Amyloid-beta pathology-induced nanoscale synaptic disruption:the case of the GABA_B-GIRK assembly

Alzheimer's disease (AD) is characterized by an imbalance between excitatory and inhibitory brain networks,leading to aberrant homeostatic synaptic plasticity.AD has progressively been recognized as syna ptopathy and syna ptic dysfunction has been identified as a key component of its pathogenesis (Schirinzi et al.,2020).Syna ptic dysfunction is believed to precede synapse loss,a primary biological correlate of cognitive decline in AD,inevita bly associated with neuronal death.

Dysregulation of genes involved in the long-chain fatty acid transport in pancreatic ductal adenocarcinoma

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is an aggressive lethal malignancy with limited options for treatment and a 5-year survival rate of 11%in the United States.As for other types of tumors,such as colorectal cancer,aberrant de novo lipid synthesis and reprogrammed lipid metabolism have been suggested to be associated with PDAC development and progression.AIM To identify the possible involvement of lipid metabolism in PDAC by analyzing in tumoral and non-tumoral tissues the expression level of the most relevant genes involved in the long-chain fatty acid(FA)import into cell.METHODS A gene expression analysis of FASN,CD36,SLC27A1,SLC27A2,SLC27A3,SLC27A4,SLC27A5,ACSL1,and ACSL3 was performed by qRT-PCR in 24 tumoral PDAC tissues and 11 samples from non-tumoral pancreatic tissues obtained via fine needle aspiration or via surgical resection.The genes were considered significantly dysregulated between the groups when the p value was<0.05 and the fold change(FC)was≤0.5 and≥2.RESULTS We found that three FA transporters and two long-chain acyl-CoA synthetases genes were significantly upregulated in the PDAC tissue compared to the non-tumoral tissue:SLC27A2(FC=5.66;P=0.033),SLC27A3(FC=2.68;P=0.040),SLC27A4(FC=3.13;P=0.033),ACSL1(FC=4.10;P<0.001),and ACSL3(FC=2.67;P=0.012).We further investigated any possible association between the levels of the analyzed mRNAs and the specific characteristics of the tumors,including the anatomic location,the lymph node involvement,and the presence of metastasis.A significant difference in the expression of SLC27A3(FC=3.28;P=0.040)was found comparing patients with and without lymph nodes involvement with an overexpression of this transcript in 17 patients presenting tumoral cells in the lymph nodes.CONCLUSION Despite the low number of patients analyzed,these preliminary results seem to be promising.Addressing lipid metabolism through a broad strategy could be a beneficial way to treat this malignancy.Future in vitro and in vivo studies on these genes may offer important insights into the mechanisms linking PDAC with the long-chain FA import pathway.

Pharmacological targeting cGAS/STING/NF-κB axis by tryptanthrin induces microglia polarization toward M2 phenotype and promotes functional recovery in a mouse model of spinal cord injury

The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury.Regulation of shifting microglia polarization from M1(neurotoxic and proinflammatory type)to M2(neuroprotective and anti-inflammatory type)after spinal cord injury appears to be crucial.Tryptanthrin possesses an anti-inflammatory biological function.However,its roles and the underlying molecular mechanisms in spinal cord injury remain unknown.In this study,we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro.Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway.Additionally,we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury,inhibited neuronal loss,and promoted tissue repair and functional recovery in a mouse model of spinal cord injury.Finally,using a conditional co-culture system,we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress-related neuronal apoptosis.Taken together,these results suggest that by targeting the cGAS/STING/NF-κB axis,tryptanthrin attenuates microglia-derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.

Expression rates of p16,p53 in head and neck cutaneous squamous cell carcinoma based on human-papillomavirus positivity

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.

Primary parenchymal squamous cell carcinoma of the kidney:A case report

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.

Scapular metastasis from acinic cell carcinoma of parotid gland:A case report

BACKGROUND Acinic cell carcinoma(ACC)is a malignant epithelial neoplasm that commonly occurs in the parotid gland.It is known to have a high recurrence rate and the potential to metastasize to the lung or cervical lymph nodes.However,few cases of ACC with bone metastasis have been reported in the medical literature.CASE SUMMARY The clinical significance of this case report lies in the unique site of occurrence of the metastasis:To the best of our knowledge,this report is the only literature documenting ACC arising in a shoulder mass.CONCLUSION Unusual presentations of uncommon malignancies can present diagnostic challenges for both surgeons and histopathologists.It is important to be aware of these rare occurrences in order to provide the best possible treatment for patients.

Targeted gene sequencing and bioinformatics analysis of patients with gallbladder neuroendocrine carcinoma:A case report

BACKGROUND Gallbladder neuroendocrine carcinoma(NEC)represents a subtype of gallbladder malignancies characterized by a low incidence,aggressive nature,and poor prognosis.Despite its clinical severity,the genetic alterations,mechanisms,and signaling pathways underlying gallbladder NEC remain unclear.CASE SUMMARY This case study presents a rare instance of primary gallbladder NEC in a 73-year-old female patient,who underwent a radical cholecystectomy with hepatic hilar lymphadenectomy and resection of liver segments IV-B and V.Targeted gene sequencing and bioinformatics analysis tools,including STRING,GeneMANIA,Metascape,TRRUST,Sangerbox,cBioPortal and GSCA,were used to analyze the biological functions and features of mutated genes in gallbladder NEC.Twelve mutations(APC,ARID2,IFNA6,KEAP1,RB1,SMAD4,TP53,BTK,GATA1,GNAS,and PRDM3)were identified,and the tumor mutation burden was determined to be 9.52 muts/Mb via targeted gene sequencing.A protein-protein interaction network showed significant interactions among the twelve mutated genes.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were used to assess mutation functions and pathways.The results revealed 40 tumor-related pathways.A key regulatory factor for gallbladder NEC-related genes was identified,and its biological functions and features were compared with those of gallbladder carcinoma.CONCLUSION Gallbladder NEC requires standardized treatment.Comparisons with other gallbladder carcinomas revealed clinical phenotypes,molecular alterations,functional characteristics,and enriched pathways.

Overexpression pattern,function,and clinical value of proteasome 26S subunit non-ATPase 6 in hepatocellular carcinoma

BACKGROUND In recent years,many studies have shown that proteasome 26S subunit non-ATPase 6(PSMD6)plays an important role in the occurrence and development of malignant tumours.Unfortunately,there are no reports on the evaluation of the potential role of PSMD6 in hepatocellular carcinoma(HCC).AIM To comprehensively evaluate the overexpression pattern and clinical significance of PSMD6 in HCC tissues.METHODS This study integrated PSMD6 mRNA expression profiles from 4672 HCC and 3667 non-HCC tissues,along with immunohistochemical scores from 383 HCC and adjacent tissues,to assess PSMD6 overexpression in HCC.Clustered regularly interspaced short palindromic repeats knockout technology evaluated PSMD6’s essential role in HCC cell growth.Functional enrichment analysis explored the molecular mechanism of PSMD6 abnormalities in HCC.Drug sensitivity analysis and molecular docking analysed the effect of abnormal expression of PSMD6 on the drug sensitivity of HCC cells.RESULTS The results of 41 external and two internal datasets showed that PSMD6 mRNA(SMD=0.26,95%CI:0.09-0.42,P<0.05)and protein(SMD=2.85,95%CI:1.19-4.50,P<0.05)were significantly overexpressed in HCC tissues.The integrated analysis results showed that PSMD6 had a significant overexpression pattern in HCC tissues(SMD=0.40,95%CI:0.15-0.66,P<0.05).PSMD6 knockout inhibited HCC cell growth(chronos scores<-1).Functional enrichment implicated ribosome biogenesis and RNA splicing.Significant enrichment of signalling pathways such as RNA degradation,ribosomes,and chemical carcinogenesis—reactive oxygen species.Drug sensitivity analysis and a molecular docking model showed that high expression of PSMD6 was associated with the tolerance of HCC cells to drugs such as ML323,sepantronium bromide,and GDC0810.Overexpressed PSMD6 effectively distinguished HCC tissues(AUC=0.75,95%CI:0.71-0.79).CONCLUSION This study was the first to discover that PSMD6 was overexpressed in HCC tissues.PSMD6 is essential for the growth of HCC cells and may be involved in ribosome biogenesis and RNA splicing.

High Expression of INF2 Predicts Poor Prognosis and Promotes Hepatocellular Carcinoma Progression

Objective INF2 is a member of the formins family.Abnormal expression and regulation of INF2 have been associated with the progression of various tumors,but the expression and role of INF2 in hepatocellular carcinoma(HCC)remain unclear.HCC is a highly lethal malignant tumor.Given the limitations of traditional treatments,this study explored the expression level,clinical value and potential mechanism of INF2 in HCC in order to seek new therapeutic targets.Methods In this study,we used public databases to analyze the expression of INF2 in pan-cancer and HCC,as well as the impact of INF2 expression levels on HCC prognosis.Quantitative real time polymerase chain reaction(RT-qPCR),Western blot,and immunohistochemistry were used to detect the expression level of INF2 in liver cancer cells and human HCC tissues.The correlation between INF2 expression and clinical pathological features was analyzed using public databases and clinical data of human HCC samples.Subsequently,the effects of INF2 expression on the biological function and Drp1 phosphorylation of liver cancer cells were elucidated through in vitro and in vivo experiments.Finally,the predictive value and potential mechanism of INF2 in HCC were further analyzed through database and immunohistochemical experiments.Results INF2 is aberrantly high expression in HCC samples and the high expression of INF2 is correlated with overall survival,liver cirrhosis and pathological differentiation of HCC patients.The expression level of INF2 has certain diagnostic value in predicting the prognosis and pathological differentiation of HCC.In vivo and in vitro HCC models,upregulated expression of INF2 triggers the proliferation and migration of the HCC cell,while knockdown of INF2 could counteract this effect.INF2 in liver cancer cells may affect mitochondrial division by inducing Drp1 phosphorylation and mediate immune escape by up-regulating PD-L1 expression,thus promoting tumor progression.Conclusion INF2 is highly expressed in HCC and is associated with poor prognosis.High expression of INF2 may promote HCC progression by inducing Drp1 phosphorylation and up-regulation of PD-L1 expression,and targeting INF2 may be beneficial for HCC patients with high expression of INF2.

LncRNA PCAT6 promotes progression and metastasis of colonic neuroendocrine carcinoma via MAPK pathway

BACKGROUND Colonic neuroendocrine carcinomas(NECs)are highly malignant and invasive with poor prognosis.Long noncoding RNAs(LncRNAs)participate in the tumorigenesis and metastasis of multiple cancers AIM To detect the roles and mechanisms of lncRNA prostate cancer associated transcript 6(PCAT6)in the progression of colonic NEC.METHODS Human NEC and adjacent normal samples were collected for immunohistochemistry staining of CgA and real-time quantitative polymerase chain reaction(RT-qPCR)of PCAT6 mRNA level.Subcutaneous xenograft tumor model and lung metastasis model were established in nude mice.The lung tissues were stained by hematoxylin and eosin to assess pulmonary metastasis.The expression of epithelial-mesenchymal transition(EMT)-related markers and pathway-related genes was measured by RT-qPCR and western blotting.CD56 expression was assessed by immunofluorescence staining.The biological functions of PCAT6 were examined by cell counting kit-8,colony formation assays,Transwell assays and wound healing assays.The interaction between PCAT6 and its potential downstream target was verified by luciferase reporter assays.RESULTS LncRNA PCAT6 was upregulated in human NEC samples and LCC-18 cells,and its high expression was positively correlated with poor prognosis in patients with colonic NEC.Additionally,the expression of PCAT6 was positively associated with the proliferation,migration,invasion,and EMT of LCC-18 cells.Moreover,PCAT6 facilitated tumor growth,lung metastasis and EMT in xenografts.Mechanistically,PCAT6 promoted the activation of MAPK to enhance the EMT in colonic NEC by targeting miR-326.CONCLUSION In conclusion,lncRNA PCAT6 accelerates the process of colonic NEC by activating ERK/p38 MAPK signaling through targeting miR-326.These results might provide useful information for exploring the potential therapeutic targets in colonic NEC.

Clinical and endoscopic characteristics of colorectal traditional serrated adenomas with dysplasia/adenocarcinoma in a Korean population

BACKGROUND Traditional serrated adenoma(TSA)is a rare and precancerous lesion of colorectal cancer.The clinical and endoscopic differentiations between TSAs without dysplasia or adenocarcinoma(TSAOs)and TSAs with dysplasia or adenocarcinoma(TSADs)remain unclear.AIM To evaluate the characteristics of colorectal TSAs and compare the characteristics of TSAOs with those of TSADs.METHODS This retrospective study included 193 patients who underwent endoscopic resection and received a pathologic diagnosis of TSA.We reviewed the medical,endoscopic,and histopathologic records of patients who underwent endoscopic resection of TSAs between January 2010 and December 2023.RESULTS TSAs were more frequently located in the rectosigmoid colon.Most TSAs had 0-Ip,0-Isp,or 0-Is morphologies.The TSAD lesions were larger than TSAO lesions.TSAD lesions more commonly had a red color and an irregular border than TSAO lesions.TSAOs were usually treated using conventional endoscopic mucosal resection,whereas TSADs were treated using conventional endoscopic mucosal resection,endoscopic submucosal dissection,and surgery.Post-polypectomy bleeding was more common with TSADs than with TSAOs.Univariate analysis showed that gastrointestinal bleeding,red color,0-IIa,irregular border,and lobular mucosal surface were significantly associated with TSADs.Multivariate analysis showed that gastrointestinal bleeding,an irregular border,and a lobular mucosal surface were significantly associated with TSADs.CONCLUSION TSAs with gastrointestinal bleeding,an irregular border,and a lobular mucosal surface are associated with an increased risk of dysplasia or adenocarcinoma.

Unveiling expression patterns,mechanisms,and therapeutic opportunities of transmembrane protein 106C:From pan-cancers to hepatocellular carcinoma

BACKGROUND Although transmembrane protein 106C(TMEM106C)has been elucidated to be overexpressed in cancers,its underlying mechanisms have not yet been fully understood.AIM To investigate the expression levels and molecular mechanisms of TMEM106C across 34 different cancer types,including liver hepatocellular carcinoma(LIHC).METHODS We analyzed TMEM106C expression patterns in pan-cancers using microenvironment cell populations counter to evaluate its association with the tumor microenvironment.Gene set enrichment analysis was conducted to identify molecular pathways related to TMEM106C.Chromatin immunoprecipitation followed by sequencing(ChIP-seq)analysis was conducted to identify upstream transcriptional regulators of TMEM106C.In LIHC,we examined mRNA profiles,performed in-house quantitative polymerase chain reaction,immunohistochemistry,and constructed a co-expression gene network.Functional assays,including cell counting kit-8,cell cycle,apoptosis,migration,and invasion,were conducted.The effect of nitidine chloride(NC)on LIHC xenograft was evaluated through RNA sequencing and molecular docking.Finally,potential therapeutic agents targeting TMEM106C were predicted.RESULTS TMEM106C was significantly overexpressed in 27 different cancer types and presaged poor prognosis in four of these types,including LIHC.Across pan-cancers,TMEM106C was inversely correlated to the abundances of immune and stromal cells.Furthermore,TMEM106C was significantly linked to cell cycle and DNA replication pathways in pan-cancers.ChIP-seq analysis predicted CCCTC-binding factor as a pivotal transcriptional factor targeting the TMEM106C gene in pan-cancers.Integrated analysis showed that TMEM106C was upregulated in 4657 LIHC compared with 3652 normal liver tissue[combined standardized mean difference=1.31(1.09,1.52)].Inhouse LIHC samples verified the expression status of TMEM106C.Higher TMEM106C expression signified worse survival conditions in LIHC patients treated with sorafenib,a tyrosine kinase inhibitor(TKI).Co-expressed analysis revealed that TMEM106C were significantly enriched in the cell cycle pathway.Knockout experiments demonstrated that TMEM106C plays a crucial role in LIHC cell proliferation,migration,and invasion,with cell cycle arrest occurring at the DNA synthesis phase,and increased apoptosis.Notably,TMEM106C upregulation was attenuated by NC treatment.Finally,TMEM106C expression levels were significantly correlated with the drug sensitivity of anti-hepatocellular carcinoma agents,including JNJ-42756493,a TKI agent.CONCLUSION Overexpressed TMEM106C was predicted as an oncogene in pan-cancers,which may serve as a promising therapeutic target for various cancers,including LIHC.Targeting TMEM106C could potentially offer a novel direction in overcoming TKI resistance specifically in LIHC.Future research directions include in-depth experimental validation and exploration of TMEM106C’s role in other cancer types.

Histopathological diagnosis of microvascular invasion in hepatocellular carcinoma:Is it reliable?

BACKGROUND Microvascular invasion(MVI)is a critical prognostic factor for postoperative hepatocellular carcinoma recurrence,but the reliability of its current pathological diagnosis remains uncertain.AIM To evaluate the accuracy of current 7-point sampling methods and propose an optimal pathological protocol using whole-mount slide imaging(WSI)for better MVI detection.METHODS We utilized 40 New Zealand white rabbits to establish VX2 liver tumor models.The entire tumor-containing liver lobe was subsequently obtained,following which five different sampling protocols(A-E)were employed to evaluate the detection rate,accuracy,quantity,and distribution of MVI,with the aim of identifying the optimal sampling method.RESULTS VX2 liver tumor models were successfully established in 37 rabbits,with an incidence of MVI of 81.1%(30/37).The detection rates[27%(10/37),43%(16/37),62%(23/37),68%(25/37),and 93%(14/15)]and quantity(15,36,107,125,and 395)of MVI increased significantly from protocols A to E.The distribution of MVI showed fewer MVIs farther away from the tumor,but the percentage of MVI detected quantity gradually increased from 6.7%to 48.3%in the distant nonneoplastic liver tissue from protocols A to E.Protocol C was identified as the optimal sampling method by comparing them in sequence.The sampling protocol of three consecutive interval WSIs at the tumor center(WSI3)was further screened to determine the optimal number of WSIs.Protocol A(7-point sampling method)exhibited only 46%accuracy and a high false-negative rate of 67%.Notably,the WSI3 protocol improved the accuracy to 78%and decreased the false-negative rate to 27%.CONCLUSION The current 7-point sampling method has a high false-negative rate in MVI detection.In contrast,the WSI3 protocol provides a practical and effective approach to improve MVI diagnostic accuracy,which is crucial for hepatocellular carcinoma diagnosis and treatment planning.

Clinicopathological features and treatment of gastrointestinal schwannomas

BACKGROUND Gastrointestinal schwannomas(GIS)are rare neurogenic tumors arising from Schwann cells in the gastrointestinal tract.Studies on GIS are limited to small case reports or focus on specific tumor sites,underscoring the diagnostic and thera-peutic challenges they pose.AIM To comprehensively examine the clinical features,pathological characteristics,treatment outcomes,associated comorbidities,and prognosis of GIS.METHODS The study population included patients diagnosed with GIS at the First Affiliated Hospital,Zhejiang University School of Medicine,between June 2007 and April 2024.Data were retrospectively collected and analyzed from medical records,including demographic characteristics,endoscopic and imaging findings,treatment modalities,pathological evaluations,and follow-up information.RESULTS In total,229 patients with GIS were included,with a mean age of 56.00 years and a male-to-female ratio of 1:1.83.The mean tumor size was 2.75 cm,and most(76.9%)were located in the stomach.Additionally,6.6%of the patients had other malig-nant tumors.Preoperative imaging and endoscopy frequently misdiagnosed GIS as gastrointestinal stromal tumors.However,accurate preoperative diagnosis was achieved using endoscopic ultrasound-guided fine-needle aspiration combined with immunohistochemical analysis,in which S100 and SOX-10 markers were mostly positive.Smaller tumors were typically managed with endoscopic resection,while larger lesions were treated with surgical resection.Follow-up results showed that most patients experienced favorable outcomes.CONCLUSION Preoperative diagnosis of GIS via clinical characteristics,endoscopy,and imaging examinations remains challenging but crucial.Endoscopic therapy provides a minimally invasive and effective option for patients.

Important role of lymphovascular and perineural invasion in prognosis of colorectal cancer patients with N1c disease

BACKGROUND Lymphovascular invasion(LVI)and perineural invasion(PNI)are associated with decreased survival in colorectal cancer(CRC),but its significance in N1c stage remains to be clearly defined.AIM We retrospectively identified 107 consecutive patients who had CRC with N1c disease radically resected at our hospital.Tumors were reviewed for LVI and PNI by one pathologist blinded to the patients’outcomes.Disease-free survival(DFS),overall survival(OS)and cancer-specific survival(CSS)were determined using the Kaplan-Meier method,with LVI and PNI prognosis differences determined by multivariate analysis using the Cox multiple hazards model.Results were compared using log-rank test.The receiver operating characteristic(ROC)curve was used to evaluate the prognostic predictive ability.RESULTS The median follow-up time was 63.17(45.33-81.37)months for DFS,with 33.64%(36/107)of patients experiencing recurrence;21.5%of tumors were found to be LVI positive and 44.9%PNI positive.The 5-year DFS rate was greater for patients with LVI-negative tumors compared with LVI-positive tumors(74.0%vs 35.6%),and PNI was similar(82.5%vs 45.1%).On multivariate analysis,LVI[hazard ratio(HR)=3.368,95%confidence interval(CI):1.628-6.966,P=0.001]and PNI(HR=3.055,95%CI:1.478-6.313,P=0.002)were independent prognostic factors for DFS.All patients could be divided into three groups of patients with different prognosis according to LVI and PNI.The 5-year ROC curve for LVI,PNI and their combination prediction of DFS was 0.646,0.709 and 0.759,respectively.Similar results were seen for OS and CSS.CONCLUSION LVI and PNI could serve as independent prognostic factors of outcomes in N1c CRC patients.Patients with LVI or PNI should be given more attention during treatment.

Five-year complete remission of super-giant hepatocellular carcinoma with hepatectomy followed by sorafenib plus camrelizumab:A case report

BACKGROUND Cirrhotic patients with super-giant hepatocellular carcinoma(HCC)and portal vein invasion generally have a poor prognosis.This paper presents a patient with super-giant HCC and portal vein invasion,who underwent hepatectomy followed by a combination of sorafenib and camrelizumab,resulting in complete remission(CR)for 5 years.CASE SUMMARY A 40-year-old male with compensated hepatitis B-related cirrhosis was diagnosed with HCC,Barcelona Clinic Liver Cancer stage C.Enhanced computed tomography imaging revealed a 152 mm×171 mm tumor in the right liver,invading the portal vein and hepatic vein.Liver function was normal.The patient successfully underwent hepatectomy on July 18,2019.However,by December 2019,HCC recurrence with lung metastases and portal vein invasion were detected.He started treatment with sorafenib(200 mg twice daily)and camrelizumab(200 mg every 3 weeks).By May 12,2020,the patient was confirmed to have CR.Camrelizumab was adjusted to 200 mg every 12 weeks from June 16,2021,with the last infusion on March 29,2024.Although no further tumor recurrence was observed,he experienced two episodes of gastrointestinal bleeding due to esophagogastric varices,which were managed with endoscopic therapy.To date,the patient has remained in CR for 5 years.CONCLUSION The combination of hepatectomy with sorafenib and camrelizumab can achieve durable CR in patients with supergiant HCC and portal vein invasion.Further research is necessary to address these challenges and improve patient outcomes.

Effect of brush rinse on the diagnostic accuracy of biliary stricture evaluation:A multicenter trial

BACKGROUND Brush cytology is the most commonly used technique for tissue acquisition during endoscopic retrograde cholangiopancreatography for the evaluation of biliary strictures.Nonetheless,brush cytology is limited by its low sensitivity due to insufficient cellular yield.AIM To evaluate the impact of the sheath-rinse technique on improving the cellularity yield.METHODS A total of 112 patients with suspected malignant biliary strictures were enrolled at two tertiary centers in South Korea.The sample cellularity and diagnostic accuracy of brush-wash and sheath-rinse specimens were compared.RESULTS A significantly increased number of total cell clusters per representative 20×field was recorded in the sheath-rinse compared with the brush-wash specimens(median:12 vs 3,P<0.001).This trend persisted when large(>50 cells)clusters(median:8 vs 3,P<0.001),medium(6-49 cells)(median:7 vs 3,P<0.001),and small(2-5 cells)clusters(median:9 vs 3,P<0.001)were evaluated.Diagnostic accuracy and sensitivity for differentiating malignancy were superior with sheath-rinsing than with the brush-wash method(72.3%vs 62.5%,P<0.001 and 69.9%vs 59.2%,P<0.001,respectively).CONCLUSION Incorporating sheath-rinse specimens significantly improved the yield and diagnostic accuracy of biliary brush cytology.Sheath-rinsing should be integrated into routine clinical practice to improve diagnostic performance for biliary strictures.

Evaluation of autoimmune phenomena in patients with nonalcoholic fatty liver disease on the basis of liver pathology

BACKGROUND Autoimmune phenomena can be used in some patients with nonalcoholic fatty liver disease(NAFLD)in the clinic,but these patients are not autoimmune hepatitis patients.AIM To determine whether autoimmunity is present in patients with NAFLD,this study was performed.METHODS A total of 104 patients with NAFLD diagnosed by liver biopsy at Tianjin Second People’s Hospital between 2019 and 2023 were enrolled.The patients were divided into three groups according to their biopsy results:The NAFL(n=36),nonalcoholic steatohepatitis(n=51),and liver cirrhosis groups(n=17).RESULTS The differences in IgA,an immune marker,among the three groups of patients were statistically significant(P=0.025).In all NAFLD patients,antinuclear antibody and anti-smooth muscle antibody were the most common autoantibodies.The antinuclear antibody detection rate was the highest at 48.1%.The cirrhosis group had the highest autoantibody positivity rate(64.7%).Portal enlargement is also common in NAFLD patients.The rates of positivity for portal lymphoplasmacytic infiltration,small bile duct hyperplasia and interfacial hepatitis were highest in the cirrhosis group;the differences between the cirrhosis group and the other two groups were significant(P<0.05).Hepatocellular rosettes were identified only in the cirrhosis group(11.8%).CONCLUSION Autoimmune phenomena occur in NAFLD patients,especially in patients with NAFLD-related cirrhosis,in whom this phenomenon may be more pronounced.

NLRP3/1-mediated pyroptosis:beneficial clues for the development of novel therapies for Alzheimer’s disease

The inflammasome is a multiprotein complex involved in innate immunity that mediates the inflammatory response leading to pyroptosis,which is a lytic,inflammatory form of cell death.There is accumulating evidence that nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3(NLRP3)inflammasome-mediated microglial pyroptosis and NLRP1 inflammasome-mediated neuronal pyroptosis in the brain are closely associated with the pathogenesis of Alzheimer’s disease.In this review,we summarize the possible pathogenic mechanisms of Alzheimer’s disease,focusing on neuroinflammation.We also describe the structures of NLRP3 and NLRP1 and the role their activation plays in Alzheimer’s disease.Finally,we examine the neuroprotective activity of small-molecule inhibitors,endogenous inhibitor proteins,microRNAs,and natural bioactive molecules that target NLRP3 and NLRP1,based on the rationale that inhibiting NLRP3 and NLRP1 inflammasome-mediated pyroptosis can be an effective therapeutic strategy for Alzheimer’s disease.

Clinical pathological characteristics of“crawling-type”gastric adenocarcinoma cancer:A case report

BACKGROUND Gastric cancer(GC)is a significant health problem worldwide,and early detection and accurate diagnosis are crucial for improving patient outcomes.Crawling-type gastric adenocarcinoma is a rare subtype of GC that has unique histopathological and clinical characteristics,and its diagnosis and management can be challenging.This pathological type of GC is also rare.CASE SUMMARY Here,we report the case of a patient who underwent ordinary endoscopy,na-rrow-band imaging,and endoscopic ultrasonography intending to determine the extent of tumor invasion and upper abdominal enhanced computed tomography and whether there was tumor metastasis.Then,endoscopic submucosal dissection was performed.After pathological and immunohistochemical examination,the pathological diagnosis was crawling-type gastric adenocarcinoma.This is a very rare and special pathological type of tumor.This case highlights the importance of using advanced endoscopic techniques and pathological examination in diagnosing and managing gastric crawling-type adenocarcinoma.Moreover,the findings underscore the need for continued research and clinical experience in this rare subtype of GC to improve patient outcomes.CONCLUSION The“crawling-type”GC is a rare and specific tumor pathology.It is difficult to identify and diagnose gliomas via endoscopy.The tumor is ill-defined,with a flat appearance and indistinct borders due to the lack of contrast against the background mucosa.Pathology revealed that the tumor cells were hand-like,so the patient has diagnosed with“crawling-type”gastric adenocarcinoma.