M2 macrophage-derived TGF-ß induces age-associated loss of adipogenesis through progenitor cell senescence.

OBJECTIVES: Adipose tissue is an endocrine and energy storage organ composed of several different cell types, including mature adipocytes, stromal cells, endothelial cells, and a variety of immune cells. Adipose tissue aging contributes to the pathogenesis of metabolic dysfunction and is likely induced by crosstalk between adipose progenitor cells (APCs) and immune cells, but the underlying molecular mechanisms remain largely unknown. In this study, we revealed the biological role of p16high senescent APCs, and investigated the crosstalk between each cell type in the aged white adipose tissue. METHODS: We performed the single-cell RNA sequencing (scRNA-seq) analysis on the p16high adipose cells sorted from aged p16-CreERT2/Rosa26-LSL-tdTomato mice. We also performed the time serial analysis on the age-dependent bulk RNA-seq datasets of human and mouse white adipose tissues to infer the transcriptome alteration of adipogenic potential within aging. RESULTS: We show that M2 macrophage-derived TGF-ß induces APCs senescence which impairs adipogenesis in vivo. p16high senescent APCs increase with age and show loss of adipogenic potential. The ligand-receptor interaction analysis reveals that M2 macrophages are the donors for TGF-ß and the senescent APCs are the recipients. Indeed, treatment of APCs with TGF-ß1 induces senescent phenotypes through mitochondrial ROS-mediated DNA damage in vitro. TGF-ß1 injection into gonadal white adipose tissue (gWAT) suppresses adipogenic potential and induces fibrotic genes as well as p16 in APCs. A gWAT atrophy is observed in cancer cachexia by APCs senescence, whose induction appeared to be independent of TGF-ß induction. CONCLUSIONS: Our results suggest that M2 macrophage-derived TGF-ß induces age-related lipodystrophy by APCs senescence. The TGF-ß treatment induced DNA damage, mitochondrial ROS, and finally cellular senescence in APCs.

Indisulam synergizes with melphalan to inhibit Multiple Myeloma malignancy via targeting TOP2A.

Multiple myeloma (MM) is the second most prevalent hematologic malignancy which remains uncurable. Numerous drugs have been discovered to inhibit MM cells. Indisulam, an aryl sulfonamide, has a potent anti-myeloma activity in vitro and in vivo. This study aims to explore the new mechanism of indisulam and investigate its potential use in combination with melphalan. We examined DNA damage in MM cells through various methods such as western blotting (WB), immunofluorescence, and comet assay. We also identified the role of topoisomerase IIα (TOP2A) using bioinformatic analyses. The impact of indisulam on the RNA and protein levels of TOP2A was investigated through qPCR and WB. Cell proliferation and apoptosis were assessed using CCK-8 assays, Annexin V/PI assays and WB. We predicted the synergistic effect of the combination treatment based on calculations performed on a website, and further explored the effect of indisulam in combination with melphalan on MM cell lines and xenografts. RNA sequencing data and basic experiments indicated that indisulam caused DNA damage and inhibited TOP2A expression by decreasing transcription and promoting degradation via the proteasome pathway. Functional experiments revealed that silencing TOP2A inhibited cell proliferation and induced apoptosis and DNA damage. Finally, Indisulam/melphalan combination treatment demonstrated a strong synergistic anti-tumor effect compared to single-agent treatments in vitro and in vivo. These findings suggest that combination therapies incorporating indisulam and melphalan have the potential to enhance treatment outcomes for MM.

Long non-coding RNA LncTUG1 regulates favourable compression force-induced cementocytes mineralization via PU.1/TLR4/SphK1 signalling.

Orthodontic tooth movement (OTM) is a highly coordinated biomechanical response to orthodontic forces with active remodelling of alveolar bone but minor root resorption. Such antiresorptive properties of root relate to cementocyte mineralization, the mechanisms of which remain largely unknown. This study used the microarray analysis to explore long non-coding ribonucleic acids involved in stress-induced cementocyte mineralization. Gain- and loss-of-function experiments, including Alkaline phosphatase (ALP) activity and Alizarin Red S staining, quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunofluorescence analyses of mineralization-associated factors, were conducted to verify long non-coding ribonucleic acids taurine-upregulated gene 1 (LncTUG1) regulation in stress-induced cementocyte mineralization, via targeting the Toll-like receptor 4 (TLR4)/SphK1 axis. The luciferase reporter assays, chromatin immunoprecipitation assays, RNA pull-down, RNA immunoprecipitation, and co-localization assays were performed to elucidate the interactions between LncTUG1, PU.1, and TLR4. Our findings indicated that LncTUG1 overexpression attenuated stress-induced cementocyte mineralization, while blocking the TLR4/SphK1 axis reversed the inhibitory effect of LncTUG1 on stress-induced cementocyte mineralization. The in vivo findings also confirmed the involvement of TLR4/SphK1 signalling in cementocyte mineralization during OTM. Mechanistically, LncTUG1 bound with PU.1 subsequently enhanced TLR4 promotor activity and thus transcriptionally elevated the expression of TLR4. In conclusion, our data revealed a critical role of LncTUG1 in regulating stress-induced cementocyte mineralization via PU.1/TLR4/SphK1 signalling, which might provide further insights for developing novel therapeutic strategies that could protect roots from resorption during OTM.

Integrative analysis of an endoplasmic reticulum stress-related signature in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a malignancy in which plasma cells proliferate abnormally, and it remains incurable. The cells are characterized by high levels of endoplasmic reticulum stress (ERS) and depend on the ERS response for survival. Thus, we aim to find an ERS-related signature of MM and assess its diagnostic value. METHODS: We downloaded three datasets of MM from the Gene Expression Omnibus database. After identifying ERS-related differentially expressed genes (ERDEGs), we analyzed them using Gene Ontology enrichment analysis. A protein-protein interaction network, a transcription factor-mRNA network, a miRNA-mRNA network and a drug-mRNA network were constructed to explore the ERDEGs. The clinical application of these genes was identified by calculating the infiltration of immune cells and using receiver operating characteistic analyses. Finally, qPCR was performed to further confirm the roles of ERDEGs. RESULTS: We obtained nine ERDEGs of MM. Gene Ontology enrichment indicated that the ERDEGs played a role in the endoplasmic reticulum membrane. Additionally, the protein-protein interaction network showed interaction among the ERDEGs, and there were 20 proteins, 107 transcription factors, 42 drugs or molecular compounds and 51 miRNAs which were likely to interact with the nine genes. In addition, immune cell infiltration analyses showed that there was a strong correlation between the nine genes and immune cells, and these potential biomarkers exhibited good diagnostic values. Finally, the expression of ERDEGs in MM cells was different from that in healthy donor samples. CONCLUSION: The nine ERS-related genes, CR2, DHCR7, DNAJC3, KDELR2, LPL, OSBPL3, PINK1, VCAM1 and XBP1 are potential biomarkers of MM, and this supports further clinical development of the diagnosis and treatment of MM.

ATP purinergic receptor signalling promotes Sca-1+ cell proliferation and migration for vascular remodelling.

AIMS: Vascular resident stem cells expressing stem cell antigen-1 (Sca-1+ cells) promote vascular regeneration and remodelling following injury through migration, proliferation and differentiation. The aim of this study was to examine the contributions of ATP signalling through purinergic receptor type 2 (P2R) isoforms in promoting Sca-1+ cell migration and proliferation after vascular injury and to elucidate the main downstream signalling pathways. METHODS AND RESULTS: ATP-evoked changes in isolated Sca-1+ cell migration were examined by transwell assays, proliferation by viable cell counting assays and intracellular Ca2+ signalling by fluorometry, while receptor subtype contributions and downstream signals were examined by pharmacological or genetic inhibition, immunofluorescence, Western blotting and quantitative RT-PCR. These mechanisms were further examined in mice harbouring TdTomato-labelled Sca-1+ cells with and without Sca-1+-targeted P2R knockout following femoral artery guidewire injury. Stimulation with ATP promoted cultured Sca-1+ cell migration, induced intracellular free calcium elevations primarily via P2Y2R stimulation and accelerated proliferation mainly via P2Y6R stimulation. Enhanced migration was inhibited by the ERK blocker PD98059 or P2Y2R-shRNA, while enhanced proliferation was inhibited by the P38 inhibitor SB203580. Femoral artery guidewire injury of the neointima increased the number of TdTomato-labelled Sca-1+ cells, neointimal area and the ratio of neointimal area to media area at 3 weeks post-injury, and all of these responses were reduced by P2Y2R knockdown. CONCLUSIONS: ATP induces Sca-1+ cell migration through the P2Y2R-Ca2+-ERK signalling pathway, and enhances proliferation through the P2Y6R-P38-MAPK signalling pathway. Both pathways are essential for vascular remodelling following injury. Video Abstract.

Sustained delivery of IL-10 by self-assembling peptide hydrogel to reprogram macrophages and promote diabetic alveolar bone defect healing.

OBJECTIVE: Delayed regeneration of alveolar bone defects because of prolonged inflammation under diabetic conditions remains a challenge for dental rehabilitation in clinic, and effective therapies are required. Cytokines-based immuotherapies might be a potential strategy to regulate inflammation and bone regeneration. Here, we report that local delivery of interleukin-10 (IL-10) by injectable self-assembling peptide (SAP) hydrogel is efficient to promote proinflammatory (M1)-to-anti-inflammatory (M2) phenotype conversion, thereby enhancing bone regeneration in diabetic alveolar bone defects. METHODS: Characteristics of SAP hydrogel were evaluated by morphology, injectable and rheological properties. The loading and release of IL-10 from the SAP hydrogel were evaluated over time in culture. The local inflammatory response and bone repair efficacy of the SAP/IL-10 hydrogel was evaluated in vivo using an alveolar bone defect model of diabetic mice. Finally, the direct effects of M2 macrophage on M1 phenotype and mineralization of MSCs were investigated. RESULTS: In vitro, encapsulated IL-10 could be sustainedly released by SAP hydrogel with preserved bioactivities. In vivo, SAP/IL-10 hydrogel showed significantly higher efficacy to attenuate M1 polarization and proinflammatory factors levels, and enhance expressions of osteogenic factors. As a result, diabetic bone regeneration induced by SAP/IL-10 hydrogel was significantly faster. Mechanistically, M2 macrophages induced by sustained IL-10 delivery might promote diabetic bone regeneration by reprogramming M1 phenotype, suppressing local inflammation and enhancing the osteogenic differentiation of mesenchymal stem cells (MSCs). SIGNIFICANCE: This study highlights that the SAP hydrogel is a promising drug delivery platform for treatment of alveolar bone defects, which might have translational potential in future clinical applications.

Mid-Term and Long-Term Outcomes of Peroral Endoscopic Myotomy for the Treatment of Achalasia: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Peroral endoscopic myotomy (POEM) achieves a satisfactory short-term clinical response in patients with achalasia. However, data on mid- and long-term clinical outcomes are limited. We aimed to assess the mid- and long-term efficacy and safety of POEM in achalasia patients. METHODS: Using the pre-designed search strategy, we identified relevant studies that evaluated the efficacy and safety of POEM with a minimum of 2-year follow-up in the Embase, Cochrane, and PubMed databases from inception to January 2021. Primary outcome was pooled mid- and long-term clinical success rate based on the Eckardt score. Secondary outcome was pooled long-term reflux-related adverse events. RESULTS: A total of 21 studies involving 2,698 patients were included. Overall, the pooled clinical success rates with 2-, 3-, 4-, and 5-year follow-ups were 91.3% (95% confidence interval [CI] 88.4-93.6%), 90.4% (95% CI 88.1-92.2%), 89.8% (95% CI 83.6-93.9%), and 82.2% (95% CI 76.6-86.7%), respectively. Besides, the pooled long-term clinical success rates for type I, II, and III achalasia were 86.1% (95% CI 80.9-90.1%; I2 = 0%), 87.9% (95% CI 84.2-90.8%; I2 = 48.354%), and 83.9% (95% CI 72.5-91.2%; I2 = 0%), respectively. Moreover, the pooled incidence of symptomatic reflux and reflux esophagitis was 23.9% (95% CI 18.7-29.9%) and 16.7% (95% CI 11.9-23.1%), respectively. CONCLUSIONS: POEM is associated with a long-term clinical success of 82.2% after 5 years of follow-up. Randomized control trials comparing POEM with laparoscopic Heller myotomy or pneumatic dilation with longer follow-up periods are needed to further demonstrate the long-term safety and efficacy of POEM.

A systematic evaluation of methodological and reporting quality of meta-analysis published in the field of gastrointestinal endoscopy.

BACKGROUND: To evaluate the methodological and reporting quality of published meta-analyses (MAs) in four major gastrointestinal endoscopic journals, and identify the predicted factors for high quality. METHODS: A systematic search was performed in PubMed to identify MAs from 1, January, 2016 to 31, December, 2020 in four major gastrointestinal endoscopic journals (including Digestive Endoscopy, Gastrointestinal Endoscopy, Surgical Endoscopy, and Endoscopy). We collected the characteristics of MAs after filtering unqualified articles, and assessed methodological and reporting qualities for eligible articles by AMSTAR tool and PRISMA checklist, respectively. Logistic regression was used for identifying predictive factors for high quality. RESULTS: A total of 289 MAs were identified after screening by predefined inclusion and exclusion criteria. The scores (mean ± SD) of AMSTAR and PRISMA were 7.73 ± 1.11 and 22.90 ± 1.85, respectively. In PRISMA checklist, some items had less than 50% complete adherence, including item 2 (structured summary), items 5 (protocol and registration), items 12 and 19 (risk of bias in studies), item 27 (funding support). Item 1 (a priori design), item 4 (gray literature research), item 5 (list of included and excluded) were inferior to 50% adherence in AMSTAR tool. We found the predictive factors for high quality through logistic regression analysis: a priori design and funding support were associated with methodological quality. Protocol and registration influenced the methodological and reporting quality closely. CONCLUSION: In general, qualities on the methodology and the reporting of MAs published in the gastrointestinal endoscopic journals are good, but both of which still potentially need further improvement.

Targeting CRL4 suppresses chemoresistant ovarian cancer growth by inducing mitophagy.

Chemoresistance has long been the bottleneck of ovarian cancer (OC) prognosis. It has been shown that mitochondria play a crucial role in cell response to chemotherapy and that dysregulated mitochondrial dynamics is intricately linked with diseases like OC, but the underlying mechanisms remain equivocal. Here, we demonstrate a new mechanism where CRL4CUL4A/DDB1 manipulates OC cell chemoresistance by regulating mitochondrial dynamics and mitophagy. CRL4CUL4A/DDB1 depletion enhanced mitochondrial fission by upregulating AMPKαThr172 and MFFSer172/Ser146 phosphorylation, which in turn recruited DRP1 to mitochondria. CRL4CUL4A/DDB1 loss stimulated mitophagy through the Parkin-PINK1 pathway to degrade the dysfunctional and fragmented mitochondria. Importantly, CRL4CUL4A/DDB1 loss inhibited OC cell proliferation, whereas inhibiting autophagy partially reversed this disruption. Our findings provide novel insight into the multifaceted function of the CRL4 E3 ubiquitin ligase complex in regulating mitochondrial fission, mitophagy, and OC chemoresistance. Disruption of CRL4CUL4A/DDB1 and mitophagy may be a promising therapeutic strategy to overcome chemoresistance in OC.

The scientific progress and prospects of hepatitis C research from 2013 to 2022.

BACKGROUND AND OBJECTIVE: Hepatitis C (HC) is a global health issue, with an estimated 350,000 people dying annually from this liver-related disease. This study determined the development trends and research hotspots regarding HC by investigating the related articles within the past ten years. METHODS: Publications on HC were retrieved from the Web of Science Core Collection (WoSCC) on June 6, 2022. Bibliometric visualization was conducted through VOSviewer and CiteSpace. Original articles and reviews served as the foundation for this analytical research. RESULTS: Of the total 17,773 records of HC research published from 2013 to 2022, the top 1,000 articles were retrieved and distributed among 78 countries and 270 journals. The US, where 7 of the top 10 institutions were located, mainly contributed to the study (51.9%). Johns Hopkins University distributed the most related articles (45 articles). Hepatology (IF 2021 = 17.298) ranked first, with 109 articles in the top 10 journals. Dore GJ was the most productive author (40 articles). The keywords of sustained virologic response, therapy, sofosbuvir, cirrhosis, ledipasvir, and hepatocellular carcinoma offered hints regarding research hotspots. The burst keywords regarding the virus, like HCV, HIV, and care and intervention showed as research frontiers. CONCLUSIONS: Treatment has been a trending topic in HC research, and future research may focus more on HCV and HIV co-infection, treatment, and elimination of HC.

Endoscopic ultrasound-guided tissue acquisition for splenic lesions: A systematic review and meta-analysis of diagnostic test accuracy.

BACKGROUND AND AIMS: At present, it is difficult and risky to diagnose splenic lesions by conventional needle biopsy using computed tomography (CT) or ultrasound (US). Endoscopic ultrasound (EUS)-guided tissue acquisition is increasingly being used as a new technique to determine the tissue diagnosis of splenic lesions. Therefore, our goal was to determine the efficacy and safety of EUS-guided tissue acquisition for splenic lesions. METHODS: We performed a systematic review and meta-analysis to evaluate the pooled sensitivity and specificity of EUS-guided tissue acquisition for the diagnosis of splenic lesions using Metadisc. The Quality Assessment of Diagnostic Accuracy Studies Questionnaire, a quality assessment tool, was used to scrutinize the quality of the studies. RESULTS: Six eligible studies between January 2000 and June 2022 were identified, and a total number of 62 patients (aged range from 19 to 84) were enrolled. One patient was excluded because of insufficient specimens. The pooled sensitivity and specificity of included studies were 0.85 [95% confidence interval (CI), 0.73-0.93] and 0.77 (95% CI, 0.46-0.95), respectively. The pooled positive likelihood ratio (LR) was 2.38 (95% CI, 1.24-4.57), the pooled negative LR was 0.31 (95% CI, 0.17-0.55), the pooled diagnostic odds ratio (DOR) was 8.67 (95% CI, 2.80-26.82), the area under the summary receiver operating characteristic (SROC) curve was 0.8100 (Standard Error 0.0813). CONCLUSION: EUS-guided tissue acquisition is a safe technique with high sensitivity in the diagnosis of splenic lesions. However, because of the small sample sizes, more studies with more cases are needed to further validate these results.

Combination treatment with hENT1 and miR-143 reverses gemcitabine resistance in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer and is susceptible to develop gemcitabine (GEM) resistance. Decreased expression of human equilibrative nucleoside transporter 1 (hENT1) accompanied by compensatory increase of glycolysis is strongly associated with GEM resistance in TNBC. In this study, we investigated the treatment feasibility of combined hENT1 upregulation and miR-143-mediated inhibition of glycolysis for reversing GEM resistance in TNBC. METHODS: Experiments were performed in vitro and in vivo to compare the efficacy of GEM therapies. In this study, we established stable drug-resistant cell line, GEM-R cells, from parental cells (MDA-MB-231) through exposure to GEM following a stepwise incremental dosing strategy. Then GEM-R cells were transfected by lentiviral plasmids and GEM-R cells overexpressing hENT1 (GEM-R-hENT1) were established. The viability and apoptosis of wild-type (MDA-MB-231), GEM-R, and GEM-R-hENT1 cells treated with GEM or GEM + miR-143 were analyzed by CCK8 assay and flow cytometry. The RNA expression and protein expression were measured by RT-PCR and western blotting respectively. GEM uptake was determined by multiple reaction monitoring (MRM) analysis. Glycolysis was measured by glucose assay and 18F-FDG uptake. The antitumor effect was assessed in vivo in a tumor xenograft model by evaluating toxicity, tumor volume, and maximum standardized uptake value in 18F-FDG PET. Immunohistochemistry and fluorescence photography were taken in tumor samples. Pairwise comparisons were performed using Student's t-test. RESULTS: Our results represented that overexpression of hENT1 reversed GEM resistance in GEM-R cells by showing lower IC50 and higher rate of apoptosis. MiR-143 suppressed glycolysis in GEM-R cells and enhanced the effect of reversing GEM resistance in GEM-R-hENT1 cells. The therapeutic efficacy was validated using a xenograft mouse model. Combination treatment decreased tumor growth rate and maximum standardized uptake value in 18F-FDG PET more effectively. CONCLUSIONS: Combined therapy of exogenous upregulation of hENT1 expression and miR-143 mimic administration was effective in reversing GEM resistance, providing a promising strategy for treating GEM-resistant TNBC.

Endoscopic ultrasound-guided drainage of pelvic abscess: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: As an emerging minimally invasive technology, endoscopic ultrasound (EUS) has been reported to treat pelvic abscess instead of surgical or image-guided percutaneous drainage (PCD) under certain conditions. The aim of this study was to assess the efficacy and safety of EUS-guided drainage for patients with pelvic abscesses. METHODS: We conducted a comprehensive literature search on PubMed, Embase, Cochrane Library, and Web of Science databases (inception-March 2022). The main outcomes were technical success, clinical success, and complications. Comprehensive meta-analysis software was used to calculate the pooled event rate. RESULTS: Twelve studies containing 272 patients were included. These pelvic abscesses most frequently developed after abdominal and pelvic surgery (n = 180, 66.2%), inflammatory bowel disease (n = 32, 11.8%), and other inflammatory conditions. Respectively, the pooled technical and clinical success rate was 100% and 88.7% [95% confidence interval (CI): 83.8-92.2%, I2 = 1.0%, p < 0.001]. After excluding an individual study, the pooled rate of complications changed from 11.5% (95% CI: 7.4-17.4%, I2 = 38.8%, p < 0.001) to 8.2% (95% CI: 5.0-13.3%, I2 = 0, p < 0.001). CONCLUSIONS: EUS-guided drainage of the pelvic abscess was feasible, effective, and safe. Further randomized-controlled studies with large-sample sizes were required in the future.

SPAG5 as a novel biomarker and potential therapeutic target via regulating AKT pathway in multiple myeloma.

SPAG5, as a spindle-associated protein in mitosis, has been observed to have oncogenic activities in solid tumors. Here, we identified that SPAG5 expression was correlated with the deterioration of plasma cell malignancy and SPAG5 overexpression (OE) predicted unfavorable outcomes in multiple myeloma (MM). SPAG5 knockdown led to anti-MM effects in MM cell lines and animal xenograft models by regulating cell growth and apoptosis. Furthermore, gene set enrichment analysis (GSEA) revealed that PI3K/AKT/mTOR pathway was enriched in MM samples with highly expressed SPAG5 from GSE datasets. There was a concurrent downregulation of phosphorylation levels in the AKT/mTOR pathway. Yet OE of SPAG5 could restore the cell growth and p-AKT levels in MM cells after treatment with the AKT inhibitor MK2206. Taken together, SPAG5 could serve as a novel biomarker, and targeting the SPAG5 might have therapeutic potential in MM.

An analysis of retracted articles in the field of pancreatic diseases.

BACKGROUND: Review of retracted articles has a positive impact on scientific research. The aim of our study was to examine the characteristics of retracted articles in the field of pancreatic diseases. METHODS: The Retraction Watch database was queried for retractions in pancreatic diseases on 7 March 2021, and the filters set were as follows: (1) the Title typed in was "pancreatitis", "pancreas", or "pancreatic"; (2) the Nature of notice selected was "retraction". RESULTS: A total of 116 retracted articles were identified as pancreatic disease-related, with over two-thirds of them pertaining to pancreatic cancer. Research article was the most common article type among these retractions. Common reasons given for retraction included scientific fraud (37.1%), duplication (26.7%), and reliability (25%). China had the largest number of retractions (n=51), followed by the United States (n=47). Most articles were retracted in recent years, particularly after 2015. CONCLUSIONS: A large proportion of retracted articles pertaining to pancreatic diseases have been retracted in recent years. The majority of publications-over three quarters-were retracted for authors who committed some type of misconduct. Differences between countries in the manner of misconduct were stark.

The role of peroral endoscopic myotomy for Zenker's diverticulum: a systematic review and meta-analysis.

BACKGROUND: Zenker's peroral endoscopic myotomy (Z-POEM) has revolutionized the therapeutic strategy for Zenker's diverticulum (ZD) with promising results. We conducted this meta-analysis to estimate the safety and efficacy of Z-POEM for ZD and compare the feasibility and effectiveness of Z-POEM with that of flexible endoscopic septotomy (FES). METHODS: A comprehensive literature search was conducted in PubMed, EMBASE, Web of Science, and Cochrane Library databases to query for studies that assessed the safety and efficacy of Z-POEM for ZD. All articles published from inception to July 31, 2021 were included. The primary outcomes were the overall technical success rate, clinical success rate, incidence of adverse events, and clinical recurrence rate. RESULTS: Eleven studies involving 357 patients undergone Z-POEM were included. Overall, the quality of included studies was above average, with five studies rated as high quality and six ranked as moderate quality. The overall pooled technical success rate for Z-POEM was 96.3% (95% confidence interval [CI] 93.6-97.9%; I2 = 0%). The total pooled clinical success rate for Z-POEM was 93.0% (95% CI 89.4-95.4%; I2 = 0%). The pooled incidence of adverse events for Z-POEM was 12.4% (95% CI 9.1-16.7%; I2 = 0%). The pooled clinical recurrence rate for Z-POEM was 11.2% (95% CI 7.6-16.2%; I2 = 0%). The clinical success for Z-POEM was significantly better than that of FES (relative risk [RR]: 1.11; CI 95% 1.03-1.18; p = 0.004, I2 = 0%), while there were no significant differences in technical success, adverse events, and clinical recurrence between Z-POEM and FES. CONCLUSION: Z-POEM could be an effective and safe therapeutic modality for ZD, and even has a slightly higher clinical success rate than FES. However, comparative studies with long-term follow-up will be needed to further confirm our finding.

Metformin-loaded ß-TCP/CTS/SBA-15 composite scaffolds promote alveolar bone regeneration in a rat model of periodontitis.

Periodontitis is a progressive infectious inflammatory disease, which leads to alveolar bone resorption and loss of periodontal attachment. It is imperative for us to develop a therapeutic scaffold to repair the alveolar bone defect of periodontitis. In this study, we designed a new composite scaffold loading metformin (MET) by using the freeze-drying method, which was composed of ß-tricalcium phosphate (ß-TCP), chitosan (CTS) and the mesoporous silica (SBA-15). The scaffolds were expected to combine the excellent biocompatibility of CTS, the good bioactivity of ß-TCP, and the anti-inflammatory properties of MET. The MET-loaded ß-TCP/CTS/SBA-15 scaffolds showed improved cell adhesion, appropriate porosity and good biocompatibility in vitro. This MET composite scaffold was implanted in the alveolar bone defects area of rats with periodontitis. After 12 weeks, Micro-CT and histological analysis were performed to evaluate different degrees of healing and mineralization. Results showed that the MET-loaded ß-TCP/CTS/SBA-15 scaffolds promoted alveolar bone regeneration in a rat model of periodontitis. To our knowledge, this is the first report that MET-loaded ß-TCP/CTS/SBA-15 scaffolds have a positive effect on alveolar bone regeneration in periodontitis. Our findings might provide a new and promising strategy for repairing alveolar bone defects under the condition of periodontitis.

JaponiconeA induces apoptosis of bortezomib-sensitive and -resistant myeloma cells in vitro and in vivo by targeting IKK.

OBJECTIVE: Multiple myeloma (MM) remains incurable with high rates of relapse. New therapeutic drugs are therefore urgently needed to improve the prognosis. JaponiconeA (JA), a natural product isolated from Inula japonica Thunb, has shown good anti-MM potential. A comprehensive study should therefore be conducted to identify both the in vitro and in vivo mechanisms of the anti-MM effects of JA. METHODS: CCK8 assays and flow cytometry were used to detect the proliferation, apoptosis, and cell cycle of MM cell lines when treated with JA. In vivo experiments were conducted using subcutaneous xenograft mouse models. We also identified possible targets and the mechanism of JA using RNA-seq and c-Map databases, and identified the specific targets of JA in bortezomib-sensitive and -resistant MM cell lines using CETSA, DARTS, and rescue experiments. Furthermore, JA and bortezomib were used separately or together to characterize their possible synergistic effects. RESULTS: In vitro, JA inhibited proliferation, and induced apoptosis and G2/M phase arrest in MM cell lines, and selectively killed primary CD138+ MM cells. In vivo, JA also demonstrated a strong anti-tumor effect with no observable toxicity. In addition, JA showed synergetic effects in combination with bortezomib, and enhanced the anti-tumor effect of bortezomib in bortezomib-resistant cells. CETSA and DARTS confirmed direct binding of JA to NF-κB inhibitor kinase beta (IKKß), and overexpression of IKKß or knockdown of IκBα partially rescued the apoptosis induced by JA. CONCLUSIONS: JA exhibited strong anti-tumor effects in MM. It sensitized myeloma cells to bortezomib and overcame NF-κB-induced drug resistance by inhibiting IKKß, providing a new treatment strategy for MM patients.

Exosomes derived from plasma: promising immunomodulatory agents for promoting angiogenesis to treat radiation-induced vascular dysfunction.

Ionizing radiation (IR)-induced vascular disorders slow down tissue regeneration. Exosomes derived from plasma exhibit potential to promote angiogenesis; meanwhile, the immune microenvironment plays a significant role in the process. This study aimed to test the hypothesis that plasma exosomes promote angiogenesis in irradiated tissue by mediating the immune microenvironment. First, we explored the impact of IR on macrophages. We found that cell viability and capacity for promoting angiogenesis were decreased in irradiated macrophages compared to control macrophages. Then, we isolated and characterized rat plasma-derived exosomes (RP-Exos) which were defined as 40-160 nm extracellular vesicles extracted from rat plasma. Afterward, we evaluated the effects of RP-Exos on the behaviors of irradiated macrophages. Our results show that RP-Exos promoted cell proliferation. More importantly, we found that RP-Exos stimulated the immune microenvironment in a manner that improved the angiogenesis-related genes and proteins of irradiated macrophages. The supernatant of macrophage cell cultures was used as conditioned medium to treat human primary umbilical vein endothelial cells, further confirming the pro-angiogenic ability of macrophages receiving RP-Exo intervention. RP-Exos were used in vivo to treat irradiated skin or calvarial defects in irradiated Sprague-Dawley male rats. The results indicated the ability of RP-Exos to enhance angiogenesis and promote tissue regeneration. Our research suggested the potential of plasma exosomes to be used as immunomodulatory agents with angiogenic capacity to treat radiation-associated vascular disorders and facilitate tissue repair.

Oral Health, Caries Risk Profiles, and Oral Microbiome of Pediatric Patients with Leukemia Submitted to Chemotherapy.

BACKGROUND: Chemotherapy is the primary treatment modality used for patients with acute lymphoblastic leukemia (ALL), but inevitably causes microbiota-related oral complications. This study is aimed at investigating the effects of chemotherapy on oral health status, caries risk, and oral microbiome in pediatric patients with ALL. METHODS: Thirty-nine children with ALL receiving chemotherapy were enrolled, and a gender-, age-, dentition stage, and socioeconomic class matched healthy counterpart were recruited. Demographic information and overall health condition were obtained through the questionnaire and medical records. Oral examination was performed to assess caries and salivary status, plaque index, and other oral manifestations. Cariogram was used to assess the overall caries risk. Supragingival samples of thirteen ALL subjects and their counterparts were randomly selected to perform a 16S ribosomal RNA gene 454 pyrosequencing. Raw sequence data were screened, trimmed, and filtered using Seqcln and MOTHUR. RESULTS: The prevalence of dental caries, gingivitis, oral mucositis, xerostomia, and candidiasis in ALL groups was higher than that of the control group (p < 0.05). Children with ALL demonstrated higher caries risk compared to healthy controls (HC) based upon Cariogram (p < 0.05). The oral microbial structure of ALL patients receiving chemotherapy is different from that of healthy controls. Oral microbiota of ALL groups showed less alpha diversity and significant differences in the composition of the oral microbiome compared to healthy controls. CONCLUSIONS: ALL patients receiving chemotherapy demonstrated compromised oral health, high caries risk, alteration of caries-related factors, and dysbiosis of oral microbiota. These findings may be of clinical importance in developing better strategies for personalized preventive management of oral diseases for pediatric children with ALL.