The association between per-/polyfluoroalkyl substances in serum and thyroid function parameters: A cross-sectional study on teenagers living near a Chinese fluorochemical industrial plant.

Thyroid hormones (THs) play an important role in a wide range of crucial biological functions related to growth and development, and thyroid antibodies (TAs) can influence the biosynthesis of THs. Epidemiological studies have indicated that per- and polyfluoroalkyl substances (PFAS) could induce thyroid disruption, but studies on teenagers living in areas with high PFAS exposure are limited. This cross-sectional study focused on 836 teenagers (11- 15 years) living near a Chinese fluorochemical industrial plant. Decreased levels of free thyroxine (FT4, ﹤9.6 pmol/L, abnormal rate = 19.0 %) and elevated levels of free triiodothyronine (FT3, ï¹¥6.15 pmol/L, abnormal rate = 29.8 %) were observed. Correlations of serum PFAS concentrations and TAs/THs were analyzed. Increased PFOA was identified as a risk factor of decreased FT4 by using unadjusted (OR: 11.346; 95 % CI: 6.029, 21.352, p < 0.001) and adjusted (OR: 12.566; 95 % CI: 6.549, 24.115, p < 0.001) logistic regression models. In addition, significantly negative correlations were found between log10 transformed PFOA and FT4 levels using linear (unadjusted: ß = -1.543, 95 % CI: -1.937, -1.148, p < 0.001; adjusted: ß = -1.534, 95 % CI: -1.930, -1.137, p < 0.001) and BKMR models. For abnormal FT3, a significantly positive association between PFHxS and FT3 levels was observed in a regression model (unadjusted: ß = -0.903, 95 % CI: -1.212, -0.595, p < 0.001; adjusted: ß = -0.894, 95 % CI: -1.204, -0.583, p < 0.001), and PFHxS was identified as a risk factor (unadjusted: OR: 4.387; 95 % CI: 2.619, 7.346, p < 0.001; adjusted: OR: 4.527; 95 % CI: 2.665, 7.688, p < 0.001). Sensitivity analyses confirmed the robustness of the above results. This study reported the elevated PFAS exposure and thyroid function of teenagers living near a fluorochemical industrial plant from China.

Identification of biomarkers co-associated with M1 macrophages, ferroptosis and cuproptosis in alcoholic hepatitis by bioinformatics and experimental verification.

Backgrounds: Alcoholic hepatitis (AH) is a major health problem worldwide. There is increasing evidence that immune cells, iron metabolism and copper metabolism play important roles in the development of AH. We aimed to explore biomarkers that are co-associated with M1 macrophages, ferroptosis and cuproptosis in AH patients. Methods: GSE28619 and GSE103580 datasets were integrated, CIBERSORT algorithm was used to analyze the infiltration of 22 types of immune cells and GSVA algorithm was used to calculate ferroptosis and cuproptosis scores. Using the "WGCNA" R package, we established a gene co-expression network and analyzed the correlation between M1 macrophages, ferroptosis and cuproptosis scores and module characteristic genes. Subsequently, candidate genes were screened by WGCNA and differential expression gene analysis. The LASSO-SVM analysis was used to identify biomarkers co-associated with M1 macrophages, ferroptosis and cuproptosis. Finally, we validated these potential biomarkers using GEO datasets (GSE155907, GSE142530 and GSE97234) and a mouse model of AH. Results: The infiltration level of M1 macrophages was significantly increased in AH patients. Ferroptosis and cuproptosis scores were also increased in AH patients. In addition, M1 macrophages, ferroptosis and cuproptosis were positively correlated with each other. Combining bioinformatics analysis with a mouse model of AH, we found that ALDOA, COL3A1, LUM, THBS2 and TIMP1 may be potential biomarkers co-associated with M1 macrophages, ferroptosis and cuproptosis in AH patients. Conclusion: We identified 5 potential biomarkers that are promising new targets for the treatment and diagnosis of AH patients.

Engineering a HEK-293T exosome-based delivery platform for efficient tumor-targeting chemotherapy/internal irradiation combination therapy.

Exosomes are nanoscale monolayer membrane vesicles that are actively endogenously secreted by mammalian cells. Currently, multifunctional exosomes with tumor-targeted imaging and therapeutic potential have aroused widespread interest in cancer research. Herein, we developed a multifunctional HEK-293T exosome-based targeted delivery platform by engineering HEK-293T cells to express a well-characterized exosomal membrane protein (Lamp2b) fused to the αv integrin-specific iRGD peptide and tyrosine fragments. This platform was loaded with doxorubicin (Dox) and labeled with radioiodine-131 (131I) using the chloramine-T method. iRGD exosomes showed highly efficient targeting and Dox delivery to integrin αvß3-positive anaplastic thyroid carcinoma (ATC) cells as demonstrated by confocal imaging and flow cytometry in vitro and an excellent tumor-targeting capacity confirmed by single-photon emission computed tomography-computed tomography after labeling with 131I in vivo. In addition, intravenous injection of this vehicle delivered Dox and 131I specifically to tumor tissues, leading to significant tumor growth inhibition in an 8505C xenograft mouse model, while showing biosafety and no side effects. These as-developed multifunctional exosomes (denoted as Dox@iRGD-Exos-131I) provide novel insight into the current treatment of ATC and hold great potential for improving therapeutic efficacy against a wide range of integrin αvß3-overexpressing tumors.

Serum concentrations of per-/polyfluoroalkyl substances and its association with renal function parameters among teenagers near a Chinese fluorochemical industrial plant: A cross-sectional study.

Currently, studies on the association between per-/polyfluoroalkyl substances (PFAS) concentrations and the renal function of residents, especially teenagers, living near fluorochemical industrial plants, are relatively rare, and not all these studies suggested associations. In this cross-sectional study, 775 local teenagers (11-15 years old) were included, and serum concentrations of 18 PFAS were measured. Perfluorooctanoic acid (PFOA) was found to be the dominant PFAS with a concentration of 22.3-3310 ng/mL (mean = 191 ng/mL), accounting for 71.5-99.1% of ΣPFAS. Statistical analyses demonstrated that internal exposure of perfluoroalkyl carboxylic acids (PFCA, C8-C10) was related to the plant. In addition, the prevalence rate of chronic kidney disease (CKD) (35.0%) in the participants was relatively high. A significantly positive association was observed between the increase in PFOA concentration and increasing risk of CKD (OR = 1.741; 95% CI: 1.004, 3.088; p = 0.048) by adjusting for gender, age, body mass index (BMI), and household income. Similar positive correlation was also observed in PFHpA with CKD (OR = 1.628, 95% CI: 1.031, 2.572; p = 0.037). However, no significant correlation was observed for concentrations of other PFAS and CKD (p > 0.05). Furthermore, linear regression analyses demonstrated that none of the PFAS concentrations were significantly correlated with estimated glomerular filtration rate (eGFR) or urine albumin/urine creatinine ratio (ACR) (p > 0.05). However, a significantly negative correlation was observed between PFOA concentration and abnormal ACR (ß = -0.141, 95% CI: -0.283, 0.001; p = 0.048) after stratifying by CKD. Sensitivity analyses further confirmed these results. This cross-sectional study is the first, to our knowledge, to investigate the association between PFAS concentrations and renal function in teenagers living near a Chinese industrial plant. Further prospective and metabonomic studies are needed to interpret the results and clarify the biological mechanisms underlying this association.

Alpinetin delays high-fat diet-aggravated lung carcinogenesis.

Alpinetin (ALP) has been reported to act as an anticancer agent. This study was carried out to elucidate the effect of ALP on high-fat diet (HFD)-induced aggressive cancer progression. C57BL/6 mice were fed with a control diet (CD) or HFD and administered with ALP. Following 6 weeks of feeding, mice were inoculated subcutaneously with Lewis lung carcinoma cells (LLC) to develop transplanted lung tumour. ALP suppressed cell proliferation which drives HFD-induced lung cancer progression. ALP inhibited lipid accumulation in tumour and tumour cells cultured in vitro. qPCR and ELISA analysis of tumour tissues revealed ALP restrained macrophages accumulation, M2s polarization and chemokine secretion. Further, in macrophages cultured in tumour cells conditioned medium (CM), ALP was confirmed to decrease M2s markers expression and chemokine production under high fat. These results demonstrate that ALP suppresses HFD-promoted harmful changes in tumour microenvironments which are crucial in curbing pulmonary tumour aggravation.

Concentration, spatial distribution, and health risk assessment of PFASs in serum of teenagers, tap water and soil near a Chinese fluorochemical industrial plant.

Discharges released from fluorochemical industrial plants lead to severe contamination of the environment with per- and polyfluoroalkyl substances (PFASs), which may pose risks to human health. In this study, 187 serum samples from teenagers (age = 14 years), 22 tap water samples and 40 soil samples were collected in areas within 0-11 km of a fluorochemical industrial plant in Huantai County, Shandong Province, and concentrations of 18 PFASs were quantified by UPLC-MS/MS. Perfluorooctanoic acid (PFOA) was found to be predominant, concentrations of which ranged from 40.4 to 845 ng/mL in serum, from 2.88 to 19.3 ng/L in tap water, from 4.40 to 189 ng/g in soil, and accounting for 84.1-98.6%, 15.9-79.8%, and 73.8-96.7% of the total PFASs, respectively. Statistical analysis demonstrated that concentrations of perfluorinated carboxylic acids (PFCAs) in soil (C5-C9) and serum (C8-C10) were associated with the industrial plant. And PFOA concentrations in tap water were not relevant to the industrial plant, which were comparable with the non-contaminated area and lower than the threshold value recommended by U.S. EPA (70 ng/mL), indicating that the contribution to the high concentration of serum PFOA of local teenagers by drinking water was limited. Moreover, PFCAs in soil only made a limited contribution to the serum PFCAs of local residents by direct inhalation and dermal exposure, but the potential health risk by the soil via food chain should be paid attention to. Furthermore, health risk assessment demonstrated that high concentrations of PFOA in serum could pose potential health risk to local teenagers. Therefore, effective measures should be taken to attenuate the health risks caused by the industrial plant to local residents, and further epidemiological studies should be carried out in the future.

Feasibility of Replacing the Range Doppler Equation of Spaceborne Synthetic Aperture Radar Considering Atmospheric Propagation Delay with a Rational Polynomial Coefficient Model.

Usually, the rational polynomial coefficient (RPC) model of spaceborne synthetic aperture radar (SAR) is fitted by the original range Doppler (RD) model. However, the radar signal is affected by two-way atmospheric delay, which causes measurement error in the slant range term of the RD model. In this paper, two atmospheric delay correction methods are proposed for use in terrain-independent RPC fitting: single-scene SAR imaging with a unique atmospheric delay correction parameter (plan 1) and single-scene SAR imaging with spatially varying atmospheric delay correction parameters (plan 2). The feasibility of the two methods was verified by conducting fitting experiments and geometric positioning accuracy verification of the RPC model. The experiments for the GF-3 satellite were performed by using global meteorological data, a global digital elevation model, and ground control data from several regions in China. The experimental results show that it is feasible to use plan 1 or plan 2 to correct the atmospheric delay error, no matter whether in plain, mountainous, or plateau areas. Moreover, the geometric positioning accuracy of the RPC model after correcting the atmospheric delay was improved to better than 3 m. This is of great significance for the efficient and high-precision geometric processing of spaceborne SAR images.

Downregulation of miR-146b-3p Inhibits Proliferation and Migration and Modulates the Expression and Location of Sodium/Iodide Symporter in Dedifferentiated Thyroid Cancer by Potentially Targeting MUC20.

The dedifferentiation of differentiated thyroid cancer (DTC) is a challenging problem for radioactive iodine (131I) treatment, also known as radioiodine refractory differentiated thyroid cancer (RAIR-DTC). The purpose of this study was to further explore the mechanism of the redifferentiation of dedifferentiated thyroid cancer. Ineffective and effective groups of 131I therapy were analyzed and compared in both our clinical and TCGA samples. Whole-exome sequencing, mutation analysis, transcriptome analysis, and in vitro functional experiments were conducted. FLG, FRG1, MUC6, MUC20, and PRUNE2 were overlapping mutation genes between our clinical cases, and the TCGA cases only appeared in the ineffective group. The expression of miR-146b-3p target MUC20 was explored. The expression levels of miR-146b-3p and MUC20 were significantly increased, and the inhibition of miR-146b-3p expression significantly inhibited proliferation and migration, promoted apoptosis, regulated the expression and location of thyroid differentiation-related genes, and sodium/iodide symporter (NIS) in dedifferentiated thyroid cancer cells (WRO). Thus, miR-146b-3p potentially targets MUC20 participation in the formation of DTC dedifferentiation, resulting in resistance to 131I and the loss of the iodine uptake ability of DTC cancer foci, promoting refractory differentiated thyroid cancer. miR-146b-3p may be a potentially therapeutic target for the reapplication of 131I therapy in dedifferentiated thyroid cancer patients.

Cardamonin attenuates chronic inflammation and tumorigenesis in colon.

Cardamonin (CAD) is a member of the aromatic ketones family that is closely related to anti-bacterial, anti-inflammatory and anti-cancer effects. Nevertheless, the physiological function of cardamonin in chronic colitis and colon cancer has not been well verified. We found that cardamonin treatment alleviates intestinal disease, including recurring colitis and colitis-associated tumorigenesis, along with the reduced secretion of IL-1ß and TNF-α. Further, cardamonin inhibits cell viability and inflammation factors of colorectal cancer cells in vitro. In tumor cells, the inhibitory effect of cardamonin on cell proliferation is closely related to decreased phosphorylation of signal transducers and activators of transcription (STAT) signals. This study reveals the crucial role of cardamonin in sustaining gastrointestinal homeostasis and offers a new strategy for colon cancer therapy.

S100A4 promotes inflammation but suppresses lipid accumulation via the STAT3 pathway in chronic ethanol-induced fatty liver.

S100A4, a member of the S100 calcium-binding protein family, has been identified in a subpopulation of liver macrophages and promotes liver fibrosis via hepatic stellate cell activation. However, the specific role of S100A4 in alcoholic liver disease (ALD) has not been well investigated. Here, S100A4 knockout (S100A4-/-) mice were used in a chronic-binge ethanol model for studying the role of S100A4 and its related molecular mechanism in ALD. S100A4 expression was increased in ethanol-induced liver tissues of wild-type (WT) mice. Macrophage-derived S100A4 promoted liver inflammation but suppressed lipid accumulation under the ethanol feeding condition. S100A4 deficiency promoted ethanol-induced liver injury and hepatic fat accumulation. Further mechanistic studies found that S100A4 inhibited liver fat accumulation mainly by activating the STAT3 pathway and downregulating lipogenic gene expression, especially that of SREBP-1c. In AML-12 cells, a STAT3 inhibitor abolished STAT3 levels and decreased the expression of SREBP1c. Furthermore, the administration of a neutralizing S100A4 antibody to WT mice significantly promoted ethanol-induced liver injury and fatty accumulation. Thus, S100A4 may represent a potential candidate target for the prevention and treatment of ethanol-induced fatty liver. In this study, we discovered the special role of S100A4 in alcoholic liver disease. S100A4 deficiency attenuated ethanol-induced hepatitis and promoted hepatic fat accumulation in ethanol-induced liver tissues. Further mechanistic studies have found that S100A4 promotes early alcoholic hepatitis mainly by activating the STAT3 pathway and its downstream proinflammatory gene expression. Interestingly, activation of the STAT3 pathway downregulates lipogenic gene expression, especially SREBP-1c. KEY MESSAGES: In this study, we discovered the special role of S100A4 in alcoholic liver disease. S100A4 deficiency attenuated ethanol-induced hepatitis and promoted hepatic fat accumulation in ethanol-induced liver tissues. Further mechanistic studies have found that S100A4 promotes early alcoholic hepatitis mainly by activating the STAT3 pathway and its downstream proinflammatory gene expression. Interestingly, activation of the STAT3 pathway downregulates lipogenic gene expression, especially SREBP-1c.

S100A4 promotes colon inflammation and colitis-associated colon tumorigenesis.

S100A4 plays important roles in tumor development and metastasis, but its role in regulating inflammation and colitis-associated tumorigenesis has not been well characterized. Here, we report that S100A4 expression was increased in azoxymethane (AOM) and dextran sulfate sodium (DSS) induced colorectal cancer (CRC) in mice. After AOM/DSS treatment, both S100A4-TK mice with the selective depletion of S100A4-expressing cells and S100A4-deficient (S100A4-/-) mice developed fewer and smaller tumors than wild-type (WT) control littermates. Furthermore, S100A4-/- mice were resistant to DSS-induced colitis, reduced infiltration of macrophages, and the diminished production of proinflammatory cytokines. Further studies revealed that reduced colon inflammation and colorectal tumor development in S100A4-/- mice were partly due to the dampening of nuclear factor (NF)-κB activation in macrophages. Furthermore, the administration of a neutralizing S100A4 antibody to WT mice significantly decreased AOM/DSS-induced colon inflammation and tumorigenesis. These results indicate that S100A4 amplifies an inflammatory microenvironment that promotes colon tumorigenesis and provides a promising therapeutic strategy for treatment of inflammatory bowel disease and prevention of colitis-associated colorectal carcinogenesis.

Combination of positron emission tomography/computed tomography and chest thin-layer high-resolution computed tomography for evaluation of pulmonary nodules: Correlation with imaging features, maximum standardized uptake value, and pathology.

This study aimed to analyze the imaging findings of F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) and chest thin-layer high-resolution computed tomography (HRCT), correlate the maximum standardized uptake value (SUVmax), and the pathological type of benign or malignant pulmonary nodules (PNs), and assess the diagnostic accuracy in differentiating malignant from benign PNs.A retrospective review of F-FDG PET/CT scans from 88 patients with PNs confirmed by pathology or clinical follow-up were included. They both accepted PET/CT and HRCT scan conventional. The final results were determined by a combination of PET/CT and HRCT. Independent samples t test was used for statistical analysis. Receiver operating curves (ROC) were generated and the optimal threshold of SUVmax was determined.The sensitivity, specificity, and accuracy of HRCT, PET/CT, and PET/CT combined with HRCT in the diagnosis of PNs were 83.3%, 70%, 77.3%; 91.7%, 62.5%, 78.4%; and 95.8%, 75%, 86.4%, respectively. The SUVmax of malignant nodules was significantly higher than that of benign nodules, and the difference was statistically significant (t = -5.668, P < .001). In the subgroup analysis, the SUVmax of squamous cell carcinoma was higher than that of the denocarcinoma (t = -5.442, P < .001), and that of bronchioloalveolar carcinoma (t = 4.678, P < .001), the difference were both statistically significant. There were both no significant difference between adenocarcinoma and bronchioloalveolar carcinoma (t = 0.36, P = .722), tuberculosis and inflammatory nodules (t = -0.18, P = .858). Higher the value of SUVmax, greater the risk of malignancy. However, when the SUVmax ranges between 2.5 and 8.0, the lesion may be benign or malignant, and a comprehensive evaluation using combination methods with HRCT are required. When SUVmax <2.5, there is still a 9.5% chance of PN malignancy. ROC curve shows SUVmax >3.635 as the best threshold, and the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of PET/CT in diagnosis of PNs were 83.3%, 62.5%, 79.2%, 71.7%, and 71.4%, respectively.PET/CT combined with HRCT should be advocated to improve the sensitivity, specificity, and accuracy of PET/CT in diagnosis of PNs.

Computational Design of Antiangiogenic Peptibody by Fusing Human IgG1 Fc Fragment and HRH Peptide: Structural Modeling, Energetic Analysis, and Dynamics Simulation of Its Binding Potency to VEGF Receptor.

Peptibodies represent a new class of biological therapeutics with combination of peptide activity and antibody-like properties. Previously, we discovered a novel peptide HRH that exhibited a dose-dependent angiogenesis-suppressing effect by targeting vascular endothelial growth factor receptors (VEGFRs). Here, we computationally designed an antiangiogenic peptibody, termed as PbHRH, by fusing the HRH peptide to human IgG1 Fc fragment using the first approved peptibody drug Romiplostim as template. The biologically active peptide of Romiplostim is similar with HRH peptide; both of them have close sequence lengths and can fold into a α-helical conformation in free state. Molecular dynamics simulations revealed that the HRH functional domain is highly flexible, which is functionally independent of Fc fragment in the designed PbHRH peptibody. Subsequently, the intermolecular interactions between VEGFR-1 domain 2 (D2) and PbHRH were predicted, clustered and refined into three representatives. Conformational analysis and energetic evaluation unraveled that the PbHRH can adopt multiple binding modes to block the native VEGF-A binding site of VEGFR-1 D2 with its HRH functional domain, although the binding effectiveness of HRH segments in peptibody context seems to be moderately decreased relative to that of free HRH peptide. Overall, it is suggested that integrating HRH peptide into PbHRH peptibody does not promote the direct intermolecular interaction between VEGFR-1 D2 and HRH. Instead, the peptibody may indirectly help to improve the pharmacokinetic profile and bioavailability of HRH.

S100A4 protects mice from high-fat diet-induced obesity and inflammation.

As a member from S100 calcium-binding protein family, S100A4 is ubiquitous and elevated in tumor progression and metastasis, but its role in regulating obesity has not been well characterized. In this study, we showed that S100A4 was mainly expressed by stromal cells in adipose tissue and the S100A4 level in adipose tissue was decreased after high-fat diet (HFD). S100A4 deficient mice exhibited aggravated symptoms of obesity and suppressed insulin signaling after 12 weeks of HFD. Aggravated obesity in S100A4 deficient mice were found to be positively correlated with higher inflammatory status of the liver. Then, we found that extracellular S100A4 or overexpressed S100A4 inhibited adipogenesis and decreased mRNA levels of inflammation gene in 3T3-L1 adipocytes in vitro; whereas small interfering RNA (siRNA)-mediated suppression of S100A4 displayed the opposite results. Additionally, the protective effect induced by S100A4 during HFD-induced obesity was tightly related with activation of Akt signaling in adipose tissues, as well as livers and muscles. Taken together, we demonstrate that S100A4 is an inhibitory factor for obesity and attenuates the inflammatory reaction, while activating the Akt signaling, which suggest that S100A4 is a potential candidate for the treatment of diet-induced obesity and its complications.

Effect of alkylglycerone phosphate synthase on the expression profile of circRNAs in the human thyroid cancer cell line FRO.

Thyroid cancer is a common primary tumor in China. Therefore, it is important to investigate the underlying molecular mechanism of thyroid cancer in order to achieve effective individualized treatments. In our previous study, a positive correlation between the expression of alkylglycerone phosphate synthase (AGPS) and the malignant phenotype of thyroid cancer cell lines was identified. The inactivation of AGPS was able to decrease the malignancy of cancer, and inhibit tumor growth and invasion. However, the function of AGPS on thyroid cancer was unclear. In the present study, it was revealed that AGPS was able to regulate the expression of circular RNAs (circRNAs), which may be the mechanism of its anticancer activity. Therefore, the effects of AGPS silencing and knockout on circRNA expression in the thyroid cancer cell line FRO were investigated using circRNAs microarray, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed in order to investigate the underlying molecular mechanism of AGPS for the regulation of thyroid cancer through circRNAs.

S100A4 promotes lung tumor development through ß-catenin pathway-mediated autophagy inhibition.

Autophagy has emerged as a critical pathway in tumor development. S100A4 plays important roles in tumor metastasis, but its role in regulating autophagy has not been well characterized. In this study, we found that S100A4 was significantly upregulated in lung adenocarcinoma tissues. Clinical investigation demonstrated that high expression level of S100A4 was associated with tumor size and advanced tumor grades of lung adenocarcinoma patients. Moreover, our results revealed that extracellular S100A4 or overexpression of S100A4 inhibited starvation-induced autophagy and promoted cell proliferation in lung cancer cells in vitro; whereas small interfering RNA (siRNA)-mediated suppression of S100A4 increased autophagy and reduced cell viability in both A549 and LLC cells. Additionally, S100A4 inhibited starvation-induced autophagy to promote tumor cell viability via the Wnt pathway. Increased expression of ß-catenin consistently led to a decreased LC3-II protein abundance. Further, the inhibitory effect of S100A4 on autophagy and its promotion role in cell proliferation was abolished in A549 and LLC cells using the receptor for advanced glycation end products (RAGE)-specific inhibitor (FPS-ZM1). S100A4-deficient mice showed retarded tumor development. This effect was well correlated with increased expression of autophagy markers. Our findings demonstrate that S100A4 promotes lung tumor development through inhibiting autophagy in a ß-catenin signaling and S100A4 receptor RAGE-dependent manner, which provides a novel mechanism of S100A4-associated promotion of tumor development.

Disrupting the intramolecular interaction between proto-oncogene c-Src SH3 domain and its self-binding peptide PPII with rationally designed peptide ligands.

Proto-oncogene non-receptor tyrosine protein kinase c-Src has been involved in the development, progression and metastasis of a variety of human cancers. This protein contains two self-binding peptide (SBP) sites separately between the SH3 domain and polyproline-II (PPII) helix and between the SH2 domain and C-terminal phosphorylatable tail (CTPT), which are potential targets of anticancer drugs to regulate the kinase activity. Here, we described an integrated protocol to systematically investigate the structural basis, energetic property and dynamics behaviour of PPII binding to SH3, and to rationally design potent peptide ligands to target the SBP site of SH3-PPII interaction. Our study found that the PPII peptide is a non-typical binder that can only interact effectively with its cognate SH3 domain when it is integrated into the full-length c-Src kinase protein; stripping the peptide from the protein would considerably impair SH3 affinity by increasing entropy penalty upon the domain-peptide binding, suggesting that the protein context plays an essential role in the SBP's biological function. Next, we identified that the PPII peptide binds to SH3 domain in a class II manner and, on this basis, we derived a series of modified versions of the wild-type PPII peptide using a structure-based rational strategy. These modified peptide mutants have been structurally optimized with respect to their molecular flexibility and interaction potency with SH3 domain, in order to minimize indirect entropy penalty and to maximize direct binding enthalpy simultaneously. Consequently, several rationally designed peptides were obtained, including PPIIm2 (TSKPQTPGRA), PPIIm5 (KPPTPPRA), PPIIm6 (FPPPPPRA) and PPIIm7 (YPPLPPRA), which exhibit a moderately or considerably increased affinity (Kd = 72, 34, 15 and 5.7 µM, respectively) relative to the wild-type PPII (TSKPQTQGLA) (Kd = 160 µM). These peptides can be used as lead molecular entities to further develop new anticancer therapeutics to regulate c-Src kinase activity by targeting the SBP site of SH3-PPII interaction.

S100A4 contributes to colitis development by increasing the adherence of Citrobacter rodentium in intestinal epithelial cells.

S100A4 has been implicated in cancer and several inflammatory diseases, but its role in inflammatory bowel disease has not been well investigated. Here, upon infection with Citrobacter rodentium, a model for enteropathogenic Escherichia coli infection in humans, induced the infiltration of a large number of S100A4+ cells into the colon in wild type (WT) mice. Deficiency of S100A4 reduced weight loss, bacterial colonization and colonic pathology. Furthermore, the expression of inflammatory cytokines and the recruitment of macrophages and neutrophils also decreased significantly in S100A4 knock out (S100A4 -/-) mice. In vitro, soluble S100A4 directly up-regulated expression of integrin ß-1 in intestinal epithelial cells and significantly increased the adherence of C. rodentium to intestinal epithelial cells. Additionally, the effects of S100A4 on the adherence of C. rodentium to epithelial cells could be abolished by a receptor for advanced glycation end products (RAGE)-specific inhibitor (FPS-ZM1). Therefore, these data indicate a novel mechanism for S100A4 that promotes colitis development by enhancing host adhesion and colonization of Citrobacter rodentium through the S100A4-mediated host inflammatory responses.

Case report: multiple systemic disseminated tuberculosis mimicking lymphoma on 18F-FDG PET/CT.

RATIONALE: F-fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) has an important role in the diagnosis of various malignancies. However, F-18 FDG can also exhibit intense accumulation in tissues in inflammatory conditions such as active tuberculosis (TB) and sarcoidosis. PATIENT CONCERNS: We report a case of a 52-year-old female with irritable cough. CT showed a lung mass with multiple bilateral lung nodules, and sarcoidosis was suspected. F-18 FDG PET/CT was undertaken for the diagnosis and showed intense uptake of FDG in the mass in the lower lobe of the right lung, multiple lymph nodes, liver, and spleen. The maximum standardized uptake value of F-18 FDG was 43.58. This pattern of involvement most likely represents lymphomatous involvement. DIAGNOSES: Histopathology suggested tubercular involvement. INTERVENTION AND OUTCOMES: The patient received anti-TB treatment and recovered. LESSONS: Abovementioned extent and distribution of F-18 FDG in tubercular lesion is relatively rare, thus, one must be observant and aware with regards to TB being a strong mimic of lymphoma in endemic regions.