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.

Oral targeted drug delivery to post-gastrointestinal sites.

As an essential branch of targeted drug delivery, oral targeted delivery is attracting growing attention in recent years. In addition to site-specific delivery for the treatment of locoregional diseases in the gastrointestinal tract (GIT), oral targeted delivery to remote sites beyond the GIT emerges as a cutting-edge research topic. This review aims to provide an overview of the fundamental concepts and most recent advances in this field. Owing to the physiological barriers existing in the GIT, carrier systems should be transported across the enteric epithelia to target remote sites. Recently, pioneer investigations have validated the transport of intact micro- or nanocarriers across gastrointestinal barriers and subsequently to various distal organs and tissues. The microfold (M) cell pathway is the leading mechanism underlying the oral absorption of particulates, but the contribution of the transcellular and paracellular pathways should not be neglected either. In addition to well-acknowledged physicochemical and biological factors, the formation of a protein corona may also influence the biological fate of carrier systems. Although in an early stage of conceptualization, oral targeted delivery to remote diseases has demonstrated promising potential for the treatment of inflammation, tumors, and diseases inflicting the lymphatic and mononuclear phagocytosis systems.

Bacteria-Based Nanoprobes for Cancer Therapy.

Surgical removal together with chemotherapy and radiotherapy has used to be the pillars of cancer treatment. Although these traditional methods are still considered as the first-line or standard treatments, non-operative situation, systemic toxicity or resistance severely weakened the therapeutic effect. More recently, synthetic biological nanocarriers elicited substantial interest and exhibited promising potential for combating cancer. In particular, bacteria and their derivatives are omnipotent to realize intrinsic tumor targeting and inhibit tumor growth with anti-cancer agents secreted and immune response. They are frequently employed in synergistic bacteria-mediated anticancer treatments to strengthen the effectiveness of anti-cancer treatment. In this review, we elaborate on the development, mechanism and advantage of bacterial therapy against cancer and then systematically introduce the bacteria-based nanoprobes against cancer and the recent achievements in synergistic treatment strategies and clinical trials. We also discuss the advantages as well as the limitations of these bacteria-based nanoprobes, especially the questions that hinder their application in human, exhibiting this novel anti-cancer endeavor comprehensively.

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).

Bacterial-Mediated Tumor Therapy: Old Treatment in a New Context.

Targeted therapy and immunotherapy have brought hopes for precision cancer treatment. However, complex physiological barriers and tumor immunosuppression result in poor efficacy, side effects, and resistance to antitumor therapies. Bacteria-mediated antitumor therapy provides new options to address these challenges. Thanks to their special characteristics, bacteria have excellent ability to destroy tumor cells from the inside and induce innate and adaptive antitumor immune responses. Furthermore, bacterial components, including bacterial vesicles, spores, toxins, metabolites, and other active substances, similarly inherit their unique targeting properties and antitumor capabilities. Bacteria and their accessory products can even be reprogrammed to produce and deliver antitumor agents according to clinical needs. This review first discusses the role of different bacteria in the development of tumorigenesis and the latest advances in bacteria-based delivery platforms and the existing obstacles for application. Moreover, the prospect and challenges of clinical transformation of engineered bacteria are also summarized.

The Reform of Basketball Curriculum Model for Students' Physical Development under the National Fitness Environment.

College sports serving national fitness are a complex system. College sports are an important part of national fitness. Basketball curriculum, as a subsystem of college sports, has always been loved by college students. The reform of college basketball curriculum mode is an important way to explore the coordinated evolution of college sports subsystem. Through the methods of questionnaire, interview, and mathematical statistics, aiming at the problems existing in the planning and design of basketball curriculum objectives and contents in colleges and universities, this study puts forward that it is necessary to establish a scientific and reasonable basketball special curriculum objective system and then combine the basketball curriculum teaching theory with the basketball training teaching mode, to cultivate students' practical application ability, and adopt a variety of teaching methods to cultivate students' practical ability. Finally, the teaching mode of basketball is improved. Through an example, the application effect of the basketball curriculum model under the background of national fitness proposed in this study is tested. The results show that the basketball curriculum teaching model proposed in this study has certain feasibility and effectiveness.

Correction: Numb Promotes Cell Proliferation and Correlates with Poor Prognosis in Hepatocellular Carcinoma.

[This corrects the article DOI: 10.1371/journal.pone.0095849.].

Intravenous Delivery of Living Listeria monocytogenes Elicits Gasdmermin-Dependent Tumor Pyroptosis and Motivates Anti-Tumor Immune Response.

The facultative intracellular bacterium Listeria monocytogenes (Lmo) has great potential for development as a cancer vaccine platform given its properties. However, the clinical application of Lmo has been severely restricted due to its rapid clearance, compromised immune response in tumors, and inevitable side effects such as severe systemic inflammation after intravenous administration. Herein, an immunotherapy system was developed on the basis of natural red blood cell (RBC) membranes encapsulated Lmo with selective deletion of virulence factors (Lmo@RBC). The biomimetic Lmo@RBC not only generated a low systemic inflammatory response but also enhanced the accumulation in tumors due to the long blood circulation and tumor hypoxic microenvironment favoring anaerobic Lmo colonization. After genome screening of tumors treated with intravenous PBS, Lmo, or Lmo@RBC, it was first found that Lmo@RBC induced extensive pore-forming protein gasdermin C (GSDMC)-dependent pyroptosis, which reversed immunosuppressive tumor microenvironment and promoted a systemic strong and durable anti-tumor immune response, resulting in an excellent therapeutic effect on solid tumors and tumor metastasis. Overall, Lmo@RBC, as an intravenous living bacterial therapy for the selective initiation of tumor pyrolysis, provided a proof-of-concept of live bacteria vaccine potentiating tumor immune therapy.

Low-temperature photothermal irradiation triggers alkyl radicals burst for potentiating cancer immunotherapy.

Although low-temperature photothermal therapy (PTT) can sensitize tumors to immune checkpoint inhibition, its efficacy is still restricted in the deep and internal tumors without enough oxygen and lymphocytic infiltration. Non-oxygen-dependent alkyl radicals have been demonstrated to synergistically enhance PTT through up-regulating lipid peroxidation and reactive oxygen species (ROS). Herein, an innovative strategy based on alkyl radicals to augment immunogenetic cell death (ICD) caused by mild PTT was proposed to improve poor efficacy of immunotherapy, which composed of a photothermal material of Chinse ink, an azo-initiator of 2,2-azobis[2-(2-imidazoline-2-acyl)propane]dihydrochloride (AIPH) and a PD-L1 inhibitor of HY19991 (HY). Upon near-infrared-II laser irradiation, low-temperature (<45℃) stimulation induced a high expression of immune checkpoint receptor (PD-L1) in tumors and triggered a large amount alkyl radicals generated by AIPH. Significantly, the alkyl radicals augmented the ICD and increased the recruitment of tumor-infiltrating lymphocytes against tumors after transformation of the immunologically cold tumor microenvironment into hot by mild PTT. The released HY further enhanced the immunotherapy effect by blocking the binding of activated T lymphocytes and PD-L1. In vivo studies exhibited that the all-in-one hydrogel with synergistic mechanisms had an extraordinary ability to reverse the immunosuppressive microenvironment, stimulate innate and adaptive immune responses to eliminate tumors and prevent metastasis.

Protein corona mediated liposomal drug delivery for bacterial infection management.

Liposomes have been widely investigated as a class of promising antibiotic delivery systems for the treatment of life-threatening bacterial infections. However, the inevitable formation of protein corona on the liposomal surface can heavily impact in vivo performance. A better understanding of the effects of protein corona on liposomal behavior can significantly improve antibacterial liposomal drug development. Here, the critical role of protein corona in mediating liposome-bacteria interactions was elucidated. Adsorption of negatively charged protein on cationic liposome weakened electrostatic attraction-enhanced liposomal binding to the bacteria. Cumulative complement deposition on anionic liposome composed of phosphatidylglycerol (DSPG sLip) contributed to a superior binding affinity of DSPG sLip to planktonic bacteria and biofilms, which was exploited to enhance bacteria-targeted drug delivery. In both S. aureus-related osteomyelitis and pneumonia mice models, DSPG sLip was demonstrated as a promising antibiotic nanocarrier for managing MRSA infection, indicating the benefits of lipid composition-based protein corona modulation in liposomal antibiotic delivery for bacterial infection treatment.

Preoperative Survival Prediction in Intrahepatic Cholangiocarcinoma Using an Ultrasound-Based Radiographic-Radiomics Signature.

OBJECTIVES: To construct a preoperative model for survival prediction in intrahepatic cholangiocarcinoma (ICC) patients using ultrasound (US) based radiographic-radiomics signatures. METHODS: Between April 2010 and September 2015, 170 patients with ICC who underwent curative resection were retrospectively recruited. Overall survival (OS)-related radiographic signatures and radiomics signatures based on preoperative US were built and assessed through a time-dependent receiver operating characteristic curve analysis. A nomogram was developed based on the selected predictors from the radiographic-radiomics signatures and clinical and laboratory results of the training cohort (n = 127), validated in an independent testing cohort (n = 43) by the concordance index (C-index), and compared with the Tumor Node Metastasis (TNM) cancer staging system as well as the radiographic and radiomics nomograms. RESULTS: The median areas under the curve of the radiomics signature and radiographic signature were higher than that of the TNM staging system in the testing cohort, although the values were not significantly different (0.76-0.82 versus 0.62, P = .485 and .264). The preoperative nomogram with CA 19-9, sex, ascites, radiomics signature, and radiographic signature had C-indexes of 0.72 and 0.75 in the training and testing cohorts, respectively, and it had significantly higher predictive performance than the 8th TNM staging system in the testing cohort (C-index: 0.75 versus 0.67, P = .004) and a higher C-index than the radiomics nomograms (0.75 versus 0.68, P = .044). CONCLUSIONS: The preoperative nomogram integrated with the radiographic-radiomics signature demonstrated good predictive performance for OS in ICC and was superior to the 8th TNM staging system.

Contrast-Enhanced Ultrasound-Based Nomogram: A Potential Predictor of Individually Postoperative Early Recurrence for Patients With Combined Hepatocellular-Cholangiocarcinoma.

PURPOSES: To evaluate the postsurgical prognostic implication of contrast-enhanced ultrasound (CEUS) for combined hepatocellular-cholangiocarcinoma (CHC). To build a CEUS-based early recurrence prediction classifier for CHC, in comparison with tumor-node-metastasis (TNM) staging. METHODS: The CEUS features and clinicopathological findings of each case were analyzed, and the Liver Imaging Reporting and Data System categories were assigned. The recurrence-free survival associated factors were evaluated by Cox proportional hazard model. Incorporating the independent factors, nomograms were built to estimate the possibilities of 3-month, 6-month, and 1-year recurrence and whose prognostic value was determined by time-dependent receiver operating characteristics, calibration curves, and hazard layering efficiency validation, comparing with TNM staging system. RESULTS: In the multivariable analysis, the levels of carbohydrate antigen 19-9, prothrombin time and total bilirubin, and tumor shape, the Liver Imaging Reporting and Data System category were independent factors for recurrence-free survival. The LR-M category showed longer recurrence-free survival than did the LR-4/5 category. The 3-month, 6-month, and 1-year area under the curves of the CEUS-clinical nomogram, clinical nomogram, and TNM staging system were 0.518, 0.552, and 0.843 versus 0.354, 0.240, and 0.624 (P = .048, .049, and .471) vs. 0.562, 0.545, and 0.843 (P = .630, .564, and .007), respectively. The calibration curves of the CEUS-clinical model at different prediction time pionts were all close to the ideal line. The CEUS-clinical model effectively stratified patients into groups of high and low risk of recurrence in both training and validation set, while the TNM staging system only works on the training set. CONCLUSIONS: Our CEUS-clinical nomogram is a reliable early recurrence prediction tool for hepatocellular-cholangiocarcinoma and helps postoperative risk stratification.

Localized disruption of redox homeostasis boosting ferroptosis of tumor by hydrogel delivery system.

Ferroptosis has received ever-increasing attention due to its unparalleled mechanism in eliminating resistant tumor cells. Nevertheless, the accumulation of toxic lipid peroxides (LPOs) at the tumor site is limited by the level of lipid oxidation. Herein, by leveraging versatile sodium alginate (ALG) hydrogel, a localized ferroptosis trigger consisting of gambogic acid (GA), 2,2'-azobis [2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH), and Ink (a photothermal agent), was constructed via simple intratumor injection. Upon 1064 â€‹nm laser irradiation, the stored AIPH rapidly decomposed into alkyl radicals (R•), which aggravated LPOs in tumor cells. Meanwhile, GA could inhibit heat shock protein 90 (HSP90) to reduce the heat resistance of tumor cells, and forcefully consume glutathione (GSH) to weaken the antioxidant capacity of cells. Systematic in vitro and in vivo experiments have demonstrated that synchronous consumption of GSH and increased reactive oxygen species (ROS) facilitated reduced expression of glutathione peroxidase 4 (GPX4), which further contributed to disruption of intracellular redox homeostasis and ultimately boosted ferroptosis. This all-in-one strategy has a highly effective tumor suppression effect by depleting and generating fatal active compounds at tumor sites, which would pave a new route for the controllable, accurate, and coordinated tumor treatments.

Hypoxia-degradable and long-circulating zwitterionic phosphorylcholine-based nanogel for enhanced tumor drug delivery.

Tumor microenvironment has been widely utilized for advanced drug delivery in recent years, among which hypoxia-responsive drug delivery systems have become the research hotspot. Although hypoxia-responsive micelles or polymersomes have been successfully developed, a type of hypoxia-degradable nanogel has rarely been reported and the advantages of hypoxia-degradable nanogel over other kinds of degradable nanogels in tumor drug delivery remain unclear. Herein, we reported the synthesis of a novel hypoxia-responsive crosslinker and the fabrication of a hypoxia-degradable zwitterionic poly(phosphorylcholine)-based (HPMPC) nanogel for tumor drug delivery. The obtained HPMPC nanogel showed ultra-long blood circulation and desirable immune compatibility, which leads to high and long-lasting accumulation in tumor tissue. Furthermore, HPMPC nanogel could rapidly degrade into oligomers of low molecule weight owing to the degradation of azo bond in hypoxic environment, which leads to the effective release of the loaded drug. Impressively, HPMPC nanogel showed superior tumor inhibition effect both in vitro and in vivo compared to the reduction-responsive phosphorylcholine-based nanogel, owing to the more complete drug release. Overall, the drug-loaded HPMPC nanogel exhibits a pronounced tumor inhibition effect in a humanized subcutaneous liver cancer model with negligible side effects, which showed great potential as nanocarrier for advanced tumor drug delivery.

Topological Phase Transitions in Disordered Electric Quadrupole Insulators.

We investigate disorder-driven topological phase transitions in quantized electric quadrupole insulators in two dimensions. We show that chiral symmetry can protect the quantization of the quadrupole moment q_{xy}, such that the higher-order topological invariant is well defined even when disorder has broken all crystalline symmetries. Moreover, nonvanishing q_{xy} and consequent corner modes can be induced from a trivial insulating phase by disorder that preserves chiral symmetry. The critical points of such topological phase transitions are marked by the occurrence of extended boundary states even in the presence of strong disorder. We provide a systematic characterization of these disorder-driven topological phase transitions from both bulk and boundary descriptions.

Anomalous Temperature Dependence of Quantum Correction to the Conductivity of Magnetic Topological Insulators.

Quantum transport in magnetic topological insulators reveals a strong interplay between magnetism and topology of electronic band structures. A recent experiment on magnetically doped topological insulator Bi_{2}Se_{3} thin films showed the anomalous temperature dependence of the magnetoconductivity while their field dependence presents a clear signature of weak antilocalization [Tkac et al., Phys. Rev. Lett. 123, 036406 (2019)PRLTAO0031-900710.1103/PhysRevLett.123.036406]. Here, we demonstrate that the tiny mass of the surface electrons induced by the bulk magnetization leads to a temperature-dependent correction to the π Berry phase and generates a decoherence mechanism to the phase coherence length of the surface electrons. As a consequence, the quantum correction to conductivity can exhibit nonmonotonic behavior by decreasing the temperature. This effect is attributed to the close relation of the Berry phase and quantum interference of the topological surface electrons in quantum topological materials.