Effectiveness of vedolizumab treatment in two different anti-tumor necrosis factor alpha refractory pouchitis: A case report

BACKGROUND Refractory pouchitis is a common cause of pouch failure,which may require surgical excision of the pouch or permanent diversion.We aimed to show the effect of vedolizumab on treatment of the patient with refractory pouchitis.CASE SUMMARY A 32-year-old male with pancolonic ulcerative colitis since the age of 25 with primary failure of infliximab and mesalamine and intolerance of azathioprine,underwent a total proctocolectomy with ileal pouch-anal anastomosis in 2012.He developed chronic diarrhea in 2014,which was watery,30 per day and accompanied with blood and mucus affecting his quality of life.CONCLUSION Vedolizumab is safe and effective in the management of anti-tumor necrosis factor alpha refractory pouchitis.

Two-year delay in ulcerative colitis diagnosis is associated with anti-tumor necrosis factor alpha use

BACKGROUND Ulcerative colitis(UC)is an uncommon inflammatory bowel disease(IBD).However,its incidence has recently increased in South Korea.Moreover,UC diagnoses are frequently delayed,and the relationship between diagnostic delay and UC prognosis has not been extensively studied in South Korean patients.AIM To identify meaningful diagnostic delay affecting UC prognosis and to evaluate risk factors associated with diagnostic delay in South Korean patients.METHODS Medical records of 718 patients with UC who visited the outpatient clinic of six university hospitals in South Korea were reviewed;167 cases were excluded because the first symptom date was unknown.We evaluated the relationship between the prognosis and a diagnostic delay of 3,6,12,18,and 24 mo by comparing the prognostic factors[anti-tumor necrosis factor(TNF)-αuse,admission history due to acute flare-ups,frequent admission due to flare-ups,surgery associated with UC,and the clinical remission state at the latest followup]at each diagnostic interval.RESULTS The mean diagnostic interval was 223.3±483.2 d(median,69 d;75th percentile,195 d).Among the prognostic factors,anti-TNFαuse was significantly increased after a diagnostic delay of 24 mo.Clinical risk factors predictive of a 24-mo diagnostic delay were age<60 years at diagnosis[odd ratio(OR)=14.778,95%confidence interval(CI):1.731-126.121],smoking history(OR=2.688,95%CI:1.239-5.747,P=0.012),and misdiagnosis of hemorrhoids(OR=11.066,95%CI:3.596-34.053).Anti-TNFαuse was associated with extensive UC at diagnosis(OR=3.768,95%CI:1.860-7.632)and 24-mo diagnostic delay(OR=2.599,95%CI:1.006-4.916).CONCLUSION A diagnostic delay>24 mo was associated with increased anti-TNFαuse.Age<60 years at diagnosis,smoking history,and misdiagnosis of hemorrhoids were risk factors for delayed diagnosis.

Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy:A single center report of 8 cases

This article describes cases of anti-tumor necrosis factor(TNF)-α-induced autoimmune hepatitis and evaluates the outcome of these patients in relation to their immunosuppressive strategy. A retrospective analysis of medical records was performed in our center, in order to detect cases of autoimmune hepatitis(AIH) associated with anti-TNF biologic agents. We describe and analyze eight cases of AIH following anti-TNF therapy, 7 with infliximab and 1 with adalimumab. A distinction should be made between induction of autoimmunity and clinically evident autoimmune disease. Liver biopsy is useful in detecting the role of the TNF-α antagonist in the development of AIH. The lack of relapse after discontinuing immunosuppressive therapy favors, as in this case series, an immune-mediated drug reaction as most patients with AIH have a relapse after treatment is suspended. Although AIH related to anti-TNF therapy is rare, a baseline immunological panel along with liver function tests should be performed in all patients with autoimmune disease before starting biologics.

Treatment of primary nasal tuberculosis with anti-tumor necrosis factor immunotherapy:A case report

BACKGROUND Primary nasal tuberculosis(TB)is a rare form of extrapulmonary TB,particularly in patients receiving anti-tumor necrosis factor(TNF)immunotherapy.As a result,its diagnosis remains challenging.CASE SUMMARY A 58-year-old male patient presented to the ear,nose,and throat department with right-sided nasal obstruction and bloody discharge for 1 month.He was diagnosed with psoriatic arthritis and received anti-TNF immunotherapy for 3 years prior to presentation.Biopsy findings revealed chronic granulomatous inammation and a few acid-fast bacilli,suggestive of primary nasal TB.He was referred to our TB management department for treatment with oral anti-TB agents.After 9 months,the nasal lesions had disappeared.No recurrence was noted during follow-up.CONCLUSION The diagnosis of primary nasal TB should be considered in patients receiving TNF antagonists who exhibit thickening and crusting of the nasal septum mucosa or inferior turbinate,particularly when pathological findings suggest granulomatous inflammation.

Joint Detection of Serum Vitamin D,Body Mass Index,and Tumor Necrosis Factor Alpha for the Diagnosis of Crohn’s Disease

Objective Vitamin D(VD)deficiency was reported to contribute to the progression of Crohn’s disease(CD)and affect the prognosis of CD patients.This study investigated the role of serum VD,body mass index(BMI),and tumor necrosis factor alpha(TNF-α)in the diagnosis of Crohn’s disease.Methods CD patients(n=76)and healthy subjects(n=76)were enrolled between May 2019 and December 2020.The serum 25-hydroxyvitamin D[25(OH)D]levels,BMI,and TNF-αlevels,together with other biochemical parameters,were assessed before treatment.The diagnostic efficacy of the single and joint detection of serum 25(OH)D,BMI,and TNF-αwas determined using receiver operating characteristic(ROC)curves.Results The levels of 25(OH)D,BMI,and nutritional indicators,including hemoglobin,total protein,albumin,and high-density lipoprotein cholesterol,were much lower,and the TNF-αlevels were much higher in the CD patients than in the healthy subjects(P<0.05 for all).The areas under the ROC curve for the single detection of 25(OH)D,BMI,and TNF-αwere 0.887,0.896,and 0.838,respectively,with the optimal cutoff values being 20.64 ng/mL,19.77 kg/m^(2),and 6.85 fmol/mL,respectively.The diagnostic efficacy of the joint detection of 25(OH)D,BMI,and TNF-αwas the highest,with an area under the ROC curve of 0.988(95%CI:0.968–1.000).Conclusion The joint detection of 25(OH)D,TNF-α,and BMI showed high sensitivity,specificity,and accuracy in CD diagnosis;thus,it would be effective for the diagnosis of CD in clinical practice.

Tumor Necrosis Factor-Alpha (TNF)-308G/A and Interleukin 8(IL-8)-251C/T Polymorphisms in Pulmonary Tuberculosis Patients from Congo

Background: Tuberculosis (TB) is one of the world’s deadliest infectious diseases. Tumor necrosis factor-Alpha (TNF-α) and Interleukin 8 (IL-8) are involved in the pathogenesis of pulmonary TB (PTB). However, the contribution of polymorphisms of these cytokines to PTB susceptibility needed more investigation across geographic regions and ethnic groups. Purpose: The aim of this study was to investigate the association of the TNF-α-308 G/A and IL-8-251T/A polymorphisms with PTB risk in the Congolese population. Methods: This case-control study included 150 PTB patients and 160 control subjects. Blood samples were collected from all participants and were used for the TNF-α-308 G/A and IL-8-251T/A genotyping by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Odds ratios (OR) were calculated to estimate the potential polymorphism associations. A P level of Results: A significant difference was found between PTB patients and controls regarding the TNF-α-308AA genotype (P = 0.035) distribution. Moreover, this genotype was associated with risk to TB (OR = 7.19, 95% CI = 0.85 - 60.65, P = 0.035). The A allele was significantly more frequent in PTB patients than in controls, and was associated with risk to PTB (OR = 1.68, 95% CI = 1.05 - 2.68, P = 0.014). Regarding the IL-8-251T/A gene, TA and AA genotypes were significantly more frequent in PTB patients compared to controls, and were associated with increased risk to PTB (OR = 2.64, 95% CI = 0.97 - 7.18, P = 0.031 and OR = 3.0, 95% CI = 1.13 - 7.98, P = 0.014, respectively). However, the IL-8-251 A allele was not associated to PTB susceptibility (OR = 0.27, 95% CI = 0.15 - 0.44). Conclusion: TNF-α-308G/A and IL-8-251T/A polymorphisms may be associated to PTB susceptibility in the Congolese population, and the AA genotype of both cytokines could be a risk factor.

Infliximab vs adalimumab:Points to consider when selecting antitumor necrosis factor agents in pediatric patients with Crohn’s disease

Biologic agents with various mechanisms against Crohn’s disease(CD)have been released and are widely used in clinical practice.However,two anti-tumor necrosis factor(TNF)agents,infliximab(IFX)and adalimumab(ADL),are the only biologic agents approved by the Food and Drug Administration for pediatric CD currently.Therefore,in pediatric CD,the choice of biologic agents should be made more carefully to achieve the therapeutic goal.There are currently no headto-head trials of biologic agents in pediatric or adult CD.There is a lack of accumulated data for pediatric CD,which requires the extrapolation of adult data for the positioning of biologics in pediatric CD.From a pharmacokinetic point of view,IFX is more advantageous than ADL when the inflammatory burden is high,and ADL is expected to be advantageous over IFX in sustaining remission in the maintenance phase.Additionally,we reviewed the safety profile,immunogenicity,preference,and compliance between IFX and ADL and provide practical insights into the choice of anti-TNF therapy in pediatric CD.Careful evaluation of clinical indications and disease behavior is essential when prescribing anti-TNF agents.In addition,factors such as the efficacy of induction and maintenance of remission,safety profile,immunogenicity,patient preference,and compliance play an important role in evaluating and selecting treatment options.

Claudin 1 mediates tumor necrosis factor alpha-induced cell migration in human gastric cancer cells

AIM:To investigate the role of claudin 1 in the regulation of genes involved in cell migration and tumor necrosis factor alpha(TNF-α)-induced gene expression in human gastric adenocarcinoma cells.METHODS:Knockdown experiments were conducted with claudin 1 small interfering RNA(si RNA),and theeffects on the cell cycle,apoptosis,migration and invasion were analyzed in human gastric adenocarcinoma MKN28 cells.The gene expression profiles of cells were analyzed by microarray and bioinformatics.RESULTS:The knockdown of claudin 1 significantly inhibited cell proliferation,migration and invasion,and increased apoptosis.Microarray analysis identified 245genes whose expression levels were altered by the knockdown of claudin 1.Pathway analysis showed that the top-ranked molecular and cellular function was the cellular movement related pathway,which involved MMP7,TNF-SF10,TGFBR1,and CCL2.Furthermore,TNFand nuclear frctor-κB were the top-ranked upstream regulators related to claudin 1.TNF-αtreatment increased claudin 1 expression and cell migration in MKN28 cells.Microarray analysis indicated that the depletion of claudin1 inhibited 80%of the TNF-α-induced m RNA expression changes.Further,TNF-αdid not enhance cell migration in the claudin 1 si RNA transfected cells.CONCLUSION:These results suggest that claudin 1 is an important messenger that regulates TNF-α-induced gene expression and migration in gastric cancer cells.A deeper understanding of these cellular processes may be helpful in establishing new therapeutic strategies for gastric cancer.

Hemozoin triggers tumor necrosis factor alpha-mediated release of lysozyme by human adherent monocytes:new evidences on leukocyte degranulation in P.falciparum malaria

Objective:Avidly phagocytosed hemozoin(malarial pigment) alters several functions of human monocytes and stimulates generation of several cytokines.Recently,we showed that phagocytosis of hemozoin by human monocytes increases expression and activity of matrix metalloproteinase-9,a proteolytic enzyme available in specific gelatinase granules,which contain several enzymes including lysozyme.Present work investigated active lysozyme release after phagocytosis of hemozoin and its dependence on production of tumor necrosis factor alpha. Methods:After phagocytosis of hemozoin,hemozoin-containing trophozoites or control meals(opsonized nonparasitized red blood cells and latex particles),monocyte supematants were monitored for 2 hours,in presence of blocking anti-human tumor necrosis factor alpha antibodies or recombinant human tumor necrosis factor alpha cytokine in selected experiments.Lysozyme release was evaluated by a specific spectrometric assay measuring lysozyme activity after coincubation of cell supematants with suspensions of Mycrococcus Lysodeikticus,while levels of soluble tumor necrosis factor alpha were analyzed by specific enzyme-linked immunodsorbent assay. Results:Levels of lysozyme activity and soluble tumor necrosis factor alpha protein were increased in hemozoin in-or trophozoites-laden monocytes supematants.Phagocytosis per se(control meals) also increased lysozyme release,but levels were significantly lower than those obtained after phagocytosis of hemozoin or trophozoites. Interestingly,all effects on lysozyme release observed after phagocytosis were abrogated by blocking anti-human tumor necrosis factor alpha antibodies,while they were mimicked by recombinant human tumor necrosis factor alpha cytokine.Conclusions:Present work shows that phagocytosis of hemozoin promotes monocyte degranulation and enhances active lysozyme release.The effect requires tumor necrosis factor alpha mediation.

Safety of anti-tumor necrosis factor therapy during pregnancy in patients with inflammatory bowel disease

Treatment of inflammatory bowel disease has significantly improved since the introduction of biological agents, such as infliximab, adalimumab, certolizumab pegol, and golimumab. The Food and Drug Administration has classified these factors in category B, which means that they do not demonstrate a fetal risk. However, during pregnancy fetuses are exposed to high anti-tumor necrosis factor(TNF) levels that are measurable in their plasma after birth. Since antibodies can transfer through the placenta at the end of the second and during the third trimesters, it is important to know the safety profile of these drugs, particularly for the fetus, and whether maintaining relapse of the disease compensates for the potential risks of fetal exposure. The limited data available for the anti-TNF drugs to date have not demonstrated any significant adverse outcomes in the pregnant women who continued their therapy from conception to the first trimester of gestation. However, data suggest that antiTNFs should be discontinued during the third trimester, as they may affect the immunological system of the newborn baby. Each decision should be individualized, based on the distinct characteristics of the patient and her disease. Considering all the above, there is a need for more clinical studies regarding the effect of antiTNF therapeutic agents on pregnancy outcomes.

Genetic associations with adverse events from anti-tumor necrosis factor therapy in inflammatory bowel disease patients

AIM To study the type and frequency of adverse events associated with anti-tumor necrosis factor(TNF)therapy and evaluate for any serologic and genetic associations.METHODS This study was a retrospective review of patients attending the inflammatory bowel disease(IBD) centers at Cedars-Sinai IBD Center from 2005-2016. Adverse events were identified via chart review. IBD serologies were measured by ELISA. DNA samples were genotyped at Cedars-Sinai using Illumina Infinium Immunochipv1 array per manufacturer's protocol. SNPs underwent methodological review and were evaluated using several SNP statistic parameters to ensure optimal allele-calling. Standard and rigorous QC criteria were applied to the genetic data, which was generated using immunochip. Genetic association was assessed by logistic regression after correcting for population structure.RESULTS Altogether we identified 1258 IBD subjects exposed to anti-TNF agents in whom Immunochip data were available. 269/1258 patients(21%) were found to have adverse events to an anti-TNF-α agent that required the therapy to be discontinued. 25% of women compared to 17% of men experienced an adverse event. All adverse events resolved after discontinuing the antiTNF agent. In total: n = 66(5%) infusion reactions; n = 49(4%) allergic/serum sickness reactions; n = 19(1.5%) lupus-like reactions, n = 52(4%) rash, n = 18(1.4%) infections. In Crohn's disease, Ig A ASCA(P = 0.04) and Ig G-ASCA(P = 0.02) levels were also lower in patients with any adverse events, and anti-I2 level in ulcerative colitis was significantly associated with infusion reactions(P = 0.008). The logistic regression/human annotation and network analyses performed on the Immunochip data implicated the following five signaling pathways: JAK-STAT(Janus Kinase-signal transducer and activator of transcription), measles, IBD, cytokine-cytokine receptor interaction, and toxoplasmosis for any adverse event. CONCLUSION Our study shows 1 in 5 IBD patients experience an adverse event to anti-TNF therapy with novel serologic, genetic, and pathways associations.

Nitric oxide and tumour necrosis factor alpha in the process of pseudoexfoliation glaucoma

AIMTo establish the role of nitric oxide (NO), ascorbic acid and tumour necrosis factor-&#x003b1; (TNF-&#x003b1;) in the pathogenesis of pseudoexfoliation glaucoma (XFG).METHODSOur study included 120 patients who were referred for cataract surgery. All patients were divided into four groups according to clinical findings: XFG, early and late pseudoexfoliation syndrome (XFS), and cataract (without pseudoexfoliation). Serum and aqueous humour levels of the ascorbic acid, NO and TNF-&#x003b1; were measured. The concentrations of the ascorbic acid and NO were measured by an appropriate spectrophotometric method. Enzyme-linked immunosorbent assay (ELISA) was used to determine TNF-&#x003b1; level.RESULTSAqueous humour concentration of ascorbic acid was significantly lower in patients with late XFS (0.61&#x000b1;0.11 mmol/L) and XFG (0.48&#x000b1;0.15 mmol/L) compared to patients with early XFS (0.9&#x000b1;0.15 mmol/L) and cataract (1.16&#x000b1;0.22 mmol/L), while there was no difference in serum concentration in all examined groups. Aqueous humour concentration of NO was significantly higher in patients with XFG (77.7&#x000b1;11.4 &#x000b5;mol/L) compared to patients with early XFS (50.27&#x000b1;9.34 &#x000b5;mol/L) and cataract (49.77&#x000b1;7.1 &#x000b5;mol/L), while serum concentration was increased in the early stage of XFS (73.26&#x000b1;8.29 &#x000b5;mol/L). Aqueous humour level of proinflammatory cytokine TNF-&#x003b1; was increased in patients with XFS (early 460.04&#x000b1;18.32 pg/mL; late 502.42&#x000b1;53.23 pg/mL) and XFG (510.34&#x000b1;43.07 pg/mL), while there was no difference in serum level in all examined groups of patients.CONCLUSIONReduced ascorbic acid and elevated NO and inflammation related cytokine TNF-&#x003b1; level in aqueous humour of the patients with developed XFG suggest that oxidative stress induces local inflammation.

Higher production of tumor necrosis factor alpha in hemozoin-fed human adherent monocytes is dependent on lipidic component of malarial pigment:new evidences on cytokine regulation in Plasmodium falciparum malaria

Objective:To investigate whether the increase of tumor necrosis factor alpha is dependent on lipidic component of malarial pigment.Methods:Adherent human monocytes were fed for 3 hours with different meals(native hemozoin;lipid free hemozoin;and control latex particles),then tumor necrosis factor alpha was monitored in cell supernatants up to 48 hours through western blotting or specific enzyme-linked immunoadsorbent assay.In selected experiments,unfed monocytes were treated with different doses of 15(S,R)-hydroxy-6,8,11,13-eicosatetraenoic acid or 4-hydroxynonenal instead of phagocytosis.Results:Hemozoin-fed monocytes produced higher levels of tumor necrosis factor alpha than unstimulated and latex-fed cells, while lipid-free hemozoin did not reproduce these results.Additionally,hemozoin effects were mimicked dose-dependently by 15(S,R)-hydroxy-6,8,11,13-eicosatetraenoic acid,but not by 4-hydroxynonenal.Conclusions:Present data suggest an essential role for lipids in hemozoindependent enhanced release of tumor necrosis factor alpha from monocytes,and 15(S,R)hydroxy -6,8,11,13-eicosatetraenoic acid could be one possible specific mediator.

Effect of tumor necrosis factor-alpha in rats with hepatic ischemia-reperfusion injury

BACKGROUND: With the development of hepatic surgery, especially liver transplantation, the pathophysiological processes of hepatic ischemia-reperfusion (I/R) injury have gained special attention. Controlling I/R injury has become one of the most important factors for successful liver transplantation. This study aimed to investigate the effects of tumor necrosis factor-alpha (TNF-alpha) in rats with hepatic I/R injury and promote the recognition of I/R injury in the liver. METHODS: Thirty-two Sprague-Dawley rats were randomly divided into 2 groups. Rats in the sham-operated (SO) group served as controls. Rats in the hepatic ischemia-reperfusion (I/R) group underwent reperfusion after 30 minutes of liver ischemia. Rats were sacrificed at 1, 6 and 12 hours. The expression of TNF-alpha mRNA in the liver was measured by RT-PCR. Histological changes in the liver were assessed. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum were measured. RESULTS: The expression of TNF-alpha mRNA in the SO group was decreased compared with that in the I/R group (P<0.05). TNF-a mRNA expression progressively increased in the I/R group. The serum levels of ALT and AST in the I/R group were higher than those in the SO group (P<0.01). The histological changes were in accord with hepatic I/R injury. CONCLUSION: ALT and AST in serum are closely related to hepatic I/R injury and inflammatory reaction. TNF-alpha production in the liver triggers hepatic I/R injury through a cascade.

Evaluation of leptin,interleukin-1 beta and tumor necrosis factor alpha in serum of malaria patients as prognostic markers of treatment outcome

Objective:To analyze scrum leptin levels in patients with malaria falciparum and compare them with healthy controls and correlate with development and outcome of malaria infection.Methods:Sixty cases of malaria falciparum were included in this study as patients.Thirty healthy individuals of comparable age,racial and body mass index were taken as controls.All patients were diagnosed by clinical picture and the presence of malaria parasites in blood film.Estimation of liver function test,kidney function test,complete blood count,fasting blood sugar,fasting serum insulin,pro-inflammatory cytokine tumor necrosis factor alpha(TNFα)and interleukin 1(IL1),estimation of morning serum leptin and calculation of body mass index(kg/m^2)were done in both groups on the day of admission,on discharge and 7 d after discharge.Results:At admission,leptin levels were significantly higher in patients group than in control while lasting serum insulin levels were not significantly different between the two groups.There were significant increases as regard to TNFαand IL1 in malaria patients.Significant differences were observed between the control and the patient group for leptin,TNFαand IL1 at the time of admission and discharge.After discharge for 7 d.a significant decline in scrum leptin levels,TNFαand IL1 in the patients group was observed as compared with time of admission and time of discharge,a positive correlation between serum leptin levels and TNFαand IL1.Conclusions:Leptin hormone level might play an important role in development and outcome of malaria infection.

Predictors of response to anti-tumor necrosis factor therapy in ulcerative colitis

Ulcerative colitis(UC) is an immune-mediated, chronic inflammatory disease of the large intestine. Its course is characterized by flares of acute inflammation and periods of low-grade chronic inflammatory activity or remission. Monoclonal antibodies against tumor necrosis factor(anti-TNF) are part of the therapeutic armamentarium and are used in cases of moderate to severe UC that is refractory to conventional treatment with corticosteroids and/or immunosuppressants. Therapeutic response to these agents is not uniform and a large percentage of patients either fail to improve(primary non-response) or lose response after a period of improvement(secondary non-response/loss of response). In addition, the use of anti-TNF agents has been related to uncommon but potentially serious adverse effects that preclude their administration or lead to their discontinuation. Finally, use of these medications is associated with a considerable cost for the health system. The identification of parameters thatmay predict response to anti-TNF drugs in UC would help to better select for patients with a high probability to respond and minimize risk and costs for those who will not respond. Analysis of the major clinical trials and the accumulated experience with the use of anti-TNF drugs in UC has resulted to the report of such prognostic factors. Included are clinical and epidemiological characteristics, laboratory markers, endoscopic indicators and molecular(immunological/genetic) signatures. Such predictive parameters of long-term outcomes may either be present at the commencement of treatment or determined during the early period of therapy. Validation of these prognostic markers in large cohorts of patients with variable characteristics will facilitate their introduction into clinical practice and the best selection of UC patients who will benefit from anti-TNF therapy.

Association between hepatocellular carcinoma and tumor necrosis factor alpha polymorphisms in South Korea

AIM: To investigate associations between the tumor necrosis factor alpha(TNF-α)-1031 T>C,-863 C>A,-857 C>T,-308 G>A,and-238 G>A polymorphisms and HCC in Korea.METHODS: Hepatocellular carcinoma(HCC) cases were diagnosed at CHA Bundang Medical Center from June 1996 to August 2008. The association between TNF-α polymorphisms and HCC was analyzed in 157HCC patients and 201 controls using a polymerase chain reaction-restriction fragment length polymorphism assay. We investigated five TNF-α polymorphisms,which are TNF-α-1031 T>C,-863 C>A,-857 C>T,-308 G>A,and-238 G>A. The TNF-α genotype frequencies,genotype combinations and haplotypes were analyzed to disclose the association with HCC.RESULTS: None of the TNF-α polymorphisms was significantly associated with HCC. However,nine genotype combinations had associations with increased likelihood of HCC. Among them,TNF-α-1031/-857/-238 TT/CC/GA(AOR = 18.849,95%CI: 2.203-161.246,P = 0.007),TNF-α-1031/-308/-238 TT/GG/GA(AOR = 26.956,95%CI: 3.071-236.584,P = 0.003),and TNF-α-1031/-238 TT/GA(AOR = 21.576,95%CI: 2.581-180.394,P = 0.005) showed marked association with HCC. There were five haplotypes of TNF-α polymorphisms which were significantly associated with HCC. They are TNF-α-1031/-863/-857/-308/-238 T-C-C-G-A(OR = 25.824,95%CI: 1.491-447.223,P = 0.0005),TNF-α-1031/-857/-308/-238 T-C-G-A(OR = 12.059,95%CI: 2.747-52.950,P < 0.0001),TNF-α-1031/-857/-238 T-C-A(OR = 10.696,95%CI: 2.428-47.110,P = 0.0001),TNF-α-1031/-308/-238 T-G-A(OR = 7.556,95%CI: 2.173-26.280,P = 0.0002) and TNF-α-1031/-238 T-A(OR = 10.865,95%CI: 2.473-47.740,P = 0.0001). Moreover,HCC Okuda stage Ⅲ cases with the TNF-α-1031 CC genotype had better survival than those with the TT genotype(AOR = 5.795,95%CI: 1.145-29.323). CONCLUSION: Although no single TNF-α polymorphism is associated with HCC in this study,some TNF-α genotype combinations and haplotypes are associated with HCC. In addition,HCC Okuda stage Ⅲ cases with the TNF-α-1031 TT genotype may have a better prognosis than those with the CC genotype.

Cytomegalovirus colitis in a patient with Behcet’s disease receiving tumor necrosis factor alpha inhibitory treatment

Anti-tumor necrosis factor alpha (TNF-α) inhibitors are effective in the treatment of various inflammatory rheumatic conditions. Increased risks of serious infections are the major issues concerning the long-term safety of these agents. We present a case of a young male Behcet’s patient whose disease was complicated by cytomegalovirus (CMV) colitis. Colitis started 10 d after the third Infliximab dose and responded to the cessation of TNF blocking treatment and administration of ganciclovir. Tumor necrosis factor alpha and interferon gamma act at several levels in combating viral infections.CMV infections should be kept in mind and included in the differential diagnosis of severe gastrointestinal symptoms in patients receiving anti-TNF agents.

Experimental Study on Inhibitory Effect of Niacinamide on Tumor Necrosis Factor-alpha-induced Matrix Degradation of Annulus Fibrous Tissue in vitro

The inhibitory effect of niacinamide on tumor necrosis factor-α （TNF-α） induced annulus fibrous （AF） degradation was assessed, and the mechanism of the inhibition was investigated. Chiba＇s intervertebral disc （IVD） culture model was established. Forty-eight IVDs from 12 adult Japanese white rabbits were randomly divided into 4 groups （12 IVDs in each group）, and various concentrations of niacinamide and TNF-α were added to the medium for intervention： negative control group, niacinamide control group （0.5 mg/mL niacinamide）, degeneration group （10 ng/mL TNF-α）, and treatment group （0.5 mg/mL niacinamide and 10 ng/mL TNF-α）. After one week＇s culture, AFs were collected for glycosaminoglycan （GS） content measurement, safranin O-fast green staining, and immunohistochemical staining for type Ⅰ , Ⅱ collagen and cysteine containing aspartate specific prote- ase-3 （Caspase-3）. It was found that the GS content in treatment group was increased by about 48% as compared with degeneration group （t=16.93, P〈0.001）, and close to that in niacinamide control group （t=0.71, P=0.667）. Safranine O-fast green staining exhibited higher staining density and better histological structure of AF in the treatment group as compared with the degeneration group. Immunohistochemical staining for both TypeⅠ and Ⅱ collagen demonstrated that lamellar structure and continuity of collagen in treatment group were better reserved than in degeneration group. Positive staining rate of Caspase-3 in AFs of negative control group, niacinamide control group, degeneration group and treatment group was 3.4%, 4.3%, 17.9% and 10.3% respectively. The positive rate in treatment group was significantly lower than in degeneration group （P〈0.01）. It was concluded that niacinamide could effectively alleviate TNF-α induced destruction and synthesis inhibition of matrix ingredients in AFs. The inhibition may be related with reduction of expression of Caspase-3. Thus, niacinamide is of potential for IVD degeneration clinical treatment.

Single nucleotide polymorphism in the tumor necrosis factor-alpha gene affects inflammatory bowel diseases risk

AIM: To investigate the role that single nucleotide polymorphisms (SNPs) in the promoter of the tumour necrosis factor-alpha (TNF-α) gene play in the risk of inflammatory bowel diseases (IBDs) in a New Zealand population, in the context of international studies. METHODS: DNA samples from 388 patients with Crohn's disease (CD), 405 ulcerative colitis (UC), 27 indeterminate colitis (IC) and 201 randomly selected controls, from Canterbury, New Zealand were screened for 3 common polymorphisms in the TNF-α receptor: -238 G→A, -308 G→A and -857C→T, using a TaqmanR assay. A meta-analysis was performed on the data obtained on these polymorphisms combined with that from other published studies. RESULTS: Individuals carrying the -308 G/A allele had a significantly (OR = 1.91, χ2 = 17.36, P < 0.0001) increased risk of pancolitis, and a 1.57-fold increased risk (OR = 1.57, χ2 = 4.34, P = 0.037) of requiring a bowel resection in UC. Carrying the -857 C/T variant decreased the risk of ileocolonic CD (OR = 0.56, χ2 =4.32, P = 0.037), and the need for a bowel resection (OR = 0.59, χ2 = 4.85, P = 0.028). The risk of UC was reduced in individuals who were smokers at diagnosis, (OR = 0.48, χ2 = 4.86, P = 0.028). CONCLUSION: TNF-α is a key cytokine known to play a role in inflammatory response, and the locus for the gene is found in the IBD3 region on chromosome 6p21, known to be associated with an increased risk for IBD. The -308 G/A SNP in the TNF-α promoter is functional, and may account in part for the increased UC risk associated with the IBD3 genomic region. The -857 C/T SNP may decrease IBD risk in certain groups. Pharmaco- or nutrigenomic approaches may be desir- able for individuals with such affected genotypes.