Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

BACKGROUND:In recent years,a variety of lasers have been widely used in various diseases related to stomatology,including the prevention and treatment of dental caries. OBJECTIVE:To investigate the effect of neodymium-doped:yttrium aluminum perovskite(Nd:YAP)laser combined with two remineralizers on early enamel caries in vitro. METHODS:Early enamel caries models in vitro were artificially established by 60 enamel blocks and randomly divided into 6 groups(n=10).Group A did not undergo any treatment but underwent extracorporeal pH circulation.Group B underwent remineralization of dentin(the main component of casein phosphopeptide-amorphous calcium phosphate composite)and extracorporeal pH circulation.Group C underwent remineralization treatment of Sensodyne toothpaste(the main component of bioactive glass)and then underwent extracorporeal pH circulation.Group D received Nd:YAP laser irradiation and extracorporeal pH circulation.Group E was treated with Nd:YAP laser irradiation,with remineralization of dentin,and then with extracorporeal pH circulation.In group F,Nd:YAP laser irradiation was performed,and then Sensodyne toothpaste was used for remineralization,and the extracorporeal pH circulation was performed;the remineralization treatment was conducted twice a day,and the experimental period was 20 days.Group G was a normal control group,without caries or remineralization,but only underwent extracorporeal pH circulation.After the experiment,the microhardness,morphology and Ca/P ratio of the dental enamel surface were measured in each group. RESULTS AND CONCLUSION:(1)The surface microhardness value of dental enamel in groups B,C and D was higher than that in group A(P<0.000 1);the surface microhardness value of dental enamel in groups E and F was significantly higher than that in groups B,C and D(P<0.000 1),and the surface microhardness value of dental enamel in group F was significantly higher than that in group E(P<0.000 1).(2)Scanning electron microscopy showed that there were a lot of demineralized pores on the enamel surface of group A.There were mineral deposits on the enamel surface of group B,which were uneven and loose.In group C,there were a lot of mineral deposits on the enamel surface,and demineralized pores were found between the calcified masses.The enamel surface of group D was relatively flat;the demineralized pores were significantly smaller than that of group A,and the enamel column interstitium was damaged.In group E,the mineral deposits on the enamel surface were thicker and the demineralized pores were significantly reduced.The mineralized substances deposited on the enamel surface of group F were most dense and uniform and the demineralized pores were small.(3)The Ca/P ratio on the enamel surface of groups B and C was significantly higher than that of group A(P<0.000 1);the Ca/P ratio on the enamel surface of group E was significantly higher than that of groups B,C and D(P<0.000 1),and the Ca/P ratio on the enamel surface of group F was higher than that of group E(P<0.001).(4)These findings indicate that bioactive glass,casein phosphopeptide-amorphous calcium phosphate composite,and Nd:YAP laser after enamel demineralization can promote the remineralization of early enamel caries.Nd:YAP laser combined with bioactive glass or casein phosphopeptide-amorphous calcium phosphate composite can further strengthen the remineralization of dental enamel caries,and the combination of Nd:YAP laser and bioactive glass has the best effect.

Objective:To discuss the effect of the force feedback perceptual rehabilitation training on finger motor function of the patients with finger motor dysfunction after stroke,and to provide the basis for the clinical application and promotion of the force feedback perceptual rehabilitation training.Methods:A total of 86 patients with hand dysfunction after stroke were randomly divided into experimental group(n=43)and control group(n=43),and 3 cases in each group fell off from the experiment,and 80 cases were ultimately completed.On this basis,the patients in two groups received the conventional rehabilitation training for 40 min.The patients in control group received the conventional hand function training for 20 min,while the patients in experimental group received the force feedback perception rehabilitation training for 20 min,once per day,5 days per week,for a total of 6 weeks.The hand function recovery of the patients were evaluated before and after treatment by Action Research Arm Test(ARAT),grip strength,modified Ashworth scale(MAS),total active motion(TAM),Fugl-Meyer motor function assessment-upper limb(FMA-UL)finger motor part score,and Barthel index(BI).Results:Before treatment,there were no statistically significant differences in ARAT total score,grip strength,MAS grade,TAM,FMA-UL finger motor part score,and BI score of the patients between two groups(P＞0.05).After treated for 6 weeks,the ARAT scores,grip strengths,TAM,FMA-UL finger motor part scores,and BI scores of the patients in two groups were all increased than those before treatment(P＜0.05),while the MAS grades of the patients had no significant differences(P＞0.05).After treated for 6 weeks,compared with control group,the grasp score and grip score in ARAT score,and the difference of total ARAT score of the patients in experimental group were increased(P＜0.05),the TAM after treatment and the differences of grip strength,TAM,and FMA-UL finger motor part score of the patients before and after treatment were increased(P＜0.05),while the pinch scores and gross movement scores in ARAT score,MAS grades,and the differences of BI score before and after treatment had no significant differences(P＞0.05).Conclusion:Force feedback perceptual rehabilitation training is helpful in improving the finger motor function of the patients with finger motor dysfunction after stroke.

Objective:To explore the application value of preoperative serum vitamin A level in the prediction of benign or malignant pulmonary nodules.Methods:It was a retrospective cohort study. A total of 1 224 patients who underwent surgery for pulmonary nodules at the General Hospital of the People′s Liberation Army from January 2016 to December 2018 were consecutively included. The demographic information, postoperative pathological results, pulmonary CT findings and preoperative serum vitamin A test results were collected. The preoperative serum vitamin A levels of patients with lung cancer and benign pulmonary nodules were compared pairwise using the χ2 test. Logistic regression analysis was used to analyze the relevant factors for the occurrence of lung cancer and a stratified analysis was performed too. Prediction models for the benignity or malignancy of pulmonary nodules were constructed based on the results of multivariate logistic regression analysis. The efficacy of the models was evaluated, and the optimal preoperative prediction model was determined. The application value of preoperative serum vitamin A levels in predicting the benignity or malignancy of pulmonary nodules was then analyzed. Results:Of the 1 224 patients, postoperative pathology confirmed 1 044 cases with lung cancer and 180 cases with benign pulmonary nodules. The mean preoperative serum vitamin A level of patients with lung cancer was significantly lower than that in patients with benign pulmonary nodules (0.90 vs 1.06 μmol/L) ( Z=-3.493; P<0.001). Preoperative serum vitamin A level was a negative related factor for the occurrence of lung cancer ( OR=0.663, 95% CI: 0.484-0.914) ( P=0.011). In patients aged<60 years ( OR=0.623, 95% CI: 0.428-0.912), male ( OR=0.649, 95% CI: 0.438-0.976), with a body mass index≥24 kg/m 2 ( OR=0.634, 95% CI: 0.420-0.974), no family history of tumors ( OR=0.634, 95% CI: 0.440-0.923), no smoking history ( OR=0.619, 95% CI: 0.412-0.941), no drinking history ( OR=0.625, 95% CI: 0.424-0.933), with pulmonary nodules measuring 1-3 cm in diameter ( OR=0.643, 95% CI: 0.455-0.920), and with solid pulmonary nodules ( OR=0.681, 95% CI: 0.466-1.001), the preoperative serum vitamin A levels were significantly negatively correlated with the occurrence of lung cancer (all P<0.05). The prediction model incorporating preoperative serum vitamin A, CT characteristics of pulmonary nodules (nodule diameter, density), and clinical characteristics (age, gender) showed the best predictive efficacy for the benignity or malignancy of pulmonary nodules (the area under the curve was 0.792). Conclusions:Among patients receiving surgical treatment for pulmonary nodules, the preoperative serum vitamin A level of patients with lung cancer is lower than that of patients with benign pulmonary nodules. The preoperative serum vitamin A level is a negative associated factor for the occurrence of lung cancer. A combined model incorporating the preoperative serum vitamin A level provides a good prediction of benign or malignant pulmonary nodules.

Objective:To evaluate the effectiveness of oral-nasal oxygen supply mouth guard in painless gastroscopy for snoring patients.Methods:The snoring patients who underwent painless gastroscopy at two Endoscopy Centers of Shanghai East Hospital, Tongji University in July 2022 were randomly divided into the observation group (using oral-nasal oxygen supply mouth guard) and the control group (using ordinary nasal oxygen tube and mouth guard). Parameters such as the wearing time and the removal time of the mouth guard, lowest pulse oxygen saturation (SpO 2), incidence of hypoxemia, and the satisfaction of medical staff were compared between the two groups. Results:The wearing time of mouth guard was 11.63±0.84 seconds and the removal time was 5.33±0.76 seconds in the observation group ( n=40), which were lower than those in the control group ( n=47) (14.91±1.21 seconds, t=-14.463, P<0.001; 10.38±0.80 seconds, t=-30.095, P<0.001). The wearing satisfaction score was 9.80±0.61, the lowest SpO 2 was (96.70±3.42)%, the removal satisfaction score was 9.75±0.67, and the anesthesiologists' satisfaction score was 9.20±1.42 in the observation group, which were higher than those in the control group [7.70±0.93, t=12.209, P<0.001; (94.06±3.72)%, t=3.417, P=0.001; 7.96±0.98, t=9.803, P<0.001; 8.13±1.35, t=3.615, P=0.001] with significant difference. There was no significant difference in the incidence of hypoxemia [10.00% (4/40) VS 14.89% (7/47), χ2=0.130, P=0.718] and endoscopic physician satisfaction score (9.30±0.97 VS 9.02±1.31, t=1.112, P=0.269) between the two groups. Conclusion:The oral-nasal oxygen supply mouth guard is easy to wear and remove, effectively reducing SpO 2 fluctuations during painless gastroscopy for snoring patients. It can enhance medical staff satisfaction with high clinical value.

BACKGROUND: Dual regimen dolutegravir (DTG) plus lamivudine (3TC) has demonstrated non-inferior efficacy compared to DTG-based three-drug regimens (3DRs), yet directly comparative data regarding the efficacy and safety of DTG + 3TC and bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) for therapy-naïve people with human immunodeficiency virus (HIV)-1 (PWH) are still limited. We aimed to assess the antiviral potency and safety profiles of DTG + 3TC vs. B/F/TAF based on antiretroviral therapy (ART)-naïve PWH in China. METHODS: This retrospective multicenter study enrolled PWH initiating ART with DTG + 3TC or B/F/TAF from 2020 to 2022 in Guangdong and Guangxi. We analyzed response rates based on target not detected (TND) status using intention-to-treat (ITT) analysis. Subgroups were formed based on baseline viral load (VL) (<100,000 vs . ≥100,000 copies/mL) and CD4 + cell count (<200 vs . ≥200 cell/µL). Median time to TND VL was assessed by Kaplan-Meier method. We also measured changes from baseline in CD4 + cell counts, CD4/CD8 ratio, lipid parameters, weight, creatinine (Cr), estimated glomerular filtration rate (eGFR), and drug-related adverse effects (DRAEs). RESULTS: We enrolled 280 participants, including 137 (48.9%) on DTG + 3TC and 143 (51.1%) on B/F/TAF. At week 48, 96.4% (132/137) on DTG+3TC and 100% (143/143) on B/F/TAF achieved TND ( P = 0.064). At week 12, TND responses were higher with B/F/TAF (78.3% [112/143]) than DTG+3TC (30.7% [42/137]) ( P <0.001). This trend held across subgroups. B/F/TAF achieved TND faster (12 weeks) than DTG+3TC (24 weeks) ( P <0.001). No differences were seen in CD4 + cell count and CD4/CD8 ratio, except in the high-VL subgroup, where B/F/TAF showed better recovery. DRAEs were significantly lower with B/F/TAF (4.9% [7/143]) than with DTG + 3TC (13.1% [18/137]) ( P = 0.016). Lipid parameters, body weight, and Cr increased in both groups over 48 weeks, with DTG+3TC showing a more favorable effect on triglycerides, high-density lipoprotein (HDL) cholesterol, and weight gain. CONCLUSIONS In this real-life study, B/F/TAF led to a faster viral decline and fewer DRAEs compared to DTG+3TC. No significant difference was observed in the TND rate at week 48, regardless of baseline VL and CD4 + cell count. CD4 + recovery was superior for B/F/TAF in participants with high VL. The DTG + 3TC regimen had less impact on metabolic changes than B/F/TAF.
Adult ; Humans ; Anti-HIV Agents/therapeutic use* ; China ; Emtricitabine/pharmacology* ; HIV Infections/drug therapy* ; HIV-1 ; Lamivudine/pharmacology* ; Lipids ; Retrospective Studies

Objective To explore the effects of ginsenoside Rg1 on blood-brain barrier, neuroinflammation and behavioral function of traumatic brain injury (TBI) mouse model.MethodsThe experiment was divided into two parts. In the first part, 27 SPF male BALB/c mice were randomly divided into blank group, sham operation group and TBI model group, with 9 mice in each group. TBI model group was made by controlled cortical impact (CCI) after craniotomy, while sham operation group was only performed craniotomy without any treatment, and the blank group was not treated at all. The effect of modeling was evaluated after operation. In the second part, 50 male BALB/c mice were randomly divided into sham operation group, three different drug dosage groups and solvent (DMSO) control group, with 8 mice in each group. The drug treatment groups were injected with ginsenoside Rg1 at the doses of 10, 20 and 40 mg/kg respectively 6 hours after TBI model had been successfully established, while the DMSO control group was given the same amount of 1% DMSO for one week, twice a day. Modified neurological severity scores (mNSS) were performed on the 1st, 3rd, 7th and 14th day after modeling, and the blood-brain barrier leakage was detected by Western blotting on the 3rd day after modeling. On the 14th and 16th day, the elevated cross maze test and water maze test were used to detect the neurobehavioral function. On the 28th day after anesthesia and perfusion, the brains were taken out, and the neuroinflammation such as activation of microglia and astrocytes was observed by immunofluorescence staining.ResultsThe expression level of MMP-9, a marker of blood-brain barrier, decreased in ginsenoside Rg1 treatment group (P<0.01). The number of microglia （Iba-1 positive) and astrocyte (GFAP positive) cells decreased significantly (P<0.05), which indicated that neuroinflammation was inhibited, and the best effect was achieved at the dosage of 20 mg/kg (P<0.01). The mNSS of mice in ginsenoside Rg1 treatment group were significantly lower than those in DMSO control group (P < 0.01), and the proportion of times they entered the open arm was significantly higher than that in DMSO control group (P < 0.05). The time ratio in the quadrant where the water maze experimental platform was located and the times of crossing the platform were significantly higher than those in control group (P < 0.05), and the dosage of 20 mg/kg had the best effect.ConclusionThe TBI mouse model was successfully constructed and applied to the study of ginsenoside Rg1 repair of mouse traumatic brain injury. Ginsenoside Rg1 can significantly improve blood-brain barrier, alleviate neuroinflammation and improve neurobehavioral function in TBI model mice, and the effect is the most significant at the dose of 20 mg/kg.

Objective To investigate the expression and clinical significance of TM9SF3 in lung adenocarcinoma (LUAD). Methods TCGA and GEPIA databases were used to screen the differentially-expressed TM9SF family molecules and analyze their effects on patient prognosis with LUAD. The expression and localization of TM9SF3 in LUAD patients were verified by a human proteomic mapping database, Western blot assay, and polymerase chain reaction assay. Herein, the GSEA was used for the signal pathway enrichment analysis of TM9SF3-related genes. Meanwhile, the TIMER database and CIBERSORT algorithm were used to analyze the correlation between differentially-expressed TM9SF3 and the degree of immune cell infiltration. Results The expression of TM9SF3 in LUAD was significantly increased and had a significant adverse effect on the prognosis of LUAD patients. In addition, immunoblotting and polymerase chain reaction confirmed that TM9SF3 was highly expressed in LUAD. Meanwhile, the genes related to TM9SF3 expression were mainly enriched in cell signaling pathways regulating immune cell activity. The expression of TM9SF3 was significantly correlated with the expression changes of six immune cells. Conclusion TM9SF3 is differentially expressed in LUAD and may be used as a potential prognostic marker for LUAD patients. TM9SF3 can also change the level of immune cell infiltration in LUAD patients and is expected to be a new potential target for LUAD immunotherapy.

Elucidating the active components of traditional Chinese medicine(TCM)is essential for understanding the mechanisms of TCM and promote its rational use as well as TCM-derived drug development.Recent studies have shown that surface plasmon resonance(SPR)technology is promising in this field.In the present study,we propose an SPR-based integrated strategy to screen and analyze the major active components of TCM.We used Radix Paeoniae Alba(RPA)as an example to identify the compounds that can account for its anti-inflammatory mechanism via tumor necrosis factor receptor type 1(TNF-R1).First,RPA extraction was analyzed using an SPR-based screening system,and the potential active in-gredients were collected,enriched,and identified as paeoniflorin and paeonol.Next,the affinity con-stants of paeoniflorin and paeonol were determined as 4.9 and 11.8 μM,respectively.Then,SPR-based competition assays and molecular docking were performed to show that the two compounds could compete with tumor necrosis factor-α(TNF-α)while binding to the subdomain 1 site of TNF-R1.Finally,in biological assays,the two compounds suppressed cytotoxicity and apoptosis induced by TNF-α in the L929 cell line.These findings prove that SPR technology is a useful tool for determining the active in-gredients of TCM at the molecular level and can be used in various aspects of drug development.The SPR-based integrated strategy is reliable and feasible in TCM studies and will shed light on the eluci-dation of the pharmacological mechanism of TCM and facilitate its modernization.

Ulcerative colitis (UC) is a chronic and recurrent inflammatory bowel disease (IBD) that has become a major gastroenterologic problem during recent decades. Numerous complicating factors are involved in UC development such as oxidative stress, inflammation, and microbiota disorder. These factors exacerbate damage to the intestinal mucosal barrier. Spirulina platensis is a commercial alga with various biological activity that is widely used as a functional ingredient in food and beverage products. However, there have been few studies on the treatment of UC using S. platensis aqueous extracts (SP), and the underlying mechanism of action of SP against UC has not yet been elucidated. Herein, we aimed to investigate the modulatory effect of SP on microbiota disorders in UC mice and clarify the underlying mechanisms by which SP alleviates damage to the intestinal mucosal barrier. Dextran sulfate sodium (DSS) was used to establish a normal human colonic epithelial cell (NCM460) injury model and UC animal model. The mitochondrial membrane potential assay 3-‍‍(4,5-dimethylthiazol-2-yl)-2,‍5-diphenyltetrazolium bromide (MTT) and staining with Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) and Hoechst 33258 were carried out to determine the effects of SP on the NCM460 cell injury model. Moreover, hematoxylin and eosin (H&E) staining, transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qPCR), western blot, and 16S ribosomal DNA (rDNA) sequencing were used to explore the effects and underlying mechanisms of action of SP on UC in C57BL/6 mice. In vitro studies showed that SP alleviated DSS-induced NCM460 cell injury. SP also significantly reduced the excessive generation of intracellular reactive oxygen species (ROS) and prevented mitochondrial membrane potential reduction after DSS challenge. In vivo studies indicated that SP administration could alleviate the severity of DSS-induced colonic mucosal damage compared with the control group. Inhibition of inflammation and oxidative stress was associated with increases in the activity of antioxidant enzymes and the expression of tight junction proteins (TJs) post-SP treatment. SP improved gut microbiota disorder mainly by increasing antioxidant enzyme activity and the expression of TJs in the colon. Our findings demonstrate that the protective effect of SP against UC is based on its inhibition of pro-inflammatory cytokine overproduction, inhibition of DSS-induced ROS production, and enhanced expression of antioxidant enzymes and TJs in the colonic mucosal barrier.
Animals ; Antioxidants/pharmacology* ; Colitis/prevention & control* ; Colitis, Ulcerative/metabolism* ; Colon/metabolism* ; Dextran Sulfate/toxicity* ; Disease Models, Animal ; Gastrointestinal Microbiome ; Inflammation/metabolism* ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Reactive Oxygen Species/metabolism* ; Spirulina