Influencing factors of effective lens position in patients with Marfan syndrome and ectopia lentis.

AIMS: The aim of this study was to analyse the effective lens position (ELP) in patients with Marfan syndrome (MFS) and ectopia lentis (EL). METHODS: Patients with MFS undergoing lens removal and primary intraocular lens (IOL) implantation were enrolled in the study. The back-calculated ELP was obtained with the vergence formula and compared with the theoretical ELPs. The back-calculated ELP and ELP error were evaluated among demographic and biometric parameters, including axial length (AL), corneal curvature radius (CCR) and white-to-white (WTW). RESULTS: A total of 292 eyes from 200 patients were included. The back-calculated ELP was lower in patients undergoing scleral-fixated IOL than those receiving in-the-bag IOL implantation (4.54 (IQR 3.65-5.20) mm vs 4.98 (IQR 4.56-5.67) mm, p<0.001). The theoretical ELP of the SRK/T formula exhibited the highest accuracy, with no difference from the back-calculated ELP in patients undergoing in-the-bag IOL implantation (5.11 (IQR 4.83-5.65) mm vs 4.98 (IQR 4.56-5.67) mm, p=0.209). The ELP errors demonstrated significant correlations with refraction prediction error (PE): a 1 mm ELP error led to PE of 2.42D (AL<22 mm), 1.47D (22 mm≤AL<26 mm) and 0.54D (AL≥26 mm). Multivariate analysis revealed significant correlations of ELP with AL (b=0.43, p<0.001), CCR (b=-0.85, p<0.001) and WTW (b=0.41, p=0.004). CONCLUSION: This study provides novel insights into the origin of PE in patients with MFS and EL and potentially refines existing formulas.

Acoustic emission features of granite from different rockburst areas in Sangzhuling Railway Tunnel.

In order to investigate the acoustic emission (AE) features of rocks in different (medium and strong) rockburst areas, the Sangzhuling Railway Tunnel granite in China was taken as an example, the mineral composition of rocks in different rockburst areas was analyzed by using XRD (X-ray diffraction) method. The Original rock cores of different rockburst areas were processed into standard rock specimens (diameter 50 mm, height 100 mm) in different directions (transverse, oblique and longitudinal). AE feature parameters (event number, ringing count and energy) of standard rock specimens during indoor uniaxial compression test were obtained by using AE technique. The variation law of AE feature parameters of rocks in different rockburst grade areas was then analyzed. The AE features of failure precursor of rocks in different rockburst areas were therefore discussed. It shows that compared with rocks in medium rockburst area, the content of quartz and feldspar of rocks in strong rockburst area is high, while the content of biotite is low; the rock in the strong rock burst area released more energy during the failure process with about 2-3 times that of the rock in the medium rock burst area; the cumulative ringing curve of rock in medium burst area is a stepped type, while the cumulative ringing curve of rock in strong burst area is the smoothed type; the end of the second and first AE quiet period may be regarded as the failure precursor of rocks in medium and strong rockburst area, respectively. The results presented herein are important for understanding the mechanisms of rockburst.

Stanniocalcin 2 governs cancer cell adaptation to nutrient insufficiency through alleviation of oxidative stress.

Solid tumours often endure nutrient insufficiency during progression. How tumour cells adapt to temporal and spatial nutrient insufficiency remains unclear. We previously identified STC2 as one of the most upregulated genes in cells exposed to nutrient insufficiency by transcriptome screening, indicating the potential of STC2 in cellular adaptation to nutrient insufficiency. However, the molecular mechanisms underlying STC2 induction by nutrient insufficiency and subsequent adaptation remain elusive. Here, we report that STC2 protein is dramatically increased and secreted into the culture media by Gln-/Glc-deprivation. STC2 promoter contains cis-elements that are activated by ATF4 and p65/RelA, two transcription factors activated by a variety of cellular stress. Biologically, STC2 induction and secretion promote cell survival but attenuate cell proliferation during nutrient insufficiency, thus switching the priority of cancer cells from proliferation to survival. Loss of STC2 impairs tumour growth by inducing both apoptosis and necrosis in mouse xenografts. Mechanistically, under nutrient insufficient conditions, cells have increased levels of reactive oxygen species (ROS), and lack of STC2 further elevates ROS levels that lead to increased apoptosis. RNA-Seq analyses reveal STC2 induction suppresses the expression of monoamine oxidase B (MAOB), a mitochondrial membrane enzyme that produces ROS. Moreover, a negative correlation between STC2 and MAOB levels is also identified in human tumour samples. Importantly, the administration of recombinant STC2 to the culture media effectively suppresses MAOB expression as well as apoptosis, suggesting STC2 functions in an autocrine/paracrine manner. Taken together, our findings indicate that nutrient insufficiency induces STC2 expression, which in turn governs the adaptation of cancer cells to nutrient insufficiency through the maintenance of redox homeostasis, highlighting the potential of STC2 as a therapeutic target for cancer treatment.

Safety and Efficacy of Capsular Tension Ring and Capsular Hook Implantation for Managing Ectopia Lentis in Marfan Syndrome: A Real-World Study.

OBJECTIVE: To evaluate the safety and efficacy of capsular tension ring and capsular hook (CTR-CH) implantation in Marfan syndrome (MFS) patients with ectopia lentis (EL). SETTING: Eye and ENT Hospital of Fudan University. DESIGN: Retrospective propensity-score matched cohort study. METHODS: This study included MFS patients who had in-the-bag intraocular lens (IOL) implantation assisted by CTR-CH or modified capsular tension ring (MCTR). The safety analysis focused on the re-surgery rate. The efficacy analysis compared the best-corrected visual acuity (BCVA) and the incidence of laser capsulotomy after propensity score matching (PSM). RESULTS: This study encompassed 148 eyes that had the CTR-CH procedure and 162 eyes that received MCTR implantation. In the CTR-CH group, the median age at the time of surgery was 5 years old, with a mean follow-up duration of 1.81 ± 0.4 years. Five eyes (3.38%) required a second surgery due to retinal detachment (2, 1.35%), IOL decentration (2, 1.35%), and CH dislocation (1, 0.68%). The re-surgery rate was comparable to that of the MCTR group (P = 0.486). After PSM, a total of 108 patients were recruited in each group. Postoperative BCVA was significantly improved in both groups (both P < 0.001), but comparable between the groups (P = 0.057). The posterior capsular opacification took place earlier (P = 0.046), while the anterior capsular opacification required laser capsulotomy at a later stage (P = 0.037) compared to the MCTR group. CONCLUSIONS: The CTR-CH procedure was a feasible, safe, and efficient approach for managing EL in MFS patients.

Eosinophilic Solid and Cystic Renal Cell Carcinoma: Morphologic and Immunohistochemical Study of 18 Cases and Review of the Literature.

CONTEXT.­: Eosinophilic solid and cystic renal cell carcinoma is now defined in the 5th edition of the 2022 World Health Organization classification of urogenital tumors. OBJECTIVE.­: To perform morphologic, immunohistochemical, and preliminary genetic studies about this new entity in China for the purpose of understanding it better. DESIGN.­: The study includes 18 patients from a regional tertiary oncology center in northern China (Tianjin, China). We investigated the clinical and immunohistochemical features of these cases. RESULTS.­: The mean age of patients was 49.6 years and the male to female ratio was 11:7. Macroscopically, 1 case had the classic cystic and solid appearance whereas the others appeared purely solid. Microscopically, all 18 tumors shared similar solid and focal macrocystic or microcystic growth pattern, and the cells were characterized by voluminous and eosinophilic cytoplasm, along with coarse amphophilic stippling. Immunohistochemically, most of the tumors had a predominant cytokeratin (CK) 20-positive feature, ranging from focal cytoplasmic staining to diffuse membranous accentuation. Initially, we separated these cases into different immunohistochemical phenotypes. Group 1 (7 of 18; 38.5%) was characterized by positive phospho-4EBP1 and phospho-S6, which can imply hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling. Group 2 (4 of 18; 23%) was negative for NF2, probably implying a germline mutation of NF2. Group 3 (7 of 18; 38.5%) consisted of the remaining cases. One case had metastatic spread and exhibited an aggressive clinical course, and we detected cyclin-dependent kinase inhibitor 2A (CDKN2A) mutation in this case; other patients were alive and without disease progression. CONCLUSIONS.­: Our research proposes that eosinophilic solid and cystic renal cell carcinoma exhibits prototypical pathologic features with CK20 positivity and has aggressive potential.

Traditional Chinese Medicine Formulae QY305 Reducing Cutaneous Adverse Reaction and Diarrhea by its Nanostructure.

Traditional Chinese medicine (TCM) is widely used in clinical practice, including skin and gastrointestinal diseases. Here, a potential TCM QY305 (T-QY305) is reported that can modulate the recruitment of neutrophil in skin and colon tissue thus reducing cutaneous adverse reaction and diarrhea induced by epidermal growth factor receptor inhibitors (EGFRIs). On another hand, the T-QY305 formula, through regulating neutrophil recruitment features would highlight the presence of N-QY305, a subunit nanostructure contained in T-QY305, and confirm its role as potentially being the biomaterial conferring to T-QY305 its pharmacodynamic features. Here, the clinical records of two patients are analyzed expressing cutaneous adverse reaction and demonstrate positive effect of T-QY305 on the simultaneous inhibition of both cutaneous adverse reaction and diarrhea in animal models. The satisfying results obtained from T-QY305, lead to further process to the isolation of N-QY305 from T-QY305, in order to demonstrate that the potency of T-QY305 originates from the nanostructure N-QY305. Compared to T-QY305, N-QY305 exhibits higher potency upon reducing adverse reactions. The data represent a promising candidate for reducing cutaneous adverse reaction and diarrhea, meanwhile proposing a new strategy to highlight the presence of nanostructures being the "King" of Chinese medicine formula as the pharmacodynamic basis.

Adverse Effects of Gefitinib on Skin and Colon in a Lung Cancer Mouse Model.

BACKGROUND: Gefitinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), frequently causes side effects when used to treat non-small cell lung cancer. OBJECTIVE: The purpose of this experiment was to investigate the side effect of gefitinib on the skin and colon of mice. METHODS: Male Balb/c nu-nu nude mice aged 4-5 weeks were used as xenograft tumor models, and gefitinib at 150 mg/kg and 225 mg/kg was started at 9 days after the xenograft tumor grew out. The mice's weights and tumor volumes were tracked concurrently, and the mouse skin adverse reactions and diarrhea were observed during the treatment. The animal tissues were subjected to biochemical and pathological evaluations after 14 days. RESULTS: Gefitinib effectively decreased the size and weight of transplanted tumors in nude mice, while also lowering body weight and raising indexes of the liver and spleen. Gefitinib could cause skin adverse reactions and diarrhea in mice. Further pathological investigation revealed tight junction- related markers in the mice's skin and colon to be reduced and macrophages and neutrophils to be increased after gefitinib treatment. CONCLUSION: The findings imply that gefitinib has negative effects on the skin and colon. Gefitinib- induced skin and colon adverse reactions in mice have been successfully modeled in this study.

Healthy plant-based diet might be inversely associated with gastric precancerous lesions: new evidence from a case-control study based on dietary pattern and fecal metabolic profiling.

Preventing the progression of gastric precancerous lesions (GPLs) can reduce the morbidity and mortality of gastric cancer (GC). The preventive effect of a plant-based diet on cancers has been widely recognised. In this case-control study, 1,130 subjects were included using 1:1 propensity score matching for age and sex. Dietary habits, anthropometry and sample collection were conducted using standard and effective methods. Plant-based diet indices (PDIs) were calculated using a previously reported method. Faecal samples were analysed by untargeted metabolomics. Our study found that adherence to a healthy plant-based diet was inversely associated with the occurrence of GPLs. Metabolomic analysis identified six different metabolites correlated with GPLs, among which luteolin-related metabolites may be used as biomarkers of the association between PDIs and GPLs. In addition, the difference in N-acyl amides found in PDIs needs further verification. Our findings suggest that a healthy plant-based diet may have a protective effect against GPLs.

Template-confined assembly of Ag nanocubes: An approach to fabricate SERS substrate with good performance.

Surface-enhanced Raman scattering (SERS) is an important analytical technique. Its detection sensitivity and reproducibility depend on the density and distribution of SERS hotspots. Self-assembly is an efficient method to produce of SERS substrates due to its easy accessibility. However, the assembled defects can hardly be avoided on large area, which could lower the density and uniformity of the hotspots, leading to poor SERS performance. Herein, we report a method to reduce the defects by taking a patterned substrate as template to confine the assembly of Ag nanocubes. The template was prepared based on the combination of photo lithography and self-assembly. Confined by the template, the Ag nanocubes were assembled closely in each dots of the pattern. The limit of detection (LOD) is down to 3.42 × 10-17 M and the enhanced factor (EF) is up to 3.44 × 1010 on the prepared substrate for detecting rhodamine 6G (R6G). In addition, the relative standard deviation (RSD) of the different substrates is 8.75 %. The assembled Ag nanocubes exhibits high sensitivity and reproducibility as SERS substrate, which are contributed by the formation of high-density and uniform hotspots. The prepared substrate can be used for detecting trace amounts of melamine in milk with LOD of 2.06 × 10-7 M and RSD of 6.91 %, so the substrate is applicable for analyzing various analytes.

Atomically Coupled 2D MnO2/MXene Superlattices for Ultrastable and Fast Aqueous Zinc-Ion Batteries.

The delta manganese dioxide (δ-MnO2) has sparked a great deal of scientific research for application as the cathode in aqueous zinc-ion batteries (AZIBs) owing to its characteristic layered structure. However, further development and commercial application of the δ-MnO2 cathode are hindered by the low rate performance and poor cycling stability, which are derived from its inherently poor electrical conductivity and structural instability during the charge/discharge process. Herein, we report the fabrication of the 2D MnO2/MXene superlattice by the solution-phase assembly of unilamellar MnO2 and Ti3C2Tx MXene nanosheets, where the unilamellar MnO2 nanosheet is separated and stabilized between unilamellar MXene nanosheets. The MXene nanosheets can not only serve as structural stabilizers to isolate the MnO2 nanosheets and prevent them from aggregating but also act as conductive contributors to strengthen the electrical conductivity, thus maintaining the overall structural stability and realizing the rapid electron transport. Additionally, the regular stacking with a repeating periodicity of the 2D MnO2/MXene can lead to highly exposed active sites, promoting ion diffusion. As a consequence, the large specific capacity of 315.1 mAh g-1 at 0.2 A g-1, prominent rate performance of 149.8 mAh g-1 at 5 A g-1, and excellent long-term cycling stability after 5000 cycles with 88.1% capacity retention are obtained for the MnO2/MXene cathode in AZIBs. Meanwhile, the superior H+/Zn2+ diffusion kinetics and desirable pseudocapacitive behaviors are elucidated by electrochemical measurements and density functional theory computations. This study provides an advanced perspective for the innovation of manganese oxide-based cathode materials in AZIBs.

Bioinformatic Analysis of The Prognostic Value of A Panel of Six Amino Acid Transporters in Human Cancers.

OBJECTIVE: Solid tumor cells utilize amino acid transporters (AATs) to increase amino acid uptake in response to nutrient-insufficiency. The upregulation of AATs is therefore critical for tumor development and progression. This study identifies the upregulated AATs under amino acid deprived conditions, and further determines the clinicopathological importance of these AATs in evaluating the prognosis of patients with cancers. MATERIALS AND METHODS: In this experimental study, the Gene Expression Omnibus (GEO) datasets (GSE62673, GSE26370, GSE125782 and GSE150874) were downloaded from the NCBI website and utilized for integrated differential expression and pathway analysis v0.96, Gene Set Enrichment Analysis (GSEA), and REACTOME analyses to identify the AATs upregulated in response to amino acid deprivation. In addition, The Cancer Genome Atlas (TCGA) datasets with prognostic information were assessed and employed to evaluate the association of identified AATs with patients' prognoses using SurvExpress analysis. RESULTS: Using analysis of NCBI GEO data, this study shows that amino acid deprivation leads to the upregulation of six AAT genes; SLC3A2, SLC7A5, SLC7A1, SLC1A4, SLC7A11 and SLC1A5. GSEA and REACTOME analyses identified altered signaling in cells exposed to amino acid deprivation, such as pathways related to stress responses, the cell cycle and apoptosis. In addition, Principal Component Analysis showed these six AAT genes to be well divided into two distinct clusters in relation to TCGA tumor tissues versus normal counterparts. Finally, Log-Rank analysis confirmed the upregulation of this panel of six AAT genes is correlated with poor prognosis in patients with colorectal, esophageal, kidney and lung cancers. CONCLUSION: The upregulation of a panel of six AATs is common in several human cancers and may provide a valuable diagnostic tool to evaluate the prognosis of patients with colorectal, esophageal, kidney and lung cancers.

Establishment and validation of a nomogram for predicting new fractures after PKP treatment of for osteoporotic vertebral compression fractures in the elderly individuals.

BACKGROUND: To investigate the risk factors for new vertebral compression fractures (NVCFs) after percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fractures (OVCFs) and to create a nomogram to predict the occurrence of new postoperative fractures. METHODS: This was a retrospective analysis of the clinical data of 529 OVCF patients who received PKP treatment in our hospital from June 2017 to June 2020. Based on whether there were new fractures within 2 years after surgery, the patients were divided into a new fracture group and a nonnew fracture group. Univariate and multivariate analyses were used to determine the risk factors for the occurrence of NVCFs after surgery. The data were randomly divided into a training set (75%) and a testing set (25%). Nomograms predicting the risk of NVCF occurrence were created based on the results of the multivariate analysis, and performance was evaluated using receiver operating characteristic curves (ROCs), calibration curves, and decision curve analyses (DCAs). A web calculator was created to give clinicians a more convenient interactive experience. RESULTS: A total of 56 patients (10.6%) had NVCFs after surgery. The univariate analysis showed significant differences in sex and the incidences of cerebrovascular disease, a positive fracture history, and bone cement intervertebral leakage between the two groups (P < 0.05). The multivariate analysis showed that sex [OR = 2.621, 95% CI (1.030-6.673), P = 0.043], cerebrovascular disease [OR = 28.522, 95% CI (8.749-92.989), P = 0.000], fracture history [OR = 12.298, 95% CI (6.250-24.199), P = 0.000], and bone cement intervertebral leakage [OR = 2.501, 95% CI (1.029-6.082), P = 0.043] were independent risk factors that were positively associated with the occurrence of NVCFs. The AUCs of the model were 0.795 (95% CI: 0.716-0.874) and 0.861 (95% CI: 0.749-0.974) in the training and testing sets, respectively, and the calibration curves showed high agreement between the predicted and actual states. The areas under the decision curve were 0.021 and 0.036, respectively. CONCLUSION: Female sex, cerebrovascular disease, fracture history and bone cement intervertebral leakage are risk factors for NVCF after PKP. Based on this, a highly accurate nomogram was developed, and a webpage calculator ( https://new-fracture.shinyapps.io/DynNomapp/ ) was created.

Fabrication of Flexible Pyramid Array as SERS Substrate for Direct Sampling and Reproducible Detection.

Rapid extraction and analysis of target molecules from irregular surfaces are in high demand in the field of on-site analysis. Herein, a flexible platform used for surface-enhanced Raman scattering (SERS) based on an ordered polymer pyramid structure with half-imbedded silver nanoparticles (AgNPs) was prepared to address this issue. The fabrication includes the following steps: (1) creating inverted pyramid arrays in silicon substrate, (2) preparing a layer of AgNPs on the surface of the inverted pyramids, and (3) obtaining a substrate with an ordered polymer pyramids array with half-imbedded AgNPs by the molding method. This flexible substrate is capable of rapid extraction via a simple and convenient "paste and peel off" method. In addition, the substrate exhibits great repeatability and good sensitivity thanks to the uniformity and larger surface area of the ordered pyramids. The density of "hot spots" (local electromagnetic field with high intensity) is increased on the structured surface. Semi-imbedding silver particles in the polymer pyramids makes "hot spots" robust on the substrate. In addition, the preprepared silicon template with the inverted pyramids can be reused, which greatly reduces the production cost. With this substrate, we successfully analyzed thiram molecules on the epidermis of apples, cucumbers, and oranges, and the detection limits are 2.4, 3, and 3 ng/cm2, respectively. These results demonstrate the great potential of the substrate for in situ analysis, which can provide reference for the design of ideal SERS substrates.

Comparison of different risk stratifications for gastric cancer and establishing a simplified risk-scoring model based on the Kyoto classification.

BACKGROUND AND AIM: The study aims to assess the value of different risk stratifications in diagnosing early gastric cancer (GC) and explore risk factors based on Kyoto gastritis classification. METHODS: This study was a single-centered cross-sectional study; all epidemiological data and endoscopic findings were obtained prospectively. To evaluate the proportion of GC in each risk stratification and to compare the diagnostic performance of different methods using the receiver operating characteristic curve, univariable and multivariable analyses were used to explore the correlation between endoscopic findings and GC. RESULTS: A total of 240 subjects were enrolled, and the diagnostic efficacy of the Kyoto Classification Score was similar to Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) stage, and the accuracy was higher than that of the Japanese scoring system and OLGA stage. Moderate atrophy (odds ratio [OR] = 3.52, 95% confidence interval [CI]: 1.52-8.16), severe atrophy (OR = 4.96, 95% CI: 1.75-14.04), map-like redness (OR = 9.89, 95% CI: 1.16-84.15), and xanthelasma (OR = 3.57, 95% CI: 1.15-11.15) were independent risk factors for GC. The simplified Kyoto classification (area under the receiver operating characteristic [AUROC] = 0.76, P = 0.58) based on multivariable analysis demonstrated favorable diagnostic value compared with traditional Kyoto classification score (AUROC = 0.74). CONCLUSIONS: This study confirms the value of the Kyoto classification score and the OLGIM stage in the risk stratification of GC. Simplified Kyoto classification is also promising in risk assessment of GC but still requires validation in the population.

Experimental Study on Drying Biomass with a Spherical Heat Carrier.

Due to the reduction of the thermal efficiency and output fluctuation of the boiler system caused by the high moisture in biomass, dewatering of fuels using low-cost processes is an important step in feedstock pretreatment for biomass power plants. In the present study, a steel ball was used as the spherical heat carrier (SHC). The effects of the SHC temperature on the dewatering of different biomasses were investigated by a mixture-drying device at 40% moisture content of biomass, and the drying process of peanut shells was analyzed. Results showed that the moisture content was effectively reduced, and the combustion performance of the biomass was significantly promoted. The work is likely to provide an economically feasible approach for biomass drying in further studies.

Nanostructures in Chinese herbal medicines (CHMs) for potential therapy.

With its long clinical history, traditional Chinese medicine (TCM) has gained acceptance for its specific efficacy and safety in the treatment of multiple diseases. Nano-sized materials study of Chinese herbal medicines (CHMs) leads to an increased understanding of assessing TCM therapies, which may be a promising way to illustrate the material basis of CHMs through their processing and extraction. In this review, we provide an overview of the nanostructures of natural and engineered CHMs, including extracted CHMs, polymer nanoparticles, liposomes, micelles, and nanofibers. Subsequently, the applications of these CHM-derived nanostructures to particular diseases are summarized and discussed. Additionally, we discuss the advantages of these nanostructures for studying the therapeutic efficacy of CHMs. Finally, the key challenges and opportunities for the development of these nanostructures are outlined.

Exploring the molecular characteristics of the malignant potential of gastric adenocarcinoma with enteroblastic differentiation.

AIMS: Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare subset of alpha-fetoprotein (AFP)-producing carcinomas with poor prognosis. However, the molecular features associated with the malignant potential of GEAD remain partially elucidated. METHODS AND RESULTS: In this study, the relationship between clinicopathological parameters and aggressive biological behaviour was analysed in 37 patients with GAED. The results showed that GAED tended to infiltrate the deep layer of the gastric wall and possessed more frequent vascular invasion than conventional gastric adenocarcinoma (CGA) (P < 0.001). All distant metastases were observed in the GAED group, not the CGA group (P < 0.001). High HER2 expression was found in nearly 24.32% of the informative cases, and none showed EBV-encoded RNA positivity or deficient mismatch repair. The most frequently mutated gene in GAED was p53. Programmed cell death-ligand 1 (PD-L1) immunostaining revealed 13 patients with a combined positive score (CPS) ≥ 5 (65%, 13 of 20). Thus, based on these molecular markers (immunostaining, in situ hybridisation and mutation analysis), GAED may be classified as a unique subgroup of the chromosomal instability subtype with HER2+ /EBV- /MSS/TP53+ /PD-L1+ . Next-generation sequencing analyses showed that mutations in the TOPI, ELOA and NOTCH3 genes were found only in GAED, and abnormally expressed genes in GAED were significantly enriched in hepatocellular carcinoma-, gland development-, and gastric cancer-related pathways. CONCLUSION: The HER2+ /EBV- /MSS/TP53+ /PD-L1+ profile and hepatocellular carcinoma-related pathways may be significant in the malignant potential of GAED. In addition to anti-HER2 therapy, immune check-point inhibitors may be an effective treatment option for patients with GAED.

Risk of lymph node metastasis and feasibility of endoscopic submucosal dissection in undifferentiated-type early gastric cancer.

BACKGROUND: Whether endoscopic submucosal dissection (ESD) applies to undifferentiated-type early gastric cancer (UEGC) remains controversial. We aimed to analyze the risk factors for lymph node metastasis (LNM) in UEGC and evaluate the feasibility of ESD. METHODS: This study included 346 patients with UEGC who underwent curative gastrectomy between January 2014 and December 2021. Univariate and multivariate analyses of the correlation between clinicopathological features and LNM were conducted, and the risk factors for exceeding the expanded ESD indications were evaluated. RESULTS: The overall LNM rate in UEGC was 19.94%. Among the preoperatively assessable factors, submucosal invasion (odds ratio [OR] = 4.77, 95% confidence interval [CI]: 2.14-10.66) and > 2 cm(OR = 2.49, 95% CI: 1.20-5.15) were independent risk factors for LNM, while postoperative independent risk factors were > 2 cm (OR = 3.35, 95% CI: 1.02-5.40) and lymphovascular invasion(OR = 13.21, 95% CI: 5.18-33.70). Patients who met the expanded indications had a low LNM risk (4.1%). Additionally, tumors located in the cardia (P = 0.03), non-elevated type (P < 0.01) were independent risk factors for exceeding the expanded indications in UEGC. CONCLUSIONS: ESD may be applicable for UEGC meeting the expanded indications, and preoperative evaluation should be cautious when the lesion is non-elevated type or located in the cardia. TRIAL REGISTRATION: Chinese Clinical Trial Registry (12/05/2022 ChiCTR2200059841 ).

ISG15 targets glycosylated PD-L1 and promotes its degradation to enhance antitumor immune effects in lung adenocarcinoma.

BACKGROUND: Immunocheckpoint inhibitors (ICIs) have been widely used in the clinical treatment of lung cancer. Although clinical studies and trials have shown that patients can benefit significantly after PD-1/PD-L1 blocking therapy, less than 20% of patients can benefit from ICIs therapy due to tumor heterogeneity and the complexity of immune microenvironment. Several recent studies have explored the immunosuppression of PD-L1 expression and activity by post-translational regulation. Our published articles demonstrate that ISG15 inhibits lung adenocarcinoma progression. Whether ISG15 can enhance the efficacy of ICIs by modulating PD-L1 remains unknown. METHODS: The relationship between ISG15 and lymphocyte infiltration was identified by IHC. The effects of ISG15 on tumor cells and T lymphocytes were assessed using RT-qPCR and Western Blot and in vivo experiments. The underlying mechanism of PD-L1 post-translational modification by ISG15 was revealed by Western blot, RT-qPCR, flow cytometry, and Co-IP. Finally, we performed validation in C57 mice as well as in lung adenocarcinoma tissues. RESULTS: ISG15 promotes the infiltration of CD4+ T lymphocytes. In vivo and in vitro experiments demonstrated that ISG15 induces CD4+ T cell proliferation and invalidity and immune responses against tumors. Mechanistically, we demonstrated that the ubiquitination-like modifying effect of ISG15 on PD-L1 increased the modification of K48-linked ubiquitin chains thus increasing the degradation rate of glycosylated PD-L1 targeting proteasomal pathway. The expression of ISG15 and PD-L1 was negatively correlated in NSCLC tissues. In addition, reduced accumulation of PD-L1 by ISG15 in mice also increased splenic lymphocyte infiltration as well as promoted cytotoxic T cell infiltration in the tumor microenvironment, thereby enhancing anti-tumor immunity. CONCLUSIONS: The ubiquitination modification of PD-L1 by ISG15 increases K48-linked ubiquitin chain modification, thereby increasing the degradation rate of glycosylated PD-L1-targeted proteasome pathway. More importantly, ISG15 enhanced the sensitivity to immunosuppressive therapy. Our study shows that ISG15, as a post-translational modifier of PD-L1, reduces the stability of PD-L1 and may be a potential therapeutic target for cancer immunotherapy.

High expression of RNF31 is associated with tumor immune cell infiltration and leads to poor prognosis in liver hepatocellular carcinoma.

Ring finger protein 31 (RNF31) has been found to play an important role in tumor immunity. However, the role of RNF31 in liver hepatocellular carcinoma (LIHC) has not been reported. Therefore, we investigated the expression and prognostic value of RNF31 in patients with LIHC and explored its relationship with immune cell infiltration. The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset was downloaded to analyse the impact of RNF31 on the prognosis and immune cell infiltration of LIHC. The Tumor Immune Estimation Resource (TIMER) database was used to analyse the correlation between RNF31 and tumor immune cell infiltration in LIHC. Additionally, we analysed the relationship between RNF31 and tumor necrosis factor (TNF) as well as the interferon-gamma (IFN-γ) signaling pathway. The expression of RNF31 in LIHC was significantly higher than that in normal tissues. Increased RNF31 expression was associated with decreased overall survival (OS) and relapse-free survival (RFS). An increase in RNF31 expression was closely related to the infiltration levels of immune cells (e.g., natural killer (NK) cells, CD8 + T cells, and B cells). RNF31 was also positively correlated with the expression of immune checkpoint genes in LIHC. Moreover, RNF31 may participate in TNF and IFN-γ signaling pathways. In conclusion, RNF31 is a potentially valuable prognostic biomarker in LIHC. RNF31 is also associated with immune cell infiltration in LIHC. RNF31 may be a potential target for immunotherapy of LIHC.