Abstract
Background
Triple negative breast cancer (TNBC) remains the most challenging breast cancer subtype so far. Specific therapeutic approaches have rarely achieved clinical improvements in ...treatment of TNBC patients and effective molecular biomarkers are largely unknown.
Methods
We used paired TNBC samples and high throughput RNA sequencing to identify differentially expressed circRNAs. Sucrose gradient polysome fractionation assay, antibody and Mass spectra were used to validate active circRNA translation. The novel protein function was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by immunoprecipitation analyses and kinase activity assay.
Results
Circular HER2 RNA (circ-HER2) encoded a novel protein, HER2–103. Unexpectedly, while HER2 mRNA and protein were barely detected, circ-HER2/HER2–103 was expressed in ~ 30% TNBC clinical samples. Circ-HER2/HER2–103 positive TNBC patients harbored worse overall prognosis than circ-HER2/HER2–103 negative patients. Knockdown circ-HER2 inhibited TNBC cells proliferation, invasion and tumorigenesis in vitro and in vivo, suggesting the critical role of circ-HER2/HER2–103 in TNBC tumorigenicity. Mechanistically, HER2–103 promoted homo/hetero dimerization of epidermal growth factor receptor (EGFR)/HER3, sustained AKT phosphorylation and downstream malignant phenotypes. Furthermore, HER2–103 shared most of the same amino acid sequences as HER2 CR1 domain which could be antagonized by Pertuzumab, a clinical used HER2 antibody. Pertuzumab markedly attenuated in vivo tumorigenicity of circ-HER2/HER2–103 expressing TNBC cells but showed no effects in circ-HER2/HER2–103 negative TNBC cells.
Conclusion
Our results not only demonstrated that certain TNBCs were not truly ‘HER2 negative’ but also highlighted the clinical implications of Pertuzumab in circ-HER2/HER2–103 expressing TNBC patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Based on the idea of harmonic extraction, the problem of reducing the damage of the coal seam waiting for upward mining. Using the theoretical analysis method, a schematic diagram of coordinated ...mining along the dip direction of coal seam is established, and the calculation method of reasonable layout parameters of coal seam working face early mining is given. Based on the upward mining problem of the No.1 coal seam in the fifth panel of Zaoquan Coal Mine, the influence parameters of the No.2 coal seam, No.6 coal seam and No.7 coal seam mining on the No.1 coal seam were determined by similar simulation test. Then, the layout parameters of working face were determined. The research method of numerical calculation was used to evaluate the degree and uniformity of movement and deformation of the No.1 coal seam, combining five indicators: subsidence, horizontal movement, inclined deformation, curvature deformation, and horizontal deformation. The results indicate that when the working face is arranged using the layout parameters provided in this article, it can promote the further subsidence of the No.1 coal seam at the position of the remaining coal pillar. The movement and deformation indicators of the No.1 coal seam all reach the most uniform degree of the geological mining conditions, which can effectively offset the uneven deformation problem of the No.1 coal seam caused by the influence of the remaining coal pillars, making multiple mining operations a favorable condition for upward mining and achieving the goal of reducing the damage of the No.1 coal seam.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Emerging studies have revealed the potent functions of circRNAs in breast cancer tumorigenesis. However, the biogenesis, biofunction and mechanism of circRNAs in triple-negative breast cancer (TNBC) ...are largely unknown.
High-throughput RNA sequencing was applied to identify dysregulated circRNAs in TNBCs and paired normal tissues. RNA pulldown and luciferase assays were performed to investigate the interaction between circular CD44 (circCD44, also annotated as hsa_circ_0021735) and miR-502-5p. RNA pulldown and RIP assays were used to investigate the interaction between circCD44 and IGF2BP2. Cell viability, colony formation, migration/invasion assays and in vivo tumorigenesis were used to investigate circCD44 biological functions.
CircCD44 is an uncharacterized circRNA, which is highly expressed in TNBC, and its expression is negatively correlated with the prognosis of TNBC patients. CircCD44 promotes TNBC proliferation, migration, invasion and tumorigenesis at least partially by sponging miR-502-5p and interacting with IGF2BP2.
Our data suggested that overexpressed circCD44 promotes TNBC progression. CircCD44 is potentially a novel diagnostic and therapeutic marker for TNBC patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ferroelastic switching in ferroelectric/multiferroic oxides plays a crucial role in determining their dielectric, piezoelectric, and magnetoelectric properties. In thin films of these materials, ...however, substrate clamping is generally thought to limit the electric-field- or mechanical-force-driven responses to the local scale. Here, we report mechanical-force-induced large-area, non-local, collective ferroelastic domain switching in PbTiO
epitaxial thin films by tuning the misfit-strain to be near a phase boundary wherein c/a and a
/a
nanodomains coexist. Phenomenological models suggest that the collective, c-a-c-a ferroelastic switching arises from the small potential barrier between the degenerate domain structures, and the large anisotropy of a and c domains, which collectively generates much larger response and large-area domain propagation. Large-area, non-local response under small stimuli, unlike traditional local response to external field, provides an opportunity of unique response to local stimuli, which has potential for use in high-sensitivity pressure sensors and switches.
Discrimination of malignancy from thyroid nodules poses challenges in clinical practice. We aimed to identify the plasma metabolomic biomarkers in discriminating papillary thyroid cancer (PTC) from ...benign thyroid nodule (BTN). Metabolomics profiling of plasma was performed in two independent cohorts of 651 subjects of PTC (n = 215), BTN (n = 230), and healthy controls (n = 206). In addition, 132 patients with thyroid micronodules (<1 cm) and 44 patients with BTN suspected malignancy by ultrasound were used for biomarker validation. Recursive feature elimination algorithm was used for metabolic biomarkers selecting. Significant differential metabolites were demonstrated in patients with thyroid nodules (PTC and BTN) from healthy controls (P = 0.0001). A metabolic biomarker panel (17 differential metabolites) was identified to discriminate PTC from BTN with an AUC of 97.03% (95% CI: 95.28-98.79%), 91.89% sensitivity, and 92.63% specificity in discovery cohort. The panel had an AUC of 92.72% (95% CI: 87.46-97.99%), 86.57% sensitivity, and 92.50% specificity in validation cohort. The metabolic biomarker signature could correctly identify 84.09% patients whose nodules were suspected malignant by ultrasonography but finally histological benign. Moreover, high accuracy of 87.88% for diagnosis of papillary thyroid microcarcinoma was displayed by this panel and showed significant improvement in accuracy, AUC and specificity when compared with ultrasound. We identified a novel metabolic biomarker signature to discriminate PTC from BTN. The clinical use of this biomarker panel would have improved diagnosis stratification of thyroid microcarcinoma in comparison to ultrasound.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Transition metal dichalcogenides (TMDs) have drawn great attention owing to their potential for electronic, optoelectronic, and spintronic applications. In TMDs/ferromagnetic bilayers, an efficient ...spin current can be generated by the TMDs to manipulate the magnetic moments in the ferromagnetic layer. In this work, we report on the electric-field modulation of spin–orbit torques (SOTs) in WS2/NiFe bilayers by the spin-torque ferromagnetic resonance technique. It is found that the radio frequency current can induce a spin accumulation at the WS2/NiFe interface because of the interfacial Rashba–Edelstein effect. As a consequence, the SOT ratio between the field-like and antidamping-like torques can be effectively controlled by applying the back-gate voltage in WS2/NiFe bilayers. These results provide a strategy for controlling the SOT by using semiconducting TMDs.
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IJS, KILJ, NUK, PNG, UL, UM
Triple-negative breast cancer (TNBC) patients with truly chemosensitive disease still represent a minority among all TNBC patients. The aim of the present study is to identify microRNAs (miRNAs) that ...correlate with TNBC chemoresistance.
In this study, we conducted miRNAs profile comparison between triple-negative breast cancer (TNBCs) and normal breast tissues by microRNA array. Quantitative real-time PCR (qRT-PCR) was utilized to confirm the specific deregulated miRNAs change trend. We used starBase 2.1 and GOrilla to predict the potential targets of the specific miRNAs. Cells viability and apoptosis assays were employed to determine the effect of alteration of the specific miRNAs in TNBC cells on the chemosensitivity.
We identified 11 specific deregulated miRNAs, including 5 up-regulated miRNAs (miR-155-5p, miR-21-3p, miR-181a-5p, miR-181b-5p, and miR-183-5p) and 6 down-regulated miRNAs (miR-10b-5p, miR-451a, miR-125b-5p, miR-31-5p, miR-195-5p and miR-130a-3p). Thereafter, this result was confirmed by qRT-PCR. We predicted the potential targets of the candidate miRNAs and found that they are involved in cancer-associated pathways. For the first time, we found that miR-130a-3p and miR-451a were down-regulated in TNBC. 9 of the 11 specific deregulated miRNAs were found to be associated with chemoresistance. In vitro assays, we found that up-regulation of either miR-130a-3p or miR-451a in MDA-MB-231 cells significantly changed the cells sensitivity to doxorubicin. The results suggest that TNBC chemotherapy might be affected by a cluster of miRNAs.
The abnormal expression miRNAs in TNBC are mainly chemoresistance related. This might be part of reason that TNBC likely to evade from chemotherapy resulting in early relapse and high risk of death. To alter their expression status might be a potential therapeutic strategy to improve the outcome of chemotherapy for TNBC patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ambipolar photoresponsivity mainly originates from intrinsic or interfacial defects. However, these defects are difficult to control and will prolong the response speed of the photodetector. Here, we ...demonstrate tunable ambipolar photoresponsivity in a photodetector built from vertical p-WSe2/n-InSe heterostructures with photogating effect, exhibiting ultrahigh photoresponsivity from −1.76 × 104 to 5.48 × 104 A/W. Moreover, the photodetector possesses broadband photodetection (365–965 nm), an ultrahigh specific detectivity (D*) of 5.8 × 1013 Jones, an external quantum efficiency of 1.86 × 107%, and a rapid response time of 20.8 ms. The WSe2/InSe vertical architecture has promising potential in developing high-performance nano-optoelectronics.
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IJS, KILJ, NUK, PNG, UL, UM
In recent years, low-dimensional materials have received extensive attention in the field of electronics and optoelectronics. Among them, photoelectric devices based on photoconductive effect in ...low-dimensional materials have a broad development space. In contrast to positive photoconductivity, negative photoconductivity (NPC) refers to a phenomenon that the conductivity decreases under illumination. It has novel application prospects in the field of optoelectronics, memory, and gas detection,
etc
. In this paper, we review reports about the NPC effect in low-dimensional materials and systematically summarize the mechanisms to form the NPC effect in existing low-dimensional materials.
Ticlopidine has inhibitory effects on platelet aggregation via ADP (adenosine diphosphate), platelet release reaction and depolymerization. In clinical practice, it is commonly used to prevent heart, ...cerebrovascular and other thromboembolic diseases. However, ticlopidine has also been reported to have teratogenic effects on the heart, though its specific molecular mechanism remains unclear. In this study, zebrafish embryos were used as model organisms to examine the toxicity effect of ticlopidine. Zebrafish embryos exposed to 6, 7.5, and 9 mg/L ticlopidine solutions manifested several abnormalities, including body curvature, smaller eyes, slower absorption of the vitella sac, pericardial edema, slower heart rate, increased mortality, longer venous sinus - arterial ball (SV-BA) distance, and increased oxidative stress, which indicated developmental and cardiac toxicity. Abnormal expression of key genes related to heart development was observed, and the level of apoptotic gene expression was up-regulated. Further experiments revealed up-regulation of embryonic oxidative stress following ticlopidine exposure, leading to a decrease in cardiomyocyte proliferation. Conversely, the aromatic hydrocarbon receptor (AHR) inhibitor CH223191 protected embryos from the cardiotoxicity effect of ticlopidine, confirming further the role of up-regulated oxidative stress as the molecular mechanism of ticlopidine-induced cardiotoxicity in zebrafish. In conclusion, ticlopidine exposure leads to developmental and cardiotoxicity in zebrafish embryos. Therefore, further studies are warranted to ascertain such potential harms of ticlopidine in humans, which are vital in providing guidance in the safe use of drugs in clinical practice.
•Ticlopidine affects early cardiac development in zebrafish, causing cardiac damage and cardiotoxicity.•Ticlopidine exposure increases oxidative stress and induces a decrease in zebrafish cardiomyocyte proliferation.•The cardiac developmental toxicity induced by ticlopidine is associated with oxidative stress.•The aromatic hydrocarbon receptor (AHR) inhibitor CH223191 can rescue the phenotype caused by ticlopidine exposure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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