SOX2 downregulation of PML increases HCMV gene expression and growth of glioma cells.

The presence of human cytomegalovirus (HCMV) in glioblastoma (GBM) and improved outcomes of GBM patients receiving therapies targeting the virus have implicated HCMV in GBM progression. However, a unifying mechanism that accounts for the contribution of HCMV to the malignant phenotype of GBM remains incompletely defined. Here we have identified SOX2, a marker of glioma stem cells (GSCs), as a key determinant of HCMV gene expression in gliomas. Our studies demonstrated that SOX2 downregulated promyelocytic leukemia (PML) and Sp100 and consequently facilitated viral gene expression by decreasing the amount of PML nuclear bodies in HCMV-infected glioma cells. Conversely, the expression of PML antagonized the effects of SOX2 on HCMV gene expression. Furthermore, this regulation of SOX2 on HCMV infection was demonstrated in a neurosphere assay of GSCs and in a murine xenograft model utilizing xenografts from patient-derived glioma tissue. In both cases, SOX2 overexpression facilitated the growth of neurospheres and xenografts implanted in immunodeficient mice. Lastly, the expression of SOX2 and HCMV immediate early 1 (IE1) protein could be correlated in tissues from glioma patients, and interestingly, elevated levels of SOX2 and IE1 were predictive of a worse clinical outcome. These studies argue that HCMV gene expression in gliomas is regulated by SOX2 through its regulation of PML expression and that targeting molecules in this SOX2-PML pathway could identify therapies for glioma treatment.

A Dual Inhibitory Mechanism Sufficient to Maintain Cell-Cycle-Restricted CENP-A Assembly.

Chromatin featuring the H3 variant CENP-A at the centromere is critical for its mitotic function and epigenetic maintenance. Assembly of centromeric chromatin is restricted to G1 phase through inhibitory action of Cdk1/2 kinases in other phases of the cell cycle. Here, we identify the two key targets sufficient to maintain cell-cycle control of CENP-A assembly. We uncovered a single phosphorylation site in the licensing factor M18BP1 and a cyclin A binding site in the CENP-A chaperone, HJURP, that mediated specific inhibitory phosphorylation. Simultaneous expression of mutant proteins lacking these residues results in complete uncoupling from the cell cycle. Consequently, CENP-A assembly is fully recapitulated under high Cdk activities, indistinguishable from G1 assembly. We find that Cdk-mediated inhibition is exerted by sequestering active factors away from the centromere. Finally, we show that displacement of M18BP1 from the centromere is critical for the assembly mechanism of CENP-A.

Intrinsic Self-Trapped Excitons in Graphitic Carbon Nitride.

Graphitic carbon nitrides (g-C3N4) as low-cost, chemically stable, and ecofriendly layered semiconductors have attracted rapidly growing interest in optoelectronics and photocatalysis. However, the nature of photoexcited carriers in g-C3N4 is still controversial, and an independent charge-carrier picture based on the band theory is commonly adopted. Here, by performing transient spectroscopy studies, we show characteristics of self-trapped excitons (STEs) in g-C3N4 nanosheets including broad trapped exciton-induced absorption, picosecond exciton trapping without saturation at high photoexcitation density, and transient STE-induced stimulated emissions. These features, together with the ultrafast exciton trapping polarization memory, strongly suggest that STEs intrinsically define the nature of the photoexcited states in g-C3N4. These observations provide new insights into the fundamental photophysics of carbon nitrides, which may enlighten novel designs to boost energy conversion efficiency.

Somatic variants of MAP3K3 are sufficient to cause cerebral and spinal cord cavernous malformations.

Cerebral cavernous malformations (CCMs) and spinal cord cavernous malformations (SCCMs) are common vascular abnormalities of the CNS that can lead to seizure, haemorrhage and other neurological deficits. Approximately 85% of patients present with sporadic (versus congenital) CCMs. Somatic mutations in MAP3K3 and PIK3CA were recently reported in patients with sporadic CCM, yet it remains unknown whether MAP3K3 mutation is sufficient to induce CCMs. Here we analysed whole-exome sequencing data for patients with CCM and found that ∼40% of them have a single, specific MAP3K3 mutation [c.1323C>G (p.Ile441Met)] but not any other known mutations in CCM-related genes. We developed a mouse model of CCM with MAP3K3I441M uniquely expressed in the endothelium of the CNS. We detected pathological phenotypes similar to those found in patients with MAP3K3I441M. The combination of in vivo imaging and genetic labelling revealed that CCMs were initiated with endothelial expansion followed by disruption of the blood-brain barrier. Experiments with our MAP3K3I441M mouse model demonstrated that CCM can be alleviated by treatment with rapamycin, the mTOR inhibitor. CCM pathogenesis has usually been attributed to acquisition of two or three distinct genetic mutations involving the genes CCM1/2/3 and/or PIK3CA. However, our results demonstrate that a single genetic hit is sufficient to cause CCMs.

Perovskite light-emitting diodes with external quantum efficiency exceeding 20 per cent.

Metal halide perovskite materials are an emerging class of solution-processable semiconductors with considerable potential for use in optoelectronic devices1-3. For example, light-emitting diodes (LEDs) based on these materials could see application in flat-panel displays and solid-state lighting, owing to their potential to be made at low cost via facile solution processing, and could provide tunable colours and narrow emission line widths at high photoluminescence quantum yields4-8. However, the highest reported external quantum efficiencies of green- and red-light-emitting perovskite LEDs are around 14 per cent7,9 and 12 per cent8, respectively-still well behind the performance of organic LEDs10-12 and inorganic quantum dot LEDs13. Here we describe visible-light-emitting perovskite LEDs that surpass the quantum efficiency milestone of 20 per cent. This achievement stems from a new strategy for managing the compositional distribution in the device-an approach that simultaneously provides high luminescence and balanced charge injection. Specifically, we mixed a presynthesized CsPbBr3 perovskite with a MABr additive (where MA is CH3NH3), the differing solubilities of which yield sequential crystallization into a CsPbBr3/MABr quasi-core/shell structure. The MABr shell passivates the nonradiative defects that would otherwise be present in CsPbBr3 crystals, boosting the photoluminescence quantum efficiency, while the MABr capping layer enables balanced charge injection. The resulting 20.3 per cent external quantum efficiency represents a substantial step towards the practical application of perovskite LEDs in lighting and display.

Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling.

Inappropriate activation of the receptor tyrosine kinase EGFR contributes to a variety of human malignancies. Here we show a mechanism to induce vulnerability to an existing first line treatment for EGFR-driven cancers. We find that inhibiting the palmitoyltransferase DHHC20 creates a dependence on EGFR signaling for cancer cell survival. The loss of palmitoylation increases sustained EGFR signal activation and sensitizes cells to EGFR tyrosine kinase inhibition. Our work shows that the reversible modification of EGFR with palmitate "pins" the unstructured C-terminal tail to the plasma membrane, impeding EGFR activation. We identify by mass spectrometry palmitoylated cysteine residues within the C-terminal tail where mutation of the cysteine residues to alanine is sufficient to activate EGFR signaling promoting cell migration and transformation. Our results reveal that the targeting of a peripheral modulator of EGFR signaling, DHHC20, causes a loss of signal regulation and susceptibility to EGFR inhibitor-induced cell death.

The relationship between duration of infertility and clinical outcomes of intrauterine insemination for younger women: a retrospective clinical study.

BACKGROUND: The objective of this research was to elucidate the association between the length of infertility and the outcomes of intrauterine insemination (IUI) in women of varying ages - a topic that has been the subject of investigation for numerous years, yet lacks a definitive consensus. METHODS: A retrospective cohort investigation involving 5268 IUI cycles was undertaken at the Reproductive Medicine Center of Nanjing Drum Tower Hospital from 2016 to 2022. Utilizing the smooth fitting curve along with threshold and saturation effect analysis, the correlation between infertility duration and IUI clinical pregnancy rates was discerned. Moreover, patients were bifurcated into two cohorts based on their respective infertility durations. A secondary examination was also performed employing propensity-score matching to mitigate the impact of confounding variables. Subsequent threshold and saturation effect analysis was carried out across various subgroups, segmented on the basis of age differentiation. RESULTS: When the duration of infertility was more than 5 years, the clinical pregnancy rate decreased with the increase of infertility duration (aOR: 0.894, 95%CI: 0.817-0.991, p = 0.043). The multivariate regression analysis suggested that longer duration of infertility (≥ 5 years) was significantly correlated with the lower clinical pregnancy rate (aOR: 0.782, 95% CI: 0.643-0.950, p = 0.01). After the propensity-score matching, the clinical pregnancy rate of women with longer infertility duration were also higher. When the duration of infertility was more than 5 years, the clinical pregnancy rate of women younger than 35 years old decreased with the increase of infertility duration (aOR: 0.906, 95%CI: 0.800-0.998, p = 0.043). CONCLUSIONS: The clinical pregnancy rate and live birth rate of IUI in young women (< 35 years old) who have been infertile for more than 5 years significantly decrease with the prolongation of infertility time. Therefore, for young women who have been infertile for more than 5 years, IUI may not be the best choice.

Transcranial direct current stimulation for upper extremity motor dysfunction in poststroke patients: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of transcranial direct current stimulation in poststroke patients with upper extremity motor dysfunction using a systematic review and meta-analysis. DATA SOURCES: We searched the Web of Science, Cochrane Library, EMBASE, and PubMed for randomized controlled trials investigating the effects of both active and sham stimulation up until January 27, 2024. REVIEW METHODS: Efficacy, including the upper extremity Fugl-Meyer Assessment, Action Research Arm Test, Barthel Index, and safety, were assessed. The risk of bias was assessed using the Cochrane Risk of Bias 2 tool and the Physiotherapy Evidence Database Scale. Meta-analysis was performed using the RevMan 5.4 software. RESULTS: Forty-four studies with 1555 participants were included. Transcranial direct current stimulation proved effective in improving upper extremity motor function (standardized mean difference = 0.22, 95% confidence interval: 0.12-0.32, P < 0.001) and Barthel Index (mean difference = 4.65, 95% confidence interval: 2.82-6.49, P < 0.001). Subgroup analysis revealed the highest transcranial direct current stimulation efficacy in patients with subacute stroke. Both anodal and cathodal stimulation were effective against upper extremity motor dysfunction. C3/C4 was the most effective stimulus target. Optimal stimulation parameters included stimulus current densities <0.057 mA/cm2 for 20-30 min and <30 sessions. Adverse effects and dropouts during follow-up showed that transcranial direct current stimulation is safe and feasible. CONCLUSIONS: Our findings suggest that both anodal and cathodal stimulation were significantly effective in subacute stroke patients, particularly when preceding other treatments and when C3/C4 is targeted.

Cost-Effectiveness Analysis of Remimazolam and Midazolam in Goal-Guided Sedation in ICU.

Objective: This study aimed to compare the direct medication costs and clinical effectiveness of using remimazolam versus midazolam for goal-guided sedation therapy in the ICU patients. Methods: This randomized controlled study was conducted in the ICU of People's Hospital Affiliated to Shandong First Medical University. Eighty adult patients admitted to the ICU and requiring sedation were enrolled and randomly assigned in a 1:1 ratio to receive either remimazolam-based sedation (study group, n=40) or midazolam-based sedation (control group, n=40). The inclusion criteria for patient selection were age 18-80 years, requirement for mechanical ventilation, and an expected ICU stay of at least 24 hours. Patients with significant liver or kidney dysfunction, neurological disorders, or contraindications to the study drugs were excluded. The target sedation depth for both groups was a Ramsay Sedation Scale score of 3-4, which was maintained by titrating the infusion rates of remimazolam or midazolam as needed. Vital signs, sedation scores, and respiratory parameters were closely monitored throughout the sedation period. Results: The time to onset of sedation, time to reach the target sedation depth, time to awakening, and length of ICU stay were all significantly shorter in the remimazolam group compared to the midazolam group (P < .05 for all). The remimazolam group had a mean time to onset of 5.2 ± 1.8 minutes versus 8.9 ± 2.4 minutes in the midazolam group. The mean time to reach the target Ramsay Sedation Scale score of 3-4 was 12.6 ± 3.1 minutes in the remimazolam group compared to 18.4 ± 4.2 minutes in the midazolam group. The mean time to awakening was 10.2 ± 2.7 minutes in the remimazolam group versus 16.5 ± 3.9 minutes in the midazolam group. The remimazolam group also had a significantly shorter mean ICU length of stay of 5.1 ± 1.3 days compared to 7.8 ± 2.1 days in the midazolam group (P < .01). The remimazolam group had a significantly higher metabolic clearance rate compared to the midazolam group (P < .001). The Ramsay sedation scores and Wong-Baker FACES pain scores were also significantly lower in the remimazolam group throughout the sedation period (P < .01). There were no significant differences in heart rate between the two groups at any timepoint. However, the overall incidence of adverse events was significantly lower in the remimazolam group compared to the midazolam group (P < .05). Conclusion: This study demonstrated that the use of remimazolam-based goal-directed sedation in the ICU setting resulted in significantly faster onset of action, quicker achievement of the target sedation depth, shorter time to awakening, and shorter ICU length of stay compared to midazolam-based sedation. The remimazolam group also had a higher metabolic clearance rate, lower sedation and pain scores, and a lower incidence of adverse events.These findings suggest that remimazolam may provide advantages over midazolam for ICU sedation, potentially leading to improved patient comfort, more efficient utilization of ICU resources, and potentially better clinical outcomes. The rapid onset, titratability, and favorable safety profile of remimazolam make it a promising sedative agent that could help optimize sedation practices in the critical care setting. Further research is warranted to fully evaluate the impact of remimazolam on long-term patient-centered outcomes and overall healthcare costs in the ICU.

Enhancing Performance of Organic Pollutant Degradation via Building Heterojunctions with ZnO Nanowires and Na Doped Conjugated 2,4,6-Triaminopyrimidin-g-C3N4.

Organic pollutants were one of the main sources of environmental pollutants. The degradation of organic pollutants through photocatalytic technology was one of the effective solutions. By preparing zinc oxide(ZnO) nanowires modified with sodium-doped conjugated 2,4,6-triaminopyrimidin-g-C3N4 (NaTCN) heterojunction (ZnO/NaTCN), the photocatalytic performance of NaTCN modified with different ratios of ZnO was systematically studied. The photocatalytic performance was studied through the degradation performance of methyl blue (MB) dye. The results showed that 22.5 wt% ZnO/NaTCN had the best degradation effect on MB dye. The degradation rate of MB reached 98.54% in 70 min. After three cycles, it shows good cycling stability (degradation rate is 96.99%) for dye degradation. It was found that there are two types of active species: ·OH and h+, of which h+ is the main active species produced by photocatalytic degradation of dyes. The excellent degradation performance was attributed to the fact that ZnO facilitated the extraction and transport of photogenerated carriers. The doping of sodium facilitated charge transfer. The NaTCN conjugated system promoted the extraction and transfer of photogenerated carriers. It provided guidance for designing efficient composite catalysts for use in other renewable energy fields.

Qingzhuan dark tea polysaccharides-zinc alleviates dextran sodium sulfate-induced ulcerative colitis.

BACKGROUND: Qingzhuan dark tea polysaccharides (QDTP) have been complexed with Zinc (Zn) to form the Qingzhuan dark tea polysaccharides-Zinc (QDTP-Zn) complex. The present study investigated the protective effects of QDTP-Zn on ulcerative colitis (UC) in mice. The UC mouse model was induced using dextran sodium sulfate (DSS), followed by oral administration of QDTP-Zn (0.2 and 0.4 g kg-1 day-1). RESULTS: QDTP-Zn demonstrated alleviation of UC symptoms in mice, as evidenced by a decrease in disease activity index scores. QDTP-Zn also regulated colon tissue injury by upregulating ZO-1 and occludin protein expression, at the same time as downregulating tumor necrosis factor-α and interleukin-6ß levels. Furthermore, QDTP-Zn induced significant alterations in the abundance of bacteroidetes and firmicutes and notably increased levels of short-chain fatty acids (SCFAs), particularly acetic acid, propionic acid, and butyric acid. CONCLUSION: In summary, QDTP-Zn exhibits therapeutic potential in alleviating enteritis by fortifying the colonic mucosal barrier, mitigating inflammation and modulating intestinal microbiota and SCFAs levels. Thus, QDTP-Zn holds promise as a functional food for both the prevention and treatment of UC. © 2024 Society of Chemical Industry.

Genomic and metabonomic methods reveal the probiotic functions of swine-derived Ligilactobacillus salivarius.

BACKGROUND: As substitutes for antibiotics, probiotic bacteria protect against digestive infections caused by pathogenic bacteria. Ligilactobacillus salivarius is a species of native lactobacillus found in both humans and animals. Herein, a swine-derived Ligilactobacillus salivarius was isolated and shown to colonize the ileal mucous membrane, thereby promoting nutritional digestion, absorption, and immunity. To evaluate its probiotic role, the entire genome was sequenced, the genetic information was annotated, and the metabolic information was analyzed. RESULTS: The phylogenetic relationship indicated that the bacteria was closer to L. salivarius MT573555.1 and MT585431.1. Functional genes included transporters, membrane proteins, enzymes, heavy metal resistance proteins, and putative proteins; metabolism-related genes were the most abundant. The six types of metabolic pathways secreted by L. salivarius were mainly composed of secretory transmembrane proteins and peptides. The secretory proteins of L. salivarius were digestive enzymes, functional proteins that regulate apoptosis, antibodies, and hormones. Non-targeted metabolomic analysis of L. salivarius metabolites suggested that ceramide, pyrrolidone- 5- carboxylic acid, N2-acetyl-L-ornithine, 2-ethyl-2-hydroxybutyric acid, N-lactoyl-phenylalanine, and 12 others were involved in antioxidation, repair of the cellular membrane, anticonvulsant, hypnosis, and appetite inhibition. Metabolites of clavaminic acid, antibiotic X14889C, and five other types of bacteriocins were identified, namely phenyllactic acid, janthitrem G, 13-demethyl tacrolimus, medinoside E, and tertonasin. The adherence and antioxidation of L. salivarius were also predicted. No virulence genes were found. CONCLUSION: The main probiotic properties of L. salivarius were identified using genomic, metabonomic, and biochemical assays, which are beneficial for porcine feeding. Our results provided deeper insights into the probiotic effects of L. salivarius.

Isolation and pathogenicity evaluation of Escherichia coli O157:H7 from common carp, Cyprinus carpio.

Escherichia coli O157:H7 is the primary serotype of enterohaemorrhagic E. coli (EHEC), which can cause diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome. It is considered as a major health concern due to it being a zoonotic disease that is transmitted through food. In this study, a pathogenic bacterium was isolated from infected carp, which identified as E. coli O157:H7 named X21 through genetic sequencing, phylogenetic analysis, physiological and biochemical tests. In the experiment, crucian carp was used as a model to study the pathogenicity of the isolate, the pathological histological observations and cytokines expression of fish tissues were determined after bacterial challenge. The results showed that severe pathological damage observed in the liver, spleen, headkidney of fish infected with isolate X21. Besides, we found that accumulation of IgT+ B cells in the lamina propria of intestine, and up-regulation of SUCH-r, IL-1ß, IL-10, IL-11, MyD88, and TNF-α gene in various tissues. After challenged, the survivability of crucian carp infected with isolate X21 stands at a mere 14.27%. To our knowledge, this is the first report that E. coli O157:H7 infected the freshwater fish C. carpio, which indicates that this bacterium is a potential threat to public health and freshwater fish aquaculture.

Th6-Based Multicomponent Heterometallic Metal-Organic Frameworks Featuring 6,12-Connected Topology for Iodine Adsorption.

Its high coordination number and tendency to cluster make Th4+ suitable for constructing metal-organic frameworks (MOFs) with novel topologies. In this work, two novel thorium-based heterometallic MOF isomers (IHEP-17 and IHEP-18) were assembled from a Th6 cluster, a multifunctional organic ligand [4-(1H-pyrazol-4-yl)benzoic acid (HPyba)], and Cu2+/Ni2+ cations via the one-pot solvothermal synthesis strategy. The framework features a 6,12-connected new topology net and contains two kinds of supramolecular cage structures, Th36M4 and Th24M2, suitable for guest exchange. Both MOF materials can efficiently adsorb I2. X-ray photoelectron spectroscopy, Raman spectroscopy, and single-crystal X-ray diffraction indicate that the adsorbed iodine is uniformly distributed within the Th36M4 cage but not the Th24M2 cage in the form of I3-.

Successful treatment of a severe Takotsubo syndrome case complicated by liver abscess.

The main manifestations of Takotsubo syndrome (TTS) are a spherical expansion of the left ventricle or near the apex and decreased systolic function. TTS is mostly thought to be induced by emotional stress, and the induction of TTS by severe infection is not often reported. A 72-year-old female patient with liver abscess reported herein was admitted due to repeated fever with a history of hypertension and impaired glucose tolerance. Her severe infection caused TTS, and her blood pressure dropped to 80/40 mmHg. IABP treatment was performed immediately and continued for 10 days, and comprehensive medication was administered. Based on her disease course and her smooth recovery, general insights and learnings may be: Adding to mental and other pathological stress reaction, serious infections from pathogenic microorganism could be of great important causation of stress reaction leading to TTS, while basic diseases such as coronary heart disease, hypertension, and diabetes were be of promoting factors; In addition to effective drug therapies for TTS, the importance of the timely using of IABP should be emphasized.

Perinatal outcomes of singletons following double vitrification-warming procedures: a retrospective study using propensity score analysis.

BACKGROUND: Although repeated cryopreservation is an occasional occurrence, the effect on perinatal outcomes is unclear. Therefore, the aim of this study was to evaluate the perinatal outcomes of singletons after embryo re-cryopreservation. METHODS: In this retrospective study, a total of 647 singleton live births after blastocyst freeze-thaw embryo transfer cycles were investigated. They were divided into two groups: vitrified-warmed blastocysts (once-vitrified group) and vitrified-warmed blastocysts derived from thawed cleaved embryos (re-vitrified group). Propensity score matching (PSM) was used to control for potential confounding factors. RESULTS: A total of 592 infants were included in the once-vitrified group, and 55 infants were included in the re-vitrified group. After PSM, 108 cases were generated for comparison. The median gestational age was 38 weeks for both groups, and the birthweights were comparable (3390.6 ± 601.5 g vs. 3412.8 ± 672.6 g, P > 0.05). The incidence of preterm birth (PTB) (20.4% vs. 16.7%), low birthweight (LBW) (3.7% vs. 7.4%), macrosomia (11.1% vs. 16.7%) and large for gestational age (LGA) (29.6% vs. 22.2%) were not significantly different between the two groups. Logistic regression analysis indicated that double vitrification-warming procedures did not affect the occurrence of PTB (OR, 2.58 [95% CI, 0.77, 8.63]), LBW (OR, 0.83 [95% CI, 0.08, 8.29]), macrosomia (OR, 0.60 [95% CI, 0.13, 2.69]), or LGA (OR, 1.51 [95% CI, 0.53, 4.27]) (P > 0.05, for all). CONCLUSION: Our findings demonstrate that double vitrification-warming procedures do not increase the risk of adverse neonatal outcomes compared with those of once-vitrified embryos.

Temperature sensitive nanogel-stabilized pickering emulsion of fluoroalkane for ultrasound guiding vascular embolization therapy.

Various X-ray imaging technologies like computed tomography (CT) and digital subtraction angiography (DSA) are widely used in transcatheter arterial embolization (TAE) therapy for treating hepatocellular cancer (HCC) patients. Although they display high-contrast imaging, they have a few disadvantages, such as complex operation and exposure to ionizing radiation. Thus, ultrasound (US) imaging plays an important role in medical diagnosis because of its advantages, like simple and fast operation, no ionizing radiation exposure, and accurate real-time imaging. Subsequently, Poly N-isopropylacrylamide-co-2,2,3,4,4,4-Hexafluorobutyl methacrylate (PNF) nanogels were synthesized for stabilizing TGFPE, the Pickering emulsions of 2H, 3H-decafluoropentane (HDFP). These emulsions displayed dual abilities of thermosensitive sol-gel transition and long-term US imaging in vitro. Thus, it was concluded that these emulsions could achieve vascular embolization and long-term US imaging in vivo as per the TAE animal model results. The emulsion droplets' flow and accumulation were visualized under the US imaging guidance. In summary, the Pickering emulsions have the potential to be used as US-guided embolization material for mediating TAE surgeries.

Homogeneous Electrochemical Aptamer Sensor Based on Two-Dimensional Nanocomposite Probe and Nanochannel Modified Electrode for Sensitive Detection of Carcinoembryonic Antigen.

A rapid and convenient homogeneous aptamer sensor with high sensitivity is highly desirable for the electrochemical detection of tumor biomarkers. In this work, a homogeneous electrochemical aptamer sensor is demonstrated based on a two-dimensional (2D) nanocomposite probe and nanochannel modified electrode, which can realize sensitive detection of carcinoembryonic antigen (CEA). Using π-π stacking and electrostatic interaction, CEA aptamer (Apt) and cationic redox probe (hexaammineruthenium(III), Ru(NH3)63+) are co-loaded on graphite oxide (GO), leading to a 2D nanocomposite probe (Ru(NH3)63+/Apt@GO). Vertically ordered mesoporous silica-nanochannel film (VMSF) is easily grown on the supporting indium tin oxide (ITO) electrode (VMSF/ITO) using the electrochemical assisted self-assembly (EASA) method within 10 s. The ultrasmall nanochannels of VMSF exhibits electrostatic enrichment towards Ru(NH3)63+ and size exclusion towards 2D material. When CEA is added in the Ru(NH3)63+/Apt@GO solution, DNA aptamer recognizes and binds to CEA and Ru(NH3)63+ releases to the solution, which can be enriched and detected by VMSF/ITO electrodes. Based on this mechanism, CEA can be an electrochemical detection ranging from 60 fg/mL to 100 ng/mL with a limit of detection (LOD) of 14 fg/mL. Detection of CEA in human serum is also realized. The constructed homogeneous detection system does not require the fixation of a recognitive aptamer on the electrode surface or magnetic separation before detection, demonstrating potential applications in rapid, convenient and sensitive electrochemical sensing of tumor biomarkers.

LncRNA XIST sponges microRNA-448 to promote malignant behaviors of colorectal cancer cells via regulating GRHL2.

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are essential regulators in human cancers, while the role of lncRNA X-inactive-specific transcript (XIST) in colorectal cancer (CRC) via regulating miR-448 remains largely unknown. Herein, we aimed to elucidate the effect of the XIST/miR-448/grainyhead-like 2 (GRHL2) axis on CRC development. XIST, miR-448, and GRHL2 expression in CRC tissues from patients and in human CRC cell lines was assessed. Loss- and gain-function assays were implemented to unveil the roles of XIST, miR-448, and GRHL2 in screened CRC cells. The tumor growth in vivo was observed in nude mice. Binding relations among XIST, miR-448, and GRHL2 were evaluated. XIST and GRHL2 expressed highly whereas miR-448 expressed lowly in CRC tissues and cells. XIST or GRHL2 downregulation, or miR-448 elevation suppressed the malignant behaviors of CRC cells in vitro, and downregulated XIST or upregulated miR-448 also inhibited the tumor growth in vivo. miR-448 upregulation reversed the role of XIST elevation in CRC cells. XIST particularly bound to miR-448, and miR-448 targeted GRHL2. Knockdown of XIST upregulates miR-448 to impede malignant behaviors of CRC cells via inhibiting GRHL2. This study may provide novel biomarkers for CRC diagnosis and treatment.

Mutational landscape of nasopharyngeal carcinoma based on targeted next-generation sequencing: implications for predicting clinical outcomes.

BACKGROUND: The aim of this study was to draw a comprehensive mutational landscape of nasopharyngeal carcinoma (NPC) tumors and identify the prognostic factors for distant metastasis-free survival (DMFS). METHODS: A total of forty primary nonkeratinizing NPC patients underwent targeted next-generation sequencing of 450 cancer-relevant genes. Analysis of these sequencing and clinical data was performed comprehensively. Univariate Cox regression analysis and multivariate Lasso-Cox regression analyses were performed to identify factors that predict distant metastasis and construct a risk score model, and seventy percent of patients were randomly selected from among the samples as a validation cohort. A receiver operating characteristic (ROC) curve and Harrell's concordance index (C-index) were used to investigate whether the risk score was superior to the TNM stage in predicting the survival of patients. The survival of patients was determined by Kaplan-Meier curves and log-rank tests. RESULTS: The twenty most frequently mutated genes were identified, such as KMT2D, CYLD, and TP53 et al. Their mutation frequencies of them were compared with those of the COSMIC database and cBioPortal database. N stage, tumor mutational burden (TMB), PIK3CA, and SF3B1 were identified as predictors to build the risk score model. The risk score model showed a higher AUC and C-index than the TNM stage model, regardless of the training cohort or validation cohort. Moreover, this study found that patients with tumors harboring PI3K/AKT or RAS pathway mutations have worse DMFS than their wild-type counterparts. CONCLUSIONS: In this study, we drew a mutational landscape of NPC tumors and established a novel four predictor-based prognostic model, which had much better predictive capacity than TNM stage.