circ_0000592 facilitates the progression of esophageal squamous cell carcinoma via miR-155-5p/FZD5 axis.

Esophageal squamous cell carcinoma (ESCC) is one of the gastrointestinal malignancies with high prevalence and poor prognosis. Previous reports suggested that circular ribose nucleic acids might exert regulatory functions in ESCC. This study aims to explore the role of circ_0000592 in ESCC progression, providing novel insights into the diagnosis and therapeutic avenues for ESCC. The GSE131969 data set was utilized to assess circ_0000592 expression in ESCC. The validation was performed in the tumorous tissues of ESCC patients (n = 80) and human-immortalized ESCC cell lines. The correlation between circ_0000592 expression and prognosis was analyzed. The impact of circ_0000592 on ESCC cell activity was evaluated through downregulating circ_0000592, as well as encompassing cell viability, migration, and invasion abilities. The downstream pathway of circ_0000592 was explored by binding site prediction from the TargetScan database, followed by in vitro and in vivo experiments. An in vivo xenograft tumor model was established to highlight the role of circ_0000592 in ESCC. Patients with ESCC exhibited higher circ_0000592 expression levels compared to noncancerous patients, which were associated with reduced survival time, higher TNM stage, and increased lymph node metastasis. The circ_0000592 downregulation suppressed cell viability, migration, and invasion abilities in vitro. Mechanistically, circ_0000592 countered the inhibitory effects on the target gene Frizzled 5 (FZD5) through interactions with miR-155-5p. The overexpression of miR-155-5p curtailed the luciferase activity of circ_0000592 in ESCC cells, inhibiting downstream molecule FZD5 protein expression and subsequently mitigating the detrimental consequences of escalated circ_0000592 expression in ESCC cells. Consistently, circ_0000592 downregulation curbed proliferation and metastasis of ESCC tumors in vivo. In summary, circ_0000592 promoted the progress of ESCC by counteracting the inhibitory impact on FZD5 through its interaction with miR-155-5p. Together, our findings highlighted circ_0000592 as a prospective therapeutic target for ESCC.

The clinical regimens and cell membrane camouflaged nanodrug delivery systems in hematologic malignancies treatment.

Hematologic malignancies (HMs), also referred to as hematological or blood cancers, pose significant threats to patients as they impact the blood, bone marrow, and lymphatic system. Despite significant clinical strategies using chemotherapy, radiotherapy, stem cell transplantation, targeted molecular therapy, or immunotherapy, the five-year overall survival of patients with HMs is still low. Fortunately, recent studies demonstrate that the nanodrug delivery system holds the potential to address these challenges and foster effective anti-HMs with precise treatment. In particular, cell membrane camouflaged nanodrug offers enhanced drug targeting, reduced toxicity and side effects, and/or improved immune response to HMs. This review firstly introduces the merits and demerits of clinical strategies in HMs treatment, and then summarizes the types, advantages, and disadvantages of current nanocarriers helping drug delivery in HMs treatment. Furthermore, the types, functions, and mechanisms of cell membrane fragments that help nanodrugs specifically targeted to and accumulate in HM lesions are introduced in detail. Finally, suggestions are given about their clinical translation and future designs on the surface of nanodrugs with multiple functions to improve therapeutic efficiency for cancers.

Radiation-primed TGF-ß trapping by engineered extracellular vesicles for targeted glioblastoma therapy.

The poor outcome of glioblastoma multiforme (GBM) treated with immunotherapy is attributed to the profound immunosuppressive tumor microenvironment (TME) and the lack of effective delivery across the blood-brain barrier. Radiation therapy (RT) induces an immunogenic antitumor response that is counteracted by evasive mechanisms, among which transforming growth factor-ß (TGF-ß) activation is the most prominent factor. We report an extracellular vesicle (EV)-based nanotherapeutic that traps TGF-ß by expressing the extracellular domain of the TGF-ß type II receptor and targets GBM by decorating the EV surface with RGD peptide. We show that short-burst radiation dramatically enhanced the targeting efficiency of RGD peptide-conjugated EVs to GBM, while the displayed TGF-ß trap reversed radiation-stimulated TGF-ß activation in the TME, offering a synergistic effect in the murine GBM model. The combined therapy significantly increased CD8+ cytotoxic T cells infiltration and M1/M2 macrophage ratio, resulting in the regression of tumor growth and prolongation of overall survival. These results provide an EV-based therapeutic strategy for immune remodeling of the GBM TME and eradication of therapy-resistant tumors, further supporting its clinical translation.

A lipid/PLGA nanocomplex to reshape tumor immune microenvironment for colon cancer therapy.

Immune checkpoint blockade therapy provides a new strategy for tumor treatment; however, the insufficient infiltration of cytotoxic T cells and immunosuppression in tumor microenvironment lead to unsatisfied effects. Herein, we reported a lipid/PLGA nanocomplex (RDCM) co-loaded with the photosensitizer Ce6 and the indoleamine 2,3-dioxygenase (IDO) inhibitor 1MT to improve immunotherapy of colon cancer. Arginine-glycine-aspartic acid (RGD) as the targeting moiety was conjugated on 1,2-distearoyl-snglycero-3-phosphoethanolamine lipid via polyethylene glycol (PEG), and programmed cell death-ligand 1 (PD-L1) peptide inhibitor DPPA (sequence: CPLGVRGK-GGG-d(NYSKPTDRQYHF)) was immobilized on the terminal group of PEG via matrix metalloproteinase 2 sensitive peptide linker. The Ce6 and 1MT were encapsulated in PLGA nanoparticles. The drug loaded nanoparticles were composited with RGD and DPPA modified lipid and lecithin to form lipid/PLGA nanocomplexes. When the nanocomplexes were delivered to tumor, DPPA was released by the cleavage of a matrix metalloproteinase 2-sensitive peptide linker for PD-L1 binding. RGD facilitated the cellular internalization of nanocomplexes via avß3 integrin. Strong immunogenic cell death was induced by 1O2 generated from Ce6 irradiation under 660 nm laser. 1MT inhibited the activity of IDO and reduced the inhibition of cytotoxic T cells caused by kynurenine accumulation in the tumor microenvironment. The RDCM facilitated the maturation of dendritic cells, inhibited the activity of IDO, and markedly recruited the proportion of tumor-infiltrating cytotoxic T cells in CT26 tumor-bearing mice, triggering a robust immunological memory effect, thus effectively preventing tumor metastasis. The results indicated that the RDCM with dual IDO and PD-L1 inhibition effects is a promising platform for targeted photoimmunotherapy of colon cancer.

Emerging Strategies to Overcome Current CAR-T Therapy Dilemmas - Exosomes Derived from CAR-T Cells.

Adoptive T cells immunotherapy, specifically chimeric antigen receptor T cells (CAR-T), has shown promising therapeutic efficacy in the treatment of hematologic malignancies. As extensive research on CAR-T therapies has been conducted, various challenges have emerged that significantly hampered their clinical application, including tumor recurrence, CAR-T cell exhaustion, and cytokine release syndrome (CRS). To overcome the hurdles of CAR-T therapy in clinical treatment, cell-free emerging therapies based on exosomes derived from CAR-T cells have been developed as an effective and promising alternative approach. In this review, we present CAR-T cell-based therapies for the treatment of tumors, including the features and benefits of CAR-T therapies, the limitations that exist in this field, and the measures taken to overcome them. Furthermore, we discuss the notable benefits of utilizing exosomes released from CAR-T cells in tumor treatment and anticipate potential issues in clinical trials. Lastly, drawing from previous research on exosomes from CAR-T cells and the characteristics of exosomes, we propose strategies to overcome these restrictions. Additionally, the review discusses the plight in large-scale preparation of exosome and provides potential solutions for future clinical applications.

Manganese dioxide nanoparticles provoke inflammatory damage in BV2 microglial cells via increasing reactive oxygen species to activate the p38 MAPK pathway.

With the widespread use of manganese dioxide nanoparticles (nano MnO2), health hazards have also emerged. The inflammatory damage of brain tissues could result from nano MnO2, in which the underlying mechanism is still unclear. During this study, we aimed to investigate the role of ROS-mediated p38 MAPK pathway in nano MnO2-induced inflammatory response in BV2 microglial cells. The inflammatory injury model was established by treating BV2 cells with 2.5, 5.0, and 10.0 µg/mL nano MnO2 suspensions for 12 h. Then, the reactive oxygen species (ROS) scavenger (20 nM N-acetylcysteine, NAC) and the p38 MAPK pathway inhibitor (10 µM SB203580) were used to clarify the role of ROS and the p38 MAPK pathway in nano MnO2-induced inflammatory lesions in BV2 cells. The results indicated that nano MnO2 enhanced the expression of pro-inflammatory cytokines IL-1ß and TNF-α, elevated intracellular ROS levels and activated the p38 MAPK pathway in BV2 cells. Controlling intracellular ROS levels with NAC inhibited p38 MAPK pathway activation and attenuated the inflammatory response induced by nano MnO2. Furthermore, inhibition of the p38 MAPK pathway with SB203580 led to a decrease in the production of inflammatory factors (IL-1ß and TNF-α) in BV2 cells. In summary, nano MnO2 can induce inflammatory damage by increasing intracellular ROS levels and further activating the p38 MAPK pathway in BV2 microglial cells.

Synthesis of compounds based on the active domain of cabotegravir and their application in inhibiting tumor cells activity.

Structural modification based on existing drugs, which ensures the safety of marketed drugs, is an essential approach in developing new drugs. In this study, we modified the structure of cabotegravir by introducing the front alkyne on the core structure through chemical reaction, resulting in the synthesis of 9 compounds resembling 1,2,3-triazoles. The potential of these new cabotegravir derivatives as tumor suppressors in gastrointestinal tumors was investigated. Based on the MTT experiment, most compounds showed a reduction in the viability of KYSE30 and HCT116 cells. Notably, derivatives 5b and 5h exhibited the most significant inhibitory effects. To further explore the effects of derivatives 5b and 5h on gastrointestinal tumors, KYSE30 cells were chosen as a representative cell line. Both derivatives can effectively curtail the migration and invasion capabilities of KYSE30 cells and induce apoptosis in a dose-dependent manner. We further demonstrated these derivatives induce cell apoptosis in KYSE30 cells by inhibiting the expression of Stat3 protein and Smad2/3 protein. Based on the above results, we suggest they show promise in developing drugs for esophageal squamous cell carcinoma.

Multi-omics reveal mechanisms of high enteral starch diet mediated colonic dysbiosis via microbiome-host interactions in young ruminant.

BACKGROUND: Although rumen development is crucial, hindgut undertakes a significant role in young ruminants' physiological development. High-starch diet is usually used to accelerate rumen development for young ruminants, but always leading to the enteral starch overload and hindgut dysbiosis. However, the mechanism behind remains unclear. The combination of colonic transcriptome, colonic luminal metabolome, and metagenome together with histological analysis was conducted using a goat model, with the aim to identify the potential molecular mechanisms behind the disrupted hindgut homeostasis by overload starch in young ruminants. RESULT: Compared with low enteral starch diet (LES), high enteral starch diet (HES)-fed goats had significantly higher colonic pathology scores, and serum diamine oxidase activity, and meanwhile significantly decreased colonic mucosal Mucin-2 (MUC2) protein expression and fecal scores, evidencing the HES-triggered colonic systemic inflammation. The bacterial taxa Prevotella sp. P4-67, Prevotella sp. PINT, and Bacteroides sp. CAG:927, together with fungal taxa Fusarium vanettenii, Neocallimastix californiae, Fusarium sp. AF-8, Hypoxylon sp. EC38, and Fusarium pseudograminearum, and the involved microbial immune pathways including the "T cell receptor signaling pathway" were higher in the colon of HES goats. The integrated metagenome and host transcriptome analysis revealed that these taxa were associated with enhanced pathogenic ability, antigen processing and presentation, and stimulated T helper 2 cell (TH2)-mediated cytokine secretion functions in the colon of HES goats. Further luminal metabolomics analysis showed increased relative content of chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA), and decreased the relative content of hypoxanthine in colonic digesta of HES goats. These altered metabolites contributed to enhancing the expression of TH2-mediated inflammatory-related cytokine secretion including GATA Binding Protein 3 (GATA3), IL-5, and IL-13. Using the linear mixed effect model, the variation of MUC2 biosynthesis explained by the colonic bacteria, bacterial functions, fungi, fungal functions, and metabolites were 21.92, 20.76, 19.43, 12.08, and 44.22%, respectively. The variation of pathology scores explained by the colonic bacterial functions, fungal functions, and metabolites were 15.35, 17.61, and 57.06%. CONCLUSIONS: Our findings revealed that enteral starch overload can trigger interrupted hindgut host-microbiome homeostasis that led to impaired mucosal, destroyed colonic water absorption, and TH2-mediated inflammatory process. Except for the colonic metabolites mostly contribute to the impaired mucosa, the nonnegligible contribution from fungi deserves more future studies focused on the fungal functions in hindgut dysbiosis of young ruminants. Video Abstract.

Circ_0023990 Promotes the Proliferation, Invasion, and Glycolysis of Esophageal Squamous Cell Carcinoma Cells Via Targeting miR-6884-5p/PAK1 Axis.

Circular RNAs are emerging players in human cancers, including esophageal squamous cell carcinoma (ESCC). Herein, we assessed the expression level of circ_0023990 and explored the molecular mechanisms of circ_0023990 in ESCC. circ_0023990, miR-6884-5p, and PAK1 expressions in ESCC tissues and cells were detected by quantitative real-time polymerase chain reaction and western blot. ESCC cells were transfected with different constructs to alter the expression of circ_0023990, miR-6884-5p, and PAK1. The effect of circ_0023990 on the proliferation, invasion, and glycolysis of ESCC cells was observed. The interaction between circ_0023990 and miR-6884-5p and between miR-6884-5p and PAK1 were explored. A mouse model of ESCC was established to study the in vivo effect of circ_0023990 knockdown on tumor formation.The expression levels of circ_0023990 was upregulated in ESCC tissues and cells. Inhibiting circ_0023990 suppressed the proliferation, invasion, and glycolysis of ESCC cells. circ_0023990 might target miR-6884-5p and consequently modulate the expression and activity of PAK1. Knockdown of circ_0023990 led to significantly reduced tumor volume and weight in mice with ESCC.These findings overall suggest an oncogenic role of circ_0023990 in ESCC. Future research is warranted to confirm the expression pattern and clinical significance of circ_0023990 in ESCC.

Spindle and kinetochore-related complex subunit 3 has a protumour function in osteosarcoma by activating the Notch pathway.

Increasing expression of spindle and kinetochore-related complex subunit 3 (SKA3) is related to the progression of multiple malignancies. However, the role of SKA3 in osteosarcoma remains unexplored. The present study aimed to investigate the relevance of SKA3 in osteosarcoma. Preliminarily, SKA3 expression in osteosarcoma was assessed through The Cancer Genome Atlas (TCGA) analysis, which revealed high levels of SKA3 transcripts in osteosarcoma tissues. Subsequent examination of clinical tissues confirmed the abundant expression of SKA3 in osteosarcoma. Downregulation of SKA3 expression in osteosarcoma cell lines resulted in repressive effects on cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT), while upregulation of SKA3 expression had the opposite effect. Gene set enrichment analysis (GSEA) revealed that the Notch pathway is enriched in SKA3 high groups based on different expressed genes from the TCGA data. Further investigation showed that the levels of Notch1, Notch1 intracellular domain (NICD1), hairy and enhancer of split 1 (HES1), and hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) were downregulated in SKA3-silenced osteosarcoma cells, and upregulated in SKA3-overexpressed osteosarcoma cells. Activation of the Notch pathway by increasing NICD1 expression reversed the antitumour effects induced by SKA3 silencing, while deactivation of the Notch pathway diminished the protumour effects induced by SKA3 overexpression. Moreover, SKA3-silenced osteosarcoma cells exhibited a reduced capacity for xenograft formation in nude mice. In conclusion, SKA3 plays a cancer-enhancing role in osteosarcoma through its effect on the Notch pathway. Reducing the expression of SKA3 could be a potential therapeutic approach for treating osteosarcoma.

Engineered mRNA Delivery Systems for Biomedical Applications.

Messenger RNA (mRNA)-based therapeutic strategies have shown remarkable promise in preventing and treating a staggering range of diseases. Optimizing the structure and delivery system of engineered mRNA has greatly improved its stability, immunogenicity, and protein expression levels, which has led to a wider range of uses for mRNA therapeutics. Herein, a thorough analysis of the optimization strategies used in the structure of mRNA is first provided and delivery systems are described in great detail. Furthermore, the latest advancements in biomedical engineering for mRNA technology, including its applications in combatting infectious diseases, treating cancer, providing protein replacement therapy, conducting gene editing, and more, are summarized. Lastly, a perspective on forthcoming challenges and prospects concerning the advancement of mRNA therapeutics is offered. Despite these challenges, mRNA-based therapeutics remain promising, with the potential to revolutionize disease treatment and contribute to significant advancements in the biomedical field.

Codelivery of CuS and DOX into Deep Tumors with Size and Charge-Switchable PAMAM Dendrimers for Chemo-photothermal Therapy.

Accurate targeting of therapeutic agents to specific tumor tissues, especially via deep tumor penetration, has been an effective strategy in cancer treatments. Here, we described a flexible nanoplatform, pH-responsive zwitterionic acylsulfonamide betaine-functionalized fourth-generation PAMAM dendrimers (G4-AB), which presented multiple advantages for chemo-photothermal therapy, including template synthesis of ultrasmall copper sulfide (CuS) nanoparticles and further encapsulation of doxorubicin (DOX) (G4-AB-DOX/CuS), long-circulating performance by a relatively large size and zwitterionic surface in a physiological environment, combined size shrinkage, and charge conversions via pH-responsive behavior in an acidic tumor microenvironment (TME). Accordingly, high tumor penetration and positive cell uptake for CuS and DOX have been determined, which triggered an excellent combination treatment under near-infrared irradiation in comparison to the monochemotherapy system and irresponsive chemo-photothermal system. Our study represented great promise in constructing multifunctional carriers for the effective delivery of photothermal nanoparticles and drugs in chemo-photothermal therapy.

Methods for extending working distance using modified photonic crystal for near-field lithography.

Near-field lithography has evident advantages in fabricating super-resolution nano-patterns. However, the working distance (WD) is limited due to the exponential decay characteristic of the evanescent waves. Here, we proposed a novel photolithography method based on a modified photonic crystal (PC), where a defect layer is embedded into the all-dielectric multilayer structure. It is shown that this design can amend the photonic band gap and enhance the desired high-kwaves dramatically, then the WD in air conditions could be extended greatly, which would drastically relax the engineering challenges for introducing the near-field lithography into real-world manufacturing applications. Typically, deep subwavelength patterns with a half-pitch of 32 nm (i.e.,λ/6) could be formed in photoresist layer at an air WD of 100 nm. Moreover, it is revealed that diversified two-dimensional patterns could be produced with a single exposure using linear polarized light. The analyses indicate that this improved dielectric PC is applicable for near-field lithography to produce super-resolution periodic patterns with large WD, strong field intensity, and great uniformity.

[Effectiveness of dorsal perforator flap of cross-finger proper digital artery in treatment of high-pressure injection injuries of the finger].

Objective: To investigate the effectiveness of dorsal perforator flap of cross-finger proper digital artery in the treatment of finger soft tissue defect caused by high-pressure injection injury. Methods: Between July 2011 and June 2020, 14 cases of finger soft tissue defect caused by high-pressure injection injury were repaired with dorsal perforator flap of cross-finger proper digital artery. All patients were male, with a mean age of 36 years (range, 22-56 years). The defects were located on the index finger in 8 cases, middle finger in 4 cases, and ring finger in 2 cases. The causes of injury include 8 cases of emulsion paint injection, 4 cases of oil paint injection, and 2 cases of cement injection. The time from injury to debridement was 2-8 hours, with a mean time of 4.5 hours. The soft tissue defects sized from 4.0 cm×1.2 cm to 6.0 cm×2.0 cm. The flaps sized from 4.5 cm×1.5 cm to 6.5 cm×2.5 cm. The donor site of the flap was repaired with skin graft. The pedicle was cut off at 3 weeks after operation, and followed by functional exercise. Results: All flaps and skin grafts at donor sites survived, and the wounds healed by first intention. Twelve patients were followed-up 16-38 months (mean, 22.6 months). The texture and appearance of all flaps were satisfactory. The color and texture of the flaps were similar to those of the surrounding tissues. The two-point discrimination of the flap was 10-12 mm, with a mean of 11.5 mm. There were different degrees of cold intolerance at the end of the affected fingers. At last follow-up, the finger function was evaluated according to the Upper Extremity Functional Evaluation Standard set up by Hand Surgery Branch of Chinese Medical Association, 3 cases were excellent, 8 cases were good, and 1 case was poor. Conclusion: The dorsal perforator flap of cross-finger proper digital artery can effectively repair finger soft tissue defect caused by high-pressure injection injury. The operation was simple, and the appearance and function of the finger recover well.

High focusing efficiency metalens with large numerical aperture at terahertz frequency.

Metalenses have been widely investigated for their features of high design freedom. For practical applications, it is necessary to maximize the efficiency of the metalens. However, it is a great challenge to realize both a high numerical aperture (NA) and high-efficiency metalens in the community. Here, we introduce a method to design a hybrid metalens with a large numerical aperture and high focusing efficiency at terahertz frequency. The hybrid metalens consists of gradient metasurfaces in the central area and metagrating in the peripheral area to achieve high-efficiency beam focusing. To verify this concept, a hybrid metalens with a numerical aperture of 0.95 was designed at λ = 118.8 µm. The simulation results demonstrate that the focusing efficiency of the hybrid metalens is 65.8%. The experimental results show that the designed metalens is able to increase the focusing efficiency from 22.8% to 41.7%. The full widths at half maxima (FWHMs) of the focused spots of the hybrid metalens in the x direction and y direction are 0.72λ and 0.45λ, respectively. The proposed high-efficiency hybrid metalens has promising application prospects in various applications of a complex optical system.

Mesenchymal stromal cell-derived magnetic nanovesicles for enhanced skin retention and hair follicle growth.

BACKGROUND AIMS: Extracellular vesicles and exosome-mimetic nanovesicles (NVs) derived from mesenchymal stromal cells (MSCs) have emerged as promising to promote hair growth. However, short local skin retention after subcutaneous administration hinders their clinical applications. METHODS: In this study, we prepared magnetic nanovesicles (MNVs) from iron oxide nanoparticle-incorporated MSCs. MNVs contained more therapeutic growth factors than NVs derived from naive MSCs, and their localization and internalization were manipulated by external magnetic field. RESULTS: Following the subcutaneous injection of MNVs into a mouse model of depilation-induced hair regeneration, the magnetic attraction increased their skin retention. Then, the cellular proliferation and ß-catenin signaling in hair follicles (HF) were markedly enhanced by MNV injection and magnetic field application. Furthermore, an acceleration of HF growth was revealed by histological analysis. CONCLUSIONS: The proposed strategy can enhance the therapeutic potential of MSC-derived NVs for hair regeneration and other dermatological diseases.

Selective activation of TGFß signaling by P. gingivalis-mediated upregulation of GARP aggravates esophageal squamous cell carcinoma.

Aberrant TGFß signaling plays critical roles in the progression of multiple cancers; however, the functional mechanism of this signaling network in the infectious milieu of Esophageal Squamous Cell Carcinoma (ESCC) remains largely unknown. In this study, by using global transcriptomic analysis, we found that Porphyromonas gingivalis infection increased TGFß secretion and promoted the activation of TGFß/Smad signaling in cultured cells and in clinical ESCC samples. Furthermore, we demonstrated for the first time that P. gingivalis enhanced the expression of Glycoprotein A repetitions predominant (GARP), thereby activating TGFß/Smad signaling. Moreover, the increased GARP expression and the subsequent TGFß activation was partially dependent on the fimbriae (FimA) of P. gingivalis. Intriguingly, eliminating P. gingivalis, inhibiting TGFß, or silencing GARP led to a decreased phosphorylation of Smad2/3, the central mediator of TGFß signaling, as well as an attenuated malignant phenotype of ESCC cells, indicating that the activation of TGFß signaling could be an adverse prognostic factor of ESCC. Consistently, our clinical data demonstrated that the phosphorylation of Smad2/3 and the expression of GARP were positively correlated to the poor prognosis of ESCC patients. Lastly, using xenograft models, we found that P. gingivalis infection remarkably activated TGFß signaling and subsequently enhanced the tumor growth and lung metastasis. Collectively, our study indicated that TGFß/Smad signaling mediates the oncogenic function of P. gingivalis in ESCC, which is augmented by the expression of GARP. Therefore, targeting either P. gingivalis or GARP-TGFß signaling could be a potential treatment strategy for patients with ESCC.

Low rumen degradable starch promotes the growth performance of goats by increasing protein synthesis in skeletal muscle via the AMPK-mTOR pathway.

Since starch digestion in the small intestine provides more energy than digestion in the rumen of ruminants, reducing dietary rumen degradable starch (RDS) content is beneficial for improving energy utilization of starch in ruminants. The present study tested whether the reduction of rumen degradable starch by restricting dietary corn processing for growing goats could improve growth performance, and further investigated the possible underlying mechanism. In this study, twenty-four 12-wk-old goats were selected and randomly allocated to receive either a high RDS diet (HRDS, crushed corn-based concentrate, the mean of particle sizes of corn grain = 1.64 mm, n = 12) or a low RDS diet (LRDS, non-processed corn-based concentrate, the mean of particle sizes of corn grain >8 mm, n = 12). Growth performance, carcass traits, plasma biochemical indices, gene expression of glucose and amino acid transporters, and protein expression of the AMPK-mTOR pathway were measured. Compared to the HRDS, LRDS tended to increase the average daily gain (ADG, P = 0.054) and decreased the feed-to-gain ratio (F/G, P < 0.05). Furthermore, LRDS increased the net lean tissue rate (P < 0.01), protein content (P < 0.05) and total free amino acids (P < 0.05) in the biceps femoris (BF) muscle of goats. LRDS increased the glucose concentration (P < 0.01), but reduced total amino acid concentration (P < 0.05) and tended to reduce blood urea nitrogen (BUN) concentration (P = 0.062) in plasma of goats. The mRNA expression of insulin receptors (INSR), glucose transporter 4 (GLUT4), L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (4F2hc) in BF muscle, and sodium-glucose cotransporters 1 (SGLT1) and glucose transporter 2 (GLUT2) in the small intestine were significantly increased (P < 0.05) in LRDS goats. LRDS also led to marked activation of p70-S6 kinase (S6K) (P < 0.05), but lower activation of AMP-activated protein kinase (AMPK) (P < 0.05) and eukaryotic initiation factor 2α (P < 0.01). Our findings suggested that reducing the content of dietary RDS enhanced postruminal starch digestion and increased plasma glucose, thereby improving amino acid utilization and promoting protein synthesis in the skeletal muscle of goats via the AMPK-mTOR pathway. These changes may contribute to improvement in growth performance and carcass traits in LRDS goats.

The combined effect and mechanism of antiangiogenic drugs and PD-L1 inhibitor on cell apoptosis in triple negative breast cancer.

Background: Breast cancer is the most common cancer worldwide, and triple-negative breast cancer (TNBC) has the worst prognosis. Standard systemic treatment includes chemotherapy and immunotherapy. Poly ADP-ribose polymerase (PARP) inhibitors are considered in breast cancer (BRCA) susceptibility genes mutated tumors. The role of antiangiogenic drugs is controversial. Immunotherapy with immune checkpoint inhibitor is now a standard of care for TNBC in the US, but its use in combination with anlotinib, an inhibitor of angiogenesis, on TNBC cells was never investigated. Methods: We tested the effects of anlotinib and programmed cell death-ligand 1 (PD-L1) inhibitor on the proliferation, apoptosis, migration, and invasion of MDA-MB-468 and BT-549 TNBC cells through 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assays, cell apoptosis assay, wound healing and transwell matrix assays, and verified whether the combination of the two drugs had synergistic effect. Western blotting was used to detect the effect of anlotinib and PD-L1 inhibitor on the protein expression levels of PI3K, p-PI3K, AKT, p-AKT, Bcl-xl in MDA-MB-468 and BT-549 cells. The effects of anlotinib, PD-L1 inhibitor and the combination of the two drugs on the transplanted tumor of TNBC mice were tested by animal experiments. Results: Anlotinib and PD-L1 inhibitor inhibited the proliferation and promote cell apoptosis of MDA-MB-468 and BT-549 cells, and the combination demonstrated the synergetic effect. Anlotinib and PD-L1 inhibitor inhibited cell migration and invasion, and the effect was strongest in the combination group. Both anlotinib and PD-L1 inhibitor reduced the expression of p-PI3K, p-AKT and Bcl-xl proteins in cells and the effects were the strongest in the combination group. Both anlotinib and PD-L1 inhibitor inhibited the growth of transplanted tumors in mice, and the combined group demonstrated the strongest growth suppression. Conclusions: Anlotinib and PD-L1 inhibitor can inhibit cell proliferation, migration, and invasion of TNBC and promote cell apoptosis, and the two drugs show combined anti-tumor effects in vivo and in vitro. The combination of anlotinib and PD-L1 inhibitor may promote apoptosis of TNBC cells through PI3K/AKT/Bcl-xl signaling pathways, which might offer potential clinical treatment roles for these.

A perspective on SARS-CoV-2 virus-like particles vaccines.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first appeared in Wuhan, China, in December 2019. The 2019 coronavirus disease (COVID-19) pandemic, caused by SARS-CoV-2, has spread to almost all corners of the world at an alarming rate. Vaccination is important for the prevention and control of the COVID-19 pandemic. Efforts are underway worldwide to develop an effective vaccine against COVID-19 using both traditional and innovative vaccine strategies. Compared to other vaccine platforms, SARS-CoV-2 virus-like particles （VLPs ）vaccines, as a new vaccine platform, have unique advantages: they have artificial nanostructures similar to natural SARS-CoV-2, which can stimulate good cellular and humoral immune responses in the organism; they have no viral nucleic acids, have good safety and thermal stability, and can be mass-produced and stored; their surfaces can be processed and modified, such as the adjuvant addition, etc.; they can be considered as an ideal platform for COVID-19 vaccine development. This review aims to shed light on the current knowledge and progress of VLPs vaccines against COVID-19, especially those undergoing clinical trials.