摘要：We have developed a protein array system,named"Phospho-Totum",which reproduces the phosphorylation state of a sample on the array.The protein array contains 1 471 proteins from 273 known signaling pathways.According to the activation degrees of tyrosine kinases in the sample,the corresponding groups of substrate proteins on the array are phosphorylated under the same conditions.In addition to measuring the phosphorylation levels of the 1 471 substrates,we have developed and performed the artificial intelligence-assisted tools to further characterize the phosphorylation state and estimate pathway activation,tyrosine kinase activation,and a list of kinase inhibitors that produce phosphorylation states similar to that of the sample.The Phospho-Totum system,which seamlessly links and interrogates the measurements and analyses,has the potential to not only elucidate pathophysiological mechanisms in diseases by reproducing the phosphorylation state of samples,but also be useful for drug discovery,particularly for screening targeted kinases for potential drug kinase inhibitors.

摘要：cis-Diamminedichloroplatinum(CDDP)is widely used for the treatment of various solid cancers.Here we reported that CDDP increased the expression and enzymatic activities of carboxylesterase 1(CES1)and carboxylesterase 2(CES2),along with the upregulation of pregnane X receptor(PXR)and the downregulation of differentiated embryonic chondrocyte-expressed gene 1(DEC1)in human hepatoma cells,primary mouse hepatocytes,mouse liver and intestine.The overexpression or knockdown of PXR alone upregulated or downregulated the CES1 and CES2 expression,respectively.The increases in CES1 and CES2 expression levels induced by CDDP abolished or enhanced by PXR knockdown or overexpression,implying that CDDP induces carboxylesterases through the activation of PXR.Likewise,the overexpression or knockdown of DEC1 alone significantly decreased or increased PXR and its targets.Moreover,the increases of PXR and its targets induced by CDDP were abolished or alleviated by the overexpression or knockdown of DEC1.The overexpression or knockdown of DEC1 affected the response of PXR to CDDP,but not vice versa,suggesting that CDDP increases carboxylesterases by upregulating PXR mediated by the decrease of DEC1.In addition,CDDP did not increase DEC1 mRNA degradation but suppressed DEC1 promoter reporter activity,indicating that it suppresses DEC1 transcriptionally.The combined use of CDDP and irinotecan had a synergistic effect on two cell lines,especially when CDDP was used first.

摘要：Pericytes are located in the stromal membrane of the capillary outer wall and contain endothelial cells.They are pivotal in regulating blood flow,enhancing vascular stability,and maintaining the integrity of the blood-retina barrier/blood-brain barrier.The pluripotency of pericytes allows them to differentiate into various cell types,highlighting their significance in vascular disease pathogenesis,as demonstrated by previous studies.This capability enables pericytes to be a potential biomarker for the diagnosis and a target for the treatment of vascular disorders.The retina,an essential part of the eyeball,is an extension of cerebral tissue with a transparent refractive medium.It offers a unique window for assessing systemic microvascular lesions.Routine fundus examination is necessary for patients with diabetes and hypertension.Manifestations,such as retinal artery tortuosity,dilation,stenosis,and abnormal arteriovenous anastomosis,serve as typical hallmarks of retinal vasculopathy.Therefore,studies of ocular vascular diseases significantly facilitate the exploration of systemic vascular diseases.

摘要：Most papillary thyroid carcinoma(PTC)patients have a good prognosis.However,lymph node metastasis(LNM),the most common manifestation of disease progression,is frequently associated with a poor prognosis.Nevertheless,few studies have focused on the underlying mechanisms of LNM.In the current study,we aimed to investigate the potential role of exosomal circRNAs that contribute to LNM in PTC.We identified 9 000 differentially expressed exosomal circRNAs in PTC patients with LNM,including 684 upregulated and 2 193 downregulated circRNAs.Functional enrichment analysis revealed that these differentially expressed circRNAs were primarily involved in a variety of molecular and signaling pathways correlated with PTC progression and LNM.Through bioinformatics analysis,we identified 14 circRNA-miRNA-mRNA networks related to LNM-associated signaling pathways in PTC.Moreover,both circTACC2-miR-7-EGFR and circBIRC6-miR-24-3p-BCL2L11 axes were verified for their potential involvement in PTC with LNM.Additionally,we identified four upregulated circRNA-related hub genes and eight hub genes correlated with downregulated circRNAs,some of which were validated as being potentially involved in LNM in PTC.Collectively,our findings provide a novel framework for an in-depth investigation of the function of dysregulated exosomal circRNAs and their potential as biomarkers in PTC patients with LNM.

摘要：Dear Editor, Treating psoriatic arthritis (PsA) is always difficult.Systemic treatments can be administered either orally or through intramuscular and intra-articular injection,including conventional synthetics,biologics and targeted synthetic disease-modifying antirheumatic drugs[1]. The alternatives,topical external therapies,are not effective on joint lesions due to drug permeability issues. Drugs injected into the articular cavity are also unsuitable for small peripheral joint lesions,the most common manifestations of PsA. The limited treatment options for PsA present a challenge.

摘要：Dear Editor, Acrodermatitis continua of Hallopeau (ACH),a rare and chronic variant of pustular psoriasis,is characterized by atrophic skin changes,sterile pustules,onychodystrophy,and osteolysis of the distal phalanges of the fingers and toes. Given the absence of international consensus guidelines and comprehensive clinical studies of high methodological rigor,the management of ACH primarily relies on antipsoriatic therapeutic approaches and empirical evidence derived from scattered case reports.

摘要：In mammals,the timing of physiological,biochemical and behavioral processes over a 24-h period is controlled by circadian rhythms.To entrain the master clock located in the suprachiasmatic nucleus of the hypothalamus to a precise 24-h rhythm,environmental zeitgebers are used by the circadian system.This is done primarily by signals from the retina via the retinohypothalamic tract,but other cues like exercise,feeding,temperature,anxiety,and social events have also been shown to act as non-photic zeitgebers.The recently identified myokine irisin is proposed to serve as an entraining non-photic signal of exercise.Irisin is a product of cleavage and modification from its precursor membrane fibronectin type Ⅲ domain-containing protein 5(FNDC5)in response to exercise.Apart from well-known peripheral effects,such as inducing the"browning"of white adipocytes,irisin can penetrate the blood-brain barrier and display the effects on the brain.Experimental data suggest that FNDC5/irisin mediates the positive effects of physical activity on brain functions.In several brain areas,irisin induces the production of brain-derived neurotrophic factor(BDNF).In the master clock,a significant role in gating photic stimuli in the retinohypothalamic synapse for BDNF is suggested.However,the brain receptor for irisin remains unknown.In the current review,the interactions of physical activity and the irisin/BDNF axis with the circadian system are reconceptualized.

摘要：Small cell lung cancer (SCLC),which accounts for about one-sixth of all lung cancer cases,is the most aggressive subtype,with a high propensity for brain involvement[1]. The role of prophylactic cranial irradiation (PCI) in reducing intracranial relapse and improving survival has been a subject of intense debate for decades. Although earlier trials demonstrated its benefits in both early and advanced stages of the disease,the advent of more advanced imaging modalities,the availability of newer systemic anti-cancer therapies,and significant improvement in radiotherapy techniques have made this practice increasingly controversial within the oncology community. This article reviews the existing evidence in light of these recent developments and explores perspectives on the future of PCI in SCLC.

摘要：Acute lung injury(ALI)linked to sepsis has a high mortality rate,with limited treatment options available.In recent studies,medical ozone has shown the potential to alleviate inflammation and infection.Here,we aimed to evaluate therapeutic potential of medical ozone in a mouse model of the sepsis-induced ALI by measuring behavioral assessments,lung function,and blood flow.Protein levels were quantified by Western blotting.In vitro,we performed experiments on bone marrow-derived macrophages(BMDMs)to investigate the effect of adenosine monophosphate(AMP)-activated protein kinase(AMPK)inhibitors and agonists on their phagocytic activity.The results showed that medical ozone significantly improved the survival rate,ameliorated lung injury,and enhanced lung function and limb microcirculation in mice with ALI.Notably,medical ozone inhibited the formation of neutrophil extracellular traps(NETs),a crucial factor in the ALI development.Additionally,medical ozone counteracted the elevated levels of tissue factor,matrix metalloproteinase-9,and interleukin-1β.In the ALI mice,the effects of ozone were abolished,and BMDMs showed an impaired capacity to engulf NETs following the Sr-a1 knockout.Under normal physiological conditions,the administration of an AMPK antagonist showed similar effects on the Sr-a1 knockout,significantly inhibiting the phagocytosis of NETs by BMDMs.In contrast,AMPK agonists enhanced this phagocytic process.In conclusion,medical ozone may alleviate the sepsis-induced lung injury through the AMPK/SR-A1 pathway,thereby enhancing the phagocytosis of NETs by macrophages.

摘要：The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2(MDM2,also termed HDM2 in humans)through a feedback mechanism.At the same time,TP53 is the most frequently mutated gene in human cancers.Mutant p53 proteins lose wild-type p53 tumor suppression functions but acquire new oncogenic properties,among which are deregulating cell proliferation,increasing chemoresistance,disrupting tissue architecture,and promoting migration,invasion and metastasis as well as several other pro-oncogenic activities.The oncogenic p53 mutation Y220C creates an extended surface crevice in the DNA-binding domain destabilizing p53 and causing its denaturation and aggregation.This cavity accommodates stabilizing small molecules that have therapeutic values.The development of suitable small-molecule stabilizers is one of the therapeutic strategies for reactivating the Y220C mutant protein.In this review,we summarize approaches that target p53-Y220C,including reactivating this mutation with small molecules that bind Y220C to the hydrophobic pocket and developing immunotherapies as the goal for the near future,which target tumor cells that express the p53-Y220C neoantigen.

摘要：Nonalcoholic fatty liver disease(NAFLD)is considered a major health epidemic with an estimated 32.4%worldwide prevalence.No drugs have yet been approved and therapeutic nodes remain a major unmet need.Long noncoding RNAs are emerging as an important class of novel regulators influencing multiple biological processes and the pathogenesis of NAFLD.Herein,we described a novel long noncoding RNA,lnc_217,which was liver enriched and upregulated in high-fat diet-fed mice,and a genetic animal model of NAFLD.We found that liver specific knockdown of lnc_217 was resistant to high-fat diet-induced hepatic lipid accumulation and decreased serum lipid in mice.Mechanistically,we demonstrated that knockdown of lnc_217 not only decreased de novo lipogenesis by inhibiting sterol regulatory element binding protein-1c cleavage but also increased fatty acid β-oxidation through activation of peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase-1α.Taken together,we conclude that lnc_217 may be a novel regulator of hepatic lipid metabolism and a potential therapeutic target for the treatment of hepatic steatosis and NAFLD-related metabolic disorders.

摘要：The current study aimed to investigate associations of circRNAs and related genetic variants with the risk of prostate cancer(PCa)as well as to elucidate biological mechanisms underlying the associations.We first compared expression levels of circRNAs between 25 paired PCa and adjacent normal tissues to identify risk-associated circRNAs by using the MiOncoCirc database.We then used logistic regression models to evaluate associations between genetic variants in candidate circRNAs and PCa risk among 4 662 prostate cancer patients and 3 114 healthy controls,and identified circHIBADH rs11973492 T>C as a significant risk-associated variant(odds ratio=1.20,95%confidence interval:1.08-1.34,P=7.06×10-4)in a dominant genetic model,which altered the secondary structure of the corresponding RNA chain.In the in silico analysis,we found that circHIBADH sponged and silenced 21 RNA-binding proteins(RBPs)enriched in the RNA splicing pathway,among which HNRNPA1 was identified and validated as a hub RBP using an external RNA-sequencing data as well as the in-house(four tissue samples)and publicly available single-cell transcriptomes.Additionally,we demonstrated that HNRNPA1 influenced hallmarks including MYC target,DNA repair,and E2F target signaling pathways,thereby promoting carcinogenesis.In conclusion,genetic variants in circHIBADH may act as sponges and inhibitors of RNA splicing-associated RBPs including HNRNPA1,playing an oncogenic role in PCa.

摘要：Hepatocellular carcinoma(HCC)is a highly heterogeneous malignancy and lacks effective treatment.Bulk-sequencing of different gene transcripts by comparing HCC tissues and adjacent normal tissues provides some clues for investigating the mechanisms or identifying potential targets for tumor progression.However,genes that are exclusively expressed in a subpopulation of HCC may not be enriched or detected through such a screening.In the current study,we performed a single cell-clone-based screening and identified galectin-14 as an essential molecule in the regulation of tumor growth.The aberrant expression of galectin-14 was significantly associated with a poor overall survival of liver cancer patients with database analysis.Knocking down galectin-14 inhibited the proliferation of tumor growth,whereas overexpressing galectin-14 promoted tumor growth in vivo.Non-targeted metabolomics analysis indicated that knocking down galectin-14 decreased glycometabolism;specifically that glycoside synthesis was significantly changed.Further study found that galectin-14 promoted the expression of cell surface heparan sulfate proteoglycans(HSPGs)that functioned as co-receptors,thereby increasing the responsiveness of HCC cells to growth factors,such as epidermal growth factor and transforming growth factor-alpha.In conclusion,the current study identifies a novel HCC-specific molecule galectin-14,which increases the expression of cell surface HSPGs and the uptake of growth factors to promote HCC cell proliferation.

摘要：Rod-shaped gold nanomaterials,known as gold nanorods(GNRs),may undergo specific surface modification,because of their straightforward surface chemistry.This feature makes them appropriate for use as functional and biocompatible nano-formulations.By optimizing the absorption of longitudinally localized surface plasmon resonance in the near-infrared region,which corresponds to the near-infrared bio-tissue window,GNRs with appropriate modifications may improve the results of photothermal treatment(PTT).In dermatology,potential noninvasive uses of GNRs to enhance wound healing,manage infections,combat cutaneous malignancies,and remodel skin tissues via PTT have attracted research attention in recent years.The review discussed the basic properties of GNRs,such as their shape,size,optical performance,photothermal efficiency,and metabolism.Then,the disadvantages of using these particles in photodynamic therapy are highlighted.Next,biological applications of GNRs-based PTT are explored in detail.Finally,the limitations and future perspectives of this research are addressed,providing a comprehensive perspective on the potential GNRs with PTT.

摘要：Liquid-liquid phase separation,a novel biochemical phenomenon,has been increasingly studied for its medical applications.It underlies the formation of membrane-less organelles and is involved in many cellular and biological processes.During transcriptional regulation,dynamic condensates are formed through interactions between transcriptional elements,such as transcription factors,coactivators,and mediators.Cancer is a disease characterized by uncontrolled cell proliferation,but the precise mechanisms underlying tumorigenesis often remain to be elucidated.Emerging evidence has linked abnormal transcriptional condensates to several diseases,especially cancer,implying that phase separation plays an important role in tumorigenesis.Condensates formed by phase separation may have an effect on gene transcription in tumors.In the present review,we focus on the correlation between phase separation and transcriptional regulation,as well as how this phenomenon contributes to cancer development.

摘要：Hypertension(HT)is a major risk factor for cardiovascular diseases.Krüppel-like factors(KLFs)are important transcription factors in eukaryotes.Studies have reported that KLF4 and KLF5 are correlated with several cardiovascular diseases,but population-based studies on associations between HT and KLF4 or KLF5 have rarely been reported.Therefore,the current study investigated the associations of genetic variants and mRNA expression levels of KLF4 and KLF5 with HT,as well as the effects of antihypertensive drugs on the expression levels of these genes.The associations of one single-nucleotide polymorphism(SNP)in KLF4 and three SNPs in KLF5 with HT were analyzed using a combination of case-control and cohort studies.The study populations were selected from a community-based cohort in four regions of Jiangsu province.The risks of HT were estimated through logistic and Cox regression analyses.In addition,mRNA expression levels of KLF4 and KLF5 were detected in 246 controls and 385 HT cases selected from the aforementioned cohort.Among the HT cases,263 were not taking antihypertensive drugs[AHD(-)]and 122 were taking antihypertensive drugs[AHD(+)].In the case-control study,SNP rs9573096(C>T)in KLF5 was significantly associated with an increased risk of HT in the additive model(adjusted odds ratio[OR],1.106;95%confidence interval[CI],1.009 to 1.212).In the cohort study of the normotensive population,rs9573096 in KLF5 was also significantly associated with an increased risk of HT in the additive model(adjusted hazards ratio[HR],1.199;95%CI,1.070 to 1.344).KLF4 and KLF5 mRNA expression levels were significantly higher in the AHD(-)group than in the control group(P<0.05),but lower in the AHD(+)group than in the AHD(-)group(P<0.05).The current study demonstrated the associations of KLF4 and KLF5 genetic variants with hypertension,as well as the association of the indicative variations in mRNA expression levels of KLF4 and KLF5 with the risk of hypertension and antihypertensive treatment.

摘要：Although p21-activated kinase 2(PAK2)is an essential serine/threonine protein kinase,its role in the progression of lung squamous cell carcinoma(LUSC)has yet to be fully understood.We analyzed PAK2 mRNA levels,DNA copy numbers,and protein levels by quantitative reverse transcription-PCR and immuno-histochemical staining in both human LUSC tissues and adjacent normal tissues.Then,we performed colony formation assays,cell counting kit-8 assays,Matrigel invasion assays,wound healing assays,and xenograft models in nude mice to investigate the functions of PAK2 in LUSC progression.We demonstrated that PAK2 mRNA levels,DNA copy numbers,and protein levels were upregulated in human LUSC tissues,compared with adjacent normal tissues.Additionally,higher PAK2 expression was associated with poorer prognosis in LUSC patients.In the in vitro study,we found that PAK2 promoted cell growth,migration,invasion,epithelial-mesenchymal transition,and cell morphology regulation in LUSC cells.Mechanistically,PAK2 promoted tumor cell proliferation,migration,and invasion by regulating actin dynamics through the LIMK1/cofilin signaling pathway.Our findings indicate that the PAK2/LIMK1/cofilin signaling pathway may serve as a potential clinical marker and therapeutic target for LUSC.

摘要：Core 1 synthase glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1(C1GALT1)is known to play a critical role in the development of gastric cancer,but few studies have elucidated associations between genetic variants in C1GALT1 and gastric cancer risk.By using the genome-wide association study data from the database of Genotype and Phenotype(dbGAP),we evaluated such associations with a multivariable logistic regression model and identified that the rs35999583 G>C in C1GALT1 was associated with gastric cancer risk(odds ratio,0.83;95%confidence interval[CI],0.75-0.92;P=3.95×10-4).C1GALT1 mRNA expression levels were sig-nificantly higher in gastric tumor tissues than in normal tissues,and gastric cancer patients with higher C1GALT1 mRNA levels had worse overall survival rates(hazards ratio,1.33;95%CI,1.05-1.68;Plog-rank=1.90×10-2).Furthermore,we found that C1GALT1 copy number differed in various immune cells and that C1GALT1 mRNA expression levels were positively correlated with the infiltrating levels of CD4+T cells and macrophages.These results suggest that genetic variants of C1GALT1 may play an important role in gastric cancer risk and provide a new insight for C1GALT1 into a promising predictor of gastric cancer susceptibility and immune status.

摘要：Given the extremely high inter-patient heterogeneity of acute myeloid leukemia(AML),the identification of biomarkers for prognostic assessment and therapeutic guidance is critical.Cell surface markers(CSMs)have been shown to play an important role in AML leukemogenesis and progression.In the current study,we evaluated the prognostic potential of all human CSMs in 130 AML patients from The Cancer Genome Atlas(TCGA)based on differential gene expression analysis and univariable Cox proportional hazards regression analysis.By using multi-model analysis,including Adaptive LASSO regression,LASSO regression,and Elastic Net,we constructed a 9-CSMs prognostic model for risk stratification of the AML patients.The predictive value of the 9-CSMs risk score was further validated at the transcriptome and proteome levels.Multivariable Cox regression analysis showed that the risk score was an independent prognostic factor for the AML patients.The AML patients with high 9-CSMs risk scores had a shorter overall and event-free survival time than those with low scores.Notably,single-cell RNA-sequencing analysis indicated that patients with high 9-CSMs risk scores exhibited chemotherapy resistance.Furthermore,PI3K inhibitors were identified as potential treatments for these high-risk patients.In conclusion,we constructed a 9-CSMs prognostic model that served as an independent prognostic factor for the survival of AML patients and held the potential for guiding drug therapy.

摘要：Dear Editor, Cardiovascular disease is the leading cause of deaths worldwide,with coronary artery disease (CAD)accounting for approximately 50％ of its mortality.Dual antiplatelet therapy,including aspirin and a P2Y12 inhibitor,is the most important treatment for CAD patients undergoing percutaneous coronary intervention (PCI) to prevent recurrent ischemic events and cardiac death. Clopidogrel is one of the commonly used P2Y12 inhibitors. However,up to 30％ of patients treated with a standard dose of clopidogrel present with high on-treatment platelet reactivity (HOPR),which is associated with the increased ischemic risks[1].