High expression of DEC2 distinguishes chondroblastic osteosarcoma and promotes tumour growth by activating the VEGFC/VEGFR2 signalling pathway.

Osteosarcoma (OS) is the most common primary malignant bone tumour in children and young adults. Account for 80% of all OS cases, conventional OS are characterized by the presence of osteoblastic, chondroblastic and fibroblastic cell types. Despite this heterogeneity, therapeutic treatment and prognosis of OS are essentially the same for all OS subtypes. Here, we report that DEC2, a transcriptional repressor, is expressed at higher levels in chondroblastic OS compared with osteoblastic OS. This difference suggests that DEC2 is disproportionately involved in the progression of chondroblastic OS, and thus, DEC2 may represent a possible molecular target for treating this type of OS. In the human chondroblastic-like OS cell line MNNG/HOS, we found that overexpression of DEC2 affects the proliferation of the cells by activating the VEGFC/VEGFR2 signalling pathway. Enhanced expression of DEC2 increased VEGFR2 expression, as well as increased the phosphorylation levels at sites Y951 and Y1175 of VEGFR2. On the one hand, activation of VEGFR2Y1175 enhanced cell proliferation through VEGFR2Y1175-PLCγ1-PKC-SPHK-MEK-ERK signalling. On the other hand, activation of VEGFR2Y951 decreased mitochondria-dependent apoptosis rate through VEGFR2Y951-VARP-PI3K-AKT signalling. Activation of these two signalling pathways resulted in enhanced progression of chondroblastic OS. In conclusion, DEC2 plays a pivotal role in cell proliferation and apoptosis-resistance in chondroblastic OS via the VEGFC/VEGFR2 signalling pathway. These findings lay the groundwork for developing focused treatments that target specific types of OS.

Study of the mechanism by which Xiaoyan decoction combined with E7449 regulates tumorigenesis in lung adenocarcinoma.

TNKS is a new target for the treatment of lung adenocarcinoma, the synergistic effects of the TCM compound Xiaoyan decoction and the TNKS inhibitor E7449 in the intervention on TNKS were investigated, and the possible underlying mechanisms involved were clarified. Immunohistochemistry was used to analyse TNKS expression in tumour tissues. The impact of targeting TNKS on cell growth, invasion, apoptosis, key genes and signalling pathways was investigated in tumour cells by Western blotting, rescue experiments, colony formation assays, flow cytometry and label-free experiments. Tumour xenografts with A549 cells were then transplanted for in vivo study. We found that TNKS high expression was closely related to the advanced tumour stage and tumour size in lung adenocarcinom. After TNKS was knocked down in vitro, the growth, proliferation, migration and invasion were markedly reduced in A549 and H1975 cells. We subsequently applied the Xiaoyan decoction and TNKS inhibitors to intervene in lung adenocarcinoma. Xiaoyan decoction and E7449 suppressed TNKS expression and inhibited adenocarcinoma cell proliferation, migration, invasion and apoptosis in vitro. Proteomic analysis revealed that E7449 treatment may be most closely associated with the classic Wnt/ß-catenin pathway, whereas Xiaoyan decoction treatment may be related to the WNT/PLAN pathway. Xenograft studies confirmed that E7449 or Xiaoyan decoction inhibited lung tumour growth in vivo and attenuated the Wnt signalling pathway in adenocarcinoma. These findings suggest that TNKS is a novel therapeutic target. TCM preparations and small molecule inhibitors are expected to constitute an effective combination strategy.

Correlation Analysis Between Tumor Deposit and Clinicopathologic Characteristics and Prognosis of Gastric Cancer: A Multicenter Retrospective Study.

BACKGROUND: The mechanism underlying the formation of gastric tumor deposits (TDs) is unclear. We aimed to explore the risk factors for the formation and prognostic value of TDs. METHODS: This retrospective analysis included 781 locally advanced gastric cancer (LAGC) patients from four medical institutions in China, from June 2014 to June 2018. The risk factors for TD formation and prognostic value were determined through univariate and multivariate analyses. RESULTS: Univariate analysis revealed that TD positivity was closely related to tumor diameter, Borrmann classification, differentiation degree, pT stage, pN stage, pTNM stage, and nerve and vascular invasion (p < 0.05). Multivariate logistic regression revealed that tumor diameter ≥ 5 cm (odds ratio [OR] 1.836, 95% confidence interval [CI] 1.165-2.894, p = 0.009) and vascular invasion (OR 2.152, 95% CI 1.349-3.433, p = 0.001) were independent risk factors for TD positivity. Multivariate Cox analysis revealed that TD positivity (OR 1.533, 95% CI 1.101-2.134, p = 0.011), tumor diameter ≥ 5 cm (OR 1.831, 95% CI 1.319-2.541, p < 0.001), pT4a stage (OR 1.652, 95% CI 1.144-2.386, p = 0.007), and vascular invasion (OR 1.458, 95% CI 1.059-2.008, p = 0.021) were independent risk factors for GC prognosis. The 5-year overall and disease-free survival of the TD-positive group showed significant effects among patients in the pT4a and pN3b stages (p < 0.05). CONCLUSIONS: TDs are closely related to tumor diameter and vascular invasion in LAGC patients, and TD positivity is an independent prognostic factor for LAGC patients, especially those at pT4a and pN3b stages.

Evaluating the Role of Neddylation Modifications in Kidney Renal Clear Cell Carcinoma: An Integrated Approach Using Bioinformatics, MLN4924 Dosing Experiments, and RNA Sequencing.

BACKGROUND: Neddylation, a post-translational modification process, plays a crucial role in various human neoplasms. However, its connection with kidney renal clear cell carcinoma (KIRC) remains under-researched. METHODS: We validated the Gene Set Cancer Analysis Lite (GSCALite) platform against The Cancer Genome Atlas (TCGA) database, analyzing 33 cancer types and their link with 17 neddylation-related genes. This included examining copy number variations (CNVs), single nucleotide variations (SNVs), mRNA expression, cellular pathway involvement, and methylation. Using Gene Set Variation Analysis (GSVA), we categorized these genes into three clusters and examined their impact on KIRC patient prognosis, drug responses, immune infiltration, and oncogenic pathways. Afterward, our objective is to identify genes that exhibit overexpression in KIRC and are associated with an adverse prognosis. After pinpointing the specific target gene, we used the specific inhibitor MLN4924 to inhibit the neddylation pathway to conduct RNA sequencing and related in vitro experiments to verify and study the specificity and potential mechanisms related to the target. This approach is geared towards enhancing our understanding of the prognostic importance of neddylation modification in KIRC. RESULTS: We identified significant CNV, SNV, and methylation events in neddylation-related genes across various cancers, with notably higher expression levels observed in KIRC. Cluster analysis revealed a potential trade-off in the interactions among neddylation-related genes, where both high and low levels of gene expression are linked to adverse prognoses. This association is particularly pronounced concerning lymph node involvement, T stage classification, and Fustat score. Simultaneously, our research discovered that PSMB10 exhibits overexpression in KIRC when compared to normal tissues, negatively impacting patient prognosis. Through RNA sequencing and in vitro assays, we confirmed that the inhibition of neddylation modification could play a role in the regulation of various signaling pathways, thereby influencing the prognosis of KIRC. Moreover, our results underscore PSMB10 as a viable target for therapeutic intervention in KIRC, opening up novel pathways for the development of targeted treatment strategies. CONCLUSION: This study underscores the regulatory function and potential mechanism of neddylation modification on the phenotype of KIRC, identifying PSMB10 as a key regulatory target with a significant role in influencing the prognosis of KIRC.

Degradation of Poly(ethylene terephthalate) Catalyzed by Nonmetallic Dibasic Ionic Liquids under UV Radiation.

Nonmetallic ionic liquids (ILs) exhibit unique advantages in catalyzing poly (ethylene terephthalate) (PET) glycolysis, but usually require longer reaction times. We found that exposure to UV radiation can accelerate the glycolysis reaction and significantly reduce the reaction time. In this work, we synthesized five nonmetallic dibasic ILs, and their glycolysis catalytic activity was investigated. 1,8-diazabicyclo [5,4,0] undec-7-ene imidazole ([HDBU]Im) exhibited better catalytic performance. Meanwhile, UV radiation is used as a reinforcement method to improve the PET glycolysis efficiency. Under optimal conditions (5 g PET, 20 g ethylene glycol (EG), 0.25 g [HDBU]Im, 10,000 µW·cm-2 UV radiation reacted for 90 min at 185 °C), the PET conversion and BHET yield were 100% and 88.9%, respectively. Based on the UV-visible spectrum, it was found that UV radiation can activate the C=O in PET. Hence, the incorporation of UV radiation can considerably diminish the activation energy of the reaction, shortening the reaction time of PET degradation. Finally, a possible reaction mechanism of [HDBU]Im-catalyzed PET glycolysis under UV radiation was proposed.

MTH1 inhibition synergizes with ROS-inducing agents to trigger cervical cancer cells undergoing parthanatos.

Cervical cancer cells possess high levels of reactive oxygen species (ROS); thus, increasing oxidative stress above the toxicity threshold to induce cell death is a promising chemotherapeutic strategy. However, the underlying mechanisms of cell death are elusive, and efficacy and toxicity issues remain. Within DNA, 8-oxo-7,8-dihydroguanine (8-oxoG) is the most frequent base lesion repaired by 8-oxoguanine glycosylase 1 (OGG1)-initiated base excision repair. Cancer cells also express high levels of MutT homolog 1 (MTH1), which prevents DNA replication-induced incorporation of 8-oxoG into the genome by hydrolyzing 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP). Here, we revealed that ROS-inducing agents triggered cervical cancer to undergo parthanatos, which was mainly induced by massive DNA strand breaks resulting from overwhelming 8-oxoG excision by OGG1. Furthermore, the MTH1 inhibitor synergized with a relatively low dose of ROS-inducing agents by enhancing 8-oxoG loading in the DNA. In vivo, this drug combination suppressed the growth of tumor xenografts, and this inhibitory effect was significantly decreased in the absence of OGG1. Hence, the present study highlights the roles of base repair enzymes in cell death induction and suggests that the combination of lower doses of ROS-inducing agents with MTH1 inhibitors may be a more selective and safer strategy for cervical cancer chemotherapy.

Therapeutic Effect of a Novel M1 Macrophage-Targeted Nanodrug in Chronic Periodontitis Mice.

Chronic periodontitis is a chronic, progressive, and destructive disease. Especially, the large accumulation of advanced glycation end products (AGEs) in a diseased body will aggravate the periodontal tissue damage, and AGEs induce M1 macrophages. In this project, the novel nanodrugs, glucose-PEG-PLGA@MCC950 (GLU@MCC), are designed to achieve active targeting with the help of glucose transporter 1 (GLUT1) which is highly expressed in M1 macrophages induced by AGEs. Then, the nanodrugs release MCC950, which is a kind of NLRP3 inhibitor. These nanodrugs not only can improve the water solubility of MCC950 but also exhibit superior characteristics, such as small size, stability, innocuity, etc. In vivo experiments showed that GLU@MCC could reduce periodontal tissue damage and inhibit cell apoptosis in periodontitis model mice. In vitro experiments verified that its mechanism of action might be closely related to the inhibition of the NLRP3 inflammatory factor in M1 macrophages. GLU@MCC could effectively reduce the damage to H400 cells caused by AGEs, decrease the expression of NLRP3, and also obviously reduce the M1-type macrophage pro-inflammatory factors such as IL-18, IL-1ß, caspase-1, and TNF-α. Meanwhile, the expression of anti-inflammatory factor Arg-1 in the M2 macrophage was increased. In brief, GLU@MCC would inhibit the expression of inflammatory factor NLRP3 and exert antiperiodontal tissue damage in chronic periodontitis via GLUT1 in the M1 macrophage as the gating target. This study provides a novel nanodrug for chronic periodontitis treatment.

Transperitoneal vs retroperitoneal laparoscopic radical nephrectomy: a double-arm, parallel-group randomized clinical trial.

OBJECTIVE: To compare the outcomes of patients undergoing Retroperitoneal laparoscopic Radical nephrectomy (RLRN) and Transperitoneal laparoscopic Radical nephrectomy (TLRN). METHODS: A total of 120 patients with localized renal cell carcinoma were randomized into either RLRN or TLRN group. Mainly by comparing the patient perioperative related data, surgical specimen integrity, pathological results and tumor results. RESULTS: Each group comprised 60 patients. The two group were equivalent in terms of perioperative and pathological outcomes. The mean integrity score was significantly lower in the RLRN group than TLRN group. With a median follow-up of 36.4 months after the operation, Kaplan-Meier survival analysis showed no significant difference between RLRN and TLRN in overall survival (89.8% vs. 88.5%; P = 0.898), recurrence-free survival (77.9% vs. 87.7%; P = 0.180), and cancer-specific survival (91.4% vs. 98.3%; P = 0.153). In clinical T2 subgroup, the recurrence rate and recurrence-free survival in the RLRN group was significantly worse than that in the TLRN group (43.2% vs. 76.7%, P = 0.046). Univariate and multivariate COX regression analysis showed that RLRN (HR: 3.35; 95%CI: 1.12-10.03; P = 0.030), male (HR: 4.01; 95%CI: 1.07-14.99; P = 0.039) and tumor size (HR: 1.23; 95%CI: 1.01-1.51; P = 0.042) were independent risk factor for recurrence-free survival. CONCLUSIONS: Our study showed that although RLRN versus TLRN had roughly similar efficacy, TLRN outperformed RLRN in terms of surgical specimen integrity. TLRN was also significantly better than RLRN in controlling tumor recurrence for clinical T2 and above cases. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( https://www.chictr.org.cn/showproj.html?proj=24400 ), identifier: ChiCTR1800014431, date: 13/01/2018.

Research on the Characteristics and Control Technology of Gas Disasters in the Gob of the Nonpillar Working Face Based on the DEM-CFD Coupled Model.

Gob-side entry retained by cutting roof (GERCR) is a novel and widely used nonpillar mining technology, but the gas emissions from gob are large, and the gas migration characteristics change obviously, which easily leads to serious safety accidents such as gas explosions and personnel suffocation. The discrete element method-computational fluid dynamics (DEM-CFD) coupled model was proposed and used to study the gas flow field in gob under this technology. Through the calculation of this coupled model, the gas distribution and emission characteristics of gob under different ventilation modes of GERCR technology were clarified, and the areas where the gas exceeds the limit in the roadway were determined. To prevent and control gas accumulation, three-dimensional gas drainage technology in the GERCR working face was proposed based on the above research conclusions. Through the field application and monitoring, the characteristics of gas emission and the effect of gas drainage in the gob of GERCR technology were verified. The on-site monitoring results show that the DEM-CFD coupled model established above can simulate well the gas emission characteristics of the GERCR gob, and the three-dimensional drainage system can well control the gas accumulation in the roadway. The research results are of great significance to control gas disasters of this novel nonpillar mining technology.

Interleukin-37 ameliorates periodontitis development by inhibiting NLRP3 inflammasome activation and modulating M1/M2 macrophage polarization.

OBJECTIVE: Our study was designed to explore the role of IL-37 in M1/M2 macrophage polarization imbalance in the pathogenesis of periodontitis. BACKGROUND: Periodontitis is a chronic progressive inflammatory disease featured by gingival inflammation and alveolar bone resorption. Recent research has revealed that regulating macrophage polarization is a viable method to ameliorate periodontal inflammation. IL-37 is an anti-inflammatory cytokine, which has been reported to inhibit innate and adaptive immunity. METHODS: For in vitro experiment, mouse macrophage RAW264.7 cells were pretreated with 0.1 ng/mL recombinant human IL-37. M1 and M2 polarizations of RAW264.7 cells were induced by 100 ng/mL LPS and 20 ng/mL IL-4, respectively. The expression of M1 (iNOS, TNF-α, and IL-6) and M2 (CD206, Arg1, and IL-10) phenotype markers in RAW264.7 cells was detected by RT-qPCR, western blotting, and immunofluorescence staining. For in vivo experiment, experimental periodontitis mouse models were established by sterile silk ligation (5-0) around the bilateral maxillary second molar of mice for 1 week. H&E staining of the maxillary alveolar bone was used to show the resorption of root cementum and dentin. Alveolar bone loss in mouse models was evaluated through micro-CT analysis. The expression of iNOS and CD206 in gingival tissues was assessed by immunohistochemistry staining. NLRP3 inflammasome activation was confirmed by western blotting. RESULTS: IL-37 pretreatment reduced iNOS, TNF-α, and IL-6 expression in LPS-treated RAW264.7 cells but increased CD206, Arg1, and IL-10 in IL-4-treated RAW264.7 cells. LPS-induced upregulation in NLRP3, GSDMD, cleaved-IL-1ß, and cleaved-caspase-1 expression was antagonized by IL-37 treatment. In addition, IL-37 administration ameliorated the resorption of root cementum and dentin in periodontitis mouse models. IL-37 prominently decreased iNOS+ cell population but increased CD206+ cell population in gingival tissues of periodontitis mice. The enhancement in NLRP3, GSDMD, cleaved-IL-1ß, and cleaved-caspase-1 expression in the gingival tissues of periodontitis mice was offset by IL-37 administration. CONCLUSION: IL-37 prevents the progression of periodontitis by suppressing NLRP3 inflammasome activation and mediating M1/M2 macrophage polarization.

Safety and efficacy of lentinan nasal drops in patients infected with the variant of COVID-19: a randomized, placebo-controlled trial.

Objective: Lentinan has antiviral, anti-tumor, immunomodulatory, stimulating interferon production, and other pharmacological effects. Previous animal experiments have shown that lentinan nasal drops can assist [Corona Virus Disease 2019) COVID-19] vaccine to induce high levels of neutralizing antibodies and can effectively resist the invasion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aimed to evaluate the safety and efficacy of lentinan nasal drops in patients infected with Omicron (SARS-CoV-2 variant) through a dose-escalation study and a placebo-controlled trial. Methods: A randomized, placebo-controlled trial. The study was divided into two phases: Phase I: a dose escalation trial in which 24 COVID-19 patients were enrolled, that is, 12 in the escalation dose group (50, 75, and 100 µg/day) and 12 in the standard treatment group. The aim was to evaluate the safety and tolerance of lentinan nasal drops. The second stage was a placebo-controlled study. The optimal dose group of the first stage was used as the therapeutic dose, and the sample size was expanded to verify the anti-COVID-19 efficacy of lentinan nasal drops. Results: In the dose-increasing study, lentinan nasal drops showed good safety, and no serious adverse reactions occurred. The virus shedding time of the 100 µg dose group was significantly shorter than that in the control group (7.75 ± 1.71 VS 13.41 ± 3.8 days) (p = 0.01), and the 100 µg/day lentinan nasal drops were tolerated well. The results of the placebo-controlled study showed that compared with that in the placebo group, the time for COVID-19 antigen to turn negative was significantly shorter in the 100 µg lentinan nasal drop group (p = 0.0298), but no significant difference was observed in symptom improvement between the two groups. In the placebo-controlled study, two patients experienced mild nasal discomfort with nasal drops, but the symptoms relieved themselves. Conclusion: Lentinan nasal drops are tolerated well and can shorten the time of virus clearance.

Respiratory variation in the internal jugular vein does not predict fluid responsiveness in the prone position during adolescent idiopathic scoliosis surgery: a prospective cohort study.

BACKGROUND: Respiratory variation in the internal jugular vein (IJVV) has not shown promising results in predicting volume responsiveness in ventilated patients with low tidal volume (Vt) in prone position. We aimed to determine whether the baseline respiratory variation in the IJVV value measured by ultrasound might predict fluid responsiveness in patients with adolescent idiopathic scoliosis (AIS) undergoing posterior spinal fusion (PSF) with low Vt. METHODS: According to the fluid responsiveness results, the included patients were divided into two groups: those who responded to volume expansion, denoted the responder group, and those who did not respond, denoted the non-responder group. The primary outcome was determination of the value of baseline IJVV in predicting fluid responsiveness (≥15% increases in stroke volume index (SVI) after 7 ml·kg-1 colloid administration) in patients with AIS undergoing PSF during low Vt ventilation. Secondary outcomes were estimation of the diagnostic performance of pulse pressure variation (PPV), stroke volume variation (SVV), and the combination of IJVV and PPV in predicting fluid responsiveness in this surgical setting. The ability of each parameter to predict fluid responsiveness was assessed using a receiver operating characteristic curve. RESULTS: Fifty-six patients were included, 36 (64.29%) of whom were deemed fluid responsive. No significant difference in baseline IJVV was found between responders and non-responders (25.89% vs. 23.66%, p = 0.73), and no correlation was detected between baseline IJVV and the increase in SVI after volume expansion (r = 0.14, p = 0.40). A baseline IJVV greater than 32.00%, SVV greater than 14.30%, PPV greater than 11.00%, and a combination of IJVV and PPV greater than 64.00% had utility in identifying fluid responsiveness, with a sensitivity of 33.33%, 77.78%, 55.56%, and 55.56%, respectively, and a specificity of 80.00%, 50.00%, 65.00%, and 65.00%, respectively. The area under the receiver operating characteristic curve for the baseline values of IJVV, SVV, PPV, and the combination of IJVV and PPV was 0.52 (95% CI, 0.38-0.65, p=0.83), 0.54 (95% CI, 0.40-0.67, p=0.67), 0.58 (95% CI, 0.45-0.71, p=0.31), and 0.57 (95% CI, 0.43-0.71, p=0.37), respectively. CONCLUSIONS: Ultrasonic-derived IJVV lacked accuracy in predicting fluid responsiveness in patients with AIS undergoing PSF during low Vt ventilation. In addition, the baseline values of PPV, SVV, and the combination of IJVV and PPV did not predict fluid responsiveness in this surgical setting. TRAIL REGISTRATION: This trial was registered at www.chictr.org (ChiCTR2200064947) on 24/10/2022. All data were collected through chart review.

Regeneration and anti-inflammatory effects of stem cells and their extracellular vesicles in gynecological diseases.

There are many gynecological diseases, among which breast cancer (BC), cervical cancer (CC), endometriosis (EMs), and polycystic ovary syndrome (PCOS) are common and difficult to cure. Stem cells (SCs) are a focus of regenerative medicine. They are commonly used to treat organ damage and difficult diseases because of their potential for self-renewal and multidirectional differentiation. SCs are also commonly used for difficult-to-treat gynecological diseases because of their strong directional differentiation ability with unlimited possibilities, their tendency to adhere to the diseased tissue site, and their use as carriers for drug delivery. SCs can produce exosomes in a paracrine manner. Exosomes can be produced in large quantities and have the advantage of easy storage. Their safety and efficacy are superior to those of SCs, which have considerable potential in gynecological treatment, such as inhibiting endometrial senescence, promoting vascular reconstruction, and improving anti-inflammatory and immune functions. In this paper, we review the mechanisms of the regenerative and anti-inflammatory capacity of SCs and exosomes in incurable gynecological diseases and the current progress in their application in genetic engineering to provide a foundation for further research.

8-Oxoguanine DNA glycosylase 1 selectively modulates ROS-responsive NF-κB targets through recruitment of MSK1 and phosphorylation of RelA/p65 at Ser276.

Nuclear factor kappa B (NF-κB) activity is regulated by various posttranslational modifications, of which Ser276 phosphorylation of RelA/p65 is particularly impacted by reactive oxygen species (ROS). This modification is responsible for selective upregulation of a subset of NF-κB targets; however, the precise mechanism remains elusive. ROS have the ability to modify cellular molecules including DNA. One of the most common oxidation products is 8-oxo-7,8-dihydroguanine (8-oxoGua), which is repaired by the 8-oxoguanine DNA glycosylase1 (OGG1)-initiated base excision repair pathway. Recently, a new function of OGG1 has been uncovered. OGG1 binds to 8-oxoGua, facilitating the occupancy of NF-κB at promoters and enhancing transcription of pro-inflammatory cytokines and chemokines. In the present study, we demonstrated that an interaction between DNA-bound OGG1 and mitogen-and stress-activated kinase 1 is crucial for RelA/p65 Ser276 phosphorylation. ROS scavenging or OGG1 depletion/inhibition hindered the interaction between mitogen-and stress-activated kinase 1 and RelA/p65, thereby decreasing the level of phospho-Ser276 and leading to significantly lowered expression of ROS-responsive cytokine/chemokine genes, but not that of Nfkbis. Blockade of OGG1 binding to DNA also prevented promoter recruitment of RelA/p65, Pol II, and p-RNAP II in a gene-specific manner. Collectively, the data presented offer new insights into how ROS signaling dictates NF-κB phosphorylation codes and how the promoter-situated substrate-bound OGG1 is exploited by aerobic mammalian cells for timely transcriptional activation of ROS-responsive genes.

Role of the NLRP3 inflammasome in gynecological disease.

The NLR family pyrin domain containing 3 (NLRP3) inflammasome is involved in the innate immune system and is a three-part macromolecular complex comprising the NLRP3 protein, apoptosis-associated speck-like protein containing a CARD (ASC) and the cysteine protease pro-caspase-1. When the NLRP3 inflammasome is activated, it can produce interleukin (IL)- 1ß and IL-18 and eventually lead to inflammatory cell pyroptosis. Related studies have demonstrated that the NLRP3 inflammasome can induce an immune response and is related to the occurrence and development of gynecological diseases, such as endometriosis, polycystic ovary syndrome and breast cancer. NLRP3 inflammasome inhibitors are beneficial for maintaining cellular homeostasis and tissue health and have been found effective in targeting some gynecological diseases. However, excessive inhibitor concentrations have been found to cause adverse effects. Therefore, proper control of NLRP3 inflammasome activity is critical. This paper summarizes the structure and function of the NLRP3 inflammasome and highlights the therapeutic potential of targeting it in gynecological diseases, such as endometriosis, polycystic ovary syndrome and breast cancer The application of NLRP3 inflammasome inhibitors is also discussed.

Effect of post-extubation high-flow nasal cannula combined with respiratory training versus conventional oxygen therapy on postoperative pulmonary complications in patients after major abdominal surgery: protocol for a single-centre randomized controlled trial.

BACKGROUND: Nearly 234 million patients undergo surgery each year, and 1.3 million among them develop complications. Patients undergoing major upper abdominal surgery (operation time > 2 h) have a really high incidence of postoperative pulmonary complications (PPCs). The occurrence of PPCs seriously affects the outcomes of patients. High-flow nasal cannula (HFNC) is as effective as noninvasive ventilation (NIV) in preventing postoperative hypoxaemia and respiratory failure. Respiratory training using positive expiratory pressure (PEP) Acapella (Choice) has been shown to help patients with rapid recovery from postoperative atelectasis. However, no relevant randomized controlled studies have been conducted to clarify the effect of HFNC combined with respiratory training in the prevention of PPCs. This study aims to investigate whether the use of HFNC combined with respiratory training could reduce the incidence of PPCs within 7 days after major upper abdominal surgery compared to that with conventional oxygen therapy (COT). METHODS: This is a randomized controlled single-centre trial. A total of 328 patients who undergo major abdominal surgery will be included. Subjects who fulfil the eligible criteria will be randomly assigned into the combination treatment group (Group A) or COT group (Group B) after extubation. The interventions will begin within 30 min of extubation. Patients in Group A will receive HFNC for at least 48 h and respiratory training three times a day for at least 72 h. Patients in Group B will receive oxygen therapy through a nasal catheter or mask for at least 48 h. Our primary endpoint is the incidence of PPCs within 7 days, and the secondary outcome measures include 28-day mortality, reintubation rate, length of hospital stay, and all-cause mortality within 1 year. DISCUSSION: This trial would help provide evidence on the effectivity of applying HFNC combined with respiratory training for the prevention of PPCs in patients undergoing major upper abdominal surgery. The objective of this study is to determine the optimal treatment approach to improve the prognosis of patients undergoing surgery. TRIAL REGISTRATION: ChiCTR2100047146. Registered on 8 June 2021. Retrospectively registered.

Anti-tumor efficacy of anti-GD2 CAR NK-92 cells in diffuse intrinsic pontine gliomas.

Background: Diffuse intrinsic pontine gliomas (DIPGs) are rare and fatal pediatric brainstem gliomas with no cure. Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have been proven effective in treating glioblastoma (GBM) in preclinical studies. However, there are no relevant studies on the CAR-NK treatment for DIPG. Our study is the first to evaluate the anti-tumor activity and safety of GD2-CAR NK-92 cells treatment for DIPG. Methods: Five patient-derived DIPG cells and primary pontine neural progenitor cell (PPC) were used to access disialoganglioside GD2 expression. Cell killing activity of GD2-CAR NK-92 cells was analyzed by in vitro cytotoxicity assays. Two DIPG patient-derived xenograft models were established to detect the anti-tumor efficacy of GD2-CAR NK-92 cells in vivo. Results: Among the five patient-derived DIPG cells, four had high GD2 expression, and one had low GD2 expression. In in vitro assays, GD2-CAR NK-92 cells could effectively kill DIPG cells with high GD2 expression while having limited activity against DIPG cells with low GD2 expression. In in vivo assays, GD2-CAR NK-92 cells could inhibit tumor growth in TT150630 DIPG patient-derived xenograft mice (high GD2 expression) and prolong the overall survival of the mice. However, GD2-CAR NK-92 showed limited anti-tumor activity for TT190326DIPG patient-derived xenograft mice (low GD2 expression). Conclusion: Our study demonstrates the potential and safety of GD2-CAR NK-92 cells for adoptive immunotherapy of DIPG. The safety and anti-tumor effect of this therapy need to be further demonstrated in future clinical trials.

Influence of Retrogression Time on the Fatigue Crack Growth Behavior of a Modified AA7475 Aluminum Alloy.

This paper investigates the effect of retrogression time on the fatigue crack growth of a modified AA7475 aluminum alloy. Tests including tensile strength, fracture toughness, and fatigue limits were performed to understand the changes in properties with different retrogression procedures at 180 °C. The microstructure was characterized using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The findings indicated that as the retrogression time increased, the yield strength decreased from 508 MPa to 461 MPa, whereas the fracture toughness increased from 48 MPa√m to 63.5 MPa√m. The highest fracture toughness of 63.5 MPa√m was seen after 5 h of retrogression. The measured diameter of η' precipitates increased from 6.13 nm at the retrogression 1 h condition to 6.50 nm at the retrogression 5 h condition. Prolonged retrogression also increased the chance of crack initiation, with slower crack growth rate in the long transverse direction compared to the longitudinal direction. An empirical relationship was established between fracture toughness and the volume fraction of age-hardening precipitates, with increasing number density of precipitates seen with increasing retrogression time.

Retroperitoneal laparoscopic radical nephrectomy (RLRN) is associated with poor integrity of Gerota's fascia and perirenal fat: A prospective comparative study.

Purpose: To figure out the difference of integrity of Gerota's fascia and perirenal fat between Retroperitoneal Laparoscopic Radical Nephrectomy (RLRN) and Transperitoneal Laparoscopic Radical Nephrectomy (TLRN). Methods: This is a prospective comparative study of patients with Renal Cell Carcinoma (RCC) from a designated tertiary center in Lanzhou, China. We have developed and propose a scoring tool to quantify the integrity of nephrectomy specimens from both approaches. The integrity score is based on 6 common conditions of nephrectomy specimens. Specimens are scored on a 1 to 6-point scale according to the integrity of Gerota's fascia and perirenal fat. We applied the integrity score to 142 consecutive patients. Integrity scores were compared between RLRN and TLRN groups. Factors associated with low integrity score were assessed by logistic regression. Results: Among 142 patients, 79 (55.6%) patients and 63 (44.4%) patients, respectively, underwent RLRN and TLRN. There was a significant difference in the distribution of integrity score between the two groups (P < 0.001). RLRN (odds ratio 10.65, 95%CI 4.29-26.45, P < 0.001), tumor size (odds ratio 1.22, 95%CI 1.04-1.42, P = 0.015) and Body Mass Index (BMI) (odds ratio 0.83, 95%CI 0.72-0.96, P = 0.010) were significantly associated with low integrity score. The logistic regression equation showed good power to predict low integrity score. Conclusion: RLRN has poor integrity of Gerota's fascia and the perirenal fat. The integrity score can be used to evaluate the extent of resection and specimen completeness in LRN. Postoperative evaluation of the integrity score is of great value for urologists to evaluate the risk of tumor residue.

Thromboxane A2-TP axis promotes adipose tissue macrophages M1 polarization leading to insulin resistance in obesity.

Aberrant arachidonic acid metabolism has been implicated in multiple pathophysiological conditions, and the downstream prostanoids levels are associated with adipocyte dysfunction in obesity. However, the role of thromboxane A2 (TXA2) in obesity remains unclear. We observed that TXA2, through its receptor TP, is a candidate mediator in obesity and metabolic disorders. Obese mice with upregulated TXA2 biosynthesis (TBXAS1) and TXA2 receptor (TP) expression in caused insulin resistance and macrophage M1 polarization in white adipose tissue (WAT), which can be prevented by treatment with aspirin. Mechanistically, the activation of TXA2-TP signaling axis leads to accumulation of protein kinase Cɛ (PKCɛ), thereby enhancing free fat acid (FFA) induced Toll-like receptor4 (TLR4) proinflammatory macrophage activation and the tumor necrosis factor-a (TNF-a) production in adipose tissues. Importantly, TP knockout mice reduced the accumulation of proinflammatory macrophages and adipocyte hypertrophy in WAT. Thus, our findings demonstrate that TXA2-TP axis plays a crucial role in obesity-induced adipose macrophage dysfunction, and rational targeting TXA2 pathway may improve obesity and its associated metabolic disorders in future. In this work, we establish previously unknown role of TXA2-TP axis in WAT. These findings might provide new insight into the molecular pathogenesis of insulin resistance, and indicate rational targeting TXA2 pathway to improve obesity and its associated metabolic disorders in future.