Early screening to identify and diagnose primary nasal tuberculosis in patients with tumor necrosis factor inhibitors

In this editorial,we comment on the article by Liu et al.Based on our analysis of a case report,we consider that early screening and recognition of primary nasal tuberculosis are crucial for patients undergoing treatment with tumor necrosis factor inhibitor(TNFi).While TNFi therapy increases the risk of reactivating latent tuberculosis,primary nasal tuberculosis remains rare due to the protective mechanisms of the nasal mucosa.Risk factors for primary nasal tuberculosis include minimally invasive nasal surgery,diabetes,and human immunodefi ciency virus.Patients with early symptoms such as nasal congestion,rhinorrhea,altered olfaction,epistaxis,or ulceration,and unresponsive to conventional antibiotics and antihistamines should undergo early rhinoscopy,possibly followed by repeated tissue biopsies and acid-fast bacilli culture when necessary.When diagnosis is challenging,it is essential to consider local tuberculosis epidemiology and the efficacy of diagnostic antituberculosis treatment.The preferred method for tuberculosis screening is the Interferon Gamma Release Assay,with a general recommendation for screening at 3 and 6 months after initial treatment and then every six months.However,the optimal frequency is not yet consensus-driven and may be increased in economically viable settings.

Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn's disease

To investigate genetic factors that might help define which Crohn’s disease (CD) patients are likely to benefit from anti-tumor necrosis factor (TNF) therapy. METHODSThis was a prospective cohort study. Patients were recruited from a university digestive disease practice database. We included CD patients who received anti-TNF therapy, had available medical records (with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood, and 7 single nucleotide polymorphisms (SNPs) were assessed. The main outcome measure (following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age, gender, race, and socioeconomic status disease, as well as disease characteristics (such as Montreal criteria). RESULTS121 patients were included. Twenty-one were non-responders, and 100 were ever-responders. Fas ligand SNP (rs763110) genotype frequencies, TNF gene -308 SNP (rs1800629) genotype frequencies, and their combination, were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype (P = 0.009, OR = 4.30, 95%CI: 1.45-12.80). The presence of the A (minor) TNF gene -308 allele correlated with three-fold higher odds of being a non-responder (P = 0.049, OR = 2.88, 95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF -308 A allele had nearly five-fold higher odds of being a non-responder (P = 0.015, OR = 4.76, 95%CI: 1.35-16.77). No difference was seen for the remaining SNPs. CONCLUSIONThe Fas-ligand SNP and TNF gene -308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.

THE ASSOCIATION BETWEEN TUMOR NECROSIS FACTORαGENE POLYMORPHISM AND ASTHMA

Objective.In this study,we investigated the hypothesis that tumor necrosis factor(TNF)α-308gene polymorphism might be of the genetic predisposition to asthma and asthma phenotypes.Methods.TNFα-308gene polymorphism was genotyped in221random unrelated Northern Chinese population(comprising125asthmatics and96healthy controls)and52individuals from12asthmatic families with Han ethnic by using polymerase chain reaction(PCR)-restriction fragment length polymor-phism(RFLP).Methacholine(Mch)broncho-challenge test,bronchial reversibility test and lung function were underwent in all asthmatics.Results.TNFα-3082homozygosity was present at a significantly higher frequency in asthmatics than that in controls(20.8%vs11.4%,P<0.05,OR2.259),the TNF allele2was also higher in asthmatics compared with controls(0.42vs0.33,P<0.01).TNFα-3082homozygosity was an weak independent risk factor for asthma etiology(OR0.226,P<0.05).Moreover,patients carrying TNFα-3082homozy-gosity had less responsive to inhaledβ 2 -agonist in20minutes than patients carrying other two genotypes(24.1%vs29.5%vs38.8%,P<0.05).Linkage analysis didn’t support that TNFαgene was linked to asthma (Likelihood of odds,LOD<1)based on familial data.Conclusion These results suggest that TNFα-3082homozygosity may be of a component contribut-ing to the genetic predisposition to asthma ,and airway responsiveness toβ2 -agonist.

Association between genetic variations in tumor necrosis factor receptor genes and survival of patients with T-cell lymphoma

The prognosis of T-cell lymphoma (TCL) has been shown to be associated with the clinical characteristics of patients. However, there is little knowledge of whether genetic variations also affect the prognosis of TCL. This study investigated the associations between single nucleotide polymorphisms(SNPs) in tumor necrosis factor receptor superfamily(TNFRSF) genes and the survival of patients with TCL. A total of 38 tag SNPs in 18 TNFRSF genes were genotyped using Sequenom platform in 150 patients with TCL. Kaplan-Meier survival estimates were plotted and significance was assessed using log-rank tests. Cox proportional hazard models were used to analyze each of these 38 SNPs with adjustment for covariates that might influence patient survival, including sex and international prognostic Index score. Hazard ratios (HRs) and their 95% confidence intervals(CIs) were calculated. Among the 38 SNPs tested, 3 were significantly associated with the survival of patients with TCL. These SNPs were located at LTβR (rs3759333C>T) and TNFRSF17(rs2017662C>T and rs2071336C>T). The 5-year survival rates were significantly different among patients carrying different genotypes and the HRs for death between the different genotypes ranged from 0.45 to 2.46. These findings suggest that the SNPs in TNFRSF genes might be important determinants for the survival of TCL patients.

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.

Role of tumor necrosis factor-alpha in zebrafish retinal neurogenesis and myelination

AIM： To investigate the role of tumor necrosis factoralpha （TNF-α） in zebrafish retinal development and myelination. METHODS： Morpholino oligonucleotides （MO）, which are complementary to the translation start site of the wild-type embryonic zebrafish TNF-α mRNA sequence, were synthesized and injected into one to four-cell embryos. The translation blocking specificity was verified by Western blotting using an anti-TNF-α antibody, whole-mount in sltuhybridization using a hepatocytespecific mRNA probe ceruloplasmin （cp）, and coinjection of TNF-α MO and TNF-α mRNA. An atonel homolog 7 （atoh7） mRNA probe was used to detect neurogenesis onset. The retinal neurodifferentiation was analyzed by immunohistochemistry using antibodies Zn12, Zprl, and Zpr3 to label ganglion cells, cones, and rods, respectively. Myelin basic protein （mbp）was used as a marker to track and observe the myelination using whole-mount in situ hybridization. RESULTS： Targeted knockdown of TNF-α resulted in specific suppression of TNF-α expression and a severely underdeveloped liver. The co-injection of TNF-α MO and mRNA rescued the liver development. Retinal neurogenesis in TNF-cc morphants was initiated on time. The retina was fully laminated, while ganglion cells, cones, and rods were well differentiated at 72 hours post-fertilization （hpf）. mbp was expressed in Schwann cells in the lateral line nerves and cranial nerves from 3 days post -fertilization （dpf） as well as in oligodendrocytes linearly along the hindbrain bundles and the spinal cord from 4 dpf, which closely resembled its endogenous profile. CONCLUSION： TNF-α is not an essential regulator for retinal neurogenesis and optic myelination.

Effect of Tumor Necrosis Factor-α on Acyl Coenzyme A: Cholesteryl Acyltransferase Activity and ACAT1 Gene Expression in THP-1 Macrophages

In order to explore the effect and mechanisms of tumor necrosis factor-α （TNF-α） on the activity of the acyl coenzyme A： cholesteryl acyltransferase （ACAT）, THP-I monocytes were cul- tured and induced to differentiate into macrophages with phorbol ester. TNF-α （60 ng/mL） was added at different time points into the macrophage-containing medium and the ACAT enzyme activity was measured by quantifying the incorporation of [1-^14C] oleoyl CoA into cholesteryl esters. The expression of ACAT-1 protein and mRNA was respectively detected by Western blotting and RT-PCR in THP-1 macrophages 24 h after treatment with TNF-α （60 ng/mL）. The results indicated that ACAT activity in THP-I macrophages treated with TNF-α was increased in a time-dependent manner. The expression levels of ACAT-1 protein and mRNA were significantly increased in THP-I macrophages after treatment with TNF-α （P〈0.05）. It was suggested that TNF-α could increase the activity of ACAT in THP-1 macrophages by up-regulating the expression of ACAT-1 gene.

Genes of tumor necrosis factors and their receptors and the primary open angle glaucoma in the population of Central Russia

AIM：To examine the association of genetic polymorphisms（-308）G/A TNFα,（＋250）A/G Ltα,（＋36）A/G TNFR1,（＋1663）A/G TNFR2 with the development of primary open angle glaucoma（POAG）among people in Central Russia.METHODS：The study sample included 443 individuals,of which 252 patients with POAG and 191 individuals in the control group.Genotyping of（-308）G/A TNFα,（＋250）A/G Ltα,（＋36）A/G TNFR1,（＋1663）A/G TNFR2 was performed using polymerase chain reaction.The distribution of alleles and genotypes of the studied DNA markers in the groups was examined by 2×2 contingency tables andχ2with the Yates’s correction for continuity and odds ratios（OR）with95%confidence intervals（CI）.RESULTS：Allele（-308）G TNFα（Р=0.01,OR=1.78,95%CI1.12-2.85）was identified as a risk factor for POAG.Homozygotes（-308）AA TNFαare at a lowest risk for development of the disease（Р=0.01,OR=0.0005）.The following combination of genetic variants of cytokines were associated with a reduced risk of POAG：（＋1663）A TNFR2 and（＋250）G Ltα（OR=0.34）CONCLUSION：Genetic polymorphisms（-308）G/A TNFα,（＋250）A/G Ltα,（＋1663）A/G TNFR2 associated with the development of POAG in the population of Central Russia.

Gene expression and cellular localizations of tumor necrosis factor-α at the site of implanted bovine cancellous bone in mice

The objective of this study was to determine if mRNA encoding for tumor necrosls factor-α(TNFα) was present at the site of implanted bovine cancellous bone and to observe the cellular localizations. The particles of bovine cancellous bone treated by special chemical reagents were implanted in the mouse’s muscle pouch. removed 5.10 and 20 days after implantation, and the specimens were processed for determining the expression and cellular localizations of TNFα mRNA, which was performed by a nonradioactive in situ hybridization technique. The results showed that (1) 5, 10 and 20 days after transplantation, the TNFα mRNA expressions were positive, andthe positive rate of expression was the highest by 10 days (P<0. 05 ). (2)There was strong hybridization signal localization to the nuclei of morphologically ldentifiable monocytes and multinucleated giant cells. (3)Similar activity was detected in the cytoplasm and (or) nuclei of partial adjacent mesenchymal cells, fibroblasts as well as striated muscle fibers. This finding tended to indicate that mRNA encoding for TNFα was intensely expressed in several kinds of cells and that TNFα seemed to be of importance for the modulation of local cellular immunity in the region of implanted xenogeneic bone.

Gene Expression of Tumor Necrosis Factor-Alpha in Etanercept-Treated Rheumatoid Arthritis Patients

Fifty-one rheumatoid arthritis (RA) patients were enrolled to assess the gene expression of tumor necrosis factor-alpha (TNF-α) by reverse transcription quantitative polymerase chain reaction (qRT-PCR) in etanercept-treated RA patients, with some emphasis on clinical and biological markers of disease. The results revealed that the ΔCt mean range in total, male and female RA patients and controls was 1.286 ± 1.226 - 4.023 ± 0.856 and the differences were not. Laboratory and clinical findings in subgroups of patients also showed no significant variations in the distribution of 2-ΔΔCt means, with the exception of anti-cyclic citrullinated peptide (ACCP) antibodies. The lowest expression was observed in moderate positive patients (1.566 ± 1.104) compared to low and high positive patients (4.061 ± 1.366 and 9.668 ± 3.518, respectively) for ACCP antibodies, and the difference was significant (p = 0.043). Inspecting the 2-ΔΔCt means in duration of disease and gender revealed that male patients recorded a lower mean than female patients (0.827 ± 0.550 vs. 4.143 ± 1.317) at 10 years duration of disease, female patients showed a lower mean than male patients (1.242 ± 0.372 vs. 5.607 ± 3.334). However, both differences were not significant. It is concluded that etanercept was effective in normalizing the TNF gene expression, but variations that were related to gender, duration of disease and some biological markers of disease, were observed.

SYNTHESIS AND EXPRESSION OF A GENE FOR HUMAN TUMOR NECROSIS FACTOR-ALPHA (TNF-α)

TNF-α was found originally In sera of Bacillus Calmette Guerln infected mice as a macrophage derived factor. It Is cytotoxlc for tumor cell and less or not toxic to normal cells in vitor. The gene for human TNF-α with E. coli-preferred codons has been designed according to the amino acid sequence deduced from the cDNA. The gene with 504 bp was divided into 27 oligonucleotide fragments having 30. to 40 nucleotides each. The solid phase phosphotriester method was used for the synthesis of these oligonucleotides. The 27 fragments were annealed to three segments and then linked by T4 DNA ligase. The entire gene was incorporated into plasmld PDR540 with Tac promoter which was used to transform E. coli 7118. The expressed protein was estimated by SDSPAGE with a molecular weight of 1. 7×104Da. The cytotoxlc activity of the product against L-929 cell was 1. 0×107units/ml culture.

Recombination Mutant Human Tumor Necrosis Factor Combined with Chemotherapy in the Treatment of Advanced Cancer

Objective: Past studies showed that tumor necrosis factor (TNF) assisted anti-tumor treatment and intensified the sensitivity of chemotherapy. However its clinical application has been curbed because of its low purity, high dosage, and strong toxicity. The objective of present study is to evaluate the therapeutic effects and adverse reactions of recombinant mutant human tumor necrosis factor (rmhTNF) combined with chemotherapy in patients with advanced malignant tumor. Methods: 105 patients with advanced malignant tumor were randomly divided into trial group, 69 patients, and control group, 36 patients. rmhTNF was injected intramuscularly to the trial group at a dose of 4×106 U/m2, from the 1st to 7th days, the 11th to 17th days combined with chemotherapy course. The chemotherapy plan was as follows: CAP for patients with the NSCLC; FAM for patients with gastric cancer; FC for patients with colorectal cancer. One treatment cycle lasted for 21 days and two cycles were scheduled. The control group was given only the same chemotherapy as the trial group. Results: In the trial group there was 1 CR case and 12 PR cases, and the response rate was 13/69 (18.84%); in the control group 1 PR case, the response rate 1/36 (2.78%). The response rate in the trial group was significantly higher than that in the control group (P=0.022). The response rate for NSCLC in the trial group was 8/17 (47.06%), and 1/6 (16.67%) in the control group. The response rates for gastric cancer and colorectal cancer in the trial groups also were higher than those in the control groups. After the treatment the KPS was 89.00±9.92 in the trial group, and 84.17±8.84 in the control group, with a significant difference between the two groups (P=0.028). The adverse reactions of rmhTNF injection included: pain in the injection area, chill, hardening and swelling and redness in the injection area, fever, ostealgia and myosalgia, and cold-like symptoms. All these adverse reactions were mild and bearable. Conclusion: The administration of rmhTNF in combination with general chemotherapy is an effective and secure means in treating advanced malignant tumor.

Uptake of bacterial lipopolysaccharide and expression of tumor necrosis factor α mRNA in isolated rat intrahepatic bile duct epithelial cells *

AIM To study the uptake of bacterial lipopolysaccharides (LPS) and expression of tumor necrosis factor α mRNA (TNF α mRNA) with cultured rat intrahepatic bile duct epithelial cells.

Relationship between tumor necrosis factor-α and liver fibrosis

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Influence of granulocyte-macrophage colonystimulating factor and tumor necrosis factor on anti-hepatoma activities of human dendritic cells

INTRODUCTIONDendritic cells (DCs) play a key regulatory role inantitumor immunity,especially in its immuneaccessory role via MHC-Ⅰ molecules.We haverecently reported that DCs were able to enhance thekilling activity of Lymphokine and PHA activatedkiller (LPAK) cells in vitro.In the presentstudy,we evaluated the effects of GM-CSF andTNF upon antitumor activities of freshly

Blood glucose changes surrounding initiation of tumor-necrosis factor inhibitors and conventional disease-modifying anti-rheumatic drugs in veterans with rheumatoid arthritis

AIM To determine the scope of acute hypoglycemic effects for certain anti-rheumatic medications in a large retrospective observational study. METHODS Patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were selected who, during follow-up, initiated treatment with tumor necrosis factor inhibitors (TNFi's, including etanercept, adalimumab, infliximab, golimumab, or certolizumab), prednisone, or conventional disease-modifying anti-rheumatic drugs(DMARDs), and for whom proximate random blood glucose (RBG) measurements were available within a window 2-wk prior to, and 6 mo following, medication initiation. Similar data were obtained for patients with proximate values available for glycosylated hemoglobin A1C values within a window 2 mo preceding, and 12 mo following, medication initiation. RBG and A1C measurements were compared before and after initiation events using paired t-tests, and multivariate regression analysis was performed including established comorbidities and demographics.RESULTS Two thousands one hundred and eleven patients contributed at least one proximate measurement surrounding the initiation of any examined medication. A significant decrease in RBG was noted surrounding 653 individual hydroxychloroquine-initiation events(-3.68 mg/dL, P = 0.04), while an increase was noted for RBG surrounding 665 prednisone-initiation events(+5.85 mg/d L, P < 0.01). A statistically significant decrease in A1C was noted for sulfasalazine initiation, as measured by 49 individual initiation events(-0.70%, P < 0.01). Multivariate regression analyses, using methotrexate as the referent, suggest sulfasalazine (β =-0.58, P = 0.01) and hydroxychloroquine(β =-5.78, P = 0.01) use as predictors of lower post-medicationinitiation RBG and A1C values, respectively. Analysis by drug class suggested prednisone (or glucocorticoids) as predictive of higher medication-initiation event RBG among all start events as compared to DMARDs, while this analysis did not show any drug class-level effect for TNFi. A diagnosis of congestive heart failure(β = 4.69, P = 0.03) was predictive for higher post-initiation RBG values among all medication-initiation events.CONCLUSION No statistically significant hypoglycemic effects surrounding TNFi initiation were observed in this large cohort. Sulfasalazine and hydroxychloroquine may have epidemiologically significant acute hypoglycemic effects.

The Change of Interleukin-6 and Tumor Necrosis Factor in Patients with Obstructive Sleep Apnea Syndrome

The levels of lipopolysaccharide (LPS) induced interleukin 6 (IL 6) and tumor necrosis factor α (TNF α) expression in culture of peripheral blood mononuclear cells (PBMC) and the plasma levels of IL 6 and TNF α in the patients with obstructive sleep apnea syndrome (OSAS) were measured and the relationship between OSAS and IL 6 or TNF α expression studied. Both IL 6 and TNF α were detected by using ELISA in 22 patients with OSAS and 16 normal controls. The levels of LPS induced IL 6 (787.82±151.97 pg/ml) and TNF α (4165.45±1501.43 pg/ml) expression in the supernatant of the culture of PBMC and plasma level of IL 6 (50.67±4.70 pg/ml) and TNF α (299.09±43.57 pg/ml) in the patients with OSAS were significantly higher than those in the normal controls (in the supernatant of the culture of PBMC: 562.69±197.54 pg/ml and 1596.25±403.08 pg/ml respectively; in the plasma: 12.69±2.75 pg/ml and 101.88±21.27 pg/ml respectively). There were significantly positive correlation between the levels of IL 6 and TNF α and the percentage of time of apnea and hyponea, as well as the percentage of time spending at SaO 2 below 90 % in the total sleep time. It was concluded that LPS induced IL 6 and TNF α levels as well as plasma IL 6 and TNF α levels in the patients with OSAS were up regulated, which may be associated with the pathogenesis of OSAS.

Tumor necrosis factor-α and interleukin-6 in cirrhotic patients with spontaneous bacterial peritonitis

AIM: To evaluate the role of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cirrhotic patients who have hepatic and renal impairment with spontaneous bacterial peritonitis (SBP).

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-&#x003b1;)-induced gene expression in human gastric adenocarcinoma cells.

Anti Cervix Cancer Activity of Co-immobilized Tumor Necrosis Factor-α and Interferon-γ

Tumor necrosis factor α （TNF-α） and interferon-γ （IFN-γ） are cytokines with strong antitumor activities. They were reacted with a photoactive arylazide-4-azidobenzoic acid, resulting in photoactive TNF-α and IFN-γ. The infrared （IR） spectra of these products showed the characteristic absorption of an azido group at 2127 cm^-1. By photo-immobilization, this modified TNF-α and IFN-γ were immobilized on polystyrene membranes for cell culture to prepare biomaterials. The micro-morphology of photoactive cytokines was observed with a scanning electron microscope （SEM）. The inhibitory effect on growth of Hela cells and inducing apoptosis activity of these two cytokines were analyzed by growth curve, transmission electron microscope （TEM） and fluorescence active cell sorter （FACS）. The results showed that co-immobilization of IFN-γ and TNF-α had significant inhibitory effect on growth of Hela cells, inhibitory rate up to 82%, and IFN-γ had obviously synergistic action.