Emerging mechanisms and implications of c GAS-STING signaling in cancer immunotherapy strategies

The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment.Within this landscape,the innate immune system,a critical sentinel protecting against tumor incursion,is a key player.The cyclic GMP-AMP synthase(c GAS)and stimulator of interferon genes(STING)pathway has been found to be a linchpin of innate immunity:activation of this signaling pathway orchestrates the production of type I interferon(IFN-α/β),thus fostering the maturation,differentiation,and mobilization of immune effectors in the tumor microenvironment.Furthermore,STING activation facilitates the release and presentation of tumor antigens,and therefore is an attractive target for cancer immunotherapy.Current strategies to activate the STING pathway,including use of pharmacological agonists,have made substantial advancements,particularly when combined with immune checkpoint inhibitors.These approaches have shown promise in preclinical and clinical settings,by enhancing patient survival rates.This review describes the evolving understanding of the c GAS-STING pathway's involvement in tumor biology and therapy.Moreover,this review explores classical and non-classical STING agonists,providing insights into their mechanisms of action and potential for optimizing immunotherapy strategies.Despite challenges and complexities,the c GAS-STING pathway,a promising avenue for enhancing cancer treatment efficacy,has the potential to revolutionize patient outcomes.

Overexpression of TRPV1 activates autophagy in human lens epithelial cells under hyperosmotic stress through Ca^(2+)-dependent AMPK/mTOR pathway

●AIM:To explore whether autophagy functions as a cellular adaptation mechanism in lens epithelial cells(LECs)under hyperosmotic stress.●METHODS:LECs were treated with hyperosmotic stress at the concentration of 270,300,400,500,or 600 mOsm for 6,12,18,24h in vitro.Polymerase chain reaction(PCR)was employed for the mRNA expression of autophagyrelated genes,while Western blotting detected the targeted protein expression.The transfection of stub-RFP-sens-GFPLC3 autophagy-related double fluorescence lentivirus was conducted to detect the level of autophagy flux.Scanning electron microscopy was used to detect the existence of autolysosome.Short interfering RNA of autophagy-related gene(ATG)7,transient receptor potential vanilloid(TRPV)1 overexpression plasmid,related agonists and inhibitors were employed to their influence on autophagy related pathway.Flow cytometry was employed to test the apoptosis and intracellular Ca^(2+)level.Mitochondrial membrane potential was measured by JC-1 staining.The cell counting kit-8 assay was used to calculate the cellular viability.The wound healing assay was used to evaluate the wound closure rate.GraphPad 6.0 software was utilized to evaluate the data.●RESULTS:The hyperosmotic stress activated autophagy in a pressure-and time-dependent manner in LECs.Beclin 1 protein expression and conversion of LC3B II to LC3B I increased,whereas sequestosome-1(SQSTM1)protein expression decreased.Transient Ca^(2+)influx was stimulated caused by hyperosmotic stress,levels of mammalian target of rapamycin(mTOR)phosphorylation decreased,and the level of AMP-activated protein kinase(AMPK)phosphorylation increased in the early stage.Based on this evidence,autophagy activation through the Ca^(2+)-dependent AMPK/mTOR pathway might represent an adaptation process in LECs under hyperosmotic stress.Hyperosmotic stress decreased cellular viability and accelerated apoptosis in LECs and cellular migration decreased.Inhibition of autophagy by ATG7 knockdown had similar results.TRPV1 overexpression increased autophagy and might be crucial in the occurrence of autophagy promoted by hyperosmotic stress.●CONCLUSION:A combination of hyperosmotic stress and autophagy inhibition may be a promising approach to decrease the number of LECs in the capsular bag and pave the way for improving prevention of posterior capsular opacification and capsular fibrosis.

Trends and hotspots in gastrointestinal neoplasms risk assessment: A bibliometric analysis from 1984 to 2022

BACKGROUND Gastrointestinal neoplasm(GN)significantly impact the global cancer burden and mortality,necessitating early detection and treatment.Understanding the evolution and current state of research in this field is vital.AIM To conducts a comprehensive bibliometric analysis of publications from 1984 to 2022 to elucidate the trends and hotspots in the GN risk assessment research,focusing on key contributors,institutions,and thematic evolution.METHODS This study conducted a bibliometric analysis of data from the Web of Science Core Collection database using the"bibliometrix"R package,VOSviewer,and CiteSpace.The analysis focused on the distribution of publications,contributions by institutions and countries,and trends in keywords.The methods included data synthesis,network analysis,and visualization of international collaboration networks.RESULTS This analysis of 1371 articles on GN risk assessment revealed a notable evolution in terms of research focus and collaboration.It highlights the United States'critical role in advancing this field,with significant contributions from institutions such as Brigham and Women's Hospital and the National Cancer Institute.The last five years,substantial advancements have been made,representing nearly 45%of the examined literature.Publication rates have dramatically increased,from 20 articles in 2002 to 112 in 2022,reflecting intensified research efforts.This study underscores a growing trend toward interdisciplinary and international collaboration,with the Journal of Clinical Oncology standing out as a key publication outlet.This shift toward more comprehensive and collaborative research methods marks a significant step in addressing GN risks.CONCLUSION This study underscores advancements in GN risk assessment through genetic analyses and machine learning and reveals significant geographical disparities in research emphasis.This calls for enhanced global collaboration and integration of artificial intelligence to improve cancer prevention and treatment accuracy,ultimately enhancing worldwide patient care.

Pathologically successful conversion hepatectomy for advanced giant hepatocellular carcinoma after multidisciplinary therapy:A case report and review of literature

BACKGROUND Hepatocellular carcinoma(HCC)is one of the leading causes of death due to its complexity,heterogeneity,rapid metastasis and easy recurrence after surgical resection.We demonstrated that combination therapy with transcatheter arterial chemoembolization(TACE),hepatic arterial infusion chemotherapy(HAIC),Epclusa,Lenvatinib and Sintilimab is useful for patients with advanced HCC.CASE SUMMARY A 69-year-old man who was infected with hepatitis C virus(HCV)30 years previously was admitted to the hospital with abdominal pain.Enhanced computed tomography(CT)revealed a low-density mass in the right lobe of the liver,with a volume of 12.9 cm×9.4 cm×15 cm,and the mass exhibited a“fast-in/fast-out”pattern,with extensive filling defect areas in the right branch of the portal vein and an alpha-fetoprotein level as high as 657 ng/mL.Therefore,he was judged to have advanced HCC.During treatment,the patient received three months of Epclusa,three TACE treatments,two HAIC treatments,three courses of sintilimab,and twenty-one months of lenvatinib.In the third month of treatment,the patient developed severe side effects and had to stop immunotherapy,and the Lenvatinib dose had to be halved.Postoperative pathological diagnosis indicated a complete response.The patient recovered well after the operation,and no tumor recurrence was found.CONCLUSION Multidisciplinary conversion therapy for advanced enormous HCC caused by HCV infection has a significant effect.Individualized drug adjustments should be made during any treatment according to the patient's tolerance to treatment.

Predicting short-term major postoperative complications in intestinal resection for Crohn’s disease:A machine learning-based study

BACKGROUND Due to the complexity and numerous comorbidities associated with Crohn’s disease(CD),the incidence of postoperative complications is high,significantly impacting the recovery and prognosis of patients.Consequently,additional stu-dies are required to precisely predict short-term major complications following intestinal resection(IR),aiding surgical decision-making and optimizing patient care.AIM To construct novel models based on machine learning(ML)to predict short-term major postoperative complications in patients with CD following IR.METHODS A retrospective analysis was performed on clinical data derived from a patient cohort that underwent IR for CD from January 2017 to December 2022.The study participants were randomly allocated to either a training cohort or a validation cohort.The logistic regression and random forest(RF)were applied to construct models in the training cohort,with model discrimination evaluated using the area under the curves(AUC).The validation cohort assessed the performance of the constructed models.RESULTS Out of the 259 patients encompassed in the study,5.0%encountered major postoperative complications(Clavien-Dindo≥III)within 30 d following IR for CD.The AUC for the logistic model was 0.916,significantly lower than the AUC of 0.965 for the RF model.The logistic model incorporated a preoperative CD activity index(CDAI)of≥220,a diminished preoperative serum albumin level,conversion to laparotomy surgery,and an extended operation time.A nomogram for the logistic model was plotted.Except for the surgical approach,the other three variables ranked among the top four important variables in the novel ML model.CONCLUSION Both the nomogram and RF exhibited good performance in predicting short-term major postoperative complic-ations in patients with CD,with the RF model showing more superiority.A preoperative CDAI of≥220,a di-minished preoperative serum albumin level,and an extended operation time might be the most crucial variables.The findings of this study can assist clinicians in identifying patients at a higher risk for complications and offering personalized perioperative management to enhance patient outcomes.

Artificial intelligence for disease diagnostics still has a long way to go

Artificial intelligence(AI)can sometimes resolve difficulties that other advanced technologies and humans cannot.In medical diagnostics,AI has the advantage of processing figure recognition,especially for images with similar characteristics that are difficult to distinguish with the naked eye.However,the mechanisms of this advanced technique should be well-addressed to elucidate clinical issues.In this letter,regarding an original study presented by Takayama et al,we suggest that the authors should effectively illustrate the mechanism and detailed procedure that artificial intelligence techniques processing the acquired images,including the recognition of non-obvious difference between the normal parts and pathological ones,which were impossible to be distinguished by naked eyes,such as the basic constitutional elements of pixels and grayscale,special molecules or even some metal ions which involved into the diseases occurrence.

Clinical Characteristics and Durations of Hospitalized Patients with COVID-19 in Beijing: A Retrospective Cohort Study

Objective:To provide information on clinical characteristics and different durations of COVID-19 and to identify the potential risk factors for longer hospitalization of patients with COVID-19.Methods:In this retrospective study,we enrolled 77 patients(age 52±20 years;44.2%males)with laboratory-confi rmed COVID-19 admitted to Beijing YouAn Hospital between January 21 and February 8,2020.Epidemiological,clinical,and radiological data on admission were collected;complications and outcomes were followed up until February 26,2020.The end point of the study was discharge alive within 2 weeks.Cox proportional-hazards regression was performed to identify risk factors for longer hospitalization.Results:Of 77 patients,there were 34 males(44.2%),24(31.2%)with comorbidities,22(28.6%)with lymphopenia,20(26.0%)with severe COVID-19,and 28(36.4%)with complications.By the end of follow-up,64 patients(83.1%)were discharged home,eight remained in hospital,and fi ve had died.Thirty-six patients(46.8%)were discharged within 14 days and thus reached the study end point,including 34 of the 57 patients with nonsevere COVID-19(59.6%)and two of the 20 patients with severe COVID-19(10%).The overall cumulative probability of the end point was 48.3%.Hospital length of stay and the duration from exposure to discharge for the 64 discharged patients were 13(10-16.5)days and 23(18-24.5)days,respectively.A multivariable stepwise Cox regression model showed that bilateral pneumonia on CT scan,shorter time from illness onset to admission,severity of disease,and lymphopenia were independently associated with longer hospitalization.Conclusions:COVID-19 has a shorter duration of disease and hospital length of stay than severe acute respiratory syndrome.Bilateral pneumonia on CT scan,shorter period from illness onset to admission,lymphopenia,and severity of disease are the risk factors for longer hospitalization of patients with COVID-19.

Future therapeutic implications of new molecular mechanism of colorectal cancer

High incidence(10.2%)and mortality(9.2%)rates led to the ranking of colorectal cancer(CRC)as the second most malignant tumor spectrum worldwide in 2020.Treatment strategies are becoming highly dependent on the molecular characteristics of CRC.The classical theories accept two models depicting the origin of CRC:The progression of adenoma to cancer and transformation from serrated polyps to cancer.However,the molecular mechanism of CRC development is very complex.For instance,CRCs originating from laterally spreading tumors(LST)do not adhere to any of these models and exhibit extremely serious progression and poor outcomes.In this article,we present another possible pathway involved in CRC development,particularly from LST,with important molecular characteristics,which would facilitate the design of a novel strategy for targeted therapy.

Adipose tissue macrophages:implications for obesity-associated cancer

Obesity is one of the most serious global health problems,with an incidence that increases yearly and coincides with the development of cancer.Adipose tissue macrophages(ATMs)are particularly important in this context and contribute to linking obesity-related inflammation and tumor progression.However,the functions of ATMs on the progression of obesity-associated cancer remain unclear.In this review,we describe the origins,phenotypes,and functions of ATMs.Subsequently,we summarize the potential mechanisms on the reprogramming of ATMs in the obesity-associated microenvironment,including the direct exchange of dysfunctional metabolites,inordinate cytokines and other signaling mediators,transfer of extracellular vesicle cargo,and variations in the gut microbiota and its metabolites.A better understanding of the properties and functions of ATMs under conditions of obesity will lead to the development of new therapeutic interventions for obesity-related cancer.

Has_circ_0000069 expression in breast cancer and its influences on prognosis and cellular activities

Circular RNA(circRNA),as a newly discovered non-coding RNA with important regulatory potential,is closely related to the occurrence and progression of various tumors.This study aimed to investigate has_circ_0000069 expression in breast cancer and its influence on cellular activities.Using real-time quantitative polymerase chain reaction,has_circ_0000069 levels were measured in 137 pairs of tissue specimens,as well as cancer cell lines.The cellular activities of cell lines were determined by cell counting kit-8(CCK-8)and Transwell assays.The potential targeting miRNAs were predicted and verified using an online database and dual-luciferase reporter assay.Has_circ_0000069 was highly expressed in breast cancer tissues and cells.The expression of has_circ_0000069 was associated with the five-year overall survival of patients.After silencing has_circ_0000069 in breast cancer cells,its expression reduced,and the ability of cell proliferation,migration,and invasion decreased.MiR-432 was verified as a targeting miRNA of has_circ_0000069.Has_circ_0000069 expression increased in breast cancer and was negatively related to patient’s prognosis.Has_circ_0000069 may facilitate breast cancer tumor progression by sponging miR-432.These findings revealed that has_circ_0000069 may be a biomarker for predicting prognosis and a therapeutic target for treating patients with breast cancer.

Recent progress in N6-methyladenosine modification in ocular surface diseases

N6-methyladenosine(m6A)modification is a reversible process promoted by“writers”,inhibited by“erasers”,and processed by“readers”.During the last decade,increasing emphasis has been placed on the underlying roles of m6A modification owing to their great importance in biological significance.The abnormal regulation of m6A modification will lead to aberrant cellular behavior and various diseases.Recently,studies have demonstrated that m6A modification is closely associated with the genesis and progression of ocular surface diseases(OSDs).This review focus on the role of m6A modification and research progress in OSDs including fungal keratitis,herpes simplex keratitis,immunerelated keratoconjunctival diseases,pterygium,ocular chemical burns,and Graves’ophthalmopathy,which may provide new insights into and prospective applications for OSDs.

Large animal models of cardiac ischemia-reperfusion injury:Where are we now?

Large animal models of cardiac ischemia-reperfusion are critical for evaluation of the efficacy of cardioprotective interventions prior to clinical translation.Nonetheless,current cardioprotective strategies/interventions formulated in preclinical cardiovascular research are often limited to small animal models,which are not transferable or reproducible in large animal models due to different factors such as:(i)complex and varied features of human ischemic cardiac disease(ICD),which are challenging to mimic in animal models,(ii)significant differences in surgical techniques applied,and(iii)differences in cardiovascular anatomy and physiology between small versus large animals.This article highlights the advantages and disadvantages of different large animal models of preclinical cardiac ischemic reperfusion injury(IRI),as well as the different methods used to induce and assess IRI,and the obstacles faced in using large animals for translational research in the settings of cardiac IR.

Inhibition of fibroblast activation protein ameliorates cartilage matrix degradation and osteoarthritis progression

Fibroblast activation protein(Fap)is a serine protease that degrades denatured type I collagen,α2-antiplasmin and FGF21.Fap is highly expressed in bone marrow stromal cells and functions as an osteogenic suppressor and can be inhibited by the bone growth factor Osteolectin(Oln).Fap is also expressed in synovial fibroblasts and positively correlated with the severity of rheumatoid arthritis(RA).However,whether Fap plays a critical role in osteoarthritis(OA)remains poorly understood.Here,we found that Fap is significantly elevated in osteoarthritic synovium,while the genetic deletion or pharmacological inhibition of Fap significantly ameliorated posttraumatic OA in mice.Mechanistically,we found that Fap degrades denatured type II collagen(Col II)and Mmp13-cleaved native Col II.Intra-articular injection of r Fap significantly accelerated Col II degradation and OA progression.In contrast,Oln is expressed in the superficial layer of articular cartilage and is significantly downregulated in OA.Genetic deletion of Oln significantly exacerbated OA progression,which was partially rescued by Fap deletion or inhibition.Intra-articular injection of r Oln significantly ameliorated OA progression.Taken together,these findings identify Fap as a critical pathogenic factor in OA that could be targeted by both synthetic and endogenous inhibitors to ameliorate articular cartilage degradation.

Uterine artery embolization combined with percutaneous microwave ablation for the treatment of prolapsed uterine submucosal leiomyoma:A case report

BACKGROUND Vaginal myomectomy is the most common form of radical treatment for prolapsed submucosal leiomyoma and is typically performed under general anesthesia.However,an alternative treatment approach is needed for patients who cannot tolerate general anesthesia.We describe a case with such a patient who was successfully treated via a minimally invasive method under local anesthesia.CASE SUMMARY A 46-year-old female suffered from abnormal uterine bleeding,severe anemia,and a reduced quality of life attributed to a massive prolapsed submucosal leiomyoma.She could not tolerate general anesthesia due to a congenital thoracic malformation and cardiopulmonary insufficiency.A new individualized combined treatment,consisting uterine artery embolization(UAE),percutaneous microwave ablation(PMWA)of the pedicle and the endometrium,and transvaginal removal of the leiomyoma by twisting,was performed.The lesion was completely removed successfully under local anesthesia without any major complications.The postoperative follow-up showed complete symptom relief and a significant improvement in the quality of life.CONCLUSION UAE combined with PMWA can be performed under local anesthesia and is a promising alternative treatment for patients who cannot tolerate general anesthesia.

On fracture behavior of inner enamel:a numerical study

The ingenious hierarchical structure of enamel composed of rods and protein produces excellent fracture resistance.However,the fracture resistance mechanism in the inner enamel is unknown.The micromechanical models of enamel are constructed to numerically analyze the mechanical behaviors of the inner enamel with different decussation angles and different decussation planes.The results show that the manner of crack propagation in the inner enamel,including crack bridging,crack deflection,and crack bifurcation,is determined by both the rod decussation angle and the decussation plane.In the case of the strong decussation plane,the fracture strength and the required energy dissipation with the decussation angles of 15°and 30°are much higher than those without decussation,demonstrating that decussation is an important mechanism in improving the fracture resistance of enamel.The maximum tensile stress of enamel with the decussation angle of 15°is slightly higher than that of enamel with the decussation angle of 30°,illustrating that an optimal decussation angle exists which balances the strength and toughness.The synergetic mechanism of the decussation angle and the decussation plane on the crack propagation provides a new design hint for bionic composites.

Road of no return——loss of TP53 paves a defined evolution path from gastric preneoplasia-to-cancer

Gastric cancer(GC),the fifth-and fourth-leading causes of morbidity and mortality worldwide,still lacks effective diagnoses and treatment.Moreover,China accounts for nearly 50%of the newly diagnosed and death cases of GC globally1.Being directly exposed to external food intake,extremely acidic content,and microorganisms,such as Helicobacter pylori and Epstein-Barr virus(EBV),stomach homeostasis is easily perturbed and disrupted.Importantly,the gastric epithelium is composed of multiple cell types,including chief,parietal,pit,and stem cells.The lineages of these gastric epithelial cells are rather plastic,giving rise to a high degree of GC heterogeneity.

TRIM72‑mediated degradation of the short form of p62/SQSTM1 rheostatically controls selective autophagy in human cells

Dear Editor,Autophagy is an evolutionarily conserved catabolic process that involves the sequestration and transport of organelles,macromolecules,or invading microorganisms to lysosomes for degradation[1].Sequestosome 1(p62/SQSTM1)was the first protein shown to bind target-associated ubiquitin(Ub)and LC3 conjugated to the phagophore membrane,thus,acting as an important autophagy receptor for ubiquitinated targets[2].

Effects of a Graded Brisk Walking Test with Different Intensity Levels on Elderly Patients with Essential Hypertension:A Prospective Study in Shanghai,China

Background:This study aimed to clarify the effects of a Graded Brisk Walking Test(GBWT)program on blood pressure(BP)control in elderly patients with essential hypertension and to determine its appropriate degree of intensity for elderly people.Methods:In total,421 out of 620 participants were randomly sampled from a community health center in Shanghai,China.Among them,200 and 221 patients were assigned to the intervened and control groups,respectively.They were all treated with the GBWT program for 8 weeks,16 weeks,and 24 weeks.Results:Based on ANOVA,there was no significant time main effect,condition main effect,or time by condition interaction both in heart rate and body mass index indicators(P>0.05).There were significant condition main effects,time by condition interaction,or time main effects in blood pressure(F=21.875,33.457,65.342,respectively;All P<0.05).After the intervention,significant differences in systolic blood pressure(SBP)and diastolic blood pressure(DBP)values were also observed in the two groups(P<0.05);the average values of the baseline and second phases of the intervention group were significantly lower than those of the control group(P<0.05).Significant differences in blood pressure values after the first two phases were also observed when compared with those before the intervention.Similarly,a significant difference in the first phase and second phase was also found between the BP group and intervention group.However,after the third phase(24 weeks,high-intensity exercise),no significant differences existed both in SBP and DBP groups compared with those before the intervention(P=0.07).Conclusion:GBWT is an effective exercise prescription to mitigate the essential hypertension in elderly Chinese patients,and the intensity,walking distance,and target number of steps can be adjusted according to the age of the patients.

Circulating tumor cells: Biological features and survival mechanisms

Circulating tumor cells(CTCs)are neoplastic cells that are detached from primary tumors and enter circulation.Enumeration and characterization of CTCs are of significance in cancer diagnosis,prognosis,and treatment monitoring.CTC survival in the bloodstream is a limiting step for the development of metastases in distant organs.Recent technological advances,especially in single-cell molecular analyses have uncovered heterogeneous CTC survival mechanisms.Undergoing epithelial-to-mesenchymal transition(EMT),increasing stem cell-like properties,and forming cell clusters enable CTCs to adapt to the harsh microenvironment of the circulation.Expressing and releasing several immunosuppressive molecules help CTCs escape from anti-cancer immune mechanisms.This review article summarizes the biological characteristics of CTCs and focuses on the recent understanding of the mechanisms by which CTCs survive in circulation.Additionally,the clinical and therapeutic implications of CTCs are discussed.

Characterization of prognosis and immune infiltration by a novel glutamine metabolism-related model in cutaneous melanoma

Glutamine metabolism(GM)plays an important role in tumor growth and proliferation.Skin cutaneous melanoma(SKCM)is a glutamine-dependent cancer.However,the molecular characteristics and action mechanism of GM on SKCM remain unclear.Therefore,we aimed to explore the effects of GM-related genes on survival,clinicopathological characteristics,and the tumor microenvironment in SKCM.In this study,682 SKCM samples were obtained from the Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.Consensus clustering was used to classify SKCM samples into distinct subtypes based on 41 GM-related genes.Differences in survival,immune infiltration,clinical characteristics,and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathways as well as differentially expressed genes(DEGs)between subgroups were evaluated.A prognostic model was constructed according to prognostic DEGs.Differential analyses in survival,immune infiltration,tumor microenvironment(TME),tumor mutation burden(TMB),stemness,and drug sensitivity between risk groups were conducted.We identified two distinct GM-related subtypes on SKCM and found that GM-related gene alterations were associated with survival probability,clinical features,biological function,and immune infiltration.Then a risk model based on six DEGs(IL18,SEMA6A,PAEP,TNFRSF17,AIM2,and CXCL10)was constructed and validated for predicting overall survival in SKCM patients.The results showed that the risk score was negatively correlated with CD8+T cells,activated CD4+memory T cells,M1 macrophages,andγδT cells.The group with a low-risk score was accompanied by a better survival rate with higher TME scores and lower stemness index.Moreover,the group with high-and low-risk score had a significant difference with the sensitivity of 75 drugs(p<0.001).Overall,distinct subtypes in SKCM patients based on GM-related genes were identified and the risk model was constructed,which might contribute to prognosis prediction,guide clinical therapy,and develop novel therapeutic strategies.