[Resistance to BRAF inhibitors: A lesson from clinical observations].

The MAPK/ERK pathway is an essential intracellular signaling pathway. Its deregulation is involved in tumor transformation and progression. The discovery of activating mutations of BRAF in various cancers has opened new therapeutic avenues with BRAF protein kinase inhibitors.

Proximal Protein Interaction Landscape of RAS Paralogs.

RAS proteins (KRAS, NRAS and HRAS) are frequently activated in different cancer types (e.g., non-small cell lung cancer, colorectal cancer, melanoma and bladder cancer).

HP1s modulate the S-Adenosyl Methionine synthesis pathway in liver cancer cells.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer in adults. Among the altered pathways leading to HCC, an increasing role is attributed to abnormal epigenetic regulation. Members of the Heterochromatin Protein (HP1) 1 family are key players in chromatin organisation, acting as docking sites for chromatin modifiers.

Dzip1 and Fam92 form a ciliary transition zone complex with cell type specific roles in .

Cilia and flagella are conserved eukaryotic organelles essential for cellular signaling and motility. Cilia dysfunctions cause life-threatening ciliopathies, many of which are due to defects in the transition zone (TZ), a complex structure of the ciliary base. Therefore, understanding TZ assembly, which relies on ordered interactions of multiprotein modules, is of critical importance.

Synovial-Fluid miRNA Signature for Diagnosis of Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory rheumatism in childhood; microRNAs (miRNAs) have been proposed as diagnostic biomarkers. Although joints are the primary targets for JIA, a synovial fluid-based miRNA signature has never been studied. We aim to identify miRNA biomarkers in JIA by comparing synovial fluid and serum samples from children with JIA and septic arthritis (SA).

FKBP4 connects mTORC2 and PI3K to activate the PDK1/Akt-dependent cell proliferation signaling in breast cancer.

Among the FKBP family members, FKBP4 has been described to have a potential role in tumorigenesis, and as a putative tissue marker. We previously showed that FKBP4, an HSP90-associated co-chaperone, can elicit immune response as a tumor-specific antigen, and are overexpressed in breast cancer. In this study, we examined how loss of FKBP4 affect breast cancer progression and exploited protein interactomics to gain mechanistic insight into this process.

Quantitative proteomic analysis reveals AK2 as potential biomarker for late normal tissue radiotoxicity.

Background: Biomarkers for predicting late normal tissue toxicity to radiotherapy are necessary to personalize treatments and to optimize clinical benefit. Many radiogenomic studies have been published on this topic. Conversely, proteomics approaches are not much developed, despite their advantages.

Protein interactions study through proximity-labeling.

: The proteome is a dynamic system in which protein-protein interactions play a crucial part in shaping the cell phenotype. However, given the current limitations of available technologies to describe the dynamic nature of these interactions, the identification of protein-protein interactions has long been a major challenge in proteomics. In recent years, the development of BioID and APEX, two proximity-tagging technologies, have opened-up new perspectives and have already started to change our conception of protein-protein interactions, and more generally, of the proteome.

[New approaches for protein-protein interaction study].

The proteome is a dynamic system in which protein-protein interactions play a crucial role to model together the cellular phenotype. However, given the inherent limitation of the available technologies to depict the dynamic nature of these interactions, identify protein-protein interaction has for a long time represented an important challenge in proteomic. The recent development of BioID and APEX, two proximity-dependent labeling technologies, opens today new perspectives and yet start changing our vision of protein-protein interaction, and more globally our vision of the proteome.

An integrated cell line-based discovery strategy identified follistatin and kallikrein 6 as serum biomarker candidates of breast carcinoma.

Unlabelled: Secreted proteins constitute a relevant source of putative cancer biomarkers. Here, we compared the secretome of a series of four genetically-related breast cancer cell lines as a model of aggressiveness using quantitative mass spectrometry. 537 proteins (59.

D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile.

Apolipoprotein C-III deficiency provides cardiovascular protection, but apolipoprotein C-III is not known to be associated with human amyloidosis. Here we report a form of amyloidosis characterized by renal insufficiency caused by a new apolipoprotein C-III variant, D25V. Despite their uremic state, the D25V-carriers exhibit low triglyceride (TG) and apolipoprotein C-III levels, and low very-low-density lipoprotein (VLDL)/high high-density lipoprotein (HDL) profile.

Anti-heat shock protein autoantibody profiling in breast cancer using customized protein microarray.

Heat shock proteins (HSPs) are over-expressed in a wide range of human cancers. It results in the stimulation of the immune system and consequently in elevated concentration of anti-HSP autoantibodies. Elevated anti-HSP autoantibodies were found in breast cancer patients, and they are associated with tumor metastasis.

Late side-effects after curative intent radiotherapy: Identification of hypersensitive patients for personalized strategy.

Radiation therapy undeniably enhances local control and thus improves overall survival in cancer patients. However, some long-term cancer survivors (less than 10%) develop severe late radio-induced toxicities altering their quality of life. Therefore, there is a need to identify patients who are sensitive to those toxicities and who could benefit from adapted care.

Use of autoantibodies to detect the onset of breast cancer.

The widespread use of screening mammography has resulted in increased detection of early-stage breast disease, particularly for in situ carcinoma and early-stage breast cancer. However, the majority of women with abnormalities noted on screening mammograms are not diagnosed with cancer because of several factors, including radiologist assessment, patient age, breast density, malpractice concerns, and quality control procedures. Although magnetic resonance imaging is a highly sensitive detection tool that has become standard for women at very high risk of developing breast cancer, it lacks sufficient specificity and costeffectiveness for use as a general screening tool.

Comparative evaluation of the new FDA approved THxID™-BRAF test with High Resolution Melting and Sanger sequencing.

Background: Since patients diagnosed with BRAF V600E and V600K mutated advanced melanoma show response to treatment with MAP kinase inhibitors, several sensitive methods have been developed to determine the V600 allele status of melanoma patients. Vemurafenib (Zelboraf) and dabrafenib (Tafinlar) are specific BRAF V600 inhibitors recently approved by the US FDA as single agent treatments for unresectable or metastatic melanoma in patients with the BRAF V600 mutation.

Methods: We assessed the new CE THxID™-BRAF diagnostic test, which is also FDA-approved as a companion diagnostic test in the US under a specific reference and compared the results of this assay with both High Resolution Melting (HRM) and Sanger sequencing in 113 melanoma FFPE samples.

A multiparametric serum marker panel as a complementary test to mammography for the diagnosis of node-negative early-stage breast cancer and DCIS in young women.

Background: The sensitivity of mammography for the detection of small lesions, including node-negative early-stage (T1N0) primary breast cancer (PBC) and ductal carcinoma in situ (DCIS), is significantly decreased in young patients. From a clinical standpoint, an inconclusive mammogram reflects the inability of clinicians to confidently decide whether patients should be referred for biopsy or for follow-up with repeat imaging.

Methods: Specific ELISAs were developed for a panel of 13 well-recognized breast autoantigens (HSP60, FKBP52, PRDX2, PPIA, MUC1, GAL3, PAK2, P53, CCNB1, PHB2, RACK1, RUVBL1, and HER2).

Elevated concentrations of milk β2-microglobulin are associated with increased risk of breastfeeding transmission of HIV-1 (Vertical Transmission Study).

There is increasing evidence to support a relationship between human immunodeficiency virus (HIV-1) transmission through breastfeeding and milk host factors. We analyzed skim milk proteome to further determine the contribution of host factors to the risk of mother-to-child transmission of HIV-1. Quantitative mass spectrometry analysis was performed on nine case-control pairs of HIV+ transmitter/nontransmitter mothers, and specific biochemical assays on two selected proteins were assessed in an independent validation set of 127 samples.

EGFR Expression and KRAS and BRAF Mutational Status in Intestinal-Type Sinonasal Adenocarcinoma.

Accumulation of molecular alterations, including EGFR overexpression and mutations in KRAS and BRAF, contribute to colorectal carcinogenesis. Since intestinal-type adenocarcinoma (ITAC) of the nasal cavity and paranasal sinus has morphologic and phenotypic features that are usually indistinguishable from colorectal cancer (CRC), it is likely that both tumor types share equivalent genetic alterations. Data from a series of 43 patients treated surgically for ITAC in Montpellier, France between November 1998 and December 2012 were collected.

Proteomic approaches to identify biomarkers predictive of radiotherapy outcomes.

To be highly successful, a radiotherapeutic dose must be sufficiently large to destroy radioresistant tumors, yet avoid injuring the surrounding healthy tissue. However, many patients exhibit high radiosensitivity and may develop radiation-induced early and late side effects. Because the identification of these radiosensitive patients remains largely problematic, general radiotherapy protocols currently limit the dose given, which risks delivering an insufficient dose to a significant number of less sensitive patients.

Improvement of protein immobilization for the elaboration of tumor-associated antigen microarrays: application to the sensitive and specific detection of tumor markers from breast cancer sera.

There is an urgent need to identify relevant tumor markers showing high sensitivity and specificity for early diagnosis and prognosis of breast cancer. Protein microarrays have demonstrated to be cost-effective, high through-put and powerful tools for screening and identifying tumor markers with only minute samples. Autoantibodies directed against tumor-associated antigens (TAAs) were shown to be relevant tumor markers.

Identification and validation of new autoantibodies for the diagnosis of DCIS and node negative early-stage breast cancers.

Evidence of circulating autoantibodies in cancer patient sera has created opportunities for exploiting them as biomarkers. We report the identification and the clinical validation of an autoantibody panel in newly diagnosed patients with early-stage breast cancer. Proteomic approach and serological screening of a discovery set of sera (n = 80) were performed to identify tumor-associated antigens (TAAs).

HDL proteome in hemodialysis patients: a quantitative nanoflow liquid chromatography-tandem mass spectrometry approach.

Aside from a decrease in the high-density lipoprotein (HDL) cholesterol levels, qualitative abnormalities of HDL can contribute to an increase in cardiovascular (CV) risk in end-stage renal disease (ESRD) patients undergoing chronic hemodialysis (HD). Dysfunctional HDL leads to an alteration of reverse cholesterol transport and the antioxidant and anti-inflammatory properties of HDL. In this study, a quantitative proteomics approach, based on iTRAQ labeling and nanoflow liquid chromatography mass spectrometry analysis, was used to generate detailed data on HDL-associated proteins.

Serum autoantibody signature of ductal carcinoma in situ progression to invasive breast cancer.

Purpose: The identification of markers associated with progression to invasive breast cancer (IBC) is a major factor that can guide physicians in the initial therapeutic decision and the management of ductal carcinoma in situ (DCIS).

Experimental Design: We examined autoantibody targets in 20 DCIS and 20 IBC patients using protein microarrays and identified humoral responses that can be used to distinguish the two groups. The five most differentially targeted antigens were selected to generate an autoantibody signature for the in situ to invasive breast cancer transition.

[Serum autoantibodies profiling and early-stage cancer detection].

It is now well established that an immune response to cancer is elicited in humans, as demonstrated in part by the identification of autoantibodies against a number of tumor-associated antigens in sera from patients with different types of cancer. During these past few years, proteomic approaches have been developed to identify tumor-associated antigens and their cognate autoantibodies. Detection of a panel of serum autoantibodies has thus been proposed as a new method for early cancer diagnosis.