Zein and tannic acid hybrid particles improving physical stability, controlled release properties, and antimicrobial activity of cinnamon essential oil loaded Pickering emulsions.

Pickering emulsion loading essential oil has demonstrated a promising strategy as delivery system in food preservation, but localization in stability and antimicrobial activity limits application. In this study, Pickering emulsions co-loaded with tannic acid and cinnamon essential oil (ZTC) have been developed based on zein and tannic acid complexes (ZT) mediated interfacial engineering. Fourier transform infrared, fluorescence spectroscopy, and molecular docking results indicated tannic acid altered the structural of zein. Interfacial tension results indicated that tannic acid accelerated the adsorbed speed of zein particles by decreased interfacial tension (11.99-9.96 mN/m). ZT5 formed a viscoelastic and dense layer in oil-water interface than that for other ZTs, which improved stability and control release performance of ZTC. Furthermore, the ZTC showed an effective antimicrobial activity against spoilage organisms Pseudomonad paralactis MN10 and Lactobacillus sakei VMR17. These findings provide new insight for developing co-loaded multiple antimicrobial agents within Pickering emulsion as a delivery system.

Overexpression of SPP1 is a prognostic indicator of immune infiltration in lung adenocarcinoma.

OBJECTIVE: The extracellular phosphoprotein, secreted phosphoprotein 1 (SPP1), plays a crucial role in various tumors and regulating the immune system. This study aimed to evaluate its prognostic value and relationship to immune infiltration in lung adenocarcinoma (LUAD). METHODS: In the TCGA and GEO datasets, the information on clinic and transcriptome analysis of SPP1 in non-small-cell lung cancer (NSCLC) was examined accordingly. The association of SPP1 expression with overall survival and clinicopathologic characteristics was investigated by univariate and multivariate analysis. CancerSEA database was utilized to investigate the role of SPP1 at the cellular level by single-cell analysis. Additionally, the CIBERSORT algorithm was utilized to assess the correlation among the immune cells that infiltrated. RESULTS: NSCLC tissues exhibited a notable rise in SPP1 expression compared with that of normal tissues. Furthermore, the overexpression of SPP1 was substantially associated with clinicopathological features and unfavorable survival outcomes in individuals with LUAD, whereas no such correlation was observed in lung squamous cell carcinoma. Immune cells that infiltrate tumors and their corresponding genes were associated with SPP1 expression levels in LUAD. CONCLUSIONS: SPP1 is a reliable indicator for assessing LUAD immune infiltration status and prognosis. With this approach, SPP1 can help earlier LUAD diagnosis and act as a possible immunotherapy target.

Ze-Qi decoction inhibits non-small cell lung cancer growth and metastasis by modulating the PI3K/Akt/p53 signaling pathway.

Background: The Ze-Qi decoction (ZQD) is a traditional Chinese herbal formula commonly applied to treat lung cancer in China. This study aimed to assess the effective ingredients and molecular mechanisms of ZQD in treating non-small cell lung cancer (NSCLC) based on network pharmacology combined with experimental validation. Methods: Network pharmacology, bioinformatics, and molecular docking analyses were conducted to explore the mechanism of ZQD for treating NSCLC, which was further confirmed by animal experiments. Results: In total, 117 bioactive ingredients and 499 target proteins of ZQD were identified. Network pharmacology revealed 7 core active ingredients and 74 core target proteins. Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that the PI3K/Akt and p53 signaling pathways may be crucial in NSCLC treatment. Molecular docking analysis revealed that the seven crucial bioactive ingredients complexed with PI3K, Akt, and p53. The animal experiment results validated that ZQD treatment promoted cell apoptosis and cell cycle arrest, thereby inhibiting NSCLC growth and metastasis. Furthermore, ZQD treatment caused a significant increase in p53 and Bax, while leading to a distinct reduction in p-PI3K (Tyr317), p-Akt (Ser473), VEGFA, CD31, MMP2, MMP9, Bcl2, and CDK2. Conclusions: ZQD inhibited the growth and metastasis of NSCLC subcutaneous tumors in C57BL/6J mice via the PI3K/Akt/p53 signaling pathway.

Development of a recombinant adenovirus-vectored vaccine against both infectious hematopoietic necrosis virus and infectious pancreatic necrosis virus in rainbow trout (Oncorhynchus mykiss).

Infectious hematopoietic necrosis virus (IHNV) and infectious pancreatic necrosis virus (IPNV) are typical pathogens of rainbow trout Oncorhynchus mykiss, and the concurrent infection of the two viruses is very common among modern trout hatcheries, which has caused huge economic losses to the rainbow trout farming industry. To prevent and control the spread of IHNV and IPNV in juvenile trout simultaneously, in this study a bivalent recombinant adenovirus vaccine with IHNV Glycoprotein (G) and IPNV VP2 genes was developed. After immunizing juvenile trout with this bivalent vaccine via the immersion route, the expression levels of IHNV G and IPNV VP2 and the representative immune genes in vaccinated and control rainbow trout were tested to evaluate the correlation of immune responses with the expression of viral genes. The neutralizing antibody level induced by this bivalent vaccine as well as the protection efficacy of the vaccine against IHNV and IPNV was also evaluated. The results showed that IHNV G and IPNV VP2 were successfully expressed in juvenile trout, and all the innate and adaptive immune genes were up-regulated. This indicated that the level of the innate and adaptive immune responses were significantly increased, which might be induced by the high expression of the two viral proteins. Compared with the controls, high levels of neutralizing antibodies against IHNV and IPNV were induced in the vaccinated trout. Besides, the bivalent recombinant adenovirus vaccine showed high protection rate against IHNV, with the relative percent survival (RPS) of 81.25%, as well as against IPNV, with the RPS of 78.95%. Taken together, our findings clearly demonstrated that replication-defective adenovirus can be developed as a qualified vector for fish vaccines and IHNV G and IPNV VP2 were two suitable antigenic genes that could induce effective immune protection against these two pathogens. This study provided new insights into developing bivalent vectored vaccines and controlling the spread of IHNV and IPNV simultaneously in juvenile trout.

Phagocytosis-Regulators-Based Signature to Predict the Prognosis and Chemotherapy Resistance for Breast Cancer Patients.

Phagocytosis is crucial in tumor surveillance and immune function. The association between phagocytosis and the outcomes of breast cancer patients has not been well-determined. In this study, data were downloaded from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases to investigate the role of phagocytosis in breast cancer. Data from the TCGA and GEO databases were used to investigate the prognostic role of phagocytosis in breast cancer. Then, we performed pathway enrichment analysis, copy number variation (CNV) and single-nucleotide variant (SNV) analyses, immune infiltration analysis, calculation of tumor purity, stromal score, and immune score, and consistent clustering. We also constructed a phagocytosis-regulators-based signature system to examine its association in survival and drug response. The genomic and expression differences in the phagocytosis regulators in breast cancer were systematically analyzed, explaining the widespread dysregulation of phagocytosis regulators. Using the investigated association of phagocytosis regulators with the prognosis and tumor immune environment, we constructed a prognostic model based on phagocytosis regulators. We discovered that patients with high risk scores had a poor prognosis and were negatively associated with immune functions. The model had preferential predictive performance and significantly consistent drug-resistance prediction results. Our findings suggest that the phagocytosis-factors-based scoring system can be used as a novel prognostic factor, serving as a powerful reference tool for predicting prognosis and developing methods against drug resistance.

Preparation of double-yolk egg-like nanoreactor: Enhanced catalytic activity in Fenton-like reaction and insight on confinement effect.

Peroxymonosulfate (PMS)-based Fenton-like reaction is an effective technique for the pollutant degradation, and the Co-based metal organic frameworks displayed the excellent activity for the PMS activation. Nevertheless, how to further improve the catalytic activity, suppress the leaching of toxic cobalt ions, and realize the rapid separation were still challenges for practical application. In this work, a novel solution was proposed: encapsulating Fe3O4 and Prussian blue analogue (PBA) into the polypyrrole (PPy) shell and constructing a "double-yolk egg-like" Fe3O4/PBA@PPy as a nanoreactor. In Fe3O4/PBA@PPy-10, the catalytic performance was remarkably enhanced with the help of confinement effect, and the degradation rate (0.38 L·min·mol-1) was 5.1 times than that of reference Fe3O4/PBA-10 (0.074 L·min·mol-1). In addition, the concentration of leached cobalt ions was reduced to only 0.174 mg/L by the protective function from the PPy shell. Moreover, the nanoreactor could be magnetically separated from the reaction solution due to the encapsulation of Fe3O4 nanospheres, and 84.5% of activity still preserved after the 4th cycle. The main active species involved in Fe3O4/PBA@PPy-10 system was 1O2, while that in reference Fe3O4/PBA-10 system was OH. Electron spin resonance analysis and radical trapping experiment revealed that the different catalytic mechanisms were attributed to the confinement effect inside the hollow cavity. This work not only presents a feasible way to prepare rarely-reported double-yolk egg-like nanoreactor, but also provides a new insight to solve the bottlenecks in Fenton-like reaction.

Effect of Intensive Psychological Care on Patients with Benign Breast Lumps after Mammotome-Assisted Tumor Resection.

Objective: The aim of the study was to evaluate the effect of intensive psychological care on patients with benign breast lumps after Mammotome-assisted tumor resection. Methods: A total of 160 patients with benign breast lumps diagnosed and treated in our hospital between May 2019 and January 2021 were recruited and divided into a study group (n = 80) and a control group (n = 80) via the random number table method. All patients received Mammotome-assisted tumor resection. Patients in the control group received conventional nursing, and those in the study group received intensive psychological care. The outcome measure included quality of life of patients, psychological states, treatment compliance, and nursing satisfaction. Results: The differences in the Functional Assessment of Cancer Therapy-General (FACT-G) scores, self-rating anxiety scale (SAS) scores, Hamilton Depression Rating Scale (HAMD) scores, and Morisky scores between the two groups were not significant before the intervention (p > 0.05). The FACT-G scores improved in both groups after the intervention, with higher results in the study group than those in the control group (p < 0.05). Patients in the study group showed a significantly greater reduction in the SAS and HAMD scores than those in the control group (p < 0.05). Intensive psychological care used in the study group resulted in significantly higher compliance scores in the body mass control, medication compliance, exercise compliance, and dietary compliance versus conventional care for the control group (p < 0.05). Conclusion: Intensive psychological care provides satisfactory outcomes in patients with benign breast lumps after Mammotome-assisted tumor resection. It effectively improves the quality of life of patients, relieves their negative emotions, and strengthens treatment compliance and patient satisfaction, which shows good potential for clinical promotion.

Repair of Breast Defect by Transfer of a Contralateral Internal Mammary Artery Perforator Flap.

This is a case report of a patient with a borderline phyllodes tumor in the left breast. Seventeen months after the resection of the phyllodes tumor from the patient's left breast, the tumor occurred again 5 months ago in the surgical region. A large defect was generated after the extended resection of the left breast mass, and it was repaired with a contralateral internal mammary artery perforator flap. After the operation, bilateral breast symmetry was good, and the patient was satisfied with the shape of the breast. Postoperative follow-up was performed for 15 months, and no local recurrence was observed.

Z-scheme Fe2(MoO4)3/Ag/Ag3PO4 heterojunction with enhanced degradation rate by in-situ generated H2O2: Turning waste (H2O2) into wealth (•OH).

Ag3PO4-based photocatalysts have been deeply studied in environmental remediation; however, two problems limited their further application: photocorrosion and quenching effect by in-situ generated H2O2. To addressed these two questions simultaneously, Fe2(MoO4)3 was coupled with Ag3PO4 to construct Z-scheme Fe2(MoO4)3/Ag/Ag3PO4 heterojunction driven by internal-electric-field. The rhodamine B degradation rate of heterojunction was 254 and 7.0 times higher than those of Fe2(MoO4)3 and Ag3PO4, respectively. The outstanding photoactivity was due to the high visible-light harvest, low interface resistance, high separation efficiency of charge carriers, long lifetime of hole (h+) and electron (e-), well-preserved oxidation potential of h+, and especially photocatalytic produced H2O2 inside the system. The in-situ generated H2O2 was fully activated to be •OH on the Fe2(MoO4)3 surface via a Fenton reaction, leading to the elimination of quenching effect on h+ and e-, and generation of more •OH. Additionally, in Z-scheme heterojunction, e- transferred from Ag3PO4 to Fe2(MoO4)3, avoiding the accumulation on Ag3PO4 surface, and hence suppressing the photocorrosion. As a result, 91.2% of degradation efficiency remained after 5 cycles. This paper provides a new method to simultaneously increase the degradation rate by utilizing the in-situ generated H2O2 and improve the stability of Ag3PO4 via constructing a Z-scheme heterojunction.

Metabolic gene signature for predicting breast cancer recurrence using transcriptome analysis.

Background: The study aimed at identifying a metabolic gene signature for stratifying the risk of recurrence in breast cancer. Materials & methods: The data of patients were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The limma package was used to identify differentially expressed metabolic genes, and a metabolic gene signature was constructed. Results: A five-gene metabolic signature was established that demonstrated satisfactory accuracy and predictive power in both training and validation cohorts. Also, a nomogram for predicting recurrence-free survival was established using a combination of the metabolism gene risk score and the clinicopathological features. Conclusions: The proposed metabolic gene signature and nomogram have a significant prognostic value and may improve the recurrence risk stratification for breast cancer patients.

Physicochemical and functional properties of Maillard reaction products derived from cod (Gadus morhua L.) skin collagen peptides and xylose.

To improve the utilization of cod skin collagen peptides (CSCP), we heated them with xylose at 80 °C, 100 °C, and 120 °C for up to 150 min to prepare xylose-CSCP Maillard reaction products (MRPs), and then investigated their physicochemical and functional properties. The results showed that Arg, Lys, Phe, and Asp were the major amino acids involved in the Maillard reaction. After being heated at 120 °C for 150 min, the ABTS scavenging activity and reducing power of xylose-CSCP MRPs were 99.59% and 0.887 absorbance units, respectively. Xylose-CSCP MRPs had better emulsifying properties and foaming properties than CSCP. Furthermore, 26 volatile compounds, including 2,5-dimethyl-pyrazine and 2-ethyl-3,5-dimethylpyrazine, were identified from xylose-CSCP MRPs by gas chromatography-ion mobility spectrometry. Newly formed heterocyclic compounds might be responsible for the flavor and antioxidant capacity of xylose-CSCP MRPs. These results suggest the potential for xylose-CSCP MRPs to serve as functional food ingredients.

Microstructure and Mechanical Properties of AlSi7Mg0.6 Aluminum Alloy Fabricated by Wire and Arc Additive Manufacturing Based on Cold Metal Transfer (WAAM-CMT).

Wire and arc additive manufacturing based on cold metal transfer (WAAM-CMT) has aroused wide public concern in recent years as one of the most advanced technologies for manufacturing components with complex geometries. However, the microstructure and mechanical properties of the parts fabricated by WAAM-CMT technology mostly are intolerable for engineering application and should be improved necessarily. In this study, heat treatment was proposed to optimize the microstructure and enhance mechanical properties in the case of AlSi7Mg0.6 alloy. After heat treatment, the division between coarse grain zone and fine grain zone of as-deposited samples seemed to disappear and the distribution of Si and Mg elements was more uniform. What is more, the yield strength and ultimate tensile strength were improved significantly, while the ductility could be sustained after heat treatment. The improvement of strength is attributed to precipitation strengthening, and the shape change of Si phase. No reduction in ductility is due to the higher work hardening rate caused by nanostructured precipitate. It is proved that heat treatment as an effective method can control the microstructure and enhance comprehensive mechanical properties, which will boost rapid development of WAAM industrial technology.

Digitoxin Inhibits Epithelial-to-Mesenchymal-Transition in Hereditary Castration Resistant Prostate Cancer.

Castration Resistant Prostate Cancer (CRPC) is thought to be driven by a collaborative mechanism between TNFα/NFκB and TGFß signaling, leading to inflammation, Epithelial-to-Mesenchymal-Transition (EMT), and metastasis. Initially, TGFß is a tumor suppressor, but in advanced metastatic disease it switches to being a tumor promoter. TGFBR2 may play a critical role in this collaboration, as its expression is driven by NFκB and it is the primary receptor for TGFß. We have previously reported that the cardenolide drug digitoxin blocks TNFα/NFκB-driven proinflammatory signaling. We therefore hypothesized that digitoxin might break the collaborative process between NFκB and TGFß by also inhibiting expression of TGFBR2. We therefore tested whether TGFß-driven EMT and resulting metastases would be suppressed. Here we show, in vitro, that digitoxin inhibits NFκB-driven TGFBR2 expression, as well as Vimentin, while elevating E-cadherin expression. Digitoxin also significantly reduces HSPB1 mRNA and the HSPB1/RBFOX2 mRNA ratio in PC3 cells. In vivo, in a syngeneic, immune competent rat model of metastatic CRPC, we show that digitoxin also suppresses Tgfbr2 expression, as well as expression of other genes classically driven by NFκB, and of multiple EMT genes associated with metastasis. Concurrently, digitoxin suppresses tumor growth and metastasis in these animals, and prolongs survival. Gross tumor recurrence following tumor resection also appears prevented in ca 30% of cases. While the existence of a collaboration between NFκB and TGFß to drive EMT and metastasis has previously been appreciated, we show here, for the first time, that chronic, low concentrations of digitoxin are able to block CRPC tumor progression, EMT and the ensuing metastatic disease.

Patulin removal from apple juice using a novel cysteine-functionalized metal-organic framework adsorbent.

Patulin (PAT) is one of the most common toxic contaminants of apple juice, which causes severe food safety issues throughout the apple industry. In order to remove PAT efficiently, a metal-organic framework-based adsorbent (UiO-66(NH2)@Au-Cys) was successfully synthesized and used for PAT removal from juice-pH simulation solution and real apple juice. Batch adsorption experiments were systematically performed to study the adsorption behavior for PAT. The results showed that adsorption process could be well described by the Pseudo-second order model and Freundlich isotherm model. The maximum adsorption capacity (4.38 µg/mg) was 10 times higher than the microbe-based biosorbents. Thermodynamic investigation demonstrated that adsorption process was spontaneous and endothermic. Furthermore, no marked cytotoxicity on NIH 3T3 cell lines was observed when the concentration of the adsorbent was lower than 10 µg/mL. Therefore, UiO-66(NH2)@Au-Cys is a potential adsorbent for PAT removal from apple juice with little quality changes.

Cryoablation with drug-loaded bead embolization in the treatment of unresectable hepatocellular carcinoma: safety and efficacy analysis.

This study aimed to explore the efficacy and safety of drug-eluting bead (DEB) embolization (DEB-TACE) when combined with cryoablation in the treatment of unresectable hepatocellular carcinoma (HCC). The study was a single-center randomized controlled trial comprised of 60 patients with HCC conducted between August 2015 and October 2017. The patients were randomly divided into two groups: DEB-TACE combined with cryoablation (DEB-TACE-Cryo group) or cryoablation alone (Cryo group). Inter-group differences in overall survival, progression-free survival, and adverse reactions were assessed. The operative success rates were 82.7% and 77.4% in the DEB-TACE-Cryo group and Cryo group, respectively, with no operative mortality. The overall survival and progression-free survival in the DEB-TACE-Cryo group were significantly higher than those in the Cryo group (16.8 months vs.13.4 months, P = 0.0493; 8.1 months vs. 6.0 months, P = 0.0089, respectively). The postoperative complications in the two groups were rated as grade 1 or grade 2, according to guidelines set by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE V4.0). We demonstrated that DEB-TACE combined with cryoablation was effective, well tolerated, and had a low complication rate. Therefore, this combination therapy may be a better choice for the treatment of unresectable hepatocellular carcinoma.

Ordered Large-Pore Mesoporous Cr2O3 with Ultrathin Framework for Formaldehyde Sensing.

A series of ordered mesoporous chromium oxides (Cr2O3) were synthesized by first replicating bicontinuous cubic Ia3d mesoporous silica (KIT-6), then a controlled mesostructural transformation from Ia3d to I4132 symmetry during the replication from KIT-6 to Cr2O3 was achieved by reducing the pore size and interconnectivities of KIT-6, accompanied with an increase in pore size from 3 to 12 nm and a decrease in framework thickness from 8.6 to 5 nm of the resultant Cr2O3 replicas. The gas-sensing behavior of the Cr2O3 replicas toward formaldehyde (HCHO) was systematically investigated. Ordered mesoporous Cr2O3 with both large accessible pores (12 nm) and an ultrathin framework (5 nm) exhibits the best sensing performance, with a response (Rgas/Rair = 119) toward 9 ppm of HCHO 4.4 times higher than that (Rgas/Rair = 27) of its counterpart with small pores and a thick framework. Moreover, it possesses excellent selectivity for detecting HCHO over other interference gases such as CO, benzene, toluene, p-xylene, NH3, H2S, and moisture. The significantly enhanced sensing performance of ordered large-pore mesoporous Cr2O3 with ultrathin framework suggests its great potential for the selective detection of HCHO.

CFTR Controls the Activity of NF-κB by Enhancing the Degradation of TRADD.

BACKGROUND/AIMS: Chronic lung infection in cystic fibrosis leads to an inflammatory response that persists because of the chronic presence of bacteria and ultimately leads to a catastrophic failure of lung function. METHODS: We use a combination of biochemistry, cell and molecular biology to study the interaction of TRADD, a key adaptor molecule in TNFα signaling, with CFTR in the regulation of NFκB. RESULTS: We show that Wt CFTR binds to and colocalizes with TRADD. TRADD is a key signaling intermediate connecting TNFα with activation of NFκB. By contrast, ΔF508 CFTR does not bind to TRADD. NF-κB activation is higher in CFBE expressing ΔF508 CFTR than in cells expressing Wt CFTR. However, this differential effect is abolished when TRADD levels are knocked down. Transfecting Wt CFTR into CFBE cells reduces NF-κB activity. However the reduction is abolished by the CFTR chloride transport inhibitor-172. Consistently, transfecting in the correctly trafficked CFTR conduction mutants G551D or S341A also fail to reduce NFκB activity. Thus CFTR must be functional if it is to regulate NF-κB activity. We also found that TNFα produced a greater increase in NF-κB activity in CFBE cells than in the same cell when Wt CFTR-corrected. Consistently, the effect is also abolished when TRADD is knocked down by shRNA. Thus, Wt CFTR control of TRADD modulates the physiological activation of NF-κB by TNFα. Based on studies with proteosomal and lysosomal inhibitors, the mechanism by which Wt CFTR, but not ΔF508 CFTR, suppresses TRADD is by lysosomal degradation. CONCLUSION: We have uncovered a novel mechanism whereby Wt CFTR regulates TNFα signaling by enhancing TRADD degradation. Thus by reducing the levels of TRADD, Wt CFTR suppresses downstream proinflammatory NFκB signaling. By contrast, suppression of NF-κB activation fails in CF cells expressing ΔF508 CFTR.

[Correlation of Twist and YB-1 up-regulation and epithelial-mesenchymal transition during tumorigenesis and progression of cervical carcinoma].

OBJECTIVE: To investigate the clinicopathological significance of Twist and YB-1 up-regulation in cervical cancer, and to correlate the expression of the two genes with E-cadherin, a marker of epithelial-mesenchymal transition (EMT). METHODS: A total of 202 tissue samples were collected during January 2008 to December 2013, including 50 cases of normal cervical tissues, 100 cases of cervical intraepithelial neoplasia (CIN) and 52 cases of squamous cell carcinoma (SCC). Twist, YB-1 and E-cadherin expression was investigated by MaxVision. RESULTS: Increased expression levels of Twist and YB-1 were found and correlated with the malignant transformation of cervical epithelium, histological progression and metastasis of cervical cancer. In addition, Twist and YB-1 overexpression was also associated with aberrant expression of E-cadherin. Regression analysis revealed that Twist expression was an independent factor for the histological progression of cervical cancer. CONCLUSIONS: It is suggested that Twist and YB-1 overexpression is significantly linked to cervical cancer tumorigenesis and progression, likely related to EMT through (YB-1)-Twist-(E-cadherin) pathway. Twist and YB-1 may be markers for determining the metastatic potential of cervical cancer.

Activation of 3-phosphoinositide-dependent kinase 1 (PDK1) and serum- and glucocorticoid-induced protein kinase 1 (SGK1) by short-chain sphingolipid C4-ceramide rescues the trafficking defect of ΔF508-cystic fibrosis transmembrane conductance regulator (ΔF508-CFTR).

Cystic fibrosis (CF) is due to a folding defect in the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, ΔF508, prevents CFTR from trafficking to the apical plasma membrane. Here we show that activation of the PDK1/SGK1 signaling pathway with C4-ceramide (C4-CER), a non-toxic small molecule, functionally corrects the trafficking defect in both cultured CF cells and primary epithelial cell explants from CF patients. The mechanism of C4-CER action involves a series of mutual autophosphorylation and phosphorylation events between PDK1 and SGK1. Detailed mechanistic studies indicate that C4-CER initially induces autophosphorylation of SGK1 at Ser(422). SGK1[Ser(P)(422)] and C4-CER coincidently bind PDK1 and permit PDK1 to autophosphorylate at Ser(241). Then PDK1[Ser(P)(241)] phosphorylates SGK1[Ser(P)(422)] at Thr(256) to generate fully activated SGK1[Ser(422), Thr(P)(256)]. SGK1[Ser(P)(422),Thr(P)(256)] phosphorylates and inactivates the E3 ubiquitin ligase Nedd4-2. ΔF508-CFTR is thus free to traffic to the plasma membrane. Importantly, C4-CER-mediated activation of both PDK1 and SGK1 is independent of the PI3K/Akt/mammalian target of rapamycin signaling pathway. Physiologically, C4-CER significantly increases maturation and stability of ΔF508-CFTR (t½ ∼10 h), enhances cAMP-activated chloride secretion, and suppresses hypersecretion of interleukin-8 (IL-8). We suggest that candidate drugs for CF directed against the PDK1/SGK1 signaling pathway, such as C4-CER, provide a novel therapeutic strategy for a life-limiting disorder that affects one child, on average, each day.

Epidemiology of esophageal cancer in Yanting - regional report of a national screening programme in China.

BACKGROUND AND OBJECTIVES: Yanting in Sichuan Province is one of the highest risk areas of esophageal cancer (EC) in the world. We here summarize the epidemiology of EC in Yanting using data from the national screening programme during 2006-2011. METHODS: Random cluster sampling was used to select a proportion of natural villages from six towns in Yanting, and residents aged 40-69 years old were invited for screening. Participants were screened using endoscopy with iodine staining and then confirmed by histological examinations. RESULTS: The overall detection rates of low-grade hyperplasia (LH), moderate hyperplasia (MH), high-grade hyperplasia (HH), carcinoma in situ (CIS), intramucosal carcinoma (IC) and invasive carcinoma (INC) were 5.33%, 1.28%, 0.68% , 0.15% , 0.06% and 0.29%, respectively. The detection rates of LH, MH, HH and INC increased with age, reaching the peak among those aged 60-65 years, and the prevalences of LH and MH were higher among men than among women. In addition, the detection rates of hyperplasia were much higher in mountainous than in hilly areas. CONCLUSIONS: Among the high risk population, there are a great number of people with early-stage EC or precancerous conditions who do not have presenting symptoms. In particular, the elderly, men, or those living in mountainous areas are the most vulnerable population. It is therefore important to reinforce health education and screening services among such high risk populations.