Resection of unresectable hepatocellular carcinoma after conversion therapy with apatinib and camrelizumab: a case report and literature review.

Hepatocellular carcinoma is a rather common malignant tumor. Most patients with hepatocellular carcinoma receive their diagnosis at an advanced stage, at which surgical resection is no longer appropriate. A growing body of research has demonstrated the value of convention therapy for patients with intermediate-stage hepatocellular carcinoma, while specific application protocols and treatment guidelines are not well developed. Emerging clinical researches suggest that a tyrosine kinase inhibitor in combination with an immune checkpoint inhibitor is a reasonable strategy for unresectable hepatocellular carcinoma. However, there are relatively few reports on the efficacy of apatinib and camrelizumab in the treatment of hepatocellular carcinoma. We were able to successfully remove one patient's hepatocellular carcinoma after 8 cycles of conversion therapy with apatinib (250 mg orally every day) and camrelizumab (200 mg intravenously every 2 weeks). The patient continued to receive the same dose of 16 cycles of apatinib and camrelizumab after hepatectomy. By the time of this study, the patient has completed 18 months of follow-up, and no tumor recurrence or metastasis was found in tumor markers and imaging examinations. Apatinib in combination with camrelizumab is an effective therapy for the treatment of advanced hepatocellular carcinoma, and surgical resection after this conversion therapy may provide patients with long-term oncological benefits. However, this requires more samples to validate the conclusion.

Influence of landform, soil properties, soil Cd pollution and rainfall on the spatial variation of Cd in rice: Contribution and pathway models based on big data.

Landform, soil properties, soil cadmium (Cd) pollution and rainfall are the important factors affecting the spatial variation of rice Cd. In this study, we conducted big data mining and model analysis of 150,000 rice-soil sampling sites to examine the effects by the above four factors on the spatial variation of rice Cd in Hunan Province, China. Specifically, the variable coefficient of rice Cd in space was significantly correlated with the partition scale according to the logistic fitting. The improved random forest results suggested that elevation (DEM) and pH were the two most important factors affecting the spatial variation of rice Cd, followed by relief, soil Cd content and rainfall. Typically, variance partitioning analysis (VPA) revealed that both the soil property and the interactive effects between the soil property and Cd pollution were the principal contributors to the rice-Cd variation, with the respective contributing rates of 30.5 % and 29.0 %. Meanwhile, the partial least square-structural equation modelling (PLS-SEM) elucidated 4 main paths of specific indirect effects on rice-Cd variation. They were landform → physicochemical property → soil acidity → rice-Cd variation, landform → soil acidity → rice-Cd variation, physicochemical property → soil acidity → rice-Cd variation, and soil texture → soil acidity → rice-Cd variation. This work can provide a general guidance for scientific zoning, accurate prediction and prevention of Cd pollution in paddy fields.

Targeted delivery of pexidartinib to tumor-associated macrophages via legumain-sensitive dual-coating nanoparticles for cancer immunotherapy.

Tumor-associated macrophage (TAM) is regarded as an appealing cell target for cancer immunotherapy. However, it remains challenging to selectively eliminate M2-like TAM in tumor microenvironment. In this work, we employed a legumain-sensitive dual-coating nanosystem (s-Tpep-NPs) to deliver CSF-1R inhibitor pexidartinib (PLX3397) for targeting TAM therapy. The PLX3397-loaded NPs exhibited uniform size of ∼240 nm in diameter, good drug loading capacity and efficiency, as well as sustained drug release profile. Compared to non-sensitive counterpart ns-Tpep-NPs, s-Tpep-NPs showed distinguished selectivity upon M1 and M2 macrophage uptake with relation to incubation time and dose. Besides, the selectivity of anti-proliferation effect was also identified for s-Tpep-NPs against M1 and M2 macrophage. In vivo imaging demonstrated that s-Tpep-NPs exhibited much higher tumoral accumulation and TAM recognition specificity as compared to non-sensitive ns-Tpep-NPs. In vivo efficacy verified that s-Tpep-NPs formulation was much more effective than ns-Tpep-NPs and other PLX3397 formulations to treat B16F10 melanoma via targeting TAM depletion and modulating tumor immune microenvironment. Overall, this study provides a robust and promising nanomedicine strategy for TAM-targeted cancer immunotherapy.

Chromosome-level genome assembly and resequencing of camphor tree (Cinnamomum camphora) provides insight into phylogeny and diversification of terpenoid and triglyceride biosynthesis of Cinnamomum.

Cinnamomum species attract attentions owing to their scents, medicinal properties, and ambiguous relationship in the phylogenetic tree. Here, we report a high-quality genome assembly of Cinnamomum camphora, based on which two whole-genome duplication (WGD) events were detected in the C. camphora genome: one was shared with Magnoliales, and the other was unique to Lauraceae. Phylogenetic analyses illustrated that Lauraceae species formed a compact sister clade to the eudicots. We then performed whole-genome resequencing on 24 Cinnamomum species native to China, and the results showed that the topology of Cinnamomum species was not entirely consistent with morphological classification. The rise and molecular basis of chemodiversity in Cinnamomum were also fascinating issues. In this study, six chemotypes were classified and six main terpenoids were identified as major contributors of chemodiversity in C. camphora by the principal component analysis. Through in vitro assays and subcellular localization analyses, we identified two key terpene synthase (TPS) genes (CcTPS16 and CcTPS54), the products of which were characterized to catalyze the biosynthesis of two uppermost volatiles (i.e. 1,8-cineole and (iso)nerolidol), respectively, and meditate the generation of two chemotypes by transcriptional regulation and compartmentalization. Additionally, the pathway of medium-chain triglyceride (MCT) biosynthesis in Lauraceae was investigated for the first time. Synteny analysis suggested that the divergent synthesis of MCT and long-chain triglyceride (LCT) in Lauraceae kernels was probably controlled by specific medium-chain fatty acyl-ACP thioesterase (FatB), type-B lysophosphatidic acid acyltransferase (type-B LPAAT), and diacylglycerol acyltransferase 2b (DGAT 2b) isoforms during co-evolution with retentions or deletions in the genome.

Identification and verification of a prognostic ferroptosis-related lncRNAs signature for patients with lung adenocarcinoma.

Lung cancer has been identified as one of the deadliest malignant tumors worldwide. Mounting evidence suggests that ferroptosis is a well-known non-apoptotic cell death process that participates in pathological mechanisms and is a new cancer treatment strategy. Aberrantly expressed long non-coding RNAs (lncRNAs) that drive lung cancer progression have attracted increasing attention. Herein, we explored the prognostic significance of ferroptosis-related lncRNAs in lung cancer patients. LUAD gene expression patterns and clinicopathological data were downloaded from The Cancer Genome Atlas (TCGA) database. Based on LASSO-Cox regression, A 14 ferroptosis-related differentially expressed lncRNAs (FRDELs) signature was constructed. Subsequently, a nomogram model for predicting the prognosis of LUAD patients was constructed based on clinicopathological data and the 14 - FRDELs signature. The signature was shown to be correlated with tumor mutational burden (TMB) and immune cell infiltration within the tumor microenvironment. Furthermore, Gene Set Enrichment Analysis (GSEA) confirmed that the signature was correlated with LUAD-related biological functions such as the P53 signaling pathway, DNA replication, and cell cycle. The roles and mechanisms of PACERR in the signature were explored by si-lncRNA-mediated knockdown and transfection-mediated overexpression via in vitro experiments in A549 and H1299 cells. PACERR was significantly upregulated in A549 and H1299 cells, and higher expression promoted LUAD cell proliferation, migration, and invasion via in vitro experiments, while knockdown of PACERR presented the opposite effects. In conclusion, our study provided information regarding ferroptosis-related lncRNA expression and established a prognostic nomogram based on 14 FRDELs to predict overall survival in LUAD accurately. Additionally, our results in vitro revealed that PACERR played an oncogenic role in LUAD proliferation and metastasis, which provides mechanistic insights into the roles of ferroptosis-related lncRNA in LUAD progression and that it may be a potential biomarker for LUAD treatment.

Influence of soil properties on cadmium accumulation in vegetables: Thresholds, prediction and pathway models based on big data.

Soil properties, such as soil pH, soil organic matter (SOM), cation exchange capacity (CEC), are the most important factors affecting cadmium (Cd) accumulation in vegetables. In this study, we conducted big data mining of 31,342 soil and vegetable samples to examine the influence of soil properties (soil pH, SOM, CEC, Zn and Mn content) on the accumulation of Cd in root, solanaceous, and leafy vegetables in Hunan Province, China. Specifically, the Cd accumulation capability was in the following order: leafy vegetables > root vegetables > solanaceous vegetables. The soil property thresholds for safety production in vegetables were determined by establishing nonlinear models between Cd bioaccumulation factor (BCF) and the individual soil property, and were 6.5 (pH), 30.0 g/kg (SOM), 13.0 cmol/kg (CEC), 100-140 mg/kg (Zn), and 300-400 mg/kg (Mn). When soil property values were higher than the thresholds, Cd accumulation in vegetables tended to be stable. Prediction models showed that pH and soil Zn were the leading factors influencing Cd accumulation in root vegetables, explaining 87% of the variance; pH, SOM, soil Zn and Mn explained 68% of the variance in solanaceous vegetables; pH and SOM were the main contributors in leafy vegetables, explaining 65% of the variance. Further, variance partitioning analysis (VPA) revealed that the interaction effect of the corresponding key soil properties contributed mostly to BCF. Meanwhile, partial least squares (PLS) path modeling was employed to analyze the path and the interactive effects of soil properties on Cd BCF. pH and SOM were found to be the biggest two players affecting BCF in PLS-models, and the most substantial interactive influence paths of soil properties on BCF were different among the three types of vegetables.

The biofunctionalization of titanium nanotube with chitosan/genipin heparin hydrogel and the controlled release of IL-4 for anti-coagulation and anti-thrombus through accelerating endothelialization.

The valve replacement is the main treatment of heart valve disease. However, thrombus formation following valve replacement has always been a major clinical drawback. Accelerating the endothelialization of cardiac valve prosthesis is the main approach to reduce thrombus. In the current study, a titanium nanotube was biofunctionalized with a chitosan/genipin heparin hydrogel and the controlled release of interleukin-4 (IL-4), and its regulation of macrophages was investigated to see if it could influence endothelial cells to eventually accelerate endothelialization. TNT60 (titanium dioxide nanotubes, 60 V) with nanoarray was obtained by anodic oxidation of 60 V, and IL-4 was loaded into the nanotube by vacuum drying. The hydrogel (chitosan : genipin = 4 : 1) was applied to the surface of the nanotubes following drying, and the heparin drops were placed on the hydrogel surface with chitosan as the polycation and heparin as the polyanion. A TNT/IL-4/G (G = gel, chitosan/genipin heparin) delivery system was prepared. Our results demonstrated that the biofunctionalization of titanium nanotube with chitosan/genipin heparin hydrogel and the controlled release of IL-4 had a significant regulatory effect on macrophage M2 polarization, reducing the inflammatory factor release and higher secretion of VEGF (vascular endothelial growth factor), which can accelerate the endothelialization of the implant.

[N2 O Emissions from Tea Plantations with Sorghum Intercropping and Application of Big Urea Pills].

A large amount of fertilizers are applied to the tea plantations resulting in high nitrous oxide (N2O) emissions. The area of Chinese tea plantations has been expanding in recent years, making them an important source of agricultural N2O emissions. There is an urgent need for effective mitigation measures for N2O emissions from tea plantations. In this study, the N2O emission flux and related environmental factors are measured in Chinese mid-subtropical typical hilly tea plantation under three kinds of management measures, namely intercropping sorghum, applying big urea pills, and under conventional fertilization conditions. The aim of this experiment is to determine the main factors controlling N2O emissions from the soils of the tea plantation and confirm the true effectiveness of the proposed N2O emission mitigation measures. The results of a 2-year field experiment show that:① N2O emissions were significantly correlated with soil chemical properties, temperature and rainfall, interaction between soil physical and chemical properties; soil chemical properties have the greatest impact on soil N2O emissions. The concentration of soil NO3--N is the most important factor determining the size of N2O flux in the tea plantation. The most important task of N2O emission mitigation research in the tea plantation is to reduce the concentration of soil NO3--N; ② sorghum intercropping reduces N2O emissions by 51.2% while not affecting the tea yield. From the perspective of mitigating global warming, sorghum intercropping is the best tea plantation management measure per the results of this study; ③ applying big urea pills effectively increases tea yield while simultaneously reducing the N2O emissions by 34.7%. From the perspective of balancing economic benefits as well as mitigating global warming, application of big urea pills is undoubtedly the best tea plantation management measure as indicated by this study.

[Nitrogen and Phosphorus Removal by Integrated Ecological Engineering Treatment System in a Small Agricultural Watershed].

Based on the discharge characteristics of agricultural non-point source pollution in the headstream region of the Kaihui River-a typical small agricultural watershed, an integrated ecological engineering treatment system (IEETS) was constructed with ecological wetland as the core unit to control the pollution. The nitrogen (N) and phosphorus (P) removal performances of the IEETS were discussed in this study. The results showed that the dominant source of N and P in the study area was livestock and poultry breeding, which was urgent to control. The monitoring results indicated that the ecological wetland treatment project resulted in average total nitrogen (TN) and total phosphorus (TP) removal rates of 87.1% and 90.9%, respectively, when treating mixed decentralized domestic and swine wastewater treatment. The multi-stage constructed wetlands had an average of 85.7% of TN and 84.9% of TP removal for mixed farmland drainage and decentralized swine wastewater. The removal rates for landscape-based ecological wetland were within the range of 27.1%-67.4% for TN and 13.3%-81.5% for TP in the catchment terminal water. The total interception amount of TN and TP by the IEETS was 5292 kg·a-1 and 1054 kg·a-1, accounting for 35.3% and 43.6% of total pollution loads in the headstream region, respectively. These findings illustrated that the IEETS presents promising treatment results on non-point source pollution, and is suitable for widespread applications to wastewater treatment in small watersheds of southern China.

[Contribution of Base Flow to Total Nitrogen Loading in Subtropical Agricultural Catchments].

With the fast development of economics and improvement of people's living standard, non-point source pollution of the agricultural catchments in subtropical China has become more and more severe, where water quality deterioration has become a main barrier for sustainable development and ecological restoration. The process of ecohydrology in catchment is greatly influenced by the process of base flow in channel. This study selected the Tuojia and Jianshan catchments located in Changsha County, Hunan Province, to quantify and compare the contribution of base flow to total nitrogen (TN) loading from January 2011 to December 2013, through field observation and model estimation. The results suggested that the Tuojia catchment with higher intensity of rice agriculture had the greater volume of base flow, higher average flow-weighted TN concentration in base flow, and greater monthly TN loading via base flow [15.2 mm · month⁻¹, 4.14 mg · L⁻¹ and 0.54 kg · (hm² · month)⁻¹, respectively] than those in the Jianshan catchment with lower intensity [11.4 mm · month⁻¹, 1.72 mg · L⁻¹ and 0.20 kg · (hm² · month)⁻¹, respectively]. The base flow contribution to TN loading showed an apparently seasonal pattern. During rice-growing seasons, the contributions of base flow to TN loading were 23.2% and 18.6% in the Tuojia and Jianshan catchments, respectively, lower than those in the fallow seasons (46.9% and 40.0% correspondingly. These results suggested that rice agriculture increased the contribution of base flow in the fallow season to TN loading. Therefore, to alleviate the suffering of non-point source pollution in the rice agriculture catchments, reasonable management measure of rice fields should be implemented to decrease contrihution of base flow to TN loading.

Efficacy of early treatment on 52 patients with preneoplastic hepatitis B virus-associated hepatocellular carcinoma by compound Phyllanthus Urinaria L.

OBJECTIVE: To observe the change in the number of antibodies of preneoplastic hepatocellular carcinoma (HCC) using early treatment by Compound Phyllanthus Urinaria L. (CPUL) on patients with preneoplastic hepatitis B virus (HBV)-associated HCC. METHODS: A total of 102 cirrhosis patients with regenerative or dysplastic nodules whose sera were tested positive for at least one of these six proteins (five up-regulated genes URG4, URG7, URG11, URG12 and URG19, and one down-regulated gene DRG2) were assigned randomly to two groups using continual random codes by SPSS software. Fifty-two patients were in the treatment group and 50 patients were in the control group. CPUL was used in the treatment group for 3 years, while the control group did not receive any treatment. The changes in HBV-DNA level, number of antibodies, and hepatocarcinogenesis occurred were observed. Patients who did not develop HCC were followed up for another 2 years. RESULTS: HBV-DNA levels decreased ⩾2log in 22.2% (10/45) of patients in the treatment group in contrast to only 5.0% (2/40) of patients in the control group (P=0.0228). The number of antibodies that were tested positive in the treatment group (1.08±1.01) was significantly lower compared with the control group (2.11±1.12) after 24 months of drug treatment (P<0.01). Both the positive rates of anti-URG11 (33/52) and anti-URG19 (31/52) were over 60% at baseline in the two groups, and were decreased to 48.1% (25/52) and 46.2% (24/52) respectively at 36 months of drug treatment, while the rates increased to 68.0% (34/50) and 66.0% (33/50) respectively (P=0.0417, P=0.0436) in the control group. The positive rate of anti-DRG2 was increased to 55.8% (29/52) at 36 months of drug treatment, while in the control group was decreased to 36.0% (18/50, P=0.0452). Among the 102 patients who developed HCC, 2 were in the treatment group and 9 were in the control group, meaning that a significant difference between the two groups (P=0.0212). In 11 patients who developed HCC, anti-URG11 and anti-URG19 were always positive, while anti-DRG2 was negative. Patients newly developing HCC were 6 (20.0%) in the control group, and only one (2.5%) in the treatment group (P=0.0441) during 2-year follow-up after the end of the treatment. CONCLUSIONS: Anti-URG11, anti-URG19 and anti-DRG2 could be used as early markers in the prediction of the therapeutic efficacy of CPUL in treating preneoplastic HCC. CPUL is useful in preventing or delaying the development of HBV-associated cirrhosis to HCC.

[Change characteristics of soil available nitrogen and phosphorus and heavy metal contents after long-term cultivation of vegetables].

Soil samples were collected from three vegetable fields under different years of cultivation in Changsha suburbs of Hunan Province, South-central China to study the accumulation characteristics, risks, and sources of soil available nitrogen and phosphorus and heavy metals in the fields. With the increasing year of vegetable cultivation, the soil NO3(-)-N, Olsen-P, and heavy metals contents in the fields increased significantly. The average contents of soil NO3(-)-N, Olsen-P, and Cd in the vegetable fields having been cultivated for 1-2 years in Ningxiang County, 10-15 years in Changsha County, and 30 years in Kaifu District were 21.1, 31.9 and 0.33 mg x kg(-1), 42.0, 146.9 and 0.52 mg x kg(-1), and 49.5, 219.9 and 1.40 mg x kg(-1), respectively. The cumulative index (CI) of soil heavy metals generally followed the sequence of Cd >> Cu > Pb > Ni > Zn. Principal component analysis and cluster analysis showed that compared with soil NH4 OAc-extracted potassium, pH, organic matter and NH4(+)-N, that were dominated by natural factors, the soil Olsen-P and NO3(-)-N had the similar accumulation characteristics with the soil heavy metals, being mainly controlled by fertilization. It was considered that the soil environment and health quality of the vegetable fields in Changsha suburbs were not optimistic. The longer the cultivation year of vegetables, the more the soil NO3(-)-N, Olsen-P, and heavy metals accumulated in the fields. The accumulation of these elements in the fields could be primarily due to the long-term fertilization.

[Preneoplastic markers of hepatitis B virus-associated hepatocellular carcinoma and their significance in clinical settings].

OBJECTIVES: To identify serologic markers that may indicate the early presence of hepatocellular carcinoma (HCC), and analyze their significance in the pathogenesis of chronic hepatitis B. METHODS: Hepatitis B x antigen (HBxAg) positive and negative HepG2 cells were subjected to PCR select cDNA subtraction to identify differentially expressed genes that may precede the development of HCC. These included the up-regulated genes URG4, URG7, URG11, and VEGFR3, and the down-regulated gene, Sui1. Specific ELISAs were constructed to measure differentially expressed antigens and their corresponding antibodies to determine whether they had prognostic and/or diagnostic value. The study population consisted of 730 people. Among them, 416 were HBsAg(-) and 298 were HBV carriers with chronic liver disease and/or HCC. In addition, 16 patients had non-viral hepatitis. Among these, serial serum samples from 53 HBsAg(+) patients with cirrhosis were collected and studied. RESULTS: Antibodies to multiple differentially regulated genes were detectable in serum samples from patients with HBV associated cirrhosis and HCC, but not in serum samples from uninfected individuals (P < 0.01). Antibodies were undetectable in serum samples from HBV patients without liver disease and in serum samples from patients with other tumor types, and among those with non viral hepatitis. Among patients at high risk of developing HCC, these antibodies were found to be independent of nationality and ethnicity. Statistical analysis of the 28 HBsAg(+) patients with HCC showed that anti-URG11 and anti-VEGFR3 were the most frequently detected antibodies. These antibodies were found to coexist in 16 (P < 0.05). In contrast, among the 25 HBsAg(+) patients without HCC, anti-Sui1 and anti-URG7 were the most prevalent antibodies. These antibodies coexisted in 11 (P < 0.05). In addition, HCC patients with four or more antibodies detected before the appearance of HCC had a poorer survival outcome. CONCLUSION: These antibodies can be detected in serum samples several months to several years before the appearance of HCC. This suggests that they may be preneoplastic markers that may help to distinguish which HBV carriers with cirrhosis are most likely to progress and develop HCC.