Early colorectal cancer screening-no time to lose.

In this editorial, we comment on the article entitled "Stage at diagnosis of colorectal cancer through diagnostic route: Who should be screened?" by Agatsuma et al. Colorectal cancer (CRC) is emerging as an important health issue as its incidence continues to rise globally, adversely affecting the quality of life. Although the public has become more aware of CRC prevention, most patients lack screening awareness. Some poor lifestyle practices can lead to CRC and symptoms can appear in the early stages of CRC. However, due to the lack of awareness of the disease, most of the CRC patients are diagnosed already at an advanced stage and have a poor prognosis.

Receptor tyrosine kinase-like orphan receptor 1: A novel antitumor target in gastrointestinal cancers.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the type I receptor tyrosine kinase family. ROR1 is pivotal in embryonic development and cancer, and serves as a biomarker and therapeutic target. It has soluble and membrane-bound subtypes, with the latter highly expressed in tumors. ROR1 is conserved throughout evolution and may play a role in the development of gastrointestinal cancer through multiple signaling pathways and molecular mechanisms. Studies suggest that overexpression of ROR1 may increase tumor invasiveness and metastasis. Additionally, ROR1 may regulate the cell cycle, stem cell characteristics, and interact with other signaling pathways to affect cancer progression. This review explores the structure, expression and role of ROR1 in the development of gastrointestinal cancers. It discusses current antitumor strategies, outlining challenges and prospects for treatment.

Oncolytic adenovirus encoding LHPP exerts potent antitumor effect in lung cancer.

LHPP has been shown to be a new tumor suppressor, and has a tendency to be under-expressed in a variety of cancers. Oncolytic virotheray is a promising therapeutics for lung cancer in recent decade years. Here we successfully constructed a new recombinant oncolytic adenovirus GD55-LHPP and investigated the effect of GD55-LHPP on the growth of lung cancer cells in vitro and in vivo. The results showed that LHPP had lower expression in either lung cancer cells or clinical lung cancer tissues compared with normal cells or tissues, and GD55-LHPP effectively mediated LHPP expression in lung cancer cells. GD55-LHPP could effectively inhibit the proliferation of lung cancer cell lines and rarely affected normal cell growth. Mechanically, the oncolytic adenovirus GD55-LHPP was able to induce stronger apoptosis of lung cancer cells compared with GD55 through the activation of caspase signal pathway. Notably, GD55-LHPP also activated autophagy-related signal pathway. Further, GD55-LHPP efficiently inhibited tumor growth in lung cancer xenograft in mice and prolonged animal survival rate compared with the control GD55 or PBS. In conclusion, the novel construct GD55-LHPP provides a valuable strategy for lung cancer-targeted therapy and develop the role of tumor suppress gene LHPP in lung cancer gene therapy.

Colorectal cancer subtyping and immune landscape analysis based on natural killer cell-related genes.

BACKGROUND AND STUDY AIMS: The prognosis of colorectal cancer (CRC) is related to natural killer (NK) cells, but the molecular subtype features of CRC based on NK cells are still unknown. This study aimed to identify NK cell-related molecular subtypes of CRC and analyze the survival status and immune landscape of patients with different subtypes. PATIENTS/MATERIAL AND METHODS: mRNA expression data, single nucleotide variant (SNV) data, and clinical information of CRC patients were obtained from The Cancer Genome Atlas. Differentially expressed genes (DEGs) were obtained through differential analysis, and the intersection was taken with NK cell-associated genes to obtain 103 NK cell-associated CRC DEGs (NCDEGs). Based on NCDEGs, CRC samples were divided into three clusters through unsupervised clustering analysis. Survival analysis, immune analysis, Gene Set Enrichment Analysis (GSEA), and tumor mutation burden (TMB) analysis were performed. Finally, NCDEG-related small-molecule drugs were screened using the CMap database. RESULTS: Survival analysis revealed that cluster2 had a lower survival rate than cluster1 and cluster3 (p < 0.05). Immune infiltration analysis found that the immune infiltration levels and immune checkpoint expression levels of cluster1_3 were substantially higher than those of cluster2, and the tumor purity was the opposite (p < 0.05). GSEA presented that cluster1_3 was significantly enriched in the chemokine signaling pathway, ECM receptor interaction, and antigen processing and presentation pathways (p < 0.05). The TMB of cluster1_3 was significantly higher than that of cluster2 (p < 0.05). Genes with the highest mutation rate in CRC were APC, TP53, TTN, and KRAS. Drug prediction results showed that small-molecule drugs that reverse the upregulation of NCDEGs, deoxycholic acid, dipivefrine, phenformin, and other drugs may improve the prognosis of CRC. CONCLUSION: NK cell-associated CRC subtypes can be used to evaluate the tumor characteristics of CRC patients and provide an important reference for CRC patients.

HAX1-Overexpression Augments Cardioprotective Efficacy of Stem Cell-Based Therapy Through Mediating Hippo-Yap Signaling.

Although stem/progenitor cell therapy shows potential for myocardial infarction repair, enhancing the therapeutic efficacy could be achieved through additional genetic modifications. HCLS1-associated protein X-1 (HAX1) has been identified as a versatile modulator responsible for cardio-protective signaling, while its role in regulating stem cell survival and functionality remains unknown. In this study, we investigated whether HAX1 can augment the protective potential of Sca1+ cardiac stromal cells (CSCs) for myocardial injury. The overexpression of HAX1 significantly increased cell proliferation and conferred enhanced resistance to hypoxia-induced cell death in CSCs. Mechanistically, HAX1 can interact with Mst1 (a prominent conductor of Hippo signal transduction) and inhibit its kinase activity for protein phosphorylation. This inhibition led to enhanced nuclear translocation of Yes-associated protein (YAP) and activation of downstream therapeutic-related genes. Notably, HAX1 overexpression significantly increased the pro-angiogenic potential of CSCs, as demonstrated by elevated expression of vascular endothelial growth factors. Importantly, implantation of HAX1-overexpressing CSCs promoted neovascularization, protected against functional deterioration, and ameliorated cardiac fibrosis in ischemic mouse hearts. In conclusion, HAX1 emerges as a valuable and efficient inducer for enhancing the effectiveness of cardiac stem or progenitor cell therapeutics.

Detection of ribophagy in yeast and mammals.

Ribophagy, the cellular process wherein ribosomes are selectively self-digested through autophagy, plays a pivotal role in maintaining ribosome turnover. Understanding the molecular regulatory mechanisms governing ribophagy is pivotal to uncover its significance. Consequently, the establishment of methods for detecting ribophagy becomes important. In this protocol, we have optimized, enriched, and advanced existing ribophagy detection techniques, including immunoblotting, fluorescence microscopy, and transmission electron microscopy (TEM), to precisely monitor and quantify ribophagic events. Particularly noteworthy is the introduction of TEM technology for yeast ribophagy detection. In summary, the delineated methods are applicable for detecting ribophagy in both yeast and mammals, laying a solid foundation for further exploring the physiological importance of ribophagy and its potential implications in diverse cellular environments.

Quadratus lumborum block vs. transversus abdominis plane block for postoperative pain control in patients with nephrectomy: A systematic review and network meta-analysis.

STUDY OBJECTIVE: This systematic review and network meta-analysis aimed to compare the analgesic efficacy of transversus abdominis plane block (TAPB) and quadratus lumborum block (QLB) on nephrectomy. DESIGN: Systematic review and network meta-analysis. PATIENTS: Patients undergoing nephrectomy. INTERVENTIONS: TAPB and QLB for postoperative analgesia. MEASUREMENTS: The primary outcome was 24 h morphine-equivalent consumptions after surgery. Secondary outcomes included postoperative pain scores, postoperative opioid consumption, postoperative rescue analgesia, postoperative nausea and vomiting (PONV), length of hospital stay after surgery, and patient satisfaction. MAIN RESULTS: Fourteen studies involving 883 patients were included. Seven studies compared TAPB to control, six studies compared QLB to control, and one study compared TAPB to QLB. For direct meta-analysis of the post-surgical 24 h morphine-equivalent consumption, QLB was lower than control (mean difference [95%CI]: -18.16 [-28.96, -7.37]; I2 = 88%; p = 0.001), while there was no difference between TAPB and control (mean difference [95%CI]: -8.34 [-17.84, 1.17]; I2 = 88%; p = 0.09). Network meta-analysis showed similar findings that QLB was ranked as the best anesthetic technique for reducing postoperative 24 h opioid consumption (p-score = 0.854). Moreover, in direct meta-analysis, as compared to control, the time of first postoperative rescue analgesia was prolonged after QLB (mean difference [95%CI]: 165.00 [128.99, 201.01]; p < 0.00001), but not TAPB (mean difference [95%CI]: 296.82 [-91.92, 685.55]; p = 0.13). Meanwhile, QLB can effectively reduce opioid usages at intraoperative period, as well as at postoperative 6 h and 48 h, while TAPB can only reduce opioid consumption at 6 h after surgery. As compared to control, both TAPB and QLB exhibited the reduction in PONV and pain scores at post-surgical some timepoints. Also, QLB (mean difference [95%CI]: -0.29 [-0.49, -0.08]; p = 0.006) but not TAPB (mean difference [95%CI]: 0.60 [-0.25, 1.45]; p = 0.17) exhibited the shorter postoperative length of hospital stay than control. CONCLUSIONS: QLB is more likely to be effective in reducing postoperative opioid use than TAPB, whereas both of them are superior to control with regard to the reduction in postoperative pain intensity and PONV. TRIAL REGISTRATION: PROSPERO identifier: CRD42022358464.

ConceptThread: Visualizing Threaded Concepts in MOOC Videos.

Massive Open Online Courses (MOOCs) platforms are becoming increasingly popular in recent years. Online learners need to watch the whole course video on MOOC platforms to learn the underlying new knowledge, which is often tedious and time-consuming due to the lack of a quick overview of the covered knowledge and their structures. In this paper, we propose ConceptThread, a visual analytics approach to effectively show the concepts and the relations among them to facilitate effective online learning. Specifically, given that the majority of MOOC videos contain slides, we first leverage video processing and speech analysis techniques, including shot recognition, speech recognition and topic modeling, to extract core knowledge concepts and construct the hierarchical and temporal relations among them. Then, by using a metaphor of thread, we present a novel visualization to intuitively display the concepts based on video sequential flow, and enable learners to perform interactive visual exploration of concepts. We conducted a quantitative study, two case studies, and a user study to extensively evaluate ConceptThread. The results demonstrate the effectiveness and usability of ConceptThread in providing online learners with a quick understanding of the knowledge content of MOOC videos.

BRD9-SMAD2/3 Orchestrates Stemness and Tumorigenesis in Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS: The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. The epigenetic mechanisms regulating CSCs are currently insufficiently understood, which hampers the development of novel strategies for eliminating CSCs. METHODS: By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodeling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFß/Activin-SMAD2/3 signaling pathway. RESULTS: Inhibition and genetic ablation of BRD9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumors from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs. CONCLUSIONS: Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.

Direct cellular reprogramming techniques for cardiovascular regenerative therapeutics.

Cardiovascular diseases remain a leading cause of hospitalization affecting approximately 38 million people worldwide. While pharmacological and revascularization techniques can improve the patient's survival and quality of life, they cannot help reversing myocardial infarction injury and heart failure. Direct reprogramming of somatic cells to cardiomyocyte and cardiac progenitor cells offers a new approach to cellular reprogramming and paves the way for translational regenerative medicine. Direct reprogramming can bypass the pluripotent stage with the potential advantage of non-immunogenic cell products, reduced carcinogenic risk, and no requirement for embryonic tissue. The process of directly reprogramming cardiac cells was first achieved through the overexpression of transcription factors such as GATA4, MEF2C, and TBX5. However, over the past decade, significant work has been focused on enhancing direct reprogramming using a mixture of transcription factors, microRNAs, and small molecules to achieve cardiac cell fate. This review discusses the evolution of direct reprogramming, recent progress in achieving efficient cardiac cell fate conversion, and describes the reprogramming mechanisms at a molecular level. We also explore various viral and non-viral delivery methods currently being used to aid in the delivery of reprogramming factors to improve efficiency. However, further studies will be needed to overcome molecular and epigenetic barriers to successfully achieve translational cardiac regenerative therapeutics.

Ectopic adrenocorticotropic hormone (ACTH) syndrome: two case reports.

BACKGROUND: Clinically, the incidence of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is often obscured, making it difficult to identify the primary lesion. This can pose challenges in both diagnosing and treating the disease. Therefore, this paper presents two cases of EAS to share insights and guide diagnosis and treatment approaches. DESCRIPTION OF CASES: Case 1 is a male patient aged 71, and Case 2 is a female patient aged 61. EAS was considered for both patients according to the medical history and auxiliary examination results. After the blood glucose and blood potassium were slightly stable, Case 1 received the total right adrenalectomy and the left subtotal adrenalectomy. After the surgery, a positron emission tomography-computed tomography (PET-CT) was used to identify the primary lesion in Case 1, and the result showed primary neuroendocrine tumors originating from the thymus with metastasis. A chest CT scan with contrast for Case 2 confirmed the presence of multiple soft tissue nodules in both lungs, suspected of being tumor lesions, along with mediastinal lymph node enlargement. A CT-guided lung puncture was not performed due to a progressive decrease in platelets, and the patient died due to severe lung infection eventually. CONCLUSIONS: PET-CT can be an effective method for diagnosing EAS. Early control of hypercortisolism is vital in preventing life-threatening infections in EAS patients.

TOR-mediated Ypt1 phosphorylation regulates autophagy initiation complex assembly.

The regulation of autophagy initiation is a key step in autophagosome biogenesis. However, our understanding of the molecular mechanisms underlying the stepwise assembly of ATG proteins during this process remains incomplete. The Rab GTPase Ypt1/Rab1 is recognized as an essential autophagy regulator. Here, we identify Atg23 and Atg17 as binding partners of Ypt1, with their direct interaction proving crucial for the stepwise assembly of autophagy initiation complexes. Disruption of Ypt1-Atg23 binding results in significantly reduced Atg9 interactions with Atg11, Atg13, and Atg17, thus preventing the recruitment of Atg9 vesicles to the phagophore assembly site (PAS). Likewise, Ypt1-Atg17 binding contributes to the PAS recruitment of Ypt1 and Atg1. Importantly, we found that Ypt1 is phosphorylated by TOR at the Ser174 residue. Converting this residue to alanine blocks Ypt1 phosphorylation by TOR and enhances autophagy. Conversely, the Ypt1S174D phosphorylation mimic impairs both PAS recruitment and activation of Atg1, thus inhibiting subsequent autophagy. Thus, we propose TOR-mediated Ypt1 as a multifunctional assembly factor that controls autophagy initiation via its regulation of the stepwise assembly of ATG proteins.

Clinical Value of Combined Detection of Serum sTim-3 and CEA or CA19-9 for Postoperative Recurrence of Colorectal Cancer Diagnosis.

Purpose: The present study aimed to evaluate the clinical value of Combined Detection of serum soluble T-cell immunoglobulin 3 (sTim-3) with carcinoembryonic antigen (CEA) or glycotype antigen 19-9 (CA19-9) for Postoperative Recurrence of Colorectal Cancer (CRC) Diagnosis. Patients and Methods: The serum sTim-3 was measured by highly sensitivity TRFIA, and serum CEA and CA19-9 were obtained through the collection of clinical data. Quantitative detection of serum sTim-3, CEA, CA19-9 in 90 patients after the CRC surgery (52 postoperative recurrence and 38 no-postoperative recurrence), 21 patients with colorectal benign tumors, and 67 healthy controls. To analyze the clinical diagnostic value of combined detection of sTim-3 with CEA or CA19-9 to test whether patients have recurrence after CRC surgery. Results: The sTim-3 (15.94±11.24ng/mL) in patients after CRC surgery was significantly higher than in healthy controls (8.95±3.34ng/mL) and colorectal benign tumors (8.39±2.28ng/mL) (P < 0.05), and sTim-3 (20.33±13.04ng/mL) in CRC postoperative recurrent group was significantly higher than in the group without recurrence after CRC surgery (9.94±2.36ng/mL) (P < 0.05). In terms of detecting postoperative recurrence after CRC surgery, combined detection of sTim-3 and CEA (AUC: 0.819, sensitivity: 80.77%, specificity: 65.79%), sTim-3 and CA19-9 test (AUC: 0.813, sensitivity: 69.23%, specificity: 97.30%) was significantly better than the CEA single test (AUC: 0.547, sensitivity: 63.16%, specificity: 48.08%) and CA19-9 single test (AUC: 0.675 sensitivity: 65.38%, specificity: 67.57%), Delong test P < 0.05. Conclusion: The efficacy of CEA and CA19-9 single test was not optimal, and the combination of sTim-3 in serum could significantly improve the sensitivity and specificity of detecting patient recurrence after CRC surgery.

Activation of MG53 Enhances Cell Survival and Engraftment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Injured Hearts.

BACKGROUND AND OBJECTIVE: Our previous studies demonstrated that MG53 protein can protect the myocardium, but its use as a therapeutic is challenging due to its short half-life in blood circulation. This study aimed to investigate the cardioprotective role of MG53 on human induced pluripotent stem cell-derived cardiomyocytes (HiPSC-CMs) in the context of myocardial ischemia/reperfusion (I/R). METHODS: In vitro: HiPSC-CMs were transfected with adenoviral MG53 (HiPSC-CMsMG53), in which the expression of MG53 can be controlled by doxycycline (Dox), and the cells were then exposed to H2O2 to mimic ischemia/reperfusion injury. In vivo: HiPSC-CMsMG53 were transplanted into the peri-infarct region in NSG™ mice after I/R. After surgery, mice were treated with Dox (+ Dox) to activate MG53 expression (sucrose as a control of -Dox) and then assessed by echocardiography and immunohistochemistry. RESULTS: MG53 can be expressed in HiPSC-CMMG53 and released into the culture medium after adding Dox. The cell survival rate of HiPSC-CMMG53 was improved by Dox under the H2O2 condition. After 14 and 28 days of ischemia/reperfusion (I/R), transplanted HiPSC-CMsMG53 + Dox significantly improved heart function, including ejection fraction (EF) and fractional shortening (FS) in mice, compared to HiPSC-CMsMG53-Dox, and reduced the size of the infarction. Additionally, HiPSC-CMMG53 + Dox mice demonstrated significant engraftment in the myocardium as shown by staining human nuclei-positive cells. In addition, the cell survival-related AKT signaling was found to be more active in HiPSC-CMMG53 + Dox transplanted mice's myocardium compared to the HiPSC-CMMG53-Dox group. Notably, the Dox treatment did not cause harm to other organs. CONCLUSION: Inducible MG53 expression is a promising approach to enhance cell survival and engraftment of HiPSC-CMs for cardiac repair.

Eco-Friendly Epoxy-Terminated Polyurethane-Modified Epoxy Resin with Efficient Enhancement in Toughness.

Polyurethane is widely used to toughen epoxy resins due to its excellent comprehensive properties and compatibility. However, some demerits of polyurethanes limit their applications, such as the harsh storage condition of isocyanate-terminated polyurethane (ITPU), the limited amount of ITPU in epoxy resin, and using solvents during the preparation of polyurethane-modified epoxy resins. To address these issues, in this study, we reported a facile and green approach for preparing epoxy-terminated polyurethane (EPU)-modified epoxy resins with different EPU contents. It was found that the toughness of the epoxy resin was significantly improved after the addition of EPU. When the EPU content was 30 wt%, the elongation at break and toughness were improved by 358.36% and 73.56%, respectively. In comparison, the toughening effect of EPU outperformed that of ITPU. Moreover, the high content of EPU did not significantly decrease the glass transition temperature and had little effect on the thermal stability of the epoxy resin.

Lipocalin 10 is essential for protection against inflammation-triggered vascular leakage by activating LDL receptor-related protein 2-slingshot homologue 1 signalling pathway.

AIMS: Systemic inflammation occurs commonly during many human disease settings and increases vascular permeability, leading to organ failure, and lethal outcomes. Lipocalin 10 (Lcn10), a poorly characterized member of the lipocalin family, is remarkably altered in the cardiovascular system of human patients with inflammatory conditions. Nonetheless, whether Lcn10 regulates inflammation-induced endothelial permeability remains unknown. METHODS AND RESULTS: Systemic inflammation models were induced using mice by injection of endotoxin lipopolysaccharide (LPS) or caecal ligation and puncture (CLP) surgery. We observed that the expression of Lcn10 was dynamically altered only in endothelial cells (ECs), but not in either fibroblasts or cardiomyocytes isolated from mouse hearts following the LPS challenge or CLP surgery. Using in vitro gain- and loss-of-function approaches and an in vivo global knockout mouse model, we discovered that Lcn10 negatively regulated endothelial permeability upon inflammatory stimuli. Loss of Lcn10 augmented vascular leakage, leading to severe organ damage and higher mortality following LPS challenge, compared to wild-type controls. By contrast, overexpression of Lcn10 in ECs displayed opposite effects. A mechanistic analysis revealed that both endogenous and exogenous elevation of Lcn10 in ECs could activate slingshot homologue 1 (Ssh1)-Cofilin signalling cascade, a key axis known to control actin filament dynamics. Accordingly, a reduced formation of stress fibre and increased generation of cortical actin band were exhibited in Lcn10-ECs, when compared to controls upon endotoxin insults. Furthermore, we identified that Lcn10 interacted with LDL receptor-related protein 2 (LRP2) in ECs, which acted as an upstream factor of the Ssh1-Confilin signalling. Finally, injection of recombinant Lcn10 protein into endotoxic mice showed therapeutic effects against inflammation-induced vascular leakage. CONCLUSION: This study identifies Lcn10 as a novel regulator of EC function and illustrates a new link in the Lcn10-LRP2-Ssh1 axis to controlling endothelial barrier integrity. Our findings may provide novel strategies for the treatment of inflammation-related diseases.

Precise peripheral design enables propeller-like squaraine dye with highly sensitive and wide-range piezochromism.

Piezochromic fluorescent (PCF) materials that feature high sensitivity and wide-range switching are attractive in intelligent optoelectronic applications but their fabrication remains a significant challenge. Here we present a propeller-like squaraine dye SQ-NMe2 decorated with four peripheral dimethylamines acting as electron donors and spatial obstacles. This precise peripheral design is expected to loosen the molecular packing pattern and facilitate more substantial intramolecular charge transfer (ICT) switching caused by conformational planarization under mechanical stimuli. As such, the pristine SQ-NMe2 microcrystal exhibits significant fluorescence changes from yellow (λem = 554 nm) to orange (λem = 590 nm) upon slight mechanical grinding and further to deep red (λem = 648 nm) upon heavy mechanical grinding. Single-crystal X-ray diffraction structural analysis of two SQ-NMe2 polymorphs provides direct evidence to illustrate the design concept of such a piezochromic molecule. The piezochromic behavior of SQ-NMe2 microcrystals is sensitive, high-contrast, and easily reversible, enabling cryptographic applications.

Myocardial IGF2R is a critical mediator of inflammation and fibrosis after ischemia-reperfusion injury.

Ischemia-reperfusion (I/R) injury is a common occurrence in various surgical procedures used to treat heart diseases. However, the role of insulin-like growth factor 2 receptor (IGF2R) during the process of myocardial I/R remains unclear. Therefore, this study aims to investigate the expression, distribution, and functionality of IGF2R in various I/R-associated models (such as reoxygenation, revascularization, and heart transplant). Loss-of-function studies (including myocardial conditional knockout and CRISPR interference) were performed to clarify the role of IGF2R in I/R injuries. Following hypoxia, IGF2R expression increased, but this effect was reversed upon restoration of oxygen levels. Loss of myocardial IGF2R was found to enhance the cardiac contractile functions, and reduced cell infiltration or cardiac fibrosis of I/R mouse models compared to the genotype control. CRISPR-inhibition of IGF2R decreased cell apoptotic death under hypoxia. RNA sequencing analysis indicated that myocardial IGF2R played a critical role in regulating the inflammatory response, innate immune response, and apoptotic process following I/R. Integrated analysis of the mRNA profiling, pulldown assays, and mass spectrometry identified granulocyte-specific factors as potential targets of myocardial IGF2R in the injured heart. In conclusion, myocardial IGF2R emerges as a promising therapeutic target to ameliorate inflammation or fibrosis following I/R injuries.

Advances in Large Gap Peripheral Nerve Injury Repair and Regeneration with Bridging Nerve Guidance Conduits.

Peripheral nerve injury is a common complication of accidents and diseases. The traditional autologous nerve graft approach remains the gold standard for the treatment of nerve injuries. While sources of autologous nerve grafts are very limited and difficult to obtain. Nerve guidance conduits are widely used in the treatment of peripheral nerve injuries as an alternative to nerve autografts and allografts. However, the development of nerve conduits does not meet the needs of large gap peripheral nerve injury. Functional nerve conduits can provide a good microenvironment for axon elongation and myelin regeneration. Herein, the manufacturing methods and different design types of functional bridging nerve conduits for nerve conduits combined with electrical or magnetic stimulation and loaded with Schwann cells, etc., are summarized. It summarizes the literature and finds that the technical solutions of functional nerve conduits with electrical stimulation, magnetic stimulation and nerve conduits combined with Schwann cells can be used as effective strategies for bridging large gap nerve injury and provide an effective way for the study of large gap nerve injury repair. In addition, functional nerve conduits provide a new way to construct delivery systems for drugs and growth factors in vivo.

STING controls opioid-induced itch and chronic itch via spinal tank-binding kinase 1-dependent type I interferon response in mice.

BACKGROUND: Patients receiving epidural or intrathecal opioids administration for neuraxial analgesia frequently suffer from an irritating itch. STING (stimulator of interferon genes), an innate immune modulator, is strongly implicated in pain pathogenesis via neuron-immune modulation. Given that pain and itch share some common neurocircuits, we evaluate the therapeutic potential of STING agonists in opioid-induced itch and chronic itch. METHODS: Opioids (morphine, fentanyl and sufentanil) were intrathecally injected to induce acute itch. Chronic itch was induced by dry skin and contact dermatitis. Opioids analgesic effect, itch-induced scratching behavior, spinal expression of STING, phosphorylation of TBK1 (tank-binding kinase 1), IRF3 (interferon regulatory factor-3) and ERK (extracellular signal-regulated kinase), as well as production of IFN-α and IFN-ß were examined. STING agonists (DMXAA and ADU-S100), TBK1 inhibitor, recombinant IFN-α and IFN-ß elucidated the mechanism and treatment of itch. Whole-brain functional connectivity was evaluated using resting-state fMRI. RESULTS: We report the primary expression of STING protein by the spinal dorsal horn neurons. Intraperitoneal injection of DMXAA dose-dependently reduces morphine-induced scratch bouts, without impairing morphine antinociception. Simultaneously, DMXAA alleviates fentanyl- and sufentanil-induced itching-like behavior, and chronic scratching behavior caused by dry skin and contact dermatitis. Furthermore, DMXAA drastically increases spinal phosphorylation of TBK1 and IRF3 following morphine exposure, dry skin and contact dermatitis. DMXAA-induced anti-pruritus effects and spinal productions of IFN-α and IFN-ß are compensated by intrathecal delivery of the TBK1 inhibitor. Also, ADU-S100, recombinant IFN-α and IFN-ß exhibits remarkable attenuation in scratching behaviors after morphine injection and dermatitis. Recombinant IFN-α inhibits morphine-induced spinal phosphorylation of ERK. Finally, DMXAA prevents dermatitis-induced the increase of cerebral functional connectivity between regions of interests such as primary somatosensory cortex, piriform cortex, retrosplenial cortex, colliculus and ventral thalamus. CONCLUSIONS: STING activation confers protection against opioid-induced itch and chronic itch through spinal up-regulation of TBK1-IRF3-type I interferon cascades in mice, suggesting that STING agonists are promising candidates in translational development for pruritus relief.