A novel preoperative inflammation score system established for postoperative prognosis predicting of intrahepatic cholangiocarcinoma.

BACKGROUND: Inflammation is implicated in tumorigenesis and has been reported as an important prognostic factor in cancers. In this study, we aimed to develop and validate a novel inflammation score (IFS) system based on 12 inflammatory markers and explore its impact on intrahepatic cholangiocarcinoma (ICC) survival after hepatectomy. METHODS: Clinical data of 446 ICC patients undergoing surgical treatment were collected from the Primary Liver Cancer Big Data, and then served as a training cohort to establish the IFS. Furthermore, an internal validation cohort including 175 patients was used as internal validation cohort of the IFS. A survival tree analysis was used to divide ICC patients into three groups (low-, median-, and high- IFS-score groups) according to different IFS values. Kaplan-Meier (KM) curves were used to compare the overall survival (OS) and recurrence-free survival (RFS) rates among three different groups. Cox regression analyses were applied to explore the independent risk factors influencing OS and RFS. RESULTS: In the training cohort, 149 patients were in the low-IFS-score group, 187 in the median-IFS-score group, and 110 in the high-IFS-score group. KM curves showed that the high-IFS-score group had worse OS and RFS rates than those of the low- and median-IFS-score groups (P < 0.001) in both the training and validation cohorts. Moreover, multivariable Cox analyses identified high IFS as an independent risk factor for OS and RFS in the training cohort. The area under the curve values for OS prediction of IFS were 0.703 and 0.664 in the training and validation cohorts, respectively, which were higher than those of the American Joint Committee on Cancer (AJCC) 7th edition TNM stage, AJCC 8th edition TNM stage, and the Child-Pugh score. CONCLUSION: Our results revealed the IFS was an independent risk factor for OS and RFS in patients with ICC after hepatectomy and could serve as an effective prognostic prediction system in daily clinical practice.

Photocatalytic Decarboxylative Coupling of Arylacetic Acids with Aromatic Aldehydes.

An efficient protocol was proposed for the preparation of secondary alcohols in good to excellent yields via photoredox-catalyzed decarboxylative couplings between readily available arylacetic acids and a variety of less reactive (hetero)aromatic aldehydes. The formation of carbanion is the key intermediate in this reaction. Various substituted arylacetic acids and aldehydes were all compatible with this transformation under mild reaction conditions. Furthermore, the current protocol was successfully applied to the direct alcoholization of several drug acids.

The combined signatures of hypoxia and cellular landscape provides a prognostic and therapeutic biomarker in hepatitis B virus-related hepatocellular carcinoma.

Prognosis and treatment options of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) are generally based on tumor burden and liver function. Yet, tumor growth and therapeutic resistance of HBV-HCC are strongly influenced by intratumoral hypoxia and cells infiltrating the tumor microenvironment (TME). We, therefore, studied whether linking parameters associated with hypoxia and TME cells could have a better prediction of prognosis and therapeutic responses. Quantification of 109 hypoxia-related genes and 64 TME cells was performed in 452 HBV-HCC tumors. Prognostic hypoxia and TME cells signatures were determined based on Cox regression and meta-analysis for generating the Hypoxia-TME classifier. Thereafter, the prognosis, tumor, and immune characteristics as well as the benefit of therapies in Hypoxia-TME defined subgroups were analyzed. Patients in the Hypoxialow /TMEhigh subgroup showed a better prognosis and therapeutic responses than any other subgroups, which can be well elucidated based on the differences in terms of immune-related molecules, tumor somatic mutations, and cancer cellular signaling pathways. Notably, our analysis furthermore demonstrated the synergistic influence of hypoxia and TME on tumor metabolism and proliferation. Besides, the classifier allowed a further subdivision of patients with early- and late-HCC stages. In addition, the Hypoxia-TME classifier was validated in another independent HBV-HCC cohort (n = 144) and several pan-cancer cohorts. Overall, the Hypoxia-TME classifier showed a pretreatment predictive value for prognosis and therapeutic responses, which might provide new directions for strategizing patients with optimal therapies.

Single-cell N6-methyladenosine regulator patterns guide intercellular communication of tumor microenvironment that contribute to colorectal cancer progression and immunotherapy.

BACKGROUND: N6-methyladenosine (m6A) RNA methylation plays a critical role in key genetic events for various cancers; yet, how m6A functions within the tumor microenvironment (TME) remains to be elucidated. METHODS: A total of 65,362 single cells from single-cell RNA-seq data derived from 33 CRC tumor samples were analyzed by nonnegative matrix factorization (NMF) for 23 m6A RNA methylation regulators. CRC and Immunotherapy cohorts from public repository were used to determine the prognosis and immune response of TME clusters. RESULTS: The fibroblasts, macrophages, T and B cells were respectively grouped into 4 to 5 subclusters and then classified according to various biological processes and different marker genes. Furthermore, it revealed that the m6A RNA methylation regulators might be significantly related to the clinical and biological features of CRC, as well as the pseudotime trajectories of main TME cell types. Bulk-seq analysis suggested that these m6A-mediated TME cell subclusters had significant prognostic value for CRC patients and distinguished immune response for patients who underwent ICB therapy, especially for the CAFs and macrophages. Notably, CellChat analysis revealed that RNA m6A methylation-associated cell subtypes of TME cells manifested diverse and extensive interaction with tumor epithelial cells. Further analysis showed that ligand-receptor pairs, including MIF - (CD74 + CXCR4), MIF - (CD74 + CD44), MDK-NCL and LGALS9 - CD45, etc. mediated the communication between m6A associated subtypes of TME cells and tumor epithelial cells. CONCLUSIONS: Taken together, our study firstly revealed the m6A methylation mediated intercellular communication of the tumor microenvironment in the regulation of tumor growth and antitumor immunomodulatory processes.

Assembly of 5H-dibenzo[a,d]cycloheptenes by a formal [5 + 2] annulation of ortho-aryl alkynyl benzyl alcohols with arenes.

A new synthetic methodology for the synthesis of 5H-dibenzo[a,d]cycloheptenes from ortho-aryl alkynyl benzyl alcohols and arenes via a Tf2O-mediated formal [5 + 2] annulation reaction has been achieved. From this transformation, structurally diverse 5H-dibenzo[a,d]cycloheptenes were achieved in moderate to good yields. This transformation probably involves an intermolecular Friedel-Crafts-type alkylation and a subsequent intramolecular 7-endo-dig cyclization in one pot, highlighting the high efficiency, regioselectivity, and step-economy of this protocol.

Development and validation of glycolysis-related prognostic score for prediction of prognosis and chemosensitivity of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with aggressive biological behaviour. Its rapid proliferation and tumour growth require reprogramming of glucose metabolism or the Warburg effect. However, the association between glycolysis-related genes with clinical features and prognosis of PDAC is still unknown. Here, we used the meta-analysis to correlate the hazard ratios (HR) of 106 glycolysis genes from MSigDB by the cox proportional hazards regression analysis in 6 clinical data sets of PDAC patients to form a training cohort, and a single group of PDAC patients from the TCGA, ICGC, Arrayexpress and GEO databases to form the validation cohort. Then, a glycolysis-related prognosis (GRP) score based on 29 glycolysis prognostic genes was established in 757 PDAC patients from the training composite cohort and validated in 267 ICGC-CA validation cohort (all P < .05). In addition, including PADC, the prognostic value was also confirmed in other 7 out of 30 pan-cancer cohorts. The GRP score was significantly related to specific metabolism pathways, immune genes and immune cells in the patients with PADC (all P < .05). Finally, by combining with immune cells, the GRP score also well-predicted the chemosensitivity of patients with PADC in the TCGA cohort (AUC = 0.709). In conclusion, this study developed a GRP score for patients with PDAC in predicting prognosis and chemosensitivity for PDAC.

Development and validation of a forensic six-dye multiplex assay with 29 STR loci.

This paper describes the development and validation of a novel 31-locus, six-dye STR multiplex system, which is designed to meet the needs of the rapidly growing Chinese forensic database. This new assay combines 20 extended-CODIS core loci (D3S1358, D5S818, TPOX, CSF1PO, TH01, vWA, D7S820, D21S11, D8S1179, D18S51, D16S539, D13S317, FGA, D1S1656, D2S441, D2S1338, D10S1248, D12S391, D19S433, and D22S1045), nine highly polymorphic loci in Chinese Han population (D3S3045, D6S1043, D6S477, D8S1132, D10S1435, D15S659, D19S253, Penta D, and Penta E), and two gender determining markers, amelogenin and Y-Indel, which could amplify DNA from extracts, as well as direct amplification from substrates. To demonstrate the suitability for forensic applications, this system was validated by precision and accuracy evaluation, concordance tests, case sample tests, sensitivity, species specificity, stability, stutter calculation, and DNA mixtures, according to the guidelines described by the Scientific Working Group on DNA Analysis Methods (SWGDAM) and regulations published by the China Ministry of Public Security. The validation results indicate the robustness and reliability of this new system, and it could be a potentially helpful tool for human identification and paternity testing in the Chinese population, as well as facilitating global forensic DNA data sharing.

Cascade Radical Annulation of 2-Alkynylthio(seleno)anisoles with Acetone or Acetonitrile: Synthesis of 3-Acetomethyl- or Cyanomethyl-Substituted Benzothio(seleno)phenes.

An efficient method for the direct preparation of 3-aceto(cyano)methyl-substituted benzothio(seleno)phenes has been achieved through C(sp3)-H bond activation of easily available acetone or acetonitrile and cascade radical cyclization reaction. In this cascade radical cyclization reaction, C(sp2)-C(sp3) and C(sp2)-S bonds, as well as benzenethio(seleno)phene skeletons, can be built along with the cleavage of the C(sp3)-S bond, demonstrating the high step-economics and efficiency of this approach.

An SNP reducing SNORD105 and PPAN expression decreases the risk of hepatocellular carcinoma in a Chinese population.

BACKGROUND: With hepatocellular carcinoma (HCC) becoming a heavy disease burden in China, it is particular to reveal its pathological mechanism. Recent researches have indicated that small nucleolar RNAs (snoRNAs) may be involved in various cancers including HCC. Polymorphisms within snoRNAs may affect its function or expression level, and even its host gene, then produce series of effects related to itself or its host gene. METHODS: The association of the single nucleotide polymorphism (SNP) rs2305789 in SNORD105 with HCC susceptibility was evaluated in two independent case-control sets (712 HCC and 801 controls). The contribution of rs2305789 to HCC risk was investigated using case-control, genotype-phenotype correlation analysis, and functional assays. RESULTS: The SNP rs2305789 was significantly associated with a decreased risk of HCC in both case-control sets (OR = 0.80, 95% CI: 0.69-0.93, p = 0.003). Compared with the AA genotype, the GG genotype was significantly correlated with lower expression of both SNORD105 and PPAN (p < 0.01). Furthermore, the overexpressed SNORD105 up-regulated PPAN expression level (p < 0.05). Finally, the in vivo experiment showed that the overexpressed SNORD105 increased cell viability and motility in both HepG2 and Huh7 cell lines (p < 0.05). CONCLUSIONS: To sum up, our results suggested that rs2305789 decreased the risk of HCC by reducing the expression of both SNORD105 and PPAN, which reduced HCC cell viability and motility.

Evaluation of Small Molecule Combinations against Respiratory Syncytial Virus In Vitro.

Respiratory syncytial virus (RSV) is a major pathogen that causes severe lower respiratory tract infection in infants, the elderly and the immunocompromised worldwide. At present no approved specific drugs or vaccines are available to treat this pathogen. Recently, several promising candidates targeting RSV entry and multiplication steps are under investigation. However, it is possible to lead to drug resistance under the long-term treatment. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we tested in vitro two-drug combinations of fusion inhibitors (GS5806, Ziresovir and BMS433771) and RNA-dependent RNA polymerase complex (RdRp) inhibitors (ALS8176, RSV604, and Cyclopamine). The statistical program MacSynergy II was employed to determine synergism, additivity or antagonism between drugs. From the result, we found that combinations of ALS8176 and Ziresovir or GS5806 exhibit additive effects against RSV in vitro, with interaction volume of 50 µM2% and 31 µM2% at 95% confidence interval, respectively. On the other hand, all combinations between fusion inhibitors showed antagonistic effects against RSV in vitro, with volume of antagonism ranging from -50 µM2 % to -176 µM2 % at 95% confidence interval. Over all, our results suggest the potentially therapeutic combinations in combating RSV in vitro could be considered for further animal and clinical evaluations.

Visible-Light-Driven Reductive Carboarylation of Styrenes with CO2 and Aryl Halides.

The first example of visible-light-driven reductive carboarylation of styrenes with CO2 and aryl halides in a regioselective manner has been achieved. A broad range of aryl iodides and bromides were compatible with this reaction. Moreover, pyridyl halides, alkyl halides, and even aryl chlorides were also viable with this method. These findings may stimulate the exploration of novel visible-light-driven Meerwein arylation-addition reactions with user-friendly aryl halides as the radical sources and the photocatalytic utilization of CO2.

Genetic analysis of type 2 tri-allelic pattern at TPOX locus in the Chinese Han population.

Tri-allelic patterns can occasionally be observed during the profiling of short tandem repeats (STRs) in routine forensic practice. In previous studies, the Type 2 tri-allelic pattern at TPOX has been widely studied in African and Brazilian populations. In this study, we investigated the incidence, rearrangement, and inheritance of the Type 2 tri-allelic pattern at the TPOX locus in a Chinese Han population. The frequency of the Type 2 pattern at TPOX was approximately 0.0189%, and the major extra allele was allele 11 in the Chinese Han population. Two major allelic combinations, 8/11 and 11/12, were observed, which are different from the configuration of that in both African and Brazilian populations. Tight linkage between alleles 11 and 12 was observed in the majority of the Type 2 pattern at TPOX in the Chinese Han population, while the location of the extra copy on chromosome 2 was validated, which shows an identical ancestral origin. The excess allelic combination 8/11 implies a homogeneous origin and tight linkage relationship. However, the rearrangement in the Type 2 pattern with the 8/11 allelic combination remained unknown. Altogether, these results show the configuration of the Type 2 tri-allelic pattern at the TPOX locus in the Chinese Han population, which will assist in the understanding of the Type 2 tri-allelic pattern at the TPOX locus in the global population.

An Eastern Hepatobiliary Surgery Hospital/Portal Vein Tumor Thrombus Scoring System as an Aid to Decision Making on Hepatectomy for Hepatocellular Carcinoma Patients With Portal Vein Tumor Thrombus: A Multicenter Study.

Portal vein tumor thrombus (PVTT) is a significant poor prognostic factor for hepatocellular carcinoma (HCC). Patients with PVTT limited to a first-order branch of the main portal vein (MPV) or above could benefit from negative margin (R0) liver resection (LR). An Eastern Hepatobiliary Surgery Hospital (EHBH)/PVTT scoring system was established to predict the prognosis of HCC patients with PVTT after R0 LR and guide selection of subgroups of patients that could benefit from LR. HCC patients with PVTT limited to a first-order branch of the MPV or above who underwent R0 LR as an initial therapy were included. The EHBH-PVTT score was developed from a retrospective cohort in the training cohort using a Cox regression model and validated in a prospective internal validation cohort and three external validation cohorts. There were 432 patients in the training cohort, 285 in the prospective internal validation cohort, and 286, 189, and 135 in three external validation cohorts, respectively. The score was calculated using total bilirubin, α-fetoprotein (AFP), tumor diameter, and satellite lesions. The EHBH-PVTT score differentiated two groups of patients (≤/>3 points) with distinct long-term prognoses (median overall survival [OS], 17.0 vs. 7.9 months; P < 0.001). Predictive accuracy, as determined by the area under the time-dependent receiver operating characteristic curves (AUCs; 0.680-0.721), was greater than that of the other commonly used staging systems for HCC and PVTT. Conclusion: The EHBH-PVTT scoring system was more accurate in predicting the prognosis of HCC patients with PVTT than other staging systems after LR. It selected appropriate HCC patients with PVTT limited to a first-order branch of the MPV or above for LR. It can be used to supplement the other HCC staging systems.

Development and validation of a novel SiFaSTRTM 23-plex system.

Human identification and paternity testing are usually based on the study of STRs depending on their particular characteristics in the forensic investigation. In this paper, we developed a sensitive genotyping system, SiFaSTR™ 23-plex, which is able to characterize 18 expanded Combined DNA Index System STRs (D3S1358, D5S818, D2S1338, TPOX, CSF1PO, TH01, vWA, D7S820, D21S11, D10S1248, D8S1179, D1S1656, D18S51, D12S391, D19S433, D16S539, D13S317, and FGA), three highly polymorphic STRs among Chinese people (Penta D, Penta E, and D6S1043), one Y-chromosome Indel and amelogenin using a multiplex PCR; the PCR amplified products were analyzed using the Applied Biosystems 3500 Genetic Analyzer. Full genotyping profiles were obtained using only 31.25 pg of control DNA; various case-type specimens, as well as ten-year-old samples were also successfully genotyped. Additionally, in the validation studies, this multiplex was demonstrated to be human-specific and compatible with the interference of multiple PCR inhibitors. The system also enabled the detection of mixtures, and complete profiles could be obtained at the mixed ratios of 1:1, 1:3, and 3:1. The development and validation study here illustrated that the SiFaSTR™ 23-plex system is accurate, powerful, and more sensitive than many other systems. What's more, the population data in our study not only illustrated that this 23-plex typing system was straightforward and efficient but also expanded the Chinese STR database, which could facilitate the appropriate application of the 23 genetic markers in forensic genetics, especially in the Chinese population.

Palladium-Catalyzed C(sp2)-H Olefination of Free Primary and Secondary 2-Phenylethylamines: Access to Tetrahydroisoquinolines.

A rapid construction of THIQs by a Pd(II)-catalyzed C(sp2)-H olefination of free primary and secondary 2-phenylethylamines with high step- and atom-economy was reported. Notably, no substituent was required at the α-position to the amino group of the 2-phenylethylamines. The substrate scope was broad, and the reaction could also be applied to generate THIQs from the biologically active molecules such as the drug molecule baclofen and phenylalanine ester.

Impact of clinically significant portal hypertension on outcomes after partial hepatectomy for hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Whether clinically significant portal hypertension (CSPH) is a contraindication of partial hepatectomy for patients with hepatocellular carcinoma (HCC) remains controversial. The aim was to assess the impact of CSPH on surgical morbidity, mortality and long-term survival of HCC patients who underwent partial hepatectomy. METHODS: A systematic review and meta-analysis was conducted through analyzing the data published before October 2016 on outcomes following partial hepatectomy for HCC patients with CSPH from the Medline, Embase and CENTRAL databases and related literature. RESULTS: A total of 16 studies involving 4029 patients met the inclusion criteria. HCC patients with CSPH had increased incidences of severe postoperative complications (pooled odds ratio [OR]: 1.66; 95% CI: 1.31-2.10), surgical mortality (2.56, 1.77-3.70) and 5-year mortality (1.29, 1.11-1.50) compared with patients without CSPH. Subgroup analysis suggested that CSPH had no impact on peri-operative mortality and long-term survival for European HCC patients whose CSPH was diagnosed by the standard surrogate criteria (1.95, 0.96-3.96; 1.24, 0.98-1.55). CONCLUSIONS: CSPH had a negative impact on short- and long-term prognoses for HCC patients undergoing partial hepatectomy. However, CSPH did not affect the prognoses in a subgroup of European HCC patients whose CSPH was diagnosed by the standard surrogate criteria.

A serological scoring system to predict lymph node metastasis in patients with hepatocellular carcinoma.

BACKGROUND: Lymph node metastasis (LNM)has widely been recognized as a poor prognostic indicator for hepatocellular carcinoma (HCC) patients. Preoperative prediction of LNM is important for clinicians to decide on treatment. This study was designed to develop a simple and convenient system to predict LNM. METHODS: Consecutive HCC patients who were suspected to have LNM were divided into a training, an internal validation and an external validation cohort. The receiver operating characteristic (ROC) analysis was used to determine the threshold value of the preoperative serological variables. A nomogram visualization system model was then established. RESULT: Of the 287 patients, there were 31 patients who had LNM (10.8%), and 21 of 203 patients (10.3%) were in the training cohort and 10 of 84 patients (11.9%) in the internal validation cohort. Sixteen of 176 patients (9.1%) in the external validation cohort had LNM. The serological indices including neutrophil/lymphocyte rate, age, platelet, prothrombin time, and total protein, were included in the nomogram. The areas of the ROC curve were 0.846, 0.679 and 0.738 in predicting LNM in the training cohort, the internal validation cohort and the external validation cohort, respectively. CONCLUSION: The scoring system constructed using the preoperative serological variables predicted LNM in HCC patients.

Postoperative adjuvant sorafenib improves survival outcomes in hepatocellular carcinoma patients with microvascular invasion after R0 liver resection: a propensity score matching analysis.

BACKGROUND: Microvascular invasion (MVI) is a major determinant of survival outcome for hepatocellular carcinoma (HCC). This study aimed to investigate the efficacy of postoperative adjuvant Sorafenib (PA-Sorafenib) in HCC patients with MVI after R0 liver resection (LR). METHODS: The data of patients who underwent R0 LR for HCC with histologically confirmed MVI at the Eastern Hepatobiliary Surgery Hospital were retrospectively analyzed. The survival outcomes for patients who underwent PA-Sorafenib were compared with those who underwent R0 LR alone. Propensity score matching (PSM) analysis was performed. RESULTS: 728 HCC patients had MVI in the resected specimens after R0 resection, with 581 who underwent LR alone and 147 patients who received in additional adjuvant sorafenib. PSM matched 113 patients in each of these two groups. The overall survival (OS) and recurrence free survival (RFS) were significantly better for patients in the PA-sorafenib group (for OS: before PSM, P = 0.003; after PSM, P = 0.007), (for RFS: before PSM, P = 0.029; after PSM, P = 0.001), respectively. Similar results were obtained in patients with BCLC 0-A, BCLC B and Child-Pugh A stages of disease. CONCLUSIONS: PA-Sorafenib was associated with significantly better survival outcomes than LR alone for HCC patients with MVI.

[Application of DNA metabarcoding technology in identification of Chinese patent medicines].

Metabarcoding technology is a research method derived from the combination of traditional DNA barcodes and highthroughput sequencing technologies. It can quickly,easily and efficiently identify and restore biological samples from multiple species.Biological species are currently widely used in environmental biology research. In the market of traditional Chinese medicines,adulteration and quality instability have severely restricted the sustainable development of the related industries. This article introduced the background of the metabarcoding technology and its preliminary application in the identification of Chinese patent medicines. It also outlined the possible problems in the research process and prospected to the development of the DNA metabarcoding technology.

[Collection and sorting of medicinal plants in Chinese Apiaceae( Umbelliferae)].

The family Apiaceae( Umbelliferae) includes some of the world's most important medicinal plants,with more than 100 species recorded in the traditional Chinese medicine,of which more than ten species are commonly used medicinal materials. However,due to morphological similarities,high market demands and regional factors,substitutes and adulterants are often mixed with genuine in the medicinal market. Therefore,a comprehensive sorting for these poorly known plants has been done in this study by combining market survey with literature review,including its species,distribution,price and substitutes. According to the statistics,there are 65 genera and 262 species of medicinal plants of Apiaceae in China,with medicinal part mostly from radix and rhizoma. Sichuan province is the most abundant in distribution and planting resources,with about 137 species,followed by Yunnan,Hubei and Gansu provinces.Furthermore,we summarized the genuine and substitutes of 11 medicinal plants,e. g. Bupleurum,Angelica and Peucedanum etc.,which found that the medicinal plants of Apiaceae were substituted or mixed in different taxonomic ranks. This study would contribute to reduce the risk of medicine misuse,as well as explore other plants of Apiaceae with potential medicinal value,to achieve sustainable development of related industries.