This letter addresses challenges in the clinical translation of BIBR1532,a promising telomerase inhibitor,for the treatment of esophageal squamous cell carcinoma(ESCC).BIBR1532 exerts its anti-cancer effect by activat...This letter addresses challenges in the clinical translation of BIBR1532,a promising telomerase inhibitor,for the treatment of esophageal squamous cell carcinoma(ESCC).BIBR1532 exerts its anti-cancer effect by activating DNA damage response(ATR/CHK1 and ATM/CHK2)pathways and downregulating telomere-binding proteins.Although its therapeutic potential is limited by poor aqueous solubility,solid dispersion(SD)technology may overcome this obstacle.Systematic analysis using PubChem-derived simplified molecular input line entry system identifiers and artificial intelligence-driven FormulationDT platform evaluation(oral formulation feasibility index:0.38)revealed that the SD technology,with superior scalability(32 approved products by 2021)and lower production risks,outperforms lipid-based formulations as an optimal dissolution strategy.Material analysis revealed hydroxypropyl methylcellulose(HPMC)as the optimal carrier with lower hygroscopicity,higher temperature and no intestinal targeting,thus enabling ESCC therapy.HPMC-based SD enhances BIBR1532 solubility and bioavailability for effective ESCC treatment.Future studies should focus on pilot tests for SD fabrication.展开更多
The presence of a positive deep surgical margin in tongue squamous cell carcinoma(TSCC)significantly elevates the risk of local recurrence.Therefore,a prompt and precise intraoperative assessment of margin status is i...The presence of a positive deep surgical margin in tongue squamous cell carcinoma(TSCC)significantly elevates the risk of local recurrence.Therefore,a prompt and precise intraoperative assessment of margin status is imperative to ensure thorough tumor resection.In this study,we integrate Raman imaging technology with an artificial intelligence(AI)generative model,proposing an innovative approach for intraoperative margin status diagnosis.This method utilizes Raman imaging to swiftly and non-invasively capture tissue Raman images,which are then transformed into hematoxylin-eosin(H&E)-stained histopathological images using an AI generative model for histopathological diagnosis.The generated H&E-stained images clearly illustrate the tissue’s pathological conditions.Independently reviewed by three pathologists,the overall diagnostic accuracy for distinguishing between tumor tissue and normal muscle tissue reaches 86.7%.Notably,it outperforms current clinical practices,especially in TSCC with positive lymph node metastasis or moderately differentiated grades.This advancement highlights the potential of AI-enhanced Raman imaging to significantly improve intraoperative assessments and surgical margin evaluations,promising a versatile diagnostic tool beyond TSCC.展开更多
Dear Editor,Local recurrence and cervical lymph node metastases are major causes of mortality in patients with head and neck squamous cell carcinoma(HNSCC).To date,none of the proposed strategies for predicting outcom...Dear Editor,Local recurrence and cervical lymph node metastases are major causes of mortality in patients with head and neck squamous cell carcinoma(HNSCC).To date,none of the proposed strategies for predicting outcomes in this disease have proven fully effective,and a comprehensive physical examination remains the primary method for early detection and monitoring of HNSCC.展开更多
Basal cell carcinoma(BCC)and cutaneous squamous cell carcinoma(cSCC),as certain forms of nonmelanoma skin cancer(NMSC)or keratinocyte carcinoma,are the most common forms of malignant neoplasms worldwide(Sharp et al.,2...Basal cell carcinoma(BCC)and cutaneous squamous cell carcinoma(cSCC),as certain forms of nonmelanoma skin cancer(NMSC)or keratinocyte carcinoma,are the most common forms of malignant neoplasms worldwide(Sharp et al.,2024).BCC and cSCC have been identified as two major components of NMSC,comprising one-third of all malignancies(Burton et al.,2016).Generally speaking,patients with NMSC tend to have relatively favorable survival outcomes,while different histopathological subtypes of NMSC exhibit distinct biological behaviors(Stătescu et al.,2023).展开更多
Dear Editor,Esophageal cancer(EC)is a malignant tumor originating from esophageal epithelium and remains a leading cause of cancer incidence and mortality worldwide1,2.According to the 2020 World Health Organization s...Dear Editor,Esophageal cancer(EC)is a malignant tumor originating from esophageal epithelium and remains a leading cause of cancer incidence and mortality worldwide1,2.According to the 2020 World Health Organization statistics,there were approx-imately 604,000 new EC cases and 544,000 EC-related deaths globally with China reporting approximately 320,000 new cases and 300,000 deaths,mainly from esophageal squamous cell carcinoma(ESCC)3.Although there has been progress in the treatment of EC,the long-term prognosis of patients with R0 resection and lymph node-positive disease contin-ues to be suboptimal4.A retrospective analysis performed by our center suggested that the median overall survival(OS)of lymph node-positive patients with EC who received postoper-ative adjuvant radiotherapy(PART)was 29 months compared to 21 months for surgery alone with 3-year survival rates of 43%and 36%,respectively,indicating a potential survival ben-efit of PART5.展开更多
AIM:To investigate the pathological features of ocular surface squamous neoplasia(OSSN)and evaluate the synergistic therapeutic effects of interferon-α2b(IFNα2b)and 5-fluorouracil(5-FU)on cellular proliferation,migr...AIM:To investigate the pathological features of ocular surface squamous neoplasia(OSSN)and evaluate the synergistic therapeutic effects of interferon-α2b(IFNα2b)and 5-fluorouracil(5-FU)on cellular proliferation,migration,apoptosis,and cell cycle of human oral squamous carcinoma cell line Cal27.METHODS:Tissue specimens from OSSN were processed with hematoxylin-eosin(HE)and immunofluorescence(IF)staining to characterize pathological changes.We analyzed the expression levels of four pivotal proteins involved in 5-FU metabolism:interferon alpha receptor(IFNAR),thymidylate synthase(TS),thymidine phosphorylase(TP),and dihydropyrimidine dehydrogenase(DPD).Cal27 cell lines were treated with a spectrum of concentrations of IFNα2b and 5-FU,either in isolation or in combination.Then,cell activity was measured utilizing CCK-8 assay and dose-effect curves were calculated,while tumor cell migration was detected by cell scratch experiments.Cal27 cells were added with IFNα2b and 5-FU in a non-constant ratio drug combination design and the corresponding combination index(CI)and fraction affected(Fa)were calculated with CompuSyn software.Western blot assay was conducted to quantify the expression of TP,TS,and DPD.Cell cycle and apoptosis were measured with flow cytometry and terminal deoxynucleotidyl transferasemediated dUTP nick and labeling(TUNEL)assay.RESULTS:Treatment with both IFNα2b and 5-FU inhibited cell proliferation.Except for the lowest and highest doses of 5-FU,CI values for all other groups were below 1,suggesting a synergistic interaction.Low concentrations of IFNα2b and 5-FU both diminished the relative mobility of Cal27 cells,instead,a stronger inhibitory effect was observed when the two drugs were co-applied.The expression levels of TP and DPD in Cal27 cells were dose-dependently increased at a low concentration of IFNα2b.Low-dose IFNα2b combined with 5-FU significantly inhibited cell proliferation in G0/G1 phase compared to 5-FU monotherapy.Medium and high doses of IFNα2b and all concentrations of 5-FU could induce apoptosis in a concentration-dependent manner.The susceptibility to 5-FU treatment and apoptosis rates of tumor cells were elevated with low doses of IFNα2b.CONCLUSION:Both IFNα2b and 5-FU,when administered individually or in combination,effectively suppress the proliferation and migration of Cal27 tumor cells,induce cell apoptosis and arrest cell cycle.Low doses of IFNα2b increase the antitumor effects of 5-FU on Cal27 potentially through up-regulating the expression of TP,demonstrating a synergistic effect between IFNα2b and 5-FU.展开更多
AIM:To evaluate the demographics,clinical characteristics,treatments,and outcomes of patients with ocular surface squamous neoplasia(OSSN)at the Philippine General Hospital.METHODS:This was a single-center,11-year ret...AIM:To evaluate the demographics,clinical characteristics,treatments,and outcomes of patients with ocular surface squamous neoplasia(OSSN)at the Philippine General Hospital.METHODS:This was a single-center,11-year retrospective,cross sectional case series on 18 cases of OSSN seen between January 2012 to June 2023.The patient’s demographics,presenting symptoms,tumor characteristics,histopathologic diagnosis,treatment,outcomes,and duration of follow-up were reviewed.RESULTS:Out of 33 identified cases of OSSN,only 18 were eligible for inclusion in the study.Mean age was 60.78y(range 31 to 80),with male predominance(66.67%).The left eye was most commonly affected(61.11%)with most presenting with fleshy mass(83.33%).Most tumors were located nasally(66.67%)and were predominantly papilliform(44.44%)in morphology with associated hyperpigmentation(38.89%).Squamous cell carcinoma(SCCA)was the most common histopathologic diagnosis(72.22%).The main primary treatment was surgical excision(94.44%)with or without adjunctive therapy,with only 1 patient undergoing first-line topical chemotherapy.Only 3 recurrences(16.67%)were noted with a median followup of 7.5mo.A statistically significant recurrence-free odds leaning towards the utilization of cryotherapy was noted.CONCLUSION:OSSN seen at the Philippine General Hospital is presented as a limbal papilliform mass,most commonly affecting elderly males.Surgical excision with adjuvant cryotherapy and/or chemotherapy is the preferred mode of treatment.展开更多
BACKGROUND The high prevalence of human papillomavirus(HPV)infection in oropharyngeal squamous cell carcinoma(SCC)is well established,and p16 expression is a strong predictor.HPV-related tumors exhibit unique mechanis...BACKGROUND The high prevalence of human papillomavirus(HPV)infection in oropharyngeal squamous cell carcinoma(SCC)is well established,and p16 expression is a strong predictor.HPV-related tumors exhibit unique mechanisms that target p16 and p53 proteins.However,research on HPV prevalence and the combined predictive value of p16 and p53 expression in head and neck cutaneous SCC(HNCSCC),particularly in Asian populations,remains limited.This retrospective study surveyed 62 patients with HNSCC(2011-2020),excluding those with facial warts or other skin cancer.AIM To explore the prevalence of HPV and the predictive value of p16 and p53 expression in HNCSCC in Asian populations.METHODS All patients underwent wide excision and biopsy.Immunohistochemical staining for HPV,p16,and p53 yielded positive and negative results.The relevance of each marker was investigated by categorizing the tumor locations into high-risk and middle-risk zones based on recurrence frequency.RESULTS Of the 62 patients,20(32.26%)were male,with an average age of 82.27 years(range 26-103 years).High-risk included 19 cases(30.65%),with the eyelid and lip being the most common sites(five cases,8.06%).Middle-risk included 43 cases(69.35%),with the cheek being the most common(29 cases,46.77%).The p16 expression was detected in 24 patients(38.71%),p53 expression in 42 patients(72.58%),and HPV in five patients(8.06%).No significant association was found between p16 expression and the presence of HPV(P>0.99),with a positive predictive value of 8.33%.CONCLUSION This study revealed that p16,a surrogate HPV marker in oropharyngeal SCC,is not reliable in HNCSCC,providing valuable insights for further research in Asian populations.展开更多
BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis th...BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis through binding to dif-ferent ligands.AIM To evaluate the correlation between single nucleotide polymorphisms(SNPs)of ACVR1C and susceptibility to esophageal squamous cell carcinoma(ESCC)in Chinese Han population.METHODS In this hospital-based cohort study,1043 ESCC patients and 1143 healthy controls were enrolled.Five SNPs(rs4664229,rs4556933,rs77886248,rs77263459,rs6734630)of ACVR1C were assessed by the ligation detection reaction method.Hardy-Weinberg equilibrium test,genetic model analysis,stratified analysis,linkage disequi-librium test,and haplotype analysis were conducted.RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC,and those with rs77886248 TA mutant were related with higher risk,especially in older male smokers.In the haplotype analysis,ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC,while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC,which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.展开更多
BACKGROUND One of the main characteristics of oral squamous cell carcinoma(OSCC)is that it metastasizes to cervical lymph nodes frequently with a high degree of local invasiveness.A primary feature of malignant tumors...BACKGROUND One of the main characteristics of oral squamous cell carcinoma(OSCC)is that it metastasizes to cervical lymph nodes frequently with a high degree of local invasiveness.A primary feature of malignant tumors is their penetration of neighboring tissues,such as lymphatic and blood arteries,due to the tumor cells'capacity to break down the extracellular matrix(ECM).Matrix metalloproteinases(MMPs)constitute a family of proteolytic enzymes that facilitate tissue remodeling and the degradation of the ECM.MMP-9 and MMP-13 belong to the group of extracellular matrix degrading enzymes and their expression has been studied in OSCC because of their specific functions.MMP-13,a collagenase family member,is thought to play an essential role in the MMP activation cascade by breaking down the fibrillar collagens,whereas MMP-9 is thought to accelerate the growth of tumors.Elevated MMP-13 expression has been associated with tumor behavior and patient prognosis in a number of malignant cases.AIM To assess the immunohistochemical expression of MMP-9 and MMP-13 in OSCC.METHODS A total of 40 cases with histologically confirmed OSCC by incisional biopsy were included in this cross-sectional retrospective study.The protocols for both MMP-9 and MMP-13 immunohistochemical staining were performed according to the manufacturer’s recommendations along with the normal gingival epithelium as a positive control.All the observations were recorded and Pearson’sχ²test with Fisher exact test was used for statistical analysis.RESULTS Our study showed no significant correlation between MMP-9 and MMP-13 staining intensity and tumor size.The majority of the patients were in advanced TNM stages(III and IV),and showed intense expression of MMP-9 and MMP-13.CONCLUSION The present study suggests that both MMP-9 and MMP-13 play an important and independent role in OSCC progression and invasiveness.Intense expression of MMP-9 and MMP-13,irrespective of histological grade of OSCC,correlates well with TNM stage.Consequently,it is evident that MMP-9 and MMP-13 are important for the invasiveness and progression of tumors.The findings may facilitate the development of new approaches for evaluating lymph node metastases and interventional therapy techniques,hence enhancing the prognosis of patients diagnosed with OSCC.展开更多
BACKGROUND Early detection of esophageal squamous neoplasms(ESN)is essential for improving patient prognosis.Optical diagnosis of ESN remains challenging.Probebased confocal laser endomicroscopy(pCLE)enables accurate ...BACKGROUND Early detection of esophageal squamous neoplasms(ESN)is essential for improving patient prognosis.Optical diagnosis of ESN remains challenging.Probebased confocal laser endomicroscopy(pCLE)enables accurate in vivo histological observation and optical biopsy of ESN.However,interpretation of pCLE images requires histopathological expertise and extensive training.Artificial intelligence(AI)has been widely applied in digestive endoscopy;however,AI for pCLE diagnosis of ESN has not been reported.AIM To develop a pCLE computer-aided diagnostic system for ESN and assess its diagnostic performance and assistant efficiency for nonexpert endoscopists.METHODS The intelligent confocal laser endomicroscopy(iCLE)system consists of image recognition(based on inception-ResNet V2),video diagnosis,and quality judgment modules.This system was developed using pCLE images and videos and evaluated through image and prospective video recognition tests.Patients between June 2020 and January 2023 were prospectively enrolled.Expert and nonexpert endoscopists and the iCLE independently performed diagnoses for pCLE videos,with histopathology as the gold standard.Thereafter,the non-expert endoscopists performed a second assessment with iCLE assistance.RESULTS A total of 25056 images from 2803 patients were selected for iCLE training and validation.Another 2442 images from 226 patients were used for testing.iCLE achieved a high accuracy of 98.3%,sensitivity of 95.3%and specificity of 98.8%for diagnosing ESN images.A total of 2581 patients underwent upper gastrointestinal pCLE examination and were prospectively screened;54 patients with suspected ESN were enrolled.Overall,187 videos from 67 lesions were assessed by iCLE,three nonexpert and three expert endoscopists.iCLE achieved a high accuracy,sensitivity and specificity of 90.9%,92.0%,and 90.2%,respectively.Compared to experts,iCLE showed significantly higher sensitivity(92.0%vs 80.4%;P<0.001)and negative predictive value(94.4%vs 87.7%;P=0.003).With iCLE assistance,nonexpert endoscopists showed significant improvements in accuracy(from 83.6%to 88.6%)and sensitivity(from 76.0%to 89.8%).CONCLUSION iCLE system demonstrated high diagnostic performance for ESN.It can assist nonexpert endoscopists in improving the diagnostic efficiency of pCLE for ESN and has the potential for reducing unnecessary biopsies.展开更多
Tongue squamous cell carcinoma(TSCC)is a prevalent malignancy that afflicts the head and neck area and presents a high incidence of metastasis and invasion.Accurate diagnosis and effective treatment are essential for ...Tongue squamous cell carcinoma(TSCC)is a prevalent malignancy that afflicts the head and neck area and presents a high incidence of metastasis and invasion.Accurate diagnosis and effective treatment are essential for enhancing the quality of life and the survival rates of TSCC patients.The current treatment modalities for TSCC frequently suffer from a lack of specificity and efficacy.Nanoparticles with diagnostic and photothermal therapeutic properties may offer a new approach for the targeted therapy of TSCC.However,inadequate accumulation of photosensitizers at the tumor site diminishes the efficacy of photothermal therapy(PTT).This study modified gold nanodots(AuNDs)with the TSCC-targeting peptide HN-1 to improve the selectivity and therapeutic effects of PTT.The Au-HN-1 nanosystem effectively targeted the TSCC cells and was rapidly delivered to the tumor tissues compared to the AuN Ds.The enhanced accumulation of photosensitizing agents at tumor sites achieved significant PTT effects in a mouse model of TSCC.Moreover,owing to its stable long-term fluorescence and high X-ray attenuation coefficient,the Au-HN-1 nanosystem can be used for fluorescence and computed tomography imaging of TSCC,rendering it useful for early tumor detection and accurate delineation of surgical margins.In conclusion,Au-HN-1 represents a promising nanomedicine for imaging-based diagnosis and targeted PTT of TSCC.展开更多
Background:Terpinen-4-ol(T4O),a key constituent of tea tree essential oil and various aromatic plants,has shown promising antiproliferative and pro-apoptotic effects in melanoma and other cancer types.However,its effi...Background:Terpinen-4-ol(T4O),a key constituent of tea tree essential oil and various aromatic plants,has shown promising antiproliferative and pro-apoptotic effects in melanoma and other cancer types.However,its efficacy against cutaneous squamous cell carcinoma(cSCC)remains unclear.Thus,in this study,we investigated the in vivo and in vitro effects of T4O on cSCC cell lines and preliminarily explored its impacting pathways.Methods:Using CCK8 and assay colony formation,we assessed the viability of cSCC A431,SCL-1,and COLO-16 cells treated with T40 at varying concentrations(0,1,2,and 4μM).Flow cytometry was employed to evaluate T4O’s effect on cSCC cell’s cycle progression and apoptosis induction.Additionally,western blotting was utilized to examine the expression intensities of N-cadherin and E-cadherin,two indicative markers of the epithelial-mesenchymal transition(EMT)pathway.T4O’s in vivo effect on inhibiting tumor progression was evaluated on an established xenograft tumor model.Then,the molecular mechanisms of T4O’s antitumor effect were explored by an integrated genome-wide transcriptomics and proteomics study on cSCC A431c cells.Finally,calpain-2’s potential mediator role in T4O’s anti-tumor mechanism was investigated in calpain-2 knockdown cell lines prepared via siRNA transfection.Result:It’s demonstrated that T4O treatment inhibited cSCC proliferation,clonogenicity,migration,and invasion while inducing apoptosis and suppressing the EMT pathway.T4O administration also inhibited cSCC tumorigenesis in the xenograft tumor model.RNA-sequencing and iTRAQ analysis detected significant upregulation of calpain-2 expression in T4O-treated cSCC cells.Western blotting confirmed that T4O significantly increased calpain-2 expression and promoted proteolytic cleavage ofβ-catenin and caspase-12,two calpain-2 target proteins.Importantly,siRNA-mediated calpain-2 knockdown relieved T4O’s suppressive effect on cSCC cell proliferation and motility.Mechanistically,T4O upregulates calpain-2 expression and promotes the cleavage ofβ-catenin and caspase-12,with siRNA-mediated calpain-2 knockdown mitigating T4O’s suppressive effects.Conclusion:These findings suggest that T4O’s antitumor activity in cSCC is mediated through the upregulation of calpain-2 expression and subsequent modulation ofβ-catenin and caspase-12.展开更多
Numerous studies have demonstrated that the high expression of CXC motif chemokine ligand 16(CXCL16)in cancer correlates with poor prognosis,as well as tumor cell proliferation,migration,and invasion.While CXCL16 can ...Numerous studies have demonstrated that the high expression of CXC motif chemokine ligand 16(CXCL16)in cancer correlates with poor prognosis,as well as tumor cell proliferation,migration,and invasion.While CXCL16 can serve as a tumor biomarker,the underlying mechanism in modulating head and neck squamous cell carcinoma(HNSCC)remains unclear.In this study,the aimed was to investigate the CXCL16 expression in HNSCC and to uncover the potential underlying mechanism.Hereby,we determined the high expression of CXCL16 in The Cancer Genome Atlas(TCGA)database,as well as in tissue samples from patients with HNSCC at our central hospital and from HNSCC cell lines.The results showed that CXCL16 knockdown inhibited the proliferation,migration,and invasion of HNSCC cells.Mechanistically,transcriptome sequencing revealed that CXCL16 may affect HNSCC cell growth by regulating the antioxidant pathway of glutathione peroxidase 1(GPX1).The reactive oxygen species(ROS)levels were elevated in small interfering CXCL16(si-CXCL16)cells,which may contribute to the inhibition of cell proliferation,migration,and invasion.Moreover,treatment of cells with the GPX1 inhibitor eldecalcitol(ED-71)revealed that HNSCC cell growth was significantly inhibited in the synergistic group of si-CXCL16 and GPX1 inhibitor compared to the si-CXCL16 group.In conclusion,CXCL16 contributed to the development of HNSCC cells by modulating the GPX1-mediated antioxidant pathway.Thus,targeting cellular CXCL16 expression seems to be a promising strategy for treating HNSCC.展开更多
BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a malignant tumor with high morbidity and mortality,and easy to develop resistance to chemotherapeutic agents.Telomeres are DNA-protein complexes located at the te...BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a malignant tumor with high morbidity and mortality,and easy to develop resistance to chemotherapeutic agents.Telomeres are DNA-protein complexes located at the termini of chro-mosomes in eukaryotic cells,which are unreplaceable in maintaining the stability and integrity of genome.Telomerase,an RNA-dependent DNA polymerase,play vital role in telomere length maintain,targeting telomerase is a promising therapeutic strategy for cancer.KYSE150 and KYSE410 cells were cultured and exposed to various concentrations of BIBR1532.Cell viability was assessed at 48 hours and 72 hours to determine the IC50 values.The effects of BIBR1532 on ESCC cell proliferation,migration,and cellular senescence were evaluated using the cell counting kit-8 assay,plate colony formation assay,scratch assay,transwell assay,andβ-galactosidase staining,respectively.Western blotting was performed to detect the expression of RESULTS The IC50 values for KYSE150 and KYSE410 cells after 48 hours of BIBR1532 exposure were 48.53μM and 39.59μM,respectively.These values decreased to 37.22μM and 22.71μM,respectively,following a longer exposure of 72 hours.BIBR1532 exhibited dose-dependent effects on KYSE150 and KYSE410 cells,including decreased hTERT expression,inhibition of proliferation and metastasis,and induction of cellular senescence.Mechanistically,BIBR1532 upregulated the expression of the DDR protein,γ-H2AX,and activated the ataxia telangiectasia and Rad3-related protein(ATR)/check point kinase 1(CHK-1)and ataxia-telangiectasia mutated gene(ATM)/CHK2 pathways.BIBR1532 downregulated the expression of telomere-binding proteins,including telomeric-repeat binding factor 1(TRF1),TRF2,protection of telomeres 1,and TIN2-interacting protein 1.In a nude mouse xenograft model,BIBR1532 significantly suppressed tumor growth,reduced hTERT expression,and increasedγ-H2AX protein levels.Hematoxylin and eosin staining of various organs,including the heart,liver,spleen,lungs,and kidneys,revealed no apparent adverse effects.CONCLUSION BIBR1532 exerts anti-cancer effects on ESCC by inducing DDR through the ATR/CHK1 and ATM/CHK2 pathways and downregulating the expression of telomere-binding proteins.展开更多
BACKGROUND Primary squamous cell carcinoma(SCC)of the renal parenchyma is extremely rare,with only nine cases reported.CASE SUMMARY This study reports a 51-year-old man with primary SCC of the renal parenchyma.The pat...BACKGROUND Primary squamous cell carcinoma(SCC)of the renal parenchyma is extremely rare,with only nine cases reported.CASE SUMMARY This study reports a 51-year-old man with primary SCC of the renal parenchyma.The patient was admitted with recurrent dull pain and discomfort in the right lumbar region,which had worsened over 2 weeks,accompanied by painful gross hematuria.SCC antigen(SCCA)levels were elevated,and imaging revealed a renal mass with associated calculi.The patient underwent laparoscopic unilateral nephrectomy and lymph node dissection.Postoperative pathology confirmed highly differentiated SCC with necrosis in the right renal parenchyma,with negative renal pelvis and ureter.The pathological stage was Pt3aN1M0.Four months after surgery,the tumor recurred with involvement of the liver,right psoas major muscle,and inferior vena cava.The patient refused chemotherapy and succumbed to the disease 6 months postoperatively due to disease progression.CONCLUSION We report a case of primary SCC of the renal parenchyma,a rare renal malignancy.The clinical symptoms,laboratory tests,and imaging findings are nonspecific,making accurate and timely diagnosis challenging.According to the literature,for patients with renal calculi accompanied by a renal mass,elevated serum SCCA levels,and magnetic resonance imaging showing cystic or cystic-solid masses within the kidney with pseudocapsules and heterogeneous mild enhancement,the possibility of this disease should be considered.展开更多
Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiolo...Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiology is multifactorial,involving tobacco use,alcohol consumption,and human papillomavirus(HPV)infection.Oral leukoplakia and erythroplakia are the main precancerous lesions lesions,with oral leukoplakia being the most common.Both OSCC and premalignant lesions are closely associated with aberrant activation of multiple signaling pathways.Post-translational modifications(such as ubiquitination and deubiquitination)play key roles in regulating these pathways by controlling protein stability and activity.Growing evidence indicates that dysregulated ubiquitination/deubiquitination can mediate OSCC initiation and progression via aberrant activation of signaling pathways.The ubiquitination/deubiquitination process mainly involves E3 ligases(E3s)that catalyze substrate ubiquitination,deubiquitinating enzymes(DUBs)that remove ubiquitin chains,and the 26S proteasome complex that degrades ubiquitinated substrates.Abnormal expression or mutation of E3s and DUBs can lead to altered stability of critical tumorrelated proteins,thereby driving OSCC initiation and progression.Therefore,understanding the aberrantly activated signaling pathways in OSCC and the ubiquitination/deubiquitination mechanisms within these pathways will help elucidate the molecular mechanisms and improve OSCC treatment by targeting relevant components.Here,we summarize four aberrantly activated signaling pathways in OSCC―the PI3K/AKT/mTOR pathway,Wnt/β-catenin pathway,Hippo pathway,and canonical NF-κB pathway―and systematically review the regulatory mechanisms of ubiquitination/deubiquitination within these pathways,along with potential drug targets.PI3K/AKT/mTOR pathway is aberrantly activated in approximately 70%of OSCC cases.It is modulated by E3s(e.g.,FBXW7 and NEDD4)and DUBs(e.g.,USP7 and USP10):FBXW7 and USP10 inhibit signaling,while NEDD4 and USP7 potentiate it.Aberrant activation of the Wnt/β-catenin pathway leads toβ-catenin nuclear translocation and induction of cell proliferation.This pathway is modulated by E3s(e.g.,c-Cbl and RNF43)and DUBs(e.g.,USP9X and USP20):c-Cbl and RNF43 inhibit signaling,while USP9X and USP20 potentiate it.Hippo pathway inactivation permits YAP/TAZ to enter the nucleus and promotes cancer cell metastasis.This pathway is modulated by E3s(e.g.,CRL4^(DCAF1) and SIAH2)and DUBs(e.g.,USP1 and USP21):CRL4^(DCAF1) and SIAH2 inhibit signaling,while USP1 and USP21 potentiate it.Persistent activation of the canonical NF-κB pathway is associated with an inflammatory microenvironment and chemotherapy resistance.This pathway is modulated by E3s(e.g.,TRAF6 and LUBAC)and DUBs(e.g.,A20 and CYLD):A20 and CYLD inhibit signaling,while TRAF6 and LUBAC potentiate it.Targeting these E3s and DUBs provides directions for OSCC drug research.Small-molecule inhibitors such as YCH2823(a USP7 inhibitor),GSK2643943A(a USP20 inhibitor),and HOIPIN-8(a LUBAC inhibitor)have shown promising antitumor activity in preclinical models;PROTAC molecules,by binding to surface sites of target proteins and recruiting E3s,achieve targeted ubiquitination and degradation of proteins insensitive to small-molecule inhibitors,for example,PU7-1-mediated USP7 degradation,offering new strategies to overcome traditional drug limitations.Currently,NX-1607(a Cbl-b inhibitor)has entered phase I clinical trials,with preliminary results confirming its safety and antitumor activity.Future research on aberrant E3s and DUBs in OSCC and the development of highly specific inhibitors will be of great significance for OSCC precision therapy.展开更多
Cervical cancer is a major malignancy that poses a significant threat to women's health[1].In 2020,an estimated 604,000 new cases and 342,000 deaths were reported globally[2].The most common pathological subtype i...Cervical cancer is a major malignancy that poses a significant threat to women's health[1].In 2020,an estimated 604,000 new cases and 342,000 deaths were reported globally[2].The most common pathological subtype is squamous cell carcinoma[3,4].However,treatment options for advanced cervical squamous cell carcinoma(CSCC)are limited.Surgery is often not feasible at this stage,resulting in poor prognosis[5,6].Therefore,identifying novel molecular markers and elucidating the mechanisms that drive CSCC growth and metastasis are crucial for improving treatment outcomes.展开更多
The strong association between human papillomavirus(HPV)infection and oropharyngeal squamous cell carcinoma(SCC)is well-documented,with p16 expression serving as a reliable predictor of HPV involvement.HPV-related tum...The strong association between human papillomavirus(HPV)infection and oropharyngeal squamous cell carcinoma(SCC)is well-documented,with p16 expression serving as a reliable predictor of HPV involvement.HPV-related tumors are characterized by distinct mechanisms affecting p16 and p53 protein pathways.However,the prevalence of HPV and the combined predictive utility of p16 and p53 expression in head and neck cutaneous SCC remain less explored,necessitating further research to understand their role in this subset of SCC.HPV,p16,and p53 statuses were determined using immunohistochemistry staining methods rather than more sensitive techniques such as polymerase chain reaction or HPV genotyping,limiting the ability to assess specific area HPV types poten-tially associated with prognosis.Further studies assessing multiple molecular markers in head and neck cutaneous patients will better predict the diverse outcomes and potentially the type of treatment targeted to those markers.展开更多
BACKGROUND Pseudoachalasia closely mimics the clinical symptoms of idiopathic achalasia in both clinical symptoms and diagnostic findings,including those from highresolution manometry and barium esophagography.The sim...BACKGROUND Pseudoachalasia closely mimics the clinical symptoms of idiopathic achalasia in both clinical symptoms and diagnostic findings,including those from highresolution manometry and barium esophagography.The similarities often lead to misdiagnosis and the delay of appropriate treatment management.Although most malignancy-associated pseudoachalasia cases are attributed to adenocarcinoma at the gastroesophageal junction,pseudoachalasia due to esophageal squamous cell carcinoma(ESCC)should also be considered.However,the diffuse infiltrative growth patterns that can occur with ESCC can make diagnosis challenging.CASE SUMMARY We report the case of a 60-year-old man who presented with progressive dysphagia,weight loss,and nocturnal cough.Esophagogastroduodenoscopy,timed barium esophagogram,and high-resolution manometry were conducted.The results of these investigations supported a diagnosis of type Ⅱ idiopathic achalasia.However,preoperative computed tomography revealed atypical findings,which prompted further evaluation.Repeat endoscopy with magnifying narrow-band imaging identified abnormal mucosal and vascular patterns,and endoscopic ultrasound demonstrated hypoechoic submucosal lesions with involvement of the muscularis propria.Targeted biopsies confirmed moderately differentiated ESCC.Positron emission tomography revealed extensive metastatic disease;therefore,the patient was diagnosed with stage IVB ESCC.Peroral endoscopic myotomy was aborted,and the patient was referred for palliative chemoradiotherapy.CONCLUSION Atypical malignant features should be critically examined.Multimodal tools such as magnifying narrow-band imaging and endoscopic ultrasound are essential for diagnosing pseudoachalasia.展开更多
基金Supported by“Continuation”Project of Excellent Doctors,Guangdong Basic and Applied Basic Research Foundation,No.2025A04J5082Guangdong Basic and Applied Basic Research Foundation,No.2024A1515011236.
文摘This letter addresses challenges in the clinical translation of BIBR1532,a promising telomerase inhibitor,for the treatment of esophageal squamous cell carcinoma(ESCC).BIBR1532 exerts its anti-cancer effect by activating DNA damage response(ATR/CHK1 and ATM/CHK2)pathways and downregulating telomere-binding proteins.Although its therapeutic potential is limited by poor aqueous solubility,solid dispersion(SD)technology may overcome this obstacle.Systematic analysis using PubChem-derived simplified molecular input line entry system identifiers and artificial intelligence-driven FormulationDT platform evaluation(oral formulation feasibility index:0.38)revealed that the SD technology,with superior scalability(32 approved products by 2021)and lower production risks,outperforms lipid-based formulations as an optimal dissolution strategy.Material analysis revealed hydroxypropyl methylcellulose(HPMC)as the optimal carrier with lower hygroscopicity,higher temperature and no intestinal targeting,thus enabling ESCC therapy.HPMC-based SD enhances BIBR1532 solubility and bioavailability for effective ESCC treatment.Future studies should focus on pilot tests for SD fabrication.
基金supported by the National Natural Science Foundation of China(Grant Nos.82272955 and 22203057)the Natural Science Foundation of Fujian Province(Grant No.2021J011361).
文摘The presence of a positive deep surgical margin in tongue squamous cell carcinoma(TSCC)significantly elevates the risk of local recurrence.Therefore,a prompt and precise intraoperative assessment of margin status is imperative to ensure thorough tumor resection.In this study,we integrate Raman imaging technology with an artificial intelligence(AI)generative model,proposing an innovative approach for intraoperative margin status diagnosis.This method utilizes Raman imaging to swiftly and non-invasively capture tissue Raman images,which are then transformed into hematoxylin-eosin(H&E)-stained histopathological images using an AI generative model for histopathological diagnosis.The generated H&E-stained images clearly illustrate the tissue’s pathological conditions.Independently reviewed by three pathologists,the overall diagnostic accuracy for distinguishing between tumor tissue and normal muscle tissue reaches 86.7%.Notably,it outperforms current clinical practices,especially in TSCC with positive lymph node metastasis or moderately differentiated grades.This advancement highlights the potential of AI-enhanced Raman imaging to significantly improve intraoperative assessments and surgical margin evaluations,promising a versatile diagnostic tool beyond TSCC.
文摘Dear Editor,Local recurrence and cervical lymph node metastases are major causes of mortality in patients with head and neck squamous cell carcinoma(HNSCC).To date,none of the proposed strategies for predicting outcomes in this disease have proven fully effective,and a comprehensive physical examination remains the primary method for early detection and monitoring of HNSCC.
基金supported by the National Natural Science Foundation of China(No.82003372)the Medical and Health Technology Project of Zhejiang Province(No.2024KY984),China.
文摘Basal cell carcinoma(BCC)and cutaneous squamous cell carcinoma(cSCC),as certain forms of nonmelanoma skin cancer(NMSC)or keratinocyte carcinoma,are the most common forms of malignant neoplasms worldwide(Sharp et al.,2024).BCC and cSCC have been identified as two major components of NMSC,comprising one-third of all malignancies(Burton et al.,2016).Generally speaking,patients with NMSC tend to have relatively favorable survival outcomes,while different histopathological subtypes of NMSC exhibit distinct biological behaviors(Stătescu et al.,2023).
基金supported by the National Natural Science Foundation of China(Grant No.82172567)the Key R&D Plan of Jiangxi Province(Grant No.2021BBG71006)the Key Project of Science and Technology Innovation of Health Commission of Jiangxi Province(Grant Nos.2023ZD005 and 2024ZD008).
文摘Dear Editor,Esophageal cancer(EC)is a malignant tumor originating from esophageal epithelium and remains a leading cause of cancer incidence and mortality worldwide1,2.According to the 2020 World Health Organization statistics,there were approx-imately 604,000 new EC cases and 544,000 EC-related deaths globally with China reporting approximately 320,000 new cases and 300,000 deaths,mainly from esophageal squamous cell carcinoma(ESCC)3.Although there has been progress in the treatment of EC,the long-term prognosis of patients with R0 resection and lymph node-positive disease contin-ues to be suboptimal4.A retrospective analysis performed by our center suggested that the median overall survival(OS)of lymph node-positive patients with EC who received postoper-ative adjuvant radiotherapy(PART)was 29 months compared to 21 months for surgery alone with 3-year survival rates of 43%and 36%,respectively,indicating a potential survival ben-efit of PART5.
基金Supported by the National Natural Science Foundation of China(No.82070934,No.82171025).
文摘AIM:To investigate the pathological features of ocular surface squamous neoplasia(OSSN)and evaluate the synergistic therapeutic effects of interferon-α2b(IFNα2b)and 5-fluorouracil(5-FU)on cellular proliferation,migration,apoptosis,and cell cycle of human oral squamous carcinoma cell line Cal27.METHODS:Tissue specimens from OSSN were processed with hematoxylin-eosin(HE)and immunofluorescence(IF)staining to characterize pathological changes.We analyzed the expression levels of four pivotal proteins involved in 5-FU metabolism:interferon alpha receptor(IFNAR),thymidylate synthase(TS),thymidine phosphorylase(TP),and dihydropyrimidine dehydrogenase(DPD).Cal27 cell lines were treated with a spectrum of concentrations of IFNα2b and 5-FU,either in isolation or in combination.Then,cell activity was measured utilizing CCK-8 assay and dose-effect curves were calculated,while tumor cell migration was detected by cell scratch experiments.Cal27 cells were added with IFNα2b and 5-FU in a non-constant ratio drug combination design and the corresponding combination index(CI)and fraction affected(Fa)were calculated with CompuSyn software.Western blot assay was conducted to quantify the expression of TP,TS,and DPD.Cell cycle and apoptosis were measured with flow cytometry and terminal deoxynucleotidyl transferasemediated dUTP nick and labeling(TUNEL)assay.RESULTS:Treatment with both IFNα2b and 5-FU inhibited cell proliferation.Except for the lowest and highest doses of 5-FU,CI values for all other groups were below 1,suggesting a synergistic interaction.Low concentrations of IFNα2b and 5-FU both diminished the relative mobility of Cal27 cells,instead,a stronger inhibitory effect was observed when the two drugs were co-applied.The expression levels of TP and DPD in Cal27 cells were dose-dependently increased at a low concentration of IFNα2b.Low-dose IFNα2b combined with 5-FU significantly inhibited cell proliferation in G0/G1 phase compared to 5-FU monotherapy.Medium and high doses of IFNα2b and all concentrations of 5-FU could induce apoptosis in a concentration-dependent manner.The susceptibility to 5-FU treatment and apoptosis rates of tumor cells were elevated with low doses of IFNα2b.CONCLUSION:Both IFNα2b and 5-FU,when administered individually or in combination,effectively suppress the proliferation and migration of Cal27 tumor cells,induce cell apoptosis and arrest cell cycle.Low doses of IFNα2b increase the antitumor effects of 5-FU on Cal27 potentially through up-regulating the expression of TP,demonstrating a synergistic effect between IFNα2b and 5-FU.
文摘AIM:To evaluate the demographics,clinical characteristics,treatments,and outcomes of patients with ocular surface squamous neoplasia(OSSN)at the Philippine General Hospital.METHODS:This was a single-center,11-year retrospective,cross sectional case series on 18 cases of OSSN seen between January 2012 to June 2023.The patient’s demographics,presenting symptoms,tumor characteristics,histopathologic diagnosis,treatment,outcomes,and duration of follow-up were reviewed.RESULTS:Out of 33 identified cases of OSSN,only 18 were eligible for inclusion in the study.Mean age was 60.78y(range 31 to 80),with male predominance(66.67%).The left eye was most commonly affected(61.11%)with most presenting with fleshy mass(83.33%).Most tumors were located nasally(66.67%)and were predominantly papilliform(44.44%)in morphology with associated hyperpigmentation(38.89%).Squamous cell carcinoma(SCCA)was the most common histopathologic diagnosis(72.22%).The main primary treatment was surgical excision(94.44%)with or without adjunctive therapy,with only 1 patient undergoing first-line topical chemotherapy.Only 3 recurrences(16.67%)were noted with a median followup of 7.5mo.A statistically significant recurrence-free odds leaning towards the utilization of cryotherapy was noted.CONCLUSION:OSSN seen at the Philippine General Hospital is presented as a limbal papilliform mass,most commonly affecting elderly males.Surgical excision with adjuvant cryotherapy and/or chemotherapy is the preferred mode of treatment.
基金Supported by the National Research Foundation of Korea,No.2020R1A2C1100891Soonchunhyang University Research Fund,No.2024-05-014.
文摘BACKGROUND The high prevalence of human papillomavirus(HPV)infection in oropharyngeal squamous cell carcinoma(SCC)is well established,and p16 expression is a strong predictor.HPV-related tumors exhibit unique mechanisms that target p16 and p53 proteins.However,research on HPV prevalence and the combined predictive value of p16 and p53 expression in head and neck cutaneous SCC(HNCSCC),particularly in Asian populations,remains limited.This retrospective study surveyed 62 patients with HNSCC(2011-2020),excluding those with facial warts or other skin cancer.AIM To explore the prevalence of HPV and the predictive value of p16 and p53 expression in HNCSCC in Asian populations.METHODS All patients underwent wide excision and biopsy.Immunohistochemical staining for HPV,p16,and p53 yielded positive and negative results.The relevance of each marker was investigated by categorizing the tumor locations into high-risk and middle-risk zones based on recurrence frequency.RESULTS Of the 62 patients,20(32.26%)were male,with an average age of 82.27 years(range 26-103 years).High-risk included 19 cases(30.65%),with the eyelid and lip being the most common sites(five cases,8.06%).Middle-risk included 43 cases(69.35%),with the cheek being the most common(29 cases,46.77%).The p16 expression was detected in 24 patients(38.71%),p53 expression in 42 patients(72.58%),and HPV in five patients(8.06%).No significant association was found between p16 expression and the presence of HPV(P>0.99),with a positive predictive value of 8.33%.CONCLUSION This study revealed that p16,a surrogate HPV marker in oropharyngeal SCC,is not reliable in HNCSCC,providing valuable insights for further research in Asian populations.
基金Supported by The National Natural Science Foundation of China,No.82350127 and No.82241013the Shanghai Natural Science Foundation,No.20ZR1411600+2 种基金the Shanghai Shenkang Hospital Development Center,No.SHDC2020CR4039the Bethune Ethicon Excellent Surgery Foundation,No.CESS2021TC04Xuhui District Medical Research Project of Shanghai,No.SHXH201805.
文摘BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis through binding to dif-ferent ligands.AIM To evaluate the correlation between single nucleotide polymorphisms(SNPs)of ACVR1C and susceptibility to esophageal squamous cell carcinoma(ESCC)in Chinese Han population.METHODS In this hospital-based cohort study,1043 ESCC patients and 1143 healthy controls were enrolled.Five SNPs(rs4664229,rs4556933,rs77886248,rs77263459,rs6734630)of ACVR1C were assessed by the ligation detection reaction method.Hardy-Weinberg equilibrium test,genetic model analysis,stratified analysis,linkage disequi-librium test,and haplotype analysis were conducted.RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC,and those with rs77886248 TA mutant were related with higher risk,especially in older male smokers.In the haplotype analysis,ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC,while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC,which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.
文摘BACKGROUND One of the main characteristics of oral squamous cell carcinoma(OSCC)is that it metastasizes to cervical lymph nodes frequently with a high degree of local invasiveness.A primary feature of malignant tumors is their penetration of neighboring tissues,such as lymphatic and blood arteries,due to the tumor cells'capacity to break down the extracellular matrix(ECM).Matrix metalloproteinases(MMPs)constitute a family of proteolytic enzymes that facilitate tissue remodeling and the degradation of the ECM.MMP-9 and MMP-13 belong to the group of extracellular matrix degrading enzymes and their expression has been studied in OSCC because of their specific functions.MMP-13,a collagenase family member,is thought to play an essential role in the MMP activation cascade by breaking down the fibrillar collagens,whereas MMP-9 is thought to accelerate the growth of tumors.Elevated MMP-13 expression has been associated with tumor behavior and patient prognosis in a number of malignant cases.AIM To assess the immunohistochemical expression of MMP-9 and MMP-13 in OSCC.METHODS A total of 40 cases with histologically confirmed OSCC by incisional biopsy were included in this cross-sectional retrospective study.The protocols for both MMP-9 and MMP-13 immunohistochemical staining were performed according to the manufacturer’s recommendations along with the normal gingival epithelium as a positive control.All the observations were recorded and Pearson’sχ²test with Fisher exact test was used for statistical analysis.RESULTS Our study showed no significant correlation between MMP-9 and MMP-13 staining intensity and tumor size.The majority of the patients were in advanced TNM stages(III and IV),and showed intense expression of MMP-9 and MMP-13.CONCLUSION The present study suggests that both MMP-9 and MMP-13 play an important and independent role in OSCC progression and invasiveness.Intense expression of MMP-9 and MMP-13,irrespective of histological grade of OSCC,correlates well with TNM stage.Consequently,it is evident that MMP-9 and MMP-13 are important for the invasiveness and progression of tumors.The findings may facilitate the development of new approaches for evaluating lymph node metastases and interventional therapy techniques,hence enhancing the prognosis of patients diagnosed with OSCC.
基金Supported by the National Key Research and Development Program of China,No.2023YFC2413800the Taishan Scholars Program of Shandong Province,No.tsqn202306344the National Natural Science Foundation of China,No.82270580 and No.82070552.
文摘BACKGROUND Early detection of esophageal squamous neoplasms(ESN)is essential for improving patient prognosis.Optical diagnosis of ESN remains challenging.Probebased confocal laser endomicroscopy(pCLE)enables accurate in vivo histological observation and optical biopsy of ESN.However,interpretation of pCLE images requires histopathological expertise and extensive training.Artificial intelligence(AI)has been widely applied in digestive endoscopy;however,AI for pCLE diagnosis of ESN has not been reported.AIM To develop a pCLE computer-aided diagnostic system for ESN and assess its diagnostic performance and assistant efficiency for nonexpert endoscopists.METHODS The intelligent confocal laser endomicroscopy(iCLE)system consists of image recognition(based on inception-ResNet V2),video diagnosis,and quality judgment modules.This system was developed using pCLE images and videos and evaluated through image and prospective video recognition tests.Patients between June 2020 and January 2023 were prospectively enrolled.Expert and nonexpert endoscopists and the iCLE independently performed diagnoses for pCLE videos,with histopathology as the gold standard.Thereafter,the non-expert endoscopists performed a second assessment with iCLE assistance.RESULTS A total of 25056 images from 2803 patients were selected for iCLE training and validation.Another 2442 images from 226 patients were used for testing.iCLE achieved a high accuracy of 98.3%,sensitivity of 95.3%and specificity of 98.8%for diagnosing ESN images.A total of 2581 patients underwent upper gastrointestinal pCLE examination and were prospectively screened;54 patients with suspected ESN were enrolled.Overall,187 videos from 67 lesions were assessed by iCLE,three nonexpert and three expert endoscopists.iCLE achieved a high accuracy,sensitivity and specificity of 90.9%,92.0%,and 90.2%,respectively.Compared to experts,iCLE showed significantly higher sensitivity(92.0%vs 80.4%;P<0.001)and negative predictive value(94.4%vs 87.7%;P=0.003).With iCLE assistance,nonexpert endoscopists showed significant improvements in accuracy(from 83.6%to 88.6%)and sensitivity(from 76.0%to 89.8%).CONCLUSION iCLE system demonstrated high diagnostic performance for ESN.It can assist nonexpert endoscopists in improving the diagnostic efficiency of pCLE for ESN and has the potential for reducing unnecessary biopsies.
基金supported by the Science and Technology Projects of Jilin Provincial Department of Science and Technology(Grant/Award Numbers:20240305037YY)National Key Research and Development Program of China(2021YFC2400603)+1 种基金the Joint Funds of the National Natural Science Foundation of China(Grant No.U23A20269)the Jilin University young teachers and students cross-disciplinary training project(Grant No.2023-JCXK-08,2024-JCXK-07)。
文摘Tongue squamous cell carcinoma(TSCC)is a prevalent malignancy that afflicts the head and neck area and presents a high incidence of metastasis and invasion.Accurate diagnosis and effective treatment are essential for enhancing the quality of life and the survival rates of TSCC patients.The current treatment modalities for TSCC frequently suffer from a lack of specificity and efficacy.Nanoparticles with diagnostic and photothermal therapeutic properties may offer a new approach for the targeted therapy of TSCC.However,inadequate accumulation of photosensitizers at the tumor site diminishes the efficacy of photothermal therapy(PTT).This study modified gold nanodots(AuNDs)with the TSCC-targeting peptide HN-1 to improve the selectivity and therapeutic effects of PTT.The Au-HN-1 nanosystem effectively targeted the TSCC cells and was rapidly delivered to the tumor tissues compared to the AuN Ds.The enhanced accumulation of photosensitizing agents at tumor sites achieved significant PTT effects in a mouse model of TSCC.Moreover,owing to its stable long-term fluorescence and high X-ray attenuation coefficient,the Au-HN-1 nanosystem can be used for fluorescence and computed tomography imaging of TSCC,rendering it useful for early tumor detection and accurate delineation of surgical margins.In conclusion,Au-HN-1 represents a promising nanomedicine for imaging-based diagnosis and targeted PTT of TSCC.
基金supported by the Basic Research Program of the Guizhou Science Cooperation Foundation Project(Grant Number:ZK[2021]466)Guizhou Provincial Health Commission(Grant Number:gzwkj2022-062).
文摘Background:Terpinen-4-ol(T4O),a key constituent of tea tree essential oil and various aromatic plants,has shown promising antiproliferative and pro-apoptotic effects in melanoma and other cancer types.However,its efficacy against cutaneous squamous cell carcinoma(cSCC)remains unclear.Thus,in this study,we investigated the in vivo and in vitro effects of T4O on cSCC cell lines and preliminarily explored its impacting pathways.Methods:Using CCK8 and assay colony formation,we assessed the viability of cSCC A431,SCL-1,and COLO-16 cells treated with T40 at varying concentrations(0,1,2,and 4μM).Flow cytometry was employed to evaluate T4O’s effect on cSCC cell’s cycle progression and apoptosis induction.Additionally,western blotting was utilized to examine the expression intensities of N-cadherin and E-cadherin,two indicative markers of the epithelial-mesenchymal transition(EMT)pathway.T4O’s in vivo effect on inhibiting tumor progression was evaluated on an established xenograft tumor model.Then,the molecular mechanisms of T4O’s antitumor effect were explored by an integrated genome-wide transcriptomics and proteomics study on cSCC A431c cells.Finally,calpain-2’s potential mediator role in T4O’s anti-tumor mechanism was investigated in calpain-2 knockdown cell lines prepared via siRNA transfection.Result:It’s demonstrated that T4O treatment inhibited cSCC proliferation,clonogenicity,migration,and invasion while inducing apoptosis and suppressing the EMT pathway.T4O administration also inhibited cSCC tumorigenesis in the xenograft tumor model.RNA-sequencing and iTRAQ analysis detected significant upregulation of calpain-2 expression in T4O-treated cSCC cells.Western blotting confirmed that T4O significantly increased calpain-2 expression and promoted proteolytic cleavage ofβ-catenin and caspase-12,two calpain-2 target proteins.Importantly,siRNA-mediated calpain-2 knockdown relieved T4O’s suppressive effect on cSCC cell proliferation and motility.Mechanistically,T4O upregulates calpain-2 expression and promotes the cleavage ofβ-catenin and caspase-12,with siRNA-mediated calpain-2 knockdown mitigating T4O’s suppressive effects.Conclusion:These findings suggest that T4O’s antitumor activity in cSCC is mediated through the upregulation of calpain-2 expression and subsequent modulation ofβ-catenin and caspase-12.
基金supported by the Scientific Research Fund of the National Health Commission-Zhejiang Provincial Health Major Science and Technology Plan Project(No.WKJ-ZJ-2415)the Key Research and Development Program of Zhejiang Province(No.2024C03166)+1 种基金the Traditional Chinese Medicine Science and Technology Project of Zhejiang Province(No.2022ZB020)the Zhejiang Provincial Natural Science Foundation of China(No.LY21H160049).
文摘Numerous studies have demonstrated that the high expression of CXC motif chemokine ligand 16(CXCL16)in cancer correlates with poor prognosis,as well as tumor cell proliferation,migration,and invasion.While CXCL16 can serve as a tumor biomarker,the underlying mechanism in modulating head and neck squamous cell carcinoma(HNSCC)remains unclear.In this study,the aimed was to investigate the CXCL16 expression in HNSCC and to uncover the potential underlying mechanism.Hereby,we determined the high expression of CXCL16 in The Cancer Genome Atlas(TCGA)database,as well as in tissue samples from patients with HNSCC at our central hospital and from HNSCC cell lines.The results showed that CXCL16 knockdown inhibited the proliferation,migration,and invasion of HNSCC cells.Mechanistically,transcriptome sequencing revealed that CXCL16 may affect HNSCC cell growth by regulating the antioxidant pathway of glutathione peroxidase 1(GPX1).The reactive oxygen species(ROS)levels were elevated in small interfering CXCL16(si-CXCL16)cells,which may contribute to the inhibition of cell proliferation,migration,and invasion.Moreover,treatment of cells with the GPX1 inhibitor eldecalcitol(ED-71)revealed that HNSCC cell growth was significantly inhibited in the synergistic group of si-CXCL16 and GPX1 inhibitor compared to the si-CXCL16 group.In conclusion,CXCL16 contributed to the development of HNSCC cells by modulating the GPX1-mediated antioxidant pathway.Thus,targeting cellular CXCL16 expression seems to be a promising strategy for treating HNSCC.
基金Supported by the Scientific Research Development Plan Project or the Scientific Research Foundation for Advanced Talents,Affiliated Hospital of North Sichuan Medical College,No.2023MPZK017,No.2023ZD001,No.2023-2ZD002,and No.2023GC009Science and Technology Support Program of Nanchong,No.22SXQT0001+1 种基金Youth Medical Innovation Research Project,or Medical Research Project of Sichuan Province,No.Q23047 and No.S23020Development of a Scientific Research Plan for the Doctoral Scientific Research Foundation of the North Sichuan Medical College,No.CBY22-ZDA03.
文摘BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a malignant tumor with high morbidity and mortality,and easy to develop resistance to chemotherapeutic agents.Telomeres are DNA-protein complexes located at the termini of chro-mosomes in eukaryotic cells,which are unreplaceable in maintaining the stability and integrity of genome.Telomerase,an RNA-dependent DNA polymerase,play vital role in telomere length maintain,targeting telomerase is a promising therapeutic strategy for cancer.KYSE150 and KYSE410 cells were cultured and exposed to various concentrations of BIBR1532.Cell viability was assessed at 48 hours and 72 hours to determine the IC50 values.The effects of BIBR1532 on ESCC cell proliferation,migration,and cellular senescence were evaluated using the cell counting kit-8 assay,plate colony formation assay,scratch assay,transwell assay,andβ-galactosidase staining,respectively.Western blotting was performed to detect the expression of RESULTS The IC50 values for KYSE150 and KYSE410 cells after 48 hours of BIBR1532 exposure were 48.53μM and 39.59μM,respectively.These values decreased to 37.22μM and 22.71μM,respectively,following a longer exposure of 72 hours.BIBR1532 exhibited dose-dependent effects on KYSE150 and KYSE410 cells,including decreased hTERT expression,inhibition of proliferation and metastasis,and induction of cellular senescence.Mechanistically,BIBR1532 upregulated the expression of the DDR protein,γ-H2AX,and activated the ataxia telangiectasia and Rad3-related protein(ATR)/check point kinase 1(CHK-1)and ataxia-telangiectasia mutated gene(ATM)/CHK2 pathways.BIBR1532 downregulated the expression of telomere-binding proteins,including telomeric-repeat binding factor 1(TRF1),TRF2,protection of telomeres 1,and TIN2-interacting protein 1.In a nude mouse xenograft model,BIBR1532 significantly suppressed tumor growth,reduced hTERT expression,and increasedγ-H2AX protein levels.Hematoxylin and eosin staining of various organs,including the heart,liver,spleen,lungs,and kidneys,revealed no apparent adverse effects.CONCLUSION BIBR1532 exerts anti-cancer effects on ESCC by inducing DDR through the ATR/CHK1 and ATM/CHK2 pathways and downregulating the expression of telomere-binding proteins.
文摘BACKGROUND Primary squamous cell carcinoma(SCC)of the renal parenchyma is extremely rare,with only nine cases reported.CASE SUMMARY This study reports a 51-year-old man with primary SCC of the renal parenchyma.The patient was admitted with recurrent dull pain and discomfort in the right lumbar region,which had worsened over 2 weeks,accompanied by painful gross hematuria.SCC antigen(SCCA)levels were elevated,and imaging revealed a renal mass with associated calculi.The patient underwent laparoscopic unilateral nephrectomy and lymph node dissection.Postoperative pathology confirmed highly differentiated SCC with necrosis in the right renal parenchyma,with negative renal pelvis and ureter.The pathological stage was Pt3aN1M0.Four months after surgery,the tumor recurred with involvement of the liver,right psoas major muscle,and inferior vena cava.The patient refused chemotherapy and succumbed to the disease 6 months postoperatively due to disease progression.CONCLUSION We report a case of primary SCC of the renal parenchyma,a rare renal malignancy.The clinical symptoms,laboratory tests,and imaging findings are nonspecific,making accurate and timely diagnosis challenging.According to the literature,for patients with renal calculi accompanied by a renal mass,elevated serum SCCA levels,and magnetic resonance imaging showing cystic or cystic-solid masses within the kidney with pseudocapsules and heterogeneous mild enhancement,the possibility of this disease should be considered.
文摘Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiology is multifactorial,involving tobacco use,alcohol consumption,and human papillomavirus(HPV)infection.Oral leukoplakia and erythroplakia are the main precancerous lesions lesions,with oral leukoplakia being the most common.Both OSCC and premalignant lesions are closely associated with aberrant activation of multiple signaling pathways.Post-translational modifications(such as ubiquitination and deubiquitination)play key roles in regulating these pathways by controlling protein stability and activity.Growing evidence indicates that dysregulated ubiquitination/deubiquitination can mediate OSCC initiation and progression via aberrant activation of signaling pathways.The ubiquitination/deubiquitination process mainly involves E3 ligases(E3s)that catalyze substrate ubiquitination,deubiquitinating enzymes(DUBs)that remove ubiquitin chains,and the 26S proteasome complex that degrades ubiquitinated substrates.Abnormal expression or mutation of E3s and DUBs can lead to altered stability of critical tumorrelated proteins,thereby driving OSCC initiation and progression.Therefore,understanding the aberrantly activated signaling pathways in OSCC and the ubiquitination/deubiquitination mechanisms within these pathways will help elucidate the molecular mechanisms and improve OSCC treatment by targeting relevant components.Here,we summarize four aberrantly activated signaling pathways in OSCC―the PI3K/AKT/mTOR pathway,Wnt/β-catenin pathway,Hippo pathway,and canonical NF-κB pathway―and systematically review the regulatory mechanisms of ubiquitination/deubiquitination within these pathways,along with potential drug targets.PI3K/AKT/mTOR pathway is aberrantly activated in approximately 70%of OSCC cases.It is modulated by E3s(e.g.,FBXW7 and NEDD4)and DUBs(e.g.,USP7 and USP10):FBXW7 and USP10 inhibit signaling,while NEDD4 and USP7 potentiate it.Aberrant activation of the Wnt/β-catenin pathway leads toβ-catenin nuclear translocation and induction of cell proliferation.This pathway is modulated by E3s(e.g.,c-Cbl and RNF43)and DUBs(e.g.,USP9X and USP20):c-Cbl and RNF43 inhibit signaling,while USP9X and USP20 potentiate it.Hippo pathway inactivation permits YAP/TAZ to enter the nucleus and promotes cancer cell metastasis.This pathway is modulated by E3s(e.g.,CRL4^(DCAF1) and SIAH2)and DUBs(e.g.,USP1 and USP21):CRL4^(DCAF1) and SIAH2 inhibit signaling,while USP1 and USP21 potentiate it.Persistent activation of the canonical NF-κB pathway is associated with an inflammatory microenvironment and chemotherapy resistance.This pathway is modulated by E3s(e.g.,TRAF6 and LUBAC)and DUBs(e.g.,A20 and CYLD):A20 and CYLD inhibit signaling,while TRAF6 and LUBAC potentiate it.Targeting these E3s and DUBs provides directions for OSCC drug research.Small-molecule inhibitors such as YCH2823(a USP7 inhibitor),GSK2643943A(a USP20 inhibitor),and HOIPIN-8(a LUBAC inhibitor)have shown promising antitumor activity in preclinical models;PROTAC molecules,by binding to surface sites of target proteins and recruiting E3s,achieve targeted ubiquitination and degradation of proteins insensitive to small-molecule inhibitors,for example,PU7-1-mediated USP7 degradation,offering new strategies to overcome traditional drug limitations.Currently,NX-1607(a Cbl-b inhibitor)has entered phase I clinical trials,with preliminary results confirming its safety and antitumor activity.Future research on aberrant E3s and DUBs in OSCC and the development of highly specific inhibitors will be of great significance for OSCC precision therapy.
基金supported by the Hebei Provincial Central Guidance Local Science and Technology Development Fund(grant number 236Z7714G).
文摘Cervical cancer is a major malignancy that poses a significant threat to women's health[1].In 2020,an estimated 604,000 new cases and 342,000 deaths were reported globally[2].The most common pathological subtype is squamous cell carcinoma[3,4].However,treatment options for advanced cervical squamous cell carcinoma(CSCC)are limited.Surgery is often not feasible at this stage,resulting in poor prognosis[5,6].Therefore,identifying novel molecular markers and elucidating the mechanisms that drive CSCC growth and metastasis are crucial for improving treatment outcomes.
文摘The strong association between human papillomavirus(HPV)infection and oropharyngeal squamous cell carcinoma(SCC)is well-documented,with p16 expression serving as a reliable predictor of HPV involvement.HPV-related tumors are characterized by distinct mechanisms affecting p16 and p53 protein pathways.However,the prevalence of HPV and the combined predictive utility of p16 and p53 expression in head and neck cutaneous SCC remain less explored,necessitating further research to understand their role in this subset of SCC.HPV,p16,and p53 statuses were determined using immunohistochemistry staining methods rather than more sensitive techniques such as polymerase chain reaction or HPV genotyping,limiting the ability to assess specific area HPV types poten-tially associated with prognosis.Further studies assessing multiple molecular markers in head and neck cutaneous patients will better predict the diverse outcomes and potentially the type of treatment targeted to those markers.
文摘BACKGROUND Pseudoachalasia closely mimics the clinical symptoms of idiopathic achalasia in both clinical symptoms and diagnostic findings,including those from highresolution manometry and barium esophagography.The similarities often lead to misdiagnosis and the delay of appropriate treatment management.Although most malignancy-associated pseudoachalasia cases are attributed to adenocarcinoma at the gastroesophageal junction,pseudoachalasia due to esophageal squamous cell carcinoma(ESCC)should also be considered.However,the diffuse infiltrative growth patterns that can occur with ESCC can make diagnosis challenging.CASE SUMMARY We report the case of a 60-year-old man who presented with progressive dysphagia,weight loss,and nocturnal cough.Esophagogastroduodenoscopy,timed barium esophagogram,and high-resolution manometry were conducted.The results of these investigations supported a diagnosis of type Ⅱ idiopathic achalasia.However,preoperative computed tomography revealed atypical findings,which prompted further evaluation.Repeat endoscopy with magnifying narrow-band imaging identified abnormal mucosal and vascular patterns,and endoscopic ultrasound demonstrated hypoechoic submucosal lesions with involvement of the muscularis propria.Targeted biopsies confirmed moderately differentiated ESCC.Positron emission tomography revealed extensive metastatic disease;therefore,the patient was diagnosed with stage IVB ESCC.Peroral endoscopic myotomy was aborted,and the patient was referred for palliative chemoradiotherapy.CONCLUSION Atypical malignant features should be critically examined.Multimodal tools such as magnifying narrow-band imaging and endoscopic ultrasound are essential for diagnosing pseudoachalasia.
