Mineralocorticoid Receptor and Sleep Quality in Chronic Kidney Disease.

The classical function of the mineralocorticoid receptor (MR) is to maintain electrolytic homeostasis and control extracellular volume and blood pressure. The MR is expressed in the central nervous system (CNS) and is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis as well as sleep physiology, playing a role in the non-rapid eye movement (NREM) phase of sleep. Some patients with psychiatric disorders have very poor sleep quality, and a relationship between MR dysregulation and this disorder has been found in them.

Obesity-Associated Colorectal Cancer.

Colorectal cancer (CRC) affects approximately 2 million people worldwide. Obesity is the major risk factor for CRC. In addition, obesity contributes to a chronic inflammatory stage that enhances tumor progression through the secretion of proinflammatory cytokines.

Multiomics insights on the onset, progression, and metastatic evolution of breast cancer.

Breast cancer is the most common malignant neoplasm in women. Despite progress to date, 700,000 women worldwide died of this disease in 2020. Apparently, the prognostic markers currently used in the clinic are not sufficient to determine the most appropriate treatment.

Involvement of Bcl-2 Family Proteins in Tetraploidization-Related Senescence.

The B-cell lymphoma 2 (Bcl-2) family of proteins is the main regulator of apoptosis. However, multiple emerging evidence has revealed that Bcl-2 family proteins are also involved in cellular senescence. On the one hand, the different expression of these proteins determines the entry into senescence.

ACBP/DBI protein neutralization confers autophagy-dependent organ protection through inhibition of cell loss, inflammation, and fibrosis.

Acyl-coenzyme A (CoA)-binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular feedback regulator of autophagy. Here, we report that injection of a monoclonal antibody neutralizing ACBP/DBI (α-DBI) protects the murine liver against ischemia/reperfusion damage, intoxication by acetaminophen and concanavalin A, and nonalcoholic steatohepatitis caused by methionine/choline-deficient diet as well as against liver fibrosis induced by bile duct ligation or carbon tetrachloride. α-DBI downregulated proinflammatory and profibrotic genes and upregulated antioxidant defenses and fatty acid oxidation in the liver.

Paradoxical implication of BAX/BAK in the persistence of tetraploid cells.

Pro-apoptotic multi-domain proteins of the BCL2 family such as BAX and BAK are well known for their important role in the induction of mitochondrial outer membrane permeabilization (MOMP), which is the rate-limiting step of the intrinsic pathway of apoptosis. Human or mouse cells lacking both BAX and BAK (due to a double knockout, DKO) are notoriously resistant to MOMP and cell death induction. Here we report the surprising finding that BAX/BAK DKO cells proliferate less than control cells expressing both BAX and BAK (or either BAX or BAK) when they are driven into tetraploidy by transient exposure to the microtubule inhibitor nocodazole.

Everolimus and plicamycin specifically target chemoresistant colorectal cancer cells of the CMS4 subtype.

Colorectal cancers (CRC) can be classified into four consensus molecular subtypes (CMS), among which CMS1 has the best prognosis, contrasting with CMS4 that has the worst outcome. CMS4 CRC is notoriously resistant against therapeutic interventions, as demonstrated by preclinical studies and retrospective clinical observations. Here, we report the finding that two clinically employed agents, everolimus (EVE) and plicamycin (PLI), efficiently target the prototypic CMS4 cell line MDST8.

Quantification of eIF2α Phosphorylation Associated with Mitotic Catastrophe by Immunofluorescence Microscopy.

Mitotic catastrophe is an oncosuppressive mechanism that drives cells toward senescence or death when an error occurs during mitosis. Eukaryotic cells have developed adaptive signaling pathways to cope with stress. The phosphorylation on serine 51 of the eukaryotic translation initiation factor (eIF2α) is a highly conserved event in stress responses, including the one that is activated upon treatment with mitotic catastrophe inducing agents, such as microtubular poisons or actin blockers.

In Vivo Imaging of Orthotopic Lung Cancer Models in Mice.

The success of anticancer interventions relies on their ability to ignite an anticancer immune response and to reinstate cancer immunosurveillance. Thus, high dose crizotinib can induce immunogenic cell death (ICD) in cancer cells. If combined with cisplatin, crizotinib sensitizes non-small cell lung cancers (NSCLC) to subsequent (but not simultaneous) immunotherapy with PD-1 immune checkpoint blockade, facilitating the cure of more than 90% of established orthotopic cancers in mice.

Publisher Correction: Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer.

Hormone receptor (HR) breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HRHER2 BC, including limited immune infiltration and poor sensitivity to ICBs.

Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer immunity.

Systemic treatment with the active transcription inhibitor lurbinectedin aims at inducing tumor cell death in hyperproliferative neoplasms. Here we show that cell death induced by lurbinectedin reinstates and enhances systemic anticancer immune responses. Lurbinectedin treatment showed traits of immunogenic cell death, including the exposure of calreticulin, the release of ATP, the exodus of high mobility group box 1 (HMGB1) and type 1 interferon responses .

Suppression of tumor antigen presentation during aneuploid tumor evolution contributes to immune evasion.

Anti-tumor immune responses impede tumor formation, and cancers have evolved many mechanisms of immune evasion. Confirming earlier findings, we show that human tumors with high chromosomal instability (CIN+) are significantly less immunogenic, as judged by tumor lymphocyte infiltration, compared to those with more stable genomes (CIN-). This finding is paradoxical, as genomic instability is expected to evoke an innate immune response.

Crizotinib-induced immunogenic cell death in non-small cell lung cancer.

Immunogenic cell death (ICD) converts dying cancer cells into a therapeutic vaccine and stimulates antitumor immune responses. Here we unravel the results of an unbiased screen identifying high-dose (10 µM) crizotinib as an ICD-inducing tyrosine kinase inhibitor that has exceptional antineoplastic activity when combined with non-ICD inducing chemotherapeutics like cisplatin. The combination of cisplatin and high-dose crizotinib induces ICD in non-small cell lung carcinoma (NSCLC) cells and effectively controls the growth of distinct (transplantable, carcinogen- or oncogene induced) orthotopic NSCLC models.

Immune effectors responsible for the elimination of hyperploid cancer cells.

The immune system avoids oncogenesis and slows down tumor progression through a mechanism called immunosurveillance. Nevertheless, some malignant cells manage to escape from immune control and form clinically detectable tumors. Tetraploidy, which consists in the intrinsically unstable duplication of the genome, is considered as a (pre)-cancerous event that can result in aneuploidy and contribute to oncogenesis.

eIF2α phosphorylation is pathognomonic for immunogenic cell death.

The phosphorylation of eIF2α is essential for the endoplasmic reticulum (ER) stress response, the formation of stress granules, as well as macroautophagy. Several successful anticancer chemotherapeutics have the property to induce immunogenic cell death (ICD), thereby causing anticancer immune responses. ICD is accompanied by the translocation of calreticulin (CALR) from the ER lumen to the plasma membrane, which facilitates the transfer of tumor-associated antigens to dendritic cells.

Immunogenic stress and death of cancer cells: Contribution of antigenicity vs adjuvanticity to immunosurveillance.

Cancer cells are subjected to constant selection by the immune system, meaning that tumors that become clinically manifest have managed to subvert or hide from immunosurveillance. Immune control can be facilitated by induction of autophagy, as well as by polyploidization of cancer cells. While autophagy causes the release of ATP, a chemotactic signal for myeloid cells, polyploidization can trigger endoplasmic reticulum stress with consequent exposure of the "eat-me" signal calreticulin on the cell surface, thereby facilitating the transfer of tumor antigens into dendritic cells.

Calcium signaling and cell cycle: Progression or death.

Cytosolic Ca concentration levels fluctuate in an ordered manner along the cell cycle, in line with the fact that Ca is involved in the regulation of cell proliferation. Cell proliferation should be an error-free process, yet is endangered by mistakes. In fact, a complex network of proteins ensures that cell cycle does not progress until the previous phase has been successfully completed.

The ratio of CD8/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma .

In a series of 248 tumor samples obtained from image-guided biopsies from patients diagnosed with ductal carcinoma of the breast, we attempted to identify biomarkers that predict microinfiltration at definitive surgery or relapse during follow-up. For this, we used immunohistochemical methods, followed by automated image analyses, to measure the mean diameter of nuclei (which correlates with ploidy), the phosphorylation of eukaryotic initiation factor 2α (eIF2α, which reflects endoplasmic reticulum stress) as well as the density and ratio of CD8 cytotoxic T lymphocytes and FOXP3 regulatory T cells. The median nuclear diameter of malignant cells correlated with eIF2α phosphorylation (in cancerous tissue), which in turn correlated with the density of the CD8 infiltrate and the CD8/FOXP3 ratio (both in cancerous and the adjacent non-cancerous parenchyma).

Image Cytofluorometry for the Quantification of Ploidy and Endoplasmic Reticulum Stress in Cancer Cells.

One of the mechanisms of cancer-associated genomic instability involves a transient phase of polyploidization, in most cases tetraploidization, followed by asymmetric divisions and chromosome loss. Increases in ploidy are consistently accompanied by the activation of an endoplasmic reticulum (ER) stress response, resulting in the translocation of calreticulin to the outer surface of the plasma membrane where it stimulates anticancer immune responses. Conversely, immunoselection leads to a coordinated reduction in ploidy, ER stress, and calreticulin exposure.

Positive impact of autophagy in human breast cancer cells on local immunosurveillance.

In human breast cancer cells, the presence of cytoplasmic dots positive for microtubule-associated proteins 1A/1B light chain 3B (LC3B) indicates enhanced autophagic flux and favorable prognosis. LC3B(+) puncta within malignant cells positively correlate with the intratumoral abundance of CD8(+) cytotoxic T lymphocytes, yet negatively correlate with the frequency of local FOXP3(+) regulatory T cells and CD68(+) tumor-associated macrophages, resulting in an improvement of CD8(+)/FOXP(+) or CD8(+)/CD68(+) ratios.

Biomarkers of immunogenic stress in metastases from melanoma patients: Correlations with the immune infiltrate.

Melanoma is known to be under latent immunosurveillance. Here, we studied four biomarkers of immunogenic cell stress and death (microtubule-associated proteins 1A/1B light chain 3B (MAP-LC3B, best known as LC3B)-positive puncta in the cytoplasm as a sign of autophagy; presence of nuclear HMGB1; phosphorylation of eIF2α; increase in ploidy) in melanoma cells, in tissue microarrays (TMA) from metastases from 147 melanoma patients. These biomarkers of immunogenicity were correlated with the density of immune cells infiltrating the metastases and expressing CD3, CD4(+), CD8(+), CD20, CD45, CD56, CD138, CD163, DC-LAMP or FOXP3.