Tumor eradication may be greatly improved by targeting cancer stem cells (CSCs), as they exhibit resistance to conventional therapy. To gain insight into the unique biology of CSCs, we developed ...patient-derived xenograft tumors (PDXs) from ER− breast cancers from which we isolated mammospheres that are enriched for CSCs. Comparative global proteomic analysis was performed on patient tumor tissues and corresponding PDXs and mammospheres. Mammospheres exhibited increased expression of proteins associated with de novo cholesterol synthesis. The clinical relevance of increased cholesterol biosynthesis was verified in a large breast cancer cohort showing correlation with shorter relapse-free survival. RNAi and chemical inhibition of the cholesterol biosynthesis pathway reduced mammosphere formation, which could be rescued by a downstream metabolite. Our findings identify the cholesterol biosynthesis pathway as central for CSC propagation and a potential therapeutic target, as well as providing a mechanistic explanation for the therapeutic benefit of statins in breast cancer.
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•Cholesterol biosynthesis is essential for breast cancer stem cell propagation•Expression of cholesterol synthesis proteins correlates with TNBC patient outcome•Inhibition of cholesterol biosynthesis reduces mammosphere formation
Ehmsen et al. identify cholesterol biosynthesis as essential for breast cancer stem cell propagation. Increased expression of multiple cholesterol biosynthesis proteins is observed in mammospheres, and the expression levels of these proteins correlate with the outcome of basal-like breast cancer patients. Inhibition of the cholesterol biosynthesis pathway reduces mammosphere formation.
Nacre-inspired metal matrix composites have received much attention due to their excellent deformation coordination ability, which can achieve the synergy of strength and ductility. The preparation ...of nacre-like Al matrix composites by freeze casting has been a promising application, but the continuous ceramic-rich layer affects the corrosion resistance of the composites, facing complex corrosion problems during service. In this work, the microstructure and corrosion behavior of the nacre-inspired (TiBw-TiB2)/Al composites fabricated by freeze casting and squeeze casting were systematically studied. The results indicated that the Al layers and ceramic-rich layers had little change, about 35 μm and 31 μm, respectively, with an increasing ratio of the Ti/TiB2. Meanwhile, a high Ti/TiB2 ratio resulted in an increase in the Fe-Ti intermetallic phases, which was detrimental to the corrosion performance of the composites and was prone to pitting. The electrochemical test results showed that the 3Ti7TiB2 composite had the lowest corrosion current density (15.9 μA) and intergranular corrosion depth (231 μm), indicating that it had the best corrosion resistance, which can be attributable to its stable and dense passivation film. Two different corrosion phenomena during the intergranular corrosion test existed in the present nacre-inspired (TiBw-TiB2)/Al composites: intergranular corrosion in the Al matrix layer and pitting corrosion in the ceramic-rich layer. Among all the composites, the corrosion depth of the 3Ti7TiB2 composite was the smallest and significantly less than that of the 2024Al alloy. In addition, the continuous ceramic-rich layer acted as a corrosion channel during corrosion, significantly degrading the corrosion resistance of the nacre-like Al composites.
The distribution of reinforcements and interfacial bonding state with the metal matrix are crucial factors in achieving excellent comprehensive mechanical properties for aluminum (Al) matrix ...composites. Normally, after heat treatment, graphene nanosheets (GNSs)/Al composites experience a significant loss of strength. Here, better performance of GNS/Al was explored with a hybrid strategy by introducing 0.9 vol.% silicon carbide nanoparticles (SiCnp) into the composite. Pre-ball milling of Al powders and 0.9 vol.% SiCnp gained Al flakes that provided a large dispersion area for 3.0 vol.% GNS during the shift speed ball milling process, leading to uniformly dispersed GNS for both as-sintered and as-extruded (0.9 vol.% SiCnp + 3.0 vol.% GNS)/Al. High-temperature heat treatment at 600 °C for 60 min was performed on the as-extruded composite, giving rise to intragranular distribution of SiCnp due to recrystallization and grain growth of the Al matrix. Meanwhile, nanoscale Al
C
, which can act as an additional reinforcing nanoparticle, was generated because of an appropriate interfacial reaction between GNS and Al. The intragranular distribution of both nanoparticles improves the Al matrix continuity of composites and plays a key role in ensuring the plasticity of composites. As a result, the work hardening ability of the heat-treated hybrid (0.9 vol.% SiCnp + 3.0 vol.% GNS)/Al composite was well improved, and the tensile elongation increased by 42.7% with little loss of the strength. The present work provides a new strategy in achieving coordination on strength-plasticity of Al matrix composites.
Levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with the incidence of coronary artery disease (CAD). However, the underlying mechanism of CAD in the context of ...elevated HDL-C levels is unclear. Our study aimed to explore the lipid signatures in patients with CAD and elevated HDL-C levels and to identify potential diagnostic biomarkers for these conditions. We measured the plasma lipidomes of forty participants with elevated HDL-C levels (men with >50 mg/dL and women with >60 mg/dL), with or without CAD, using liquid chromatography-tandem mass spectrometry. We analyzed four hundred fifty-eight lipid species and identified an altered lipidomic profile in subjects with CAD and high HDL-C levels. In addition, we identified eighteen distinct lipid species, including eight sphingolipids and ten glycerophospholipids; all of these, except sphingosine-1-phosphate (d20:1), were higher in the CAD group. Pathways for sphingolipid and glycerophospholipid metabolism were the most significantly altered. Moreover, our data led to a diagnostic model with an area under the curve of 0.935, in which monosialo-dihexosyl ganglioside (GM3) (d18:1/22:0), GM3 (d18:0/22:0), and phosphatidylserine (38:4) were combined. We found that a characteristic lipidome signature is associated with CAD in individuals with elevated HDL-C levels. Additionally, the disorders of sphingolipid as well as glycerophospholipid metabolism may underlie CAD.
Remote ischemic postconditioning (RIPostC) induced by brief episodes of the limb ischemia is a potential therapeutic strategy for myocardial ischemia/reperfusion injury, achieved by reducing ...cardiomyocyte death, inflammation and so on. The actual mechanisms underlying cardioprotection conferred by RIPostC remain unclear. Exploring gene expression profiles in myocardium at transcriptional level is helpful to deepen the understanding on the cardioprotective mechanisms of RIPostC. This study aims to investigate the effect of RIPostC on gene expressions in rat myocardium using transcriptome sequencing.
Rat myocardium samples from the RIPostC group, the control group (myocardial ischemia/reperfusion group) and the sham group were performed transcriptome analysis using RNA sequencing. The levels of cardiac IL-1β, IL-6, IL-10 and TNFα were analyzed by Elisa. The expression levels of candidate genes were verified by qRT-PCR technique. Infarct size was measured by Evans blue and TTC staining. Apoptosis was assessed by TUNEL assays and caspase-3 levels were detected using western blotting.
RIPostC can markedly decrease infarct size and reduce the levels of cardiac IL-1β, IL-6 and increase the level of cardiac IL-10. This transcriptome analysis showed that 2 genes were up-regulated (Prodh1 and ADAMTS15) and 5 genes (Caspase-6, Claudin-5, Sccpdh, Robo4 and AABR07011951.1) were down-regulated in the RIPostC group. Go annotation analysis showed that Go terms mainly included cellular process, metabolic process, cell part, organelle, catalytic activity and binding. The KEGG annotation analysis of DEGs found only one pathway, amino acid metabolism, was up-regulated. The relative mRNA expression levels of ADAMTS15, Caspase-6, Claudin-5 and Prodh1 were verified by qRT-PCR, which were consistent with the RNA-seq results. In addition, the relative expression of ADAMTS15 was negatively correlated with the level of cardiac IL-1β (
= -0.748,
= 0.005) and positively correlated with the level of cardiac IL-10 (
= 0.698,
= 0.012). A negative correlation statistical trend was found between the relative expression of ADAMTS15 and the level of cardiac IL-6 (
= -0.545,
= 0.067).
ADAMTS15 may be a potential inflammation-related gene in regulation of cardioprotection conferred by remote ischemic postconditioning and a possible therapeutic target for myocardial ischemia reperfusion injury in the future.
The protective effect of Neuregulin-1 (NRG-1) on heart failure is well established. In this study, we assessed whether NRG-1 could protect the heart by mimicking the cardioprotective effects of ...ischaemic postconditioning (IP).
We used a myocardial reperfusion injury rat model in vivo to compare the cardioprotective effects of NRG-1(3 μg/kg, iv. at the onset of reperfusion) and IP. In Langendorff isolated heart perfusion experiments, we used the erythroblastic leukaemia viral oncogene homolog 4 (ErbB4) inhibitor AG1478, a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and a mitogen-activated protein/extracellular signal regulated kinase (MEK) inhibitor PD98059 to clarify whether the protective effects of NRG-1and IP depend on the NRG-1/ErbB4 signals and the reperfusion injury salvage kinase (RISK) pathway. Infarct size was detected by Evans blue and TTC. Apoptosis was detected by TUNEL assays. The expression of NRG-1/ErbB4 and downstream ERK1/2, AKT, AMPK and p70s6K were detected by western blotting. Hematoxylin/eosin (H&E) staining was used for histological analysis.
We found that NRG-1 and IP had similar effects on reducing myocardial infarct size and apoptosis in vivo. NRG-1 heart protein levels were upregulated in the IP group. Phosphorylation of AKT, ERK1/2 and ErbB4 were also increased in both the IP and NRG-1 groups. Furthermore, in Langendorff analyses, the ErbB4 inhibitor AG1478 suppressed the phosphorylation of ErbB4 and the RISK pathway and aggravated myocardial edema and fiber fracture, thereby inhibited the cardioprotective effects in both the IP and NRG-1 groups. For assessment of downstream signals, the PI3K inhibitor LY294002 and the MEK inhibitor PD98059 suppressed the phosphorylation of AKT and ERK1/2 respectively and abolished the cardioprotective effects induced by IP and NRG-1.
In conclusion, both IP and NRG-1 could reduce infarct size and apoptosis through ErbB4-dependent activation of the RISK pathway in the same model; these results indicated the therapeutic potential of NRG-1 as a pharmacological postconditioning agent against myocardial reperfusion injury.
Purpose
To compare the safety and efficacy of left versus right internal jugular vein access for portal vein puncture during transjugular intrahepatic portosystemic shunt (TIPS) creation in patients ...with a small liver and short vertical puncture distance.
Materials and Methods
The vertical distance from the hepatic vein orifice to the puncture point of the portal vein was measured by CT and DSA. A distance ≤ 30 mm is defined as a short vertical puncture distance. After 1:1 propensity score matching (PSM), 29 patients of left internal jugular vein-TIPS (LIJ-TIPS) and 29 patients of right internal jugular vein-TIPS (RIJ-TIPS) were included. The number of needle punctures, fluoroscopy time, and radiation dose during the puncture process were statistically analyzed.
Results
There was no significant difference in the average vertical puncture distances on CT or DSA between LIJ-TIPS and RIJ-TIPS (19.10 ± 0.60 mm
vs.
19.30 ± 0.60 mm,
P
= 0.840; 22.02 ± 0.69 mm
vs.
22.23 ± 0.64 mm,
P
= 0.822, respectively). The average number of needle punctures, fluoroscopy time, and radiation dose in LIJ-TIPS were significantly lower than those in RIJ-TIPS (2.07 ± 0.20
vs.
4.10 ± 0.24,
P
< 0.001; 78.45 ± 12.80 s
vs.
201.16 ± 23.71 s,
P
< 0.001; 31.55 ± 7.04 mGy
vs.
136.69 ± 16.38 mGy,
P
< 0.001, respectively). Within three punctures, the technical success rate in LIJ-TIPS was significantly higher than that in RIJ-TIPS (86.2
vs.
27.6%,
P
< 0.001). The incidence of hemoperitoneum in LIJ-TIPS was significantly lower than that in RIJ-TIPS (0%
vs.
13.8%,
P
= 0.038).
Conclusion
The left internal jugular vein could be used as primary access for TIPS creation in patients with a small liver and short vertical puncture distance.
Background
Repeated remote ischemic conditioning (RIC) after myocardial infarction (MI) has been shown to improve left ventricular (LV) remodeling in the experimental studies, but its ...cardioprotective effect in patients with ST-segment elevation myocardial infarction (STEMI) is still unknown.
Objective
To investigate whether repeated RIC started early after primary percutaneous coronary intervention (PCI) can improve LV function in patients with STEMI.
Methods
Patients with STEMI treated by primary PCI were included and randomized to the repeated RIC group (
n
= 30) or the control group (
n
= 30). RIC was started within 24 h after PCI and repeated daily for 1 week, using an Auto RIC device. 3D speckle-tracking echocardiography (STE) was used to assessed LV function. The primary study endpoint was the change in LV global longitudinal strain (GLS) from baseline to 1 month after PCI.
Results
The repeated RIC group and the control group were well-matched at baseline including mean GLS (−9.8 ± 2.6% vs. −10.1 ± 2.5%,
P
= 0.62). Despite there was no significant difference in mean GLS at 1 month between the two groups (−11.9 ± 2.1% vs. −10.9 ± 2.7%,
P
= 0.13), the mean change in GLS from baseline to 1 month was significantly higher in the treatment group than in the control group (−2.1 ± 2.5% vs. −0.8 ± 2.3%,
P
= 0.04). There were no significant differences in the changes in global circumferential strain (GCS), global area strain (GAS), global radial strain (GRS), LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV) between the two groups. Peak creatine kinase isoenzyme-MB, peak high-sensitivity troponin T, and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at 24 h after PCI did not differ significantly between the two groups, but NT-proBNP levels at 1 week were significantly lower in the treatment group than in the control group 357.5 (184.8–762.8) vs. 465.0 (305.8–1525.8) pg/ml,
P
= 0.04.
Conclusion
Daily repeated RIC started within 24 h after PCI can improve GLS and reduce plasma NT proBNP levels in patients with STEMI.
The effects of La addition on the microstructure, thermal conductivity and mechanical properties of as-cast and as-extruded Mg-3Al-xLa-0.3Mn (x = 1, 3 and 5 wt.%) alloys were studied. The results ...showed that the thermal conductivity of the alloys increased with the addition of La element, which was due to the formation of the Al
La
phases by consuming the solute Al and the added La element. The yield strength of the as-cast Mg-3Al-xLa-0.3Mn alloys increased with the increase in La concentration. The thermal conductivity of the as-extruded alloys was lower than that of as-cast counterparts owing to lots of defects generated in the process of hot extrusion deformation, particularly the grain boundaries. The anisotropy of thermal conductivity was discovered in the as-extruded alloys on account of the formation of texture. As the La content increases, the tensile strength and yield strength of the as-extruded alloys decreased gradually. In contrast, the elongation first increased and then decreased, resulting from the combined effect of the texture strengthening and second phase strengthening.
High density lipoprotein (HDL) cholesterol levels and cholesterol efflux capacity (CEC) are inversely correlated with coronary artery disease (CAD) risk. Myeloperoxidase (MPO) derived oxidants and ...HDL proteome changes are implicated in HDL dysfunction in subjects with CAD in the United States; however, the effect of MPO on HDL function and HDL proteome in ethnic Chinese population is unknown. We recruited four matched ethnic Chinese groups (20 patients each): subjects with 1) low HDL levels (HDL levels in men <40mg/dL and women <50mg/dL) and non-CAD (identified by coronary angiography or cardiac CT angiography); 2) low HDL and CAD; 3) high HDL (men >50mg/dL; women >60mg/dL) with no CAD; and 4) high HDL with CAD. Serum cytokines, serum MPO levels, serum CEC, MPO-oxidized HDL tyrosine moieties, and HDL proteome were assessed by mass spectrometry individually in the four groups. The cytokines, MPO levels, and HDL proteome profiles were not significantly different between the four groups. As expected, CEC was depressed in the entire CAD group but more specifically in the CAD low-HDL group. HDL of CAD subjects had significantly higher 3-nitrotyrosine than non-CAD subjects, but the MPO-specific 3-chlorotyrosine was unchanged; CEC in the CAD low-HDL group did not correlate with either HDL 3-chlorotyrosine or 3-nitrotyrosine levels. Neither 3-chlorotyrosine, which is MPO-specific, nor 3-nitrotyrosine generated from MPO or other reactive nitrogen species was associated with CEC. MPO mediated oxidative stress and HDL proteome composition changes are not the primary cause HDL dysfunction in Chinese subjects with CAD. These studies highlight ethnic differences in HDL dysfunction between United States and Chinese cohorts raising possibility of unique pathways of HDL dysfunction in this cohort.
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