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Purpose: Pulmonary hypertension (PH) is characterized by a significant increase in pulmonary vascular resistance, which results in ventricular failure and death. Ambrisentan appears to be an effective treatment in the pathogenesis and progression of ambrisentan, but some researchers disagree. Therefore, this meta-analysis aims to examine the clinical efficacy of ambrisentan in the treatment of PH. Methods: A search of the scientific literature using the Embase, Cochrane, and CHINAHL databases retrieved published studies related to our topic of interest. Eight cohort studies related to ambrisentan and PH treatment were selected on the basis of our strict inclusion and exclusion criteria for a systematic meta-analysis. Statistical analyses were conducted using STATA version 12.0 statistical software (Stata- Corp LP, College Station, Texas). Findings: Our meta-analysis retrieved 124 studies using our search criteria (90 studies in English and 34 studies in Chinese), and 8 studies (4 studies in English and 4 studies in Chinese) were eventually selected for this meta-analysis. The 8 studies contained data on a total of 172 PH patients. Pooled data in our metaanalysis revealed that 6-minute walking distance in PH patients significantly improved after ambrisentan treatment compared with before treatment. The mean pulmonary arterial pressure, brain natriuretic peptide level, and systolic pulmonary artery pressure in PH patients decreased measurably after ambrisentan treatment compared with before treatment. Sensitivity analysis results confirmed that the included studies had no publication bias (all P > 0.05). Implications: Our meta-analysis results demonstrated that ambrisentan is highly effective in improving exercise tolerance and cardiac function in PH patients, and the mean pulmonary arterial pressure, systolic pulmonary artery pressure, and brain natriuretic peptide level levels in PH patients significantly decreased. However, with the limitations of small sample size, insufficient data, and ethnic difference in the study, further studies with larger sample sizes and sufficient information are essential to validate our findings of the high safety profile and efficacy of ambrisentan in treatment of PH. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to analyze the structure and functional consequences of 3 novel mutations (A82D, R125X, and C442R) of the CYP17A1 gene found in 2 patients with combined 17α-hydroxylase/17,20-lyase deficiency (17OHD). Two Chinese 46, XY female patients were diagnosed with 17OHD based on clinical findings and biochemical results. The CYP17A1 gene was analyzed by polymerase chain reaction direct sequencing. An in vitro expression system was performed in HEK293 cells to analyze the mutant P450c17 activity compared with the wild type. Analysis of the CYP17A1 gene sequences in patient 1 showed compound heterozygous mutations A82D (g.417 C > A) in exon 1 and Y329fs (g.4869 T > A, 4871del) in exon 6; DNA sequencing analysis in patient 2 revealed compound heterozygous mutations R125X (g.2045 C > T) in exon 2 and C442R (g.6457 T > C) in exon 8. The mutations A82D, R125X, and C442R have not been reported previously. The functional study demonstrated that the A82D, R125X, and C442R mutations almost completely eliminate enzymatic activity. These results, which indicate that Ala 82 and Cys 442 are crucial for both 17-hydroxylase and 17,20-lyase activities, help define the structure-function relationship of the CYP17A1 gene. The novel mutations A82D, R125X, and C442R further clarify the patients'' clinical manifestations of combined 17OHD. [Copyright &y& Elsevier]

Abstract: Aim of the study: To evaluate the pharmacokinetics of phenolic compounds after oral administration of Danshen extract in rat brain. Materials and methods: Blood and brain microdialysis probes were inserted into jugular vein and cerebral cortex of rat under anesthesia and perfused with ringer''s solution at the rate of 2.0 and 0.8μL/min, respectively. Blank microdialysates were collected after 2h post-implantation equilibrium time. Danshen extract (danshensu 40mg/kg BW, protocatechuic aldehyde 149mg/kg BW, and salvianolic acid B 50mg/kg BW) was administrated intragastrically, and then blood and brain microdialysates were collected at 15 and 30min time intervals for 4h, respectively. The concentrations of phenolic compounds were determined by high-performance liquid chromatography coupled with chemiluminescence detection. Pharmacokinetic parameters were estimated using non-compartmental methods. Results: Danshensu and protocatechuic acid could be detected in both blood and brain microdialysates, while protocatechuic aldehyde and salvianolic acid B were not detected. Brain-to-blood (AUCbrain/AUCblood) distribution ratio were 0.25±0.04 and 0.09±0.02 for danshensu and protocatechuic acid, respectively. Conclusions: Danshensu can readily permeate the blood brain barrier after oral administration of Danshen extract, and protocatechuic acid is a potential oxidative metabolite of protocatechuic aldehyde. [Copyright &y& Elsevier]

• Volatile compounds were identified from 306 black teas using HS-GC/MS. • Forty-eight aroma compounds were common among global tea samples. • Full-spectrum GC/MS data was analyzed using k -Nearest Neighbor. • Discriminant rates of tea from 10 origins were 100%. • Geraniol to linalool ratio in black tea is key for identification of origin. Some black teas demand high market prices. Black tea samples (306) collected from 10 geographic origins, including China (Guxi, Likou, Jinzipai, Guichi, Dongzhi, Changning, Wuyishan, Shaowu), India (Darjeeling), and Sri Lanka (Kandy), were analyzed using headspace volatilization followed by GC/MS (HS-GC/MS). Forty-eight volatile compounds were identified. The aroma compounds were mainly identified as alcohols, aldehydes, ketones, and esters. Analysis of either full-spectrum data or 22 tea compounds shared among the samples with k -Nearest Neighbor (k -NN) and Random Forest (RF) models discriminated all origins at 100% using KNN and 95% with RF using either data set. The discrimination rates using 2 key aroma compounds (linalool and geraniol) by k -NN were 100% for nine origins, with the rate for Guxi area at 89%, because 3 samples were classified to Jinzipai. The findings support the use of HS-GC/MS combined with chemometrics as a tool to identify the origin of black tea. [ABSTRACT FROM AUTHOR]

The prognostic value and clinical relevance of tertiary lymphoid structures (TLSs) in intrahepatic cholangiocarcinoma (iCCA) remain unclear. Thus, we aimed to investigate the prognostic value and functional involvement of TLSs in iCCA. We retrospectively included 962 patients from 3 cancer centers across China. The TLSs at different anatomic subregions were quantified and correlated with overall survival (OS) by Cox regression and Kaplan-Meier analyses. Multiplex immunohistochemistry (mIHC) was applied to characterize the composition of TLSs in 39 iCCA samples. A quaternary TLS scoring system was established for the intra-tumor region (T score) and peri-tumor region (P score) respectively. T scores positively correlated with favorable prognosis (p < 0.001), whereas a high P score signified worse survival (p < 0.001). mIHC demonstrated that both T follicular helper and regulatory T cells were significantly increased in intra-tumoral TLSs compared to peri-tumoral counterparts (p < 0.05), and regulatory T cell frequencies within intra-tumoral TLSs were positively associated with P score (p < 0.05) rather than T score. Collectively, the combination of T and P scores stratified iCCAs into 4 immune classes with distinct prognoses (p < 0.001) that differed in the abundance and distribution pattern of TLSs. Patients displaying an immune-active pattern had the lowest risk, with 5-year OS rates of 68.8%, whereas only 3.4% of patients with an immune-excluded pattern survived at 5 years (p < 0.001). The C-index of the immune class was statistically higher than the TNM staging system (0.73 vs. 0.63, p < 0.001). These results were validated in an internal and 2 external cohorts. The spatial distribution and abundance of TLSs significantly correlated with prognosis and provided a useful immune classification for iCCA. T follicular helper and regulatory T cells may play a critical role in determining the functional orientation of spatially different TLSs. Tertiary lymphoid structures (TLSs) are associated with favorable prognosis in a number of cancers. However, their role in intrahepatic cholangiocarcinoma (iCCA) remains unclear. Herein, we comprehensively evaluated the spatial distribution, abundance, and cellular composition of TLSs in iCCA, and revealed the opposite prognostic impacts of TLSs located within or outside the tumor. This difference could be mediated by the different immune cell subsets present within the spatially distinct TLSs. Based on our analysis, we were able to stratify iCCAs into 4 immune subclasses associated with varying prognoses. [Display omitted] • Tertiary lymphoid structures (TLSs) within and outside the tumor have opposite prognostic impacts on patients with iCCA. • The heterogeneous distribution of Tfh and Treg cells within distinct TLSs might be a determinant of their functional state. • The geographic integration of TLSs stratified iCCAs into 4 immune subclasses with distinct clinical outcomes. [ABSTRACT FROM AUTHOR]

Abstract: The peroxynitrite/porphyrin biomimetic system was established to investigate the effects of peroxynitrite on benzo[a]pyrene (B[a]P) metabolism. Three model systems consisting of different iron porphyrins were compared, and the results showed that the peroxynitrite/T(p-Cl)PPFeCl system was the highest catalytic efficiency in the metabolism of B[a]P. We analyzed the B[a]P metabolites produced from this system by RP-HPLC method and firstly identified the formation of nitrobenzo[a]pyrenes which are the special metabolites of B[a]P induced by peroxynitrite. [Copyright &y& Elsevier]

Background High-sensitivity cardiac troponin T (hs-cTnT) is detectable in elderly patients without clinical diagnosed cardiovascular disease. Elevated hs-cTnT levels predict increased cardiovascular risks and poor prognosis. The aim of this study was to determine the distribution and associated factors of hs-cTnT in geriatric inpatients without acute coronary syndrome (ACS). Methods Hs-cTnT was measured with a highly sensitive assay in 679 geriatric inpatients without ACS. Patients were further divided into 3 groups according to the tertile of hs-cTnT levels and single and multiple variable analyses were performed to assess the association of hs-cTnT to cardiovascular risk factors, biochemical measurements and echocardiographic abnormalities. Results Hs-cTnT was detectable (≥3 ng/L) in 98.4% of the subjects and 52.0% of the subjects had hs-cTnT levels ≥14 ng/L, which is at the 99th percentile Upper Reference Limit (URL). The levels of hs-cTnT were independently associated with N-terminal pro-brain natriuretic peptide (NT-proBNP), male gender, older age, estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMI), diabetes mellitus (DM) and left ventricular ejection fraction (LVEF). There were no significant differences in hs-cTnT levels between geriatrics patients with stable coronary artery disease (SCAD) and those without SCAD. Conclusion Hs-cTnT elevation caused by non-ischemic acute conditions was very common in geriatric hospitalized patients. Due to increases in baseline hs-cTnT in the elderly, detection of a rise and/or fall in hs-cTnT levels is essential for determining a diagnosis of ACS or AMI in geriatric patients. Further studies are needed to establish age-specific 99th percentile values of hs-cTnT for elderly individuals. [ABSTRACT FROM AUTHOR]

A new type of thermo-sensitive receptor carbon dots/SiO 2 /molecularly imprinted polymer (CDs/SiO 2 /MIP) was prepared by surface imprinting procedure and the epitope approach. The synthetic CDs/SiO 2 /MIP was able to selectively capture target protein with fluorescence quenching via the special interaction between them and the recognition cavities. The receptor exhibited the linear fluorescence quenching to cytochrome c (cyt c) in the range of 0.1–40 μM, and the detection limit was 89 nM. The precision for five replicate detection of cyt c at 20 μM was 3.11%. Moreover, the receptor owned the temperature-sensitive element that allowed for swelling and shrinking in response to temperature changes to realize recognition of the target cytochrome c. The proposed strategy revealed the feasibility of fabrication of a thermo-sensitive imprinted polymer based on CDs and surface imprinting procedure and the epitope approach. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) play a pivotal role in connecting tumor cells with their local and distant microenvironments. Herein, we aimed to understand the role (on a molecular basis) patient-derived EVs play in modulating cancer stemness and tumorigenesis in the context of hepatocellular carcinoma (HCC). EVs from patient sera were isolated, quantified and characterized. The EVs were vigorously tested, both in vitro and in vivo , through various functional assays. Proteomic analysis was performed to identify the functional components of EVs. The presence and level of polymeric immunoglobulin receptor (pIgR) in circulating EVs and tumor and non-tumorous tissues of patients with HCC were determined by ELISA, immunoblotting, immunohistochemistry and quantitative PCR. The functional role and underlying mechanism of EVs with enhanced pIgR expression were elucidated. Blockade of EV-pIgR with neutralizing antibody was performed in nude mice implanted with patient-derived tumor xenografts (PDTXs). Circulating EVs from patients with late-stage HCC (L-HCC) had significantly elevated pIgR expression compared to the EVs released by control individuals. The augmenting effect of L–HCC–EVs on cancer stemness and tumorigenesis was hindered by an anti-pIgR antibody. EVs enriched with pIgR consistently promoted cancer stemness and cancerous phenotypes in recipient cells. Mechanistically, EV-pIgR-induced cancer aggressiveness was abrogated by Akt and β-catenin inhibitors, confirming that the role of EV-pIgR depends on the activation of the PDK1/Akt/GSK3β/β-catenin signaling axis. Furthermore, an anti-pIgR neutralizing antibody attenuated tumor growth in mice implanted with PDTXs. This study illustrates a previously unknown role of EV-pIgR in regulating cancer stemness and aggressiveness: EV-pIgR activates PDK1/Akt/GSK3β/β-catenin signaling cascades. The blockade of the intercellular communication mediated by EV-pIgR in the tumor microenvironment may provide a new therapeutic strategy for patients with cancer. The World Health Organization estimates that more than 1 million patients will die from liver cancer, mostly hepatocellular carcinoma (HCC), in 2030. Understanding the underlying mechanism by which HCC acquires aggressive attributes is crucial to improving the diagnosis and treatment of patients. Herein, we demonstrated that nanometer-sized extracellular vesicles released by tumors promote cancer stemness and tumorigenesis. Within these oncogenic vesicles, we identified a key component that functions as a potent modulator of cancer aggressiveness. By inhibiting this functional component of EVs using a neutralizing antibody, tumor growth was profoundly attenuated in mice. This hints at a potentially effective therapeutic alternative for patients with cancer. [Display omitted] • Elevated pIgR levels are found in circulating extracellular vesicles from patients with liver cancer. • EV-pIgR promotes cancer stemness and cancerous phenotypes in recipient liver cancer cells. • EV-pIgR promotes liver cancer cell aggressiveness by activating the PDK1/Akt/GSK3β/β-catenin signaling axis. • Combined treatment using sorafenib and anti-pIgR antibody attenuates growth of patient-derived xenografts in mice. [ABSTRACT FROM AUTHOR]

Abstract: Background: The aim of this study was to observe the contraceptive effectiveness and reversibility of the oviduct plug with nickel–titanium (Ni-Ti) shape memory alloy and silicone rubber in rabbits. Study Design: The oviduct plugs with Ni-Ti shape memory alloy and silicone rubber were made as contraceptive devices. The frame of the oviduct plug is made of silicone rubber and Ni-Ti shape memory alloy wire. The central part of the frame resembles a circular cylinder and the amphi-terminal of the frame is like a spigot which is formed with three mounting rings. Thirty-five New Zealand adult female rabbits were randomly divided into three groups. Thirty rabbits in Group 1 were used to test the contraceptive effect of the oviduct plug. Ten rabbits in Group 2 were used to assess the reproductive reversibility of the rabbits; 3 months after the operation, the oviduct plugs were removed from the junction of the uterus and tubes by incision of the abdomen. Another five rabbits (Group 3) served as the control group. In 30 female rabbits (Group 1), the plugs were inserted into the oviducts via a 0.5-cm incision of the uterus by using an inserter that contained the plug, then the female rabbits copulated with male rabbits once a week after the operation for 1 month. The plugs were then taken out from 10 rabbits (Group 2) 3 months after the operation. Results: Out of 30 cases (Group 1), only one rabbit from Group 1 was pregnant 2 months after the insertion of the plugs due to improper insertion. However, five rabbits in the control group were all pregnant. All 10 rabbits from Group 2 were pregnant 1 month after the plug was removed. Conclusion: The oviduct plug with Ni-Ti shape memory alloy and silicone rubber is a new, effective and reversible contraceptive tool. [Copyright &y& Elsevier]

Nuclear pore complex (NPC) embedded in the nuclear envelope, is the only channel for macromolecule nucleocytoplasmic transportation and has important biological functions. However, the deregulation of specific nucleoporins (Nups) and NPC-Nup-based mechanisms and their function in tumour progression remain poorly understood. Here, we aimed to identify the Nups that contribute to HCC progression and metastasis in 729 primary hepatocellular carcinoma (HCC) cases using molecular, cytological, and biochemical techniques. Our results revealed elevated Nup93 expression in HCC tissues, especially in cases with metastasis, and was linked to worse prognosis. Furthermore, Nup93 knockdown suppressed HCC cell metastasis and proliferation, while Nup93 overexpression promoted these activities. We observed that Nup93 promotes HCC metastasis and proliferation by regulating β-catenin translocation. In addition, we found that Nup93 interacted with β-catenin directly, independent of importin. Furthermore, LEF1 and β-catenin facilitated the Nup93-mediated metastasis and proliferation in HCC via a positive feedback loop. Thus, our findings provide novel insights into the mechanisms underlying the Nup93-induced promotion of HCC metastasis and suggest potential therapeutic targets in the LEF1-Nup93-β-catenin pathway for HCC therapeutics. [ABSTRACT FROM AUTHOR]

Little is known about Epstein-Barr virus (EBV)-associated intrahepatic cholangiocarcinoma (EBVaICC) because of its rarity. We aimed to comprehensively investigate the clinicopathology, tumor immune microenvironment (TIME) and genomic landscape of this entity in southern China. We evaluated 303 intrahepatic cholangiocarcinomas (ICCs) using in situ hybridization for EBV. We compared clinicopathological parameters between EBVaICC and nonEBVaICC, and we analyzed EBV infection status, tumor-infiltrating lymphocytes (TILs) and genomic features of EBVaICC by immunohistochemistry, double staining, nested PCR, multiplex immunofluorescence staining, fluorescence in situ hybridization and whole-exome sequencing. EBVaICC accounted for 6.6% of ICCs and was associated with EBV latency type I infection and clonal EBV isolates. Patients with EBVaICC were more often female and younger, with solitary tumors, higher HBV infection rates and less frequent cirrhosis; the lymphoepithelioma-like (LEL) subtype was more common in EBVaICC. EBVaICC was associated with a significantly larger TIME component than nonEBVaICC. The LEL subtype of EBVaICC – associated with a significantly increased density and proportion of CD20+ B cells and CD8+ T cells – was associated with significantly higher 2-year survival rates than conventional EBVaICC and nonEBVaICC. Both PD-1 and PD-L1 in TILs, and PD-L1 in tumor cells, were overexpressed in EBVaICC. High PD-L1 expression in tumor cells and high CD8+ TIL densities were significantly more common in EBVaICC than in nonEBVaICC. Seven genes (MUC4 , DNAH1, GLI2 , LIPE , MYH7 , RP11-766F14.2 and WDR36) were mutated in at least 3 patients. EBVaICC had a different mutational pattern to liver fluke-associated cholangiocarcinoma and HBV-associated ICC. EBVaICC, as a subset of ICC, has unique etiological, clinicopathological and genetic characteristics, with a significantly larger TIME component. Paradoxically, patients with EBVaICC could be candidates for immune checkpoint therapy. Epstein-Barr virus (EBV) is associated with a subtype of intrahepatic cholangiocarcinoma, with unique clinicopathological and genetic characteristics. The tumor immune microenvironment is also different in this tumor subtype and patients with EBV-associated intrahepatic cholangiocarcinoma may respond well to immune checkpoint inhibitors. [Display omitted] • EBVaICC accounted for 6.6% of ICCs and was associated with EBV latency type I infection and clonal EBV isolates. • EBVaICChas unique characteristics related to etiology, clinicopathology and molecular genetics. • Both PD-1 and PD-L1 in tumor-infiltrating lymphocytes and PD-L1 in tumor cells are overexpressed in EBVaICC. • Patients with EBVaICC may respond well to immune checkpoint inhibitors. • The lymphoepithelioma-like subtype of EBVaICC is related to favorable survival. [ABSTRACT FROM AUTHOR]

Autophagy is a critical survival factor for cancer cells, whereby it maintains cellular homeostasis by degrading damaged organelles and unwanted proteins and supports cellular biosynthesis in response to stress. Cancer cells, including hepatocellular carcinoma (HCC), are often situated in a hypoxic, nutrient-deprived and stressful microenvironment where tumor cells are yet still able to adapt and survive. However, the mechanism underlying this adaptation and survival is not well-defined. We report deficiency of the post-translational modification enzyme protein arginine N-methyltransferase 6 (PRMT6) in HCC to promote the induction of autophagy under oxygen/nutrient-derived and sorafenib drug-induced stress conditions. Enhanced autophagic flux in HCC cells negatively correlated with PRMT6 expression, with the catalytic domain of PRMT6 critically important in mediating these autophagic activities. Mechanistically, PRMT6 physically interacts and methylates BAG5 to enhance the degradation of its interacting partner HSC70, a well-known autophagy player. The therapeutic potential of targeting BAG5 using genetic approach to reverse tumorigenicity and sorafenib resistance mediated by PRMT6 deficiency in HCC is also demonstrated in an in vivo model. The clinical implications of these findings are highlighted by the inverse correlative expressions of PRMT6 and HSC70 in HCC tissues. Collectively, deficiency of PRMT6 induces autophagy to promote tumorigenicity and cell survival in hostile microenvironments of HCC tumors by regulating BAG5-associated HSC70 stability through post-translational methylation of BAG5. Targeting BAG5 may therefore be an attractive strategy in HCC treatment by suppressing autophagy and inducing HCC cell sensitivity to sorafenib for treatment. [ABSTRACT FROM AUTHOR]

White matter fiber tracts demonstrate heterogeneous vulnerabilities to aging effects. Here, we estimated age-related differences in tract properties using UK Biobank diffusion magnetic resonance imaging data of 7167 47- to 76-year-old neurologically healthy people (3368 men and 3799 women). Tract properties in terms of generalized fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity were sampled on 76 fiber tracts; for each tract, age-related differences were estimated by fitting these indices against age in a linear model. This cross-sectional study demonstrated 4 age-difference patterns. The dominant pattern was lower generalized fractional anisotropy and higher axial diffusivity, radial diffusivity, and mean diffusivity with age, constituting 45 of 76 tracts, mostly involving the association, projection, and commissure fibers connecting the prefrontal lobe. The other 3 patterns constituted only 14 tracts, with atypical age differences in diffusion indices, and mainly involved parietal, occipital, and temporal cortices. By analyzing the large volume of diffusion magnetic resonance imaging data available from the UK Biobank, the study has provided a detailed description of heterogeneous age-related differences in tract properties over the whole brain which generally supports the myelodegeneration hypothesis. • Diffusion MRI data of 7167 neurologically healthy people aged 47–76 years were analyzed. • Age-related differences in diffusion MRI parameters of 76 tracts were characterized. • A dominant pattern of age-related difference was found in the association fibers and prefrontal tracts. • Sensorimotor and visual tracts showed distinct patterns of age-related difference suggesting different fiber organizations. • Female participants had lower generalized fractional anisotropy in some tracts than male participants of similar age. [ABSTRACT FROM AUTHOR]

Solid evidence shows that tumor-initiating cells (T-ICs) are the root of tumor relapse and drug resistance, which lead to a poor prognosis in patients with hepatocellular carcinoma (HCC). Through an in vitro liver T-IC enrichment approach, we identified nuclear factor (erythroid-derived 2)-like 2 (NRF2) as a transcription regulator that is significantly activated in enriched liver T-IC populations. In human HCCs, NRF2 was found to be overexpressed, which was associated with poor patient survival. Through a lentiviral based knockdown approach, NRF2 was found to be critical for regulating liver T-IC properties, including self-renewal, tumorigenicity, drug resistance and expression of liver T-IC markers. Furthermore, we found that ROS-induced NRF2 activation regulates sorafenib resistance in HCC cells. Mechanistically, NRF2 was found to physically bind to the promoter of sonic hedgehog homolog (SHH), which triggers activation of the sonic hedgehog pathway. The effect of NRF2 knockdown was eliminated upon administration of recombinant SHH, demonstrating that NRF2 mediated T-IC function via upregulation of SHH expression. Our study suggests a novel regulatory mechanism for the canonical sonic hedgehog pathway that may function through the NRF2/SHH/GLI signaling axis, thus mediating T-IC phenotypes. [ABSTRACT FROM AUTHOR]

Abstract The absolute configuration of cepharanthine (1), a strongly bioactive bisbenzylisoquinoline alkaloid exhibiting 12 specific bioactivities without any reported negative side-effects, has been reassigned from (1 R ,1′ S) to (1 R ,1′ R) using quantum theory. The absolute configurations (ACs) of 13 other analogues of 1 were also systematically reassigned. Six quaternary salts were prepared from 1 and one exhibited strong anti-bacterial activity against Bacillus subtilis with MIC 0.31 μ M, while Ciprofloxacin, the positive control medicine was 3.88 μ M. This work established the critical importance of correlating chiroptical experimental spectra with their quantum mechanically predicted spectra for accurate stereogenic center assignments. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Epstein–Barr virus-associated intrahepatic cholangiocarcinoma (EBVaICC) has a distinct genomic profile and increased CD3+ and CD8+ T cells infiltration. However, the efficacy of immunotherapy in EBVaICC remains largely unknown. This study aimed to assess the efficacy of programmed cell death protein 1 (PD-1) antibody therapy in EBVaICC. Patients with metastatic biliary tract cancer (BTC) diagnosed at Sun Yat-sen University Cancer Center from January 2016 to December 2021 were identified. In situ hybridisation was performed to detect EBV. Overall survival (OS) and progression-free survival (PFS) were measured. A total of 698 patients with metastatic BTC were identified, of whom 39 (5.6%) had EBVaICC. Among the 136 patients who were not administered PD-1 antibody, the OS was similar between patients with EBVaICC and EBV-negative ICC (median OS 12.5 versus 9.5 months, respectively; P = 0.692). For the 205 patients who were administered PD-1 antibody, patients with EBVaICC had significantly longer OS than patients with EBV-negative ICC (median OS 24.9 versus 11.9 months, respectively; P = 0.004). Seventeen patients with EBVaICC were administered PD-1 antibody. Eight patients (47%) achieved a partial response, and 17 patients achieved disease control. The median PFS was 17.5 months. This study identified a clinically actionable subset of patients with EBVaICC with a promising response to the PD-1 antibody. • Immunotherapy effect in EBV-associated intrahepatic cholangiocarcinoma is unknown. • Overall survival improved in patients with PD-1 treatment. • Recommend test for EBV intrahepatic cholangiocarcinoma patients. • Identified EBVaICC patients with a promising response to PD-1 antibody. [ABSTRACT FROM AUTHOR]

Stable axial conformations generally exist only when the single bond's (axis') rotation was sterically hindered in solution. Herein, we firstly show that two stable conformations could be observed in solution by 1 H and 13 C NMR experiments when the single bond rotates freely. Its coalescence temperature was measured up to 120 °C when we took compound 13 as an example. The ratio of the two stable conformations was computed using quantum methods. The predicted results matched with the experimental results well. The conversion barrier between two conformers was estimated by potential energy scan (PES) and transition state (TS) calculations at the B3LYP/6-311 + G(d) level. Furthermore, its stereochemistry was also well studied by comparing theoretical electronic circular dichroism (ECD) spectra with the experimental one. [ABSTRACT FROM AUTHOR]

Background: Gene expression patterns can be used as prognostic biomarkers in various types of cancers. We aimed to identify a gene expression pattern for individual distant metastatic risk assessment in patients with locoregionally advanced nasopharyngeal carcinoma.Methods: In this multicentre, retrospective, cohort analysis, we included 937 patients with locoregionally advanced nasopharyngeal carcinoma from three Chinese hospitals: the Sun Yat-sen University Cancer Center (Guangzhou, China), the Affiliated Hospital of Guilin Medical University (Guilin, China), and the First People's Hospital of Foshan (Foshan, China). Using microarray analysis, we profiled mRNA gene expression between 24 paired locoregionally advanced nasopharyngeal carcinoma tumours from patients at Sun Yat-sen University Cancer Center with or without distant metastasis after radical treatment. Differentially expressed genes were examined using digital expression profiling in a training cohort (Guangzhou training cohort; n=410) to build a gene classifier using a penalised regression model. We validated the prognostic accuracy of this gene classifier in an internal validation cohort (Guangzhou internal validation cohort, n=204) and two external independent cohorts (Guilin cohort, n=165; Foshan cohort, n=158). The primary endpoint was distant metastasis-free survival. Secondary endpoints were disease-free survival and overall survival.Findings: We identified 137 differentially expressed genes between metastatic and non-metastatic locoregionally advanced nasopharyngeal carcinoma tissues. A distant metastasis gene signature for locoregionally advanced nasopharyngeal carcinoma (DMGN) that consisted of 13 genes was generated to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter distant metastasis-free survival (hazard ratio [HR] 4·93, 95% CI 2·99-8·16; p<0·0001), disease-free survival (HR 3·51, 2·43-5·07; p<0·0001), and overall survival (HR 3·22, 2·18-4·76; p<0·0001) than patients with low-risk scores. The prognostic accuracy of DMGN was validated in the internal and external cohorts. Furthermore, among patients with low-risk scores in the combined training and internal cohorts, concurrent chemotherapy improved distant metastasis-free survival compared with those patients who did not receive concurrent chemotherapy (HR 0·40, 95% CI 0·19-0·83; p=0·011), whereas patients with high-risk scores did not benefit from concurrent chemotherapy (HR 1·03, 0·71-1·50; p=0·876). This was also validated in the two external cohorts combined. We developed a nomogram based on the DMGN and other variables that predicted an individual's risk of distant metastasis, which was strengthened by adding Epstein-Barr virus DNA status.Interpretation: The DMGN is a reliable prognostic tool for distant metastasis in patients with locoregionally advanced nasopharyngeal carcinoma and might be able to predict which patients benefit from concurrent chemotherapy. It has the potential to guide treatment decisions for patients at different risk of distant metastasis.Funding: The National Natural Science Foundation of China, the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, the Natural Science Foundation of Guang Dong Province, the National Key Research and Development Program of China, the Innovation Team Development Plan of the Ministry of Education, the Health & Medical Collaborative Innovation Project of Guangzhou City, China, and the Program of Introducing Talents of Discipline to Universities. [ABSTRACT FROM AUTHOR]