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Ciarloni L.,Diagnoplex | Ciarloni L.,Novigenix SA | Hosseinian S.,Diagnoplex | Hosseinian S.,Novigenix SA | And 9 more authors.
PLoS ONE | Year: 2015

Colorectal cancer (CRC) is the second leading cause of cancer-related death in developed countries. Early detection of CRC leads to decreased CRC mortality. A blood-based CRC screening test is highly desirable due to limited invasiveness and high acceptance rate among patients compared to currently used fecal occult blood testing and colonoscopy. Here we describe the discovery and validation of a 29-gene panel in peripheral blood mononuclear cells (PBMC) for the detection of CRC and adenomatous polyps (AP). Blood samples were prospectively collected from a multicenter, case-control clinical study. First, we profiled 93 samples with 667 candidate and 3 reference genes by high throughput real-time PCR (OpenArray system). After analysis, 160 genes were retained and tested again on 51 additional samples. Low expressed and unstable genes were discarded resulting in a final dataset of 144 samples profiled with 140 genes. To define which genes, alone or in combinations had the highest potential to discriminate AP and/or CRC from controls, data were analyzed by a combination of univariate and multivariate methods. A list of 29 potentially discriminant genes was compiled and evaluated for its predictive accuracy by penalized logistic regression and bootstrap. This method discriminated AP >1cm and CRC from controls with a sensitivity of 59% and 75%, respectively, with 91% specificity. The behavior of the 29-gene panel was validated with a LightCycler 480 real-time PCR platform, commonly adopted by clinical laboratories. In this work we identified a 29-gene panel expressed in PBMC that can be used for developing a novel minimally-invasive test for accurate detection of AP and CRC using a standard real-time PCR platform. © 2015 Ciarloni et al.


Laurent J.,University of Lausanne | Faes-van't Hull E.,University of Lausanne | Touvrey C.,University of Lausanne | Kuonen F.,University of Lausanne | And 21 more authors.
Cancer Research | Year: 2011

Tumor-mobilized bone marrow-derived CD11b+ myeloid cells promote tumor angiogenesis, but how and when these cells acquire proangiogenic properties is not fully elucidated. Here, we show that CD11b+ myelomonocytic cells develop proangiogenic properties during their differentiation from CD34+ hematopoietic progenitors and that placenta growth factor (PlGF) is critical in promoting this education. Cultures of human CD34+ progenitors supplemented with conditioned medium from breast cancer cell lines or PlGF, but not from nontumorigenic breast epithelial lines, generate CD11b+ cells capable of inducing endothelial cell sprouting in vitro and angiogenesis in vivo. An anti-Flt-1 mAb or soluble Flt-1 abolished the generation of proangiogenic activity during differentiation from progenitor cells. Moreover, inhibition of metalloproteinase activity, but not VEGF, during the endothelial sprouting assay blocked sprouting induced by these proangiogenic CD11b+ myelomonocytes. In a mouse model of breast cancer, circulating CD11b+ cells were proangiogenic in the sprouting assays. Silencing of PlGF in tumor cells prevented the generation of proangiogenic activity in circulating CD11b+ cells, inhibited tumor blood flow, and slowed tumor growth. Peripheral blood of breast cancer patients at diagnosis, but not of healthy individuals, contained elevated levels of PlGF and circulating proangiogenic CD11b+ myelomonocytes. Taken together, our results show that cancer cells can program proangiogenic activity in CD11b+ myelomonocytes during differentiation of their progenitor cells in a PlGF-dependent manner. These findings impact breast cancer biology, detection, and treatment. ©2011 AACR.


Imaizumi N.,University of Lausanne | Imaizumi N.,Ecole Polytechnique Federale de Lausanne | Imaizumi N.,Diagnoplex | Monnier Y.,University of Lausanne | And 7 more authors.
PLoS ONE | Year: 2010

Background: Radiotherapy is widely used to treat cancer. While rapidly dividing cancer cells are naturally considered the main target of radiotherapy, emerging evidence indicates that radiotherapy also affects endothelial cell functions, and possibly also their angiogenic capacity. In spite of its clinical relevance, such putative anti-angiogenic effect of radiotherapy has not been thoroughly characterized. We have investigated the effect of ionizing radiation on angiogenesis using in vivo, ex vivo and in vitro experimental models in combination with genetic and pharmacological interventions. Principal Findings: Here we show that high doses ionizing radiation locally suppressed VEGF- and FGF-2-induced Matrigel plug angiogenesis in mice in vivo and prevented endothelial cell sprouting from mouse aortic rings following in vivo or ex vivo irradiation. Quiescent human endothelial cells exposed to ionizing radiation in vitro resisted apoptosis, demonstrated reduced sprouting, migration and proliferation capacities, showed enhanced adhesion to matrix proteins, and underwent premature senescence. Irradiation induced the expression of P53 and P21 proteins in endothelial cells, but p53 or p21 deficiency and P21 silencing did not prevent radiation-induced inhibition of sprouting or proliferation. Radiation induced Smad-2 phosphorylation in skin in vivo and in endothelial cells in vitro. Inhibition of the TGF-b type I receptor ALK5 rescued deficient endothelial cell sprouting and migration but not proliferation in vitro and restored defective Matrigel plug angiogenesis in irradiated mice in vivo. ALK5 inhibition, however, did not rescue deficient proliferation. Notch signaling, known to hinder angiogenesis, was activated by radiation but its inhibition, alone or in combination with ALK5 inhibition, did not rescue suppressed proliferation. Conclusions: These results demonstrate that irradiation of quiescent endothelial cells suppresses subsequent angiogenesis and that ALK5 is a critical mediator of this suppression. These results extend our understanding of radiotherapy-induced endothelial dysfunctions, relevant to both therapeutic and unwanted effects of radiotherapy. © 2010 Imaizumi et al.


Nichita C.,University of Lausanne | Ciarloni L.,Diagnoplex | Ciarloni L.,Ecole Polytechnique Federale de Lausanne | Monnier-Benoit S.,Diagnoplex | And 4 more authors.
Alimentary Pharmacology and Therapeutics | Year: 2014

Background Early detection and treatment of colorectal adenomatous polyps (AP) and colorectal cancer (CRC) is associated with decreased mortality for CRC. However, accurate, non-invasive and compliant tests to screen for AP and early stages of CRC are not yet available. A blood-based screening test is highly attractive due to limited invasiveness and high acceptance rate among patients. Aim To demonstrate whether gene expression signatures in the peripheral blood mononuclear cells (PBMC) were able to detect the presence of AP and early stages CRC. Methods A total of 85 PBMC samples derived from colonoscopy-verified subjects without lesion (controls) (n = 41), with AP (n = 21) or with CRC (n = 23) were used as training sets. A 42-gene panel for CRC and AP discrimination, including genes identified by Digital Gene Expression-tag profiling of PBMC, and genes previously characterised and reported in the literature, was validated on the training set by qPCR. Logistic regression analysis followed by bootstrap validation determined CRC- and AP-specific classifiers, which discriminate patients with CRC and AP from controls. Results The CRC and AP classifiers were able to detect CRC with a sensitivity of 78% and AP with a sensitivity of 46% respectively. Both classifiers had a specificity of 92% with very low false-positive detection when applied on subjects with inflammatory bowel disease (n = 23) or tumours other than CRC (n = 14). Conclusion This pilot study demonstrates the potential of developing a minimally invasive, accurate test to screen patients at average risk for colorectal cancer, based on gene expression analysis of peripheral blood mononuclear cells obtained from a simple blood sample. © 2014 John Wiley & Sons Ltd.


Patent
Diagnoplex | Date: 2013-11-04

The present invention relates to methods and kits for the detection of predetermined biomarkers for early diagnosis and management of cancer, and in particular, colorectal tumors.


Trademark
Diagnoplex | Date: 2012-05-24

Measuring and checking apparatus and instruments, namely thermocyclers, for DNA and RNA quantification; testing apparatus for diagnostic purposes other than medical; computer hardware for use in blood analysis; computer software for processing and analyzing cancer and tumour screening results and for analyzing colorectal cancer screening methods and procedures in the medical and veterinary fields. Medical apparatus and instruments for diagnostic use, namely, apparatus for medical diagnostic testing in the fields of cancer or other tissue-based diagnostic testing, cytology and cell-based testing; medical articles, namely blood collection tubes, 384-well plate for polymerase chain reaction, DNA oligonucleotides; blood testing apparatus; medical apparatus for cancer, tumour and colorectal cancer screening for medical and veterinary use. Medical and veterinary services; medical and veterinary analysis in the fields of cancer, tumour and colorectal cancer screening.


Trademark
Diagnoplex | Date: 2012-05-24

Blood for medical purposes; blood plasma; reagents for medical or veterinary use. Measuring and checking apparatus and instruments, namely thermocyclers, for DNA and RNA quantification; testing apparatus for diagnostic purposes other than medical; computer hardware for use in blood analysis; computer software for processing and analyzing cancer and tumour screening results and for analyzing colorectal cancer screening methods and procedures in the medical and veterinary fields. Medical apparatus and instruments for diagnostic use, namely, apparatus for medical diagnostic testing in the fields of cancer or other tissue-based diagnostic testing, cytology and cell-based testing; medical articles, namely blood collection tubes, 384-well plate for polymerase chain reaction, DNA oligonucleotides; blood testing apparatus; medical apparatus for cancer, tumour and colorectal cancer screening for medical and veterinary use. Scientific and technological analyses; computer software developments in the field of processing and analysis software for medical or veterinary testing procedures and methods in the field of cancer, tumour screening and colorectal cancer screening. Medical and veterinary services; medical and veterinary analysis in the fields of cancer, tumour and colorectal cancer screening.


Patent
Diagnoplex | Date: 2013-01-09

The present invention relates to methods and kits for the detection of predetermined biomarker BIRC4BP for early diagnosis and management of colorectal cancer.


PubMed | University of Lausanne, Ecole Polytechnique Federale de Lausanne, Diagnoplex and University of Fribourg
Type: Comparative Study | Journal: PloS one | Year: 2015

Colorectal cancer (CRC) is the second leading cause of cancer-related death in developed countries. Early detection of CRC leads to decreased CRC mortality. A blood-based CRC screening test is highly desirable due to limited invasiveness and high acceptance rate among patients compared to currently used fecal occult blood testing and colonoscopy. Here we describe the discovery and validation of a 29-gene panel in peripheral blood mononuclear cells (PBMC) for the detection of CRC and adenomatous polyps (AP). Blood samples were prospectively collected from a multicenter, case-control clinical study. First, we profiled 93 samples with 667 candidate and 3 reference genes by high throughput real-time PCR (OpenArray system). After analysis, 160 genes were retained and tested again on 51 additional samples. Low expressed and unstable genes were discarded resulting in a final dataset of 144 samples profiled with 140 genes. To define which genes, alone or in combinations had the highest potential to discriminate AP and/or CRC from controls, data were analyzed by a combination of univariate and multivariate methods. A list of 29 potentially discriminant genes was compiled and evaluated for its predictive accuracy by penalized logistic regression and bootstrap. This method discriminated AP >1cm and CRC from controls with a sensitivity of 59% and 75%, respectively, with 91% specificity. The behavior of the 29-gene panel was validated with a LightCycler 480 real-time PCR platform, commonly adopted by clinical laboratories. In this work we identified a 29-gene panel expressed in PBMC that can be used for developing a novel minimally-invasive test for accurate detection of AP and CRC using a standard real-time PCR platform.

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