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BACKGROUND Atopic dermatitis (AD) is a chronic skin inflammation with a heterogeneous immunological profile. Leukocyte cell-derived chemotaxin 2 (LECT2) is a liver-derived multifunctional cytokine that has been studied due to its important role in inflammatory and autoimmune diseases. However, the relationship between AD and LECT2 has not been defined. This study was performed to investigate the levels of LECT2 in patients with AD and to determine whether it was associated with the severity and clinical characteristics of AD. METHODS The study included 42 AD patients and 30 healthy controls from the Affiliated Hospital of Medical School of Ningbo University. Participants' serum levels of LECT2 were measured using enzyme-linked immunosorbent assay kits. The values in the patient group and control group were statistically compared. The relationships between the different markers were evaluated by correlation analysis. RESULTS The serum levels of LECT2 were significantly higher in AD patients than those in the controls. In addition, LECT2 was significantly correlated with the Scoring of Atopic Dermatitis (SCORAD) index, the level of immunoglobulin E (IgE), and eosinophils (P

MicroRNAs (miRNAs) are important regulators in the process of cardiac hypertrophy and heart failure. Previous studies have shown that miR-199a is upregulated in pressure-overload cardiac hypertrophy and that inhibition of miR-199a attenuates cardiac hypertrophy in vitro. However, the therapeutic role of anti-miR-199a treatment in the cardiac hypertrophy in vivo model is less known. Here, we show an efficient and useful method to treat mouse cardiac hypertrophy and restore cardiac function through injection of adeno-associated virus (AAV)-mediated anti-miR-199a tough decoys (TuDs). RNA-seq transcriptome analysis indicated that genes related to cytoplasmic translation and mitochondrial respiratory chain complex assembly were upregulated in anti-miR-199a-treated recovered hearts. We further validated that PGC-1α is the direct target of miR-199a involved in the therapeutic effect and the regulation of the PGC-1α/ERRα axis and that the downstream pathway of mitochondrial fatty acid oxidation and oxidative phosphorylation constitute the underlying mechanism of the restored mitochondrial structure and function in our anti-miR-199a-treated mice. Our study highlights the important regulatory role of miR-199a in cardiac hypertrophy and the value of the AAV-mediated miRNA delivery system., Graphical Abstract, Previous studies showed that miR-199a is upregulated in pressure-overload cardiac hypertrophy, and inhibition of miR-199a attenuated cardiac hypertrophy in vitro. This study showed an efficient and useful way to treat mice cardiac hypertrophy and restored cardiac function through injection of adeno-associated virus-mediated anti-miR-199a tough decoys targeting the PGC-1α/ERR axis.

At present, whole-brain radiation therapy/stereotactic radiosurgery is one of the main local treatments for brain metastasis of non-small-cell lung cancer (NSCLC). Currently, it has been proved that radiotherapy (RT) can regulate the immune response, and small-sample studies have shown that patients with NSCLC brain metastases (BMs) can benefit from RT combined with immunotherapy (IO). However, the efficacy and safety of the combination treatment have not been deeply elaborated. Notably, as a challenge that is still being explored, the timing of RT combined with IO is likely to be an important factor affecting efficacy and prognosis. This article reviews the current application and challenges of RT combined with IO from the perspectives of molecular mechanism, combination timing, safety, and efficacy. The purpose is to provide information on clinical evidence-based medicine of combination between RT with IO. For further investigation, we also discuss the major challenges and prospects of RT combined with IO in NSCLC BMs.

Background: Gonadotropin-releasing hormone analogs (GnRHas) are used for treating central precocious puberty (CPP). However, their roles in the regulation of immune cells especially regulatory T cells (Tregs) remains elusive. Therefore, we characterized buserelin-induced phenotypical and functional changes of Tregs.Methods: A rat CPP model was established followed by administration of buserelin acetate. Flow cytometry was used to evaluate the expression of functional molecules in splenic Tregs. The suppressive activity of Tregs was determined by the suppression assay. GnRHR expression in Tregs was assessed by flow cytometry analysis and Immunoblotting. Normal Tregs were then stimulated and treated with buserelin acetate in vitro. After that, Foxp3 expression, Treg proliferation, and cytokine production were analyzed by flow cytometry. Intracellular signaling was evaluated by Immunoblotting, and Treg function was determined by the suppression assay.Results: After in vivo buserelin treatment, the frequency of splenic Tregs was decreased, with the reduction in the expression of Foxp3, IL-10, and TGF-β. The suppressive activity of Tregs was weakened. Buserelin down-regulated Foxp3 expression while promoting the expression of RORγt and IL-17 in Tregs through activating the protein kinase A (PKA) pathway in vitro. The PKA inhibitor H-89 abolished the effect of buserelin and enhanced Treg function.Conclusion: Buserelin impaired the immunosuppressive activity of Tregs through the PKA signal pathway. Buserelin-induced activation of PKA signaling down-regulated Foxp3 expression while promoting RORγt expression in Tregs, and subsequently weakened Treg function. Our study indicates the necessity of monitoring Treg activity in CPP patients to avoid potential autoimmunity or inflammation.

Background: Chronic spontaneous urticaria (CSU) is a skin disorder with an important immunologic profile. S100A8, S100A9, and S100A12 are the members of S100 family that have been reported to play important role in autoimmune diseases, but the characteristics of these three S100 members have not been defined in CSU. Aims: This study was performed to investigate the levels of these three S100s in patients with CSU and to study whether they were associated with the severity and clinical characteristics of CSU. Materials and Methods: The levels of plasma S100A8, S100A9, and S100A12 were measured in 51 CSU patients and 20 healthy controls using enzyme linked immunosorbent assay kits. The values in the patient group and that of the healthy controls were statistically compared. The relationships between the different markers were evaluated by correlation analysis. Results: The plasma levels of S100A8, S100A9, and S100A12 were significantly higher in CSU patients than those in controls. Interestingly, the level of S100A12 was significantly correlated with S100A8 and S100A9 in CSU patients (P < 0.05 and P < 0.001, respectively). In addition, S100A8, S100A9, and S100A12 were all significantly inversely correlated with blood basophil percentage. Conclusions: Plasma S100A8, S100A9, and S100A12 levels were elevated in CSU patients. They might be useful biomarkers of CSU, with the potential role in the pathogenesis of CSU.

Background Oral mucositis is probably the most debilitating complication that can arise in treating a patient with head and neck cancer. Little is known about the impacts of oral microbiota on the initiation and progression of mucositis. Methods Based on 16S rRNA gene sequencing, dynamic changes in oral bacterial profile as well as correlations between the severity of mucositis and bacterial shifts during radiotherapy were investigated. Findings Our results revealed that bacterial community structure altered progressively during radiation therapy, in parallel with a marked increase in the relative abundance of some Gram-negative bacteria. Patients who eventually developed severe mucositis harbored a significantly lower bacterial alpha diversity and higher abundance of Actinobacillus during the phase of erythema – patchy mucositis. Accordingly, a random forest model for predicting exacerbation of mucositis was generated, which achieved a high predictive accuracy (AUC) of 0.89. Interpretation Oral microbiota changes correlate with the progression and aggravation of radiotherapy-induced mucositis in patients with nasopharyngeal carcinoma. Microbiota-based strategies can be used for the early prediction and prevention of the incidence of severe mucositis during radiotherapy., Highlights • The oral microbiota of NPC patients are different to that of healthy persons. • The biodiversity of oral microbiota changed significantly as mucositis progressed during radiotherapy. • Oral microbiota represents a potential strategy for predicting the aggravation of severe mucositis during radiotherapy. Oral or oropharyngeal mucositis is the most common side effect of radiation therapy for head and neck cancers. In this prospective cohort study, we found that changes in an oral microbial community correlated with the progression and aggravation of radiotherapy-induced mucositis in the patients with nasopharyngeal carcinoma; and patients who eventually developed severe mucositis transiently harbored a notably higher proportion of Actinobacillus during a mild phase of mucositis, which may potentially play a role in the aggravation of severe mucosal lesions. Moreover, our findings also showed that microbiota-based strategies can be used for the early prediction of the incidence of severe mucositis during radiotherapy.

Background: Because there is no clear consensus for the prognostic implication of KRAS mutations in patients with non-small cell lung cancer (NSCLC), we conducted a meta-analysis based on 12 randomized trials to draw a more accurate conclusion. Materials and Methods: A systematic computer search of articles from inception to May 1, 2014 using the PubMed, EMBASE, and Cochrane databases was conducted. The enrollment of articles and extraction of data were independently performed by two authors. Results: Our analysis was based on the endpoints overall survival (OS) and progression-free survival (PFS). Nine records (All for OS, 7 for PFS) comprising 12 randomized trials were identified with 3701 patients who underwent a test for KRAS mutations. In the analysis of the pooled hazard ratios (HRs) for OS (HR: 1.39; 95% confidence interval (CI) 1.23-1.56) and PFS (HR: 1.33; 95% CI 1.17-1.51), we found that KRAS mutations are related to poor survival benefit for NSCLC. According to a subgroup analysis stratified by disease stage and line of therapy, the combined HRs for OS and PFS coincided with the finding that the presence of a KRAS mutation is a dismal prognostic factor. However, the prognostic role of KRAS mutations are not statistically significant in a subgroup analysis of patients treated with chemotherapy in combination with cetuximab based on the endpoints OS (P=0.141) and PFS (P=0.643). Conclusions: Our results indicate that KRAS mutations are associated with inferior survival benefits for NSCLC but not for those treated with chemotherapies integrating cetuximab.

A series of hydrogels based on N -isopropylacrylamide, sodium acrylate, and N -tert-butylacrylamide were synthesized by free radical polymerization in a mixture of dioxane and water with tetra(ethylene glycol) diacrylate as the crosslinker and benzoyl peroxide as the initiator. The swelling behavior including the swelling rate of the crosslinked gels in water was studied with gravimetric method. The swelling ratio of the gel (0.1 mol% crosslinking) can reach 420 g/g at 20 °C and such a gel can release 96% of the water absorbed at 40 °C. The lower critical swelling temperature (LCST) of the copolymers can be adjusted by changing the chemical composition of the polymers. Such crosslinked gels can be potentially used as thermosensitive superabsorbent because of their high water uptake and thermal sensitivity.

Regarding the controversial investigations characterizing the role of KRAS status for predicting patients' response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small-cell lung cancer (NSCLC), we conducted a meta-analysis in unselected patients and a further subset analysis in EGFR wild-type advanced NSCLC to get a more accurate evaluation.We did systematically searches following the retrieval strategies. The end points were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR).Twelve prospective intervention trials comprised of 1,859 unselected advanced NSCLC patients were identified. KRAS mutation was associated with shorter OS and PFS [hazard ratio (HR) 2.09, 95 % confidence interval (CI) 1.56-2.80; HR 1.82, 95 % CI 1.50-2.20] and lower ORR (relative ratio 0.25, 95 % CI 0.11-0.59) in unselected advanced NSCLC. After subgroup analysis, the association with survival was strengthened in second- or later-line EGFR-TKIs treatment group, with an HR of 2.45 for OS (95 % CI 1.27-4.74) and 1.86 for PFS (95 % CI 1.51-2.29), while the association with response to EGFR-TKIs became nonsignificant (P = 0.153). Four retrospective studies on the role of KRAS status in EGFR wild-type advanced NSCLC were deemed eligible and presented that KRAS mutation was associated with none of the outcomes in EGFR wild-type patients treated with EGFR-TKIs.In unselected advanced NSCLC patients, KRAS mutations could be used as a potential negative predictor of clinical benefit from EGFR-TKIs. However, KRAS testing is of limited value to identify patients for EGFR-TKIs when EGFR status is considered.

Gastric cancer (GC) is one of the most common malignancies in China. B-cell translocation gene 3 (BTG3) has been identified as a tumor suppressor in several tumors, but its role in GC remains unknown. This study aimed to detect the expression of BTG3 and its prognostic value in GC tissues and determine its function in the progression of GC.The expression of BTG3 was detected in GC cell lines and tissues by real-time RT-PCR, Western blot or immunohistochemistry. A series of in vitro and in vivo assays were performed to evaluate the effect of BTG3 on proliferation, migration and invasion of GC cells.B-cell translocation gene 3 was obviously down-regulated in GC tissues. Its expression was positively correlated with distant metastasis (P0.05). Patients with lower BTG3 expression had shorter overall survival time (P = 0.015). BTG3 suppressed the proliferation of GC cells in vitro and in vivo. It also inhibited migration and invasion of GC cells in vitro.Down-regulation of BTG3 is closely associated with proliferation, migration and invasion in GC. It may be a novel prognostic biomarker for GC patients.

We have shown that the addition of cholestyramine (CHA, a resin known to bind bile salts in the gastrointestinal tract) to ochratoxin A (OTA)-contaminated rat diets reduced plasma levels of the toxin and prevented OTA-induced nephrotoxicity. To elucidate the mechanism of action of CHA, we carried out in vitro experiments to determine whether the resin may bind the toxin. For comparative purposes, binding of bile salts to the resin was also examined. Results showed that CHA binds both OTA and bile salts (taurodeoxycholate [TDC] and taurocholate [TCA]). Also, CHA showed greater affinity for OTA and TDC than for TCA. At 1 mM concentration, 96% of OTA and 80% of TDC were bound to the resin, while for TCA binding was only 50%. However, saturation of the resin was reached at higher levels with bile acids compared to OTA (3.67 mmol/g resin for TCA and 3.71 mmol/g resin for TDC versus 2.85 mmol/g resin for OTA). To characterize the nature of the binding of the toxin to CHA, NaCl (0 to 200 mM) was added to a fixed amount of OTA or bile acids. As expected, TCA absorption was decreased by the addition of NaCl (50 mM), indicating electrostatic binding. However, OTA and TDC sorption was decreased only at high concentrations of NaCl (150 mM), suggesting a stronger binding to the resin than that shown with TCA. Sequential competitive studies demonstrated that CHA binds more OTA than TCA. The results of the in vivo study show the role of bile salts in OTA absorption. The toxin's plasma levels at 1 and 3 h after a single oral dose of OTA were significantly decreased in bile salt-depleted rats compared to the control. Thus, the alteration of the bile salt biliary pool and OTA enterohepatic circulation may be an additional mechanism of action of the resin against mycotoxin toxicity.

To explore the correlation of the expressions of metastatic tumor antigen 1 (MTA1) and hypoxia-inducible-factor l alpha (HIF-1alpha) to the clinical features of lung cancer.The expressions of MTA1 and HIF-1alpha proteins in 59 lung cancer patients were detected by immunohistochemistry.Positive staining of MTA1 and HIF-1alpha was found in 54.24% and 50.85% of the patients, respectively. MTA1 expression was not found to correlated to any of the clinical parameters. HIF-1alpha expression was significantly lower in poorly differentiated than in moderately and well differentiated lung cancer (P0.05), and a positive association between the expressions of MTA1 and HIF-17alpha were noted (P0.05).MTA1 and HIF-1alpha overexpression occurs in lung cancer possibly as an important factor of lung carcinogenesis. MTA1 may promote lung carcinogenesis by enhancing HIF-1alpha protein activity.

To study the pathological basis of radiological reaction types of radiation-induced liver disease on multiphasic CT scans.Three pigs (tagged with A, B, and C) were subjected to single-dose radiation of 40, 40 and 30 Gy on the right or left lobe of the liver, respectively. At 42, 56, 133, and 168 days after irradiation, all pigs were examined with non-enhanced scan and contrast-enhanced scans at different time points after contrast injection. Hounsfield units (HU) were measured in each CT study to evaluate the density of irradiated and non-irradiated liver tissue to determine the reaction type. Liver tissues in the irradiation area obtained by needle biopsy with CT guidance were examined with electron microscopy, and specimens of the tissue corresponding to the region of interest on CT were obtained from necropsies for pathological examination.Radiologically, the 3 pig models presented with 3 reaction types on the multiphasic CT scans on days 133, 56, and 168 after radiation, respectively. Type 1 presented constant low-density change in all phases, the pathological basis of which was radiation hepatitis; type 2 showed pre-contrast phase isodense, arterial phase hyperdense, portal phase isodense and later phase hyperdense changes; type 3 was characterized by pre-contrast phase isodense, arterial phase hyperdense, portal phase hypodense and later phase hyperdense changes. The pathological basis of the last two radiological reaction types was radiation cirrhosis (postnecrotic cirrhosis).Different radiological reaction types of radiation liver injury on multiphase CT have different pathological basis, and multiphase contrast-enhanced CT may help distinguish the radiation reactions from tumor recurrence.

To review the appearance of radiation-induced liver injury on computer tomography for quantitative assessment of dosimetric changes in different radiological reactions and the influence of time-effect.The focal liver reactions of 35 patients treated with three-dimensional conformal radiation therapy (3-D CRT) for liver malignancies were evaluated, with the applied doses of 36-65 Gy in 4-28 fractions completed in 8-41 days. All patients received nonenhanced CT scan and arterial-dominant phase contrast-enhanced CT scan 1-6 months after therapy. The liver tissue density in irradiated and nonirradiated liver was compared, and the reaction type and the threshold dose determined radiologically.On at least one follow-up examination, 51.4% of patients were found to have a focal radiation reaction in the liver. The radiation reaction was hypodense in 43.75% of the follow-up nonenhanced CT examinations and in 19.23% of arterial-dominant phase contrast-enhanced CT scans. It was hyperdense in 42.31% of arterial-dominant phase contrast-enhanced CT scans. The median threshold dose inducing a radiation reaction was 30.8 Gy (range 18-42.8 Gy). The detected threshold dose was positively correlated with the time of detection of the reaction (P=0.041), with a correlation coefficient of -0.473. On arterial-dominant phase contrast-enhanced CT scans, the threshold dose was significantly higher for hyperdense than for hypodense changes (P=0.017). In additional follow-up, the reaction volume decreased and the reaction types changed on arterial-dominant phase contrast-enhanced CT scans.The threshold dose can be different in different radiological reaction types on multiphase CT scans. The detected threshold dose is inversely correlated with the time of detection of the early reaction. Multiphase contrast-enhanced CT is helpful to distinguish radiation reactions from recurrent tumors.