The synchrosqueezing transform (SST) is a novel approach for time-frequency (T-F) representation of non-stationary signals. By synchrosqueezing and reassigning the T-F spectrum of the wavelet ...transform (WT) or the short time Fourier transform (STFT) of a signal, the SST can obtain a high-resolution T-F spectrum. In the light of the superiority of S-transform (ST) over the WT and the STFT, especially, in representing a high-frequency weak-amplitude signal on its T-F spectrum, we propose a synchrosqueezing S-transform (SSST) which is realized by synchrosqueezing the spectrum of the ST. The formulas for the SSST and its inverse transform are derived. Synthetic examples show that the SSST has obviously higher resolution than the ST, and is superior to the SST like the ST to the WT. We then applied the SSST to perform the spectral decomposition of a marine seismic data for natural gas hydrate exploration. The results illustrate that the SSST can be used to well detect frequency spectral anomalies correlated with the gas hydrate and free-gas accumulations. We can also conclude that the SSST is a good potential technique to assist seismic interpretation.
The aim of this study was to: (a) explore the potential mechanism of cancer cell sensitivity to cisplatin, docetaxel, and 5‐fluorouracil (TPF) in oral squamous cell carcinoma (OSCC) patients ...overexpressing growth differentiation factor 15 (GDF15); and (b) identify potential alternative agents for patients who might not benefit from inductive TPF chemotherapy. The results indicated that OSCC cells overexpressing GDF15 were sensitive to TPF through a caspase‐9‐dependent pathway both in vitro and in vivo. Immunoprecipitation combined with mass spectrometry revealed that the erbB2 protein was a potential GDF15‐binding protein, which was verified by coimmunoprecipitation. Growth differentiation factor 15 overexpression promoted OSCC cell proliferation through erbB2 phosphorylation, as well as downstream AKT and Erk signaling pathways. When GDF15 expression was blocked, the phosphorylation of both the erbB2 and AKT/Erk pathways was downregulated. When OSCC cells with GDF15 overexpression were treated with the erbB2 phosphorylation inhibitor, CI‐1033, cell proliferation and xenograft growth colony formation were significantly blocked (P < .05). Thus, GDF15‐overexpressing OSCC tumors are sensitive to TPF chemoagents through caspase‐9‐dependent pathways. Growth differentiation factor 15 overexpression promotes OSCC proliferation through erbB2 phosphorylation. Thus, ErbB2 inhibitors could represent potential targeted drugs or an alternative therapy for OSCC patients with GDF15 overexpression.
Growth differentiation factor 15 (GDF15)‐overexpressing oral squamous cell carcinoma (OSCC) tumors are sensitive to cisplatin, docetaxel, and 5‐fluorouracil chemoagents through caspase‐9‐dependent pathways. GDF15 overexpression promotes OSCC proliferation through erbB2 phosphorylation. Thus, erbB2 inhibitors could represent potential targeted drugs or an alternative therapy for OSCC patients with GDF15 overexpression.
Background
This study was designed to verify whether enhancer of zeste homolog 2 (EZH2) affects intervertebral disc degeneration (IVDD) development through regulation of microRNA (miR)‐129‐5p/MAPK1.
...Methods
Initially, we collected lumbar nucleus pulposus (NP) tissue samples from patients with juvenile idiopathic scoliosis (n = 14) and IVDD (n = 34). We measured the expression of related genes in clinical IVDD tissues and a lipopolysaccharide (LPS)‐induced NP cell model. After loss‐ and gain‐of‐function assays, NP cell proliferation and senescence were examined. The targeting relationship between miR‐129‐5p and MAPK1 was explored by dual luciferase reporter gene and RNA immunoprecipitation (RIP) assays. The enrichment of EZH2 and H3K27me3 in miR‐129‐5p promoter was verified by chromatin immunoprecipitation (ChIP). Finally, an IVDD rat model was established to test the effects of transduction with lentiviral vector carrying miR‐129‐5p agomir and/or oe‐EZH2 in vivo.
Results
miR‐129‐5p was underexpressed, and EZH2 and MAPK1 levels were overexpressed in lumbar nucleus pulposus from human IVDD patients and in LPS‐induced NP cells. miR‐129‐5p overexpression or silencing of MAPK1 promoted proliferation of NP cells, while inhibiting their senescence. EZH2 inhibited miR‐129‐5p through H3K27me3 modification in the miR‐129‐5p promoter. miR‐129‐5p could target the downregulation of MAPK1 expression. EZH2 overexpression increased the release of inflammatory factors and cell senescence factors, which was reversed by miR‐129‐5p agomir in vivo.
Conclusions
Taken together, EZH2 inhibits miR‐129‐5p through H3K27me3 modification, which upregulates MAPK1, thereby promoting the development of IVDD.
EZH2 can inhibit the transcription of miR‐129‐5p through epigenetic regulation of H3K27me3 modification in the miR‐129‐5p promoter, which upregulates the expression of MAPK1, inhibits the proliferation of NP cells, and promotes their senescence to promote IVDD development.
Reverse-time migration (RTM) of the towed-streamer seismic data is widely used for imaging subseabed layers. In the areas with high-velocity shielding layers, the RTM images of the deep layers may be ...severely damaged by the coherent noises. The pressure component of ocean bottom nodes (OBNs) data contains abundant reflection waves from deep layers and can be used as supplementary to the towed-streamer data. Joint RTM of these two kinds of data has the potential to acquire better migration images. However, using the traditional cross-correlation imaging condition, the joint RTM images of low signal-to-noise ratio (SNR) seismic data are disappointing due to the imaging noises. In this letter, we propose a new imaging condition to improve the joint migration images. The proposed imaging condition decreases or enhances the imaging values according to the similarity between the backward-propagating receiver wavefields of the towed-streamer and OBN pressure data. In this way, the SNR of the joint migration images is increased. The proposed imaging condition is applied to the synthetic datasets of a complex velocity model containing a high-velocity salt body. The tests demonstrate that joint RTM images obtained using the proposed imaging condition are much better than ones obtained using only the towed-streamer data.
Geomorphic evidence suggests that shorelines of 100–200 m above the modern lake levels were common across the Tibetan Plateau during late Marine Isotope Stage (MIS) 3. The timing of this lake‐level ...highstand is mainly based on radiocarbon ages. Problems surrounding the ages of lacustrine sediments at or beyond the limit of the radiocarbon‐dating method have created a need for alternative geochronometers. Chronological advances during the last decade have renewed interest in the timing of events beyond the limit of radiocarbon dating. Here, we synthesize published data for elevated lacustrine landforms of 48 lakes on the Tibetan Plateau, in order to provide a thorough perspective on the timing and pattern of lake‐level changes in this alpine area during the late Quaternary. The ages of these elevated shore features reveal a long‐term trend of relative lake‐level fall from at least MIS 5, instead of a peak in MIS 3, as previously thought. Dating lacustrine terrace sequences reveals that the rate of lake‐level fall ranged from ~1 to 3 mm a−1, comparable with that of related river downcutting across the plateau. Palaeoclimatic proxy records point to a sustained drying since the Last Interglacial, suggesting that long‐term aridification might be the culprit for this widespread and progressive lake‐level fall.
To evaluate induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) followed by surgery and postoperative radiotherapy versus up-front surgery and postoperative radiotherapy in ...patients with locally advanced resectable oral squamous cell carcinoma (OSCC).
A prospective open-label phase III trial was conducted. Eligibility criteria included untreated stage III or IVA locally advanced resectable OSCC. Patients received two cycles of TPF induction chemotherapy (docetaxel 75 mg/m(2) on day 1, cisplatin 75 mg/m(2) on day 1, and fluorouracil 750 mg/m(2) on days 1 to 5) followed by radical surgery and postoperative radiotherapy (54 to 66 Gy) versus up-front radical surgery and postoperative radiotherapy. The primary end point was overall survival (OS). Secondary end points included local control and safety.
Of the 256 patients enrolled onto this trial, 222 completed the full treatment protocol. There were no unexpected toxicities, and induction chemotherapy did not increase perioperative morbidity. The clinical response rate to induction chemotherapy was 80.6%. After a median follow-up of 30 months, there was no significant difference in OS (hazard ratio HR, 0.977; 95% CI, 0.634 to 1.507; P = .918) or disease-free survival (HR, 0.974; 95% CI, 0.654 to 1.45; P = .897) between patients treated with and without TPF induction. Patients in the induction chemotherapy arm with a clinical response or favorable pathologic response (≤ 10% viable tumor cells) had superior OS and locoregional and distant control.
Our study failed to demonstrate that TPF induction chemotherapy improves survival compared with up-front surgery in patients with resectable stage III or IVA OSCC.
Background and Purpose
Protein palmitoylation is involved in learning and memory, and in emotional disorders. Yet, the underlying mechanisms in these processes remain unclear. Herein, we describe ...that A‐kinase anchoring protein 150 (AKAP150) is essential and sufficient for depressive‐like behaviours in mice via a palmitoylation‐dependent mechanism.
Experimental Approach
Depressive‐like behaviours in mice were induced by chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS). Palmitoylated proteins in the basolateral amygdala (BLA) were assessed by an acyl‐biotin exchange assay. Genetic and pharmacological approaches were used to investigate the role of the DHHC2‐mediated AKAP150 palmitoylation signalling pathway in depressive‐like behaviours. Electrophysiological recording, western blotting and co‐immunoprecipitation were performed to define the mechanistic pathway.
Key Results
Chronic stress successfully induced depressive‐like behaviours in mice and enhanced AKAP150 palmitoylation in the BLA, and a palmitoylation inhibitor was enough to reverse these changes. Blocking the AKAP150‐PKA interaction with the peptide Ht‐31 abolished the CRS‐induced AKAP150 palmitoylation signalling pathway. DHHC2 expression and palmitoylation levels were both increased after chronic stress. DHHC2 knockdown prevented CRS‐induced depressive‐like behaviours, as well as attenuating AKAP150 signalling and synaptic transmission in the BLA in CRS‐treated mice.
Conclusion and Implications
These results delineate that DHHC2 modulates chronic stress‐induced depressive‐like behaviours and synaptic transmission in the BLA via the AKAP150 palmitoylation signalling pathway, and this pathway may be considered as a promising novel therapeutic target for major depressive disorder.
The survival benefit from docetaxel, cisplatin and 5‐fluorouracil (TPF) induction chemotherapy in oral squamous cell carcinoma (OSCC) patients is not satisfactory. Previously, we identified that ...stathmin, a microtubule‐destabilizing protein, is overexpressed in OSCC. Here, we further investigated its role as a biomarker that impacts on OSCC chemosensitivity. We analyzed the predictive value of stathmin on TPF induction chemotherapy and its impact on OSCC cell chemosensitivity. Then, we further investigated the therapeutic effects of the combination therapy of TPF chemotherapy and PI3K‐AKT‐mTOR inhibitors in vitro and in vivo. We found that OSCC patients with low stathmin expression benefited from TPF induction chemotherapy, while OSCC patients with high stathmin expression could not benefit from TPF induction chemotherapy. Stathmin overexpression promoted cellular proliferation and decreased OSCC cell sensitivity to TPF treatment. In addition, inhibition of the PI3K‐AKT‐mTOR signaling pathway decreased stathmin expression and phosphorylation. The combination therapy of TPF chemotherapy and PI3K‐AKT‐mTOR inhibitors exhibited a potent antitumor effect both in vitro and in vivo. Therefore, stathmin can be used as a predictive biomarker for TPF induction chemotherapy and a combination therapy regimen based on stathmin expression might improve the survival of OSCC patients.
The evaluation of stathmin in biopsy tissues has potential as a clinical tool for predicting the outcomes of oral cancer patients undergoing docetaxel, cisplatin, and 5‐fluorouracil (TPF) induction chemotherapy. Combination of TPF chemotherapy and PI3K signaling pathway inhibitors showed potent inhibition of oral cancer cells and xenografts, in which stathmin is highly expressed. Therefore, we are exploring personalized strategies of stathmin expression‐based induction chemotherapy in oral cancer.
Abstract
Novel neoadjuvant therapy regimens are warranted for oral squamous cell carcinoma (OSCC). In this phase I trial (NCT04393506), 20 patients with locally advanced resectable OSCC receive three ...cycles of camrelizumab (200 mg, q2w) and apatinib (250 mg, once daily) before surgery. The primary endpoints are safety and major pathological response (MPR, defined as ≤10% residual viable tumour cells). Secondary endpoints include 2-year survival rate and local recurrence rate (not reported due to inadequate follow-up). Exploratory endpoints are the relationships between PD-L1 combined positive score (CPS, defined as the number of PD-L1-stained cells divided by the total number of viable tumour cells, multiplied by 100) and other immunological and genomic biomarkers and response. Neoadjuvant treatment is well-tolerated, and the MPR rate is 40% (8/20), meeting the primary endpoint. All five patients with CPS ˃10 achieve MPR. Post-hoc analysis show 18-month locoregional recurrence and survival rates of 10.5% (95% CI: 0%–24.3%) and 95% (95% CI: 85.4%–100.0%), respectively. Patients achieving MPR show more CD4+ T-cell infiltration than those without MPR (P = 0.02), and decreased CD31 and ɑ-SMA expression levels are observed after neoadjuvant therapy. In conclusion, neoadjuvant camrelizumab and apatinib is safe and yields a promising MPR rate for OSCC.
A comprehensive study on zircon U-Pb age dating, whole-rock geochemistry and Sr-Nd isotope data has been conducted on the mafic rocks of the Xiazhuang uranium ore district and adjacent regions in ...South China. Based on field work and petrographic features, three rock types (the Kuzhukeng gabbro, the WNW-trending dolerite dykes and the NNE-trending lamprophyre dykes) are distinguished. Early Jurassic SHRIMP and LA-ICPMS ages of zircon for the Kuzhukeng gabbro (198±1Ma) and WNW-trending dolerite dykes (193±4Ma) have been obtained, which are 50Ma older than previously thought (being Cretaceous). These geochronologic data provide new evidence for the rarely identified Early Jurassic magmatisms in South China.
Whole-rock geochemical data for the Kuzhukeng gabbro and WNW-trending dolerite dykes are similar, both of which being higher in FeO and TiO2 but lower in SiO2 and K2O than the NNE-trending lamprophyre dykes. Trace element characteristics and Sr-Nd isotope data indicate arc-like signatures similar to the Cretaceous southeast coast basalts of China for the lamprophyre dykes, but an OIB-like geochemical affinity for the high-TiO2 mafic rocks similar to the Permo/Triassic Emeishan flood basalts and the Middle Jurassic Ningyuan alkaline basalts. We propose that the lamprophyre dykes formed in an arc volcanic system driven by the subduction of the paleo-Pacific plate. In contrast, the Kuzhukeng gabbro and associated dolerite dykes record the post-orogenic (Indosinian) extension event in the Tethyan tectonic regime. This further implies that the Indosinian extension may have lasted until the Early Jurassic, and therefore, the subduction of the paleo-Pacific plate in south China was probably later than this period.
Most U deposits of the Xiazhuang area are located at the intersection between the WNW-trending dolerite dykes and the NNE-trending faults within the Triassic granites of eastern Guidong complex, South China. Previous metallogenesis studies assumed that intrusion of the WNW-trending mafic dykes induced upward migration of mantle-derived CO2-rich fluids, which leached U from the Triassic granite and subsequently precipitated at the intersection between mafic dykes and NEE-trending faults. Our new age data for the WNW-trending dolerite dykes reveal an age gap with respect to the associated U deposits (85–135Ma) of at least 50Ma, arguing against this model. Here, we propose that the role played by the dolerite dykes for U mineralizations is more likely to provide a favorable physicochemical environment promoting the precipitation of U from oxidized fluids. The fluids themselves, however, are probably related to the NNE-trending fault system and associated lamprophyre dykes rather than to the dolerites.
•Three mafic rock types are distinguished in the Xiazhuang U ore district.•Kuzhukeng gabbro and WNW-trending dolerite dykes show Early Jurassic ages.•NNE-trending lamprophyre dykes are caused by subduction of paleo-Pacific plate.•The gabbro and dolerite dykes are controlled by the Tethyan tectonic regime.•The dolerite dykes provide appropriate reduced environments for U precipitation.
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