Design and synthesis of 7-membered lactam fused hydroxypyridinones as potent metal binding pharmacophores (MBPs) for inhibiting influenza virus PAN endonuclease.

Since influenza virus RNA polymerase subunit PAN is a dinuclear Mn2+ dependent endonuclease, metal-binding pharmacophores (MBPs) with Mn2+ coordination has been elucidated as a promising strategy to develop PAN inhibitors for influenza treatment. However, few attentions have been paid to the relationship between the optimal arrangement of the donor atoms in MBPs and anti-influenza A virus (IAV) efficacy. Given that, the privileged hydroxypyridinones fusing a seven-membered lactam ring with diverse side chains, chiral centers or cyclic systems were designed and synthesized. A structure-activity relationship study resulted in a hit compound 16l (IC50 = 2.868 ± 0.063 µM against IAV polymerase), the seven-membered lactam ring of which was fused a pyrrolidine ring. Further optimization of the hydrophobic binding groups on 16l afforded a lead compound (R, S)-16s, which exhibited a 64-fold more potent inhibitory activity (IC50 = 0.045 ± 0.002 µM) toward IAV polymerase. Moreover, (R, S)-16s demonstrated a potent anti-IAV efficacy (EC50 = 0.134 ± 0.093 µM) and weak cytotoxicity (CC50 = 15.35 µM), indicating the high selectivity of (R, S)-16s. Although the lead compound (R, S)-16s exhibited a little weaker activity than baloxavir, these findings illustrated the utility of a metal coordination-based strategy in generating novel MBPs with potent anti-influenza activity.

Microscopic Factors Affecting the Performance of Pervious Concrete.

The impacts of various aggregate particle sizes and cement contents on the internal structure of pervious concrete were investigated. Accordingly, test blocks with different aggregate particle sizes and cement contents were dissected and photographed. Subsequently, the captured images were processed using the ImageJ software (1.53i) to analyze the profiles of the test blocks and identify the internal mesoscopic parameters of the pervious concrete. This study discusses the relationship between microscopic parameters and macroscopic factors based on experimental results. It also fits functional equations linking the permeability coefficient with pore parameters, matrix parameters, and compressive strength. The results indicated that, as the aggregate size increased, the internal pore diameter of the pervious concrete increased, whereas the total area and width of the cement matrix decreased. This resulted in a low permeability coefficient and high compressive strength of the test block. Increasing the cement content in pervious concrete reduced the porosity and increased the width and area of the internal matrix. Consequently, the permeability coefficient decreased, and the compressive strength of the test block increased.

Overexpression of MTFR1 promotes cancer progression and drug-resistance on cisplatin and is related to the immune microenvironment in lung adenocarcinoma.

OBJECTIVE: The roles of MTFR1 in the drug resistance of lung adenocarcinoma (LAC) to cisplatin remain unexplored. In this study, the expression, clinical values and mechanisms of MTFR1 were explored, and the relationship between MTFR1 expression and immune microenvironment was investigated in LAC using bioinformatics analysis, cell experiments, and meta-analysis. METHODS: MTFR1 expression and clinical values, and the relationship between MTFR1 expression and immunity were explored, through bioinformatics analysis. The effects of MTFR1 on the growth, migration and cisplatin sensitivity of LAC cells were identified using cell counting kit-8, wound healing and Transwell experiments. Additionally, the mechanisms of drug resistance of LAC cells involving MTFR1 were investigated using western blotting. RESULTS: MTFR1 was elevated in LAC tissues. MTFR1 overexpression was associated with sex, age, primary therapy outcome, smoking, T stage, unfavourable prognosis and diagnostic value and considered an independent risk factor for an unfavourable prognosis in patients with LAC. MTFR1 co-expressed genes involved in the cell cycle, oocyte meiosis, DNA replication and others. Moreover, interfering with MTFR1 expression inhibited the proliferation, migration and invasion of A549 and A549/DDP cells and promoted cell sensitivity to cisplatin, which was related to the inhibition of p-AKT, p-P38 and p-ERK protein expression. MTFR1 overexpression was associated with stromal, immune and estimate scores along with natural killer cells, pDC, iDC and others in LAC. CONCLUSIONS: MTFR1 overexpression was related to the unfavourable prognosis, diagnostic value and immunity in LAC. MTFR1 also participated in cell growth and migration and promoted the drug resistance of LAC cells to cisplatin via the p-AKT and p-ERK/P38 signalling pathways.

Inhibition of UFM1 expression suppresses cancer progression and is linked to the dismal prognosis and immune infiltration in oral squamous cell carcinoma.

BACKGROUND: Ubiquitin fold modifier 1 (UFM1) overexpression is associated with cancer cell proliferation, migration and invasion. However, the roles and pathways of UFM1 in oral squamous cell carcinoma (OSCC) has remained undefined. METHODS: The expression of UFM1 and the relationship between UFM1 expression and prognosis were investigated using data of OSCC patients from The Cancer Genome Atlas (TCGA) database. The UFM1 co-expressed genes, and the association between the UFM1 expression and immune cells and ubiquitination were explored. The effects of UFM1 expression on the growth and migration of OSCC cells were investigated by siRNA interference, Cell Counting Kit-8 (CCK-8), Transwell, Western blotting, and wound healing experiments. RESULTS: UFM1 was highly expressed in OSCC. UFM1 overexpression was associated with short overall survival, disease-specific survival, and progression-free interval, and was an adverse factor for prognosis in OSCC. UFM1-related nomograms were significantly associated with poor prognosis in OSCC patients. Decreased UFM1 expression could inhibit the proliferation, migration, and invasion of OSCC cells. UFM1 was associated with the immune cells (such as the Th17 cells, T helper cells, and cytotoxic cells) and ubiquitination. CONCLUSION: Elevated UFM1 expression was associated with poor prognosis, ubiquitination and immune infiltration in OSCC, and inhibition of UFM1 expression delayed OSCC progression, showing that UFM1 could be a biomarker for prognosis and treating OSCC patients.

GSH-depleting metal-polyphenol-network nanoparticles with dual enzyme activities induce enhanced ferroptosis.

Ferroptosis is a non-apoptotic form of regulated cell death. The efficiency of ferroptosis is restrained in the tumor microenvironment (TME) by overexpression of glutathione (GSH) and insufficient production of hydrogen peroxide (H2O2). In this work, theranostic nanoparticles Ce-aMOFs@Fe3+-EGCG, termed MEFs, are developed by coating uniform Ce-based amorphous metal-organic frameworks (Ce-aMOFs) with epigallocatechin gallate (EGCG) and Fe3+. Fe3+ is chelated by the adjacent phenol hydroxyl groups in EGCG. In the tumor cell interior, overexpressed GSH and weak acidic medium degrade the coating to release Fe3+ and EGCG accompanied by exposure of Ce-aMOFs. Fe3+ and EGCG consume GSH along with turning Fe3+ into Fe2+. Ce-aMOFs act as a nanozyme possessing dual-enzymatic activities, i.e. superoxide dismutase (SOD)- and phosphatase-like activities. In the TME, Ce-aMOFs catalyze the conversion of endogenous superoxide (O2˙-) into H2O2, and Fe2+ catalyzes H2O2 to generate toxic hydroxyl radicals (˙OH), which may further induce tumor cell death through ferroptosis. In addition, the phosphatase-like activity of Ce-aMOFs may sustainably dephosphorylate NADPH and effectively inhibit intracellular biosynthesis of GSH. Therefore, MEFs ensure down-regulation of intracellular GSH levels and up-regulation of oxidative pressure, which enhance the ferroptosis effect.

Photo-Induced Construction and Recovery of Cu+ Sites in Metal-Organic Frameworks.

The adjustment of the valence state of metal ions is crucial for various applications because peculiar activity originates from metal ions with specific valence. Cu+ can interact with molecules possessing unsaturated bonds like CO via π-complexation, while Cu2+ doesn't have such ability. Meanwhile, Cu+ sites are easily oxidized to Cu2+ , leading to the loss of activity. Despite great efforts, the development of a facile method to construct and recover Cu+ sites remains a pronounced challenge. Here, for the first time a facile photo-induced strategy is reported to fabricate Cu+ sites in metal-organic frameworks (MOFs) and recover Cu+ after oxidation. The Cu2+ precursor was loaded on NH2 -MIL-125, a typical visible-light responsive Ti-based MOF. Visible light irradiation triggers the formation of Ti3+ from Ti4+ in framework, which reduces the supported Cu2+ in the absence of any additional reducing agent, thus simplifying the process for Cu+ generation significantly. Due to π-complexation interaction, the presence of Cu+ results in remarkably enhanced CO capture capacity (1.16 mmol g-1 ) compared to NH2 -MIL-125 (0.49 mmol g-1 ). More importantly, Cu+ can be recovered conveniently via re-irradiation when it is oxidized to Cu2+ , and the oxidation-recovery process is reversible.

ATG10 overexpression is related to the dismal prognosis and promotes the growth and migration of hepatocellular carcinoma cells via cyclin B1/CDK1 and CDK2.

Although the expression of autophagy-related 10 (ATG10) is known to be associated with the poor prognosis of cancer patients by enhancing cancer cell growth and migration, the roles of ATG10 in hepatocellular carcinoma (HCC) remains to be determined. In this study, the expression of ATG10 in HCC was analyzed using the data from TCGA databases and was further verified in the clinical samples from our patients. In addition, the relationships of ATG10 expression with clinical features, diagnosis and prognosis, as well as the predictive values of ATG10 expression in overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI) were explored. Furthermore, the expression and the prognostic values of ATG10 co-expressed genes were also identified in HCC, which was used to construct prognostic nomograms. Our data showed that the expression level of ATG10 was significantly increased in HCC, and the elevated ATG10 expression was associated with poor prognosis. Moreover, cells with ATG10 knockdown were used to investigate the effects of ATG10 on HCC cell proliferation and migration. We found that silencing ATG10 inhibited the proliferation, migration, and invasion of HCC cells, which was related to the protein expression of cyclin B1, CDK1, and CDK2. Similarly, the overexpression of ATG10 co-expressed genes ATG12, LARS1, CWC27, and SLC30A5 in HCC patients were also associated with the OS, DSS, and PFI. The risk models and nomograms based on ATG10 and ATG10 co-expressed genes indicated the correclation between their expression and the dismal prognosis in HCC patients. In conclusion, ATG10 expression was elevated in HCC and was associated with poor prognosis. Inhibition of ATG10 expression could attenuate cancer progression. ATG10-related nomograms and risk models could be used clinically to evaluate the prognosis of HCC patients.

Two new isoflavones from the barks of Dalbergia hancei Benth.

Two new isoflavone compounds, Dalhancei A (1) and Dalhancei B (2), along with a known compound epicatechin (3) were isolated from 80% methanol extract of the barks of Dalbergia hancei Benth. The structures of compounds 1-3 were elucidated by comparison with the literature and physical data analysis, including optical rotation, MS, 1D and 2D NMR spectra. Compounds 1 and 2 showed weak inhibitory activity against tyrosinase at 16.22 mmol/L, with inhibition rates of 42.23 ± 0.18% and 45.68 ± 0.17%, respectively; compound 1 exhibited weak inhibitory activity against α-glucosidase with the inhibition rate of 43.72 ± 0.22% at 5.41 mmol/L, compounds 2 and 3 had better α-glucosidase inhibitory activity than compound 1 with IC50 values of 0.90 ± 0.18 and 0.41 ± 0.17 mmol/L, respectively.

SLC25A25-AS1 over-expression could be predicted the dismal prognosis and was related to the immune microenvironment in prostate cancer.

It has been established that long-chain coding RNA (lncRNA) SLC25A25-AS1 is associated with cancer progression. However, the roles and mechanisms of SLC25A25-AS1 in prostate cancer (PC) have not been reported in the literature. The present study explored the relationship between SLC25A25-AS1 expression and PC progression via comprehensive analysis. The pan-cancer expression of SLC25A25-AS1 was identified using data from The Cancer Genome Atlas (TCGA) database and tissue specimens from our hospital. The expression levels of SLC25A25-AS1 in various subgroups based on the clinical features were identified. The prognostic value of SLC25A25-AS1 and SLC25A25-AS1 co-expressed lncRNAs in PC patients was assessed by survival analysis and ROC analysis, and prognosis-related risk models of SLC25A25-AS1 were constructed. The relationship between SLC25A25-AS1 and the PC immune microenvironment was investigated using correlation analysis. SLC25A25-AS1 expression in PC was significantly increased and correlated with the T stage, clinical stage, Gleason score (GS), and dismal prognosis. SLC25A25-AS1 overexpression exhibited good performance in evaluating the prognosis of PC patients. The area under the curves (AUCs) of the 1-, 3-, and 5-year overall survival (OS) for SLC25A25-AS1 was 1, 0.876, and 0.749. Moreover, the AUCs for the 1-, 3-, and 5-year progress free interval (PFI) for SLC25A25-AS1 were 0.731, 0.701, and 0.718. SLC25A25-AS1 overexpression correlated with the infiltration of CD8 T cells, interstitial dendritic cells (IDC), macrophages and other cells. AC020558.2, ZNF32-AS2, AP4B1-AS1, AL355488.1, AC109460.3, SNHG1, C3orf35, LMNTD2-AS1, and AL365330.1 were significantly associated with SLC25A25-AS1 expression, and short OS and PFI in PC patients. The risk models of the SLC25A25-AS1-related lncRNAs were associated with a dismal prognosis in PC. Overall, SLC25A25-AS1 expression was increased in PC and related to the prognosis and PC immune microenvironment. The risk model of SLC25A25-AS1 have huge prospect for application as prognostic tools in PC.

Three-in-one incidence of hepatocellular carcinoma, cholangiocellular carcinoma, and neuroendocrine carcinoma: A case report.

BACKGROUND: Primary hepatic neuroendocrine carcinoma (NEC) is rare, and a combination with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) is extremely rare. To date, only four combination cases have been reported. The present paper describes the fifth patient. CASE SUMMARY: A 32-year-old Chinese man with chronic hepatitis B was hospitalized for persistent upper abdominal pain. Abdominal computed tomography (CT) examination revealed a liver mass. The tumor was located in the 7th and 8th segments of the liver, and CT and magnetic resonance imaging findings were consistent with the diagnosis of HCC. Laboratory examinations revealed the following: Alanine aminotransferase, 243 U/L; aspartate aminotransferase, 167 U/L; alpha-fetoprotein, 4519 µg/L. Laparoscopic right lobe hepatectomy was performed on the liver mass. Postoperative pathology showed low differentiation HCC plus medium and low differentiation CCA combined with NEC. One month after the surgery, the patient suffered from epigastric pain again. Liver metastasis was detected by CT, and tumor transcatheter arterial chemoembolization was performed. Unfortunately, the liver tumor was progressively increased and enlarged, and after 1 mo, the patient died of liver failure. CONCLUSION: This is a rare case, wherein the tumor is highly aggressive, grows rapidly, and metastasizes in a short period. Imaging and laboratory tests can easily misdiagnose or miss such cases; thus, the final diagnosis relies on pathology.

Primary signet-ring cell carcinoma of the extrahepatic bile duct: A case report.

BACKGROUND: Signet ring cell carcinoma (SRCC) is a specific type of mucinous secretory adenocarcinoma, which contains abundant mucus in the cytoplasm and pushes the nucleus to one side of the cell membrane, forming a round or oval, and the nuclear deviations give the cells a signet ring-like appearance. SRCC often originates in the gastrointestinal tract, especially in the stomach. However, primary SRCC of the extrahepatic bile duct is extremely rare. Therefore, little is known about its epidemiology, treatment, and prognosis. CASE SUMMARY: An 82-year-old female was admitted with abdominal pain, jaundice, and skin pruritus for 2 mo. She had no specific family history. Physical examination presented normal vital signs, icteric sclera, visible jaundice, and mild tenderness in the right upper abdominal quadrant. Tumor-related cell markers were within normal values. Contrast-enhanced computed tomography revealed a thickened wall of the common bile duct, strengthened with intrahepatic bile duct dilation and multiple round-like lesions in the liver. In addition, the lymph nodes in the hepatic hilum area, the pancreatic head area, and around the abdominal aorta were enlarged. Thus, a preoperative diagnosis of cholangiocarcinoma was established. To alleviate jaundice and prolong the overall survival, percutaneous transhepatic cholangiopancreatic drainage (PTCD) was performed. During the operation, segmental stenosis of the extrahepatic bile duct and a vine-like expansion of the intrahepatic bile duct was observed. Furthermore, a biliary biopsy was performed under fluoroscopy to determine the nature and origin of the lesion. The pathological diagnosis of the biopsy was SRCC. Finally, a diagnosis of primary SRCC of extrahepatic bile duct with distant lymph node metastasis and multiple liver metastases was made based on the radiographic, PTCD, and pathological characteristics. The tumor was diagnosed as T3N1M1 stage IV. Despite our aggressive approach, the patient died of liver failure after 1 mo. CONCLUSION: This is the only case report on primary SRCC of the extrahepatic bile duct with distant organ metastasis to date.

Interfering with ITGB1-DT expression delays cancer progression and promotes cell sensitivity of NSCLC to cisplatin by inhibiting the MAPK/ERK pathway.

Long non-coding RNA ITGB1-DT is involved in the regulation of cancer growth and metastasis. However, the roles of ITGB1-DT in non-small cell lung cancer (NSCLC) progression and sensitivity to cisplatin has not been elucidated. ITGB1-DT expression in NSCLC tissues, and the relationship between ITGB1-DT expression with NSCLC diagnosis, prognosis, clinicopathological features, and immune cell infiltration were investigated in The Cancer Gene Atlas (TCGA) database. The roles and mechanisms of ITGB1-DT in cell growth, migration, and drug sensitivity of NSCLC cells were explored in the cell model. The prognostic nomograms of ITGB1-DT-related genes were evaluated using bioinformatics. ITGB1-DT was overexpressed in NSCLC. Elevated ITGB1-DT expression was related to the late T stage, N stage, M stage, short overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) of NSCLC patients. ITGB1-DT was the independent risk factors for poor prognosis, and had diagnostic value for NSCLC patients. Interfering with the ITGB1-DT expression can inhibit the proliferation, migration, and invasion of A549, H1299, and drug-resistant A549/DDP, possibly due to the inhibition of p38 MAPK and ERK phosphorylation levels. ITGB1-DT expression was correlated with the levels of NSCLC immune infiltration cells, such as the TReg, Th, and NK cells. ITGB1-DT-related gene nomograms were associated with the prognosis, and were expected to evaluate the prognosis of NSCLC patients. In conclusion, inhibition of ITGB1-DT expression delayed the growth and metastasis of NSCLC using the MAPK/ERK signaling mechanism and enhanced the sensitivity of NSCLC to cisplatin drugs. These results indicate that ITGB1-DT might be a biomarker for evaluating the diagnosis and prognosis of NSCLC patients.

Bisphenol A analogues in associations with serum hormone levels among reproductive-aged Chinese men.

BACKGROUND: Bisphenol A (BPA) as an endocrine disrupting chemical has been shown to alter reproductive endocrine function, but little is known on its analogues such as bisphenol F (BPF) and bisphenol S (BPS) with increasing usage and exposure. OBJECTIVE: To explore the associations between exposures to BPA, BPF and BPS and serum reproductive hormones among reproductive-aged Chinese men. METHODS: We measured BPA, BPF and BPS concentrations in repeated urine samples and multiple reproductive hormones in the serum samples collected from 462 men attending an infertility clinic in Wuhan, China. Linear regression models were applied to assess the associations between averaged urinary BPA, BPF and BPS levels and serum hormone concentrations, and restricted cubic spline (RCS) models were further utilized to explore potential non-linear associations. We also examined potential modifying effects by age and body mass index (BMI). RESULTS: There was little evidence of associations between BPA exposure and altered reproductive hormones. However, we found that elevated BPF and BPS exposures were in negative associations with estrogen (E2) levels and E2/T (total testosterone) ratio (all P for trends < 0.05), and that elevated BPS exposure was negatively associated with SHBG levels (P for trend = 0.09). Based on the RCS models, these linear negative associations except that between BPS exposure and E2/T ratio were further confirmed. In stratified analyses, BPF and BPS exposures in relation to reduced E2 and E2/T ratio were more pronounced among men aged > 30 years, whereas their associations with reduced SHBG levels were more pronounced among men aged ≤ 30. Also, BPS exposure in negative association with FSH only emerged among men with BMI ≥ 24 kg/m2 (P for interaction = 0.03). CONCLUSION: BPF and BPS exposures were negatively associated with male serum E2, E2/T ratio and SHBG levels, and these associations varied by age and BMI.

The m6A/m5C/m1A Regulated Gene Signature Predicts the Prognosis and Correlates With the Immune Status of Hepatocellular Carcinoma.

RNA modification of m6A/m5C/m1A contributes to the occurrence and development of cancer. Consequently, this study aimed to investigate the functions of m6A/m5C/m1A regulated genes in the prognosis and immune microenvironment of hepatocellular carcinoma (HCC). The expression levels of 45 m6A/m5C/m1A regulated genes in HCC tissues were determined. The functional mechanisms and protein-protein interaction network of m6A/m5C/m1A regulated genes were investigated. The Cancer Genome Atlas (TCGA) HCC gene set was categorized based on 45 m6A/m5C/m1A regulated genes, and survival analysis was used to determine the relationship between the overall survival of HCC patients in subgroups. Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were used to construct the risk model and nomogram for m6A/m5C/m1A regulated genes. The relationships between m6A/m5C/m1A regulated gene subsets and risk model and immune cell infiltration were analyzed using CIBERSORT. m6A/m5C/m1A regulated genes were involved in mRNA and RNA modifications, mRNA and RNA methylation, mRNA and RNA stability, and other processes. There was a statistically significant difference between cluster1 and cluster2 groups of genes regulated by m6A/m5C/m1A. The prognosis of cluster1 patients was significantly better than that of cluster2 patients. There were statistically significant differences between the two cluster groups in terms of fustat status, grade, clinical stage, and T stage of HCC patients. The risk model comprised the overexpression of YBX1, ZC3H13, YTHDF1, TRMT10C, YTHDF2, RRP8, TRMT6, LRPPRC, and IGF2BP3, which contributed to the poor prognosis of HCC patients. The high-risk score was associated with prognosis, fustat status, grade, clinical stage, T stage, and M stage and was an independent risk factor for poor prognosis in HCC patients. High-risk score mechanisms included spliceosome, RNA degradation, and DNA replication, among others, and high-risk was closely related to stromal score, CD4 memory resting T cells, M0 macrophages, M1 macrophages, resting mast cells, CD4 memory activated T cells, and follicular helper T cells. In conclusion, the cluster subgroup and risk model of m6A/m5C/m1A regulated genes were associated with the poor prognosis and immune microenvironment in HCC and are expected to be the new tools for assessing the prognosis of HCC patients.

Construction of AP003469.4-miRNAs-mRNAs ceRNA network to reveal potential biomarkers for hepatocellular carcinoma.

Studies have reported that the competing endogenous RNA (ceRNA) networks are related to disease progression and prognosis in patients with hepatocellular carcinoma (HCC). The roles and mechanisms of long-chain non-coding RNA AP003469.4 in HCC have remained unclear. Here, we explored the roles of AP003469.4 in HCC progression using bioinformatics, CCK-8, Transwell assay, etc. AP003469.4 targets miRNAs and these target genes were predicted by the LncBase Predicted v.2, miRDB, miRTarBase, and TargetScan databases. Then, AP003469.4-associated ceRNA network was constructed. Biological functions and mechanisms of differentially expressed genes in the ceRNA network were explored using GO and KEGG. Survival analysis and Cox regression analysis were used to screen prognostic genes and construct a prognostic risk model. The results revealed that AP003469.4, with the area under the curve of 0.9048, was highly expressed in HCC tissues. Increased expression of AP003469.4 was an independent risk factor for the dismal prognosis of HCC patients and was associated with the short overall and disease-free survival. Downregulation of AP003469.4 expression inhibited cell proliferation, cycle transition, invasion, and migration, and promoted cell apoptosis. There were 489 differentially expressed target genes in the ceRNA network, which were involved in several pathways, such as the MAPK signaling pathway, cell cycle, and p53 signaling pathway. The risk model was based on the DTYMK, ZFC3H1, CBX2, PKM, TTC26, ATG10, TAGLN2, CD3EAP, SHISA9, SLC1A5, KPNA2, SCML2, E2F7, and SMARCD1, which were the independent risk factors for poor prognosis of HCC patients. In general, interference with AP003469.4 expression might delay the progression of HCC. AP003469.4 related network could help to identify the hub target molecules in HCC progression, which might be candidate biomarkers for evaluating the prognosis of HCC patients.

Organochlorine pesticide exposures, metabolic enzyme genetic polymorphisms and semen quality parameters among men attending an infertility clinic.

The associations of organochlorine pesticides (OCPs) with semen quality from human studies are conflicting, and also it is largely unknown whether the associations are modified by genetic polymorphisms. We aimed to evaluate the associations between serum concentrations of 18 OCPs and semen quality among 387 Chinese men, and further to examine the modifying effects by genetic polymorphisms in cytochrome P450 (CYP2E1) and glutathione S-transferase (GSTT1). Multivariable linear regressions were used to evaluate the relationships between serum OCP concentrations and semen quality, and the role of CYP2E1 and GSTT1 polymorphisms in modifying the associations were assessed. Multiple testing was adjusted using the false discovery rate (FDR). We observed that men with detectable concentrations of serum ɤ-HCH had a decrease in sperm motility of 7.07% (95% CI: -10.9%, -3.24%) compared to those with undetectable concentrations (FDR-P value = 0.02). Men with TT of CYP2E1 rs 915906 genotypes had higher median concentrations of serum dieldrin compared with those with CT/CC of CYP2E1 rs 915906 genotypes. There were interactions between CYP2E1 and GSTT1 polymorphisms and certain OCPs namely ɤ-HCH, δ-HCH, dieldrin, endosulfan I, and endrin aldehyde on semen quality. For example, elevated dieldrin levels in relation to decreased sperm concentration, sperm count, and sperm motility were only observed among men with CC of CYP2E1 rs2031920 genotypes (all Pinteraction < 0.05). However, these interactions were not statistically significant after the FDR adjustment. Our results suggested that CYP2E1 and GSTT1 polymorphisms may modify the effects of OCP exposures on semen quality. Due to the relatively small size samples, further investigation is warranted to confirm the findings.

Automatic phantom-less QCT system with high precision of BMD measurement for osteoporosis screening: Technique optimisation and clinical validation.

BACKGROUND: Currently dual-energy X-ray absorptiometry (DXA) and phantom-based quantitative computed tomography (PB-QCT) have been utilized to diagnose osteoporosis widely in clinical practice. While traditional phantom-less QCT (PL-QCT) is limited by the precision of manual calibration using body tissues, such as fat and muscle. OBJECTIVE: The aim of this study is to validate the accuracy and precision of one newly-developed automatic PL-QCT system to measure spinal bone mineral density (BMD) and diagnose osteoporosis. METHODS: A total of 36 patients were enrolled for comparison of BMD measurement between DXA and QCT. CT images of 63 patients were analyzed by both PB-QCT and newly developed automatic PL-QCT system, then the BMD results generated by the automatic PL-QCT were utilized to diagnose osteoporosis. The diagnostic outcomes were compared with that of DXA and PB-QCT to assess the performance of the new system. RESULTS: BMD test results showed that the automatic PL-QCT system had higher precision than previous studies performed with QCT, while maintaining similar capability to diagnose osteoporosis as DXA and PB-QCT. Area under curve (AUC) result of PL-QCT was larger than 0.8 for predicting spine DXA T-score in receiver operating characteristic (ROC) analysis. Pearson correlation analysis (r â€‹= â€‹0.99) showed strong linear correlation and Bland-Altman analysis (bias â€‹= â€‹3.0mg/cc) indicated little difference between the two methods. The precision result (CV â€‹= â€‹0.89%) represented good reproducibility of the new system. CONCLUSION: The traditional PL-QCT system has relatively low reproducibility due to the manual selection of the region of interest (ROI) of body tissues. Automatic selection of ROI in this new system makes the BMD testing more convenient and improves precision significantly. Compared with traditional BMD measurement methods, the automatic PL-QCT system had higher precision in accurate diagnosis of osteoporosis with great potential in translational research and wide clinical application. TRANSLATIONAL POTENTIAL STATEMENT: With high accuracy and precision, the automatic PL-QCT system could serve as an opportunistic screening tool for osteoporosis patients in the future. It could also facilitate related researches by providing more reliable data collection, both retrospectively and longitudinally.

Boronic-Acid-Accelerated Electrophilic Activation of Unprotected Maltols to N-Substituted Hydroxypyridinones in Water.

3,4-Hydroxypyridinone (3,4-HOPO) is a vital metal-chelating pharmacophore. However, the efficient synthesis has been a long-standing problem in drug development. In this paper, we report an efficient electrophilic activation of unprotected maltols via reversible covalent bonds between boronic acid and 3-hydroxyl/4-carbonyl. This one-pot reaction proceeded well on a gram scale in water with excellent efficiencies up to 97%. Moreover, taking advantage of the covalent interactions via the transient boronate, most of the previously tough amine donors, including sterically hindered amines, aromatic amines, and amino acids and amino alcohols, were well-tolerated. Importantly, the potential of this strategy in the pharmaceutical industry was highlighted with a successful synthesis of 3,4-HOPOs containing iron-chelating active pharmaceutical ingredients on 10 g and kilogram scales.

Research on the innovation of time-honored brands from the perspective of dual ethical patterns.

Introduction: Innovation has become an important means to promote the high-quality development of time-honored brands. However, the research on how to stimulate innovation investment in time-honored brands, especially that conducted in the local context, is still rare. To supplement the research limitations, this study adopts the perspective of dual ethical patterns and is set in the domestic context to explore the ethical influence of traditional cultures and marketization on the innovation investment of time-honored brands. Methods: We proposed two complementary methods, which are OLS regression and fsQCA analysis respectively, to systematically analyze the mechanism and key path of the dual ethical pattern to promote the innovation of time-honored brands. Results: The results show that traditional culture and marketization level are both positively related to the innovation of time-honored brands. However, traditional culture and marketization level are mutually exclusive in their process of affecting the innovation of time-honored brands. Discussion: This paper advances time-honored brands literature by highlighting the dual ethic pattern formed by traditional culture and marketization level on the innovation investment of time-honored brands. The findings respond to the academic debate between traditional culture and the innovation of time-honored brands, while enriching the research scope on the innovation mechanism of time-honored brands in the local context.

Comparison of robotic and open pancreaticoduodenectomy for primary nonampullary duodenal adenocarcinoma: a retrospective cohort study.

PURPOSE: Robotic surgery has been increasingly applied in pancreatic surgery and showed many advantages over conventional open surgery. The robotic pancreaticoduodenectomy (RPD) is a surgical option for primary nonampullary duodenal adenocarcinoma (PNDA). However, whether RPD is superior to open pancreaticoduodenectomy (OPD) for PNDA has not been reported. The comparative study was designed to analyze the short- and long-term outcomes of RPD versus OPD on patients with PNDA. METHODS: Demographics, perioperative, and survival outcomes among patients who underwent RPD (n = 49) versus OPD (n = 43) for PNDAs between January 2013 and March 2018 were collected and analyzed RESULTS: Demographic characteristics were comparable between the RPD group and the OPD group. The RPD group demonstrated a decreased estimated blood loss (100 vs. 200 ml, p < 0.001), time to oral intake (4.0 vs. 4.0 days, p = 0.04), and postoperative hospital stay (12.9 vs. 15.0 days, p = 0.01) compared with the OPD group. However, no differences were observed between the two groups in terms of operative time and the rates of major complications, grade B and C POPF, PPH, grade B and C DGE, biliary fistular, reoperation, and 90-day readmission. No patient died within 90 days. There were no significant differences in tumor size, differentiation, TNM stage, number of harvested lymph nodes, and the rates of nerve invasion, lymph node invasion, R0 resection, and the median overall survival between the two groups (p > 0.05) CONCLUSIONS: RPD is a safe, feasible, and effective treatment for PNDA compared with OPD and can be used as an alternative for surgeons in the treatment of PNDA. Further multicenter randomized controlled trials are needed to evaluate the effectiveness of RPD in patients with PNDA.