Tag Archives: atipamezole

Tissue factor pathway inhibitor TFPI is also known as

Tissue factor pathway inhibitor-2 (TFPI-2) is also known as matrix-associated serine protease inhibitor (MSPI) and placental protein 5 (PP5) (Rao et al., 1995; Kisiel et al., 1994). TFPI-2 is a kunitz-type serine proteinase inhibitor, which is abundantly expressed in a variety of human tissues such as liver, pancreas, skeletal and directionally secreted into the extracellular matrix (ECM) (Miyagi et al., 1994; Sugiyama et al., 2002; Herman et al., 2001). TFPI-2 is thought to negatively regulate the enzymatic activity including matrix metalloproteinase (MMP), plasmin, cathepsin G, trypsin, and plasma kallikrein (Stamenkovic, 2003; Kempaiah et al., 2007). Previous studies have suggested that the expression of TFPI-2 is down-regulated in many malignant tumors, including breast cancer, gastric stromal tumor, cervical cancer, gliomas and non-small-cell lung cancer, and low expression of TFPI-2 was associated with poor prognosis in cancer patients (Wang et al., 2014; Zhang et al., 2013; Rao et al., 2001; Rollin et al., 2005; Xu et al., 2013).
The therapy of induced differentiation of tumors is proposed in recent years, which indicates a new direction for the treatment of hepatocellular carcinoma. Commonly used differentiation-inducing agents are mostly substances that might work on other malignancies. But generally speaking, the therapy of induced differentiation of hepatocellular carcinoma has not yet yielded satisfactory results. It has been reported that transmembrane protease, serine 4 (TMPRSS4) is upregulated by the silencing of TFPI-2 through aberrant DNA methylation in non-small-cell lung cancer (Hamamoto et al., 2015). TMPRSS4 has been shown to be an important regulator during the epithelial-mesenchymal transition (EMT) in human epithelial cancer atipamezole (Li et al., 2011). EMT is a physiological mechanism which is present during development, including mesoderm formation and neural tube formation (Kalluri and Weinberg, 2009). Previous studies showed that the EMT process may facilitate the generation of cancer cells with the mesenchymal traits needed for dissemination as well as the self-renewal properties needed for initiating secondary tumors (Hollier et al., 2009). Our previous studies indicated that TFPI-2 could not only inhibit the proliferation, invasion and metastasis of Hep3B and HepG2, but also significantly reduce the expression and secretion of alpha-fetal protein (AFP), a maker of HCC (Xu et al., 2011). Therefore, we hypothesize that TFPI-2 may show an effect on inducing the differentiation of hepatocellular carcinoma cells (HCC) into mature hepatocytes and serve as a novel way for the treatment of hepatocellular carcinoma.

Materials and methods


TFPI-2, also known as placental protein (PP5), is identified as a tumor suppressor gene (Bretz et al., 2012). As a member of the Kunitz structure superfamily, TFPI-2 is a broad-spectrum inhibitor of serine protease. Since the promoter of TFPI-2 is rich in CPG islands, its expression is silenced in many malignant tumors through epigenetic modifications, including promoter methylation and histone deacetylation (Dong et al., 2015; Glockner et al., 2009). In addition, the aberrant splicing form of TFPI-2 was detected during cancer progression, which represented an untranslated form providing another mechanism (Bretz et al., 2012). Moreover, TFPI-2 could mediate dephosphorylation of residues outside the T-loop of ERK, which may directly impact kinase function (Mazalouskas et al., 2014). The ERK1/2 pathway integrates various cytosolic signals to regulate cellular proliferation, differentiation, and apoptosis, which contributes to the formation and development of a variety of tumors (Deng et al., 2013; George et al., 2007).
Tumors are organized in a hierarchy of heterogeneous cell populations with different biologic properties comprising proliferating transit-amplifying cells, terminally differentiated cells, and dying cells and that the populations consist of cancer stem cells (CSCs). Some of the proliferating cells do not differentiate into mature cells, which could continue to proliferate. The CSCs are thought to maintain tumor cells self-renewal capacity, high proliferation rate and are more resistant to chemotherapy than differentiated cancer cells (Ciurea et al., 2014; Puglisi et al., 2013). Differentiation therapy could force hepatocellular carcinoma cells to differentiate and lose self-renewal capacity. Cell differentiation is assumed to be regulated by an informational network, including transacting factors, soluble transmitters and cell-matrix adhesion molecules. But, to our knowledge, little is known on the role of TFPI-2 inducing differentiation in hepatocellular carcinoma.

br Our study demonstrated that

Our study demonstrated that the average excursions of the bilateral atipamezole during tidal breathing (right: 11.0 mm, 95% CI 10.4 to 11.6 mm; left: 14.9 mm, 95% CI 14.2 to 15.5 mm) were numerically less than those during forced breathing in previous studies using other modalities 2; 7 ;  8. Using fluoroscopy, Alexander reported that the average right excursion was 27.5 mm and the average left excursion was 31.5 mm during forced breathing in the standing position in 127 patients (2). Using ultrasound, Harris et al. reported that the average right diaphragm excursion was 48 mm during forced breathing in the supine position in 53 healthy adults (7). Using MR fluoroscopy, Gierada et al. reported that the average right excursion was 44 mm and the average left excursion was 42 mm during forced breathing in the supine position in 10 healthy volunteers (8). The difference in diaphragmatic excursion during tidal breathing versus forced breathing is unsurprising.

Our study showed that the excursion and peak motion speed of the left diaphragm are significantly greater and faster than those of the right. With regard to the excursion, the results of our study are consistent with those of previous reports using fluoroscopy in a standing position 2 ;  3. However, in the previous studies evaluating diaphragmatic motion in the supine position, the asymmetric diaphragmatic motion was not mentioned 7 ;  8. The asymmetric excursion of the bilateral diaphragm may be more apparent in the standing position, but may not be detectable or may disappear in the supine position. Although we cannot explain the reason for the asymmetry in diaphragmatic motion, we speculate that the presence of the liver may limit the excursion of the right diaphragm. Regarding the motion speed, to the best of our knowledge this study is the first to evaluate it. The faster motion speed of the left diaphragm compared to that of the right diaphragm would be related to the greater excursion of the left diaphragm.

We found that higher BMI and higher tidal volume were independently associated with the increased excursions of the bilateral diaphragm by both univariate and multivariate analyses, although the strength of these associations was weak. We cannot explain the exact reason for the correlation between BMI and the excursion of the diaphragm. However, a previous study showed that BMI is associated with peak oxygen consumption (23), and the increased oxygen consumption in an obese participant may affect diaphragmatic movement. Another possible reason is that lower thoracic compliance due to higher BMI may cause increased movement of the diaphragm for compensation. Regarding the correlation between tidal volume and excursion of the diaphragm, given that diaphragmatic muscle serves as the most important respiratory muscle, the result is to be expected. Considering our results, the excursion evaluated by dynamic X-ray phrenicography could potentially predict tidal volume.

Our study has several limitations. First, we included only 172 volunteers, and additional studies on larger participant populations are required to confirm these preliminary findings. Second, we evaluated only the motion of the highest point of the diaphragms for the sake of simplicity, and three-dimensional motion of the diaphragm could not be completely reflected in our results. However, we believe that this simple method would be practical and more easily applicable in a clinical setting.


The time-resolved quantitative analysis of the diaphragms with dynamic X-ray phrenicography is feasible. The average excursions of the diaphragms are 11.0 mm (right) and 14.9 mm (left) during tidal breathing in a standing position in our health screening center cohort. The diaphragmatic motion of the left is significantly larger and faster than that of the right. Higher tidal volume and BMI are associated with increased excursions of the bilateral diaphragm.