Do testosterone and sex hormone-binding globulin affect cancer risk? A Mendelian randomization and bioinformatics study.

Using Mendelian Randomization (MR) and large-scale Genome-Wide Association Study (GWAS) data, this study aimed to investigate the potential causative relationship between testosterone and sex hormone-binding globulin (SHBG) levels and the onset of several cancers, including pathway enrichment analyses of single nucleotide polymorphisms (SNPs) associated with cancer allowed for a comprehensive bioinformatics approach, which offered a deeper biological understanding of these relationships. The results indicated that increased testosterone levels in women were associated with a higher risk of breast and cervical cancers but a lower risk of ovarian cancer. Conversely, increased testosterone was linked to lower stomach cancer risk for men, whereas high SHBG levels were related to decreased risks of breast and prostate cancers. The corresponding genes of the identified SNPs, as revealed by pathway enrichment analysis, were involved in significant metabolic and proliferative pathways. These findings emphasize the need for further research into the biological mechanisms behind these associations, paving the way for potential targeted interventions in preventing and treating these cancers.

Erythropoietin induces odontoblastic differentiation of human-derived pulp stem cells via EphB4-Mediated MAPK signaling pathway.

OBJECTIVES: Human-derived pulp stem cells play key roles during dentinogenesis. Erythropoietin is reportedly involved in osteoblastogenesis and facilitates bone formation. However, the mechanism is still unknown. This research was to study the potential of erythropoietin in enhancing odontoblastic differentiation of human-derived pulp stem cells and to determine the underlying mechanism. METHODS: The human-derived pulp stem cells were treated with erythropoietin, EphB4 inhibitor, and MAPK inhibitors, and the odontoblastic differentiation was measured by ALP staining, ALP activity assay, alizarin red S staining, and their quantitative analysis, and RT-qPCR of DSPP, DMP1, OCN, and RUNX2. The direct pulp capping model was established to evaluate the formation of tertiary dentin after treatment with erythropoietin. Western blot assay was conducted to assess relevant protein expressions in the phosphorylated EphB4 and MAPK pathway. RESULTS: The results showed that erythropoietin promoted odontoblastic differentiation of human-derived pulp stem cells at 20 U/ml. Erythropoietin induced tertiary dentin formation in vivo. The potential mechanism of this was upregulating phosphorylated EphB4 and phosphorylated MAPK; furthermore, this effect could be decreased by EphB4 inhibitors, which inhibited MAPK phosphorylation. Blockage of MAPK pathways attenuated human-derived pulp stem cells' odontoblastic differentiation, suggesting that MAPK pathways are involved. CONCLUSION: Erythropoietin induced tertiary dentin formation in vivo. And erythropoietin enhanced human-derived pulp stem cells' odontoblastic differentiation via the EphB4-mediated MAPK signaling pathway.

Effects of betaine supplementation on inflammatory markers: a systematic review and meta-analysis of randomised controlled trials.

Several studies have suggested that betaine is closely related to inflammatory biomarkers that contribute to the development of metabolic diseases, but the effect remains controversial. This meta-analysis aimed to assess the effects of betaine supplementation on inflammatory markers based on randomised controlled trials (RCTs). PubMed, Web of Science and ResearchGate databases were searched up to March 2023. A total of 6 RCTs with 7 intervention trials involving 277 participants were included. Betaine supplementation led to a slight reduction in levels of circulating IL-1ß of 0.65 pg/mL (95% CI, -1.23 to -0.06) with high heterogeneity (I2 = 95%). Betaine produced a small but nonsignificant reduction in levels of circulating CRP (0.33 mg/L; 95% CI, -1.79 to 1.14), IL-6 (0.47 pg/mL; 95% CI, -1.13 to 0.18) and TNF-α (0.25 pg/mL; 95% CI, -0.98 to 0.48). The present meta-analysis does not provide sufficient evidence to conclude that betaine supplementation improved the inflammation state.

SAHA Inhibits Somatic Hyperalgesia Induced by Stress Combined with Orofacial Inflammation Through Targeting Different Spinal 5-HT Receptor Subtypes.

Epigenetic regulation of gene expression has been implicated in the development of chronic pain. However, little is known about whether this regulation is involved in the development and treatment of chronic pain comorbidities such as fibromyalgia syndrome (FMS) and temporomandibular disorder (TMD), a comorbidity predominantly occurring among women. Here we explored the impact of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) on somatic hyperalgesia induced by stress or stress combined with orofacial inflammation, which mimicked the comorbidity of FMS and TMD in rats. Our data showed that somatic thermal hyperalgesia and mechanical allodynia induced by both conditions were completely prevented by intrathecal injection of SAHA, which upregulated 5-HT2C receptors but downregulated 5-HT3 receptors in the spinal dorsal horn. Subsequent spinal administration of RS102221 to inhibit 5-HT2C receptors or SR57227 to activate 5-HT3 receptors reversed the analgesic effect of SAHA under both conditions. These results indicate that SAHA attenuates the pro-nociceptive effects of stress combined with orofacial inflammation and the effects of stress alone. This likely occurs through epigenetic regulation of spinal 5-HT2C and 5-HT3 receptor expression, suggesting that SAHA has potential therapeutic value in FMS or comorbid FMS-TMD patients with somatic hyperalgesia.

Evaluation of the toxicity of herbicide topramezone to Chlorella vulgaris: Oxidative stress, cell morphology and photosynthetic activity.

Topramezone is a new, highly selective herbicide of pyrazole structure for the post-emergence control of broadleaf and grass weeds in corn. In this study, the effects of topramezone on C. vulgaris, especially in relation to the cell growth, oxidative stress, cell morphology and photosynthetic activity were assessed. Results showed that topramezone treatment was detrimental to C. vulgaris growth during the 24-96h of exposure. The changes in cells pigments content and relative transcript of photosynthesis-related genes, which implies that topramezone disrupted the photosynthetic system. Moreover, topramezone induced membrane permeability in a significant proportion of cells with a maximum damage rate of 40.40%, and morphology of cells was more complicated than the control group. TEM images also revealed that topramezone compromised the integrity of the cells. The data corroborated topramezone induced ROS triggered oxidative stress, leading to an increase of MDA. These results suggested that topramezone could have significant effects on growth and physiological functions in algae species, and we supposed that this herbicide affected all of these parameters and the observed effects can be explained by the generation of oxidative stress. This research helps to understand how topramezone affects C. vulgaris and provides a scientific basis for applications of topramezone in aquatic environment.

Optimization of land use planning under multi-objective demand-the case of Changchun City, China.

Modeling and scenario analysis are the core elements of land use change research, and in the face of the increasingly serious ecological and environmental problems in urbanization, it is important to carry out land use simulation studies under different protection constraints for scientific planning and policy formulation. Taking Changchun City, the capital of Jilin Province, a pilot national eco-province, as an example, a CLUE-S model with coupled landscape ecological security patterns was constructed to predict and simulate the land use structure and layout under multi-objective optimization scenarios in the planning target year (2030), and the results were analyzed based on landscape index evaluation. The study found the following: (i) the proportion of ecological land area under low, medium, and high security levels in the study area was 8.7%, 64.8%, and 26.5%, respectively; (ii) under the current development trend scenario, the trend of increasing fragmentation of cultivated land patches in Changchun in 2030 will remain unchanged, with construction land spreading along the periphery in a compact and continuous pattern, while ecological land will be seriously encroached upon; and (iii) in the 2030 multi-objective optimization scenario, land use patches of all types will begin to show a tendency to cluster, with less landscape fragmentation and more connectivity, while cultivated land and construction land will also begin to converge and do not deteriorate as a result of spatial conflicts over ecological land.

Comparative study of robotic-assisted single-incision-plus-one port and single-incision laparoscopic choledochal cyst excision.

Objective: To compare the efficacy of robotic-assisted single-incision-plus-one-port laparoscopic choledochal cyst excision (R-SILC + 1) and single-incision laparoscopic choledochal cyst (SILC) in treating pediatric choledochal cyst (CDC). Methods: We retrospectively analyzed the clinical data of patients diagnosed with CDC in our hospital from June 2021 to October 2023. Among them, patients underwent either R-SILC + 1 or SILC procedures. Demographic parameters, operative details, and postoperative outcomes were studied. Results: A total of forty-nine patients were included, with 23 children undergoing R-SILC + 1 and 26 children undergoing SILC. There were no statistically significant differences in demographic data, postoperative pain scores, and postoperative complication rates between the two groups (all p > 0.05). Compared with the SILC group, the R-SILC + 1 group demonstrated less intraoperative bleeding volume (10.4 ± 3.6 vs. 15.0 ± 3.6 ml, p < 0.05), a shorter indwelling time of the abdominal drainage tube [5(5,6) vs. 7(5.8,8.3) d, p < 0.05], a shorter postoperative fasting time [4(3,4) vs. 6(5,7) d, p < 0.05], and a shorter postoperative discharge time [6(6,7) vs. 8(6,11) d, p < 0.05]. However, the R-SILC + 1 group had a longer operation time [388(295,415) vs. 341(255.8,375.2) min, p < 0.05] and higher hospitalization cost (7.9 ± 0.4 vs. 3.2 ± 0.3 ten thousand, p < 0.05). Conclusion: Compared with the SILC group, the R-SILC + 1 group demonstrated clear advantages in treating pediatric CDC, but it is associated with a prolonged learning curve and operation time, and high costs. With improvements in physician experience and technological advancements, its potential will be further unleashed.

Effect of Fiber Content on Mechanical Properties of Fiber-Reinforced CGF All-Solid-Waste Binder-Solidified Soil.

In order to realize the resource utilization of solid waste and improve the tensile strength and toughness of soil, CCR-GGBS-FA all-solid-waste binder (CGF) composed of general industrial solid waste calcium carbide residue (CCR), ground granulated blast furnace slag (GGBS) and fly ash (FA) was used instead of cement and combined with polypropylene fiber to strengthen the silty soil taken from Dongying City, China. An unconfined compressive strength test (UCS test) and a uniaxial tensile test (UT test) were carried out on 10 groups of samples with five different fiber contents to uncover the effect of fiber content on tensile and compressive properties, and the reinforcement mechanism was studied using a scanning electron microscopy (SEM) test. The test results show that the unconfined compressive strength, the uniaxial tensile strength, the deformation modulus, the tensile modulus, the fracture energy and the residual strength of fiber-reinforced CGF-solidified soil are significantly improved compared with nonfiber-solidified soil. The compressive strength and the tensile strength of polypropylene-fiber-reinforced CGF-solidified soil reach the maximum value when the fiber content is 0.25%, as the unconfined compressive strength and the tensile strength are 3985.7 kPa and 905.9 kPa, respectively, which are 116.60% and 186.16% higher than those of nonfiber-solidified soil, respectively. The macro-micro tests identify that the hydration products generated by CGF improve the compactness through gelling and filling in solidified soil, and the fiber enhances the resistance to deformation by bridging and forming a three-dimensional network structure. The addition of fiber effectively improves the toughness and stiffness of solidified soil and makes the failure mode of CGF-solidified soil transition from typical brittle failure to plastic failure. The research results can provide a theoretical basis for the application of fiber-reinforced CGF-solidified soil in practical engineering.

Construction of nomogram based on clinical factors for the risk prediction of postoperative complications in children with choledochal cyst.

Objective: The aim of the study was to develop a prediction nomogram based on clinical factors to assess the risk of postoperative complications in children with congenital choledochal cyst. Methods: The clinical data from 131 children who underwent choledochal cyst resection and Roux-en-Y hepaticojejunostomy in our hospital between January 2016 and December 2022 were retrospectively analyzed. The general information, clinical symptoms, procedure, biochemical indicators, and imaging data were recorded. A prolonged hospital stay induced by postoperative complications or a follow-up over 6 months was assessed as the event outcome. A logistics regression analysis was performed to screen for risk factors with statistical significance in inducing postoperative complications. Then, with the dataset split into the training group and internal validation group, the nomogram for the prediction of postoperative complications was developed based on a computer algorithm. In addition, the receiver operating characteristic (ROC) curve and calibration curve were performed for nomogram verification. Results: Of 131 children, the multivariate logistics regression analysis suggested that age ≤2 years [odds ratio (OR) 0.93; 95% confidence interval (CI) 0.15-5.65; p = 0.938], Todani classification type 1 (OR 36.58; 95% CI 4.14-871.74; p = 0.005), cyst wall thickness >0.4 cm (OR 10.82; 95% CI 2.88-49.13; p < 0.001), with chronic cholecystitis (OR 7.01; 95% CI 1.62-38.52; p = 0.014), and choledochal cyst diameter (OR 1.01; 95% CI 0.99-1.03; p = 0.370) were predictors associated with the postoperative complications of choledochal cysts. The data were randomly divided into the training group (n = 92) and internal validation group (n = 39) to build the prediction nomogram including the appeal factors. The accuracy and discrimination of the model were evaluated using a ROC curve and calibration curve. The results showed that the nomogram area under the ROC curve [area under the curve (AUC) = 0.894; 95% CI 0.822-0.966; p < 0.001], validation (AUC = 0.844; 95% CI 0.804-0.952; p < 0.001), and Brier = 0.120 (95% CI 0.077-0.163p; p < 0.001) were indicative of the good stability and calibration of the predictive nomogram. Conclusion: The prognosis of congenital choledochal cysts was associated with multiple aspects of clinical factors. Combined with the internal validation, the novel prediction nomogram was suitable for evaluating the individualized risk of postoperative complications of choledochal cysts. The prediction nomogram could provide a more accurate strategy of procedure and postoperative follow-up for children with choledochal cysts.

Research of wet string grid dust removal vehicle and creation of dust control area on tunnel working face.

The spread of blast dust throughout the tunnel becomes a common problem in drill and blast tunneling,the key to breaking through the problem is the creation of a dust control area on the working face.In view of this key problem, a wet string grid dust removal crawler vehicle was developed, the power of the vehicle came from the diesel generator, and further, the air cooler of the diesel generator was used to generate airflow, and the suction process formed by the on-board axial flow fan was coupled to create a dust control area of the working face after blasting.The results show that when the frequency of the axial flow fan is adjusted to 30 Hz, the airflow speed of the wet chord grid section reaches 3.34 m/s, and the dust removal efficiency is the highest, with a value of 94.3%.Compared with the non-use of the dust removal vehicle, when the air outlet of the air cooler is front, horizontal front, horizontal rear, the dust concentration is reduced by 74.37, 92.39 and 50.53%.Finally, the optimized wet grid dust removal crawler was installed in the Dading tunnel, and the actual dust reduction efficiency was about 78.49%. The results obtained provide an important technical way to improve the working environment of the drilling and blasting construction tunnel.

A trans-umbilical single-site plus one robotic-assisted surgery for choledochal cyst resection in children.

Objective: The purpose of this study is to compare the intraoperative and postoperative outcomes of a trans-umbilical single-site plus one robot-assisted surgery and a trans-umbilical single-site laparoscopic surgery in the treatment of choledochal cysts. Methods: We retrospectively analyzed clinical data from 49 children diagnosed with choledochal cysts who were admitted to our hospital between June 2020 and December 2023. Among these patients, 24 underwent a trans-umbilical single-site plus one Da Vinci robot-assisted surgery (the robot group) and 25 underwent a trans-umbilical single-site laparoscopic-assisted surgery (the laparoscopic group). We compared differences in intraoperative and postoperative outcomes between the two groups. Results: There was no significant difference between the two groups of patients in terms of gender, age, weight, clinical symptoms, maximum cyst diameter, type, postoperative complications, and facial expression, leg movement, activity, crying, and comfortability (FLACC) scoring (p > 0.05). Compared with the patients in the laparoscopic group, those in the robot group had less intraoperative bleeding [10 (8-12) vs. 15 (11.5-18) ml, p < 0.001] and required less postoperative drainage tube indwelling time [5 (4-6) vs. 7 (5.5-8) day, p < 0.001], less postoperative fasting time [4 (3-4) vs. 6 (5-7) days, p < 0.001], and less postoperative hospitalization time [6 (6-7) vs. 8 (6-10) days, p < 0.001], but they required more operative time [385.5 (317.0-413.3) vs. 346.0 (287.0-376.5) min, p = 0.050] and consumed more hospitalization expenses (79,323 ± 3,124 vs. 31,121 ± 2,918 yuan, p < 0.001). Conclusion: The results of this study showed a shorter hospitalization time, quicker postoperative recovery, and less tissue damage but a higher cost and a longer operation time in patients who chose robotic surgery rather than laparoscopic surgery. With the continuous expansion of the scale of installed robot-assisted surgical systems and the gradual accumulation of the technical experience of surgeons, robot-assisted surgery may slowly surpass, and shows a trend to replace, laparoscopy because of its advantages.

A Glutathione Peroxidase-Mimicking Nanozyme Precisely Alleviates Reactive Oxygen Species and Promotes Periodontal Bone Regeneration.

The use of oxidoreductase nanozymes to regulate reactive oxygen species (ROS) has gradually emerged in periodontology treatments. However, current nanozymes for treating periodontitis eliminate ROS extensively and non-specifically, ignoring the physiological functions of ROS under normal conditions, which may result in uncontrolled side effects. Herein, using the MIL-47(V)-F (MVF) nanozyme, which mimics the function of glutathione peroxidase (GPx), it is proposed that ROS can be properly regulated by specifically eliminating H2 O2 , the most prominent ROS. Through H2 O2 elimination, MVF contributes to limiting inflammation, regulating immune microenvironment, and promoting periodontal regeneration. Moreover, MVF stimulates osteogenic differentiation of periodontal stem cells directly, further promoting regeneration due to the vanadium in MVF. Mechanistically, MVF regulates ROS by activating the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) pathway and promotes osteogenic differentiation directly through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. A promising periodontitis therapy strategy is presented using GPx-mimicking nanozymes through their triple effects of antioxidation, immunomodulation, and bone remodeling regulation, making nanozymes an excellent tool for developing precision medicine.

Injectable CNPs/DMP1-loaded self-assembly hydrogel regulating inflammation of dental pulp stem cells for dentin regeneration.

Vital pulp preservation, which is a clinical challenge of aseptic or iatrogenic accidental exposure of the pulp, in cases direct pulp capping is the main technology. Human dental pulp stem cells (hDPSCs) play a critical role in pulp tissue repair, but their differentiative ability could be inhibited by the potential infection and inflammatory response of the exposed pulp. Therefore, inflammatory regulation and differentiated promotion of hDPSCs are both essential for preserving living pulp teeth. In this study, we constructed a functional dental pulp-capping hydrogel by loading cerium oxide nanoparticles (CNPs) and dentin matrix protein-1 (DMP1) into an injectable Fmoc-triphenylalanine hydrogel (Fmoc-phe3 hydrogel) as CNPs/DMP1/Hydrogel for in situ drugs delivery. With a view to long-term storage and release of CNPs (anti-inflammatory and antioxidant) to regulate the local inflammatory environment and DMP1 to promote the regeneration of dentin. Results of CCK-8, LDH release, hemolysis, and Live/Dead assessment of cells demonstrated the good biocompatibility of CNPs/DMP1/Hydrogel. The levels of alkaline phosphatase activity, quantification of the mineralized nodules, expressions of osteogenic genes and proteins demonstrated CNPs/DMP1/Hydrogel could protect the activity of hDPSCs' osteogenic/dentinogenic differentiation by reducing the inflammation response via releasing CNPs. The therapy effects were further confirmed in rat models, CNPs/DMP1/Hydrogel reduced the necrosis rate of damaged pulp and promoted injured pulp repair and reparative dentin formation with preserved vital pulps. In summary, the CNPs/DMP1/Hydrogel composite is an up-and-coming pulp-capping material candidate to induce reparative dentin formation, as well as provide a theoretical and experimental basis for developing pulp-capping materials.

Valproate attenuates somatic hyperalgesia induced by orofacial inflammation combined with stress through inhibiting spinal IL-6 and STAT1 phosphorylation.

Temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS) may present as comorbid conditions, but treatment options are ineffective. The purpose of this study was to investigate whether valproate (VPA) attenuates somatic hyperalgesia induced by orofacial inflammation combined with stress, which represents a model of pain associated with TMD and FMS comorbidity, and to explore the potential mechanisms. The results showed that VPA inhibited somatic hyperalgesia induced by orofacial inflammation combined with stress, and down-regulated the interleukin-6 (IL-6) expression in the L4-L5 spinal dorsal horn of female rats. The anti-nociceptive effect of VPA was blocked by single or 5 consecutive day intrathecal administration of recombinant rat IL-6. Orofacial inflammation combined with stress up-regulated the ratio of phosphorylated signal transducer and activator of transcription 1 (p-STAT1) to STAT1 (p-STAT1/STAT1) in the spinal cord. VPA did not affect the STAT1 expression, while it down-regulated the ratio of p-STAT1/STAT1. The expression of STAT3 and the ratio of p-STAT3/STAT3 were not affected by orofacial inflammation combined with stress and VPA treatment. Intrathecal administration of exogenous IL-6 up-regulated the ratio of p-STAT1/STAT1. These data indicate that VPA attenuated somatic hyperalgesia induced by orofacial inflammation combined with stress via inhibiting spinal IL-6 in female rats, and the mechanism may involve the alteration of activation status of spinal STAT1. Thus, VPA may be a new candidate analgesic that targets IL-6 and STAT1 for the treatment of pain associated with the comorbidity of TMD and FMS.

Remodeling periodontal osteoimmune microenvironment through MAPK/NFκB phosphorylation pathway of macrophage via intelligent ROS scavenging.

Periodontitis is an inflammatory disorder which leads to the defect of tooth-supporting tissue, especially in alveolar bone. During this process, the polarization behavior of macrophages affects immune inflammation and bone regeneration in which reactive oxygen species (ROS) play an essential role. ROS level should be regulated to the physiological level to protect stem cells from the inflammatory immune microenvironment. Our previous study constructed a ROS-responsive nanoplatform (Pssl-NAC), which possessed ROS-responsive antioxidative effect and could be potentially applied in periodontitis. However, the connection among bone regeneration, inflammation and oxidative stress remained in osteoimmune regulation is not clear. To further investigate the mechanism of the way how Pssl-NAC works in the treatment of periodontitis would be meaningful. Here, we investigated the effect of PssL-NAC in the regulation of the osteoimmune microenvironment through macrophage polarization. Results show PssL-NAC regulated the macrophage polarization direction in an inflammatory environment by maintaining an appropriate level of intracellular ROS, in which the MAPK/NFκB phosphorylation pathway is particularly important. In the macrophage-human periodontal ligament stem cells (hPDLSCs) co-culture system, PssL-NAC treatment significantly enhanced the osteogenic differentiation of hPDLSCs. In vivo experiment further confirmed the M2-like macrophages increased in the periodontal tissue of rats, and the expression of iNOS and p65 decreased after PssL-NAC treatment. In conclusion, PssL-NAC regulates the osteoimmune microenvironment and protects stem cells from oxidative stress injury for bone regeneration, which provides a strategy for the treatment of periodontitis.

Cooling Effect of Urban Blue and Green Spaces: A Case Study of Changsha, China.

The cooling effects of blue-green spaces on the urban heat island effect are complex and different. The purpose of this study is to simulate how the cooling effect of blue-green space changes with its size and shape. The cooling effects of 53 green patches and 28 water bodies in Changsha were extracted based on Landsat images. A surface fitting model was used to quantitatively reveal the relationship between the cooling effect of blue-green space and its size and shape. The results show that the cooling effects of blue-green spaces were enhanced with the increasing size, and then would become stable after a certain range (threshold). Certain thresholds were identified between the blue and green space areas (2.98 ha and 3.15 ha, respectively) and the cooling distance, and between the blue and green space areas (4.84 ha and 4.92 ha, respectively) and the cooling magnitude. In addition, the green space with an area of 9.08 ha and landscape shape index (LSI) of 2.97 could achieve a better cooling distance (413.46 m); and the blue space with an area of 29.4 ha and LSI of 1.75 could achieve a better cooling magnitude (5.17 °C). These findings provide useful guidelines for urban planning and improving urban livability in other regions with terrain and climate conditions similar to Changsha.

Construction and Validation of a Prognostic Model Based on Novel Senescence-Related Genes in Non-Small Cell Lung Cancer Patients with Drug Sensitivity and Tumor Microenvironment.

Cellular senescence contributes to cancer pathogenesis and immune regulation. Using the LASSO Cox regression, we developed a 12-gene prognostic signature for lung adenocarcinoma (LUAD) from The Cancer Genome Atlas (TCGA) and a Gene Expression Omnibus (GEO) dataset. We assessed gene expression, drug sensitivity, immune infiltration, and conducted cell line experiments. High-risk LUAD patients showed increased mortality risk and shorter survival (P < 0.001). Senescence-related gene analysis indicated differences in protein phosphorylation and DNA methylation between normal individuals and LUAD patients. The high-risk group showed a positive association with PD-L1 expression (P = 0.003). Single-cell sequencing data suggested PEBP1 might significantly impact T cell infiltration. We predicted potential sensitive compounds for 12 senescence genes and found GAPDH promoted cell line proliferation. We established a novel prognostic system based on a newly identified senescence gene. High-risk patients had elevated immunosuppressive markers, and PEBP1 might influence T cell infiltration significantly. GAPDH, expressed at higher levels in tumors, could affect cancer progression. Our drug prediction model may guide treatment selection.

Sex difference in response to non-small cell lung cancer immunotherapy: an updated meta-analysis.

BACKGROUND: Studying sex differences in the efficacy of immunotherapy may contribute to the practice of the precision medicine, especially in non-small cell lung cancer (NSCLC), a kind of cancer with sexual bimorphism. METHODS: Published randomized controlled trials (RCTs), published by PubMed, Medline, Embase, and Scopus, before 15 June 2022, testing immunotherapy (CTLA-4 or PD-1/L1 inhibitor alone, combination or with chemotherapy) versus non-immunotherapy (receiving chemotherapy or placebo only) were included to assess different efficacy between males and females. The primary endpoint was overall survival (OS). This meta-analysis was registered with PROSPERO (CRD42022298439). RESULTS: Sixteen RCTs, involving 10,155 patients with advanced NSCLC, was collected in this meta-analysis. The pooled HR comparing immunotherapy vs non-immunotherapy were 0.76 (95%CI 0.71-0.81) for males and 0.74 (95%CI 0.63-0.87) for females. The pooled HRs comparing immune-checkpoint inhibitors (ICIs) plus chemotherapy versus chemotherapy were 0.79 (95%CI 0.70-0.89) for males and 0.63 (95%CI 0.42-0.92) for females. The pooled HRs comparing ICIs versus chemotherapy were 0.74 (95%CI 0.67-0.81) for males and 0.83 (95%CI 0.73-0.95) for females. In squamous NSCLC, the pooled HRs comparing immunotherapy vs non-immunotherapy were 0.73 (95%CI 0.58-0.91) for males and 0.74 (95%CI 0.37-1.48) for females. In non-squamous NSCLC, the pooled HRs comparing immunotherapy versus non-immunotherapy were 0.62 (95%CI 0.71-0.94) for males and 0.59 (95%CI 0.39-0.89) for females. CONCLUSION: Compared to chemotherapy, immunotherapy can improve the prognosis of patients with advanced NSCLC. Meanwhile, there are sex differences in the efficacy of immunotherapy.KEY MESSAGECompared to chemotherapy, immunotherapy can improve the prognosis of patients with advanced NSCLC.The most interesting thing in this study is that immunotherapy showed significant sex differences in the treatment of squamous NSCLC.

Remodeling the periodontitis microenvironment for osteogenesis by using a reactive oxygen species-cleavable nanoplatform.

Modestly removing the excessive reactive oxygen species (ROS) plays a crucial role in regulating the microenvironment of periodontitis and provides favorable conditions for osteogenesis. However, the current strategy for scavenging ROS is not controllable, substantially limiting the outcomes in periodontitis. Herein, we introduced a controllable ROS-scavenging nanoplatform by encasing N-acetylcysteine (NAC, (a well-known ROS scavenger) into tailor-made ROS-cleavable amphiphilic polymer nanoparticles (PEG-ss-PCL NPs) as an intracellular delivery carrier. The existing ROS in the inflammatory microenvironment facilitated polymer degradation via breakage of thioketal bonds, and then led to encapsulated NAC release. NAC eliminated all ROS induced by lipopolysaccharide (LPS), while PssL-NAC adjusted the ROS level slightly higher than that of the control group. The percentage of apoptotic cells cultured with NAC and PssL-NAC decreased observably compared with that of cells cultured with 10 µg/ml LPS. The microenvironment regulated by PssL-NAC was highly suitable for osteogenic differentiation based on PCR and Western blot results, which showed higher expression levels of BMP2, Runx2, and PKA. Analysis of ALP activity and Alizarin red S staining showed consistent results. Additionally, the injection of PssL-NAC into the periodontitis area could alleviate the tissue destruction induced by ligation of the maxillary second molar. PssL-NAC showed a better ability to decrease osteoclast activity and inflammation, consequently improving the restoration of destroyed tissue. Our study suggests that ROS-responsive polymer nanoparticles loaded with NAC (PssL-NAC) can be new promising materials for the treatment of periodontitis. STATEMENT OF SIGNIFICANCE: More and more studies indicate that periodontal tissue damage is closely related to the high reactive oxygen species (ROS) environment. Excessive ROS will aggravate periodontal tissue damage and is not conducive to tissue repair. However, as an essential signal molecule in human physiological activities, ROS absence is also useless for tissue repair. In this study, we proposed to improve ROS imbalance in the environment of periodontitis as a strategy to promote periodontal regeneration and successfully synthesized a smart drug-releasing nanoplatform that can respond to ROS. Besides, we validated its ability to regulate the ROS environment and promote osteogenesis through experimental data in vivo and in vitro.

Spinal CCK contributes to somatic hyperalgesia induced by orofacial inflammation combined with stress in adult female rats.

In some chronic primary pain conditions such as temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS), mild or chronic stress enhances pain. TMD and FMS often occur together, but the underlying mechanisms are unclear. The purpose of this study was to investigate the role of cholecystokinin (CCK) in the spinal cord in somatic hyperalgesia induced by orofacial inflammation combined with stress. Somatic hyperalgesia was detected by the thermal withdrawal latency and mechanical withdrawal threshold. The expression of CCK1 receptors, CCK2 receptors, ERK1/2 and p-ERK1/2 in the spinal cord was examined by Western blot. After the stimulation of orofacial inflammation combined with 3 day forced swim, the expression of CCK2 receptors and p-ERK1/2 protein in the L4-L5 spinal dorsal horn increased significantly, while the expression of CCK1 receptors and ERK1/2 protein remained unchanged. Intrathecal injection of the CCK2 receptor antagonist YM-022 or mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor PD98059 blocked somatic hyperalgesia induced by orofacial inflammation combined with stress. Intrathecal administration of the MEK inhibitor blocked somatic sensitization caused by the CCK receptor agonist CCK8. The CCK2 receptor antagonist YM-022 significantly reduced the expression of p-ERK1/2. These data indicate that upregulation of CCK2 receptors through the MAPK pathway contributes to somatic hyperalgesia in this comorbid pain model. Thus, CCK2 receptors and MAPK pathway may be potential targets for the treatment of TMD comorbid with FMS.