Targeting NPM1 inhibits proliferation and promotes apoptosis of hepatic progenitor cells via suppression of mTOR signalling pathway.

BACKGROUND: Hepatic progenitor cells serve not only as the origin of combined hepatocellular cholangiocarcinoma (cHCC-CCA) but are also responsible for malignancy recurrence after surgical resection. Nucleophosmin 1 (NPM1) has been implicated in cancer metastasis and poor prognosis. This study aimed to determine the expression of NPM1 by hepatic progenitor cells in cHCC-CCA and the effects of targeting NPM1 on hepatic progenitor cells and BEL-7402 cells with characteristics of both progenitor cells and cHCC-CCA. METHODS: First, NPM1 was detected by RT‒PCR, western blotting, and double-immunofluorescence staining in cHCC-CCA tissues. NPM1 expression was subsequently analysed in rat hepatic progenitor cells cultured in vitro and in interleukin 6 (IL6)-treated cells. The effects and mechanism of NPM1 on hepatic progenitor cells were determined by knocking down NPM1 and performing RNA sequencing analysis. Finally, NSC348884, a small-molecule inhibitor that disrupts NPM1 dimer formation, was used to confirm the function of NPM1 in BEL-7402 cells. RESULTS: Both human hepatic progenitor cells in cHCC-CCA tissues and rat in vitro cultured hepatic progenitor cells highly expressed NPM1. IL6, a cytokine involved in the malignant transformation of hepatic progenitor cells, dose-dependently increased NPM1 and PCNA expression. Knocking down NPM1 reduced IL6R transcription (P < 0.0001) and inhibited the proliferation (P = 0.0065) of hepatic progenitor cells by suppressing the mTOR signalling pathway and activating the apoptosis pathway. Furthermore, knocking down NPM1 in hepatic progenitor cells resulted in more apoptotic cells (7.33 ± 0.09% vs. 3.76 ± 0.13%, P < 0.0001) but fewer apoptotic cells in the presence of NSC348884 (47.57 ± 0.49% vs. 63.40 ± 0.05%, P = 0.0008) than in the control cells, suggesting that low-NPM1-expressing cells are more resistant to NSC348884. In addition, NSC348884 induced the apoptosis of BEL-7402 cells with an IC50 of 2.77 µmol/L via the downregulation of the IL-6R and mTOR signalling pathways and inhibited the growth of BEL-7402 cells in a subcutaneous xenograft tumour model (P = 0.0457). CONCLUSIONS: Targeting NPM1 inhibits proliferation and induces apoptosis in hepatic progenitor cells and BEL-7402 cells, thus serving as a potential therapy for cHCC-CCA.

Clinical features and CPS1 variants in Chinese patients with carbamoyl phosphate synthetase 1 deficiency.

BACKGROUND: Carbamoyl phosphate synthetase 1 (CPS1) deficiency (OMIM 237300), an autosomal recessive rare and severe urea cycle disorder, is associated with hyperammonemia and high mortality. METHODS: Herein we present 12 genetic variants identified in seven clinically well-characterized Chinese patients with CPS1 deficiency who were admitted to the Children's Medical Center of Peking University First Hospital from September 2014 to August 2023. RESULTS: Seven patients (two male and five female patients including two sisters) experienced symptoms onset between 2 days and 13 years of age, and they were diagnosed with CPS1 deficiency between 2 months and 20 years. Peak blood ammonia levels ranged from 160 to 1,000 µmol/L. Three patients showed early-onset CPS1 deficiency, with only one surviving after treatment with sodium phenylbutyrate, N-carbamoyl-L-glutamate, and liver transplantation at 4 months, showing a favorable outcome. The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets. Among the 12 CPS1 variants identified in these patients, 10 were novel, with all patients exhibiting compound heterozygosity for CPS1 mutant alleles. Seven variants (c.149T > C, c.616 A > T, c.1145 C > T, c.1294G > A, c.3029 C > T, c.3503 A > T, and c.3793 C > T) resulted in single amino acid substitutions. Three frameshift variations (c.2493del, c.3067dup, and c.3241del) were identified, leading to enzyme truncation. One mutation (c.3506_3508del) caused an in-frame single amino acid deletion, while another (c.2895 + 2T > C) resulted in aberrant splicing. CONCLUSIONS: Except for two known variants, all other variants were identified as novel. No hotspot variants were observed among the patients. Our data contribute to expanding the mutation spectrum of CPS1.

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Polycystic ovary syndrome (PCOS) is one of the most common gynecological endocrine disorders. Most pathophysiological changes of PCOS begin in the peripubertal phase, and these pathophysiological changes will continuously affect women's health in the later stages of their lives. The pathogenic mechanisms of PCOS remain unclear, involving key aspects such as the regulation of hypothalamic-pituitary function, ovarian cellular functions, androgen levels, and insulin resistance. Herein, we summarized the latest findings on the pathogenesis of PCOS from the perspectives of the genetic background, intrauterine development, neuroendocrine function, inflammatory factors, gut microbiome, and environmental factors. This review will help provide new ideas for a deeper understanding of the disease, as well as its clinical diagnosis and treatment.

Fibroblast growth factor 2 promotes osteo/odontogenic differentiation in stem cells from the apical papilla by inhibiting PI3K/AKT pathway.

Fibroblast growth factor 2 (FGF2) is a crucial factor in odontoblast differentiation and dentin matrix deposition, which facilitates pulpodentin repair and regeneration. Nevertheless, the specific biological function of FGF2 in odontoblastic differentiation remains unclear because it is controlled by complex signalling pathways. This study aimed to investigate the mechanism underlying the effect of FGF2 on osteo/odontogenic differentiation of stem cells from the apical papilla (SCAP). SCAP were pretreated with conditioned media containing FGF2 for 1 week, followed by culturing in induced differentiation medium for another week. RNA sequencing (RNA-seq) combined with quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to evaluate the pathways affected by FGF2 in SCAP. Osteo/odontogenic differentiation of SCAP was determined using Alizarin red S staining, alkaline phosphatase staining, RT-qPCR, and western blotting. Pretreatment with FGF2 for 1 week increased the osteo/odontogenic differentiation ability of SCAP. RNA-seq and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that phosphatidylinositol 3-kinase (PI3K)/AKT signalling is involved in the osteogenic function of FGF2. RT-qPCR results indicated that SCAP expressed FGF receptors, and western blotting showed that p-AKT was reduced in FGF2-pretreated SCAP. The activation of the PI3K/AKT pathway partially reversed the stimulatory effect of FGF2 on osteo/odontogenic differentiation of SCAP. Our findings suggest that pretreatment with FGF2 enhances the osteo/odontogenic differentiation ability of SCAP by inhibiting the PI3K/AKT pathway.

Identification of a novel member of the genus Laulavirus (family Phenuiviridae) from the entomopathogenic ascomycete fungus Cordyceps javanica.

The virus family Phenuiviridae (order Hareavirales, comprising segmented negative-sense single stranded RNA viruses) has highly diverse members that are known to infect animals, plants, protozoans, and fungi. In this study, we identified a novel phenuivirus infecting a strain of the entomopathogenic fungus Cordyceps javanica isolated from a small brown plant hopper (Laodelphax striatellus), and this virus was tentatively named "Cordyceps javanica negative-strand RNA virus 1" (CjNRSV1). The CjNRSV1 genome consists of three negative-sense single stranded RNA segments (RNA1-3) with lengths of 7252, 2401, and 1117 nt, respectively. The 3'- and 5'-terminal regions of the RNA1, 2, and 3 segments have identical sequences, and the termini of the RNA segments are complementary to each other, reflecting a common characteristic of viruses in the order Hareavirales. RNA1 encodes a large protein (∼274 kDa) containing a conserved domain for the bunyavirus RNA-dependent RNA polymerase (RdRP) superfamily, with 57-80% identity to the RdRP encoded by phenuiviruses in the genus Laulavirus. RNA2 encodes a protein (∼79 kDa) showing sequence similarity (47-63% identity) to the movement protein (MP, a plant viral cell-to-cell movement protein)-like protein (MP-L) encoded by RNA2 of laulaviruses. RNA3 encodes a protein (∼28 kDa) with a conserved domain of the phenuivirid nucleocapsid protein superfamily. Phylogenetic analysis using the RdRPs of various phenuiviruses and other unclassified phenuiviruses showed CjNRSV1 to be grouped with established members of the genus Laulavirus. Our results suggest that CjNRSV1 is a novel fungus-infecting member of the genus Laulavirus in the family Phenuiviridae.

Synthesis of a Metalla[2]catenane, Metallarectangles and Polynuclear Assemblies from Di(N-Heterocyclic Carbene) Ligands.

The 2,7-fluorenone-linked bis(6-imidazo[1,5-a]pyridinium) salt H2-1(PF6)2 reacts with Ag2O in CH3CN to yield the [2]catenane [Ag4(1)4](PF6)4. The [2]catenane rearranges in DMF to yield two metallamacrocycles [Ag2(1)2](PF6)2. 2,7-Fluorenone-bridged bis-(imidazolium) salts H2-L(PF6)2 (L=2 a, 2 b) react with Ag2O in CH3CN to yield metallamacrocycles [Ag2(L)2](PF6)2 with interplanar distances between the fluorenone rings too small for [2]catenane formation. Intra- and intermolecular π⋅⋅⋅π interactions between the fluorenone groups were observed by X-ray crystallography. The strongly kinked 2,7-fluorenone bridged bis(5-imidazo[1,5-a]pyridinium) salt H2-4(PF6)2 reacts with Ag2O to yield [Ag2(4)(CN)](PF6), while the tetranuclear assembly [Ag4(4)2(CO3)](PF6)2 was obtained in the presence of K2CO3.

Myeloid-derived suppressor cells-induced exhaustion of CD8 + T-cell participates in rejection after liver transplantation.

Liver transplantation (LT) rejection remains the most pervasive problem associated with this procedure, while the mechanism involved is still complicated and undefined. One promising solution may involve the use of myeloid-derived suppressor cells (MDSC). However, the immunological mechanisms underlying the effects of MDSC after LT remain unclear. This study is meant to clarify the role MDSCs play after liver transplantation. In this study, we collected liver tissue and peripheral blood mononuclear cells (PBMC) from LT patients showing varying degrees of rejection, as well as liver and spleen tissue samples from mice LT models. These samples were then analyzed using flow cytometry, immunohistochemistry and multiple immunofluorescence. M-MDSCs and CD8 + T-cells extracted from C57/BL6 mice were enriched and cocultured for in vitro experiments. Results, as obtained in both LT patients and LT mice model, revealed that the proportion and frequency of M-MDSC and PD-1 + T-cells increased significantly under conditions associated with a high degree of LT rejection. Within the LT rejection group, our immunofluorescence results showed that a close spatial contiguity was present between PD-1 + T-cells and M-MDSCs in these liver tissue samples and the proportion of CD84/PD-L1 double-positive M-MDSC was greater than that of G-MDSC. There was a positive correlation between the activity of CD84 and immunosuppressive function of M-MDSCs including PD-L1 expression and reactive oxygen species (ROS) production, as demonstrated in our in vitro model. M-MDSCs treated with CD84 protein were able to induce co-cultured CD8 + T-cells to express high levels of exhaustion markers. We found that CD84 regulated M-MDSC function via expression of PD-L1 through activation of the Akt/Stat3 pathway. These results suggest that the capacity for CD84 to regulate M-MDSC induction of CD8 + T-cell exhaustion may play a key role in LT rejection. Such findings provide important, new insights into the mechanisms of tolerance induction in LT.

Peking University First Hospital Procedure for Culturing Pathogenic Microorganisms for Bone and Joint Infection.

Background: This retrospective cohort study explores a practical approach to acquiring pathogenic microorganisms in patients with bone and joint infections. Methods: From Aug 2018 to Mar 2022, 68 consecutive patients (87 cultures) with bone and joint infection were recruited in this study. All cultures followed the Peking University First Hospital Procedure of Culturing Pathogenic microorganisms for bone and joint infection. Tissue samples were obtained through fluoroscopy-guided biopsy or open debridement. Tissue samples were divided into manual homogenization (MH), manual mixture (MM), and pathological examination. The baseline, antibiotic exposure, laboratory, surgical, and microbial data were reviewed. Independent sample T-test, Mann-Whitney U-test, and Chi-square test were used to detect the difference between patients who received different processing measures. Results: The average age was 55.8±2.4 years old. Thirty-nine patients were male. The total positive culture rate of the manual homogenization group was 80.5% (70/87). Thirty-five patients had mixed infections with more than one microorganism cultured. Staphylococci accounted for 60.23% of all microorganisms. Staphylococcus aureus (18.2%) and Staphylococcus epidermidis (15.9%) were the two most common bacteria cultured in this study. Patients with positive culture in the manual mixture group had significantly higher WBC (p = 0.006), NE% (p = 0.024), ESR (p = 0.003), CRP (p = 0.020) and IL6 (0.050) compared to patients with negative culture. After tissue homogenization, only ESR is still statistically different. Patients without SIRS had a low positive culture rate (59.4%). Tissue homogenization could significantly increase the positive culture rate of patients without SIRS. Pre-culture antibiotic exposure was not an independent risk factor for culture results. Conclusion: Peking University First Hospital Procedure for Culturing Pathogenic microorganisms for Bone and Joint Infections was a practical approach for obtaining pathogenic microorganisms.

Virological and Mitochondriopathogical Characteristics of the SARS-CoV-2 Omicron XBB.1.16 Spike.

The emergence of XBB.1.16 has gained rapid global prominence. Previous studies have elucidated that the infection of SARS-CoV-2 induces alterations in the mitochondrial integrity of host cells, subsequently influencing the cellular response to infection. In this study, we compared the differences in infectivity and pathogenicity between XBB.1.16 and the parental Omicron sublineages BA.1 and BA.2 and assessed their impact on host mitochondria. Our findings suggest that, in comparison with BA.1 and BA.2, XBB.1.16 exhibits more efficient spike protein cleavage, more efficient mediating syncytia formation, mild mitochondriopathy, and less pathogenicity. Altogether, our investigations suggest that, based on the mutation of key sites, XBB.1.16 exhibited enhanced infectivity but lower pathogenicity. This will help us to further investigate the biological functions of key mutation sites.

An international, multicenter, survey-based analysis of practice and management of acute liver failure.

Acute liver failure (ALF) is an acute liver dysfunction with coagulopathy and HE in a patient with no known liver disease. As ALF is rare and large clinical trials are lacking, the level of evidence regarding its management is low-moderate, favoring heterogeneous clinical practice. In this international multicenter survey study, we aimed to investigate the current practice and management of patients with ALF. An online survey targeting physicians who care for patients with ALF was developed by the International Liver Transplantation Society ALF Special-Interest Group. The survey focused on the management and liver transplantation (LT) practices of ALF. Survey questions were summarized overall and by geographic region. A total of 267 physicians completed the survey, with a survey response rate of 21.36%. Centers from all continents were represented. More than 90% of physicians specialized in either transplant hepatology/surgery or anesthesiology/critical care. Two hundred fifty-two (94.4%) respondents' institutions offered LT. A total of 76.8% of respondents' centers had a dedicated liver-intensive or transplant-intensive care unit ( p < 0.001). The median time to LT was within 48 hours in 12.7% of respondents' centers, 72 hours in 35.6%, 1 week in 37.6%, and more than 1 week in 9.6% ( p < 0.001). Deceased donor liver graft (49.6%) was the most common type of graft offered. For consideration of LT, 84.8% of physicians used King's College Criteria, and 41.6% used Clichy Criteria. Significant differences were observed between Asia, Europe, and North America for offering LT, number of LTs performed, volume of patients with ALF, admission to a dedicated intensive care unit, median time to LT, type of liver graft, monitoring HE and intracranial pressure, management of coagulopathy, and utilization of different criteria for LT. In our study, we observed significant geographic differences in the practice and management of ALF. As ALF is rare, multicenter studies are valuable for identifying global practice.

ICTV Virus Taxonomy Profile: Fusariviridae 2024.

Fusariviridae is a family of mono-segmented, positive-sense RNA viruses with genome sizes of 5.9-10.7 kb. Most genomic RNAs are bicistronic, but exceptions have up to four predicted ORFs. In bicistronic genomes, the 5'-proximal ORF codes for a single protein with both RNA-directed RNA polymerase (RdRP) and RNA helicase (Hel) domains; little is known about the protein encoded by the second ORF. Fusarivirids do not appear to form virions. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Fusariviridae, which is available at ictv.global/report/fusariviridae.

Isolation and Characterization of a Lytic Bacteriophage RH-42-1 of Erwinia amylovora from Orchard Soil in China.

Fire blight, caused by the bacterium Erwinia amylovora, is a major threat to pear production worldwide. Bacteriophages, viruses that infect bacteria, are a promising alternative to antibiotics for controlling fire blight. In this study, we isolated a novel bacteriophage, RH-42-1, from Xinjiang, China. We characterized its biological properties, including host range, plaque morphology, infection dynamics, stability, and sensitivity to various chemicals. RH-42-1 infected several E. amylovora strains but not all. It produced clear, uniform plaques and exhibited optimal infectivity at a multiplicity of infection (MOI) of 1, reaching a high titer of 9.6 × 109 plaque-forming units (PFU)/mL. The bacteriophage had a short latent period (10 min), a burst size of 207 PFU/cell, and followed a sigmoidal one-step growth curve. It was stable at temperatures up to 60 °C but declined rapidly at higher temperatures. RH-42-1 remained viable within a pH range of 5 to 9 and was sensitive to extreme pH values. The bacteriophage demonstrates sustained activity upon exposure to ultraviolet radiation for 60 min, albeit with a marginal reduction. In our assays, it exhibited a certain level of resistance to 5% chloroform (CHCl3), 5% isopropanol (C3H8O), and 3% hydrogen peroxide (H2O2), which had little effect on its activity, whereas it showed sensitivity to 75% ethanol (C2H5OH). Electron microscopy revealed that RH-42-1 has a tadpole-shaped morphology. Its genome size is 14,942 bp with a GC content of 48.19%. Based on these characteristics, RH-42-1 was identified as a member of the Tectiviridae family, Alphatectivirus genus. This is the first report of a bacteriophage in this genus with activity against E. amylovora.

MiR-3682-3p promotes esophageal cancer progression by targeting FHL1 and activating the Wnt/ß-catenin signaling pathway.

BACKGROUND: Esophageal cancer (EC) is highly ranked among all cancers in terms of its incidence and mortality rates. MicroRNAs (miRNAs) are considered to play key regulatory parts in EC. Multiple research studies have indicated the involvement of miR-3682-3p and four and a half LIM domain protein 1 (FHL1) in the achievement of tumors. The aim of this research was to clarify the significance of these genes and their possible molecular mechanism in EC. METHODS: Data from a database and the tissue microarray were made to analyze the expression and clinical significance of miR-3682-3p or FHL1 in EC. Reverse transcription quantitative PCR and Western blotting were used to detect the expression levels of miR-3682-3p and FHL1 in EC cells. CCK8, EdU, wound healing, Transwell, flow cytometry, and Western blotting assays were performed to ascertain the biological roles of miR-3682-3p and FHL1 in EC cells. To confirm the impact of miR-3682-3p in vivo, a subcutaneous tumor model was created in nude mice. The direct interaction between miR-3682-3p and FHL1 was demonstrated through a luciferase assay, and the western blotting technique was employed to assess the levels of crucial proteins within the Wnt/ß-catenin pathway. RESULTS: The noticeable increase in the expression of miR-3682-3p and the decrease in the expression of FHL1 were observed, which correlated with a negative impact on the patients' overall survival. Upregulation of miR-3682-3p expression promoted the growth and metastasis of EC, while overexpression of FHL1 partially reversed these effects. Finally, miR-3682-3p motivates the Wnt/ß-catenin signal transduction by directly targeting FHL1. CONCLUSION: MiR-3682-3p along the FHL1 axis activated the Wnt/ß-catenin signaling pathway and thus promoted EC malignancy.

Identification of a negative-strand RNA virus with natural plant and fungal hosts.

The presence of viruses that spread to both plant and fungal populations in nature has posed intriguingly scientific question. We found a negative-strand RNA virus related to members of the family Phenuiviridae, named Valsa mali negative-strand RNA virus 1 (VmNSRV1), which induced strong hypovirulence and was prevalent in a population of the phytopathogenic fungus of apple Valsa canker (Valsa mali) infecting apple orchards in the Shaanxi Province of China. Intriguingly, VmNSRV1 encodes a protein with a viral cell-to-cell movement function in plant tissue. Mechanical leaf inoculation showed that VmNSRV1 could systemically infect plants. Moreover, VmNSRV1 was detected in 24 out of 139 apple trees tested in orchards in Shaanxi Province. Fungal inoculation experiments showed that VmNSRV1 could be bidirectionally transmitted between apple plants and V. mali, and VmNSRV1 infection in plants reduced the development of fungal lesions on leaves. Additionally, the nucleocapsid protein encoded by VmNSRV1 is associated with and rearranged lipid droplets in both fungal and plant cells. VmNSRV1 represents a virus that has adapted and spread to both plant and fungal hosts and shuttles between these two organisms in nature (phyto-mycovirus) and is potential to be utilized for the biocontrol method against plant fungal diseases. This finding presents further insights into the virus evolution and adaptation encompassing both plant and fungal hosts.

Favorable Outcomes of Liver Transplantation for Hepatopulmonary Syndrome.

BACKGROUND: Hepatopulmonary syndrome (HPS) is a pulmonary vascular complication of chronic liver disease, which develops insidiously as a result of chronic liver disease. The prognosis for untreated patients with HPS is extremely poor, and liver transplantation (LT) serves as the only effective means for treating this condition. Here, we performed a retrospective analysis to evaluate the efficacy of LT on the survival and long-term prognosis of patients with HPS. METHODS: Clinical data, including survival and postoperative efficacy, from patients with HPS from records as obtained over the period from January 1 to December 31, 2022. All records were from a waiting list for LT at the Beijing Friendship Hospital Affiliated with Capital Medical University. RESULTS: Among the 274 patients on the LT waiting list, 37 were diagnosed with HPS (13.50%) and were enrolled. Survival rates of patients with HPS receiving an LT were greater, whereas a statistically significant difference was obtained between patients with LT vs non-LT with moderate to severe HPS (P = .003). The overall time until death without LT was 4-72 days after their initial HPS diagnosis. Patients with HPS receiving an LT showed a significant improvement in the state of oxygenation after surgery (P = .001). CONCLUSION: Comprehensive preoperative screening of patients on the waiting list for LT is critical to identify those patients with HPS who would maximally benefit from LT. Survival rates of patients with moderate to severe HPS are significantly increased after LT, a procedure that should be performed as soon as possible in these patients with HPS.

Updated epithelial barrier dysfunction in chronic rhinosinusitis: Targeting pathophysiology and treatment response of tight junctions.

Tight junction (TJ) proteins establish a physical barrier between epithelial cells, playing a crucial role in maintaining tissue homeostasis by safeguarding host tissues against pathogens, allergens, antigens, irritants, etc. Recently, an increasing number of studies have demonstrated that abnormal expression of TJs plays an essential role in the development and progression of inflammatory airway diseases, including chronic obstructive pulmonary disease, asthma, allergic rhinitis, and chronic rhinosinusitis (CRS) with or without nasal polyps. Among them, CRS with nasal polyps is a prevalent chronic inflammatory disease that affects the nasal cavity and paranasal sinuses, leading to a poor prognosis and significantly impacting patients' quality of life. Its pathogenesis primarily involves dysfunction of the nasal epithelial barrier, impaired mucociliary clearance, disordered immune response, and excessive tissue remodeling. Numerous studies have elucidated the pivotal role of TJs in both the pathogenesis and response to traditional therapies in CRS. We therefore to review and discuss potential factors contributing to impair and repair of TJs in the nasal epithelium based on their structure, function, and formation process.

Proteomic alterations associated with the formation of monocyte extracellular trap induced by Candida albicans hyphae.

Background: The interaction between the host and Candida albicans is dynamic and intricate. We performed proteomic analysis to explore monocyte-C. albicans hyphae interaction. Materials & methods: Primary human monocytes were stimulated by heat-killed C. albicans hyphae and their proteins were profiled by tandem liquid chromatography with mass spectrometry (LC-MS/MS). Results: Based on the protein database of different species for analysis, we found that stimulation of monocytes by hyphae was accompanied by upregulation of histones and activation of extracellular traps (ETs) formation pathway. Meanwhile, monocyte ETs (MoETs) were evoked by synthesis or alteration of C. albicans cell wall proteins expression during the morphological switch to hyphal. Conclusion: MoETs formation is linked to cell wall proteins of C. albicans hyphae.

Long noncoding RNA TMPO-AS1 accelerates glycolysis by regulating the miR-1270/PKM2 axis in colorectal cancer.

BACKGROUND: Long noncoding RNA thymopoietin-antisense RNA 1 (TMPO-AS1) is recognized as a participant in cancer progression. Nevertheless, its biological function in colorectal cancer remains obscure and needs further elucidation. METHODS AND RESULTS: First, we discovered enriched TMPO-AS1 in the tumor tissues that were related to poor prognosis. TMPO-AS1 knockdown enhanced SW480 cell apoptosis but inhibited invasion, proliferation, migration, and glucose metabolism. Further, MiR-1270 is directly bound with TMPO-AS1. MiR-1270 mimics were confirmed to inhibit cell proliferation, invasion, and glucose metabolism in our study. Mechanistically, miR-1270 directly is bound with the 3' untranslated regions (3'UTR) of PKM2 to downregulate PKM2. MiR-1270 inhibitors reversed the TMPO-AS1 knockdown's effect on suppressing the tumor cell proliferation, invasion, and glycolysis, while the knockdown of PKM2 further inverted the function of miR-1270 inhibitors on the TMPO-AS1 knockdown. CONCLUSIONS: This study illustrated that TMPO-AS1 advanced the development and the glycolysis of colorectal cancer by modulating the miR-1270/PKM2 axis, which provided a new insight into the colorectal cancer therapeutic strategy.

The Ratio of Intraoperative Red Blood Cell Transfusion to Blood Loss Associated with Early Postoperative Complications in Pediatric Liver Transplantation Patients.

Introduction: Liver transplantation (LT) is an operation purposed to save the lives of children with acute or chronic liver diseases, hepatic tumors, and some genetic and metabolic diseases. However, patients who underwent LT have a significant risk of intraoperative blood loss and red blood cell (RBC) transfusion, especially in pediatric patients. Methods: In this study, 569 pediatric patients (<18 years old) who underwent LT at a tertiary university hospital between 2013 and 2020 were included. Multiple logistic regression was used to analyze the association between the ratio of intraoperative RBC transfusion to blood loss (IRTBL) and the complications after LT in pediatric patients. IRTBL was divided into quartiles in the adjusted model. Odds ratios, 95% confidence intervals, and p values for trends were calculated. Restricted cubic spline (RCS) regression was used to evaluate the nonlinear association between IRTBL and complications. Results: Compared with the lowest level and the highest level of IRTBL, Q2 and Q3 quartiles of IRTBL showed significantly positive association with early complications. A significantly nonlinear association was observed between the IRTBL and early complications in the RCS model with the multiple adjustments of potential covariates (P overall<0.01, P nonlinear<0.01). However, no significant association was observed between late complications and IRTBL. Conclusion: In this study, we found there was a nonlinear relationship between the ratio of IRTBL and early postoperative complications in pediatric LT patients, which provides a theoretical basis for RBC transfusion in pediatric LT patients.

The homologous tumor-derived-exosomes loaded with miR-1270 selectively enhanced the suppression effect for colorectal cancer cells.

BACKGROUND: Colorectal cancer (CRC), known as prevalent cancer, has risen to be the leading cause of cancer-related death. Engineered exosomes had attracted much attention since they acted as carriers to deliver small molecule drugs, therapeutic nucleic acids, and polypeptides to treat a series of cancers. METHODS AND RESULTS: Here, we found that the PKH-26 labeled exosomes, which were derived from the CRC cells, could be efficiently absorbed by SW1116 cells and had an abundant fluorescence distribution in tumors, compared with the exosomes derived from mesenchymal stem cells (MSC) and HepG2 cells. This Research demonstrated that engineered CRC-exosomes loaded with functional miR-1270 (Exo-miR-1270) enriched in miR-1270 strongly inhibited the proliferation by CCK-8 and EdU assays, migration by wound-healing and transwell assays, and promoted the apoptosis for CRC cells through flow cytometry. MiR-1270 overexpression delivered by CRC exosomes contributed to inhibiting the tumor growth potential of CRC in vivo and increasing the overall survival of the mice. Moreover, the safety evaluation results showed that CRC-exosomes loaded with functional miR-1270-mimics had no toxicity for other organs by histopathological analysis and no influence on the vital chemistry and hematology parameters for mice in vivo safety evaluation. CONCLUSION: These results indicate that Exo-miR-1270 can effectively treat CRC tumors by intravenous administration. Our work provided a foundation that the homologous tumor-derived exosomes mediated miRNA delivery for the treatment of CRC.