Predictive value of PD-L1 and TMB for short-term efficacy prognosis in non-small cell lung cancer and construction of prediction models.

Objective: To investigate the correlation between programmed death ligand 1(PD-L1), tumor mutation burden (TMB) and the short-term efficacy and clinical characteristics of anti-PD-1 immune checkpoint inhibitor combination chemotherapy in NSCLC patients. The efficacy of the prediction model was evaluated. Methods: A total of 220 NSCLC patients receiving first-line treatment with anti-PD-1 immune checkpoint inhibitor combined with chemotherapy were retrospectively collected. The primary endpoint was short-term efficacy ORR. The correlation between short-term efficacy, PD-L1, TMB, and clinical characteristics using χ2 test or t-test was evaluated. Screen the independent prognostic factors using univariate and multivariate logistic regression analyses, and construct a nomogram prediction model using the "rms" package in R software. Using receiver operating characteristic (ROC) curve analysis to evaluate the independent Prognostic factors and the prediction model. Using decision curve analysis (DCA) to verify the superiority of the prediction model. Results: The mean values of PD-L1, TMB, neutrophils, lymphocytes, neutrophil-to-lymphocyte ratio, and albumin were the highest in the ORR group, PD-L1 expression and TMB correlated with epidermal growth factor receptor expression. Multivariate analyses showed that PD-L1, TMB, and neutrophil were independent prognostic factors for ORR. The area under the ROC curve (AUC) values of the ROC constructed based on these three indicators were 0.7104, 0.7139, and 0.7131, respectively. The AUC value under the ROC of the nomogram model was 0.813. The DCA of the model showed that all three indicators used together to build the prediction model of the net return were higher than those of the single indicator prediction model. Conclusion: PD-L1, TMB, and neutrophils are independent prognostic factors for short-term efficacy. The nomogram prediction model constructed using these three indicators can further improve predictive efficacy of ICIs in patients with NSCLC.

A phase I clinical trial of sonodynamic therapy combined with temozolomide in the treatment of recurrent glioblastoma.

PURPOSE: The prognosis of recurrent glioblastoma (rGBM) is poor, and there is currently no effective treatment strategy. Sonodynamic therapy (SDT) is a new method for cancer treatment that uses a combination of low-frequency ultrasound and sonosensitisers to produce antitumor effects, which have shown good therapeutic effects in preclinical studies. Therefore, we initiated an open, prospective pilot study to evaluate the safety, tolerability, and efficacy of SDT for the treatment of rGBM. METHODS: Nine patients with rGBM were enrolled who had received multiple treatments, but the nidus continued to progress without additional standard treatments. After MRI localisation, porphyrin drugs were injected, and intermittent low-frequency ultrasound therapy was performed for five days. RESULTS: None of the nine patients in this clinical trial showed any clinical, neurological, haematological, or skin-targeted adverse effects associated with SDT. After the completion of the trial, one patient maintained stable disease, and eight patients experienced disease progression. Among the eight with progressive disease, the median progression-free survival time was 84 days. Four patients died, and the median overall survival duration after recurrence was 202.5 days. CONCLUSION: The number of patients in this study was small; therefore, a long-term survival benefit was not demonstrated. However, this study suggests that SDT has potential as a treatment for rGBM and warrants further exploration. Trial information: Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ): ChiCTR2200065992. November 2, 2022, retrospectively registered.

CircMAN1A2 contributes to nasopharyngeal carcinoma progression via enhancing the ubiquitination of ATMIN through miR-135a-3p/UBR5 axis.

Recently, the dysregulation of circRNAs has been increasingly implicated in the pathogenesis of nasopharyngeal carcinoma (NPC). Among these circRNAs, circMAN1A2 has been highlighted for the up-regulated expression in NPC, whereas the underlying mechanisms have not been clearly established. Thus, the aim of this study was to delineate the tumor-supporting role of circMAN1A2 in the oncogenesis and metastases of NPC. We validated through qRT-PCR that circMAN1A2 was highly expressed in NPC tissues and NPC cells. Survival analysis through Kaplan-Meier method showed that the overall survival, disease-free survival, and distant metastasis-free survival of patients was negatively correlated with the expression of circMAN1A2. Then, gain- and loss-of function assays demonstrated that circMAN1A2 knockdown could impede the proliferation, migration, invasion, and EMT in NPC cells. Further, we conducted dual luciferase reporter gene, RIP, and RNA pull down assays, unveiling that circMAN1A2 functioned as a sponge of miR-135a-3p, and miR-135a-3p targeted UBR5. Additionally, UBR5 interacted with ATMIN to foster the ubiquitination of ATMIN, thereby expediting the malignant behaviors of NPC cells as well as the lung and inguinal lymph node metastases of NPC tumors in vivo. Together, our study uncovered the tumor-initiating and pro-metastatic role of circMAN1A2-miR-135a-3p-UBR5-ATMIN axis in NPC regulation that may be a potential therapeutic target for human NPC.

Evidence for genetic causal relationships between gut microbiome, metabolites, and myasthenia gravis: a bidirectional Mendelian randomization study.

Background: Myasthenia gravis (MG) is an autoimmune disease observed to have connections with gut microbiome. We aimed to systematically assess the causal relationships between gut microbiome, gut microbiome-derived metabolites, and MG using Mendelian randomization (MR) approach. Methods: Summary-level genetic datasets from large-scale genome-wide association studies regarding 196 gut microbial taxa from the MiBioGen consortium (n=18,340), 72 derived metabolites from the TwinsUK and KORA studies (n=7,824), and antiacetylcholine receptor (AChR) antibody-positive MG (case=1,873, control=36,370) were employed for MR causal estimates. The inverse-variance weighted (IVW) method was utilized as the main analysis with MR-Egger, maximum likelihood, simple mode, and weighted median as complements. The tests of Cochran's Q, MR-Egger intercept, Steiger, MR-PRESSO and leave-one-out were implemented for sensitivity analyses. Results: The forward MR estimates of IVW revealed significant causal associations of the abundance of phylum Actinobacteria, class Gammaproteobacteria, family Defluviitaleac, family Family XIII, and family Peptococcaceae with a reduced risk of MG. Conversely, the abundance of phylum Lentisphaerae, order Mollicutes RF9, order Victivallales, and genus Faecalibacterium was causally associated with an increased risk of MG. The reversed MR analysis proved negative causal correlations between the MG and the abundance of family Peptostreptococcaceae, genus Romboutsia, and genus Subdoligranulum. Regarding the derived metabolites, the IVW estimates revealed that elevated levels of beta-hydroxyisovalerate and methionine were causally associated with a decreased risk of MG, while increased levels of choline and kynurenine were linked to an increased risk of MG. Furthermore, genetically predicted MG was associated with a decreased level of cholesterol. The results obtained from complementary MR methods were similar. These findings remained robust in all sensitivity analyses. Conclusion: Our MR findings support the causal effects of specific gut microbiome taxa and derived metabolites on AChR antibody-positive MG, and vice versa, yielding novel insights into prevention and therapy targets of MG. Future studies may be warranted for validation and pursuing the precise mechanisms.

[The changes in subjective visual vertical after otolith reduction in patients with BPPV].

Objective:To observe and analyze the changes in subjective visual vertical（SVV） after otolith reduction in patients with BPPV. Methods:46 patients with confirmed BPPV recieving successful otolith reduction were selected as the test group. 31 cases of posterior canal stones and 15 cases of horizontal semicircular canal stones, 29 cases of right ear and 17 cases of left ear. Fifty cases of healthy young volunteers were in the control group. Using the virtual reality SVV examination system, 0° SVV in the positive head were tested in the test group patients before and after the reduction of SVV , and were tested in the control group .The deviation angle of the SVV before and after the otolith reduction in the test group were analyzed. Results:Before otoliths reduction, the SVV was （0.08±3.83）° of right BPPV and was （-1.69±2.23）° of left BPPV. After otoliths reduction, the SVV was （-1.52±3.74）° of right BPPV and was （-1.04±2.50）° of left BPPV. In the control group, the SVV was（-1.57±2.28）° . The changes of SVV deflection angle between the control group and the right BPPV before the otolith reduction, and before and after the otolith reduction in the right BPPV were analyzed, and the differences were all statistically significant. There was no significant difference in SVV deflection angle between the left BPPV（before and after reduction） and the control group. In the test group, after the otolith reduction, 18 cases had larger bias angles, 28 cases had smaller bias angle among which 13 cases the deviation angle even turned to the contralateral side. Conclusion:Utriculare dysfunction in patients with BPPV leads to the judgment error of SVV. Reduction of otolithoid can cause new stimulation to the eutricule and affect its functional status. SVV detection can provide help for the evaluation of utricular function in patients with BPPV.

Dynamic Tannic Acid Hydrogel with Self-Healing and pH Sensitivity for Controlled Release.

Dynamic hydrogels constructed with dynamic chemical bonds often have mechanical strength and self-healing properties. In this paper, tannic acid is combined with lysine-containing F127 through Schiff base. A series of FLaT hydrogels cross-linked by hydrogen bonds and dynamic chemical bonds is prepared, and the influence of Schiff base amount on the performance is discussed. The FLaT hydrogel exhibits reversible sol-gel transition, self-healing, injectability, and pH sensitivity. Increasing the amount of Schiff base can improve the strength, stability, and self-healing ability of the hydrogel. Owing to their low cytotoxicity, linear release pattern, and pH-controlled release rate, the FLaT hydrogels show potential use in drug delivery systems for cancer treatment.

Thermally induced and physically cross-linked hydrogel doped with graphene oxide for controlled release.

Graphene oxide (GO) is an ideal hydrogel material because of its water solubility, non-toxicity, and excellent mechanical properties. Here, we added GO to oligo(lysine)-modified F127 to prepare a series of FLGO composite hydrogels. The FLGO hydrogel was thermally induced, stable and injectable. And the content of GO would affect the sol-gel transition, rheological properties and glass transition temperature of the FLGO hydrogel. GO was connected to the matrix through electrostatic interactions and hydrogen bonds. The cross-linking effect of GO enhanced the FLGO hydrogel. We also studied the release properties of the FLGO hydrogel loaded with anticancer drug 5-fluorouracil. Compared with F127 hydrogel, the FLGO hydrogel showed a linear, slower and stable release pattern within one week. The release rate of FLGO hydrogel could be adjusted by the pH and it was faster under acidic conditions. Therefore, the FLGO hydrogel is expected to be used as a drug release system in the field of biomedicine.

Multiple Physically Cross-Linked F127-α-CD Hydrogels: Preparation, Sol-Gel Transformation, and Controlled Release of 5-Fluorouracil.

Pluronic F127 is a thermosensitive polymer that has been extensively studied and utilized in biomedicine. To improve the gelation properties of F127, α-cyclodextrin was introduced by physical interactions, such as forming inclusion complexes, hydrogen bond self-assembly, and hydrophobic interactions, to prepare F127-α-CD hydrogels. This study explored the temperature-dependent sol-gel transition behavior, gelation mechanism, interior morphology, and controlled release of the anticancer drug 5-fluorouracil. Results showed that hydrogel could be obtained at 1.0%-8.0% weight content of F127. The cross-linking points in this system were PEO-α-CD microcrystalline region and micelle with poly(propylene oxide) as the core. The network inside F127-α-CD hydrogels made it stable and conducive for controlled release. Therefore, this hydrogel is a promising drug release system.

[Cohort study on fuzheng capsule and quxie capsule in reducing relapse and metastasis of cancer in patients with stage II and III colorectal carcinoma after operation].

OBJECTIVE: To study the effect of Fuzheng Capsule (FC) and Quxie Capsule (QC) in reducing relapse and metastasis of colorectal cancer in stage II and III after the cancer had been treated by radical operation and succedent routine radiotherapy and chemotherapy. METHODS: A prospective cohort controlled study was conducted in 101 patients with colorectal cancer in stage II and III after radical operation and routine radiotherapy and chemotherapy, among whom 53 patients were treated with FC and QC and 48 were given no treatment, they were followed up regularly. The rate and time of relapse and metastasis were observed after 1, 2 and 3 years. RESULTS: One-year, 2-year and 3-year relapse-metastasis rate was 0, 2.7% and 14.8% respectively in the treated group, and 6.2% , 24.2% and 30.8% in the control group. Significant difference was found only in the 2-year rate between the two groups (chi-squared = 5.428, P < 0.05). Average time of relapse and metastasis was 26.2 +/- 4.5 months in the treated group and 14.2 +/- 4.2 months in the control group, showing significant difference between the two groups (P < 0.05). CONCLUSION: FC and QC applying in the succedent consolidating treatment for stage II and III colorectal cancer after radical operation might be favourable to reduce relapse and metastasis and improve quality of life, further clinical study with randomized and controlled method is worthwhile to be conducted.