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Human cytomegalovirus (HCMV), whose genome is around 235 kb, is a ubiquitous human herpesvirus that infects between 40% and 95% of the population. Though HCMV infection is commonly asymptomatic and leads to subtle clinical symptoms, it can promote robust immune responses and establish lifelong latency. In addition, in immunocompromised hosts, including individuals with acquired immunodeficiency syndrome (AIDS), transplant recipients, and developing fetuses it can lead to severe diseases. Immunosenescence, well-defined as the alterations in the immune system, is linked mainly to aging and has been recently gathering considerable attention. Senescence was characterized by an elevated inflammation and hence considered a powerful contributor to “inflammaging” that is measured mainly by tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP) levels as well as latent viral infections, for instance, cytomegalovirus (CMV). Inflammaging resulted in a senescence-associated secretory phenotype (SASP). HCMV is markedly associated with accelerated aging of the immune system as well as several age-associated diseases that accumulate and subsequently deteriorate the immune responses, thus have been linked to mortality, declined vaccine efficacy, serious diseases, and tumors in the elderly. HCMV triggers or exacerbates immunosenescence; on the other hand, the weakened immune responses and inflammaging favor viral reactivation and highlight the role of HCMV in aging as well as viral-associated tumors. HCMV reactivation resulting in sequential lytic and latent viral cycles could contribute to HCMV genomic variability. Besides the oncomodulatory role and transforming capacities of HCMV, the immune-privileged tumor microenvironment has been considered the main element in tumor progression and aggressiveness. Therefore, the interplay between HCMV, immunosenescence, and cancer will aid in discovering new therapeutic approaches that target HCMV and act as immune response boosters mainly to fight cancers of poor prognosis, particularly in the elderly population.

International audience; Recently, many types of 3D culture systems have been developed to preserve the physicochemical environment and biological characteristics of the original tumors better than the conventional 2D monolayer culture system. There are various types of models belonging to this culture, such as the culture based on non-adherent and/or scaffold-free matrices to form the tumors. Agarose mold has been widely used to facilitate tissue spheroid assembly, as it is essentially non-biodegradable, bio-inert, biocompatible, low-cost, and low-attachment material that can promote cell spheroidization. As no studies have been carried out on the development of a fluorescent bicellular tumoroid mimicking ductal carcinoma in situ (DCIS) using human cell lines, our objective was to detail the practical approaches developed to generate this model, consisting of a continuous layer of myoepithelial cells (MECs) around a previously formed in situ breast tumor. The practical approaches developed to generate a bi-cellular tumoroid mimicking ductal carcinoma in situ (DCIS), consisting of a continuous layer of myoepithelial cells (MECs) around a previously formed in situ breast tumoroid. Firstly, the optimal steps and conditions of spheroids generation using a non-adherent agarose gel were described, in particular, the appropriate medium, seeding density of each cell type and incubation period. Next, a lentiviral transduction approach to achieve stable fluorescent protein expression (integrative system) was used to characterize the different cell lines and to track tumoroid generation through immunofluorescence, the organization of the two cell types was validated, specific merits and drawbacks were compared to lentiviral transduction. Two lentiviral vectors expressing either EGFP (Enhanced Green Fluorescent Protein) or m-Cherry (Red Fluorescent Protein) were used. Various rates of a multiplicity of infection (MOI) and multiple types of antibodies (anti-p63, anti-CK8, anti-Maspin, anti-Calponin) for immunofluorescence analysis were tested to determine the optimal conditions for each cell line. At MOI 40 (GFP) and MOI 5 (m-Cherry), the signals were almost homogeneously distributed in the cells which could then be used to generate the DCIS-like tumoroids. Images of the tumoroids in agarose molds were captured with a confocal microscope Micro Zeiss Cell Observer Spinning Disk or with IncuCyte (R) to follow the progress of the generation. Measurement of protumoral cytokines such as IL-6, IL8 and leptin confirmed their secretion in the supernatants, indicating that the properties of our cells were not altered. Finally the advantages and disadvantages of each fluorescent approach were discussed. This model could also be used for other solid malignancies to study the complex relationship between different cells such as tumor and myoepithelial cells in various microenvironments (inflammatory, adipose and tumor, obesity, etc.). Although, this new model is well established to monitor drug screening applications and perform pharmacokinetic and pharmacodynamic analyses.

Supplementary Table 1 from Thymoquinone Triggers Inactivation of the Stress Response Pathway Sensor CHEK1 and Contributes to Apoptosis in Colorectal Cancer Cells

Supplementary Figure Legends 1-2 from Thymoquinone Triggers Inactivation of the Stress Response Pathway Sensor CHEK1 and Contributes to Apoptosis in Colorectal Cancer Cells

There are few reports describing the role of p53-dependent gene repression in apoptotic cell death. To identify such apoptosis-associated p53 target genes, we used the pro-oxidant plant-derived drug thymoquinone and compared p53+/+ and p53−/− colon cancer cells HCT116. The p53 wild-type (wt) status correlated with more pronounced DNA damage and higher apoptosis after thymoquinone treatment. A significant up-regulation of the survival gene CHEK1 was observed in p53−/− cells in response to thymoquinone due to the lack of transcriptional repression of p53. In p53−/− cells, transfection with p53-wt vector and CHEK1 small interfering RNA treatment decreased CHEK1 mRNA and protein levels and restored apoptosis to the levels of the p53+/+ cells. p53−/− cells transplanted to nude mice treated with thymoquinone up-regulated CHEK1 expression and did not undergo apoptosis unlike p53+/+ cells. Immunofluorescence analysis revealed that the apoptosis resistance in p53−/− cells after thymoquinone treatment might be conveyed by shuttling of CHEK1 into the nucleus. We confirmed the in vivo existence of this CHEK1/p53 link in human colorectal cancer, showing that tumors lacking p53 had higher levels of CHEK1, which was accompanied by poorer apoptosis. CHEK1 overexpression was correlated with advanced tumor stages (P = 0.03), proximal tumor localization (P = 0.02), and worse prognosis (1.9-fold risk, univariate Cox regression; Kaplan-Meier, P = 0.04). We suggest that the inhibition of the stress response sensor CHEK1 might contribute to the antineoplastic activity of specific DNA-damaging drugs. [Cancer Res 2008;68(14):5609–18]

Supplementary Figure 1 from Thymoquinone Triggers Inactivation of the Stress Response Pathway Sensor CHEK1 and Contributes to Apoptosis in Colorectal Cancer Cells

Supplementary Methods and Materials from Thymoquinone Triggers Inactivation of the Stress Response Pathway Sensor CHEK1 and Contributes to Apoptosis in Colorectal Cancer Cells

Supplementary Figure 2 from Thymoquinone Triggers Inactivation of the Stress Response Pathway Sensor CHEK1 and Contributes to Apoptosis in Colorectal Cancer Cells

International audience; Several immune and immunocompetent cells, including dendritic cells, macrophages, adipocytes, natural killer cells, T cells, and B cells, are significantly correlated with the complex discipline of oncology. Cytotoxic innate and adaptive immune cells can block tumor proliferation, and others can prevent the immune system from rejecting malignant cells and provide a favorable environment for tumor progression. These cells communicate with the microenvironment through cytokines, a chemical messenger, in an endocrine, paracrine, or autocrine manner. These cytokines play an important role in health and disease, particularly in host immune responses to infection and inflammation. They include chemokines, interleukins (ILs), adipokines, interferons, colony-stimulating factors (CSFs), and tumor necrosis factor (TNF), which are produced by a wide range of cells, including immune cells, such as macrophages, B-cells, T-cells, and mast cells, as well as endothelial cells, fibroblasts, a variety of stromal cells, and some cancer cells. Cytokines play a crucial role in cancer and cancer-related inflammation, with direct and indirect effects on tumor antagonistic or tumor promoting functions. They have been extensively researched as immunostimulatory mediators to promote the generation, migration and recruitment of immune cells that contribute to an effective antitumor immune response or pro-tumor microenvironment. Thus, in many cancers such as breast cancer, cytokines including leptin, IL-1B, IL-6, IL-8, IL-23, IL-17, and IL-10 stimulate while others including IL-2, IL-12, and IFN-γ, inhibit cancer proliferation and/or invasion and enhance the body’s anti-tumor defense. Indeed, the multifactorial functions of cytokines in tumorigenesis will advance our understanding of cytokine crosstalk pathways in the tumor microenvironment, such as JAK/STAT, PI3K, AKT, Rac, MAPK, NF-κB, JunB, cFos, and mTOR, which are involved in angiogenesis, cancer proliferation and metastasis. Accordingly, targeting and blocking tumor-promoting cytokines or activating and amplifying tumor-inhibiting cytokines are considered cancer-directed therapies. Here, we focus on the role of the inflammatory cytokine system in pro- and anti-tumor immune responses, discuss cytokine pathways involved in immune responses to cancer and some anti-cancer therapeutic applications.

Colorectal cancer (CRC) is becoming one of the most prevalent cancers worldwide. Among cancers, it ranks the third place in terms of incidence and the second in terms of mortality. Even though immunological test allows fast and easy diagnostic method, there is no specific and reliable methods for early detection of CRC. Despite different treatments, high risk of re-occurrence is associated with advanced and metastatic CRC stages. An exhaustive knowledge on specific biomarkers or molecular actors involved in CRC could help to eradicate tumors or limit cancer recurrence. In this study, we focused on PAMR1 (Peptidase Domain Containing Associated with Muscle Regeneration 1), which is already considered as a tumor suppressor in breast and cervical cancers. In silico analysis of RNASeq data showed that PAMR1 was significantly downregulated in CRC tissues compared to their adjacent normal ones, as well as in cervical cancer. Our analysis showed that this downregulation, probably due to promoter hypermethylation, such as in breast cancer tissues, appeared in the four cancer stages as early as the first stage. In consistency with in silico analyses, the expression of PAMR1 was found to be lower at the transcript and protein levels in CRC tissue samples compared to normal ones, as well as in different CRC cell lines (HCT116, HT29, and SW620) compared to normal colon cell line (CCD841CoN). To understand the role of PAMR1 in CRC cancer, recombinant purified PAMR1 or concentrated secretome from CHO overexpressing PAMR1 were used to exogenously treat CRC cell lines with a focus on HT-29 cells as well as Hela cervical cancer cell line known to be sensitive to PAMR1. Transient or stable transfections were also performed to determine the impact of PAMR1 overexpression in HT29 and/or HeLa cells. In this study, we finally showed that presence of PAMR1 could reduce both cell proliferation and cell migration with a positive correlation between these biological effects and PAMR1’s quantity. This implies that PAMR1 expresses anti-proliferative and anti-migrative effects in CRC. Further studies to be done in order to confirm the tumor suppressive role of PAMR1 in CRC.

Background: Human cytomegalovirus (HCMV) oncomodulation, molecular mechanisms, and ability to support polyploid giant cancer cells (PGCCs) generation might underscore its contribution to oncogenesis, especially breast cancers. The heterogeneity of strains can be linked to distinct properties influencing the virus-transforming potential, cancer types induced, and patient’s clinical outcomes. Methods: We evaluated the transforming potential in vitro and assessed the acquired cellular phenotype, genetic and molecular features, and stimulation of stemness of HCMV strains, B544 and B693, isolated from EZH2HighMycHigh triple-negative breast cancer (TNBC) biopsies. Therapeutic response assessment after paclitaxel (PTX) and ganciclovir (GCV) treatment was conducted in addition to the molecular characterization of the tumor microenvironment (TME). Findings: HCMV-B544 and B693 transformed human mammary epithelial cells (HMECs). We detected multinucleated and lipid droplet-filled PGCCs harboring HCMV. Colony formation was detected and Myc was overexpressed in CMV-Transformed-HMECs (CTH cells). CTH-B544 and B693 stimulated stemness and established an epithelial/mesenchymal hybrid state. HCMV-IE1 was detected in CTH long-term cultures indicating a sustained viral replication. Biopsy B693 unveiled a tumor signature predicting a poor prognosis. CTH-B544 cells were shown to be more sensitive to PTX/GCV therapy. Conclusion: The oncogenic and stemness signatures of HCMV strains accentuate the oncogenic potential of HCMV in breast cancer progression thereby leading the way for targeted therapies and innovative clinical interventions that will improve the overall survival of breast cancer patients.

Menin, encoded by the MEN1 gene, has been identified as a critical factor regulating ESR1 transcription, playing an oncogenic role in ER+ breast cancer (BC) cells. Here, we further dissected the consequences of menin inactivation in ER+ BC cells by focusing on factors within two major pathways involved in BC, mTOR and MYC. MEN1 silencing in MCF7 and T-47D resulted in an increase in phosphor-p70S6K1, phosphor-p85S6K1 and phosphor-4EBP1 expression. The use of an AKT inhibitor inhibited the activation of S6K1 and S6RP triggered by MEN1 knockdown (KD). Moreover, MEN1 silencing in ER+ BC cells led to increased formation of the eIF4E and 4G complex. Clinical studies showed that patients with menin-low breast cancer receiving tamoxifen plus everolimus displayed a trend toward better overall survival. Importantly, MEN1 KD in MCF7 and T-47D cells led to reduced MYC expression. ChIP analysis demonstrated that menin bound not only to the MYC promoter but also to its 5’ enhancer. Furthermore, E2-treated MEN1 KD MCF7 cells displayed a decrease in MYC activation, suggesting its role in estrogen-mediated MYC transcription. Finally, expression data mining in tumors revealed a correlation between the expression of MEN1 mRNA and that of several mTORC1 components and targets and a significant inverse correlation between MEN1 and two MYC inhibitory factors, MYCBP2 and MYCT1, in ER+ BC. The current work thus highlights altered mTORC1 and MYC pathways after menin inactivation in ER+ BC cells, providing insight into the crosstalk between menin, mTORC1 and MYC in ER+ BC.

Epigenetics play an important role in viral replication and in viral associated pathogenesis. In fact, viruses interact with epigenetic factors to promote the viral replication by stimulating the entry into the lytic cycle, but also by promoting viral latency. Furthermore, epigenetics control the immune response implemented by the host to counteract viral infections. Thus, epigenetic modifications are identified as potential therapeutic targets to control viral infections. Several studies have already shown the efficiency of inhibitors of histone deacetylases, demethylases, acetyltransferases and methyltransferases, as well as inhibitors of DNA methyltransferases in viral infections repression or in latency reactivation. In this review, we will examine the epigenetic regulation of viral infections by several DNA viruses, e.g. HSV, EBV, HCMV, KSHV, HBV, HPV and HAdV, and RNA viruses, e.g. HCV, HIV, IAV and CoV. Also, we will discuss the potential use of therapeutic approaches targeting epigenetics for the control of viral infections.

While studying c-Myc protein expression in several Burkitt lymphoma cell lines and in lymph nodes from a mouse model bearing a translocated

Excess weight and obesity are the fifth leading cause of death globally, and sustained efforts from health professionals and researchers are required to mitigate this pandemic-scale problem. Polyphenols and flavonoids found in Aspalathus linearis—a plant widely consumed as Rooibos tea—are increasingly being investigated for their positive effects on various health issues including inflammation. The aim of our study was to examine the effect of Rooibos extract on obesity and the associated low-grade chronic inflammatory state by testing antioxidant activity, cytokine secretions, macrophage polarization and the differentiation of human adipocytes through the development of adipospheroids. Rooibos extract significantly decreased ROS production and the secretion of pro-inflammatory cytokines (IFN-γ, IL-12, IL-2 and IL-17a) in human leukocytes. Additionally, Rooibos extract down-regulated LPS-induced macrophage M1 polarization, shown by a significant decrease in the expression of pro-inflammatory cytokines: TNFα, IL-8, IL-6, IL-1β and CXCL10. In addition, Rooibos inhibited intracellular lipid accumulation and reduced adipogenesis by decreasing the expression of PPARγ, Ap2 and HSL in adipospheroids. A significant decrease in leptin expression was noted and this, more interestingly, was accompanied by a significant increase in adiponectin expression. Using a co-culture system between macrophages and adipocytes, Rooibos extract significantly decreased the expression of all studied pro-inflammatory cytokines and particularly leptin, and increased adiponectin expression. Thus, adding Rooibos tea to the daily diet is likely to prevent the development of obesity associated with chronic low-level inflammation.

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide and one of the main causes of cancer deaths in the global population. First-line treatment usually includes surgical procedures followed by combination chemotherapy. Despite the improvements in CRC treatments, the mortality rate remains very high, leading consequently to conventional treatment resistance. Several therapies were enrolled to this content in a way to find the best solutions for this disease. Photodynamic therapy (PDT) using photosensitizers (PS) presents itself as an original innovative therapeutic strategy that strongly limits the undesirable side effects of conventional treatment. However, low physiological solubility and a lack of selectivity of PS towards tumor sites are the principal restrictions of their current clinical use. Indeed, drug delivery systems are currently a key issue in cancer therapy. To overcome the problem of solubility and stability of PS such as porphyrins and their derivatives, metallic assemblies based on arene-ruthenium (Ru) units have begun to attract considerable attention as PS delivery systems. The purpose of this study was to demonstrate firstly the interest in the vectorization of tetrapyridylporphin (TPyP-arene-Ru) and Zn-tetrapyridylporphin arene-ruthenium (Zn-TPyP-arene-Ru) metallacages to increase their solubility in biological media and then, consequently their anticancer efficacy in PDT. Secondly, to elucidate the anticancer mechanism as well as identify the cell death process mediated by these new vectorized PS. The results showed that the two PS-arene-Ru complexes have a strong photocytotoxic effect after photoactivation on human HCT116 and HT-29 colorectal cancer cell lines. TPyP-arene-Ru-PDT induced outstanding cytotoxicity when compared to the Zn-TPyP-arene-Ru analogue. The two complexes show no significant effect on proliferation in the dark. In addition, results demonstrated that these two PS-arene-Ru complexes-PDT induce an apoptotic process through the appearance of a sub-G1 peak, phosphatidylserines externalization, poly-ADP ribose polymerase (PARP) cleavage and DNA fragmentation. Thus, our data contribute to highlighting that the incorporation of porphyrins in Ru-based assemblies could be an efficient vectorized system to treat CRC by PDT.

The E551 food additive is composed of synthetic amorphous silica particles. The current regulation does not mention any specifications regarding their size and granulometric distribution, thus allowing the presence of silica nanoparticles despite their potential toxicity. The digestion process could modify their physicochemical properties and then influence their toxicological profile. After physicochemical characterization, subacute toxicity of engineered silica nanoparticles from 20 to 200 nm, native and digested E551 additives were evaluated from in vitro models of the intestinal barrier. Single cultures and a co-culture of enterocytes and mucus-secreting cells were established to investigate the mucus role. Toxicological endpoints including cytotoxicity, ROS production, intestinal permeability increase, and actin filament disruption were addressed after a 7-day exposure. The results showed a size-dependent effect of silica nanoparticles on cytotoxicity and intestinal permeability. A time-dependent disruption of actin filaments was observed in Caco-2 cells. The mucus layer spread on the HT29-MTX single culture acted as an efficient protective barrier while in the co-culture, small nanoparticles were able to cross it to reach the cells. From a hydrodynamic diameter of 70 nm, nanoparticles were not internalized in the intestinal cells, even in mucus-free models. Digestion did not affect the physicochemical properties of the additive. Due to a mean hydrodynamic diameter close to 200 nm, both native and digested E551 additives did not induce any toxic effect in intestinal barrier models. This study emphasized a cutoff size of 70 nm from which the interactions of the E551 additive with intestinal cells would be limited.

International audience; The traditional two-dimensional (2D) in vitro cell culture system (on a flat support) has long been used in cancer research. However, this system cannot be fully translated into clinical trials to ideally represent physiological conditions. This culture cannot mimic the natural tumor microenvironment due to the lack of cellular communication (cell-cell) and interaction (cell-cell and cell-matrix). To overcome these limitations, three-dimensional (3D) culture systems are increasingly developed in research and have become essential for tumor research, tissue engineering, and basic biology research. 3D culture has received much attention in the field of biomedicine due to its ability to mimic tissue structure and function. The 3D matrix presents a highly dynamic framework where its components are deposited, degraded, or modified to delineate functions and provide a platform where cells attach to perform their specific functions, including adhesion, proliferation, communication, and apoptosis. So far, various types of models belong to this culture: either the culture based on natural or synthetic adherent matrices used to design 3D scaffolds as biomaterials to form a 3D matrix or based on non-adherent and/or matrix-free matrices to form the spheroids. In this review, we first summarize a comparison between 2D and 3D cultures. Then, we focus on the different components of the natural extracellular matrix that can be used as supports in 3D culture. Then we detail different types of natural supports such as matrigel, hydrogels, hard supports, and different synthetic strategies of 3D matrices such as lyophilization, electrospiding, stereolithography, microfluid by citing the advantages and disadvantages of each of them. Finally, we summarize the different methods of generating normal and tumor spheroids, citing their respective advantages and disadvantages in order to obtain an ideal 3D model (matrix) that retains the following characteristics: better biocompatibility, good mechanical properties corresponding to the tumor tissue, degradability, controllable microstructure and chemical components like the tumor tissue, favorable nutrient exchange and easy separation of the cells from the matrix.

The gastrointestinal tract represents one of primary routes of entry for many nanomaterials. Their size in the nanometer range and their high surface area confer them very interesting properties as food additives. They are used as texturizing, opacifying or anticaking agents. Food packaging contains nanomaterials with antimicrobial properties. Humans are also orally exposed to nanoparticles (NPs) present in the air or drinking water. Ingested NPs can then reach the intestinal lumen and interact with the gastrointestinal fluids, microbiota, mucus layers and the epithelial barrier, allowing a potential translocation. The toxicological profile of ingested NPs is still unclear due to their variety in terms of composition and physicochemical properties as well as the limited number of investigations. Their unique properties related to their small size could however affect the intestinal ecosystem but also the physical and functional properties of the intestinal barrier. This review focuses on the fate of ingested organic and inorganic NPs in the intestinal lumen and their toxicity on the microbiota and epithelial cells.

Natural agents have been used to restart the process of differentiation that is inhibited during leukemic transformation of hematopoietic stem or progenitor cells. Autophagy is a housekeeping pathway that maintains cell homeostasis against stress by recycling macromolecules and organelles and plays an important role in cell differentiation. In the present study, an experimental model was established to investigate the involvement of autophagy in the megakaryocyte differentiation of human erythroleukemia (HEL) cells induced by diosgenin [also known as (25R)-Spirosten-5-en-3b-ol]. It was demonstrated that Atg7 expression was upregulated from day 1 of diosgenin-induced differentiation and was accompanied by a significant elevation in the conversion of light chain 3 A/B (LC3-A/B)-I to LC3-A/B-II. Autophagy was modulated before or after the induction of megakaryocyte differentiation using 3-methyladenine (3-MA, autophagy inhibitor) and metformin (Met, autophagy initiation activator). 3-MA induced a significant accumulation of the LC3 A/B-II form at day 8 of differentiation. It was revealed that 3-MA had a significant repressive effect on the nuclear (polyploidization) and membrane glycoprotein V [(GpV) expression] maturation. On the other hand, autophagy activation increased GpV genomic expression, but did not change the nuclear maturation profile after HEL cells treatment with Met. It was concluded that autophagy inhibition had a more prominent effect on the diosgenin-differentiated cells than autophagy activation.

The Toll-like receptors (TLRs) 7 and 8 play an important role in the immune system activation, and their agonists may therefore serve as promising candidate vaccine adjuvants. However, the chronic immune activation by excessive TLR stimulation is a hallmark of several clinically important infectious and autoimmune diseases, which warrants the search for TLR antagonists. In this study, we have synthesized and characterized a variety of compounds belonging to three heterocyclic chemical series: imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline, and pyrazolo[1,5-a]quinoxaline. These compounds have been tested for their TLR7 or TLR8 agonistic and antagonistic activities. Several of them are shown to be selective TLR7 antagonists without any TLR7 or TLR8 agonistic activity. The selectivity was confirmed by a comparative ligand-docking study in TLR7 antagonist pocket. Two compounds of the pyrazolo[1,5-a]quinoxaline series (10a and 10b) are potent selective TLR7 antagonists and may be considered as promising starting points for the development of new therapeutic agents.

Brain tumors can present with various psychiatric symptoms, with or without neurological symptoms, an aspect that complicates the clinical picture. However, no systematic description of symptoms that should prompt a neurological investigation has been provided. This review aims to summarize available case reports describing patients with brain tumors showing psychiatric symptoms before brain tumor diagnosis, in order to provide a comprehensive description of these symptoms as well as their potential relationship with delay in the diagnosis. A systematic literature review on case reports of brain tumors and psychiatric symptoms from 1970 to 2020 was conducted on PubMed, Ovid, Psych Info, and MEDLINE. Exclusion criteria comprised tumors not included in the World Health Organization (WHO) Classification 4th edition and cases in which psychiatric symptoms were absent or followed the diagnosis. A total of 165 case reports were analyzed. In a subset of patients with brain tumors, psychiatric symptoms can be the only manifestation or precede focal neurological signs by months or even years. The appearance of focal or generalized neurological symptoms after, rather than along with, psychiatric symptoms was associated with a significant delay in the diagnosis in adults. A timely assessment of psychiatric symptoms might help to improve early diagnosis of brain tumors.

International audience; Purpose High plasma vitamin D (VitD) level and regular exercise (Ex) are known to have anti-cancer and immunomodulatory effects. This study aimed to evaluate the impact of VitD supplementation and imposed physical Ex on mammary tumour growth and immune response in ovariectomised mice fed high-fat (HF) diet. Methods Ovariectomised 33-week-old mice C57BL/6 (n = 60), housed in enriched environment (EE), were fed HF diet (450 kcal/100 g) supplemented or not with VitD (HF/HF + D: 125/1225 IU/100 g) for 12 weeks and submitted or not to Ex (HF + Ex; HF + D + Ex) on treadmill (45 min/day, 5 days/week). At w8, syngeneic tumour cells EO771 were orthotopically injected into the 4th mammary gland. Spontaneous activity (SPA), maximal speed (MS) and forelimb grip strength (GS) were measured. Tumour immune cells infiltrate was phenotyped by FACS. Data (mean +/- SEM) were analysed by two-way ANOVA + Tukey post-test. Results Ex (p = 0.01) and VitD (p = 0.05) reduced body weight gain. Exercise decreased visceral fat mass [g: 1.5 +/- 0.8 (HF); 1.2 +/- 0.65 (HF + Ex); 0.9 +/- 0.6 (HF + D + Ex); p = 0.03]. SPA (p < 0.0001) and GS (p = 0.01) were higher in HF + D + Ex mice vs others. No effect of Ex or VitD on tumour growth was detected. In tumour, VitD decreased the proportion of NK (p = 0.03), while Ex increased it (p = 0.03). The Th1/Th2 ratio is lowered by VitD (p = 0.05), while Tc/Treg ratio was not affected either by Exercise or VitD. Conclusion In our experimental conditions, VitD supplementation and physical exercise have synergetic effects reducing the weight gain under HF diet and improving the physical capacities of mice. VitD coupled with exercise induces an immunosuppressive response without effect on tumour growth.

Simple Summary Members of the adamalysin family are multi-domain proteins involved in many cancer-related functions. In this review, we will examine the literature on the involvement of adamalysins in hepatocellular carcinoma progression and their importance in the tumor microenvironment where they regulate the inflammatory response and the epithelial–mesenchymal transition. We complete this review with an analysis of adamalysin expression in a large cohort of patients with hepatocellular carcinoma from The Cancer Genome Atlas (TCGA) database. These original results give a new insight into the involvement of all adamalysins in the primary liver cancer. Abstract The tumor microenvironment plays a major role in tumor growth, invasion and resistance to chemotherapy, however understanding how all actors from microenvironment interact together remains a complex issue. The tumor microenvironment is classically represented as three closely connected components including the stromal cells such as immune cells, fibroblasts, adipocytes and endothelial cells, the extracellular matrix (ECM) and the cytokine/growth factors. Within this space, proteins of the adamalysin family (ADAM for a disintegrin and metalloproteinase; ADAMTS for ADAM with thrombospondin motifs; ADAMTSL for ADAMTS-like) play critical roles by modulating cell–cell and cell–ECM communication. During last decade, the implication of adamalysins in the development of hepatocellular carcinoma (HCC) has been supported by numerous studies however the functional characterization of most of them remain unsettled. In the present review we propose both an overview of the literature and a meta-analysis of adamalysins expression in HCC using data generated by The Cancer Genome Atlas (TCGA) Research Network.

A growing body of evidence is recognizing human cytomegalovirus (HCMV) as a potential oncogenic virus. We hereby provide the first experimental in vitro evidence for HCMV as a reprogramming vector, through the induction of dedifferentiation of mature human mammary epithelial cells (HMECs), generation of a polyploid giant cancer cell (PGCC) phenotype characterized by sustained growth of blastomere-like cells, in concordance with the acquisition of embryonic stem cells characteristics and epithelial-mesenchymal plasticity. HCMV presence parallels the succession of the observed cellular and molecular events potentially ensuing the transformation process. Correlation between PGCCs detection and HCMV presence in breast cancer tissue further validates our hypothesis in vivo. Our study indicates that some clinical HCMV strains conserve the potential to transform HMECs and fit with a "blastomere-like" model of oncogenesis, which may be relevant in the pathophysiology of breast cancer and other adenocarcinoma, especially of poor prognosis.

The malignant transformation of melanocytes causes several thousand deaths each year, making melanoma an important public health concern. Melanoma is the most aggressive skin cancer, which incidence has regularly increased over the past decades. We described here the preparation of new compounds based on the 1-(3,4-dihydroxyphenyl)imidazo[1,2-a]quinoxaline structure. Different positions of the quinoxaline moiety were screened to introduce novel substituents in order to study their influence on the biological activity. Several alkylamino or alkyloxy groups were also considered to replace the methylamine of our first generation of Imiqualines. Imidazo[1,2-a]pyrazine derivatives were also designed as potential minimal structure. The investigation on A375 melanoma cells displayed interesting in vitro low nanomolar cytotoxic activity. Among them, 9d (EAPB02303) is particularly remarkable since it is 20 times more potent than vemurafenib, the reference clinical therapy used on BRAF mutant melanoma. Contrary to the first generation, EAPB02303 does not inhibit tubulin polymerization, as confirmed by an in vitro assay and a molecular modelisation study. The mechanism of action for EAPB02303 highlighted by a transcriptomic analysis is clearly different from a panel of 12 well-known anticancer drugs. In vivo EAPB02303 treatment reduced tumor size and weight of the A375 human melanoma xenografts in a dose-dependent manner, correlated with a low mitotic index but not with necrosis.

Marine macroalgae have attracted much attention in recent years as a valuable source of bioactive metabolites. The cytotoxic potential of the Laurencia papillosa red alga collected from the Lebanese coast has been investigated on human breast cancer cells MCF-7. The crude extract of Laurencia papillosa (L. papillosa) was fractionated by column chromatography using a series of increasingly polar solvents (methylene chloride, acetone and methanol). Cytotoxicity of the crude extract and fractions was determined by MTT assay in MCF-7 cells. Apoptosis was detected by annexin V/propidium iodide assay and by measurement of Bcl-2 expression. Flotillin-2 expression was examined using RT-qPCR and Western blot. The crude extract, and the fractions of CH2Cl2 and acetone exhibited a dose-dependent cytotoxic effect on MCF-7 cells. Apoptosis was specifically induced by one of the acetone fractions having the highest cytotoxicity. It has been demonstrated by an increase in late phase apoptotic cell populations, and a decrease in Bcl-2 anti-apoptotic marker expression on mRNA and protein levels in a dose- and time- dependent manner. Furthermore, this active fraction decreased Flotillin-2 expression associated with cancer progression. Our data suggest that L. papillosa is an important source of cytotoxic metabolites. Further studies are needed for the chemical characterization of the metabolite associated with observed biological activities.

The co-occurrence of colorectal cancer (CRC) and diabetes mellitus along with inflammation and dismicrobism has been frequently reported. Several studies shed light on the antioncogenic potential of metformin on colorectal carcinogenesis. This study aimed to demonstrate that metformin in association with probiotics acts in a synergic effect in breaking the crosstalk, thus inhibiting CRC progression, improving diabetes, and reducing inflammation. Ninety-six male Balb/c mice, 6&ndash, 8 weeks old, were divided into 16 control and experimental groups to assess the effect of the different treatments and combinations at the clinical, histological, and molecular levels. Metformin and probiotics showed beneficial outcomes on CRC and diabetes, alone and most importantly in combination. Their effects were exerted by inhibiting the inflammatory process whereby a downregulation of IL-6 and TNF-&alpha, as well as oxidative stress were depicted. The characterization of the effects of probiotics and metformin on CRC and diabetes sheds light on the role of inflammation and microbiota in this crosstalk. Deciphering the downstream signaling pathways elicited by these compounds will help in developing new effective targeted treatment modalities.

Introduction: Adult T-cell leukemia (ATL) is an aggressive form of malignancy caused by human T- cell lymphotropic virus 1 (HTLV-1). Currently, there is no effective treatment for ATL. Thymoquinone has been reported to have anti-cancer properties. Objective: The aim of this study is to investigatthe effects of TQ on proliferation, apoptosis induction and the underlying mechanism of action in both HTLV-1 positive (C91-PL and HuT-102) and HTLV-1 negative (CEM and Jurkat) malignant T-lymphocytes. Materials and Methods: Cells were incubated with different thymoquinone concentrations for 24h. Cell cytotoxicity was assayed using the CytoTox 96® Non-Radioactive Cytotoxicity Assay Kit. Cell proliferation was determined using CellTiter 96® Non-Radioactive Cell Proliferation. Cell cycle analysis was performed by staining with propidium iodide. Apoptosis was assessed using cell death ELISA kit. The effect of TQ on p53, p21, Bcl-2 protein expression was determined using Western blot analysis while TGF mRNA expression was determined by RT-PCR. Results: At non-cytotoxic concentrations of TQ, it resulted in the inhibition of proliferation in a dose dependent manner. Flow cytometric analysis revealed a shift in the cell cycle distribution to the PreG1 phase which is a marker of apoptosis. Also TQ increase DNA fragmentation. TQ mediated its anti-proliferative effect and apoptosis induction by an up-regulation of TGFβ1, p53 and p21 and a down-regulation of TGF-α and Bcl-2α. Conclusion: Thymoquinone presents antiproliferative and proapoptotic effects in ATL cells. For this reason, further research is required to investigate its possible application in the treatment of ATL.

The Suzuki–Miyaura cross coupling is a versatile and powerful reaction for carbon–carbon bond formation which nevertheless requires optimization of conditions. While the coupling of arylboron derivatives with aryl or alkenyl halides has been widely explored, alkylation has attracted less attention. We describe herein the methylation of bromo derivatives of imidazopyrazine, imidazoquinoxaline, and pyrazoloquinoxaline having biologically interesting structures. As the challenging Suzuki–Miyaura reaction is highly substratedependent, the choices of the base, solvent, and additive are also discussed.

Although chemotherapy is the standard treatment for ovarian cancer (OC), recent studies have focused on its coupling with hypoglycemic drugs to decrease glucose availability. Similarly to cancer antigen 125 (Ca-125), telomerase, the key protein for telomere lengthening, is overexpressed in 90% of OC cases. The aim of the present study was to investigate the effect of the combination of glucose restriction and chemotherapy on telomere length and Ca-125 secretion in OC cells. SKOV-3, OVCAR-3 and Igrov-1 cells were treated with 20 µM cisplatin and 100 nM paclitaxel for 48 h in three different glucose concentrations: i) 4.5 g/l, ii) 1 g/l and iii) 0.5 g/l. The same treatment was repeated once per week for 6 consecutive weeks. The surviving cells were considered platinum-taxane escape (PTES) cells. The expression levels of telomerase and Ca-125 in treated and PTES cells were quantified by qPCR, and Ca-125 secretion by ELISA. Telomere length was evaluated by qPCR according to the Cawthon method. The modulation of Ca-125 by telomerase was assessed using inhibitors, small interfering RNA and transfection with human telomerase reverse transcriptase (hTERT) vectors. The implication of phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR) in Ca-125 modulation was investigated using specific inhibitors. An increase in hTERT and Ca-125 expression levels (range, 1.5–3 fold) was observed in short-term treated cells. However, an opposite effect was detected in PTES cells, where the rate of decrease in the expression levels of hTERT and Ca-125 reached 60% after treatment in 0.5 g/l glucose. Moreover, telomere length was decreased by 30% in cells treated with 0.5 g/l glucose. Inhibition of hTERT expression significantly decreased Ca-125 secretion, suggesting a potential modulation of Ca-125 by hTERT. The inhibition of the PI3K/Akt/mTOR pathway also decreased Ca-125 secretion; however, the effect of this treatment was not enhanced when coupled with telomerase inhibitors. In conclusion, the combination of chemotherapy and glucose restriction was observed to decrease Ca-125 secretion and telomerase expression leading to shortening in telomere length. Thus, decreasing glucose availability for OC cells during treatment may lead to a better clinical outcome and potentially improve the prognosis of patients with OC.