Electric-field-controlled electronic structures and quantum transport in monolayer InSe nanoribbons.

Electronic structures and quantum transport properties of the monolayer InSe nanoribbons are studied by adopting the tight-binding model in combination with the lattice Green function method. Besides the normal bulk and edge electronic states, a unique electronic state dubbed as edge-surface is found in the InSe nanoribbon with zigzag edge type. In contrast to the zigzag InSe nanoribbon, a singular electronic state termed as bulk-surface is observed along with the normal bulk and edge electronic states in the armchair InSe nanoribbons. Moreover, the band gap, the transversal electron probability distributions in the two sublayers, and the electronic state of the topmost valence subband can be manipulated by adding a perpendicular electric field to the InSe nanoribbon. Further study shows that the charge conductance of the two-terminal monolayer InSe nanoribbons can be switched on or off by varying the electric field strength. In addition, the transport of the bulk electronic state is delicate to even a weak disorder strength, however, that of the edge and edge-surface electronic states shows a strong robustness against to the disorders. These findings may be helpful to understand the electronic characteristics of the InSe nanostructures and broaden their potential applications in two-dimensional nanoelectronic devices as well.

Protein Hydrolysates from Pleurotus geesteranus Modified by Bacillus amyloliquefaciens γ-Glutamyl Transpeptidase Exhibit a Remarkable Taste-Enhancing Effect.

Long-term high salt intake exerts a negative impact on human health. The excessive use of sodium substitutes in the food industry can lead to decreased sensory quality of food. γ-Glutamyl peptides with pronounced taste-enhancing effects can offer an alternative approach to salt reduction. However, the content and yield of γ-glutamyl peptides in natural foods are relatively low. Enzyme-catalyzed synthesis of γ-glutamyl peptides provides a feasible solution. In this study, Pleurotus geesteranus was hydrolyzed by Flavourzyme to generate protein hydrolysates. Subsequently, they were modified by Bacillus amyloliquefaciens γ-glutamyl transpeptidase to generate γ-glutamyl peptides. The reaction conditions were optimized and their taste-enhancing effects were evaluated. Their peptide sequences were identified by parallel reaction monitoring with liquid chromatography-tandem mass spectrometry and analyzed using molecular docking. The optimal conditions for generation of γ-glutamyl peptides were a pH of 10.0, an enzyme condition of 1.2 U/g, and a reaction time of 2 h, which can elicit a strong kokumi taste. Notably, it exhibited a remarkable taste-enhancing effect for umami intensity (76.07%) and saltiness intensity (1.23-fold). Several novel γ-glutamyl peptide sequences were found by liquid chromatography-tandem mass spectrometry, whereas the binding to the calcium-sensing receptor was confirmed by molecular docking analysis. Overall, γ-glutamyl peptides from P. geesteranus could significantly enhance the umami and salt tastes, which can serve as promising taste enhancers.

GABPA-activated TGFBR2 transcription inhibits aggressiveness but is epigenetically erased by oncometabolites in renal cell carcinoma.

BACKGROUND: The ETS transcription factor GABPA has long been thought of as an oncogenic factor and recently suggested as a target for cancer therapy due to its critical effect on telomerase activation, but the role of GABPA in clear cell renal cell carcinoma (ccRCC) is unclear. In addition, ccRCC is characterized by metabolic reprograming with aberrant accumulation of L-2-hydroxyglurate (L-2HG), an oncometabolite that has been shown to promote ccRCC development and progression by inducing DNA methylation, however, its downstream effectors remain poorly defined. METHODS: siRNAs and expression vectors were used to manipulate the expression of GABPA and other factors and to determine cellular/molecular and phenotypic alterations. RNA sequencing and ChIP assays were performed to identify GABPA target genes. A human ccRCC xenograft model in mice was used to evaluate the effect of GABPA overexpression on in vivo tumorigenesis and metastasis. ccRCC cells were incubated with L-2-HG to analyze GABPA expression and methylation. We carried out immunohistochemistry on patient specimens and TCGA dataset analyses to assess the effect of GABPA on ccRCC survival. RESULTS: GABPA depletion, although inhibiting telomerase expression, robustly enhanced proliferation, invasion and stemness of ccRCC cells, whereas GABPA overexpression exhibited opposite effects, strongly inhibiting in vivo metastasis and carcinogenesis. TGFBR2 was identified as the GABPA target gene through which GABPA governed the TGFß signaling to dictate ccRCC phenotypes. GABPA and TGFBR2 phenocopies each other in ccRCC cells. Higher GABPA or TGFBR2 expression predicted longer survival in patients with ccRCC. Incubation of ccRCC cells with L-2-HG mimics GABPA-knockdown-mediated phenotypic alterations. L-2-HG silenced the expression of GABPA in ccRCC cells by increasing its methylation. CONCLUSIONS: GABPA acts as a tumor suppressor by stimulating TGFBR2 expression and TGFß signaling, while L-2-HG epigenetically inhibits GABPA expression, disrupting the GABPA-TGFß loop to drive ccRCC aggressiveness. These results exemplify how oncometabolites erase tumor suppressive function for cancer development/progression. Restoring GABPA expression using DNA methylation inhibitors or other approaches, rather than targeting it, may be a novel strategy for ccRCC therapy.

SETD8 stabilized by USP17 epigenetically activates SREBP1 pathway to drive lipogenesis and oncogenesis of ccRCC.

Recently, epigenetic modifications, including DNA methylation, histone modification and noncoding RNA (ncRNA)-associated gene silencing, have received increasing attention from the scientific community. Many studies have demonstrated that epigenetic regulation can render dynamic alterations in the transcriptional potential of a cell, which then affects the cell's biological function. The initiation and development of clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell cancer (RCC), is also closely related to genomic alterations by epigenetic modification. For ccRCC, lipid accumulation is one of the most typical characteristics. In other words, dysregulation of lipid uptake and synthesis occurs in ccRCC, which inversely promotes cancer proliferation and progression. However, the link among epigenetic alterations, lipid biosynthesis and renal cancer progression remains unclear. SETD8 is a histone methyltransferase and plays pivotal roles in cell cycle regulation and oncogenesis of various cancers, but its role in RCC is not well understood. In this study, we discovered that SETD8 was significantly overexpressed in RCC tumors, which was positively related to lipid storage and correlated with advanced tumor grade and stage and poor patient prognosis. Depletion of SETD8 by siRNAs or inhibitor UNC0379 diminished fatty acid (FA) de novo synthesis, cell proliferation and metastasis in ccRCC cells. Mechanistically, SETD8, which was posttranslationally stabilized by USP17, could transcriptionally modulate sterol regulatory element-binding protein 1 (SREBP1), a key transcription factor in fatty acid biosynthesis and lipogenesis, by monomethylating the 20th lysine of the H4 histone, elevating lipid biosynthesis and accumulation in RCC and further promoting cancer progression and metastasis. Taken together, the USP17/SETD8/SREBP1 signaling pathway plays a pivotal role in promoting RCC progression. SETD8 might be a novel biomarker and potential therapeutic target for treating RCC.

Huaier Extract Inhibits Prostate Cancer Growth via Targeting AR/AR-V7 Pathway.

The androgen receptor (AR) plays a pivotal role in prostatic carcinogenesis, and it also affects the transition from hormone sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). Particularly, the persistent activation of the androgen receptor and the appearance of androgen receptor splicing variant 7 (AR-V7), could partly explain the failure of androgen deprivation therapy (ADT). In the present study, we reported that huaier extract, derived from officinal fungi, has potent antiproliferative effects in both HSPC and CRPC cells. Mechanistically, huaier extract downregulated both full length AR (AR-FL) and AR-V7 mRNA levels via targeting the SET and MYND domain-containing protein 3 (SMYD3) signaling pathway. Huaier extract also enhanced proteasome-mediated protein degradation of AR-FL and AR-V7 by downregulating proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). Furthermore, huaier extract inhibited AR-FL/AR-V7 transcriptional activity and their nuclear translocation. More importantly, our data demonstrated that huaier extract could re-sensitize enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vitro and in vivo models. Our work revealed that huaier extract could be effective for treatment of prostate cancer either as monotherapy or in combination with enzalutamide.

Sunitinib treatment promotes metastasis of drug-resistant renal cell carcinoma via TFE3 signaling pathway.

Receptor tyrosine kinase (RTK) inhibitors, such as sunitinib and sorafenib, remain the first-line drugs for the treatment of mRCC. Acquired drug resistance and metastasis are the main causes of treatment failure. However, in the case of metastasis Renal Cell Cancer (mRCC), which showed a good response to sunitinib, we found that long-term treatment with sunitinib could promote lysosome biosynthesis and exocytosis, thereby triggering the metastasis of RCC. By constructing sunitinib-resistant cell lines in vivo, we confirmed that TFE3 plays a key role in the acquired resistance to sunitinib in RCC. Under the stimulation of sunitinib, TFE3 continued to enter the nucleus, promoting the expression of endoplasmic reticulum (ER) protein E-Syt1. E-Syt1 and the lysosomal membrane protein Syt7 form a heterodimer, which induces ER fragmentation, Ca2+ release, and lysosomal exocytosis. Lysosomal exocytosis has two functions: pumping sunitinib out from the cytoplasm, which promotes resistance to sunitinib in RCC, releasing cathepsin B (CTSB) into the extracellular matrix (ECM), which can degrade the ECM to enhance the invasion and metastasis ability of RCC. Our study found that although sunitinib is an effective drug for the treatment of mRCC, once RCC has acquired resistance to sunitinib, sunitinib treatment will promote metastasis.

Integral Analysis of the RNA Binding Protein-associated Prognostic Model for Renal Cell Carcinoma.

RNA binding protein (RBPs) dysregulation has been reported in various malignant tumors and plays a pivotal role in tumor carcinogenesis and progression. However, the underlying mechanisms in renal cell carcinoma (RCC) are still unknown. In the present study, we performed a bioinformatics analysis using data from TCGA database to explore the expression and prognostic value of RBPs. We identified 125 differently expressed RBPs between tumor and normal tissue in RCC patients, including 87 upregulated and 38 downregulated RBPs. Eight RBPs (RPL22L1, RNASE2, RNASE3, EZH2, DDX25, DQX1, EXOSC5, DDX47) were selected as prognosis-related RBPs and used to construct a risk score model. In the risk score model, the high-risk subgroup had a poorer overall survival (OS) than the low-risk subgroup, and we divided the 539 RCC patients into two groups and conducted a time-dependent receiver operating characteristic (ROC) analysis to further test the prognostic ability of the eight hub RBPs. The area under the curve (AUC) of the ROC curve was 0.728 in train-group and 0.688 in test-group, indicating a good prognostic model. More importantly, we established a nomogram based on the selected eight RBPs. The eight selected RBPS have predictive value for RCC patients, with potential applications in clinical decision-making and individualized treatment.

TP53 alterations of hormone-naïve prostate cancer in the Chinese population.

BACKGROUND: Prostate cancer (PCa) shows racial disparity in clinical and genomic characteristics, and Asian patients with PCa often present with more aggressive phenotypes at diagnosis. The ability of TP53 to serve as a prognostic biomarker of PCa has been well studied in Western populations. However, no studies to date have examined the role of TP53 in the disparities of primary hormone-naïve prostate cancer (HNPC) between Chinese and Western populations. METHODS: We collected prostate tumors and matched normal tissues or blood samples to perform targeted next-generation sequencing of 94 Chinese primary localized HNPC samples, and correlated these genomic profiles with clinical outcomes. The OncoKB knowledge database was used to identify and classify actionable alterations. RESULTS: The aberrations of PTEN, CDK12, and SPOP in Chinese HNPC samples were similar to those in the Western samples. However, we demonstrated an association of a high frequency of TP53 alterations (21/94) with a relatively higher percentage of alterations in the Wnt signaling pathway (15/94) in Chinese HNPC. Additionally, we highlighted alterations of LRP1B as accounting for a high proportion of PCa and found more frequent alterations in CDH1 in Chinese PCa. Of these, only CDH1 alteration was associated with rapid biochemical recurrence (BCR). However, we verified that TP53 status was at the core of the genomic alteration landscape in Chinese HNPC with putative driver mutations because of the strong connections with other signaling pathways. The mutually exclusive relationship between alterations in TP53 and Wnt/CTNNB1 further molecularly characterizes subsets of prostate cancers. Moreover, the alteration of KMT2C was more likely to co-occur with TP53 alteration, indicating a more aggressive phenotype of PCa, which was associated with sensitivity to treatment with poly ADT-ribose polymerase (PARP) inhibitors. CONCLUSIONS: Detection of TP53 alterations has clinical utility for guiding precision cancer therapy for HNPC, especially in the Chinese population.

Predictive value of serum soluble B7-H4 in acute pancreatitis.

BACKGROUND: Studies reported that soluble B7-H4 (sB7-H4) was significantly related to the progression and prognosis of inflammatory diseases, and whether sB7-H4 is related to the severity and prognosis of acute pancreatitis (AP) timely has not been reported. MATERIALS AND METHODS: Clinical database data of 446 AP patients were retrospectively collected, and the correlation between the expression serum levels of sB7-H4 with inflammatory factors and prognostic scores was analysed in AP patients. RESULTS: Soluble B7-H4 was significantly correlated with IL-6, IL-8, TNF-α, PCT, CRP levels and WBC count (P < .01), with correlation coefficients of R = .61, .53, .46, .60, .57 and .47, respectively, and AUCs were 0.905, 0.837, 0.797, 0.858, 0.890, 0.841 and 0.855, respectively. In addition, sB7-H4 was significantly correlated with the Ranson score, APACHE II score and BISAP score (P < .001), with correlation coefficients of R = .58, .63 and .59, respectively. The AUCs of assessing local complications of AP were 0.908, 0.863, 0.785 and 0.844, respectively; assessing organ failure were 0.872, 0.790, 0.796 and 0.857, respectively; and assessing in-hospital mortality were 0.839, 0.821, 0.796 and 0.823, respectively. CONCLUSIONS: Soluble B7-H4 could be used as a marker for the diagnosis, severity assessment and poor prognosis assessment of AP patients, which may have potential clinical applications.

Retraction notice to "Design, synthesis, and biological evaluation of heterotetracyclic quinolinone derivatives as anticancer agents targeting topoisomerases" [Eur. J. Med. Chem. 190 (2020) 112074].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the authors. The authors regret to inform that they would like to withdraw this accepted article, due to serious errors in authorship, affiliations, material sources and supporting grant names/numbers. The authors sincerely apologize for these oversights and miscommunications the study caused.

VHL-HIF-2α axis-induced SMYD3 upregulation drives renal cell carcinoma progression via direct trans-activation of EGFR.

It has been well established that the von Hippel-Lindau/hypoxia-inducible factor α (VHL-HIFα) axis and epidermal growth factor receptor (EGFR) signaling pathway play a critical role in the pathogenesis and progression of renal cell carcinoma (RCC). However, few studies have addressed the relationship between the two oncogenic drivers in RCC. SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase involved in gene transcription and oncogenesis, but its expression and function in RCC remain unclear. In the present study, we found that SMYD3 expression was significantly elevated in RCC tumors and correlated with advanced tumor stage, histological and nuclear grade, and shorter survival. Depletion of SMYD3 inhibited RCC cell proliferation, colony numbers, and xenograft tumor formation, while promoted apoptosis. Mechanistically, SMYD3 cooperates with SP1 to transcriptionally promote EGFR expression, amplifying its downstream signaling activity. TCGA data analyses revealed a significantly increased SMYD3 expression in primary RCC tumors carrying the loss-of-function VHL mutations. We further showed that HIF-2α can directly bind to the SMYD3 promoter and subsequently induced SMYD3 transcription and expression. Taken together, we identify the VHL/HIF-2α/SMYD3 signaling cascade-mediated EGFR hyperactivity through which SMYD3 promotes RCC progression. Our study suggests that SMYD3 is a potential therapeutic target and prognostic factor in RCC.

Electric-Controlled Valley Pseudomagnetoresistance in Graphene with Y-Shaped Kekulé Lattice Distortion.

We propose a new method for regulating valley pseudomagnetoresistance in ballistic graphene-based valley field-effect transistors by taking into account the Y-shaped Kekulé lattice distortion and electric barrier. The device involves valley injection and valley detection by ferromagnetic-strain source and drain. The valley manipulation in the channel is achieved via the Y-shaped Kekulé lattice distortion and electric barrier. The central mechanism of these devices lies on Y-shaped Kekulé lattice distortion in graphene can induce a valley precession, thus controlling the valley orientation of channel electrons and hence the current collected at the drain. We found that the tuning external bias voltage makes the valley pseudomagnetoresistance oscillate between positive and negative values and colossal tunneling valley pseudomagnetoresistance of over 30,000% can be achieved. Our results suggest that the synergy of valleytronics and digital logics may provide new paradigms for valleytronic-based information processing and reversible computing.

Design, synthesis, and biological evaluation of heterotetracyclic quinolinone derivatives as anticancer agents targeting topoisomerases.

A series of thiochromeno[2,3-c]quinolin-12-one derivatives with various substitutions were synthesized and evaluated as topoisomerase (Topo) inhibitors. Six (8, 10, 12, 14, 19, and 26) of 23 compounds showed strong inhibitory activities against Topo-mediated DNA relaxation and proliferation of five human cell lines including breast (MDA-MB-231, MDA-MB-468 and MCF7), colorectal (HCT116) and non-small cell lung (H1299) cancers. Among these, compounds 14 and 26 exhibited full inhibitory activities against Topo I at 3 µM and Topo IIα at 1 µM. Cancer cells treated with 26 accumulated DNA damage and were arrested at the G2/M phase. With time, cells proceeded to apoptosis, as revealed by increased amounts of cells with fragmented DNA and cleavage of caspase-8 and -9. In contrast, normal breast epithelial cells showed low sensitivity to 26. Taken together, our study identifies 26 as a potent Topo dual-inhibitor with low toxicity to normal cells, and elucidates that the terminal amino group of N-2-aminoethylamino or N-3-aminopropylamino at the 6th position and 8,10-di-halogen substituents on thiochromeno[2,3-c]quinolin-12-one are critical for the Topo-inhibiting and cancer-killing activities.

Electric Field Controlled Indirect-Direct-Indirect Band Gap Transition in Monolayer InSe.

Electronic structures of monolayer InSe with a perpendicular electric field are investigated. Indirect-direct-indirect band gap transition is found in monolayer InSe as the electric field strength is increased continuously. Meanwhile, the global band gap is suppressed gradually to zero, indicating that semiconductor-metal transformation happens. The underlying mechanisms are revealed by analyzing both the orbital contributions to energy band and evolution of band edges. These findings may not only facilitate our further understanding of electronic characteristics of layered group III-VI semiconductors, but also provide useful guidance for designing optoelectronic devices.

The Anticancer Effect of Huaier Extract in Renal Cancer 786-O Cells.

BACKGROUND: Trametes robiniophila Murr (Huaier) has been used as an adjuvant therapy of tumor in traditional Chinese medicine for many years, but the underlying mechanisms are largely unknown. In the present study, we tested the inhibitory effect of Huaier extract on renal cancer 786-O cells and explored the possible mechanisms. METHODS: 786-O cells were treated by gradient concentrations of Huaier extract, cell viability, invasion, migration and apoptosis were assessed by cell counting kit 8, cell scratch, transwell, and flow cytometry assay in vitro. The changes in protein level were detected by western blot analysis. Finally, the anticancer effect of Huaier was tested in vivo by nude mouse tumorigenicity assay. RESULTS: Viability of 786-O cells was suppressed by Huaier in a time- and dose-dependent manner; cell invasion and migration were also dramatically inhibited. Flow cytometry assays showed that Huaier could induce cell apoptosis. Western blotting analysis indicated that Huaier suppressed the activation of PI3K/AKT/mTOR/p70S6K/4E-BP1 signaling pathway. We also found that Huaier could partly reverse the epithelialmesenchymal transition (EMT) process. In vivo experiment indicated that tumor growth in the xenograft mouse model was suppressed by Huaier. CONCLUSION: Huaier plays an anticancer effect partially through the suppression of the PI3K/AKT/mTOR/p70S6K/4E-BP1 pathway and by reversing the EMT process. Huaier may act as an effective agent for treating renal cell carcinoma.

Microencapsulation of Phosphorylated Human-Like Collagen-Calcium Chelates for Controlled Delivery and Improved Bioavailability.

The bioavailability of Phosphorylated Human-like Collagen-calcium chelates (PHLC-Ca) as calcium supplement is influenced by the extremely low pH and proteolytic enzymes in the gastrointestinal tract. This study addresses these issues by microencapsulation technology using alginate (ALG) and chitosan (CS) as wall materials. The different ratio of ALG to PHLC-Ca on microcapsules encapsulation efficiency (EE) and loading capacity (LC) was evaluated and 1:1/2 was selected as the optimal proportion. The microcapsules were micron-sized and spherical in shape. PHLC-Ca was successfully entrapped into the matrix of ALG through forming intermolecular hydrogen bonding or other interactions. The confocal laser scanning microscopy (CLSM) indicated that CS was coated on ALG microspheres. The MTT assay exhibited that CS/ALG-(PHLC-Ca) microcapsules extracts were safe to L929. The animal experiment showed that CS/ALG-(PHLC-Ca) microcapsules was superior to treating osteoporosis than PHLC-Ca. These results illustrated that the bioavailability of PHLC-Ca was improved by microencapsulated.

Tunable Dirac points and high spin polarization in ferromagnetic-strain graphene superlattices.

Spin-dependent energy bands and transport properties of ferromagnetic-strain graphene superlattices are studied. The high spin polarization appears at the Dirac points due to the presence of spin-dependent Dirac points in the energy band structure. A gap can be induced in the vicinity of Dirac points by strain and the width of the gap is enlarged with increasing strain strength, which is beneficial for enhancing spin polarization. Moreover, a full spin polarization can be achieved at large strain strength. The position and number of the Dirac points corresponding to high spin polarization can be effectively manipulated with barrier width, well width and effective exchange field, which reveals a remarkable tunability on the wavevector filtering behavior.

Helical edge states and edge-state transport in strained armchair graphene nanoribbons.

A helical type edge state, which is generally supported only on graphene with zigzag boundaries, is found to also appear in armchair graphene nanoribbons in the presence of intrinsic spin-orbit coupling and a suitable strain. At a critical strain, there appears a quantum phase transition from a quantum spin Hall state to a trivial insulator state. Further investigation shows that the armchair graphene nanoribbons with intrinsic spin-orbit coupling, Rashba spin-orbit coupling, effective exchange fields and strains also support helical-like edge states with a unique spin texture. In such armchair graphene nanoribbons, the spin directions of the counterpropogating edge states on the same boundary are always opposite to each other, while is not conserved and the spins are canted away from the -direction due to the Rashba spin-orbit coupling, which is different from the case of the zigzag graphene nanoribbons. Moreover, the edge-state energy gap is smaller than that in zigzag graphene nanoribbons, even absent in certain cases.

Valley precession and valley polarization in graphene with inter-valley coupling.

We theoretically investigate the valley precession and valley polarization in graphene under inter-valley coupling. Our results show that the inter-valley coupling can induce valley polarization in graphene and also precess valleys in real space in a manner similar to the Rashba spin-orbit interaction rotating spins. Moreover, using strain modulation, we can achieve high valley polarization with large valley-polarized currents. These findings provide a new way to create and manipulate valley polarization in graphene.