Construction and validation of an innovative prognostic nomogram for overall survival in cervical cancer patients with lung metastasis: an analysis utilizing the SEER database.

Purpose: To facilitate patient consultation and assist in clinical decision-making, we developed a predictive model to analyze the overall survival (OS) rate of cervical cancer patients with concurrent lung metastasis for 6 months, 1 year, or 2 years. Methods: We extracted data on patients diagnosed with cervical cancer and concurrent lung metastasis between 2010 and 2020 from the Surveillance, Epidemiology, and End Results (SEER) database. Through a random assignment process, these patients were allocated to either a training cohort or a validation cohort, maintaining a 7:3 ratio. Utilizing both univariate and multivariate Cox regression analyses, we determined the independent prognostic factors influencing OS. To enhance predictive accuracy, we developed a nomogram model incorporating these identified independent prognostic variables. Model effectiveness was subsequently assessed using various metrics, including receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA). Results: We gathered data on 1330 patients diagnosed with cervical cancer with lung metastases. An OS nomogram was developed, accounting for factors such as histological type, presence of metastases in other organs (brain, liver), surgical interventions, radiation therapy, and chemotherapy. The ROC curves, calibration plots, and DCA curves demonstrated the commendable predictive performance of the nomogram in assessing the prognosis of cervical cancer patients with lung metastases in both the training and validation cohorts. Conclusion: By utilizing clinical data from the SEER database, we have effectively devised a nomogram capable of predicting the 6-month, 1-year, and 2-year survival rates of cervical cancer patients with lung metastases. The nomogram boasts high accuracy, offering precise prognostic predictions. Its implementation can guide the formulation of individualized follow-up and treatment plans for enhanced patient care.

Development and validation of a prognostic model for cervical cancer by combination of machine learning and high-throughput sequencing.

BACKGROUND: Cervical cancer holds the highest morbidity and mortality rates among female reproductive tract tumors. However, the curative outcomes for patients with persistent, recurrent, or metastatic cervical cancer remain unsatisfactory. There is a lack of comprehensive prognostic indicators for cervical cancer. This study aims to develop a model that evaluates the prognosis of cervical cancer in combination of high-throughput sequencing and various machine learning algorithms. METHODS: In this study, we combined two single-cell RNA sequencing (scRNA-seq) projects and TCGA data for cervical cancer to obtain shared differentially expressed genes (DEGs). A LASSO regression and several learners were applied for signature feature selection. Six machine learning algorithms including Linear Discriminant Analysis, Naive Bayes, K Nearest Neighbors, Decision Tree, Random Forest, and eXtreme Gradient Boosting were utilized to construct a prognostic model for cervical cancer. External validation was conducted using the CGCI-HTMCP-CC dataset, and the accuracy of the model was assessed through ROC curve analysis. RESULTS: The results demonstrated the successful construction of a prognostic model based on DEGs from bulk- and scRNA-seq data. Ten genes CXCL8, DLC1, GRN, MPLKIP, PRDX1, RUNX1, SNX3, TFRC, UBE2V2, and UQCRC1 were screened by feature selection and applied for model construction. Random Forest exhibited the best performance in predicting the risk of cervical cancer. Patients in the high-risk group presented worse overall survival compared to those in the low-risk group. CONCLUSION: Conclusively, our model based on DEGs from bulk-seq and scRNA-seq data effectively evaluates the prognosis of cervical cancer and provides valuable insights for comprehensive clinical management.

Design, synthesis and biological evaluation of structurally new 4-indolyl quinazoline derivatives as highly potent, selective and orally bioavailable EGFR inhibitors.

Targeting the epidermal growth factor receptor (EGFR) has been recognized as an effective strategy for treating non-small-cell lung cancer (NSCLC). Although several representative EGFR inhibitors have been approved for clinical use, it is highly desirable to develop highly potent and selective EGFR inhibitors with novel scaffolds because of the occurrence of acquired resistance after treatment. Here we first demonstrate that the 4-indolyl quinazoline derivatives could potently inhibit EGFR in vitro and in vivo, of which YS-67 effectively and selectively inhibits EGFR[WT] (IC50 = 5.2 nM), EGFR[d746-750] (IC50 = 9.6 nM) and EGFR[L858R] (IC50 = 1.9 nM). The TREEspot™ kinase interaction map further reveals the binding selectivity toward 468 kinases. YS-67 not only potently suppresses p-EGFR and p-AKT, but also effectively inhibits proliferation of A549 (IC50 = 4.1 µM), PC-9 (IC50 = 0.5 µM) and A431 cells (IC50 = 2.1 µM). YS-67 treatment also causes colony formation inhibition, arrests cell cycle progression at G0/G1 phases and induces apoptosis. More importantly, YS-67 is well tolerated in A431 xenograft model after oral administration, showing effective tumor growth suppression and low toxicity. Collectively, YS-67 represents an underexplored scaffold for developing new EGFR inhibitors.

Structure-Activity Relationship Study of Antimicrobial Peptide PE2 Delivered Novel Linear Derivatives with Potential of Eradicating Biofilms and Low Incidence of Drug Resistance.

The ongoing emergence of antibiotic-resistant pathogens had been dramatically stimulating and accelerating the need for new drugs. PE2 is a kind of cyclic lipopeptide with broad-spectrum antimicrobial activity. Herein, its structure-activity relationship was systematically investigated by employing 4 cyclic analogues and 23 linear analogues for the first time. The screened linear analogues 26 and 27 bearing different fatty acyls at N-termini and a Tyr residue at the 9th position had superior potency compared to the cyclic analogues and showed equivalent antimicrobial activity compared with PE2. Notably, 26 and 27 exhibited significant ability against multidrug-resistant bacteria, favorable resistance to protease, excellent performance against biofilm, low drug resistance, and high effectiveness against the mice pneumonia model. The antibacterial mechanisms of PE2 and linear derivatives 26 and 27 were also preliminarily explored in this study. As described above, 26 and 27 are promising antimicrobial candidates for the treatment of infections associated with drug-resistant bacteria.

One New Acid-Activated Hybrid Anticancer Peptide by Coupling with a Desirable pH-Sensitive Anionic Partner Peptide.

Anticancer peptides (ACPs) are promising antitumor resources, and developing acid-activated ACPs as more effective and selective antitumor drugs would represent new progress in cancer therapy. In this study, we designed a new class of acid-activated hybrid peptides LK-LE by altering the charge shielding position of the anionic binding partner LE based on the cationic ACP LK and investigated their pH response, cytotoxic activity, and serum stability, in hoping to achieve a desirable acid-activatable ACP. As expected, the obtained hybrid peptides could be activated and exhibit a remarkable antitumor activity by rapid membrane disruption at acidic pH, whereas its killing activity could be alleviated at normal pH, showing a significant pH response compared with LK. Importantly, this study found that the peptide LK-LE3 with the charge shielding in the N-terminal of LK displayed notably low cytotoxicity and more stability, demonstrating that the position of charge masking is extremely important for the improvement of peptide toxicity and stability. In short, our work opens a new avenue to design promising acid-activated ACPs as potential targeting agents for cancer treatment.

The Association between Deoxyribonucleic Acid Hypermethylation in Intron VII and Human Leukocyte Antigen-C∗07 Expression in Patients with Endometriosis.

Objective: Endometriosis, which is a common disease affecting approximately 10% of women of reproductive age, usually causes dysmenorrhea and infertility, thus seriously harming the patients' physical and mental health. However, there is a mean delay of 6.7 years between the onset of the symptoms and the surgical diagnosis of endometriosis. There is an increasing amount of evidence that suggests that epigenetic aberrations, including deoxyribonucleic acid (DNA) methylation, play a definite role in the pathogenesis of endometriosis. This study aimed to explore the noninvasive or minimally invasive biomarkers of this disease. Materials and Methods: Six patients with surgically confirmed ovarian endometriosis and six patients who received IUD implantation for contraception without endometriosis were recruited in the East Hospital of Tongji University in 2018. The genome methylation profiling of the eutopic and ectopic endometrium of ovarian endometriosis patients and normal endometrial specimens from healthy women was determined using a methylation microarray test. The test screened methylation-differentiated 5'-C-phosphate-G-3' (CpG) sites and then located the target genes affected by these sites following sequence alignment. Then, an additional 22 patients and 26 healthy controls were enrolled to further verify the difference in the selected genes between endometriosis patients and healthy women. The differential DNA methylation of the selected genes was validated via direct bisulfite sequencing and analysis of their messenger ribonucleic acid (mRNA) levels using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results: Fifteen differentially methylated CpG sites were found among the patients and healthy women, and five CpG sites were mapped to the introns of the human leukocyte antigen-C (HLA-C) gene; these were highly polymorphic between different HLA-C alleles and were HLA-C∗07 specific. The results indicated that the HLA-C∗07 carrier patients exhibited significantly higher DNA methylation levels at the intron VII of HLA-C compared to the HLA-C∗07 carrier healthy controls. High HLA-C∗07 mRNA levels were also observed using qRT-PCR with HLA-C∗07-specific primers, which indicated that the hypermethylation of CpG in intron VII might suppress a silencer that regulates HLA-C∗07 expressions. Conclusion: Deoxyribonucleic acid hypermethylation in the intron VII of the HLA-C∗07 gene appears to regulate the expression of HLA-C∗07. The aberrant DNA methylation in this region was positively correlated with the occurrence of endometriosis.

Prognostic Value and Immune Infiltration of HPV-Related Genes in the Immune Microenvironment of Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma.

Mounting evidence has highlighted the immune environment as a critical feature in the development of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). However, the relationship between the clinical characteristics of the immune environment and CESC remain unclear. Therefore, the aim of this study was to further characterize the relationship between the tumor and immune microenvironment and the clinical features of CESC using a variety of bioinformatic methods. Expression profiles (303 CESCs and three control samples) and relevant clinical data were obtained from The Cancer Genome Atlas. We divided CESC cases into different subtypes and performed a differential gene expression analysis. In addition, gene ontology (GO) and gene set enrichment analysis (GSEA) were performed to identify potential molecular mechanisms. Furthermore, data from 115 CESC patients from East Hospital were used to help identify the relationship between the protein expressions of key genes and disease-free survival using tissue microarray technology. Cases of CESC (n = 303) were divided into five subtypes (C1-C5) based on their expression profiles. A total of 69 cross-validated differentially expressed immune-related genes were identified. Subtype C4 demonstrated a downregulation of the immune profile, lower tumor immune/stroma scores, and worse prognosis. In contrast, the C1 subtype showed an upregulation of the immune profile, higher tumor immune/stroma scores, and better prognosis. A GO analysis suggested that changes in CESC were primarily enriched nuclear division, chromatin binding, and condensed chromosomes. In addition, GSEA demonstrated that cellular senescence, the p53 signaling pathway, and viral carcinogenesis are critical features of CESC. Moreover, high FOXO3 and low IGF-1 protein expression were closely correlated with decreased clinical prognosis. In summary, our findings provide novel insight into the relationship between the immune microenvironment and CESC. As such, our results may provide guidance for developing potential immunotherapeutic targets and biomarkers for CESC.

Role of microglia in HIV-1 infection.

The usage of antiretroviral treatment (ART) has considerably decreased the morbidity and mortality related to HIV-1 (human immunodeficiency virus type 1) infection. However, ART is ineffective in eradicating the virus from the persistent cell reservoirs (e.g., microglia), noticeably hindering the cure for HIV-1. Microglia participate in the progression of neuroinflammation, brain aging, and HIV-1-associated neurocognitive disorder (HAND). Some methods have currently been studied as fundamental strategies targeting microglia. The purpose of this study was to comprehend microglia biology and its functions in HIV-1 infection, as well as to look into potential therapeutic approaches targeting microglia.

Targeted therapy in NPM1-mutated AML: Knowns and unknowns.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by malignant proliferation of myeloid hematopoietic stem/progenitor cells. NPM1 represents the most frequently mutated gene in AML and approximately 30% of AML cases carry NPM1 mutations. Mutated NPM1 result in the cytoplasmic localization of NPM1 (NPM1c). NPM1c interacts with other proteins to block myeloid differentiation, promote cell proliferation and impair DNA damage repair. NPM1 is a good prognostic marker, but some patients ultimately relapse or fail to respond to therapy. It is urgent for us to find optimal therapies for NPM1-mutated AML. Efficacy of multiple drugs is under investigation in NPM1-mutated AML, and several clinical trials have been registered. In this review, we summarize the present knowledge of therapy and focus on the possible therapeutic interventions for NPM1-mutated AML.

Short, mirror-symmetric antimicrobial peptides centered on "RRR" have broad-spectrum antibacterial activity with low drug resistance and toxicity.

The increasingly severe bacterial resistance worldwide pushes people to discover and design potential antibacterial drugs unavoidably. In this work, a series of short, mirror-symmetric peptides were designed and successfully synthesized, centered on "RRR" and labeled with hydrophobic amino acids at both ends. Based on the structure-activity relationship analysis, LWWR (LWWRRRWWL-NH2) was screened as a desirable mirror-symmetric peptide for further study. As expected, LWWR displayed broad-spectrum antibacterial activity against the standard bacteria and antibiotic-resistant strains. Undoubtedly, the high stability of LWWR in a complex physiological environment was an essential guarantee to maximizing its antibacterial activity. Indeed, LWWR also exhibited a rapid bactericidal speed and a low tendency to develop bacterial resistance, based on the multiple actions of non-receptor-mediated membrane actions and intra-cellular mechanisms. Surprisingly, although LWWR showed similar in vivo antibacterial activity compared with Polymyxin B and Melittin, the in vivo safety of LWWR was far higher than that of them, so LWWR had better therapeutic potential. In summary, the desirable mirror-symmetric peptide LWWR was promised as a potential antibacterial agent to confront the antibiotics resistance crisis. STATEMENT OF SIGNIFICANCE: Witnessing the growing problem of antibiotic resistance, a series of short, mirror-symmetric peptides based on the symmetric center "RRR" and hydrophobic terminals were designed and synthesized in this study. Among, LWWR (LWWRRRWWL-NH2) presented broad-spectrum antibacterial activity both in vitro and in vivo due to its multiple mechanisms and good stability. Meanwhile, the low drug resistance and toxicity of LWWR also suggested its potential for clinical application. The findings of this study will provide some inspiration for the design and development of potential antibacterial agents, and contribute to the elimination of bacterial infections worldwide as soon as possible.

Genome-Wide Identification, Characterization, and Expression Analysis of Tubby-like Protein (TLP) Gene Family Members in Woodland Strawberry (Fragaria vesca).

Tubby-like proteins (TLPs) play important roles in plant growth and development and in responses to abiotic stress. However, TLPs in strawberry remain poorly studied. In this study, eight TLPs were identified in woodland strawberry (Fragaria vesca subspecies vesca 'Ruegen'). Protein structure analysis revealed that the structure of FvTLPs is highly conserved, but evolutionary and gene structure analyses revealed that the evolutionary pattern of FvTLP family members differs from that of their orthologous genes in Arabidopsis, poplar, and apple. Subcellular localization assays revealed that FvTLPs were localized to the nucleus and plasma membrane. FvTLPs showed no transcriptional activity. Yeast two-hybrid assays revealed that FvTLPs interact with specific FvSKP1s. The expression patterns of FvTLPs in different tissues and under various abiotic stresses (salt, drought, cold, and heat) and hormone treatments (ABA (abscisic acid) and MeJA (methyl jasmonate)) were determined. The expression patterns of FvTLPs indicated that they play a role in regulating growth and development and responses to abiotic stress in F. vesca. The GUS (beta-glucuronidase) activity of FvTLP1pro::GUS plants in GUS activity assays increased under salt and drought stress and abscisic acid treatment. The results of this study provide new insights into the molecular mechanisms underlying the functions of TLPs.

Improving the Antimicrobial Performance of Amphiphilic Cationic Antimicrobial Peptides Using Glutamic Acid Full-Scan and Positive Charge Compensation Strategies.

Nonselective toxicity of antimicrobial peptides (AMPs) needs to be solved urgently for their application. Temporin-PE (T-PE, FLPIVAKLLSGLL-NH2), an AMP extracted from skin secretions of frogs, has high toxicity and specific antimicrobial activity against Gram-positive bacteria. To improve the antimicrobial performance of T-PE, a series of T-PE analogues were designed and synthesized by glutamic acid full-scan, and then their key positions were replaced with lysine. Finally, E11K4K10, the highest therapeutic indicial AMP, was screened out. E11K4K10 was not easy to induce and produce drug-resistant bacteria when used alone, as well as it could also inhibit the development of the drug resistance of traditional antibiotics when it was used in combination with the traditional antibiotics. In addition, E11K4K10 had an excellent therapeutic effect on a mouse model of pulmonary bacterial infection. Taken together, this study provides a new approach for the further improvement of new antimicrobial peptides against the antimicrobial-resistance crisis.

Chromosome-level genome assembly of Fragaria pentaphylla using PacBio and Hi-C technologies.

Fragaria pentaphylla, a wild diploid quinquefoliolate species of Fragaria, is native to Southwest China. It has two morphs of red and white fruit color in nature and has characteristics of unique fragrance and resistance, which made it not only a valuable breeding material but also a potential model plant for molecular function researches. Here, we generate a high-quality chromosome-level genome assembly of a F. pentaphylla accession, BAAFS-FP039 employing a combination of PacBio Long-Read Sequencing, Illumina Short-Read Sequencing, and Hi-C Sequencing. The assembled genome contained 256.74 Mb and a contig N50 length of 32.38 Mb, accounting for 99.9% of the estimated genome (256.77 Mb). Based on Hi-C data, seven pseudo-chromosomes of F. pentaphylla-FP039 genome were assembled, covering 99.39% of the genome assembly. The genome was composed of 44.61% repetitive sequences and 29,623 protein-coding genes, 97.62% of protein-coding genes could be functionally annotated. Phylogenetic and chromosome syntenic analysis revealed that F. pentaphylla-FP039 was closely related to F. nubicola. This high-quality genome could provides fundamental molecular resources for evolutionary studies, breeding efforts, and exploring the unique biological characteristics of F. pentaphylla.

FaAKR23 Modulates Ascorbic Acid and Anthocyanin Accumulation in Strawberry (Fragaria × ananassa) Fruits.

Strawberry (Fragaria × ananassa) fruits are rich in ascorbic acid (AsA) and anthocyanin, which are essential antioxidants for human health. However, the underlying regulatory mechanism of these antioxidant accumulation, especially AsA accumulation in strawberry fruits, remains largely unknown. In this study, we identified FaAKR23 was a regulator of AsA and anthocyanin accumulation. We transiently expressed FaAKR23 in strawberry fruits and conducted metabolic and molecular analyses to explore the role of FaAKR23 in AsA and anthocyanin accumulation. Transient silencing of FaAKR23 (FaAKR23-RNAi) in strawberry fruits significantly decreased the AsA and anthocyanin contents compared with control (empty vector-RNAi, EV-RNAi). Correspondingly, expression of some structural genes and regulatory factors involved in these two antioxidants' accumulation was dramatically repressed. In addition, transcriptome analysis of EV-RNAi and FaAKR23-RNAi fruits suggested that FaAKR23 was also involved in starch and sucrose metabolism as well as plant-pathogen interaction. Overall, these results not only provide the coordinated regulatory function of FaAKR23 on AsA and anthocyanin accumulation but also offer a promising candidate gene for strawberry breeding with high antioxidants.

Combined transcriptomic and metabolomic analysis reveals a role for adenosine triphosphate-binding cassette transporters and cell wall remodeling in response to salt stress in strawberry.

Strawberry (Fragaria × ananassa Duch) are sensitive to salt stress, and breeding salt-tolerant strawberry cultivars is the primary method to develop resistance to increased soil salinization. However, the underlying molecular mechanisms mediating the response of strawberry to salinity stress remain largely unknown. This study evaluated the salinity tolerance of 24 strawberry varieties, and transcriptomic and metabolomic analysis were performed of 'Sweet Charlie' (salt-tolerant) and 'Benihoppe' (salt-sensitive) to explore salt tolerance mechanisms in strawberry. Compared with the control, we identified 3412 differentially expressed genes (DEGs) and 209 differentially accumulated metabolites (DAMs) in 'Benihoppe,' and 5102 DEGs and 230 DAMs in 'Sweet Charlie.' DEGs Gene Ontology (GO) enrichment analyses indicated that the DEGs in 'Benihoppe' were enriched for ion homeostasis related terms, while in 'Sweet Charlie,' terms related to cell wall remodeling were over-represented. DEGs related to ion homeostasis and cell wall remodeling exhibited differential expression patterns in 'Benihoppe' and 'Sweet Charlie.' In 'Benihoppe,' 21 ion homeostasis-related DEGs and 32 cell wall remodeling-related DEGs were upregulated, while 23 ion homeostasis-related DEGs and 138 cell wall remodeling-related DEGs were downregulated. In 'Sweet Charlie,' 72 ion homeostasis-related DEGs and 275 cell wall remodeling-related DEGs were upregulated, while 11 ion homeostasis-related DEGs and 20 cell wall remodeling-related DEGs were downregulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed only four KEGG enriched pathways were shared between 'Benihoppe' and 'Sweet Charlie,' including flavonoid biosynthesis, phenylalanine metabolism, phenylpropanoid biosynthesis and ubiquinone, and other terpenoid-quinone biosynthesis. Integrating the results of transcriptomic and metabolomics analyses showed that adenosine triphosphate-binding cassette (ABC) transporters and flavonoid pathway genes might play important roles in the salt stress response in strawberry, and DAMs and DEGs related to ABC transporter and flavonoid pathways were differentially expressed or accumulated. The results of this study reveal that cell wall remodeling and ABC transporters contribute to the response to salt stress in strawberry, and that related genes showed differential expression patterns in varieties with different salt tolerances. These findings provide new insights into the underlying molecular mechanism of strawberry response to salt stress and suggest potential targets for the breeding of salt-tolerant strawberry varieties.

The Emerging Roles of Human Gut Microbiota in Gastrointestinal Cancer.

The gut microbiota is composed of a large number of microorganisms with a complex structure. It participates in the decomposition, digestion, and absorption of nutrients; promotes the development of the immune system; inhibits the colonization of pathogens; and thus modulates human health. In particular, the relationship between gut microbiota and gastrointestinal tumor progression has attracted widespread concern. It was found that the gut microbiota can influence gastrointestinal tumor progression in independent ways. Here, we focused on the distribution of gut microbiota in gastrointestinal tumors and further elaborated on the impact of gut microbiota metabolites, especially short-chain fatty acids, on colorectal cancer progression. Additionally, the effects of gut microbiota on gastrointestinal tumor therapy are outlined. Finally, we put forward the possible problems in gut microbiota and the gastrointestinal oncology field and the efforts we need to make.

Genome-Wide Analysis of Ascorbic Acid Metabolism Related Genes in Fragaria × ananassa and Its Expression Pattern Analysis in Strawberry Fruits.

Ascorbic acid (AsA) is an important antioxidant for scavenging reactive oxygen species and it is essential for human health. Strawberry (Fragaria × ananassa) fruits are rich in AsA. In recent years, strawberry has been regarded as a model for non-climacteric fruit ripening. However, in contrast to climacteric fruits, such as tomato, the regulatory mechanism of AsA accumulation in strawberry fruits remains largely unknown. In this study, we first identified 125 AsA metabolism-related genes from the cultivated strawberry "Camarosa" genome. The expression pattern analysis using an available RNA-seq data showed that the AsA biosynthetic-related genes in the D-mannose/L-galactose pathway were downregulated remarkably during fruit ripening which was opposite to the increasing AsA content in fruits. The D-galacturonate reductase gene (GalUR) in the D-Galacturonic acid pathway was extremely upregulated in strawberry receptacles during fruit ripening. The FaGalUR gene above belongs to the aldo-keto reductases (AKR) superfamily and has been proposed to participate in AsA biosynthesis in strawberry fruits. To explore whether there are other genes in the AKR superfamily involved in regulating AsA accumulation during strawberry fruit ripening, we further implemented a genome-wide analysis of the AKR superfamily using the octoploid strawberry genome. A total of 80 FaAKR genes were identified from the genome and divided into 20 subgroups based on phylogenetic analysis. These FaAKR genes were unevenly distributed on 23 chromosomes. Among them, nine genes showed increased expression in receptacles as the fruit ripened, and notably, FaAKR23 was the most dramatically upregulated FaAKR gene in receptacles. Compared with fruits at green stage, its expression level increased by 142-fold at red stage. The qRT-PCR results supported that the expression of FaAKR23 was increased significantly during fruit ripening. In particular, the FaAKR23 was the only FaAKR gene that was significantly upregulated by abscisic acid (ABA) and suppressed by nordihydroguaiaretic acid (NDGA, an ABA biosynthesis blocker), indicating FaAKR23 might play important roles in ABA-mediated strawberry fruit ripening. In a word, our study provides useful information on the AsA metabolism during strawberry fruit ripening and will help understand the mechanism of AsA accumulation in strawberry fruits.

In-situ compatibilized starch/polyacylonitrile composite fiber fabricated via dry-wet spinning technique.

An in-situ compatibilized starch (St) and polyacrylonitrile (PAN) composite spinning solution was designed by preparing starch-graft-polyacrylonitrile (St-g-PAN) through graft copolymerizing acrylonitrile from soluble starch and using ammonium cerium nitrate (CAN) as initiator. As dimethyl sulfoxide (DMSO) was used as the solvent, St/St-g-PAN/PAN/DMSO spinning solution was prepared and St/St-g-PAN/PAN composite fibers were obtained by dry-wet spinning technique. The effects of air gap, coagulation bath, hot drawing and stretching, and thermal-setting process were studied in detail. Fourier transform infrared spectroscopy (FT-IR), solid state nuclear magnetic resonance (13C NMR), thermogravimetric analysis (TGA), X-ray diffraction analysis (XRD), and scanning electron microscopy (SEM) were used to characterize the structure and morphology of the copolymer and the fibers. Single fiber strength tester and sonic orientation instrument were performed to measure the fiber mechanical properties and orientation degrees. The results showed that as the grafting ratio ~150.0% and the reacting mixture containing St ~9.8%, St-g-PAN ~81.6%, and homo-PAN ~8.6% in DMSO solution with 6.0 wt% in concentration were used, the spinning parameters such as air gap ~35 mm, coagulation bath concentration ~70%, temperature ~25 °C, and positive stretching ~48%, hot drawing and stretching 6 times at 80 °C, thermal-setting at 90 °C for 3 h under constant length mode were met, composite fibers with breaking strength 3.41 cN·dtex-1, breaking elongation 14.41%, sonic orientation factor 0.625, moisture recovery ratio 10.53% under standard condition (1 atm, 22 °C, and relative humidity 65%), and boiling water shrinkage ratio 9.60% were obtained. The as prepared composite fiber was better than common viscose fiber 2.11 cN·dtex-1 and cotton fiber ~3.24 cN·dtex-1 and expected to be used in the fields of medical gauze, bandage, protective clothing, et al. besides of common textiles. The in-situ compatibilization method can be applied in preparation of other composite polymer materials.

Constructing new acid-activated anticancer peptide by attaching a desirable anionic binding partner peptide.

Improving the cell selectivity of anticancer peptides (ACPs) is a major hurdle in their clinical utilisation. In this study, a new acid-activated ACP was designed by conjugating a cationic ACP LK to its anionic binding partner peptide (LEH) via a disulphide linker to trigger antitumor activity at acidic pH while masking its killing activity at normal pH. Three anionic binding peptides containing different numbers of glutamic acid (Glu) and histidine were engineered to obtain an efficient acid-activated ACP. The conjugates LK-LEH2 and LK-LEH3 exhibited 6.1- and 8.0-fold higher killing activity at pH 6.0 relative to at pH 7.4, respectively, suggesting their excellent pH-dependent antitumor activity; and their cytotoxicity was 10-fold lower than that of LK. However, LK-LEH4 had no pH-responsive killing effect. Interestingly, increasing the number of Glu from 2 to 4 increased the pH-response of the physical mixture of LK and LEH; conversely, they weakly decreased the cytotoxicity of LK, suggesting that the conjugate connection is required to achieve excellent pH dependence while maintaining minimum toxicity. LK-LEH2 and LK-LEH3 were more enzymatically stable than LK, indicating their potential for in vivo application. Our work provided a basis for designing promising ACPs with good selectivity and low toxicity.

AKR1C1 promotes non-small cell lung cancer proliferation via crosstalk between HIF-1α and metabolic reprogramming.

Non-small cell lung cancer (NSCLC) ranks first among cancer death worldwide. Despite efficacy and safety priority, targeted therapy only benefits ∼30% patients, leading to the unchanged survival rates for whole NSCLC patients. Metabolic reprogramming occurs to offer energy and intermediates for fuelling cancer cells proliferation. Thus, mechanistic insights into metabolic reprogramming may shed light upon NSCLC proliferation and find new proper targets for NSCLC treatment. Herein, we used loss- and gain-of-function experiments to uncover that highly expressed aldo-keto reductase family1 member C1 (AKR1C1) accelerated NSCLC cells proliferation via metabolic reprogramming. Further molecular profiling analyses demonstrated that AKR1C1 augmented the expression of hypoxia-inducible factor 1-alpha (HIF-1α), which could drive tumour metabolic reprogramming. What's more, AKR1C1 significantly correlated with HIF-1α signaling, which predicted poor prognosis for NSCLC patients. Collectively, our data display that AKR1C1 reprograms tumour metabolism to promote NSCLC cells proliferation by activating HIF-1α. These newly acquired data not only establish the specific role for AKR1C1 in metabolic reprogramming, but also hint to the possibility that AKR1C1 may be a new therapeutic target for NSCLC treatment.