and without liver metastases, we determined CpG methylation frequencies of miR-34a and miR-34b/c promoters, expression of miR-34a, and its targets c-Met, Snail, and β-catenin and their prognostic value.
Results: miR-34a methylation was detected in 45.1% (n = 42 of 93) of the samples and strongly associated with metastases to the liver (P = 0.003) and lymph nodes (P = 0.006). miR-34b/c methylation was detected in 91.9% of the samples (n = 79/86). A significant inverse correlation between miR-34a methylation and expression of mature miR-34a (P = 0.018) was detected. Decreased miR-34a expression was associated with upregulation of c-Met, Snail, and β-catenin protein levels (P = 0.031, 0.132, and 0.004), which were associated with distant metastases (P = 0.001, 0.017, and 0.005). In a confounder-adjusted multivariate regression model miR-34a methylation, high c-Met and β-catenin levels provided the most significant prognostic information about metastases to the liver (P = 0.014, 0.031, and 0.058) and matched pairs showed a higher prevalence of these risk factors in the samples with distant spread (P = 0.029). Finally, we obtained statistical evidence indicating that the simultaneous detection of these three markers has the highest prognostic value.
Conclusions: Silencing of miR-34a and upregulation of c-Met, Snail, and β-catenin expression is associated with liver metastases of colon cancer. Detection of miR-34a silencing in resected primary colon cancer may be of prognostic value, especially in combination with detection of c-Met and β-catenin expression. Clin Cancer Res; 19(3); 710–20. ©2012 AACR.