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].

摘要：The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current study,we found that the mRNA levels of scavenger receptor A1(Sr-a1)were elevated in patients with critical limb ischemia,based on an analysis of the Gene Expression Omnibus data.We then investigated the role and underlying mechanisms of macrophage SR-A1 in a mouse hindlimb ischemia(HLI)model.Compared with the Sr-a1fl/fl mice,the LyzCre/+/Sr-a1flox/flox(Sr-a1ΔMΦ)mice showed significantly reduced laser Doppler blood flow in the ischemic limb on day seven after HLI.Consistently,histological analysis revealed that the ischemic limb of the Sr-a1ΔMΦ mice exhibited more severe and prolonged necrotic morphology,inflammation,fibrosis,decreased vessel density,and delayed regeneration than that of the control Sr-a1fl/fl mice.Furthermore,restoring wild-type myeloid cells to the Sr-a1 knockout mice effectively improved the Doppler perfusion in the ischemic limb and mitigated skeletal muscle damage seven days after HLI.Consistent with these in vivo findings,co-cultivating macrophages with the mouse myoblast cell line C2C12 revealed that the Sr-a1-/-bone marrow macrophages significantly inhibited myoblast differentiation in vitro.Mechanistically,SR-A1 enhanced the skeletal muscle regeneration in response to HLI by inhibiting oncostatin M production via suppression of the NF-κB signaling activation.These findings indicate that SR-A1 may be a promising candidate protein to improve tissue repair and regeneration in peripheral ischemic arterial disease.

摘要：Interleukin (IL)-18,a member of the IL-1 family,is commonly known as an interferon-γ inducer and is expressed in both hematopoietic and non-hematopoietic cells,such as intestinal epithelial cells,keratinocytes,and endothelial cells. In the immune system,the mature IL-18 plays a critical role in eliminating tumors and infectious agents by activating NK cells and T-lymphocytes,and by synergizing with other cytokines like IL-12 and IL-1β to induce inflammation[1-2]. However,excessive activation of IL-18 may cause a variety of immune-inflammatory diseases,including psoriasis,atherosclerosis,Alzheimer's disease,and inflammatory bowel disease[3-4]. Regarding the activation mechanism of IL-18,similar to immune cells,mouse non-immune cells rely on caspase-1 for its processing and maturation.However,the activation mechanism of IL-18 in human non-immune cells remains unclear.

摘要：Endometriosis is defined as a condition with endometrium-like tissues migrating outside of the pelvic cavity.However,the mechanism of endometriosis is still unclear.Lactate can be covalently modified to lysine residues of histones and other proteins,which is called lactylation.The results showed that the higher level of lactate and lactate dehydrogenase A enhanced the histone H3 lysine 18 lactylation(H3K18lac)in ectopic endometrial tissues and ectopic endometrial stromal cells than that in normal endometrial tissues and normal endometrial stromal cells.Lactate promoted cell proliferation,migration,and invasion in endometriosis.Mechanistically,lactate induced H3K18lac to promote the expression of high-mobility group box 1(HMGB1)in endometriosis,and HMGB1 knockdown significantly reduced the cell proliferation,migration,and invasion of the lactate-treated cells through the phosphorylation of AKT.In conclusion,lactate could induce histone lactylation to promote endometriosis progression by upregulating the expression of HMGB1,which may provide a novel target for the prevention and treatment of endometriosis.

摘要：Inflammation plays a crucial role in the initiation and progression of sepsis and induces alterations in brain neurotransmission,thereby contributing to the development of sepsis-associated encephalopathy(SAE).Parvalbumin(PV)interneurons are pivotal contributors to cognitive processes and have been implicated in various central nervous system dysfunctions,including SAE.Oxytocin,known for its ability to augment the firing rate of gamma-aminobutyric acid(GABA)-ergic interneurons and directly stimulate inhibitory interneurons to enhance the tonic inhibition of pyramidal neurons,has prompted an investigation into its potential therapeutic effects on cognitive dysfunction in SAE.In the current study,we administered intranasal oxytocin to SAE mice induced by lipopolysaccharide.Behavioral assessments,including open field,Y-maze,and fear conditioning,were used to evaluate cognitive performance.Golgi staining revealed hippocampal synaptic deterioration,local field potential recordings showed weakened gamma oscillations,and immunofluorescence staining demonstrated decreased PV expression in the cornu ammonis 1(CA1)region of the hippocampus following lipopolysaccharide treatment,all of which were alleviated by oxytocin administration.Furthermore,immunofluorescence staining of PV co-localization with vesicular glutamate transporter 1 or vesicular GABA transporter indicated a balanced excitation/inhibition effect of neurotransmitters on PV interneurons after oxytocin administration in the SAE mice,leading to an improved cognitive function.In conclusion,oxytocin treatment improved cognitive function by increasing the number of PV+neurons in the hippocampal CA1 region,restoring the balance of excitatory/inhibitory synaptic transmission on PV interneurons,and enhancing hippocampal CA1 local field potential gamma oscillations.These findings suggest a potential mechanism underlying the beneficial effects of oxytocin in SAE.

摘要：Bladder cancer(BC)is the tenth most prevalent malignancy globally,presenting significant clinical and societal challenges because of its high incidence,rapid progression,and frequent recurrence.Presently,cystoscopy and urine cytology serve as the established diagnostic methods for BC.However,their efficacy is limited by their invasive nature and low sensitivity.Therefore,the development of highly specific biomarkers and effective non-invasive detection strategies is imperative for achieving a precise and timely diagnosis of BC,as well as for facilitating an optimal tumor treatment and an improved prognosis.microRNAs(miRNAs),short noncoding RNA molecules spanning around 20-25 nucleotides,are implicated in the regulation of diverse carcinogenic pathways.Substantially altered miRNAs form robust functional regulatory networks that exert a notable influence on the tumorigenesis and progression of BC.Investigations into aberrant miRNAs derived from blood,urine,or extracellular vesicles indicate their potential roles as diagnostic biomarkers and prognostic indicators in BC,enabling miRNAs to monitor the progression and predict the recurrence of the disease.Simultaneously,the investigation centered on miRNA as a potential therapeutic agent presents a novel approach for the treatment of BC.This review comprehensively analyzes biological roles of miRNAs in tumorigenesis and progression,and systematically summarizes their potential as diagnostic and prognostic biomarkers,as well as therapeutic targets for BC.Additionally,we evaluate the progress made in laboratory techniques within this field and discuss the prospects.

摘要：Premature ovarian insufficiency(POI)caused by chemotherapy is a common complication in female cancer survivors of childbearing age.Traditional methods,including mesenchymal stem cell(MSC)transplant and hormone replacement therapy,have limited clinical application because of their drawbacks,and more methods need to be developed.In the current study,the potential effects and underlying mechanisms of human umbilical cord MSC-derived extracellular vesicles(hUCMSC-EVs)were investigated in a cisplatin(CDDP)-induced POI mouse model and a human granulosa cell(GC)line.The results showed that hUCMSC-EVs significantly attenuated body weight loss,ovarian weight loss,ovary atrophy,and follicle loss in moderate-dose(1.5 mg/kg)CDDP-induced POI mice,similar to the effects observed with hUCMSCs.We further found that the hUCMSC-EVs inhibited CDDP-induced ovarian GC apoptosis by upregulating anti-apoptotic miRNA levels in GCs,thereby downregulating the mRNA levels of multiple pro-apoptotic genes.In general,our findings indicate that the moderate-dose chemotherapy may be a better choice for clinical oncotherapy,considering effective rescue of the oncotherapy-induced ovarian damage with hUCMSC-EVs.Additionally,multiple miRNAs in hUCMSC-EVs may potentially be used to inhibit the chemotherapy-induced ovarian GC apoptosis,thereby restoring ovarian function and improving the life quality of female cancer patients.

摘要：Intracranial hemorrhage(ICH)causes numerous neurological deficits and deaths worldwide each year,leaving a significant health burden on the public.The pathophysiology of ICH is complicated and involves both primary and secondary injuries.Hematoma,as the primary pathology of ICH,undergoes metabolism and triggers biochemical and biomechanical alterations in the brain,leading to the secondary injury.Past endeavors mainly aimed at biochemical-initiated mechanisms for causing secondary injury,which have made limited progress in recent years,although ICH itself is also highly biomechanics-related.The discovery of the mechanically-activated cation channel Piezo1 provides a new avenue to further explore the mechanisms underlying the secondary injury.The current article reviews the structure and gating mechanisms of Piezo1,its roles in the physiology/pathophysiology of neurons,astrocytes,microglia,and bone-marrow-derived macrophages,and especially its roles in erythrocytic turnover and iron metabolism,revealing a potential interplay between the biomechanics and biochemistry of hematoma in ICH.Collectively,these advances provide deeper insights into the secondary injury of ICH and lay the foundations for future research.