A cost-effectiveness analysis of the combination of serplulimab with chemotherapy for advanced esophageal squamous cell carcinoma: insights from the ASTRUM-007 trial.

BACKGROUND: Combined serplulimab and chemotherapy demonstrated improved clinical survival outcomes in patients with advanced esophageal squamous cell carcinoma (ESCC) and PD-L1 combined positive scores (CPS) ≥ 1. The present study aimed to evaluate the economic viability of integrating serplulimab in combination with chemotherapy as a potential therapeutic approach for treating ESCC in China. METHODS: A Markov model was constructed to evaluate the economic and health-related implications of combining serplulimab with chemotherapy. With the incremental cost-effectiveness ratio (ICER), costs and results in terms of health were estimated. For assessing parameter uncertainty, one-way and probabilistic sensitivity studies were carried out. RESULTS: The combination of serplulimab and chemotherapy yielded incremental costs and QALYs of $3,163 and 0.14, $2,418 and 0.10, and $3,849 and 0.15, respectively, for the overall population as well as patients with PD-L1 CPS1-10 and PD-L1 CPS ≥ 10. This corresponds to ICER values per QALY of $23,657, $23,982, and $25,134. At the prespecified WTP limit, the probabilities of serplulimab with chemotherapy being the preferred intervention option were 74.4%, 61.3%, and 78.1% for the entire patient population, those with PD-L1 1 ≤ CPS < 10, and those with PD-L1 CPS ≥ 10, respectively. The stability of the presented model was confirmed through sensitivity studies. CONCLUSIONS: In conclusion, the combination of Serplulimab and chemotherapy showed excellent cost-effectiveness compared to chemotherapy alone in treating PD-L1-positive patients with ESCC in China.

miR-128-3p is involved in aluminum-induced cognitive impairment by regulating the Sirt1-Keap1/Nrf2 pathway.

Aluminum (Al) is a common neurotoxicant in the environment, but the molecular mechanism of its toxic effects is still unclear. Studies have shown that aluminum exposure causes an increase in neuronal apoptosis. The aim of this study was to investigate the mechanism and signaling pathway of neuronal apoptosis induced by aluminum exposure. The rat model was established by intraperitoneal injection of maltol aluminum for 90 days. The results showed that the escape latency of the three groups exposed to maltol aluminum was higher than that of the control group on the 3rd, 4th and 5th days of the positioning cruise experiment (P < 0.05). On the 6th day of the space exploration experiment, compared with the control group(6.00 ± 0.71,15.33 ± 1.08) and the low-dose group(5.08 ± 1.69,13.67 ± 1.09), the number of times that the high-dose group crossed the platform(2.25 ± 0.76) and the platform quadrant(7.58 ± 1.43) was significantly reduced (P < 0.01). The relative expression levels of Sirt1 and Nrf2 in hippocampal tissues of all groups decreased gradually with increasing maltol aluminum exposure dose the relative expression levels of Sirt1 and Nrf2 in high-dose group (0.261 ± 0.094,0.325 ± 0.108) were significantly lower than those in control group (1.018 ± 0.222,1.009 ± 0.156)(P < 0.05). The relative expression level of Keap1 increased gradually with increasing maltol aluminum exposure dose (P < 0.05). The relative expression level of miR-128-3p in the high-dose group(1.520 ± 0.280) was significantly higher than that in the control group(1.000 ± 0.420) (P < 0.05). The content of GSH-Px in the hippocampus of rats decreased with increasing dose. ROS levels gradually increased. We speculated that subchronic aluminum exposure may lead to the activation of miR-128-3p in rat hippocampus of rats, thereby inhibiting the Sirt1-Keap1/Nrf2 pathway so that the Sirt1-Keap1/Nrf2 pathway could not be activated to exert antioxidant capacity, resulting in an imbalance in the antioxidant system of rats and the apoptosis of neurons, which caused reduced cognitive impairment in rats.

Fine particulate matter promotes airway inflammation and mucin production by activating endoplasmic reticulum stress and the IRE1α/NOD1/NF­κB pathway.

Fine particulate matter (PM2.5) is a type of small particle that is <2.5 µm in diameter that may cause airway inflammation. Thus, the present study aimed to explore the effects of PM2.5 on endoplasmic reticulum (ER) stress and airway inflammation in human airway epithelial cells. For this purpose, HBE135­E6E7 airway epithelial cells were cultured and exposed to specific concentrations of PM2.5 for various periods of time, and cell viability was determined using a Cell Counting Kit­8 assay. The results of the present study demonstrated that exposure to PM2.5 increased the mRNA and protein expression levels of interleukin (IL)­6, tumor necrosis factor (TNF)­α and mucin 5AC (MUC5AC). Moreover, the expression levels of ER stress­related proteins, such as glucose­regulated protein 78, CCAAT­enhancer binding protein homologous protein, activating transcription factor 6, protein kinase R­like ER kinase (PERK), phosphorylated (p­)PERK, inositol­requiring enzyme 1α (IRE1α) and p­IRE1α, and nucleotide­binding oligomerization domain 1 (NOD1) expression levels were increased following exposure to PM2.5. Transfection with IRE1α small interfering RNA (siRNA) led to the increased production of IL­6, TNF­α and MUC5AC. Moreover, the expression of NOD1 and the translocation of NF­κB p65 were inhibited following transfection with IRE1α siRNA. In addition, the results of the present study demonstrated that transfection with NOD1 siRNA decreased the production of IL­6, TNF­α and MUC5AC, and decreased the translocation of NF­κB p65. The expression levels of IL­6, TNF­α and MUC5AC were increased in the HBE135­E6E7 cells following treatment with C12­iE­DAP, a NOD1 agonist. Moreover, treatment with C12­iE­DAP led to the activation of NF­κB p65. Collectively, the results of the present study suggest that PM2.5 promotes airway inflammation and mucin production by activating ER stress in HBE135­E6E7 airway epithelial cells, and that the IRE1α/NOD1/NF­κB pathway may be involved in this process.

Inventory of cadmium-transporter genes in the root of mangrove plant Avicennia marina under cadmium stress.

Mangrove Avicennia marina has the importantly potential for cadmium (Cd) pollution remediation in coastal wetlands. Unfortunately, the molecular mechanisms and transporter members for Cd uptake by the roots of A. marina are not well documented. In this study, photosynthetic and phenotypic analysis indicated that A. marina is particularly tolerant to Cd. The content and flux analysis indicated that Cd is mainly retained in the roots, with greater Cd influx in fine roots than that in coarse roots, and higher Cd influx in the root meristem zone as well. Using transcriptomic analysis, a total of 5238 differentially expressed genes were identified between the Cd treatment and control group. Moreover, we found that 54 genes were responsible for inorganic ion transport. Among these genes, AmHMA2, AmIRT1, and AmPCR2 were localized in the plasma membrane and AmZIP1 was localized in both plasma membrane and cytoplasm. All above gene encoding transporters showed significant Cd transport activities using function assay in yeast cells. In addition, the overexpression of AmZIP1 or AmPCR2 in Arabidopsis improved the Cd tolerance of transgenic plants. This is particularly significant as it provides insight into the molecular mechanism for Cd uptake by the roots of mangrove plants and a theoretical basis for coastal wetland phytoremediation.

Proteomic analysis reveals differential responsive mechanisms in Solanum nigrum exposed to low and high dose of cadmium.

Cadmium (Cd) contamination is becoming a widespread environmental problem. However, the differential responsive mechanisms of Cd hyperaccumulator Solanum nigrum to low or high dose of Cd are not well documented. In this study, phenotypic and physiological analysis firstly suggested that the seedlings of S. nigrum showed slight leaf chlorosis symptoms under 25 µM Cd and severe inhibition on growth and photosynthesis under 100 µM Cd. Further proteomic analysis identified 105 differentially expressed proteins (DEPs) in the Cd-treated leaves. Under low dose of Cd stress, 47 DEPs are mainly involved in primary metabolic processes, while under high dose of Cd stress, 92 DEPs are mainly involved in photosynthesis, energy metabolism, production of phytochelatin and reactive oxygen species (ROS). Protein-protein interaction (PPI) network analysis of DEPs support above differential responses in the leaves of S. nigrum to low and high dose of Cd treatments. This work provides the differential responsive mechanisms in S. nigrum to low and high dose of Cd, and the theoretical foundation for the application of hyperaccumulating plants in the phytoremediation of Cd-contaminated soils.

Structures of human TR4LBD-JAZF1 and TR4DBD-DNA complexes reveal the molecular basis of transcriptional regulation.

Testicular nuclear receptor 4 (TR4) modulates the transcriptional activation of genes and plays important roles in many diseases. The regulation of TR4 on target genes involves direct interactions with DNA molecules via the DNA-binding domain (DBD) and recruitment of coregulators by the ligand-binding domain (LBD). However, their regulatory mechanisms are unclear. Here, we report high-resolution crystal structures of TR4DBD, TR4DBD-DNA complexes and the TR4LBD-JAZF1 complex. For DNA recognition, multiple factors come into play, and a specific mutual selectivity between TR4 and target genes is found. The coactivators SRC-1 and CREBBP can bind at the interface of TR4 originally occupied by the TR4 activation function region 2 (AF-2); however, JAZF1 suppresses the binding through a novel mechanism. JAZF1 binds to an unidentified surface of TR4 and stabilizes an α13 helix never reported in the nuclear receptor family. Moreover, the cancer-associated mutations affect the interactions and the transcriptional activation of TR4 in vitro and in vivo, respectively. Overall, our results highlight the crucial role of DNA recognition and a novel mechanism of how JAZF1 reinforces the autorepressed conformation and influences the transcriptional activation of TR4, laying out important structural bases for drug design for a variety of diseases, including diabetes and cancers.

A Novel 3-O-rhamnoside: 2″-O-xylosyltransferase Responsible for Terminal Modification of Prenylflavonol Glycosides in Epimedium pubescens Maxim.

Prenylated flavonol glycosides in Epimedium plants, as key medicinal components, are known to have great pharmaceutical activities for human health. Among the main prenylated flavonol glycosides, the modification mechanism of different sugar moieties is still not well understood. In the current study, a novel prenylated flavonol rhamnoside xylosyltransferase gene (EpF3R2″XylT) was cloned from E. pubescens, and the enzymatic activity of its decoding proteins was examined in vitro with different prenylated flavonol rhamnoside substrates and different 3-O-monosaccharide moieties. Furthermore, the functional and structural domains of EpF3R2″XylT were analyzed by bioinformatic approaches and 3-D protein structure remodeling. In summary, EpF3R2″XylT was shown to cluster with GGT (glycosyltransferase that glycosylates sugar moieties of glycosides) through phylogenetic analysis. In enzymatic analysis, EpF3R2″XylT was proven to transfer xylose moiety from UDP-xylose to prenylated flavonol rhamnoside at the 2″-OH position of rhamnose. The analysis of enzymatic kinetics showed that EpF3R2″XylT had the highest substrate affinity toward icariin with the lowest Km value of 75.96 ± 11.91 mM. Transient expression of EpF3R2″XylT in tobacco leaf showed functional production of EpF3R2″XylT proteins in planta. EpF3R2″XylT was preferably expressed in the leaves of E. pubescens, which is consistent with the accumulation levels of major prenylflavonol 3-O-triglycoside. The discovery of EpF3R2″XylT will provide an economical and efficient alternative way to produce prenylated flavonol trisaccharides through the biosynthetic approach.

Publication delays and associated factors in ophthalmology journals.

Introduction: This study aimed to evaluate the publication delays and correlative factors of peer-reviewed ophthalmology journals. Methods: The ophthalmology journals listed in the Journal Citation Report 2020 were retrieved from the Web of Science database. The first original research article of each journal issue from January to December 2020 was extracted, and its submission, final revision, acceptance, and publication dates were obtained. Information on impact factors, advance online publication (AOP) status, open access (OA) rate and acceptance rate in 2020 was also collected. The correlations between publication delays and potential associated factors were analyzed. Results: A total of 58 ophthalmology journals were included and information on 685 articles was collected. The median times from submission to acceptance, from acceptance to publication, and from submission to publication were 118.0 (IQR, 74.0-185.0) days, 31.0 (IQR, 15.0-64.0) days, and 161.0 (IQR, 111.0-232.0) days, respectively. A higher impact factor was correlated with shorter delays of acceptance and publication (P < 0.05). There was a positive correlation between acceptance rates and publication delays (r = 0.726, P = 0.007). Forty-seven (81.03%) journals provided AOP. There was no statistically significant difference for impact factors and publication delays between journal with and without AOP (all P > 0.05). No correlation between OA rate and publication delays or impact factors was detected (all P > 0.05). Conclusions: Journals with higher impact factors and lower acceptance rates tend to have quicker publication processes. No significant associations were detected between publication delays and AOP or OA rate.

Cadmium promotes the absorption of ammonium in hyperaccumulator Solanum nigrum L. mediated by ammonium transporters and aquaporins.

Cadmium (Cd) is a toxic heavy metal affecting the normal growth of plants. Nitrate (NO3-) and ammonium (NH4+) are the primary forms of inorganic nitrogen (N) absorbed by plants. However, the mechanism of N absorption and regulation under Cd stress remains unclear. This study found that: (1) Cd treatment affected the biomass, root length, and Cd2+ flux in Solanum nigrum seedling roots. Specifically, 50 µM Cd significantly inhibited NO3- influx while increased NH4+ influx compared with 0 and 5 µM Cd treatments measured by non-invasive micro-test technology. (2) qRT-PCR analysis showed that 50 µM Cd inhibited the expressions of nitrate transporter genes, SnNRT2;4 and SnNRT2;4-like, increased the expressions of ammonium transporter genes, SnAMT1;2 and SnAMT1;3, in the roots. (3) Under NH4+ supply, 50 µM Cd significantly induced the expressions of the aquaporin genes, SnPIP1;5, SnPIP2;7, and SnTIP2;1. Our results showed that 50 µM Cd stress promoted NH4+ absorption by up-regulating the gene expressions of NH4+ transporter and aquaporins, suggesting that high Cd stress can affect the preference of N nutrition in S. nigrum.

Exposure to Tobacco Smoking Induces a subset of Activated Tumor-resident Tregs in Non-Small Cell Lung Cancer.

Tobacco smoking is the major cause of non-small-cell-lung cancer (NSCLC). However, it is barely known how smoking impact the tumor immune environment (TIME) of lung cancer. We integrated single-cell RNA-seq and bulk RNA-seq data from several studies to systematically study the impact of smoking on T cells in treatment naïve NSCLC patients. We defined a set of smoking-induced differentially expressed genes (SIDEGs) in different cells in TIME.. Specifically, we defined a smoking-related tumor-specific Treg subset, ADAM12+ CTLA4+ Tregs according to the trajectory analysis and highly express genes in cell adhesion pathways and lipid metabolism. Using independent datasets from treatment naïve patients, we found that the fraction of ADAM12+ CTLA4+ Tregs are significantly increased in patients with smoking history. Moreover, the fraction of ADAM12+ CTLA4+ Tregs are positively correlated with the fraction of exhausted T cells. Additionally, we reconstructed the spatial organization of the tumor immune microenvironment and found that ADAM12+ CTLA4+ Tregs more actively communicate with LAYN+CD8+ exhausted T cells compared with ADAM12-CTLA4+ Tregs. Our data demonstrate that smoking induced a unique subset of tumor-specific activated Tregs which interact with exhausted T cells in the TIME. Our findings not only explained how smoking impact the TIME but also provide new targets and biomarkers for precision immunotherapy of lung cancer.

Genetic Determinants of Somatic Selection of Mutational Processes in 3,566 Human Cancers.

The somatic landscape of the cancer genome results from different mutational processes represented by distinct "mutational signatures." Although several mutagenic mechanisms are known to cause specific mutational signatures in cell lines, the variation of somatic mutational activities in patients, which is mostly attributed to somatic selection, is still poorly explained. Here, we introduce a quantitative trait, mutational propensity (MP), and describe an integrated method to infer genetic determinants of variations in the mutational processes in 3,566 cancers with specific underlying mechanisms. As a result, we report 2,314 candidate determinants with both significant germline and somatic effects on somatic selection of mutational processes, of which, 485 act via cancer gene expression and 1,427 act through the tumor-immune microenvironment. These data demonstrate that the genetic determinants of MPs provide complementary information to known cancer driver genes, clonal evolution, and clinical biomarkers. SIGNIFICANCE: The genetic determinants of the somatic mutational processes in cancer elucidate the biology underlying somatic selection and evolution of cancers and demonstrate complementary predictive power across cancer types.

Exonic variants undergoing allele-specific selection in cancers.

BACKGROUND: Allelic imbalance (AI) in tumors is caused by chromosomal and sub-chromosomal gains and losses. RESULTS: We evaluated AI at 109,086 germline exonic SNP loci in four cancer types, and identified a set of SNPs that demonstrate strong tumor allele specificity in AI events. Further analyses demonstrated that these alleles show consistently different frequencies in the cancer population compared to the healthy population and are significantly enriched for predicted protein-damaging variants. Moreover, genes harboring SNPs that demonstrate allele specificity are enriched for cancer-related biological processes and are more likely to be essential in cancer cells. CONCLUSIONS: In summary, our study provides a unique and complementary method to identify genes and variants that are relevant to carcinogenesis.

The targetable nanoparticle BAF312@cRGD-CaP-NP represses tumor growth and angiogenesis by downregulating the S1PR1/P-STAT3/VEGFA axis in triple-negative breast cancer.

BACKGROUND: Overexpressed vascular endothelial growth factor A (VEGFA) and phosphorylated signal transducer and activator of transcription 3 (P-STAT3) cause unrestricted tumor growth and angiogenesis of breast cancer (BRCA), especially triple-negative breast cancer (TNBC). Hence, novel treatment strategy is urgently needed. RESULTS: We found sphingosine 1 phosphate receptor 1 (S1PR1) can regulate P-STAT3/VEGFA. Database showed S1PR1 is highly expressed in BRCA and causes the poor prognosis of patients. Interrupting the expression of S1PR1 could inhibit the growth of human breast cancer cells (MCF-7 and MDA-MB-231) and suppress the angiogenesis of human umbilical vein endothelial cells (HUVECs) via affecting S1PR1/P-STAT3/VEGFA axis. Siponimod (BAF312) is a selective antagonist of S1PR1, which inhibits tumor growth and angiogenesis in vitro by downregulating the S1PR1/P-STAT3/VEGFA axis. We prepared pH-sensitive and tumor-targeted shell-core structure nanoparticles, in which hydrophilic PEG2000 modified with the cyclic Arg-Gly-Asp (cRGD) formed the shell, hydrophobic DSPE formed the core, and CaP (calcium and phosphate ions) was adsorbed onto the shell; the nanoparticles were used to deliver BAF312 (BAF312@cRGD-CaP-NPs). The size and potential of the nanoparticles were 109.9 ± 1.002 nm and - 10.6 ± 0.056 mV. The incorporation efficacy for BAF312 was 81.4%. Results confirmed BAF312@cRGD-CaP-NP could dramatically inhibit tumor growth and angiogenesis in vitro and in MDA-MB-231 tumor-bearing mice via downregulating the S1PR1/P-STAT3/VEGFA axis. CONCLUSIONS: Our data suggest a potent role for BAF312@cRGD-CaP-NPs in treating BRCA, especially TNBC by downregulating the S1PR1/P-STAT3/VEGFA axis.

MiR-3130-5p is an intermediate modulator of 2q33 and influences the invasiveness of lung adenocarcinoma by targeting NDUFS1.

Genome-wide association studies (GWAS) have reported a handful of loci associated with lung cancer risk, of which the pathogenic pathways are largely unknown. We performed cis-expression quantitative trait loci (eQTL) mapping for 376 lung cancer related GWAS loci in 227 TCGA lung adenocarcinoma (LUAD) and reported two risk loci as eQTL of miRNA. Among the miRNAs in association with lung cancer risk, we further predicted and validated miR-3130-5p as an intermediate modulator of risk loci 2q33 and the tumor suppressor NDUFS1. We assessed the phenotypic impacts of the interaction between miR-3130-5p and NDUFS1 in both lung cancer cell lines and mice xenograft models. As a result, miR-3130-5p directly regulates the expression of NDUFS1 and the corresponding tumor invasiveness, migration and epithelial-mesenchymal transition (EMT). Our findings provide important clues for the pathogenic mechanism of 2q33 in lung carcinogenesis which informs clinical diagnosis and prognosis of LUAD. We performed a cis-eQTL analysis for 376 lung cancer risk loci based on the expression profiles of 251 miRNAs in a cohort of 227 TCGA lung adenocarcinoma. We report a novel pathogenic pathway of 2q33 via miR-3130-5p and NDUFS1.

Rapid pH-responsive self-disintegrating nanoassemblies balance tumor accumulation and penetration for enhanced anti-breast cancer therapy.

The dilemma of tumor accumulation and deep penetration has always been a barrier in antitumor therapy. Stimuli-responsive size changeable drug delivery systems provide possible solutions. Nevertheless, the low size-shrinkage efficiency limited the antitumor effects. In this study, an instant pH-responsive size shrinkable nanoassemblies named self-aggregated DOX@HA-CD (SA-DOX@HA-CD) was formulated using small-sized hyaluronic acid modified carbon dots (HA-CD) as monomers, which could self-aggregate into raspberry-like structure via hydrophobicity force in neutral pH and rapidly disassemble into shotgun-like DOX-loaded CD monomer in simulated tumor microenvironment (pH 6.5), owing to the transformation in electrical charge and hydrophobicity/hydrophilicity of this system. The transmission electron microscopy showed that the clustered SA-DOX@HA-CD had a diameter of ~150 nm, and thoroughly disassembled into ~30 nm nanoparticles in response to acidic environment. The disassemble efficiency was approximately 100%. Attributed to this property, SA-DOX@HA-CD led to enhanced cellular internalization and accumulation in 4T1 cells in simulated tumor microenvironment, as well as deep tumor penetration in 3D tumor spheroid model. Besides, the imine bond between DOX and HA-CD endowed DOX with pH-responsive release profile in the acidic lysosome environment. Furthermore, in the orthotopic 4T1 tumor-bearing mouse model, SA-DOX@HA-CD demonstrated higher tumor accumulation than non-aggregated DOX-HA-CD. Meanwhile, in response to the acid tumor microenvironment, the dissociated DOX-HA achieved deep tumor penetration, which consequently resulted in 2.5-fold higher antitumor efficiency. The formulation of self-aggregated SA-DOX@HA-CD provides a simple and effective alternative to prepare pH-responsive size-shrinkable nanodrug delivery systems. STATEMENT OF SIGNIFICANCE: The heterogeneity of tumor vasculature and the high tumor interstitial pressure lead to the barriers in tumor accumulation and deep penetration, which calls for opposite properties (e.g. size) of drug delivery systems. To address this dilemma, various size changeable nanoparticles have been developed utilizing special features of tumor microenvironment, such as pH, enzyme and reactive oxygen species. Nevertheless, the current strategies face the problems of incomplete hydrolysis of chemical bonds or insufficient enzyme degradation, which result in only partial size shrinkage, hindering the tumor deep penetration effects. Here we developed a self-assembled nanocluster, which could respond to acidic pH rapidly and thoroughly disassemble into small nanodots due to the alteration of hydrophobicity/hydrophilicity/charge, leading to approximately 100% dissociation. This strategy provides a new concept for design of size changeable drug delivery systems.

Cis- and Trans-Acting Expression Quantitative Trait Loci of Long Non-Coding RNA in 2,549 Cancers With Potential Clinical and Therapeutic Implications.

Many cancer risk loci act as expression quantitative trait loci (eQTLs) of transcripts including non-coding RNA. Long non-coding RNAs (lncRNAs) are implicated in various human cancers. However, the pathological and clinical impacts of the genetic determinants of lncRNAs in cancers remain largely unknown. In this study, we performed eQTL mapping of lncRNA expression (elncRNA) in 11 TCGA cancer types and characterized the biological processes of elncRNAs in the setting of genomic location, cancer treatment responses, and immune microenvironment. As a result, 10.86% of the cis-eQTLs and 1.67% of the trans-eQTLs of lncRNA were related to known genome-wide association studies (GWAS) cancer risk loci. The elncRNAs are significantly enriched for those which are previously annotated as predictive of drug sensitivities in cancer cell lines. We further revealed the downstream transcriptomic effectors of eQTL-elncRNA pairs. Our data specifically suggested that the genes affected by eQTL-elncRNA associations are enriched in the immune system processes and eQTL-elncRNA associations influence the constitution of tumor infiltrating lymphocytes. In ovarian cancer, the "rs34631313-AC092580.4" pair was associated with increased fraction of CD8+ T cells and M1 Macrophage; whereas in KIRC, the "rs9546285-LINC00426" pair was associated with increased fraction of CD8+ T cells and a decreased fraction of M2 macrophages. Our findings provide a systematic view of the transcriptomic impacts of the eQTL landscape of lncRNA in human cancers and suggest its strong potential relevance to cancer immunity and treatment.

Highly biocompatible thermosensitive nanocomposite gel for combined therapy of hepatocellular carcinoma via the enhancement of mitochondria related apoptosis.

Primary hepatocellular carcinoma (HCC) is a common malignant tumor. Surgery is the main treatment, but HCC patients have a potential risk of tumor recurrence. Besides, many limitations arise during the application of single first-line antitumor drugs. Here, we selected Pluronic F-127 and sodium alginate (SA) to prepare a thermosensitive gel (Gel). The optimal synergistic ratio of PTX and DOX on the SMMC-7721 cells was 1: 2 (w/w), calculated by the Chou-Talalay analysis. Then, PTX and DOX coloaded liposomes (PD-LPs) with such drugs ratios presented enhanced anticancer ability in vitro. Upon local injection, the PD-LPs Gel formed a nanoparticles reservoir at tumor via sol-gel transformation, while exhibiting a long-term effective anti-tumor ability in vivo. The relative tumor volume after the PD-LPs Gel treatment was reduced over 62%. Effective mitochondria related apoptosis induction was observed. Therefore, the local delivery of PD-LPs Gel can be a promising alternative method for the HCC therapy.

Tumor-Targeted Chemoimmunotherapy with Immune-Checkpoint Blockade for Enhanced Anti-Melanoma Efficacy.

Chemoimmunotherapy with chemotherapeutics and immunoadjuvant inhibits tumor growth by activating cytotoxic T cells. However, this process also upregulates the expression of PD-1/PD-L1 and consequently leads to immune suppression. To maximize the anti-tumor immune responses and alleviate immunosuppression, PD-L1 antibody was combined with paclitaxel (PTX) and the immunoadjuvant α-galactosylceramide (αGC), which were coencapsulated into pH-sensitive TH peptide-modified liposomes (PTX/αGC/TH-Lip) to treat melanoma and lung metastasis. Compared to treatment with PD-L1 antibody or PTX/αGC/TH-Lip alone, the combination of PD-L1 antibody and PTX/αGC/TH-Lip further elevated the tumor-specific cytotoxic T cell responses and promoted apoptosis in tumor cells, leading to enhanced anti-tumor and anti-metastatic effects. In adoptive therapy, PD-L1 antibody further alleviated immunosuppression and enhanced the anti-tumor effect of CD8+ T cells. The combination of PD-L1 antibody and chemoimmunotherapy PTX/αGC/TH-Lip provides a promising strategy for enhancing treatment for melanoma and lung metastasis.

Integrative analysis reveals distinct subtypes with therapeutic implications in KRAS-mutant lung adenocarcinoma.

BACKGROUND: KRAS-mutant lung adenocarcinomas (LUADs) are heterogeneous and frequently occur in smokers. The heterogeneity of KRAS-mutant LUAD has been an obstacle for the drug discovery. METHODS: We integrated multiplatform datatypes and identified two corresponding subtypes in the patients and cell lines. We further characterized the features of these two subtypes and performed drug screening to identify subtype-specific drugs. Finally, we used the defining features of the KRAS subtypes for drug sensitivity prediction. FINDINGS: Patient-Subtype 1 (PS1) was characterized by increased smoking-related mutational signature activity, a low tumor-infiltrating lymphocyte (TIL)-associating score and STK11/KEAP1 co-mutations. Patient-Subtype 2 (PS2) was characterized by an increased smoking-related methylation signature activity, a high TIL-associating score and increased KRAS dependency. The cell line subtypes faithfully recapitulated all the patients' features. Drug screening of the two cell line subtypes yielded several potential candidates, such as cytarabine and enzastaurin for Cell-line-Subtype 1 (CS1) and a BTK inhibitor QL-XII-61 for Cell-line-Subtype 2 (CS2). The defining features, such as smoking-related methylation signature, were significantly associated with the sensitivity to several drugs. INTERPRETATION: The heterogeneity of KRAS-mutant LUAD is associated with smoking-related genomic and epigenomic aberration along with other features such as immunogenicity, KRAS dependency and STK11/KEAP1 co-mutations. These features might be used as biomarkers for drug sensitivity prediction. FUND: This research was funded by the Young Scientists Fund of the National Natural Science Foundation of China, the Natural Science Foundation of Fujian Province, China and the Education and Research Foundation for Young Scholars of Education Department of Fujian Province, China.

Transcriptome-derived stromal and immune scores infer clinical outcomes of patients with cancer.

The stromal and immune cells that form the tumor microenvironment serve a key role in the aggressiveness of tumors. Current tumor-centric interpretations of cancer transcriptome data ignore the roles of stromal and immune cells. The aim of the present study was to investigate the clinical utility of stromal and immune cells in tissue-based transcriptome data. The 'Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data' (ESTIMATE) algorithm was used to probe diverse cancer datasets and the fraction of stromal and immune cells in tumor tissues was scored. The association between the ESTIMATE scores and patient survival data was asessed; it was indicated that the two scores have implications for patient survival, metastasis and recurrence. Analysis of a colorectal cancer progression dataset revealed that decreased levels immune cells could serve an important role in cancer progression. The results of the present study indicated that trasncriptome-derived stromal and immune scores may be a useful indicator of cancer prognosis.