Lachnoclostridium intestinal flora is associated with immunotherapy efficacy in nasopharyngeal carcinoma.

BACKGROUND: Effective biomarkers for assessing anti-PD-1/PD-L1 therapy efficacy in patients with nasopharyngeal carcinoma (NPC) are still lacking. The human gut microbiota has been shown to influence clinical response to anti-PD-1/PD-L1 therapy in many cancers. However, the relationship between the gut microbiota and the efficacy of immunotherapy in patients with nasopharyngeal carcinoma has not been determined. METHODS: We conducted a prospective study in which fecal and blood samples from patients with NPC were subjected to 16S rDNA sequencing and survival analysis. To investigate potential differences in the gut microbiome between these groups and to identify potential biomarkers indicative of immunotherapy efficacy, patients were categorized into two groups according to their clinical response to immunotherapy, the responder group (R group) and the non-responder group (NR group). Progression-free survival (PFS) between these subgroups was analyzed using Kaplan-Meier survival analysis with the log-rank test. Additionally, we performed univariate and multivariate analyses to evaluate prognostic factors. Finally, we carried out non-targeted metabolomics to examine the metabolic effects associated with the identified microbiome. RESULTS: Our 16S rDNA sequencing results showed that the abundance of Lachnoclostridium was higher in the NR group than in the R group (p = 0.003), and alpha diversity analysis showed that the abundance of microbiota in the NR group was higher than that in the R group (p = 0.050). Patients with a lower abundance of Lachnoclostridium had better PFS (p = 0.048). Univariate (p = 0.017) and multivariate analysis (p = 0.040) showed that Lachnoclostridium was a predictor of PFS. Non-targeted metabolomics analysis revealed that Lachnoclostridium affects the efficacy of immunotherapy through the usnic acid. CONCLUSIONS: High abundance of Lachnoclostridium predicts poor prognosis in patients with NPC receiving immunotherapy.

Disulfiram/copper complex improves the effectiveness of the WEE1 inhibitor Adavosertib in p53 deficient non-small cell lung cancer via ferroptosis.

Cancer cells lacking functional p53 exhibit poor prognosis, necessitating effective treatment strategies. Inhibiting WEE1, the G2/M cell cycle checkpoint gatekeeper, represents a promising approach for treating p53-deficient NSCLC. Here, we investigate the connection between p53 and WEE1, as well as explore a synergistic therapeutic approach for managing p53-deficient NSCLC. Our study reveals that p53 deficiency upregulates both protein levels and kinase activity of WEE1 by inhibiting its SUMOylation process, thereby enhancing the susceptibility of p53-deficient NSCLC to WEE1 inhibitors. Furthermore, we demonstrate that the WEE1 inhibitor Adavosertib induces intracellular lipid peroxidation, specifically in p53-deficient NSCLC cells, suggesting potential synergy with pro-oxidant reagents. Repurposing Disulfiram (DSF), an alcoholism medication used in combination with copper (Cu), exhibits pro-oxidant properties against NSCLC. The levels of WEE1 protein in p53-deficient NSCLC cells treated with DSF-Cu exhibit a time-dependent increase. Subsequent evaluation of the combination therapy involving Adavosertib and DSF-Cu reveals reduced cell viability along with smaller tumor volumes and lighter tumor weights observed in both p53-deficient cells and xenograft models while correlating with solute carrier family 7-member 11 (SLC7A11)/glutathione-regulated ferroptosis pathway activation. In conclusion, our findings elucidate the molecular interplay between p53 and WEE1 and unveil a novel synergistic therapeutic strategy for treating p53-deficient NSCLC.

Biomechanical characteristics of maxillary anterior incisor, conventional immediate implantation and socket shield technique - A finite element analysis and case report.

BACKGROUND: To prevent the absorption and collapse of the labial bone plate of the anterior teeth, immediate implantation and socket shield technique have been increasingly applied to anterior dental aesthetic implant restoration. OBJECTIVE: To provide a biomechanical basis for implant restoration of maxillary anterior teeth, finite element analysis was used to investigate the stress peak and distribution in different anatomical sites of natural teeth, conventional immediate implantation and socket shield technique. METHODS: Three maxillary finite element models were established, including a maxillary incisor as a natural tooth, a conventional immediate implantation and a socket shield technique. A mechanical load of 100 N was applied to simulate and analyze the biomechanical behavior of the root, periodontal ligament (PDL), implant and surrounding bone interface. RESULTS: The stress distribution of the natural tooth was relatively uniform under load. The maximum von Mises stress of the root, periodontal ligament, cortical bone and cancellous bone were 20.14 MPa, 2.473 MPa, 19.48 MPa and 5.068 MPa, respectively. When the conventional immediate implantation was loaded, the stress was mainly concentrated around the neck of implant. Maximum stress on the surface of the implant was 102 MPa, the cortical bone was 16.13 MPa, and the cancellous bone was 18.29 MPa. When the implantation with socket shield technique was loaded, the stress distribution of the implant was similar to that of immediate implantation. Maximum stress on the surface of the implant was 100.5 MPa, the cortical bone was 23.11 MPa, the cancellous bone was 21.66 MPa, the remaining tooth fragment was 29.42 MPa and the periodontal ligament of the tooth fragment was 1.131 MPa. CONCLUSIONS: 1. Under static loading, both socket shield technology and conventional immediate implantation can support the esthetic restoration of anterior teeth biomechanically. 2.Under short-term follow-up, both immediate implant and socket shield technology achieved satisfactory clinical results, including bone healing and patient satisfaction. 3.The stress distribution is mainly located on the buccal bone surface of the implant and is associated with resorption of the buccal bone plate after implant replacement in both socket shield technology and conventional immediate implantation. 4.The presence of retained root fragment had an impact on the bone graft gap. In immediate implantation, the peak stress was located in the cortical bone near the implant position, while in socket shield technology, the peak stress was at the neck of the cortical bone corresponding to the retained root fragment.

Near-Infrared Responsive Biomimetic Titanate/TiO2-X Heterostructure: A Therapeutic Strategy for Combating Implant-Associated Infection and Enhancing Osseointegration.

Implant-associated infections and delayed osseointegration are major challenges for the clinical success of titanium implants. To enhance antibacterial effects and promote early osseointegration, we developed a synergistic photothermal (PTT)/photodynamic (PDT) therapy strategy based on near-infrared (NIR) responsive biomimetic micro/nano titanate/TiO2-X heterostructure coatings (KMNW and NaMNS) in situ constructed on the surface of titanium implants. Specifically, KMNW and NaMNS significantly enhanced photothermal conversion capabilities, achieving localized high temperatures of 48-51 °C and promoting substantial amounts of reactive oxygen species production under 808 nm irradiation. In vitro antibacterial experiments demonstrated that KMNW achieved the highest antibacterial rates against Staphylococcus aureus and Escherichia coli, at 98.78 and 98.33% respectively. Moreover, by mimicking the three-dimensional fibrous network of the extracellular matrix during bone healing, both KMNW and NaMNS markedly promoted the proliferation and osteogenic differentiation of osteoblasts. In vivo implantation studies further confirmed these findings, with KMNW and NaMNS exhibiting superior antibacterial performance under NIR irradiation─94.45% for KMNW and 92.66% for NaMNS. Moreover, KMNW and NaMNS also significantly promoted new bone formation and improved osseointegration in vivo. This study presents a promising PTT/PDT therapeutic strategy for dentistry and orthopedics by employing NIR-responsive biomimetic coatings to combat implant-associated infection and accelerate osseointegration.

Transcriptomic Analysis Reveals That Excessive Thyroid Hormone Signaling Impairs Phototransduction and Mitochondrial Bioenergetics and Induces Cellular Stress in Mouse Cone Photoreceptors.

Thyroid hormone (TH) plays an essential role in cell proliferation, differentiation, and metabolism. Experimental and clinical studies have shown a potential association between TH signaling and retinal degeneration. The suppression of TH signaling protects cone photoreceptors in mouse models of retinal degeneration, whereas excessive TH signaling induces cone degeneration, manifested as reduced light response and a loss of cones. This work investigates the genes/transcriptomic alterations that might be involved in TH-induced cone degeneration in mice using single-cell RNA sequencing (scRNAseq) analysis. One-month-old C57BL/6 mice received triiodothyronine (T3, 20 µg/mL in drinking water) for 4 weeks as a model of hyperthyroidism/excessive TH signaling. At the end of the experiments, retinal cells were dissociated, and cell viability was analyzed before being subjected to scRNAseq. The resulting data were analyzed using the Seurat package and visualized using the Loupe browser. Among 155,866 single cells, we identified 14 cell clusters, representing various retinal cell types, with rod and cone clusters comprising 76% and 4.1% of the total cell population, respectively. Cone cluster transcriptomes demonstrated the most alterations after the T3 treatment, with 450 differentially expressed genes (DEGs), accounting for 38.5% of the total DEGs. Statistically significant changes in the expression of genes in the cone cluster revealed that phototransduction and oxidative phosphorylation were impaired after the T3 treatment, along with mitochondrial dysfunction. A pathway analysis also showed the activation of the sensory neuronal/photoreceptor stress pathways after the T3 treatment. Specifically, the eukaryotic initiation factor-2 signaling pathway and the cAMP response element-binding protein signaling pathway were upregulated. Thus, excessive TH signaling substantially affects cones at the transcriptomic level. The findings from this work provide an insight into how excessive TH signaling induces cone degeneration.

Breeding a new Ganoderma lucidum strain with increased contents of individual ganoderic acids by mono-mono crossing of genetically modified monokaryons.

Ganoderic acids (GAs) are major functional components of Ganoderma lucidum. The study aimed to breed a new G. lucidum strain with increased contents of individual GAs. Two mating-compatible monokaryotic strains, G. 260125 and G. 260124, were successfully isolated from the dikaryotic G. lucidum CGMCC 5.0026 via protoplast formation and regeneration. The Vitreoscilla hemoglobin gene (vgb) and squalene synthase gene (sqs) were overexpressed in the monokaryotic G. 260124 and G. 260125 strain, respectively. Mating between the G. 260124 strain overexpressing vgb and the G. 260125 strain overexpressing sqs resulted in the formation of the new hybrid dikaryotic G. lucidum strain sqs-vgb. The maximum contents of ganoderic acid (GA)-T, GA-Me, and GA-P in the fruiting body of the mated sqs-vgb strain were 23.1, 15.3, and 39.8 µg/g dry weight (DW), respectively, 2.23-, 1.75-, and 2.69-fold greater than those in G. lucidum 5.0026. The squalene and lanosterol contents increased 2.35- and 1.75-fold, respectively, in the fruiting body of the mated sqs-vgb strain compared with those in the G. lucidum 5.0026. In addition, the maximum expression levels of the sqs and lanosterol synthase gene (ls) were increased 3.23- and 2.13-fold, respectively, in the mated sqs-vgb strain. In summary, we developed a new G. lucidum strain with higher contents of individual GAs in the fruiting body by integrating genetic engineering and mono-mono crossing.

Analysis of risk factors related to early implant failure: A retrospective study.

STATEMENT OF PROBLEM: Factors influencing early implant failure (failure during the healing period) in the rehabilitation and restoration of oral function in partially edentulous patients are unclear. PURPOSE: The purpose of this clinical study was to investigate several factors that may be associated with early implant failure. MATERIAL AND METHODS: This retrospective study was conducted on 3247 implants in 2061 patients between 2009 and 2022. Patient-related and surgery-related factors, including smoking; sex; diabetes; bone grafting; implant length, diameter, and design; adjacent teeth; and insertion torque, were manually retrieved and analyzed. Using univariate and multivariate analyses, a generalized estimating equation (GEE) model with chi-squared tests was employed to evaluate factors related to early implant failure (the failure before restoration) (α=.05). RESULTS: The mean ±standard deviation age of the study patients was 49.2 ±15.0 years (range 18 to 91). Ninety-nine implants (3.05%) failed during the healing period. Three factors were statistically significant regarding early implant failure: smoking (odds ratio [OR]=1.92, P=.008), implant design (tapered implants) (OR=1.84, P=.007), and implant length <10 mm (OR=2.98, P=.011). Factors including diabetes, bone grafting, anatomic location, adjacent teeth (endodontic therapy in the adjacent teeth and the distance between implant and adjacent teeth), healing method, and insertion torque did not exhibit a statistically significant higher early implant failure rate. Ninety-three sites with failed implants received new implants, and 6 of these 93 implants failed during the healing period. CONCLUSIONS: Within the limitation of sample size, smokers, implant length (<10 mm), and implant design (tapered implant) exhibited higher risk of early implant failure in this retrospective study. Implant insertion torque, healing method, adjacent teeth, and diabetes did not significantly influence the risk of early implant failure.

Systematic profiling of Taxol resistance and sensitivity to tubulin missence mutations at molecular and cellular levels.

Taxol (paclitaxel) is the first approved microtubule-stabilizing agent (MSA) by binding stoichiometrically to tubulin, which is considered to be one of the most significant advances in first-line chemotherapy against diverse tumors. However, a large number of residue missence mutations harboring in the tubulin have been observed to cause acquired drug resistance, largely limiting the clinical application of Taxol and its analogs in chemotherapy. A systematic investigation of the intermolecular interactions between the Taxol and various tubulin mutants would help to establish a comprehensive picture of drug response to tubulin mutations in clinical treatment of cancer, and to design new MSA agents with high potency and selectivity to overcome drug resistance. In this study, we described an integration of in silico analysis and in vitro assay (iSiV) to profile Taxol against a panel of 149 clinically observed, cancer-associated missence mutations in ß-tubulin at molecular and cellular levels, aiming to a systematic understanding of molecular mechanism and biological implication underlying drug resistance and sensitivity conferring from tubulin mutations. It is revealed that the Taxol-resistant mutations can be classified into three types: (I) nonbonded interaction broken due to mutation, (II) steric hindrance caused by mutation, and (III) conformational change upon mutation. In addition, we identified three new Taxol-resistant mutations (C239Y, T274I, and R320P) that can largely reduce the binding affinity of Taxol to tubulin at molecular level, in which the T274I and R320P were observed to considerably impair the antitumor activity of Taxol at cellular level. Moreover, a novel drug-susceptible mutation (M363T) was also identified, which improves Taxol affinity by 2.6-fold and decreases Taxol antitumor EC50 values from 29.4 to 18.7 µM.

PROTAC EZH2 degrader-1 overcomes the resistance of podophyllotoxin derivatives in refractory small cell lung cancer with leptomeningeal metastasis.

BACKGROUND: Leptomeningeal metastasis (LM) of small cell lung cancer (SCLC) is a highly detrimental occurrence associated with severe neurological disorders, lacking effective treatment currently. Proteolysis-targeting chimeric molecules (PROTACs) may provide new therapeutic avenues for treatment of podophyllotoxin derivatives-resistant SCLC with LM, warranting further exploration. METHODS: The SCLC cell line H128 expressing luciferase were mutated by MNNG to generate H128-Mut cell line. After subcutaneous inoculation of H128-Mut into nude mice, H128-LM and H128-BPM (brain parenchymal metastasis) cell lines were primarily cultured from LM and BPM tissues individually, and employed to in vitro drug testing. The SCLC-LM mouse model was established by inoculating H128-LM into nude mice via carotid artery and subjected to in vivo drug testing. RNA-seq and immunoblotting were conducted to uncover the molecular targets for LM. RESULTS: The SCLC-LM mouse model was successfully established, confirmed by in vivo live imaging and histological examination. The upregulated genes included EZH2, SLC44A4, VEGFA, etc. in both BPM and LM cells, while SLC44A4 was particularly upregulated in LM cells. When combined with PROTAC EZH2 degrader-1, the drug sensitivity of cisplatin, etoposide (VP16), and teniposide (VM26) for H128-LM was significantly increased in vitro. The in vivo drug trials with SCLC-LM mouse model demonstrated that PROTAC EZH2 degrader-1 plus VM26 or cisplatin/ VP16 inhibited H128-LM tumour significantly compared to VM26 or cisplatin/ VP16 alone (P < 0.01). CONCLUSION: The SCLC-LM model effectively simulates the pathophysiological process of SCLC metastasis to the leptomeninges. PROTAC EZH2 degrader-1 overcomes chemoresistance in SCLC, suggesting its potential therapeutic value for SCLC LM.

Relationship Between Urinary Iodine Concentration and the Prevalence of Thyroid Nodules and Subclinical Hypothyroidism.

The aim of the study was to investigate the iodine intake in the resident population in Xi'an and analyze the relationship between iodine nutritional status and the prevalence of subclinical hypothyroidism and thyroid nodules (TNs). A total of 2507 people were enrolled in Xi'an. Venous serum thyroid stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb), urinary iodine concentration (UIC), and thyroid ultrasonography were collected. Patients with abnormal TSH were checked for free thyroxine (FT4) and triiodothyronine (FT3). Adults in Xi'an had median UICs of 220.80 µg/L and 178.56 µg/l, respectively. A sum of 16.78% of people had subclinical hypothyroidism. Both iodine excess and iodine deficit increased the frequency of subclinical hypothyroidism. The lowest was around 15.09% in females with urine iodine levels between 200 and 299 µg/l. With a rate of 10.69%, the lowest prevalence range for males was 100-199 µg/l. In Xi'an, 11.37% of people have TNs. In comparison to other UIC categories, TN occurrences were higher in females (18.5%) and males (12%) when UIC were below 100 µg/l. In conclusion, iodine intake was sufficient in the Xi'an area, while the adults' UIC remains slightly higher than the criteria. Iodine excess or deficiency can lead to an increase in the prevalence of subclinical hypothyroidism. Patients with iodine deficiency are more likely to develop TNs.

KIF2A Upregulates PI3K/AKT Signaling through Polo-like Kinase 1 (PLK1) to Affect the Proliferation and Apoptosis Levels of Eriocheir sinensis Spermatogenic Cells.

E. sinensis is an animal model for studying the reproduction and development of crustaceans. In this study, we knocked down the Es-Kif2a gene by injecting dsRNA into E. sinensis and inhibited Es-Plk1 gene expression by injecting PLK1 inhibitor BI6727 into E. sinensis. Then, the cell proliferation level, apoptosis level, and PI3K/AKT signaling expression level were detected. Our results showed that the proliferation level of spermatogenic cells decreased, while the apoptosis level increased after Es-Kif2a knockdown or Es-Plk1 inhibition. In order to verify whether these changes are caused by regulating the PI3K/AKT pathway, we detected the expression of PI3K and AKT proteins after Es-Kif2a knockdown or Es-Plk1 inhibition. Western Blot showed that in both the Es-Kif2a knockdown group and the Es-Plk1 inhibition group, the expression of PI3K and AKT proteins decreased. In addition, immunofluorescence showed that Es-KIF2A and Es-PLK1 proteins were co-localized during E. sinensis spermatogenesis. To further explore the upstream and downstream relationship between Es-KIF2A and Es-PLK1, we detected the expression level of Es-PLK1 after Es-Kif2a knockdown as well as the expression level of Es-KIF2A after Es-Plk1 inhibition. Western Blot showed that the expression of Es-PLK1 decreased after Es-Kif2a knockdown, while there was no significant change of Es-KIF2A after Es-Plk1 inhibition, indicating that Es-PLK1 may be a downstream factor of Es-KIF2A. Taken together, these results suggest that Es-KIF2A upregulates the PI3K/AKT signaling pathway through Es-PLK1 during the spermatogenesis of E. sinensis, thereby affecting the proliferation and apoptosis levels of spermatogenic cells.

Transformation to small cell lung cancer is irrespective of EGFR and accelerated by SMAD4-mediated ASCL1 transcription independently of RB1 in non-small cell lung cancer.

OBJECTIVES: Histological transformation to small cell lung cancer (SCLC) has been identified as a mechanism of TKIs resistance in EGFR-mutant non-small cell lung cancer (NSCLC). We aim to explore the prevalence of transformation in EGFR-wildtype NSCLC and the mechanism of SCLC transformation, which are rarely understood. METHODS: We reviewed 1474 NSCLC patients to investigate the NSCLC-to-SCLC transformed cases and the basic clinical characteristics, driver gene status and disease course of them. To explore the potential functional genes in SCLC transformation, we obtained pre- and post-transformation specimens and subjected them to a multigene NGS panel involving 416 cancer-related genes. To validate the putative gene function, we established knocked-out models by CRISPR-Cas 9 in HCC827 and A549-TP53-/- cells and investigated the effects on tumor growth, drug sensitivity and neuroendocrine phenotype in vitro and in vivo. We also detected the expression level of protein and mRNA to explore the molecular mechanism involved. RESULTS: We firstly reported an incidence rate of 9.73% (11/113) of SCLC transformation in EGFR-wildtype NSCLC and demonstrated that SCLC transformation is irrespective of EGFR mutation status (P = 0.16). We sequenced 8 paired tumors and identified a series of mutant genes specially in transformed SCLC such as SMAD4, RICTOR and RET. We firstly demonstrated that SMAD4 deficiency can accelerate SCLC transition by inducing neuroendocrine phenotype regardless of RB1 status in TP53-deficient NSCLC cells. Further mechanical experiments identified the SMAD4 can regulate ASCL1 transcription competitively with Myc in NSCLC cells and Myc inhibitor acts as a potential subsequent treatment agent. CONCLUSIONS: Transformation to SCLC is irrespective of EFGR status and can be accelerated by SMAD4 in non-small cell lung cancer. Myc inhibitor acts as a potential therapeutic drug for SMAD4-mediated resistant lung cancer. Video Abstract.

Effect of bone mass density and alveolar bone resorption on stress in implant restoration of free-end edentulous posterior mandible: Finite element analysis of double-factor sensitivity.

BACKGROUND: Osseous condition of the mandible was regarded as a key factor influencing stability of implants in the early stage. Finite element analysis was used to assess the effect of bone mass density and alveolar bone resorption (double factors) on stress in a four-unit implant restoration of a free-end edentulous posterior mandible. METHODS: A 3D finite element model was constructed for a single-sided free-end edentulous mandible (from mandibular first premolar to mandibular second molar) containing threaded dental implants. Mandible sensitivity modes were constructed with different alveolar bone resorption levels for normal conditions as well as mild, moderate and severe periodontitis, respectively. Based on the mass density of cancellous bone for four types of bones as the sensitivity parameter, two implant design modes were constructed: Model A (four-unit fixed bridge supported by three implants, implant positions were 34, 36 and 37) and model B: 34 × 36, 37 (37: a single implant crown) (34 × 36: three-unit fixed bridge supported by two implants, implant positions were 34 and 36). A total of 32 sensitivity-based finite element models, grouped in two groups, were constructed. Stress distribution and maximum von Mises stress on cortical bone and cancellous bone around the implant, as well as the surface of implant were investigated by using ABAQUS when vertical loading and 45° oblique loading were applied, respectively. RESULTS: When vertical loading was applied on the implant, maximum von Mises stress on the cortical bone around the implant was assessed to be 4.726 MPa - 13.15 MPa and 6.254 MPa - 13.79 MPa for groups A and B, respectively; maximum stress on the cancellous bone around the implant was 2.641 MPa - 3.773 MPa and 2.864 MPa - 4.605 MPa, respectively; maximum stress on the surface of implant was 14.7 MPa - 21.17 MPa and 21.64 MPa - 30.70 MPa, respectively. When 45° oblique loading was applied on the implant restoration, maximum von Mises stress on the cortical bone around the implant was assessed to be 42.08 MPa - 92.71 MPa and 50.84 MPa - 102.5 MPa for groups A and B, respectively; maximum stress on the cancellous bone around the implant was 4.88 MPa - 25.95 MPa and 5.227 MPa - 28.43 MPa, respectively; maximum stress on the surface of implant was 77.91 MPa - 124.8 MPa and 109.2 MPa - 150.7 MPa, respectively. Stress peak on the cortical bone and that on cancellous bone around the implant increased and decreased with the decrease in bone mass density, respectively. Stress peak on alveolar bone increased with alveolar bone resorption when oblique loading was applied. CONCLUSION: 1. Both alveolar bone resorption and bone mass density (double factors) are critical to implant restoration. Bone mass density may exhibit a more pronounced impact than alveolar bone resorption. 2. From the biomechanical perspective, types I and II bones are preferred for implant restoration, while implantation should be considered carefully in the case of type III bones, or those with less bone mass density accompanied by moderate to severe alveolar bone loss. 3. Splinting crowns restoration is biomechanically superior to single crown restoration.

A novel endoscopic nasopharyngectomy by low-temperature plasma radiofrequency ablation in localized recurrent nasopharyngeal carcinoma.

OBJECTIVE: Endoscopic nasopharyngectomy (ENPG) with en bloc resection has been well accepted in resectable localized recurrent nasopharyngeal carcinoma (rNPC), but it is a difficult technique to master for most otorhinolaryngology head and neck surgeons. Ablation surgery is a new and simplified method to remove tumors. We designed a novel method using low-temperature plasma radiofrequency ablation (LPRA) and evaluated the survival benefit. METHODS: A total of 56 localized rNPC patients were explained in detail and retrospectively analyzed. The surgery method was ablated from the resection margin to the center of the tumor. The postmetastatic overall survival (OS), local relapse-free survival (LRFS) rate, progression-free survival (PFS) and distant metastasis-free survival (DMFS) were analyzed using the Kaplan-Meier method and compared by the log-rank test. RESULTS: All surgeries were successfully performed without any severe postoperative complications or deaths. The median operation time of ablation and harvested NSFF respectively were 29 min (range, 15-100 min) and 101 min (range, 30-180 min). The average number of hospital days postoperation was 3 days (range, 2-5 days). All cases (100.0%) had radical ablation with negative resection margins. The nasopharyngeal defects were completely re-epithelialized in 54 (96.4%) patients. As of the data cutoff (September 3, 2023), the median follow-up time was 44.3 months (range, 17.1-52.7 months, 95% CI: 40.4-48.2). The 3-year OS, LRFS, PFS and DMFS of the entire cohort were 92.9% (95% CI: 0.862-0.996), 89.3% (95% CI: 0.813-0.973), 87.5% (95% CI: 0.789-0.961), and 92.9% (95% CI: 0.862-0.996), respectively. Cycles of radiotherapy were independent risk factors for OS (p = 0.003; HR, 32.041; 95% CI: 3.365-305.064), LRFS (p = 0.002; HR, 10.762; 95% CI: 2.440-47.459), PFS (p = 0.004; HR, 7.457; 95% CI: 1.925-28.877), and DMFS (p = 0.002; HR, 34.776; 95% CI: 3.806-317.799). CONCLUSION: Radical endoscopic nasopharyngectomy by using low-temperature plasma radiofrequency ablation is a novel, safe and simplified method to master and disseminate for treating resectable rNPC. However, further data and longer follow-up time are needed to prove its efficacy.

The effect of periapical bone defects on stress distribution in teeth with periapical periodontitis: a finite element analysis.

BACKGROUND: Apical periodontitis directly affects the stress state of the affected tooth owing to the destruction of the periapical bone. Understanding the mechanical of periapical bone defects/tooth is clinically meaningful. In this study, we evaluate the effect of periapical bone defects on the stress distribution in teeth with periapical periodontitis using finite element analysis. METHODS: Finite element models of normal mandibular second premolars and those with periapical bone defects (spherical defects with diameters of 5, 10, 15, and 20 mm) were created using a digital model design software. The edges of the mandible were fixed and the masticatory cycle was simplified as oblique loading (a 400 N force loaded obliquely at 45° to the long axis of the tooth body) to simulate the tooth stress state in occlusion and analyze the von Mises stress distribution and tooth displacement distribution in each model. RESULTS: Overall analysis of the models: Compared to that in the normal model, the maximum von Mises stresses in all the different periapical bone defect size models were slightly lower. In contrast, the maximum tooth displacement in the periapical bone defect model increased as the size of the periapical bone defect increased (2.11-120.1% of increase). Internal analysis of tooth: As the size of the periapical bone defect increased, the maximum von Mises stress in the coronal cervix of the tooth gradually increased (2.23-37.22% of increase). while the von Mises stress in the root apical region of the tooth showed a decreasing trend (41.48-99.70% of decrease). The maximum tooth displacement in all parts of the tooth showed an increasing trend as the size of the periapical bone defect increased. CONCLUSIONS: The presence of periapical bone defects was found to significantly affect the biomechanical response of the tooth, the effects of which became more pronounced as the size of the bone defect increased.

The effect of root canal treatment and post-crown restorations on stress distribution in teeth with periapical periodontitis: a finite element analysis.

AIM: To evaluate the effects of root canal treatment (RCT) and post-crown restoration on stress distribution in teeth with periapical bone defects using finite element analysis. METHODOLOGY: Finite element models of mandibular second premolars and those with periapical bone defects (spherical defects with diameters of 5, 10, 15, and 20 mm) were created using digital model design software. The corresponding RCT and post-crown restoration models were constructed based on the different sizes of periapical bone defect models. The von Mises stress and tooth displacement distributions were comprehensively analyzed in each model. RESULTS: Overall analysis of the models: RCT significantly increased the maximum von Mises stresses in teeth with periapical bone defects, while post-crown restoration greatly reduced the maximum von Mises stresses. RCT and post-crown restoration slightly reduced tooth displacement in the affected tooth. Internal analysis of tooth: RCT dramatically increased the maximum von Mises stress in all regions of the tooth, with the most pronounced increase in the coronal surface region. The post-crown restoration balances the internal stresses of the tooth and is most effective in periapical bone defect - 20-mm model. RCT and post-crown restoration slightly reduced the tooth displacement in all regions of the affected tooth. CONCLUSIONS: Root canal treatment seemed not to improve the biomechanical state of teeth with periapical bone defects. In contrast, post-crown restoration might effectively balance the stress concentrations caused by periapical bone defects, particularly extensive ones.

Assessment tools for stigma in breast cancer patients based on COSMIN guidelines: a systematic review.

OBJECTIVE: The objective of this study was to conduct a systematic review of the measurement properties and methodological quality of stigma assessment tools designed for breast cancer patients. The aim was to provide clinical medical staff with a foundation for selecting high-quality assessment tools. METHODS: A comprehensive computer search was carried out across various databases, including SinoMed, China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database(VIP), Embase, PubMed, Web of Science, The Cochrane Library, and Scopus, which were searched from the inception of the databases until March 20, 2023. Literature screening and data extraction were performed independently by two researchers, adhering to predefined inclusion and exclusion criteria. The assessment tools were evaluated using the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) systematic evaluation guidelines. RESULTS: In the final analysis, a total of 9 assessment tools were included. However, none of these tools addressed measurement error, cross-cultural validity, criterion validity, and responsiveness. Following the COSMIN guidelines, BCSS and CSPDS were assigned to Class A recommendations, while the remaining tools received Class B recommendations. CONCLUSION: The BCSS and CSPDS scales demonstrated comprehensive assessment in terms of their measurement characteristics, exhibiting good methodological quality, measurement attribute quality, and supporting evidence. Therefore, it is recommended to utilize these scales for evaluating breast cancer stigma. However, further validation is required for the remaining assessment tools.

Combining the Tyrosine Kinase Inhibitor Cabozantinib and the mTORC1/2 Inhibitor Sapanisertib Blocks ERK Pathway Activity and Suppresses Tumor Growth in Renal Cell Carcinoma.

Current treatment approaches for renal cell carcinoma (RCC) face challenges in achieving durable tumor responses due to tumor heterogeneity and drug resistance. Combination therapies that leverage tumor molecular profiles could offer an avenue for enhancing treatment efficacy and addressing the limitations of current therapies. To identify effective strategies for treating RCC, we selected ten drugs guided by tumor biology to test in six RCC patient-derived xenograft (PDX) models. The multitargeted tyrosine kinase inhibitor (TKI) cabozantinib and mTORC1/2 inhibitor sapanisertib emerged as the most effective drugs, particularly when combined. The combination demonstrated favorable tolerability and inhibited tumor growth or induced tumor regression in all models, including two from patients who experienced treatment failure with FDA-approved TKI and immunotherapy combinations. In cabozantinib-treated samples, imaging analysis revealed a significant reduction in vascular density, and single-nucleus RNA sequencing (snRNA-seq) analysis indicated a decreased proportion of endothelial cells in the tumors. SnRNA-seq data further identified a tumor subpopulation enriched with cell-cycle activity that exhibited heightened sensitivity to the cabozantinib and sapanisertib combination. Conversely, activation of the epithelial-mesenchymal transition pathway, detected at the protein level, was associated with drug resistance in residual tumors following combination treatment. The combination effectively restrained ERK phosphorylation and reduced expression of ERK downstream transcription factors and their target genes implicated in cell-cycle control and apoptosis. This study highlights the potential of the cabozantinib plus sapanisertib combination as a promising treatment approach for patients with RCC, particularly those whose tumors progressed on immune checkpoint inhibitors and other TKIs. SIGNIFICANCE: The molecular-guided therapeutic strategy of combining cabozantinib and sapanisertib restrains ERK activity to effectively suppress growth of renal cell carcinomas, including those unresponsive to immune checkpoint inhibitors.

Efficacy of sequential chemoradiotherapy combined with toripalimab in de novo metastatic nasopharyngeal carcinoma: A phase II trial.

Locoregional radiotherapy added to chemotherapy has significantly improved survival in de novo metastatic nasopharyngeal carcinoma (mNPC). However, only 54% of de novo mNPC patients who received sequential chemoradiotherapy have complete or partial response 3 months after radiotherapy. This Simon's optimal two-stage design phase II study (NCT04398056) investigates whether PD-1 inhibitor could improve tumor control in combination with chemoradiation. The primary endpoint is objective response rate (ORR) at 3 months after radiotherapy. Twenty-two patients with primary mNPC are enrolled. The ORR at 3 months after radiotherapy is 81.8% (22.7% complete response, n = 5; 59.1% partial response, n = 13), and the disease control rate is 81.8%. The 3-year progression-free survival (PFS) rate is 44.9% (95% confidence interval 26.4%-76.3%). Fifteen patients (68.2%) experienced grade 3-4 adverse events. Patients with high baseline plasma Epstein-Barr virus DNA copy number (>104 cps/mL) show worse PFS. Addition of toripalimab to sequential chemoradiotherapy suggests promising tumor response in patients with primary mNPC.

Reliability and validity of the Chinese version of the trauma-specific frailty index (TSFI) for geriatric trauma patients.

BACKGROUND: Pre-traumatic frailty in geriatric trauma patients has caught attention from emergency medical workers and the assessment of it thus become one of the important aspects of risk management. Several tools are available to identify frailty, but limited tools have been validated for geriatric trauma patients in China to assess pre-traumatic frailty.The aim of this study is to translate the Trauma-Specific Frailty Index(TSFI) into Chinese, and to evaluate the reliability and validity of the translated version in geriatric trauma patients. METHODS: A cross-sectional study was conducted. The TSFI was translated with using the Brislin model, that included forward and backward translation. A total of 184 geriatric trauma patients were recruited by a convenience sampling between October and December 2020 in Hospital of Chengdu University of Traditional Chinese Medicine, Sichuan. Using reliability or internal consistency tests assessed with Cronbach's alpha coefficient, split-half reliability and test-retest reliability. Content validity and construct validity analysis were both performed. Sensitivity, specificity and maximum Youden index(YI) were used to determine the optimal cut-off value. The screening performance was examined by Kappa value. RESULTS: The total study population included 184 subjects, of which 8 participants were excluded, resulting in a study sample size of 176 elderly trauma patients (the completion rate was 95.7%). The Chinese version of Trauma-Specific Frailty Index(C-TSFI) have 15 items with 5 dimensions. Cronbach's alpha coefficient of the C-TSFI was 0.861, Cronbach's alpha coefficient of dimensions ranged from 0.837 to 0.875, the split-half reliability of the C-TSFI were 0.894 and 0.880 respectively, test-retest reliability ranged from 0.692 to 0.862. The correlation coefficient between items and the C-TSFI ranged from 0.439 to 0.761. The content validity index for items (I-CVI) of the C-TSFI scale was 0.86~1.00, and the scale of content validity index (S-CVI) was 0.93. The area under curve (AUC) of the C-TSFI was 0.932 (95%CI 0.904-0.96, P < 0.05), the maximum YI was 0.725, the sensitivity was 80.2%, the specificity was 92.3%, and the critical value was 0.31. Kappa value was 0.682 (P < 0.05). CONCLUSIONS: The Chinese version of TSFI could be used as a general assessment tool in geriatric trauma patients, and both its reliability and validity have been demonstrated.