Treatment patterns and survival in T4b esophageal cancer: a retrospective cohort study.

PURPOSE: This study aims to evaluate the efficacy of various treatment approaches in stage T4b esophageal cancer patients. MATERIALS AND METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results databases, covering patients diagnosed with esophageal cancer between 2000 and 2020. Kaplan-Meier analysis was used to assess cancer-specific survival (CSS) and overall survival (OS) across different treatment patterns. RESULTS: The study included 482 patients: 222 (46.1%) received chemoradiotherapy, 58 (12.0%) underwent radiotherapy alone, 37 (7.7%) received chemotherapy alone, 50 (10.4%) underwent surgery, and 115 (23.8%) received no treatment. Median CSS were 12, 4, 6, 18, and 1 month for chemoradiotherapy, radiotherapy alone, chemotherapy alone, surgery, and non-treatment groups. Median OS for these groups were 11, 3, 6, 17, and 1 month, respectively. Multivariable proportional hazard regression analysis revealed that patients who underwent surgery experienced significantly improved CSS (hazard ratio [HR] = 0.42, 95% confidence interval [CI]: 0.24-0.72; P = 0.002) and OS (HR = 0.45, 95% CI: 0.28-0.74; P = 0.002) compared to those receiving chemoradiotherapy after propensity score matching. CONCLUSIONS: Esophagectomy, with or without radiotherapy and/or chemotherapy, results in better survival outcomes than chemoradiotherapy in patients with stage T4b esophageal cancer.

Adjuvant treatment patterns for pT3N0M0 esophageal cancer undergoing surgery.

To assess adjuvant treatment patterns on survival in patients with pT3N0M0 esophageal cancer who underwent esophagectomy without neoadjuvant chemoradiotherapy. Stage pT3N0M0 esophageal cancer patients were assessed between 2000 and 2020 from the Surveillance, Epidemiology, and End Results databases. Kaplan-Meier analysis was used to compare overall survival (OS) among various treatment patterns. We identified 445 patients: 252 (56.6%) received surgery alone, 85 (19.1%) received surgery+chemoradiotherapy, 80 (18.0%) underwent surgery+chemotherapy, and 28 (6.3%) received surgery+ radiotherapy. For squamous cell carcinoma, surgery+chemoradiotherapy ([hazard ratio] HR = 1.04, 95% confidence interval (CI): 0.65-1.66; P = 0.873), surgery+chemotherapy (HR = 0.72, 95% CI: 0.42-1.22; P = 0.221), and surgery+radiotherapy (HR = 1.33, 95% CI: 0.74-2.39; P = 0.341) had similar OS compared to surgery alone. For adenocarcinoma, surgery+chemoradiotherapy (HR = 0.51, 95% CI: 0.36-0.74; P < 0.001) and surgery+chemotherapy (HR = 0.61, 95% CI: 0.42-0.87; P = 0.006) had better OS compared to surgery alone. However, surgery+radiotherapy had a comparable OS (HR = 0.81, 95% CI: 0.44-1.49; P = 0.495).Adjuvant treatments did not improve survival in stage pT3N0M0 esophageal squamous cell carcinoma patients. In contrast, adjuvant chemoradiotherapy and chemotherapy were recommended for esophageal adenocarcinoma patients.

Consolidation chemotherapy after definitive concurrent chemoradiotherapy in patients with inoperable esophageal squamous cell carcinoma: a multicenter non-inferiority phase III randomized clinical trial.

BACKGROUND: Definitive concurrent chemoradiotherapy (dCCRT) is the gold standard for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). However, the potential benefits of consolidation chemotherapy after dCCRT in patients with esophageal cancer remain debatable. Prospective randomized controlled trials comparing the outcomes of dCCRT with or without consolidation chemotherapy in patients with ESCC are lacking. In this study, we aim to generate evidence regarding consolidation chemotherapy efficacy in patients with locally advanced, inoperable ESCC. METHODS: This is a multicenter, prospective, open-label, phase-III randomized controlled trial comparing non-inferiority of dCCRT alone to consolidation chemotherapy following dCCRT. In total, 600 patients will be enrolled and randomly assigned in a 1:1 ratio to receive either consolidation chemotherapy after dCCRT (Arm A) or dCCRT alone (Arm B). Overall survival will be the primary endpoint, whereas progression-free survival, locoregional progression-free survival, distant metastasis-free survival, and treatment-related toxicity will be the secondary endpoints. DISCUSSION: This study aid in further understanding the effects of consolidation chemotherapy after dCCRT in patients with locally advanced, inoperable ESCC. TRIAL REGISTRATION: ChiCTR1800017646.

Immune checkpoint inhibitors combined with concurrent chemoradiotherapy in locally advanced esophageal squamous cell carcinoma.

Purpose: This study aims to evaluate the efficacy of immune checkpoint inhibitors (ICIs) combined with concurrent chemoradiotherapy (CCRT) versus CCRT alone in patients with locally advanced esophageal squamous cell carcinoma. Materials and methods: This retrospective cohort study included patients diagnosed with locally advanced esophageal squamous cell carcinoma who received either CCRT alone or CCRT combined with ICIs from April 2019 to February 2023. The primary endpoint was progression-free survival (PFS), and the secondary endpoint was overall survival (OS). Results: A total of 101 patients were enrolled, with 58 undergoing CCRT alone and 43 receiving CCRT+ICI. The CCRT+ICI group demonstrated a higher complete response rate compared to the CCRT alone group (11.6% vs. 1.7%, P = 0.037). However, no significant difference was observed in 1-year PFS (58.9% vs. 55.2%; hazard ratio [HR] = 1.26, 95% confidence interval [CI]: 0.70-2.26; P = 0.445) or 1-year OS (70.8% vs. 75.9%; HR = 1.21, 95% CI: 0.58-2.53; P = 0.613) between CCRT+ICI and CCRT alone groups. The CCRT alone group experienced a higher incidence of leukopenia of any grade (93.1% vs. 76.7%, P = 0.039) but a lower incidence of pneumonitis of any grade (36.2% vs. 65.1%, P = 0.008). Conclusion: CCRT+ICI may not lead to improved survival outcomes compared to CCRT alone in patients with locally advanced esophageal squamous cell carcinoma. These findings indicate the need for further investigation into this treatment approach.

Network pharmacology analysis and experimental validation to explore the effect and mechanism of tetramethylpyrazine for spinal cord injury.

OBJECTIVE: To investigate the effect and mechanism of Tetramethylpyrazine (TMP) in treating Spinal Cord Injury (SCI) using network pharmacology analysis and animal experiments. METHODS: This study was based on public databases, including PharmMapper, BATMAN-TCM, and STRING, as well as KEGG pathway analysis and other methods of network pharmacology were used to preliminarily explore the molecular mechanism of TMP in the treatment of SCI. Using a mouse SCI compression injury model, the efficacy of TMP was evaluated, and the expression of predictive targets on the PI3K/AKT and MAPK signaling pathways was measured using Western blotting and q-PCR. RESULTS: Network pharmacology analysis showed that TMP may exert therapeutic effects through the MAPK and PI3K/AKT signaling pathways. In animal experimental validation studies, it was shown that after treatment with TMP, the hind limb motor function scores and ramp test scores of the TMP-treated mice improved significantly. HE staining showed that after treatment with TMP, cavities decreased, fewer glial cells proliferated, and fewer inflammatory cells infiltrated; Nielsen staining showed less neuronal loss. Western blot studies showed that compared with the model group, expression of RAS, ERK1/2, RAF1, PI3K, and p-AKT proteins in the spinal cord tissue of mice treated with high-dose TMP was significantly lower. Accordingly, q-PCR studies showed that compared with the model group, the expression levels of RAS, ERK1/2, RAF1, PI3K, and p-AKT genes in the spinal cords of mice in the high-dose TMP group were significantly lower. CONCLUSION: TMP exhibits a good neuroprotective effect after SCI, which may be related to inhibition of the MAPK and PI3K/AKT signaling pathways.

Lymph Node Ratio Enhances Predictive Value for Treatment Outcomes in Patients with Non-Small Cell Lung Cancer Undergoing Surgery: A Retrospective Cohort Study.

Purpose: To compare the prognostic value of lymph node ratio (LNR) and pN in patients with non-small cell lung cancer (NSCLC) undergoing surgery. Materials and methods: NSCLC patients were investigated between 2004 and 2015 from the Surveillance, Epidemiology, and End Results databases. The X-tile software was used to determine LNR cut-off values. Kaplan-Meier analysis was employed to assess cancer-specific survival (CSS) and overall survival (OS). Results: The identified cut-off values of LNR were 0.19 and 0.73. Median CSS for LNR1 (LNR < 0.19), LNR2 (0.19 ≤ LNR ≤ 0.73), and LNR3 (LNR > 0.73) were 71, 41, and 17 months. Both LNR2 (HR = 1.46, 95% CI: 1.36-1.57; P < 0.001) and LNR3 (HR = 2.85, 95% CI: 2.58-3.15; P < 0.001) demonstrated poorer median CSS compared to LNR1. Similarly, median OS for LNR1, LNR2, and LNR3 were 50, 35, and 16 months. LNR2 (HR = 1.36, 95% CI: 1.27-1.45; P < 0.001) and LNR3 (HR = 2.60, 95% CI: 2.37-2.85; P < 0.001) exhibited worse median OS compared to LNR1. A revised pN (r-pN) classification incorporating LNR and pN demonstrated superior penalized goodness-of-fit and discriminative ability in predicting CSS and OS compared to both LNR and pN. Conclusion: LNR outperformed pN in predicting CSS and OS in NSCLC patients undergoing surgery, potentially leading to more precise adjuvant treatment decisions.

Neutrophil extracellular trap-related mechanisms in acne vulgaris inspire a novel treatment strategy with adipose-derived stem cells.

Acne vulgaris is a type of chronic skin disorder caused by Propionibacterium acnes (P. acnes). Neutrophil extrinsic traps (NETs) play key role in many types of inflammatory skin diseases. Adipose-derived stem cells (ADSCs) was reported modulate immune responses and neutrophil activity. Here, we explored the potential role of ADSCs and the potential mechanism associated with neutrophil extracellular traps (NETs) in relieving acne vulgaris. In the P. acnes-infected ear skin model, histological staining was used to evaluate the inflammatory infiltration and NET formation in control, P. acnes, and P. acnes + ADSCs groups. Besides, western blot was used to detect the expression levels of cit-H3, MPO, and Nrf2 in ear tissue. In vitro, the immunofluorescence staining of MPO and cit-H3, and SYTOX green staining were performed to measure the NET formation. CCK-8 assay, EdU staining, and wound healing assay were used to detect the proliferation and migration abilities of keratinocytes. ELISA assay was utilized to detect the secretion of inflammatory cytokines. In P. acnes-infected ear skin, ADSC treatment significantly attenuated inflammation and NET formation via activating Nrf2 signaling pathway. In vitro, the conditioned medium of ADSCs reduced the formation of P. acne-induced NETs. Besides, ADSCs could inhibit that the NETs efficiently promoted the proliferation, migration, and inflammatory cytokine secretion of keratinocytes. Our study suggested that ADSCs could attenuate P. acne-related inflammation by inhibiting NET formation. This study provides a novel therapeutic perspective of ADSCs in combating acne vulgaris.

Treatment Patterns and Survival Outcomes in Patients With Stage T1-2N0M0 Small Cell Lung Cancer Undergoing Surgery: A Retrospective Cohort Study.

Background: The aim of the study was to delineate the treatment modalities and survival outcomes in patients with stage T1-2N0M0 small cell lung cancer (SCLC) who underwent surgery. Methods: SCLC patients from the Surveillance, Epidemiology, and End Results databases between 2000 and 2020 were investigated. Kaplan-Meier survival analysis was employed to assess cancer-specific survival (CSS) and overall survival (OS) across diverse therapeutic strategies. Results: The study included 190 patients. Treatment modalities included surgery alone in 65 patients (34.2%), surgery + chemotherapy in 70 patients (36.8%), surgery + radiotherapy in three patients (1.6%), and surgery + chemoradiotherapy in 52 patients (27.4%). The median CSS remained undetermined for the surgery alone group, whereas it was 123 and 113 months for the surgery + chemotherapy and surgery + chemoradiotherapy groups. Median OS was 47, 84, and 50 months for these groups. Multivariate Cox regression analysis revealed that patients receiving surgery + chemotherapy exhibited a significantly enhanced OS (hazard ratio (HR) = 0.60, 95% confidence interval (CI): 0.38 - 0.94; P = 0.028) compared to those undergoing surgery alone. However, the integration of radiotherapy did not improve OS compared to surgery alone (HR = 0.72, 95% CI: 0.44 - 1.15; P = 0.170). Conclusion: Adjuvant chemotherapy improved OS compared to surgery alone. However, the addition of radiotherapy did not prolong OS.

One-Pot Assembly of Mannose-Capped Lipoarabinomannan Motifs up to 101-Mer from the Mycobacterium tuberculosis Cell Wall.

Lipoarabinomannan (LAM) from the Mycobacterium tuberculosis cell envelope represents important targets for the development of new therapeutic agents against tuberculosis, which is a deadly disease that has plagued mankind for a long time. However, the accessibility of long, branched, and complex lipoarabinomannan over 100-mer remains a long-standing challenge. Herein, we report the modular synthesis of mannose-capped lipoarabinomannan 101-mer from the M. tuberculosis cell wall using a one-pot assembly strategy on the basis of glycosyl ortho-(1-phenylvinyl)benzoates (PVB), which not only accelerates the modular synthesis but also precludes the potential problems associated with one-pot glycosylation with thioglycosides. Shorter sequences including 18-mer, 19-mer, and 27-mer are also synthesized for in-depth structure-activity relationship biological studies. Current synthetic routes also highlight the following features: (1) streamlined synthesis of various linear and branched glycans using one-pot orthogonal glycosylation on the combination of glycosyl N-phenyltrifluoroacetimidates, glycosyl ortho-alkynylbenzoates, and glycosyl PVB; (2) highly stereoselective construction of 10 1,2-cis-arabinofuranosyl linkages using 5-O-(2-quinolinecarbonyl)-directing 1,2-cis-arabinofuranosylation via a hydrogen-bond-mediated aglycone delivery strategy; and (3) convergent [(18 + 19) × 2 + 27] one-pot synthesis of the 101-mer LAM polysaccharide. The present work demonstrates that this orthogonal one-pot glycosylation strategy can highly streamline the chemical synthesis of long, branched, and complex polysaccharides.

Regulatory mechanisms of dopamine metabolism in a marine Meyerozyma guilliermondii GXDK6 under NaCl stress as revealed by integrative multi-omics analysis.

Dopamine can be used to treat depression, myocardial infarction, and other diseases. However, few reports are available on the de novo microbial synthesis of dopamine from low-cost substrate. In this study, integrated omics technology was used to explore the dopamine metabolism of a novel marine multi-stress-tolerant aromatic yeast Meyerozyma guilliermondii GXDK6. GXDK6 was found to have the ability to biosynthesize dopamine when using glucose as the substrate. 14 key genes for the biosynthesis of dopamine were identified by whole genome-wide analysis. Transcriptomic and proteomic data showed that the expression levels of gene AAT2 encoding aspartate aminotransferase (regulating dopamine anabolism) were upregulated, while gene AO-I encoding copper amine oxidase (involved in dopamine catabolism) were downregulated under 10 % NaCl stress compared with non-NaCl stress, thereby contributing to biosynthesis of dopamine. Further, the amount of dopamine under 10 % NaCl stress was 2.51-fold higher than that of zero NaCl, which was consistent with the multi-omics results. Real-time fluorescence quantitative PCR (RT-qPCR) and high-performance liquid chromatography (HPLC) results confirmed the metabolic model of dopamine. Furthermore, by overexpressing AAT2, AST enzyme activity was increased by 24.89 %, the expression of genes related to dopamine metabolism was enhanced, and dopamine production was increased by 56.36 % in recombinant GXDK6AAT2. In conclusion, Meyerozyma guilliermondii GXDK6 could utilize low-cost carbon source to synthesize dopamine, and NaCl stress promoted the biosynthesis of dopamine.

Vulto-van Silfhout-de Vries syndrome caused by de novo variants of DEAF1 gene: a case report and literature review.

Vulto-van Silfhout-de Vries syndrome (VSVS; MIM 615828) is an extremely rare autosomal dominant disorder with unknown incidence. It is always caused by de novo heterozygous pathogenic variants in the DEAF1 gene, which encodes deformed epidermal autoregulatory factor-1 homology. VSVS is characterized by mild to severe intellectual disability (ID) and/or global developmental delay (GDD), seriously limited language expression, behavioral abnormalities, somnipathy, and reduced pain sensitivity. In this study, we present a Chinese boy with moderate GDD and ID, severe expressive language impairment, behavioral issues, autism spectrum disorder (ASD), sleeping dysfunction, high pain threshold, generalized seizures, imbalanced gait, and recurrent respiratory infections as clinical features. A de novo heterozygous pathogenic missense variant was found in the 5th exon of DEAF1 gene, NM_021008.4 c.782G>C (p. Arg261Pro) variant by whole exome sequencing (WES). c.782G>C had not been previously reported in genomic databases and literature. According to the ACMG criteria, this missense variant was considered to be "Likely Pathogenic". We diagnosed the boy with VSVS both genetically and clinically. At a follow-up of 2.1 years, his seizures were well controlled after valproic acid therapy. In addition, the child's recurrent respiratory infections improved at 3.5 years of age, which has not been reported in previous individuals. Maybe the recurrent respiratory infections like sleep problems reported in the literature are not permanent but may improve naturally over time. The literature review showed that there were 35 individuals with 28 different de novo pathogenic variants of DEAF1-related VSVS. These variants were mostly missense and the clinical manifestations were similar to our patient. Our study expands the genotypic and phenotypic profiles of de novo DEAF1.

Opportunities and challenges of computer aided diagnosis in new millennium: A bibliometric analysis from 2000 to 2023.

BACKGROUND: After entering the new millennium, computer-aided diagnosis (CAD) is rapidly developing as an emerging technology worldwide. Expanding the spectrum of CAD-related diseases is a possible future research trend. Nevertheless, bibliometric studies in this area have not yet been reported. This study aimed to explore the hotspots and frontiers of research on CAD from 2000 to 2023, which may provide a reference for researchers in this field. METHODS: In this paper, we use bibliometrics to analyze CAD-related literature in the Web of Science database between 2000 and 2023. The scientometric softwares VOSviewer and CiteSpace were used to visually analyze the countries, institutions, authors, journals, references and keywords involved in the literature. Keywords burst analysis were utilized to further explore the current state and development trends of research on CAD. RESULTS: A total of 13,970 publications were included in this study, with a noticeably rising annual publication trend. China and the United States are major contributors to the publication, with the United States being the dominant position in CAD research. The American research institutions, lead by the University of Chicago, are pioneers of CAD. Acharya UR, Zheng B and Chan HP are the most prolific authors. Institute of Electrical and Electronics Engineers Transactions on Medical Imaging focuses on CAD and publishes the most articles. New computer technologies related to CAD are in the forefront of attention. Currently, CAD is used extensively in breast diseases, pulmonary diseases and brain diseases. CONCLUSION: Expanding the spectrum of CAD-related diseases is a possible future research trend. How to overcome the lack of large sample datasets and establish a universally accepted standard for the evaluation of CAD system performance are urgent issues for CAD development and validation. In conclusion, this paper provides valuable information on the current state of CAD research and future developments.

Adropin inhibits the progression of atherosclerosis in ApoE-/-/Enho-/- mice by regulating endothelial-to-mesenchymal transition.

Adropin, a secreted protein, coded by energy homeostasis-associated gene (Enho), is recently reported to modulate atherogenesis, with endothelial-to-mesenchymal transition (EndMT) involved in the early process. We explored whether adropin may alleviate atherosclerosis by regulating EndMT. We found that an intraperitoneal injection of adropin [105 µg/(kg·d) for 13 weeks] inhibited the progression of high-fat diet (HFD)-induced aortic atherosclerosis in apolipoprotein E-deficient mice (ApoE-/-) and those with double gene deletion (ApoE-/-/Enho-/-), as detected by Oil Red O and haematoxylin-eosin staining. In the aortas of ApoE-/- mouse, adropin treatment ameliorated the decrease in the mRNA expression of endothelial cell markers (leukocyte differentiation antigen 31, CD31, and vascular endothelial cadherin, VE-cadherin), but increased that of EndMT markers (alpha smooth muscle actin, α-SMA, and fibroblasts specific protein-1). In vitro, an adropin treatment (30 ng/ml) arrested the hydrogen peroxide (H2O2)-induced EndMT in human umbilical vein endothelial cells (HUVECs), attenuated the morphological changes of HUVECs, reduced the number of immunofluorescence-positive α-SMA, increased the mRNA and protein expressions of CD31 and VE-cadherin, and decreased those of α-SMA. Furthermore, the adropin treatment decreased the mRNA and protein expressions of transforming growth factor (TGF)-ß1 and TGF-ß2, and suppressed the phosphorylation of downstream signal protein Smad2/3 in HUVECs. These mitigative effects of adropin on H2O2-induced EndMT were reversed by the transfection of TGF-ß plasmid. The findings signify that adropin treatment may alleviate the atherosclerosis in ApoE-/-/Enho-/- mice by inhibiting EndMT via the TGF-ß/Smad2/3 signaling pathway.

Time to change? Present and prospects of hemorrhoidal classification.

As a common benign anal condition, the high incidence and recurrence of hemorrhoids pose challenges for both patients and doctors. The classification of hemorrhoids plays a crucial role in assessing, diagnosing, and treating the condition. By using appropriate classification and corresponding treatment strategies, we can achieve higher cure rates and lower recurrence rates of hemorrhoids. Since the introduction of the Miles classification in 1919, various classifications have been developed, which include objective classifications based on anatomical or instrumental assessment and subjective classifications based on symptoms and patient sensations. These classifications aim to accurately evaluate the condition. In this study, we discuss the evaluation values of each classification in terms of their advantages, disadvantages, treatment relevance, reproducibility, practicality, and assessment value. We also analyze the significant and essential factors, principles of use, and components of assessment indicators of hemorrhoidal classification. This study proposes several strategies to address the limitations of current hemorrhoidal assessment methods. All these will provide a reference for the development regarding the assessment and classification of hemorrhoids and clinical diagnosis and management of hemorrhoids.

Efficacy and safety of allogeneic umbilical cord-derived mesenchymal stem cells for the treatment of complex perianal fistula in Crohn's disease: a pilot study.

OBJECTIVES: The aim of the study was to evaluate the efficacy and safety of allogeneic umbilical cord-derived mesenchymal stem cells (TH-SC01) for complex perianal fistula in patients with Crohn's disease (CD). METHODS: This was an open-label, single-arm clinical trial conducted at Jinling Hospital. Adult patients with complex treatment-refractory CD perianal fistulas (pfCD) were enrolled and received a single intralesional injection of 120 million TH-SC01 cells. Combined remission was defined as an absence of suppuration through an external orifice, complete re-epithelization, and absence of collections larger than 2 cm measured by magnetic resonance imaging (MRI) at 24 weeks after cell administration. RESULTS: A total of 10 patients were enrolled. Six patients (60.0%) achieved combined remission at 24 weeks. The number of draining fistulas decreased in 9 (90.0%) and 7 (70.0%) patients at weeks 12 and 24, respectively. Significant improvement in Perianal Crohn Disease Activity Index, Pelvic MRI-Based Score, Crohn Disease Activity Index, and quality of life score were observed at 24 weeks. No serious adverse events occurred. The probability of remaining recurrence-free was 70% at week 52. CONCLUSION: The study demonstrated that local injection of TH-SC01 cells might be an effective and safe treatment for complex treatment-refractory pfCD after conventional and/or biological treatments fail (ClinicalTrials.gov ID, NCT04939337). TRIAL REGISTRATION: The study was retrospectively registered on www. CLINICALTRIALS: gov (NCT04939337) on June 25, 2021.

BET proteins inhibitor JQ1 impairs GM-CSF-promoted peritoneal macrophage self-renewal and IL-4-induced alternative polarization.

Peritoneal macrophages (PMs), which resided in peritoneal cavity, are crucial to maintain tissue homeostasis and immunity. Macrophage self-renewal and polarization states are critical for PM population homeostasis and function. However, the underlying molecular mechanism that regulates self-renewal and polarization of PMs is still unclear and needs to be explored. Here, we demonstrated that PMs self-renewal was stimulated by granulocyte macrophage colony-stimulating factor (GM-CSF), but not by macrophage colony-stimulating factor (M-CSF). Pharmacological inhibition of Bromodomain & Extraterminal (BET) Proteins by either JQ1 or ARV-825 significantly reduced GM-CSF-dependent peritoneal macrophage self-renewal by abrogating cell proliferation and decreasing self-renewal-related gene expression, such as MYC and Klf4, at transcriptional and protein levels. In addition, transcriptomic analysis showed that JQ1 blocked alternative PMs polarization by downregulating key transcriptional factor IRF4 expression, but not the activation of AKT or STAT6 in PMs. These findings illustrated that the significance of BET family proteins in GM-CSF-induced PMs self-renewal and IL-4-induced alternative polarization.

[Neuroprotective effect of tetramethylpyrazine on mice after spinal cord injury].

This study aims to investigate the neuroprotective effect of tetramethylpyrazine on mice after spinal cord injury and its mechanism. Seventy-five female C57BL/6 mice were randomly divided into 5 groups, namely, a sham operation group, a model group, a tetramethylpyrazine low-dose group(25 mg·kg~(-1)), a tetramethylpyrazine medium-dose group(50 mg·kg~(-1)), and a tetramethylpyrazine high-dose group(100 mg·kg~(-1)), with 15 mice in each group. Modified Rivlin method was used to establish the mouse model of acute spinal cord injury. After 14 d of tetramethylpyrazine intervention, the motor function of hind limbs of mice was evaluated by basso mouse scale(BMS) and inclined plate test. The levels of inflammatory cytokines tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-1ß(IL-1ß) in the spinal cord homogenate were determined by enzyme-linked immunosorbent assay(ELISA). Hematoxylin-eosin(HE) staining was used to observe the histology of the spinal cord, and Nissl's staining was used to observe the changes in the number of neurons. Western blot and immunofluorescence method were used to detect the expression of glial fibrillary acidic protein(GFAP) and C3 protein. Tetramethylpyrazine significantly improved the motor function of the hind limbs of mice after spinal cord injury, and the BMS score and inclined plate test score of the tetramethylpyrazine high-dose group were significantly higher than those of the model group(P<0.01). The levels of TNF-α, IL-6, and IL-1ß in spinal cord homogenate of the tetramethylpyrazine high-dose group were significantly decreased(P<0.01). After tetramethylpyrazine treatment, the spinal cord morphology recovered, the number of Nissl bodies increased obviously with regular shape, and the loss of neurons decreased. As compared with the model group, the expression of GFAP and C3 protein was significantly decreased(P<0.05,P<0.01) in tetramethylpyrazine high-dose group. In conclusion, tetramethylpyrazine can promote the improvement of motor function and play a neuroprotective role in mice after spinal cord injury, and its mechanism may be related to inhibiting inflammatory response and improving the hyperplasia of glial scar.

Macrophages in immunoregulation and therapeutics.

Macrophages exist in various tissues, several body cavities, and around mucosal surfaces and are a vital part of the innate immune system for host defense against many pathogens and cancers. Macrophages possess binary M1/M2 macrophage polarization settings, which perform a central role in an array of immune tasks via intrinsic signal cascades and, therefore, must be precisely regulated. Many crucial questions about macrophage signaling and immune modulation are yet to be uncovered. In addition, the clinical importance of tumor-associated macrophages is becoming more widely recognized as significant progress has been made in understanding their biology. Moreover, they are an integral part of the tumor microenvironment, playing a part in the regulation of a wide variety of processes including angiogenesis, extracellular matrix transformation, cancer cell proliferation, metastasis, immunosuppression, and resistance to chemotherapeutic and checkpoint blockade immunotherapies. Herein, we discuss immune regulation in macrophage polarization and signaling, mechanical stresses and modulation, metabolic signaling pathways, mitochondrial and transcriptional, and epigenetic regulation. Furthermore, we have broadly extended the understanding of macrophages in extracellular traps and the essential roles of autophagy and aging in regulating macrophage functions. Moreover, we discussed recent advances in macrophages-mediated immune regulation of autoimmune diseases and tumorigenesis. Lastly, we discussed targeted macrophage therapy to portray prospective targets for therapeutic strategies in health and diseases.

Stem cell-derived exosomes: emerging therapeutic opportunities for wound healing.

Wound healing is a dynamic and highly sequential process involving a series of overlapping spatial and temporal phases, including hemostasis, inflammation, proliferation, and tissue remodeling. Mesenchymal stem cells (MSCs) are multipotent stem cells with self-renewal, multidirectional differentiation potential, and paracrine regulation. Exosomes are subcellular vesicular components 30-150 nm in size and are novel carriers of intercellular communication in regulating the biological behaviors of skin cells. Compared to MSCs, MSC-derived exosomes (MSC-exos) possess lower immunogenicity, easy storage, and highly effective biological activity. MSC-exos, mainly derived from adipose-derived stem cells (ADSCs), bone marrow-derived MSCs (BMSCs), human umbilical cord MSCs (hUC-MSCs), and other stem cell types, play a role in shaping the activity of fibroblasts, keratinocytes, immune cells, and endothelial cells in diabetic wounds, inflammatory wound repair, and even wound-related keloid formation. Therefore, this study focuses on the specific roles and mechanisms of different MSC-exos in wound healing, as well as the current limitations and various perspectives. Deciphering the biological properties of MSC-exos is crucial to providing a promising cell-free therapeutic tool for wound healing and cutaneous regeneration.

Long-term prognostic value of Murray law-based quantitative flow ratio in jailed left circumflex coronary artery after left main crossover stenting.

We aimed to evaluate the impact of new Murray law-based QFR of jailed left circumflex coronary artery (LCx) on long-term clinical outcomes after left main coronary artery (LM) simple crossover stenting. 164 patients who underwent LM-to-left anterior descending coronary artery simple crossover stenting and had appropriate angiographic view of LCx for QFR computation were enrolled. The primary clinical outcome was the 5-year target lesion failure (TLF), defined as a composite of cardiac death, a target vessel myocardial infarction or target lesion repeat revascularization. The mean QFR of the LCx after LM stent implantation was 0.88 ± 0.09, and 29 patients (17.7%) had a low QFR (< 0.80), which was significantly associated with a higher 5-year rate of TLF when compared with the high QFR group (27.6% vs. 6.7%; HR: 4.235; 95% CI 1.21-14.95; p = 0.0015). The 5-year LCx ostium-related TLR rate in the low QFR group was also higher (17.2% vs. 3.0% in the high QFR group; HR: 6.07, 95% CI 1.63-22.59, p = 0.002). In a multivariate Cox regression analysis, a low QFR in the LCx after LM stenting was an independent predictor of the 5-year TLF rate (HR: 3.21, 95% CI 1.21-8.53; p = 0.019). ROC analysis showed that QFR a negative predictive value (NPV) of 89.6% ([AUC] 0.73, 95% CI 0.58-0.88, p < 0.05), the cutoff point is 0.85. The patients with a low QFR (< 0.80) in jailed LCX after LM simple crossover stenting had worse 5-year outcomes than those with a high QFR. Conversely, a QFR ≥ 0.85 of jailed LCx could serve as a good predictor of low risk of adverse outcome in LCx ostium. The QFR computation of the jailed LCx may be helpful to determine whether an additional procedure is required for the jailed side branch.