The emerging role of MMP14 in brain tumorigenesis and future therapeutics.

Glioblastoma is a malignant brain tumor of glial origin. These tumors are thought to be derived from astrocytic cells that undergo malignant transformation. A growing body of evidence suggests that upregulation of MMP expression plays a significant role in promoting glioma pathogenesis. Elevated expression of MMP14 not only promotes glioma invasion and tumor cell proliferation but also plays a role in angiogenesis. Despite the fact that levels of MMP14 correlate with breast cancer progression, the controversial role of MMP14 in gliomagenesis needs to be elucidated. In the present review, we discuss the role of MMP14 in glioma progression as well as the mechanisms of MMP14 regulation in the context of future therapeutic manipulations.

Aliphatic chain length by isotropic mixing (ALCHIM): determining composition of complex lipid samples by ¹H NMR spectroscopy.

Quantifying the amounts and types of lipids present in mixtures is important in fields as diverse as medicine, food science, and biochemistry. Nuclear magnetic resonance (NMR) spectroscopy can quantify the total amounts of saturated and unsaturated fatty acids in mixtures, but identifying the length of saturated fatty acid or the position of unsaturation by NMR is a daunting challenge. We have developed an NMR technique, aliphatic chain length by isotropic mixing, to address this problem. Using a selective total correlation spectroscopy technique to excite and transfer magnetization from a resolved resonance, we demonstrate that the time dependence of this transfer to another resolved site depends linearly on the number of aliphatic carbons separating the two sites. This technique is applied to complex natural mixtures allowing the identification and quantification of the constituent fatty acids. The method has been applied to whole adipocytes demonstrating that it will be of great use in studies of whole tissues.

The prognosis and clinicopathology of CXCR4 in gastric cancer patients: a meta-analysis.

The chemokine receptor 4 (CXCR4) has been widely investigated in diagnosis and prognosis of gastric cancer (GC). However, the impact of CXCR4 on GC patients remains controversial; Here, we conducted a meta-analysis to obtain the precise role of CXCR4 in GC prognosis and clinicopathology. Thirteen published studies with a total of 1,936 patients were included. Original data included the hazard ratio (HR) of overall survival (OS) and odds ratio (OR) in GC patients. We combined HR/OR with 95% confidence interval (CI) to estimate the hazard. In this study, OS was significantly related to CXCR4 expression, with the HR 2.63 (95% CI 1.69-4.09; p < 0.0001), and a significant correlation was also revealed between CXCR4 expression and stage (I + II, +) (OR 0.52, 95% CI 0.32-0.83; p = 0.007), depth of invasion (T1/T2, +) (OR 0.44, 95% CI 0.27-0.73; p = 0.001), lymph node metastasis (LN, +) (OR 2.30, 95% CI 1.57-3.36; p < 0.0001), as well as vascular invasion (vas.inv, +) (OR 0.72, 95% CI 0.53-0.98; p = 0.04). Heterogeneity was observed among the included studies with OS (I(2) = 51%), stage (I(2) = 78%), depth of invasion (I(2) = 74%), lymph node metastasis (I(2) = 64%), and histology differentiation (I(2) = 79%). No publication bias was observed. In conclusion, this meta-analysis showed CXCR4 expression indicates poor prognosis in GC patients with advanced stage or deep invasion in GC tissues, which also implied lymph node metastasis and vascular invasion. Thus, CXCR4 could help predict patient prognosis and guide clinical diagnosis and treatment.

The association of Crk-like adapter protein with poor prognosis in glioma patients.

Glioma is the most common of brain tumors that greatly affects patient survival. In our precious study, Crk-like adapter protein (CrkL) was identified as a key regulator in glioblastoma development [1]. Here, we aimed to investigate the correlation of CrkL with patient prognosis as well as pathological indicators. Immunohistochemistry was available to evaluate CrkL expression in 49 gliomas of distinct malignancy grade, and positive stained sites were analyzed. CrkL protein was detected in cell lines by Western blot as well. We observed CrkL protein stained in 59.2 % (29 out of 49) of all glioma tissues, including 41.4 % of low-grade (I + II) gliomas, and 85.0 % of high-grade (III + IV) gliomas. Of four grades, grade IV exhibited the highest CrkL level. CrkL protein was also identified in cell lines NHA, U87, U251, T98G, and A172 by Western blot. On the other hand, CrkL expression was significantly associated with the patient's age and WHO grade, and patients with high CrkL expression had a significantly shorter median survival time (17 months) than those (median survival time 52 months) with low CrkL expression (p<0.001). According to Cox regression, CrkL can be suggested as an independent prognostic factor. In conclusion, CrkL is differently expressed in different grades of gliomas, and correlated to WHO grade. CrkL also independently indicates poor prognosis in old glioma patients, which can further be recommended as an effective prognostic biomarker or therapeutic target.

A Rare Presentation of Indirect Hyperbilirubinemia: Coexistence of Multiple UGT1A1 Gene Variants.

Indirect hyperbilirubinemia is a common clinical finding and rarely can be attributed to Crigler-Najjar syndrome type 2 or Gilbert syndrome. This case displays a rare presentation of indirect hyperbilirubinemia in a patient with multiple UGT1A1 gene variants. We aim to discuss the complexity of multiple UGT1A1 gene variants and its effect on the degree of observed hyperbilirubinemia.

Efficacy of minimally invasive therapies on unresectable pancreatic cancer.

For patients with unresectable pancreatic cancer, current chemotherapies have negligible survival benefits. Thus, developing effective minimally invasive therapies is currently underway. This study was conducted to evaluate the efficacy of transarterial chemoembolization plus radiofrequency ablation and/or 125I radioactive seed implantation on unresectable pancreatic cancer. We analyzed the outcome of 71 patients with unresectable pancreatic carcinoma who underwent chemoembolization plus radiofrequency ablation and/or radioactive seed implantation. Of the 71 patients, the median survival was 11 months, and the 1-, 2-, and 3-year overall survival rates were 32.4%, 9.9%, and 6.6%, respectively. Patients who had no metastasis, who had oligonodular liver metastases (≤3 lesions), and who had multinodular liver metastases (>3 lesions) had median survival of 12, 18, and 8 months, respectively, and 1-year overall survival rates of 50.0%, 68.8%, and 5.7%, respectively. Although the survival of patients without liver metastases was worse than that of patients with oligonodular liver metastasis, the result was not significant (P = 0.239). In contrast, the metastasis-negative patients had significantly better survival than did patients with multinodular liver metastases (P < 0.001). Patients with oligonodular liver lesions had a significant longer median survival than did patients with multinodular lesions (P < 0.001). In conclusion, combined minimally invasive therapies had good efficacy on unresectable pancreatic cancer and resulted in a good control of liver metastases. In addition, the number of liver metastases was a significant factor in predicting prognosis and response to treatment.

Ablation versus medication as initial therapy for paroxysmal atrial fibrillation: An updated meta-analysis of randomized controlled trials.

BACKGROUND: Recent randomized controlled trials (RCTs) suggest that ablation is superior to antiarrhythmic drugs (AADs) as an initial therapy for paroxysmal atrial fibrillation (pAF) to prevent arrhythmia recurrences. We performed an updated meta-analysis of RCTs, to include recent data from cryoballoon-based ablation and to compare arrhythmia-free survival and adverse events between ablation and AADs. METHODS: We searched MEDLINE and EMBASE from inception to December 2020. We included RCT comparing patients with pAF undergoing ablation or receiving AADs as an initial therapy. We combined data using the random-effects model to calculate hazards ratio (HR) for arrhythmia-free survival and odds ratio (OR) for adverse events. RESULTS: Five studies from 2005 to 2020 involving 985 patients were included (495 patients and 490 patients underwent ablation and medication as initial therapy, respectively). Patients who underwent ablation had higher freedom from atrial tachyarrhythmias (ATs) during the 12-24 months follow-up period (pooled HR = 0.48, 95% CI: 0.40-0.59, P < .001). In a subgroup analysis of ablation method used, both cryoablation group (pooled HR = 0.49, 95% CI: 0.38-0.64, P < .001) and radiofrequency ablation group (pooled HR = 0.47, 95%CI: 0.35-0.64, P < .001) showed reduction in AT recurrence compared with AAD group. There were no differences in adverse events including cerebrovascular accident, pericardial effusion or tamponade, pulmonary vein stenosis, acute coronary syndrome, deep vein thrombosis and pulmonary embolism, and bradycardia requiring a pacemaker. CONCLUSION: Catheter ablation (both cryoablation and radiofrequency ablation) is superior to AAD as an initial therapy for pAF in efficacy for reducing AT recurrences without a compromise in adverse events.

Pre-Procedural Hyperglycemia Increases the Risk of Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography: A Systematic Review and Meta-Analysis.

BACKGROUND: Contrast-induced nephropathy (CIN) frequently occurs following coronary angiography (CAG) and is associated with worse outcomes, including both short and long-term mortality. Previous studies reported an association between procedural hyperglycemia (PH) and CIN, with or without diabetes mellitus (DM). We performed a systematic review and meta-analysis to explore the association of PH and CIN in patients undergoing CAG. METHODS: We searched the databases of MEDLINE and EMBASE from inception to January 2020. Included studies investigated CIN incidence in patients undergoing CAG. Data from each study were combined using the random-effects model. RESULTS: A total of eight studies were included in this meta-analysis. We found that PH was associated with an increased risk of CIN following CAG (pooled OR = 1.71, 95%CI:1.35-2.16, where PH was defined as ≥140 mg/dl; and pooled OR = 2.07, 95%CI:1.80-2.37, where PH was defined as ≥200 mg/dl). In subgroup analysis of non-diabetic patients and STEMI patients undergoing primary percutaneous coronary intervention, we found that PH was associated with an increased risk of CIN in both subgroups, where PH was defined as ≥140 mg/dl and ≥200mg/dl (p-value < 0.05). CONCLUSIONS: Our meta-analysis demonstrated that PH significantly increases the risk of CIN following CAG, in both diabetic and non-diabetic populations. Further studies are needed to evaluate whether strict blood glucose control can reduce the incidence of CIN in this population.

Identification of low frequency and rare variants for hypertension using sparse-data methods.

Availability of genomic sequence data provides opportunities to study the role of low-frequency and rare variants in the etiology of complex disease. In this study, we conduct association analyses of hypertension status in the cohort of 1943 unrelated Mexican Americans provided by Genetic Analysis Workshop 19, focusing on exonic variants in MAP4 on chromosome 3. Our primary interest is to compare the performance of standard and sparse-data approaches for single-variant tests and variant-collapsing tests for sets of rare and low-frequency variants. We analyze both the real and the simulated phenotypes.

CrkL efficiently mediates cell proliferation, migration, and invasion induced by TGF-ß pathway in glioblastoma.

Crk-like (CrkL) is an adapter protein that has crucial roles in cell proliferation, adhesion, and migration. However, the expression pattern and potential mechanism of CrkL protein in glioblastoma multiforme (GBM) have not been fully elucidated. To determine roles of CrkL in cell signaling, proliferation, and migration, small interfering RNAs and plasmids transfection were used to suppress or overexpress CrkL in U87 and U251; soft-agar assay and wound-healing assay were used to observe cell invasiveness, migration, and proliferation. Erk1/2, Smad2, and matrix metalloproteinase 9 (MMP9) were also analyzed by western blot. CrkL was expressed in U87 and U251 cell lines and can be activated by transforming growth factor-beta 1 (TGF-ß1) in vitro; CrkL knockdown significantly suppressed the expression of phosph-ERK1/2 and MMP9 but enhanced phosph-Smad2 expression compared with control (p <0.001). Overexpression of CrkL against control upregulated phosph-ERK1/2 and MMP9 and, at the same time, downregulated phosph-Smad2 (p <0.01). On the other hand, CrkL knockdown could significantly affect U87 and U251 invasiveness (p <0.01) and wound closure (p <0.01) using soft-agar assay and wound-healing assay. These studies suggest that CrkL efficiently mediates cell proliferation, migration, and invasion induced by TGF-ß pathway in glioblastoma. Furthermore, CrkL can be used as a potential and efficient therapeutic target of GBM and may also mediate other signaling pathway.

Inhibition of MMP14 potentiates the therapeutic effect of temozolomide and radiation in gliomas.

Metalloproteinases are membrane-bound proteins that play a role in the cellular responses to antiglioma therapy. Previously, it has been shown that treatment of glioma cells with temozolomide (TMZ) and radiation (XRT) induces the expression of metalloproteinase 14 (MMP14). To investigate the role of MMP14 in gliomagenesis, we used several chemical inhibitors which affect MMP14 expression. Of all the inhibitors tested, we found that Marimastat not only inhibits the expression of MMP14 in U87 and U251 glioma cells, but also induces cell cycle arrest. To determine the relationship between MMP14 inhibition and alteration of the cell cycle, we used an RNAi technique. Genetic knockdown of MMP14 in U87 and U251 glioma cells induced G2/M arrest and decreased proliferation. Mechanistically, we show that TMZ and XRT regulated expression of MMP14 in clinical samples and in vitro models through downregulation of microRNA374. In vivo genetic knockdown of MMP14 significantly decreased tumor growth of glioma xenografts and improved survival of glioma-bearing mice. Moreover, the combination of MMP14 silencing with TMZ and XRT significantly improved the survival of glioma-bearing mice compared to a single modality treatment group. Therefore, we show that the inhibition of MMP14 sensitizes tumor cells to TMZ and XRT and could be used as a future strategy for antiglioma therapy.