Pedobacter deserti sp. nov., a novel species isolated from desert soil.

An aerobic, Gram-stain-negative bacterium, designated as SYSU D00382T, was sourced from soil of Gurbantunggut Desert, PR China. The strain was short-rod-shaped, oxidase-positive and catalase-negative, with yellow-colored, convex, round, and smooth colonies on TSA plate. Growth and proliferation occurred at 4-37 °C (optimal: 28-30 °C), pH 5.0-8.0 (optimal: pH 6.0-7.0) and NaCl concentration of 0-2.5% (optimal: 0-0.5%). The 16S rRNA gene based phylogenetic assessment showed that SYSU D00382T belonged to the genus Pedobacter, and was most closely related to Pedobacter ginsengisoli Gsoil 104T with similarity of 97.7%. The genomic DNA G+C content of SYSU D00382T was 46.4%. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between SYSU D00382T and P. ginsengisoli Gsoil 104T were 75.7% and 17.5%, respectively. The main polar lipid was phosphatidylethanolamine. The major fatty acids (> 5%) were iso-C15:0, iso-C17:0 3-OH, summed features 3 and 9. The sole respiratory quinone identified was MK-7. The phylogeny based on 16S rRNA gene and whole-genome sequences revealed that SYSU D00382T formed a robust lineage with P. ginsengisoli Gsoil 104T. Based on phenotypic, phylogenetic and genotypic data, a novel specie named Pedobacter deserti sp. nov. is proposed. The type strain is SYSU D00382T (= CGMCC 1.18627T = MCCC 1K04972T = KCTC 82279T).

Circ-ABCB10 knockdown inhibits the malignant progression of cervical cancer through microRNA-128-3p/ZEB1 axis.

AIMS: We focused on the detailed functions of circ-ABCB10 in cervical cancer (CC) development and its mechanisms. BACKGROUND: The increasing findings have proposed the central roles of circular RNAs (circRNAs) in the tumorigenesis of various human cancers. Circ-ABCB10 displays promising oncogenic effect in several tumors. METHODS: Circ-ABCB10 and miR-128-3p production levels in CC tissues and cells were tested through RT-qPCR. The association of circ-ABCB10 expression with clinicopathologic parameters of CC patients was statistically analyzed. Cell proliferation, invasion, apoptosis, and epithelial-mesenchymal transition (EMT) were evaluated by MTT, transwell invasion assays, flow cytometry analyses, and western blot examination of EMT markers. The binding activity between miR-128-3p and circ-ABCB10 or zinc finger E-box binding homeobox 1 (ZEB1) was explored through pull-down assay or luciferase reporter assay. The influence of circ-ABCB10 on CC tumorigenesis was evaluated by in vivo xenograft experiments. RESULTS: The elevated circ-ABCB10 expression was determined in CC tissues and cells. Moreover, higher production level of circ-ABCB10 was close related to lymph-node metastasis, Federation of Gynecology and Obstetrics (FIGO) stage, and tumor size in CC patients. Loss of circ-ABCB10 weakened cell proliferative and invasive abilities, inhibited EMT, and induced apoptosis in CC. Loss of circ-ABCB10 inhibited ZEB1 expression by serving as a sponge of miR-128-3p in CC cells. Circ-ABCB10 sponged miR-128-3p to enhance cell proliferation, invasion, EMT and inhibit apoptosis in CC cells. Xenograft tumor assays confirmed that circ-ABCB10 knockdown inhibited CC tumor growth. CONCLUSION: Our study suggests that circ-ABCB10 depletion inhibits proliferation, invasion and EMT and promotes apoptosis of cervical cancer cells through miR-128-3p/ZEB1 axis and represses CC tumor growth.

Antitumor activity of SR splicing-factor 5 knockdown by downregulating pyruvate kinase M2 in non-small cell lung cancer cells.

SR splicing-factors (SRSFs) play a vital role in carcinogenesis. SRSF5 was demonstrated to be upregulated in lung cancer and identified as a novel prognostic indicator for small-cell lung cancer. However, the role of SRSF5 in the pathogenesis of non-small cell lung cancer (NSCLC) and the molecular mechanism involved are still undefined. The expression of SRSF5 in NSCLC cells was detected by quantitative real-time polymerase chain reaction and Western blot analysis. The proliferation of cells was evaluated by cell counting kit-8 and BrdU assays. Apoptosis was assessed by flow cytometry and Western blot analysis of apoptosis-associated proteins including B-cell lymphoma 2 (Bcl-2), Bax, and cytochrome C (Cyt C). Glycolysis was detected by determining glucose consumption, lactate production, and pyruvate kinase M2 (PKM2) expression. We found that SRSF5 messenger RNA and protein levels were elevated in NSCLC cells. SRSF5 knockdown inhibited the proliferation and Ki67 expression in NSCLC cells. SRSF5 silencing increased the apoptotic rate, upregulated Bax and Cyt C, and decreased Bcl-2 level in NSCLC cells. Moreover, Knockdown of SRSF5 repressed glycolysis in NSCLC cells via reducing PKM2 expression. Enhanced glycolysis by PKM2 overexpression attenuated the effects of SRSF5 silencing on NSCLC cell proliferation and apoptosis. Overall, knockdown of SRSF5 inhibited proliferative ability and induced apoptosis by suppressing PKM2 expression in NSCLC cells.

A novel stromal lncRNA signature reprograms fibroblasts to promote the growth of oral squamous cell carcinoma via LncRNA-CAF/interleukin-33.

Stromal carcinoma-related fibroblasts (CAFs) are the main type of non-immune cells in the tumor microenvironment (TME). CAFs interact with cancer cells to promote tumor proliferation. Long non-coding RNAs (lncRNAs) are known to regulate cell growth, apoptosis and metastasis of cancer cells, but their role in stromal cells is unclear. Using RNA sequencing, we identified a stromal lncRNA signature during the transformation of CAFs from normal fibroblasts (NFs) in oral squamous cell carcinoma (OSCC). We uncovered an uncharacterized lncRNA, FLJ22447, which was remarkably up-regulated in CAFs, referred to LncRNA-CAF (Lnc-CAF) hereafter. Interleukin-33 (IL-33) was mainly located in the stroma and positively co-expressed with Lnc-CAF to elevate the expression of CAF markers (α-SMA, vimentin and N-cadherin) in fibroblasts. In a co-culture system, IL-33 knockdown impaired Lnc-CAF-mediated stromal fibroblast activation, leading to decreased proliferation of tumor cells. Mechanistically, Lnc-CAF up-regulated IL-33 levels and prevented p62-dependent autophagy-lysosome degradation of IL-33, which was independent of LncRNA-protein scaffold effects. Treatment with the autophagy inducer, rapamycin, impaired the proliferative effect of Lnc-CAF/IL-33 by promoting IL-33 degradation. In turn, tumor cells further increased Lnc-CAF levels in stromal fibroblasts via exosomal Lnc-CAF. In patients with OSCC, high Lnc-CAF/IL-33 expression correlated with high TNM stage (n = 140). Moreover, high Lnc-CAF expression predicted poor prognosis. In vivo, Lnc-CAF knockdown restricted tumor growth and was associated with decreased Ki-67 expression and α-SMA+ CAF in the stroma. In conclusion, we identified a stromal lncRNA signature, which reprograms NFs to CAFs via Lnc-CAF/IL-33 and promotes OSCC development.

LncRNA HOTAIR Regulates CCND1 and CCND2 Expression by Sponging miR-206 in Ovarian Cancer.

BACKGROUND/AIMS: The long noncoding RNA homeobox (HOX) transcript antisense intergenic RNA (HOTAIR) has been demonstrated to be a vital modulator in the proliferation and metastasis of ovarian cancer cells, but its potential molecular mechanism remains to be elucidated. In the current study, we aimed to uncover the biological role of lncRNA HOTAIR and its underlying regulatory mechanism in the progression and metastasis of ovarian cancer. METHODS: HOTAIR expression was detected by quantitative RT-PCR (qRT-PCR) and northern blotting. The SKOV3 ovarian cancer cell line was chosen for the subsequent assays. In addition, the molecular mRNA and protein expression levels were examined by qRT-PCR and western blotting. The competitive endogenous RNA (ceRNA) mechanism was validated by bioinformatics analysis and a dual luciferase reporter gene assay. RESULTS: HOTAIR expression was significantly higher in ovarian carcinoma tissues and cell lines than in the control counterparts. Both CCND1 and CCND2 were downstream targets of miR-206. The inhibition of HOTAIR elevated the expression of miR-206 and inhibited the expression of CCND1 and CCND2. Moreover, CCND1 and CCND2 were highly expressed in ovarian cancer tissues, and their expression was positively correlated with HOTAIR expression. Finally, the functional assays indicated that the anticancer effects of miR-206 could be rescued by the simultaneous overexpression of either CCND1 or CCND2 in ovarian cancer. CONCLUSION: HOTAIR enhanced CCND1 and CCND2 expression by negatively modulating miR-206 expression and stimulating the proliferation, cell cycle progression, migration and invasion of ovarian cancer cells.

Long noncoding RNA LUCAT1 promotes malignancy of ovarian cancer through regulation of miR-612/HOXA13 pathway.

Emerging evidence shows that long noncoding RNA (lncRNA) is implicated in numerous kinds of malignant cancers, including ovarian cancer. In this study, we focused on the expression and function of long noncoding RNA lung cancer associated transcript 1 (LUCAT1) in ovarian cancer progression. We indicated that LUCAT1 expression was significantly upregulated in ovarian cancer tissues. Moreover, LUCAT1 expression was positively associated with tumor metastasis and clinical stage. Elevated expression of LUCAT1 decreased the survival rate of patients with ovarian cancer. In addition, we revealed that repression of LUCAT1 significantly suppressed the proliferation, migration and invasion, whereas promoted apoptotic rate. Through online predictive tools and functional experiments, we demonstrated that LUCAT1 and HOXA13 were targets of miR-612. We showed that LUCAT1 and miR-612 suppressed each other in a reciprocal way. Moreover, LUCAT1 promoted HOXA13 expression through inhibition of miR-612, eventually leading to ovarian cancer development. In conclusion, our findings revealed a novel molecular mechanism that LUCAT1/miR-612/HOXA13 pathway modulates ovarian cancer progression.

A metagenome-wide association study of gut microbiota in type 2 diabetes.

Assessment and characterization of gut microbiota has become a major research area in human disease, including type 2 diabetes, the most prevalent endocrine disease worldwide. To carry out analysis on gut microbial content in patients with type 2 diabetes, we developed a protocol for a metagenome-wide association study (MGWAS) and undertook a two-stage MGWAS based on deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals. We identified and validated approximately 60,000 type-2-diabetes-associated markers and established the concept of a metagenomic linkage group, enabling taxonomic species-level analyses. MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. An analysis of 23 additional individuals demonstrated that these gut microbial markers might be useful for classifying type 2 diabetes.

Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer.

OBJECTIVE: To evaluate the potential for diagnosing colorectal cancer (CRC) from faecal metagenomes. DESIGN: We performed metagenome-wide association studies on faecal samples from 74 patients with CRC and 54 controls from China, and validated the results in 16 patients and 24 controls from Denmark. We further validated the biomarkers in two published cohorts from France and Austria. Finally, we employed targeted quantitative PCR (qPCR) assays to evaluate diagnostic potential of selected biomarkers in an independent Chinese cohort of 47 patients and 109 controls. RESULTS: Besides confirming known associations of Fusobacterium nucleatum and Peptostreptococcus stomatis with CRC, we found significant associations with several species, including Parvimonas micra and Solobacterium moorei. We identified 20 microbial gene markers that differentiated CRC and control microbiomes, and validated 4 markers in the Danish cohort. In the French and Austrian cohorts, these four genes distinguished CRC metagenomes from controls with areas under the receiver-operating curve (AUC) of 0.72 and 0.77, respectively. qPCR measurements of two of these genes accurately classified patients with CRC in the independent Chinese cohort with AUC=0.84 and OR of 23. These genes were enriched in early-stage (I-II) patient microbiomes, highlighting the potential for using faecal metagenomic biomarkers for early diagnosis of CRC. CONCLUSIONS: We present the first metagenomic profiling study of CRC faecal microbiomes to discover and validate microbial biomarkers in ethnically different cohorts, and to independently validate selected biomarkers using an affordable clinically relevant technology. Our study thus takes a step further towards affordable non-invasive early diagnostic biomarkers for CRC from faecal samples.

Emergency Pacing via the Umbilical Vein and Subsequent Permanent Pacemaker Implantation in a Neonate.

A dying neonate with congenital complete atrioventricular block underwent an emergency temporary pacing via the umbilical vein 1 h after birth. Implantation of a permanent epicardial pacemaker system was performed at the age of 10 days. During the follow-up period of 3 months, the child had been growing well with the VVIR pacemaker.

Inhibition of Cervical Cancer by Promoting IGFBP7 Expression Using Ellagic Acid from Pomegranate Peel.

BACKGROUND The aim of this study was to explore the mechanism by which cervical cancer is inhibited by promoting IGFBP7 expression using ellagic acid from pomegranate peel extract. MATERIAL AND METHODS HeLa cells were divided into 6 groups: control group (NC), blank control group (BL), and IGFBP7 overexpression group (IGFBP7), and 2.5 uM, 5. 0 uM, and 10.0 uM ellagic acid-treated groups. The cell proliferation ability was detected and the degree of invasion in the 6 groups was measured by Transwell assay. The expression levels of IGFBP7 and AKT/mTOR in the 6 groups of cells were detected by RT-PCR technique. RESULTS Compared with NC and BL groups, The IGFBP7 gene expressions of the IGFPB7 and ellagic acid-treated groups were significantly increased (P<0.05). There was a dose-effect dependence in the ellagic acid-treated groups. The invasion ability of the IGFBP7 group and ellagic acid-treated groups was significantly lower than that of NC and BL groups in HeLa cells (P<0.05). The apoptosis rate of the IGFBP7 group and ellagic acid-treated groups was significantly higher than that of the NC and BL groups in HeLa cells (P<0.05). AKT and mTOR mRNA and protein expressions of the IGFBP7 group and ellagic acid-treated groups were significantly lower than that of the NC and BL groups (P<0.05). There was a dose-effect dependence in the ellagic acid-treated groups. CONCLUSIONS The ellagic acid in pomegranate peel extract can inhibit the AKT/mTOR signaling pathway by enhancing the expression level of IGFBP7, which can inhibit the HeLa cells in cervical cancer.

Management of polycystic ovarian syndrome with Diane-35 or Diane-35 plus metformin.

In this study, we assessed the efficacy and safe usage of the oral contraceptive, Diane-35, in the treatment of polycystic ovary syndrome (PCOS) when combined with the drug metformin. Eighty-two patients with PCOS were randomly divided into two equal groups: Diane-35 treatment group and Diane-35 plus metformin group. Three treatment cycles were administered. Patients' biomedical data such as height, weight, waist circumference, hip circumference, body fat percentage, acne score, hirsutism score and serum hormone levels were selected, which were tested between the second and the fifth day of the menstrual cycle and follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), blood glucose, blood lipids and insulin levels(IR) were analyzed. Significant reduction in body mass index (BMI), acne score, LH and T levels were observed in both groups after three months of treatment; on the other hand, high-density lipoprotein cholesterol (HDL) concentration elevated (p < 0.05). Combined treatment group had a significant change in BMI index and fasting blood glucose levels compared to Diane-35 alone treatment group (p < 0.05). With personalized nutrition and exercise program, Diane-35 only group or Diane-35 plus metformin group had both significantly lowered their serum testosterone levels and had improved acne symptoms. Diane-35 plus metformin combination had shown reduced fat percentage levels in patients with PCOS, and had shown improved glucose and lipid metabolism.

Serum IL-17F combined with VEGF as potential diagnostic biomarkers for oral squamous cell carcinoma.

Although interleukin (IL) 17A can promote angiogenesis in several tumors, there are limited clinical evidences on cancer about the correlation between serum vascular endothelial growth factor (VEGF) and IL-17F, which is the most homologous to IL-17A. In this study, serum concentration of IL-17F and VEGF from healthy (n = 28), leukoplakia (n = 15), and oral squamous cell carcinoma (OSCC) groups (n = 85) were assessed and showed that IL-17F level was remarkably downregulated from healthy group (394.3 pg/ml) to OSCC group (82.96 pg/ml). Conversely, the OSCC group had a highest level of VEGF (P < 0.05) in whole groups, and there was a negative correlation between IL-17F and VEGF in serum or in the peripheral blood mononuclear cells (PBMCs) at mRNA level. Moreover, the lowest ratio of IL-17F/VEGF was found in OSCC patients (P < 0.05) and lower ratio of IL-17F/VEGF correlated to higher tumor stage and lymph node metastasis. Furthermore, the serum level of IL-17F and the ratio of IL-17F/VEGF were positively associated with the numbers of CD3(+) CD4(+) T cells, which indicated that serum IL-17F could originate from PBMCs during the development of OSCC, and could be used for the diagnosis by effectively distinguishing OSCC patients from healthy individuals.

Characterizations of multi-kingdom gut microbiota in immune checkpoint inhibitor-treated hepatocellular carcinoma.

BACKGROUND: The association between gut bacteria and the response to immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) has been studied; however, multi-kingdom gut microbiome alterations and interactions in ICI-treated HCC cohorts are not fully understood. METHODS: From November 2018 to April 2022, patients receiving ICI treatment for advanced HCC were prospectively enrolled. Herein, we investigated the multi-kingdom microbiota characterization of the gut microbiome, mycobiome, and metabolome using metagenomic, ITS2, and metabolomic data sets of 80 patients with ICI-treated HCC. RESULTS: Our findings demonstrated that bacteria and metabolites differed significantly between the durable clinical benefit (DCB) and non-durable clinical benefit (NDB) groups, whereas the differences were smaller for fungi. The overall diversity of bacteria and fungi before treatment was higher in the DCB group than in the NDB group, and the difference in diversity began to change with the use of immunotherapy after 6-8 weeks. We also explored the alterations of gut microbes in the DCB and NDB groups, established 18 bacterial species models as predictive biomarkers for predicting whether immunotherapy is of sustained benefit (area under the curve=75.63%), and screened two species of bacteria (Actinomyces_sp_ICM47, and Senegalimassilia_anaerobia) and one metabolite (galanthaminone) as prognostic biomarkers for predicting survival in patients with HCC treated with ICI. CONCLUSIONS: In this study, the status and characterization of the multi-kingdom microbiota, including gut bacteria, fungi, and their metabolites, were described by multiomics sequencing for the first time in patients with HCC treated with ICI. Our findings demonstrate the potential of bacterial taxa as predictive biomarkers of ICI clinical efficacy, and bacteria and their metabolites as prognostic biomarkers.

Gut microbiota and metabolites signatures of clinical response in anti-PD-1/PD-L1 based immunotherapy of biliary tract cancer.

BACKGROUND: Accumulating evidence suggests that the gut microbiota and metabolites can modulate tumor responses to immunotherapy; however, limited data has been reported on biliary tract cancer (BTC). This study used metagenomics and metabolomics to identify characteristics of the gut microbiome and metabolites in immunotherapy-treated BTC and their potential as prognostic and predictive biomarkers. METHODS: This prospective cohort study enrolled 88 patients with BTC who received PD-1/PD-L1 inhibitors from November 2018 to May 2022. The microbiota and metabolites significantly enriched in different immunotherapy response groups were identified through metagenomics and LC-MS/MS. Associations between microbiota and metabolites, microbiota and clinical factors, and metabolites and clinical factors were explored. RESULTS: Significantly different bacteria and their metabolites were both identified in the durable clinical benefit (DCB) and non-durable clinical benefit (NDB) groups. Of these, 20 bacteria and two metabolites were significantly associated with survival. Alistipes were positively correlated with survival, while Bacilli, Lactobacillales, and Pyrrolidine were negatively correlated with survival. Predictive models based on six bacteria, four metabolites, and the combination of three bacteria and two metabolites could all discriminated between patients in the DCB and NDB groups with high accuracy. Beta diversity between two groups was significantly different, and the composition varied with differences in the use of immunotherapy. CONCLUSIONS: Patients with BTC receiving immunotherapy have specific alterations in the interactions between microbiota and metabolites. These findings suggest that gut microbiota and metabolites are potential prognostic and predictive biomarkers for clinical outcomes of anti-PD-1/PD-L1-treated BTC.

Jinhong decoction protects sepsis-associated acute lung injury by reducing intestinal bacterial translocation and improving gut microbial homeostasis.

Background: Currently no specific treatments are available for sepsis and the associated syndromes including acute lung injury (ALI). Jinhong Decoction (JHD) is a traditional Chinese prescription, and it has been applied clinically as an efficient and safe treatment for sepsis, but the underlying mechanism remains unknown. The aim of the study was to explore the potential mechanisms of JHD ameliorating sepsis and concurrent ALI. Methods: The cecum ligation puncture (CLP)- induced murine sepsis model was established for determining the efficacy of JHD protecting CLP and ALI. The role of gut microbiota involved in the efficacy of JHD was evaluated by 16S rRNA sequencing and fecal microbiota transplantation (FMT). Translocation of intestinal Escherichia coli (E. coli) to lungs after CLP was verified by qPCR and in vivo-imaging. Intestinal permeability was analyzed by detecting FITC-dextran leakness. Junction proteins were evaluated by Western blotting and immunofluorescence. Results: JHD treatment remarkably increased survival rate of septic mice and alleviated sepsis-associated lung inflammation and injury. FMT suggested that the protective role for JHD was mediated through the regulation of gut microbiota. We further revealed that JHD administration partially restored the diversity and configuration of microbiome that was distorted by CLP operation. Of interest, the intestinal bacteria, E. coli particularly, was found to translocate into the lungs upon CLP via disrupting the intestinal mucosal barrier, leading to the inflammatory response and tissue damage in lungs. JHD impeded the migration and hence lung accumulation of intestinal E. coli, and thereby prevented severe ALI associated with sepsis. This effect is causatively related with the ability of JHD to restore intestinal barrier by up-regulating tight junctions. Conclusion: Our study unveils a mechanism whereby the migration of gut bacteria leads to sepsis-associated ALI, and we demonstrate the potential of JHD as an effective strategy to block this bacterial migration for treating sepsis and the associated immunopathology in the distal organs.

Strategy and technique for surgical treatment of Ebstein's anomaly.

BACKGROUND: Ebstein's anomaly (EA) is a rare and complex congenital heart anomaly, and the effect of surgical treatment is not ideal. This study aims to introduce our experience in management strategies, surgical techniques, and operative indications for patients with Ebstein's anomaly. METHODS: A retrospective study of 258 operations was performed in 253 patients by the same cardiac surgeon in The First Hospital of Tsinghua University between March 2004 and January 2020. 32 patients had previously received cardiac surgery in other hospitals. The clinical data including diagnosis, operative indications, techniques, pathological changes, and survival rates were collected and analyzed. RESULTS: Anatomical correction was performed in 203 (78.7%) operations, 1½ ventricle repair in 38 (14.7%) operations, tricuspid valve repair only in four operations (1.6%), tricuspid valve replacement in ten (3.9%), total cavopulmonary connection (TCPC) in two (0.8%), and Glenn operation in one operation (0.4%). Reoperation was performed in five patients (2.0%) during hospitalization. Among them, tricuspid valve replacement was performed in one patient, 1½ ventricle repair in two patients, and tricuspid valve annulus reinforcement in two patients. Five patients died with an early mortality rate of 2.0%. Complete atrioventricular conduction block was complicated in one patient (0.4%). A total of 244 patients was followed up (four in the 253 patients lost) with a duration of 3.0-168.0 (87.6 ± 38.4) months. Cardiac function of 244 patients improved significantly with mean New York Heart Association (NYHA) functional class recovery from 3.5 to 1.1. The mean grade of tricuspid valve regurgitation improved from 3.6 to 1.5. Three late deaths (1.2%) occurred. The survival rates at five and ten years after surgery were 98.6% and 98.2%, respectively. Reoperation was performed in five patients (2.0%) during the follow-up period. CONCLUSION: Based on our management strategies and operative principles and techniques, anatomical correction of EA is capable of achieving excellent long-term results, and low rates of TCPC, 1½ ventricle repair and valvular replacement.

Cancer cell-mitochondria hybrid membrane coated Gboxin loaded nanomedicines for glioblastoma treatment.

Glioblastoma (GBM) remains the most lethal malignant tumours. Gboxin, an oxidative phosphorylation inhibitor, specifically restrains GBM growth by inhibiting the activity of F0F1 ATPase complex V. However, its anti-GBM effect is seriously limited by poor blood circulation, the blood brain barrier (BBB) and non-specific GBM tissue/cell uptake, leading to insufficient Gboxin accumulation at GBM sites, which limits its further clinical application. Here we present a biomimetic nanomedicine (HM-NPs@G) by coating cancer cell-mitochondria hybrid membrane (HM) on the surface of Gboxin-loaded nanoparticles. An additional design element uses a reactive oxygen species responsive polymer to facilitate at-site Gboxin release. The HM camouflaging endows HM-NPs@G with unique features including good biocompatibility, improved pharmacokinetic profile, efficient BBB permeability and homotypic dual tumour cell and mitochondria targeting. The results suggest that HM-NPs@G achieve improved blood circulation (4.90 h versus 0.47 h of free Gboxin) and tumour accumulation (7.73% ID/g versus 1.06% ID/g shown by free Gboxin). Effective tumour inhibition in orthotopic U87MG GBM and patient derived X01 GBM stem cell xenografts in female mice with extended survival time and negligible side effects are also noted. We believe that the biomimetic Gboxin nanomedicine represents a promising treatment for brain tumours with clinical potential.

Capturing the microbial dark matter in desert soils using culturomics-based metagenomics and high-resolution analysis.

Deserts occupy one-third of the Earth's terrestrial surface and represent a potentially significant reservoir of microbial biodiversity, yet the majority of desert microorganisms remain uncharacterized and are seen as "microbial dark matter". Here, we introduce a multi-omics strategy, culturomics-based metagenomics (CBM) that integrates large-scale cultivation, full-length 16S rRNA gene amplicon, and shotgun metagenomic sequencing. The results showed that CBM captured a significant amount of taxonomic and functional diversity missed in direct sequencing by increasing the recovery of amplicon sequence variants (ASVs) and high/medium-quality metagenome-assembled genomes (MAGs). Importantly, CBM allowed the post hoc recovery of microbes of interest (e.g., novel or specific taxa), even those with extremely low abundance in the culture. Furthermore, strain-level analyses based on CBM and direct sequencing revealed that the desert soils harbored a considerable number of novel bacterial candidates (1941, 51.4%), of which 1095 (from CBM) were culturable. However, CBM would not exactly reflect the relative abundance of true microbial composition and functional pathways in the in situ environment, and its use coupled with direct metagenomic sequencing could provide greater insight into desert microbiomes. Overall, this study exemplifies the CBM strategy with high-resolution is an ideal way to deeply explore the untapped novel bacterial resources in desert soils, and substantially expands our knowledge on the microbial dark matter hidden in the vast expanse of deserts.

IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis.

Diffuse infiltration is the main reason for therapeutic resistance and recurrence in glioblastoma (GBM). However, potential targeted therapies for GBM stem-like cell (GSC) which is responsible for GBM invasion are limited. Herein, we report Insulin-like Growth Factor-Binding Protein 5 (IGFBP5) is a ligand for Receptor tyrosine kinase like Orphan Receptor 1 (ROR1), as a promising target for GSC invasion. Using a GSC-derived brain tumor model, GSCs were characterized into invasive or non-invasive subtypes, and RNA sequencing analysis revealed that IGFBP5 was differentially expressed between these two subtypes. GSC invasion capacity was inhibited by IGFBP5 knockdown and enhanced by IGFBP5 overexpression both in vitro and in vivo, particularly in a patient-derived xenograft model. IGFBP5 binds to ROR1 and facilitates ROR1/HER2 heterodimer formation, followed by inducing CREB-mediated ETV5 and FBXW9 expression, thereby promoting GSC invasion and tumorigenesis. Importantly, using a tumor-specific targeting and penetrating nanocapsule-mediated delivery of CRISPR/Cas9-based IGFBP5 gene editing significantly suppressed GSC invasion and downstream gene expression, and prolonged the survival of orthotopic tumor-bearing mice. Collectively, our data reveal that IGFBP5-ROR1/HER2-CREB signaling axis as a potential GBM therapeutic target.