The continental slopes of the South China Sea (SCS), the largest marginal sea on the continental shelf of Southeast Asia, are among the most significant shelf-margin basins in the world because of their abundant petroleum resources and a developmental history related to sea floor spreading since Late Oligocene time. Based on integrated analyses of seismic, well-logging and core data, we systematically document the sequence architecture and depositional evolution of the northern continental slope of the SCS and reveal its responses to tectonism, sea-level change and sediment supply. The infill of this shelf-margin basin can be divided into seven composite sequences (CS1-CS7) that are bounded by regional unconformities. Composite sequences CS3 to CS7 have formed since Late Oligocene time, and each of them generally reflects a regional transgressive-regressive cycle. These large cycles can be further divided into 20 sequences that are defined by local unconformities or transgressive-regressive boundaries. Depositional-geomorphological systems represented on the continental slope mainly include shelf-edge deltas, prodelta-slope fans, clinoforms of the shelf-margin slope, unidirectionally migrating slope channels, incised slope valleys, muddy slope fans, slope slump-debris-flow complexes and large-scale soft-sediment deformation of bedding. Changing sea levels, reflected by evidence from sequence architecture in the study area, are generally comparable with those of the Haq (1987) global sea level curve, whereas the regional transgressions and regressions were apparently controlled by tectonic uplift and subsidence. Composite sequences CS3 and CS4 formed from Late Oligocene to Middle Miocene time and represent continental-slope deposition during a time of northwest-northeast seafloor spreading and subsequent development of subbasins in the southwest-central SCS. The development of composite sequences CS5 to CS7 after Middle Miocene time was obviously influenced by the Dongsha Movement during convergence between the SCS and Philippine Sea plates. Climatic variations and monsoon intensification may have enhanced sediment supply during Late Oligocene-Early Miocene (25-21 Ma) and Late Pliocene-Pleistocene (3-0.8 Ma) times. This study indicates that shelf-edge delta and associated slope fan systems are the most important oil/gas-bearing reservoirs in the SCS continental-slope area.

OBJECTIVE Primary spinal cord H3 K27M-mutant diffuse midline glioma (DMG) is a rare and devastating pathological entity. However, little attention has been paid to this disease. As a result, its clinicoradiological characteristics have yet to be described. The aim of this study was to describe the clinicoradiological characteristics of primary intramedullary H3 K27M-mutant DMG and to compare this tumor with the H3 K27 wild-type to explore potential features that could differentiate the two. METHODS A total of 59 patients with pathologically confirmed intramedullary astrocytoma were included in this study. The cohort was divided into an H3 K27M-mutant group and H3 K27 wild-type group based on the status of H3 K27M according to an immunohistochemistry method. Demographic data, MRI features, and molecular information were collected. Multivariate logistic regression was conducted to investigate variables that might have a role in differentiating an H3 K27M DMG from an H3 K27 wild-type tumor. RESULTS Only symptom duration showed an independent association with the H3 K27M mutation (OR 0.82, 95% CI 0.68–0.94, p = 0.016). Patients with spinal cord H3 K27M-mutant DMG had a shorter symptom duration than patients with H3 K27 wild-type glioma. No significant difference was found in terms of MRI features between the H3 K27M-mutant and H3 K27 wild-type groups. Additionally, H3 K27M-mutant DMG frequently demonstrated overexpression of p53. Survival outcome did not show a statistical difference between the H3 K27-mutant subgroup and H3 K27 wild-type subgroup in histologically high-grade astrocytoma. CONCLUSIONS Symptom duration was associated with an H3 K27M mutation in intramedullary astrocytoma. MRI features were heterogeneous, and no imaging feature was able to predict the H3 K27M mutation. The H3 K27M mutation did not impact survival outcome in spinal histologically high-grade astrocytoma.

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Recent evidence shows that dopamine D2-like receptor (D2DR) antagonists, such as trifluoperazine and thioridazine, are effective for cancer therapy and inhibition of cancer stem-like cells (CSCs). In this study, we investigated the anti-cancer effects of combination therapy of dexamethasone (DEX) and sulpiride (SUL), an atypical antipsychotic, against drug-resistant and metastatic breast cancers and further explored the underlying mechanisms. Oral administration of SUL (25, 100 mg·kg·d) alone did not inhibit the tumor growth in human breast cancer MCF-7/Adr xenograft model, but dose-dependently decreased the proportion of CSCs in vitro and in vivo. In contrast, combination therapy of SUL (50 mg·kg·d) and DEX (8 mg·kg·d) markedly suppressed the tumor growth in MCF-7/Adr xenograft model with little systemic toxicity and lung metastasis in murine metastatic breast cancer 4T1 xenograft model. Among the metastasis-associated biomarkers analyzed, the combination therapy significantly decreased the levels of MMP-2, but increased E-cadherin levels in 4T1 xenograft tumors. Moreover, the combination therapy significantly inhibited the cell colony formation, migration and invasion of 4T1 and human breast cancer MDA-MB-231 cells in vitro. Addition of a specific D2DR agonist 7-OH-DPAT to the combination therapy reversed the enhanced anti-cancer effects in vivo and CSC population loss in tumor tissues. Our data demonstrate that SUL remarkably enhances the efficacy of DEX in the treatment of drug-resistant and metastatic breast cancer via the antagonism of D2DR, which might result from the eradication of CSCs.

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Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid E equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an E equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.