Global petroleum exploration is currently undergoing a strategic shift from conventional to unconventional hydrocarbon resources. Unconventional hydrocarbons in tight reservoirs show characteristics ...distinct from those of conventional hydrocarbon sources hosted in structural and stratigraphic traps. The characteristic features include the following: a hydrocarbon source and reservoir coexist; porosity and permeability are ultra-low; nano-pore throats are widely distributed; hydrocarbon-bearing reservoir bodies are continuously distributed; there is no obvious trap boundary; buoyancy and hydrodynamics have only a minor effect, and Darcy's law does not apply; phase separation is poor; there is no uniform oil–gas–water interface or pressure system; and oil or gas saturation varies. Examples of unconventional hydrocarbon accumulations are the Mesozoic tight sandstone oil province and the Upper Paleozoic tight sandstone gas province in the Ordos Basin, north-central China. Generally, continuous hydrocarbon accumulation over a large area is a distinguishing characteristic of unconventional hydrocarbon sources. Because of the great potential of unconventional petroleum resources, it is believed that research on such resources will be at the forefront of the future development of petroleum geology.
The Paleotethyan tectonic history of northeast Tibet remains hotly debated, particularly regarding the nature of the Jinsha suture. Different interpretations of the Jinsha suture lead to different ...tectonic reconstructions of northeast Tibet, southern Eurasian continent. We identified three tectonic units along the western segment of the Jinsha suture in the Yushu–Zhiduo region: the Bayan Har–Songpan–Garzê fold belt (BSB), the Yushu mélange, and the eastern portion of the Qiangtang block (EQ). New geochemical and geochronological studies help to identify a Triassic continental magmatic arc (the Yushu arc) that developed upon the EQ and that is geochemically similar to magmatism in the Yidun arc. Structural studies, combined with 40Ar/39Ar analyses, reveal a complex deformational history of the Yushu–Zhiduo region: earlier‐stage top‐to‐the‐north asymmetrical fabrics are preserved exclusively in the Yushu mélange, which yields a phengite 40Ar/39Ar age of 230.5 ± 0.8 Ma; later‐stage orthogonal fabrics developed in the BSB and EQ (superposed upon the earlier fabrics in the Yushu mélange), likely resulted from a collision between the BSB and the Yushu arc that continued until ∼195 Ma. The structural patterns and deformation history of Yushu arc region are comparable with those recorded in the Yidun arc region. Thus, the previously defined Jinsha suture should be subdivided into western and southern segments. The western Jinsha suture is continuous with the Garzê‐Litang suture, while the southern Jinsha‐Ailaoshan suture marks the site of the closure of several intracontinental rift basins that have likely been overprinted by intra or back‐arc extension.
Key Points
The Yidun and Yushu arcs, northeast Tibet, have identical tectonothermal history
The southern Jinsha‐Ailaoshan suture doesn't represent a mature ocean
The western Jinsha suture extends eastward and connects to Garze‐Litang suture
In addition to the role in regulating leukocyte trafficking, chemokines recently have been shown to be involved in cancer growth and metastasis. Chemokine network in tumor neovascularity may be ...regulated by decoy receptors. Duffy antigen receptor for chemokines (DARC) is a specific decoy receptor binding with the angiogenic CC and CXC chemokines. To investigate the effects of DARC on the tumorigenesis and the metastasis potential of human breast cancer cells, human DARC cDNA was reintroduced into the MDA-MB-231 and MDA-MB-435HM cells which have a high capability of spontaneous pulmonary metastasis. We demonstrated that DARC overexpression induced inhibition of tumorigenesis and/or metastasis through interfering with the tumor angiogenesis in vivo. This inhibition is associated with decreasing CCL2 protein levels, and MVD and MMP-9 expression in xenograft tumors. In human breast cancer samples, we also demonstrated that low expression of the DARC protein is significantly associated with estrogen receptor (ER) status, MVD, lymph node metastasis, distant metastasis and poor survival. Our results suggest for the first time that DARC is a negative regulator of growth in breast cancer, mainly by sequestration of angiogenic chemokines and subsequent inhibition of tumor neovascularity.
Summary
Our study focused on the associations of metabolites with BMD and osteoporosis, finding that several metabolites are associated with BMD, and metabolites combined with bone turnover markers ...tend to be more sensitive in distinguishing osteoporosis in both males and postmenopausal females, which might be meaningful for the early diagnosis of osteoporosis.
Introduction
Our study aimed to evaluate the association of metabolites with bone, trying to find new metabolic markers that are distinguishing for low bone mineral density (BMD).
Methods
Our study recruited 320 participants, including 138 males and 182 postmenopausal females from the Shanghai area. Bone turnover markers (BTMs), including osteocalcin, PINP and β-CTX, and other biochemical traits were tested. BMD values of the lumber spine (L1–4), femoral neck and total hip were determined using dual-energy X-ray absorptiometry and the serum metabolome profiles including 221 metabolites from five groups (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, sphingolipids and hexose) were assessed by mass spectrometry.
Results
No visual separation in the metabolic profiles between different BMD groups was observed in principal component analysis (PCA) or partial least squares discriminant analysis (PLS-DA) models. We compared metabolites in three groups with different BMD levels in males and postmenopausal females separately and further filtering these metabolites via random forest-based feature selection, a commonly applied machine learning algorithm which could select the features with the greatest impact on osteoporosis, then metabolites with the highest importance (≥ 5%) (5 in males and 9 in postmenopausal females) were selected to construct better models for osteoporosis classification. After adding these selected metabolites to the model, the area under the curve (AUC) of receiver operating characteristic (ROC) curves increased significantly (BTMs: AUC 0.729, 95% CI 0.647–0.802,
p
< 0.0001, model 1: AUC = 0.828, 95% CI 0.754–0.888,
p
< 0.0001; model 1 versus model of BTMs:
p
= 0.0158) compared to the AUC of the BTM-only model in males. Similar results were also observed in postmenopausal females (BTMs: AUC = 0.638, 95% CI 0.562–0.708,
p
= 0.0025; model 2: AUC = 0.741, 95% CI 0.669–0.803,
p
< 0.0001; model 1 versus model of BTMs:
p
= 0.0182).
Conclusion
Metabolites combined with traditional BTMs tend to better markers for distinguishing osteoporosis in both males and postmenopausal females than BTMs alone.
This study evaluated maintenance treatment with niraparib, a potent inhibitor of poly(ADP-ribose) polymerase 1/2, in patients with platinum-sensitive recurrent ovarian cancer.
In this phase III, ...double-blind, placebo-controlled study conducted at 30 centers in China, adults with platinum-sensitive recurrent ovarian cancer who had responded to their most recent platinum-containing chemotherapy were randomized 2 : 1 to receive oral niraparib (300 mg/day) or matched placebo until disease progression or unacceptable toxicity (NCT03705156). Following a protocol amendment, patients with a bodyweight <77 kg or a platelet count <150 × 103/μl received 200 mg/day, and all other patients 300 mg/day, as an individualized starting dose (ISD). Randomization was carried out by an interactive web response system and stratified by BRCA mutation, time to recurrence following penultimate chemotherapy, and response to most recent chemotherapy. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review.
Between 26 September 2017 and 2 February 2019, 265 patients were randomized to receive niraparib (n = 177) or placebo (n = 88); 249 patients received an ISD (300 mg, n = 14; 200 mg, n = 235) as per protocol. In the intention-to-treat population, median PFS was significantly longer for patients receiving niraparib versus placebo: 18.3 95% confidence interval (CI), 10.9-not evaluable versus 5.4 (95% CI, 3.7-5.7) months hazard ratio (HR) = 0.32; 95% CI, 0.23-0.45; P < 0.0001, and a similar PFS benefit was observed in patients receiving an ISD, regardless of BRCA mutation status. Grade ≥3 treatment-emergent adverse events occurred in 50.8% and 19.3% of patients who received niraparib and placebo, respectively; the most common events were neutrophil count decreased (20.3% versus 8.0%) and anemia (14.7% versus 2.3%).
Niraparib maintenance treatment reduced the risk of disease progression or death by 68% and prolonged PFS compared to placebo in patients with platinum-sensitive recurrent ovarian cancer. Individualized niraparib dosing is effective and safe and should be considered standard practice in this setting.
•Chinese patients with platinum-sensitive recurrent ovarian cancer received maintenance niraparib (n = 177) or placebo (n = 88).•Median PFS was longer for niraparib versus placebo: 18.3 versus 5.4 months (HR = 0.32; 95% CI, 0.23-0.45; P < 0.0001).•Niraparib had a similar PFS benefit for 249 patients receiving individualized dosing based on bodyweight and platelet count.•Grade ≥3 treatment-emergent adverse events occurred in 50.8% and 19.3% of patients who received niraparib and placebo, respectively.•In the niraparib group, Grade ≥3 platelet count decreased/thrombocytopenia occurred in 11.3% of patients.
The hot compression tests of AA7050 aluminum alloy were conducted under conditions of 603–693K and 0.001–10s−1, and the related microstructures were observed. Physically based constitutive analysis ...was conducted to describe the flow behaviors, which can relate the microstructural evolution with flow behaviors for high stacking fault energy (SFE) and/or precipitation-strengthened alloys. A revised model considering the coupling effects of lattice diffusion and grain boundary diffusion was proposed to characterize the transition of diffusion mechanisms under different deformation conditions. The main diffusion mechanism is determined as lattice diffusion at 633–693K and grain boundary diffusion at 603K. The microstructural evolution can be reflected by the deviation of creep exponent n' from the theoretical value (n'=5). The reasons for the creep exponent n'>5 could be related to the change of internal stress and creep rate by dynamic precipitates at lower temperatures. At higher strain rates, it could be related to the impediment of dislocations motion by defects and the change of rate controlling mechanism. The operation of grain boundary sliding (GBS) may lead to n'<5 at higher temperatures and lower strain rates. Moreover, the mechanisms of dynamic recrystallization under wide conditions and high-strain-rate superplasticity were discussed.
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•The physically based model could relate the flow behaviors with microstructural evolution for AA7050 aluminum alloy.•The transition of diffusion mechanism under different deformation conditions was determined by constitutive analyses.•The influences of microstructural evolution on the variation of creep exponentn' were discussed.•The mechanisms of dynamic recrystallization under wide conditions and high-strain-rate superplasticity were discussed.
The effects of systematic variation of Mg and Cu contents (Mg: ~1.5, 2.0, and 2.5, Cu: ~1.5, 2.0, 2.5, and 2.9wt%) on the microstructures and mechanical properties of high-Zn (8.5wt%) Al–Zn–Mg–Cu ...alloys are investigated. Fracture toughness is experimentally approached by the Kahn tear test. Results showed that, under same ageing condition, the conductivity, hardness, strength and toughness of the designed alloys are primarily determined by Mg content: the higher the Mg content, the higher the hardness and strength, but the lower the conductivity and toughness. Increasing Cu content can produce a similar phenomenon, but with weak effects compared with Mg. The experiments and thermodynamic/kinetic simulation indicate that, increasing Mg/Cu content can improve the volume fraction of matrix precipitates, so as to improve the strength and hardness, and the effects of Mg are stronger than Cu. Additionally, increasing Mg content can somewhat reduce the sizes of the matrix precipitates especially in overaged condition, which is also good for the strength and hardness. However, with increasing Mg content the area fraction of the grain boundary precipitates (GBPs) and the yield stress contrast between grain interiors and precipitate free zones (PFZs) at grain boundary can be increased greatly, consequently promoting intergranular fracture and decreasing toughness. For the alloys with low/middle Mg content (e.g., 1.5/2.0wt%), increasing Cu content will improve the yield stress contrast between grain interiors and PFZs as well as the recrystallization degree, so that intergranular fracture will be promoted for toughness reduction. For the alloys with high Mg content (e.g., 2.5wt%), the increased undissolved phases induced by high Cu content will promote fracture at/near coarse constituent particles, favoring further toughness reduction.
Nd-rich phase plays a critical role in wetting grain boundary and facilitating texture formation for hot deformed (HD) Nd-Fe-B magnets. In this study, a non-uniform distribution of Nd-rich phase with ...dimension up to a few micrometers was observed in nanocrystalline HD magnets. The aggregation of the Nd-rich phase is confirmed to result from the low density precursor prepared by spark plasma sintering (SPS). The large local demagnetizing fields induced by Nd-rich phase aggregation led to the open recoil loops and reduced coercivity. Upon reducing recoil loop openness by eliminating Nd-rich phase aggregation, the coercivity of the HD magnet was significantly improved from 226 kA/m to 995 kA/m, and a high maximum energy product of 293 kJ/m3 was obtained. The dependences of microstructure and coercivity on the recoil loop characteristics suggest an essential approach for improving the magnetic properties of nanocrystalline HD Nd-Fe-B magnets.
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Aberrant p62 overexpression has been implicated in breast cancer development. Here, we found that p62 expression was elevated in breast cancer stem cells (BCSCs), including CD44
CD24
fractions, ...mammospheres, ALDH1
populations and side population cells. Indeed, short-hairpin RNA (shRNA)-mediated knockdown of p62 impaired breast cancer cells from self-renewing under anchorage-independent conditions, whereas ectopic overexpression of p62 enhanced the self-renewal ability of breast cancer cells in vitro. Genetic depletion of p62 robustly inhibited tumor-initiating frequencies, as well as growth rates of BCSC-derived tumor xenografts in immunodeficient mice. Consistently, immunohistochemical analysis of clinical breast tumor tissues showed that high p62 expression levels were linked to poorer clinical outcome. Further gene expression profiling analysis revealed that p62 was positively correlated with MYC expression level, which mediated the function of p62 in promoting breast cancer stem-like properties. MYC mRNA level was reduced upon p62 deletion by siRNA and increased with p62 overexpression in breast cancer cells, suggesting that p62 positively regulated MYC mRNA. Interestingly, p62 did not transactivate MYC promoter. Instead, p62 delayed the degradation of MYC mRNA by repressing the expression of let-7a and let-7b, thus promoting MYC mRNA stabilization at the post-transcriptional level. Consistently, let-7a and let-7b mimics attenuated p62-mediated MYC mRNA stabilization. Together, these findings unveiled a previously unappreciated role of p62 in the regulation of BCSCs, assigning p62 as a promising therapeutic target for breast cancer treatments.
To identify more therapeutic targets and clarify the detailed mechanisms of Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PA-MSHA) on breast cancer cells both in vitro and in vivo. PA-MSHA ...was administered to epidermal growth factor receptor (EGFR)-positive human breast cancer cell lines MDA-MB-231HM and MDA-MB-468 in vitro and to mice bearing tumor xenografts. The mannose cocultured test was used to detect the effect of mannose on PA-MSHA-induced cell proliferation, cell cycle arrest, apoptosis, and EGFR pathway signaling. We found that cells stimulated with PA-MSHA exhibited a downregulation of EGFR signaling. The addition of mannose partially inhibited the PA-MSHA-stimulated cell anti-proliferative effect, cell apoptosis, cell cycle arrest, activation of apoptosis-associated caspases, and even downregulation of the EGFR signaling pathway. In vivo, PA-MSHA treatment significantly suppressed mammary tumorigenesis in xenografts in mice and decreased lung metastasis in MDA-MB-231HM cell-transplanted mice. Tumor sample analyses confirmed inhibition of the EGFR pathway in the PA-MSHA-treated mice. In conclusion, this study showed that the involvement of the mannose-mediated EGFR pathway has a critical function in the preclinical rationale for the development of PA-MSHA for the treatment of human breast cancer. It also suggests the potentially beneficial use of PA-MSHA in adjuvant therapy for breast tumors with EGFR overexpression.
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