Serum Adipokines, Growth Factors, and Cytokines Are Independently Associated with Stunting in Bangladeshi Children.

Growth in young children is controlled through the release of several hormonal signals, which are affected by diet, infection, and other exposures. Stunting is clearly a growth disorder, yet limited evidence exists documenting the association of different growth biomarkers with child stunting. This study explored the association between different growth biomarkers and stunting in Bangladeshi children. A quasi-experimental study was conducted among 50 stunted (length-for-age Z-score (LAZ) < -2 SD) and 50 control (LAZ ≥ -2 SD) children, aged 12-18 months, residing in a Bangladeshi slum. The enrolled stunted children received an intervention package, which included food supplementation for three months, psychosocial stimulation for six months, and routine clinical care on community nutrition center at the study field site. The controls received routine clinical care only. All children were clinically screened over the study period. Length, weight, fasting blood and fecal biomarkers were measured. All biomarkers levels were similar in both groups except for oxyntomodulin at enrolment. Leptin (adjusted odds ratio, AOR: 4.0, p < 0.01), leptin-adiponectin ratio (AOR 5.07 × 108, p < 0.01), insulin-like growth factor-1 (IGF-1) (AOR 1.02, p < 0.05), and gamma interferon (IFN-γ) (AOR 0.92, p < 0.05) levels were independently associated with stunting at enrolment. Serum leptin, leptin-adiponectin ratio, interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha (TNF-α), and fecal alpha-1-antitrypsin (AAT) levels increased significantly (p < 0.001), while IFN-γ levels significantly decreased among stunted children after six months of intervention. Leptin, leptin-adiponectin ratio, IGF-1, and IFN-γ are independently associated with stunting in Bangladeshi children. This trial was registered at clinicaltrials.gov as NCT02839148.

YKL-40 is a local marker for inflammation in patients with pseudoexfoliation syndrome.

PURPOSE: To investigate the YKL-40, as a marker of inflammation, in aqueous humor and serum of cataract patients with and without pseudoexfoliation syndrome (PEX). METHODS: Aqueous humor and serum samples were obtained from 44 patients who underwent phacoemulsification surgery. All patients were divided into two groups: PEX (n = 24) and control (n = 20). YKL-40 levels were measured with enzyme-linked immunosorbent assay (ELISA). The differences between the groups were assessed by using Chi-square and independent sample t-tests. The Pearson correlation coefficient was used to evaluate the correlation between variables. RESULTS: There was a significant difference between the mean YKL-40 levels in the aqueous humor of PEX group (112.0 ± 35.8 ng/mL) and control subjects (88.2 ± 30.6 ng/mL) (P = 0.025). However, the difference between the mean YKL-40 levels in the serum of PEX group (53.5 ± 29.1 ng/mL) and control subjects (44.6 ± 30.2 ng/mL) was non-significant (P = 0.326). The correlation between aqueous humor and serum YKL-40 concentrations was significant in both the groups (r = 0.833, P < 0.001; r = 0.840, P < 0.001, respectively). CONCLUSIONS: Increased aqueous humor levels of YKL-40 demonstrate that it is local, but not a systemic marker for inflammation in patients with PEX.

Association between soluble immune mediators and tumor responses in patients with nonsmall cell lung cancer treated with anti-PD-1 inhibitor.

Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNα2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.

Angiogenic potential of YKL-40 in the dynamics of tumor niche.

A multitude of clinical studies showed the elevation of YKL-40 in subjects with different kinds of tumors. It is predicted that an inherent correlation exists between survivals of cancer patients with total YKL-40 serum levels, making this factor as a potential novel biomarker. However, the crucial role of YKL-40 in the dynamics of cancers, especially angiogenesis, has not yet been completely addressed. In this review, we highlighted the various facets of YKL-40 and its importance in cancer biology as a bio-shuttle in gene therapy.

Growth Factors Levels Determine Efficacy of Platelets Rich Plasma Injection in Knee Osteoarthritis: A Randomized Double Blind Noninferiority Trial Compared With Viscosupplementation.

PURPOSE: To assess the noninferiority of a single platelet-rich plasma (PRP) injection compared with hyaluronic acid (HA), to alleviate pain and enhance functional capacity in knee osteoarthritis, and identify biological characteristics of PRP that may affect their efficacy. METHODS: Fifty-four patients with symptomatic knee osteoarthritis received a single injection of either PRP (26 patients) or HA (28 patients). They were assessed at baseline and at 1, 3, and 6 months. The primary endpoint was the change in Western Ontario and McMaster Universities Arthritis Index (WOMAC) score at 3 months, and secondary endpoints were responders' rate (improvement of at least 5 points or 40% of WOMAC total score at 3 months) of pain evaluation and patient's subjective satisfaction. Cell counts and the contents of vascular endothelial growth factor (VEGF), platelet-derived growth factor-AB (PDGF-AB), transforming growth factor beta 1 (TGF-ß1) content of injected PRP were assessed to analyze their relationship with clinical outcome. RESULTS: Both treatments proved their improvement in knee functional status and symptom relief, with a significant decrease observed at 1 month on all scores except for pain VAS in PRP group and WOMAC function score in the HA group. No difference between groups regarding WOMAC and VAS scores was observed. A higher percentage of responders was observed in the PRP group (72.7%) than in the HA group (45.8%) without significance (P = .064). The quantity of injected PDGF-AB and TGF-ß1 correlated with the change in WOMAC scores at 3 months and was lower in responders than in nonresponders (P = .009 and P = .003, respectively). CONCLUSIONS: Current results indicated that a single injection of very pure PRP offers a significant clinical improvement in the management of knee osteoarthritis, equivalent to a single HA injection in this patient population. Moreover, a significant correlation between the doses of TGF-ß1 and PDGF-AB and the worsening of WOMAC score 3 months after the procedure was found. LEVEL OF EVIDENCE: Level II, randomized double blind controlled trial.

Simultaneous detection of 15 antibiotic growth promoters in bovine muscle, blood and urine by UPLC-MS/MS.

An analytical method was established for the rapid detection of antibiotic growth promoters (AGPs) in bovine muscle, and bovine blood and bovine urine, using ultra high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). After the addition of an aqueous solution of EDTA-Na2, the pH of bovine urine samples was directly adjusted to 5.2 by acetic acid-ammonium acetate and purified by HLB solid-phase extraction cartridge; bovine muscle and bovine blood samples processing were extracted with acetonitrile (ACN) and ACNwater (90:10; v/v) without any purification step. The samples were then centrifuged, concentrated and analysed by UPLC-MS/MS on an ACQUITY UPLC® BEH C18 column using gradient elution. The developed method was validated and mean recovery percentages at three spiked levels were 74-119%, 76-115% and 76-119%, respectively, in bovine muscle, bovine blood, and bovine urine. The relative standard deviation (RSD) ranged from 1.0% to 14.7% in spiked bovine muscle, bovine blood and bovine urine. The limits of detection (LOD) of all analytes were in the ranges 0.11-3.82 µg kg-1, 0.10-2.49 µg kg-1 and 0.06-4.53 µg kg-1 in bovine muscle, bovine blood, and bovine urine, respectively. The method was sensitive, accurate and was applied to monitor real samples. To the best of our knowledge, this is first method available for simultaneous determination of several classes of APGs in bovine muscle, and bovine blood and bovine urine.

YKL-40 in allogeneic hematopoietic cell transplantation after AML and myelodysplastic syndrome.

YKL-40, also called chitinase-3-like-1 protein, is an inflammatory biomarker that has been associated with disease severity in inflammatory and malignant diseases, including AML, multiple myeloma and lymphomas. The objective of the current study was to assess the prognostic value of pretransplant recipient and donor plasma YKL-40 concentrations in patients with AML (n=624) or myelodysplastic syndrome (n=157) treated with allogeneic hematopoietic cell transplantation (HCT). In recipients, the plasma YKL-40 concentrations were increased when the HCT-comorbidity index was ⩾5 (P=0.028). There were no significant associations between plasma YKL-40 concentrations in recipients and any outcome measures. In donors with YKL-40 plasma concentrations above the age-adjusted 95th percentile, a trend toward increased grade II-IV acute GvHD in recipients was observed (adjusted hazard ratio 1.39 (95% confidence interval 1.00-1.94), P=0.050), with no significant associations with overall survival, treatment-related mortality or relapse. In conclusion, our study shows that YKL-40 does not aid risk stratification of patients undergoing allogeneic HCT, but suggests that YKL-40 may aid donor selection when multiple, otherwise equal, donors are available.

Biomarkers in systemic sclerosis: Their potential to predict clinical courses.

The concept of a biomarker was defined as "a characteristic marker that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention" by the National Institutes of Health Biomarkers Definitions Working group in 2001. Clinical features, disease progress, therapeutic response and prognosis are heterogeneous among patients with systemic sclerosis (SSc). Therefore, biomarkers that can predict these matters are required for the progress of clinical practice. At present, SSc-specific autoantibodies are the most useful biomarkers for diagnosis and predicting clinical features. Otherwise, biomarkers specific only for SSc have not been identified yet. The glycoprotein krebs von den Lungen-6, surfactant protein-D and CCL18 are promising serum biomarkers of SSc-related interstitial lung diseases. Serum/plasma levels of brain natriuretic peptide and serum N-terminal pro-brain natriuretic peptide have been used as biomarkers for SSc-related pulmonary arterial hypertension. Other potential serum/plasma biomarkers for fibrosis and vascular involvement of SSc are connective tissue growth factor, interleukin-6, CCL2, CXCL4, intercellular adhesion molecule (ICAM)-1, P-selectin, vascular endothelial growth factor, von Willebrand factor, endostatin, endoglin and endothelin-1. In our multicenter prospective studies of Japanese early SSc, serum ICAM-1 levels were predictive for subsequent respiratory dysfunction and serum levels of CXCL8 and P-selectin were predictive for subsequent physical disability. Further large, multicenter, prospective, longitudinal studies will be needed to identify and validate critical biomarkers of SSc.

Cytokine and growth factor profiling in patients with the metabolic syndrome.

The metabolic syndrome (MetS) is associated with a pro-inflammatory milieu that may partially account for its association with an increased cardiovascular risk. We aimed to (1) evaluate the serum concentrations of twelve cytokines and growth factors (epidermal growth factor (EGF), interferon-γ (IFN-γ), IL-1α/-1ß/-2/-4/-6/-8/-10, monocyte chemoattractant protein-1 (MCP-1), TNF-α and vascular endothelial growth factor (VEGF)) in 303 individuals with or without the MetS; and (2) explore their relationship with the presence of the MetS. Patients with the MetS had significantly higher serum concentrations of IFN-γ, EGF, IL-1α/-1ß/-2/-4/-6/-8/-10, MCP-1 and TNF-α, whilst serum VEGF concentrations were markedly lower compared with the control group (e.g. 38·55 v. 82·18 pg/ml; P< 0·05). Amongst these parameters, IFN-γ and IL-1α emerged as the most significant independent predictors of the MetS. In conclusion, our findings demonstrate that patients with the MetS had an altered blood cytokine and growth factor profile that may partially account for its adverse clinical outcomes. Further prospective studies in larger multi-centre settings are required to unravel the role and association of the emerging biomarkers with the MetS and their implication in therapeutic intervention.

Serum YKL-40 is increased in patients with slow coronary flow.

OBJECTIVES: There is accumulating evidence that inflammation plays a major role in the development of the slow coronary flow (SCF) phenomenon. YKL-40 has been suggested to be a potential biomarker of inflammation. In this study, we aimed to study YKL-40 as it relates to SCF. MATERIALS AND METHODS: Patients who underwent coronary angiography before and had angiographically normal coronary arteries of varying coronary flow rates without any atherosclerotic lesion were enrolled in this study. Patients who had thrombolysis in myocardial infarction frame counts (TFC) above the normal cutoffs were considered to have SCF and those within normal limits were considered to have normal coronary flow (NCF). The YKL-40 levels and biochemical profiles of all patients were studied and analyzed. RESULTS: There were 41 patients in the SCF group and 209 patients in the NCF group. Compared with the NCF patients, SCF patients had higher serum high-sensitivity C-reactive protein (hs-CRP) (P=0.0003) and YKL-40 (P=0.0007) levels. A positive correlation was detected between the YKL-40 levels and hs-CRP (r=0.7021, P<0.001), and the mean TFC (r=0.4038, P=0.0088) in SCF patients. CONCLUSION: Our study showed that YKL-40 levels are higher and correlated positively with TFC and hs-CRP in SCF patients. This finding suggests that YKL-40 may be a useful marker and predictor for SCF.

Serum YKL-40 for monitoring myocardial ischemia after revascularization in patients with stable coronary artery disease.

AIM: The aim was to investigate the inflammatory biomarker YKL-40 as a monitor of myocardial ischemia in patients with coronary artery disease (CAD). METHODS: A total of 311 patients with stable CAD were included. Blood samples were taken at baseline, the day after coronary angiography and/or after percutaneous coronary intervention and after 6 months. RESULTS: A total of 148 (48%) patients were revascularized and 163 patients underwent only coronary angiography. In the entire population, serum YKL-40 increased significantly from baseline to 6 months (p = 0.05). This tendency was seen in nonrevascularized patients (p = 0.06), but not in revascularized patients (p = 0.46). Serum YKL-40 increased approximately 25% the day after the invasive procedure (p < 0.001) and then decreased significantly to nearly baseline after 6 months (p = 0.002). CONCLUSION: Serum YKL-40 is a potential promising biomarker of disease progression but not of myocardial ischemia in patients with stable CAD.

Alpha fetoprotein DNA prime and adenovirus boost immunization of two hepatocellular cancer patients.

BACKGROUND: Alpha fetoprotein (AFP) is an oncofetal antigen over-expressed by many hepatocellular cancers (HCC). We previously demonstrated that HLA-A2-restricted epitopes derived from AFP are immunogenic in vitro and in vivo despite high circulating levels of this oncofetal antigen. In order to test a more broadly applicable, HLA-unrestricted, inexpensive, cell-free vaccine platform capable of activating tumor antigen-specific CD8+ and CD4+ T cells, we tested full length AFP in a plasmid DNA construct in combination with an AFP-expressing replication-deficient adenovirus (AdV) in a prime-boost vaccine strategy. METHODS: HCC patients who had an AFP+ tumor and previous treatment for HCC were screened and two patients received vaccination with three plasmid DNA injections followed by a single AdV injection, all delivered intramuscularly (i.m.). RESULTS: The vaccine was well tolerated and safe. Both patients showed immunologic evidence of immunization. The first patient had a weak AFP-specific T cell response, a strong AdV-specific cellular response and recurred with an AFP-expressing HCC at nine months. The second patient developed a strong AFP-specific CD8+ and CD4+ cellular response and an AdV neutralizing antibody response, and recurred at 18 months without an increase in serum AFP. CONCLUSIONS: The AFP DNA prime-AdV boost vaccine was safe and immunogenic. Circulating anti-AdV neutralizing antibodies at baseline did not prohibit the development of AFP-specific cellular immunity. The patient who developed CD8+ and CD4+ AFP-specific T cell immunity had more favorable progression-free survival. The observations with these two patients support development of this vaccine strategy in a larger clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00093548.

The chitinase-like protein YKL-40: a possible biomarker of inflammation and airway remodeling in severe pediatric asthma.

BACKGROUND: Problematic severe childhood asthma includes a subgroup of patients who are resistant to therapy. The specific mechanisms involved are unknown, and novel biomarkers are required to facilitate treatment and diagnosis of therapy-resistant asthma. The chitinase-like protein YKL-40 has been related to asthma and airway remodeling. OBJECTIVES: To compare serum YKL-40 levels in children with severe, therapy-resistant asthma (n = 34), children with controlled persistent asthma (n = 39), and healthy controls (n = 27), and to investigate correlations with biomarkers of inflammation and airway remodeling. METHODS: The study protocol included questionnaires, measurement of exhaled nitric oxide in exhaled air, blood sampling for inflammatory biomarkers, and high-resolution computed tomography of the lungs to identify bronchial wall thickening (therapy-resistant only). Serum YKL-40 levels were measured by ELISA, and all asthmatic children were genotyped for a CHI3L1 promoter single nucleotide polymorphism (rs4950928). RESULTS: Serum YKL-40 levels were significantly higher in children with therapy-resistant asthma than in healthy children (19.2 ng/mL vs 13.8 ng/mL, P = .03). Among children with severe, therapy-resistant asthma, YKL-40 levels correlated with fraction of exhaled nitric oxide in exhaled air (r = 0.48, P = .004), blood neutrophils (r = 0.63, P < .001), and bronchial wall thickening on high-resolution computed tomography (r = 0.45, P = .01). Following adjustment for CHI3L1 genotype, significantly greater levels of YKL-40 were found in children with therapy-resistant asthma than in children with controlled asthma. CONCLUSIONS: YKL-40 levels are increased in children with severe, therapy-resistant asthma compared to healthy children, and also compared to children with controlled asthma following correction for genotype.

Tooth extractions in intravenous bisphosphonate-treated patients: a refined protocol.

PURPOSE: The aim of this prospective hospital-based study was to refine a surgical protocol for tooth extractions in patients with a history of intravenous use of a potent bisphosphonate by modifying a previously reported protocol to produce a significantly shortened operating time. PATIENTS AND METHODS: Prospective patients with a follow-up of at least 4 months were included. Tooth extractions were performed without a vestibular split-thickness flap; healing was stimulated by filling the extraction site with autologous plasma rich in growth factors (PRGF System, BTI Biotechnology Institute, Vitoria, Spain). Local and systemic infection control was obtained with dental hygiene and antibiotic therapy. RESULTS: Sixty-three patients participated in the study. Two hundred two tooth extractions were performed. Differences between the present and previous protocols (the previous protocol used a vestibular flap) were analyzed and the surgical time proved significantly shorter for the present approach (P = .00). CONCLUSIONS: The proposed surgical protocol appears to be a better choice for patients treated with intravenous bisphosphonates who need tooth extraction, because it seems to be faster and simpler than the previously reported successful protocol.

Trefoil factor 1 gene alternations and expression in colorectal carcinomas.

AIMS AND BACKGROUND: Aberrant expression of the trefoil factor family (TFF) has been recognized to be involved in the development and/or progression of various solid tumors. Increased trefoil factor 1 (TFF1) expression is found associated with tumor progression in some tumors, and TFF1 missense mutations have been detected in gastric cancer. The aim of the study was to analyze TFF1 alternations and expression in colorectal carcinoma and their correlation with cancer progression and pathological aspects. METHODS: TFF1 mutations were detected in colorectal carcinomas by DNA sequencing. TFF1 mRNA and protein levels in subsets of the primary tumors were determined using quantitative reverse transcription polymerase chain reaction and immunohistochemistry analyses. The serum level of TFF1 was also detected by enzyme-linked immunosorbent assay for patients with colorectal carcinoma. RESULTS: Five variants were detected in the 5'-untranslation region and intron 1 of TFF1. TFF1 expression was increased in colorectal carcinoma compared to paired distal colonic mucosa. Immunohistochemistry in primary colorectal carcinoma showed no significant differences in tumor TFF1 levels with respect to clinicopathological parameters such as the patient's sex, cancer differentiation, stage and lymph node metastasis. However, serum TFF1 levels were significantly elevated in patients with colorectal carcinoma compared to healthy individuals. CONCLUSIONS: The results indicate that TFF1 missense mutations seem to be a rare event in colorectal carcinogenesis. Serum TFF1 may be a potential useful marker for patients with colorectal carcinoma.

The diagnostic and prognostic value of serum YKL-40 in endometrial cancer.

PURPOSE: To evaluate the diagnostic and prognostic value of serum YKL-40 in endometrial cancer (EC). METHODS: Serum YKL-40 levels were detected and compared in 34 of the 50 cases with EC before surgery, in 22 of the 34 with EC after surgery, in 30 cases with uterine myoma, and in 30 healthy women as normal controls. Receiver operating characteristics (ROC) curves were adopted for diagnosis and calculation of area under each ROC curve in EC. The progression-free survival (PFS) and overall survival (OS) between YKL-40 positive and negative patients were compared in the follow-up. RESULTS: The mean pre-operative serum YKL-40 values were significantly higher than that in the uterine myoma cases and in the healthy women (P = 0.000). The mean post-operative serum YKL-40 in the 22 EC cases was significantly lower than pre-operative serum YKL-40 levels in these cases (P = 0.000). There were critical differences between the area under ROC curve for YKL-40 and CA125 (P = 0.053). The PFS and OS for the YKL-40-positive patients were significantly shorter than those for the YKL-40-negative patients. CONCLUSION: Preliminary investigations have shown that serum YKL-40 level may have a definite clinical value in the diagnosis and prognosis of EC.

A wax ester and astaxanthin-rich extract from the marine copepod Calanus finmarchicus attenuates atherogenesis in female apolipoprotein E-deficient mice.

The aim of this study was to investigate the effect of dietary supplementation with an oil extracted from the zooplankton copepod Calanus finmarchicus [calanus oil (CO)] on atherosclerosis in apoE-deficient (apoE(-/-)) mice. Thirty 6-wk-old female apoE(-/-) mice (n = 10/group) were fed: 1) a Western-type, high-fat diet (HFD); 2) HFD supplemented with 1% (wt:wt) CO; or 3) HFD supplemented with 0.88% (wt:wt) corn oil + 0.12% (wt:wt) EPA+DHA ethyl esters (EPA+DHA) for 13 wk. Dietary CO supplementation lowered total aorta atherogenesis by 36.5% compared to the HFD (P < 0.01), whereas the reduction in the lesion prone aortic arch was 34.8% (P < 0.01). The degree of aortic atherogenesis was intermediate in mice fed EPA+DHA compared to those fed HFD and CO. The effect on atherogenesis was paralleled by reduced expression of hepatic genes for the proinflammatory cytokines, Ccl2, Icam1, Il1b, and Nfkb1, in mice fed CO compared to those fed HFD. For mice fed EPA+DHA, gene expression did not differ compared to those fed CO or HFD. Plasma concentrations of total cholesterol, TG, and cytokines did not differ between the groups at the end of the study. However, mice fed CO gained more weight compared to those fed HFD but not compared to those fed EPA+DHA. In conclusion, dietary CO supplementation attenuated atherosclerotic lesion formation in female apoE(-/-) mice and may be an effective and safe dietary intervention to reduce the development of atherosclerosis. However, further studies are warranted to elucidate the underlying physiological and molecular mechanisms.