Decoding the secret of extracellular vesicles in the immune tumor microenvironment of the glioblastoma: on the border of kingdoms.

Over the last decades, extracellular vesicles (EVs) have become increasingly popular for their roles in various pathologies, including cancer and neurological and immunological disorders. EVs have been considered for a long time as a means for normal cells to get rid of molecules it no longer needs. It is now well established that EVs play their biological roles also following uptake or by the interaction of EV surface proteins with cellular receptors and membranes. In this review, we summarize the current status of EV production and secretion in glioblastoma, the most aggressive type of glioma associated with high mortality. The main purpose is to shed light on the EVs as a universal mediator of interkingdom and intrakingdom communication in the context of tumor microenvironment heterogeneity. We focus on the immunomodulatory EV functions in glioblastoma-immune cross-talk to enhance immune escape and reprogram tumor-infiltrating immune cells. We critically examine the evidence that GBM-, immune cell-, and microbiome-derived EVs impact local tumor microenvironment and host immune responses, and can enter the circulatory system to disseminate and drive premetastatic niche formation in distant organs. Taking into account the current state of the art in intratumoral microbiome studies, we discuss the emerging role of bacterial EV in glioblastoma and its response to current and future therapies including immunotherapies.

Phospholipase C zeta: a hidden face of sperm for oocyte activation and early embryonic development.

Oocyte activation is a fundamental event in mammalian fertilization and is initiated by a cascade of calcium signaling and oscillation pathways. Phospholipase C zeta (PLCζ) is involved in modulating cortical granule exocytosis, releasing oocyte meiotic arrest, regulating gene expression, and early embryogenesis. These processes are considered to be initiated and controlled by PLCζ activity via the inositol-1,4,5-triphosphate pathway. The decrease or absence of functional PLCζ due to mutational defects in protein expression or maintenance can impair male fertility. In this literature review, we highlight the significance of PLCζ as a sperm factor involved in oocyte activation, its mechanism of action, the signaling pathway involved, and its close association with oocyte activation. Finally, we discuss the relationship between male infertility and PLCζ deficiency.

CAR T-cells for colorectal cancer immunotherapy: Ready to go?

Chimeric antigen receptor (CAR) T-cells represent a new genetically engineered cell-based immunotherapy tool against cancer. The use of CAR T-cells has revolutionized the therapeutic approach for hematological malignancies. Unfortunately, there is a long way to go before this treatment can be developed for solid tumors, including colorectal cancer. CAR T-cell therapy for colorectal cancer is still in its early stages, and clinical data are scarce. Major limitations of this therapy include high toxicity, relapses, and an impermeable tumor microenvironment for CAR T-cell therapy in colorectal cancer. In this review, we summarize current knowledge, highlight challenges, and discuss perspectives regarding CAR T-cell therapy in colorectal cancer.

Why Do We Need Serological Tests for Severe Acute Respiratory Syndrome Coronavirus-2 Diagnosis?

Considering the COVID-19 emerging and rapidly evolving situation associated with increased levels of mortality and infectivity risks, the detection and identification of new tests in a fast, safe, and accurate measures would have a high impact regarding prompt clinical and epidemiological management decisions. The combination of real-time polymerase chain reaction and the immunoglobulin class M-immunoglobulin class G antibody serology testing can be a powerful strategy for more accurate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection diagnosis with less false results slipping through the cracks. The following viewpoint is describing the immunological response to SARS-Cov-2 infection and its implication in the selection of the appropriate diagnosis tools.

microRNA-10 and -221 modulate differential expression of Hippo signaling pathway in human astroglial tumors.

Gliomas represent over 70% of all brain tumors, they are highly invasive and structurally vascular neoplasms. Despite the latest technological advance in neuro-surgery the survival of patients with high-grade glioma remains poor. The lack of robust treatment options has propelled the search for new markers that may able allow the identification of patients who can benefit from molecularly targeted therapies. The Hippo signaling pathway is considered as a key regulator of tissue homeostasis, cell proliferation and apoptosis, and alterations of this pathway seem to contribute to tumorigenesis. Yes-associated protein (YAP1) is a downstream target of the Hippo pathway which acts as a transcription co-activator. In cancer, YAP1 has been reported to function either as an oncogene or tumor suppressor, depending on the cell context. The aim of this study was to examine the expression of YAP1, Survivin and LATS1 kinase activity in human astroglial tumors with different grades of malignancy. Moreover, we also investigated the expression of miR-221 and miR-10b and their relationship with core molecules of the Hippo pathway. Our results showed the overexpression of YAP1 and Survivin as well as a decreased activity of large tumor suppressor 1 (LATS1) in high-grade glioblastoma versus anaplastic astrocytoma and low-grade glioma. Furthermore, we also demonstrated that miR-221 and miR-10b are specifically involved in Hippo signaling via LATS1 regulation and that their knockdown significantly decreased glioma cell proliferation. This preliminary data confirmed the crucial role of the Hippo pathway in cancer and suggested that miR-221 and miR-10b could be potential therapeutic targets for glioma treatment.

Serum Lipidomic Profiling in Breast Cancer to Identify Screening, Diagnostic, and Prognostic Biomarkers.

Breast cancer is the major mortality cause of women worldwide. In the course of management of breast cancer, the identification of a biomarker is important in enhancing our knowledge on cancer pathology, predicting the response to treatment, and selecting the patients who are more favorable to receive certain treatments. These biomarkers have a prognostic value. In addition to traditional breast cancer prognosis factors such as the tumor size and grade, the axillary lymph node micrometastasis, and biomarkers such as HER2/neu, newly discovered biomarkers have been discovered. Some of these factors are genetic signature in tissue or in peripheral blood. Lipid profil, a simple and accessible biological examination, has been a novel path on the prediction of breast cancer risk of occurrence and recurrence in many studies. The main goal of our review is to evaluate lipid profile and breast cancer risk with an emphasis on the prognosis value of lipid profiles in breast cancer patient management.

Decoding colorectal cancer epigenomics.

Colorectal cancer (CRC) is very heterogeneous and presents different types of epigenetic alterations including DNA methylation, histone modifications and microRNAs. These changes are considered as characteristics of various observed clinical phenotypes. Undoubtedly, the discovery of epigenetic pathways with novel epigenetic-related mechanisms constitutes a promising advance in cancer biomarker discovery. In this review, we provide an evidence-based discussing of the current understanding of CRC epigenomics and its role in initiation, epithelial-to-mesenchymal transition and metastasis. We also discuss the recent findings regarding the potential clinical perspectives of these alterations as potent biomarkers for CRC diagnosis, prognosis, and therapy in the era of liquid biopsy.

KIR3DL2/CpG ODN interaction mediates Sézary syndrome malignant T cell apoptosis.

We previously identified the NK cell receptor KIR3DL2 as a valuable diagnostic and prognostic marker for the detection of the tumoral T cell burden of Sézary syndrome (SS) patients. However, the function of this receptor on the malignant T lymphocyte population remained unexplored. We here demonstrate that engagement of KIR3DL2 by its recently identified ligand CpG oligodeoxynucleotide (ODN) induces the internalization of the receptor and leads to a caspase-dependent apoptosis of malignant T cells. This process of cellular death is correlated to a dephosphorylation of the transcription factor STAT3 (signal transducer and activator of transcription 3), which is found constitutively phosphorylated and activated in Sézary cells. Our results indicate that KIR3DL2 can directly promote SS malignant cell death through the use of CpG ODN.

Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type.

Biopsies and cell lines of natural killer/T-cell lymphoma, nasal type (NKTCL) were subject to combined gene expression profiling and array-based comparative genomic hybridization analyses. Compared with peripheral T-cell lymphoma, not otherwise specified, NKTCL had greater transcript levels for NK-cell and cytotoxic molecules, especially granzyme H. Compared with normal NKcells, tumors were closer to activated than resting cells and overexpressed several genes related to vascular biology, Epstein-Barr Virus-induced genes, and PDGFRA. Notably, platelet-derived growth factor receptor alpha and its phosphorylated form were confirmed at the protein level, and in vitro the MEC04 NKTCL cell line was sensitive to imatinib. Deregulation of the AKT, Janus kinase-signal transducers and activators of transcription, and nuclear factor-kappaB pathways was corroborated by nuclear expression of phosphorylated AKT, signal transducers and activators of transcription 3, and RelA in NKTCL, and several deregulated genes in these pathways mapped to regions of recurrent copy number aberrations (AKT3 [1q44], IL6R [1q21.3], CCL2 [17q12], TNFRSF21 [6p12.3]). Several features of NKTCL uncovered by this analysis suggest perturbation of angiogenic pathways. Integrative analysis also evidenced deregulation of the tumor suppressor HACE1 in the frequently deleted 6q21 region. This study highlights emerging oncogenic pathways in NKTCL and identifies novel diagnostic and therapeutic targets.

NK cells and surveillance in humans.

Natural killer (NK) cells are part of the innate immune system and help to protect against infections and tumour transformation by eliminating affected cells. NK cells become activated upon target cell recognition through the integration of signals provided by both activating and inhibitory receptors. Ligands recognized by these receptors include major histocompatibility complex class I, stress-induced molecules, adhesion proteins and other molecules that are used by NK cells to identify cells to be killed. This recognition constitutes the basis of NK immunosurveillance, and its full understanding is important for therapeutic purposes, such as haploidentical bone marrow transplantation for haematological malignancies. Human NK cells are also found abundantly in the uterine decidua during early pregnancy. Besides a detrimental role in reaction to the semi-allogeneic fetus, these uterine NK cells help to create a balanced environment for the conceptus, influencing important processes such as blastocyst implantation, trophoblast invasion and spiral artery development. This review summarizes the different aspects of human NK cell biology implicated in immunosurveillance.