Camrelizumab plus famitinib in previously chemo-immunotherapy treated patients with advanced NSCLC: results from an open-label multicenter phase 2 basket study.

BACKGROUND: The combination of immune checkpoint inhibitors and antiangiogenic agents has been effective in treating multiple cancers. This was further explored in an open-label, multicenter phase 2 basket study (NCT04346381), which evaluated the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients with advanced solid tumors. We herein report the findings from the cohort of advanced NSCLC patients who progressed after treatment with platinum-doublet chemotherapy and immunotherapy. METHODS: Eligible patients were enrolled and treated with camrelizumab (200 mg once every 3 weeks via intravenous infusion) and oral famitinib (20 mg once daily). The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled in this cohort, with a median follow-up duration of 11.5 months. Three patients (7.5%) achieved a partial response, and 29 patients (72.5%) achieved stable disease. The ORR and DCR with this combination regimen were 7.5% (95% CI, 1.6-20.4) and 80.0% (95% CI, 64.4-90.9), respectively. The median DoR was 12.1 months (95% CI, 10.3-not reached). The median PFS was 5.4 months (95% CI, 4.1-7.5), and the median OS was 12.1 months (95% CI, 9.1-16.7). The estimated 12-month OS rate was 51.5% (95% CI, 34.9-65.9). The most frequent grade 3 or higher treatment-related adverse events occurring in more than 5% of patients included hypertension (27.5%), palmar-plantar erythrodysesthesia syndrome (10%), decreased neutrophil count (10%), and proteinuria (7.5%). CONCLUSION: Camrelizumab plus famitinib demonstrated favorable benefits in PFS and OS, along with manageable safety profiles, in patients with advanced NSCLC who progressed after platinum-doublet chemotherapy and immunotherapy. This finding warrants further exploration.

[Cloning and functional analysis of flavanone synthase â ¡ from Dendrobium huoshanense].

Flavonoid C-glycosides are a class of natural products that are widely involved in plant defense responses and have diverse pharmacological activities. They are also important active ingredients of Dendrobium huoshanense. Flavanone synthase Ⅱ has been proven to be a key enzyme in the synthesis pathway of flavonoid C-glycosides in plants, and their catalytic product 2-hydroxyflavanone is the precursor compound for the synthesis of various reported flavonoid C-glycosides. In this study, based on the reported amino acid sequence of flavanone synthase Ⅱ, a flavanone synthase Ⅱ gene(DhuFNSⅡ) was screened and verified from the constructed D. huoshanense genome localization database. Functional validation of the enzyme showed that it could in vitro catalyze naringenin and pinocembrin to produce apigenin and chrysin, respectively. The open reading frame(ORF) of DhuFNSⅡ was 1 644 bp in length, encoding 547 amino acids. Subcellular localization showed that the protein was localized on the endoplasmic reticulum. RT-qPCR results showed that DhuFNSⅡ had the highest expression in stems, followed by leaves and roots. The expression levels of DhuFNSⅡ and other target genes in various tissues of D. huoshanense were significantly up-regulated after four kinds of abiotic stresses commonly encountered in the growth process, but the extent of up-regulation varied among treatment groups, with drought and cold stress having more significant effects on gene expression levels. Through the identification and functional analysis of DhuFNSⅡ, this study is expected to contribute to the elucidation of the molecular mechanism of the formation of quality metabolites of D. huoshanense, flavonoid C-glycosides, and provide a reference for its quality formation and scientific cultivation.

A strategy combining chemical analysis and network pharmacology to investigate the mechanism of Xiao'er Qingre Zhike Oral solution in cough.

Xiao'er Qingre Zhike Oral Solution (XQZS) is a commonly used TCM formula to treat cough in children in China. Its complicated composition renders its chemical analysis and mechanism elucidation difficult. To evaluate the bioactive components and mechanism of XQZS against cough, we used a combination strategy of chemical analysis and network pharmacology. A UHPLC/Q-Orbitrap-MS method was established for the identification and qualitative analysis of components of XQZS, and a total of 33 components were unambiguously identified. Aiming at identifying the components, network pharmacology revealed 107 potential targets related to cough. Using protein-protein interactions analysis, nine core targets were selected. Several cough-related pathways were enriched using the Kyoto Encyclopedia of Genes and Genomes, including neuroactive ligand-receptor interaction, serotonergic synapse and dopaminergic synapse. The herb-compound-target-pathway network indicated that PTGS2 (COX-2) was the core target of XQZS against cough. To demonstrate the inhibition effects of the major components against the key target, a COX-2 inhibitor screening assay was used. Compounds P2, P4, P23 and P49 exhibited promising inhibition effects on COX-2 at 20 µm, with inhibitory rates of 55.80-69.87%. In conclusion, this study demonstrates that XQZS may alleviate cough via the inhibition of PTGS2 (COX-2) and the regulation of the serotonergic synapse pathway. The chemical analysis and network pharmacology integrated evaluation provided an efficient strategy for discovering the key pharmacological mechanism of XQZS.

[Comparison of planting modes of Dendrobium huoshanense and analysis of advantages of simulated cultivation].

Dendrobium huoshanense is a precious medicinal plant belonging to Dendrobium of Orchidaceae. It is a special medicinal material and extremely scarce in Huoshan county, Anhui province. At present, D. huoshanense has been greatly protected, which also makes it possible to industrialize relying on tissue culture and artificial cultivation technology. Three main planting methods were utilized for cultivating D. huoshanense including facility cultivation, under forest cultivation and simulative habitat cultivation. Firstly, the three cultivation modes and technical characteristics of D. huoshanense were compared and analyzed, and it was found that the ecological environment of D. huoshanense cultivated in the simulated environment was closer to that of wild D. huoshanense. Secondly, based on comparing the characters and quality of three cultivation modes, the results showed that the shape of D. huoshanense cultivated in simulated environment was more similar to that of "grasshopper thigh" recorded in Bencao Jing Jizhu, and its quality was better than that of facilities and under forest cultivation. The comprehensive benefit comparison of three modes showed that the simulated cultivation had high income, the lowest input-output ratio and significant economic benefit. The quality of cultivated D. huoshanense was further evaluated from four aspects of "excellent environment" "excellent shape" "high quality" "excellent effect", which summarized the comprehensive advantages of simulative habitat cultivation of D. huoshanense as follows: the original habitat and site environment of simulated wild D. huoshanense, the closer shape to the wild, the more content of main medicinal components, and higher economic benefit and better efficacy. The quality of D. huoshanense was improved by the use of simulative habitat cultivation, which has practical significance to guide its large-scale cultivation.

Oil body bound oleosin-rhFGF9 fusion protein expressed in safflower (Carthamus tinctorius L.) stimulates hair growth and wound healing in mice.

BACKGROUND: Fibroblast growth factor 9 (FGF9) is a heparin-binding growth factor, secreted by both mesothelial and epithelial cells, which participates in hair follicle regeneration, wound healing, and bone development. A suitable source of recombinant human FGF9 (rhFGF9) is needed for research into potential clinical applications. We present that expression of oleosin-rhFGF9 fusion protein in safflower (Carthamus tinctorius L.) seeds stimulates hair growth and wound healing. RESULTS: The oleosin-rhFGF9 expressed in safflower seeds, in which it localizes to the surface of oil bodies. The expression of oleosin-rhFGF9 was confirmed by polyacrylamide gel electrophoresis and western blotting. According to BCA and Enzyme-linked immunosorbent assay (ELISA) assay, the results show that the expression level of oleosin-rhFGF9 was 0.14% of oil body protein. The oil body bound oleosin-rhFGF9 showed mitogenic activity towards NIH3T3 cells in a methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. The efficacy of oil body bound oleosin-rhFGF9 in promoting hair growth and wound healing was investigated in C57BL/6 mice. In a hair regeneration experiment, 50 µg/µl oil body bound oleosin-rhFGF9 was applied to the dorsal skin of mice in the resting phase of the hair growth cycle. After 15 days, thicker hair and increased number of new hairs were seen compared with controls. Furthermore, the number of new hairs was greater compared with rhFGF9-treated mice. The hair follicles of mice treated with oil body bound oleosin-rhFGF9 expressed ß-catenin more abundantly. In a wound healing experiment, dorsal skin wounds were topically treated with 50 µg/µl oil body bound oleosin-rhFGF9. Wound healing was quicker compared with mice treated with rhFGF9 and controls, especially in the earlier stages of healing. CONCLUSIONS: The oil body bound oleosin-rhFGF9 promotes both hair growth and wound healing. It appears to promote hair growth, at least in part, by up-regulating ß-catenin expression. The potential of oil body bound oleosin-rhFGF9 as an external drug can treat the alopecia and wounds or use in further clinical application.

Expression of bioactive recombinant human fibroblast growth factor 10 in Carthamus tinctorius L. seeds.

Fibroblast growth factor 10 (FGF10) is a member of the FGF superfamily. It exhibits diverse biological functions, and is extensively used for fundamental research and clinical applications involving hair growth, tissue repair, and burn wounds. Oil bodies, obtained from oil seeds, have been exploited for a variety of biotechnology applications. The use of oil bodies reduces purification steps and costs associated with the production of heterogonous proteins. Here, recombinant human FGF10 (rhFGF10) was expressed in safflower (Carthamus tinctorius L.) seeds using oilbody-oleosin technology. A plant expression vector, pOTBar-oleosin-rhFGF10, was constructed and introduced into safflower using Agrobacterium tumefaciens transformation, and mature safflower plants were obtained by grafting. Oleosin-rhFGF10 was successfully transformed and expressed in safflower seeds and inherited to the T3 generation. Moreover, MTT assays demonstrated that oil bodies expressed oleosin-FGF10 had a dose-dependent effect on cellular proliferation. In conclusion, this may provide a method of producing oleosin-rhFGF10, and help us meet the increasing pharmacological demands for the protein.

Expression of bioactive recombinant human fibroblast growth factor 9 in oil bodies of Arabidopsis thaliana.

Fibroblast growth factor 9 (FGF9) has autocrine and paracrine functions in chondrogenesis osteogenesis, hair growth, and gonadal differentiation. We have expressed recombinant human FGF9 (rhFGF9) in the oil bodies of Arabidopsis thaliana via the floral dip method. The expression vector pOTB-rhFGF9 contained an oleosin-rhFGF9 fusion gene and a glufosinate resistance gene for selection. This plasmid was transformed into A. thaliana and expression of the fusion protein oleosin-rhFGF9 confirmed by SDS-PAGE and Western blotting. Furthermore, MTT assays demonstrated that the oil bodies expressed oleosin-rhFGF9 from the transgenic A. thaliana had a remarkable proliferation effect on NIH/3T3 cells.

Implications of Bit1 and AIF overexpressions in esophageal squamous cell carcinoma.

Overwhelming evidence has demonstrated that Bit1 and AIF as mitochondrial proteins are implicated in the development and progression of a variety of tumors. However, their expressions and biological functions in esophageal squamous cell carcinoma (ESCC) remain to be delineated. In the present study, we found that Bit1, AIF, and Bcl-2 levels in ESCC tissues were significantly higher than those in normal esophageal epithelial tissues and dysplasia tissues (P < 0.05). Stepwise investigation demonstrated that Bit1 and Bcl-2 levels were both tightly associated with lymphatic metastasis and TNM staging (P < 0.05), and the levels of Bit1 mRNA as well as AIF and Bcl-2 proteins were both closely related to tumor differentiation (P < 0.05), but not related to the patients' age and gender (P > 0.05). Importantly, Bit1 mRNA and protein levels in ESCC with lymphatic metastasis and TNM staging in III and IV were markedly higher than that without lymphatic metastasis and TMN staging in I and II. Further analysis showed that expression of Bit1 protein was both positively correlated with expressions of AIF and Bcl-2 proteins (r = 0.408 and 0.405, respectively; P < 0.05). Correctively, our data cited earlier suggest that Bit1 plays pivotal roles in the development and progression of ESCC, and its biological functions in ESCC may be closely associated with AIF and Bcl-2 levels.

Targeted immunotherapy to cancer stem cells: A novel strategy of anticancer immunotherapy.

Cancer is a major disease that endangers human health. Cancer drug resistance and relapse are the two main causes contributing to cancer treatment failure. Cancer stem cells (CSCs) are a small fraction of tumor cells that are responsible for tumorigenesis, metastasis, relapse, and resistance to conventional anticancer therapies. Therefore, CSCs are considered to be the root of cancer recurrence, metastasis, and drug resistance. Novel anticancer strategies need to face this new challenge and explore their efficacy against CSCs. Recently, immunotherapy has made rapid advances in cancer treatment, and its potential against CSCs is also an interesting area of research. Meanwhile, immunotherapy strategies are novel therapeutic modalities with promising results in targeting CSCs. In this review, we summarize the targeting of CSCs by various immunotherapy strategies such as monoclonal antibodies(mAb), tumor vaccines, immune checkpoint inhibitors, and chimeric antigen receptor-T cells(CAR-T) in pre-clinical and clinical studies. This review provides new insights into the application of these immunotherapeutic approaches to potential anti-tumor therapies in the future.

Chloroplast genome of Justicia procumbens: genomic features, comparative analysis, and phylogenetic relationships among Justicieae species.

Justicia procumbens L. is a traditional medicinal plant that is widely distributed in China. However, little is known about the genetic diversity and evolution of this genus, and no genomic studies have been carried out on J. procumbens previously. In this study, we aimed to assemble and annotate the first complete chloroplast genome (cpDNA) of J. procumbens and compare it with all previously published cpDNAs within the tribe Justicieae. Genome structure and comparative and phylogenetic analyses were performed. The 150,454 bp-long J. procumbens cpDNA has a circular and quadripartite structure consisting of a large single copy, a small single copy, and two inverted repeat regions. It contains 133 genes, of which 88 are protein-coding genes, 37 are tRNA genes, and eight are rRNA genes. Twenty-four simple sequence repeats (SSRs) and 81 repeat sequences were identified. Comparative analyses with other Justicieae species revealed that the non-coding regions of J. procumbens cpDNA showed greater variation than did the coding regions. Moreover, phylogenetic analysis based on 14 cpDNA sequences from Justicieae species showed that J. procumbens and J. flava were most closely related. This study provides valuable genetic information to support further research on the genetic diversity and evolutionary development of the tribe Justicieae.

Chromosome-level genome assembly of Cnidium monnieri, a highly demanded traditional Chinese medicine.

Cnidium monnieri, a medicinal herb of the Cnidium genus and the Apiaceae family, is among the most important traditional Chinese medicines and is widely distributed in China. However, to date, no C. monnieri-related genomic information has been described. In this study, we assembled the C. monnieri genome of approximately 1210.23 Mb with a contig N50 of 83.14 Mb. Using PacBio HiFi and Hi-C sequencing data, we successfully anchored 93.86% of the assembled sequences to 10 pseudochromosomes (2n = 20). We predicted a total of 37,460 protein-coding genes, with 97.02% of them being functionally annotated in Non-Redundant, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and other databases. In addition, we identified 2,778 tRNAs, 4,180 rRNAs, 258 miRNAs, and 1,700 snRNAs in the genome. This is the first reported C. monnieri genome. Hopefully, the availability of this chromosome-level reference genome provides a significant basis for upcoming natural product-related biosynthetic pathway assessment in C. monnieri.

Mutability landscape guided engineering of a promiscuous microbial glycosyltransferase for regioselective synthesis of salidroside and icariside D2.

Microbial glycosyltransferases efficiently synthesize glucosides and have garnered increasing interest. However, limited regioselectivity has impeded their broad application, particularly in the pharmaceutical industry. In this study, the UDP-glycosyltransferase YjiC from Bacillus licheniformis (BlYjiC) was engineered to achieve the bidirectional regioselective glycosylation of tyrosol and its derivatives. Initially, site-directed saturation mutagenesis was performed on two newly identified substrate-binding cavities in the acceptor pocket of BlYjiC to provide a comprehensive blueprint of the interplay between mutations and function (mutability landscape). Iterative saturation mutagenesis was performed, guided by the mutability landscape. Two highly regioselective mutants M6 (M112L/I325Y/L70R/Q136E/I67E/M77R) and M2' (M112D/I62L) were generated, exhibiting >99 % regioselectivity toward the alcoholic and phenolic hydroxyl of tyrosol, respectively, compared with the wild-type (product mixture: 51:49 %). Both mutants exhibited excellent regioselectivity toward several dihydroxy phenolic substrates, offering valuable biocatalysts for the regioselective synthesis of glucosides. Their application was confirmed in a short synthesis of salidroside (3.6 g/L) and icariside D2 (2.4 g/L), which exhibited near-perfect regioselectivity. This study provides valuable insights into future protein engineering of similar enzymes and opens new avenues for their practical applications.

A chromosome-scale genome of Peucedanum praeruptorum provide insights into Apioideae evolution and medicinal ingredient biosynthesis.

Peucedanum praeruptorum Dunn, a traditional Chinese medicine rich in coumarin, belongs to the Apiaceae family. A high-quality assembled genome of P. praeruptorum is lacking, which has posed obstacles to functional identification and molecular evolution studies of genes associated with coumarin production. Here, a chromosome-scale reference genome of P. praeruptorum, an important medicinal and aromatic plant, was first sequenced and assembled using Oxford Nanopore Technologies and Hi-C sequencing. The final assembled genome size was 1.83 Gb, with a contig N50 of 11.12 Mb. The entire BUSCO evaluation and second-generation read comparability rates were 96.0 % and 99.31 %, respectively. Furthermore, 99.91 % of the genome was anchored to 11 pseudochromosomes. The comparative genomic study revealed the presence of 18,593 orthogroups, which included 476 species-specific orthogroups and 1211 expanded gene families. Two whole-genome duplication (WGD) events and one whole-genome triplication (WGT) event occurred in P. praeruptorum. In addition to the γ-WGT shared by core eudicots or most eudicots, the first WGD was shared by Apiales, while the most recent WGD was unique to Apiaceae. Our study demonstrated that WGD events that occurred in Apioideae highlighted the important role of tandem duplication in the biosynthesis of coumarins and terpenes in P. praeruptorum. Additionally, the expansion of the cytochrome P450 monooxygenase, O-methyltransferase, ATP-binding cassette (ABC) transporter, and terpene synthase families may be associated with the abundance of coumarins and terpenoids. Moreover, we identified >170 UDP-glucosyltransferase members that may be involved in the glycosylation post-modification of coumarins. Significant gene expansion was observed in the ABCG, ABCB, and ABCC subgroups of the ABC transporter family, potentially facilitating the transmembrane transport of coumarins after bolting. The P. praeruptorum genome provides valuable insights into the machinery of coumarin biosynthesis and enhances our understanding of Apiaceae evolution.

First-line treatment with camrelizumab plus famitinib in advanced or metastatic NSCLC patients with PD-L1 TPS ≥1%: results from a multicenter, open-label, phase 2 trial.

BACKGROUND: The combination of immune-checkpoint inhibitors and antiangiogenic agents can synergistically modulate the tumor microenvironment and represents a promising treatment option. Here, we evaluated the efficacy and safety of camrelizumab plus famitinib (a receptor tyrosine kinase inhibitor) as a first-line treatment for advanced or metastatic NSCLC patients with a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥1%, in an open-label, multicenter, phase 2 basket trial. METHODS: Eligible patients received camrelizumab (200 mg once every 3 weeks via intravenous infusion) plus oral famitinib at an initial dose of 20 mg once daily. The primary endpoint was the objective response rate (ORR), as assessed by the investigator per Response Evaluation Criteria in Solid Tumors V.1.1. Key secondary endpoints included disease control rate (DCR), duration of respons, progression-free survival (PFS), overall survival (OS), 12-month OS rate, and safety profile. RESULTS: Of the enrolled 41 patients, 21 (51.2%) had a PD-L1 TPS of 1-49%. As of the cut-off date on June 22, 2022, the combination regimen of camrelizumab and famitinib achieved an ORR of 53.7% (95% CI 37.4% to 69.3%) and a DCR of 92.7% (95% CI 80.1% to 98.5%). The median PFS was 16.6 months (95% CI 8.3 to not reached), and OS data were not yet mature, with an estimated 12-month OS rate of 76.8% (95% CI 60.0% to 87.3%). The most common treatment-related adverse events of grade 3 or higher included hypertension (22.0%), increased alanine aminotransferase (12.2%), decreased neutrophil count (9.8%), proteinuria (7.3%), decrease platelet count (7.3%), and hypokalemia (7.3%). One (2.4%) patient died from grade 5 hemoptysis, which was considered possibly related to the study treatment by the investigator. CONCLUSION: Camrelizumab plus famitinib demonstrated promising antitumor activity in advanced or metastatic NSCLC patients and had an acceptable safety profile. These findings suggest that this combination regimen could be an alternative therapeutic option and warrant further investigation. TRIAL REGISTRATION NUMBER: NCT04346381.

Genome sequencing-based transcriptomic analysis reveals novel genes in Peucedanum praeruptorum.

BACKGROUND: Peucedanum praeruptorum Dunn, a traditional Chinese herbal medicine, contains coumarin and volatile oil components that have clinical application value. However, early bolting often occurs in the medicinal materials of Apiaceae plants. The rhizomes of the medicinal parts are gradually lignified after bolting, resulting in a sharp decrease in the content of coumarins. At present, the link between coumarin biosynthesis and early bolting in P. praeruptorum has not been elucidated. RESULTS: Combining the genome sequencing and the previous transcriptome sequencing results, we reanalyzed the differential transcripts of P. praeruptorum before and after bolting. A total of 62,088 new transcripts were identified, of which 31,500 were unknown transcripts. Functional classification and annotation showed that many genes were involved in the regulation of transcription, defense response, and carbohydrate metabolic processes. The main domains are the pentatricopeptide repeat, protein kinase, RNA recognition motif, leucine-rich repeat, and ankyrin repeat domains, indicating their pivotal roles in protein modification and signal transduction. Gene structure analysis showed that skipped exon (SE) was the most dominant alternative splicing, followed by the alternative 3' splice site (A3SS) and the alternative 5' splice site (A5SS). Functional enrichment of differentially expressed genes showed that these differentially expressed genes mainly include transmembrane transporters, channel proteins, DNA-binding proteins, polysaccharide-binding proteins, etc. In addition, genes involved in peroxisome, hexose phosphate pathway, phosphatidylinositol signaling system, and inositol phosphate metabolism pathway were greatly enriched. A protein-protein interaction network analysis discoverd 1,457 pairs of proteins that interact with each other. The expression levels of six UbiA genes, three UGT genes, and four OMT genes were higher during the bolting stage. This observation suggests their potential involvement in the catalytic processes of prenylation, glycosylation, and methylation of coumarins, respectively. A total of 100 peroxidase (PRX) genes were identified being involved in lignin polymerization, but only nine PRX genes were highly expressed at the bolting stage. It is worth noting that 73 autophagy-related genes (ATGs) were first identified from the KEGG pathway-enriched genes. Some ATGs, such as BHQH00009837, BHQH00013830, and novel8944, had higher expression levels after bolting. CONCLUSIONS: Comparative transcriptome analysis and large-scale genome screening provide guidance and new opinions for the identification of bolting-related genes in P. praeruptorum.

The α1 adrenoceptor antagonist prazosin potentiates morphine induced conditioned place preference in rats.

The norepinephrine (NE) system is involved in pathways that regulate morphine addiction. Here, we investigated the role of α1 adrenoceptor in the ventrolateral orbital cortex (VLO) of rats with repeated morphine treatment and underlying molecular mechanisms. The rewarding properties of morphine were assessed by the conditioned place preference (CPP) paradigm. Prazosin, an α1 adrenoceptor antagonist, was microinjected into the VLO. The expression of α1 adrenoceptor, p-CaMKII/CaMKII, CRTC1, BDNF and PSD95 in the VLO were determined by immunohistochemistry or western blotting. Neurotransmitter NE in the VLO and inflammatory factors in serum were detected separately through high-performance liquid chromatography and enzyme-linked immunosorbent assay. Our experimental results showed that repeated morphine administration induced stable CPP and prazosin promoted the morphine-induced CPP. Microinjection of prazosin in the VLO not only blocked the activity of α1 adrenoceptor, decreased CaMKII phosphorylation and CRTC1, which eventually resulted in a regression of synaptic plasticity-related proteins, but also was accompanied by significantly decreasing of NE in the VLO and increasing of inflammatory cytokines in peripheral blood. These findings suggested that prazosin potentiates the addictive effects of morphine. The effect of increased CPP through reducing α1 adrenoceptor and NE was associated with the CaMKII-CRTC1 pathway and synaptic plasticity-related proteins in the VLO and inflammatory cytokines in the peripheral blood. The NE system may therefore be an underlying therapeutic target in morphine addiction. Additionally, we believe that the clinical use of prazosin in hypertensive patients with morphine abuse may be a potential risk because of its reinforcing effect on addiction.

Central nervous system efficacy of rezivertinib (BPI-7711) in advanced NSCLC patients with EGFR T790M mutation: A pooled analysis of two clinical studies.

BACKGROUND: Rezivertinib (BPI-7711) is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) which revealed the systematic and central nervous system (CNS) antitumor activities for EGFR T790M-mutated advanced NSCLC in previous clinical studies and is further analyzed here. METHODS: Eligible patients from the previous phase I and phase IIb studies of rezivertinib were included for pooled analysis. Post-progressive patients who received a prescribed dosage (≥180 mg) of rezivertinib orally once daily were included in full analysis set (FAS), while those with stable, asymptomatic CNS lesions, including measurable and non-measurable ones at baseline were included in CNS full analysis set (cFAS). Patients with measurable CNS lesions were included in CNS evaluable for response set (cEFR). BICR-assessed CNS objective response rate (CNS-ORR), CNS disease control rate (CNS-DCR), CNS duration of response (CNS-DoR), CNS progression-free survival (CNS-PFS), and CNS depth of response (CNS-DepOR) were evaluated. RESULTS: 355 patients were included in FAS, among whom 150 and 45 patients were included in cFAS and cEFR. This pooled analysis showed the CNS-ORR was 32.0% (48/150; 95% CI: 24.6-40.1%) and the CNS-DCR was 42.0% (63/150; 95% CI: 34.0-50.3%) in cFAS, while that in cEFR were 68.9% (31/45; 95% CI: 53.4-81.8%) and 100% (45/45; 95% CI: 92.1-100.0%). In cEFR, the median CNS-DepOR and the mean of CNS-DepOR were -52.0% (range: -100.0 to 16.1%) and -46.8% (95% CI: -55.5 to -38.1%). In cFAS, the median CNS-DoR and CNS-PFS were 13.8 (95% CI: 9.6-not calculable [NC]) and 16.5 (95% CI: 13.7-NC) months. CONCLUSIONS: Rezivertinib demonstrated encouraging clinical CNS efficacy among advanced NSCLC patients with EGFR T790M mutation and CNS metastases.

Characteristics and phylogenetic analysis of the complete chloroplast genome of Rubus quinquefoliolatus T.T.Yu & L.T.Lu (family Rosaceae).

Rubus quinquefoliolatus T.T.Yu & L.T.Lu is a climbing shrub belonging to the Rosaceae family. It is widely distributed in the provinces of Yunnan and Guizhou in China. In this study, we sequenced the first complete chloroplast genome (cpDNA) sequence of R. quinquefoliolatus. The results showed a genome length of 156,489 bp, which is composed of a large single-copy (LSC) of 86,103 bp, small single-copy (SSC) of 18,844 bp, and two inverted repeats of 25,771 bp each. The whole chloroplast genome encodes 131 genes, including 86 coding sequences, 37 tRNAs, and eight rRNAs. Phylogenetic analysis revealed that R. quinquefoliolatus is closely related to R. lineatus and R. pentagonus.

De Novo Transcriptome Analysis Reveals Putative Genes Involved in Anthraquinone Biosynthesis in Rubia yunnanensis.

Rubia yunnanensis Diels (R. yunnanensis), a Chinese perennial plant, is well-known for its medicinal values such as rheumatism, contusion, and anemia. It is rich in bioactive anthraquinones, but the biosynthetic pathways of anthraquinones in R. yunnanensis remain unknown. To investigate genes involved in anthraquinone biosynthesis in R. yunnanensis, we generated a de novo transcriptome of R. yunnanensis using the Illumina HiSeq 2500 sequencing platform. A total of 636,198 transcripts were obtained, in which 140,078 transcripts were successfully annotated. A differential gene expression analysis identified 15 putative genes involved in anthraquinone biosynthesis. Additionally, the hairy roots of R. yunnanensis were treated with 200 µM Methyl Jasmonate (MeJA). The contents of six bioactive anthraquinones and gene expression levels of 15 putative genes were measured using ultra performance liquid chromatography coupled with mass spectrometry (UPLC-MS/MS) and real-time quantitative polymerase chain reaction (RT-qPCR), respectively. The results showed that the expressions levels for 11 of the 15 genes and the contents of two of six anthraquinones significantly increased by MeJA treatment. Pearson's correlation analyses indicated that the expressions of 4 of the 15 putative genes were positively correlated with the contents of rubiquinone (Q3) and rubiquinone-3-O-ß-d-xylopranosyl-(1→6)-ß-d-glucopyranoside (Q20). This study reported the first de novo transcriptome of R. yunnanensis and shed light on the anthraquinone biosynthesis and genetic information for R. yunnanensis.

The complete chloroplast genome sequence of Exochorda racemosa (Lindl.) Rehd.

Exochorda racemosa (Lindl.) Rehd. is a traditional medicinal herb widely distributed in China. Here, we reported the complete chloroplast genome sequence of E. racemosa. The chloroplast genome (160,398 bp) was composed of four regions, with a large single-copy (LSC, 88,458 bp) region, a small single-copy (SSC, 19,190 bp) region, and two inverted repeat (IR, 26,375 bp) regions. The overall GC content was 36.48%. A total of 131 genes were predicted with 86 protein-coding genes, 37 tRNA genes, and eight rRNA genes. The phylogenetic analysis showed that E. racemosa had a close relationship with E. serratifolia.