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Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to a high rate of tumour metastasis and disease recurrence. In physiological conditions, tetraspanins interact with specific partner proteins in tetraspanin‐enriched microdomains and regulate their subcellular localization and function. However, the function of Tspan5 in pathological processes, particularly in cancer biology and its clinical significance, are still unclear. Here, we describe that a high expression of Tspan5 is significantly associated with some clinicopathological features including invasive length, vascular invasion, clinical stage and poor overall survival of HCC patients. Alterations of Tspan5 expression by lentivirus transductions in HCC cells demonstrated that Tspan5 promotes wound healing and cell migration in vitro and tumour metastasis of HCC cells in vivo. Mechanistic studies revealed that Tspan5 promoted cell migration and tumour metastasis by increasing the enzymatic maturation of ADAM10 and activating Notch signalling via the increase of the cleavage of the Notch1 receptor catalysed by the γ‐secretase complex. Activation of Notch signalling by Tspan5 was shown further to enhance the epithelial–mesenchymal transition (EMT) and actin skeleton rearrangement of tumour cells. In clinical HCC samples, Tspan5 expression is strongly correlated with many key molecules acting in Notch signalling and EMT, highlighting the role of Tspan5 in the regulation of Notch signalling, EMT and tumour metastasis of HCC. Our findings provide new insights into the mechanism of tumour metastasis and disease progression of HCC and may facilitate the development of novel clinical intervention strategies against HCC., We demonstrated that Tspan5 promotes the enzymatic maturation of ADAM10 and activates Notch signalling. The γ‐secretase complex catalyses the cleavage of Notch1 for the release of NICD, which is then translocated to the nucleus where it activates Notch target gene transcription. By activating Notch signalling, Tspan5 promoted epithelial–mesenchymal transition, actin skeleton rearrangement, tumour migration and metastasis of HCC, resulting in poor patient survival.

We compute global sections of tensor products and symmetric products of several secant bundles of a nonsingular projective curve. We closely follow the approach of Gentiana Danila’s work on the similar problem for nonsingular projective surfaces.

Existing nanoparticle-mediated drug delivery systems for glioma systemic chemotherapy remain a great challenge due to poor delivery efficiency resulting from the blood brain barrier/blood-(brain tumor) barrier (BBB/BBTB) and insufficient tumor penetration. Here, we demonstrate a distinct design by patching doxorubicin-loaded heparin-based nanoparticles (DNs) onto the surface of natural grapefruit extracellular vesicles (EVs), to fabricate biomimetic EV-DNs, achieving efficient drug delivery and thus significantly enhancing antiglioma efficacy. The patching strategy allows the unprecedented 4-fold drug loading capacity compared to traditional encapsulation for EVs. The biomimetic EV-DNs are enabled to bypass BBB/BBTB and penetrate into glioma tissues by receptor-mediated transcytosis and membrane fusion, greatly promoting cellular internalization and antiproliferation ability as well as extending circulation time. We demonstrate that a high-abundance accumulation of EV-DNs can be detected at glioma tissues, enabling the maximal brain tumor uptake of EV-DNs and great antiglioma efficacy in vivo.

We establish projective normality, Property N p and effective very ampleness for line bundles on a Calabi–Yau variety, as well as for pluricanonical bundles of a variety of general type. We also prove a result on the degrees of generators of canonical rings under the condition that the image of the canonical map has minimal degree.

Chang’E-3 landed at the north part of the Mare Imbrium on 14 December 2013, Chang’E-4 landed at South Pole’s Aitken Basin on 3 January 2019 and Chang’E-5 landed at Rümker region in northern Oceanus Procellarum on 1 December 2020. The microwave range and velocity sensor (MRVS) on the lander provided the range and velocity information relative to the lunar surface during the powered descent phase, ensuring landing softly. In this paper, we use the lunar surface backscatter coefficient of Ka-band which was analyzed from the telemetry of MRVS equipped on Chang’E-3 and Chang’E-4, as for the important design basis of Chang’E-5 MRVS; at the same time, actual data is analyzed from the telemetry of Chang’E-5 sensor, and the accumulated analysis of lunar surface backscatter coefficient as the important reference will be used in the future MRVS design and lunar detection.

In recent years, the equations defining secant varieties and their syzygies have attracted considerable attention. The purpose of the present paper is to conduct a thorough study on secant varieties of curves by settling several conjectures and revealing interaction between singularities and syzygies. The main results assert that if the degree of the embedding line bundle of a nonsingular curve of genus $g$ is greater than $2g+2k+p$ for nonnegative integers $k$ and $p$, then the $k$-th secant variety of the curve has normal Du Bois singularities, is arithmetically Cohen--Macaulay, and satisfies the property $N_{k+2, p}$. In addition, the singularities of the secant varieties are further classified according to the genus of the curve, and the Castelnuovo--Mumford regularities are also obtained as well. As one of the main technical ingredients, we establish a vanishing theorem on the Cartesian products of the curve, which may have independent interests and may find applications elsewhere., 36 pages. Comments are welcome

Correlation between RAS gene mutation and microsatellite instability (MSI) status in cancer tissues and clinicopathological parameters of patients with stage III colorectal cancer (CRC) were investigated. Tissues were collected from 180 patients diagnosed with stage III CRC in the Department of Gastrointestinal Surgery of the Fourth Hospital of Hebei Medical University from 2012 to 2016. RAS gene mutations in paraffin sections were detected by PCR and Sanger sequencing. Expression of mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 was detected by immunohistochemistry, and MSI status was determined based on the positive and negative expression combinations of the above proteins, and the correlation with clinicopathological parameters of CRC was analyzed. Mutation rates of KRAS and NRAS were 48.33% (87/180) and 2.78% (5/180), respectively. Mutation rate of p.G12D in codon 12 of exon 2 in KRAS gene was the highest (31/87, 35.63%). Mutation rate of p.G12D in codon 12 of exon 2 in NRAS gene was the highest (2/5, 40%). Mutation rate of KRAS gene in right colon was higher than that in left colon and rectum (p

Atmospheric plasma-sprayed (APS) coatings have a layered structure as well as lower strain tolerance and a shorter lifetime than EB-PVD coatings. In this study, TBCs composed of a LaMgAl11O19 (LMA) top coat and a NiCrAlY bond coat were prepared by APS coupled with dry-ice blasting to implant vertical microcracks in the top coat. The thermal cycling lifetime and CMAS corrosion behaviour of LMA-TBCs with pre-implanted vertical microcracks were investigated in detail. The results show that the LMA top coat possesses an improved proportion of vertical microcracks and that the corresponding TBC has an improved thermal cycling lifetime. The vertical microcracks in the top coats, which not only reduce the thermal stress but also improve the strain tolerance of TBCs, dramatically contribute to the improvement in the thermal cycling lifetime. Surprisingly, the CMAS corrosion resistance of LMA-type TBCs with implanted vertical microcracks is better than that of conventional TBCs with a typical layered structure.

In this paper, we prove a formula of Grauert-Riemenschneider canonical sheaf and log canonical thresholds for a general residual intersection as well as an equality of minimal log discrepancies under a general link. We also prove an evidence that MJ-singularities can be preserved under a general residual intersection., Comment: 13 pages, to appear in Contemp. Math

Let X ⊆ P r be a scroll of codimension e and degree d over a smooth projective curve of genus g . The purpose of this paper is to prove a linear Castelnuovo–Mumford regularity bound that reg ( X ) ≤ d − e + 1 + g ( e − 1 ) . This bound works over an algebraically closed field of arbitrary characteristic.

The aim of this study is to investigate the influencing factors associated with no/low response to preoperative concurrent chemoradiotherapy (CCRT) for locally advanced rectal cancer (LARC) patients. A total of 79 patients were included in this prospective study. Fifteen factors that might affect the resistance to CCRT were included in this logistic regression analysis, these factors include the general clinical data of patients, the expression status of tumor stem cell marker CD44v6 and the volumetric imaging parameters of primary tumor lesions. We found that the no/low response status to preoperative CCRT was positively correlated with the real tumor volume (RTV), the total surface area of tumor (TSA), and CD44v6 expression, whereas negatively correlated with the tumor compactness (TC). According to the results of logistic regression analysis, two formulas that could predict whether or not no/low response to preoperative CCRT were established. The Area Under Curve (AUC) of the two formulas and those significant measurement data (RTV, TC, TSA) were 0.900, 0.858, 0.771, 0.754, 0.859, the sensitivity were 95.8%, 79.17%, 62.50%, 95.83%, 62.5%, the specificity were 70.9%, 74.55%, 83.64%,47.27%, 96.36%, the positive predictive values were 58.96%, 57.58%, 62.51%,44.23%, 88.23%, the negative predictive values were 97.48%, 89.13%, 83.64%, 96.29%, and 85.48%, respectively.

In this paper, we show that for a nonsingular projective curve and a positive integer \begin{document}$ k $\end{document}, the \begin{document}$ k $\end{document}-th secant bundle is the blowup of the \begin{document}$ k $\end{document}-th secant variety along the \begin{document}$ (k-1) $\end{document}-th secant variety. This answers a question raised in the recent paper of the authors on secant varieties of curves.

// Peirong He 1, 2, * , Suihai Wang 1, * , Xuefeng Zhang 1 , Yanjun Gao 1 , Wenbo Niu 1 , Ningning Dong 1 , Xiangyi Shi 1 , Yan Geng 2 , Qiang Ma 1 , Ming Li 1 , Bo Jiang 2 , Ji-Liang Li 1, 3 1 School of Biotechnology, Southern Medical University, Guangzhou 510515, China 2 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China 3 Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth PL6 8BU, U.K * These authors have contributed equally to this work Correspondence to: Bo Jiang, e-mail: drjiang@163.com Ji-Liang Li, e-mail: ji-liang.li@plymouth.ac.uk Keywords: gastric cancer, tetraspanin, tumour suppressor, cell cycle, biomarker Received: February 27, 2016 Accepted: April 26, 2016 Published: May 20, 2016 ABSTRACT Tetraspanins are believed to interact with specific partner proteins forming tetraspanin-enriched microdomains and regulate some aspects of partner protein functions. However, the role of Tspan5 during pathological processes, particularly in cancer biology, remains unknown. Here we report that Tspan5 is significantly downregulated in gastric cancer (GC) and closely associated with clinicopathological features including tumour size and TNM stage. The expression of Tspan5 is inversely correlated with patient overall survival and is an independent prognostic factor in GC. Upregulation of Tspan5 in tumour cells results in inhibition of cell proliferation and colony formation in vitro and suppression of xenograft growth of GC by reducing tumour cell proliferation in vivo. Thus, Tspan5 functions as a tumour suppressor in stomach to control the tumour growth. Mechanistically, Tspan5 inhibits the cell cycle transition from G1-S phase by increasing the expression of p27 and p15 and decreasing the expression of cyclin D1, CDK4, pRB and E2F1. The correlation of Tspan5 expression with the expression of p27, p15, cyclin D1, CDK4, pRB and E2F1 in vivo are also revealed in xenografted tumours. Reconstitution of either cyclin D1 or CDK4 in Tspan5-overexpressing GC cells rescues the inhibitory phenotype produced by Tspan5, suggesting that cyclin D1/CDK4 play a dominant role in mediating the suppression of tumour growth by Tspan5 in GC. Our results suggest that Tspan5 may serve as a prognostic biomarker for predicting outcome of GC patients and provide new insights into the pathogenesis of GC and rational for the development of clinical intervention strategies against GC.

One of the treatment failures for colorectal cancer (CRC) is resistance to chemotherapy drugs. miRNAs have been demonstrated to be a new regulator of pathobiological processes in various tumors. While few studies have explored the specific role of miR-141 in mediating 5-fluorouracil (5-FU) sensitivity of CRC cells, the present study aimed to detect the contribution of miR-141 in 5-FU sensitivity. The CRC cells viability was measured by MTS assay and cell colony forming. The expression of miR-141 and its downstream targets were assessed by reverse transcription quantitative PCR, Western blotting, and immunohistochemistry. The functional assays were conducted using CRC cells and nude mice. At the present study, we found overexpression of miR-141 could inhibit proliferation, migration, tumor-forming and invasive potential of CRC cells in vitro and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was verified as a directed target of miR-141. The combination treatment of miR-141 with 5-FU, directly targetting MAP4K4, could better inhibit invasion and metastasis of CRC cells colony than either one alone. Furthermore, overexpression of miR-141, targetting MAP4K4, enhanced the effected of 5-FU and suppressed the malignant biological behaviors, in vivo. Our findings showed that 5-FU inhibited malignant behavior of human CRC cells in vitro and in vivo by enhancing the efficiency of miR-141. Our data suggested that targetting the miR-141/MAP4K4 signaling pathway could be a potential molecular target that may enhance chemotherapeutic efficacy in the treatment of CRC.

The multidrug resistance‑associated protein 1 (MRP1) gene has been found to be consistently overexpressed in the majority of patients with non‑small cell lung cancer (NSCLC). MRP1 is known for its ability to actively decrease intracellular drug concentration, limiting the efficacy of cancer chemotherapy; however, data on the clinical relevance of MRP1 is inconclusive. In the present meta‑analysis, all available published data were combined to provide an updated view on the clinicopathological relevance of MRP1 in patients with NSCLC. A systematic search was conducted to obtain relevant studies published in English, Chinese and Japanese databases. All data from patients with NSCLC who underwent testing for MRP1, by either immunohistochemistry or reverse transcription‑polymerase chain reaction, were extracted and combined for further analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each selected study, with either the fixed‑effects model or the random‑effects model where appropriate. The quality of methodology, heterogeneities and publication bias of the included articles were also analyzed. A total of 36 clinical studies involving 3,278 patients were included in the study. It was found that the increased expression of the MRP1 gene was associated with the following subgroups of patients: Non‑smokers vs. smokers (OR, 2.54; 95% CI, 1.17‑5.54; P=0.019); adenocarcinoma vs. squamous cell carcinoma (OR, 1.58; 95% CI, 1.16‑2.17; P=0.004); clinical stage III‑IV vs. stage I‑II (OR, 1.36; 95% CI, 1.11‑1.66; P=0.003); lymph node metastases (OR, 1.32; 95% CI, 1.09‑1.61; P=0.005); poor response to chemotherapy (OR, 0.41; 95% CI, 0.23‑0.72; P=0.002) and reduced 3‑year survival rate (OR, 0.40; 95% CI, 0.23‑0.68; P=0.001). In conclusion, the findings from this study suggest that increase in MRP1 gene expression is associated with being a non‑smoker, adenocarcinoma, advanced clinical stages and a poor response to chemotherapy in patients with NSCLC. The results from the most extensive and updated data on MRP1 support the requirement for continued investigation into the potential use of MRP1 as a biomarker/clinical indicator for NSCLC.

Preoperative concurrent chemoradiotherapy (CCRT) as the standard treatment for locally advanced rectal cancer (LARC) has been widely used in clinic. Its efficiency influences the prognosis and the selection of subsequent treatment. The current criteria for evaluating the prognosis of patients with extremely sensitive preoperative CCRT include the clinical complete remission response (cCR) and pathological complete response (pCR), but those with cCR may not necessarily achieve pCR, and the pCR can be confirmed only after surgery. Some scholars believe that patients with pCR after CCRT can be categorized as ‘watch and wait’. Therefore, it is extremely important to find a way to predict the pCR status of patients before therapy. In this study, we examined the expression of stem cell markers and obtained direct and derivative volumetric imaging parameters before treatment. Subsequently, these factors and the general clinical data were adopted into a regression model, and the correlation between them and the pCR was analyzed. We found that the pCR of LARC was positively correlated with tumor compactness (TC), whereas it was negatively correlated with approximate tumor volume (ATV), real tumor volume (RTV), total surface area of the tumor (TSA) and tumor maximum longitudinal length (TML). In these meaningful predictors, the positive predictive values and the negative predictive values of TC were 74.73% and 94.61%, respectively. Compared with other possible predictors, TC is the most encouraging predictor of pCR. Our findings provide a way for clinicians to predict the sensitivity of preoperative CCRT and will help to select individualized treatment options for LARC patients.

Stomatin-like protein-2 (SLP-2) gene belongs to the stomatin supergene family, and previous studies have revealed up-regulated SLP-2 expression in gallbladder cancer, lung cancer, and esophageal cancer, while the role of SLP-2 in colorectal cancer (CRC) remains unclear and needs further investigation. Therefore, the expression levels of SLP-2 in CRC tissue and cell lines were tested in this study. Besides, we further explored the role of SLP-2 in CRC invasion and metastasis at molecular level via gene intervention technique. Our results demonstrated that the positive rate of SLP-2 expression in CRC tissues was higher than that in the adjacent non-cancerous tissues (P 0.05); positive SLP-2 expression predicted poorer prognosis of CRC patients as an independent risk factor (P 0.05). Cell activities and the capacity of migration and invasion significantly decreased after the suppression of SLP-2 in SW620 cells (P 0.05). Furthermore, the suppression of SLP-2 in SW620 cells resulted in varieties of invasion and metastasis-related genes and Wnt/β-catenin signal pathway (P 0.05). The present study identified that SLP-2 may predict a poor prognosis in CRC patients as a novel marker, and SLP-2 may facilitate the migration and invasion of CRC via regulating Wnt/β-catenin pathway activities.

One of the treatment failures for colorectal cancer (CRC) is resistance to chemotherapy drugs. miRNAs have been demonstrated to be a new regulator of pathobiological processes in various tumors. While few studies have explored the specific role of miR-141 in mediating 5-fluorouracil (5-FU) sensitivity of CRC cells, the present study aimed to detect the contribution of miR-141 in 5-FU sensitivity. The CRC cells viability was measured by MTS assay and cell colony forming. The expression of miR-141 and its downstream targets were assessed by reverse transcription quantitative PCR, Western blotting, and immunohistochemistry. The functional assays were conducted using CRC cells and nude mice. At the present study, we found overexpression of miR-141 could inhibit proliferation, migration, tumor-forming and invasive potential of CRC cells in vitro and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was verified as a directed target of miR-141. The combination treatment of miR-141 with 5-FU, directly targetting MAP4K4, could better inhibit invasion and metastasis of CRC cells colony than either one alone. Furthermore, overexpression of miR-141, targetting MAP4K4, enhanced the effected of 5-FU and suppressed the malignant biological behaviors, in vivo. Our findings showed that 5-FU inhibited malignant behavior of human CRC cells in vitro and in vivo by enhancing the efficiency of miR-141. Our data suggested that targetting the miR-141/MAP4K4 signaling pathway could be a potential molecular target that may enhance chemotherapeutic efficacy in the treatment of CRC.

We prove the regularity conjecture, namely Eisenbud–Goto conjecture, for a normal surface with rational, Gorenstein elliptic and log canonical singularities. Along the way, we bound the regularity for a dimension zero scheme by its Loewy length and for a curve allowing embedded or isolated point components by its arithmetic degree.

Let $\mathscr{I}$ be an ideal sheaf on $P^n$ defining a subscheme $X$. Associated to $\mathscr{I}$ there are two elementary invariants: the invariant $s$ which measures the positivity of $\mathscr{I}$, and the minimal number $d$ such that $\mathscr{I}(d)$ is generated by its global sections. It is now clear that the asymptotic behavior of $\reg \mathscr{I}^t$ is governed by $s$ but usually not linear. In this paper, we first describe the linear behavior of the asymptotic regularity by showing that if $s=d$, i.e., $s$ reaches its maximal value, then for $t$ large enough $\reg \mathscr{I}^t=dt+e$ for some positive constant $e$. We then turn to concrete geometric settings to study the asymptotic regularity of $\mathscr{I}$ in the case that $X$ is a nonsingular variety embedded by a very ample adjoint line bundle. Our approach also gives regularity bounds for $\mathscr{I}^t$ once we know $\reg \mathscr{I}$ and assume that $X$ is a local complete intersection., 15 pages, all comments welcome

In order to reduce the gear whine noise of a DCT oil pump, a model is established based on loaded tooth contact analysis method, and the gear transmission error and acceleration of the DCT housing are calculated in different torques. The influences of gear macro-geometry and assembled errors on housing acceleration are researched, and the primary factors influencing gear whine noise have been found. Finally gear design is refined, and the oil pump gear noise is dissipated in vehicle NVH test.

In recent years, a multiplier ideal defined on arbitrary varieties, so called Mather multiplier ideal, has been developed independently by Ein-Ishii-Mustata, and de Fernex-Docampo. With this new tool, we have a chance of extending some classical results proved in nonsingular case to arbitrary varieties to establish their general forms. In this paper, we first extend a result of geometric nullstellensatz due to Ein-Lazarsfeld in nonsingular case to any projective varieties. Then we prove a result on comparison of symbolic powers with ordinary powers on any varieties, which extends results of Ein-Lazarsfeld-Smith and Hochster-Huneke., Comment: 11 pages, main theorems are improved, comments are welcome

Let $Y$ be a generic link of a subvariety $X$ of a nonsingular variety $A$. We give a description of the Grauert-Riemenschneider canonical sheaf of $Y$ in terms of the multiplier ideal sheaves associated to $X$ and use it to study the singularities of $Y$. As the first application, we give a criterion when $Y$ has rational singularities and show that log canonical threshold increases and log canonical pairs are preserved in generic linkage. As another application we give a quick and simple liaison method to generalize the results of de Fernex-Ein and Chardin-Ulrich on the Castelnuovo-Mumford regularity bound for a projective variety., Comment: 21 pages, all comments welcome

Let $\mathscr{I}$ be an ideal sheaf on $P^n$. In the first part of this paper, we bound the asymptotic regularity of powers of $\mathscr{I}$ as $ps-3\leq \reg \mathscr{I}^p\leq ps+e$, where $e$ is a constant and $s$ is the $s$-invariant of $\mathscr{I}$. We also give the same upper bound for the asymptotic regularity of symbolic powers of $\mathscr{I}$ under some conditions. In the second part, by using multiplier ideal sheaves, we give a vanishing theorem of powers of $\mathscr{I}$ when it defines a local complete intersection subvariety with log canonical singularities., 13 pages; Corrected typos, added references, improve one of the main theorems