Expression and localisation of insulin receptor substrate 2 in normal intestine and colorectal tumours. Regulation by intestine-specific transcription factor CDX2.

BACKGROUND AND AIMS: Self-renewal and differentiation of intestinal epithelium is a tightly regulated process, whose perturbations are implicated in human colorectal tumourigenesis. The insulin/insulin-like growth factor (IGF) signalling pathway may play an important role in intestinal epithelium homeostasis. Insulin receptor substrate 2 (IRS2) is a poorly characterised component in this pathway. METHODS: Using complementary in vitro and in vivo human and murine models, expression (mRNA and protein levels), localisation (immunohistochemistry) and regulation of IRS2 were investigated in the normal intestine and colorectal tumours. In silico analysis of the human IRS2 promoter was performed together with reporter and chromatin immunoprecipitation assays. RESULTS: Significant IRS2 expression was detected in the intestine, with specific protein localisation in the villus region of the ileum and in the surface epithelium of the colon. In human HT29 and Caco2 cells, IRS2 mRNA levels increased with spontaneous and induced differentiation, together with CDX2 (caudal-related homeobox protein 2), P21 and KLF4 (Krüppel-like factor 4). Adenoviral infection with human CDX2 induced IRS2 expression in APC- (adenomatous polyposis coli) and beta-catenin-mutated cells. On the other hand, IRS2 downregulation was observed in differentiated enterocytes after adenoviral infection with short hairpin CDX2 (shCDX2), in the intestine of CDX2 heterozygous mice and in colorectal tumours of Apc(Min/+) and patients with familial adenomatous polyposis (FAP). The human IRS2 promoter region presents several CDX2-binding sites where CDX2 immunoprecipitated in vivo. IRS2 reporters were functionally activated via CDX2 and blocked via a dominant-negative CDX2 protein. CONCLUSIONS: Combining gain- and loss-of-function approaches, an intriguing scenario is presented whereby IRS2 is significantly expressed in the apical intestinal compartment and is directly controlled by CDX2 in normal intestine and tumours.

Paleopathology of the Copper Age mummy from the Val senales glacier.

The unique conditions of preservation of the Copper age mummy found in the Val Senales glacier permit to analyze the general state of health of a man of the late European prehistory. Investigations conducted within the organizational framework of an International Research Project revealed the presence of a series of alterations, that, in a broad sense, can be considered of paleopathological interest. These can be classified as: 1) post mortem lesions, including scalp erosion, alopecia, soft tissue loss in the right gluteal region, right coxo-femoral disarticulation, right sacro-iliac dislocation; 2) lesions that occurred intra vitam, including tattooings, dental wear, trichorrexis nodosa, nail hypoplasia, moderate osteoarthrosis of the lumbar vertebral column and of the coxo-femoral joints, tibio-tarsal osteosclerosis. The palaeopathological analysis of this unique mummy shed vivid light on the mutual interactions between disease, environment, and culture, that shaped human life in a distant past.

Healing rituals and sacred serpents.

Votive tablets found during the excavation of shrines of the Graeco-Roman god of medicine (Asklepios or Aesculapius) associate the healing of superficial lesions with contact with the oral cavity of non-poisonous serpents. We suggest that this may have been the empirical exploitation of the healing properties of salivary growth factors. By immunohistochemistry and immunoblotting we demonstrate the expression of the epidermal growth factor and its receptor in the oral, upper digestive, and salivary epithelia of Elaphe quatuorlineata, a species probably used in healing rituals.