Cancer pain is one of the most prevalent and debilitating symptoms in patients with advanced malignancies,arising from multifactorial mechanisms involving peripheral,central,and systemic pathways.Conventional analgesi...Cancer pain is one of the most prevalent and debilitating symptoms in patients with advanced malignancies,arising from multifactorial mechanisms involving peripheral,central,and systemic pathways.Conventional analgesics,including opioids and nonsteroidal anti-inflammatory drugs,are often limited by their insufficient efficacy,tolerance,and risk of dependence.Traditional Chinese Medicine(TCM),characterized by its multi-component,multi-target,and systemic regulatory properties,has shown promising potential in cancer pain management.This review provides a comprehensive overview of the clinical classification and underlying mechanisms of cancer pain(including nerve infiltration,dysregulation of inflammatory mediators and ion channels,central sensitization,neuro-immune crosstalk,metabolic reprogramming,and gut-brain axis impairment),as well as the analgesic effects of representative TCM agents in cancer pain management.For example,bioactive components such as tetrahydroberberine,levo-tetrahydropalmatine,and piperine exert analgesic effects,thereby improving the quality of life of patients by inhibiting inflammatory cascades,regulating neurotransmitter systems,and preserving neural integrity.Commonly used preclinical models,including bone cancer pain,pancreatic cancer pain,and chemotherapy-induced peripheral neuropathy models,are summarized for their utility in mechanistic studies and efficacy evaluations.This review also discusses the current limitations of clinical evidence,such as small sample sizes,short follow-up periods,and limited translation from animal models,alongside major challenges in standardization,mechanistic elucidation,and clinical trial design.Future directions should focus on precise pain phenotyping,integrated multi-target interventions,rigorous efficacy safety validation,and innovations in drug delivery to facilitate the standardization and global adoption of TCM in cancer pain management.展开更多
Cancer continues to pose a formidable challenge in global health,with conventional treatments such as chemotherapy and radiotherapy often resulting in severe toxicities that significantly degrade patients’quality of ...Cancer continues to pose a formidable challenge in global health,with conventional treatments such as chemotherapy and radiotherapy often resulting in severe toxicities that significantly degrade patients’quality of life and restrict therapeutic outcomes.Addressing this pressing issue,this review presents a thorough and systematic analysis of innovative and emerging strategies designed to minimize the toxicity induced by treatment,while maintaining or even enhancing antitumor efficacy.The focus is on six promising therapeutic approaches:combination therapies utilizing natural bioactive products,molecularly targeted therapies,immunotherapies,nanotechnology-mediated drug delivery systems,adjunct traditional Chinese medicine interventions,and low-dose spatiotemporally concerted regimens.Each approach employs unique mechanisms—such as enhanced targeting precision,immune system activation,tumor microenvironment reprogramming,and multi-component synergistic effects—to mitigate damage to normal tissues and reduce systemic adverse reactions.Despite promising preclinical and clinical advancements,several challenges persist,including drug resistance,high economic costs,a lack of reliable predictive biomarkers,and complexities in clinical translation and regulatory approval.Looking ahead,the incorporation of artificial intelligence,multi-omics profiling,and novel biomimetic nanotechnologies offers unprecedented opportunities for developing highly personalized,low-toxicity treatment frameworks.This review highlights a fundamental shift in oncology towards precision medicine that balances efficacy with safety,demonstrating the transformative potential of these strategies in shaping the future of cancer therapy and enhancing patient care globally.展开更多
Background:In clinical practice,approximately 80%of prostate cancer(PC)cases are localized and can achieve favorable outcomes with appropriate treatment.Conversely,some remaining cases exhibit an aggressive phenotype ...Background:In clinical practice,approximately 80%of prostate cancer(PC)cases are localized and can achieve favorable outcomes with appropriate treatment.Conversely,some remaining cases exhibit an aggressive phenotype or develop resistance to therapeutic interventions,leading to tumor metastasis and a poorer prognosis.When PC metastasizes to distant sites,the bone remains the predominant location,and brain metastases are regarded as exceedingly rare.Case Description:The current study focused on a rare clinical PC case that presented multiple brain metastases after prostate surgery.The patient was initially diagnosed with PC through prostate biopsy and subsequently underwent prostate debulking surgery while continuing androgen deprivation therapy,which maintained low prostatespecific antigen(PSA)levels for 4 years.However,a sudden PSA surge to 7.858 ng/mL led to the emergence of two brain metastatic tumors,which were confirmed to have originated from the prostate.Conclusions:Patients with advanced PC require comprehensive evaluations to detect rare metastatic sites,such as the brain,to avoid missed diagnoses.For patients with brain metastases,a multimodal approach combining surgical resection,postoperative radiotherapy,and endocrine therapy can effectively alleviate symptoms and enhance survival.展开更多
Colorectal cancer remains one of the leading causes of morbidity and mortality worldwide.Despite notable advances in early detection and therapeutic strategies,the molecular mechanisms underlying tumor survival,chemot...Colorectal cancer remains one of the leading causes of morbidity and mortality worldwide.Despite notable advances in early detection and therapeutic strategies,the molecular mechanisms underlying tumor survival,chemotherapy resistance,and metastasis are not yet fully understood.MicroRNAs(miRNAs)have emerged as pivotal regulators of cancer development,as they modulate gene expression and orchestrate key signaling pathways.However,the epigenetic mechanisms that control miRNA expression and their downstream gene targets remain largely unclear.In this review,we highlight the critical role of the colorectal cancer microenvironment in influencing miRNA expression and discuss how this regulation contributes to tumorigenesis.A better understanding of these processes may lead to the identification of novel therapeutic targets and strategies to prevent recurrence.展开更多
Lung cancer is the most common but fatal malignant tumor worldwide.Patients with lung cancer experienced a relatively low 5-year overall survival rate,and issues such as metastasis and drug resistance remain prominent...Lung cancer is the most common but fatal malignant tumor worldwide.Patients with lung cancer experienced a relatively low 5-year overall survival rate,and issues such as metastasis and drug resistance remain prominent challenges in its clinical management.Neddylation,a novel type of post-translational modification,was overactivated in lung cancer and was closely associated with its occurrence,development,metastasis,and drug resistance.This review systematically summarizes the biological process of neddylation and deeply explores the latest research progress on how neddylation affects lung cancer cell proliferation,metastasis,and drug resistance mechanisms,with a focus on its regulation of key molecules such as Cullin-RING E3 ligases and the SCCRO family.Meanwhile,it concludes the current advances in potential therapeutic agents targeting neddylation-related targets,including small-molecule compounds(such as Pevonedistat)and natural extracts(such as arctigenin).Finally,the review prospectively evaluates the application potential and questions requiring further exploration of neddylation in lung cancer treatment.In conclusion,we aim to systematically summarize the biological process of neddylation,critically explore its roles in lung cancer proliferation,metastasis,and drug resistance,and evaluate the therapeutic potential of neddylation-targeting agents.展开更多
Realistic models for cancer research representing disease progression that commensurately respond to therapeutics consistent with clinical observation are the holy grail for pre-clinical research and screening.Althoug...Realistic models for cancer research representing disease progression that commensurately respond to therapeutics consistent with clinical observation are the holy grail for pre-clinical research and screening.Although such an ideal is elusive,well-characterized in vivo models facilitate our understanding of disease,progression,and therapeutic opportunities.Here,we characterize a commonly used syngeneic BALB/c mouse model of triple negative breast cancer(4T1)after establishing tumors in their flanks.Tumors developed at the subcutaneous injection site for all experimental mice and their volumes were monitored.We quantified a rare subset of breast cancer stemlike cells(CSCs),classified as CD44^(+)/CD24^(−)phenotypes in in vitro and ex vivo cell populations.Chromosome numbers in ex vivo metaphase cells were greater than cells cultured in vitro(89.4±3.4,range of 70-132 and 82.6±1.1,range of 70-128;respectively).Further,we observed different types of chromosome aberrations,including gap,deletion,exchange,interstitial deletion,terminal deletion,ring,dicentric,and Robertsonian translocations.For both sources of cells,the number of aberrations was dominated by deletions,terminal deletions,and Robertsonian translocations.Ex vivo cells exhibited greater prevalence of deletions and terminal deletions,whereas in vitro cells displayed more ring aberrations and Robertsonian translocations.In conclusion,we successfully characterized cancer cells from a syngeneic mouse model of breast cancer in terms of rare CSC proportion and a variety of chromosomal aberrations,which is useful for understanding tumor traits associated with cancer development and therapeutic action.The data act as a valuable resource for other studies using the 4T1 BALB/c model.展开更多
BACKGROUND Gastric cancer(GC)is one of the most common malignant tumors of the digestive system worldwide,the prognosis of patients with advanced GC remains poor.AIM To evaluate the combined expression characteristics...BACKGROUND Gastric cancer(GC)is one of the most common malignant tumors of the digestive system worldwide,the prognosis of patients with advanced GC remains poor.AIM To evaluate the combined expression characteristics of cancer stem cell markers CD24 and CD133 in GC pathological tissues,and to explore their association with patients’clinicopathological parameters and postoperative survival outcomes.METHODS A total of 304 GC patients who underwent surgical treatment in our hospital from January 2018 to January 2020 were retrospectively included.Immunohistochemistry was used to detect the protein expression of CD24 and CD133 in tumor tissues,adjacent tissues,and normal gastric mucosa tissues.Based on staining intensity and the proportion of positive cells,expression levels were classified into low and high expression,while clinicopathological parameters were recorded.χ2 test was used to evaluate the correlation between expression and categorical variables,Spearman rank correlation analysis was performed to assess the correlation between the expression intensities of the two markers,and multivariate regression models were applied to identify independent risk factors influencing co-expression.Kaplan-Meier survival curves and Log-rank test were used to compare survival differences among groups with different expression patterns.RESULTS Among the 304 patients,155 cases(50.99%)were CD24 positive,including 91 low-expression and 64 highexpression;133 cases(43.75%)were CD133 positive,including 81 low-expression and 52 high-expression.There were 74 cases(24.34%)with double positivity and 81 cases(26.64%)with double negativity.Compared with tumor tissues,the positive rates of CD24 and CD133 in normal gastric tissues and adjacent tissues were significantly lower(P<0.05).Univariate analysis showed that co-expression of CD24 and CD133 in GC tissues was significantly correlated with tumor size,Lauren classification,T stage,N stage,and vascular invasion(P<0.05),but not with patient age,gender,tumor site,World Health Organization histological classification,or M stage(P>0.05).Further multivariate regression analysis suggested that tumor size,T stage,N stage,and vascular invasion were independent risk factors promoting CD24 and CD133 double positivity.Spearman rank correlation analysis indicated a moderate positive correlation between their expression intensities(r=0.420,P<0.001).During follow-up,29 of 304 patients were lost(loss rate 9.54%);146 deaths occurred.According to expression combination,there were 89 cases of CD24 single positivity(39 deaths),68 cases of CD133 single positivity(31 deaths),81 cases of double negativity(25 deaths),and 66 cases of double positivity(51 deaths).Log-rank test showed significant differences in overall survival among the four groups(χ2=20.89,P<0.001),with CD24+/CD133+group showing the worst prognosis.CONCLUSION CD24 and CD133 exhibit high positive detection rates in GC tissues,and their co-positivity is closely associated with tumor stage progression and significantly indicates unfavorable survival outcomes.The co-expression of CD24/CD133 may reflect higher aggressiveness and metastatic potential of GC,serving as a potential prognostic marker and a direction for targeted therapeutic strategies.However,as this is a single-center retrospective study with limitations such as patient loss to follow-up and sample size,further prospective,multicenter,and mechanistic studies are required to validate its clinical applicability and biological role.展开更多
BACKGROUND Esophageal cancer is highly malignant and frequently metastasizes to bones.Concomitant depression worsens prognosis;however,its incidence and determinants in this specific population remain poorly defined.A...BACKGROUND Esophageal cancer is highly malignant and frequently metastasizes to bones.Concomitant depression worsens prognosis;however,its incidence and determinants in this specific population remain poorly defined.AIM To determine the incidence of depression and its independent risk factors in patients with esophageal cancer and bone metastasis.METHODS A total of 100 consecutive eligible patients admitted between March 2022 and March 2025 were recruited.Depression was assessed with the Beck Depression Inventory-II;scores>4 defined the depression group(n=42)and scores≤4 the non-depression group(n=58).Demographic,clinical,and laboratory variables were compared between the groups.Multivariate logistic regression was used to identify independent risk factors.RESULTS Depression prevalence was 42.0%(42/100).Univariate analysis demonstrated significant differences in monthly per-capita household income,education level,social support,sleep disorders,and serum high-sensitivity C-reactive protein(all P<0.05);no differences were observed in sex,age,tumor characteristics,or other laboratory indices(all P>0.05).Multivariable analysis revealed the following independent risk factors for depression:Low income[odds ratio(OR)=2.66,95%confidence interval(CI):1.17-6.03],low education(OR=2.46,95%CI:1.08-5.61),low social support(OR=5.10,95%CI:1.81-14.39),sleep disorders(OR=2.79,95%CI:1.23-6.35),and elevated high-sensitivity C-reactive protein(OR=1.31 per unit increase,95%CI:1.18-1.46).CONCLUSION Depression is common among patients with esophageal cancer and bone metastasis.Low socioeconomic status,limited education,insufficient social support,sleep disturbances,and systemic inflammation were independent predictors.Interventions that address these modifiable factors may reduce depression risk in this population.展开更多
The last research focuses on the role of exosomes in cancer treatment.Exosomes are extracellular vesicles.They can be secreted by cancer cells,and they can modulate chemotherapy sensitivity.Determining exosomal conten...The last research focuses on the role of exosomes in cancer treatment.Exosomes are extracellular vesicles.They can be secreted by cancer cells,and they can modulate chemotherapy sensitivity.Determining exosomal content opens the possibility for guiding treatment strategies for cancer diseases.Exosomal microRNA are considered one of the prime candidates for exosomal biomarkers.Exosomal circular RNAs represent excellent biomarkers for liquid biopsy because of their stability in many types of cancer.Exosomal proteins remain reliable biomarkers also.Exosomes have emerged as promising therapeutic candidates.Their biological properties render them ideal vectors for drug delivery.Genetic modification of exosomes is an effective way to deliver material capable of modulating cellular pathways involved in drug resistance.Furthermore,exosomes have been explored as carriers for metal-chelating agents.Integrating exosome-based therapies with traditional anticancer agents aims to exploit the natural targeting abilities of exosomes to enhance drug delivery.Despite the dynamic development of this field,many mechanisms of exosome action remain incompletely understood.Therefore,it is necessary to conduct further studies that will allow for a better understanding of their role in the process of resistance and will enable the development of effective therapeutic strategies.展开更多
Objectives:Tamoxifen is a key drug that provides endocrine therapy for estrogen receptor(ER)α-positive breast cancer;however,resistance remains a significant clinical challenge.This study aims to investigate the mole...Objectives:Tamoxifen is a key drug that provides endocrine therapy for estrogen receptor(ER)α-positive breast cancer;however,resistance remains a significant clinical challenge.This study aims to investigate the molecular mechanisms of tamoxifen resistance in ERα-positive breast cancer,with particular focus on the role of SET Domain Containing 1A(SETD1A)-driven forkhead box A2(FOXA2)as a key regulator of this resistance.Methods:FOXA2 expression and its regulation by SETD1A were assessed via(quantitative polymerase chain reaction),western blotting,transcriptome profiling,and chromatin immunoprecipitation analyses.The effects of FOXA2 on cell proliferation,migration,invasion,and cancer stem cell traits were evaluated using small interfering RNA(siRNA)-mediated silencing.Clinical relevance was examined by analyzing patient datasets and tumor tissue microarrays.Results:FOXA2 expression was significantly elevated in tamoxifen-resistant(TamR)and ERα-negative breast cancer cells compared to that in ERα-positive MCF-7 cells,regardless of tamoxifen treatment or ERαdepletion.Transcriptome and chromatin immunoprecipitation analyses revealed that SETD1A,a histone methyltransferase,directly regulated FOXA2 expression.Functionally,FOXA2 knockdown inhibited the proliferation,migration,invasion,and cancer stem cell properties of TamR cells while restoring tamoxifen sensitivity.High FOXA2 expression was correlated with poor survival and reduced responsiveness to tamoxifen in patients with ER-positive breast cancer.Conclusion:Our findings identified FOXA2 as a key mediator of tamoxifen resistance regulated by SETD1A and suggested that targeting the SETD1A-FOXA2 axis may offer a novel strategy for overcoming endocrine resistance in breast cancer.展开更多
Background:Minimally invasive distal pancreatectomy(MIDP)is increasingly being used,although its oncologic safety for pancreatic ductal adenocarcinoma(PDAC)remains controversial.In Japan,MIDP for PDAC has limited endo...Background:Minimally invasive distal pancreatectomy(MIDP)is increasingly being used,although its oncologic safety for pancreatic ductal adenocarcinoma(PDAC)remains controversial.In Japan,MIDP for PDAC has limited endorsement due to insufficient data.This study aimed to compare the perioperative and long-term outcomes of open distal pancreatectomy(ODP)and MIDP for PDAC.Methods:We retrospectively analyzed patients with resectable pancreatic body and tail cancer treated with ODP or MIDP(laparoscopic or robotic)between January 2007 and July 2022.The surgical procedures(ODP and MIDP)were compared and the patient characteristics,perioperative outcomes,and long-term outcomes were analyzed.We also compared the outcomes of patients with neoadjuvant chemotherapy(NAC)and without NAC.Results:A total of 72 distal pancreatectomies were performed(37 ODPs and 35 MIDPs).In the upfront group,MIDP resulted in significantly less blood loss than ODP(P<0.01),despite similar operative time.There was no statistically significant difference in the 2-year recurrence-free survival(RFS)rates between ODP and MIDP(39.7%vs.57.8%,P=0.60)or in the overall survival(OS)rates(66.7%vs.74.1%,P=0.43).Similarly,in the NAC group,MIDP resulted in significantly less blood loss than ODP(P=0.01);ODP and MIDP had similar 2-year RFS rates(41.7%and 60.0%,P=0.75)and OS rates(50.0%and 70.0%,P=0.36).The interval from surgery to adjuvant chemotherapy initiation did not significantly differ between the ODP and MIDP subgroups in both the upfront group(P=0.13)and the NAC group(P=0.14).The incidence of recurrence was 64.8%for ODP and 42.8%for MIDP(P=0.06).Both procedures showed similar distributions of local and distant recurrence.Conclusions:MIDP caused less blood loss and had similar oncologic safety compared with ODP.MIDP could become a feasible,minimally invasive option with sufficient oncologic safety for pancreatic body and tail cancers.展开更多
BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes...BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment.展开更多
Naphthalene,anthracene and pyridone endoperoxides are known to thermally release singlet oxygen.However,in the cycloreversion reaction,singlet oxygen is produced stoichiometrically;therefore,multiple singlet oxygen re...Naphthalene,anthracene and pyridone endoperoxides are known to thermally release singlet oxygen.However,in the cycloreversion reaction,singlet oxygen is produced stoichiometrically;therefore,multiple singlet oxygen releasing modules are expected to be very useful in inducing apoptosis of cancer cells.Herein,we present a potential therapeutic agent presenting three-pyridone endoperoxide modules and a mitochondria targeting group.Compared to previously reported pyridone-based monofunctional endoperoxides,the triple endoperoxide is highly effective as evidenced by assays and fluorescence microscopy.展开更多
Poly(ADP-ribose)polymerase(PARP)is a family of proteins that play a crucial role in diverse cellular processes,including DNA repair,cell death,and changes in chromatin structure.PARP inhibitors(PARPi)have been recogni...Poly(ADP-ribose)polymerase(PARP)is a family of proteins that play a crucial role in diverse cellular processes,including DNA repair,cell death,and changes in chromatin structure.PARP inhibitors(PARPi)have been recognized as notable agents in the realm of anticancer therapeutics owing to their capacity to specifically impact DNA repair pathways,thereby inducing targeted death of cancerous cells,particularly in cancers with homologous recombination deficiency(HRD).These inhibitors have been approved for the treatment of several cancers,such as ovarian,breast,and pancreatic cancers.Despite their promising therapeutic attributes,developing resistance to PARPi presents a formidable obstacle,curtailing their overall efficacy.This article presents a comprehensive description of the potential mechanisms related to PARPi resistance,an in-depth study of potential strategies to overcome resistance,and an assessment of the therapeutic potential of the PARPi in combination with alternative therapies.展开更多
Breast cancer is one of the most prevalent malignancies among women and comprises a heterogeneous spectrum of molecular subtypes with distinct biological behaviors.Among various regulatory molecules,sphingolipids play...Breast cancer is one of the most prevalent malignancies among women and comprises a heterogeneous spectrum of molecular subtypes with distinct biological behaviors.Among various regulatory molecules,sphingolipids play pivotal roles in dynamically modulating fundamental cellular processes such as proliferation,apoptosis,and metastasis through metabolic interconversions,including phosphorylation,glycosylation,and the generation of sphingosine-1-phosphate.This review aims to elucidate the mechanisms through which sphingolipid metabolism orchestrates cancer cell fate and drives breast cancer progression.Particular emphasis is placed on the balance between proapoptotic ceramides and pro-survival metabolites,such as sphingosine-1-phosphate,which collectively influence tumor growth and the therapeutic response.Additional sphingolipid species,including glucosylceramide and gangliosides(GD2,GD3,GM1,and GM3),have also been implicated in promoting breast cancer development.Furthermore,sphingolipid-based therapeutic strategies,including immunotherapy and antibody therapy,are discussed.By providing a comprehensive overview of sphingolipid metabolism,this review aims to identify novel therapeutic targets that may help overcome treatment resistance and improve clinical outcomes in breast cancer.展开更多
Objectives:Breast cancer(BC)is the leading cause of cancer-related mortality in women,largely due to metastasis.This study aims to explore the role of purine nucleoside phosphorylase(PNP),a key enzyme in purine metabo...Objectives:Breast cancer(BC)is the leading cause of cancer-related mortality in women,largely due to metastasis.This study aims to explore the role of purine nucleoside phosphorylase(PNP),a key enzyme in purine metabolism,in the aggressiveness and metastatic behavior of BC.Methods:A comprehensive analysis was performed using in silico transcriptomic data(n=2509 patients),immunohistochemical profiling of BC tissues(n=103),and validation through western blotting in multiple BC cell lines.Gene expression and survival analyses were conducted using Tumor Immune Estimation Resource(TIMER),Gene Expression Profiling Interactive Analysis 2(GEPIA2),and the cBioPortal for cancer genomics(cBioPortal)platforms.Correlations between PNP and key epithelial–mesenchymal transition(EMT)markers,molecular subtypes,tumor grades,and stages were examined.Results:PNP was significantly overexpressed in human epidermal growth factor receptor 2(HER-2)-positive and triple-negative BCs compared to luminal subtypes.High PNP levels were strongly associated with advanced BC stages,high-grade tumors,EMT phenotypes,and poor overall survival.Notably,HER-2 inhibition suppressed PNP expression,while PNP gene silencing induced HER-2 upregulation,revealing a reciprocal regulatory loop.Dual inhibition of PNP and HER-2 resulted in a significant reduction in cell viability compared to HER-2 inhibition alone.Conclusion:Collectively,PNP emerges as a promising biomarker of BC aggressiveness and progression.Its reciprocal interaction with HER-2 underscores its potential as a therapeutic target.Dual targeting of PNP and HER-2 may offer a novel strategy for improving outcomes in aggressive BC subtypes.展开更多
Objective:To investigate the expression of pyruvate kinase M2(PKM2)and RNA binding proteins 1(SERBP1)in colorectal cancer(CRC)and their clinical significance.Methods:A total of 101 cases of colorectal adenocarcinoma t...Objective:To investigate the expression of pyruvate kinase M2(PKM2)and RNA binding proteins 1(SERBP1)in colorectal cancer(CRC)and their clinical significance.Methods:A total of 101 cases of colorectal adenocarcinoma tissues and their corresponding adjacent tissues were collected from our hospital from December 2020 to December 2023.The immunohistochemical Elivision method was used to detect the expression of PKM2 and SERBP1 in CRC and corresponding adjacent tissues.The experimental data were analyzed using statistical software SPSS 27.0.Results:The expression rates of PKM2 and SERBP1 in CRC were higher than those in adjacent tissues.The expression of PKM2 was positively correlated with lymph node metastasis and TNM stage.The expression of SERBP1 was positively correlated with the degree of differentiation,lymph node metastasis,and TNM stage of CRC.Conclusion:PKM2 and SERBP1 may promote the occurrence and tumor progression of CRC,but further experimental research is still needed.展开更多
Background:Although light-intensity physical activity(LPA)has been suggested to be associated with a lower risk of mortality,the minimal and optimal volumes of LPA remain unclear.We aimed to examine the minimal and op...Background:Although light-intensity physical activity(LPA)has been suggested to be associated with a lower risk of mortality,the minimal and optimal volumes of LPA remain unclear.We aimed to examine the minimal and optimal volumes of LPA associated with the risks of mortality and disease incidence(i.e.,cardiovascular diseases and cancer).Methods:Data were derived from the population-based UK Biobank cohort study,including 69,492 adults aged 43-78 years.Accelerometermeasured LPA was defined using a validated,published machine learning-based Random Forest activity method,which was categorized into 4 quartile groups.All-cause and cause-specific mortality(cardiovascular disease-and cancer-specific)were determined according to the International Classification of Diseases,10th version codes.Disease incidence was defined based on primary care,hospitalization,or death records.Results:During a median follow-up period of 8.04 years,2024 adults died from all causes,539 from cardiovascular disease,and 1175 from cancer.For all-cause mortality,compared with participants in the lowest quartile of LPA(<3.9 h/day),the hazard ratios(HRs)and 95%confidence intervals(95%CIs)were 0.82(95%CI:0.73-0.93)for those with 3.9 to<5.0 h/day,0.75(95%CI:0.66-0.85)for those with 5.0 to<6.1 h/day,and 0.77(95%CI:0.68-0.88)for those with≥6.1 h/day,respectively.There was an inverse non-linear dose-response association between LPA and all-cause mortality,with an optimal dose of 5.72 h/day(95%CI:5.45-6.41;HR=0.63,95%CI:0.56-0.71)and a minimal dose of 3.59 h/day(95%CI:3.53-8.56;HR=0.81,95%CI:0.78-0.86),with the 5th percentile as the reference.Similar patterns were observed for cause-specific mortality and disease incidence(cardiovascular disease and cancer).Conclusion:Engaging in LPA for~3.5 h/day was conservatively associated with lower risk of mortality and disease incidence,with further risk reductions observed up to an optimal dose of~6.0 h/day.These findings suggest that sufficient LPA offers important health benefits,which can inform the development of future PA guidelines.展开更多
Breast cancer(BRCA)is characterized by high heterogeneity,with aggressive subtypes frequently showing poor prognosis and resistance to conventional therapies,making the discovery of new therapeutic targets and strateg...Breast cancer(BRCA)is characterized by high heterogeneity,with aggressive subtypes frequently showing poor prognosis and resistance to conventional therapies,making the discovery of new therapeutic targets and strategies imperative.Although elevated expression of discs large homolog 3(DLG3)has been reported in BRCA,its functional role in disease progression remains unclear.We performed bioinformatic analyses of clinical datasets to evaluate the prognostic significance of DLG3 expression in BRCA patients.In vitro gain-and loss-of-function experiments were conducted to assess the impact of DLG3 on BRCA cell proliferation,migration,and colony formation.Transcriptomic profiling,coupled with pharmacological inhibition,was employed to identify and validate downstream signaling pathways.Additionally,we extended our validation to an in vivo model to assess the role of DLG3 in tumor progression.We found that elevated DLG3 levels correlated with poor prognosis in breast cancer patients.Functionally,DLG3 overexpression significantly promoted cell proliferation and migration in estrogen receptor-positive MCF7 and triple-negative MDA-MB-231 breast cancer cells,whereas its knockdown suppressed these effects.Transcriptomic analyses revealed that DLG3 activates signal transducer and activator of transcription 3(STAT3)signaling,a finding further corroborated by Western blot.Critically,treatment with the STAT3 inhibitor Stattic attenuated DLG3-driven proliferation and migration,supporting a DLG3-STAT3 oncogenic axis.Furthermore,in vivo studies validated the role of DLG3 in promoting tumor growth and its correlation with elevated STAT3 signaling,consistent with our in vitro findings.Our findings establish DLG3 as a novel driver of breast cancer progression that directly activates STAT3 signaling.DLG3 thus represents both a potential prognostic biomarker and a promising therapeutic target for aggressive breast cancer subtypes,including triple-negative breast cancer.展开更多
Background:Stomach cancer(SC)is one of the most lethal malignancies worldwide due to late-stage diagnosis and limited treatment.The transcriptomic,epigenomic,and proteomic,etc.,omics datasets generated by high-through...Background:Stomach cancer(SC)is one of the most lethal malignancies worldwide due to late-stage diagnosis and limited treatment.The transcriptomic,epigenomic,and proteomic,etc.,omics datasets generated by high-throughput sequencing technology have become prominent in biomedical research,and they reveal molecular aspects of cancer diagnosis and therapy.Despite the development of advanced sequencing technology,the presence of high-dimensionality in multi-omics data makes it challenging to interpret the data.Methods:In this study,we introduce RankXLAN,an explainable ensemble-based multi-omics framework that integrates feature selection(FS),ensemble learning,bioinformatics,and in-silico validation for robust biomarker detection,potential therapeutic drug-repurposing candidates’identification,and classification of SC.To enhance the interpretability of the model,we incorporated explainable artificial intelligence(SHapley Additive exPlanations analysis),as well as accuracy,precision,F1-score,recall,cross-validation,specificity,likelihood ratio(LR)+,LR−,and Youden index results.Results:The experimental results showed that the top four FS algorithms achieved improved results when applied to the ensemble learning classification model.The proposed ensemble model produced an area under the curve(AUC)score of 0.994 for gene expression,0.97 for methylation,and 0.96 for miRNA expression data.Through the integration of bioinformatics and ML approach of the transcriptomic and epigenomic multi-omics dataset,we identified potential marker genes,namely,UBE2D2,HPCAL4,IGHA1,DPT,and FN3K.In-silico molecular docking revealed a strong binding affinity between ANKRD13C and the FDA-approved drug Everolimus(binding affinity−10.1 kcal/mol),identifying ANKRD13C as a potential therapeutic drug-repurposing target for SC.Conclusion:The proposed framework RankXLAN outperforms other existing frameworks for serum biomarker identification,therapeutic target identification,and SC classification with multi-omics datasets.展开更多
基金supported by the National Natural Science Foundation of China(No.82360238,82071245)。
文摘Cancer pain is one of the most prevalent and debilitating symptoms in patients with advanced malignancies,arising from multifactorial mechanisms involving peripheral,central,and systemic pathways.Conventional analgesics,including opioids and nonsteroidal anti-inflammatory drugs,are often limited by their insufficient efficacy,tolerance,and risk of dependence.Traditional Chinese Medicine(TCM),characterized by its multi-component,multi-target,and systemic regulatory properties,has shown promising potential in cancer pain management.This review provides a comprehensive overview of the clinical classification and underlying mechanisms of cancer pain(including nerve infiltration,dysregulation of inflammatory mediators and ion channels,central sensitization,neuro-immune crosstalk,metabolic reprogramming,and gut-brain axis impairment),as well as the analgesic effects of representative TCM agents in cancer pain management.For example,bioactive components such as tetrahydroberberine,levo-tetrahydropalmatine,and piperine exert analgesic effects,thereby improving the quality of life of patients by inhibiting inflammatory cascades,regulating neurotransmitter systems,and preserving neural integrity.Commonly used preclinical models,including bone cancer pain,pancreatic cancer pain,and chemotherapy-induced peripheral neuropathy models,are summarized for their utility in mechanistic studies and efficacy evaluations.This review also discusses the current limitations of clinical evidence,such as small sample sizes,short follow-up periods,and limited translation from animal models,alongside major challenges in standardization,mechanistic elucidation,and clinical trial design.Future directions should focus on precise pain phenotyping,integrated multi-target interventions,rigorous efficacy safety validation,and innovations in drug delivery to facilitate the standardization and global adoption of TCM in cancer pain management.
文摘Cancer continues to pose a formidable challenge in global health,with conventional treatments such as chemotherapy and radiotherapy often resulting in severe toxicities that significantly degrade patients’quality of life and restrict therapeutic outcomes.Addressing this pressing issue,this review presents a thorough and systematic analysis of innovative and emerging strategies designed to minimize the toxicity induced by treatment,while maintaining or even enhancing antitumor efficacy.The focus is on six promising therapeutic approaches:combination therapies utilizing natural bioactive products,molecularly targeted therapies,immunotherapies,nanotechnology-mediated drug delivery systems,adjunct traditional Chinese medicine interventions,and low-dose spatiotemporally concerted regimens.Each approach employs unique mechanisms—such as enhanced targeting precision,immune system activation,tumor microenvironment reprogramming,and multi-component synergistic effects—to mitigate damage to normal tissues and reduce systemic adverse reactions.Despite promising preclinical and clinical advancements,several challenges persist,including drug resistance,high economic costs,a lack of reliable predictive biomarkers,and complexities in clinical translation and regulatory approval.Looking ahead,the incorporation of artificial intelligence,multi-omics profiling,and novel biomimetic nanotechnologies offers unprecedented opportunities for developing highly personalized,low-toxicity treatment frameworks.This review highlights a fundamental shift in oncology towards precision medicine that balances efficacy with safety,demonstrating the transformative potential of these strategies in shaping the future of cancer therapy and enhancing patient care globally.
基金supported by the National Natural Science Foundation[Grant Number:82102788]Anhui Province Key Project for Clinical Medical Research Translation and Advancement[202204295107020031,202204295107020007]Anhui Provincial University Excellent Scientific Research and Innovation Team Project[2022AH010071].
文摘Background:In clinical practice,approximately 80%of prostate cancer(PC)cases are localized and can achieve favorable outcomes with appropriate treatment.Conversely,some remaining cases exhibit an aggressive phenotype or develop resistance to therapeutic interventions,leading to tumor metastasis and a poorer prognosis.When PC metastasizes to distant sites,the bone remains the predominant location,and brain metastases are regarded as exceedingly rare.Case Description:The current study focused on a rare clinical PC case that presented multiple brain metastases after prostate surgery.The patient was initially diagnosed with PC through prostate biopsy and subsequently underwent prostate debulking surgery while continuing androgen deprivation therapy,which maintained low prostatespecific antigen(PSA)levels for 4 years.However,a sudden PSA surge to 7.858 ng/mL led to the emergence of two brain metastatic tumors,which were confirmed to have originated from the prostate.Conclusions:Patients with advanced PC require comprehensive evaluations to detect rare metastatic sites,such as the brain,to avoid missed diagnoses.For patients with brain metastases,a multimodal approach combining surgical resection,postoperative radiotherapy,and endocrine therapy can effectively alleviate symptoms and enhance survival.
文摘Colorectal cancer remains one of the leading causes of morbidity and mortality worldwide.Despite notable advances in early detection and therapeutic strategies,the molecular mechanisms underlying tumor survival,chemotherapy resistance,and metastasis are not yet fully understood.MicroRNAs(miRNAs)have emerged as pivotal regulators of cancer development,as they modulate gene expression and orchestrate key signaling pathways.However,the epigenetic mechanisms that control miRNA expression and their downstream gene targets remain largely unclear.In this review,we highlight the critical role of the colorectal cancer microenvironment in influencing miRNA expression and discuss how this regulation contributes to tumorigenesis.A better understanding of these processes may lead to the identification of novel therapeutic targets and strategies to prevent recurrence.
基金supported by the National Natural Science Foundation of China(No.82574683)the National Natural Science Foundation of Science and Technology Department of Sichuan Province(Nos.2023NSFSC1928 and 2023NSFSC1992)+2 种基金Project of State Administration of Traditional Chinese Medicine of China(No.ZYYCXTD-D-202209)Project of Sichuan Provincial Administration of Traditional Chinese Medicine(No.2022C001)Fundamental Research Funds for the Central Universities(No.YJ201880).
文摘Lung cancer is the most common but fatal malignant tumor worldwide.Patients with lung cancer experienced a relatively low 5-year overall survival rate,and issues such as metastasis and drug resistance remain prominent challenges in its clinical management.Neddylation,a novel type of post-translational modification,was overactivated in lung cancer and was closely associated with its occurrence,development,metastasis,and drug resistance.This review systematically summarizes the biological process of neddylation and deeply explores the latest research progress on how neddylation affects lung cancer cell proliferation,metastasis,and drug resistance mechanisms,with a focus on its regulation of key molecules such as Cullin-RING E3 ligases and the SCCRO family.Meanwhile,it concludes the current advances in potential therapeutic agents targeting neddylation-related targets,including small-molecule compounds(such as Pevonedistat)and natural extracts(such as arctigenin).Finally,the review prospectively evaluates the application potential and questions requiring further exploration of neddylation in lung cancer treatment.In conclusion,we aim to systematically summarize the biological process of neddylation,critically explore its roles in lung cancer proliferation,metastasis,and drug resistance,and evaluate the therapeutic potential of neddylation-targeting agents.
基金National Research,Development and Innovation Fund of the Ministry of Culture and Innovation under the National Laboratories Program(National Tumor Biology Laboratory,Grant/Award Number:2022-2.1.1-NL-2022-00010)Senior Research Fellowship from National Health and Medical Research Council of Australia,Grant/Award Number:1156693+1 种基金Hungarian Thematic Excellence Program,Grant/Award Number:TKP2021-EGA-44Tour de Cure,Pioneering Grant,Grant/Award Number:RSP-253-18/19。
文摘Realistic models for cancer research representing disease progression that commensurately respond to therapeutics consistent with clinical observation are the holy grail for pre-clinical research and screening.Although such an ideal is elusive,well-characterized in vivo models facilitate our understanding of disease,progression,and therapeutic opportunities.Here,we characterize a commonly used syngeneic BALB/c mouse model of triple negative breast cancer(4T1)after establishing tumors in their flanks.Tumors developed at the subcutaneous injection site for all experimental mice and their volumes were monitored.We quantified a rare subset of breast cancer stemlike cells(CSCs),classified as CD44^(+)/CD24^(−)phenotypes in in vitro and ex vivo cell populations.Chromosome numbers in ex vivo metaphase cells were greater than cells cultured in vitro(89.4±3.4,range of 70-132 and 82.6±1.1,range of 70-128;respectively).Further,we observed different types of chromosome aberrations,including gap,deletion,exchange,interstitial deletion,terminal deletion,ring,dicentric,and Robertsonian translocations.For both sources of cells,the number of aberrations was dominated by deletions,terminal deletions,and Robertsonian translocations.Ex vivo cells exhibited greater prevalence of deletions and terminal deletions,whereas in vitro cells displayed more ring aberrations and Robertsonian translocations.In conclusion,we successfully characterized cancer cells from a syngeneic mouse model of breast cancer in terms of rare CSC proportion and a variety of chromosomal aberrations,which is useful for understanding tumor traits associated with cancer development and therapeutic action.The data act as a valuable resource for other studies using the 4T1 BALB/c model.
基金National Natural Science Foundation of China,No.82003223and China Postdoctoral Science Foundation,No.2020M671398.
文摘BACKGROUND Gastric cancer(GC)is one of the most common malignant tumors of the digestive system worldwide,the prognosis of patients with advanced GC remains poor.AIM To evaluate the combined expression characteristics of cancer stem cell markers CD24 and CD133 in GC pathological tissues,and to explore their association with patients’clinicopathological parameters and postoperative survival outcomes.METHODS A total of 304 GC patients who underwent surgical treatment in our hospital from January 2018 to January 2020 were retrospectively included.Immunohistochemistry was used to detect the protein expression of CD24 and CD133 in tumor tissues,adjacent tissues,and normal gastric mucosa tissues.Based on staining intensity and the proportion of positive cells,expression levels were classified into low and high expression,while clinicopathological parameters were recorded.χ2 test was used to evaluate the correlation between expression and categorical variables,Spearman rank correlation analysis was performed to assess the correlation between the expression intensities of the two markers,and multivariate regression models were applied to identify independent risk factors influencing co-expression.Kaplan-Meier survival curves and Log-rank test were used to compare survival differences among groups with different expression patterns.RESULTS Among the 304 patients,155 cases(50.99%)were CD24 positive,including 91 low-expression and 64 highexpression;133 cases(43.75%)were CD133 positive,including 81 low-expression and 52 high-expression.There were 74 cases(24.34%)with double positivity and 81 cases(26.64%)with double negativity.Compared with tumor tissues,the positive rates of CD24 and CD133 in normal gastric tissues and adjacent tissues were significantly lower(P<0.05).Univariate analysis showed that co-expression of CD24 and CD133 in GC tissues was significantly correlated with tumor size,Lauren classification,T stage,N stage,and vascular invasion(P<0.05),but not with patient age,gender,tumor site,World Health Organization histological classification,or M stage(P>0.05).Further multivariate regression analysis suggested that tumor size,T stage,N stage,and vascular invasion were independent risk factors promoting CD24 and CD133 double positivity.Spearman rank correlation analysis indicated a moderate positive correlation between their expression intensities(r=0.420,P<0.001).During follow-up,29 of 304 patients were lost(loss rate 9.54%);146 deaths occurred.According to expression combination,there were 89 cases of CD24 single positivity(39 deaths),68 cases of CD133 single positivity(31 deaths),81 cases of double negativity(25 deaths),and 66 cases of double positivity(51 deaths).Log-rank test showed significant differences in overall survival among the four groups(χ2=20.89,P<0.001),with CD24+/CD133+group showing the worst prognosis.CONCLUSION CD24 and CD133 exhibit high positive detection rates in GC tissues,and their co-positivity is closely associated with tumor stage progression and significantly indicates unfavorable survival outcomes.The co-expression of CD24/CD133 may reflect higher aggressiveness and metastatic potential of GC,serving as a potential prognostic marker and a direction for targeted therapeutic strategies.However,as this is a single-center retrospective study with limitations such as patient loss to follow-up and sample size,further prospective,multicenter,and mechanistic studies are required to validate its clinical applicability and biological role.
文摘BACKGROUND Esophageal cancer is highly malignant and frequently metastasizes to bones.Concomitant depression worsens prognosis;however,its incidence and determinants in this specific population remain poorly defined.AIM To determine the incidence of depression and its independent risk factors in patients with esophageal cancer and bone metastasis.METHODS A total of 100 consecutive eligible patients admitted between March 2022 and March 2025 were recruited.Depression was assessed with the Beck Depression Inventory-II;scores>4 defined the depression group(n=42)and scores≤4 the non-depression group(n=58).Demographic,clinical,and laboratory variables were compared between the groups.Multivariate logistic regression was used to identify independent risk factors.RESULTS Depression prevalence was 42.0%(42/100).Univariate analysis demonstrated significant differences in monthly per-capita household income,education level,social support,sleep disorders,and serum high-sensitivity C-reactive protein(all P<0.05);no differences were observed in sex,age,tumor characteristics,or other laboratory indices(all P>0.05).Multivariable analysis revealed the following independent risk factors for depression:Low income[odds ratio(OR)=2.66,95%confidence interval(CI):1.17-6.03],low education(OR=2.46,95%CI:1.08-5.61),low social support(OR=5.10,95%CI:1.81-14.39),sleep disorders(OR=2.79,95%CI:1.23-6.35),and elevated high-sensitivity C-reactive protein(OR=1.31 per unit increase,95%CI:1.18-1.46).CONCLUSION Depression is common among patients with esophageal cancer and bone metastasis.Low socioeconomic status,limited education,insufficient social support,sleep disturbances,and systemic inflammation were independent predictors.Interventions that address these modifiable factors may reduce depression risk in this population.
文摘The last research focuses on the role of exosomes in cancer treatment.Exosomes are extracellular vesicles.They can be secreted by cancer cells,and they can modulate chemotherapy sensitivity.Determining exosomal content opens the possibility for guiding treatment strategies for cancer diseases.Exosomal microRNA are considered one of the prime candidates for exosomal biomarkers.Exosomal circular RNAs represent excellent biomarkers for liquid biopsy because of their stability in many types of cancer.Exosomal proteins remain reliable biomarkers also.Exosomes have emerged as promising therapeutic candidates.Their biological properties render them ideal vectors for drug delivery.Genetic modification of exosomes is an effective way to deliver material capable of modulating cellular pathways involved in drug resistance.Furthermore,exosomes have been explored as carriers for metal-chelating agents.Integrating exosome-based therapies with traditional anticancer agents aims to exploit the natural targeting abilities of exosomes to enhance drug delivery.Despite the dynamic development of this field,many mechanisms of exosome action remain incompletely understood.Therefore,it is necessary to conduct further studies that will allow for a better understanding of their role in the process of resistance and will enable the development of effective therapeutic strategies.
基金supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF),funded by the Ministry of Education(RS-2023-00248378 and NRF-2020R1A6A1A03043708).
文摘Objectives:Tamoxifen is a key drug that provides endocrine therapy for estrogen receptor(ER)α-positive breast cancer;however,resistance remains a significant clinical challenge.This study aims to investigate the molecular mechanisms of tamoxifen resistance in ERα-positive breast cancer,with particular focus on the role of SET Domain Containing 1A(SETD1A)-driven forkhead box A2(FOXA2)as a key regulator of this resistance.Methods:FOXA2 expression and its regulation by SETD1A were assessed via(quantitative polymerase chain reaction),western blotting,transcriptome profiling,and chromatin immunoprecipitation analyses.The effects of FOXA2 on cell proliferation,migration,invasion,and cancer stem cell traits were evaluated using small interfering RNA(siRNA)-mediated silencing.Clinical relevance was examined by analyzing patient datasets and tumor tissue microarrays.Results:FOXA2 expression was significantly elevated in tamoxifen-resistant(TamR)and ERα-negative breast cancer cells compared to that in ERα-positive MCF-7 cells,regardless of tamoxifen treatment or ERαdepletion.Transcriptome and chromatin immunoprecipitation analyses revealed that SETD1A,a histone methyltransferase,directly regulated FOXA2 expression.Functionally,FOXA2 knockdown inhibited the proliferation,migration,invasion,and cancer stem cell properties of TamR cells while restoring tamoxifen sensitivity.High FOXA2 expression was correlated with poor survival and reduced responsiveness to tamoxifen in patients with ER-positive breast cancer.Conclusion:Our findings identified FOXA2 as a key mediator of tamoxifen resistance regulated by SETD1A and suggested that targeting the SETD1A-FOXA2 axis may offer a novel strategy for overcoming endocrine resistance in breast cancer.
文摘Background:Minimally invasive distal pancreatectomy(MIDP)is increasingly being used,although its oncologic safety for pancreatic ductal adenocarcinoma(PDAC)remains controversial.In Japan,MIDP for PDAC has limited endorsement due to insufficient data.This study aimed to compare the perioperative and long-term outcomes of open distal pancreatectomy(ODP)and MIDP for PDAC.Methods:We retrospectively analyzed patients with resectable pancreatic body and tail cancer treated with ODP or MIDP(laparoscopic or robotic)between January 2007 and July 2022.The surgical procedures(ODP and MIDP)were compared and the patient characteristics,perioperative outcomes,and long-term outcomes were analyzed.We also compared the outcomes of patients with neoadjuvant chemotherapy(NAC)and without NAC.Results:A total of 72 distal pancreatectomies were performed(37 ODPs and 35 MIDPs).In the upfront group,MIDP resulted in significantly less blood loss than ODP(P<0.01),despite similar operative time.There was no statistically significant difference in the 2-year recurrence-free survival(RFS)rates between ODP and MIDP(39.7%vs.57.8%,P=0.60)or in the overall survival(OS)rates(66.7%vs.74.1%,P=0.43).Similarly,in the NAC group,MIDP resulted in significantly less blood loss than ODP(P=0.01);ODP and MIDP had similar 2-year RFS rates(41.7%and 60.0%,P=0.75)and OS rates(50.0%and 70.0%,P=0.36).The interval from surgery to adjuvant chemotherapy initiation did not significantly differ between the ODP and MIDP subgroups in both the upfront group(P=0.13)and the NAC group(P=0.14).The incidence of recurrence was 64.8%for ODP and 42.8%for MIDP(P=0.06).Both procedures showed similar distributions of local and distant recurrence.Conclusions:MIDP caused less blood loss and had similar oncologic safety compared with ODP.MIDP could become a feasible,minimally invasive option with sufficient oncologic safety for pancreatic body and tail cancers.
文摘BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment.
基金supported by the National Natural Science Foundation of China(22007008,22178048).
文摘Naphthalene,anthracene and pyridone endoperoxides are known to thermally release singlet oxygen.However,in the cycloreversion reaction,singlet oxygen is produced stoichiometrically;therefore,multiple singlet oxygen releasing modules are expected to be very useful in inducing apoptosis of cancer cells.Herein,we present a potential therapeutic agent presenting three-pyridone endoperoxide modules and a mitochondria targeting group.Compared to previously reported pyridone-based monofunctional endoperoxides,the triple endoperoxide is highly effective as evidenced by assays and fluorescence microscopy.
基金supported by the Agricultural Science and Technology Innovation Program of the Chinese Academy of Agricultural Sciences(No.25-LZIHPS-03)the Regional Innovation System&Education(RISE)program through the Chungbuk Regional Innovation System&Education Center,funded by the Ministry of Education(MOE)and the Chungcheongbuk-do,Republic of Korea(No.2025-RISE-11-014-03).
文摘Poly(ADP-ribose)polymerase(PARP)is a family of proteins that play a crucial role in diverse cellular processes,including DNA repair,cell death,and changes in chromatin structure.PARP inhibitors(PARPi)have been recognized as notable agents in the realm of anticancer therapeutics owing to their capacity to specifically impact DNA repair pathways,thereby inducing targeted death of cancerous cells,particularly in cancers with homologous recombination deficiency(HRD).These inhibitors have been approved for the treatment of several cancers,such as ovarian,breast,and pancreatic cancers.Despite their promising therapeutic attributes,developing resistance to PARPi presents a formidable obstacle,curtailing their overall efficacy.This article presents a comprehensive description of the potential mechanisms related to PARPi resistance,an in-depth study of potential strategies to overcome resistance,and an assessment of the therapeutic potential of the PARPi in combination with alternative therapies.
基金supported by National Research Foundation(NRF)of Korea grants funded by the Korean government,the Ministry of Science and ICT[NRF-2022R1A2C1006737 to Joo-Won Park,NRF-2022R1I1A1A0106408112 to Min Hee Kim].
文摘Breast cancer is one of the most prevalent malignancies among women and comprises a heterogeneous spectrum of molecular subtypes with distinct biological behaviors.Among various regulatory molecules,sphingolipids play pivotal roles in dynamically modulating fundamental cellular processes such as proliferation,apoptosis,and metastasis through metabolic interconversions,including phosphorylation,glycosylation,and the generation of sphingosine-1-phosphate.This review aims to elucidate the mechanisms through which sphingolipid metabolism orchestrates cancer cell fate and drives breast cancer progression.Particular emphasis is placed on the balance between proapoptotic ceramides and pro-survival metabolites,such as sphingosine-1-phosphate,which collectively influence tumor growth and the therapeutic response.Additional sphingolipid species,including glucosylceramide and gangliosides(GD2,GD3,GM1,and GM3),have also been implicated in promoting breast cancer development.Furthermore,sphingolipid-based therapeutic strategies,including immunotherapy and antibody therapy,are discussed.By providing a comprehensive overview of sphingolipid metabolism,this review aims to identify novel therapeutic targets that may help overcome treatment resistance and improve clinical outcomes in breast cancer.
基金funded by Al Jalila Foundation-Research Grant(AJF2023-078)to SSMS.
文摘Objectives:Breast cancer(BC)is the leading cause of cancer-related mortality in women,largely due to metastasis.This study aims to explore the role of purine nucleoside phosphorylase(PNP),a key enzyme in purine metabolism,in the aggressiveness and metastatic behavior of BC.Methods:A comprehensive analysis was performed using in silico transcriptomic data(n=2509 patients),immunohistochemical profiling of BC tissues(n=103),and validation through western blotting in multiple BC cell lines.Gene expression and survival analyses were conducted using Tumor Immune Estimation Resource(TIMER),Gene Expression Profiling Interactive Analysis 2(GEPIA2),and the cBioPortal for cancer genomics(cBioPortal)platforms.Correlations between PNP and key epithelial–mesenchymal transition(EMT)markers,molecular subtypes,tumor grades,and stages were examined.Results:PNP was significantly overexpressed in human epidermal growth factor receptor 2(HER-2)-positive and triple-negative BCs compared to luminal subtypes.High PNP levels were strongly associated with advanced BC stages,high-grade tumors,EMT phenotypes,and poor overall survival.Notably,HER-2 inhibition suppressed PNP expression,while PNP gene silencing induced HER-2 upregulation,revealing a reciprocal regulatory loop.Dual inhibition of PNP and HER-2 resulted in a significant reduction in cell viability compared to HER-2 inhibition alone.Conclusion:Collectively,PNP emerges as a promising biomarker of BC aggressiveness and progression.Its reciprocal interaction with HER-2 underscores its potential as a therapeutic target.Dual targeting of PNP and HER-2 may offer a novel strategy for improving outcomes in aggressive BC subtypes.
基金Research Project of Xi’an Health Commission(Project No.:2023yb11)。
文摘Objective:To investigate the expression of pyruvate kinase M2(PKM2)and RNA binding proteins 1(SERBP1)in colorectal cancer(CRC)and their clinical significance.Methods:A total of 101 cases of colorectal adenocarcinoma tissues and their corresponding adjacent tissues were collected from our hospital from December 2020 to December 2023.The immunohistochemical Elivision method was used to detect the expression of PKM2 and SERBP1 in CRC and corresponding adjacent tissues.The experimental data were analyzed using statistical software SPSS 27.0.Results:The expression rates of PKM2 and SERBP1 in CRC were higher than those in adjacent tissues.The expression of PKM2 was positively correlated with lymph node metastasis and TNM stage.The expression of SERBP1 was positively correlated with the degree of differentiation,lymph node metastasis,and TNM stage of CRC.Conclusion:PKM2 and SERBP1 may promote the occurrence and tumor progression of CRC,but further experimental research is still needed.
基金supported by the National Key Research and Development Plan:Real-Time Intelligent Active Intervention on Integration of Ten Important Chronic Diseases(2020YFC2003504-2,to BX)。
文摘Background:Although light-intensity physical activity(LPA)has been suggested to be associated with a lower risk of mortality,the minimal and optimal volumes of LPA remain unclear.We aimed to examine the minimal and optimal volumes of LPA associated with the risks of mortality and disease incidence(i.e.,cardiovascular diseases and cancer).Methods:Data were derived from the population-based UK Biobank cohort study,including 69,492 adults aged 43-78 years.Accelerometermeasured LPA was defined using a validated,published machine learning-based Random Forest activity method,which was categorized into 4 quartile groups.All-cause and cause-specific mortality(cardiovascular disease-and cancer-specific)were determined according to the International Classification of Diseases,10th version codes.Disease incidence was defined based on primary care,hospitalization,or death records.Results:During a median follow-up period of 8.04 years,2024 adults died from all causes,539 from cardiovascular disease,and 1175 from cancer.For all-cause mortality,compared with participants in the lowest quartile of LPA(<3.9 h/day),the hazard ratios(HRs)and 95%confidence intervals(95%CIs)were 0.82(95%CI:0.73-0.93)for those with 3.9 to<5.0 h/day,0.75(95%CI:0.66-0.85)for those with 5.0 to<6.1 h/day,and 0.77(95%CI:0.68-0.88)for those with≥6.1 h/day,respectively.There was an inverse non-linear dose-response association between LPA and all-cause mortality,with an optimal dose of 5.72 h/day(95%CI:5.45-6.41;HR=0.63,95%CI:0.56-0.71)and a minimal dose of 3.59 h/day(95%CI:3.53-8.56;HR=0.81,95%CI:0.78-0.86),with the 5th percentile as the reference.Similar patterns were observed for cause-specific mortality and disease incidence(cardiovascular disease and cancer).Conclusion:Engaging in LPA for~3.5 h/day was conservatively associated with lower risk of mortality and disease incidence,with further risk reductions observed up to an optimal dose of~6.0 h/day.These findings suggest that sufficient LPA offers important health benefits,which can inform the development of future PA guidelines.
文摘Breast cancer(BRCA)is characterized by high heterogeneity,with aggressive subtypes frequently showing poor prognosis and resistance to conventional therapies,making the discovery of new therapeutic targets and strategies imperative.Although elevated expression of discs large homolog 3(DLG3)has been reported in BRCA,its functional role in disease progression remains unclear.We performed bioinformatic analyses of clinical datasets to evaluate the prognostic significance of DLG3 expression in BRCA patients.In vitro gain-and loss-of-function experiments were conducted to assess the impact of DLG3 on BRCA cell proliferation,migration,and colony formation.Transcriptomic profiling,coupled with pharmacological inhibition,was employed to identify and validate downstream signaling pathways.Additionally,we extended our validation to an in vivo model to assess the role of DLG3 in tumor progression.We found that elevated DLG3 levels correlated with poor prognosis in breast cancer patients.Functionally,DLG3 overexpression significantly promoted cell proliferation and migration in estrogen receptor-positive MCF7 and triple-negative MDA-MB-231 breast cancer cells,whereas its knockdown suppressed these effects.Transcriptomic analyses revealed that DLG3 activates signal transducer and activator of transcription 3(STAT3)signaling,a finding further corroborated by Western blot.Critically,treatment with the STAT3 inhibitor Stattic attenuated DLG3-driven proliferation and migration,supporting a DLG3-STAT3 oncogenic axis.Furthermore,in vivo studies validated the role of DLG3 in promoting tumor growth and its correlation with elevated STAT3 signaling,consistent with our in vitro findings.Our findings establish DLG3 as a novel driver of breast cancer progression that directly activates STAT3 signaling.DLG3 thus represents both a potential prognostic biomarker and a promising therapeutic target for aggressive breast cancer subtypes,including triple-negative breast cancer.
基金the Deanship of Research and Graduate Studies at King Khalid University,KSA,for funding this work through the Large Research Project under grant number RGP2/164/46.
文摘Background:Stomach cancer(SC)is one of the most lethal malignancies worldwide due to late-stage diagnosis and limited treatment.The transcriptomic,epigenomic,and proteomic,etc.,omics datasets generated by high-throughput sequencing technology have become prominent in biomedical research,and they reveal molecular aspects of cancer diagnosis and therapy.Despite the development of advanced sequencing technology,the presence of high-dimensionality in multi-omics data makes it challenging to interpret the data.Methods:In this study,we introduce RankXLAN,an explainable ensemble-based multi-omics framework that integrates feature selection(FS),ensemble learning,bioinformatics,and in-silico validation for robust biomarker detection,potential therapeutic drug-repurposing candidates’identification,and classification of SC.To enhance the interpretability of the model,we incorporated explainable artificial intelligence(SHapley Additive exPlanations analysis),as well as accuracy,precision,F1-score,recall,cross-validation,specificity,likelihood ratio(LR)+,LR−,and Youden index results.Results:The experimental results showed that the top four FS algorithms achieved improved results when applied to the ensemble learning classification model.The proposed ensemble model produced an area under the curve(AUC)score of 0.994 for gene expression,0.97 for methylation,and 0.96 for miRNA expression data.Through the integration of bioinformatics and ML approach of the transcriptomic and epigenomic multi-omics dataset,we identified potential marker genes,namely,UBE2D2,HPCAL4,IGHA1,DPT,and FN3K.In-silico molecular docking revealed a strong binding affinity between ANKRD13C and the FDA-approved drug Everolimus(binding affinity−10.1 kcal/mol),identifying ANKRD13C as a potential therapeutic drug-repurposing target for SC.Conclusion:The proposed framework RankXLAN outperforms other existing frameworks for serum biomarker identification,therapeutic target identification,and SC classification with multi-omics datasets.
