Parasitic helminth infections in humans modulate Trefoil Factor levels in a manner dependent on the species of parasite and age of the host.

Helminth infections, including hookworms and Schistosomes, can cause severe disability and death. Infection management and control would benefit from identification of biomarkers for early detection and prognosis. While animal models suggest that Trefoil Factor Family proteins (TFF2 and TFF3) and interleukin-33 (IL-33) -driven type 2 immune responses are critical mediators of tissue repair and worm clearance in the context of hookworm infection, very little is known about how they are modulated in the context of human helminth infection. We measured TFF2, TFF3, and IL-33 levels in serum from patients in Brazil infected with Hookworm and/or Schistosomes, and compared them to endemic and non-endemic controls. TFF2 was specifically elevated by Hookworm infection in females, not Schistosoma or co-infection. This elevation was correlated with age, but not worm burden. TFF3 was elevated by Schistosoma infection and found to be generally higher in females. IL-33 was not significantly altered by infection. To determine if this might apply more broadly to other species or regions, we measured TFFs and cytokine levels (IFNγ, TNFα, IL-33, IL-13, IL-1ß, IL-17A, IL-22, and IL-10) in both the serum and urine of Nigerian school children infected with S. haematobium. We found that serum levels of TFF2 and 3 were reduced by infection, likely in an age dependent manner. In the serum, only IL-10 and IL-13 were significantly increased, while in urine IFN-γ, TNF-α, IL-13, IL-1ß, IL-22, and IL-10 were significantly increased in by infection. Taken together, these data support a role for TFF proteins in human helminth infection.

Circulating trefoil factors in relation to lung cancer, age and lung function: a cross-sectional study in patients referred for suspected lung cancer.

The trefoil factor family proteins: TFF1, TFF2 and TFF3 are secreted by epithelial cells in the respiratory tract. Here, we explore circulating concentrations of the trefoil factors in relation to lung cancer, age and lung function. We included 751 patients suspected of lung cancer. Lung cancer diagnosis was based on data reported to a national database. Serum TFF1, TFF2 and TFF3 concentrations were measured by ELISA, and spirometry was performed within ±3 days of blood sampling. Forced expiratory volume in the first second (FEV1) in relation to forced vital capacity (FVC), FEV1/FVC (a parameter used to quantify reduced lung function) was recorded. Lung cancer was diagnosed in 163 (22%) patients. Circulating concentrations of TFF3 (p = .021), but not TFF1 and TFF2, were significantly elevated in cancer patients. All three trefoil factors showed an increase in concentration with increasing age (p < .001) and declining lung function (p < .004). In the present cohort, concentrations of all three peptides were elevated compared with previous results published for healthy individuals. In conclusion, we report higher concentrations of TFF3 in patients with lung cancer, while increasing age and reduced lung function are associated with increasing concentrations of all trefoil factors in this specific patient population. The results emphasize that age and lung function should be taken into consideration when evaluating concentrations of trefoil factors in patients. However, the increases in trefoil factor concentrations were relatively small, and consequently, it is unlikely that circulating trefoil factor concentrations may have a role in the diagnosis of lung cancer and lung function impairment.

Blood Biomarkers of Intestinal Epithelium Damage Regenerating Islet-derived Protein 3α and Trefoil Factor 3 Are Persistently Elevated in Patients with Alcoholic Hepatitis.

BACKGROUND: Heavy alcohol consumption disrupts gut epithelial integrity, leading to increased permeability of the gastrointestinal tract and subsequent translocation of microbes. Regenerating islet-derived protein 3α (REG3α) and Trefoil factor 3 (TFF3) are mainly secreted to the gut lumen by Paneth and Goblet cells, respectively, and are functionally linked to gut barrier integrity. Circulating levels of REG3α and TFF3 have been identified as biomarkers for gut damage in several human diseases. We examined whether plasma levels of REG3α and TFF3 were dysregulated and correlated with conventional markers of microbial translocation (MT) and pro-inflammatory mediators in heavy drinkers with and without alcoholic hepatitis (AH). METHODS: Cross-sectional and longitudinal studies were performed to monitor plasma levels of REG3α and TFF3 in 79 AH patients, 66 heavy drinkers without liver disease (HDC), and 46 healthy controls (HC) at enrollment and at 6- and 12-month follow-ups. Spearman correlation was used to measure the relationships of REG3α and TFF3 levels with MT, disease severity, inflammation, and effects of abstinence from alcohol. RESULTS: At enrollment, AH patients had significantly higher levels of REG3α and TFF3 than HDC and HC. The elevated REG3α levels were positively correlated with the 30-day fatality rate. Plasma levels of REG3α and TFF3 in AH patients differentially correlated with conventional MT markers (sCD14, sCD163, and LBP) and several highly up-regulated inflammatory cytokines/chemokines/growth factors. At follow-ups, although REG3α and TFF3 levels were decreased in AH patients with alcohol abstinence, they did not fully return to baseline levels. CONCLUSIONS: Circulating levels of REG3α and TFF3 were highly elevated in AH patients and differentially correlated with AH disease severity, MT, and inflammation, thereby serving as potential biomarkers of MT and gut epithelial damage in AH patients.

Screening of Multiple Biomarkers Associated With Ischemic Stroke in Atrial Fibrillation.

Background To explore the pathophysiological features of ischemic stroke in patients with atrial fibrillation (AF), we evaluated the association between 268 plasma proteins and subsequent ischemic stroke in 2 large AF cohorts receiving oral anticoagulation. Methods and Results A case-cohort sample of patients with AF from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, including 282 cases with ischemic stroke or systemic embolism and a random sample of 4124 without these events, during 1.9 years of follow-up was used for identification. Validation was provided by a similar case-cohort sample of patients with AF from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, including 149 cases with ischemic stroke/systemic embolism and a random sample of 1062 without these events. In plasma obtained before randomization, 268 unique biomarkers were measured with OLINK proximity extension assay panels (CVD II, CVD III, and Inflammation) and conventional immunoassays. The association between biomarkers and outcomes was evaluated by random survival forest and adjusted Cox regression. According to random survival forest or Cox regression analyses, the biomarkers most strongly and consistently associated with ischemic stroke/systemic embolism were matrix metalloproteinase-9, NT-proBNP (N-terminal pro-B-type natriuretic peptide), osteopontin, sortilin, soluble suppression of tumorigenesis 2, and trefoil factor-3. The corresponding hazard ratios (95% CIs) for an interquartile difference were as follows: 1.18 (1.00-1.38), 1.55 (1.28-1.88), 1.28 (1.07-1.53), 1.19 (1.02-1.39), 1.23 (1.05-1.45), and 1.19 (0.97-1.45), respectively. Conclusions In patients with AF, of 268 unique biomarkers, the 6 biomarkers most strongly associated with subsequent ischemic stroke/systemic embolism represent fibrosis/remodeling (matrix metalloproteinase-9 and soluble suppression of tumorigenesis 2), cardiac dysfunction (NT-proBNP), vascular calcification (osteopontin), metabolism (sortilin), and mucosal integrity/ischemia (trefoil factor-3). Registration URL: https://www.clinicaltrials.gov. Unique Identifiers: NCT00412984 and NCT00262600.

Cytokine Profiling in Chinese SLE Patients: Correlations with Renal Dysfunction.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease that commonly causes kidney damage. Therefore, we measured plasma levels of cytokines that may be related to renal dysfunction in SLE patients. METHODS: To explore the differences between SLE patients with renal dysfunction and healthy volunteers, the levels of cytokines in plasma were screened using a human cytokine antibody array. Then, we chose fourteen of the elevated cytokines for verification with an expanded sample size by a human magnetic Luminex assay. Plasma samples were isolated from SLE patients (n = 72) and healthy volunteers (n = 8). RESULTS: Cytokine antibody array data showed elevated plasma cytokines in SLE patients with renal dysfunction compared with healthy volunteers. By using the human magnetic Luminex assay, we found that plasma levels of CHI3L1, GDF-15, IGFBP-2, MIF, ST2, TFF3, and uPAR were significantly higher in SLE patients than in healthy volunteers. Plasma levels of CXCL4 were significantly lower in the active group than in the inactive group, and plasma levels of CHI3L1, IGFBP-2, MIF, and MPO were significantly higher in the active group than in the inactive group. We also analyzed the correlation between plasma cytokine levels and the SLEDAI-2K, and our results showed that the plasma levels of the fourteen selected cytokines were weakly correlated or not correlated with the SLEDAI-2K. We further analyzed the correlation between cytokines and renal dysfunction. Plasma levels of GDF-15 and TFF3 were highly positively correlated with serum creatinine levels and 24-hour urine protein levels. CONCLUSION: Our data suggest that plasma levels of GDF-15 and TFF3 are potential renal dysfunction markers in SLE patients, but plasma levels of these cytokines are not correlated with the SLEDAI-2K. Further study is warranted to determine how these cytokines regulate inflammatory responses and renal dysfunction in SLE.

Biomarkers associated with early stages of kidney disease in adolescents with type 1 diabetes.

OBJECTIVES: To identify biomarkers of renal disease in adolescents with type 1 diabetes (T1D) and to compare findings in adults with T1D. METHODS: Twenty-five serum biomarkers were measured, using a Luminex platform, in 553 adolescents (median [interquartile range] age: 13.9 [12.6, 15.2] years), recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Associations with baseline and final estimated glomerular filtration rate (eGFR), rapid decliner and rapid increaser phenotypes (eGFR slopes <-3 and > 3 mL/min/1.73m2 /year, respectively), and albumin-creatinine ratio (ACR) were assessed. Results were also compared with those obtained in 859 adults (age: 55.5 [46.1, 64.4) years) from the Scottish Diabetes Research Network Type 1 Bioresource. RESULTS: In the adolescent cohort, baseline eGFR was negatively associated with trefoil factor-3, cystatin C, and beta-2 microglobulin (B2M) (B coefficient[95%CI]: -0.19 [-0.27, -0.12], P = 7.0 × 10-7 ; -0.18 [-0.26, -0.11], P = 5.1 × 10-6 ; -0.12 [-0.20, -0.05], P = 1.6 × 10-3 ), in addition to clinical covariates. Final eGFR was negatively associated with osteopontin (-0.21 [-0.28, -0.14], P = 2.3 × 10-8 ) and cystatin C (-0.16 [-0.22, -0.09], P = 1.6 × 10-6 ). Rapid decliner phenotype was associated with osteopontin (OR: 1.83 [1.42, 2.41], P = 7.3 × 10-6 ), whereas rapid increaser phenotype was associated with fibroblast growth factor-23 (FGF-23) (1.59 [1.23, 2.04], P = 2.6 × 10-4 ). ACR was not associated with any of the biomarkers. In the adult cohort similar associations with eGFR were found; however, several additional biomarkers were associated with eGFR and ACR. CONCLUSIONS: In this young population with T1D and high rates of hyperfiltration, osteopontin was the most consistent biomarker associated with prospective changes in eGFR. FGF-23 was associated with eGFR increases, whereas trefoil factor-3, cystatin C, and B2M were associated with baseline eGFR.

Comparison of Serum Trefoil Factor-3 to Endoscopy in Diagnosing Helicobacter Pylori Associated Gastric Ulcer.

BACKGROUND AND AIM OF THE WORK: Helicobacter pylori-associated gastric ulcer (H.pylori-GU) is a serious condition, not only because H.pylori is identified as a grade 1 carcinogen but also because GU is a precancerous condition. Identification and treatment of H.pylori-GU may prevent the sequential progression of dysplasia to carcinoma. Trefoil factor 3 (Tf3) has been implicated in gastric mucosal repair. We compared serum Tf3 to gastric endoscopy in diagnosing H.pylori-GU. SUBJECTS AND METHODS: The study included eighty patients suffering from H.pylori induced gastritis, forty of which presented with GU. Gastric endoscopy with slide urease test was used to diagnose H.pylori-GU. Serum Tf3 level was determined using an enzyme immunoassay in all patients as well as thirty healthy volunteers. RESULTS: Serum Tf3 showed a significant stepwise decrease among the studied groups. It was significantly lower in patients compared to the control group (p<0.001). Furthermore, it was lower in those with GU compared to those without GU (p=0.023). Based on a receiver operating characteristic curve generated cut off value of 2.4 ng/mL, the diagnostic performance of serum Tf3 as a biomarker of H.pylori-GU revealed a diagnostic specificity of 42.5%, sensitivity of 67.5%, positive and negative predictive values of 54% and 56.67% respectively. CONCLUSION: Although serum Tf3 showed significant variation in H.pylori-GU, further studies are warranted to confirm its role in the pathogenesis of gastric ulcers.
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Elevated trefoil factor 3 plasma levels in critically ill patients with abdominal sepsis or non-infectious abdominal illness.

Trefoil factor 3 (TFF3) is a small peptide secreted mainly by goblet cells in the gut, where it plays a key role in gastrointestinal defence and repair. Plasma TFF3 has been reported as a biomarker of intestinal injury and as such it has been evaluated as a marker of disease activity in colitis. Impaired gut barrier function has been postulated as the "motor" of critical illness. We here sought to determine the temporal dynamics of plasma TFF3 in adult patients admitted to intensive care unit with abdominal sepsis or after major abdominal surgery for a non-infectious condition (post-op GI patients). TFF3 was measured in plasma obtained from 143 patients with abdominal sepsis and 98 post-op GI patients on admission to the intensive care (day 0) and at days 2 and 4 thereafter. Abdominal sepsis patients showed sustained elevated plasma TFF3 levels from day 0 to 4 relative to healthy control values, while in post-op GI patients admission TFF3 levels were not increased, only rising at day 2 and 4. In both patient groups, the presence of shock was associated with higher TFF3 levels. Moreover, patients with 3 or more organs failing had higher plasma TFF3 concentrations. While plasma TFF3 was higher in sepsis patients who did not survive until day 30, TFF3 levels were not independently associated with 30-day mortality in a Cox regression analysis. These results could support the theory that intestinal injury contributes to the pathogenesis of critical illness. Future studies are needed to elucidate whether the proposed gut dysfunction precedes or supersedes organ dysfunction in time.

Contrasting serum biomarker profiles in two Colombian populations with different risks for progression of premalignant gastric lesions during chronic Helicobacter pylori infection.

BACKGROUND: Colombians in coastal Tumaco have a lower incidence of Helicobacter pylori-associated gastric cancer compared to individuals from Tuquerres in the high Andes. This is despite nearly universal prevalence of H. pylori infection and chronic gastritis. METHODS: H. pylori infection was confirmed by Steiner stain and serology using African and European-origin strains. Gastric histology and serum inflammatory biomarkers in dyspeptic Tumaco or Tuquerres patients were evaluated to predict progression of gastric lesions. RESULTS: H. pylori infection was nearly universal by Steiner stain and serology. IgG response to European-origin H. pylori strains were greater than African-origin. High gastric cancer-risk Tuquerres patients, compared to low-risk Tumaco, had significant odds ratios for lesion progression associated with serum IL-5, trefoil factor 3 (TFF3), and low pepsinogen I/II ratio. Sensitivity and specificity for these parameters was 63.8% and 67.9%, respectively, with correctly classifying patients at 66.7%. Most odds ratios for 26 other biomarkers were significant for the town of residency, indicating an environmental impact on Tumaco patients associated with decreased lesion progression. CONCLUSION: An IL-5 association with progression of gastric lesions is novel and could be evaluated in addition to TFF3 and pepsinogen I/II ratio as a non-invasive prognostic screen. Results suggest Tumaco patients were exposed to infectious diseases beyond H. pylori such as the documented high incidence of helminthiasis and toxoplasmosis. IMPACT: Results support a prior recommendation to evaluate TFF3 and pepsinogen I/II together to predict aggressive gastric histology. Our data indicate IL-5 should be further evaluated as prognostic parameter.

Factor trefoil-3 y galectina-4 como nuevos candidatos para biomarcadores pronósticos en infarto de miocardio con elevación del segmento ST / Trefoil factor-3 and galectin-4 as new candidates for prognostic biomarkers in ST-segment elevation myocardial infarction

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Evaluation of inflammatory bowel disease activity in children using serum trefoil factor peptide.

BACKGROUND: The diagnosis of IBD and evaluation of treatment require endoscopy, which is difficult in children. This study evaluated the use of TFF3 as a biomarker. METHODS: Permeability of the intestinal mucosa and serum TFF3 were assayed and colon tissue was harvested 7 days after inducing IBD in mice with TNBSA. TFF3 was monitored in 51 pediatric IBD patients stratified by active disease or remission and in 20 healthy children. Mucosal healing was assessed by the Simple Endoscopic Score for Crohn Disease and Baron scores in CD and UC patients. RESULTS: Histological evaluation revealed transmural inflammation of the colon in IBD model mice. Permeability of the intestinal mucosa and serum TFF3 were both higher in TNBSA-treated than in control mice (P < 0.05). TFF3 was higher in children with active IBD than in those in remission and in healthy children (P < 0.05). TFF3 was positively correlated with the SES-CD score (P < 0.05) but not with either the pediatric CDAI score or the serum CRP. The sensitivity of serum TFF3 for monitoring CD activity was 100% and the specificity was 76.2%. CONCLUSIONS: TFF3 level increased with CD activity, which is of significance for diagnosis and for evaluation of mucosal healing. TFF3 could also be a marker in pediatric UC, as TFF3 positively correlated with UCAI. IMPACT: The diagnosis and evaluation of IBD is difficult; endoscopy provides objective assessment; TFF3 can be a useful marker instead of endoscopy. TFF3 was increased in active CD of children; TFF3 can be used as a clinical marker of pediatric CD; TFF3 can diagnose and evaluate mucosal healing of CD. Pediatrician should pay attention to clinical marker; TFF3 level may be a key evaluation of mucosal healing of CD; the value of diagnosis of TFF3 in CD is important.

New serum tumor markers S100, TFF3 and AIF-1 and their possible use in oncogynecology.

OBJECTIVE: To review a literature about possible new blood serum gynecologic tumor markers, S100 proteins family, trefoil factor 3 and AIF-1. DESIGN: Literature review. SETTING: Department of Obstetrics and Gynecology, Faculty of Medicine, Palacky University and University Hospital in Olomouc. METHODS: Literature review of articles published in PubMed database till January 2019. RESULTS: The association of S100A2, S100A4, S100A6, S100A7, S100A8, S100A9 and S100A11 with breast carcinoma has been demonstrated in the literature. The association of S100A2, S100A4, S100A6, S100A7A, S100A10, S100A14, S100A16, S100B, S100P (up-regulation associated with a lower survival) and S100A1, S100A13, S100A5, S100A13 and S100G proteins (up-regulation associated with a better survival) have been demonstrated in ovarian cancer patients. Cervical carcinoma has been shown to be associated with the S100A9 protein. TFF3 association with endometrial cancer, breast cancer (worse prognosis) and ovarian cancer (better prognosis) has been demonstrated. AIF-1 has been shown to increase expression in cervical cancer. CONCLUSION: Tumor markers can be a very useful tool for patient management when used appropriately. Further research in this area and the search for new tumor markers, including S100, TFF3 and AIF-1, are needed. In future studies, scientists should focus not only on one time point, but assess the trend of the tumor markers for a specific time axis.

sICAM-1 as potential additional parameter in the discrimination of the Sjögren syndrome and non-autoimmune sicca syndrome: a pilot study.

OBJECTIVE: Both Sjögren's syndrome (SS) and non-autoimmune sicca syndrome (nSS) can show symptoms of dry eyes and a dry mouth, and objective reductions in tear and saliva production. Dry eyes and dry mouth are frequent but they are distinct pathological entities that require diagnostic discrimination. METHODS: The aim of present study was to compare the serum levels of sICAM-1, TFF3, RANTES, adiponectin, and FGF in primary (pSS), secondary due to rheumatoid arthritis (sSS), non-autoimmune sicca syndrome (nSS), and healthy groups. The serum levels of selected molecules were determined by enzyme-linked immunosorbent assay (ELISA) in 29 patients with pSS, 30 with sSS, 17 with nSS, and 15 healthy subjects. RESULTS: sICAM-1 was significantly elevated in pSS and sSS patients compared with nSS group. Levels of FGF, TFF3, and RANTES were significantly increased in pSS, sSS, and nSS patients compared with healthy controls. No significant correlations were found between the levels of measured molecules and the clinical parameters. CONCLUSIONS: Our study showed that sICAM-1 might be useful as an additional parameter for differential diagnosis of SS and nSS, and TFF could be additional diagnostic marker for SS diagnosis. KEY POINTS: • sICAM-1 was significantly elevated in Sjögren syndrome patients compared with non-autoimmune sicca syndrome group. • TFF was significantly elevated in Sjögren syndrome patients compared with healthy controls. • They might be useful as additional parameters for differential diagnosis.

Trefoil Factor 3 is Highly Predictive of Complete Mucosal Healing Independently and in Combination with C-Reactive Protein in Patients with Ulcerative Colitis.

AIM: In the current study we aimed to evaluate the role of trefoil factor 3 (TFF3) as a marker for complete mucosal healing (MH) in patients with ulcerative colitis (UC). METHODS: We enrolled 116 consecutive UC patients. Trefoil factor 3 levels were measured by ELISA and were compared to the clinical activity, assessed by Lichtiger Index, fecal calprotectin (FCP) and C-reactive protein (CRP) levels. Colonoscopy was performed in all the patients and the findings were graded according to Mayo endoscopic score (EMS) and UC endoscopic index of severity (UCEIS). RESULTS: Trefoil factor 3 levels were significantly correlated with Lichtiger Index (r=0.736, p<0.001), EMS (r=0.811, p<0.001), UCEIS (r=0.820, p<0.001), FCP (r=0.696, p<0.001) and CRP (r=0.405, p<0.001). The TFF3 cut-off level of 6.74 ng/ml indicated complete MH (EMS=0; UCEIS=0) with a sensitivity and specificity of 0.879 and 0.869, respectively (area under the curve, AUC 0.927; 95% confidence interval, 0.877-0.976). The DeLong's test revealed no significant difference between the AUC of TFF3+CRP and the AUC of FCP (Z=1.717, p=0.086), AUC of TFF3+FCP (Z=1.908, p=0.056), and AUC of TFF3+CRP+FCPP (Z=1.915, p=0.056). However, the AUC of TFF3+CRP showed significant difference compared with the AUC of TFF3 (Z=2.210, p=0.027) and the AUC of CRP (Z=3.145, p=0.002) for predicting complete MH. CONCLUSIONS: Trefoil factor 3 levels correlated significantly with clinical activity, endoscopic indices, CRP and FCP in our patients. TFF3 is a highly predictive marker of complete MH independently and in combination with CRP in patients with UC.

Serum trefoil factor 3 predicts disease activity in patients with ulcerative colitis.

OBJECTIVE: In this study, we aimed to evaluate the role of serum trefoil factor 3 (TFF3) as a biomarker of disease activity in patients with inflammatory bowel disease (IBD) and to compare TFF3 values with those of fecal calprotectin (FC). PATIENTS AND METHODS: 128 patients with IBD were divided into four groups: 1) active ulcerative colitis (UC); 2) quiescent UC; 3) active Crohn's disease (CD); 4) quiescent CD. The serum levels of TFF3 and FC levels were assessed in all patients and 16 controls. RESULTS: Patients with active UC had higher TFF3 levels than those with quiescent UC (p<0.001), those with active (p<0.001) or quiescent CD (p<0.001) and controls (p <0.001). We found a correlation between TFF3 and FC values in patients with active (r = 0.478, p = 0.006) and quiescent UC (r=0.528, p=0.002). TFF3 levels correlated with endoscopic activity in UC (evaluated by UC Endoscopic Index of Severity - UCEIS) (r=0.662, p<0.001). CONCLUSIONS: Serum TFF3 is able to identify patients with active UC. It could be used as a marker to predict disease activity in patients with UC.

A Mendelian Randomization-Based Approach to Identify Early and Sensitive Diagnostic Biomarkers of Disease.

BACKGROUND: Identifying markers of chronic kidney disease (CKD) that occur early in the disease process and are specific to loss of kidney function rather than other underlying causes of disease may allow earlier, more accurate identification of patients who will develop CKD. We therefore sought to identify diagnostic blood markers of early CKD that are caused by loss of kidney function by using an innovative "reverse Mendelian randomization" (MR) approach. METHODS: We applied this technique to genetic and biomarker data from 4147 participants in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, all with known type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance. Two-sample MR was conducted using variants associated with creatinine-based eGFR (eGFRcrea) from the CKDGen Consortium (n = 133814) to estimate the effect of genetically decreased eGFRcrea on 238 serum biomarkers. RESULTS: With reverse MR, trefoil factor 3 (TFF3) was identified as a protein that is increased owing to decreased eGFRcrea (ß = 1.86 SD per SD decrease eGFRcrea; 95% CI, 0.95-2.76; P = 8.0 × 10-5). Reverse MR findings were consistent with epidemiological associations for incident CKD in ORIGIN (OR = 1.28 per SD increase in TFF3; 95% CI, 1.18-1.38; P = 4.58 × 10-10). Addition of TFF3 significantly improved discrimination for incident CKD relative to eGFRcrea alone (net reclassification improvement = 0.211; P = 9.56 × 10-12) and in models including additional risk factors. CONCLUSIONS: Our results suggest TFF3 is a valuable diagnostic marker for early CKD in dysglycemic populations and acts as a proof of concept for the application of this novel MR technique to identify diagnostic biomarkers for other chronic diseases. CLINICALTRIALSGOV IDENTIFIER: NCT00069784.

The predictive powers of plasma trefoil factor 3 or its related micro RNAs for patients with hepatocellular carcinoma.

BACKGROUND: Earlier diagnosis is beneficial for the prognosis of hepatocellular carcinoma (HCC). Alpha fetoprotein (AFP) is the most widely used biomarker for HCC, but its sensitivity and specificity are only 60 and 90%, respectively. Therefore, it is of great clinical significance to identify early prognostic biomarkers for HCC, especially a blood-based biomarker as it offers several advantages over tissue-based biomarkers. Trefoil factor 3 (TFF3), a novel secretory protein, was over-expressed in HCC tissues, indicating it might be a blood-based biomarker for HCC. In addition, circulating microRNAs have been investigated as biomarkers for HCC, indicating that miR-7-5p and miR-203a-3p, which are reported or predicted to target TFF3, also hold promise as blood-based biomarkers for HCC. METHODS: We enrolled 43 patients who were firstly diagnosed HCC and matched 47 control subjects without HCC. The levels of TFF3, miR-7-5p and miR-203a-3p were tested in the plasma of HCC patients. Moreover, we assayed the correlation of TFF3 with its related micro RNAs, miR-7-5p and miR-203a-3p, and evaluated their predictive powers for HCC. RESULTS: Decrease of TFF3 was associated with increase of miR-203a-3p in the plasma of HCC patients and they displayed potent predictive powers for HCC diagnosis. However, there was no significant change of plasma miR-7-5p between HCC and control group. CONCLUSION: Decrease of TFF3 correlated with increase of miR-203a-3p in the plasma of HCC patients and they could be additional biomarkers to improve sensitivity and specificity in the diagnosis of HCC.

Prognostic Value of Trefoil Factor 3 Expression in Patients with Gastric Cancer.

BACKGROUND: Trefoil factor 3 (TFF3) is a small molecule secreted by the mammalian gastrointestinal tract and is overexpressed in some human malignant tumors. We investigated the prognostic values of immunohistochemical (IHC) TFF3 expression and serum TFF3 levels in patients with gastric cancer, and whether TFF3 influenced tumor proliferation and invasion in vitro. METHODS: We examined 111 patients who underwent R0 gastrectomy for gastric cancer between April 2012 and April 2015. IHC TFF3 expression and serum TFF3 levels were evaluated regarding their associations with clinicopathological factors and recurrence-free survival (RFS). In vitro cell proliferation and migration assays were used to explore the biological role of TFF3 in human gastric cancer cell lines following transfection with a lentivirus-based shRNA plasmid. RESULTS: IHC TFF3 expression showed significant associations with depth of invasion (p = 0.024), lymph node metastasis (p = 0.008), and RFS (log-rank p = 0.002). Serum TFF3 levels were correlated with IHC TFF3 expression (p = 0.013). RFS was significantly poorer in patients with high (n = 27) compared to low (n = 84) serum TFF3 levels (log-rank p = 0.003). Cox multivariate analysis indicated that serum TFF3 level was an independent prognostic factor for RFS (p = 0.024). In vitro assays, TFF3 downregulation significantly inhibited both proliferation and invasion of gastric cancer cells. CONCLUSIONS: Serum TFF3 levels could be useful prognostic markers in patients with gastric cancer. TFF3 may play various biological roles in proliferation and invasion of gastric cancer cells.

Serum TFF1 and TFF3 but not TFF2 are higher in women with breast cancer than in women without breast cancer.

Breast cancer remains a common malignancy in women, but the take-up for breast cancer screening programs in Japan is still low, possibly due to its perceived inconvenience. TFF1 and TFF3 are expressed in both breast cancer tissue and normal breast. Serum trefoil proteins were reported as cancer screening markers for gastric, prostate, lung, pancreatic cancer and cholangio carcinoma. The purpose of this study was to examine whether serum trefoil proteins could be screening biomarkers for breast cancer. Serum trefoil proteins in 94 breast cancer patients and 84 health check females were measured by ELISA. Serum TFF1 and TFF3 were significantly higher and serum TFF2 was significantly lower in breast cancer patients. Area under the curve of receiver operating characteristic of TFF1, TFF2, and TFF3 was 0.69, 0.83, and. 0.72, respectively. AUC of the combination of TFF1, TFF2, and TFF3 was 0.96. Immunohistochemically, TFF1 expression was positive in 56.5% and TFF3 was positive in 73.9% of breast cancers, while TFF2 was negative in all tumors. Serum TFF1 had positive correlation with expression of TFF1 in breast cancer tissue. Serum concentrations of TFF1 and TFF3 but not TFF2 are higher in women with breast cancer than in women without breast cancer.

Diagnostic value evaluation of trefoil factors family 3 for the early detection of colorectal cancer.

AIM: The purpose of this study was to evaluate the diagnostic value of trefoil factor family 3 (TFF3) for the early detection of colorectal cancer (CC). METHODS: Serum TFF3 and carcino-embryonic antigen (CEA) were detected in 527 individuals, including 115 healthy control (HC), 198 colorectal adenoma (CA), and 214 CC individuals in the training group. RESULTS: Serum TFF3 showed no significant correlation with age, gender, or tumor location but showed significant correlation with the tumor stage. Serum TFF3 in the CC group was significantly higher than in the HC or CA group. The AUC values of TFF3 for discriminating between HC and CC and between CA and CC were 0.930 (0.903, 0.958) and 0.834 (0.796, 0.873). A multivariate model combining TFF3 and CEA was built. Compared to TFF3 or CEA alone, the multivariate model showed significant improvement (P < 0.001). For discriminating between HC and CC, HC and early stage CC, HC and advanced stage CC, CA and CC, CA and early stage CC, and CA and advanced stage CC in the training group, the sensitivities were 92.99%, 91.46%, 93.18%, 73.83%, 76.83%, and 81.82%, and the specificities were 91.30%, 91.30%, 93.91%, 88.38%, 77.27%, and 88.38%, respectively. After validation, the sensitivities were 89.39%, 85.71%, 90.79%, 72.73%, 71.43%, and 78.95%, and the specificities were 87.85%, 87.85%, 2.52%, 87.85%, 80.77%, and 87.50%, respectively. CONCLUSION: The multivariate diagnostic model that included TFF3 and CEA showed significant improvement over the conventional biomarker CEA and might provide a potential method for the early detection of CC.