Combination of aloe emodin, emodin, and rhein from Aloe with EDTA sensitizes the resistant Acinetobacter baumannii to polymyxins.

Background: The continuous emergence and spread of polymyxin-resistant Acinetobacter baumannii pose a significant global health challenge, necessitating the development of novel therapeutic strategies. Aloe, with its long-standing history of medicinal use, has recently been the subject of substantial research for its efficacy against pathogenic infections. Methods: This study investigates the potential application of anthraquinone components in aloe against polymyxin-resistant A. baumannii by liquid chromatography-mass spectrometry, in vitro activity assessment, and construction of animal infection models. Results: The findings demonstrate that aloe emodin, emodin, rhein, and their mixtures in equal mass ratios (EAR) exhibit strain-specific antibacterial activities against polymyxin-resistant A. baumannii. Co-administration of EAR with EDTA synergistically and universally enhanced the antibacterial activity and bactericidal efficacy of polymyxins against polymyxin-resistant A. baumannii, while also reducing the frequency of polymyxin-resistant mutations in polymyxinssensitive A. baumannii. Following toxicity assessment on human hepatic and renal cell lines, the combination therapy was applied to skin wounds in mice infected with polymyxin-resistant A. baumannii. Compared to monotherapy, the combination therapy significantly accelerated wound healing and reduced bacterial burden. Conclusions: The combination of EAR and EDTA with polymyxins offers a novel therapeutic approach for managing skin infections caused by polymyxinresistant A. baumannii.

Spatial transcriptomic analysis deciphers adipocyte-to-fibroblast transformation in bleomycin-induced murine skin fibrosis.

BACKGROUND: Scleroderma is characterized by inflammation and fibrosis, predominantly occurring in the skin and extending to various parts of the body. The pathophysiology of scleroderma is multifaceted, with the current understanding including endothelial damage, inflammatory cell infiltration, and fibroblast activation in its progression. Nonetheless, the mechanism of cellular interactions and the precise spatial distribution of these cellular events within the fibrotic tissues remain elusive, highlighting a critical gap in our comprehensive understanding of scleroderma's pathogenesis. METHODS: In this study, we administered bleomycin intradermally to the dorsal skin of four individual murine models. Subsequently, skin tissues were harvested at predetermined intervals for comprehensive spatial transcriptomic analysis to determine the spatial dynamics influencing scleroderma pathogenesis. To validate the possible results from bioinformatic analysis, further in vitro and in vivo experiments were conducted. RESULTS: Analysis of the spatial transcriptome revealed significant alterations in cell clusters during the progression of scleroderma. Gene Ontology analysis identified disruptions in lipid metabolism as the disease advanced. Pseudotime analysis provided evidence for a phenotypic transition from adipocytes to fibroblasts. In vitro studies demonstrated increased expression of Col1a1 and α-SMA as the disease progressed. These fibroblasts have been identified as key contributors to the increasing inflammation. Co-culturing TGF-ß induced adipocytes with RAW264.7 cells resulted in overexpression of pro-inflammatory cytokines in the RAW264.7 cells. Both in vitro and in vivo experiments confirmed adipocyte loss and fibroblast formation, with transformed fibroblasts showing pronounced pro-inflammatory characteristics, highlighting their crucial role in the disease mechanism. CONCLUSIONS: Our study showed the spatial distribution and dynamic alterations of various cell types during scleroderma progression. Crucially, we identified the transformation of adipocytes into fibroblasts as a key factor promoting disease advancement. These emergent fibroblasts intensify inflammation, indicating that research on these cell clusters could reveal key scleroderma mechanisms and guide future therapies.

Advanced glycation end products mediate biomineralization disorder in diabetic bone disease.

Patients with diabetes often experience fragile fractures despite normal or higher bone mineral density (BMD), a phenomenon termed the diabetic bone paradox (DBP). The pathogenesis and therapeutics opinions for diabetic bone disease (DBD) are not fully explored. In this study, we utilize two preclinical diabetic models, the leptin receptor-deficient db/db mice (DB) mouse model and the streptozotocin-induced diabetes (STZ) mouse model. These models demonstrate higher BMD and lower mechanical strength, mirroring clinical observations in diabetic patients. Advanced glycation end products (AGEs) accumulate in diabetic bones, causing higher non-enzymatic crosslinking within collagen fibrils. This inhibits intrafibrillar mineralization and leads to disordered mineral deposition on collagen fibrils, ultimately reducing bone strength. Guanidines, inhibiting AGE formation, significantly improve the microstructure and biomechanical strength of diabetic bone and enhance bone fracture healing. Therefore, targeting AGEs may offer a strategy to regulate bone mineralization and microstructure, potentially preventing the onset of DBD.

Metabolomic landscape of renal cell carcinoma in von Hippel-Lindau syndrome in a Chinese cohort.

Von Hippel-Lindau (VHL) syndrome is a rare autosomal dominant disorder, where renal cell carcinoma (RCC) serves as a significant cause of mortality. We collected peripheral blood from 61 VHL-RCC patients and 31 healthy individuals, along with 19 paired RCC tumor and adjacent non-malignant samples. Using liquid chromatography-mass spectrometry, we identified 238 plasma and 241 tissue differentially abundant metabolites (DAMs), highlighting key pathways such as arginine and proline metabolism. The top 10 of the 23 DAMs, common to both plasma and tissue, were instrumental in constructing a high-performance diagnostic model. These DAMs demonstrated significant correlations with VHL gene mutation types. Cox regression analysis revealed that plasma levels of N2,N2-dimethylguanosine were associated with the timing of RCC onset in VHL patients, acting as an independent predictive factor. This study enhances diagnostic accuracy for this rare condition and opens new avenues for exploring metabolic mechanisms of the disease and potential therapeutic directions.

Two natural compounds as potential inhibitors against the Helicobacter pylori and Acinetobacter baumannii IspD enzymes.

In a vast majority of bacteria, protozoa and plants, the methylerythritol phosphate (MEP) pathway is utilized for the synthesis of isopentenyl diphosphate (IDP) and dimethylallyl diphosphate (DMADP), which are precursors for isoprenoids. Isoprenoids, such as cholesterol and coenzyme Q, play a variety of crucial roles in physiological activities, including cell-membrane formation, protein degradation, cell apoptosis, and transcription regulation. In contrast, humans employ the mevalonate (MVA) pathway for the production of IDP and DMADP, rendering proteins in the MEP pathway appealing targets for antimicrobial agents. This pathway consists of seven consecutive enzymatic reactions, of which 4-diphosphocytidyl-2C-methyl-D-erythritol synthase (IspD) and 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (IspF) catalyze the third and fifth steps, respectively. In this study, we characterized the enzymatic activities and protein structures of Helicobacter pylori IspDF and Acinetobacter baumannii IspD. Then, using the direct interaction-based thermal shift assay, we conducted a compound screening of an approved drug library and identified 27 hit compounds potentially binding to AbIspD. Among them, two natural products, rosmarinic acid and tanshinone IIA sodium sulfonate, exhibited inhibitory activities against HpIspDF and AbIspD, by competing with one of the substrates, MEP. Moreover, tanshinone IIA sodium sulfonate also demonstrated certain antibacterial effects against H. pylori. In summary, we identified two IspD inhibitors from approved ingredients, broadening the scope for antibiotic discovery targeting the MEP pathway.

Alteration of bacterial community composition in the sediments of an urban artificial river caused by sewage discharge.

Background: Urbanization has an ecological and evolutionary effect on urban microorganisms. Microorganisms are fundamental to ecosystem functions, such as global biogeochemical cycles, biodegradation and biotransformation of pollutants, and restoration and maintenance of ecosystems. Changes in microbial communities can disrupt these essential processes, leading to imbalances within ecosystems. Studying the impact of human activities on urban microbes is critical to protecting the environment, human health, and overall urban sustainability. Methods: In this study, bacterial communities in the sediments of an urban artificial river were profiled by sequencing the 16S rRNA V3-V4 region. The samples collected from the eastern side of the Jiusha River were designated as the JHE group and were marked by persistent urban sewage discharges. The samples collected on the western side of the Jiusha River were categorized as the JHW group for comparative analysis. Results: The calculated alpha diversity indices indicated that the bacterial community in the JHW group exhibited greater species diversity and evenness than that of the JHE group. Proteobacteria was the most dominant phylum between the two groups, followed by Bacteroidota. The relative abundance of Proteobacteria and Bacteroidota accumulated in the JHE group was higher than in the JHW group. Therefore, the estimated biomarkers in the JHE group were divided evenly between Proteobacteria and Bacteroidota, whereas the biomarkers in the JHW group mainly belonged to Proteobacteria. The Sulfuricurvum, MND1, and Thiobacillus genus were the major contributors to differences between the two groups. In contrast to JHW, JHE exhibited higher enzyme abundances related to hydrolases, oxidoreductases, and transferases, along with a prevalence of pathways associated with carbohydrate, energy, and amino acid metabolisms. Our study highlights the impact of human-induced water pollution on microorganisms in urban environments.

piRNA mmu_piR_037459 suppression alleviated the degeneration of chondrocyte and cartilage.

OBJECTIVE: Osteoarthritis (OA) is a prevalent chronic degenerative joint ailment. Its primary pathological characteristics encompass degeneration of articular cartilage, inflammation of the synovium, and alterations in the subchondral bone proximate to the cartilage. Chondrocytes, as the sole cell type within articular cartilage, assume a crucial role in upholding the dynamic equilibrium between anabolic and catabolic processes within the extracellular matrix of articular cartilage. IL-1ß stands as a pivotal inflammatory factor that instigates cartilage degeneration. piRNA, categorized as a subset of brief non-coding RNAs spanning nucleotide lengths of 26-31nt, assumes a significant regulatory role in cellular function. METHODS: Small RNA sequencing and quantitative PCR (qPCR) were employed to investigate the impact of the inflammatory factor IL-1ß on piRNA expression within chondrocytes. The regulation of mmu_piR_037459 expression in chondrocytes was achieved using piRNA mimics and inhibitors. Additionally, collagen II expression was assessed through both qPCR and Western blot analysis. Chondrocyte apoptosis was evaluated via flow cytometry and clonogenesis assays. To assess the influence of mmu_piR_037459 on osteoarthritis, a mouse model of anterior cruciate ligament transection (ACLT) was established. Furthermore, the regulatory effect of mmu_piR_037459 on USP7 was investigated using bioinformatics and a luciferase reporter gene assay. RESULTS: mmu_piR_037459 inhibited the expression of collagen II in chondrocytes, inhibited the proliferation of chondrocytes, and promoted the apoptosis of chondrocytes. mmu_piR_037459 affected the function of chondrocytes by regulating the expression of USP7. Inhibition of mmu_piR_037459 expression could promote chondrocyte proliferation, inhibit chondrocyte apoptosis, and alleviate the degeneration of OA cartilage. CONCLUSIONS: This study suggests that mmu_piR_037459 maybe a new therapeutic targets and strategies for the treatment of OA.

PiRNA hsa_piR_019949 promotes chondrocyte anabolic metabolism by inhibiting the expression of lncRNA NEAT1.

BACKGROUND: Osteoarthritis is a prevalent degenerative joint condition typically found in individuals who are aged 50 years or older. In this study, the focus is on PIWI-interacting RNA (piRNA), which belongs to a category of small non-coding RNAs. These piRNAs play a role in the regulation of gene expression and the preservation of genomic stability. The main objective of this research is to examine the expression of a specific piRNA called hsa_piR_019949 in individuals with osteoarthritis, to understand its impact on chondrocyte metabolism within this condition. METHODS: We analyzed piRNA expression in osteoarthritis cartilage using the GEO database. To understand the impact of inflammatory factors on piRNA expression in chondrocytes, we conducted RT-qPCR experiments. We also investigated the effect of piRNA hsa_piR_019949 on chondrocyte proliferation using CCK-8 and clone formation assays. Furthermore, we assessed the influence of piRNA hsa_piR_019949 on chondrocyte apoptosis by conducting flow cytometry analysis. Additionally, we examined the differences in cartilage matrix composition through safranine O staining and explored the downstream regulatory mechanisms of piRNA using transcriptome sequencing. Lentiviral transfection of NEAT1 and NLRP3 was performed to regulate the metabolism of chondrocytes. RESULTS: Using RNA sequencing technology, we compared the gene expression profiles of 5 patients with osteoarthritis to 3 normal controls. We found a gene called hsa_piR_019949 that showed differential expression between the two groups. Specifically, hsa_piR_019949 was downregulated in chondrocytes when stimulated by IL-1ß, an inflammatory molecule. In further investigations, we discovered that overexpression of hsa_piR_019949 in vitro led to increased proliferation and synthesis of the extracellular matrix in chondrocytes, which are cells responsible for cartilage formation. Conversely, suppressing hsa_piR_019949 expression resulted in increased apoptosis (cell death) and degradation of the extracellular matrix in chondrocytes. Additionally, we found that the NOD-like receptor signaling pathway is linked to the low expression of hsa_piR_019949 in a specific chondrocyte cell line called C28/I2. Furthermore, we observed that hsa_piR_019949 can inhibit the expression of a long non-coding RNA called NEAT1 in chondrocytes. We hypothesize that NEAT1 may serve as a downstream target gene regulated by hsa_piR_019949, potentially influencing chondrocyte metabolism and function in the context of osteoarthritis. CONCLUSIONS: PiRNA hsa_piR_019949 has shown potential in promoting the proliferation of chondrocytes and facilitating the synthesis of extracellular matrix in individuals with osteoarthritis. This is achieved by inhibiting the expression of a long non-coding RNA called NEAT1. The implication is that by using hsa_piR_019949 mimics, which are synthetic versions of the piRNA, as a therapeutic approach, it may be possible to effectively treat osteoarthritis.

Proguanil and chlorhexidine augment the antibacterial activities of clarithromycin and rifampicin against Acinetobacter baumannii.

The emergence of Acinetobacter baumannii infections as a significant healthcare concern in hospital settings, coupled with their association with poorer clinical outcomes, has prompted extensive investigation into novel therapeutic agents and innovative treatment strategies. Proguanil and chlorhexidine, both categorized as biguanide compounds, have displayed clinical efficacy as antimalarial and topical antibacterial agents, respectively. In this study, we conducted an investigation to assess the effectiveness of combining proguanil and chlorhexidine with clarithromycin or rifampicin against both laboratory strains and clinical isolates of A. baumannii. The combination therapy demonstrated rapid bactericidal activity against planktonic multidrug-resistant A. baumannii, exhibiting efficacy in eradicating mature biofilms and impeding the development of antibiotic resistance in vitro. Additionally, when administered in conjunction with clarithromycin or rifampicin, proguanil enhanced the survival rate of mice afflicted with intraperitoneal A. baumannii infections, and chlorhexidine expedited wound healing in mice with skin infections. These findings are likely attributable to the disruption of A. baumannii cell membrane integrity by proguanil and chlorhexidine, resulting in heightened membrane permeability and enhanced intracellular accumulation of clarithromycin and rifampicin. Overall, this study underscores the potential of employing proguanil and chlorhexidine in combination with specific antibiotics to effectively combat A. baumannii infections and improve treatment outcomes in clinically challenging scenarios.

Genetic components of Escherichia coli involved in its complex prey-predator interaction with Myxococcus xanthus.

Myxococcus xanthus and Escherichia coli represent a well-studied microbial predator-prey pair frequently examined in laboratory settings. While significant progress has been made in comprehending the mechanisms governing M. xanthus predation, various aspects of the response and defensive mechanisms of E. coli as prey remain elusive. In this study, the E. coli MG1655 large-scale chromosome deletion library was screened, and a mutant designated as ME5012 was identified to possess significantly reduced susceptibility to predation by M. xanthus. Within the deleted region of ME5012 encompassing seven genes, the significance of dusB and fis genes in driving the observed phenotype became apparent. Specifically, the deletion of fis resulted in a notable reduction in flagellum production in E. coli, contributing to a certain level of resistance against predation by M. xanthus. Meanwhile, the removal of dusB in E. coli led to diminished inducibility of myxovirescin A production by M. xanthus, accompanied by a slight decrease in susceptibility to myxovirescin A. These findings shed light on the molecular mechanisms underlying the complex interaction between M. xanthus and E. coli in a predatory context.

Changes in the small noncoding RNA transcriptome in osteosarcoma cells.

BACKGROUND: Osteosarcoma has the highest incidence among bone malignant tumors and mainly occurs in adolescents and the elderly, but the pathological mechanism is still unclear, which makes early diagnosis and treatment very difficult. Bone marrow mesenchymal stem cells (BMSCs) are considered to be one of the sources of osteosarcoma cells. Therefore, a full understanding of the gene expression differences between BMSCs and osteosarcoma cells is very important to explore the pathogenesis of osteosarcoma and facilitate the early diagnosis and treatment of osteosarcoma. Small noncoding RNAs (sncRNAs) are a class of RNAs that do not encode proteins but directly play biological functions at the RNA level. SncRNAs mainly include Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), repeat RNAs and microRNAs (miRNAs). METHODS: In this study, we compared the expression of sncRNAs in BMSCs and osteosarcoma cells by high-throughput sequencing and qPCR and looked for differentially expressed sncRNAs. CCK-8, clone formation and transwell assay were used to detect the effect of sncRNA in MG63 cells. RESULTS: We found that 66 piRNAs were significantly upregulated and 70 piRNAs were significantly downregulated in MG63 cells. As for snoRNAs, 71 snoRNAs were significantly upregulated and 117 snoRNAs were significantly downregulated in MG63 cells. As for snRNAs, 35 snRNAs were significantly upregulated and 17 snRNAs were significantly downregulated in MG63 cells. As for repeat RNAs, 6 repeat RNAs were significantly upregulated and 7 repeat RNAs were significantly downregulated in MG63 cells. As for miRNAs, 326 miRNAs were significantly upregulated and 281 miRNAs were significantly downregulated in MG63 cells. Overexpression of piRNA DQ596225, snoRNA ENST00000364830.2, snRNA ENST00000410533.1 and miRNA hsa-miR-369-5p inhibited the proliferation and migration of MG63 cells. CONCLUSIONS: Our results provide a theoretical basis for the pathogenesis, early diagnosis and treatment of osteosarcoma.

M2 Microglia Extracellular Vesicle miR-124 Regulates Neural Stem Cell Differentiation in Ischemic Stroke via AAK1/NOTCH.

BACKGROUND: Small extracellular vesicles (sEVs) derived from M2 microglia (M2-microglia-derived small extracellular vesicles [M2-sEVs]) contribute to central nervous system repair, although the underlying mechanism remains unknown. In this study, we aimed to identify the mechanism through which microRNA-124 (miR-124) carried in sEVs promotes neural stem cell (NSC) proliferation and neuronal differentiation in the ischemic mouse brain. METHODS: M2-sEVs with or without miR-124 knockdown were injected intravenously for 7 consecutive days after transient middle cerebral artery occlusion surgery. The atrophy volume, neurological score, and degree of neurogenesis were examined at different time points after ischemic attack. NSCs treated with different sEVs were subjected to proteomic analysis. Target protein concentrations were quantified, and subsequent bioinformatic analysis was conducted to explore the key signaling pathways. RESULTS: M2-sEV transplantation promoted functional neurological recovery following transient middle cerebral artery occlusion injury. M2-sEV treatment decreased the brain atrophy volume, neurological score, and mortality rate. The effect was reserved by knockdown of miR-124 in M2-sEVs. M2-sEVs promoted proliferation and differentiation of mature neuronal NSCs in vivo. Proteomic analysis of NSC samples treated with M2-sEVs with and without miR-124 knockdown revealed that AAK1 (adaptor-associated protein kinase 1) was the key responding protein in NSCs. The binding of AAK1 to Notch promoted the differentiation of NSCs into neurons rather than astrocytes. CONCLUSIONS: Our data suggest that AAK1/Notch is the key pathway in NSCs that responds to the miR-124 carried within M2-sEVs in the ischemic brain. M2-sEVs carrying ample quantities of miR-124 promote functional recovery after ischemic stroke by enhancing NSC proliferation and differentiation. Targeting of M2-sEVs could represent a potential therapeutic strategy for brain recovery.

Evaluation of the antibacterial activity of Elsholtzia ciliate essential oil against halitosis-related Fusobacterium nucleatum and Porphyromonas gingivalis.

The broad-spectrum antimicrobial activity of Elsholtzia ciliate essential oil (ECO) has been previously reported, but its effectiveness against halitosis-causing bacteria such as Fusobacterium nucleatum and Porphyromonas gingivalis is not well understood. In this study, we investigated the bacteriostatic activity of ECO against planktonic cells and biofilms of F. nucleatum and P. gingivalis, as well as its ability to inhibit bacterial metabolism and production of volatile sulfur compounds (VSCs) at sub-lethal concentrations. Our findings revealed that ECO exhibited comparable activities to chlorhexidine against these oral bacteria. Treatment with ECO significantly reduced the production of VSCs, including hydrogen sulfide, dimethyl disulfide, and methanethiol, which are major contributors to bad breath. As the major chemical components of ECO, carvacrol, p-cymene, and phellandrene, were demonstrated in vitro inhibitory effects on F. nucleatum and P. gingivalis, and their combined use showed synergistic and additive effects, suggesting that the overall activity of ECO is derived from the cumulative or synergistic effect of multiple active components. ECO was found to have a destructive effect on the bacterial cell membrane by examining the cell morphology and permeability. Furthermore, the application of ECO induced significant changes in the bacterial composition of saliva-derived biofilm, resulting in the elimination of bacterial species that contribute to halitosis, including Fusobacterium, Porphyromonas, and Prevotella. These results provide experimental evidence for the potential clinical applications of ECOs in the prevention and treatment of halitosis.

Intermittent cyclic mechanical compression promotes endplate chondrocytes degeneration by disturbing Nrf2/PINK1 signaling pathway-dependent mitophagy.

An abnormal mechanical load is a pivotal inducer of endplate cartilage degeneration, which subsequently promotes intervertebral disc degeneration. Our previous study indicated that intermittent cyclic mechanical compression (ICMC) promotes endplate chondrocyte degeneration, but the mechanism underlying this effect is unclear. In this study, we investigated PTEN-induced kinase 1(PINK1) dependent mitophagy during ICMC-induced endplate chondrocyte degeneration. Furthermore, we determined whether NF-E2-related factor 2 (Nrf2) activation correlated with PINK1-dependent mitophagy regulation and increased oxidation resistance of endplate chondrocytes under ICMC application. First, we generated a mechanical compression-induced endplate chondrocyte degeneration model in vitro and in vivo. ICMC was found to promote endplate chondrocyte extracellular matrix degradation. PINK1-mediated mitophagy was suppressed in the ICMC-stimulated endplate chondrocytes, while increased mitochondrial reactive oxygen species generation suggested that mitophagy is involved in the protective effect of mechanical strain on endplate chondrocytes. Moreover, Nrf2 expression, interaction with Kelch-like ECH-associated protein (Keap1), and nuclear translocation were inhibited by ICMC. Nrf2 overexpression inhibited reactive oxygen species production and reversed ICMC-induced endplate chondrocyte degeneration. Transfection with PINK1 shRNA abolished this effect and partially blocked Nrf2-induced mitophagy. Our findings suggested that ICMC could inhibit the Nrf2/PINK1 signaling pathway to reduce the mitophagy levels which significantly promote oxidative stress and thereby endplate chondrocyte degeneration. Therapeutic regulation of the Nrf2/PINK1 signaling pathway may be an efficient anabolic strategy for inhibiting this process.

The emerging role of snoRNAs in human disease.

Small nucleolar RNAs (snoRNAs) play critical roles in various biological processes. The aberrant expression or depletion of snoRNAs is related to various diseases. In previous research, most of the snoRNAs were categorized as C/D box snoRNAs and H/ACA box snoRNAs, whose typical functions were thought of as regulation of 2'-O-ribose methylation and pseudouridylation of ribosome RNAs, respectively. However, in the past two decades, studies have revealed an increasing number of snoRNAs without specific targets or determined cell functions. These findings indicated that some potential roles of snoRNAs are still unknown. Numerous studies have indicated the correlation of snoRNAs with human diseases. SnoRNAs play various roles in abundant biological processes, and they have great potential in controlling human diseases. This new and rising field could benefit from investigations of the disease pathogenesis, biomarker identification, and the determination of novel therapeutic targets. This review summarized the reports on snoRNAs and the regulation of different diseases in recent years.

Safety and efficacy of laparoscopic digestive tract nutrition reconstruction combined with conversion therapy for patients with unresectable and obstructive gastric cancer.

Background: To explore the safety, efficacy, and survival benefits of laparoscopic digestive tract nutrition reconstruction (LDTNR) combined with conversion therapy in patients with unresectable gastric cancer with obstruction. Methods: The clinical data of patients with unresectable gastric cancer with obstruction who was treated in Fujian Provincial Hospital from January 2016 to December 2019, were analyzed. LDTNR was performed according to the type and degree of obstruction. All patients received the epirubicin + oxaliplatin + capecitabine regimen as conversion therapy. Results: Thirty-seven patients with unresectable obstructive gastric cancer underwent LDTNR, while thirty-three patients received chemotherapy only. In LDTNR group patients, the proportion of nutritional risks gradually decreased, the rate of severe malnutrition decreased, the proportion of neutrophil-lymphocyte ratio (NLR) <2.5 increased, the proportion of prognosis nutrition index (PNI) ≥45 increased, and the Spitzer QOL Index significantly increased at day 7 and 1 month postoperatively (P<0.05). One patient (6.3%) developed grade III anastomotic leakage and was discharged after the endoscopic intervention. The median chemotherapy cycle of patients in LDTNR group was 6 cycles (2-10 cycles), higher than that in Non-LDTNR group (P<0.001). Among those who received LDTNR therapy, 2 patients had a complete response, 17 had a partial response, 8 had stable disease, and 10 had progressive disease, which was significantly better than the response rate in Non-LDTNR group(P<0.001). The 1-year cumulative survival rates of the patients with or without LDTNR were 59.5% and 9.1%. The 3-year cumulative survival rate with or without LDTNR was 29.7% and 0%, respectively (P<0.001). Conclusions: LDTNR can improve the inflammatory and immune status, increase compliance with chemotherapy, and have potential benefits in improving the safety and effectiveness of and survival after conversion treatment.

Efficacy and long-term prognosis of gastrojejunostomy for malignant gastric outlet obstruction: A systematic review and Bayesian network meta-analysis.

BACKGROUND: Gastrojejunostomy (GJ) is becoming a standard surgical treatment for ameliorating malignant gastric outlet obstruction (MGOO). However, data on the long-term outcomes of MGOO treatment are lacking. This network meta-analysis aimed to compare overall survival (OS) rates and subsequent anticancer treatment outcomes of GJwith other therapies in MGOO. METHODS: We searched four electronic databases, including PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials, from inception to August 1, 2022. Studies reporting OS associated with GJ versus other treatments for MGOO were selected. The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary outcome assessed was OS, whereas the secondary outcome was subsequent anticancer treatment. We performed a Bayesian network meta-analysis to produce hazard ratios (HR) and odds ratios (OR) with 95% credible intervals (CrIs). RESULTS: We identified 24 retrospective studies that included 2473 patients. The studies assessed the outcomes of six treatments to alleviate MGOO. Results showed that GJ (hazard ratio: 0.83, 95% CrI: 0.78-0.88) was the most effective treatment for patients with MGOO, with the greatest surface under the cumulative ranking curve (SUCRA) values (79.9%) versus non-resection, palliative chemotherapy (13.9%) in terms of OS. Similarly, GJ (SUCRA: 46.5%) improved subsequent anticancer treatment requirements, ranking second only to jejunostomy/gastrostomy (JT/GT) (SUCRA: 95.9%). CONCLUSIONS: Our study demonstrates that GJ improves OS and follow-up treatments versus other non-resection treatments in patients with MGOO. These findings may serve for selecting appropriate therapy for MGOO.

Co-culture bioprinting of tissue-engineered bone-periosteum biphasic complex for repairing critical-sized skull defects in rabbits.

Tissue engineering based on bioprinting technology has broad prospects in the treatment of critical-sized bone defect. Nevertheless, it is challenging to construct composite tissues or organs with structural integrity. Periosteum and stem cells are important in bone regeneration, and it has been shown that co-culture engineering system could successfully repair bone defects. Here, a strategy of co-culture bioprinting was proposed, and a tissue-engineered bone-periosteum biphasic complex was designed. Poly-L-lactic acid/hydroxyapatite (PLLA/HA) was used to construct the supporting scaffold of bone phase. Gelatin methacryl (GelMA) loaded with rabbit bone mesenchymal stem cells (BMSCs) and periosteum-derived stem cells (PDSCs) were used to simulate the extracellular matrix and cellular components of bone and periosteum, respectively, and a co-culture layer was formed between the bone and the periosteum phase. By adjusting material ratios of PLLA/HA and crosslinking time of GelMA, a complex with good mechanical strength and cell activity was constructed and then implanted into the defect area of rabbit skull. The quantitative results of imaging and histology showed that the repair effect of bone-periosteum biphasic complex group was significantly better than that of other control groups, which demonstrated that the bone-periosteum biphasic complex was advantageous to both bone repair and regeneration. In general, using the co-culture bioprinting to construct engineered tissue is a very promising strategy, which is expected to be applied in the construction of more complex tissues and solid organs for tissue repair and organ transplantation.

Intraoperative and postoperative short-term outcomes of intracorporeal anastomosis versus extracorporeal anastomosis in laparoscopic right hemicolectomy.

Background: Intracorporeal anastomosis (IA) is a difficult but popular anastomotic approach for reconstruction of digestive tract after laparoscopic right hemicolectomy, which may reduce some limitations faced during extracorporeal anastomosis (EA). Methods: A retrospective review of 78 patients who underwent laparoscopic right hemicolectomy by a veteran surgeon in a high-volume public tertiary hospital, including 50 patients with IA and 28 patients with EA. The intraoperative-related factors and short-term results of the two anastomotic approaches were compared. Results: There was no significant difference in demographics and clinical characteristics between the two groups (P>0.05). The intraoperative blood loss was less (P=0.010) and the incision length was shorter (P<0.001) in the intracorporeal group. Postoperative farting time was faster (P=0.005) and postoperative pain score (VAS) was lower (P<0.001) in IA group. Although the anastomotic time of IA was shorter (P<0.001), the operative time of the two groups were similar. And number of lymph nodes harvested, NLR from POD1 to POD3, postoperative hospital stay and overall hospital stay between the two groups were comparable. Except for significant difference in abdominal infection rate, the Clavien-Dindo classification and the incidence of other postoperative complications were not statistically different. Moreover, the morbidity of abdominal infection decreased with time in the IA group (P=0.040). Conclusion: IA is a reliable and feasible procedure, which has faster anastomotic time, earlier return of bowel function and superior postoperative comfort of patient, compared to EA. The postoperative complication rate of IA is similar to that of EA, and may be improved with the IA technical maturity of surgeons, which potentially contributes to the development of ERAS.