Tissue-resident memory CD103+CD8+ T cells in colorectal cancer: its implication as a prognostic and predictive liver metastasis biomarker.

BACKGROUND: Tissue-resident memory CD103+CD8+ T cells (CD103+CD8+ TRMs) are important components of anti-tumor immunity. However, the significance of CD103+CD8+ TRMs in colorectal cancer (CRC) and their advantages remain unclear. METHODS: Clinical data and specimens were used to evaluate the significance of CD103+CD8+ TRMs in CRC. A mouse subcutaneous tumorigenesis model and colony-formation assay were conducted to evaluate the anti-tumor effects of CD103+CD8+ TRMs. Finally, the infiltration density and function of CD103+CD8+ TRMs in the tumors were evaluated using flow cytometry. RESULTS: In this study, we showed that highly infiltrated CD103+CD8+ TRMs were associated with earlier clinical stage and negative VEGF expression in CRC patients and predicted a favorable prognosis for CRC/CRC liver metastases patients. Interestingly, we also found that CD103+CD8+ TRMs may have predictive potential for whether CRC develops liver metastasis in CRC. In addition, we found a positive correlation between the ratio of the number of α-SMA+ vessels to the sum of the number of α-SMA+ and CD31+ vessels in CRC, and the infiltration level of CD103+CD8+ TRMs. In addition, anti-angiogenic therapy promoted infiltration of CD103+CD8+ TRMs and enhanced their ability to secrete interferon (IFN)-γ, thus further improving the anti-tumor effect. Moreover, in vivo experiments showed that compared with peripheral blood CD8+ T cells, CD103+CD8+ TRMs infused back into the body could also further promote CD8+ T cells to infiltrate the tumor, and they had a stronger ability to secrete IFN-γ, which resulted in better anti-tumor effects. CONCLUSION: We demonstrated that CD103+CD8+ TRMs have the potential for clinical applications and provide new ideas for combined anti-tumor therapeutic strategies, such as anti-tumor angiogenesis therapy and CAR-T combined immunotherapy.

Monitoring imatinib decreasing pericyte coverage and HIF-1α level in a colorectal cancer model by an ultrahigh-field multiparametric MRI approach.

BACKGROUND: Excessive pericyte coverage promotes tumor growth, and a downregulation may solve this dilemma. Due to the double-edged sword role of vascular pericytes in tumor microenvironment (TME), indiscriminately decreasing pericyte coverage by imatinib causes poor treatment outcomes. Here, we optimized the use of imatinib in a colorectal cancer (CRC) model in high pericyte-coverage status, and revealed the value of multiparametric magnetic resonance imaging (mpMRI) at 9.4T in monitoring treatment-related changes in pericyte coverage and the TME. METHODS: CRC xenograft models were evaluated by histological vascular characterizations and mpMRI. Mice with the highest pericyte coverage were treated with imatinib or saline; then, vascular characterizations, tumor apoptosis and HIF-1α level were analyzed histologically, and alterations in the expression of Bcl-2/bax pathway were assessed through qPCR. The effects of imatinib were monitored by dynamic contrast-enhanced (DCE)-, diffusion-weighted imaging (DWI)- and amide proton transfer chemical exchange saturation transfer (APT CEST)-MRI at 9.4T. RESULTS: The DCE- parameters provided a good histologic match the tumor vascular characterizations. In the high pericyte coverage status, imatinib exhibited significant tumor growth inhibition, necrosis increase and pericyte coverage downregulation, and these changes were accompanied by increased vessel permeability, decreased microvessel density (MVD), increased tumor apoptosis and altered gene expression of apoptosis-related Bcl-2/bax pathway. Strategically, a 4-day imatinib effectively decreased pericyte coverage and HIF-1α level, and continuous treatment led to a less marked decrease in pericyte coverage and re-elevated HIF-1α level. Correlation analysis confirmed the feasibility of using mpMRI parameters to monitor imatinib treatment, with DCE-derived Ve and Ktrans being most correlated with pericyte coverage, Ve with vessel permeability, AUC with microvessel density (MVD), DWI-derived ADC with tumor apoptosis, and APT CEST-derived MTRasym at 1 µT with HIF-1α. CONCLUSIONS: These results provided an optimized imatinib regimen to achieve decreasing pericyte coverage and HIF-1α level in the high pericyte-coverage CRC model, and offered an ultrahigh-field multiparametric MRI approach for monitoring pericyte coverage and dynamics response of the TME to treatment.

Liquiritin Carbomer Gel Cold Paste Promotes Healing of Solar Dermatitis in Mice.

Ultraviolet radiation (UVR) has various effects on human cells and tissues, which can lead to a variety of skin diseases and cause inconvenience to people's lives. Among them, solar dermatitis is one of the important risk factors for malignant melanoma, so prevention and treatment of solar dermatitis is very necessary. Additionally, liquiritin (LQ) has anti-inflammatory effects. In this study, we aimed to evaluate the anti-inflammatory and pro-wound healing effects of liquiritin carbomer gel cold paste (LQ-CG-CP) in vitro and in vivo. The results of MTT experiments showed no cytotoxicity of LQ at concentrations of 40 µg/mL and below and cell damage at UVB irradiation doses above 60 mJ/cm2. Moreover, LQ can promote cell migration. ELISA results also showed that LQ inhibited the elevation of the inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) after UVB irradiation. In the mouse model of solar dermatitis, 2% LQ-CG-CP showed the best therapeutic efficacy for wound healing and relief of itching compared to MEIBAO moist burn moisturizer (MEBO). What is more, the results of skin histopathological examination show that LQ-CG-CP promotes re-epithelialization, shrinks wounds, and promotes collagen production, thus promoting wound healing. Simultaneously, LQ-CG-CP reduced TNF-α, IL-1ß, and IL-6 expression. In addition, LQ-CG-CP was not observed to cause histopathological changes and blood biochemical abnormalities in mice. Overall, LQ-CG-CP has great potential for the treatment of solar dermatitis.

Novel TCF21high pericyte subpopulation promotes colorectal cancer metastasis by remodelling perivascular matrix.

OBJECTIVE: Haematogenous dissemination is a prevalent route of colorectal cancer (CRC) metastasis. However, as the gatekeeper of vessels, the role of tumour pericytes (TPCs) in haematogenous metastasis remains largely unknown. Here, we aimed to investigate the heterogeneity of TPCs and their effects on CRC metastasis. DESIGN: TPCs were isolated from patients with CRC with or without liver metastases and analysed by single-cell RNA sequencing (scRNA-seq). Clinical CRC specimens were collected to analyse the association between the molecular profiling of TPCs and CRC metastasis. RNA-sequencing, chromatin immunoprecipitation-sequencing and bisulfite-sequencing were performed to investigate the TCF21-regulated genes and mechanisms underlying integrin α5 on TCF21 DNA hypermethylation. Pericyte-conditional Tcf21-knockout mice were constructed to investigate the effects of TCF21 in TPCs on CRC metastasis. Masson staining, atomic force microscopy, second-harmonic generation and two-photon fluorescence microscopy were employed to observe perivascular extracellular matrix (ECM) remodelling. RESULTS: Thirteen TPC subpopulations were identified by scRNA-seq. A novel subset of TCF21high TPCs, termed 'matrix-pericytes', was associated with liver metastasis in patients with CRC. TCF21 in TPCs increased perivascular ECM stiffness, collagen rearrangement and basement membrane degradation, establishing a perivascular metastatic microenvironment to instigate colorectal cancer liver metastasis (CRCLM). Tcf21 depletion in TPCs mitigated perivascular ECM remodelling and CRCLM, whereas the coinjection of TCF21high TPCs and CRC cells markedly promoted CRCLM. Mechanistically, loss of integrin α5 inhibited the FAK/PI3K/AKT/DNMT1 axis to impair TCF21 DNA hypermethylation in TCF21high TPCs. CONCLUSION: This study uncovers a previously unidentified role of TPCs in haematogenous metastasis and provides a potential diagnostic marker and therapeutic target for CRC metastasis.

Evolutionary characterization and pathogenicity of Getah virus from pigs in Guangdong Province of China.

Getah virus (GETV) is an emerging zoonotic virus that can infect humans and many mammals through mosquitoes. In this study, a novel pathogenic GETV strain, GDQY2022, was isolated from a pig farm in Guangdong Province, China. Sequence comparisons and phylogenetic analysis showed that GDQY2022 belongs to group III (GIII) and was most closely related to strain HeN202009-2, with 99.78% nucleotide sequence identity. Histopathological examination revealed significant pathological changes, such as widened alveolar septum in the lungs with mild congestion and hemorrhage. Differences in viral load between tissues were assessed by real-time RT-PCR, and significantly higher levels of GETV were found in abdominal lymph nodes and lungs of subclinically and clinically affected pigs (P < 0.01). This study provides valuable data for understanding the risk of GETV infection in the pig industry and a reliable basis for studying the pathogenic mechanisms and diagnostic surveillance of GETV.

Excitonic solar cells based on van der Waals heterojunctions of Janus III-VI chalcogenide monolayers.

We construct the two-dimensional (2D) excitonic solar cells based on type II vdW heterojunctions of Janus III-VI chalcogenide monolayers and investigate the performance of the device using the first principle. The calculated solar energy absorbance of In2SSe/GaInSe2and In2SeTe/GaInSe2heterojunctions is the order of 105cm-1. The predicted photoelectric conversion efficiency of the In2SeTe/GaInSe2heterojunction can reach up to 24.5%, which compares favorably with other previously studied 2D heterojunctions. The excellent performance of In2SeTe/GaInSe2heterojunction originates from the fact that the built-in electric field at the interface of In2SeTe/GaInSe2promote the flow of the photogenerated electrons. The results suggest that 2D Janus Group-III chalcogenide heterojunction can be a good candidate for new optoelectronic nanodevices.

Thrombospondin-2 holds prognostic value and is associated with metastasis and the mismatch repair process in gastric cancer.

BACKGROUND: This study aims to investigate thrombospondin 2 (TSP2) expression levels in gastric cancer (GC) and determine the relationship between TSP2 and clinical characteristics and prognosis. METHODS: The online database Gene Expression Profile Interactive Analysis (GEPIA) was used to analyse TSP2 mRNA expression levels in GC. The Kaplan-Meier plotter prognostic analysis tool was used to evaluate the influence of TSP2 expression on clinical prognosis in GC patients. TSP2 expression levels were analysed in paraffin-embedded GC samples and adjacent normal tissues by immunohistochemistry. The relationship between the clinicopathological characteristics and prognosis of GC patients was assessed. Transwell experiments were used to evaluate the effect of TSP2 on HGC27 and AGS cell invasion and migration. The EdU experiment was used to detect the effect of transfection of TSP2 on cell proliferation, and the flow cytometry experiment was used to detect the effect of TSP2 on cell apoptosis and the cell growth cycle. Western blotting (Wb) technology was used to detect MMP, E-cadherin, N-cadherin, Vimentin, Snail, AKT, PI3K, and VEGF protein expression in HGC27 cells. RESULTS: Compared with normal tissues, TSP2 mRNA expression in GC was significantly upregulated and was closely related to the clinical stage of GC. High TSP2 expression significantly affected the OS, FP and PPS of patients with GC. Among these patients, TSP2 expression levels did not affect the prognosis of patients with GC in the N0 subgroup but significantly affected the prognosis of patients with GC in the N (1 + 2 + 3) subgroup. TSP2 protein expression levels were significantly higher in GC tissue compared with normal tissues (P < 0.01). The overall survival (OS) and relapse-free survival (RFS) of patients with high TSP2 expression were lower than those of patients with low TSP2 expression. Cells transfected with the TSP2-silencing sequence exhibited increased apoptosis and inhibition of proliferation, migration and invasion. AKT and PI3K expression in cells was significantly downregulated (P < 0.01). AKT, PI3K and VEGF expression in cells transfected with the TSP2 silencing sequence was significantly reduced. Proliferation, migration, invasion ability, and TSP2 expression levels significantly correlated with mismatch repair genes, such as PMS2, MSH6, MSH2, and MLH1 (P < 0.05). CONCLUSION: TSP2 expression is significantly increased in GC. TSP2 expression is closely related to metastasis and the mismatch repair process in GC patients and affects GC patient prognosis. The mechanism may involve regulating gastric cancer cell proliferation and migration by modulating the VEGF/PI3K/AKT signalling pathway. TSP2 is a potential marker and therapeutic target for the prognosis of GC patients.

The in-plane metal contacted 5.1 nm Janus WSSe Schottky barrier field-effect transistors.

Edge contact between two-dimensional materials and metal can achieve small contact resistance because of strong interaction. In this work, we investigated the electronic transport of in-plane (IP) heterojunctions based on Ti/WSSe and Sn/WSSe using first principle calculations. The results showed that the interface bonding and metallization are found on the IP Ti/WSSe and Sn/WSSe contact interface, indicating that the Ohmic contacts are formed between Ti, Sn and WSSe. Then, we constructed double-gate model to investigate the performance of the IP Ti and Sn contacted 5.1 nm WSSe Schottky barrier field-effect transistors (SBFETs). The calculated on-state current of the IP Ti contacted 5.1 nm WSSe SBFETs is 406.3 µA/µm. While, the on-state current of the Sn contacted 5.1 nm WSSe SBFETs reachs up to 1104.2 µA/µm, which is far beyond the requirements of the requirements of International Technology Roadmap for Semiconductor (ITRS) HP application targets. Our study will provide a guide for high performance transistors based on IP metal/WSSe configurations in the future.

Relationship between Tertiary Lymphoid Structure and the Prognosis and Clinicopathologic Characteristics in Solid Tumors.

Background: An increasing number of studies had shown that tertiary lymphoid structure (TLS) plays an important role in tumor progression. However, the prognostic role of TLS in various tumors remains controversial. This meta-analysis aims to investigate the clinicopathological and prognostic values of TLS in solid tumors. Methods: A systematic search was conducted in PubMed, EMBASE and Cochrane Library undated to November 2, 2020. Odds ratios of clinical parameters, hazard ratio (HR) of overall survival (OS), relapse-free survival (RFS), disease-free survival (DFS) and relapse rate were calculated in order to evaluate the relationship between TLS expression and clinicopathological or prognostic values in different tumors. Result: 27 eligible studies including 6647 patients with different types of tumors were analyzed. High TLS expression was associated with a longer OS (HR = 0.66, 95% CI: 0.50 - 0.86, P = 0.002) and RFS (HR = 0.61, 95% CI: 0.47 - 0.79, P = 0.0001). Moreover, high TLS levels in tumor were associated with a low risk of recurrence (HR = 0.43, 95% CI: 0.32 - 0.57, P < 0.0001). However, there was no relationship between TLS expression and DFS. Meanwhile, high TLS expression was associated with smaller tumor size (P < 0.00001) and higher tumor infiltrating lymphocytes (TILs). Furthermore, the subgroup analysis showed high TLS expression that may be associated with a lower clinical grading and N stage in breast cancer and colorectal cancer. Conclusion: High TLS expression is associated with the longer OS and RFS in solid tumors, and a lower risk of cancer relapse. Meanwhile, high TLS expression is also associated with a smaller tumor size, higher infiltration of TILs, lower clinical grading and N stage in the tumor. Therefore, high TLS expression in the tumor is a favorable prognostic biomarker for solid tumor patients.

Nicotinamide phosphoribosyl transferase regulates cell growth via the Sirt1/P53 signaling pathway and is a prognosis marker in colorectal cancer.

Colorectal cancer (CRC) is the third most common malignancy, and the metabolic properties of CRC cells include enhanced aerobic glycolysis (the Warburg effect). Nicotinamide phosphoribosyl transferase (NAMPT) is one of the crucial enzymes that regulate the activity of nicotinamide adenine dinucleodinucleotide dependent enzymes. Targeting NAMPT is a potential method of CRC therapy. Nevertheless, the underlying clinical implications and regulatory mechanisms of NAMPT in CRC remain unclear. In this study, we showed that NAMPT protein expression was increased in subjects with rectal localization compared with those with colon localization, and NAMPT was a poor prognostic marker for the overall survival rate in patients with CRC. In addition, the NAMPT inhibitor FK866 or lentivirus-mediated silencing induced CRC cell growth inhibition. Mechanistically, NAMPT regulated Sirt1 and P53 expression and induced G0/G1 cell cycle arrest, along with the upregulation of downstream p21 and downregulation of cyclin D1, cyclin E1, and cyclin E2 expression. FK866 administration or knockdown of NAMPT induced CRC cell apoptosis via upregulation of caspase-3. In conclusion, NAMPT regulated Sirt1/P53 signaling during CRC cell growth and warrants further investigation for clinical administration in CRC.

Robotic thyroidectomy versus conventional open thyroidectomy for thyroid cancer: a systematic review and meta-analysis.

BACKGROUND: Despite the new technical alternative offered by the robotic surgery for minimally invasive thyroid surgery, the role of the robotic thyroidectomy (RT) in thyroid cancer has been highly disputed. This paper gives a systematic review and meta-analysis aiming to compare RT and open thyroidectomy (OT) based on the surgical outcomes and oncologic results. METHODS: Relevant literature was searched from various databases up to July 2016, including PubMed, MEDLINE, EMBASE, Cochrane Library, Web of science and Clinical Trials. gov. Outcomes of interest included patient characteristics, surgical outcomes, adverse events and complications, recurrence rate, and surgical completeness. RESULTS: The systematic review and meta-analysis were based on the 5200 cases selected from the twenty-three publications. RT was associated with an equivalent adverse event and complication rate including transient hypocalcemia, permanent hypocalcemia, transient hoarseness, permanent recurrent laryngeal nerve (RLN) palsy, transient hypoparathyroidism, permanent hypoparathyroidism, hematoma, postoperative bleeding, seroma, chyle leakage, the Voice Handicap Index-10 (VHI-10) score, as well as equivalent surgical completeness including postoperative radioactive iodine (RAI) ablation rate, number of RAI ablation sessions, mean total RAI ablation dose, mean stimulated Tg of postoperation RAI, and proportion of stimulated Tg < 1.0 ng/ml on first ablation. Moreover, RT had lesser blood loss (WMD - 1.47, p = 0.04), smaller number of retrieved lymph nodes (WMD - 1.21, p = 0.0002), a low level of swallowing impairment (WMD - 4.17, p < 0.00001), and better cosmetic satisfaction (OR 4.05, p < 0.00001). However, OT was associated with shorter operation time (WMD 69.80, p < 0.00001), less total drain amount (WMD 66.53, p < 0.0001), and lower postoperative serum Tg level (WMD 0.21, p < 0.00001). CONCLUSIONS: RT is as safe as OT for the treatment of thyroid cancer. Based on the long-time follow-up and surgical completeness, the adverse events and complications, and recurrence rate of RT were comparable with OT. RT was associated with a significantly lesser blood loss, smaller number of retrieved lymph nodes, a lower level of swallowing impairment, and better cosmetic satisfaction. In contrast, OT was associated with shorter operation time, smaller total drain amount, and lower postoperative serum Tg level. Overall, randomized clinical trials and larger patient cohort with long-term follow-up are still essential to further demonstrate the value of the robotic approach.

Long-term oncological outcomes in robotic gastrectomy versus laparoscopic gastrectomy for gastric cancer: a meta-analysis.

BACKGROUND: Robotic gastrectomy (RG) has been a new technical alternative for gastric cancer. However, the long-term oncological outcomes of RG still should be further evaluated. In this meta-analysis, the long-term oncological outcomes of RG and laparoscopic gastrectomy (LG) are compared. METHODS: Comprehensive searches from various databases are compared in February 2017 to identify that the oncological outcomes of RG and LG are evaluated in gastric cancer patients. The pooled oncological outcomes of the overall survival (OS), disease-free survival (DFS), and the recurrence rate were performed by adopting the meta-analysis to calculate the hazard ratio (HR) or the odds ratio with 95% confidence intervals (CIs). RESULTS: Five studies that concern retrospective design and prospective data collection and involve 1614 patients were included. All the five studies evaluated OS. Two studies evaluated DFS, while four studies reported the recurrence rate or recurrence cases in RG and LG groups with the long-term follow-up. The pooled analysis showed no significant difference in OS and DFS between RG and LG, without significant between-study heterogeneity. Besides, the recurrence rate between RG and LG had no significant difference without heterogeneity. CONCLUSIONS: RG could provide comparable long-term oncological outcomes as well as LG for the treatment of gastric cancer. OS, DFS, and the recurrence rate by the long-time follow-up of RG were comparable with LG. Generally speaking, more randomized clinical trials and a larger patient cohort with longer follow-up are still essential to further demonstrate the value of the robotic surgery for gastric cancer.

Treatment with Rhizoma Dioscoreae extract has protective effect on osteopenia in ovariectomized rats.

The aims of this study were to evaluate the osteoprotective effect of aqueous extract from Rhizoma Dioscoreae (RDE) on rats with ovariectomy- (OVX-) induced osteopenia. Our results show that RDE could inhibit bone loss of OVX rats after a 12-week treatment. The microarray analysis showed that 68 genes were upregulated and that 100 genes were downregulated in femurs of the RDE group rats compared to those in the OVX group. The Ingenuity Pathway Analysis (IPA) showed that several downregulated genes had the potential to code for proteins that were involved in the Wnt/ ß -catenin signaling pathway (Sost, Lrp6, Tcf7l2, and Alpl) and the RANKL/RANK signaling pathway (Map2k6 and Nfatc4). These results revealed that the mechanism for an antiosteopenic effect of RDE might lie in the synchronous inhibitory effects on both the bone formation and the bone resorption, which is associated with modulating the Wnt/ ß -catenin signaling and the RANKL/RANK signaling.

High-dose diosgenin reduces bone loss in ovariectomized rats via attenuation of the RANKL/OPG ratio.

The aim of this study was to evaluate effect of diosgenin (DG) on rats that had osteoporosis-like features induced by ovariectomy (OVX). Seventy-two six-month-old female Wistar rats were subjected to either ovariectomy (n = 60) or Sham operation (SHAM group, n = 12). Beginning at one week post-ovariectomy, the OVX rats were treated with vehicle (OVX group, n = 12), estradiol valerate (EV group, n = 12), or DG at three doses (DG-L, -M, -H group, n = 12, respectively). After a 12-week treatment, administration of EV or DG-H inhibited OVX-induced weight gain, and administration of EV or DG-H or DG-M had a significantly uterotrophic effect. Bone mineral density (BMD) and indices of bone histomorphometry of tibia were measured. Levels of protein and mRNA expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) in tibia were evaluated by immunohistochemistry and in situ hybridization. Our results show that DG at a high dose (DG-H) had a significant anti-osteoporotic effect compared to OVX control. DG-H treatment down-regulated expression of RANKL and up-regulated expression of OPG significantly in tibia from OVX rats compared to control, and thus lowered the RANKL/OPG ratio. This suggests that the anti-osteoporotic effect of DG might be associated with modulating the RANKL/OPG ratio and DG had potential to be developed as alternative therapeutic agents of osteoporosis induced by postmenopause.

Protective role of seleno-amino acid against IBD via ferroptosis inhibition in enteral nutrition therapy.

The interplay between intestinal barrier degradation and trace element insufficiency worsens inflammatory bowel disease (IBD). Selenium (se) is essential for glutathione peroxidase 4 (GPX4) synthesis, which protects against intestinal epithelial cell injury in IBD. However, malnutrition and malabsorption limit the availability of dietary selenium. This study investigated the protective effects of naturally occurring seleno-amino acids on the intestinal barrier in an IBD animal model by promoting GPX4 synthesis. L-se-methylselenocystine (seMc) supplementation reversed decreased GPX4 expression levels, alleviated glutathione depletion and scavenged reactive oxygen species in vitro. In vivo, enteral nutrition combined with seMc protected the intestinal barrier and alleviated IBD-related symptoms by inhibiting ferroptosis and reversing lipid peroxidation in epithelial cells while reducing immune cell infiltration. Our findings suggest that seleno-amino acid-based nutritional formulations may provide a basis for nutritional support to alleviate complex cycles between intestinal barrier damage and malnutrition in IBD patients.

PTPLAD1 Regulates PHB-Raf Interaction to Orchestrate Epithelial-Mesenchymal and Mitofusion-Fission Transitions in Colorectal Cancer.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The poor prognosis of this malignancy is attributed mainly to the persistent activation of cancer signaling for metastasis. Here, we showed that protein tyrosine phosphatase-like A domain containing 1 (PTPLAD1) is down-regulated in highly metastatic CRC cells and negatively associated with poor survival of CRC patients. Systematic analysis reveals that epithelial-to-mesenchymal transition (EMT) and mitochondrial fusion-to-fission (MFT) transition are two critical features for CRC patients with low expression of PTPLAD1. PTPLAD1 overexpression suppresses the metastasis of CRC in vivo and in vitro by inhibiting the Raf/ERK signaling-mediated EMT and mitofission. Mechanically, PTPLAD1 binds with PHB via its middle fragment (141-178 amino acids) and induces dephosphorylation of PHB-Y259 to disrupt the interaction of PHB-Raf, resulting in the inactivation of Raf/ERK signaling. Our results unveil a novel mechanism in which Raf/ERK signaling activated in metastatic CRC induces EMT and mitochondrial fission simultaneously, which can be suppressed by PTPLAD1. This finding may provide a new paradigm for developing more effective treatment strategies for CRC.

Targeting FAPα-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis.

Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.

Semen Astragali Complanati- and Rhizoma Cibotii-enhanced bone formation in osteoporosis rats.

BACKGROUND: Growing evidence shows that herb medicines have some anti-osteoporotic effects, the mechanism underlying is unknown. This study aims to investigate the therapeutic effect of Chinese herb supplements on rats that had osteoporosis-like symptom induced by ovariectomy (OVX). METHODS: OVX or sham operations were performed on virgin Wistar rats at three-month old, which were randomly divided into eight groups: sham (sham); OVX control group (OVX); OVX rats with treatments [either diethylstilbestrol (DES) or Semen Astragali Complanati decoction (SACD) or Rhizoma Cibotii decoction (RCD) or Herba Cistanches decoction (HCD) or Semen Allii Tuberosi decoction (SATD)]. Non-surgical rats were served as a normal control (NC). The treatments began 4 weeks after surgery, and lasted for 12 weeks. Bone mass and its turnover were analyzed by histomorphometry. Levels of protein and mRNA of osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) in osteoblasts (OB) and bone marrow stromal cells (bMSC) were evaluated by immunohistochemistry and in situ hybridization. RESULTS: Compared to OVX control, TBV% in both SACD and RCD groups was increased significantly, while TRS%, TFS%, MAR, and mAR were decreased remarkably in the SACD group, only TRS% decreased dramatically in the RCD group. No significant changes in bone formation were observed in either HCD or SATD groups. OPG levels in both protein and mRNA were reduced consistantly in OB and bMSC from OVX control rats, in contrast, RANKL levels in both protein and mRNA were increased significantly. These effects were substantially reversed by treatments with either DES or SACD or RCD. No significant changes in both OPG and RANKL expression were observed in OB and bMSC from OVX rats treated with SATD and HCD. CONCLUSIONS: Our study showed that SACD and RCD increased bone formation by stimulating OPG expression and downregulating RANKL expression in OB and bMSC. This suggests that SACD and RCD may be developed as alternative anti-osteoporotic agents for therapy of postmenopausal osteoporosis.

Research progress on the E protein of porcine reproductive and respiratory syndrome virus.

Porcine reproductive and respiratory syndrome (PRRS) is an economically important disease impacting the global pig industry, and it is characterized by reproductive disorder in sows and respiratory disorder in pigs of all ages. The PRRSV E protein is a nonglycosylated structural protein encoded by the ORF2b gene. The E protein is not necessary for the assembly of virus particles, but deletion of the E protein leads to transmissible virus particles not being produced. To better understand the structure and function of the E protein, we reviewed its genetic and evolutionary analysis, characteristics, subcellular localization and topology, ion channel activity, cellular immune response, additional biological functions, interactions with host proteins, interactions with PRRSV proteins, roles in infection, pathogenicity, and drugs. Therefore, this review can provide a theoretical basis for gaining an in-depth understanding of the E protein of PRRSV-2.

Research Progress on the detection methods of porcine reproductive and respiratory syndrome virus.

Porcine reproductive and respiratory syndrome virus (PRRSV) causes clinical syndromes typified as reproductive disorders in sows and respiratory diseases in piglets. PRRSV remains one of the most prevalent pathogens affecting the pig industry, because of its complex infection profile and highly heterogeneous genetic and recombination characteristics. Therefore, a rapid and effective PRRSV detection method is important for the prevention and control of PRRS. With extensive in-depth research on PRRSV detection methods, many detection methods have been improved and promoted. Laboratory methods include techniques based on virus isolation (VI), enzyme-linked immunosorbent assays (ELISA), indirect immunofluorescence assays (IFA), immunoperoxidase monolayer assays (IPMA), polymerase chain reaction (PCR), quantitative real-time PCR (qPCR), digital PCR (dPCR), loop-mediated isothermal amplification (LAMP), recombinase polymerase amplification (RPA), clustered regularly interspaced short palindromic repeats (CRISPR), metagenomic next-generation sequencing (mNGS), and other methods. This study reviews the latest research on improving the main PRRSV detection methods and discusses their advantages and disadvantages.