Transient receptor potential melastatin-related 7 channel is overexpressed in human pancreatic ductal adenocarcinomas and regulates human pancreatic cancer cell migration

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of cancer with a tendency to invade surrounding healthy tissues, leading to a largely incurable disease. Despite many advances in modern medicine, there is still a lack of early biomarkers as well as efficient therapeutical strategies. The melastatin-related transient receptor potential 7 channel (TRPM7) is a nonselective cation channel that is involved in maintaining Ca(2+) and Mg(2+) homeostasis. It has been recently reported to regulate cell differentiation, proliferation and migration. However, the role of TRPM7 in PDAC progression is far to be understood. In our study, we show that TRPM7 is 13-fold overexpressed in cancer tissues compared to the healthy ones. Furthermore, TRPM7 staining is stronger in tumors with high grade, suggesting a correlation between TRPM7 expression and PDAC progression. Importantly, TRPM7 expression is inversely related to patient survival. In BxPC-3 cell line, dialyzing the cytoplasm during the patch-clamp whole-cell recording with a 0-Mg(2+) solution activated a nonselective current with a strong outward rectification. This cation current is inhibited by intracellular Mg(2+) and by TRPM7 silencing. The downregulation of TRPM7 by small interference RNA dramatically inhibited intracellular Mg(2+) fluorescence and cell migration without affecting cell proliferation, suggesting that TRPM7 contributes to Mg(2+) entry and cell migration. Moreover, external Mg(2+) following TRPM7 silencing fully restored the cell migration. In summary, our results indicate that TRPM7 is involved in the BxPC-3 cell migration via a Mg(2+)-dependent mechanism and may be a potential biomarker of poor prognosis of PDAC.     

Development of a Physiology-Based Whole-Body Population Model for Assessing the Influence of Individual Variability on the Pharmacokinetics of Drugs

In clinical development stages, an a priori assessment of the sensitivity of the pharmacokinetic behavior with respect to physiological and anthropometric properties of human (sub-) populations is desirable. A physiology-based pharmacokinetic (PBPK) population model was developed that makes use of known distributions of physiological and anthropometric properties obtained from the literature for realistic populations. As input parameters, the simulation model requires race, gender, age, and two parameters out of body weight, height and body mass index. From this data, the parameters relevant for PBPK modeling such as organ volumes and blood flows are determined for each virtual individual. The resulting parameters were compared to those derived using a previously published model (P³M). Mean organ weights and blood flows were highly correlated between the two models, despite the different methods used to generate these parameters. The inter-individual variability differed greatly especially for organs with a log-normal weight distribution (such as fat and spleen). Two exemplary population pharmacokinetic simulations using ciprofloxacin and paclitaxel as model drugs showed good correlation to observed variability. A sensitivity analysis demonstrated that the physiological differences in the virtual individuals and intrinsic clearance variability were equally influential to the pharmacokinetic variability but were not additive. In conclusion, the new population model is well suited to assess the influence of individual physiological variability on the pharmacokinetics of drugs. It is expected that this new tool can be beneficially applied in the planning of clinical studies.     

Transient receptor potential melastatin 7 is involved in oestrogen receptor-negative metastatic breast cancer cells migration through its kinase domain

Oestrogen receptor negative (ER^?) invasive ductal carcinoma (IDC) represents a significant clinical challenge and therefore prompts the discovery of novel biomarkers. Transient receptor potential melastatin 7 (TRPM7), a channel protein that also contains a regulatory kinase domain, is overexpressed in IDC and regulates migration. However, the molecular mechanism remains poorly defined. Here, we examined whether TRPM7 regulates migration by its channel function or by its kinase domain. A Magnesium Inhibited Cation current was recorded in two ER^? highly metastatic breast cancer cell lines. Down-regulation of TRPM7 neither affected Ca²⁺-, nor Mg²⁺-homoeostasis but significantly reduced cell migration via a Ca²⁺-independent pathway. Notably, the overexpression of the truncated kinase domain form of TRPM7 decreased cell migration, while the overexpression of the wild-type form strongly increased it. Concomitantly, TRPM7 silencing reduced the myosin IIA heavy chain phosphorylation. Furthermore, we found higher TRPM7 expression in ER^? IDC tissues and lymph nodes than in the non-invasive tumoural samples. In conclusion, TRPM7 plays a critical role in breast cancer cell migration through its kinase domain, and our data support the consideration of using TRPM7 as a novel biomarker and a potential therapeutic target in the treatment of human ER^? IDC.     

“Porcelain Liver” appearance due to Glisson's capsule phleboliths

A case of multiple Glisson's capsule phleboliths is reported in a 29-year-old-woman who had portal vein obstruction with spontaneous shunting resulting in hepatic siderosis and cirrhosis. The phleboliths were visible as multiple linear calcifications on plain film and computed tomography. Diagnosis was established by surgical liver biopsy. The potential mechanisms of this unique entity is discussed.     

Co‐transplantation of Wharton's jelly mesenchymal stem cell‐derived osteoblasts with differentiated endothelial cells does not stimulate blood vessel and osteoid formation in nude mice models

A major challenge in bone tissue engineering is the lack of post‐implantation vascular growth into biomaterials. In the skeletal system, blood vessel growth appears to be coupled to osteogenesis—suggesting the existence of molecular crosstalk between endothelial cells (ECs) and osteoblastic cells. The present study (performed in two murine ectopic models) was designed to determine whether co‐transplantation of human Wharton's jelly mesenchymal stem cell‐derived osteoblasts (WJMSC‐OBs) and human differentiated ECs enhances bone regeneration and stimulates angiogenesis, relative to the seeding of WJMSC‐OBs alone. Human WJMSC‐OBs and human ECs were loaded into a silicate‐substituted calcium phosphate (SiCaP) scaffold and then ectopically implanted at subcutaneous or intramuscular sites in nude mice. At both subcutaneous and intramuscular implantation sites, we observed ectopic bone formation and osteoids composed of host cells when WJMSC‐OBs were seeded into the scaffold. However, the addition of ECs was associated with a lower level of osteogenesis, and we did not observe stimulation of blood vessel ingrowth. in vitro studies demonstrated that WJMSC‐OBs lost their ability to secrete vascular endothelial growth factor and stromal cell‐derived factor 1—including when ECs were present. In these two murine ectopic models, our cell‐matrix environment combination did not seem to be optimal for inducing vascularized bone reconstruction.