Bacterial Biohybrids for Invasion of Tumor Cells Promote Antigen Cross-Presentation Through Gap Junction.

Due to inherent differences in cellular composition and metabolic behavior with host cells, tumor-harbored bacteria can discriminatorily affect tumor immune landscape. However, the mechanisms by which intracellular bacteria affect antigen presentation process between tumor cells and antigen-presenting cells (APCs) are largely unknown. The invasion behavior of attenuated Salmonella VNP20009 (VNP) into tumor cells is investigated and an attempt is made to modulate this behavior by modifying positively charged polymers on the surface of VNP. It is found that non-toxic chitosan oligosaccharide (COS) modified VNP (VNP@COS) bolsters the formation of gap junction between tumor cells and APCs by enhancing the ability of VNP to infect tumor cells. On this basis, a bacterial biohybrid is designed to promote in situ antigen cross-presentation through intracellular bacteria induced gap junction. This bacterial biohybrid also enhances the expression of major histocompatibility complex class I molecules on the surface of tumor cells through the incorporation of Mdivi-1 coupled with VNP@COS. This strategic integration serves to heighten the immunogenic exposure of tumor antigens; while, preserving the cytotoxic potency of T cells. A strategy is proposed to precisely controlling the function and local effects of microorganisms within tumors.

Immunoadjuvant-Modified Rhodobacter sphaeroides Potentiate Cancer Photothermal Immunotherapy.

Photothermal immunotherapy has become a promising strategy for tumor treatment. However, the intrinsic drawbacks like light instability, poor immunoadjuvant effect, and poor accumulation of conventional inorganic or organic photothermal agents limit their further applications. Based on the superior carrying capacity and active tumor targeting property of living bacteria, an immunoadjuvant-intensified and engineered tumor-targeting bacterium was constructed to achieve effective photothermal immunotherapy. Specifically, immunoadjuvant imiquimod (R837)-loaded thermosensitive liposomes (R837@TSL) were covalently decorated onto Rhodobacter sphaeroides (R.S) to obtain nanoimmunoadjuvant-armed bacteria (R.S-R837@TSL). The intrinsic photothermal property of R.S combined R837@TSL to achieve in situ near-infrared (NIR) laser-controlled release of R837. Meanwhile, tumor immunogenic cell death (ICD) caused by photothermal effect of R.S-R837@TSL, synergizes with released immunoadjuvants to promote maturation of dendritic cells (DCs), which enhance cytotoxic T lymphocytes (CTLs) infiltration for further tumor eradication. The photosynthetic bacteria armed with immunoadjuvant-loaded liposomes provide a strategy for immunoadjuvant-enhanced cancer photothermal immunotherapy.

Inhalable Capsular Polysaccharide-Camouflaged Gallium-Polyphenol Nanoparticles Enhance Lung Cancer Chemotherapy by Depleting Local Lung Microbiota.

Local lung microbiota is closely associated with lung tumorigenesis and therapeutic response. It is found that lung commensal microbes induce chemoresistance in lung cancer by directly inactivating therapeutic drugs via biotransformation. Accordingly, an inhalable microbial capsular polysaccharide (CP)-camouflaged gallium-polyphenol metal-organic network (MON) is designed to eliminate lung microbiota and thereby abrogate microbe-induced chemoresistance. As a substitute for iron uptake, Ga3+ released from MON acts as a "Trojan horse" to disrupt bacterial iron respiration, effectively inactivating multiple microbes. Moreover, CP cloaks endow MON with reduced immune clearance by masquerading as normal host-tissue molecules, significantly increasing residence time in lung tissue for enhanced antimicrobial efficacy. In multiple lung cancer mice models, microbe-induced drug degradation is remarkably inhibited when drugs are delivered by antimicrobial MON. Tumor growth is sufficiently suppressed and mouse survival is prolonged. The work develops a novel microbiota-depleted nanostrategy to overcome chemoresistance in lung cancer by inhibiting local microbial inactivation of therapeutic drugs.

Yeast cell membrane-camouflaged PLGA nanoparticle platform for enhanced cancer therapy.

Temozolomide (TMZ) is an oral DNA-alkylating drug used in colorectal cancer (CRC) chemotherapy. In this work, we proposed a safe and biomimetic platform for macrophages-targeted delivery of TMZ and O6-benzylguanine (O6-BG). TMZ was loaded in poly (D, l-lactide-coglycolide) (PLGA) nanoparticles, followed by sequential coating with O6-BG-grafted chitosan (BG-CS) layers and yeast shell walls (YSW) via layer-by-layer assembly (LBL) process, forming TMZ@P-BG/YSW biohybrids. Due to the yeast cell membrane-camouflage, TMZ@P-BG/YSW particles exhibited significantly enhanced colloidal stability as well as low premature drug leakage in simulated gastrointestinal conditions. In vitro drug release profiles of TMZ@P-BG/YSW particles revealed noticeable higher TMZ release in simulated tumor acidic environment within 72 h. Meanwhile, O6-BG could down-regulate MGMT expression in CT26 colon carcinoma cells, ultimately facilitating TMZ-induced tumor cell death. After oral delivery of yeast cell membrane-camouflaged particles containing fluorescent tracer (Cy5), TMZ@P-BG/YSW and bare YSW displayed high retention time of 12 h in the colon and small intestine (ileum). Correspondingly, oral gavage administration of TMZ@P-BG/YSW particles afforded favorable tumor-specific retention and superior tumor growth inhibition. Overall, TMZ@P-BG/YSW is validated to be a safe, targetable and effective formulation, paving a new avenue towards highly effective and precise treatment of malignancies.

Colon-targeted bacterial hydrogel for tumor vascular normalization and improved chemotherapy.

The endogenous H2S plays an important role in the occurrence and development of colon cancer, and is related to the abnormal blood vessels. Here, we reported on a sulfhydryl hyaluronid-based hydrogel (HA-SH) synthesized by amide reaction and further obtained a bacterial hydrogel by loading Thiobacillus denitrificans to the hydrogel for targeting adhesion to the colon. It was found that the loaded bacteria in HA-SH hydrogel can scavenge excess H2S in colon cancer, then promote tumor vascular normalization and improve the delivery of chemotherapy drug CPT to inhibit tumor progression. Both in vivo and in vitro experiments show that the self-crosslinked bacterial hydrogel has satisfactory effects in inhibiting tumor progression and promoting tumor vascular normalization in colon cancer. This study presents an efficient method to target the colon and consume overexpressed H2S in colon cancer to inhabit tumor progression, providing a new way for oral drug treatment of colon cancer.

LncRNA BC promotes lung adenocarcinoma progression by modulating IMPAD1 alternative splicing.

BACKGROUND: The therapeutic value of targeted therapies in patients with lung cancer is reduced when tumours acquire secondary resistance after an initial period of successful treatment. However, the molecular events behind the resistance to targeted therapies in lung cancer remain largely unknown. AIMS: To discover the important role and mechanism of lncRNA BC in promoting tumor metastasis and influencing clinical prognosis of LUAD. MATERIALS & METHODS: Microarrays were used to screen a comprehensive set of lncRNAs with differential expression profiles in lung cancer cells. The functional role and mechanism of lncRNA were further investigated by gain- and loss-of-function assays. RNA pull-down, protein assays, and mass spectrometry were used to identify proteins that interacted with lncRNA. TaqMan PCR was used to measure lncRNA in lung adenocarcinoma and adjacent nontumor tissues from 428 patients. The clinical significance of lncRNA identified was statistically confirmed in this cohort of patients. RESULTS: In this study, we show that the long non-coding RNA BC009639 (BC) is involved in acquired resistance to EGFR-targeted therapies. Among the 235 long non-coding RNAs that were differentially expressed in lung cancer cell lines, with different metastatic potentials, BC promoted growth, invasion, metastasis, and resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), both in vitro and in vivo. BC was highly expressed in 428 patients with lung adenocarcinoma (LUAD) and high BC expression correlated with reduced efficacy of EGFR-TKI therapy. To uncover the molecular mechanism of BC-mediated EGFR-TKI resistance in lung cancer, we screened and identified nucleolin and hnRNPK that interact with BC. BC formed the splicing complex with nucleolin and hnRNPK to facilitate the production of a non-protein-coding inositol monophosphatase domain containing 1 (IMPAD1) splice variant, instead of the protein-coding variant. The BC-mediated alternative splicing (AS) of IMPAD1 resulted in the induction of the epithelial-mesenchymal transition and resistance to EGFR-TKI in lung cancer. High BC expression correlated with clinical progress and poor survival among 402 patients with LUAD. DISSCUSSION: Through alternative splicing, BC boosted the non-coding IMPAD1-203 transcript variant while suppressing the IMPAD1-201 variant. In order to control the processing of pre-mRNA, BC not only attracted RNA binding proteins (NCL, IGF2BP1) or splicing factors (hnRNPK), but also controlled the formation of the splicing-regulator complex by creating RNA-RNA-duplexes. CONCLUSION: Our results reveal an important role for BC in mediating resistance to EGFR-targeted therapy in LUAD through IMPAD1 AS and in implication for the targeted therapy resistance.

Polymeric nano-system for macrophage reprogramming and intracellular MRSA eradication.

Intracellular Methicillin-Resistant Staphylococcus aureus (MRSA) remains a major factor of refractory and recurrent infections, which cannot be well addressed by antibiotic therapy. Here, we design a cellular infectious microenvironment-activatable polymeric nano-system to mediate targeted intracellular drug delivery for macrophage reprogramming and intracellular MRSA eradication. The polymeric nano-system is composed of a ferrocene-decorated polymeric nanovesicle formulated from poly(ferrocenemethyl methacrylate)-block-poly(2-methacryloyloxyethyl phosphorylcholine) (PFMMA-b-PMPC) copolymer with co-encapsulation of clofazimine (CFZ) and interferon-γ (IFN-γ). The cellular-targeting PMPC motifs render specific internalization by macrophages and allow efficient intracellular accumulation. Following the internalization, the ferrocene-derived polymer backbone sequentially undergoes hydrophobic-to-hydrophilic transition, charge reversal and Fe release in response to intracellular hydrogen peroxide over-produced upon infection, eventually triggering endosomal escape and on-site cytosolic drug delivery. The released IFN-γ reverses the immunosuppressive status of infected macrophages by reprogramming anti-inflammatory M2 to pro-inflammatory M1 phenotype. Meanwhile, intracellular Fe2+-mediated Fenton reaction together with antibiotic CFZ contributes to increased intracellular hydroxyl radical (•OH) generation. Ultimately, the nano-system achieves robust potency in ablating intracellular MRSA and antibiotic-tolerant persisters by synchronous immune modulation and efficient •OH killing, providing an innovative train of thought for intracellular MRSA control.

In Situ Sprayed Biotherapeutic Gel Containing Stable Microbial Communities for Efficient Anti-Infection Treatment.

Systematic administration of antibiotics to treat infections often leads to the rapid evolution and spread of multidrug-resistant bacteria. Here, an in situ-formed biotherapeutic gel that controls multidrug-resistant bacterial infections and accelerates wound healing is reported. This biotherapeutic gel is constructed by incorporating stable microbial communities (kombucha) capable of producing antimicrobial substances and organic acids into thermosensitive Pluronic F127 (polyethylene-polypropylene glycol) solutions. Furthermore, it is found that the stable microbial communities-based biotherapeutic gel possesses a broad antimicrobial spectrum and strong antibacterial effects in diverse pathogenic bacteria-derived xenograft infection models, as well as in patient-derived multidrug-resistant bacterial xenograft infection models. The biotherapeutic gel system considerably outperforms the commercial broad-spectrum antibacterial gel (0.1% polyaminopropyl biguanide) in pathogen removal and infected wound healing. Collectively, this biotherapeutic strategy of exploiting stable symbiotic consortiums to repel pathogens provides a paradigm for developing efficient antibacterial biomaterials and overcomes the failure of antibiotics to treat multidrug-resistant bacterial infections.

Interference of Glucose Bioavailability of Tumor by Engineered Biohybrids for Potentiating Targeting and Uptake of Antitumor Nanodrugs.

The chemotherapy efficacy of nanodrugs is restricted by poor tumor targeting and uptake. Here, an engineered biohybrid living material (designated as EcN@HPB) is constructed by integrating paclitaxel and BAY-876 bound human serum albumin nanodrugs (HPB) with Escherichia coli Nissle 1917 (EcN). Due to the inherent tumor tropism of EcN, EcN@HPB could actively target the tumor site and competitively deprive glucose through bacterial respiration. Thus, albumin would be used as an alternative nutrient source for tumor metabolism, which significantly promotes the internalization of HPB by tumor cells. Subsequently, BAY-876 internalized along with HPB nanodrugs would further depress glucose uptake of tumor cells via inhibiting glucose transporter 1 (GLUT1). Together, the decline of glucose bioavailability of tumor cells would activate and promote the macropinocytosis in an AMP-activated protein kinase (AMPK)-dependent manner, resulting in more uptake of HPB by tumor cells and boosting the therapeutic outcome of paclitaxel.

Probiotic Spore-Based Oral Drug Delivery System for Enhancing Pancreatic Cancer Chemotherapy by Gut-Pancreas-Axis-Guided Delivery.

The chemotherapeutic effectiveness of pancreatic ductal adenocarcinoma (PDAC) is severely hampered by insufficient intratumoral delivery of antitumor drugs. Here, we demonstrate that enhanced pancreatic cancer chemotherapy can be achieved by probiotic spore-based oral drug delivery system via gut-pancreas axis translocation. Clostridium butyricum spores resistant to harsh external stress are extracted as drug carriers, which are further covalently conjugated with gemcitabine-loaded mesoporous silicon nanoparticles (MGEM). The spore-based oral drug delivery system (SPORE-MGEM) migrates upstream into pancreatic tumors from the gut, which increases intratumoral drug accumulation by ∼3-fold compared with MGEM. In two orthotopic PDAC mice models, tumor growth is markedly suppressed by SPORE-MGEM without obvious side effects. Leveraging the biological contact of the gut-pancreas axis, this probiotic spore-based oral drug delivery system reveals a new avenue for enhancing PDAC chemotherapy.

Prognostic significance of CNSL at diagnosis of childhood B-cell acute lymphoblastic leukemia: A report from the South China Children's Leukemia Group.

Objectives: The prognostic significance of acute lymphoblastic leukemia (ALL) patients with central nervous system leukemia (CNSL) at diagnosis is controversial. We aimed to determine the impact of CNSL at diagnosis on the clinical outcomes of childhood B-cell ALL in the South China Children's Leukemia Group (SCCLG). Methods: A total of 1,872 childhood patients were recruited for the study between October 2016 and July 2021. The diagnosis of CNSL depends on primary cytological examination of cerebrospinal fluid, clinical manifestations, and imaging manifestations. Patients with CNSL at diagnosis received two additional courses of intrathecal triple injections during induction. Results: The frequency of CNLS at the diagnosis of B-cell ALL was 3.6%. Patients with CNSL at diagnosis had a significantly higher mean presenting leukocyte count (P = 0.002) and poorer treatment response (P <0.05) compared with non-CNSL patients. Moreover, CNSL status was associated with worse 3-year event-free survival (P = 0.030) and a higher risk of 3-year cumulative incidence of relapse (P = 0.008), while no impact was observed on 3-year overall survival (P = 0.837). Multivariate analysis revealed that CNSL status at diagnosis was an independent predictor with a higher cumulative incidence of relapse (hazard ratio = 2.809, P = 0.016). Conclusion: CNSL status remains an adverse prognostic factor in childhood B-cell ALL, indicating that additional augmentation of CNS-directed therapy is warranted for patients with CNSL at diagnosis.

Biomedical polymers: synthesis, properties, and applications.

Biomedical polymers have been extensively developed for promising applications in a lot of biomedical fields, such as therapeutic medicine delivery, disease detection and diagnosis, biosensing, regenerative medicine, and disease treatment. In this review, we summarize the most recent advances in the synthesis and application of biomedical polymers, and discuss the comprehensive understanding of their property-function relationship for corresponding biomedical applications. In particular, a few burgeoning bioactive polymers, such as peptide/biomembrane/microorganism/cell-based biomedical polymers, are also introduced and highlighted as the emerging biomaterials for cancer precision therapy. Furthermore, the foreseeable challenges and outlook of the development of more efficient, healthier and safer biomedical polymers are discussed. We wish this systemic and comprehensive review on highlighting frontier progress of biomedical polymers could inspire and promote new breakthrough in fundamental research and clinical translation.

A Nomogram for Predicting Event-Free Survival in Childhood Acute Lymphoblastic Leukemia: A Multicenter Retrospective Study.

Objective: Even though childhood acute lymphoblastic leukemia (ALL) has an encouraging survival rate in recent years, some patients are still at risk of relapse or even death. Therefore, we aimed to construct a nomogram to predict event-free survival (EFS) in patients with ALL. Method: Children with newly diagnosed ALL between October 2016 and July 2021 from 18 hospitals participating in the South China children's leukemia Group (SCCLG) were recruited and randomly classified into two subsets in a 7:3 ratio (training set, n=1187; validation set, n=506). Least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were adopted to screen independent prognostic factors. Then, a nomogram can be build based on these prognostic factors to predict 1-, 2-, and 3-year EFS. Concordance index (C-index), area under the curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance and clinical utility of nomogram. Result: The parameters that predicted EFS were age at diagnosis, white blood cell at diagnosis, immunophenotype, ETV6-RUNX1/TEL-AML1 gene fusion, bone marrow remission at day 15, and minimal residual disease at day 15. The nomogram incorporated the six factors and provided C-index values of 0.811 [95% confidence interval (CI) = 0.792-0.830] and 0.797 (95% CI = 0.769-0.825) in the training and validation set, respectively. The calibration curve and AUC revealed that the nomogram had good ability to predict 1-, 2-, and 3-year EFS. DCA also indicated that our nomogram had good clinical utility. Kaplan-Meier analysis showed that EFS in the different risk groups stratified by the nomogram scores was significant differentiated. Conclusion: The nomogram for predicting EFS of children with ALL has good performance and clinical utility. The model could help clinical decision-making.

Harnessing in situ glutathione for effective ROS generation and tumor suppression via nanohybrid-mediated catabolism dynamic therapy.

The overexpression of glutathione (GSH) in cancer cells has long been regarded as the primary obstacle for reactive oxygen species (ROS)-involved anti-tumor therapies. To solve this issue, a ferric ion and selenite-codoped calcium phosphate (Fe/Se-CaP) nanohybrid here is fabricated to catabolize endogenous GSH, instead of directly deleting it, to trigger a ROS storm for tumor suppression. The selenite component in Fe/Se-CaP can catabolize GSH to superoxide anion (O2•-) and hydroxyl radicals (•OH) via cascade catalytic reactions, elevating oxidative stress while destroying antioxidant system. The doped Fe can further catalyze the soaring hydrogen peroxide (H2O2) originated from O2•- to •OH via Fenton reactions. Collectively, Fe/Se-CaP mediated self-augmented catabolism dynamic therapy finally induces apoptosis of cancer cells owing to the significant rise of ROS and, combined with CaP adjuvant, evokes adaptive immune responses to suppress tumor progression, providing an innovative train of thought for ROS-involved anti-tumor therapies.

A Self-Driven Bioreactor Based on Bacterium-Metal-Organic Framework Biohybrids for Boosting Chemotherapy via Cyclic Lactate Catabolism.

The excessive lactate in the tumor microenvironment always leads to poor therapeutic outcomes of chemotherapy. In this study, a self-driven bioreactor (defined as SO@MDH, where SO is Shewanella oneidensis MR-1 and MDH is MIL-101 metal-organic framework nanoparticles/doxorubicin/hyaluronic acid) is rationally constructed via the integration of doxorubicin (DOX)-loaded metal-organic framework (MOF) MIL-101 nanoparticles with SO to sensitize chemotherapy. Owing to the intrinsic tumor tropism and electron-driven respiration of SO, the biohybrid SO@MDH could actively target and colonize hypoxic and eutrophic tumor regions and anaerobically metabolize lactate accompanied by the transfer of electrons to Fe3+, which is the key component of the MIL-101 nanoparticles. As a result, the intratumoral lactate would undergo continuous catabolism coupled with the reduction of Fe3+ to Fe2+ and the subsequent degradation of MIL-101 frameworks, leading to an expeditious drug release for effective chemotherapy. Meanwhile, the generated Fe2+ will be promptly oxidized by the abundant hydrogen peroxide in the tumor microenvironment to reproduce Fe3+, which is, in turn, beneficial to circularly catabolize lactate and boost chemotherapy. More importantly, the consumption of intratumoral lactic acid could significantly inhibit the expression of multidrug resistance-related ABCB1 protein (also named P-glycoprotein (P-gp)) for conquering drug-resistant tumors. SO@MDH demonstrated here holds high tumor specificity and promising chemotherapeutic efficacy for suppressing tumor growth and overcoming multidrug resistance, confirming its potential prospects in cancer therapy.

Customized materials-assisted microorganisms in tumor therapeutics.

Microorganisms have been extensively applied as active biotherapeutic agents or drug delivery vehicles for antitumor treatment because of their unparalleled bio-functionalities. Taking advantage of the living attributes of microorganisms, a new avenue has been opened in anticancer research. The integration of customized functional materials with living microorganisms has demonstrated unprecedented potential in solving existing questions and even conferring microorganisms with updated antitumor abilities and has also provided an innovative train of thought for enhancing the efficacy of microorganism-based tumor therapy. In this review, we have summarized the emerging development of customized materials-assisted microorganisms (MAMO) (including bacteria, viruses, fungi, microalgae, as well as their components) in tumor therapeutics with an emphasis on the rational utilization of chosen microorganisms and tailored materials, the ingenious design of biohybrid systems, and the efficacious antitumor mechanisms. The future perspectives and challenges in this field are also discussed.

Photoelectric Bacteria Enhance the In Situ Production of Tetrodotoxin for Antitumor Therapy.

Engineered bacteria are promising bioagents to synthesize antitumor drugs at tumor sites with the advantages of avoiding drug leakage and degradation during delivery. Here, we report an optically controlled material-assisted microbial system by biosynthesizing gold nanoparticles (AuNPs) on the surface of Shewanella algae K3259 (S. algae) to obtain Bac@Au. Leveraging the dual directional electron transport mechanism of S. algae, the hybrid biosystem enhances in situ synthesis of antineoplastic tetrodotoxin (TTX) for a promising antitumor effect. Because of tumor hypoxia-targeting feature of facultative anaerobic S. algae, Bac@Au selectively target and colonize at tumor. Upon light irradiation, photoelectrons produced by AuNPs deposited on bacterial surface are transferred into bacterial cytoplasm and participate in accelerated cell metabolism to increase the production of TTX for antitumor therapy. The optically controlled material-assisted microbial system enhances the efficiency of bacterial drug synthesis in situ and provides an antitumor strategy that could broaden conventional therapy boundaries.

Prognostic Value and Outcome for ETV6/RUNX1-Positive Pediatric Acute Lymphoblastic Leukemia: A Report From the South China Children's Leukemia Group.

PURPOSE: To analyzed the outcome of ETV6/RUNX1-positive pediatric acute B lymphoblastic leukemia (B-ALL) with the aim of identifying prognostic value. METHOD: A total of 2,530 pediatric patients who were diagnosed with B-ALL were classified into two groups based on the ETV6/RUNX1 status by using a retrospective cohort study method from February 28, 2008, to June 30, 2020, at 22 participating ALL centers. RESULTS: In total, 461 (18.2%) cases were ETV6/RUNX1-positive. The proportion of patients with risk factors (age <1 year or ≥10 years, WB≥50×109/L) in ETV6/RUNX1-positive group was significantly lower than that in negative group (P<0.001), while the proportion of patients with good early response (good response to prednisone, D15 MRD < 0.1%, and D33 MRD < 0.01%) in ETV6/RUNX1-positive group was higher than that in the negative group (P<0.001, 0.788 and 0.004, respectively). Multivariate analysis of 2,530 patients found that age <1 or ≥10 years, SCCLG-ALL-2016 protocol, and MLL were independent predictor of outcome but not ETV6/RUNX1. The EFS and OS of the ETV6/RUNX1-positive group were significantly higher than those of the negative group (3-year EFS: 90.11 ± 4.21% vs 82 ± 2.36%, P<0.0001, 3-year OS: 91.99 ± 3.92% vs 88.79 ± 1.87%, P=0.017). Subgroup analysis showed that chemotherapy protocol, age, prednisone response, and D15 MRD were important factors affecting the prognosis of ETV6/RUNX1-positive children. CONCLUSIONS: ETV6/RUNX1-positive pediatric ALL showed an excellent outcome but lack of independent prognostic significance in South China. However, for older patients who have the ETV6/RUNX1 fusion and slow response to therapy, to opt for more intensive treatment.

Inhibition of Tumor Progression through the Coupling of Bacterial Respiration with Tumor Metabolism.

By leveraging the ability of Shewanella oneidensis MR-1 (S. oneidensis MR-1) to anaerobically catabolize lactate through the transfer of electrons to metal minerals for respiration, a lactate-fueled biohybrid (Bac@MnO2 ) was constructed by modifying manganese dioxide (MnO2 ) nanoflowers on the S. oneidensis MR-1 surface. The biohybrid Bac@MnO2 uses decorated MnO2 nanoflowers as electron receptor and the tumor metabolite lactate as electron donor to make a complete bacterial respiration pathway at the tumor sites, which results in the continuous catabolism of intercellular lactate. Additionally, decorated MnO2 nanoflowers can also catalyze the conversion of endogenous hydrogen peroxide (H2 O2 ) into generate oxygen (O2 ), which could prevent lactate production by downregulating hypoxia-inducible factor-1α (HIF-1α) expression. As lactate plays a critical role in tumor development, the biohybrid Bac@MnO2 could significantly inhibit tumor progression by coupling bacteria respiration with tumor metabolism.

[Differential expression of immediately early gene c-fos in THP-1 macrophage subtype polarization].

Objective: To investigate the expression of immediate early gene c-fos in THP-1 macrophage subtype polarization. Methods: PMA was used to induce the polarization of THP-1 monocytes to macrophages, and the expression of c-fos in the polarization process was observed. After PMA treatment, LPS or IL-4 were used alone to induce the polarization of THP-1 macrophages to the M1 or M2 subtypes. Subsequently, real-time quantitative PCR and western-blot were used to analyze the changes in the expressions of the cell subtype markers CD274, CD86 and CD163. Meanwhile, the expression of c-fos in the polarization process was observed dynamically. Results: The levels of c-fos protein and mRNA expressions were up-regulated during PMA-induced polarization of THP-1 monocytes. The protein and mRNA expressions of c-fos were significantly decreased during the polarization of THP-1 cells into M1 macrophages induced by LPS. The specific markers showed the characteristics of M1 macrophages polarization at 24 h (CD86 protein increased, CD274 and CD163 protein decreased). The protein and mRNA expressions of c-fos were significantly increased during the polarization of THP-1 cells into M2 macrophages induced by IL-4. The specific markers showed the characteristics of M2 macrophages polarization at 24 h (CD86 protein decreased, CD274 and CD163 protein increased). Conclusion: C-fos plays an important role in the polarization of THP-1 monocytes to macrophages. Moreover, it may be involved in the regulation of macrophage subtype polarization, by inhibiting the formation of M1 macrophage and promoting the polarization of macrophages to the M2 subtype.