FDA-Approved Tedizolid Phosphate Prevents Cisplatin-Induced Hearing Loss Without Decreasing Its Anti-tumor Effect.

PURPOSE: Cisplatin is a low-cost clinical anti-tumor drug widely used to treat solid tumors. However, its use could damage cochlear hair cells, leading to irreversible hearing loss. Currently, there appears one drug approved in clinic only used for reducing ototoxicity associated with cisplatin in pediatric patients, which needs to further explore other candidate drugs. METHODS: Here, by screening 1967 FDA-approved drugs to protect cochlear hair cell line (HEI-OC1) from cisplatin damage, we found that Tedizolid Phosphate (Ted), a drug indicated for the treatment of acute infections, had the best protective effect. Further, we evaluated the protective effect of Ted against ototoxicity in mouse cochlear explants, zebrafish, and adult mice. The mechanism of action of Ted was further explored using RNA sequencing analysis and verified. Meanwhile, we also observed the effect of Ted on the anti-tumor effect of cisplatin. RESULTS: Ted had a strong protective effect on hair cell (HC) loss induced by cisplatin in zebrafish and mouse cochlear explants. In addition, when administered systemically, it protected mice from cisplatin-induced hearing loss. Moreover, antitumor studies showed that Ted had no effect on the antitumor activity of cisplatin both in vitro and in vivo. RNA sequencing analysis showed that the otoprotective effect of Ted was mainly achieved by inhibiting phosphorylation of ERK. Consistently, ERK activator aggravated the damage of cisplatin to HCs. CONCLUSION: Collectively, these results showed that FDA-approved Ted protected HCs from cisplatin-induced HC loss by inhibiting ERK phosphorylation, indicating its potential as a candidate for preventing cisplatin ototoxicity in clinical settings.

Inhibition of Gpx4-mediated ferroptosis alleviates cisplatin-induced hearing loss in C57BL/6 mice.

Cisplatin-induced hearing loss is a common side effect of cancer chemotherapy in clinics; however, the mechanism of cisplatin-induced ototoxicity is still not completely clarified. Cisplatin-induced ototoxicity is mainly associated with the production of reactive oxygen species, activation of apoptosis, and accumulation of intracellular lipid peroxidation, which also is involved in ferroptosis induction. In this study, the expression of TfR1, a ferroptosis biomarker, was upregulated in the outer hair cells of cisplatin-treated mice. Moreover, several key ferroptosis regulator genes were altered in cisplatin-damaged cochlear explants based on RNA sequencing, implying the induction of ferroptosis. Ferroptosis-related Gpx4 and Fsp1 knockout mice were established to investigate the specific mechanisms associated with ferroptosis in cochleae. Severe outer hair cell loss and progressive damage of synapses in inner hair cells were observed in Atoh1-Gpx4-/- mice. However, Fsp1-/- mice showed no significant hearing phenotype, demonstrating that Gpx4, but not Fsp1, may play an important role in the functional maintenance of HCs. Moreover, findings showed that FDA-approved luteolin could specifically inhibit ferroptosis and alleviate cisplatin-induced ototoxicity through decreased expression of transferrin and intracellular concentration of ferrous ions. This study indicated that ferroptosis inhibition through the reduction of intracellular ferrous ions might be a potential strategy to prevent cisplatin-induced hearing loss.

Association of ctDNA detection and recurrence assessment in patients with neoadjuvant treatment.

BACKGROUND: The utilization of neoadjuvant therapy is progressively expanding in various clinical settings. However, the absence of a clinically validated biomarker to evaluate the treatment response remains a significant challenge in the field. Circulating tumor DNA (ctDNA) detection, a novel and emerging monitoring approach in the field of oncology, holds promise as a potential prognostic biomarker for patients with cancer. This meta-analysis investigated the clinical significance of ctDNA detection as a predictive tool for cancer recurrence in patients receiving neoadjuvant treatment. METHODS: A comprehensive systematic literature search was conducted using public databases to identify relevant studies that investigated the association between ctDNA detection and cancer recurrence in patients receiving neoadjuvant treatment. Hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CI) were calculated to assess the relationship between cancer recurrence and relevant factors. Cancer recurrence was considered the primary outcome. RESULTS: A total of 23 studies encompassing 1590 patients across eight different cancer types were included in the final analysis. Positive ctDNA detection was significantly associated with higher cancer recurrence, especially at post-neoadjuvant treatment and post-surgery time points. The risk values for the different cancer categories and geographic areas also differed significantly. CONCLUSION: Our comprehensive meta-analysis revealed a significant positive correlation between ctDNA detection and a higher risk of cancer recurrence in patients receiving neoadjuvant treatment. In addition, the risk of recurrence was influenced by variations in cancer type, timing of detection, and geographic region. These findings highlight the promising clinical applicability of ctDNA as a prognostic marker and monitoring approach for patients with cancer. However, the precise mechanism is unknown and more evidence is needed for further research.

The correlation between the influencing factors and efficacy of immune checkpoint inhibitor therapy: an umbrella meta-analysis of randomized controlled trials.

OBJECTIVE: We performed an umbrella meta-analysis to explore the factors that influence the efficacy of immune checkpoint inhibitor (ICI) therapy. MATERIALS AND METHODS: We systematically searched three databases (PubMed, Web of Science and Embase) up to 20 February 2023. Extracting the effect size and 95% confidence intervals for overall survival (OS), progression-free survival (PFS) and the objective response rate (ORR). RESULTS: A total of 65 articles were included. We identified the following factors that benefit ICI therapy: smoking status (PFS: 0.72 [0.62, 0.84], p < .001), chemotherapy (PFS: 0.68 [0.58, 0.79], p < .001), expression of programmed cell death ligand 1(PD-L1) (≥1%, ≥5%, or ≥10%) (≥1%: 0.76 [0.71,0.82], p < .001; ≥5%: 0.62 [0.52, 0.74], p < .001; ≥10%: 0.42 [0.30, 0.59], p < .001). We also identified three adverse factors: epidermal growth factor receptor mutations (OS: 1.57 [1.06, 2.32], p = .02), with liver metastases (OS: 1.16 [1.02,1.32], p = .02) and antibiotics (OS: 3.13 [1.25,7.84], p < .001; PFS: 2.54 [1.38, 4.68], p = .003). CONCLUSION: The results of this umbrella meta-analysis first supported pre-existing understandings of the relationship between beneficial and adverse factors with the efficacy of ICI therapy. In addition, the overexpression of PD-L1 may adversely affect patients.

The umbrella meta-analysis first supported pre-existing understandings of the relationship between beneficial and adverse factors with the efficacy of immune checkpoint inhibitor therapy.This study found three factors that are not conducive to the efficacy of immune checkpoint inhibitor: epidermal growth factor receptor mutations, with liver metastases and antibiotics.We found the overexpression of PD-L1 may adversely affect patients.

Targeting LAYN inhibits colorectal cancer metastasis and tumor-associated macrophage infiltration induced by hyaluronan oligosaccharides.

The accumulation of hyaluronan oligosaccharides (oHA) in colorectal cancer (CRC) is closely related to tumor metastasis, but the underlying mechanism remains unclear. In this study, we first described that LAYN, a novel HA receptor, was upregulated in CRC tissue. Aberrant LAYN expression correlated with CRC metastasis and poor prognosis and positively correlated with tumor-associated macrophage (TAM) infiltration and M2 macrophage polarization in the tumor environment. Both in vitro and in vivo studies demonstrated that LAYN is activated by oHA and subsequently induces CRC metastasis and macrophage infiltration. Mechanistic studies demonstrated that oHA activates LAYN by binding to the 60-68th amino acid region of the extracellular segment. oHA-induced LAYN activation promoted metastasis and CCL20 secretion through the NF-kB pathway in CRC cells. Furthermore, targeting LAYN using a blocking antibody prevented oHA-mediated tumor metastasis, TAM infiltration and M2 polarization. This study revealed the LAYN activation mechanism and identified a potential target for the treatment of CRC tumor exhibiting high oHA levels.

Long-term prognosis of 35 patients with methionine adenosyltransferase deficiency based on newborn screening in China.

Methionine adenosyltransferase deficiency (MATD) is a rare metabolic disorder caused by mono- or biallelic MAT1A mutations that are not yet well understood. Of the 4,065,644 neonates screened between November 2010 and December 2021, 35 individuals have been diagnosed with an estimated incidence of 1: 116,161 by a cutoff value of methionine 82.7 µmol/L and follow-up over 11 years. MATD patients with autosomal recessive (AR) type had higher clinical and genetic heterogeneity than those with autosomal dominant (AD) type. Fifteen unrelated AD patients harbored one well-known dominant variant, c.791 G>A or c.776 C>T, and were clinically unaffected with a mean plasma methionine (Met) value <300 µmol/L. Twenty AR cases have unique genotypes and presented a wide range of clinical abnormalities from asymptomatic to white matter lesions. Of them, 10 AR patients displayed severe manifestations, such as verbal difficulty, motor delay, development delay, and white matter lesions, with mean Met >500 µmol/L and thereby were treated with a methionine-restricted diet alone or in combination with betaine, folate, or vitamin B6, and were healthy finally. Neurological abnormalities were evidenced in two patients (P16 and P27) with Met values >800 µmol/L by MRI scan. Neurological abnormalities were reversed here by liver transplantation or by the determination of S-adenosylmethionine supplementation. Additionally, 38 variants of MAT1A were distributed within patients and carriers, of which 24 were novel and mostly predicted to be damaged. Our findings with an extensive clinical and genetic dataset provided new insights into its diagnosis and treatment and will be helpful for its optimal management in the future.

Iron Single Atom Catalyzed Quinoline Synthesis.

The production of high-value chemicals by single-atom catalysis is an attractive proposition for industry owing to its remarkable selectivity. Successful demonstrations to date are mostly based on gas-phase reactions, and reports on liquid-phase catalysis are relatively sparse owing to the insufficient activation of reactants by single-atom catalysts (SACs), as well as, their instability in solution. Here, mechanically strong, hierarchically porous carbon plates are developed for the immobilization of SACs to enhance catalytic activity and stability. The carbon-based SACs exhibit excellent activity and selectivity (≈68%) for the synthesis of substituted quinolines by a three-component oxidative cyclization, affording a wide assortment of quinolines (23 examples) from anilines and acetophenones feedstock in an efficient, atom-economical manner. Particularly, a Cavosonstat derivative can be synthesized through a one-step, Fe1 -catalyzed cyclization instead of traditional Suzuki coupling. The strategy is also applicable to the deuteration of quinolines at the fourth position, which is challenging by conventional methods. The synthetic utility of the carbon-based SAC, together with its reusability and scalability, renders it promising for industrial scale catalysis.

Long Noncoding RNA KCNQ1OT1 is a Prognostic Biomarker and mediates CD8+ T cell exhaustion by regulating CD155 Expression in Colorectal Cancer.

Background: Long noncoding RNA KCNQ1 opposite strand/antisense transcript 1 (lncRNA KCNQ1OT1) is abnormally expressed in various solid tumors. The purpose of this study was to explore the prognostic value and potential functional role of lncRNA KCNQ1OT1 across cancers. Methods: We performed a meta-analysis of published literature to evaluate the prognostic value of lncRNA KCNQ1OT1 across cancers. Verification, functional analysis, and genomic variation analysis were performed using the GEPIA, TIMER, and LnCeVar databases. According to the immune cell infiltration level, we established a prognostic model of lncRNA KCNQ1OT1 expression using public datasets of TIMER. We used quantitative real-time polymerase chain reaction (RT-qPCR) and western blot to detect the expression levels of lncRNA KCNQ1OT1 and the CD155 protein in colorectal cancer (CRC) tissues and cell lines. Then, a lncRNA KCNQ1OT1-knockdown cell line was cocultured to explore the role of lncRNA KCNQ1OT1 and CD155 in the T cell response by flow cytometric analysis. Results: Our results showed that the high expression of lncRNA KCNQ1OT1 was significantly related to poor overall survival across cancers, especially CRC. Interestingly, we found that COAD patients with high lncRNA KCNQ1OT1 expression and high CD8+ T cell infiltration levels had a worse prognosis than those with low lncRNA KCNQ1OT1 expression and high CD8+ T cell infiltration levels. Moreover, lncRNA KCNQ1OT1 and CD155 showed significantly higher expression in CRC tissue than in normal tissue, and lncRNA KCNQ1OT1 expression was positively correlated with CD155 expression in CRC. Finally, knockdown of lncRNA KCNQ1OT1 reduced CD155 expression in HCT116 and SW620 cells and enhanced the immune response in coculture with CD8+ T cells. Conclusions: High lncRNA KCNQ1OT1 expression is significantly correlated with poor prognosis of CRC patients and mediates the CD8+ T cell response in CRC. These findings indicate that lncRNA KCNQ1OT1 is a prognostic biomarker and potential immune therapeutic target for enhancing the CD8+ T cell response in CRC.

Anti-allergic drug azelastine suppresses colon tumorigenesis by directly targeting ARF1 to inhibit IQGAP1-ERK-Drp1-mediated mitochondrial fission.

This study aimed to screen novel anticancer strategies from FDA-approved non-cancer drugs and identify potential biomarkers and therapeutic targets for colorectal cancer (CRC). Methods: A library consisting of 1056 FDA-approved drugs was screened for anticancer agents. WST-1, colony-formation, flow cytometry, and tumor xenograft assays were used to determine the anticancer effect of azelastine. Quantitative proteomics, confocal imaging, Western blotting and JC-1 assays were performed to examine the effects on mitochondrial pathways. The target protein of azelastine was analyzed and confirmed by DARTS, WST-1, Biacore and tumor xenograft assays. Immunohistochemistry, gain- and loss-of-function experiments, WST-1, colony-formation, immunoprecipitation, and tumor xenograft assays were used to examine the functional and clinical significance of ARF1 in colon tumorigenesis. Results: Azelastine, a current anti-allergic drug, was found to exert a significant inhibitory effect on CRC cell proliferation in vitro and in vivo, but not on ARF1-deficient or ARF1-T48S mutant cells. ARF1 was identified as a direct target of azelastine. High ARF1 expression was associated with advanced stages and poor survival of CRC. ARF1 promoted colon tumorigenesis through its interaction with IQGAP1 and subsequent activation of ERK signaling and mitochondrial fission by enhancing the interaction of IQGAP1 with MEK and ERK. Mechanistically, azelastine bound to Thr-48 in ARF1 and repressed its activity, decreasing Drp1 phosphorylation. This, in turn, inhibited mitochondrial fission and suppressed colon tumorigenesis by blocking IQGAP1-ERK signaling. Conclusions: This study provides the first evidence that azelastine may be novel therapeutics for CRC treatment. ARF1 promotes colon tumorigenesis, representing a promising biomarker and therapeutic target in CRC.

Overexpression of microRNA-29b inhibits epithelial-mesenchymal transition and angiogenesis of colorectal cancer through the ETV4/ERK/EGFR axis.

BACKGROUND: Recent studies have reported the involvement of microRNA-29 (miR-29) family members in human cancers through their ability to regulate cellular functions. The present study investigated biological function of miR-29b in colorectal cancer (CRC). METHODS: CRC tissues and adjacent normal tissues were collected and the expression of ETV4 and miR-29b in the tissues were identified. The relationship between ETV4 and miR-29b or ETV4 expression and the EGFR promoter was identified using dual-luciferase reporter gene and CHIP assays. The proliferation, invasion, migration, and apoptosis of CRC HCT116 cells were assayed using MTT assay, Scratch test, Transwell assay, and flow cytometry, respectively. Also, expression of epithelial-mesenchymal transition (EMT) markers, angiogenic factors, and vasculogenic mimicry formation were evaluated using RT-qPCR and Western blot. RESULTS: ETV4 was upregulated, while miR-29b expression was decreased in CRC tissues. ETV4 was identified as a target gene of miR-29b, which in turn inactivated the ERK signaling pathway by targeting ETV4 and inhibiting EGFR transcription. Transfection with miR-29b mimic, siRNA-ETV4, or ERK signaling pathway inhibitor U0126 increased expression of E-cadherin and TSP-1, and CRC cell apoptosis, yet reduced expression of ERK1/2, MMP-2, MMP-9, Vimentin, and VEGF, as well as inhibiting EMT, angiogenesis, and CRC cell migration and invasion. The EMT, angiogenesis and cancer progression induced by miR-29b inhibitor were reversed by siRNA-mediated ETV4 silencing. CONCLUSIONS: miR-29b suppresses angiogenesis and EMT in CRC via the ETV4/ERK/EGFR axis.

A comparison of free-hand method and electromagnetic navigation technique for the distal locking during intramedullary nailing procedures: a meta-analysis.

BACKGROUND: Some studies have reported that the electromagnetic navigation (EN) technique is better than the free-hand (FH) method. Nevertheless, there are few clinical trials. In recent years, several clinical trials have been conducted, providing sufficient information to compare the two methods. METHODS: We compared the FH and EN techniques (SURESHOT, Smith and Nephew, Inc., Memphis, TN) in terms of the distal locking time, exposure time, first success rate, healing time and operative time. We comprehensively searched the Medline, Embase, and Cochrane library databases according to predetermined inclusion and exclusion criteria, and then we extracted data for specific variables from these reports. The risk of bias was assessed. Stata 13.0 was used for analysis. RESULTS: Nine studies involving 579 patients were pooled in this study. The meta-analysis showed that EN was associated with a shorter distal locking time (P = 0.001) and exposure time (P = 0.001) than FH performed by surgeons who are not proficient in using the FH technique. No significant differences were found in the first success rate (P = 0.231), healing time (P = 0.09) or operative time (P = 0.510). CONCLUSION: The EN technique has the advantages of a shorter distal locking time and smaller amount of ionizing radiation exposure compared with the FH technique.

PRICKLE3 linked to ATPase biogenesis manifested Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease. X-linked nuclear modifiers were proposed to modify the phenotypic manifestation of LHON-associated mitochondrial DNA (mtDNA) mutations. By whole-exome sequencing, we identified the X-linked LHON modifier (c.157C>T, p.Arg53Trp) in PRICKLE3 encoding a mitochondrial protein linked to biogenesis of ATPase in 3 Chinese families. All affected individuals carried both ND4 11778G>A and p.Arg53Trp mutations, while subjects bearing only a single mutation exhibited normal vision. The cells carrying the p.Arg53Trp mutation exhibited defective assembly, stability, and function of ATP synthase, verified by PRICKLE3-knockdown cells. Coimmunoprecipitation indicated the direct interaction of PRICKLE3 with ATP synthase via ATP8. Strikingly, cells bearing both p.Arg53Trp and m.11778G>A mutations displayed greater mitochondrial dysfunction than those carrying only a single mutation. This finding indicated that the p.Arg53Trp mutation acted in synergy with the m.11778G>A mutation and deteriorated mitochondrial dysfunctions necessary for the expression of LHON. Furthermore, we demonstrated that Prickle3-deficient mice exhibited pronounced ATPase deficiencies. Prickle3-knockout mice recapitulated LHON phenotypes with retinal deficiencies, including degeneration of retinal ganglion cells and abnormal vasculature. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutations and X-linked nuclear modifiers.

Highly Efficient 2D NIR-II Photothermal Agent with Fenton Catalytic Activity for Cancer Synergistic Photothermal-Chemodynamic Therapy.

Photothermal therapy (PTT) has emerged as a promising cancer therapeutic modality with high therapeutic specificity, however, its therapeutic effectiveness is limited by available high-efficiency photothermal agents (PTAs), especially in the second near-infrared (NIR-II) biowindow. Here, based on facile liquid-exfoliated FePS3 nanosheets, a highly efficient NIR-II PTA with its photothermal conversion efficiency of up to 43.3% is demonstrated, which is among the highest reported levels in typical PTAs. More importantly, such Fe-based 2D nanosheets also show superior Fenton catalytic activity facilitated by their ultrahigh specific surface area, simultaneously enabling cancer chemodynamic therapy (CDT). Impressively, the efficiency of CDT could be further remarkably enhanced by its photothermal effect, leading to cancer synergistic PTT/CDT. Both in vitro and in vivo studies reveal a highly efficient tumor ablation under NIR-II light irradiation. This work provides a paradigm for cancer CDT and PTT in the NIR-II biowindow via a single 2D nanoplatform with desired therapeutic effect. Furthermore, with additional possibilities for magnetic resonance imaging, photoacoustic tomography, as well as drug loading, this Fe-based 2D material could potentially serve as a 2D "all-in-one" theranostic nanoplatform.

TSP-1 as a novel biological marker of tumor vasculature normalization in colon carcinoma induced by Endostar.

Blood vessels in tumors often exhibit abnormal morphology and function, which promotes the growth, metastasis and resistance of tumors to conventional therapies. Therefore, vascular normalization is an emerging strategy to enhance the effectiveness of radiotherapy and chemotherapy when used in combination; however, there is a lack of evidence regarding the optimal schedule for the co-administration of anti-angiogenic and chemotherapeutic drugs. Scheduling treatment is important as the period for normalization is transient, also known as the 'time window'; however, no biomarker has been identified to detect this window. In the present study, recombinant human endostatin (rhES) was employed as an anti-angiogenic agent in xenograft tumor tissue in mice. Following rhES or control (saline) treatment, the density and integrity of tumor vessels were detected by immunofluorescence staining for cluster of differentiation 31 and α-smooth muscle actin; the level of hypoxia in tumor tissue was examined by immunohistochemistry with pimonidazole; the necrotic area was evaluated by hematoxylin and eosin staining; and the level of thrombospondin-1 (TSP-1) in plasma was tested by ELISA. The Cell Counting Kit-8 assay was also used to evaluate the effect of rhES on the proliferation of colon carcinoma SW620 cells. A 'time window' normalized vasculature was determined between day 4 and 6 following rhES treatment, and accompanied by a decrease in hypoxia in tumor tissue. Decreasing plasma TSP-1 levels were consistent with changes in vascular morphology and hypoxia, which exhibited features of normalization. In addition, rhES had no effect on the proliferation of SW620 cells, suggesting that the reduction in TSP-1 was associated with increased oxygen content during vascular normalization, rather than inhibited cell proliferation. In conclusion, TSP-1 may be a potential biomarker for predicting the normalization window of colon cancer vessels.

The overexpression of ZWINT in integrated bioinformatics analysis forecasts poor prognosis in breast cancer.

BACKGROUND: Zeste White 10 interactor (ZW10 interactor, ZWINT) is a centromeric complex required for a mitotic spindle checkpoint. According to previous studies, it was overexpressed in people with recurrent tumors. However, the expression of ZWINT in breast cancer has not been thoroughly studied. In addition, the correlations of ZWINT to prognosis in breast cancer remain unclear. METHODS: In this study, the expression of ZWINT in different types of tumors was analyzed based on the Oncomine database, and the effect of ZWINT expression on clinical prognosis was evaluated by Kaplan-Meier plotter. RESULTS: In breast cancer, lung cancer, sarcoma, ovarian cancer, bladder cancer, liver cancer and cervical cancer, the expression of ZWINT was higher than that in normal tissues, but in gastric cancer, prostate cancer, myeloma, renal cancer and pancreatic cancer, the expression of ZWINT was lower. In addition, a meta-analysis of 22 cancer database studies found that the ZWINT gene was over-expressed in breast cancer tissues compared with normal tissues (P=4.05×10-6). Through the survival analysis of Kaplan-Meier plotter, it is found that the high expression of ZWINT is related to the worse overall survival (OS) [hazard ratio (HR) =1.73, 95% confidence interval (CI): 1.39-2.51, P=5.4×10-7], RFS (HR =1.68, 95% CI: 1.51-1.88, P<1×10-16) and distant metastasis-free survival (DMFS) (HR =1.55, 95% CI: 1.28-1.89, P=7.9×10-6) in all BC patients. CONCLUSIONS: Our results strongly suggest that over expression of ZWINT is closely related to poor prognosis of breast cancer. ZWINT may be a prognostic biomarker for the treatment of BC.

Identification of key biomarkers and potential signaling pathway associated with poor progression of gastric cancer.

BACKGROUND: We aimed to identify the key differentially expressed genes (DEGs) associated with poor prognosis in gastric cancer (GC) and to elucidate the underlying molecular mechanisms in order to provide a therapeutic target for this disease. METHODS: The DEGs common in two datasets, GSE54129 and GSE79973, were screened. GO and KEGG enrichment analyses were then performed for these DEGs using DAVID's tool. STRING and the Cytoscope software were also used to analyze the protein-protein interaction (PPI) networks of the DEGs common between the two datasets. RESULTS: A total of 164 common DEGs were identified from GSE79973 and GSE54129 datasets, 42 were up-regulated and 122 were down-regulated in GC. KEGG analysis demonstrated that up-regulated DEGs were mainly enriched for focal adhesion, ECM-receptor interaction, PI3K-Akt signaling pathway, protein digestion and absorption, and vascular smooth muscle contraction, while down-regulated DEGs were enriched for chemical carcinogenesis, metabolism of xenobiotics by cytochrome P450, drug metabolism-cytochrome P450, and retinol metabolism (P<0.05). Obtained PPI network for the 164 DEGs via Cytotype software, using MCODE app of Cytotype software we identified 13 hub genes. Twelve of these genes were found to be associated with poor prognosis in GC by survival analysis. Post validation by the GEPIA, Oncomine, and Human Protein Atlas databases, eight genes (COL4A1, COL6A3, COL1A2, COL1A1, THBS2, COL11A1, SPP1, and FN1) were found to be up-regulated in GC tissues and correlated with poor prognosis of GC. CONCLUSIONS: COL4A1, COL6A3, COL1A2, COL1A1, THBS2, COL11A1, SPP1, and FN1 could serve as potential targets for GC diagnosis and prognosis.

Single-Atom Coated Separator for Robust Lithium-Sulfur Batteries.

Lithium-sulfur (Li-S) batteries are strong contenders among lithium batteries due to superior capacity and energy density, but the polysulfide shuttling effect limits the cycle life and reduces energy efficiency due to a voltage gap between charge and discharge. Here, we demonstrate that graphene foam impregnated with single-atom catalysts (SACs) can be coated on a commercial polypropylene separator to catalyze polysulfide conversion, leading to a reduced voltage gap and a much improved cycle life. Also, among Fe/Co/Ni SACs, Fe SACs may be a better option to be used in Li-S systems. By deploying SACs in the battery separator, cycling stability improves hugely, especially considering relatively high sulfur loading and ultralow SAC contents. Even at a metal loading of ∼2 µg in the whole cell, an Fe SAC-modified separator delivers superior Li-S battery performance even at high sulfur loading (891.6 mAh g-1, 83.7% retention after 750 cycles at 0.5C). Our work further enriches and expands the application of SACs catalyzing polysulfide blocking and conversion and improving round trip efficiencies in batteries, without side effects such as electrolyte and electrode decomposition.

Silver Nanoparticle-Induced Phosphorylation of Histone H3 at Serine 10 Involves MAPK Pathways.

The phosphorylation of histone H3 at serine 10 (p-H3S10) has been shown to be closely correlated with mitotic chromosome condensation. We previously reported that intracellular silver nanoparticles (AgNPs) release Ag ions that alter actin filament dynamics, leading to the activation of Aurora kinases and the formation of p-H3S10 through a mechanism clearly different from that occurring during mitosis. In the present study, we examined other mechanisms underlying the induction of p-H3S10 formation by AgNPs. We observed that the early formation of p-H3S10 induced by AgNPs occurred via the activation of mitogen-activated protein kinase (MAPK) pathways, specifically the Jun N-terminal protein kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways. The late AgNP-induced p-H3S10 formation occurred via the activation of the entire MAPK cascade. On the other hand, p-H3S10 formation was not due to DNA damage induced by AgNPs, or the activation of the kinases ataxia telangiectasia-mutated (ATM) and ATM-Rad3-related (ATR). Several studies have compared the mechanism of AgNP toxicity to a Trojan horse-type molecular pathway. We observed different effects of AgNO3 (Ag⁺) and AgNPs on cells, and only the JNK inhibitor suppressed the temporary AgNO3-induced formation of p-H3S10. These results strongly indicate that AgNP-induced p-H3S10 formation does not rely solely on one signaling pathway, but rather may involve two or more pathways.

LAYN Is a Prognostic Biomarker and Correlated With Immune Infiltrates in Gastric and Colon Cancers.

Background: Layilin (LAYN) is a critical gene that regulates T cell function. However, the correlations of LAYN to prognosis and tumor-infiltrating lymphocytes in different cancers remain unclear. Methods: LAYN expression was analyzed via the Oncomine database and Tumor Immune Estimation Resource (TIMER) site. We evaluated the influence of LAYN on clinical prognosis using Kaplan-Meier plotter, the PrognoScan database and Gene Expression Profiling Interactive Analysis (GEPIA). The correlations between LAYN and cancer immune infiltrates was investigated via TIMER. In addition, correlations between LAYN expression and gene marker sets of immune infiltrates were analyzed by TIMER and GEPIA. Results: A cohort (GSE17536) of colorectal cancer patients showed that high LAYN expression was associated with poorer overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). In addition, high LAYN expression was significantly correlated with poor OS and progression-free survival (PFS) in gastric cancers (OS HR = 1.97, P = 3.6e-10; PFS HR = 2.12, P = 2.3e-10). Moreover, LAYN significantly impacts the prognosis of diverse cancers via The Cancer Genome Atlas (TCGA). Specifically, high LAYN expression was correlated with worse OS and PFS in stage 2 to 4 but not stage 1 and stage N0 gastric cancer patients (P = 0.28, 0.34; P = 0.073, 0.092). LAYN expression was positively correlated with infiltrating levels of CD4+ T and CD8+ T cells, macrophages, neutrophils, and dendritic cells (DCs) in colon adenocarcinoma (COAD) and stomach adenocarcinoma (STAD). LAYN expression showed strong correlations with diverse immune marker sets in COAD and STAD. Conclusions: These findings suggest that LAYN is correlated with prognosis and immune infiltrating levels of, including those of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in multiple cancers, especially in colon and gastric cancer patients. In addition, LAYN expression potentially contributes to regulation of tumor-associated macrophages (TAMs), DCs, T cell exhaustion and Tregs in colon and gastric cancer. These findings suggest that LAYN can be used as a prognostic biomarker for determining prognosis and immune infiltration in gastric and colon cancers.

Nicotinamide phosphoribosyl transferase regulates cell growth via the Sirt1/P53 signaling pathway and is a prognosis marker in colorectal cancer.

Colorectal cancer (CRC) is the third most common malignancy, and the metabolic properties of CRC cells include enhanced aerobic glycolysis (the Warburg effect). Nicotinamide phosphoribosyl transferase (NAMPT) is one of the crucial enzymes that regulate the activity of nicotinamide adenine dinucleodinucleotide dependent enzymes. Targeting NAMPT is a potential method of CRC therapy. Nevertheless, the underlying clinical implications and regulatory mechanisms of NAMPT in CRC remain unclear. In this study, we showed that NAMPT protein expression was increased in subjects with rectal localization compared with those with colon localization, and NAMPT was a poor prognostic marker for the overall survival rate in patients with CRC. In addition, the NAMPT inhibitor FK866 or lentivirus-mediated silencing induced CRC cell growth inhibition. Mechanistically, NAMPT regulated Sirt1 and P53 expression and induced G0/G1 cell cycle arrest, along with the upregulation of downstream p21 and downregulation of cyclin D1, cyclin E1, and cyclin E2 expression. FK866 administration or knockdown of NAMPT induced CRC cell apoptosis via upregulation of caspase-3. In conclusion, NAMPT regulated Sirt1/P53 signaling during CRC cell growth and warrants further investigation for clinical administration in CRC.