Large-pore covalent organic framework as solid phase extraction absorbentforefficientdetermination of polypeptide antibiotics in animal-derived foods.

The precise determination of polypeptide antibiotics (PPTs) in foods has been always challenging because of the interference of various endogenous peptides in complex matrix. Herin, a novel large-pore covalent organic framework (TABPT-SPDA-COF) with accessible pore size of 7.9 nm was synthesized as a solid phase extraction (SPE) absorbent for efficiently enriching four PPTs existed in foods originating from animals. The parameters of SPE process were systematically optimized. Subsequently, four PPTs were determined by UHPLC-MS/MS. Under the optimal conditions, TABPT-SPDA-COF shows outstanding enrichment capacity for PPTs in contrast to commercial absorbents ascribed to size selectivity and multiple interaction effects. The method exhibits excellent linear range (0.005-100 ng mL-1), satisfactory limits of detection (0.1 pg mL-1) as well as relative recoveries (86.2-116 %). This work offers a practicable platform to monitor trace PPTs from complex animal-derived foodstuffs.

Online solid-phase extraction based on size-controllable spherical covalent organic framework for efficient determination of polybrominated diphenyl ethers in foods.

An analytical method of microspheric brominated covalent organic framework (Br-COF)-online solid-phase extraction integrated with high-performance liquid chromatography (online SPE-HPLC) was proposed for efficiently enriching six polybrominated diphenyl ethers (PBDEs) in foods. The Br-COF microspheres were facilely prepared with uniformity and dispersion by a size-controllable synthesis at the room temperature. Attributed to multiple interactions of the halogen bonding, Van der Waals forces, hydrophobic interaction along with size-matching effect, Br-COF performed satisfactory extraction capacity for PBDEs compared with commercial adsorbents. Five primary influencing factors were optimized, including loading solvent, loading flow rate, elution solvent, elution flow rate and elution volume. Under the optimal parameters, the implement displayed excellent linear ranges (0.5-500 ng mL-1) and low detection limits (0.01-0.05 ng mL-1). The relative recoveries in six spiked food samples ranged from 87.8 to 119.7 % with relative standard deviations below 10 %. This research estabished a promising platform for quantitatively determining trace PBDEs in complex foods.

Single-cell Transcriptomics Reveals Early Molecular and Immune Alterations Underlying the Serrated Neoplasia Pathway Toward Colorectal Cancer.

BACKGROUND & AIMS: Approximately one-third of colorectal cancers develop from serrated lesions (SLs), including hyperplastic polyp (HP), sessile serrated lesion (SSL), traditional serrated adenoma (TSA), and SSL with dysplasia (SSLD) through the serrated neoplasia pathway, which progresses faster than the conventional adenoma-carcinoma pathway. We sought to depict the currently unclarified molecular and immune alterations by the single-cell landscape in SLs. METHODS: We performed single-cell RNA sequencing of 16 SLs (including 4 proximal HPs, 5 SSLs, 2 SSLDs, and 5 TSAs) vs 3 normal colonic tissues. RESULTS: A total of 60,568 high-quality cells were obtained. Two distinct epithelial clusters with redox imbalance in SLs were observed, along with upregulation of tumor-promoting SerpinB6 that regulated ROS level. Epithelial clusters of SSL and TSA showed distinct molecular features: SSL-specific epithelium manifested overexpressed proliferative markers with Notch pathway activation, whereas TSA-specific epithelium showed Paneth cell metaplasia with aberrant lysozyme expression. As for immune contexture, enhanced cytotoxic activity of CD8+ T cells was observed in SLs; it was mainly attributable to increased proportion of CD103+CD8+ tissue-resident memory T cells, which might be regulated by retinoic acid metabolism. Microenvironment of SLs was generally immune-activated, whereas some immunosuppressive cells (regulatory T cells, anti-inflammatory macrophages, MDK+IgA+ plasma cells, MMP11-secreting PDGFRA+ fibroblasts) also emerged at early stage and further accumulated in SSLD. CONCLUSION: Epithelial, immune, and stromal components in the serrated pathway undergo fundamental alterations. Future molecular subtypes of SLs and potential immune therapy might be developed.

Natural Sunlight Photocatalytic Synthesis of Benzoxazole-Bridged Covalent Organic Framework for Photocatalysis.

Although natural sunlight-mediated photocatalysis is a clean, efficient, and green approach to access organic products, its application in the synthesis of covalent organic frameworks (COFs), however, is still unprecedented. Herein, we first report the sunlight photocatalytic synthesis of COF under ambient conditions. Furthermore, this "window ledge" reaction generated benzoxazole-linked COF is stable and can be applied as a reusable photocatalyst to highly promote visible-light-driven aerobic oxidation of sulfides to sulfoxides. These results not only enrich the COF synthetic methodology but also open a new route to access COFs in a green and sustainable way.

Neo-adjuvant radiation therapy provides a survival advantage in T3-T4 nodal positive gastric and gastroesophageal junction adenocarcinoma: a SEER database analysis.

BACKGROUND: Due to negative results in clinical trials of postoperative chemoradiation for gastric cancer, at present, there is a tendency to move chemoradiation therapy forward in gastric and gastroesophageal junction (GEJ) adenocarcinoma. Several randomized controlled trials (RCTs) are currently recruiting subjects to investigate the effect of neo-adjuvant radiotherapy (NRT) in gastric and GEJ cancer. Large retrospective studies may be beneficial in clarifying the potential benefit of NRT, providing implications for RCTs. METHODS: We retrieved the clinicopathological and treatment data of gastric and GEJ adenocarcinoma patients who underwent surgical resection and chemotherapy between 2004 and 2015 from Surveillance, Epidemiology, and End Results (SEER) database. We compared survival between NRT and non-NRT patients among four clinical subgroups (T1-2N-, T1-2N+, T3-4N-, and T3-4N+). RESULTS: Overall, 5272 patients were identified, among which 1984 patients received NRT. After adjusting confounding variables, significantly improved survival between patients with and without NRT was only observed in T3-4N+ subgroup [hazard ratio (HR) 0.79, 95% confidence interval (CI): 0.66-0.95; P = 0.01]. Besides, Kaplan-Meier plots showed significant cause-specific survival advantage of NRT in intestinal type (P <  0.001), but not in diffuse type (P = 0.11) for T3-4N+ patients. In the multivariate competing risk model, NRT still showed survival advantage only in T3-4 N+ patients (subdistribution HR: 0.77; 95% CI: 0.64-0.93; P = 0.006), but not in other subgroups. CONCLUSIONS: NRT might benefit resectable gastric and GEJ cancer patients of T3-4 stages with positive lymph nodes, particularly for intestinal-type. Nevertheless, these results should be interpreted with caution, and more data from ongoing RCTs are warranted.

Specific epigenetic age acceleration patterns among four molecular subtypes of gastric cancer and their prognostic value.

Aims: To determine the association of the methylation age (Horvath epigenetic clock) of gastric cancer (GC) tissues with molecular subtypes and patient survival. Materials & methods: Multivariate regression models were used to determine the association of methylation age acceleration (AA) with the clinical and molecular characteristics of 333 GC patients. Results: Relative to the chromosomal instability subtype, the epigenetic AA was 49.8 (95% CI: 42.7-56.9) years for Epstein-Barr virus, 16.1 (10.6-21.6) years for microsatellite instability, and 6.05 (0.1-11.1) years for genomic stability subtype. GC patients with accelerated aging of tumor tissues had better outcomes (adjusted hazard ratio: 3.13; p = 0.03). Differentially methylated probes in patients with accelerated and decelerated methylation aging enriched in pathways including BMP signaling, HMGB1 signaling, STAT3 signaling and human embryonic stem cell pluripotency. Conclusions: Our results highlight the prognostic value of epigenetic AA in GC and suggest that epigenetic AA is also an indicator of molecular subtype in GC.

Qualitative Transcriptional Signature for the Pathological Diagnosis of Pancreatic Cancer.

It is currently difficult for pathologists to diagnose pancreatic cancer (PC) using biopsy specimens because samples may have been from an incorrect site or contain an insufficient amount of tissue. Thus, there is a need to develop a platform-independent molecular classifier that accurately distinguishes benign pancreatic lesions from PC. Here, we developed a robust qualitative messenger RNA signature based on within-sample relative expression orderings (REOs) of genes to discriminate both PC tissues and cancer-adjacent normal tissues from non-PC pancreatitis and healthy pancreatic tissues. A signature comprising 12 gene pairs and 17 genes was built in the training datasets and validated in microarray and RNA-sequencing datasets from biopsy samples and surgically resected samples. Analysis of 1,007 PC tissues and 257 non-tumor samples from nine databases indicated that the geometric mean of sensitivity and specificity was 96.7%, and the area under receiver operating characteristic curve was 0.978 (95% confidence interval, 0.947-0.994). For 20 specimens obtained from endoscopic biopsy, the signature had a diagnostic accuracy of 100%. The REO-based signature described here can aid in the molecular diagnosis of PC and may facilitate objective differentiation between benign and malignant pancreatic lesions.

Marital status, an independent predictor for survival of gastric neuroendocrine neoplasm patients: a SEER database analysis.

BACKGROUND: Marital status proves to be an independent prognostic factor in a variety of cancers. However, its prognostic impact on gastric neuroendocrine neoplasms (G-NEN) has not been investigated. METHODS: We identified 3947 G-NEN patients from the Surveillance, Epidemiology, and End Results (SEER) database. Meanwhile, propensity scores for marital status were used to match 506 unmarried patients with 506 married patients. We used Kaplan-Meier method and multivariate Cox regression to analyse the association between marital status and the overall survival (OS) and G-NEN cause-specific survival (CSS) before matching and after matching. RESULTS: Married patients enjoyed better OS and CSS, compared with divorced/separated, single, and widowed patients. Multivariate Cox regression analysis indicated that unmarried status was associated with higher mortality hazards for both OS and CSS among G-NEN patients. Additionally, widowed individuals had the highest risks of overall (adjusted hazard ratio (HR): 1.56, 95% confidence interval (CI): 1.35-1.81, P < 0.001) and cancer-specific mortality (adjusted HR: 1.33, 95% CI: 1.05-1.68, P = 0.02) compared to other unmarried groups in both males and females. Furthermore, unmarried status remained an independent prognostic and risk factor for both OS (HR 1.51, 95% CI 1.19-1.90, P = 0.001) and CSS (HR 1.50, 95% CI 1.10-2.05, P = 0.01) in 1:1 propensity score-matched analysis. CONCLUSION: Marital status was an independent prognostic factor for G-NEN. Meanwhile, widowed patients with G-NEN had the highest risk of death compared with single, married, and divorced/separated patients.

Multiple neurofibromas plus fibrosarcoma with familial NF1 pathogenicity: A case report.

BACKGROUND: Neurofibromatosis (NF) is a genetic disease consisting of seven types, of which types 1 to 4 are caused by a dominant autosomal gene mutation; such disease sometimes arises in patients with NF type 1. However, it remains unclear whether the origin of neurofibrosarcoma is directly linked to the incidence of NF type 1, as no reports have been published on this issue. Here, we report a case of NF1-positive multiple neurofibromas with malignant fibrosarcomatous transformation in the pleural cavity. CASE SUMMARY: A 51-year-old male was admitted to our hospital due to fever accompanied by coughing, chest tightness and asthma for more than one month. The preliminary diagnosis was NF type 1, which was pathologically confirmed by a subsequent thoracoabdominal subcutaneous biopsy. The definitive diagnosis was neurofibrosarcoma with a pathogenic NF1 gene. The patient refused surgery and chemoradiotherapy, and died two months later. NF is a genetic disease consisting of seven types, of which types 1 to 4 are caused by a dominant autosomal gene mutation. The case reported belongs to the class of NF1-positive dominant inheritance. Neurofibrosarcoma is a malignant tumor derived from cells surrounding the peripheral nerves. However, due to the lack of previous reports, it remains unclear whether the origin of neurofibrosarcoma is directly linked to the incidence of NF type 1. CONCLUSION: We report the first case of NF1-positive multiple neurofibromas with malignant fibrosarcomatous transformation in the pleural cavity.

Identification and validation of tumour microenvironment-based immune molecular subgroups for gastric cancer: immunotherapeutic implications.

BACKGROUND: Immunotherapy could trigger durable response in advanced gastric cancer, but it only benefits a minority of patients. We aimed to propose a robust molecular classification of gastric cancer microenvironment to identify ideal candidates for tailoring effective immunotherapy. METHODS: A training cohort of 375 gastric cancer samples with RNA sequencing data was analysed. We virtually microdissected tumour, stromal, and immune cell gene expression patterns employing a non-negative matrix factorization algorithm. These expression patterns were annotated using immune- and stromal-related gene signatures. Validation of immunogenomic classification was performed across six microarray datasets of 1406 samples. RESULTS: We found approximately half of gastric cancer samples to have higher immune cell infiltrates, PD-L1 expression, markers of cytolytic activity, and fewer copy number aberrations (all P < 0.05). We termed this group of tumours the Immune Class, which incorporated two components, namely Immune Activation and Immunosuppressive Subtype, according to immunosuppressive or activated microenvironment. Immune Activation Subtype was associated with improved survival in multivariate survival analysis and shared similar genomic characteristics with responders of anti-PD-1 therapy. Immunosuppressive Subtype featured high immune infiltration, stromal enrichment, and transforming growth factor (TGF)-ß signalling pathway activation and correlated with non-responsiveness signature of checkpoint blockade therapy, which might be suitable for anti-PD-L1 and anti-TGF-ß combined therapy. CONCLUSIONS: We proposed and independently validated three reproducible immune molecular subtypes of gastric cancer, which may provide implications for patient selection of immunotherapy.

Amino-modified covalent organic framework as solid phase extraction absorbent for determination of carboxylic acid pesticides in environmental water samples.

The amino-modified covalent organic framework (NH2@COF) was synthesized via the thiol-ene click reaction of vinyl covalent organic framework (COF) with 4-aminobenzenethiol. The introduction of amino groups can interact with the anionic headgroup of carboxylic acid pesticides. Moreover, ample hydrophilic surface area can boost absorption in the water media. The NH2@COF was fully characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. Compared with vinyl COF and four commercial absorbents, the NH2@COF shows higher extraction efficiency for carboxylic acid pesticides. The solid phase extraction (SPE) conditions, involving flow rate, ionic strength, sample pH, desorption solvent, and desorption solvent volume, were optimized in details. Under the optimized conditions, the NH2@COF was successfully applied for the enrichment and determination of six carboxylic acid pesticides in environmental water samples combined with high performance liquid chromatography. The method features wide linearity (0.2-100 ng mL-1, r > 0.999), low limits of quantification (0.04-0.20 ng mL-1), and excellent precision (RSDs ≤ 8.7%). The recoveries range from 89.6% to 102.4% with RSDs ≤ 7.1%. Therefore, the NH2@COF-SPE method is an efficient pretreatment procedure and can be utilized for the selective extraction of carboxylic acid pesticides from environmental water samples.

Identification of Six Potentially Long Noncoding RNAs as Biomarkers Involved Competitive Endogenous RNA in Clear Cell Renal Cell Carcinoma.

Background. Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma (RCC), usually is representative of metastatic heterogeneous neoplasm that links with poor prognosis, but the pathogenesis of ccRCC remains unclear. Currently, numerous evidences prove that long noncoding RNAs (lncRNAs) are considered as competing endogenous RNA (ceRNA) to participate in cellular processes of tumors. Therefore, to investigate the underlying mechanisms of ccRCC, the expression profiles of lncRNAs, miRNAs, and mRNAs were downloaded from the Cancer Genome Atlas (TCGA) database. A total of 1526 differentially expressed lncRNAs (DElncRNAs), 54 DEmiRNAs, and 2352 DEmRNAs were identified. To determine the connection of them, all DElncRNAs were input to the miRcode database. The results indicated that 85 DElncRNAs could connect with 9 DEmiRNAs in relation to our study. Then, databases of TargetScan and miRDB were used to search for targeted genes with reference to DEmiRNAs. The results showed that 203 out of 2352 targeted genes were identified in our TCGA set. Subsequently, ceRNA network was constructed according to Cytoscape and the targeted genes were functionally analyzed to elucidate the mechanisms of DEmRNAs. The results of survival analysis and regression analysis indicated that 6 DElncRNAs named COL18A1-AS1, WT1-AS, LINC00443, TCL6, AL356356.1, and SLC25A5-AS1 were significantly correlative with the clinical traits of ccRCC patients and could be served as predictors for ccRCC. Finally, these findings were validated by quantitative RT-PCR (qRT-PCR). Based on these discoveries, we believe that this identified ceRNA network will provide a novel perspective to elucidate ccRCC pathogenesis.

Preparation and Reactivation of Heterogeneous Palladium Catalysts and Applications in Sonogashira, Suzuki, and Heck Reactions in Aqueous Media.

A new type of heterogeneous palladium catalyst, PdMgAl-LDH, was facilely prepared by the immobilization of Pd2+ species in the layers of a Mg-Al layered double hydroxide (LDH) with co-precipitation, and then fully characterized by using powder XRD, thermogravimetric differential thermal analysis, TEM, energy-dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy techniques. These catalysts can efficiently catalyze copper-free Sonogashira, Suzuki and Heck coupling reactions of various aryl iodides, bromides, and chlorides in aqueous media under phosphine-ligand- and organic-base-free conditions. These catalysts feature easy recovery through simple filtration and could be reused at least six times without a marked loss in activity. Notably, they can be facilely reactivated by a combination of nitrolysis with co-precipitation. The basic LDH skeletons could effectively stabilize the Pd0 species created in situ and donate electron density to the Pd0 center to facilitate the oxidative addition of aryl halides, thus the PdMgAl-LDH catalysts are stable during catalysis.

Dusuqing granules (DSQ) suppress inflammation in Klebsiella pneumonia rat via NF-κB/MAPK signaling.

BACKGROUND: Dusuqing granules (DSQ) have been used in the treatment of bacterial pneumonia clinically, with remarkable benefits. This study was initiated to explore the effects of DSQ on pulmonary inflammation by regulating nuclear factor (NF)-κB/mitogen-activated protein kinase (MAPK) signaling in bacterial pneumonia rats. METHODS: Rat model was duplicated with Klebsiella pneumonia by a one-time intratracheal injection. Rats were randomized into control, model, DSQ and levofloxacin (LVX) groups. After administrated with appropriate medicines for 7 days, lung tissues were harvested and prepared for pathological analysis, and interleukin (IL)-1, IL-6, monocyte chemotactic protein (MCP)-1and macrophage inflammatory protein (MIP)-2 detections. NF-κB mRNA was measured by real-time qPCR, and the phosphorylation and total proteins of P38MAPK, JNK46/54, ERK42/44 were determined by Western blotting. RESULTS: Marked pathological impairments were observed in model rats, whereas were improved in DSQ group. The cytokines levels, NF-κB mRNA expression and the phosphorylation of P38MAPK, JNK46/54 and ERK42/44 proteins were significantly higher in model group, and were significantly depressed in DSQ group. CONCLUSION: The protective effects of DSQ on Klebsiella pneumonia might be attributed to its inactivative effects of NF-κB/ MAPK pathway.

[HPLC enantioseparation, absolute configuration determination and anti-HIV-1 activity of (±)-F18 enantiomers].

Racemic (±)-F18 (10-chloromethyl-11-demethyl-12-oxo-calanolide A), an analog of nature product (+)-calanolide A, is a new anti-HIV-1 nonnucleoside reverse transcript inhibitor (NNRTI). A successful enantioseparation of (±)-F18 offering (R)-F18 and (S)-F18 was achieved by a chiral stationary phase prepared HPLC. Their absolute configurations were determined by measurement of their electronic circular dichroisms combined with modem quantum-chemical calculations. Further investigation revealed that (R)-F18 and (S)-F18 shared a similar anti-HIV activities, however, (R)-F18 was more potent than (S)-F18 against wild-type virus, K101E mutation and P225H mutation pseudoviruses.

Long-term effects of three Tiao-Bu Fei-Shen therapies on NF-κB/TGF-ß1/smad2 signaling in rats with chronic obstructive pulmonary disease.

BACKGROUND: The three Tiao-Bu Fei-Shen (Bufei Jianpi, Bufei Yishen, Yiqi Zishen) granules have been confirmed for their beneficial clinical efficacy in chronic obstructive pulmonary disease (COPD) patients on reducing frequency and duration of acute exacerbation, improving syndromes, pulmonary function and exercise capacity. But the short- or long-term mechanism of them is not fully clear. Nuclear factor (NF)-κB/transforming growth factor (TGF)-ß1/smad2 signaling pathway is involved in the progress of inflammation and remodeling in chronic obstructive pulmonary disease COPD. This study aimed to explore the long-term effects mechanism of Tiao-Bu Fei-Shen granules by regulating NF-κB/TGF-ß/Smads signaling in rats with COPD. METHODS: Sprague Dawley rats were randomized into control, model, Bufei Jianpi, Bufei Yishen, Yiqi Zishen and aminophylline groups. COPD rats, induced by cigarette smoke and bacterial infections exposures, were administrated intragastricly by normal saline, Bufei Jianpi, Bufei Yishen, Yiqi Zishen granules or aminophylline from week 9 through 20, respectively. At week 20 and 32, lung tissues were harvested. Immunohistochemistry was used to detect interleukin (IL)-1ß and tumor necrosis factor (TNF)-α, quantitative real-time polymerase chain reaction (qRT-PCR) was used for TGF-ß1 and Smad2 mRNA analysis, western blotting was used to determine the phosphorylation of NF-κB (p-NF-κB) and IκBα (p-IκBα). RESULTS: COPD rats had marked airway injury, such as chronic airway inflammation and remodeling, emphysema, which were improved in the three traditional Chinese medicines (TCM)-treated animals. The levels of IL-1ß, TNF-α, p-NF-κB, p-IκBα, TGF-ß1 and Smad2 were significantly higher in COPD rats than in controls, while they were dramatically reduced in the three TCM- and aminophylline-treated groups. At the meantime, all these endpoints were significantly lower in three TCM-treated groups than in aminophylline group, especially in Bufei Jianpi and Bufei Yishen groups. Compared to week 20, all endpoints decreased significantly in three TCM groups at week 32. CONCLUSION: The three Tiao-Bu Fei-Shen therapies can reduce pulmonary inflammation and remodeling in COPD and have significant long-term effects. NF-κB/TGF-ß1/smad2 signaling might be involved in the mechanism.

The development of anti-HIV-1 drugs.

Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency disease syndrome (AIDS). After over 26 years of efforts, there is still not a therapeutic cure or an effective vaccine against HIV/AIDS. The clinical management of HIV-1 infected people largely relies on antiretroviral therapy (ART). Although highly active antiretroviral therapy (HAART) has provided an effective way to treat AIDS patients, the huge burden of ART in developing countries, together with the increasing incidence of drug resistant viruses among treated people, calls for continuous efforts for the development of anti-HIV-1 drugs. Currently, four classes of over 30 licensed antiretrovirals (ARVs) and combination regimens of these ARVs are in use clinically including: reverse transcriptase inhibitors (RTIs) (e.g. nucleoside reverse transcriptase inhibitors, NRTIs; and non-nucleoside reverse transcriptase inhibitors, NNRTIs), protease inhibitors (PIs), integrase inhibitors and entry inhibitors (e.g. fusion inhibitors and CCR5 antagonists). Here, we intend to provide updated information of currently available antiretroviral drugs for ART to promote the development of novel anti-HIV-1 drugs.