Photoactivated Formation of an Extravascular Dynamic Hydrogel as an Intelligent Blood Flow Regulator to Reprogram the Immunogenic Landscape.

Long-term tumor starvation may be a potential strategy to elevate the antitumor immune response by depriving nutrients. However, combining long-term starvation therapy with immunotherapy often yields limited efficacy due to the blockage of immune cell migration pathways. Herein, an intelligent blood flow regulator (BFR) is first established through photoactivated in situ formation of the extravascular dynamic hydrogel to compress blood vessels, which can induce long-term tumor starvation to elicit metabolic stress in tumor cells without affecting immune cell migration pathways. By leveraging methacrylate-modified nanophotosensitizers (HMMAN) and biodegradable gelatin methacrylate (GelMA), the developed extravascular hydrogel dynamically regulates blood flow via enzymatic degradation. Additionally, aPD-L1 loaded into HMMAN continuously blocks immune checkpoints. Systematic in vivo experiments demonstrate that the combination of immune checkpoint blockade (ICB) and BFR-induced metabolic stress (BIMS) significantly delays the progression of Lewis lung and breast cancers by reshaping the tumor immunogenic landscape and enhancing antitumor immune responses.

Thioredoxin facilitates hepatocellular carcinoma stemness and metastasis by increasing BACH1 stability to activate the AKT/mTOR pathway.

Thioredoxin (TXN) is essential for preserving balance and controlling the intracellular redox state. Most studies have focused on the function of TXN in redox reactions, which is critical for tumor progression. Here, we showed that TXN promotes hepatocellular carcinoma (HCC) stemness properties in a non-redox-dependent manner, which has rarely been reported in previous studies. TXN exhibited upregulated expression in human HCC specimens, which was associated with a poor prognosis. Functional studies showed that TXN promoted HCC stemness properties and facilitated HCC metastasis both in vitro and in vivo. Mechanistically, TXN promoted the stemness of HCC cells by interacting with BTB and CNC homology 1 (BACH1) and stabilized BACH1 expression by inhibiting its ubiquitination. BACH1 was positively correlated with TXN expression and was significantly upregulated in HCC. In addition, BACH1 promotes HCC stemness by activating the AKT/mammalian target of rapamycin (mTOR) pathway. Furthermore, we found that the specific inhibition of TXN in combination with lenvatinib in mice significantly improved the treatment of metastatic HCC. In summary, our data demonstrate that TXN plays a crucial role in HCC stemness and BACH1 plays an integral part in regulating this process by activating the AKT/mTOR pathway. Thus, TXN is a promising target for metastatic HCC therapy.

The climate changes promoted the chloroplast genomic evolution of Dendrobium orchids among multiple photosynthetic pathways.

Dendrobium orchids have multiple photosynthetic pathways, which can be used as a model system for studying the evolution of crassulacean acid metabolism (CAM). In this study, based on the results of the net photosynthetic rates (Pn), we classified Dendrobium species into three photosynthetic pathways, then employed and compared their chloroplast genomes. The Dendrobium chloroplast genomes have typical quartile structures, ranging from 150,841-153,038 bp. The apparent differences in GC content, sequence variability, and IR junctions of SSC/IRB junctions (JSBs) were measured within chloroplast genomes among different photosynthetic pathways. The phylogenetic analysis has revealed multiple independent CAM origins among the selected Dendrobium species. After counting insertions and deletions (InDels), we found that the occurrence rates and distribution densities among different photosynthetic pathways were inconsistent. Moreover, the evolution patterns of chloroplast genes in Dendrobium among three photosynthetic pathways were also diversified. Considering the diversified genome structure variations and the evolution patterns of protein-coding genes among Dendrobium species, we proposed that the evolution of the chloroplast genomes was disproportional among different photosynthetic pathways. Furthermore, climatic correlation revealed that temperature and precipitation have influenced the distribution among different photosynthetic pathways and promoted the foundation of CAM pathway in Dendrobium orchids. Based on our study, we provided not only new insights into the CAM evolution of Dendrobium but also provided beneficial genetic data resources for the further systematical study of Dendrobium.

Mitochondrial genome comparison and phylogenetic analysis of Dendrobium (Orchidaceae) based on whole mitogenomes.

BACKGROUND: Mitochondrial genomes are essential for deciphering the unique evolutionary history of seed plants. However, the rules of their extreme variation in genomic size, multi-chromosomal structure, and foreign sequences remain unresolved in most plant lineages, which further hindered the application of mitogenomes in phylogenetic analyses. RESULTS: Here, we took Dendrobium (Orchidaceae) which shows the great divergence of morphology and difficulty in species taxonomy as the study focus. We first de novo assembled two complete mitogenomes of Dendrobium wilsonii and Dendrobium henanense that were 763,005 bp and 807,551 bp long with multichromosomal structures. To understand the evolution of Dendrobium mitogenomes, we compared them with those of four other orchid species. The results showed great variations of repetitive and chloroplast-derived sequences in Dendrobium mitogenomes. Moreover, the intergenic content of Dendrobium mitogenomes has undergone expansion during evolution. We also newly sequenced mitogenomes of 26 Dendrobium species and reconstructed phylogenetic relationships of Dendrobium based on genomic mitochondrial and plastid data. The results indicated that the existence of chloroplast-derived sequences made the mitochondrial phylogeny display partial characteristics of the plastid phylogeny. Additionally, the mitochondrial phylogeny provided new insights into the phylogenetic relationships of Dendrobium species. CONCLUSIONS: Our study revealed the evolution of Dendrobium mitogenomes and the potential of mitogenomes in deciphering phylogenetic relationships at low taxonomic levels.

Cytocompatibility of Ti3C2Tx MXene with Red Blood Cells and Human Umbilical Vein Endothelial Cells and the Underlying Mechanisms.

Two-dimensional (2D) nanomaterials have been widely used in biomedical applications because of their biocompatibility. Considering the high risk of exposure of the circulatory system to Ti3C2Tx, we studied the cytocompatibility of Ti3C2Tx MXene with red blood cells (RBCs) and human umbilical vein endothelial cells (HUVECs) and showed that Ti3C2Tx had excellent compatibility with the two cell lines. Ti3C2Tx at a concentration as high as 200 µg/mL caused a negligible percent hemolysis of 0.8%. By contrast, at the same treatment concentration, graphene oxide (GO) caused a high percent hemolysis of 50.8%. Scanning electron microscopy revealed that RBC structures remained intact in the Ti3C2Tx treatment group, whereas those in the GO group completely deformed, sunk, and shrunk, which resulted in the release of cell contents. This difference can be largely ascribed to the distinct surficial properties of the two nanosheets. In specific, the fully covered surface-terminating -O and -OH groups leading to Ti3C2Tx had a very hydrophilic surface, thereby hindering its penetration into the highly hydrophobic interior of the cell membrane. However, the strong direct van der Waals attractions coordinated with hydrophobic interactions between the unoxidized regions of GO and the lipid hydrophobic tails can still damage the integrity of the cell membranes. In addition, the sharp and keen-edged corners of GO may also facilitate its relatively strong cell membrane damage effects than Ti3C2Tx. Thus, the excellent cell membrane compatibility of Ti3C2Tx nanosheets and their ultraweak capacity to provoke excessive ROS generation endowed them with much better compatibility with HUVECs than GO nanosheets. These results indicate that Ti3C2Tx has much better cytocompatibility than GO and provide a valuable reference for the future biomedical applications of Ti3C2Tx.

d-Band Center of Rare Earth Oxides Determines Biotransformation-Induced Cell Membrane Damage.

Biotransformation of rare earth oxide (REO) nanoparticles on biological membranes may trigger a series of adverse health effects in biosystems. However, the physicochemical mechanism of the complicated biotransformation behavior remains elusive. By investigating the distinctly different biotransformation behavior of two typical REOs (Gd2O3 and CeO2) on erythrocyte membranes, we demonstrate that dephosphorylation by stripping phosphate from phospholipids correlates highly with the membrane destructive effects of REOs. Density functional theory calculations decode the decisive role of the d-band center in dephosphorylation. Furthermore, using the d-band center as an electronic descriptor, we unravel a universal structure-activity relationship of the membrane-damaging capability of 13 REOs (R2 = 0.82). The effect of ion release on dephosphorylation and physical damage to cell membranes by Gd2O3 are largely excluded. Our findings depict a clear physicochemical microscopic picture of the biotransformation of REOs on the nano-bio interface, providing a theoretical basis for safe application of REOs.

Size-changeable nanoprobes for the combined radiotherapy and photodynamic therapy of tumor.

PURPOSE: Radiation therapy (RT) and photodynamic therapy (PDT) are promising while challenging in treating tumors. The potential radiation resistance of tumor cells and side effects to healthy tissues restrict their clinical treatment efficacy. Effective delivery of therapeutic agents to the deep tumor tissues would be available for tumor-accurate therapy and promising for the tumor therapy. Thus, developing nanoprobes with effectively delivering radiotherapy sensitizers and photosensitizers to the interior of tumors is needed for the accurate combined RT and PDT of tumor. METHODS: The size-changeable nanoprobes of Gd2O3@BSA-BSA-Ce6 (BGBC) were synthesized with a crosslinking method. Magnetic resonance imaging (MRI) and in vivo near-infrared (NIR) imaging were measured to evaluate the nanoprobes' tumor accumulation and intratumor penetration effect. The tumor suppression effect of combined RT and PDT with these nanoprobes was also studied for the 4T1 bearing Balb/c mice. RESULTS: The nanoprobes BGBC showed high tumor accumulation and disintegrated into small particles responding to the photo-irradiation-produced reactive oxygen species (ROS), allowing for tumor penetration. Abundant radiotherapy sensitizers and photosensitizers were delivered to the deep tumor tissues, which is available for the accurate therapy of tumor. In addition, the BGBC displayed outstanding MRI and fluorescence imaging effects for evaluating the biodistribution and tumor suppression effect of nanoprobes. Consequently, significant tumor suppression effect was obtained based on the accurate tumor treatment with the combined RT and PDT. CONCLUSION: The designed size-changeable nanoprobes BGBC showed excellent tumor accumulation and deep tumor penetration, resulting in a significant tumor suppression effect based on the combined RT and PDT. This study provides a novel strategy for dual delivery of radiotherapy sensitizers and photosensitizers into the deep tumor tissues and is promising for the accurate theranostics of tumor.

Drug-related adverse events potentially predict the efficacy of apatinib on advanced hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide every year, and most HCC patients are diagnosed with advanced disease and can only receive systemic treatment. TKIs are the most important components of the systemic treatment of HCC and have both good efficacy and adverse events (AEs).  METHODS: This analysis included 207 patients with locally advanced unresectable or metastatic HCC who received oral treatment with apatinib. We analyzed the overall survival (OS) and progression-free survival (PFS) of patients with or without corresponding AEs to evaluate which AEs can predict the efficacy of apatinib. RESULTS: Patients with hand-foot syndrome (HFS; p = 0.005), proteinuria (p = 0.006) and diarrhea (p < 0.001) had significantly better OS than those without corresponding AEs, and the appearance of HFS (p = 0.006) and proteinuria (p = 0.004) was associated with longer PFS. CONCLUSION: Among all the AEs induced by apatinib in the treatment of advanced HCC, proteinuria could potentially predict PFS, and diarrhea was a potential predictor of OS.

In Vivo Repeatedly Activated Persistent Luminescence Nanoparticles by Radiopharmaceuticals for Long-Lasting Tumor Optical Imaging.

Persistent luminescence nanoparticles (PLNPs) with rechargeable near-infrared afterglow properties attract much attention for tumor diagnosis in living animals since they can avoid tissue autofluorescence and greatly improve the signal-to-background ratio. Using UV, visible light, or X-ray as excitation sources to power up persistent luminescence (PL) faces the challenges such as limited tissue penetration, inefficient charging capability, or tissue damage caused by irradiation. Here, it is proved that radiopharmaceuticals can efficiently excite ZnGa2 O4 :Cr3+ nanoparticles (ZGCs) for both fluorescence and afterglow luminescence via Cerenkov resonance energy transfer as well as ionizing radiation. 18 F-FDG, a clinically approved tumor-imaging radiopharmaceutical with a short decay half-life around 110 min, is successfully used as the internal light source to in vivo excite intravenously injected ZGCs for tumor luminescence imaging over 3 h. The luminescence with similar decay time can be re-obtained for multiple times upon injection of 18 F-FDG at any time needed with no health concern. It is believed this strategy can not only provide tumor luminescence imaging with high sensitivity, high contrast, and long decay time at desired time, but also guarantee the patients much less radiation exposure, greatly benefiting image-guided surgery in the future.

Single-cell profiling reveals altered immune landscape and impaired NK cell function in gastric cancer liver metastasis.

Gastric cancer (GC) is a substantial global health concern, and the development of liver metastasis (LM) in GC represents a critical stage linked to unfavorable patient prognoses. In this study, we employed single-cell RNA sequencing (scRNA-seq) to investigate the immune landscape of GC liver metastasis, revealing several immuno-suppressive components within the tumor immune microenvironment (TIM). Our findings unveiled an increased presence of cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cell (MDSC)-like macrophages, tumor-associated macrophage (TAM)-like macrophages, and naive T cells, while conventional dendritic cells (cDCs) and effector CD8 T cells declined in LM. Additionally, we identified two distinct natural killer (NK) cell clusters exhibiting differential cytotoxicity-related gene expression, with cytotoxic NK cells notably reduced in LM. Strikingly, TGFß was identified as an inducer of NK cell dysfunction, potentially contributing to immune evasion and tumor metastasis. In preclinical LM models, the combined approach of inhibiting TGFß and transferring NK cells exhibited a synergistic impact, resulting in a significant reduction in liver metastasis. This work highlights the importance of understanding the complex immune dynamics within GC liver metastasis and presents a promising strategy combining TGFß inhibition and NK-based immunotherapy to improve patient outcomes.

Vortex signal model based Kalman filter of vortex signal processing method.

To improve the performance of the vortex flowmeter, a vortex signal model based Kalman filter of the vortex signal processing method is proposed. According to the characteristics of the vortex signal, a linear vortex signal model is designed. Combining the fuzzy search and iterative algorithm, the Kalman filter algorithm is improved by analyzing the principle and key parameters of the Kalman filter algorithm. The proposed method is verified by simulation and real flow experiments and compared with other methods; the experimental results show that the proposed method has the advantages of adaptive filtering, better anti-interference ability, and faster filtering speed.

Improving large-scale biomass and total alkaloid production of Dendrobium nobile Lindl. using a temporary immersion bioreactor system and MeJA elicitation.

BACKGROUND: Dendrobium nobile Lindl. is an important pharmacopeial plant with medicinal and ornamental value. This study sought to provide a technical means for the large-scale production of total alkaloid in D. nobile. Seedlings were cultured in vitro using a temporary immersion bioreactor system (TIBS). The four tested immersion frequencies (min/h; 5/2, 5/4, 5/6, and 5/8) influenced the production of biomass and total alkaloid content. In addition, to compare the effects of different concentrations of the phytohormone methyl jasmonate (MeJA) and treatment time on biomass and total alkaloid accumulation, MeJA was added to the TIBS medium after 50 days. Finally, total alkaloid production in semi-solid system (SSS), TIBS, and TIBS combined with the MeJA system (TIBS-MeJA) were compared. RESULTS: The best immersion frequency was found to be 5/6 (5 min every 6 h), which ensured appropriate levels of biomass and total alkaloid content in plantlets. The alkaloid content and production level of seedlings were the highest after treatment with 10 µM MeJA separately for 20 and 30 days using TIBS. The maximum content (7.41 mg/g DW) and production level (361.24 mg/L) of total alkaloid on use of TIBS-MeJA were 2.32- and 4.69-fold, respectively, higher in terms of content, and 2.07- and 10.49-fold, respectively, higher in terms of production level than those on using of TIBS (3.20 mg/g DW, 174.34 mg/L) and SSS (1.58 mg/g DW, 34.44 mg/L). CONCLUSIONS: Our results show TIBS-MeJA is suitable for large-scale production of total alkaloid in in vitro seedlings. Therefore, this study provides a technical means for the large-scale production of total alkaloid in D. nobile.

Microwave Synthesized 2D WO3 Nanosheets for VOCs Gas Sensors.

As an n-type semiconductor material, tungsten oxide (WO3) has good application prospects in the field of gas sensing. Herein, using oxalic acid (OA), citric acid (CA) and tartaric acid (TA) as auxiliary agents, three homogeneous tungsten oxide nanosheets were prepared by the rapid microwave-assisted hydrothermal method. The potential exhaled gases of various diseases were screened for the gas sensitivity test. Compared with WO3-OA and WO3-TA, WO3-CA exhibits significant sensitivity to formaldehyde, acetone and various alkanes. Photoluminescence (PL) chromatography and photoelectric properties show that its excellent gas sensitivity is due to its abundant oxygen vacancies and high surface charge migration rate, which can provide more preferential reaction sites with gas molecules. The experiment is of great significance for the sensor selection of the large disease exhaled gas sensor array.

Upregulation of CRABP2 by TET1-mediated DNA hydroxymethylation attenuates mitochondrial apoptosis and promotes oxaliplatin resistance in gastric cancer.

Oxaliplatin is the main chemotherapy drug for gastric cancer (GC), but quite a few patients are resistant to oxaliplatin, which contributes to the poor prognosis of GC patients. There is therefore an urgent need to identify potential targets for reversing chemotherapy resistance in GC patients. In this study, we analyzed the tumor samples of GC patients who received neoadjuvant chemotherapy based on oxaliplatin through quantitative proteomics and identified the potential chemoresistance-related protein cellular retinoic acid binding protein 2 (CRABP2). CRABP2 was significantly upregulated in the tumor tissues of chemoresistant GC patients and was closely related to prognosis. The results of cell function experiments showed that CRABP2 can promote the oxaliplatin resistance of GC cells in vitro. Coimmunoprecipitation and GST pulldown assays showed that CRAPB2 expedited the binding of BAX and PARKIN in GC cells and facilitated the ubiquitination-mediated degradation of BAX. Furthermore, both the in vitro assay and cell-derived xenograft (CDX) in vivo model verified that CRABP2 promoted oxaliplatin resistance by inhibiting BAX-dependent cell apoptosis. Further experiments proved that the abnormally high expression of CRABP2 in oxaliplatin-resistant GC cells was affected by TET1-mediated DNA hydroxymethylation. The patient-derived xenograft (PDX) model suggested that interference with CRABP2 reversed oxaliplatin resistance in GC in vivo. In conclusion, the results of our study show that CRABP2 was a key molecule in oxaliplatin resistance regulation and could be a new target for reversing the chemoresistance of GC.

Biodegradable Metal-Organic-Framework-Gated Organosilica for Tumor-Microenvironment-Unlocked Glutathione-Depletion-Enhanced Synergistic Therapy.

The clinical employment of cisplatin (cis-diamminedichloroplatinum(II) (CDDP)) is largely constrained due to the non-specific delivery and resultant serious systemic toxicity. Small-sized biocompatible and biodegradable hollow mesoporous organosilica (HMOS) nanoparticles show superior advantages for targeted CDDP delivery but suffer from premature CDDP leakage. Herein, the smart use of a bimetallic Zn2+ /Cu2+ co-doped metal-organic framework (MOF) is made to block the pores of HMOS for preventing potential leakage of CDDP and remarkably increasing the loading capacity of HMOS. Once reaching the acidic tumor microenvironment (TME), the outer MOF can decompose quickly to release CDDP for chemotherapy against cancer. Besides, the concomitant release of dopant Cu2+ can deplete the intracellular glutathione (GSH) for increased toxicity of CDDP as well as catalyzing the decomposition of intratumoral H2 O2 into highly toxic •OH for chemodynamic therapy (CDT). Moreover, the substantially reduced GSH can also protect the yielded •OH from scavenging and thus greatly improve the •OH-based CDT effect. In addition to providing a hybrid HMOS@MOF nanocarrier, this study is also expected to establish a new form of TME-unlocked nanoformula for highly efficient tumor-specific GSH-depletion-enhanced synergistic chemotherapy/chemodynamic therapy.

Adaptive kernel independent component analysis and UV spectrometry applied to characterize the procedure for processing prepared rhubarb roots.

By determination of the number of absorptive chemical components (ACCs) in mixtures using median absolute deviation (MAD) analysis and extraction of spectral profiles of ACCs using kernel independent component analysis (KICA), an adaptive KICA (AKICA) algorithm was proposed. The proposed AKICA algorithm was used to characterize the procedure for processing prepared rhubarb roots by resolution of the measured mixed raw UV spectra of the rhubarb samples that were collected at different steaming intervals. The results show that the spectral features of ACCs in the mixtures can be directly estimated without chemical and physical pre-separation and other prior information. The estimated three independent components (ICs) represent different chemical components in the mixtures, which are mainly polysaccharides (IC1), tannin (IC2), and anthraquinone glycosides (IC3). The variations of the relative concentrations of the ICs can account for the chemical and physical changes during the processing procedure: IC1 increases significantly before the first 5 h, and is nearly invariant after 6 h; IC2 has no significant changes or is slightly decreased during the processing procedure; IC3 decreases significantly before the first 5 h and decreases slightly after 6 h. The changes of IC1 can explain why the colour became black and darkened during the processing procedure, and the changes of IC3 can explain why the processing procedure can reduce the bitter and dry taste of the rhubarb roots. The endpoint of the processing procedure can be determined as 5-6 h, when the increasing or decreasing trends of the estimated ICs are insignificant. The AKICA-UV method provides an alternative approach for the characterization of the processing procedure of rhubarb roots preparation, and provides a novel way for determination of the endpoint of the traditional Chinese medicine (TCM) processing procedure by inspection of the change trends of the ICs.

Boron nitride nanosheets elicit significant hemolytic activity via destruction of red blood cell membranes.

Boron nitride (BN) nanosheets have emerged as promising nanomaterials in a wide range of biomedical applications. Despite extensive studies on these bio-nano interfacial systems, the underlying molecular mechanisms remain elusive. In this study, we used hemolysis assays and morphology observations to demonstrate for the first time that BN nanosheets can cause damages to the red-blood-cell membranes, leading to significant hemolysis. Further molecular dynamics simulations revealed that BN nanosheets can penetrate into the cell membrane and also extract considerable amount of phospholipid molecules directly from the lipid bilayer. The potential of mean force calculations then showed that their penetration effect was thermodynamically favorable due to the strong attractive van der Waals interactions between BN nanosheets and phospholipids. Overall, these findings provided valuable insights into the interaction of BN nanosheets with cell membranes at the atomic level, which can help future de novo design of BN-based nanodevices with better biocompatibility.

Radioiodinated Persistent Luminescence Nanoplatform for Radiation-Induced Photodynamic Therapy and Radiotherapy.

Radionuclide with Cerenkov radiation (CR) can serve as an internal excitation source to activate photosensitizers for photodynamic therapy (PDT) in deep tumor. However, the low efficiency of CR limits its therapeutic efficacy. A 131 I labeled zinc tetra(4-carboxyphenoxy) phthalocyaninate (ZnPcC4) conjugated Cr3+ -doped zinc gallate (ZnGa2 O4 :Cr3+ , ZGCs) nanoplatform (131 I-ZGCs-ZnPcC4) is developed for radiotherapy (RT) and radiation-induced PDT. 131 I can not only activate ZGCs for long-lasting luminescence via both Cerenkov luminescence (CL) and ionizing radiation, which further continuously activate photosensitizer ZnPcC4 for PDT, but also can directly kill cancerous cells. This 131 I-ZGCs-ZnPcC4 exhibits excellent tumor inhibition both in vitro and in vivo. Combining self-activated PDT and RT, it is believed that the 131 I-ZGCs-ZnPcC4 can greatly benefit the deep tumor therapy.

The Neutrophil-to-Lymphocyte Ratio (NLR) Predicts the Prognosis of Unresectable Intermediate and Advanced Hepatocellular Carcinoma Treated with Apatinib.

PURPOSE: Patients with hepatocellular carcinoma (HCC) who might benefit most from anti-angiogenesis therapy remain unknown. In recent years, neutrophil-to-lymphocyte ratio (NLR), an indicator of inflammatory response, has received particular attention in HCC. Herein, we explored the prognostic value of pre-treatment NLR in individuals with unresectable intermediate and advanced hepatocellular carcinoma treated with apatinib, a second-line angiogenesis inhibitor. The findings of this study would assist in precision medicine and provide clinical decision support. PATIENTS AND METHODS: This is a retrospective study in which 171 HCC patients attending Tianjin Medical University Cancer Institute and Hospital and treated with apatinib between January 2016 and July 2018 were enrolled. The prognosis of the patients based on NLR signatures was then analyzed. RESULTS: Patients with a low pre-treatment NLR (NLR < 2.49) presented a significantly longer overall survival (OS) (P < 0.001) and progression-free survival (PFS) (P = 0.043). Furthermore, a low pre-treatment NLR level could be used to predict a longer OS in patients with non-macrovascular invasion (P < 0.001). Independent of serum alpha-fetoprotein (AFP) levels, a low NLR level in this cohort of patients is associated with a longer OS. CONCLUSION: Pre-treatment NLR predicts the prognosis of patients with unresectable intermediate and advanced HCC treated with apatinib.

The chromosome-level reference genome assembly for Dendrobium officinale and its utility of functional genomics research and molecular breeding study.

Dendrobium officinale, an important medicinal plant of the genus Dendrobium in Orchidaceae family, has been used as traditional Chinese medicine (TCM) for nearly thousands of years. Here, we report the first chromosome-level reference genome of D. officinale, based on PacBio long-reads, Illumina short-reads and Hi-C data. The high-quality assembled genome is 1.23 Gb long, with contig N50 of 1.44 Mb. A total of 93.53% genome sequences were assembled into 19 pseudochromosomes with a super scaffold N50 of 63.07 Mb. Through comparative genomic analysis, we explored the expanded gene families of D. officinale, and also their impact on environmental adaptation and biosynthesis of secondary metabolites. We further performed detailed transcriptional analysis of D. officinale, and identified the candidate genes involved in the biosynthesis of three main active ingredients, including polysaccharides, alkaloids and flavonoids. In addition, the MODIFYING WALL LIGNIN-1 (MWL1) gene, which inferred from Genome-Wide Association Studies (GWAS) based on the resequencing date from D. officinale and five related species and their morphologic features, may contribute to the plant production (yield of stems) of D. officinale. Therefore, the high-quality reference genome reported in this study could benefits functional genomics research and molecular breeding of D. officinale.