SLC34A2 promotes cell proliferation by activating STX17-mediated autophagy in esophageal squamous cell carcinoma.

BACKGROUND: Solute carrier family 34 member 2 (SLC34A2) has been implicated in the development of various malignancies. However, the clinical significance and underlying molecular mechanisms of SLC34A2 in esophageal squamous cell carcinoma (ESCC) remain elusive. METHODS: Western blotting, quantitative real-time PCR and immunohistochemistry were utilized to evaluate the expression levels of SLC34A2 mRNA/protein in ESCC cell lines or tissues. Kaplan-Meier curves were employed for survival analysis. CCK-8, colony formation, EdU and xenograft tumor model assays were conducted to determine the impact of SLC34A2 on ESCC cell proliferation. Cell cycle was examined using flow cytometry. RNA-sequencing and enrichment analysis were carried out to explore the potential signaling pathways. The autophagic flux was evaluated by western blotting, mRFP-GFP-LC3 reporter system and transmission electron microscopy. Immunoprecipitation and mass spectrometry were utilized for identification of potential SLC34A2-interacting proteins. Cycloheximide (CHX) chase and ubiquitination assays were conducted to test the protein stability. RESULTS: The expression of SLC34A2 was significantly upregulated in ESCC and correlated with unfavorable clinicopathologic characteristics particularly the Ki-67 labeling index and poor prognosis of ESCC patients. Overexpression of SLC34A2 promoted ESCC cell proliferation, while silencing SLC34A2 had the opposite effect. Moreover, SLC34A2 induced autophagy to promote ESCC cell proliferation, whereas inhibition of autophagy suppressed the proliferation of ESCC cells. Further studies showed that SLC34A2 interacted with an autophagy-related protein STX17 to promote autophagy and proliferation of ESCC cells by inhibiting the ubiquitination and degradation of STX17. CONCLUSIONS: These findings indicate that SLC34A2 may serve as a prognostic biomarker for ESCC.

Deep learning assists detection of esophageal cancer and precursor lesions in a prospective, randomized controlled study.

Endoscopy is the primary modality for detecting asymptomatic esophageal squamous cell carcinoma (ESCC) and precancerous lesions. Improving detection rate remains challenging. We developed a system based on deep convolutional neural networks (CNNs) for detecting esophageal cancer and precancerous lesions [high-risk esophageal lesions (HrELs)] and validated its efficacy in improving HrEL detection rate in clinical practice (trial registration ChiCTR2100044126 at www.chictr.org.cn). Between April 2021 and March 2022, 3117 patients ≥50 years old were consecutively recruited from Taizhou Hospital, Zhejiang Province, and randomly assigned 1:1 to an experimental group (CNN-assisted endoscopy) or a control group (unassisted endoscopy) based on block randomization. The primary endpoint was the HrEL detection rate. In the intention-to-treat population, the HrEL detection rate [28 of 1556 (1.8%)] was significantly higher in the experimental group than in the control group [14 of 1561 (0.9%), P = 0.029], and the experimental group detection rate was twice that of the control group. Similar findings were observed between the experimental and control groups [28 of 1524 (1.9%) versus 13 of 1534 (0.9%), respectively; P = 0.021]. The system's sensitivity, specificity, and accuracy for detecting HrELs were 89.7, 98.5, and 98.2%, respectively. No adverse events occurred. The proposed system thus improved HrEL detection rate during endoscopy and was safe. Deep learning assistance may enhance early diagnosis and treatment of esophageal cancer and may become a useful tool for esophageal cancer screening.

The safety, feasibility and oncological outcomes of laparoscopic completion total gastrectomy for remnant gastric cancer: a prospective study with 3-year follow-up (FUGES-004 study).

BACKGROUND: The efficacy of laparoscopic completion total gastrectomy (LCTG) for remnant gastric cancer (RGC) remains controversial. METHODS: The primary outcome was postoperative morbidity within 30 days after surgery. Secondary outcomes included 3-year disease-free survival (DFS), 3-year overall survival (OS), and recurrence. Inverse probability treatment weighted (IPTW) was used to balance the baseline between LCTG and OCTG. RESULTS: Final analysis included 46 patients with RGC who underwent LCTG at the FJMUUH between June 2016 and June 2020. The historical control group comprised of 160 patients who underwent open completion total gastrectomy (OCTG) in the six tertiary teaching hospitals from CRGC-01 study. After IPTW, no significant difference was observed between the LCTG and OCTG groups in terms of incidence (LCTG vs. OCTG: 28.0% vs. 35.0%, P=0.379) or severity of complications within 30 days after surgery. Compared with OCTG, LCTG resulted in better short-term outcomes and faster postoperative recovery. However, the textbook outcome rate was comparable between the two groups (45.9% vs. 32.8%, P=0.107). Additionally, the 3-year DFS and 3-year OS of LCTG were comparable to those of OCTG (DFS: log-rank P=0.173; OS: log-rank P=0.319). No significant differences in recurrence type, mean recurrence time, or 3-year cumulative hazard of recurrence were observed between the two groups (all P>0.05). Subgroup analyses and concurrent comparisons demonstrated similar trends. CONCLUSIONS: This prospective study suggested that LCTG was non-inferior to OCTG in both short- and long-term outcomes. In experienced centers, LCTG may be considered as a viable treatment option for RGC.

The relationship between glycemic risk and longitudinal changes in total physiological atherosclerotic burden in patients with coronary artery disease.

Background: The effects of glycemic status on coronary physiology have not been well evaluated. This study aimed to investigate changes in coronary physiology by using angiographic quantitative flow ratio (QFR), and their relationships with diabetes mellitus (DM) and glycemic control status. Methods: This retrospective cohort study included 530 patients who underwent serial coronary angiography (CAG) measurements between January 2016 and December 2021 at Tongji Hospital of Tongji University. Based on baseline and follow-up angiograms, 3-vessel QFR (3V-QFR) measurements were performed. Functional progression of coronary artery disease (CAD) was defined as a change in 3V-QFR (Δ3V-QFR = 3V-QFRfollow-up - 3V-QFRbaseline) ≤-0.05. Univariable and multivariable logistic regression analyses were applied to identify the independent predictors of coronary functional progression. Subgroup analysis according to diabetic status was performed. Results: During a median interval of 12.1 (10.6, 14.3) months between the two QFR measurements, functional progression was observed in 169 (31.9%) patients. Follow-up glycosylated hemoglobin (HbA1c) was predictive of coronary functional progression with an area under the curve (AUC) of 0.599 [95% confidence interval (CI): 0.546-0.651; P<0.001] in the entire population. Additionally, the Δ3V-QFR values were significantly lower in diabetic patients with HbA1c ≥7.0% compared to those with well-controlled HbA1c or non-diabetic patients [-0.03 (-0.09, 0) vs. -0.02 (-0.05, 0.01) vs. -0.02 (-0.05, 0.02); P=0.002]. In a fully adjusted multivariable logistics analysis, higher follow-up HbA1c levels were independently associated with progression in 3V-QFR [odds ratio (OR), 1.263; 95% CI: 1.078-1.479; P=0.004]. Furthermore, this association was particularly strong in diabetic patients (OR, 1.353; 95% CI: 1.082-1.693; P=0.008) compared to patients without DM. Conclusions: Among patients with established CAD, on-treatment HbA1c levels were independently associated with progression in physiological atherosclerotic burden, especially in patients with DM.

SPARC stabilizes ApoE to induce cholesterol-dependent invasion and sorafenib resistance in hepatocellular carcinoma.

Dysregulation of cholesterol homeostasis is implicated in the development and progression of hepatocellular carcinoma (HCC) that is characterized by intrahepatic and early extrahepatic metastasis. A better understanding of the underlying mechanisms regulating cholesterol metabolism in HCC could help identify strategies to circumvent the aggressive phenotype. Here, we found that high expression of intracellular SPARC was significantly associated with elevated cholesterol levels and an enhanced invasive phenotype in HCC. SPARC potentiated cholesterol accumulation in HCC cells during tumor progression by stabilizing the ApoE protein. Mechanistically, SPARC competitively bound to ApoE, impairing its interaction with the E3 ligase tripartite motif containing 21 (TRIM21) and preventing its ubiquitylation and subsequent degradation. ApoE accumulation led to cholesterol enrichment in HCC cells, stimulating PI3K-AKT signaling and inducing epithelial-mesenchymal transition (EMT). Importantly, sorafenib-resistant HCC cells were characterized by increased expression of intracellular SPARC, elevated cholesterol levels, and enhanced invasive capacity. Inhibiting SPARC expression or reducing cholesterol levels enhanced the sensitivity of HCC cells to sorafenib treatment. Together, these findings unveil interplay between SPARC and cholesterol homeostasis. Targeting SPARC-triggered cholesterol-dependent oncogenic signaling is a potential therapeutic strategy for advanced HCC.

Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling.

Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.

Limonoids from the roots of Melia azedarach and their anti-inflammatory activity.

Twelve undescribed limonoids, meliazedarines J-U (1-12), along with a known one, were isolated from the roots of Melia azedarach. Their structures were elucidated by extensive spectroscopic investigations, X-ray diffraction analyses, and ECD calculations. Compounds 1-8 were identified as ring intact limonoids, while compounds 9-12 were established as ring C-seco ones. The anti-inflammatory potential of compounds 1-4, 6, 8, 9, and 11-13 was evaluated on macrophages. Compounds 1, 3, 4, 6, and 9 significantly suppressed nitric oxide production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages, among them compound 3 showed the best inhibitory effect with an IC50 value of 7.07 ± 0.48 µΜ. Furthermore, compound 3 effectively reduced interleukin-1ß secretion in LPS plus nigericin-induced THP-1 macrophages by inhibiting NLRP3 inflammasome activation. The results strongly suggested that limonoids from the roots of M. azedarach might be candidates for treating inflammation-related diseases.

Curcumin Alleviates Singapore Grouper Iridovirus-Induced Intestine Injury in Orange-Spotted Grouper (Epinephelus coioides).

Singapore grouper iridovirus (SGIV) is a new ranavirus species in the Iridoviridae family, whose high lethality and rapid spread have resulted in enormous economic losses for the aquaculture industry. Curcumin, a polyphenolic compound, has been proven to possess multiple biological activities, including antibacterial, antioxidant, and antiviral properties. This study was conducted to determine whether curcumin protected orange-spotted grouper (Epinephelus coioides) from SGIV-induced intestinal damage by affecting the inflammatory response, cell apoptosis, oxidative stress, and intestinal microbiota. Random distribution of healthy orange-spotted groupers (8.0 ± 1.0 cm and 9.0 ± 1.0 g) into six experimental groups (each group with 90 groupers): Control, DMSO, curcumin, SGIV, DMSO + SGIV, and curcumin + SGIV. The fish administered gavage received DMSO dilution solution or 640 mg/L curcumin every day for 15 days and then were injected intraperitoneally with SGIV 24 h after the last gavage. When more than half of the groupers in the SGIV group perished, samples from each group were collected for intestinal health evaluation. Our results showed that curcumin significantly alleviated intestine damage and repaired intestinal barrier dysfunction, which was identified by decreased intestine permeability and serum diamine oxidase (DAO) activity and increased expressions of tight junction proteins during SGIV infection. Moreover, curcumin treatment suppressed intestinal cells apoptosis and inflammatory response caused by SGIV and protected intestinal cells from oxidative injury by enhancing the activity of antioxidant enzymes, which was related to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Moreover, we found that curcumin treatment restored the disruption of the intestinal microbiota caused by SGIV infection. Our study provided a theoretical basis for the functional development of curcumin in aquaculture by highlighting the protective effect of curcumin against SGIV-induced intestinal injury.

Anti-melanoma differentiation-associated gene 5 and anti-Ro52 antibody-dual positive dermatomyositis accompanied by rapidly lung disease: Three case reports.

BACKGROUND: Clinically amyopathic deramatomyositis was manifested as the various cutaneous dermatomyositis (DM) manifestations without muscle weakness. Anti-melanoma differentiation-associated gene 5 (anti-MDA5) and anti-Ro52 antibody-dual positive clinically amyopathic DM patients are at a high risk of developing rapidly progressive interstitial lung disease, and they exhibit an immensely high half-year mortality. CASE SUMMARY: We presented three patients with anti-MDA5 and anti-Ro52 antibody-dual positive DM patients and we reviewed the previous studies on the link between anti-MDA5 and anti-Ro52 antibody-dual positive DM. Although we aggressively treated these patients similarly, but they all exhibited different prognoses. We reviewed the importance of clinical cutaneous rashes as well as the pathogenesis and treatment in the dual positive anti-MDA5 and anti-Ro52 associated DM. CONCLUSION: Patients with anti-MDA5 anti-Ro52 antibody-dual positive DM should be accurately diagnosed at an early stage and should be treated aggressively, thus, the patient's prognosis can be significantly modified.

Prospective study of quantitative liver MRI in cystic fibrosis: feasibility and comparison to PUSH cohort ultrasound.

BACKGROUND: Pediatric radiologists can identify a liver ultrasound (US) pattern predictive of progression to advanced liver disease. However, reliably discriminating these US patterns remains difficult. Quantitative magnetic resonance imaging (MRI) may provide an objective measure of liver disease in cystic fibrosis (CF). OBJECTIVE: The purpose of this study was to determine if quantitative MRI, including MR elastography, is feasible in children with CF and to determine how quantitative MRI-derived metrics compared to a research US. MATERIALS AND METHODS: A prospective, multi-institutional trial was performed evaluating CF participants who underwent a standardized MRI. At central review, liver stiffness, fat fraction, liver volume, and spleen volume were obtained. Participants whose MRI was performed within 1 year of US were classified by US pattern as normal, homogeneous hyperechoic, heterogeneous, or nodular. Each MRI measure was compared among US grade groups using the Kruskal-Wallis test. RESULTS: Ninety-three participants (51 females [54.8%]; mean 15.6 years [range 8.1-21.7 years]) underwent MRI. MR elastography was feasible in 87 participants (93.5%). Fifty-eight participants had an US within 1 year of MRI. In these participants, a nodular liver had significantly higher stiffness (P<0.01) than normal or homogeneous hyperechoic livers. Participants with a homogeneous hyperechoic liver had a higher fat fraction (P<0.005) than others. CONCLUSION: MR elastography is feasible in children with CF. Participants with a nodular pattern had higher liver stiffness supporting the US determination of advanced liver disease. Participants with a homogeneous hyperechoic pattern had higher fat fractions supporting the diagnosis of steatosis.

Serum granulosa cell-derived TNF-α promotes inflammation and apoptosis of renal tubular cells and PCOS-related kidney injury through NF-κB signaling.

Polycystic ovary syndrome (PCOS) is a disorder with endocrinal and metabolic problems in reproductive aged women. Evidence shows that PCOS is in a high prone trend to develop kidney diseases. In this study, we investigated the mediators responsible for PCOS-related kidney injury. We found that tumor necrosis factor (TNF-α) levels were significantly increased in serum and primary cultured granulosa cells (GCs) from PCOS patients. Serum TNF-α levels were positively correlated with serum testosterone and luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratio, suggesting its positive role in the severity of PCOS. Serum TNF-α levels were also positively correlated with the levels of urinary KapU, LamU, α1-MU and ß2-MU, the markers for renal tubular cell-derived proteinuria. We established a PCOS mouse model by resection of the right kidney, followed by daily administration of dihydrotestosterone (DHT, 27.5 µg, i.p.) from D7 for 90 days. We found that TNF-α levels were significantly increased in the ovary and serum of the mice, accompanied by increased renal tubular cell apoptosis, inflammation and fibrosis in kidneys. Furthermore, the receptor of TNF-α, tumor necrosis factor receptor 1 (TNFR1), was significantly upregulated in renal tubular cells. We treated human ovarian granulosa-like tumor cells (KGN) with DHT (1 µg/ml) in vitro, the conditioned medium derived from the granulosa cell culture greatly accelerated apoptotic injury in human proximal tubular epithelial cells (HKC-8), which was blocked after knockdown of TNF-α in KGN cells. Furthermore, knockdown of TNFR1 in renal tubular epithelial cells greatly ameliorated cell injury induced by granulosa cell-derived conditioned medium. These results suggest that serum TNF-α plays a key role in mediating inflammation and apoptosis in renal tubular cells associated with PCOS-related kidney injury.

Comparing genomes of Fructus Amomi-producing species reveals genetic basis of volatile terpenoid divergence.

Wurfbainia longiligularis and Wurfbainia villosa are both rich in volatile terpenoids and are 2 primary plant sources of Fructus Amomi used for curing gastrointestinal diseases. Metabolomic profiling has demonstrated that bornyl diphosphate (BPP)-related terpenoids are more abundant in the W. villosa seeds and have a wider tissue distribution in W. longiligularis. To explore the genetic mechanisms underlying the volatile terpenoid divergence, a high-quality chromosome-level genome of W. longiligularis (2.29 Gb, contig N50 of 80.39 Mb) was assembled. Functional characterization of 17 terpene synthases (WlTPSs) revealed that WlBPPS, along with WlTPS 24/26/28 with bornyl diphosphate synthase (BPPS) activity, contributes to the wider tissue distribution of BPP-related terpenoids in W. longiligularis compared to W. villosa. Furthermore, transgenic Nicotiana tabacum showed that the GCN4-motif element positively regulates seed expression of WvBPPS and thus promotes the enrichment of BPP-related terpenoids in W. villosa seeds. Systematic identification and analysis of candidate TPS in 29 monocot plants from 16 families indicated that substantial expansion of TPS-a and TPS-b subfamily genes in Zingiberaceae may have driven increased diversity and production of volatile terpenoids. Evolutionary analysis and functional identification of BPPS genes showed that BPP-related terpenoids may be distributed only in the Zingiberaceae of monocot plants. This research provides valuable genomic resources for breeding and improving Fructus Amomi with medicinal and edible value and sheds light on the evolution of terpenoid biosynthesis in Zingiberaceae.

CircRNAs in colorectal cancer: potential biomarkers and therapeutic targets.

Globally, colorectal cancer (CRC) is the third most prevalent cancer and the second leading cause of cancer-related deaths. Circular RNAs (circRNAs) are single-stranded RNA with covalently closed-loop structures and are highly stable, conserved, and abundantly expressed in various organs and tissues. Recent research found abnormal circRNA expression in CRC patients' blood/serum, cells, CRC tissues, and exosomes. Furthermore, mounting data demonstrated that circRNAs are crucial to the development of CRC. CircRNAs have been shown to exert biological functions by acting as microRNA sponges, RNA-binding protein sponges, regulators of gene splicing and transcription, and protein/peptide translators. These characteristics make circRNAs potential markers for CRC diagnosis and prognosis, potential therapeutic targets, and circRNA-based therapies. However, further studies are still necessary to improve the understanding of the roles and biological mechanisms of circRNAs in the development of CRC. In this review, up-to-date research on the role of circRNAs in CRC was examined, focusing on their potential application in CRC diagnosis and targeted therapy, which would advance the knowledge of the functions of circRNAs in the development and progression of CRC.

Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de-palmitoylation.

BACKGROUND: Ferroptosis is an important iron-dependent form of cell death in hepatocellular carcinoma (HCC). Sorafenib, a potent ferroptosis inducer, is used to treat advanced HCC but its efficacy is limited by the development of drug resistance. METHODS: The effects of DUXAP8 expression on HCC progression were evaluated by TCGA database, Kaplan-Meier analysis, and in situ hybridization analysis. Sorafenib resistant HCC cell lines were modeled in vitro to study the regulation of DUXAP8 on ferroptosis in HCC induced by sorafenib. We used RNA pull-down, immunofluorescence assays, acyl-biotinyl exchange assay and mass spectrometry analysis to assess the molecular mechanism of ferroptosis regulation by DUXAP8. Syngeneic subcutaneous and orthotopic CDX models were used to assess whether DUXAP8 inhibition improves HCC in vivo. RESULTS: LncRNA DUXAP8, which is highly expressed in liver cancer and associated with poor prognosis, contributes to sorafenib resistance through suppression of ferroptosis. In vitro tests revealed that DUXAP8 reduced the sensitivity of HCC to sorafenib-induced ferroptosis by acting on SLC7A11, a subunit of the amino acid antiporter system xc-. DUXAP8 facilitates SLC7A11 palmitoylation and impedes its lysosomal degradation, thereby enhancing SLC7A11 action and suppressing ferroptosis. RNA pull-down and immunofluorescence assays confirmed that DUXAP8 decreased membrane translocation and promoted sorting of de-palmitoylated SLC7A11 to lysosomes by binding of DUXAP8 to SLC7A11. In addition, mass spectrometric analysis found that the Cys414 residue of SLC7A11 might be the predominant mutant site responsible for molecular masking of SLC7A11 lysosomal sorting. Further, the antitumor effect of DUXAP8 knockdown was verified in orthotopic and subcutaneous CDX models. CONCLUSIONS: Our findings suggest that a novel translational strategy combining sorafenib with DUXAP8 silencing to overcome drug resistance may improve treatment efficacy in patients with advanced HCC.

Mesenchymal stromal cell exosomes enhance dental pulp cell functions and promote pulp-dentin regeneration.

Mesenchymal stromal/stem cell (MSC) therapies are currently being explored for dental pulp regeneration. As the therapeutic effects of MSCs in tissue repair are mediated mainly through the release of extracellular vesicles (EVs) including exosomes, we investigated here the cellular processes and molecular mechanisms modulated by MSC exosomes in dental pulp regeneration. Using dental pulp cell (DPC) cultures, we demonstrated that MSC exosomes could increase DPC migration, proliferation, and odontogenic differentiation. The enhancement of these cellular processes was mediated through exosomal CD73-mediated adenosine receptor activation of AKT and ERK signaling. Consistent with these observations, MSC exosomes increased the expression of dentin matrix proteins and promoted the formation of dentin-like tissue and bridge-like structures in a rat pulp defect model. These effects were comparable to that of mineral trioxide aggregate (MTA) treatment. MSC exosomes also yielded recellularized pulp-dentin tissues in the root canal of endodontically-treated human premolars, following subcutaneous implantation in the mouse dorsum. Together, our findings suggest that MSC exosomes could exert a multi-faceted effect on DPC functions including migration, proliferation and odontogenic differentiation to promote dental pulp regeneration. This study provides the basis for development of MSC exosomes as a cell-free MSC therapeutic alternative for pulp-dentin regeneration.

TRIM21 is a druggable target for the treatment of metastatic colorectal cancer through ubiquitination and activation of MST2.

Metastatic colorectal cancer (mCRC) is characterized by poorer prognosis of patients and limited therapeutic approach, partly due to the lack of effective target. Using mouse models and tumor organoids, this study reported a tripartite motif 21 (TRIM21) protein, exerting potential inhibitory effects on the invasion and metastasis of CRC. Mechanistically, TRIM21 directly interacted with and ubiquitinated MST2 at lysine 473 (K473) via K63-linkage. This ubiquitination enabled the formation of MST2 homodimer and enhanced its kinase activity, ultimately resulting in the functional inactivation of yes-associated protein (YAP) and inhibition of an epithelial-mesenchymal transition (EMT) feature. We identified that vilazodone, an antidepressant, directly bound to TRIM21 to exert effective anti-metastatic action both in vitro and in vivo. Collectively, these findings revealed a previously unrecognized interplay between TRIM21 and the Hippo-YAP signaling. These results suggested that vilazodone could be repositioned as an anti-tumor drug to inhibit CRC metastasis by targeting TRIM21.

Small extracellular vesicles from mesenchymal stromal cells: the next therapeutic paradigm for musculoskeletal disorders.

Musculoskeletal disorders are one of the biggest contributors to morbidity and place an enormous burden on the health care system in an aging population. Owing to their immunomodulatory and regenerative properties, mesenchymal stromal/stem cells (MSCs) have demonstrated therapeutic efficacy for treatment of a wide variety of conditions, including musculoskeletal disorders. Although MSCs were originally thought to differentiate and replace injured/diseased tissues, it is now accepted that MSCs mediate tissue repair through secretion of trophic factors, particularly extracellular vesicles (EVs). Endowed with a diverse cargo of bioactive lipids, proteins, nucleic acids and metabolites, MSC-EVs have been shown to elicit diverse cellular responses and interact with many cell types needed in tissue repair. The present review aims to summarize the latest advances in the use of native MSC-EVs for musculoskeletal regeneration, examine the cargo molecules and mechanisms underlying their therapeutic effects, and discuss the progress and challenges in their translation to the clinic.

The combination of a prolonged treatment time window and alpha-fetoprotein benefits the tumor response of hepatocellular carcinoma patients as evaluated by the imRECIST: a single-center, retrospective study.

Background: The combined immunotargeting therapy of hepatocellular carcinoma (HCC) have brought remarkable results. There are still some drawbacks to the application of the immune-modified Response Evaluation Criteria in Solid Tumors to Immunotherapy (imRECIST). How many weeks does it take to confirm the true disease progression for HCC patients who had reported disease progression for the first time based on imRECIST. Whether alpha-fetoprotein (AFP), an important indicator in the progression and prognosis of liver cancer, has the same value in immunotherapy. This prompted more clinical data to gather evidence that the immunotherapy time window issue contradicts the potential benefit of therapy. Methods: This study retrospectively analyzed the clinical data of 32 patients who had undergone immunotherapy plus targeted therapy at the First Affiliated Hospital of Chongqing Medical University from June 2019 to June 2022. ImRECIST was used to evaluate the therapeutic efficacy among the patients. Before initial treatment and each immunotherapy cycle, each patient underwent standard abdominal computed tomography (CT) imaging and some biochemical indicators to assess physical condition and tumor response. All patients included will be divided into 8 groups. The differences in the survival outcomes of each treatment group were analysed. Results: Among the 32 advanced HCC patients, 9 patients achieved stable disease (SD), 12 patients showed progressive disease (PD), 3 patients showed a complete response (CR), and 8 patients showed a partial response (PR). There is no difference in baseline characteristics between subgroups. In relation to patients with PD, a prolonged therapeutic time window and the provision of continuous medication may lead to a PR, prolonging their overall survival (P=0.5864). Compared to the patients with continuous PD, there was no significant difference in the survival of patients with increased AFP concentrations after treatment who achieved PR or SD and ultimately showed PD (P=0.6600). Conclusions: In our study, the time window for treatment may need to be extended in the process of immunotherapy for HCC patients. An analysis of AFP may assist the imRECIST by providing a more accurate evaluation of tumor progression.

Mesenchymal Stromal Cell Exosomes Mediate M2-like Macrophage Polarization through CD73/Ecto-5'-Nucleotidase Activity.

Mesenchymal stem/stromal cell (MSC) exosomes have been shown to alleviate immune dysfunction and inflammation in preclinical animal models. This therapeutic effect is attributed, in part, to their ability to promote the polarization of anti-inflammatory M2-like macrophages. One polarization mechanism has been shown to involve the activation of the MyD88-mediated toll-like receptor (TLR) signaling pathway by the presence of extra domain A-fibronectin (EDA-FN) within the MSC exosomes. Here, we uncovered an additional mechanism where MSC exosomes mediate M2-like macrophage polarization through exosomal CD73 activity. Specifically, we observed that polarization of M2-like macrophages by MSC exosomes was abolished in the presence of inhibitors of CD73 activity, adenosine receptors A2A and A2B, and AKT/ERK phosphorylation. These findings suggest that MSC exosomes promote M2-like macrophage polarization by catalyzing the production of adenosine, which then binds to adenosine receptors A2A and A2B to activate AKT/ERK-dependent signaling pathways. Thus, CD73 represents an additional critical attribute of MSC exosomes in mediating M2-like macrophage polarization. These findings have implications for predicting the immunomodulatory potency of MSC exosome preparations.

Integrated proteogenomic characterization reveals an imbalanced hepatocellular carcinoma microenvironment after incomplete radiofrequency ablation.

BACKGROUND: Efforts to precisely assess tumor-specific T-cell immune responses still face major challenges, and the potential molecular mechanisms mediating hepatocellular carcinoma (HCC) microenvironment imbalance after incomplete radiofrequency ablation (iRFA) are unclear. This study aimed to provide further insight into the integrated transcriptomic and proteogenomic landscape and identify a new target involved in HCC progression following iRFA. METHODS: Peripheral blood and matched tissue samples were collected from 10 RFA-treated HCC patients. Multiplex immunostaining and flow cytometry were used to assess local and systemic immune responses. Differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were explored via transcriptomic and proteogenomic analyses. Proteinase-3 (PRTN3) was identified in these analyses. And then, the ability of PRTN3 to predict overall survival (OS) was assessed in 70 HCC patients with early recurrence after RFA. In vitro CCK-8, wound healing and transwell assays were conducted to observe interactions between Kupffer cells (KCs) and HCC cells induced by PRTN3. The protein levels of multiple oncogenic factors and signaling pathway components were detected by western blotting. A xenograft mouse model was built to observe the tumorigenic effect of PRTN3 overexpression on HCC. RESULTS: Multiplex immunostaining revealed no immediate significant change in local immune cell counts in periablational tumor tissues after 30 min of iRFA. Flow cytometry showed significantly increased levels of CD4+ T cells, CD4+CD8+ T cells, and CD4+CD25+CD127- Tregs and significantly decreased the levels of CD16+CD56+ natural killer cells on day 5 after cRFA (p < 0.05). Transcriptomics and proteomics revealed 389 DEGs and 20 DEPs. Pathway analysis showed that the DEP-DEGs were mainly enriched in the immunoinflammatory response, cancer progression and metabolic processes. Among the DEP-DEGs, PRTN3 was persistently upregulated and closely associated with the OS of patients with early recurrent HCC following RFA. PRTN3 expressed in KCs may affect the migration and invasion of heat stress-treated HCC cells. PRTN3 promotes tumor growth via multiple oncogenic factors and the PI3K/AKT and P38/ERK signaling pathways. CONCLUSIONS: This study provides a comprehensive overview of the immune response and transcriptomic and proteogenomic landscapes of the HCC milieu induced by iRFA, revealing that PRTN3 promotes HCC progression after iRFA. TRIAL REGISTRATION: ChiCTR2200055606, http://www.chictr.org.cn/showproj.aspx?proj=32588 .