Non-pathogenic Trojan horse Nissle1917 triggers mitophagy through PINK1/Parkin pathway to discourage colon cancer.

Bacteria-mediated antitumor therapy has gained widespread attention for its innate tumor-targeting capability and excellent immune activation properties. Nevertheless, the clinical approval of bacterial therapies remains elusive primarily due to the formidable challenge of balancing safety with enhancing in vivo efficacy. In this study, leveraging the probiotic Escherichia coli Nissle1917 (EcN) emerges as a promising approach for colon cancer therapy, offering a high level of safety attributed to its lack of virulence factors and its tumor-targeting potential owing to its obligate anaerobic nature. Specifically, we delineate the erythrocyte (RBC) membrane-camouflaged EcN, termed as Trojan horse EcN@RBC, which triggers apoptosis in tumor cells by mitigating mitochondrial membrane potential (MMP) and subsequently activating the PINK1/Parkin pathway associated with mitophagy. Concurrently, the decline in MMP induced by mitophagy disrupts the mitochondrial permeability transition pore (MPTP), leading to the release of Cytochrome C and subsequent apoptosis induction. Moreover, synergistic effects were observed through the combination of the autophagy activator rapamycin, bolstering the antitumor efficacy in vivo. These findings offer novel insights into probiotic-mediated antitumor mechanisms and underscore the therapeutic potential of EcN@RBC for colon cancer patients.

Comparison of the biomechanical effects of the post-core crown, endocrown and inlay crown after deep margin elevation and its clinical significance.

BACKGROUND: The purpose of this in vitro study was to compare and evaluate the stress distribution of maxillary first premolar residual crowns restored with post-core crowns, endocrowns and inlay crowns after deep margin elevation, to explore the fitting restoration for residual crowns using finite element analysis. METHODS: A healthy complete right maxillary first premolar from a male adult was scanned by cone beam computed tomography (CBCT). The finite element model of the tooth was established by reverse engineering software such as Mimics, Geomagic and Hypermesh. On this basis, the residual crown model after deep margin elevation was made, and the experimental group models were divided into three groups, those restored with post core crowns, endocrowns and inlay crowns. Vertical and oblique static loads were applied to the experimental models to simulate the force on the tooth during mastication (the loading position was located in the central fossa of the occipital surface, and the load was 100 N) using Abaqus software. RESULTS: The peak value and distribution of von Mises stress in each part of the experimental model were observed. After deep margin elevation, the peak dentin von Mises stresses were lower than the tensile strength of normal dentin in the post-core crown, endocrown, and inlay crown groups; the lowest stress results were found in the post-core crown group for the dentin, restoration, enamel, and deep margin elevation (DME) layers under vertical and oblique loading. In terms of stress distribution clouds, the peak stresses in the dentin tissue were located in the apical 1/3 of the root after postcore crown restorations for both loads, while stress concentrations were evident in the cervical and root areas after endocrown and inlay crown restorations; regardless of the load and restoration method, the corresponding stress concentration areas appeared at the junction of the DME and dentin tissue at the loading site of the restorations; CONCLUSIONS: Post-core crowns, endocrowns and inlay crowns can be used to restore residual crowns after deep margin elevation, and post-core crowns can better protect the residual tooth tissue.

AI-powered omics-based drug pair discovery for pyroptosis therapy targeting triple-negative breast cancer.

Due to low success rates and long cycles of traditional drug development, the clinical tendency is to apply omics techniques to reveal patient-level disease characteristics and individualized responses to treatment. However, the heterogeneous form of data and uneven distribution of targets make drug discovery and precision medicine a non-trivial task. This study takes pyroptosis therapy for triple-negative breast cancer (TNBC) as a paradigm and uses data mining of a large TNBC cohort and drug databases to establish a biofactor-regulated neural network for rapidly screening and optimizing compound pyroptosis drug pairs. Subsequently, biomimetic nanococrystals are prepared using the preferred combination of mitoxantrone and gambogic acid for rational drug delivery. The unique mechanism of obtained nanococrystals regulating pyroptosis genes through ribosomal stress and triggering pyroptosis cascade immune effects are revealed in TNBC models. In this work, a target omics-based intelligent compound drug discovery framework explores an innovative drug development paradigm, which repurposes existing drugs and enables precise treatment of refractory diseases.

Higher body mass index was associated with a lower mortality of idiopathic pulmonary fibrosis: a meta-analysis.

PURPOSE: In the past few years, there has been a notable rise in the incidence and prevalence of idiopathic pulmonary fibrosis (IPF) on a global scale. A considerable body of research has highlighted the 'obesity paradox,' suggesting that a higher body mass index (BMI) can confer a protective effect against numerous chronic diseases. However, the relationship between BMI and the risk of mortality in IPF patients remains underexplored in the existing literature. We aim to shed light on this relationship and potentially offer novel insights into prevention strategies for IPF. METHODS: We conducted a systematic search of the PubMed, Embase, and Web of Science databases to collect all published studies examining the correlation between Body Mass Index (BMI) and the mortality risk in patients with IPF, up until February 14, 2023. For the synthesis of the findings, we employed random-effects models. The statistical significance of the association between BMI and the mortality risk in IPF patients was evaluated using the hazard ratio (HR), with the 95% Confidence Interval (CI) serving as the metric for effect size. RESULTS: A total of 14 data sets involving 2080 patients with IPF were included in the meta-analysis. The combined results of the random-effects models were suggestive of a significant association between lower BMI and a higher risk of death (HR = 0.94, 95% CI = 0.91-0.97, P < 0.001). For baseline BMI, the risk of death from IPF decreased by 6% for each unit increase. The results of the subgroup analysis suggest that geographic location (Asian subgroup: HR = 0.95, 95%CI = 0.93-0.98, P = 0.001; Western subgroup: HR = 0.91, 95%CI = 0.84-0.98, P = 0.014), study type (RCS subgroup: HR = 0.95, 95%CI = 0.92-0.98, P = 0.004; PCS subgroup: HR = 0.89, 95%CI = 0.84-0.94, P < 0.001), and sample size (< 100 groups: HR = 0.93, 95%CI = 0.87-1.01, P = 0.079; >100 groups: HR = 0.94, 95%CI = 0.91-0.97, P < 0.001 ) were not significant influences on heterogeneity. Of the included literature, those with confounding factors corrected and high NOS scores reduced heterogeneity (HR = 0.93, 95%CI = 0.90-0.96, P < 0.001). Sensitivity analyses showed that the combined results were stable and not significantly altered by individual studies (HR = 0.93 to 0.95, 95% CI = 0.90-0.96 to 0.92-0.98). Egger's test suggested no significant publication bias in the included studies (P = 0.159). CONCLUSIONS: Higher BMI (BMI ≥ 25 kg/m2) is negatively correlated to some extent with the risk of death in IPF patients, and BMI may become a clinical indicator for determining the prognosis of IPF patients.

Gut microbiota metabolite indole-3-acetic acid maintains intestinal epithelial homeostasis through mucin sulfation.

The global incidence and prevalence of inflammatory bowel disease (IBD) are gradually increasing. A high-fat diet (HFD) is known to disrupt intestinal homeostasis and aggravate IBD, yet the underlying mechanisms remain largely undefined. Here, a positive correlation between dietary fat intake and disease severity in both IBD patients and murine colitis models is observed. A HFD induces a significant decrease in indole-3-acetic acid (IAA) and leads to intestinal barrier damage. Furthermore, IAA supplementation enhances intestinal mucin sulfation and effectively alleviates colitis. Mechanistically, IAA upregulates key molecules involved in mucin sulfation, including 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (Papss2) and solute carrier family 35 member B3 (Slc35b3), the synthesis enzyme and the transferase of 3'-phosphoadenosine-5'-phosphosulfate (PAPS), via the aryl hydrocarbon receptor (AHR). More importantly, AHR can directly bind to the transcription start site of Papss2. Oral administration of Lactobacillus reuteri, which can produce IAA, contributes to protecting against colitis and promoting mucin sulfation, while the modified L. reuteri strain lacking the iaaM gene (LactobacillusΔiaaM) and the ability to produce IAA fail to exhibit such effects. Overall, IAA enhances intestinal mucin sulfation through the AHR-Papss2-Slc35b3 pathway, contributing to the protection of intestinal homfeostasis.

A HFD can lead to the development of colitis by disrupting tryptophan metabolism in the gut microbiome and lowering levels of IAA. Supplementation with IAA has been shown to alleviate colitis in mice and improve intestinal barrier function. It is believed that IAA may activate the AHR to upregulate the expression of Papss2 and Slc35b3, promoting sulfation modification of mucins and protecting the intestinal barrier. HFD, high-fat diet; AHR, aryl hydrocarbon receptor; IAA, indole-3-acetic acid; Papss2, 3'-phosphoadenosine 5'-phosphosulfate synthase 2; Slc35b3, solute carrier family 35 member B3.

The Research of a Large-Scale Analysis Platform for MNS Blood Group Identification Based on Long-Read Sequencing.

The objective of this study was to devise a novel approach for determining MNS blood group utilizing long-read sequencing (LRS) and to identify intricate genome variations associated with this blood group system. In this study, a total of 60 blood samples were collected from randomly selected Chinese Han blood donors. The amplification of the full-length sequences of GYPA exon 2-7 (11 kb) and GYPB exon 2-6 (7 kb) was conducted on the blood samples obtained from these 60 donors. Subsequently, the sequencing of these amplified sequences was performed using the PacBio platform. The obtained sequencing data were then compared with the reference sequence of the human genome (GRCh38) utilizing the pbmm2 software, resulting in the acquisition of the haploid sequences of GYPA and GYPB. The serological typing prediction was conducted using the International Society of Blood Transfusion (ISBT) database, while the analysis of SNVs sites was performed using deepvariant v1.2.0 software and reference sequence alignment. A total of 60 samples yielded unambiguous high-quality haplotypes, which can serve as a standardized reference sequence for molecular biology typing of MNSs in the Chinese population. In a total of 60 serological samples, the LRS method successfully identified the M, N, S, and s blood group antigens by analyzing specific genetic variations (c.59, c.71, c.72 for GYPA, and c.143 for GYPB), which aligned with the results obtained through conventional serological techniques. 4 Mur samples that had been previously validated through serology and molecular biology were successfully confirmed, and complete haploid sequences were obtained. Notably, one of the Mur samples exhibited a novel breakpoint, GYP (B1-136-B ψ 137-212-A213-229-B230-366), thereby representing a newly identified subtype. Single molecule sequencing, which eliminates the necessity for PCR amplification, effectively encompasses GC and high repeat regions, enhancing accuracy in quantifying mutations with low abundance or frequency. By employing LRS analysis of the core region of GYPA and GYPB, diverse genotypes of MNS can be precisely and reliably identified in a single assay. This approach presents a comprehensive, expeditious, and precise novel method for the categorization and investigation of MNS blood group system.

Influence of High-Risk Pathological Factors and their Interaction on the Survival Benefit of Adjuvant Chemotherapy in Stage II Rectal Cancer: A Retrospective Study.

Objectives: We investigated the impact of high-risk factors in stage II (TNM stage) rectal cancer patients to determine whether they benefit from adjuvant chemotherapy after surgery. Additionally, we explored the interaction between high-risk factors and adjuvant chemotherapy. Our study provides refined guidance for postoperative treatment in patients with stage II rectal cancer. Methods: The retrospective study included 570 stage II rectal adenocarcinoma patients who underwent total mesorectal excision surgery at Tianjin Union Medical Center from August 2012 to July 2019. We employed Cox regression models to assess the collected pathological and clinical factors, identifying the risk factors for overall survival (OS) and disease-free survival (DFS). Additionally, we thoroughly examined the interaction between various high-risk pathological factors and postoperative chemotherapy (ACT), including multiplicative interaction (INTM) and additive interaction (RERI). Results: Among the 570 stage II rectal cancer patients in this study, the average age was 62 years, with 58.9% (N=336) of the population being older than 60. Males accounted for the majority at 64.9% (N=370). Age was found to have an impact on whether patients received adjuvant chemotherapy after surgery (P<=0.001).Furthermore, age (HR: 1.916, 95% CI: 1.158-3.173, P=0.011; HR: 1.881, 95% CI: 1.111-3.186, P=0.019), TNM stage (HR: 2.216, 95% CI: 1.003-4.897, P=0.029; HR: 2.276, 95% CI: 1.026-5.048, P=0.043), the number of lymph nodes cleared during surgery (HR: 1.968, 95% CI: 1.112-3.483, P=0.017; HR: 1.864, 95% CI: 0.995-3.493, P=0.045), and lymphovascular invasion (HR: 2.864, 95% CI: 1.567-5.232, P=0.001; HR: 3.161, 95% CI: 1.723-5.799, P<0.001) were identified as independent risk factors for patients' overall survival (OS) and disease-free survival (DFS). Moreover, the interaction analysis, both multiplicative and additive, revealed significant interactions between the number of lymph nodes cleared during surgery and the administration of adjuvant chemotherapy. For OS (HR for multiplicative interaction: 0.477, p=0.045; RERI: -0.531, 95% CI: -1.061, -0.002) and for DFS (HR for multiplicative interaction: 0.338, p=0.039; RERI: -1.097, 95% CI: -2.190, -0.005). Conclusions: This study provides insights into the complex relationship between adjuvant chemotherapy (ACT) and survival outcomes in stage II rectal cancer patients with high-risk pathological factors. The findings suggest that the number of cleared lymph nodes plays a significant role in the efficacy of ACT and underscores the need for individualized treatment decisions in this patient population.

Taking SCFAs produced by Lactobacillus reuteri orally reshapes gut microbiota and elicits antitumor responses.

BACKGROUND: Colorectal cancer (CRC) incidence is increasing in recent years due to intestinal flora imbalance, making oral probiotics a hotspot for research. However, numerous studies related to intestinal flora regulation ignore its internal mechanisms without in-depth research. RESULTS: Here, we developed a probiotic microgel delivery system (L.r@(SA-CS)2) through the layer-by-layer encapsulation technology of alginate (SA) and chitosan (CS) to improve gut microbiota dysbiosis and enhance anti-tumor therapeutic effect. Short chain fatty acids (SCFAs) produced by L.r have direct anti-tumor effects. Additionally, it reduces harmful bacteria such as Proteobacteria and Fusobacteriota, and through bacteria mutualophy increases beneficial bacteria such as Bacteroidota and Firmicutes which produce butyric acid. By binding to the G protein-coupled receptor 109A (GPR109A) on the surface of colonic epithelial cells, butyric acid can induce apoptosis in abnormal cells. Due to the low expression of GPR109A in colon cancer cells, MK-6892 (MK) can be used to stimulate GPR109A. With increased production of butyrate, activated GPR109A is able to bind more butyrate, which further promotes apoptosis of cancer cells and triggers an antitumor response. CONCLUSION: It appears that the oral administration of L.r@(SA-CS)2 microgels may provide a treatment option for CRC by modifying the gut microbiota.

Advances in the Study of Non-Coding RNA in the Signaling Pathway of Pulmonary Fibrosis.

Pulmonary fibrosis is a group of chronic, progressive, and irreversible interstitial lung diseases, which are common to most end-stage lung diseases and are one of the most difficult diseases of the respiratory system. In recent years, due to the frequent occurrence of air pollution and smog, the incidence of pulmonary fibrosis in China has increased year by year, the morbidity and mortality rates of pulmonary fibrosis have gradually increased and the age of the disease tends to be younger. However, the pathogenesis of pulmonary fibrosis is not yet fully understood and is needed to further explore new drug targets. Studies have shown that non-coding RNAs play an important role in regulating the process of pulmonary fibrosis, non-coding RNAs and their specifically expressed can promote or inhibit the process. Here, we review the role of some in the regulation of pulmonary fibrosis signaling pathways and provide new ideas for the clinical diagnosis and treatment of pulmonary fibrosis.

Extracellular Vehicles from Commensal Skin Malassezia restricta Inhibit Staphylococcus aureus Proliferation and Biofilm Formation.

The colonizing microbiota on the body surface play a crucial role in barrier function. Staphylococcus aureus (S. aureus) is a significant contributor to skin infection, and the utilization of colonization resistance of skin commensal microorganisms to counteract the invasion of pathogens is a viable approach. However, most studies on colonization resistance have focused on skin bacteria, with limited research on the resistance of skin fungal communities to pathogenic bacteria. Extracellular vehicles (EVs) play an important role in the colonization of microbial niches and the interaction between distinct strains. This paper explores the impact of Malassezia restricta (M. restricta), the fungus that dominates the normal healthy skin microbiota, on the proliferation of S. aureus by examining the distribution disparities between the two microorganisms. Based on the extraction of EVs, the bacterial growth curve, and biofilm formation, it was determined that the EVs of M. restricta effectively suppressed the growth and biofilm formation of S. aureus. The presence of diverse metabolites was identified as the primary factor responsible for the growth inhibition of S. aureus, specifically in relation to glycerol phospholipid metabolism, ABC transport, and arginine synthesis. These findings offer valuable experimental evidence for understanding microbial symbiosis and interactions within healthy skin.

Oral probiotics microgel plus Galunisertib reduced TGF-ß blockade resistance and enhanced anti-tumor immune responses in colorectal cancer.

Transforming growth factor ß (TGF-ß), a versatile immunosuppressive cytokine, has gained increasing attention as a potential target for cancer immunotherapy. However, current strategies are constrained by tumor heterogeneity and drug resistance. Therapeutic probiotics, such as Escherichia coli Nissle1917 (EcN), not only regulate the gut microbiota to increase beneficial bacteria with anti-tumor effects, but also modulate immune factors within the body, thereby enhancing immunity. In this study, we developed an oral microgel delivery system of EcN@(CS-SA)2 by electrostatic interaction between chitosan (CS) and sodium alginate (SA), aiming to enhance its bioavailability in the gastrointestinal tract (GIT). Notably, EcN@(CS-SA)2 microgel showed a synergistic enhancement of the anti-tumor efficacy of Galunisertib (Gal, a TGF-ß inhibitor) by inducing apoptosis and immunogenic cell death (ICD) in tumor cells, as well as promoting increased infiltration of CD8+ T cells into the tumor microenvironment (TME).

LNCGM1082 in Gut Epithelial Cells Promotes Expulsion of Infected Epithelial Cells and Release of IL-18.

Inflammasome NLRC4 (NLR family CARD domain containing 4) can protect mucosal barriers such as intestine from invading bacterial pathogens. However, it was incompletely clear how NLRC4 was activated in intestinal epithelial cells. In this study, we demonstrated that LNCGM1082 could mediate the activation of NLRC4 via binding NLRC4 with protein kinase C (PKC)δ. LNCGM1082 knockout (KO) mice had reduced resistance against Salmonella Typhimurium infection, as well as impaired expulsion of infected gut epithelial cells and release of IL-18 upon exposure to S. Typhimurium. Similar to NLRC4 KO and PKCδ knockdown gut organoids, there also was impaired expulsion of gut epithelial cells and release of IL-18 in LNCGM1082 KO gut organoids. Furthermore, there also was reduced activation of caspase-1 and caspase-8 in these LNCGM1082 KO, NLRC4 KO, and PKCδ knockdown gut organoids upon exposure to S. Typhimurium. Our results show that LNCGM1082 in the ICEs plays a critical role in mediating activation of NLRC4 through binding NLRC4 and PKCδ and promoting expulsion of infected epithelial cells and release of IL-18 upon exposure to bacteria such as S. Typhimurium.

Desulfovibrio vulgaris interacts with novel gut epithelial immune receptor LRRC19 and exacerbates colitis.

BACKGROUND: The overgrowth of Desulfovibrio, an inflammation promoting flagellated bacteria, has been found in ulcerative colitis (UC) patients. However, the molecular mechanism in promoting colitis remains unestablished. METHODS: The relative abundance Desulfovibrio vulgaris (D. vulgaris) in stool samples of UC patients was detected. Mice were treated with dextran sulfate sodium to induce colitis with or without administration of D. vulgaris or D. vulgaris flagellin (DVF), and the severity of colitis and the leucine-rich repeat containing 19 (LRRC19) signaling were assessed. The interaction between DVF and LRRC19 was identified by surface plasmon resonance and intestinal organoid culture. Lrrc19-/- and Tlr5-/- mice were used to investigate the indispensable role of LRRC19. Finally, the blockade of DVF-LRRC19 interaction was selected through virtual screening and the efficacy in colitis was assessed. RESULTS: D. vulgaris was enriched in fecal samples of UC patients and was correlated with the disease severity. D. vulgaris or DVF treatment significantly exacerbated colitis in germ-free mice and conventional mice. Mechanistically, DVF could interact with LRRC19 (rather than TLR5) in colitis mice and organoids, and then induce the production of pro-inflammatory cytokines. Lrrc19 knockdown blunted the severity of colitis. Furthermore, typhaneoside, a blockade of binding interfaces, blocked DVF-LRRC19 interaction and dramatically ameliorated DVF-induced colitis. CONCLUSIONS: D. vulgaris could promote colitis through DVF-LRRC19 interaction. Targeting DVF-LRRC19 interaction might be a new therapeutic strategy for UC therapy. Video Abstract.

Exploring techniques for encoding spoken instructions in working memory: a comparison of verbal rehearsal, motor imagery, self-enactment and action observation.

Encoding and recalling spoken instructions is subject to working memory capacity limits. Previous research suggests action-based encoding facilitates instruction recall, but has not directly compared benefits across different types of action-based techniques. The current study addressed this in two experiments with young adults. In Experiment 1, participants listened to instructional sequences containing four action-object pairs, and encoded these instructions using either a motor imagery or verbal rehearsal technique, followed by recall via oral repetition or enactment. Memory for instructions was better when participants used a motor imagery technique during encoding, and when recalling the instructions by enactment. The advantage of using a motor imagery technique was present in both verbal and enacted recall. In Experiment 2, participants encoded spoken instructions whilst implementing one of four techniques (verbal rehearsal, motor imagery, observation of others' actions or self-enactment), and then recalled the instructions by oral repetition or enactment. For both verbal and enacted recall, memory for instructions was least accurate in the rehearsal condition, while the other encoding conditions did not differ from each other. These novel findings indicate similar benefits of imagining, observation and execution of actions in encoding spoken instructions, and enrich current understanding of action-based benefits in working memory.

Gut microbiota: A double-edged sword in immune checkpoint blockade immunotherapy against tumors.

Tumor cells can evade immune surveillance by expressing immune checkpoint molecule ligands, resulting in effective immune cell inactivation. Immune checkpoint blockades (ICBs) have dramatically improved survival of patients with multiple types of cancers. However, responses to ICB immunotherapy are heterogeneous with lower patient response rates. The advances have established that the gut microbiota can be as a promising target to overcome resistance to ICB immunotherapy. Furthermore, some bacterial species have shown to promote improved responses to ICBs. However, gut microbiota is critical in maintaining gut and systemic immune homeostasis. It not only promotes differentiation and function of immunosuppressive immune cells but also inhibits inflammatory cells via gut microbiota derived products such as short chain fatty acids (SCFAs), tryptophan (Trp) and bile acid (BA) metabolites, which play an important role in tumor immunity. Since the gut microbiota can either inhibit or enhance immune against tumor, it should be a double-edged sword in ICBs against tumor. In this review, we discuss the effects of gut microbiota on immune cells and also tumor cells, especially enhances of gut microbiota on ICB immunotherapy. These discussions can hopefully promote the development of ICB immunotherapy.

Immune signatures of the POLE mutation in endometrial carcinomas: a systematic study based on TCGA data and clinical cohort validation.

Background: POLE is a critical biomarker for endometrial cancer (ECs) prognosis and therapeutic decision. However, the immune infiltration and immunotherapy-related gene expression in the tumor microenvironment (TME) of POLE-mutated ECs remain unresolved. Methods: The TCGA database was used to characterize the TME of POLE mutants, which primarily included immune cells and co-expression genes. We used immunohistochemistry (IHC) to determine immune cell abundance and PD-L1 expression in 104 EC tissues, including 11 POLE mutants and 93 wild-type. Results: The bioinformatic study found significant differences in gene expression of the chemokine family, immune-cell markers, and lysozyme in POLE mutants, along with immune response activation. In POLE-mutated ECs, the abundance of CD4+T, CD8+T, M1 macrophages, and dendritic cells increased considerably. Furthermore, POLE mutations may enhance immune cell recruitment or activation and lymphocyte homing in ECs. POLE mutants also had increased expression of immune-checkpoint suppressor genes such as PD-L1, CTLA-4, TIM-3, and others. The tumor mutation burden (TMB) was higher in ECs with POLE mutation. In the validation cohort, we discovered that POLE mutations were related to the immune infiltration abundance of CD8+, CD4+, and Foxp3+ cells and PD-L1 expression by IHC. The prognosis of TCGA-ECs showed that the survival time of the CD8, CD4, PD-L1, or Foxp3 over-expression subgroup of the POLE mutants was significantly prolonged compared to the down-regulation subgroup or the POLE wild-type. Conclusion: The infiltration abundance of CD8+ T, CD4+ T, Foxp3+ T cells, and the expression of PD-L1 harbor crucial value for the prognosis or individualized therapy of POLE-mutated ECs.

Low-temperature photothermal-induced alkyl radical release facilitates dihydroartemisinin-triggered "valve-off" starvation therapy.

The high nutrient and energy demand of tumor cells compared to normal cells to sustain rapid proliferation offer a potentially auspicious avenue for implementing starvation therapy. However, conventional starvation therapy, such as glucose exhaustion and vascular thrombosis, can lead to systemic toxicity and exacerbate tumor hypoxia. Herein, we developed a new "valve-off" starvation tactic, which was accomplished by closing the valve of glucose transporter protein 1 (GLUT1). Specifically, dihydroartemisinin (DHA), 2,20-azobis [2-(2-imidazolin-2-yl) propane] dihydrochloride (AI), and Ink were co-encapsulated in a sodium alginate (ALG) hydrogel. Upon irradiation with the 1064 nm laser, AI rapidly disintegrated into alkyl radicals (R•), which exacerbated the DHA-induced mitochondrial damage through the generation of reactive oxygen species and further reduced the synthesis of adenosine triphosphate (ATP). Simultaneously, the production of R• facilitated DHA-induced starvation therapy by suppressing GLUT1, which in turn reduced glucose uptake. Systematic in vivo and in vitro results suggested that this radical-enhanced "valve-off" strategy for inducing tumor cell starvation was effective in reducing glucose uptake and ATP levels. This integrated strategy induces tumor starvation with efficient tumor suppression, creating a new avenue for controlled, precise, and concerted tumor therapy.

Gut fungal mycobiome: A significant factor of tumor occurrence and development.

A variety of bacteria, viruses, fungi, protists, archaea and protozoa coexists within the mammalian gastrointestinal (GI) tract such as that fungi are detectable in all intestinal and colon segments in almost all healthy adults. Although fungi can cause infectious diseases, they are also related to gut and systemic homeostasis. Importantly, through transformation of different forms such as from yeast to hyphae, interaction among gut microbiota such as fungal and bacterial interaction, host factors such as immune and host derived factors, and fungus genetic and epigenetic factors, fungi can be transformed from commensal into pathogenic lifestyles. Recent studies have shown that fungi play a significant role in the occurrence and development of tumors such as colorectal cancer. Indeed, evidences have shown that multiple species of different fungi exist in different tumors. Studies have also demonstrated that fungi are related to the occurrence and development of tumors, and also survival of patients. Here we summarize recent advances in the transformation of fungi from commensal into pathogenic lifestyles, and the effects of gut pathogenic fungi on the occurrence and development of tumors such as colorectal and pancreatic cancers.

Targeting ESM1/ VEGFα signaling axis: a promising therapeutic avenue for angiogenesis in cervical squamous cell carcinoma.

Background: Endothelial-specific molecule 1 (ESM1) dysregulation is widespread in various malignancies. However, the exact significance of ESM1 in cervical squamous cell carcinoma (CSCC) is not yet well understood. Methods: The expression of ESM1 in CSCC was probed by immunohistochemistry (IHC) assay using human specimens and validated and explored ESM1 in CSCC based on TNMplot and TCGA (The Cancer Genome Atlas Program) data repository. Further, the GSEA analysis and in vitro experiments of human CSCC cell lines, including SiHa and ME-180, were performed to investigate the masked molecular mechanisms of ESM1 in CSCC. Results: ESM1 was overexpressed in clinical CSCC tissues compared with paracancer controls, was an independent prognostic factor and was associated with poor prognosis in CSCC patients. These findings were further confirmed in the TNMplot and TCGA datasets. Furthermore, GSEA analysis revealed that the ESM1 high expression group was significantly enriched in carcinoma angiogenesis and the VEGFα signaling pathway. In addition, in vitro assays with human CSCC cell lines, including SiHa and ME-180, demonstrated that knockdown of ESM1 expression inhibited tumor cell proliferation, migration and invasion, resulting in attenuated VEGFα expression and blocked phosphorylation of VEGFR2 and ERK-1/2. Conclusion: In CSCC patients, ESM1 was considerably overexpressed. Upregulation of ESM1 is predictive of poor clinical outcomes in CSCC. Furthermore, ESM1 overexpression promoted carcinoma angiogenesis and CSCC progression through the VEGF/ERK signaling pathway. Hence, ESM1 and associated genes might be useful prognostic biomarkers or therapeutic targets for CSCC individuals.