The role of SUMOylation in the neurovascular dysfunction after acquired brain injury.

Acquired brain injury (ABI) is the most common disease of the nervous system, involving complex pathological processes, which often leads to a series of nervous system disorders. The structural destruction and dysfunction of the Neurovascular Unit (NVU) are prominent features of ABI. Therefore, understanding the molecular mechanism underlying NVU destruction and its reconstruction is the key to the treatment of ABI. SUMOylation is a protein post-translational modification (PTM), which can degrade and stabilize the substrate dynamically, thus playing an important role in regulating protein expression and biological signal transduction. Understanding the regulatory mechanism of SUMOylation can clarify the molecular mechanism of the occurrence and development of neurovascular dysfunction after ABI and is expected to provide a theoretical basis for the development of potential treatment strategies. This article reviews the role of SUMOylation in vascular events related to ABI, including NVU dysfunction and vascular remodeling, and puts forward therapeutic prospects.

Biological gel-based microchamber array for tumor cell proliferation and migration studies in well-controlled biochemical gradients.

Breast cancer metastasis is a complex process controlled by multiple factors, including various cell-cell interactions, cell-environment coupling, and oxygen, nutrient and drug gradients that are intimately related to the heterogeneous breast tissue structure. In this study, we constructed a high-throughput in vitro biochip system containing an array of 642 microchambers arranged in a checkerboard configuration, with each chamber embedded in a composite extracellular matrix (ECM) composed of engineered collagen and Matrigel to mimic local heterogeneous environment in vivo. In addition, a controllable complex tetragonal chemical concentration profile can be achieved by imposing chemical compounds at the four boundaries of the chip, leading to distinct local nutrient and/or drug gradients in the individual microchambers. Here, the microchamber array with composite ECM (MACECM) device aims to simulate multiple tumor cell niches composed of both breast epithelial cells (MCF-10A-GFP) and metastatic breast cancer cells (MDA-MB-231-RFP), which enables systematic studies of cell responses to a variety of biochemical conditions. The results obtained from the MACECM studies indicate that discoidin domain receptor 1 (DDR1) inhibitor 7rh and matrix metalloproteinase inhibitor batimastat, in association with epidermal growth factor (EGF) had no significant effects on the growth of MCF-10A-GFP cells, but had significant effects on DDR1 expression and the related migratory behavior of MDA-MB-231-RFP cells. The MACECM design not only enables the construction of a more realistic in vitro model for investigating cancer cell migration mechanisms but also has considerable potential for further development as a platform for next-generation high-throughput and therapeutic screening (e.g., anti-cancer drug evaluation) and personalized medicine.

Shannon entropy for time-varying persistence of cell migration.

Cell migration, which can be significantly affected by intracellular signaling pathways and extracellular matrix, plays a crucial role in many physiological and pathological processes. Cell migration is typically modeled as a persistent random walk, which depends on two critical motility parameters, i.e., migration speed and persistence time. It is generally very challenging to efficiently and accurately quantify the migration dynamics from noisy experimental data. Here, we introduce the normalized Shannon entropy (SE) based on the FPS of cellular velocity autocovariance function to quantify migration dynamics. The SE introduced here possesses a similar physical interpretation as the Gibbs entropy for thermal systems in that SE naturally reflects the degree of order or randomness of cellular migration, attaining the maximal value of unity for purely diffusive migration (i.e., SE = 1 for the most "random" dynamics) and the minimal value of 0 for purely ballistic dynamics (i.e., SE = 0 for the most "ordered" dynamics). We also find that SE is strongly correlated with the migration persistence but is less sensitive to the migration speed. Moreover, we introduce the time-varying SE based on the WPS of cellular dynamics and demonstrate its superior utility to characterize the time-dependent persistence of cell migration, which typically results from complex and time-varying intra- or extracellular mechanisms. We employ our approach to analyze experimental data of in vitro cell migration regulated by distinct intracellular and extracellular mechanisms, exhibiting a rich spectrum of dynamic characteristics. Our analysis indicates that the SE and wavelet transform (i.e., SE-based approach) offers a simple and efficient tool to quantify cell migration dynamics in complex microenvironment.

Deriving time-varying cellular motility parameters via wavelet analysis.

Cell migration, which is regulated by intracellular signaling pathways (ICSP) and extracellular matrix (ECM), plays an indispensable role in many physiological and pathological process such as normal tissue development and cancer metastasis. However, there is a lack of rigorous and quantitative tools for analyzing the time-varying characteristics of cell migration in heterogeneous microenvironment, resulted from, e.g. the time-dependent local stiffness due to microstructural remodeling by migrating cells. Here, we develop a wavelet-analysis approach to derive the time-dependent motility parameters from cell migration trajectories, based on the time-varying persistent random walk model. In particular, the wavelet denoising and wavelet transform are employed to analyze migration velocities and obtain the wavelet power spectrum. Subsequently, the time-dependent motility parameters are derived via Lorentzian power spectrum. Our results based on synthetic data indicate the superiority of the method for estimating the intrinsic transient motility parameters, robust against a variety of stochastic noises. We also carry out a systematic parameter study and elaborate the effects of parameter selection on the performance of the method. Moreover, we demonstrate the utility of our approach via analyzing experimental data ofin vitrocell migration in distinct microenvironments, including the migration of MDA-MB-231 cells in confined micro-channel arrays and correlated migration of MCF-10A cells due to ECM-mediated mechanical coupling. Our analysis shows that our approach can be as a powerful tool to accurately derive the time-dependent motility parameters, and further analyze the time-dependent characteristics of cell migration regulated by complex microenvironment.

Oncogenic miR­132 sustains proliferation and self­renewal potential by inhibition of polypyrimidine tract­binding protein 2 in glioblastoma cells.

Glioblastoma multiforme (GBM) is the leading type of brain tumor, exhibiting unlimited proliferation and invasion potential. The present study indicated that a high expression level of miR­132 was detected in the neural subtype of GBM and predicted an unfavorable prognosis for patients from The Cancer Genome Atlas cohort (n=526). Cox hazard regression analysis demonstrated miR­132 as an independent prognostic indicator for GBM patients. Further in vitro experiments indicated that miR­132 promoted the proliferation and sphere formation of U87 cells. Unsupervised hierarchical clustering analysis was performed to compare differently expressed genes between two Gene Expression Omnibus (GEO) datasets and Gene Ontology analysis was applied to evaluate the significant signaling pathways modulated by miR­132 in GBM cells within a genetic bioinformatic lab, the Gene­Cloud of Biotechnology Information. By combining the results based on GEO datasets and the miRNA bioinformatic prediction, polypyrimidine tract­binding protein 2 (PTBP2), a brain tissue­specific post­transcriptional protein, was identified as a potential downstream target of miR­132 in GBM. Thus, miR­132 overexpression in GBM cells predicted an unfavorable outcome for patients, and sustained the proliferation and self­renewal abilities of GBM cells in an miR­132/PTBP2 signaling pathway.

Primary Spinal Cord Glioblastoma Multiforme: A Retrospective Study of Patients at a Single Institution.

BACKGROUND AND OBJECTIVE: Primary spinal cord (PSC) glioblastoma multiforme (GBM) is extremely rare and accounts for only 1.5% of all spinal cord tumors. Therefore, its treatment is still ill defined. To elucidate prognostic factors, we performed a single-institutional retrospective review of the largest series to date of patients with PSC GBM who underwent surgical resection in West China Hospital between 2008 and 2014. A total of 14 patients with PSC GBM were reviewed. METHODS: Demographic, operative, and postoperative factors were recorded. Overall survival (OS) and progression-free survival (PFS) were calculated and compared with the Kaplan-Meier method. RESULTS: Eight males (57%) and 6 females (43%) were involved in the study. Their median age was 28 years (range, 14-56 years). Median Karnofsky Performance Status score was 60 (range, 20-90). Four patients (28.6%) received gross total resection, 5 (35.7%) partial resection, and the remaining 5 (35.7%) biopsy only. Nine patients (64.3%) received postoperative radiotherapy and chemotherapy, 3 (21.4%) chemotherapy only, and 2 (14.3%) neither. Median follow-up period was 15 months (range, 5-26 months). One-year and 2-year survival was 78.5% (11/14) and 7.1% (1/14), respectively. Median OS was 15 months, and median PFS 8 months. Univariate log-rank analysis showed that OS and PFS were significantly associated with patients' age (P = 0.007 and P = 0.04, respectively) and postoperative radiotherapy (P = 0.001 and P = 0.002, respectively). However, preoperative Karnofsky Performance Status score affected only OS and did not affect PFS (P = 0.033 and P = 0.106, respectively). CONCLUSIONS: According to our study, the combination of postoperative radiotherapy and temozolomide chemotherapy can improve prognosis and may serve as a feasible postoperative adjuvant treatment of PSC GBM.

[Expression levels of ubiquitin C-terminal hydrolase-L1 and serum glial fibrillary acidic protein and its clinical significance in patients with acute cerebral infarction].

OBJECTIVE: To determine expression levels of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and serum glial fibrillary acidic protein (GFAP) in patients with acute cerebral infarction and their clinical significance.
 Methods: A total of 80 patients with acute cerebral infarction in Chongqing Cancer Hospital from January 2014 to February 2016 were enrolled as an observation group. Another 80 healthy people served as a control group. The expression levels of UCH-L1 and GFAP in the 2 groups were detected.
 Results: Sensibility and specificity for UCH-L1 and GFAP were 75.0%, 87.5% and 81.3%, 90.0%, respectively. Receiver operating characteristic curve areas of UCH-L1 and GFAP were 0.670 and 0.757, respectively. There were no significant significance in age, gender, drinking, smoke, diabetes, and hyperlipidemia in the 2 groups (P>0.05). High blood pressure rate in the observation group was higher than that in the control group (P<0.05). Spearson/Pearson analysis showed that serum UCH-L1 and GFAP levels were positively correlated with hypertension, but they were negatively correlated with sex, age, diabetes, hyperlipidemia, alcohol consumption, smoking, and other factors. General data at different time in the observation group was not statistically different (P>0.05). The expression levels of UCH-L1 and GFAP in the observation group was higher than that in the control group (P<0.05). UCH-L1 and GFAP levels at different time in the 2 groups were not statistically different (P>0.05). UCH-L1 and GFAP levels in the light, medium, and heavy groups were higher than those in the control group (P<0.05), while UCH-L1 and GFAP levels in the medium and heavy groups were higher than those in the light group (P<0.05). There was significant difference between levels of UCH-L1 or GFAP and infarction size at different time in the observation group (P<0.05). The results of Pearson correlation analysis showed that the levels of serum UCH-L1 and GFAP were positively correlated (r=0.634, P=0.001).
 Conclusion: The levels of serum UCH-L1 and GFAP are significantly increased at the early stage of acute cerebral infarction, and they have a certain correlation with the severity of cerebral infarction, which can provide a basis for early clinical diagnosis and treatment.

Tumor suppressor miR-181c attenuates proliferation, invasion, and self-renewal abilities in glioblastoma.

Glioblastoma multiforme (GBM) is well known for its aggressiveness, but the underlying mechanisms are unclear, limiting the treatment. In the present study, we showed that miR-181c, a commonly downregulated miRNA in GBM reported by several miRNA profiles, was associated with the mesenchymal subtype of GBM and predicted the outcome for patients from a GBM cohort (n=518) obtained from The Cancer Genome Atlas database. A multivariate analysis showed that miR-181c was an independent prognostic indicator for GBM patients. Quantitative reverse transcription PCR showed that miR-181c was expressed poorly in neurospheres of glioma cells that resemble glioma stem cells. Proliferation and invasion assays showed that miR-181c also blocked the proliferation and invasion abilities of glioma cells. Limiting dilution and colony formation assays showed that miR-181c attenuated the self-renewal ability of glioma cells. Finally, investigation of the mechanism defined Notch2, a key molecular of Notch signaling, as the functional downstream target of miR-181c. An inverse correlation was found between miR-181c and Notch2 in glioma cells and verified in fresh glioma samples. Taken together, the present study showed that miR-181c can be considered a valuable indicator for the outcome of GBM patients. miR-181c acts as a tumor suppressor that attenuates proliferation, invasion, and self-renewal capacities by downregulation of Notch2 in glioma cells.