Immunogenomic features of radiologically distinctive nodules in multiple primary lung cancer.

OBJECTIVES: To provide molecular and immunological attributes mechanistic insights for the management of radiologically distinctive multiple primary lung cancer (MPLC). METHODS: The Bulk RNA-seq data of MPLC were obtained from our center. The Bulk RNA-seq data and CT images of patients with single primary lung cancer (SPLC) were obtained from GSE103584. Immune infiltration algorithms were performed to investigate the disparities in the immunological microenvironment between the two groups. Single-cell gene analysis was used to explore immune cells composition and communication relationships between cells in MPLC. RESULTS: In MPLC, 11 pure ground-glass opacity nodules (pGGN) and 10 mixed GGN (mGGN) were identified, while in SPLC, the numbers were 18 pGGN and 22 mGGN, respectively. In MPLC, compared to pGGN, mGGN demonstrated a significantly elevated infiltration of CD8+ T cells. Single-cell gene analysis demonstrated that CD8+ T cells play a central role in the signaling among immune cells in MPLC. The transcription factors including MAFG, RUNX3, and TBX21 may play pivotal roles in regulation of CD8+ T cells. Notably, compared to SPLC nodules for both mGGN and pGGN, MPLC nodules demonstrated a significantly elevated degree of tumor-infiltrating immune cells, with this difference being particularly pronounced in mGGN. There was a positive correlation between the proportion of immune cells and consolidation/tumor ratio (CTR). CONCLUSIONS: Our findings provided a comprehensive description about the difference in the immune microenvironment between pGGN and mGGN in early-stage MPLC, as well as between MPLC and SPLC for both mGGN and pGGN. The findings may provide evidence for the design of immunotherapeutic strategies for MPLC.

Skin-Inspired, Highly Sensitive, Broad-Range-Response and Ultra-Strong Gradient Ionogels Prepared by Electron Beam Irradiation.

Skin, characterized by its distinctive gradient structure and interwoven fibers, possesses remarkable mechanical properties and highly sensitive attributes, enabling it to detect an extensive range of stimuli. Inspired by these inherent qualities, a pioneering approach involving the crosslinking of macromolecules through in situ electron beam irradiation (EBI) is proposed to fabricate gradient ionogels. Such a design offers remarkable mechanical properties, including excellent tensile properties (>1000%), exceptional toughness (100 MJ m-3), fatigue resistance, a broad temperature range (-65-200°C), and a distinctive gradient modulus change. Moreover, the ionogel sensor exhibits an ultra-fast response time (60 ms) comparable to skin, an incredibly low detection limit (1 kPa), and an exceptionally wide detection range (1 kPa-1 MPa). The exceptional gradient ionogel material holds tremendous promise for applications in the field of smart sensors, presenting a distinct strategy for fabricating flexible gradient materials.

Low-dose Olaparib improves septic cardiac function by reducing ferroptosis via accelerated mitophagy flux.

Sepsis is a dysregulated response to infection that can result in life-threatening organ failure, and septic cardiomyopathy is a serious complication involving ferroptosis. Olaparib, a classic targeted drug used in oncology, has demonstrated potential protective effects against sepsis. However, the exact mechanisms underlying its action remain to be elucidated. In our study, we meticulously screened ferroptosis genes associated with sepsis, and conducted comprehensive functional enrichment analyses to delineate the relationship between ferroptosis and mitochondrial damage. Eight sepsis-characterized ferroptosis genes were identified in sepsis patients, including DPP4, LPIN1, PGD, HP, MAPK14, POR, GCLM, and SLC38A1, which were significantly correlated with mitochondrial quality imbalance. Utilizing DrugBank and molecular docking, we demonstrated a robust interaction of Olaparib with these genes. Lipopolysaccharide (LPS)-stimulated HL-1 cells and monocytes were used to establish an in vitro sepsis model. Additionally, an in vivo model was developed using mice subjected to cecal ligation and perforation (CLP). Intriguingly, low-dose Olaparib (5 mg/kg) effectively targeted and mitigated markers associated with ferroptosis, concurrently improving mitochondrial quality. This led to a marked enhancement in cardiac function and a significant increase in survival rates in septic mice (p < 0.05). The mechanism through which Olaparib ameliorates ferroptosis in cardiac and leukocyte cells post-sepsis is attributed to its facilitation of mitophagy, thus favoring mitochondrial integrity. In conclusion, our findings suggest that low-dose Olaparib can improve mitochondrial quality by accelerating mitophagy flux, consequently inhibiting ferroptosis and preserving cardiac function after sepsis.

mTOR/miR-142-3p/PRAS40 signaling cascade is critical for tuberous sclerosis complex-associated renal cystogenesis.

BACKGROUND: Patients with tuberous sclerosis complex (TSC) develop renal cysts and/or angiomyolipomas (AMLs) due to inactive mutations of either TSC1 or TSC2 and consequential mTOR hyperactivation. The molecular events between activated mTOR and renal cysts/AMLs are still largely unknown. METHODS: The mouse model of TSC-associated renal cysts were constructed by knocking out Tsc2 specifically in renal tubules (Tsc2f/f; ksp-Cre). We further globally deleted PRAS40 in these mice to investigate the role of PRAS40. Tsc2-/- cells were used as mTOR activation model cells. Inhibition of DNA methylation was used to increase miR-142-3p expression to examine the effects of miR-142-3p on PRAS40 expression and TSC-associated renal cysts. RESULTS: PRAS40, a component of mTOR complex 1, was overexpressed in Tsc2-deleted cell lines and mouse kidneys (Tsc2f/f; ksp-Cre), which was decreased by mTOR inhibition. mTOR stimulated PRAS40 expression through suppression of miR-142-3p expression. Unleashed PRAS40 was critical to the proliferation of Tsc2-/- cells and the renal cystogenesis of Tsc2f/f; ksp-Cre mice. In contrast, inhibition of DNA methylation increased miR-142-3p expression, decreased PRAS40 expression, and hindered cell proliferation and renal cystogenesis. CONCLUSIONS: Our data suggest that mTOR activation caused by TSC2 deletion increases PRAS40 expression through miR-142-3p repression. PRAS40 depletion or the pharmacological induction of miR-142-3p expression impaired TSC2 deficiency-associated renal cystogenesis. Therefore, harnessing mTOR/miR-142-3p/PRAS40 signaling cascade may mitigate hyperactivated mTOR-related diseases.

Iron deficiency at birth and risk of hidden hearing loss in infants modification by socioeconomic status: mother-newborn cohort in Shenyang, China.

OBJECTIVE: The diagnosis of hidden hearing loss (HHL) in calm state has not yet been determined, while the nutritional status is not involved in its pathogenic risk factors. In utero iron deficiency (ID) may delay auditory neural maturation in infants. We evaluated the association between ID and HHL as well as the modification effect of socioeconomic status (SES) on this association in newborns. STUDY DESIGN: We included 859 mother-newborns from the baseline of this observational northeast cohort. Data on exposure assessment included iron status [maternal hemoglobin (Hb) and neonatal heel prick serum ferritin (SF)] and SES (occupation, education and income). Auditory neural maturation was reflected by auditory brainstem response (ABR) testing and electrocochleography (ECochG). RESULTS: Iron status and SES were independently and jointly associated with the prediction of neonatal HHL by logistic and linear regression model. The mediation effects were performed by Process. ID increased absolute latency wave V, interpeak latency (IPL) III-V, and summting potentials (SP) /action potentials (AP), which were combined as HHL. Low SES showed the highest risk of HHL and the highest levels of related parameters in ID newborns. Moreover, after Corona Virus Disease 2019 (COVID-19) were positive, preschool children who experience ID in neonatal period were more likely to suffer from otitis media with effusion (OME). High SES also showed similar risk effects. CONCLUSION: Both low and high SES may strengthen the risk of ID on neonatal HHL in Northeast China.

Infrared and Visible Image Fusion Algorithm Based on Double-Domain Transform Filter and Contrast Transform Feature Extraction.

Current challenges in visible and infrared image fusion include color information distortion, texture detail loss, and target edge blur. To address these issues, a fusion algorithm based on double-domain transform filter and nonlinear contrast transform feature extraction (DDCTFuse) is proposed. First, for the problem of incomplete detail extraction that exists in the traditional transform domain image decomposition, an adaptive high-pass filter is proposed to decompose images into high-frequency and low-frequency portions. Second, in order to address the issue of fuzzy fusion target caused by contrast loss during the fusion process, a novel feature extraction algorithm is devised based on a novel nonlinear transform function. Finally, the fusion results are optimized and color-corrected by our proposed spatial-domain logical filter, in order to solve the color loss and edge blur generated in the fusion process. To validate the benefits of the proposed algorithm, nine classical algorithms are compared on the LLVIP, MSRS, INO, and Roadscene datasets. The results of these experiments indicate that the proposed fusion algorithm exhibits distinct targets, provides comprehensive scene information, and offers significant image contrast.

Notoginsenoside R1 improves intestinal microvascular functioning in sepsis by targeting Drp1-mediated mitochondrial quality imbalance.

CONTEXT: Sepsis can result in critical organ failure, and notoginsenoside R1 (NGR1) offers mitochondrial protection. OBJECTIVE: To determine whether NGR1 improves organ function and prognosis after sepsis by protecting mitochondrial quality. MATERIALS AND METHODS: A sepsis model was established in C57BL/6 mice using cecum ligation puncture (CLP) and an in vitro model with lipopolysaccharide (LPS, 10 µg/mL)-stimulated primary intestinal microvascular endothelial cells (IMVECs) and then determine NGR1's safe dosage. Groups for each model were: in vivo-a control group, a CLP-induced sepsis group, and a CLP + NGR1 treatment group (30 mg/kg/d for 3 d); in vitro-a control group, a LPS-induced sepsis group, and a LPS + NGR1 treatment group (4 µM for 30 min). NGR1's effects on survival, intestinal function, mitochondrial quality, and mitochondrial dynamic-related protein (Drp1) were evaluated. RESULTS: Sepsis resulted in approximately 60% mortality within 7 days post-CLP, with significant reductions in intestinal microvascular perfusion and increases in vascular leakage. Severe mitochondrial quality imbalance was observed in IMVECs. NGR1 (IC50 is 854.1 µM at 30 min) targeted Drp1, inhibiting mitochondrial translocation, preventing mitochondrial fragmentation and restoring IMVEC morphology and function, thus protecting against intestinal barrier dysfunction, vascular permeability, microcirculatory flow, and improving sepsis prognosis. DISCUSSION AND CONCLUSIONS: Drp1-mediated mitochondrial quality imbalance is a potential therapeutic target for sepsis. Small molecule natural drugs like NGR1 targeting Drp1 may offer new directions for organ protection following sepsis. Future research should focus on clinical trials to evaluate NGR1's efficacy across various patient populations, potentially leading to novel treatments for sepsis.

[Exploration of cancer biological characteristics in people with different five movements and six climates constitution based on pan-cancer Bulk RNA-Seq].

According to the theory of five movements and six climates, the innate constitution plays a crucial role in determining the underlyingpa thological mechanisms of diseases later in life. Previous studies have demonstrated a close association between the constitution, as defined by the theory of five movements and six climates, and the development of various types of tumors. Furt hermore,the tumorsubtype determined by the constitution has prognostic implications. This highlights the potential of utilizing the fivemovements and six climates theory to guide the implementation of precision medicine strategies in thefield of oncology. However, no resear ch has yet been conducted to investigate the use of this theory in guiding the development of tumor molecular classification and precisi onmedicine strategies. The objective of this research is to uncover the biological characteristics of each constitution within a pancanc ercohort and identify potential anti-tumor drugs that are applicable to patients with different constitutional types. By doing so, we aimto c ontribute to the establishment of a precision medicine strategy for tumors derived from the original concepts of traditional Chi nesemedicine(TCM). In this study, we obtainedpan-cancer Bulk RNA-Seq data from UCSC Xena, GWAS cohort data from the UKBiobank, and cis-eQTLs data from eQ TLGen and GTEx V8. We employed machine learning methods to screen for hub genes associated with each constitution. Subsequently, we utilized informatics tools to explore the biological characteristics of each constitut iondefined by the theory of five movements and six bioclimates. Further, potential anti-tumor drugs suitable for patients with differen tconstitutional types were identified through mendelian randomization, molecular docking, and drug-like prediction techniques. Withinthe pan-cancer cohort, significant differences were observed among different constitutions in terms of progression-free interval, biological f unctions, immune cell abundance, tumor drug sensitivity, and immunotherapy response. These findings suggest that the five movements and six climates theory can guide tumor molecular classification and the development of precision medicine strategies. Moreover,the biological characteristics inherent to each constitution partially shed light on the scientific implications of Chinese medicinetheories, offering a fresh perspective towards clinical cancer treatment. Through molecular docking and drug-like prediction, several po tential anti-tumor drugs such as 17-beta-estradiol, serotonin, trans-resveratrol, and linoleic acid were identified. Overall, the util izationof multi-omics approaches pro vides a powerful tool to unravel the scientific foundations of TCM theories. The elucidation of themu lti-omics features associated witheach constitution in tumors serves as the basis for applying the five movements and six climates theoryto tumor molecular classification and the development of precision medicine strategies.

Association between residual islet beta-cell function and achieving the target of time in range in inpatients with type 2 diabetes undergoing antidiabetic treatment: An observation study.

AIM: To assess whether the beta-cell function of inpatients undergoing antidiabetic treatment influences achieving time in range (TIR) and time above range (TAR) targets. MATERIALS AND METHODS: This cross-sectional study included 180 inpatients with type 2 diabetes. TIR and TAR were assessed by a continuous glucose monitoring system, with target achievement defined as TIR more than 70% and TAR less than 25%. Beta-cell function was assessed by the insulin secretion-sensitivity index-2 (ISSI2). RESULTS: Following antidiabetic treatment, logistic regression analysis showed that lower ISSI2 was associated with a decreased number of inpatients achieving TIR (OR = 3.10, 95% CI: 1.19-8.06) and TAR (OR = 3.40, 95% CI: 1.35-8.55) targets after adjusting for potential confounders. Similar associations still existed in those participants treated with insulin secretagogues (TIR: OR = 2.91, 95% CI: 0.90-9.36, P = .07; TAR, OR = 3.14, 95% CI: 1.01-9.80) or adequate insulin therapy (TIR: OR = 2.84, 95% CI: 0.91-8.81, P = .07; TAR, OR = 3.24, 95% CI: 1.08-9.67). Furthermore, receiver operating characteristic curves showed that the diagnostic value of the ISSI2 for achieving TIR and TAR targets was 0.73 (95% CI: 0.66-0.80) and 0.71 (95% CI: 0.63-0.79), respectively. CONCLUSIONS: Beta-cell function was associated with achieving TIR and TAR targets. Stimulating insulin secretion or exogenous insulin treatment could not overcome the disadvantage of lower beta-cell function on glycaemic control.

Prognostic impact of deep learning-based quantification in clinical stage 0-I lung adenocarcinoma.

OBJECTIVES: To evaluate the performance of automatic deep learning (DL) algorithm for size, mass, and volume measurements in predicting prognosis of lung adenocarcinoma (LUAD) and compared with manual measurements. METHODS: A total of 542 patients with clinical stage 0-I peripheral LUAD and with preoperative CT data of 1-mm slice thickness were included. Maximal solid size on axial image (MSSA) was evaluated by two chest radiologists. MSSA, volume of solid component (SV), and mass of solid component (SM) were evaluated by DL. Consolidation-to-tumor ratios (CTRs) were calculated. For ground glass nodules (GGNs), solid parts were extracted with different density level thresholds. The prognosis prediction efficacy of DL was compared with that of manual measurements. Multivariate Cox proportional hazards model was used to find independent risk factors. RESULTS: The prognosis prediction efficacy of T-staging (TS) measured by radiologists was inferior to that of DL. For GGNs, MSSA-based CTR measured by radiologists (RMSSA%) could not stratify RFS and OS risk, whereas measured by DL using 0HU (2D-AIMSSA0HU%) could by using different cutoffs. SM and SV measured by DL using 0 HU (AISM0HU% and AISV0HU%) could effectively stratify the survival risk regardless of different cutoffs and were superior to 2D-AIMSSA0HU%. AISM0HU% and AISV0HU% were independent risk factors. CONCLUSION: DL algorithm can replace human for more accurate T-staging of LUAD. For GGNs, 2D-AIMSSA0HU% could predict prognosis rather than RMSSA%. The prediction efficacy of AISM0HU% and AISV0HU% was more accurate than of 2D-AIMSSA0HU% and both were independent risk factors. CLINICAL RELEVANCE STATEMENT: Deep learning algorithm could replace human for size measurements and could better stratify prognosis than manual measurements in patients with lung adenocarcinoma. KEY POINTS: • Deep learning (DL) algorithm could replace human for size measurements and could better stratify prognosis than manual measurements in patients with lung adenocarcinoma (LUAD). • For GGNs, maximal solid size on axial image (MSSA)-based consolidation-to-tumor ratio (CTR) measured by DL using 0 HU could stratify survival risk than that measured by radiologists. • The prediction efficacy of mass- and volume-based CTRs measured by DL using 0 HU was more accurate than of MSSA-based CTR and both were independent risk factors.

Construction and validation of a survival prognostic model for stage III hepatocellular carcinoma: a real-world, multicenter clinical study.

OBJECTIVE: To construct a survival prediction model for patients with TNM stage III hepatocellular carcinoma (HCC) to guide the clinical diagnosis and treatment of HCC patients and improve prognosis. METHODS: Based on data from patients with stage III (AJCC 7th TNM stage) recorded by the American Institute of Cancer Research from 2010 to 2013, risk factors affecting the prognosis were screened by Cox univariate and multivariate regression, line plots was constructed, and the credibility of the model was verified by Boostrap method. ROC operating curves, calibration curves and DCA clinical decision curves were used to evaluate the model, and Kaplan-Meier was used for survival analysis was used to evaluate the efficacy of the model. External survival data from patients newly diagnosed with stage III hepatocellular carcinoma during 2014-2015 were used to validate and fit the model and to optimize the model. RESULTS: Age > 75 years vs.18-53 years [HR = 1.502; 95%CI(1.134-1.990)], stage IIIC vs. Stage IIIA [HR = 1.930; 95%CI(1.509-2.470)], lobotomy vs. non-surgery [HR = 0.295; 95%CI(0.228-0.383)], radiotherapy vs. non-radiotherapy [HR = 0.481; 95%CI(0.373-0.619)], chemotherapy vs. Non-chemotherapy [HR = 0.443; 95%CI(0.381-0.515)], positive serum AFP before treatment vs. negative [HR = 1.667; 95%CI(1.356-2.049)], the above indicators are independent prognostic factors for patients with stage III hepatocellular carcinoma, and the P values for the above results were less than 0.05. A joint prediction model was constructed based on age, TNM stage, whether and how to operate, whether to receive radiotherapy, whether to receive chemotherapy, pre-treatment serum AFP status and liver fibrosis score. The consistency index of the improved prognosis model was 0.725. CONCLUSIONS: The traditional TNM staging has limitations for clinical diagnosis and treatment, while the Nomogram model modified by TNM staging has good predictive efficacy and clinical significance.

Diabetic Ketoacidosis and Long-term Insulin Requirements in Youths with Newly Diagnosed Type 2 Diabetes During the SARS-CoV-2 Pandemic.

OBJECTIVE: SARS-CoV-2 infection increases the risk of diabetes and diabetic ketoacidosis (DKA) in both adults and children. We investigated the clinical course of new-onset type 2 diabetes in youth presenting with DKA during the COVID-19 pandemic. METHODS: This single-center retrospective cohort study included 148 subjects with obesity aged 10 to 21 years, admitted with DKA from January 2018 to January 2022. Groups were defined by the presence of DKA precipitant: any infection (n = 38, 26%), which included the SARS-CoV-2 (n = 10, 7%) and other infection (n = 28, 19%) groups, and no infection (n = 110, 74%). The primary outcome was insulin discontinuation within a 12-month follow-up. RESULTS: The mean age was 14.9 years (IQR, 13.8-16.5), and age-adjusted body mass index (%) was 99.1 (IQR, 98.0-99.5) with 85.8% identifying as Black or Hispanic. There were no differences in DKA severity among groups. The incidence of DKA was higher during the pandemic (March 2020-January 2022, n = 117) than in the prepandemic period (January 2018-February 2020, n = 31). Within the first year after the acute DKA episode, 46 patients discontinued all insulin within 9 months (IQR, 4-14). Sixteen subjects restarted insulin 10 months (IQR, 6.5-11.0) after insulin discontinuation. Infection with SARS-CoV-2 at diagnosis was not associated with the likelihood (P =.57) or timing (P =.27) of discontinuing all insulin within 1 year, nor was having any infection. CONCLUSION: The incidence of DKA at the onset of type 2 diabetes was higher during the SARS-CoV-2 pandemic than in the prepandemic period. SARS-CoV-2 infection was not associated with DKA severity or insulin discontinuation within the first year of diagnosis in youth with new-onset type 2 diabetes and DKA.

Application of low-dose etomidate combined with oxycodone and midazolam in endoscopic injection sclerotherapy.

OBJECTIVE: To evaluate the adverse effects and particularly the anesthetic effect of low-dose etomidate combined with oxycodone and midazolam in endoscopic injection sclerotherapy. MATERIALS AND METHODS: We herein report a prospective, double-blind, randomized controlled trial. It included patients with liver cirrhosis (age, 18 - 65 years; BMI, 18 - 25 kg/m2) who were treated with endoscopic injection sclerotherapy, and the patients were randomly assigned to the propofol group or the etomidate group. The incidence of respiratory depression was the primary outcome measure. The occurrence of various adverse effects and endoscopist satisfaction score were the secondary outcome measures. RESULTS: In this study, we enrolled a total of 96 patients. The incidence of respiratory depression in the propofol group was 19%, while that in the etomidate group was only 4% (9/47 vs. 2/49; p = 0.026). Regarding the secondary outcome measures, the incidence of hypoxia in the propofol group was 15%, while that in the etomidate group was only 2% (7/47 vs. 1/49; p = 0.029). Injection-site pain occurred in 0% and 23% of the patients in the etomidate group and propofol group, respectively (p < 0.001). Endoscopist satisfaction scores were classified as "poor", "fair", "good", and "very good". The scores were 17% higher (46/49 vs. 36/47; p = 0.026) for the "very good" level and 15% lower (3/49 vs. 10/47; p = 0.038) for the "good" level in the etomidate group than in the propofol group. CONCLUSION: Low-dose etomidate combined with oxycodone and midazolam for endoscopic injection sclerotherapy could reduce the incidence of hypoxia without increasing the incidence of complications.

A radiomics nomogram prediction for survival of patients with "driver gene-negative" lung adenocarcinomas (LUAD).

BACKGROUND: To study the role of computed tomography (CT)-derived radiomics features and clinical characteristics on the prognosis of "driver gene-negative" lung adenocarcinoma (LUAD) and to explore the potential molecular biological which may be helpful for patients' individual postoperative care. METHODS: A total of 180 patients with stage I-III "driver gene-negative" LUAD in the First Affiliated Hospital of Sun Yat-Sen University from September 2003 to June 2015 were retrospectively collected. The Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model was used to screen radiomics features and calculated the Rad-score. The prediction performance of the nomogram model based on radiomics features and clinical characteristics was validated and then assessed with respect to calibration. Gene set enrichment analysis (GSEA) was used to explore the relevant biological pathways. RESULTS: The radiomics and the clinicopathological characteristics were combined to construct a nomogram resulted in better performance for the estimation of OS (C-index: 0.815; 95% confidence interval [CI]: 0.756-0.874) than the clinicopathological nomogram (C-index: 0.765; 95% CI: 0.692-0.837). Decision curve analysis demonstrated that in terms of clinical usefulness, the radiomics nomogram outperformed the traditional staging system and the clinicopathological nomogram. The clinical prognostic risk score of each patient was calculated based on the radiomics nomogram and divided by X-tile into high-risk (> 65.28) and low-risk (≤ 65.28) groups. GSEA results showed that the low-risk score group was directly related to amino acid metabolism, and the high-risk score group was related to immune and metabolism pathways. CONCLUSIONS: The radiomics nomogram was promising to predict the prognosis of patients with "driver gene-negative" LUAD. The metabolism and immune-related pathways may provide new treatment orientation for this genetically unique subset of patients, which may serve as a potential tool to guide individual postoperative care for those patients.

Oxidative stress genes in patients with esophageal squamous cell carcinoma: construction of a novel prognostic signature and characterization of tumor microenvironment infiltration.

BACKGROUND: Oxidative stress plays an important role in the progression of various types of tumors. However, its role in esophageal squamous cell carcinoma (ESCC) has seldom been explored. This study aimed to discover prognostic markers associated with oxidative stress in ESCC to improve the prediction of prognosis and help in the selection of effective immunotherapy for patients. RESULTS: A consensus cluster was constructed using 14 prognostic differentially expressed oxidative stress-related genes (DEOSGs) that were remarkably related to the prognosis of patients with ESCC. The infiltration levels of neutrophils, plasma cells, and activated mast cells, along with immune score, stromal score, and estimated score, were higher in cluster 1 than in cluster 2. A prognostic signature based on 10 prognostic DEOSGs was devised that could evaluate the prognosis of patients with ESCC. Calculated risk score proved to be an independent clinical prognostic factor in the training, testing, and entire sets. P53 signaling pathway was highly enriched in the high-risk group. The calculated risk score was positively related to the infiltration levels of resting mast cells, memory B cells, and activated natural killer (NK) cells and negatively associated with the infiltration levels of M1 and M2 macrophages. The relationship between clinical characteristics and risk score has not been certified. The half-maximal inhibitory concentration (IC50) values for sorafenib and gefitinib were lower for patients in the low-risk group. CONCLUSION: Our prognostic signature based on 10 prognostic DEOSGs could predict the disease outcomes of patients with ESCC and had strong clinical value. Our study improves the understanding of oxidative stress in tumor immune microenvironment (TIME) and provides insights for developing improved and efficient immunotherapy strategies.

Thymic epithelial tumors: examining the GTF2I mutation and developing a novel prognostic signature with LncRNA pairs to predict tumor recurrence.

BACKGROUND: General transcription factor IIi (GTF2I) mutations are very common in thymic epithelial tumors (TETs) and are related to a more favorable prognosis in TET patients. However, limited research has been conducted on the role of GTF2I in the tumor immune microenvironment (TIME). Further, long non-coding RNAs (lncRNAs) have been associated with the survival of patients with TETs. Therefore, this study aimed to explore the relationship between GTF2I mutations and TIME and build a new potential signature for predicting tumor recurrence in the TETs. Research data was downloaded from The Cancer Genome Atlas database and the CIBERSORT algorithm was used to evaluate TIME differences between GTF2I mutant and wild-type TETs. Relevant differentially expressed lncRNAs based on differentially expressed immune-related genes were identified to establish lncRNA pairs. We constructed a signature using univariate and multivariate Cox regression analyses. RESULTS: GTF2I is the most commonly mutated gene in TETs, and is associated with an increased number of early-stage pathological types, as well as no history of myasthenia gravis or radiotherapy treatment. In the GTF2I wild-type group, immune score and immune cell infiltrations with M2 macrophages, activated mast cells, neutrophils, plasma, T helper follicular cells, and activated memory CD4 T cells were higher than the GTF2I mutant group. A risk model was built using five lncRNA pairs, and the 1-, 3-, and 5-year area under the curves were 0.782, 0.873, and 0.895, respectively. A higher risk score was related to more advanced histologic type. CONCLUSION: We can define the GTF2I mutant-type TET as an immune stable type and the GTF2I wild-type as an immune stressed type. A signature based on lncRNA pairs was also constructed to effectively predict tumor recurrence.

Tumour inhibitory activity on pancreatic cancer by bispecific nanobody targeting PD-L1 and CXCR4.

BACKGROUND: Antibodies and derivative drugs targeting immune checkpoints have been approved for the treatment of several malignancies, but there are fewer responses in patients with pancreatic cancer. Here, we designed a nanobody molecule with bi-targeting on PD-L1 and CXCR4, as both targets are overexpressed in many cancer cells and play important roles in tumorigenesis. We characterized the biochemical and anti-tumour activities of the bispecific nanobodies in vitro and in vivo. METHODS: A nanobody molecule was designed and constructed. The nanobody sequences targeting PD-L1 and CXCR4 were linked by the (G4S)3 flexible peptide to construct the anti-PD-L1/CXCR4 bispecific nanobody. The bispecific nanobody was expressed in E. coli cells and purified by affinity chromatography. The purified nanobody was biochemically characterized by mass spectrometry, Western blotting and flow cytometry to confirm the molecule and its association with both PD-L1 and CXCR4. The biological function of the nanobody and its anti-tumour effects were examined by an in vitro tumour cell-killing assay and in vivo tumour inhibition in mouse xenograft models. RESULTS: A novel anti-PD-L1/CXCR4 bispecific nanobody was designed, constructed and characterized. The molecule specifically bound to two targets on the surface of human cancer cells and inhibited CXCL12-induced Jurkat cell migration. The bispecific nanobody increased the level of IFN-γ secreted by T-cell activation. The cytotoxicity of human peripheral blood mononuclear cells (hPBMCs) against pancreatic cancer cells was enhanced by the molecule in combination with IL-2. In a human pancreatic cancer xenograft model, the anti-PD-L1/CXCR4 nanobody markedly inhibited tumour growth and was superior to the combo-treatment by anti-PD-L1 nanobody and anti-CXCR4 nanobody or treatment with atezolizumab as a positive control. Immunofluorescence and immunohistochemical staining of xenograft tumours showed that the anti-tumour effects were associated with the inhibition of angiogenesis and the infiltration of immune cells. CONCLUSION: These results clearly revealed that the anti-PD-L1/CXCR4 bispecific nanobody exerted anti-tumour efficacy in vitro and inhibited tumour growth in vivo. This agent can be further developed as a therapeutic reagent to treat human pancreatic cancer by simultaneously blocking two critical targets.

Pyrotinib treatment enhances the radiosensitivity in HER2-positive brain metastatic breast cancer patients.

Brain metastasis is a common cause of death in HER2-positive breast cancer patients. Currently, it is mainly treated by whole-brain radiotherapy. Pyrotinib is an irreversible pan-ErbB inhibitor, which has demonstrated promising tumor-suppressing activity and acceptable tolerance in previous phase trials. In the present study, we evaluated the efficacy of pyrotinib on HER2-positive brain metastatic breast cancer patients treated with whole-brain radiotherapy. A total of 20 such patients were separated into pyrotinib plus capecitabine and capecitabine-only groups in a 1:1 ratio. All patients met either the primary or secondary endpoints. Oral admission of pyrotinib together with radiotherapy can significantly increase the overall response rate, progression-free survival, time to progression and duration of response of HER2+ brain metastatic breast cancer patients, without causing extra adverse events. In addition, pyrotinib can enhance the radiosensitivity of in-vitro cultured HER2+ breast cancer cell lines. The outcome of our study suggests that pyrotinib might be an effective medication to enhance the tumor radiosensitivity of HER2-positive brain metastatic breast cancer patients.

Face-lifting the surface of LiNi0.8Co0.15Al0.05O2cathode via Y(PO3)3to form anin situtriple composite Li-ion conductor coating layer with the enhanced electrochemical performance.

Due to the assets such as adequate discharge capacity and rational cost, LiNi0.8Co0.15Al0.05O2(NCA), a high-nickel ternary layered oxide, is regarded to be a favorable cathode contender for lithium-ion batteries. However, the superior commercial application is restricted by the surface residual alkaline lithium salt (LiOH or/and Li2CO3) of nickel-rich cathode materials, which will expedite the disintegration of the structure and the engendering of gas (CO2). Therefore, in this paper, we devise and fabricate a Y(PO3)3modified LiNi0.8Co0.15Al0.05O2(NCA), intending to optimize the surface residual alkaline lithium salt (antecedent deportation of H2O and CO2) while forming anin situtriple composite Li-ion conductor coating (Y(PO3)3-Li3PO4-YPO4) to enhance the electrochemical behavior. Under this method, the 2 mol% Y(PO3)3modified NCA electrode reveals exceptional rate capability (5 C/156.3 mAh g-1) and extraordinary cycle stability after 200 cycles (2 C/88.3%), whereas the original sample is only 5 C/123.1 mAh g-1and 2 C/71.2% after 200 cycles. Conspicuously, even under the draconian circumstances of the high temperature and the high rate at 55 °C/1 C, the 2 mol% Y(PO3)3modified NCA electrode sustains a high reversible capacity, with an admirable capacity retention rate of 89.4% after 100 cycles. These contented results signify that the surface remodeling tactic presents a viable scheme for ameliorating high-nickel materials' performance and appropriateness.

Utilizing dual functions of LaPO4to enhance the electrochemical performance of LiNi0.87Co0.09Al0.04O2cathode material.

In this paper, via a facile wet coating method, the LaPO4coating layer has been introduced onto the LiNi0.87Co0.09Al0.04O2(NCA) surface while a small part of La3+has also been doped on the surface to realize the dual functions modification of coating and doping. The morphology and structure of the samples were investigated by XRD, SEM and TEM measurements. The chemical compositions of the samples were analyzed via EDS and XPS data. The results showed that the coating of LaPO4and the doping of La3+were successfully achieved on the surface of NCA. Electrochemical tests indicate that the sample modified with 2 wt% LaPO4(L2-NCA) possesses the best electrochemical performance. After 100 cycles, compared with the capacity retention rate of pristine NCA of 87.1%/74.2% at 0.5 C at 25 °C/60 °C, L2-NCA showed better cycling stability, and the capacity retention rate increased to 96.0%/85.1%, respectively. Besides, the rate performance of the modified samples at 1 C, 2 C and 5 C were also significantly improved. These satisfactory results reveal that the surface modification of LaPO4provides a feasible scheme to uprate the performance of Ni-rich cathode materials.