Alboukadel Kassambara

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Alboukadel verified their affiliation via an institutional email.

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• PhD, Cancer Biology & Bioinformatics
• Associate Director at Veracyte

408 Background: DPAI models have recently demonstrated the potential to improve risk stratification beyond routine clinical and pathologic variables. However, it is not known whether integrating DPAI information will enhance the prognostic accuracy of validated gene expression tests. In this study, the prognostic performance of novel DPAI algorithm...

335 Background: Recent advances in AI have brought innovation to digital pathology problems with H&E whole slide images (WSI). Though some digital pathology AI (DPAI) models have been developed for survival analysis with TCGA data, there is a lack of understanding as to how DPAI models predict progression free survival (PFS) in the TCGA prostate da...

Multiple myeloma (MM) is the second most common hematological malignancy characterized by the uncontrolled accumulation of tumor plasma cells within the bone marrow. During the last 10 years, the development of new therapeutics, including the immune based therapies, significantly improved the life quality and survival of patients. However, the high...

Background Tumor-infiltrating immune cells play an important role against cancer and are critical to controlling tumor growth and spread. Immunotherapy drugs such as immune checkpoint inhibitors, despite inducing long-term responses in many cancer types, remain ineffective for a majority of patients. A better understanding of the tumor microenviron...

Background Immune checkpoint inhibitors (ICIs) are associated with long-term survival in ~20% of advanced NSCLC patients while biological mechanisms triggering resistance are not fully elucidated. The PIONeeR project (NCT03493581, ANR-17-RHUS-0007) aims to predict the response/resistance to PD1/L1 ICIs in advanced NSCLC patients through comprehensi...

Background: Anti-PD-1 and PD-L1 antibodies (mAbs) are approved immunotherapy agents to treat metastatic non-small cell lung cancer (NSCLC) patients. Only a minority of patients responds to these treatments and biomarkers predicting response are currently lacking. Methods: Immunoscore-Immune-Checkpoint (Immunoscore-IC), an in vitro diagnostic tes...

Background Tumor immune cells influence the efficacy of immune-checkpoint inhibitors (ICIs) and many efforts aim at identifying features of tumor immune microenvironment able to predict benefit from ICIs in proficient mismatch repair (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Methods We characterized tumor immune cell...

Tumor-infiltrating immune cells play an important role against cancer and are critical to control tumor growth and spread. Immunotherapy and immune checkpoint blockade, which aim to reinvigorate exhausted T cells have revolutionized cancer therapy. Despite inducing long-term response in many cancer types, these therapies remain ineffective for a ma...

(a) Understanding the immune contribution has deeply modified the standard of care of patients, especially with the advent of immunotherapies (ITs). However, ITs are still efficient only on a minority of the patients, especially for colorectal cancer (CRC), a high-incidence cancer. One hypothesis to explain the heterogeneity of the response to IT i...

Background Immune Checkpoint Inhibitors (ICIs) are associated with long-term survival in ~20% of advanced NSCLC patients while biological mechanisms triggering resistance are not fully elucidated. Myeloid-Derived Suppressor Cells (MDSC) might however play a key role. The PIONeeR project (NCT03493581, ANR-17-RHUS-0007) aims to predict the response/r...

Background Tumor-infiltrating immune cells play an important role against cancer and are critical to control tumor growth and spread. Immunotherapy and immune checkpoint inhibitors, which aim to reinvigorate exhausted T cells have revolutionized cancer therapy. Despite inducing long-term response in many cancer types, these therapies remain ineffec...

2509 Background: Anti-PD1 and PD-L1 antibodies (mAb) are immune checkpoint inhibitors (ICIs) to treat patients with metastatic non–small cell lung cancer (NSCLC). Unfortunately, only a handful of patients respond to ICIs. Methods: A cohort of patients with metastatic NSCLC (n=133) treated with anti-PD1 or anti-PD-L1 mAb in two independent care cent...

Background Immune checkpoint inhibitors have not shown clinical benefit to patients with metastatic colorectal cancer who had proficient mismatch repair (pMMR) or microsatellite stable (MSS) tumours in previous studies. Both an active combination chemotherapy (FOLFOXIRI; fluorouracil, leucovorin, oxaliplatin, and irinotecan) and bevacizumab seem ab...

Adjunction of immune response into the TNM classification system improves the prediction of colon cancer (CC) prognosis. However, immune response measurements have not been used as robust biomarkers of pathology in clinical practice until the introduction of Immunoscore (IS), a standardized assay based on automated artificial intelligence assisted...

196 Background: The ESMO clinical practice guidelines recommend consideration of Immunoscore (IS) for risk assessment of early colon cancer patients. IS clinical performance was assessed in the SCOT and IDEA-HORG trials evaluating 3 vs. 6 months (3m vs. 6m) of mFOLFOX6 adjuvant chemotherapy in stage III colorectal cancer (CRC). Methods: 1,002 forma...

Multiple myeloma (MM) is the second most common hematological malignancy characterized by an abnormal clonal proliferation of malignant plasma cells. Despite the introduction of novels agents that have significantly improved clinical outcomes, MM patients invariably relapse. A better understanding of the drug resistance mechanisms and development o...

Background PD1/L1 Immune Checkpoint Inhibitors (ICI) have significantly improved long-term outcome in about 20% of advanced Non Small Cells Lung Cancer (NSCLC) patients (pts), but 80% present primary or secondary resistance. The PIONeeR project ( NCT03493581 ) aims to predict the response/resistance to PD1/L1 ICIs in advanced NSCLC pts through a co...

Multiple myeloma (MM) is the second most frequent hematological cancer and is characterized by the clonal proliferation of malignant plasma cells. Genome-wide expression profiling (GEP) analysis with DNA microarrays has emerged as a powerful tool for biomedical research, generating a huge amount of data. Microarray analyses have improved our unders...

Plasma cells (PCs) play an important role in the adaptive immune system through a continuous production of antibodies. We have demonstrated that PC differentiation can be modeled in vitro using complex multistep culture systems reproducing sequential differentiation process occurring in vivo. Here we present a comprehensive, temporal program of gen...

Artificial Intelligence (AI) along with Machine Learning (ML) techniques has long promised to accelerate Digital Pathology (DP) based cancer diagnosis. Despite the consensus regarding the value of AI, the lack of visibility of how ML algorithms work, prevents their wider adoption for human in vitro diagnostic (IVD) in a highly regulated environment...

Multiparameter flow cytometry (MFC) is a fast and cost-effective technique to evaluate the expression of many lymphoid markers in mature B-cell neoplasms, including diffuse large B cell lymphoma (DLBCL), which is the most frequent non-Hodgkin lymphoma. In this study, we first characterized by MFC the expression of 27 lymphoid markers in 16 DLBCL-de...

Multiple myeloma (MM) account for approximately 10% of hematological malignancies and is the second most common hematological disorder. Kinases inhibitors are widely used and their efficiency for the treatment of cancers has been demonstrated. Here, in order to identify kinases of potential therapeutic interest for the treatment of MM, we investiga...

Brightplex is a multiplexing solution developed by HalioDx to analyze the tumor microenvironment on FFPE tissue. It leverages chromogenic immunohistochemistry performed by iterative automated immunostaining on the same slide followed by whole slide digital pathology analysis based on proprietary software combined to Halo from Indica Lab. Stained ce...

Brightplex is a multiplexing solution developed by HalioDx to analyze the tumor microenvironment on FFPE tissue. It leverages chromogenic immunohistochemistry performed by iterative automated immunostaining on the same slide followed by whole slide digital pathology analysis based on proprietary software combined to Halo from Indica Lab. Stained ce...

Cell identity relies on the cross-talk between genetics and epigenetics and their impact on gene expression. Oxidation of 5-methylcytosine into 5-hydroxymethylcytosine is the first step of an active DNA demethylation process occurring mainly at enhancers and gene bodies and, as such, participates in processes governing cell identity in normal and p...

Plasma cells (PCs) secrete large amounts of antibodies and develop from B cells that have been activated. PCs are rare cells located in the bone marrow or mucosa and ensure humoral immunity. Due to their low frequency and location, the study of PCs is difficult in human. We reported a B to PC in vitro differentiation model using selected combinatio...

Human multiple myeloma tumor cell lines (HMCLs) have been a cornerstone of research in multiple myeloma (MM) and have helped to shape our understanding of molecular processes that drive tumor progression. A comprehensive characterization of genomic mutations in HMCLs will provide a basis for choosing relevant cell line models to study a particular...

Multiple Myeloma (MM) is an incurable malignancy of terminally differentiated plasma cells, which are predominantly localized in the bone marrow. Myeloid-derived suppressor cells (MDSC) are described to promote MM progression by immunosuppression and induction of angiogenesis. However, their direct role in drug resistance and tumor survival is stil...

Background Multiple myeloma (MM) is a malignant plasma cell disease with a poor survival, characterized by the accumulation of myeloma cells (MMCs) within the bone marrow. Epigenetic modifications in MM are associated not only with cancer development and progression, but also with drug resistance. Methods We identified a significant upregulation...

DNA microarrays have considerably helped to improve the understanding of biological processes and diseases including multiple myeloma (MM). GEP analyses have been successful to classify MM, define risk, identify therapeutic targets, predict treatment response, and understand drug resistance. This generated large amounts of publicly available data t...

Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma and shows considerable clinical and biological heterogeneity. Much research is currently focused on the identification of prognostic markers for more specific patients' risk stratification and on the development of therapeutic approaches to improve the long-term outcome. Epig...

Background: Multiple myeloma (MM) is the second most common hematologic malignancy. Aberrant epigenetic modifications have been reported in MM and could be promising therapeutic targets. As response rates are overall limited but deep responses occur, it is important to identify those patients who could indeed benefit from epigenetic-targeted thera...

RAS mutations occur frequently in multiple myeloma (MM), but apart from driving progression, they can also stimulate antitumor effects by activating tumor-suppressive RASSF proteins. Although this family of death effector molecules are often silenced in cancers, functional data about RASSF proteins in MM are lacking. Here, we report that RASSF4 is...

Dysregulated expression of S100 protein family members is associated with cancer proliferation, invasion, angiogenesis, and inflammation. S100A9 induces myeloid-derived suppressor cell (MDSC) accumulation and activity. MDSCs, immunosuppressive cells that contribute to tumor immune escape, are the main producers of S100A9. In this study, we evaluate...

FCRL4 is an immunoregulatory receptor that belongs to the Fc receptor-like (FCRL) family. In healthy individuals, FCRL4 is specifically expressed by memory B cells (MBCs) localized in sub-epithelial regions of lymphoid tissues. Expansion of FCRL4⁺ B cells has been observed in blood and other tissues in various infectious and autoimmune disorders. C...

Expression of cytoplasmic IgH isotypes by D10 PCs generated by D4-sorted FCRL4+ and FCRL4- cells. At D10 of culture, cells were labeled with mAbs against surface CD20 and CD138, then fixed, permeabilized and labeled with anti-human IgM, IgA and IgG mAbs. Results are the percentage of cytoplasmic (cy) IgM, IgA and IgG in CD20- CD138+ PCs (mean ± SD...

Phenotype and cytoplasmic IgH isotypes expression by cells generated from D1-sorted FCRL4+ and FCRL4- cells at each step of PC differentiation. (A) Percentage of FCRL4+ cells generated at D4, D7 and D10. (B) Percentage of prePBs generated at D4, of PBs at D7 and of PCs at D10. (C) Expression of cytoplasmic IgH isotypes by FCRL4+ and FCRL4- generate...

Pathway enrichment analysis using Reactome. (XLSX)

General characteristics of FCRL4+ cells generated in vitro, purified from tonsils, and from different tissues in various infectious and autoimmune diseases. (XLSX)

Gene expression analysis of FCRL family members during B cell differentiation, from naive B cells to PCs. Gene expression was evaluated using Affymetrix microarrays as previously described (19, 20, 28). Data are the mean signal from five purified primary naive B cell samples, four purified centroblast and centrocyte samples and five purified MBC sa...

SAM supervised analysis to identify genes that are differentially expressed in D4 FCRL4+ and D4 FCRL4- cells. (XLSX)

SAM supervised analysis to compare gene expression in D4 FCRL4+ cells and D0 FCRL4- MBCs. (XLSX)

Genes overexpressed in D4 FCRL4+ cells and in FCRL4+ MBCs puified from tonsils (Ehrhardt et al 2008). (XLSX)

Plasma cells (PCs) generation occurs in hypoxic conditions in vivo, whereas the relevance of O2 pressure in PC differentiation remains unknown. Using our in vitro PC differentiation model, we investigated the role of hypoxia in PC generation. Hypoxia increases the generation of plasmablasts (PBs) starting from memory B cells, by increasing cell cyc...

MicroRNAs (miRNAs) are small noncoding RNAs that attenuate expression of their mRNA targets. Here, we developed a new method and an R package, to easily infer candidate miRNA-mRNA target interactions that could be functional during a given biological process. Using this method, we described, for the first time, a comprehensive integrated analysis o...

Background: MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression either via the degradation of target mRNAs or the inhibition of protein translation. miRNAs have been involved in fine-tuning critical cellular processes and play critical roles in cell differentiation and tumor development. Furthermore, there is an increasing rec...

Multiple Myeloma is a B cell neoplasia characterized by the accumulation of clonal plasma cells within the bone marrow.Epigenetics is characterized by a wide range of changes that are reversible and orchestrate gene expression. Recent studies have shown that epigenetic modifications play a role in multiple myeloma (MM) by silencing various cancer-r...

Multiple myeloma (MM) is a genetic highly heterogeneous plasma cell malignancy. In MM, the RAS/MAPK pathway is the most frequently mutated pathway, leading to aberrant MEK/ERK and PI3K/Akt signaling and thus stimulating MM cell growth and survival. Increasing evidence indicates that next to their classical oncogenic effects, RAS proteins can also i...

Redox homeostasis is fundamental for normal cellular functioning and is maintained by the net physiologic balance between production and removal of ROS. Redox signaling has been shown to coordinate the global signal transduction pattern critical for the control of key cellular processes including differentiation and tumorogenesis. In the present st...

Background: Inpatients with relaspsed/refractoryMultiple Myeloma (MM), outcomes are far from optimal, especially in patients refractory to current treatments Recent studies and clinical trials have highlighted the therapeutic potential of Palbociclib, a CDK4/6 inhibitor, in various cancers including MM. Deregulation of CDK4/6 is involved in the los...

A role of the transcription factor Krüppel-like factor 4 (KLF4) in the generation of mature plasma cells (PC) is unknown. Indeed, KLF4 is critical in controlling the differentiation of various cell linages, particularly monocytes and epithelial cells. KLF4 is expressed at low levels in pro-B cells and its expression increases as they mature into pr...

RECQ helicase family members act as guardians of the genome to assure proper DNA metabolism in response to genotoxic stress. Hematological malignancies are characterized by genomic instability that is possibly related to underlying defects in DNA repair of genomic stability maintenance. We have investigated the expression of RECQ helicases in diffe...

Acute myeloid leukemia (AML) is a heterogeneous disease at molecular level, in response to therapy and prognosis. The molecular landscape of AML is evolving with new technologies revealing complex panorama of genetic abnormalities where genomic instability and aberrations of epigenetic regulators play a key role in pathogenesis. The characterizatio...

The anaphase promoting complex/cyclosome (APC/C) is an ubiquitin ligase involved in cell cycle. During the metaphase-anaphase transition the APC/C is activated by Cdc20. The aim of this study is to elucidate the importance and therapeutic potential of APC/C and its co-activator Cdc20 in multiple myeloma (MM). Gene expression analysis revealed that...

DNA microarrays have considerably helped to improve the understanding of biological processes and diseases. Large amounts of publicly available microarray data are accumulating, but are poorly exploited due to a lack of easy-to-use bioinformatics resources. The aim of this study is to build a free and convenient data-mining web site (www.genomicsca...

Resistance to chemotherapy is a major limitation of cancer treatments with several molecular mechanisms involved, in particular altered local drug metabolism and detoxification process. The role of drug metabolism and clearance system has not been satisfactorily investigated in Multiple Myeloma (MM), a malignant plasma cell cancer for which a major...

Histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) are in early clinical development for multiple myeloma (MM) therapy. Despite all encouraging pre-clinical data, clinical activity of HDACi and DNMTi is mostly lacking. To optimize the trials, characterization of the in vivo response towards HDACi and DNMTi will be c...

Multiple myeloma (MM) is a hematological malignancy characterized by a plasma cell accumulation in the bone marrow (BM), for which novel treatment options are urgently needed. Epigenetic modulating agents such as histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) are under intense investigation for cancer therapy. A...

DNA repair is critical to resolve extrinsic or intrinsic DNA damage to ensure regulated gene transcription and DNA replication. These pathways control repair of double strand breaks, interstrand crosslinks, and nucleotide lesions occurring on single strands. Distinct DNA repair pathways are highly inter-linked for the fast and optimal DNA repair. A...

Every day, cells are faced with thousands of DNA lesions, which have to be repaired to preserve cell survival and function. DNA repair is more or less accurate and could result in genomic instability and cancer. We review here the current knowledge of the links between molecular features, treatment, and DNA repair in multiple myeloma (MM), a diseas...

High throughput DNA microarray has made it possible to outline genes whose expression in malignant plasma cells is associated with short overall survival of patients with Multiple Myeloma (MM). A further step is to elucidate the mechanisms encoded by these genes yielding to drug resistance and/or patients' short survival. We focus here on the biolo...

Kinetics of DEPDC1A gene expression after doxycycline treatment. XG19-TR-shD1 cells were treated for various days with or without doxycycline (dox) and DEPDC1A gene expression assayed using real time PCR. Results are the mean percentages of DEPDC1A gene expression in dox-treated cells compared to dox-untreated cells in 3 separate experiments. *indi...

Overexpression of DEPDC1A abrogated the growth delay induced by a DEPDC1A siRNA. DEPDC1A gene was overexpressed 8 fold in XG7 cells by lentiviral delivery of DEPDC1A coding sequence. DEPDC1A RNA was quantified by real time RT-PCR and results are mean values of 3 representative experiments. A. The siRNA targeting the non-coding part of DEPDC1A mRNA...

DEPDC1A knockdown increases expression of markers of mature plasma cells in myeloma cell lines. XG7-TR-shD1 cells were cultured with or without doxycycline (dox) for 6 days and cells were stained with phycoerythrin-conjugated anti-CXCR4 mAb, anti-IL6R mAb, anti-CD38 mAb (continuous line) or isotype-matched control mAbs (black full histogram). Facs...

Genes overexpressed in DEPDC1A high patients compared to DEPDC1 low patients. (XLS)

Krüppel-like factor 4 is a transcription factor with anti-proliferative effects in differentiated cells, but with the ability to reprogram adult cells into cell-cycling pluripotent cells. In cancer, Krüppel-like factor 4 acts either as anti-oncogene or oncogene. Krüppel-like factor 4 gene expression was analyzed using Affymetrix microarrays in Mult...

In culture, human pluripotent stem cells (PSCs) are phenotypically (for instance, SSEA3 expression level) and functionally (capacity to survive after single-cell dissociation) heterogeneous. We report here that the side scatter (SSC) signal measured by flow cytometry, a variable correlated with membrane irregularity and cell granularity, is very hi...