Maud Kamal - Academia.edu (original) (raw)
Papers by Maud Kamal
PLoS medicine, 2016
Major advances have been achieved in the characterization of early breast cancer (eBC) genomic pr... more Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing. Whole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate [FDR] < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were ...
BMC Cancer, 2015
Cervical cancer (CC) is -second to breast cancer- a dominant cause of gynecological cancer-relate... more Cervical cancer (CC) is -second to breast cancer- a dominant cause of gynecological cancer-related deaths worldwide. CC tumor biopsies and blood samples are of easy access and vital for the development of future precision medicine strategies. BIO-RAIDs is a prospective multicenter European study, presently recruiting patients in 6 EU countries. Tumor and liquid biopsies from patients with previously non-treated cervical cancer (stages IB2-IV) are collected at defined time points. Patients receive standard primary treatment according to the stage of their disease. 700 patients are planned to be enrolled. The main objectives are the discovery of -dominant molecular alterations, -signalling pathway activation, and -tumor micro-environment patterns that may predict response or resistance to treatment. An exhaustive molecular analysis is performed using 1° Next generation sequencing, 2° Reverse phase protein arrays and 3° Immuno-histochemistry. The clinical study BIO-RAIDs is activated in all planned countries, 170 patients have been recruited till now. This study will make an important contribution towards precision medicine treatments in cervical cancer. The results will support the development of clinical practice guidelines for cervical cancer patients to improve their prognosis and their quality of life. Clinicaltrials.gov: NCT02428842 , registered 10 February 2015.
After transplantation, corticosteroid-resistant Idiopathic Nephrotic Syndrome (INS) rapidly recur... more After transplantation, corticosteroid-resistant Idiopathic Nephrotic Syndrome (INS) rapidly recurs in 30-50% of recipients, suggesting the presence of (a) circulating factor(s) which alter(s) the glomerular filtration barrier. In this paper, we investigated the possible implication of the soluble ST2 protein (sST2), a product of the c-maf pathway and a marker of Th2 cells, in the development of INS recurrence, as an association between INS relapse and an atypical Th2 polarization involving activation of c-maf has recently been reported. We analyzed sST2 levels in the serum of kidney recipients with INS as their primary kidney disease but with (n=31) and without (n=40) recurrence after transplantation and of recipients with primary glomerular diseases different from INS (n=34). We found a significant increase of sST2 levels in the sera of patients suffering INS recurrence, but not in those of nonrecurrent INS and non-INS patients. No differences were detected in these sera before transplantation. Moreover, recurrent patients displayed the same sST2 isoform as the two control groups. In vitro, a mouse podocyte cell line was profoundly altered by incubation with sera of recurrent patients. However, purified sST2 from these patients was not able to reproduce these damages. In addition, induction of high sST2 levels in rats did not trigger proteinuria. Collectively, these data suggest that sST2 is a marker of INS recurrence that could be of interest for its diagnosis in ambiguous clinical situations. Nonetheless, sST2 does not seem to be directly implicated in INS development.
Canadian Journal of Physiology and Pharmacology, 2003
The use of an ET-1 fluorescent probe in human heart and vascular smooth muscle cells showed that ... more The use of an ET-1 fluorescent probe in human heart and vascular smooth muscle cells showed that ET-1 receptors are present at both the sarcolemma and nuclear envelope membranes. The use of immunofluorescence studies showed that the ETA receptor was mainly present at the sarcolemma and cytosolic levels. However, the ETB receptor was present at the sarcolemma and the cytosol, as well as the nuclear envelope membranes and the nucleoplasm. In addition, ET-1 immunoreactivity was seen in the cytosol and the nucleus. Using Ca2+ fluorescent probes such as Fluo-3, Indo 1, and yellow cameleon, as well as confocal microscopy three-dimensional image measurement technique, stimulation of ET-1 receptors at the sarcolemma membranes induced an increase of cytosolic and nuclear free Ca2+ levels. This effect of extracellular ET-1 was blocked by removal of extracellular calcium. Direct stimulation of ET-1 receptors at the nuclear envelope membranes also induced an increase of intranuclear free Ca2+ level. Our results suggest that the stimulation of sarcolemmal Ca2+ influx by ET-1 seems to be due to the activation of ETA and ETB receptors. However, the increase of nucleoplasmic Ca2+ levels by cytosolic ET-1 seems to be mediated via the activation of ETB receptors. Activation of nuclear membranes ETB receptors seems to prevent nuclear Ca2+ overload and may protect the cell from apoptosis.
Canadian Journal of Physiology and Pharmacology, 2003
The present study was designed to verify if human (h) Angiotensin II (Ang II) type-1 receptor (hA... more The present study was designed to verify if human (h) Angiotensin II (Ang II) type-1 receptor (hAT1R) undergoes internalization, nuclear translocation, and de novo synthesis in primary culture of human aortic vascular smooth muscle cells (hVSMCs) and if overexpression of this receptor modulates sustained free cytosolic ([Ca]c) and nuclear ([Ca]n) calcium. 3-dimensional (3-D) confocal microscopy was used to monitor free intracellular Ca2+ and hAT1R-green fluorescence protein (GFP) fusion protein in cultured hVSMCs. Immunofluorescence studies showed the presence of hAT1R and the absence of hAT2R in normal hVSMCs. Using 3-D imaging technique, hAT1 receptors were localized at the sarcolemma and in the cytosolic and nuclear compartments. In native as well as in normal hAT1R or hAT1R-GFP overexpressing hVSMCs, Ang II (10(-9) and 10(-4) M) induced internalization and nuclear translocation of this type of receptor. The internalization of hAT1Rs is mediated via clathrin-coated pits and vesicles pathway. This phenomenon of trancellular trafficking of receptors was associated with an increase of hAT1R. The Ang II induced increase of hAT1R density was prevented by the protein synthesis inhibitor cycloheximide. Overexpression of hAT1R and hAT1R-GFP decreased both basal cytosolic and nuclear Ca2+. In normal hVSMCs and low hAT1R-GFP overexpressing hVSMCs, Ang II (10(-15) to 10(-4) M) induced a dose-dependent sustained increase of [Ca]c and [Ca]n with an EC50 near 5 x 10(-11) and 5 x 10(-9) M, respectively. Our results suggest that hAT1Rs are the predominant type of Ang II receptors in aortic hVSMCs and are present in the sarcolemma, the cytosolic and the nuclear compartments. Ang II rapidly induces hAT1R internalization, nuclear translocation, as well as nuclear de novo synthesis of this receptor. The hAT1R overexpression in hVSMCs modulates sustained [Ca]c and [Ca]n.
American Journal of Kidney Diseases, 2009
After transplantation, corticosteroid-resistant Idiopathic Nephrotic Syndrome (INS) rapidly recur... more After transplantation, corticosteroid-resistant Idiopathic Nephrotic Syndrome (INS) rapidly recurs in 30-50% of recipients, suggesting the presence of (a) circulating factor(s) which alter(s) the glomerular filtration barrier. In this paper, we investigated the possible implication of the soluble ST2 protein (sST2), a product of the c-maf pathway and a marker of Th2 cells, in the development of INS recurrence, as an association between INS relapse and an atypical Th2 polarization involving activation of c-maf has recently been reported. We analyzed sST2 levels in the serum of kidney recipients with INS as their primary kidney disease but with (n=31) and without (n=40) recurrence after transplantation and of recipients with primary glomerular diseases different from INS (n=34). We found a significant increase of sST2 levels in the sera of patients suffering INS recurrence, but not in those of nonrecurrent INS and non-INS patients. No differences were detected in these sera before transplantation. Moreover, recurrent patients displayed the same sST2 isoform as the two control groups. In vitro, a mouse podocyte cell line was profoundly altered by incubation with sera of recurrent patients. However, purified sST2 from these patients was not able to reproduce these damages. In addition, induction of high sST2 levels in rats did not trigger proteinuria. Collectively, these data suggest that sST2 is a marker of INS recurrence that could be of interest for its diagnosis in ambiguous clinical situations. Nonetheless, sST2 does not seem to be directly implicated in INS development.
Chinese clinical oncology, 2015
Most molecularly targeted agents (MTAs) are expected to work in subgroups of cancer patients char... more Most molecularly targeted agents (MTAs) are expected to work in subgroups of cancer patients characterized by the presence of molecular alterations in the tumor cells. However, clinical development is generally carried out according to tumor type. The SHIVA randomized trial on the contrary has been set up to investigate which of tumor biology or tumor location and histology is the most important to select treatment in patients with cancer refractory to standard of care. Statistical principles, specificities, strengths and limitations of this trial that evaluates an omic-based algorithm to select the targeted agent are reviewed. In particular, the need for a randomized trial where the various steps to build the algorithm are explicitly described and standardized is emphasized. The impact of an algorithm that would be partly misspecified (i.e., that would lead to correct treatment selection for some tumor molecular profile but not for all) is quantified.
The Lancet Oncology, 2015
Background Molecularly targeted agents have been reported to have anti-tumour activity for patien... more Background Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off -label use of molecularly targeted agents on the basis of identifi ed molecular alterations. We assessed the effi cacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profi ling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed.
Personalized Medicine, 2014
ABSTRACT During recent decades, major advances in the comprehension of biology and in biotechnolo... more ABSTRACT During recent decades, major advances in the comprehension of biology and in biotechnologies have paved the way for what is commonly named personalized medicine. For cancer therapy, personalized medicine represents a paradigm shift in which patient treatment is based on biology in addition to histology and tumor location. Here, we report the major personalized medicine trials in oncology that are either based on molecular alterations from tumor tissue or from circulating blood markers. We next review important challenges facing the implementation of personalized medicine in daily clinical practice, including tumor heterogeneity, reliability of high-throughput technologies, the key role of bioinformatics and the assessment of biomarkers and synthetic models, in order to use big data in actual cancer biology.
European Journal of Cancer, 2013
Frontiers in endocrinology, 2011
Clustering of proteins in higher order complexes is a common theme in biology and profoundly infl... more Clustering of proteins in higher order complexes is a common theme in biology and profoundly influences protein function. The idea that seven-transmembrane spanning G protein-coupled receptors (GPCRs) might form dimers or higher order oligomeric complexes has been formulated more than 20 years ago. Since then, this phenomenon has been investigated with many different biochemical and biophysical techniques. The more recent notion of GPCR heteromerization describes the specific association of two different GPCRs. GPCR heteromerization may be of primary importance in neuroendocrinology, as this may explain at least some of the functional crosstalks described between different hormonal systems. Importantly, many GPCR heteromers have distinct functional properties compared to their corresponding homomers. Heteromer-specific pharmacological profiles might be exploited for drug design and open new therapeutic options. GPCR heteromerization has been first studied in heterologous expression ...
Médecine sciences : M/S, 2012
G protein-coupled receptors (GPCR), also called seven transmembrane domain (7TM) proteins, repres... more G protein-coupled receptors (GPCR), also called seven transmembrane domain (7TM) proteins, represent the largest family of membrane receptors with approximately 900 members in humans. Although a substantial number of 7TM proteins have been matched with endogenous ligands, for many of them no ligand has been identified raising questions about their function. Ligand-independent functions have been proposed for several of these so-called orphan 7TM proteins such as the modulation of the function of 7TM proteins with identified ligand through the formation of heteromeric complexes. Interestingly, viruses are using a similar strategy to hijack the host cell signaling machinery and to promote virus replication and dissemination. Indeed, to affect host cell function, several viruses encode orphan 7TM proteins that heteromerize either with other virally-encoded or with host-encoded 7TM proteins with identified ligands. This highlights the strategic importance of 7TM protein signaling and he...
Advances in pharmacology (San Diego, Calif.), 2011
G protein-coupled receptors (GPCRs) are, with approximately 800 members, among the most abundant ... more G protein-coupled receptors (GPCRs) are, with approximately 800 members, among the most abundant membrane proteins in humans. They are responding to a plethora of ligands and are involved in the transmission of extracellular signals inside the cell. GPCRs are synthesized in the endoplasmatic reticulum and are then transported to the cell surface where they are typically activated. Receptor activation triggers several processes such as signaling and receptor endocytosis. Along their life cycle, GPCRs are accompanied by a range of specialized GPCR-interacting proteins (GIPs) to assist nascent receptors in proper folding, to target them to the appropriate subcellular compartments and to fulfill their signaling tasks. Differential expression of GIPs and rapid alterations of GPCR/GIP interaction networks are efficient means to regulate GPCR function in a tissue-specific and spatiotemporal manner to trigger appropriate cellular responses. Interfering with a GPCR/GIP interaction might beco...
Science Signaling, 2013
This information is current as of 9 October 2013.
The Journal of biological chemistry, Jan 13, 2015
Inasmuch as the neurohormone melatonin is synthetically derived from serotonin (5-HT), a close in... more Inasmuch as the neurohormone melatonin is synthetically derived from serotonin (5-HT), a close interrelationship between both has long been suspected. The present study reveals a hitherto-unrecognized crosstalk mediated via physical association of melatonin MT2 and 5-HT2C receptors into functional heteromers. This is of particular interest in light of the "synergistic" melatonin agonist/5-HT2C antagonist profile of the novel antidepressant, agomelatine. A suite of co-immunoprecipitation, BRET and pharmacological techniques was exploited to demonstrate formation of functional MT2 and 5-HT2C receptor heteromers both in transfected cells and in human cortex and hippocampus. MT2/5-HT2C heteromers amplified the 5-HT-mediated Gq/PLC response and triggered melatonin-induced unidirectional trans-activation of the 5-HT2C protomer of MT2/5-HT2C heteromers. Pharmacological studies revealed distinct functional properties for agomelatine, which shows "biased signaling". These...
Bioinformatics, 2014
Motivation: Because of its low cost, amplicon sequencing, also known as ultra-deep targeted seque... more Motivation: Because of its low cost, amplicon sequencing, also known as ultra-deep targeted sequencing, is now becoming widely used in oncology for detection of actionable mutations, i.e. mutations influencing cell sensitivity to targeted therapies. Amplicon sequencing is based on the polymerase chain reaction amplification of the regions of interest, a process that considerably distorts the information on copy numbers initially present in the tumor DNA. Therefore, additional experiments such as single nucleotide polymorphism (SNP) or comparative genomic hybridization (CGH) arrays often complement amplicon sequencing in clinics to identify copy number status of genes whose amplification or deletion has direct consequences on the efficacy of a particular cancer treatment. So far, there has been no proven method to extract the information on gene copy number aberrations based solely on amplicon sequencing. Results: Here we present ONCOCNV, a method that includes a multifactor normalization and annotation technique enabling the detection of large copy number changes from amplicon sequencing data. We validated our approach on high and low amplicon density datasets and demonstrated that ONCOCNV can achieve a precision comparable with that of array CGH techniques in detecting copy number aberrations. Thus, ONCOCNV applied on amplicon sequencing data would make the use of additional array CGH or SNP array experiments unnecessary. Availability and implementation:
F1000 Biology Reports, 2009
Natural ligands of G-protein-coupled receptors interact with the orthosteric ligand binding site,... more Natural ligands of G-protein-coupled receptors interact with the orthosteric ligand binding site, as do most of the classical synthetic ligands. The discovery of ligands targeting different, allosteric binding sites considerably expanded the repertoire of G-protein-coupled receptor ligands. More recently, bitopic ligands have been described that target both orthosteric and allosteric sites at the same time.
Science Signaling, 2010
This information is current as of 12 December 2011.
PLoS medicine, 2016
Major advances have been achieved in the characterization of early breast cancer (eBC) genomic pr... more Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing. Whole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate [FDR] < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were ...
BMC Cancer, 2015
Cervical cancer (CC) is -second to breast cancer- a dominant cause of gynecological cancer-relate... more Cervical cancer (CC) is -second to breast cancer- a dominant cause of gynecological cancer-related deaths worldwide. CC tumor biopsies and blood samples are of easy access and vital for the development of future precision medicine strategies. BIO-RAIDs is a prospective multicenter European study, presently recruiting patients in 6 EU countries. Tumor and liquid biopsies from patients with previously non-treated cervical cancer (stages IB2-IV) are collected at defined time points. Patients receive standard primary treatment according to the stage of their disease. 700 patients are planned to be enrolled. The main objectives are the discovery of -dominant molecular alterations, -signalling pathway activation, and -tumor micro-environment patterns that may predict response or resistance to treatment. An exhaustive molecular analysis is performed using 1° Next generation sequencing, 2° Reverse phase protein arrays and 3° Immuno-histochemistry. The clinical study BIO-RAIDs is activated in all planned countries, 170 patients have been recruited till now. This study will make an important contribution towards precision medicine treatments in cervical cancer. The results will support the development of clinical practice guidelines for cervical cancer patients to improve their prognosis and their quality of life. Clinicaltrials.gov: NCT02428842 , registered 10 February 2015.
After transplantation, corticosteroid-resistant Idiopathic Nephrotic Syndrome (INS) rapidly recur... more After transplantation, corticosteroid-resistant Idiopathic Nephrotic Syndrome (INS) rapidly recurs in 30-50% of recipients, suggesting the presence of (a) circulating factor(s) which alter(s) the glomerular filtration barrier. In this paper, we investigated the possible implication of the soluble ST2 protein (sST2), a product of the c-maf pathway and a marker of Th2 cells, in the development of INS recurrence, as an association between INS relapse and an atypical Th2 polarization involving activation of c-maf has recently been reported. We analyzed sST2 levels in the serum of kidney recipients with INS as their primary kidney disease but with (n=31) and without (n=40) recurrence after transplantation and of recipients with primary glomerular diseases different from INS (n=34). We found a significant increase of sST2 levels in the sera of patients suffering INS recurrence, but not in those of nonrecurrent INS and non-INS patients. No differences were detected in these sera before transplantation. Moreover, recurrent patients displayed the same sST2 isoform as the two control groups. In vitro, a mouse podocyte cell line was profoundly altered by incubation with sera of recurrent patients. However, purified sST2 from these patients was not able to reproduce these damages. In addition, induction of high sST2 levels in rats did not trigger proteinuria. Collectively, these data suggest that sST2 is a marker of INS recurrence that could be of interest for its diagnosis in ambiguous clinical situations. Nonetheless, sST2 does not seem to be directly implicated in INS development.
Canadian Journal of Physiology and Pharmacology, 2003
The use of an ET-1 fluorescent probe in human heart and vascular smooth muscle cells showed that ... more The use of an ET-1 fluorescent probe in human heart and vascular smooth muscle cells showed that ET-1 receptors are present at both the sarcolemma and nuclear envelope membranes. The use of immunofluorescence studies showed that the ETA receptor was mainly present at the sarcolemma and cytosolic levels. However, the ETB receptor was present at the sarcolemma and the cytosol, as well as the nuclear envelope membranes and the nucleoplasm. In addition, ET-1 immunoreactivity was seen in the cytosol and the nucleus. Using Ca2+ fluorescent probes such as Fluo-3, Indo 1, and yellow cameleon, as well as confocal microscopy three-dimensional image measurement technique, stimulation of ET-1 receptors at the sarcolemma membranes induced an increase of cytosolic and nuclear free Ca2+ levels. This effect of extracellular ET-1 was blocked by removal of extracellular calcium. Direct stimulation of ET-1 receptors at the nuclear envelope membranes also induced an increase of intranuclear free Ca2+ level. Our results suggest that the stimulation of sarcolemmal Ca2+ influx by ET-1 seems to be due to the activation of ETA and ETB receptors. However, the increase of nucleoplasmic Ca2+ levels by cytosolic ET-1 seems to be mediated via the activation of ETB receptors. Activation of nuclear membranes ETB receptors seems to prevent nuclear Ca2+ overload and may protect the cell from apoptosis.
Canadian Journal of Physiology and Pharmacology, 2003
The present study was designed to verify if human (h) Angiotensin II (Ang II) type-1 receptor (hA... more The present study was designed to verify if human (h) Angiotensin II (Ang II) type-1 receptor (hAT1R) undergoes internalization, nuclear translocation, and de novo synthesis in primary culture of human aortic vascular smooth muscle cells (hVSMCs) and if overexpression of this receptor modulates sustained free cytosolic ([Ca]c) and nuclear ([Ca]n) calcium. 3-dimensional (3-D) confocal microscopy was used to monitor free intracellular Ca2+ and hAT1R-green fluorescence protein (GFP) fusion protein in cultured hVSMCs. Immunofluorescence studies showed the presence of hAT1R and the absence of hAT2R in normal hVSMCs. Using 3-D imaging technique, hAT1 receptors were localized at the sarcolemma and in the cytosolic and nuclear compartments. In native as well as in normal hAT1R or hAT1R-GFP overexpressing hVSMCs, Ang II (10(-9) and 10(-4) M) induced internalization and nuclear translocation of this type of receptor. The internalization of hAT1Rs is mediated via clathrin-coated pits and vesicles pathway. This phenomenon of trancellular trafficking of receptors was associated with an increase of hAT1R. The Ang II induced increase of hAT1R density was prevented by the protein synthesis inhibitor cycloheximide. Overexpression of hAT1R and hAT1R-GFP decreased both basal cytosolic and nuclear Ca2+. In normal hVSMCs and low hAT1R-GFP overexpressing hVSMCs, Ang II (10(-15) to 10(-4) M) induced a dose-dependent sustained increase of [Ca]c and [Ca]n with an EC50 near 5 x 10(-11) and 5 x 10(-9) M, respectively. Our results suggest that hAT1Rs are the predominant type of Ang II receptors in aortic hVSMCs and are present in the sarcolemma, the cytosolic and the nuclear compartments. Ang II rapidly induces hAT1R internalization, nuclear translocation, as well as nuclear de novo synthesis of this receptor. The hAT1R overexpression in hVSMCs modulates sustained [Ca]c and [Ca]n.
American Journal of Kidney Diseases, 2009
After transplantation, corticosteroid-resistant Idiopathic Nephrotic Syndrome (INS) rapidly recur... more After transplantation, corticosteroid-resistant Idiopathic Nephrotic Syndrome (INS) rapidly recurs in 30-50% of recipients, suggesting the presence of (a) circulating factor(s) which alter(s) the glomerular filtration barrier. In this paper, we investigated the possible implication of the soluble ST2 protein (sST2), a product of the c-maf pathway and a marker of Th2 cells, in the development of INS recurrence, as an association between INS relapse and an atypical Th2 polarization involving activation of c-maf has recently been reported. We analyzed sST2 levels in the serum of kidney recipients with INS as their primary kidney disease but with (n=31) and without (n=40) recurrence after transplantation and of recipients with primary glomerular diseases different from INS (n=34). We found a significant increase of sST2 levels in the sera of patients suffering INS recurrence, but not in those of nonrecurrent INS and non-INS patients. No differences were detected in these sera before transplantation. Moreover, recurrent patients displayed the same sST2 isoform as the two control groups. In vitro, a mouse podocyte cell line was profoundly altered by incubation with sera of recurrent patients. However, purified sST2 from these patients was not able to reproduce these damages. In addition, induction of high sST2 levels in rats did not trigger proteinuria. Collectively, these data suggest that sST2 is a marker of INS recurrence that could be of interest for its diagnosis in ambiguous clinical situations. Nonetheless, sST2 does not seem to be directly implicated in INS development.
Chinese clinical oncology, 2015
Most molecularly targeted agents (MTAs) are expected to work in subgroups of cancer patients char... more Most molecularly targeted agents (MTAs) are expected to work in subgroups of cancer patients characterized by the presence of molecular alterations in the tumor cells. However, clinical development is generally carried out according to tumor type. The SHIVA randomized trial on the contrary has been set up to investigate which of tumor biology or tumor location and histology is the most important to select treatment in patients with cancer refractory to standard of care. Statistical principles, specificities, strengths and limitations of this trial that evaluates an omic-based algorithm to select the targeted agent are reviewed. In particular, the need for a randomized trial where the various steps to build the algorithm are explicitly described and standardized is emphasized. The impact of an algorithm that would be partly misspecified (i.e., that would lead to correct treatment selection for some tumor molecular profile but not for all) is quantified.
The Lancet Oncology, 2015
Background Molecularly targeted agents have been reported to have anti-tumour activity for patien... more Background Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off -label use of molecularly targeted agents on the basis of identifi ed molecular alterations. We assessed the effi cacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profi ling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed.
Personalized Medicine, 2014
ABSTRACT During recent decades, major advances in the comprehension of biology and in biotechnolo... more ABSTRACT During recent decades, major advances in the comprehension of biology and in biotechnologies have paved the way for what is commonly named personalized medicine. For cancer therapy, personalized medicine represents a paradigm shift in which patient treatment is based on biology in addition to histology and tumor location. Here, we report the major personalized medicine trials in oncology that are either based on molecular alterations from tumor tissue or from circulating blood markers. We next review important challenges facing the implementation of personalized medicine in daily clinical practice, including tumor heterogeneity, reliability of high-throughput technologies, the key role of bioinformatics and the assessment of biomarkers and synthetic models, in order to use big data in actual cancer biology.
European Journal of Cancer, 2013
Frontiers in endocrinology, 2011
Clustering of proteins in higher order complexes is a common theme in biology and profoundly infl... more Clustering of proteins in higher order complexes is a common theme in biology and profoundly influences protein function. The idea that seven-transmembrane spanning G protein-coupled receptors (GPCRs) might form dimers or higher order oligomeric complexes has been formulated more than 20 years ago. Since then, this phenomenon has been investigated with many different biochemical and biophysical techniques. The more recent notion of GPCR heteromerization describes the specific association of two different GPCRs. GPCR heteromerization may be of primary importance in neuroendocrinology, as this may explain at least some of the functional crosstalks described between different hormonal systems. Importantly, many GPCR heteromers have distinct functional properties compared to their corresponding homomers. Heteromer-specific pharmacological profiles might be exploited for drug design and open new therapeutic options. GPCR heteromerization has been first studied in heterologous expression ...
Médecine sciences : M/S, 2012
G protein-coupled receptors (GPCR), also called seven transmembrane domain (7TM) proteins, repres... more G protein-coupled receptors (GPCR), also called seven transmembrane domain (7TM) proteins, represent the largest family of membrane receptors with approximately 900 members in humans. Although a substantial number of 7TM proteins have been matched with endogenous ligands, for many of them no ligand has been identified raising questions about their function. Ligand-independent functions have been proposed for several of these so-called orphan 7TM proteins such as the modulation of the function of 7TM proteins with identified ligand through the formation of heteromeric complexes. Interestingly, viruses are using a similar strategy to hijack the host cell signaling machinery and to promote virus replication and dissemination. Indeed, to affect host cell function, several viruses encode orphan 7TM proteins that heteromerize either with other virally-encoded or with host-encoded 7TM proteins with identified ligands. This highlights the strategic importance of 7TM protein signaling and he...
Advances in pharmacology (San Diego, Calif.), 2011
G protein-coupled receptors (GPCRs) are, with approximately 800 members, among the most abundant ... more G protein-coupled receptors (GPCRs) are, with approximately 800 members, among the most abundant membrane proteins in humans. They are responding to a plethora of ligands and are involved in the transmission of extracellular signals inside the cell. GPCRs are synthesized in the endoplasmatic reticulum and are then transported to the cell surface where they are typically activated. Receptor activation triggers several processes such as signaling and receptor endocytosis. Along their life cycle, GPCRs are accompanied by a range of specialized GPCR-interacting proteins (GIPs) to assist nascent receptors in proper folding, to target them to the appropriate subcellular compartments and to fulfill their signaling tasks. Differential expression of GIPs and rapid alterations of GPCR/GIP interaction networks are efficient means to regulate GPCR function in a tissue-specific and spatiotemporal manner to trigger appropriate cellular responses. Interfering with a GPCR/GIP interaction might beco...
Science Signaling, 2013
This information is current as of 9 October 2013.
The Journal of biological chemistry, Jan 13, 2015
Inasmuch as the neurohormone melatonin is synthetically derived from serotonin (5-HT), a close in... more Inasmuch as the neurohormone melatonin is synthetically derived from serotonin (5-HT), a close interrelationship between both has long been suspected. The present study reveals a hitherto-unrecognized crosstalk mediated via physical association of melatonin MT2 and 5-HT2C receptors into functional heteromers. This is of particular interest in light of the "synergistic" melatonin agonist/5-HT2C antagonist profile of the novel antidepressant, agomelatine. A suite of co-immunoprecipitation, BRET and pharmacological techniques was exploited to demonstrate formation of functional MT2 and 5-HT2C receptor heteromers both in transfected cells and in human cortex and hippocampus. MT2/5-HT2C heteromers amplified the 5-HT-mediated Gq/PLC response and triggered melatonin-induced unidirectional trans-activation of the 5-HT2C protomer of MT2/5-HT2C heteromers. Pharmacological studies revealed distinct functional properties for agomelatine, which shows "biased signaling". These...
Bioinformatics, 2014
Motivation: Because of its low cost, amplicon sequencing, also known as ultra-deep targeted seque... more Motivation: Because of its low cost, amplicon sequencing, also known as ultra-deep targeted sequencing, is now becoming widely used in oncology for detection of actionable mutations, i.e. mutations influencing cell sensitivity to targeted therapies. Amplicon sequencing is based on the polymerase chain reaction amplification of the regions of interest, a process that considerably distorts the information on copy numbers initially present in the tumor DNA. Therefore, additional experiments such as single nucleotide polymorphism (SNP) or comparative genomic hybridization (CGH) arrays often complement amplicon sequencing in clinics to identify copy number status of genes whose amplification or deletion has direct consequences on the efficacy of a particular cancer treatment. So far, there has been no proven method to extract the information on gene copy number aberrations based solely on amplicon sequencing. Results: Here we present ONCOCNV, a method that includes a multifactor normalization and annotation technique enabling the detection of large copy number changes from amplicon sequencing data. We validated our approach on high and low amplicon density datasets and demonstrated that ONCOCNV can achieve a precision comparable with that of array CGH techniques in detecting copy number aberrations. Thus, ONCOCNV applied on amplicon sequencing data would make the use of additional array CGH or SNP array experiments unnecessary. Availability and implementation:
F1000 Biology Reports, 2009
Natural ligands of G-protein-coupled receptors interact with the orthosteric ligand binding site,... more Natural ligands of G-protein-coupled receptors interact with the orthosteric ligand binding site, as do most of the classical synthetic ligands. The discovery of ligands targeting different, allosteric binding sites considerably expanded the repertoire of G-protein-coupled receptor ligands. More recently, bitopic ligands have been described that target both orthosteric and allosteric sites at the same time.
Science Signaling, 2010
This information is current as of 12 December 2011.