Medulloblastoma (MB) is a highly malignant pediatric brain tumor. In the latest classification, medulloblastoma is divided into four distinct groups: wingless (WNT), sonic hedgehog (SHH), Group 3, ...and Group 4. We analyzed the magnetic resonance imaging radiomics features to find the imaging surrogates of the 4 molecular subgroups of MB. Frozen tissue, imaging data, and clinical data of 38 patients with medulloblastoma were included from Taipei Medical University Hospital and Taipei Veterans General Hospital. Molecular clustering was performed based on the gene expression level of 22 subgroup-specific signature genes. A total 253 magnetic resonance imaging radiomic features were generated from each subject for comparison between different molecular subgroups. Our cohort consisted of 7 (18.4%) patients with WNT medulloblastoma, 12 (31.6%) with SHH tumor, 8 (21.1%) with Group 3 tumor, and 11 (28.9%) with Group 4 tumor. 8 radiomics gray-level co-occurrence matrix texture (GLCM) features were significantly different between 4 molecular subgroups of MB. In addition, for tumors with higher values in a gray-level run length matrix feature-Short Run Low Gray-Level Emphasis, patients have shorter survival times than patients with low values of this feature (p = 0.04). The receiver operating characteristic analysis revealed optimal performance of the preliminary prediction model based on GLCM features for predicting WNT, Group 3, and Group 4 MB (area under the curve = 0.82, 0.72, and 0.78, respectively). The preliminary result revealed that 8 contrast-enhanced T1-weighted imaging texture features were significantly different between 4 molecular subgroups of MB. Together with the prediction models, the radiomics features may provide suggestions for stratifying patients with MB into different risk groups.
A single-layer dual-circularly polarized cavity-backed patch filtenna with wide axial-ratio (AR) bandwidth is presented in this letter. The degenerated substrate-integrated waveguide (SIW) cavity ...modes TE 120 /TE 210 cooperating with the patch modes TM 01 /TM 10 are utilized to achieve a wide AR bandwidth. Simultaneously, two radiation nulls, which are inherently introduced by the SIW-cavity mode TE 110 and mixed electromagnetic coupling between the cavity and patch, respectively, are realized at both band edges to achieve a bandpass filtering response. For demonstration, a sample was fabricated and tested. The measured results show that the proposed filtenna achieves an operating bandwidth of 12% with the center frequency of 10 GHz, a peak gain of 7.4 dBic, an in-band average gain of 6.7 dBic, and an out-of-band rejection level over −13 dB.
Scope
The accumulation of misfolded α‐synuclein in dopaminergic neurons is the leading cause of Parkinson's disease (PD). Resveratrol (RV), a polyphenolic compound derived from grapes and red wine, ...exerts a wide range of beneficial effects via activation of sirtuin 1 (SIRT1) and induction of vitagenes. Here, we assessed the role of RV in a 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP) induced mouse model of PD and explored its potential mechanisms.
Methods and results
RV and EX527, a specific inhibitor of SIRT1, were administered before and after MPTP treatment. RV protected against MPTP‐induced loss of dopaminergic neurons, and decreases in tyrosine hydroxylase and dopamine levels, as well as behavioral impairments. Meanwhile, RV administration activated SIRT1. Microtubule‐associated protein 1 light chain 3 (LC3) was then deacetylated and redistributed from the nucleus to the cytoplasm, which provoked the autophagic degradation of α‐synuclein in dopaminergic neurons. Furthermore, EX527 antagonized the neuroprotective effects of RV by reducing LC3 deacetylation and subsequent autophagic degradation of α‐synuclein.
Conclusion
We showed that RV ameliorated both motor deficits and pathological changes in MPTP‐treated mice via activation of SIRT1 and subsequent LC3 deacetylation‐mediated autophagic degradation of α‐synuclein. Our observations suggest that RV may be a potential prophylactic and/or therapeutic agent for PD.
In dopaminergic neurons, resveratrol (RV) directly or indirectly activates sirtuin1 (SIRT1; while EX527 inhibits SIRT1), LC3 is then deacetylated by SIRT1 and redistributed from the nucleus to the cytoplasm, which provokes the autophagic degradation of α‐synuclein, thus preventing the neuron loss in substantia nigra, attenuating pathological changes and behavior impairments.We think these findings propose a mechanism to support RV as a prophylactic or therapeutic agent for Parkinson's disease.
Several serum biomarkers have been investigated for their potential as diagnostic tools in aortic disease; however, no study has investigated the association between serum biomarkers and outcomes ...after aortic surgery. This study explored the predictive ability of serum soluble lumican in postoperative outcomes after aortic surgery.
In total, 58 patients receiving aortic surgery for aortic dissection or aneurysm at Linkou Chang Gung Memorial Hospital in Taiwan in December 2011-September 2018 were enrolled. Blood samples were collected immediately upon patients' arrival in the intensive care unit after aortic surgery. The diagnostic properties of soluble lumican levels were assessed by performing receiver operating characteristic (ROC) curve analysis. The confidence interval (CI) of the area under the ROC curve (AUC) was measured using DeLong's nonparametric method and the optimal cutoff was determined using the Youden index.
The serum soluble lumican level distinguished prolonged ventilation (AUC, 73.5%; 95% CI, 57.7%-89.3%) and hospital stay for >30 days (AUC, 78.2%; 95% CI, 61.6%-94.7%). The optimal cutoffs of prolonged ventilation and hospital stay for >30 days were 1.547 and 5.992 ng/mL, respectively. The sensitivity and specificity were respectively 100% (95% CI, 71.5%-100%) and 40.4% (95% CI, 26.4%-55.7%) for prolonged ventilation and 58% (95% 27.7%-84.8%) and 91.3% (95% CI, 79.2%-97.6%) for hospital stay for >30 days.
The serum soluble lumican level can be a potential prognostic factor for predicting poor postoperative outcomes after aortic surgery. However, more studies are warranted in the future.
Centriole duplication involves the growth of a procentriole next to the parental centriole. Mutations in STIL and CPAP/CENPJ cause primary microcephaly (MCPH). Here, we show that human STIL has an ...asymmetric localization to the daughter centriole and is required for procentriole formation. STIL levels oscillate during the cell cycle. Interestingly, STIL interacts directly with CPAP and forms a complex with hSAS6. A natural mutation of CPAP (E1235V) that causes MCPH in humans leads to significantly lower binding to STIL. Overexpression of STIL induced the formation of multiple procentrioles around the parental centriole. STIL depletion inhibited normal centriole duplication, Plk4‐induced centriole amplification, and CPAP‐induced centriole elongation, and resulted in a failure to localize hSAS6 and CPAP to the base of the nascent procentriole. Furthermore, hSAS6 depletion hindered STIL targeting to the procentriole, implying that STIL and hSAS6 are mutually dependent for their centriolar localization. Together, our results indicate that the two MCPH‐associated proteins STIL and CPAP interact with each other and are required for procentriole formation, implying a central role of centriole biogenesis in MCPH.
Several genes mutated in human primary microcephaly encode key centrosome proteins. STIL/MCPH7 now joins this cast, with centriole biogenesis roles similar to those played by its distant relatives CeSAS‐5/DmAna2 in invertebrates.
Medulloblastomas (MBs) are one of the most common malignant brain tumor types in children. MB prognosis, despite improvement in recent years, still depends on clinical and biological risk factors. ...Metastasis is the leading cause of MB-related deaths, which highlights an unmet need for risk stratification and targeted therapy to improve clinical outcomes. Among the four molecular subgroups, sonic-hedgehog (SHH)-MB harbors clinical and genetic heterogeneity with a subset of high-risk cases. Recently, long non-coding (lnc)RNAs were implied to contribute to cancer malignant progression, but their role in MB remains unclear. This study aimed to identify pro-malignant lncRNAs that have prognostic and therapeutic significance in SHH-MB.
The Daoy SHH-MB cell line was engineered for ectopic expression of MYCN, a genetic signature of SHH-MB. MYCN-associated lncRNA genes were identified using RNA-sequencing data and were validated in SHH-MB cell lines, MB tissue samples, and patient cohort datasets. SHH-MB cells with genetic manipulation of the candidate lncRNA were evaluated for metastatic phenotypes in vitro, including cell migration, invasion, sphere formation, and expressions of stemness markers. An orthotopic xenograft mouse model was used to evaluate metastasis occurrence and survival. Finally, bioinformatic screening and in vitro assays were performed to explore downstream mechanisms.
Elevated lncRNA LOXL1-AS1 expression was identified in MYCN-expressing Daoy cells and MYCN-amplified SHH-MB tumors, and was significantly associated with lower survival in SHH-MB patients. Functionally, LOXL1-AS1 promoted SHH-MB cell migration and cancer stemness in vitro. In mice, MYCN-expressing Daoy cells exhibited a high metastatic rate and adverse effects on survival, both of which were suppressed under LOLX1-AS1 perturbation. Integrative bioinformatic analyses revealed associations of LOXL1-AS1 with processes of cancer stemness, cell differentiation, and the epithelial-mesenchymal transition. LOXL1-AS1 positively regulated the expression of transforming growth factor (TGF)-β2. Knockdown of TGF-β2 in SHH-MB cells significantly abrogated their LOXL1-AS1-mediated prometastatic functions.
This study proved the functional significance of LOXL1-AS1 in SHH-MB metastasis by its promotion of TGF-β2-mediated cancer stem-like phenotypes, providing both prognostic and therapeutic potentials for targeting SHH-MB metastasis.
Medulloblastoma is the most common embryonic brain tumor in children. We investigated a cohort of 52 Asian medulloblastoma patients aged between 0 and 19 years old, who received surgical resections ...and post-resection treatments in the Taipei Medical University Hospital and the Taipei Veterans General Hospital. Genome-wide RNA sequencing was performed on fresh-frozen surgical tissues. These data were analyzed using the CIBERSORTx immune deconvolution software. Two external clinical and molecular datasets from United States (n = 62) and Canada (n = 763) were used to evaluate the transferability of the gene-signature scores across ethnic populations. The abundance of 13 genes, including DLL1, are significantly associated with overall survival (All Cox regression P < 0.001). A gene-signature score was derived from the deep transcriptome, capable of indicating patients' subsequent tumor recurrence (Hazard Ratio HR 1.645, confidence interval CI 1.337-2.025, P < 0.001) and mortality (HR 2.720, CI 1.798-4.112, P < 0.001). After the adjustment of baseline clinical factors, the score remains indicative of recurrence-free survival (HR 1.604, CI 1.292-1.992, P < 0.001) and overall survival (HR 2.781, CI 1.762-4.390, P < 0.001). Patients stratified by this score manifest not only distinct prognosis but also different molecular characteristics: Notch signaling ligands and receptors are comparatively overexpressed in patients with poorer prognosis, while tumor infiltrating natural killer cells are more abundant in patients with better prognosis. Additionally, immunohistochemical staining showed the DLL1 protein, a major ligand in the Notch signaling pathway, and the NCAM1 protein, a representative biomarker of natural killer cells, are present in the surgical tissues of patients of four molecular subgroups, WNT, SHH, Group 3 and Group 4. NCAM1 RNA level is also positively associated with the mutation burden in tumor (P = 0.023). The gene-signature score is validated successfully in the Canadian cohort (P = 0.009) as well as its three molecular subgroups (SHH, Group 3 and Group 4; P = 0.047, 0.018 and 0.040 respectively). In conclusion, pediatric medullablastoma patients can be stratified by gene-signature scores with distinct prognosis and molecular characteristics. Ligands and receptors of the Notch signaling pathway are overexpressed in the patient stratum with poorer prognosis. Tumor infiltrating natural killer cells are more abundant in the patient stratum with better prognosis.
Triple-negative breast cancer (TNBC) lacks specific therapeutic target and limits to chemotherapy and is essential to develop novel therapeutic regimens. Increasing studies indicated that tamoxifen, ...a selective estrogen receptor modulators (SERMs), has anti-tumor therapeutic effect in estrogen receptor α (ERα)-negative tumor. Here, we determined whether autophagy was activated by tamoxifen in TNBC cells. Moreover, CSC-3436 displayed strong and selective growth inhibition on cancer cells. Next, we investigated the anti-proliferation effect of combination of CSC-3436 plus tamoxifen on cell death in TNBC cells.
Our study found that tamoxifen induces autophagy in TNBC cells. Endoplasmic reticulum stress and AMPK/mTOR contributed tamoxifen-induced autophagy. Interestingly, in combination treatment with CSC-3436 enhanced the anti-proliferative effect of tamoxifen. We found that CSC-3436 switched tamoxifen-induced autophagy to apoptosis via cleavage of ATG-5. Moreover, AMPK/mTOR pathway may involve in CSC-3436 switched tamoxifen-induced autophagy to apoptosis. The combination of tamoxifen and CSC-3436 produced stronger tumor growth inhibition compared with CSC-3436 or tamoxifen alone treatments in vivo.
These data indicated that CSC-3436 combined with tamoxifen may be a potential approach for treatment TNBC.
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