Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.     

Influencia de la concentración de calcio en el líquido de hemodiálisis sobre el control de la tensión arterial

Background

Hypertension is a highly prevalent disorder among patients undergoing haemodialysis. It contributes to greater cardiovascular risk and must be controlled. However, despite dietary measures, haemodialysis regimen optimisation and pharmacological treatment, some patients in our units continue to maintain high blood pressure levels. The objective of the study is to demonstrate that reducing calcium in dialysis fluid can help treat hypertension patients undergoing haemodialysis.

Non-union and use of proton pump inhibitors in the treatment of femoral and tibial shaft fractures: a nested case–control study

European Journal of Orthopaedic Surgery & Traumatology - Proton pump inhibitors (PPIs) are one of the most frequently used drugs worldwide. Previous research has shown that they could increase...     

T Cell Receptor (TCR) Engagement in Apoptosis-defective, but Interleukin 2 (IL-2)–producing, T Cells Results in Impaired ZAP70/CD3-ζ Association

We have previously shown that a tyrosine to leucine replacement in the transmembrane region of T cell receptor (TCR)-β results in a deficient induction of CD95-L and apoptosis upon TCR triggering in a transfected T cell line. By contrast, interleukin (IL)-2 production and the expression of CD25 and CD69 were normally induced. Since the mutation in TCR-β also resulted in impaired association of CD3-ζ, it was proposed that this chain is specifically required for the induction of apoptosis. We now show that the deficient induction of CD95-L and apoptosis does not derive from a general lower production of second messengers, since intracellular Ca²⁺ fluxes and tyrosine phosphorylation of total proteins were elicited at wild-type levels. Unlike in T cell clones stimulated with partial agonists, both p21 and p18 forms of tyrosine-phosphorylated CD3-ζ were detected, although the overall level of tyrosine-phosphorylated CD3-ζ was low. More strikingly, inducible association of ZAP70 to CD3-ζ was strongly inhibited, despite a normal induction of ZAP70 tyrosine phosphorylation. Finally, ZAP70 was not concentrated near the plasma membrane in the apoptosis-deficient cells. These results suggest that CD3-ζ is necessary for engagement of a specific signaling pathway leading to CD95-L expression that also needs the recruitment of ZAP70.