Galectin-3 (Gal3) has important roles in tumor transformation and metastasis. This study shows that c-Abl and Abl-related gene (Arg) associate with and phosphorylate Gal3. The SH (Src homology)3 domains of c-Abl/Arg bind to a P 80 GPPSGP motif of Gal3, and Tyr79 and Tyr118 are the major tyrosine phosphorylation sites. A consequence of this interaction and phosphorylation is the significant impairment of chaperone-mediated autophagy of Gal3. Cells expressing Gal3 and treated with the c-Abl/Arg inhibitor STI571, Gal3-depleted cells, and Gal3-depleted cells expressing Gal3 phosphorylation mutants all display an increased sensitivity to apoptosis-inducing agents. In addition, tumor cells expressing the phosphorylation mutants show impaired tumorigenicity. These results partially explain the antiapoptotic effect of Abl and Arg. As tumors frequently overexpress Gal3, a c-Abl/Arg-specific inhibitor may potentially be applied along with other antitumor drugs to target the lysosomal degradation of Gal3 in tumor therapy.

Metastasis is responsible for more than 90% of the mortality observed among patients with breast cancer. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of the PEBP family and functions as an anti-apoptotic molecule. Here, we found that the metastatic MDA-MB-231 breast cancer cells expressed much higher levels of hPEBP4 than the nonmetastatic MCF-7 breast cancer cells and that the expression levels of hPEBP4 were positively correlated with the metastasis of clinical breast cancer. The hPEBP4 overexpression in the MDA-MB-231 cells significantly promoted cell invasion in vitro and increased the development of lymph node metastasis in vivo. Conversely, the silencing of hPEBP4 suppressed the cell-invasive ability both in vitro and in vivo. Further investigation showed that hPEBP4 promoted the expression or activity of the metastasis-related proteinases MMP (matrix metalloproteinase) 2, MMP9 and MMP13. This hPEBP4-potentiated cell invasion and MMP expression is due to an increase in Akt activation. Knockdown of Akt restored hPEBP4-induced breast tumor metastasis in the hPEBP4-MDA-MB-231 xenograft mouse model. Moreover, we found that hPEBP4 functioned as a scaffolding molecule and enhanced the association of Akt with Src to promote Akt tyrosine phosphorylation, a prerequisite for the full activation of Akt, in a phosphatidylethanolamine-binding domain-dependent manner. Given the present information about human breast cancer, these functional data from cell culture and animal studies suggest that, in human breast cancer hPEBP4 is a novel and clinically relevant metastasis accelerator gene and may be a new diagnostic marker and therapeutic target for breast cancer metastasis.

Current evidence implies that differentiated bone marrow mesenchymal stem cells (BMMSCs) can act as progenitor cells and transdifferentiate across lineage boundaries. However, whether this unrestricted lineage has specificities depending on the stem cell type is unknown. Placental-derived mesenchymal stem cells (PDMSCs), an easily accessible and less invasive source, are extremely useful materials in current stem cell therapies. No studies have comprehensively analyzed the transition in morphology, surface antigens, metabolism and multilineage potency of differentiated PDMSCs after their dedifferentiation. In this study, we showed that after withdrawing extrinsic factors, adipogenic PDMSCs reverted to a primitive cell population and retained stem cell characteristics. The mitochondrial network during differentiation and dedifferentiation may serve as a marker of absent or acquired pluripotency in various stem cell models. The new population proliferated faster than unmanipulated PDMSCs and could be differentiated into adipocytes, osteocytes and hepatocytes. The cell adhesion molecules (CAMs) signaling pathway and extracellular matrix (ECM) components modulate cell behavior and enable the cells to proliferate or differentiate during the differentiation, dedifferentiation and redifferentiation processes in our study. These observations indicate that the dedifferentiated PDMSCs are distinguishable from the original PDMSCs and may serve as a novel source in stem cell biology and cell-based therapeutic strategies. Furthermore, whether PDMSCs differentiated into other lineages can be dedifferentiated to a primitive cell population needs to be investigated.

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Background Crohn’s disease (CD) is a heterogeneous and complicated condition that often has delayed diagnoses and poor outcomes. Disease location and site-specific mechanisms have received increasing attention in recent studies. Suboptimal classification adds complexity to clinical management for CD and the interpretation of its characteristics. This study aims to clarify the clinicopathological characteristics of CD patients through a prospective cohort. Methods The clinical data from 1173 patients with definite CD diagnoses and a simplified location classification based on anatomical traits (G1: esophagus+stomach+duodenum; G2: jejunum+ileum; G3: ileocecum; G4: colon+rectum) were used to clarify the feature patterns (Figure 1). Results Of the enrolled patients, 437 were newly diagnosed, and 736 were prevalent patients. A higher proportion of L4 involvement (45.8%) and a lower proportion of L2 (6.8%) patients were observed under the Montreal location classification. Single G2 (17.8%), G2+G3 (22.2%), G3+G4 (12.5%) and G2+G3+G4 (27.8%) were the four major types in the simplified location classification (Figure 2A-2B). The patients with G4 presented with higher C-reactive protein, G2 patients had more stricturing/penetrating behavior, and single G2 patients had the oldest age at diagnosis (Table 1). A clinicomic study with machine learning methods including principal component analysis, cluster analysis and partial least squares discriminant analysis, identified hemoglobin, platelet count and C-reactive protein as the three key indicators. A decision tree based on the three indicators and disease behavior stratified all patients into six feature patterns (simply/complicatedly active, simply/complicatedly anemia and simply/complicatedly stable), which formed a two-twisted-cycle model for natural disease history (Figure 2C). Most patients started their cycles at the active phase, and the “simply” cycle was mainly advanced by medications, while most patients in the “complicatedly” cycle needed multidisciplinary care. Comparisons among the six subgroups showed that age at diagnosis had the same rise-and-fall pattern as the G2+G4- proportion, while the G2-G4+ proportion showed the opposite trend (Table 2, Figure 2D-2E). An external validation group (n=301) confirmed the above results. The role of disease location could be interpreted as an important factor determining its start point and site-specific trajectory in the two-twisted-cycle model. Conclusion Site-specific clinical characteristics clarified by the simplified location classification, the new feature patterns profiled by the clinicomic study may provide new insights into CD phenotyping, risk stratification and precision treatment.

Objective: To investigate the antibacterial activities of blowfly larval induced by natural infection. Methods: The sterile larvae were mixed in a test tube containing a bacterial Escherichia coli (E coli) which was suspended in phosphate buffered saline (PBS), and incubated at 25 °C for given periods, with sterilized PBS as the control group. Then the haemolymph was collected and tested against Staphylococcus aureus (S aureus) and Pseudomonas aeruginosa (P aeruginosa), respectively. Diameter ring was recorded to indicate the antibacterial activities. Results: Infected larvae had better antibacterial capacities than sterile larvae. Antibacterial activities peak appeared at 24 hours and disappeared after 48 hours. The induced haemolymph from the larva possesses stronger antibacterial activity against S aureus than P aeruginosa. Conclusion: The sterile larva of blowfly, Lucilia sericata, antibacterial activities could be induced by a natural infection model.

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