Overexpression of low-density lipoprotein receptor prevents neurotoxic polarization of astrocytes via inhibiting NLRP3 inflammasome activation in experimental ischemic stroke.

JOURNAL/nrgr/04.03/01300535-202502000-00027/figure1/v/2024-05-28T214302Z/r/image-tiff Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury. Low-density lipoprotein receptor, a classic cholesterol regulatory receptor, has been found to inhibit NLR family pyrin domain containing protein 3 (NLRP3) inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer's disease. However, little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke. To address this issue in the present study, we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models. First, we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis. We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation. Second, we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus. Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype. Finally, we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin, an NLRP3 agonist, restored the neurotoxic astrocyte phenotype. These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.

The ERF transcription factor ZbERF3 promotes ethylene-induced anthocyanin biosynthesis in Zanthoxylum bungeanum.

Ethylene regulates fruit ripening, and in Zanthoxylum bungeanum, fruit color deepened with increasing of ethylene during fruit ripening. However, the molecular mechanism of this physiological process was still unclear. In this study, through the combined analysis of transcriptome and metabolome, it was found that ethylene release was consistent with anthocyanin synthesis, and ethylene response factors (ERFs) were significantly related to anthocyanin biosynthesis during the fruit ripening of Z. bungeanum. Ethylene treatment significantly induced fruit coloration and promoted anthocyanin synthesis and the expression of ZbERF3. Furthermore, Yeast one-hybrid assays and Luciferase reporter assays demonstrated that ZbERF3 directly bound to the promoter of ZbMYB17 and transcriptionally activated its expression. What's more, it was demonstrated that ZbMYB17 directly bound to the promoter of ZbANS, promoting anthocyanin biosynthesis. Overall, this study revealed the mechanism of ERF and MYB synergistically regulating the coloration of Z. bungeanum fruit.

The Association Between Renal Desaturation Measured Using Near-Infrared Spectroscopy and Postoperative Acute Kidney Injury: A Systematic Review.

OBJECTIVES: The objective of this systematic review was to clarify the status of near-infrared spectroscopy (NIRS) in monitoring perioperative renal regional tissue oxygen saturation (rSO2) and determine whether there is evidence supporting its use in predicting postoperative acute kidney injury (AKI). DESIGN: A systematic search of electronic databases was conducted to identify all clinical studies that utilized NIRS to monitor renal rSO2 during the perioperative period to observe postoperative AKI. SETTING: Studies published online as of May 31, 2024, were included in the review. PARTICIPANTS: Studies involving human participants undergoing surgery with a predefined outcome of AKI were included. INTERVENTIONS: Regional tissue oxygen saturation was measured using NIRS. MEASUREMENTS AND MAIN RESULTS: A total of 144 records were identified in the primary search after removing duplicates. After screening, 18 studies were included in the analysis, consisting of 3 case-control studies and 15 prospective cohort studies. Thirteen reports focused on pediatric surgery, whereas five reports focused on adult surgery. Sixteen studies involved cardiovascular surgery with cardiopulmonary bypass, and two studies focused on liver surgery. All studies received a quality score of 7 or above. Significant heterogeneity and mostly short follow up periods were noted. CONCLUSION: Renal desaturation may indicate AKI in patients; however, further studies are required to substantiate this relationship. Additional clinical trials are necessary to evaluate normal values and establish the exact threshold of renal rSO2 that signifies a meaningful decline in renal function.

Efgartigimod as a fast-acting add-on therapy in manifest and impending myasthenic crisis: A single-center case series.

Efgartigimod was the first-in-class neonatal Fc receptor antagonist approved for the treatment of acetylcholine receptor antibody positive (AChR+), Myasthenia Gravis Foundation of America (MGFA) Class II-IV generalized myasthenia gravis (gMG) patients. As a novel therapy, the clinical experiences are still lacking, especially for the use of efgartigimod in manifest and impending myasthenic crisis (IMC). We reported three AChR+, gMG patients, two with myasthenic crisis (MC) and one with IMC, treated with efgartigimod. MGFA class, MG-Activity of Daily Living score (MG-ADL), Quantitative MG score (QMG), and Muscle Research Council sum score (MRC), concentration of anti-AChR antibody, IgG, globulin, and albumin, subsets of T and B lymphocyte were evaluated or measured before, during and after efgartigimod treatment. All patients showed fast and robust response to efgartigimod with marked improvement in MGFA, MG-ADL, QMG, and MRC scores. Patient 1 did not respond effectively to IVIg but was successfully rescued by add-on efgartigimod. She extubated at 7 days after the first infusion and got rid of NIV after 14-days treatment. Patient 2 and patient 3 directly used efgartigimod when symptoms were not ameliorated by adjusting of oral drugs. Patient 2 wean from BiPAP at seven days after the first infusion. Patient 3 in IMC status, overcame the severe dysphagia at three days after the first infusion. Clinical symptoms continued to improve 1-2 weeks after discharge. Concentration of anti-AChR antibody, IgG and globulin were remarkably reduced by efgartigimod treatment. Our study supported that efgartigimod could act as a fast-acting rescue therapy for patients with MC or IMC. Larger studies from multicenter are required to provide further evidence.

Endoplasmic Reticulum Membrane Protein Complex Regulates Cancer Stem Cells and is Associated with Sorafenib Resistance in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for novel therapeutic targets. This study aimed to elucidate the role of endoplasmic reticulum membrane protein complex subunit 1 (EMC1) in HCC progression and its therapeutic potential. Methods: Publicly available sequencing data and biopsy specimens were analyzed to assess EMC's clinical value and functions in HCC. In vitro experiments validated EMC functions, and multiplex immunofluorescence analysis examined EMC-associated sorafenib resistance mechanisms. EMC1 expression was knocked down in HCC cell lines, followed by cell viability, wound healing, and transwell migration assays. Tumor growth and response to sorafenib treatment were evaluated in mouse models. Metabolomic analysis assessed changes in the TCA cycle. Results: EMC genes were aberrantly expressed in HCC, and high EMC1 expression correlated with poorer survival rates. EMC1 disruption enhanced HCC cells' sensitivity to sorafenib, reducing cell viability, increasing apoptosis, and decreasing tumor size and weight. EMC1 maintained cancer cell stemness and promoted M2 macrophage infiltration. Metabolomic analysis revealed significant changes in the TCA cycle, indicating EMC1's role in HCC metabolic reprogramming. Importantly, EMC1 is highly associated with sorafenib resistance, potentially linked to CTNNB1 mutation or activation. Conclusion: EMC1 plays a critical role in regulating the sorafenib resistance in HCC. Targeting EMC1 may improve HCC treatment efficacy.

Tislelizumab plus neoadjuvant chemotherapy and concurrent chemoradiotherapy versus neoadjuvant chemotherapy and concurrent chemoradiotherapy for locally advanced nasopharyngeal carcinoma: A retrospective study.

BACKGROUND: The efficacy of immunotherapy plus neoadjuvant chemotherapy and concurrent chemoradiotherapy (CCRT) for locally advanced nasopharyngeal carcinoma (LA-NPC) has not been reported. This study retrospectively compared the efficacy of tislelizumab plus neoadjuvant chemotherapy and CCRT with neoadjuvant chemotherapy followed by CCRT. METHODS: Ninety patients with stages III-IVa NPC were identified between January 2020 and March 2021 at the Affiliate Hospital of Guangdong Medical University. Forty-three patients in the observation group (OG) received tislelizumab plus nano albumin-paclitaxel and cisplatin (nab-TP) regimen, followed by CCRT, while forty-seven patients in the control group (CG) received nab-TP regimen followed by CCRT. RESULTS: The complete response rate after neoadjuvant therapy was significantly higher in the OG compared to the CG (37.2% vs. 12.8 %). The objective response rates were 88.4 % in the OG and 70.2 % in the CG. The 3-year progression-free survival (PFS) rates for OG and CG patients were 93.0 % and 78.7 %, respectively (P = 0.04, HR = 0.31). The overall survival (OS) rates for the OG and the CG were 95.3 % and 87.2 %, respectively (P = 0.15, HR = 0.36). Locoregional relapse-free survival (LRFS) rates were 90.7 % for the OG and 72.3 % for the CG (P = 0.04, HR = 0.38), and distant metastasis-free survival (DMFS) rates were 95.3 % for the OG, and 80.9 % for the CG (P = 0.04, HR = 0.30). For PD-L1 high-expression and low-expression rates, the 3-year PFS rates were 89.2 % and 85.7 % (P = 0.77, HR = 1.21), and the OS rates were 90.2 % and 89.2 % (P = 0.65, HR = 1.36), respectively. CONCLUSION: Tislelizumab combined with neoadjuvant chemotherapy and CCRT showed encouraging therapeutic effects and good tolerability in patients with LA-NPC compared to the standard treatment.

[Effects of Dexmedetomidine on the Recovery Quality of Donors Undergoing Pure Laparoscopic Donor Hepatectomy]. / å³ç¾Žæ‰˜å’ªå®šå¯¹è ¹è ”é•œä¾›è‚èŽ·å–æœ¯ä¾›è€ è‹é†’æœŸæ¢å¤è´¨é‡çš„å½±å“.

Objective: To investigate the effects of intraoperative intravenous administration of dexmedetomidine (DEX) on the recovery quality of donors undergoing pure laparoscopic donor hepatectomy. Methods: A total of 56 liver donors who were going to undergo scheduled pure laparoscopic donor hepatectomy were enrolled and randomly assigned to two groups, a DEX group ( n=28) and a control group ( n=28). Donors in the DEX group received DEX infusion at a dose of 1 µg/kg over 15 minutes through a continuous pump, which was followed by DEX at 0.4 µg/(kg·h) until the disconnection of the portal branch. Donors in the control group were given an equal volume of 0.9% normal saline at the same infusion rate and over the same period of time as those of the dex infusion in the DEX group. The primary outcome was the incidence of emergence agitation (EA). The Aono's Four-point Scale (AFPS) score was used to assess EA. The secondary observation indicators included intraoperative anesthesia and surgery conditions, spontaneous respiration recovery time, recovery time, extubation time, scores for the Ramsay Sedation Scale, the incidence of chills, numeric rating scale (NRS) score for pain, and blood pressure and heart rate after extubation. Results: The incidence of EA was 10.7% and 39.3% in the DEX group and the control group, respectively, and the incidence of EA was significantly lower in the DEX group than that in the control group ( P=0.014). The APFS scores after extubation in the DEX group were lower than those in the control group (1 [1, 1] vs. 2 [1, 3], P=0.005). Compared to the control group, the dosages of intraoperative propofol and remifentanil were significantly reduced in the DEX group ( P<0.05). During the recovery period, the number of donors requiring additional boluses of analgesia, the blood pressure, and the heart rate were all lower in the DEX group than those in the control group ( P<0.05). No significant differences between the two groups were observed in the spontaneous respiration recovery time, recovery time, extubation time, the incidence of chills, NRS score, scores for the Ramsay Sedation Scale, and the length-of-stay in postanesthesia care unit (PACU) ( P>0.05). Conclusion: DEX can reduce the incidence of EA after pure laparoscopic donor hepatectomy and improve the quality of recovery without prolonging postoperative recovery time or extubation time.

Ultrasound-guided Hydrogel Injection Provides Better Therapeutic Effects After Hand Tendon Surgery Than Intraoperative Injection: A Randomized Controlled Trial.

BACKGROUND: Hydrogels are used to provide a barrier against peritendinous adhesion formation, but when implanted intraoperatively, they degrade rapidly and aggravate early inflammatory pain. It is uncertain whether clinical efficacy can be improved by avoiding the inflammatory phase when hydrogels are delivered during adhesion formation. QUESTIONS/PURPOSES: (1) Compared with intraoperative hydrogel application, does ultrasound-guided postoperative application result in better total active motion (TAM) at 12 months after tendon injury? (2) Does ultrasound-guided postoperative application of hydrogels result in lower pain, better function, and better satisfaction? METHODS: This open-label, prospective, single-center, randomized controlled trial was conducted by reparative and reconstructive surgeons at the National Orthopedics Clinical Medical Center, Shanghai, People's Republic of China. Between May 2021 and December 2022, 53% (168 of 317) of patients who met our inclusion criteria were recruited, and 47% (149 of 317) of patients were excluded because of the exclusion criteria. Finally, 84 patients were randomized to the postoperative group to receive ultrasound-guided carboxymethyl chitosan (CMC) hydrogel delayed injection, and 84 patients were randomized to the intraoperative group to receive CMC hydrogel intraoperative application. Another 8% (7 of 84) of patients in the postoperative group and 10% (8 of 84) of patients in the intraoperative group were lost before the minimum study follow-up time of 1 year or had incomplete datasets, leaving 91% (153 of 168) of patients with data for analysis. Data on outcome events were analyzed according to the intention-to-treat principle, which included all patients who underwent randomization. Follow-up visits were completed at 3 weeks, 6 weeks, 3 months, 6 months, and 12 months after tendon repair. The primary outcome was TAM (ie, the sum of the degrees of active metacarpophalangeal joint, proximal interphalangeal joint, and distal interphalangeal joint flexion less the degrees from full extension; minimum clinically important difference [MCID] 20°) at 12 months. Secondary outcomes included pain (measured with a VAS; range 0 to 10, a higher score indicating worse pain; MCID 0.6), Michigan Hand Outcomes Questionnaire activities of daily living (MHQ-ADL) score (range 0 to 100, a higher score indicating better outcomes; MCID 10.1), and MHQ satisfaction (MHQ-SAT) score (range 0 to 100, a higher score indicating better outcomes; MCID 33.0). RESULTS: At 12 months, the ultrasound-guided postoperative injection group had improved TAM (intraoperative 189° [95% CI 179° to 199°] versus postoperative 209° [95% CI 199° to 219°], mean difference 20° [95% CI 6° to 35°]; p = 0.006; the mean difference in the primary outcome fulfilled the MCID value at all time points). At 6 weeks, we found no clinically important difference in VAS pain scores among groups (intraoperative mean ± SD 2.0 ± 1.0 versus postoperative 1.7 ± 1.0, mean difference 0.3 [95% CI 0.1 to 0.7]; p = 0.02); however, at 3 weeks, the VAS pain scores showed clinically important difference among groups (3.6 ± 1.4 versus 2.9 ± 1.2, mean difference 0.7 [95% CI 0.3 to 1.1]; p = 0.001). At 3 months, the ultrasound-guided postoperative injection group had higher MHQ-ADL scores (intraoperative 62 ± 10 versus postoperative 75 ± 10, mean difference 13 [95% CI 11 to 17]; p < 0.001), and the mean difference of MHQ-ADL scores reached the MCID value at all time points. At 3 months, there was no clinically important difference in MHQ-SAT scores between groups (intraoperative 62 ± 8 versus postoperative 70 ± 8, mean difference 8 [95% CI 6 to 11]; p < 0.001). CONCLUSION: Compared with intraoperative CMC hydrogel injection, postoperative ultrasound-guided injection improved the TAM and function of the affected limb, showed a short-term pain control effect, and did not increase the risk of complications. Clinical trials are needed to confirm the safety and efficacy of ultrasound-guided postoperative injection of CMC hydrogels and to determine the most effective dose and the health and economic benefits of treatment. LEVEL OF EVIDENCE: Level I, therapeutic study.

Developing Machine Learning-Based Predictive Models for Hallux Valgus Recurrence Based on Measurements From Radiographs.

BACKGROUND: Machine learning (ML) is increasingly used to predict the prognosis of numerous diseases. This retrospective analysis aimed to develop a prediction model using ML algorithms and to identify predictors associated with the recurrence of hallux valgus (HV) following surgery. METHODS: A total of 198 symptomatic feet that underwent chevron osteotomy combined with a distal soft tissue procedure were enrolled and analyzed from 2 independent medical centers. The feet were grouped according to nonrecurrence or recurrence based on 1-year follow-up outcomes. Preoperative weightbearing radiographs and immediate postoperative nonweightbearing radiographs were obtained for each HV foot. Radiographic measurements (eg, HV angle and intermetatarsal angle) were acquired and used for ML model training. A total of 9 commonly used ML models were trained on the data obtained from one institute (108 feet), and tested on the other data set from another independent institute (90 feet) for external validation. Optimal feature sets for each model were identified based on a 2000-resample bootstrap-based internal validation via an exhaustive search. The performance of each model was then tested on the external validation set. The area under the curve (AUC), classification accuracy, sensitivity, and specificity of each model were calculated to evaluate the performance of each model. RESULTS: The support vector machine (SVM) model showed the highest predictive accuracy compared to other methods, with an AUC of 0.88 and an accuracy of 75.6%. Preoperative hallux valgus angle, tibial sesamoid position, postoperative intermetatarsal angle, and postoperative tibial sesamoid position were identified as the most selected features by several ML models. CONCLUSION: ML classifiers such as SVM could predict the recurrence of HV (an HVA >20 degrees) at a 1-year follow-up while identifying associated predictors in a multivariate manner. This study holds the potential for foot and ankle surgeons to effectively identify individuals at higher risk of HV recurrence postsurgery.

GJA4 expressed on cancer associated fibroblasts (CAFs)-A 'promoter' of the mesenchymal phenotype.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide. Connexin is a transmembrane protein involved in gap junctions (GJs) formation. Our previous study found that connexin 37 (Cx37), encoded by gap junction protein alpha 4 (GJA4), expressed on fibroblasts acts as a promoter of CRC and is closely related to epithelial-mesenchymal transition (EMT) and tumor immune microenvironment. However, to date, the mechanism concerning the malignancy of GJA4 in tumor stroma has not been studied. METHODS: Hematoxylin-eosin (HE) and immunohistochemical (IHC) staining were used to validate the expression and localization of GJA4. Using single-cell analysis, enrichment analysis, spatial transcriptomics, immunofluorescence staining (IF), Sirius red staining, wound healing and transwell assays, western blotting (WB), Cell Counting Kit-8 (CCK8) assay and in vivo experiments, we investigated the possible mechanisms of GJA4 in promoting CRC. RESULTS: We discovered that in CRC, GJA4 on fibroblasts is involved in promoting fibroblast activation and promoting EMT through a fibroblast-dependent pathway. Furthermore, GJA4 may act synergistically with M2 macrophages to limit T cell infiltration by stimulating the formation of an immune-excluded desmoplasic barrier. Finally, we found a significantly correlation between GJA4 and pathological staging (P < 0.0001) or D2 dimer (R = 0.03, P < 0.05). CONCLUSION: We have identified GJA4 expressed on fibroblasts is actually a promoter of the tumor mesenchymal phenotype. Our findings suggest that the interaction between GJA4+ fibroblasts and M2 macrophages may be an effective target for enhancing tumor immunotherapy.

IFIT1 + neutrophil is a causative factor of immunosuppressive features of poorly cohesive carcinoma (PCC).

The importance of the immune microenvironment in poorly cohesive carcinoma (PCC) has been highlighted due to its limited response rate to conventional therapy and emerging treatment resistance. A combination of clinical cohorts, bioinformatics analyses, and functional/molecular experiments revealed that high infiltration of Interferon Induced Protein with Tetratricopeptide Repeats 1 (IFIT1) + tumor-associated neutrophils (TANs) is a distinguishing feature of PCC patients. Upregulation of IFIT1 + TANs promote migration and invasion of gastric cancer (GC) cell lines (MKN45 and MKN74) and stimulates the growth of cell-derived xenograft models. Besides, by promoting macrophage secreted phosphoprotein 1 (SPP1) expression and facilitating cancer-associated fibroblast and endothelial cell recruitment and activation through TANs, IFIT1 promotes a mesenchymal phenotype, which is associated with a poor prognosis. Importantly, compared to non-PCC (NPCC), PCC tumors is more immunosuppressive. Mechanistically, IFIT1 can be stimulated by IFN-γ and contributes to the expression of Programmed Cell Death 1 Ligand (PDL1) in TANs. We demonstrated in mouse models that IFIT1 + PDL1 + TANs can induce acquired resistance to anti-PD-1 immunotherapy, which may be responsible for the difficulty of PCC patients to benefit from immunotherapy. This work highlights the role of IFIT1 + TANs in mediating the remodeling of the tumor immune microenvironment and immunotherapeutic resistance and introduces IFIT1 + TANs as a promising target for precision therapy of PCC.

Safety and effectiveness of the sutureless integrated stented graft prosthesis in an animal model.

Background: Prolonged circulatory arrest time is an independent risk factor for postoperative adverse events of type A aortic dissection (TAAD) surgery. Further reduction of the circulatory arrest time is essential to improve surgical outcomes. This study aimed to evaluate the safety and effectiveness of the novel Sutureless Integrated Stented (SIS) graft prosthesis in an animal experiment. Materials and methods: Straight type of the SIS graft prosthesis was implanted into the descending aorta of 10 adult male sheep, and the use of the device was scored on a scale of 1-10. Aortic digital subtraction angiography (DSA) was performed at 4, 14, and 26 weeks to investigate the prostheses. After 26 weeks, the animals were sacrificed for histological analysis. Results: The immediate success rate of the surgery was 100 %, and the overall mean score of the use of the device was 9.65 ± 0.99. Three animals died from non-device-related causes during follow-up. Aortic DSA showed filling defects in 5 animals. Histological analysis revealed that all prostheses were intact. Except for 2 early deaths, the other 8 prostheses were endothelialized with mild inflammation, foreign body reactions, and intimal fibrosis. The mean cross-sectional area of the sutureless region was reduced by 26.4 % (range, 1.3-39.1 %). Conclusions: The safety and effectiveness of the novel SIS graft prosthesis were acceptable, and the delivery system exhibited a promising performance. Using the SIS graft prosthesis in TAAD surgery was expected to simplify the procedures and shorten the circulatory arrest time. Further large-scale clinical trials are required to verify these findings.

Outcomes and Risk Factors Associated with Pericardiectomy in Patients with Constrictive Pericarditis: A Retrospective Study from China.

PURPOSE: Pericardiectomy is the definitive treatment option for constrictive pericarditis and is associated with a high prevalence of morbidity and mortality. However, information on the associated outcomes and risk factors is limited. We aimed to report the mid-term outcomes of pericardiectomy from a single center in China. METHODS: We retrospectively reviewed data collected from patients who underwent pericardiectomy at our institute from April 2018 to January 2023. RESULTS: Eighty-six consecutive patients (average age, 46.1 ± 14.7 years; 68.6 men) underwent pericardiectomy through midline sternotomy. The most common etiology was idiopathic (n = 60, 69.8%), and 82 patients (95.3%) were in the New York Heart Association function class III/IV. In all, 32 (37.2%) patients underwent redo sternotomies, 36 (41.9%) underwent a concomitant procedure, and 39 (45.3%) required cardiopulmonary bypass. The 30-day mortality rate was 5.8%, and the 1-year and 5-year survival rates were 88.3% and 83.5%, respectively. Multivariable analysis revealed that preoperative mitral insufficiency (MI) ≥moderate (hazard ratio [HR], 6.435; 95% confidence interval [CI] [1.655-25.009]; p = 0.007) and partial pericardiectomy (HR, 11.410; 95% CI [3.052-42.663]; p = 0.000) were associated with increased 5-year mortality. CONCLUSION: Pericardiectomy remains a safe operation for constrictive pericarditis with optimal mid-term outcomes.

Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration.

Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies, resulting in severe disability. Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation. However, different clusters of macrophages have various functions and receive multiple regulation, which are both still unknown. In our current study, multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury. The transcriptomes of over 74 000 human single cells were profiled. As results, we found that SPP1+ macrophages, RGCC+ endothelial cells, ACKR1+ endothelial cells and ADAM12+ fibroblasts participated in tendon adhesion formation. Interestingly, despite specific fibrotic clusters in tendon adhesion, FOLR2+ macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells. Furthermore, ACKR1 was verified to regulate FOLR2+ macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26RtdTomato mice to lethally irradiated Ackr1-/- mice (Ackr1-/- chimeras; deficient in ACKR1) and control mice (WT chimeras). Compared with WT chimeras, the decline of FOLR2+ macrophages was also observed, indicating that ACKR1 was specifically involved in FOLR2+ macrophages migration. Taken together, our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis, but also uncovered a novel antifibrotic cluster of macrophages and their origin. These results provide potential therapeutic targets against human tendon adhesion.

Diamond-Like Carbon Depositing on the Surface of Polylactide Membrane for Prevention of Adhesion Formation During Tendon Repair.

Post-traumatic peritendinous adhesion presents a significant challenge in clinical medicine. This study proposes the use of diamond-like carbon (DLC) deposited on polylactic acid (PLA) membranes as a biophysical mechanism for anti-adhesion barrier to encase ruptured tendons in tendon-injured rats. The results indicate that PLA/DLC composite membrane exhibits more efficient anti-adhesion effect than PLA membrane, with histological score decreasing from 3.12 ± 0.27 to 2.20 ± 0.22 and anti-adhesion effectiveness increasing from 21.61% to 44.72%. Mechanistically, the abundant C=O bond functional groups on the surface of DLC can reduce reactive oxygen species level effectively; thus, the phosphorylation of NF-κB and M1 polarization of macrophages are inhibited. Consequently, excessive inflammatory response augmented by M1 macrophage-originated cytokines including interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) is largely reduced. For biocompatibility evaluation, PLA/DLC membrane is slowly absorbed within tissue and displays prolonged barrier effects compared to traditional PLA membranes. Further studies show the DLC depositing decelerates the release of degradation product lactic acid and its induction of macrophage M2 polarization by interfering esterase and PLA ester bonds, which further delays the fibrosis process. It was found that the PLA/DLC membrane possess an efficient biophysical mechanism for treatment of peritendinous adhesion.

ATPR induces acute promyelocytic leukemia cells differentiation and cycle arrest via the lncRNA CONCR/DDX11/PML-RARα signaling axis.

Acute promyelocytic leukemia (APL) is a type of acute myeloid leukemia (AML) with a high mortality rate, and the production of PML-RARα fusion protein is the cause of its pathogenesis. Our group has synthesized a novel compound, 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), by structural modification of All-trans retinoic acid (ATRA), which has strong cell differentiation-inducing effects and inhibits the expression of PML-RARα. In this study, acute promyelocytic leukemia NB4 cells before and after ATPR induction were analyzed by whole transcriptome microarray, and the expression of lncRNA CONCR was found to be significantly downregulated. The role of CONCR in ATPR-induced cell differentiation and cycle arrest was explored through overexpression and silencing of CONCR. And then the database was used to predict that CONCR may bind to DEAD/H-Box Helicase 11 (DDX11) protein to further explore the role of CONCR binding to DDX11. The results showed that ATPR could reduce the expression of CONCR, and overexpression of CONCR could reverse the ATPR-induced cell differentiation and cycle blocking effect, and conversely silencing of CONCR could promote this effect. RNA immunoprecipitation (RIP) experiments showed that CONCR could bind to DDX11, the protein expression levels of DDX11 and PML-RARα were elevated after overexpression of CONCR. These results suggest that ATPR can regulate the expression of DDX11 through CONCR to affect the expression of PML-RARα fusion protein, which in turn induces the differentiation and maturation of APL cells.

Palliative primary tumor resection may not offer survival benefits for patients with unresectable metastatic colorectal neuroendocrine neoplasms, one multicenter retrospective cohort study.

BACKGROUND: The efficacy of palliative primary tumor resection (PTR) in improving prognosis for patients with unresectable metastatic colorectal neuroendocrine neoplasms (NENs) has not been fully explored. METHODS: We performed one retrospective cohort study and recruited 68 patients with unresectable metastatic colorectal NENs from two Chinese medical centers between 2000 and 2022. All patients were assigned to PTR group and no PTR group. The clinicopathological manifestation data were carefully collected, and the survival outcomes were compared between the two groups using Kaplan-Meier methods. Propensity score matching (PSM) was conducted to minimize confounding bias. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify prognostic factors. RESULTS: A total of 32 patients received PTR, and the other 36 patients did not. The median progression-free survival (PFS) and overall survival (OS) times were 4 and 22 months in the whole cohort, respectively. For patients who received no PTR, the median OS was 16 months, and the 1-year OS rate and 3-year OS rate were 56.4% and 39.6%, respectively. For patients who received PTR, the median OS was 24 months, and the 1-year OS rate and 3-year OS rate were 67.9% and 34.1%, respectively. However, the Kaplan-Meier survival curves and log-rank test demonstrated no significant survival difference between the two groups (P = 0.963). Moreover, palliative PTR was also not confirmed as a prognostic factor in subsequent univariable and multivariable Cox proportional hazards regression analyses in both the original and matched cohorts. Only histological differentiation was identified as an independent prognostic factor affecting PFS [hazard ratio (HR) = 1.86, 95% confidence interval (CI): 1.02-3.41, P = 0.043] and OS [HR = 3.70, 95% CI: 1.09-12.48, P = 0.035] in the original cohort. CONCLUSIONS: Palliative PTR may not offer survival benefits for patients with unresectable metastatic colorectal NENs.

Targeted Macrophage CRISPR-Cas13 mRNA Editing in Immunotherapy for Tendon Injury.

CRISPR-Cas13 holds substantial promise for tissue repair through its RNA editing capabilities and swift catabolism. However, conventional delivery methods fall short in addressing the heightened inflammatory response orchestrated by macrophages during the acute stages of tendon injury. In this investigation, macrophage-targeting cationic polymers are systematically screened to facilitate the entry of Cas13 ribonucleic-protein complex (Cas13 RNP) into macrophages. Notably, SPP1 (OPN encoding)-producing macrophages are recognized as a profibrotic subtype that emerges during the inflammatory stage. By employing ROS-responsive release mechanisms tailored for macrophage-targeted Cas13 RNP editing systems, the overactivation of SPP1 is curbed in the face of an acute immune microenvironment. Upon encapsulating this composite membrane around the tendon injury site, the macrophage-targeted Cas13 RNP effectively curtails the emergence of injury-induced SPP1-producing macrophages in the acute phase, leading to diminished fibroblast activation and mitigated peritendinous adhesion. Consequently, this study furnishes a swift RNA editing strategy for macrophages in the inflammatory phase triggered by ROS in tendon injury, along with a pioneering macrophage-targeted carrier proficient in delivering Cas13 into macrophages efficiently.

Advanced postoperative tissue antiadhesive membranes enabled with electrospun nanofibers.

Tissue adhesion is one of the most common postoperative complications, which is frequently accompanied by inflammation, pain, and even dyskinesia, significantly reducing the quality of life of patients. Thus, to prevent the formation of tissue adhesions, various strategies have been explored. Among these methods, placing anti-adhesion membranes over the injured site to separate the wound from surrounding tissues is a simple and prominently favored method. Recently, electrospun nanofibers have been the most frequently investigated antiadhesive membranes due to their tunable porous structure and high porosities. They not only can act as an essential barrier and functional carrier system but also allow for high permeability and nutrient transport, showing great potential for preventing tissue adhesion. Herein, we provide a short review of the most recent applications of electrospun nanofibrous antiadhesive membranes in tendons, the abdominal cavity, dural sac, pericardium, and meninges. Firstly, each section highlights the most representative examples and they are sorted based on the latest progress of related research. Moreover, the design principles, preparation strategies, overall performances, and existing problems are highlighted and evaluated. Finally, the current challenges and several future ways to develop electrospun nanofibrous antiadhesive membranes are proposed. The systematic discussion and proposed directions can shed light on ideas and guide the reasonable design of electrospun nanofibrous membranes, contributing to the development of exceptional tissue anti-adhesive materials in the foreseeable future.