Adaptation of a mutual exclusivity framework to identify driver mutations within oncogenic pathways.

Distinguishing genomic alterations in cancer-associated genes that have functional impact on tumor growth and disease progression from the ones that are passengers and confer no fitness advantage have important clinical implications. Evidence-based methods for nominating drivers are limited by existing knowledge on the oncogenic effects and therapeutic benefits of specific variants from clinical trials or experimental settings. As clinical sequencing becomes a mainstay of patient care, applying computational methods to mine the rapidly growing clinical genomic data holds promise in uncovering functional candidates beyond the existing knowledge base and expanding the patient population that could potentially benefit from genetically targeted therapies. We propose a statistical and computational method (MAGPIE) that builds on a likelihood approach leveraging the mutual exclusivity pattern within an oncogenic pathway for identifying probabilistically both the specific genes within a pathway and the individual mutations within such genes that are truly the drivers. Alterations in a cancer-associated gene are assumed to be a mixture of driver and passenger mutations with the passenger rates modeled in relationship to tumor mutational burden. We use simulations to study the operating characteristics of the method and assess false-positive and false-negative rates in driver nomination. When applied to a large study of primary melanomas, the method accurately identifies the known driver genes within the RTK-RAS pathway and nominates several rare variants as prime candidates for functional validation. A comprehensive evaluation of MAGPIE against existing tools has also been conducted leveraging the Cancer Genome Atlas data.

Innovative super-resolution in spatial transcriptomics: a transformer model exploiting histology images and spatial gene expression.

Spatial transcriptomics technologies have shed light on the complexities of tissue structures by accurately mapping spatial microenvironments. Nonetheless, a myriad of methods, especially those utilized in platforms like Visium, often relinquish spatial details owing to intrinsic resolution limitations. In response, we introduce TransformerST, an innovative, unsupervised model anchored in the Transformer architecture, which operates independently of references, thereby ensuring cost-efficiency by circumventing the need for single-cell RNA sequencing. TransformerST not only elevates Visium data from a multicellular level to a single-cell granularity but also showcases adaptability across diverse spatial transcriptomics platforms. By employing a vision transformer-based encoder, it discerns latent image-gene expression co-representations and is further enhanced by spatial correlations, derived from an adaptive graph Transformer module. The sophisticated cross-scale graph network, utilized in super-resolution, significantly boosts the model's accuracy, unveiling complex structure-functional relationships within histology images. Empirical evaluations validate its adeptness in revealing tissue subtleties at the single-cell scale. Crucially, TransformerST adeptly navigates through image-gene co-representation, maximizing the synergistic utility of gene expression and histology images, thereby emerging as a pioneering tool in spatial transcriptomics. It not only enhances resolution to a single-cell level but also introduces a novel approach that optimally utilizes histology images alongside gene expression, providing a refined lens for investigating spatial transcriptomics.

Identification and validation of SOCS1/2/3/4 as potential prognostic biomarkers and correlate with immune infiltration in glioblastoma.

Suppressor of cytokine signalling (SOCS) 1/2/3/4 are involved in the occurrence and progression of multiple malignancies; however, their prognostic and developmental value in patients with glioblastoma (GBM) remains unclear. The present study used TCGA, ONCOMINE, SangerBox3.0, UALCAN, TIMER2.0, GENEMANIA, TISDB, The Human Protein Atlas (HPA) and other databases to analyse the expression profile, clinical value and prognosis of SOCS1/2/3/4 in GBM, and to explore the potential development mechanism of action of SOCS1/2/3/4 in GBM. The majority of analyses showed that SOCS1/2/3/4 transcription and translation levels in GBM tissues were significantly higher than those in normal tissues. qRT-PCR, western blotting (WB) and immunohistochemical staining were used to verify that SOCS3 was expressed at higher mRNA and protein levels in GBM than in normal tissues or cells. High SOCS1/2/3/4 mRNA expression was associated with poor prognosis in patients with GBM, especially SOCS3. SOCS1/2/3/4 were highly contraindicated, which had few mutations, and were not associated with clinical prognosis. Furthermore, SOCS1/2/3/4 were associated with the infiltration of specific immune cell types. In addition, SOCS3 may affect the prognosis of patients with GBM through JAK/STAT signalling pathway. Analysis of the GBM-specific protein interaction (PPI) network showed that SOCS1/2/3/4 were involved in multiple potential carcinogenic mechanisms of GBM. In addition, colony formation, Transwell, wound healing and western blotting assays revealed that inhibition of SOCS3 decreased the proliferation, migration and invasion of GBM cells. In conclusion, the present study elucidated the expression profile and prognostic value of SOCS1/2/3/4 in GBM, which may provide potential prognostic biomarkers and therapeutic targets for GBM, especially SOCS3.

Multi-omics analyses of CD276 in pan-cancer reveals its clinical prognostic value in glioblastoma and other major cancer types.

BACKGROUND: CD276 (also known as B7-H3) is one of the most important immune checkpoints of the CD28 and B7 superfamily, and its abnormal expression is closely associated with various types of cancer. It has been shown that CD276 is able to inhibit the function of T cells, and that this gene may potentially be a promising immunotherapy target for different types of cancer. METHODS: Since few systematic studies have been published on the role of CD276 in cancer to date, the present study has employed single-cell sequencing and bioinformatics methods to analyze the expression patterns, clinical significance, prognostic value, epigenetic alterations, DNA methylation level, tumor immune cell infiltration and immune functions of CD276 in different types of cancer. In order to analyze the potential underlying mechanism of CD276 in glioblastoma (GBM) to assess its prognostic value, the LinkedOmics database was used to explore the biological function and co-expression pattern of CD276 in GBM, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. In addition, a simple validation of the above analyses was performed using reverse transcription-quantitative (RT-q)PCR assay. RESULTS: The results revealed that CD276 was highly expressed, and was often associated with poorer survival and prognosis, in the majority of different types of cancer. In addition, CD276 expression was found to be closely associated with T cell infiltration, immune checkpoint genes and immunoregulatory interactions between lymphoid and a non-lymphoid cell. It was also shown that the CD276 expression network exerts a wide influence on the immune activation of GBM. The expression of CD276 was found to be positively correlated with neutrophil-mediated immunity, although it was negatively correlated with the level of neurotransmitters, neurotransmitter transport and the regulation of neuropeptide signaling pathways in GBM. It is noteworthy that CD276 expression was found to be significantly higher in GBM compared with normal controls according to the RT-qPCR analysis, and the co-expression network, biological function and chemotherapeutic drug sensitivity of CD276 in GBM were further explored. In conclusion, the findings of the present study have revealed that CD276 is strongly expressed and associated with poor prognosis in most types of cancer, including GBM, and its expression is strongly associated with T-cell infiltration, immune checkpoint genes, and immunomodulatory interactions between lymphocytes and non-lymphoid cells. CONCLUSIONS: Taken together, based on our systematic analysis, our findings have revealed important roles for CD276 in different types of cancers, especially GBM, and CD276 may potentially serve as a biomarker for cancer.

Phenylacetyl glutamine: a novel biomarker for stroke recurrence warning.

BACKGROUND: Stroke is the second leading cause of disease-related death and the third leading cause of disability worldwide. However, how to accurately warn of stroke onset remains extremely challenging. Recently, phenylacetyl glutamine (PAGln) has been implicated in the onset of stroke, but evidences from cohort studies of onset are lacking, especially in patients with first-onset or recurrent. It is necessary to deeply demonstrate the effectiveness of PAGln level on warning stroke onset. METHODS: One hundred fifteen first onset stroke patients, 33 recurrent stroke patients, and 135 non-stroke controls were included in the analysis. Risk factors associated with stroke attacking were evaluated, and plasma PAGln levels were detected via HPLC-MS based method. LASSO regression, Pearson correlation analysis, and univariate analysis were carried out to demonstrate the associations between PAGln levels and risk factors of stroke. Random forest machine learning algorithm was used to build classification models to achieve the distinction of first-onset stroke patients, recurrent stroke patients, and non-stroke controls, and further demonstrate the contribution of PAGln levels in the distinction of stroke onset. RESULTS: The median level of PAGln in the first-onset stroke group, recurrent stroke group, and non-stroke group was 933 ng/mL, 1014 ng/mL, and 556 ng/mL, respectively. No statistical correlation was found between PAGln level and subject's living habits, eating preferences, and concomitant diseases (hypertension, hyperlipidemia, and diabetes). Stroke severity indicators, mainly age and NIHSS score, were found associate with the PAGln levels. Machine learning classification models confirmed that PAGln levels, as the main contributing variable, could be used to distinguish recurrent stroke patients (but not first-onset stroke patients) from non-stroke controls. CONCLUSION: PAGln may be an effective indicator to monitor the recurrence in stroke patients.

LncRNA BBOX1-AS1 promotes pituitary adenoma progression via sponging miR-361-3p/E2F1 axis.

Pituitary adenoma is one of the most common intracranial tumors, more and more studies have shown that long non-coding RNA (lncRNA) plays a very important role in pituitary adenoma. However, there are few reports on the function of lncRNA BBOX1-AS1 in pituitary adenomas, and further exploration is needed. The objective of this research is to figure out what function BBOX1-AS1 plays in pituitary adenoma and how it regulates it. The expression of the E2F1, miR-361-3p and BOX1-AS1 genes was measured using a quantitative real-time PCR method. The functional involvement of BBOX1-AS1 in pituitary adenoma was examined utilizing the Transwell assay, western blot assays and the cell counting kit-8. RNA immunoprecipitation and luciferase reporter assays revealed that miR-361-3p binds to E2F1 or BBOX1-AS1. In addition, in-vivo assays were carried out. The expression of BBOX1-AS1 in pituitary adenoma tissues and cells has been increased, according to our findings. Furthermore, it is also noted that downregulation of BBOX1-AS1causes the inhibition of pituitary adenoma cells which result in invasion, apoptosis and proliferation, as well as boosting tumor development in vivo . In addition, BBOX1-AS1 knockdown inhibited tumor development in vivo . We identify BBOX1-AS1 bind to miR-361-3p and to suppress its expression in a negative way. Moreover, miR-361-3p has been shown to bind with E2F1 and inhibit its expression. E2F1 also corrected miR-361-3p-mediated cell invasion, proliferation and apoptosis in BBOX1-AS1-dysregulated pituitary adenoma cells in rescue tests. BBOX1-AS1 increases pituitary adenoma malignant activity by sponging miR-361-3p to upregulate E2F1 expression, which may lead to a new path in pituitary adenoma therapeutic attempts.

Linoleic acid pathway disturbance contributing to potential cancerization of intrahepatic bile duct stones into intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy with poor prognosis. Intrahepatic bile duct stone (IBDS) is one of the key causes to ICC occurrence and can increase morbidity rate of ICC about forty times. However, the specific carcinogenesis of IBDS is still far from clarified. Insight into the metabolic phenotype difference between IBDS and ICC can provide potential mechanisms and therapeutic targets, which is expected to inhibit the carcinogenesis of IBDS and improve the prognosis of ICC. METHODS: A total of 34 participants including 25 ICC patients and 9 IBDS patients were recruited. Baseline information inclusive of liver function indicators, tumor biomarkers, surgery condition and constitution parameters etc. from patients were recorded. ICC and IBDS pathological tissues, as well as ICC para-carcinoma tissues, were collected for GC-MS based metabolomics experiments. Multivariate analysis was performed to find differentially expressed metabolites and differentially enriched metabolic pathways. Spearman correlation analysis was then used to construct correlation network between key metabolite and baseline information of patients. RESULTS: The IBDS tissue and para-carcinoma tissue have blurred metabolic phenotypic differences, but both of them essentially distinguished from carcinoma tissue of ICC. Metabolic differences between IBDS and ICC were enriched in linoleic acid metabolism pathway, and the level of 9,12-octadecadienoic acid in IBDS tissues was almost two times higher than in ICC pathological tissues. The correlation between 9,12-octadecadienoic acid level and baseline information of patients demonstrated that 9,12-octadecadienoic acid level in pathological tissue was negative correlation with gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) level in peripheral blood. These two indicators were all cancerization marker for hepatic carcinoma and disease characteristic of IBDS. CONCLUSION: Long-term monitoring of metabolites from linoleic acid metabolism pathway and protein indicators of liver function in IBDS patients has important guiding significance for the monitoring of IBDS carcinogenesis. Meanwhile, further insight into the causal relationship between linoleic acid pathway disturbance and changes in liver function can provide important therapeutic targets for both IBDS and ICC.

Trophinin-associated protein expression correlates with shorter survival of patients with glioma: a study based on multiple data fusion analysis.

BACKGROUND: Trophinin-associated protein (TROAP) mediates embryonic transfer, regulates microtubules, and is associated with the biological behavior of various cancers. However, there is limited information on the role of TROAP in glioma. METHODS AND RESULTS: We obtained clinical information on 1948 patients with glioma from The Cancer Genome Atlas, Gene Expression Omnibus and the Chinese Glioma Genome Atlas. Basal assays were used to measure changes in TROAP expression levels in high-grade glioma cell lines and in normal human astrocytes. Quantitative reverse transcription polymerase chain reaction assays showed that TROAP expression was higher in glioma cell lines than in normal astrocytes. The expression level of TROAP in 749 glioma was significantly higher than that in 228 normal brain tissues using Student's t test. The expression of TROAP has a positive relationship with the clinical characteristics of poor prognosis, such as WHO grade, age and has negatively correlated with the indicators of beneficial prognosis, such as IDH mutation and 1p19q co-deletion. Kaplan-Meier survival curves, single multifactor analysis were used to analyze correlations between TROAP and clinical features and prognosis of gliomas. In addition, TROAP overexpression was an independent risk factor for glioma and was associated with reduced overall survival of patients with glioma particularly in patients with WHO grade III and grade IV glioma. Gene set enrichment analysis showed that homologous recombination, cell cycle, and p53 signaling pathways were enriched in samples overexpressing TROAP. CONCLUSION: TROAP is a potential risk factor associated with poor prognosis in patients with glioma and may act as a highly specific biomarker, offering the possibility of individualized glioma treatment.

BREM-SC: a bayesian random effects mixture model for joint clustering single cell multi-omics data.

Droplet-based single cell transcriptome sequencing (scRNA-seq) technology, largely represented by the 10× Genomics Chromium system, is able to measure the gene expression from tens of thousands of single cells simultaneously. More recently, coupled with the cutting-edge Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq), the droplet-based system has allowed for immunophenotyping of single cells based on cell surface expression of specific proteins together with simultaneous transcriptome profiling in the same cell. Despite the rapid advances in technologies, novel statistical methods and computational tools for analyzing multi-modal CITE-Seq data are lacking. In this study, we developed BREM-SC, a novel Bayesian Random Effects Mixture model that jointly clusters paired single cell transcriptomic and proteomic data. Through simulation studies and analysis of public and in-house real data sets, we successfully demonstrated the validity and advantages of this method in fully utilizing both types of data to accurately identify cell clusters. In addition, as a probabilistic model-based approach, BREM-SC is able to quantify the clustering uncertainty for each single cell. This new method will greatly facilitate researchers to jointly study transcriptome and surface proteins at the single cell level to make new biological discoveries, particularly in the area of immunology.

Confident identification of subgroups from SNP testing in RCTs with binary outcomes.

In modern drug development, genotype information becomes more frequently collected in randomized controlled trials (RCTs) for individualized risk prediction and personalized medicine development. Finding single nucleotide polymorphisms (SNPs) that are predictive of differential treatment efficacy, measured by a clinical outcome, is fundamentally different and more challenging than the traditional association test for a quantitative trait. With the objective to confidently identify and infer genetic subgroups with enhanced treatment efficacy from a large RCT for an eye disease, age-related macular degeneration (AMD), where the clinical endpoint is binary (progressed or not), we propose a novel SNP-testing procedure for binary clinical outcomes. Specifically, we formulate four contrasts to simultaneously assess all possible genetic effects on a logic-respecting efficacy measure, the relative risk (between treatment and control). Our method controls both within- and across-SNP multiplicity rigorously. We then use real genotype data to perform chromosome-wide simulations to evaluate our method performance and to provide practical recommendations. Finally, we apply the proposed method to perform a genome-wide SNP testing for the AMD trial and successfully identify multiple gene regions with genetic subgroups exhibiting enhanced efficacy in terms of decreasing the AMD progression rate.

Gallic acid-gold nanoparticles enhance radiation-induced cell death of human glioma U251 cells.

Glioblastoma multiforme (GBM) is among the most common adult brain tumors with invariably fatal character. Following the limited conventional therapies, almost all patients, however, presented with symptoms at the time of recurrence. It is dire to develop novel therapeutic strategies to improve the current treatment of GBM. Gallic acid is a well-established antioxidant, presenting a promising new selective anti-cancer drug, while gold nanoparticles (GNPs) can be developed as versatile nontoxic carriers for anti-cancer drug delivery. Here, we prepared gallic acid-GNPs (GA-GNPs) by loading gallic acid onto GNPs, reduction products of tetrachloroauric acid by sodium citrate, through physical and agitation adsorption. GA-GNPs, rather than GNPs alone, significantly inhibited the survival of U251 GBM cells, as well as enhanced radiation-induced cell death. Moreover, GA-GNPs plus radiation arrested the cell cycle of U251 at the S and G2/M phases and triggered apoptotic cell death, which is supported by increased BAX protein levels and decreased expression of BCL-2. Thus, GA-GNPs have great potential in the combination with radiation therapy in future studies for GBM treatment.

miR-93 regulates liver tumor initiating cells expansion and predicts chemotherapeutic response of patients.

Tumor initiating cells (T-ICs) play an important role in tumorigenesis, progression, metastasis, recurrence and drug resistance, but the underlying mechanism was not clearly elucidated. In our study, we found that miR-93 was highly expressed in liver T-ICs. Self-renewal and tumorigenesis ability of liver T-ICs were enhanced by miR-93 overexpression and attenuated by miR-93 interference. Mechanically, miR-93 regulated liver T-ICs by binding to 3'-UTR of myotubularin-related protein 3 (MTMR3). In addition, miR-93 was found highly expressed in cisplatin or sorafenib-resistant liver cancer tissues. Interference of miR-93 sensitizes hepatoma cells to cisplatin or sorafenib treatment. Clinical cohort analysis showed that Hepatocellular carcinoma (HCC) patients with low miR-93 were benefit more from TACE or sorafenib treatment. In conclusion, our study demonstrates a new regulation mechanism of liver T-ICs, a new target for HCC, and a biomarker for postoperative TACE or sorafenib.

Efficacy and safety of polyethylene glycol loxenatide monotherapy in type 2 diabetes patients: A multicentre, randomized, double-blind, placebo-controlled phase 3a clinical trial.

AIM: To evaluate the efficacy and safety of polyethylene glycol loxenatide (PEX168) monotherapy in type 2 diabetes (T2D) patients in China. MATERIALS AND METHODS: In a multicentred, randomized, double-blinded, placebo-controlled phase 3a clinical trial, 361 patients with inadequate glycaemic control (HbA1c 7.0%-10.5%, fasting plasma glucose <13.9 mmol/L) were randomized (1:1:1) for weekly subcutaneous injections: placebo, PEX168/100 µg or PEX168/200 µg. The 24-week treatment was followed by a 28-week extension, during which placebo-treated patients were randomly assigned to PEX168/100 µg or PEX168/200 µg. The primary efficacy endpoint was the HbA1c change from baseline to week 24. RESULTS: The three groups had similar demographics and baseline characteristics. The HbA1c least-square mean (95% CI) change from baseline to week 24 was greater for PEX168/100 µg (-1.02% [-1.21%, -0.83%]) and PEX168/200 µg (-1.34% [-1.54%, -1.15%]) than for placebo (-0.17% [-0.36%, 0.02%]); (superiority: P < .0001). The proportions of patients with less than 7% HbA1c in the placebo, PEX168/100 µg and PEX168/200 µg groups were 15.7%, 34.7% and 46.6%, respectively. Common gastrointestinal adverse events (AEs) were nausea (5.6%, 10.0% and 0% for PEX168/100 µg, PEX168/200 µg and placebo, respectively) and vomiting (2.4%, 8.3% and 0% for PEX168/100 µg, PEX168/200 µg and placebo, respectively). Six (1.6%) patients (PEX168/100 µg: N = 2 [1.6%], PEX168/200 µg: N = 3 [2.5%] and placebo: N = 1 [0.8%]) discontinued treatment because of AEs. Four (1.2%) patients (PEX168/100 µg: N = 3 [2.5%] and PEX168/200 µg: N = 1 [0.9%]) developed PEX168 antidrug antibodies. CONCLUSION: PEX168 monotherapy significantly improved glycaemic control in T2D patients with a safety profile resembling that of other glucagon-like peptide-1 receptor agonists.

SLC7A11 negatively associates with mismatch repair gene expression and endows glioblastoma cells sensitive to radiation under low glucose conditions.

The cystine/glutamate antiporter xCT (SLC7A11) is frequently upregulated in many cancers, including glioblastoma (GBM). SLC7A11-mediated cystine taken up is reduced to cysteine, a precursor amino acid for glutathione synthesis and antioxidant cellular defense. However, little is known about the biological functions of SLC7A11 and its effect on therapeutic response in GBM. Here, we report that the expression of SLC7A11 is higher in GBM compared with normal brain tissue, but is negatively associated with tumor grades and positively impacts survival in the bioinformatic analysis of TCGA and CGGA database. Additionally, a negative association between SLC7A11 and mismatch repair (MMR) gene expression was identified by Pearson correlation analysis. In the GBM cells with glucose-limited culture conditions, overexpression of SLC7A11 significantly decreased MMR gene expression, including MLH1, MSH6, and EXO1. SLC7A11-overexpressed GBM cells demonstrated elevated double-strand break (DSB) levels and increased sensitivity to radiation treatment. Taken together, our work indicates that SLC7A11 might be a potential biomarker for predicting a better response to radiotherapy in GBM.

Enhanced store-operated calcium entry (SOCE) exacerbates motor neurons apoptosis following spinal cord injury.

Spinal cord injury is pathologically characterized by the loss of motor function caused by neurons apoptosis. Store-operated calcium entry (SOCE) is widely known to dictate the apoptosis of various cell types. To examine SOCE in spinal cord injury and explore the role of SOCE in apoptosis, patients with spinal cord injury (SCI) and SCI mouse models were included. Expression of SOCE components and apoptosis-related proteins were examined by Western blotting. Calcium imaging was used to assess SOCE activity. As a result, we confirmed the enhanced levels of ORAI1 and STIM1 in SCI patients and SCI mouse models. In vitro study, tunicamycin impaired the viability of VSC4.1 cells (motoneuron-neuroblastoma hybrid cell line) and increased SOCE activity, the effects of which could be abolished by 2-APB. Furthermore, tunicamycinreduced BCL-2/BAX ratio was also reversed by 2-APB. Additionally, EdU assay and DCFH-DA staining confirmed the regulatory role of 2-APB in proliferation and ROS production. Of note is the improved hindlimb motor function and alleviated depression by 2-APB administration. Therefore, we conclude that SOCE may contribute to the pathogenesis of SCI by exacerbating the apoptosis of motoneurons.

All-Optical Manipulation of Magnetization in Ferromagnetic Thin Films Enhanced by Plasmonic Resonances.

In this paper, we report all-optical manipulation of magnetization in ferromagnetic Co/Pt thin films enhanced by plasmonic resonances. By annealing a thin Au layer, we fabricate large-area Au nanoislands on top of the Co/Pt magnetic thin films, which show plasmonic resonances around the wavelength of 606 nm. Using a customized magneto-optical Kerr effect setup, we experimentally observe an 18.5% decrease in the minimum laser power required to manipulate the magnetization, comparing the on- and off-resonance conditions. The results are in very good agreement with numerical simulations. Our research findings demonstrate the possibility to achieve an all-optical magnetic recording with low energy consumption, low cost, and high areal density by integrating plasmonic nanostructures with magnetic media.

Near-Infrared Light-Switched MoS2 Nanoflakes@Gelatin Bioplatform for Capture, Detection, and Nondestructive Release of Circulating Tumor Cells.

The integrative bioplatform for capture, detection and release of circulating tumor cells (CTCs) is of great significance in clinical diagnosis and biomedical research. To fulfill this demand, we introduced a near-infrared (NIR) light-switched bioplatform for efficient isolation and downstream analysis of CTCs. The platform was created by first modifying the PEG-MoS2 nanoflakes (NFs)@gelatin nanocomposite on the ITO surface, and then introducing the MUC1 aptamer as a specific recognition element via coupling reaction between aptamer and gelatin to achieve the specific capture for CTCs. Subsequently, the captured cells are released under a NIR light irradiation (808 nm) by using MoS2 NFs as the NIR-regulated control element. Significantly, this platform could capture and release of CTCs with an excellent capture/release efficiency of 89.5% and 92.5%, respectively. Furthermore, the electrochemical bioplatform exhibited a wide linear range for the detection of CTCs from 50 to 1 × 106 cells mL-1 with a detection limit of 15 cells mL-1. After 5 days of reculture, the released cells still maintain good cell shape and proliferation capacity. Moreover, the bioplatfrom is a simple, versatile, and universal system for the recognition, capture, release, and detection of different types of CTCs. Therefore, this bioplatform shows potential applications on the early diagnosis of cancers.

Effect of oblique versus normal deposition orientation on the properties of perpendicularly magnetized L10 FePd thin films.

Materials such as L10 Fe-based alloys with perpendicular magnetic anisotropy derived from crystal structure have the potential to deliver higher thermal stability of magnetic memory elements compared to materials whose anisotropy is derived from surfaces and interfaces. A number of processing parameters enable control of the quality and texture of L10 FePd among them, including substrate, deposition temperature, pressure and seed and buffer layer. The angle of inclination between the substrate and the sputtering target can also impact the texture of L10 crystallization of sputtered Fe-Pd and magnetic properties of the derived thin films. This study examines the difference between FePd layers that have been magnetron sputter deposited on Cr(15 nm)/Pt, Ir, or Ru(4 nm)/FePd (8 nm)/Ru(2 nm)/Ta(3 nm) substrate layers at an oblique angle (30° tilt from the sputtering target) versus normal incidence (target facing the substrate). X-ray diffraction, ferromagnetic resonance spectroscopy and vibrating sample magnetometry were used to compare the degree of L10 order and static and dynamic properties of films deposited under both conditions. The films grown using the oblique orientation exhibit a stronger degree of L10 orientation, a larger magnetic anisotropy energy and a lower Gilbert damping, on all three buffer layers.

Neddylation inhibition upregulates PD-L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma.

Pevonedistat (MLN4924), a specific NEDD8-activating enzyme inhibitor, has been considered as a promising treatment for glioblastoma, which is currently in Phase I/II clinical trials. On the other hand, inhibition of neddylation pathway substantially upregulates the expression of T cell negative regulator programmed death-ligand 1 (PD-L1), which might account for the potential resistance via evasion of immune surveillance checkpoints. Whether administration of anti-PD-L1 enhances the efficacy of pevonedistat through a cytotoxic T cell-dependent mechanism in glioblastoma needs to be investigated. Here, we report that depletion of neddylation pathway key enzymes markedly elevates PD-L1 expression in glioblastoma cancer cells. Consistently, neddylation inhibitor pevonedistat significantly enhances PD-L1 expression in both glioblastoma cancer cell lines and animal models. Mechanistically, pevonedistat increases PD-L1 mRNA levels mainly through inhibiting Cullin1-F-box and WD repeat domain-containing 7 E3 ligase activity and accumulating c-MYC proteins, a direct transcriptional activator of PD-L1 gene expression. In addition, inhibition of Cullin3 activity by pevonedistat also blocks PD-L1 protein degradation. Importantly, pevonedistat attenuates T cell killing through PD-L1 induction, and blockade of PD-L1 restores the sensitivity of pevonedistat-treated glioblastoma cancer cells to T cell killing. The combination of pevonedistat and anti-PD-L1 therapy compared to each agent alone significantly increased the therapeutic efficacy in vivo. Our study demonstrates inhibition of neddylation pathway suppresses cancer-associated immunity and provides solid evidence to support the combination of pevonedistat and PD-L1/programmed cell death protein 1 immune checkpoint blockade as a potential therapeutic strategy to treat glioblastoma.

Electroacupuncture via chronically implanted electrodes improves gastrointestinal motility by balancing sympathovagal activities in a rat model of constipation.

Electroacupuncture (EA) has been reported for treating constipation in clinical studies. However, little is known of the possible mechanisms involved in the prokinetic effect of EA. The aim of this study was to investigate the effects and underlying autonomic mechanisms of EA via chronically implanted electrodes for constipation in rat induced by Loperamide (Lop). Lop was given to regular rats to induce constipation. EA was performed via a pair of electrodes chronically implanted at bilateral acupoint ST-36. Feces characteristics, gastric emptying, small intestinal transit, distal colon transit time (dCTT), and whole gut transit time (WGTT) were measured in various sessions with EA or sham EA in rats with constipation induced by Lop. Heart rate variability (HRV) derived from the electrocardiogram was analyzed to evaluate autonomic functions. The number of fecal pellets was reduced by 27% with Lop (P < 0.01) and normalized by 7-day EA. Similar results were also observed in pellet weight. In normal rats compared with sham EA, EA shortened dCTT by 74% (P < 0.05 vs. sham EA), increased small intestinal transit by 28% (P < 0.01) and gastric emptying by 27% (P < 0.05), and accelerated whole gut transit by 14% (P < 0.05). In Lop-treated rats, the dCTT and WGTT were prolonged by Lop and normalized by EA. Lop significantly decreased vagal activity and increased sympathetic nerve activity; however, EA reversed these effects. EA at ST-36 via chronically implanted electrodes improves Lop-induced constipation by enhancing GI motility via the autonomic mechanisms. NEW & NOTEWORTHY The findings of the present study suggest that the proposed electroacupuncture (EA) may have great therapeutic potential for treating patients with opioid-induced constipation. It was demonstrated that EA at ST-36 improved transit of every organ along the gut mediated via the autonomic mechanisms in normal rats and rats with Lop-induced constipation. It is advised to administrate EA daily instead of two or three times weekly as reported in most of the clinical studies.