Jejunal sarcomatoid carcinoma:A case report and review of literature

BACKGROUND Sarcomatoid carcinoma(SCA)of the jejunum is a rare and aggressive neoplasm affecting the smooth muscle cells of the jejunum.This study presents a recent case of jejunal SCA,detailing its diagnosis and treatment,thereby providing a reference for clinical practice.CASE SUMMARY A 65-year-old male presented to Yichang Central People's Hospital with a chief complaint of hemorrhoids.A computed tomography(CT)scan incidentally revealed multiple abnormal signals in the liver.Subsequent positron emission tomography/CT at Wuhan Union Hospital indicated malignant tumor progression,with a primary duodenal tumor and multiple metastases in the upper left abdomen.Intraoperatively,a large tumor was identified on the omentum.Histopathological and immunohistochemical analyses of the resected specimen confirmed the diagnosis of jejunal SCA.The patient received a combination therapy of sintilimab,nanoparticle albumin-bound paclitaxel,and anlotinib.Follow-up imaging demonstrated significant reduction of hepatic and peritoneal lesions.The patient has remained stable for over one year postoperatively.CONCLUSION This case suggests that chemotherapy,immunotherapy,plus targeted therapy may represent an optimal treatment for intestinal SCA,meriting further investigation.

The lactylation index predicts the immune microenvironment and prognosis of pan-cancer patients

Background:Protein lactylation is a new way for the“metabolic waste”lactic acid to perform novel functions.Nevertheless,our understanding of the contribution of protein lactylation to both tumor progression and therapeutic interventions remains imited.The construction of a scoring system for lactylation to predict the prognosis of pancancer patients and to evaluate the tumor immune microenvironment(TIME)would improve our understanding of the clinical significance of lactylation.Methods:Consensus clustering analysis of lactylation-related genes was used to cluster 177 pancreatic adenocarcinoma(PAAD)patients.Subsequently,a scoring system was developed using the least absolute shrinkage and selection operator(LASSO)regression.Internal validation and external validation were both conducted to assess and confirm the predictive accuracy of the scoring system.Finally,leucine rich repeat containing 1(LRRC1),a newly discovered lactylation-related gene,was analyzed in PAAD in vitro.Results:Utilizing the profiles of 332 lactylation-related genes,a total of 177 patients with PAAD were segregated into two distinct groups.LacCluster^(high) patients had a poorer prognosis than LacCluster^(low) patients.Through the differential analysis between the LacCluster^(high) and LacCluster^(low) groups,we identified additional genes associated with lactylation.These genes were then integrated to construct the LacCluster-enhanced system,which enabled more accurate prognosis prediction for patients with PAAD.Then,a lactylation index containing three genes(LacI-3)was constructed using LASSO regression.This was done to enhance the usability of the LacCluster-enhanced system in the clinic.Compared to those in the LacI-3^(high) subgroup,patients in the LacI-3^(low) subgroup exhibited increased expression of immune checkpoint-related genes,more immune cell infiltration,lower tumor mutation burdens,and better prognoses,indicating a“hot tumor”phenotype.Moreover,knocking down the expression of LRRC1,the hub gene in the LacI-3 scoring system,inhibited PAAD cell invasion,migration,and proliferation in vitro.Ultimately,the significance of LacI-3 across cancers was confirmed.Conclusion:Our findings strongly imply that protein lactylation may represent a new approach to diagnosing and treating malignant tumors.

In vivo and in vitro study of resorbable magnesium wires for medical implants:Mg purity,surface quality,Zn alloying and polymer coating

Magnesium is an excellent material in terms of biocompatibility and its corrosion products can serve as an active source for new bone formation.However,localized corrosion and H_(2)generation limit the potential of Mg-based implants.Utilizing low-alloyed Mg-Zn wires can strongly reduce problems with large H_(2)bubbles and improve the mechanical properties considerably while maintaining excellent long-term biocompatibility.Acidic pickling and a polymer coating can be effectively used to lower the rate of in vivo degradation.In this work,microstructural,mechanical,and in vitro characterization of 250μm and 300μm extruded wires made from ultra-pure Mg,commercially pure Mg,Mg-0.15Zn,Mg-0.4Zn and Mg-1Zn was performed.Additionally,Mg-0.4Zn wires together with a variant coated with a copolymer of L-lactide andε-caprolactone were tested in vivo on artificially damaged Wistar rat femurs.Based on the observed Mg-induced osteogenesis,polymer-coated Mg wires with a small addition of Zn are a perspective material for bone-support applications,such as cerclage and fixation wires.

Pathology of pancreatic ductal adenocarcinoma:Facts,challenges and future developments

Despite major improvements concerning its diagnosis and treatment,pancreatic ductal adenocarcinoma(PDAC) remains an aggressive disease with an extremely poor prognosis. Pathology,as interface discipline between basic and clinical medicine,has substantially contributed to the recent developments and has laid the basis for further progress. The definition and classification of precursor lesions of PDAC and their molecular characterization is a fundamental step for the potential identification of biomarkers and the development of imaging methods for early detection. In addition,by integrating findings in humans with the knowledge acquired through the investigation of transgenic mouse models for PDAC,a new model for pancreatic carcinogenesis has been proposed and partially validated in individuals with genetic predisposition for PDAC. The introduction and validation of a standardized system for pathology reporting based on the axial slicing technique has shown that most pancreatic cancer resections are R1 resections and that this is due to inherent anatomical and biological properties of PDAC.This standardized assessment of prognostic relevant parameters represents the basis for the successful conduction of multicentric studies and for the interpretation of their results.Finally,recent studies have shown that distinct molecular subtypes of PDAC exist and are associated with different prognosis and therapy response.The prospective validation of these results and the integration of molecular analyses in a comprehensive pathology report in the context of individualised cancer therapy represent a major challenge for the future.

Intraprocedural gastric juice analysis as compared to rapid urease test for real-time detection of Helicobacter pylori

BACKGROUND Endofaster is an innovative technology that can be combined with upper gastrointestinal endoscopy(UGE)to perform gastric juice analysis and real-time detection of Helicobacter pylori(H.pylori).AIM To assess the diagnostic performance of this technology and its impact on the management of H.pylori in the real-life clinical setting.METHODS Patients undergoing routine UGE were prospectively recruited.Biopsies were taken to assess gastric histology according to the updated Sydney system and for rapid urease test(RUT).Gastric juice sampling and analysis was performed using the Endofaster,and the diagnosis of H.pylori was based on real-time ammonium measurements.Histological detection of H.pylori served as the diagnostic gold standard for comparing Endofaster-based H.pylori diagnosis with RUT-based H.pylori detection.RESULTS A total of 198 patients were prospectively enrolled in an H.pylori diagnostic study by Endofasterbased gastric juice analysis(EGJA)during the UGE.Biopsies for RUT and histological assessment were performed on 161 patients(82 men and 79 women,mean age 54.8±19.2 years).H.pylori infection was detected by histology in 47(29.2%)patients.Overall,the sensitivity,specificity,accuracy,positive predictive value,and negative predictive value(NPV)for H.pylori diagnosis by EGJA were 91.5%,93.0%,92.6%,84.3%,and 96.4%,respectively.In patients on treatment with proton pump inhibitors,diagnostic sensitivity was reduced by 27.3%,while specificity and NPV were unaffected.EGJA and RUT were comparable in diagnostic performance and highly concordant in H.pylori detection(κ-value=0.85).CONCLUSION Endofaster allows for rapid and highly accurate detection of H.pylori during gastroscopy.This may guide taking additional biopsies for antibiotic susceptibility testing during the same procedure and then selecting an individually tailored eradication regimen.

Carcinoid syndrome caused by a pulmonary carcinoid mimics intestinal manifestations of ulcerative colitis:A case report

BACKGROUND Pulmonary carcinoids are rare,low-grade malignant tumors characterized by neuroendocrine differentiation and relatively indolent clinical behavior.Most cases present as a slow-growing polypoidal mass in the major bronchi leading to hemoptysis and pulmonary infection due to blockage of the distal bronchi.Carcinoid syndrome is a paraneoplastic syndrome caused by the systemic release of vasoactive substances that presents in 5%of patients with neuroendocrine tumors.Due to such nonspecific presentation,most patients are misdiagnosed or diagnosed late and may receive several courses of antibiotics to treat recurrent pneumonia before the tumor is diagnosed.CASE SUMMARY We report the case of a 48-year-old male who presented with cough,dyspnea,a history of recurrent pneumonitis,and therapy-refractory ulcerative colitis that completely subsided after the resection of a pulmonary carcinoid.CONCLUSION We report and emphasize pulmonary carcinoid as a differential diagnosis in patients with nonresponding inflammatory bowel diseases and recurrent pneumonia.

Surgical treatments of recurrent small intestine metastatic melanoma manifesting with gastrointestinal hemorrhage and intussusception:A case report

BACKGROUND Melanoma is the most aggressive form of skin cancer,with a tendency to metastasize to any organ.Malignant melanoma is the most frequent cause of skin cancer-related deaths worldwide.Small intestine cancers especially small intestine metastases are relatively rare.Small intestine metastases are seldom described and likely underdiagnosed.Intussusception is most common in pediatric age,and in adults are almost 5%of all cases.CASE SUMMARY A 75-year-old man with a history of acral malignant melanoma was admitted to the Gastroenterology Department of our hospital,complaining of intermittent melena for 1 mo.Magnetic resonance enterography showed partial thickening of the jejunal wall and formation of a soft tissue mass,indicating a neoplastic lesion with jejunojejunal intussusception.The patient underwent partial small bowel resection.Pathological findings and immunohistochemical staining indicated small intestine metastatic melanoma.The patient refused further anti-tumor treatment after the surgery.Ten months after the first surgery,the patient presented with melena again.Computed tomography enterography showed the anastomotic stoma was normal without thickening of the intestinal wall,and routine conservative treatment was given.Three months later,the patient developed melena again.The patient underwent a second surgery,and multiple metastatic melanoma lesions were found.The patient refused adjuvant anti-tumor treatment and was alive at the latest follow-up.CONCLUSION Small intestine metastatic melanoma should be suspected in any patient with a history of malignant melanoma and gastrointestinal symptoms.

Giant cavernous hemangioma of the liver with satellite nodules:Aspects on tumour/tissue interface:A case report

BACKGROUND Giant hepatic cavernous hemangioma with multiple satellite nodules is a rare subtype of hepatic cavernous hemangioma,the most common vascular liver tumor.We report on a tumor with unusual histologic features:(1)Finger-like infiltration pattern;(2)lack of encapsulation;(3)blurred tumor/liver interface;and(4)massive satellitosis-referring to the article“Hepatic cavernous hemangioma:underrecognized associated histologic features”.CASE SUMMARY A 60-year-old man presented with increasing uncharacteristic abdominal discomfort and mildly elevated blood parameters of acute inflammation.Imaging revealed an unclear,giant liver tumor of the left liver lobe.A massive vascular tumor with extensive satellitosis broadly infiltrating the adjacent liver parenchyma was resected via hemihepatectomy of segmentsⅡ/Ⅲ.Histopathological diagnosis was giant hepatic cavernous hemangioma with multiple satellite nodules,featuring unusual characteristics hardly portrayed in the literature.Retrospectively,this particular morphology can explain the difficult pre-and perioperative diagnosis of a vascular liver tumor that is usually readily identifiable by modern imaging methods.CONCLUSION This case emphasizes the exact histological workup of tumor and tumor-induced parenchyma changes in radiologically unclassifiable liver tumors.

Duodenojejunostomy treatment of groove pancreatitis-induced stenosis and obstruction of the horizontal duodenum:A case report

BACKGROUND Groove pancreatitis(GP)is a rare condition affecting the pancreatic groove region within the dorsal-cranial part of the pancreatic head,duodenum,and common bile duct.As a rare form of chronic pancreatitis,GP poses a diagnostic and therapeutic challenge for clinicians.GP is frequently misdiagnosed or not considered;thus,the diagnosis is often delayed by weeks or months.The treatment of GP is complicated and often requires surgical intervention,especially pancreatoduodenectomy.CASE SUMMARY A 66-year-old man with a history of long-term drinking was admitted to the gastroenterology department of our hospital,complaining of vomiting and acid reflux.Upper gastrointestinal endoscopy showed luminal stenosis in the descending part of the duodenum.Abdominal computed tomography showed slight exudation in the descending and horizontal parts of the duodenum with broadening of the groove region,indicating local pancreatitis.The symptoms of intestinal obstruction were not relieved with conservative therapy,and insertion of an enteral feeding tube was not successful.Exploratory laparoscopy was performed and revealed a hard mass with scarring in the horizontal part of the duodenum and stenosis.Intraoperative frozen section analysis showed no evidence of malignancy,and side-to-side duodenojejunostomy was performed.Routine pathologic examination showed massive proliferation of fibrous tissue,hyaline change,and the proliferation of spindle cells.Based on the radiologic and pathologic characteristics,a diagnosis of GP was made.The patient presented with anastomotic obstruction postoperatively and took a long time to recover,requiring supportive therapy.CONCLUSION GP often involves the descending and horizontal parts of the duodenum and causes duodenal stenosis,impaired duodenal motility,and gastric emptying due to fibrosis.

Reactivation of the insulin-like growth factor-Ⅱsignaling pathway in human hepatocellular carcinoma

Constitutive activation of the insulin-like growth factor (IGF)-signaling axis is frequently observed in human hepatocellular carcinoma(HCC).Especially the over- expression of the fetal growth factor IGF-Ⅱ,IGF-Ⅰ receptor(IGF-IR),and cytoplasmic downstream effectors such as insulin-receptor substrates(IRS)contribute to proliferation,anti-apoptosis,and invasive behavior. This review focuses on the relevant alterations in this signaling pathway and independent in vivo models that support the central role IGF-Ⅱsignaling during HCC development and progression.Since this pathway has become the center of interest as a target for potential anti-cancer therapy in many types of malignancies,various experimental strategies have been developed,including neutralizing antibodies and selective receptor kinase inhibitors,with respect to the specific and efficient reduction of oncogenic IGF-Ⅱ/IGF-IR-signaling.

Role of the receptor for advanced glycation end products in hepatic fibrosis

AIM： To study the role of advanced glycation end products （AGE） and their specific receptor （RAGE） in the pathogenesis of liver fibrogenesis. METHODS： In vitro RAGE expression and extracellular matrix-related gene expression in both rat and human hepatic stellate cells （HSC） were measured after stimulation with the two RAGE ligands, advanced glycation end product-bovine serum albumin （AGE- BSA） and N＇-（carboxymethyl） lysine （CML）-BSA, or with tumor necrosis factor-α （TNF-α）. In vivo RAGE expression was examined in models of hepatic fibrosis induced by bile duct ligation or thioacetamide. The effects of AGE-BSA and CML-BSA on HSC proliferation, signal transduction and profibrogenic gene expression were studied in vitro. RESULTS： In hepatic fibrosis, RAGE expression was enhanced in activated HSC, and also in endothelial cells, inflammatory cells and activated bile duct epithelia. HSC expressed RAGE which was upregulated after stimulation with AGE-BSA, CML-BSA, and TNF-α.RAGE stimulation with AGE-BSA and CML-BSA did not alter HSC proliferation, apoptosis, fibrogenic signal transduction and fibrosis- or fibrolysis-related gene expression, except for marginal upregulation of procollagen α1（ I ） mRNA by AGE-BSA. CONCLUSION： Despite upregulation of RAGE in activated HSC, RAGE stimulation by AGE does not alter their fibrogenic activation. Therefore, RAGE does not contribute directly to hepatic fibrogenesis.

Natural history of cytomegalovirus infection in a series of patients diagnosed with moderate-severe ulcerative colitis

AIM： To evaluate the natural history of human cytomegalovirus （HCMV） infection in a series of 28 ulcerative colitis patients in whom the search for HCMV was positive. METHODS： A series of 85 patients with moderate-se- vere ulcerative colitis flare-up were evaluated for a HCMV search by performing a haematoxylin and eosin stain, immunohistochemical assay and nested polymerase chain reaction on rectal biopsies. Among 85 screened patients （19 of whom were steroid resistant/dependant）, 28 were positive for HCMV; after remission the patients were followed up clinically and histologically. RESULTS： Among the 22 patients with complete follow- up, in 8 （36%） patients HCMV-DNA persisted in the in- testinal specimens. Among the HCMV positive patients, 4 （50%） experienced at least one moderate-severeflare-up of colitis without evidence of peripheral HCMV. Among the 14 HCHV negative patients, 3 with pouches developed pouchiUs and 5 out of 11 （45%） experienced a colitis flare-up. CONCLUSION： Our preliminary results suggest that HCHV may remain in the colon afber an acute coltis flare- up despite remission; it seems that the virus is not responsible for the disease relapse.

Co-expression of CDX2 and MUC2 in gastric carcinomas: Correlations with clinico-pathological parameters and prognosis

AIM: To evaluate the role of CDX2 homeobox protein as a predictor for cancer progression and prognosis as well as its correlation with MUC2 expression. CDX2 represents a transcription factor for various intestinal genes (including MUC2) and thus an important regulator of intestinal differentiation, which could previously be identified in gastric carcinomas and intestinal metaplasia. METHODS: Formalin-fixed and paraffin-embedded tissues from 190 gastric carcinoma patients were stained with monodonal antibodies recognizing CDX2 and MUC2, respectively. Immunoreactivity was evaluated semiquantitatively and statistical analyses including x2 tests, uni- and multi-variate survival analyses were performed. RESULTS: CDX2 was mostly expressed in a nuclear or supranuclear pattern,whereas MUC2 showed an almost exclusive supranuclear reactivity.Both antigens were present in >80% of areas exhibiting intestinal metaplasia. An immunoreactivity in >5% of the tumor area was observed in 57% (CDX2) or in 21% (MUC2) of the carcinomas.The presence of both molecules did not correlate with WHO, Lauren and Goseki classification (with the exception of a significantly stronger MUC2 expression in mucinous tumors). CDX2 correlated with a lower pT and pN stage in the subgroups of intestinal and stage I cancers and was associated with MUC2 positivity.A prognostic impact of CDX2 or MUC2 was not observed. CONCLUSION: CDX2 and MUC2 play an important role in the differentiation of normal, inflamed, and neoplastic gastric tissues. According to our results, loss of CDX2 may represent a marker of tumor progression in early gastric cancer and carcinomas with an intestinal phenotype.

Intravenous administration of glutathione protects parenchymal and non-parenchymal liver cells against reperfusion injury following rat liver transplantation

AIM:To investigate the effects of intravenous administration of the antioxidant glutathione (GSH) on reperfusion injury following liver transplantation. METHODS:Livers of male Lewis rats were transplanted after 24 h of hypothermic preservation in University of Wisconsin solution in a syngeneic setting.During a 2-h reperfusion period either saline (controls,n=8) or GSH (50 or 100 μmol/(h·kg),n=5 each) was continuously administered via the jugular vein. RESULTS:Two hours after starting reperfusion plasma ALT increased to 1 457±281 U/L (mean±SE) in controls but to only 908±187 U/L (P<0.05) in animals treated with 100 μmol GSH/(h·kg).No protection was conveyed by 50μmol GSH/(h·kg).Cytoprotection was confirmed by morphological findings on electron microscopy:GSH treatment prevented detachment of sinusoidal endothelial cells (SECs) as well as loss of microvilli and mitochondrial swelling of hepatocytes.Accordingly,postischemic bile flow increased 2-fold.Intravital fluorescence microscopy revealed a nearly complete restoration of sinusoidal blood flow and a significant reduction of leukocyte adherence to sinusoids and postsinusoidal venules.Following infusion of 50μmol and 100 μmol GSH/(h·kg),plasma GSH increased to 65±7 mol/L and 97±18 mol/L,but to only 20±3 mol/L in untreated recipients. Furthermore,plasma glutathione disulfide (GSSG) increased to 7.5±1.0 mol/L in animals treated with 100μmol/(h·kg) GSH but infusion of 50μmol GSH/(h·kg) did not raise levels of untreated controls (1.8±0.5 mol/L vs 2.2±0.2 mol/L). CONCLUSION:Plasma GSH levels above a critical level may act as a “sink” for ROS produced in the hepatic vasculature during reperfusion of liver grafts.Therefore,GSH can be considered a candidate antioxidant for the Drevention of reperfusion injury after liver transplantation,in particular since it has a low toxicity in humans.

ACUTE ULTRASTRUCTURAL CHANGES OF THE TRABECULAR MESHWORK AFTER SELECTIVE LASER TRABECULOPLASTY AND LOW POWER ARGON LASER TRA- BECULOPLASTY

Purpose: To compare the histopathological changes in the human trabecular meshwork after low power argon laser trabeculoplasty (ALT) and selective laser trabeculoplasty (SLT) with a Q-switched, frequency-doubled, neodymium:yttrium-alumini-um-garnet (Nd:YAG) laser. Methods: In gonioscopically normal trabecular meshwork of three patients awaiting enucleation due to malignant melanoma of the choroid SLT and ALT were per-

Cellular and molecular basis of chronic constipation: Taking the functional/idiopathic label out

In recent years, the improvement of technology and the increase in knowledge have shifted several strongly held paradigms. This is particularly true in gastroenterology, and specifically in the field of the so-called "functional" or "idiopathic" disease, where conditions thought for decades to be based mainly on alterations of visceral perception or aberrant psychosomatic mechanisms have, in fact, be reconducted to an organic basis (or, at the very least, have shown one or more demonstrable abnormalities). This is particularly true, for instance, for irritable bowel syndrome, the prototype entity of "functional" gastrointestinal disorders, where low-grade inflammation of both mucosa and myenteric plexus has been repeatedly demonstrated. Thus, researchers have also investigated other functional/idiopathic gastrointestinal disorders, and found that some organic ground is present, such as abnormal neurotransmission and myenteric plexitis in esophageal achalasia and mucosal immune activation and mild eosinophilia in functional dyspepsia. Here we show evidence, based on our own and other authors' work, that chronic constipation has several abnormalities reconductable to alterations in the enteric nervous system, abnormalities mainly characterized by a constant decrease of enteric glial cells and interstitial cells of Cajal (and, sometimes, of enteric neurons). Thus, we feel that (at least some forms of) chronic constipation should no more be considered as a functional/idiopathic gastrointestinal disorder, but instead as a true enteric neuropathic abnormality.

Aquaporin-8 expression is reduced in ileum and induced in colon of patients with ulcerative colitis

AIM： To study susceptibility genes which may play a potential role in the pathogenesis and etiology of inflammatory bowel disease （IBD）. METHODS： To identify potential susceptibility genes we performed global gene expression profiling in patients with IBD and control specimens. For determination of an intrinsic gene expression profile in ulcerative colitis （UC） and Crohn＇s disease （CD） compared to normal subjects, mucosal biopsies of non-inflamed regions of the colon and the terminal ileum were subjected to DNA microarray analysis. Real-time RT-PCR and immunohistochemistry were used for verification of selected regulated candidate genes and a genetic analysis was performed. RESULTS： We could show that aquaporin-8 （AQP8） mRNA and protein levels were significantly increased in the colon of UC patients compared to controls. Genetic analysis of the six exons and the promoter region of AQPS, however, revealed no mutations or polymorphisms in IBD patients. CONCLUSION： Our results suggest that upregulation of AQP8 in the colon of UC patients represents a secondary phenomenon which may, due to altered water exchange of the distal intestinal mucosa, disturb the physiologic colonic mucus barrier and thus lead to chronic inflao mmation and ulceration.

Frequency, localization, and types of gastrointestinal stromal tumor-associated neoplasia

BACKGROUND In recent years,increasing evidence of second neoplasms associated with gastrointestinal stromal tumors(GIST)has been found.Numerous case reports,mostly retrospective studies and a few reviews,have been published.To our knowledge,however,no systematic review or meta-analysis of the existing data has been performed so far.AIM To prepare a compilation,as complete as possible,of all reported second tumor entities that have been described in association with GIST and to systematically analyze the published studies with regard to frequency,localization,and types of GIST-associated neoplasms.METHODS The MEDLINE and EBSCO databases were searched for a combination of the keywords GIST/secondary,synchronous,coincident/tumor,neoplasm,and relevant publications were selected by two independent authors.RESULTS Initially,3042 publications were found.After deletion of duplicates,1631 remained,and 130 papers were selected;22 of these were original studies with a minimum of 20 patients,and 108 were case reports.In the 22 selected studies,comprising a total number of 12050 patients,an overall rate of GIST-associated neoplasias of 20%could be calculated.Most second neoplasias were found in the gastrointestinal tract(32%)and in the male and female urogenital tract(30%).The specific risk scores of GISTs associated with other tumors were significantly lower than those without associated neoplasias.CONCLUSION In this first systematic review,we could confirm previously reported findings of a more than coincidental association between GIST and other neoplasias.The question whether there is an underlying causal association will need further investigation.Our data suggest that even GIST with a very low risk of disease progression should prompt screening for second neoplasia and subsequent frequent controls or extended staging.

Enhanced migration of tissue inhibitor of metalloproteinase overexpressing hepatoma cells is attributed to gelatinases: Relevance to intracellular signaling pathways

AIM: To study the effect of gelatinases (especially MMP-9) on migration of tissue inhibitor of metalloproteinase (TIMP-1) overexpressing hepatoma cells. METHODS: Wild type HepG2 cells, cells stably transfected with TIMP-1 and TIMP-1 antagonist (MMP-9-H401A, a catalytically inactive matrix metalloproteinase (MMP) which still binds and neutralizes TIMP-1) were incubated in Boyden chambers either with or without Galardin (a synthetic inhibitor of MMP-1, -2, -3, -8, -9) or a specific inhibitor of gelatinases. RESULTS: Compared to wild type HepG2 cells, the cells overexpressing TIMP-1 showed 115% migration (P<0.05) and the cells overexpressing MMP-9-H401A showed 62% migration (P<0.01). Galardin reduced cell migration dose dependently in all cases. The gelatinase inhibitor reduced migration in TIMP-1 overexpressing cells predominantly. Furthermore, we examined intracellular signal transduction pathways of TIMP-1-dependent HepG2 cells. TIMP-1 deactivates cell signaling pathways of MMP-2 and MMP-9 involving p38 mitogen-activated protein kinase. Specific blockade of the ERK pathway suppresses gelatinase expression either in the presence or absence of TIMP-1. CONCLUSION: Overexpressing functional TIMP-1-enhanced migration of HepG2-TIMP-l cells depends on enhanced MMP-activity, especially MMP-9.

Correlation of IL-8 with induction, progression and metastatic potential of colorectal cancer

AIM： To investigate the expression profile of IL-8 in inflammatory and malignant colorectal diseases to evaluate its potential role in the regulation of colorectal cancer （CRC） and the development of colorectal liver metastases （CRLM）.METHODS： IL-8 expression was assessed by quantitative real-time PCR （Q-RT-PCR） and the enzyme-linked immunosorbent assay （ELISA） in resected specimens from patients with ulcerative colitis （UC, n = 6） colorectal adenomas （CRA, n = 8）, different stages of colorectal cancer （n = 48） as well as synchronous and metachronous CRLM along with their corresponding primary colorectal tumors （n = 16）.RESULTS： IL-8 mRNA and protein expression was significantly up-regulated in all pathological colorectal entities investigated compared with the corresponding neighboring tissues. However, in the CRC specimens IL-8 revealed a significantly more pronounced overexpression in relation to the CRA and UC tissues with an average 30-fold IL-8 protein up-regulation in the CRC specimens in comparison to the CRA tissues. Moreover, [L-8 expression revealed a close correlation with tumor grading. Most interestingly, IL-8 up-regulation was most enhanced in synchronous and metachronous CRLM, if compared with the corresponding primary CRC tissues. Herein, an up to 80-fold IL-8 overexpression in individual metachronous metastases compared to normal tumor neighbor tissues was found.CONCLUSION： Our results strongly suggest an association between IL-8 expression, induction and progression of colorectal carcinoma and the development of colorectal liver metastases.