Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells

Intestinal region-specific Wnt signalling profiles reveal interrelation between cell identity and oncogenic pathway activity in cancer development.

BACKGROUND: Cancer results from the accumulation of mutations leading to the acquisition of cancer promoting characteristics such as increased proliferation and resistance to cell death. In colorectal cancer, an early mutation leading to such features usually occurs in the APC or CTNNB1 genes, thereby activating Wnt signalling. However, substantial phenotypic differences between cancers originating within the same organ, such as molecular subtypes, are not fully reflected by differences in mutations. Indeed, the phenotype seems to result from a complex interplay between the cell-intrinsic features and the acquired mutations, which is difficult to disentangle when established tumours are studied. METHODS: We use a 3D in vitro organoid model to study the early phase of colorectal cancer development. From three different murine intestinal locations we grow organoids. These are transformed to resemble adenomas after Wnt activation through lentiviral transduction with a stable form of β-Catenin. The gene expression before and after Wnt activation is compared within each intestinal origin and across the three locations using RNA sequencing. To validate and generalize our findings, we use gene expression data from patients. RESULTS: In reaction to Wnt activation we observe downregulation of location specific genes and differentiation markers. A similar effect is seen in patient data, where genes with significant differential expression between the normal left and right colon are downregulated in the cancer samples. Furthermore, the signature of Wnt target genes differs between the three intestinal locations in the organoids. The location specific Wnt signatures are dominated by genes which have been lowly expressed in the tissue of origin, and are the targets of transcription factors that are activated following enhanced Wnt signalling. CONCLUSION: We observed that the region-specific cell identity has a substantial effect on the reaction to Wnt activation in a simple intestinal adenoma model. These findings provide a way forward in resolving the distinct biology between left- and right-sided human colon cancers with potential clinical relevance

Is this a seizure?

We describe a case of a 65-year-old woman admitted to the hospital for suspected of epileptic crisis. She was affected by diabetes and hiatal hernia for which she was taking Proton Pump Inhibitors (PPIs) for about 8 years. She showed hypocalcaemia, hypomagnesaemia, hyperparathyroidism and severe hypovitaminosis D. We exclude malabsorption and magnesium loss. After restored vitamin D levels, stopped use of PPI, start calcium and magnesium supplementation normal values of the ions were restored. This case underlies the importance of evaluate magnesium routinely, other than calcium and vitamin D, and use PPI more carefully

Sudden death with massive hemoptysis from aortobronchial fistula

Aortobronchial fistula is an uncommon clinical entity, with unpredictable clinical course and significant mortality. Here, we describe a case of fistulous tract between a descending aortic graft and a branch of the left upper lobar bronchus leading to massive hemoptysis causing death for hemorrhagic shock in a 72-year-old man

A Perspective on Organoids for Virology Research

Animal models and cell lines are invaluable for virology research and host–pathogen interaction studies. However, it is increasingly evident that these models are not sufficient to fully understand human viral diseases. With the advent of three-dimensional organotypic cultures, it is now possible to study viral infections in the human context. This perspective explores the potential of these organotypic cultures, also known as organoids, for virology research, antiviral testing, and shaping the virology landscape.</jats:p

Evolutionarily conserved requirement of Cdx for post-occipital tissue emergence

Mouse Cdx genes are involved in axial patterning and partial Cdx mutants exhibit posterior embryonic defects. We found that mouse embryos in which all three Cdx genes are inactivated fail to generate any axial tissue beyond the cephalic and occipital primordia. Anterior axial tissues are laid down and well patterned in Cdx null embryos, and a 3' Hox gene is initially transcribed and expressed in the hindbrain normally. Axial elongation stops abruptly at the post-occipital level in the absence of Cdx, as the posterior growth zone loses its progenitor activity. Exogenous Fgf8 rescues the posterior truncation of Cdx mutants, and the spectrum of defects of Cdx null embryos matches that resulting from loss of posterior Fgfr1 signaling. Our data argue for a main function of Cdx in enforcing trunk emergence beyond the Cdx-independent cephalo-occipital region, and for a downstream role of Fgfr1 signaling in this function. Cdx requirement for the post-head section of the axis is ancestral as it takes place in arthropods as well

A perspective on organoids for virology research

Animal models and cell lines are invaluable for virology research and host-pathogen interaction studies. However, it is increasingly evident that these models are not sufficient to fully understand human viral diseases. With the advent of three-dimensional organotypic cultures, it is now possible to study viral infections in the human context. This perspective explores the potential of these organotypic cultures, also known as organoids, for virology research, antiviral testing, and shaping the virology landscape