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Abstract Colorectal cancer (CRC) patients with mismatch repair (MMR)-deficient (dMMR) but not MMR-proficient (pMMR) tend to benefit from immune checkpoint blockade (ICB) therapy. To profile the tumor microenvironments (TME) underlying these varied therapeutic responses, we integrate spatial enhanced resolution omics-sequencing (Stereo-seq), single-cell RNA sequencing, and multiplexed imaging analysis to create high-definition spatial maps of tumors from treatment-naïve and ICB-treated CRC patients. Our results identify the spatial organization and immune status of the tumor-stroma boundary as a distinctive feature of dMMR and pMMR CRCs, which associates with ICB response. The physical interactions and abundance of LAMP3 +DCs and CXCL13 +T cells may shape the ICB-responsive tumor-stroma boundary, whereas CXCL14 +cancer-associated fibroblasts tend to remodel extracellular matrix to form a structural barrier in non-responders. Our work therefore points out the importance of the molecular and cellular spatial structures of tumors in ICB response, raising the possibility of reprogramming tumor-stroma boundary for sensitizing immunotherapies in the majority of CRCs.

Abstract Background In recent years, clinical cases of Chlamydia psittaci pneumonia have gradually increased. Chlamydia psittaci pneumonia can quickly progress to severe pneumonia, leading to respiratory failure. Chlamydia psittaci cannot be detected by commonly used detection methods, leading to difficulties in clinical diagnosis and treatment, which may eventually develop into severe Chlamydia psittaci pneumonia. Therefore, we should improve our diagnostic and treatment capabilities for this disease. Methods This article retrospectively studied 61 cases of pneumonia from 12 different provinces in China, and classified them into severe pneumonia and non-severe pneumonia. Divided into two groups, with 23 cases of severe pneumonia and 38 cases of non-severe pneumonia. We compared the two groups in terms of imaging, laboratory testing, treatment, prognosis, etc., hoping to provide better explanations and help clinical physicians better diagnose the disease. Results There is no difference in age, gender, contact history, smoking history, or basic disease between severe and non-severe Chlamydia psittaci pneumonia. The most prominent symptom is fever, with a median body temperature of 39.7 ℃, and other symptoms similar to common respiratory infections. White blood cells and neutrophils may not show significant elevation, but C-reactive protein (CRP) and procalcitonin (PCT) will both show significant elevation, often accompanied by a decrease in arterial oxygen pressure. Some patients may experience liver and kidney dysfunction, but there is no statistically significant difference between the two groups. Doxycycline remains the preferred drug for severe Chlamydia psittaci pneumonia. The imaging mainly shows consolidation and bronchial inflation sign, and may also present with pleural effusion. Conclusions The imaging of Chlamydia psittaci pneumonia usually shows consolidation with bronchial inflation sign, which can also be manifested as ground glass changes or solid masses. Atypical images are prone to misdiagnosis in the early stages. There are some differences in laboratory examination and imaging between severe pneumonia and non-severe pneumonia, which can help identify severe patients in the early stage. Metagenomic next-generation sequencing (mNGS) played an important role in the diagnosis of all cases in this article. Timely treatment has a good prognosis for the disease, and imaging lesions can be completely absorbed.

Abstract The role of collagen and its receptor, discoidin domain receptor 1 (DDR1) in immune response of colorectal cancer (CRC) remains unclear. We identified DDR1 as a promising target of immunotherapy resistance using a pooled in vivo CRISPR/sgRNA screening in microsatellite stable (MSS) CRC mouse models. Our findings demonstrated that knockdown or inhibition of DDR1 could enhance infiltration of CD8+ T cells and sensitize MSS CRC to PD-1 blockade. Furthermore, DDR1 was found to facilitate kinase domain phosphorylation, upregulate EZH2, consequently elevating H3K27me3 levels at the CXCL10 promotor, which led to the suppression of CXCL10 transcription once bound to collagen in ECM. Lastly, DDR1 was found positively correlated with collagen I expression in MSS CRC specimens. These findings indicated that targeting DDR1 or its inhibitor 7rh might be potential strategy for overcoming immunotherapy resistance in MSS CRC.

BackgroundAnimal studies have shown that exposure to organophosphate esters (OPEs) disturbs the composition of gut microbiome in rodents and zebrafish. However, current associated evidence in humans is limited. Considering the importance of gut microbiome in neonatal development, we need to investigate the impact of OPEs exposure on the early development stage of neonatal microbiome. ObjectiveTo investigate the associations between umbilical OPEs exposure and the diversity and composition of gut microbiome in newborns. MethodsBased on the Shanghai Maternal-Child Pairs Cohort (MCPC), 391 mother-infant pairs with comprehensive follow-up information and bio-samples were enrolled in this study. Concentrations of OPEs in neonatal cord blood were quantified using ultra performance liquid chromatography-tandem mass spectrometry. Meconium samples were collected after delivery and measured through 16S rRNA sequencing on the Illumina Miseq platform. Multiple linear regression models were used to assess the effects of OPEs exposure on the alpha diversity of meconium microbiome. Principal coordinate analysis and permutational multivariate analysis of variance based on unweighted UniFrac distance were used to compare the beta diversity differences between high and low exposure groups of OPEs. Linear discriminant analysis effect size (LEfSe) was utilized to analyze the differential gut microbiome taxa between high and low OPEs exposure groups. The functional pathways involved in the meconium microbiome were predicted based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and multivariate analysis by linear models (MaAsLin2) were conducted to explore the effects of OPEs exposure on gut microbiome pathways. ResultsSeven OPEs were detectable in the neonatal cord blood samples, of which four were detected higher than 50% including tributyl phosphate (TBP), tris (2-butoxyethyl) phosphate (TBEP), 2-ethylhexyl diphenyl phosphate (EHDPP), and tris (2-chloro-1 (chloromethyl) ethyl) phosphate (TDCPP), and the median concentrations of these four congeners were as follows: 0.52 μg·L−1 for TBP, 2.41 μg·L−1 for TBEP, 0.13 μg·L−1 for EHDPP, and 2.23 μg·L−1 for TDCPP. A significant association was observed between umbilical TBEP and TDCPP exposure and alpha diversity indices in neonatal meconium microbiome. Beta diversity significantly differed across varied high and low OPEs exposure groups. The results of LEfSe analysis indicated a significant correlation between umbilical OPEs exposure and 27 genera, including Streptococcus, Corynebacterium, Neisseria, Haemophilus, and Parabacteroides. The MaAsLin2 analysis identified associations between OPEs exposure and upregulation of pathways related to linoleic acid metabolism, steroid biosynthesis, Toll and Imd signaling pathway, retinol metabolism, NOD like receptor signaling pathway, and fatty acid biosynthesis . ConclusionUmbilical OPEs exposure is associated increased alpha diversity indices, increased relative abundances of Neisseria, Streptococcus, Parabacteroides, and Corynebacterium in the gut microbiome, as well as predicted metabolic pathway alterations in linoleic acid metabolism, fatty acid biosynthesis, etc. These findings indicate that umbilical OPEs exposure may disrupt meconium microbiome equilibrium.

Abstract Background Patients with glioblastoma (GBM) have a poor prognosis and limited treatment options. The mRNA decapping enzyme scavenger (DCPS) is a cap-hydrolyzing enzyme. The DCPS inhibitor RG3039 exhibited excellent central nervous system bioavailability in vivo and was safe and well tolerated in healthy volunteers in a phase 1 clinical trial. In this study, we investigated the expression of DCPS in GBM and the anti-tumor activity of RG3039 in various preclinical models of GBM. Methods DCPS expression was examined in human GBM and paired peritumoral tissues. Its prognostic role was evaluated together with clinicopathological characteristics of patients. The anti-GBM effect of RG3039 was determined using GBM cell lines, patient-derived organoids, and orthotopic mouse models. The therapeutic mechanisms of DCPS inhibition were explored. Results DCPS is overexpressed in GBM and is associated with poor survival of patients with GBM. The DCPS inhibitor RG3039 exhibited robust anti-GBM activities in GBM cell lines, patient-derived organoids and orthotopic mouse models, with drug exposure achievable in humans. Mechanistically, RG3039 downregulated STAT5B expression, thereby suppressing proliferation, survival and colony formation of GBM cells. Conclusions DCPS is a promising target for GBM. Inhibition of DCPS with RG3039 at doses achievable in humans downregulates STAT5B expression and reduces proliferation, survival and colony formation of GBM cells. Given the excellent anti-cancer activity and central nervous system bioavailability in vivo and good tolerance in humans, RG3039 warrants further study as a potential GBM therapy.

Abstract Background Extreme Risk Protection Orders (ERPOs) are civil court orders that prohibit firearm purchase and possession when someone is behaving dangerously and is at risk of harming themselves and/or others. As of June 2024, ERPOs are available in 21 states and the District of Columbia to prevent firearm violence. This paper describes the design and protocol of a six-state study of ERPO use. Methods The six states included are California, Colorado, Connecticut, Florida, Maryland, and Washington. During the 3-year project period (2020–2023), ERPO case files were obtained through public records requests or through agreements with agencies with access to these data in each state. A team of over four dozen research assistants from seven institutions coded 6628 ERPO cases, abstracting 80 variables per case under domains related to respondent characteristics, events and behaviors leading to ERPO petitions, petitioner types, and court outcomes. Research assistants received didactic training through an online learning management system that included virtual training modules, quizzes, practice coding exercises, and two virtual synchronous sessions. A protocol for gaining strong interrater reliability was used. Research assistants also learned strategies for reducing the risk of experiencing secondary trauma through the coding process, identifying its occurrence, and obtaining help. Discussion Addressing firearm violence in the U.S. is a priority. Understanding ERPO use in these six states can inform implementation planning and ERPO uptake, including promising opportunities to enhance safety and prevent firearm-related injuries and deaths. By publishing this protocol, we offer detailed insight into the methods underlying the papers published from these data, and the process of managing data abstraction from ERPO case files across the multi-state and multi-institution teams involved. Such information may also inform future analyses of this data, and future replication efforts. Registration This protocol is registered on Open Science Framework ( https://osf.io/kv4fc/ ).

Unnecessary exposure to ionizing radiation (IR) often causes acute and chronic oxidative damages to normal cells and organs, leading to serious physiological and even life-threatening consequences. Amifostine (AMF) is a validated radioprotectant extensively applied in radiation and chemotherapy medicine, but the short half-life limits its bioavailability and clinical applications, remaining as a great challenge to be addressed. DNA-assembled nanostructures especially the tetrahedral framework nucleic acids (tFNAs) are promising nanocarriers with preeminent biosafety, low biotoxicity, and high transport efficiency. The tFNAs also have a relative long-term maintenance for structural stability and excellent endocytosis capacity. We therefore synthesized a tFNA-based delivery system of AMF for multi-organ radioprotection (tFNAs@AMF, also termed nanosuit). By establishing the mice models of accidental total body irradiation (TBI) and radiotherapy model of Lewis lung cancer, we demonstrated that the nanosuit could shield normal cells from IR-induced DNA damage by regulating the molecular biomarkers of anti-apoptosis and anti-oxidative stress. In the accidental total body irradiation (TBI) mice model, the nanosuit pretreated mice exhibited satisfactory alteration of superoxide dismutase (SOD) activities and malondialdehyde (MDA) contents, and functional recovery of hematopoietic system, reducing IR-induced pathological damages of multi-organ and safeguarding mice from lethal radiation. More importantly, the nanosuit showed a selective radioprotection of the normal organs without interferences of tumor control in the radiotherapy model of Lewis lung cancer. Based on a conveniently available DNA tetrahedron-based nanocarrier, this work presents a high-efficiency delivery system of AMF with the prolonged half-life and enhanced radioprotection for multi-organs. Such nanosuit pioneers a promising strategy with great clinical translation potential for radioactivity protection.

Abstract Background LARC patients commonly receive adjuvant therapy, however, hidden micrometastases still limit the improvement of OS. This study aims to investigate the impact of VASN in rectal cancer with pulmonary metastasis and understand the underlying molecular mechanisms to guide adjuvant chemotherapy selection. Methods Sequencing data from rectal cancer patients with pulmonary metastasis from Sun Yat-sen University Cancer Center (SYSUCC) and publicly available data were meticulously analyzed. The functional role of VASN in pulmonary metastasis was validated in vivo and in vitro. Coimmunoprecipitation (co-IP), immunofluorescence, and rescue experiments were conducted to unravel potential molecular mechanisms of VASN. Moreover, VASN expression levels in tumor samples were examined and analyzed for their correlations with pulmonary metastasis status, tumor stage, adjuvant chemotherapy benefit, and survival outcome. Results Our study revealed a significant association between high VASN expression and pulmonary metastasis in LARC patients. Experiments in vitro and in vivo demonstrated that VASN could promote the cell proliferation, metastasis, and drug resistance of colorectal cancer. Mechanistically, VASN interacts with the NOTCH1 protein, leading to concurrent activation of the NOTCH and MAPK pathways. Clinically, pulmonary metastasis and advanced tumor stage were observed in 90% of VASN-positive patients and 53.5% of VASN-high patients, respectively, and VASN-high patients had a lower five-year survival rate than VASN-low patients (26.7% vs. 83.7%). Moreover, the Cox analysis and OS analysis indicated that VASN was an independent prognostic factor for OS (HR = 7.4, P value

Abstract Background Radiomics provided opportunities to quantify the tumor phenotype non-invasively. This study extracted contrast-enhanced computed tomography (CECT) radiomic signatures and evaluated clinical features of bone metastasis in non-small-cell lung cancer (NSCLC). With the combination of the revealed radiomics and clinical features, the predictive modeling on bone metastasis in NSCLC was established. Methods A total of 318 patients with NSCLC at the Tianjin Medical University Cancer Institute & Hospital was enrolled between January 2009 and December 2019, which included a feature-learning cohort (n = 223) and a validation cohort (n = 95). We trained a radiomics model in 318 CECT images from feature-learning cohort to extract the radiomics features of bone metastasis in NSCLC. The Kruskal-Wallis and the least absolute shrinkage and selection operator regression (LASSO) were used to select bone metastasis-related features and construct the CT radiomics score (Rad-score). Multivariate logistic regression was performed with the combination of the Rad-score and clinical data. A predictive nomogram was subsequently developed. Results Radiomics models using CECT scans were significant on bone metastasis prediction in NSCLC. Model performance was enhanced with each information into the model. The radiomics nomogram achieved an AUC of 0.745 (95% confidence interval [CI]: 0.68,0.80) on predicting bone metastasis in the training set and an AUC of 0.808(95% confidence interval [CI]: 0.71,0.88) in the validation set. Conclusion The revealed invisible image features were of significance on guiding bone metastasis prediction in NSCLC. Based on the combination of the image features and clinical characteristics, the predictive nomogram was established. Such nomogram can be used for the auxiliary screening of bone metastasis in NSCLC.

Purpose: To evaluate the diagnosis performance of digital mammography (DM) and digital breast tomosynthesis (DBT), DM combined DBT with AI-based strategies for breast mass ≤ 2 cm. Materials and methods: DM and DBT images in 483 patients including 512 breast masses were acquired from November 2018 to November 2019. Malignant and benign tumours were determined by biopsies using histological analysis and follow-up within 24 months. The radiomics and deep learning methods were employed to extract the breast mass features in images and finally for benign and malignant classification. The DM, DBT and DM combined DBT (DM + DBT) images were fed into radiomics and deep learning models to construct corresponding models, respectively. The area under the receiver operating characteristic curve (AUC) was employed to estimate model performance. An external dataset of 146 patients from March 2021 to December 2022 from another center was enrolled for external validation. Results: In the internal testing dataset, compared with the DM model and the DBT model, the DM + DBT models based on radiomics and deep learning both showed statistically significant higher AUCs [0.810 (RA-DM), 0.823 (RA-DBT) and 0.869 (RA-DM + DBT), P ≤ 0.001; 0.867 (DL-DM), 0.871 (DL-DBT) and 0.908 (DL-DM + DBT), P = 0.001]. The deep learning models present superior to the radiomics models in the experiments with only DM (0.867 vs 0.810, P = 0.001), only DBT (0.871 vs 0.823, P = 0.001) and DM + DBT (0.908 vs 0.869, P = 0.003). Conclusions: DBT has a clear additional value for diagnosing breast mass less than 2 cm compared with only DM. AI-based methods, especially deep learning, can help achieve excellent performance.

COVID-19 vaccine hesitancy remains prevalent globally. However, national data on this issue in the general population after the termination of the zero-COVID policy in China are limited. In March 2023, we conducted a nationwide cross-sectional survey among Chinese adults using a self-administered questionnaire. Descriptive statistics and multivariate logistic regressions were employed. Among 4,966 participants, 43.8% reported COVID-19 vaccine hesitancy following the end of the zero-COVID policy in China. Higher rates of vaccine hesitancy were associated with being married (married: OR 1.36, 95%CI 1.17–1.57; other marital status: OR 1.86, 95%CI 1.36–2.55), working in healthcare (OR 1.64, 95%CI 1.38–1.96), having both minors and older adults in the household (OR 1.45, 95%CI 1.20–1.75), having no minors and older adults in the household (OR 1.44, 95%CI 1.17–1.77), having chronic diseases (OR 1.42, 95%CI 1.23–1.64), experiencing adverse events post-vaccination (OR 1.39, 95%CI 1.19–1.61), and uncertainty about previous COVID-19 infection (OR 1.45, 95%CI 1.13–1.86). Conversely, participants who had received the influenza vaccine in the past three years (OR 0.62, 95%CI 0.54–0.72), had previously taken the COVID-19 vaccine (OR 0.44, 95%CI 0.32–0.59), and had higher confidence in vaccines (OR 0.63, 95%CI 0.60–0.67) were less likely to exhibit hesitancy. Our findings indicate a significant level of vaccine hesitancy, underscoring the urgent need for tailored public health strategies to address vaccine hesitancy and improve uptake post-zero-COVID policy in China. A comprehensive understanding of public concerns and related factors is essential for developing effective vaccine communication strategies.

PurposeCurrently, chemoimmunotherapy is effective only in a subset of patients with advanced non-squamous non-small cell lung cancer. Robust biomarkers for predicting the efficacy of chemoimmunotherapy would be useful to identify patients who would benefit from chemoimmunotherapy. The primary objective of our study was to develop an artificial intelligence-based immunoscore and to evaluate the value of patho-immunoscore in predicting clinical outcomes in patients with advanced non-squamous non-small cell lung cancer (NSCLC).MethodsWe have developed an artificial intelligence–powered immunoscore analyzer based on 1,333 whole-slide images from TCGA-LUAD. The predictive efficacy of the model was further validated in the CPTAC-LUAD cohort and the biomarker cohort of the ORIENT-11 study, a randomized, double-blind, phase 3 study. Finally, the clinical significance of the patho-immunoscore was evaluated using the ORIENT-11 study cohort.ResultsOur immunoscore analyzer achieved good accuracy in all the three cohort mentioned above (TCGA-LUAD, mean AUC: 0.783; ORIENT-11 cohort, AUC: 0.741; CPTAC-LUAD cohort, AUC: 0.769). In the 259 patients treated with chemoimmunotherapy, those with high patho-immunoscore (n = 146) showed significantly longer median progression-free survival than those with low patho-immunoscore (n = 113) (13.8 months vs 7.13 months, hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.38 – 0.73; p < 0.001). In contrast, no significant difference was observed in patients who were treated with chemotherapy only (5.07 months vs 5.07 months, HR: 1.04, 95% CI: 0.71 – 1.54; p = 0.83). Similar trends were observed in overall survival.ConclusionOur study indicates that AI-powered immunoscore applied on LUAD digital slides can serve as a biomarker for survival outcomes in patients with advanced non-squamous NSCLC who received chemoimmunotherapy. This methodology could be applied to other cancers and facilitate cancer immunotherapy.

Abstract End-stage nasopharyngeal carcinoma (NPC) has unsatisfactory survival. The limited benefit of chemotherapy and the scarcity of targeted drugs are major challenges in NPC. New approaches to treat late-stage NPC are urgently required. In this study, we explored whether the dual PI3K/mTOR inhibitor, PQR309, exerted a favorable antineoplastic effect and sensitized the response to gemcitabine in NPC. We observed that PI3K expression was positive and elevated in 14 NPC cell lines compared with that in normal nasopharygeal cell lines. Patients with NPC with higher PI3K levels displayed poorer prognosis. We subsequently showed that PQR309 alone effectively decreased the viability, invasiveness, and migratory capability of NPC cells and neoplasm development in mice xenograft models, and dose-dependently induced apoptosis. More importantly, PQR309 remarkably strengthened the anti-NPC function of gemcitabine both in vivo and in vitro. Mechanistically, PQR309 sensitized NPC to gemcitabine by increasing caspase pathway-dependent apoptosis, blocking GSK-3β and STAT3/HSP60 signaling, and ablating epithelial-mesenchyme transition. Thus, targeting PI3K/mTOR using PQR309 might represent a treatment option to promote the response to gemcitabine in NPC, and provides a theoretical foundation for the study of targeted drugs combined with chemotherapy for NPC.

Abstract Diabetic osteoporosis (DOP) is a significant complication that poses continuous threat to the bone health of patients with diabetes; however, currently, there are no effective treatment strategies. In patients with diabetes, the increased levels of ferroptosis affect the osteogenic commitment and differentiation of bone mesenchymal stem cells (BMSCs), leading to significant skeletal changes. To address this issue, we aimed to target ferroptosis and propose a novel therapeutic approach for the treatment of DOP. We synthesized ferroptosis-suppressing nanoparticles, which could deliver curcumin, a natural compound, to the bone marrow using tetrahedral framework nucleic acid (tFNA). This delivery system demonstrated excellent curcumin bioavailability and stability, as well as synergistic properties with tFNA. Both in vitro and in vivo experiments revealed that nanoparticles could enhance mitochondrial function by activating the nuclear factor E2-related factor 2 (NRF2)/glutathione peroxidase 4 (GPX4) pathway, inhibiting ferroptosis, promoting the osteogenic differentiation of BMSCs in the diabetic microenvironment, reducing trabecular loss, and increasing bone formation. These findings suggest that curcumin-containing DNA tetrahedron-based ferroptosis-suppressing nanoparticles have a promising potential for the treatment of DOP and other ferroptosis-related diseases.

Abstract Background Combined small-cell lung carcinoma (cSCLC) represents a rare subtype of SCLC, the mechanisms governing the evolution of cancer genomes and their impact on the tumor immune microenvironment (TIME) within distinct components of cSCLC remain elusive. Methods Here, we conducted whole-exome and RNA sequencing on 32 samples from 16 cSCLC cases. Results We found striking similarities between two components of cSCLC-LCC/LCNEC (SCLC combined with large-cell carcinoma/neuroendocrine) in terms of tumor mutation burden (TMB), tumor neoantigen burden (TNB), clonality structure, chromosomal instability (CIN), and low levels of immune cell infiltration. In contrast, the two components of cSCLC-ADC/SCC (SCLC combined with adenocarcinoma/squamous-cell carcinoma) exhibited a high level of tumor heterogeneity. Our investigation revealed that cSCLC originated from a monoclonal source, with two potential transformation modes: from SCLC to SCC (mode 1) and from ADC to SCLC (mode 2). Therefore, cSCLC might represent an intermediate state, potentially evolving into another histological tumor morphology through interactions between tumor and TIME surrounding it. Intriguingly, RB1 inactivation emerged as a factor influencing TIME heterogeneity in cSCLC, possibly through neoantigen depletion. Conclusions Together, these findings delved into the clonal origin and TIME heterogeneity of different components in cSCLC, shedding new light on the evolutionary processes underlying this enigmatic subtype.

Background The sustained effectiveness of anti-programmed cell death protein-1/programmed death-ligand 1 treatment is limited to a subgroup of patients with advanced nasopharyngeal carcinoma (NPC), and the specific biomarker determining the response to immunotherapy in NPC remains uncertain.Methods We assessed the associations between pre-immunotherapy and post-immunotherapy serum lipoproteins and survival in a training cohort (N=160) and corroborated these findings in a validation cohort (N=100). Animal studies were performed to explore the underlying mechanisms. Additionally, the relationship between high-density lipoprotein-cholesterol (HDL-C) levels and M1/M2-like macrophages, as well as activated CD8+T cells in tumor tissues from patients with NPC who received immunotherapy, was investigated.Results The lipoproteins cholesterol, HDL-C, low-density lipoprotein-cholesterol, triglycerides, apolipoprotein A-1 (ApoA1), and apolipoprotein B, were significantly altered after immunotherapy. Patients with higher baseline HDL-C or ApoA1, or those with increased HDL-C or ApoA1 after immunotherapy had longer progression-free survival, a finding verified in the validation cohort (p

Abstract TP53 comutation is related to poor prognosis of non‐small cell lung cancer. However, there is limited study focusing on the structural influence of TP53 mutation on third‐generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) treatment. We retrospectively analyzed the clinical and molecular data of patients treated with third‐generation EGFR‐TKIs in two independent cohorts. A total of 117 patients from the Sun Yat‐sen University Cancer Center (SYSUCC) and 141 patients from the American Association for Cancer Research Project GENIE database were included. In the SYSUCC cohort, TP53 comutations were found in 59 patients (50.4%) and were associated with poor median progress‐free survival (mPFS) and median overall survival (mOS). The additional subtype analysis found that TP53 mutation in the alpha‐helix region had shorter mOS compared with those with TP53 mutations in other regions in the SYSUCC cohort (mOS, 12.2 vs. 21.7 months; p = 0.027). Similar findings were confirmed in the GENIE cohort. Specifically, the presence of TP53 mutation in the alpha‐helix region was an independent negative predictive factor for PFS [hazard ratio (HR) 2.05(1.01–4.18), p = 0.048] and OS [HR 3.62(1.60–8.17), p = 0.002] in the SYSUCC cohort. TP53 mutation in alpha‐helix region was related to inferior clinical outcomes in patients treated with third‐generation EGFR‐TKIs.

Pecan seed oil is a valuable source of essential fatty acids and various bioactive compounds; however, the functions of microRNAs and their targets in oil biosynthesis during seed development are still unknown. Here, we found that the oil content increased rapidly in the three early stages in three cultivars, and that oleic acid was the predominant fatty acid component in the mature pecan embryos. We identified, analyzed, and validated the expression levels of miRNAs related to seed development and oil biosynthesis, as well as their potential target genes, using small RNA sequencing data from three stages (120, 135, and 150 days after flowering). During the seed development process, 365 known and 321 novel miRNAs were discovered. In total, 91 known and 181 novel miRNAs were found to be differentially expressed, and 633 target genes were further investigated. The expression trend analysis revealed that the 91 known miRNAs were classified into eight groups, approximately two-thirds of which were up-regulated, whereas most novel miRNAs were down-regulated. The qRT–PCR and degradome sequencing data were used to identify five miRNA- target pairs. Overall, our study provides valuable insights into the molecular regulation of oil biosynthesis in pecan seeds.

BackgroundIn recent years, ozone (O3) has gradually become a key air pollutant affecting public health. Studies have been conducted to evaluate O3 pollution-associated disease burden for general population, but there is a lack of research on O3 pollution-associated disease burden of gestational complications. ObjectiveTo assess the disease burden of O3 pollution on pregnancy complications in the Yangtze River Delta region and the changes in the disease burden resulting from the improvement of O3 pollution levels. MethodsThrough Chinese databases such as China National Knowledge Infrastructure (CNKI) and Wanfang, as well as English databases including PubMed and Web of Science, a systematic search was conducted to retrieve epidemiological studies investigating the association between O3 exposure and pregnancy complications from January 1, 2010 to February 28, 2023. Using predetermined inclusion and exclusion criteria, retrieved studies were screened and assessed for heterogeneity using the Higgins I2 statistic. The exposure increment was standardized to 10 µg·m−3, and a meta-analysis was conducted to evaluate the exposure-response relationship. Spatial analysis and environmental health risk assessment were then employed, using O3 monitoring data at national air monitoring stations, population data, and related disease burden parameters in the Yangtze River Delta region, to evaluate changes in the disease burden of pregnancy complications associated with improvements in O3 pollution levels. ResultsThe meta-analysis revealed a significant association between maternal O3 exposure and increased risks of gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP), particularly in early pregnancy, and the related odds ratios (OR) and 95% confidence intervals (CI) were 1.028 (1.002, 1.055) and 1.031 (1.023, 1.040), respectively. The cities with higher attribution fractions (AF) of GDM and HDP related to O3 exposure in 2017 and 2020 in the Yangtze River Delta region were Xuzhou, Huaibei, Suzhou (Anhui Province), Changzhou, and Wuxi, with most cities showing a significant decrease in AF in 2020. Except for Hefei, the cases of GDM and HDP attributable to O3 exposure in the remaining cities of the Yangtze River Delta region decreased by 16.31% to 57.41% in 2020 compared to 2017. In addition, except for Hefei, Suqian, Anqing, and Wuxi, the direct medical costs attributed to O3 exposure in the remaining cities decreased by 1.12% to 45.36% in 2020 compared to 2017. ConclusionExposure to O3 during pregnancy is associated with increased risks of GDM and HDP. There are differences in the disease burden of GDM and HDP related to O3 pollution among cities in the Yangtze River Delta region in 2017 and 2020. In 2020, compared to 2017, the disease burden in most cities is decreased.

The preexistence of immune cells in the tumor microenvironment substantiates the efficacy of immunotherapy in cancer patients. Although the complex intratumoral immune heterogeneity has been extensively studied in single cell resolution, hi-res spatial investigations are limited. In this study, we performed a spatial transcriptome analysis of 4 colorectal adenocarcinoma specimens and 2 paired distant normal specimens to identify the molecular pattern involved in a discontinuous inflammatory response in pathologically annotated cancer regions. Based on the location of spatially varied gene expression, we unmasked the spatially-varied immune ecosystem and identified the locoregional “warmed-up” immune response in predefined “cold” tumor with substantial infiltration of immune components. This “warmed-up” immune profile was found to be associated with the in-situ copy number variance and the tissue remodeling process. Further, “warmed-up” signature genes indicated improved overall survival in CRC patients obtained from TCGA database.

Abstract Background Osteosarcoma is the most common primary malignant bone tumor. The current study was conducted to describe the general condition of patients with primary osteosarcoma in a single cancer center in Tianjin, China and to investigate the associated factors in osteosarcoma patients with lung metastasis. Methods From February 2009 to October 2020, patients from Tianjin Medical University Cancer Institute and Hospital, China were retrospectively analyzed. The Kaplan–Meier method was used to evaluate the overall survival of osteosarcoma patients. The Cox proportional hazard regression analysis was performed to analyze the prognostic factors of all osteosarcoma patients and those patients with lung metastasis, respectively. Furthermore, risk factors for developing lung metastasis were identified in synchronous lung metastasis (SLM) and metachronous lung metastasis (MLM) patients. Results A total of 203 patients were involved and 150 patients were successfully followed up for survival status. The 5-year survival rate of osteosarcoma was 70.0% and the survival months for patients with SLM and MLM were 33.3 ± 12.6 and 45.8 ± 7.4 months, respectively. The presence of lung metastasis was one of the independent prognostic factors for prognosis of osteosarcoma. In patients with lung metastasis, twenty-one (10.3%) showed lung metastasis at the diagnosis of osteosarcoma and 67 (33%) were diagnosed with lung metastases during the later course. T3 stage (OR = 11.415, 95%CI 1.362–95.677, P = 0.025) and bone metastasis (OR = 6.437, 95%CI 1.69–24.51, P = 0.006) were risk factors of SLM occurrence. Bone metastasis (OR = 1.842, 95%CI 1.053–3.224, P = 0.032), good necrosis (≥ 90%, OR = 0.032, 95%CI 0.050–0.412, P

Background: The pathological mechanism of heat stroke (HS) involves the acute phase response, unbalanced immunological/inflammatory reactions, and coagulation initiation, especially platelet activation. Although exosomes contain proteins involved in these biological processes, their protein cargo levels and potential roles in HS remain unknown. This study explored the serum exosome protein expression patterns after HS and their potential roles in the pathogenesis of HS. Methods: Blood samples were collected from ten patients diagnosed with HS upon admission to the intensive care unit (six with severe HS and four with mild HS). Samples from six healthy volunteers were included as control. Using ultracentrifugation, exosomes were prudently isolated, and their protein contents were profiled using liquid chromatography–tandem mass spectrometry analysis with isobaric tags for relative and absolute quantification-based proteomics. Results: Compared with healthy volunteers, patients with HS showed significant changes in the levels of 33 exosomal proteins (23 upregulated and 10 downregulated). The most upregulated proteins included serum amyloid A-1 (SAA-1), von Willebrand factor (vWF), S100A8, and histone H3. In addition, SAA-1, vWF, platelet membrane glycoprotein, S100A8, and histone H3 were more enriched in the exosomes from patients with severe HS than from those with mild HS. Gene ontology analysis revealed that the HS-modulated exosomal proteins were mostly related to inflammatory response, including the acute-phase response, platelet activation/degranulation, and innate immune response. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed significant enrichment of proteins in the IL-17 signaling pathway, platelet activation, neutrophil extracellular trap formation, Fc epsilon RI signaling pathway, chemokine signaling pathway, and NOD-like receptor signaling pathway, among others. Several serum exosomal proteins, including SAA-1, vWF, and S100A8, which are related to the acute phase, inflammatory response, and platelet activation, were confirmed to be elevated in patients with HS, and were significantly correlated with disease severity, organ dysfunction, and death. Conclusion: Overall, this study explores the potential role of the serum exosomal proteome in the inflammatory response and platelet activation in HS, suggests the pathological mechanisms underlying HS-induced injuries, and recommends reliable exosomal biomarkers for predicting HS prognosis.

AbstractBackground Immune checkpoint inhibitors (ICIs) have achieved substantial advancements in clinical care. However, there is no strong evidence for identified biomarkers of ICIs in NPC.Methods In this retrospective study, 284 patients were enrolled into a training or validation cohort. Inflammatory indexes based on peripheral blood parameters were evaluated, including the systemic immune-inflammation index (SII), the neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), the lymphocyte-to-C-reactive protein ratio (LCR), and the lymphocyte-monocyte ratio (LMR). The optimum cut-off value for patient stratification was identified using X-tile. The Kaplan-Meier method and Cox’s proportional regression analyses were used to identify prognostic factors.Results Immunotherapy significantly changed the levels of SII, NLR, PLR, LCR and LMR in NPC patients. Patients with lower SII, NLR, and PLR, as well as those with higher LCR and LMR, before immunotherapy had superior PFS (all p

Abstract Background Breast cancer has become the most common malignant tumour worldwide. Distant metastasis is one of the leading causes of breast cancer-related death. To verify the performance of clinicomics-guided distant metastasis risk prediction for breast cancer via artificial intelligence and to investigate the accuracy of the created prediction models for metachronous distant metastasis, bone metastasis and visceral metastasis. Methods We retrospectively enrolled 6703 breast cancer patients from 2011 to 2016 in our hospital. The figures of magnetic resonance imaging scanning and ultrasound were collected, and the figures features of distant metastasis in breast cancer were detected. Clinicomics-guided nomogram was proven to be with significant better ability on distant metastasis prediction than the nomogram constructed by only clinical or radiographic data. Results Three clinicomics-guided prediction nomograms on distant metastasis, bone metastasis and visceral metastasis were created and validated. These models can potentially guide metachronous distant metastasis screening and lead to the implementation of individualized prophylactic therapy for breast cancer patients. Conclusion Our study is the first study to make cliniomics a reality. Such cliniomics strategy possesses the development potential in artificial intelligence medicine.

Abstract Objectives Distant metastasis remains the main cause of death in breast cancer. Breast cancer risk is strongly influenced by pathogenic mutation.This study was designed to develop a multiple-feature model using clinicopathological and imaging characteristics adding pathogenic mutations associated signs to predict recurrence or metastasis in breast cancers in high familial risk women. Methods Genetic testing for breast-related gene mutations was performed in 54 patients with breast cancers. Breast MRI findings were retrospectively evaluated in 64 tumors of the 54 patients. The relationship between pathogenic mutation, clinicopathological and radiologic features was examined. The disease recurrence or metastasis were estimated. Multiple logistic regression analyses were performed to identify independent factors of pathogenic mutation and disease recurrence or metastasis. Based on significant factors from the regression models, a multivariate logistic regression was adopted to establish two models for predicting disease recurrence or metastasis in breast cancer using R software. Results Of the 64 tumors in 54 patients, 17 tumors had pathogenic mutations and 47 tumors had no pathogenic mutations. The clinicopathogenic and imaging features associated with pathogenic mutation included six signs: biologic features (p = 0.000), nuclear grade (p = 0.045), breast density (p = 0.005), MRI lesion type (p = 0.000), internal enhancement pattern (p = 0.004), and spiculated margin (p = 0.049). Necrosis within the tumors was the only feature associated with increased disease recurrence or metastasis (p = 0.006). The developed modelIincluding clinico-pathologic and imaging factors showed good discrimination in predicting disease recurrence or metastasis. Comprehensive model II, which included parts of modelIand pathogenic mutations significantly associated signs, showed significantly more sensitivity and specificity for predicting disease recurrence or metastasis compared to Model I. Conclusions The incorporation of pathogenic mutations associated imaging and clinicopathological parameters significantly improved the sensitivity and specificity in predicting disease recurrence or metastasis. The constructed multi-feature fusion model may guide the implementation of prophylactic treatment for breast cancers at high familial risk women.

Although growth arrest‐specific protein 2 (GAS2) promotes the growth of T‐cell acute lymphoblastic leukemia (T‐ALL) cells in culture, the effect of GAS2 on T‐cell leukemogenesis has not been studied, and the mechanism remains unclear. In the present study, xenograft studies showed that GAS2 silencing impaired T‐cell leukemogenesis and decreased leukemic cell infiltration. Mechanistically, GAS2 regulated the protein expression of C‐X‐C chemokine receptor type 4 (CXCR4) rather than its transcript expression. Immunoprecipitation revealed that GAS2 interacted with CXCR4, and confocal analysis showed that GAS2 was partially co‐expressed with CXCR4, which provided a strong molecular basis for GAS2 to regulate CXCR4 expression. Importantly, CXCR4 overexpression alleviated the inhibitory effect of GAS2 silencing on the growth and migration of T‐ALL cells. Moreover, GAS2 or CXCR4 silencing inhibited the expression of NOTCH1 and c‐MYC. Forced expression of c‐MYC rescued the growth suppression induced by GAS2 or CXCR4 silencing. Meanwhile, GAS2 deficiency, specifically in blood cells, had a mild effect on normal hematopoiesis, including T‐cell development, and GAS2 silencing did not affect the growth of normal human CD3+ or CD34+ cells. Overall, our data indicate that GAS2 promotes T‐cell leukemogenesis through its interaction with CXCR4 to activate NOTCH1/c‐MYC, whereas impaired GAS2 expression has a mild effect on normal hematopoiesis. Therefore, our study suggests that targeting the GAS2/CXCR4 axis is a potential therapeutic strategy for T‐ALL.

The induction of adventitious roots is a key factor restricting the vegetative propagation of apple dwarf rootstocks. PLETHORA (PLT) transcription factors are involved in the regulation of plant stem cell niche and adventitious root development. In this study, we identified the PLT1 gene in apples by bioinformatics and analyzed its evolutionary relationship. The MdPLT1 gene was cloned from M9-T337 to verify its subcellular localization and analyze its function in transgenic tobacco. The MdPLT1 protein contained two conserved AP2 domains which may be similar to those of poplar the PtrPLT2a and PtrPLT2b with 85% support. The CDS sequence of the MdPLT1 gene was 1638 bp, encoding 545 amino acids. The transcription factor MdPLT1 was localized in the nucleus. The number of adventitious roots of tobacco plants overexpressing MdPLT1 significantly increased. In the adventitious roots of MdPLT1-overexpressed plants, the expression levels of genes related to the NtPINs family and the NtYUCCAs family were significantly increased. The results showed that MdPLT1 positively regulated adventitious root formation. This study provided a theoretical basis for the establishment of the fast vegetative propagation of apple dwarf rootstocks.

With global climate changing, the carbon dioxide (CO2) absorption rates increased in marginal seas. Due to the limited availability of in-situ spatial and temporal distribution data, the current status of the sea surface carbon dioxide partial pressure (pCO2) in the Yellow Sea is unclear. Therefore, a pCO2 model based on a random forest algorithm has been developed, which was trained and tested using 14 cruise data sets from 2011 to 2019, and remote sensing satellite sea surface temperature, chlorophyll concentration, diffuse attenuation of downwelling irradiance, and in-situ salinity were used as the input variables. The seasonal and interannual variations of modeled pCO2 were discussed from January 2003 and December 2021 in the Yellow Sea. The results showed that the model developed for this study performed well, with a root mean square difference (RMSD) of 43 μatm and a coefficient of determination (R2) of 0.67. Moreover, modeled pCO2 increased at a rate of 0.36 μatm year-1 (R2 = 0.27, p < 0.05) in the YS, which is much slower than the rate of atmospheric pCO2 (pCO2air) rise. The reason behind it needs further investigation. Compared with pCO2 from other datasets, the pCO2 derived from the RF model exhibited greater consistency with the in-situ pCO2 (RMSD = 55 μatm). In general, the RF model has significant improvement over the previous models and the global data sets.

Large-scale 3D sparse maps generated by Structure-from-Motion (SfM) from images play an important role in many applications, including visual localization, augmented reality, etc. In these scenarios, the timeliness of the map i.e., detecting changes in the map and performing partial updates, is crucial. To solve this problem, in this paper we propose a novel method for 3D sparse map change detection and updating, to maintain the SfM map continuously over time. The core idea of this paper is to simultaneously detect the appearance and geometry changes of 3D map points, so as to find regions with significant changes, and update these regions locally without changing most of the stable map regions. In the proposed method, a local 3D map containing changing areas is computed from newly captured images by SfM and aligned to the old map according to the locations of new images in the new local map and their registration in the old map. Next, the overlapping map is partitioned into regular grids and the appearance uncertainty and geometry uncertainty are measured on each grid cell individually. Then the grid cells are labeled as changed or unchanged using Markov Random Field optimization by taking both cell uncertainty and consistency of adjacent cells into consideration. Finally, the visible old images of the point cloud in the changed cells are replaced with the corresponding visible new images, and the old map is updated by a local Bundle Adjustment. Experimental results on 3D maps reconstructed by aerial and ground images demonstrate the effectiveness and robustness of the proposed method.

Abstract Background Calcium (Ca2+) serves as a ubiquitous second messenger and plays a pivotal role in signal transduction. Calcineurin B-like proteins (CBLs) are plant-specific Ca2+ sensors that interact with CBL-interacting protein kinases (CIPKs) to transmit Ca2+ signals. CBL-CIPK complexes have been reported to play pivotal roles in plant development and response to drought stress; however, limited information is available about the CBL and CIPK genes in pecan, an important nut crop. Results In the present study, a total of 9 CBL and 30 CIPK genes were identified from the pecan genome and divided into four and five clades based on phylogeny, respectively. Gene structure and distribution of conserved sequence motif analysis suggested that family members in the same clade commonly exhibited similar exon-intron structures and motif compositions. The segmental duplication events contributed largely to the expansion of pecan CBL and CIPK gene families, and Ka/Ks values revealed that all of them experienced strong negative selection. Phylogenetic analysis of CIPK proteins from 14 plant species revealed that CIPKs in the intron-poor clade originated in seed plants. Tissue-specific expression profiles of CiCBLs and CiCIPKs were analysed, presenting functional diversity. Expression profiles derived from RNA-Seq revealed distinct expression patterns of CiCBLs and CiCIPKs under drought treatment in pecan. Moreover, coexpression network analysis helped to elucidate the relationships between these genes and identify potential candidates for the regulation of drought response, which were verified by qRT–PCR analysis. Conclusions The characterization and analysis of CBL and CIPK genes in pecan genome could provide a basis for further functional analysis of CiCBLs and CiCIPKs in the drought stress response of pecan.

Objective Based on a large public cohort, we aimed to investigate the prevalence of distant metastases in patients with osteosarcoma, to evaluate the survival of patients with different metastases and to reveal the related risk and prognostic factors for distant metastases. Methods The information of osteosarcoma patients with or without distant metastases was retrospectively extracted from the Surveillance, Epidemiology, and End Result database from January 2010 to December 2015. Patients were excluded if they were diagnosed at autopsy or via death certification. The Kaplan–Meier method was used to calculate the overall survival in the entire cohort and across patients with metastases to different organs. The related prognostic factors were investigated by univariate and multivariate Cox proportional hazard regression analysis. The logistic regression method was used to reveal the risk factors for the development of different metastases. The effects of different variables on the survival and prevalence of distant metastases were compared using subgroup analysis. Variables with P

BackgroundCommunity-based organizations deliver peer-led support services to people living with HIV. Systematic reviews have found that peer-led community-based support services can improve HIV treatment outcomes; however, few studies have been implemented to evaluate its impact on mortality using long-term follow-up data. ObjectiveWe aimed to evaluate the associations between the receipt of peer-led community-based support services and HIV treatment outcomes and survival among people living with HIV in Wuxi, China. MethodsWe performed a propensity score–matched retrospective cohort study using data collected from the Chinese National HIV/AIDS Comprehensive Information Management System for people living with HIV in Wuxi, China, between 2006 and 2021. People living with HIV who received adjunctive peer-led community-based support for at least 6 months from a local community-based organization (exposure group) were matched to people living with HIV who only received routine clinic-based HIV care (control group). We compared the differences in HIV treatment outcomes and survival between these 2 groups using Kaplan-Meier curves. We used competing risk and Cox proportional hazards models to assess correlates of AIDS-related mortality (ARM) and all-cause mortality. We reported adjusted subdistribution hazard ratio and adjusted hazard ratio with 95% CIs. ResultsA total of 860 people living with HIV were included (430 in the exposure group and 430 in the control group). The exposure group was more likely to adhere to antiretroviral therapy (ART; 396/430, 92.1% vs 360/430, 83.7%; P

Abstract DNA, a genetic material, has been employed in different scientific directions for various biological applications as driven by DNA nanotechnology in the past decades, including tissue regeneration, disease prevention, inflammation inhibition, bioimaging, biosensing, diagnosis, antitumor drug delivery, and therapeutics. With the rapid progress in DNA nanotechnology, multitudinous DNA nanomaterials have been designed with different shape and size based on the classic Watson–Crick base-pairing for molecular self-assembly. Some DNA materials could functionally change cell biological behaviors, such as cell migration, cell proliferation, cell differentiation, autophagy, and anti-inflammatory effects. Some single-stranded DNAs (ssDNAs) or RNAs with secondary structures via self-pairing, named aptamer, possess the ability of targeting, which are selected by systematic evolution of ligands by exponential enrichment (SELEX) and applied for tumor targeted diagnosis and treatment. Some DNA nanomaterials with three-dimensional (3D) nanostructures and stable structures are investigated as drug carrier systems to delivery multiple antitumor medicine or gene therapeutic agents. While the functional DNA nanostructures have promoted the development of the DNA nanotechnology with innovative designs and preparation strategies, and also proved with great potential in the biological and medical use, there is still a long way to go for the eventual application of DNA materials in real life. Here in this review, we conducted a comprehensive survey of the structural development history of various DNA nanomaterials, introduced the principles of different DNA nanomaterials, summarized their biological applications in different fields, and discussed the current challenges and further directions that could help to achieve their applications in the future.

Background: Associations of air pollution with anxiety and depression were found in previous studies. However, whether air pollution exposure during pregnancy contributes to prenatal anxiety and depression or not is under-investigated. In this study, we aimed to analyze associations between fine particulate matter (PM2.5) exposure with anxiety and depression during pregnancy and to explore the critical window of PM2.5 exposure. Methods: This study was based on the Shanghai Maternal-Child Pairs Cohort (Shanghai MCPC). We used a gap-filling random forest model to estimate PM2.5 exposure concentration during pregnancy of each participant. The Self-Rating Anxiety Scale (SAS) and the Center for Epidemiological Survey-Depression Scale (CES-D) were used to quantify the anxiety and depression levels in late pregnancy. Covariate information was obtained from medical records and questionnaires. We performed generalized linear regression and logistic regression models to assess the association and the critical window. Results: Totally 3731 pregnant women were included, with the age of 28.85 ± 3.97 years old. Anxiety and depression rates were 10.8 % and 11.5 % respectively, according to the cut-off value of SAS and CES-D. Generalized linear regression results showed that the increase of PM2.5 concentration in three stages (gestational 0–13 weeks, 0–26 weeks, 0–36 weeks) was related to the increase of scale score. The PM2.5 concentration in 0–13 weeks could increase the risk of anxiety and depression by approximately 23 % and 25 %, respectively. And the gestational weeks 4th–13th were the suspicious critical window of PM2.5 exposure. Conclusion: The increased risk of anxiety or depression was related to PM2.5 exposure during pregnancy, especially early pregnancy.

ABSTRACT Oral squamous cell carcinoma (OSCC) is a fatal disease, and periodontitis is associated with OSCC development. However, the pathogenesis in the context of OSCC with periodontitis has not been fully understood. Here, we demonstrated that periodontitis promoted OSCC development, accompanied by alterations in the oral bacterial community and the tumor immune microenvironment. The oral microbiota from periodontitis maintained the dominant position throughout the whole process of OSCC with periodontitis, of which Porphyromonas was the most abundant genus. The oral microbiota from periodontitis could activate interleukin-17-positive (IL-17+) γδ T cells directly. The activated γδ T cells were necessary for the IL-17/signal transducer and activator of transcription 3 (STAT3) pathway and promoted M2-tumor-associated macrophage (TAM) infiltration in OSCC proliferation. Our data provide insight into the carcinogenesis of OSCC with periodontitis by outlining the tumor-associated immune response shaped by the oral microbiota from periodontitis. Thus, oral commensal bacteria and IL-17+ γδ T cells might be potential targets for monitoring and treating OSCC. IMPORTANCE The work reveals the role of the oral microbiota from periodontitis in carcinogenesis. Furthermore, our study provides insight into the pathogenesis of OSCC with periodontitis by outlining the tumor-associated immune response shaped by the oral microbiota from periodontitis, which might identify new research and intervention targets for OSCC with periodontitis.

Backgrounds: To evaluate the predictive power of 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) derived radiomics in molecular subtype classification of breast cancer (BC). Methods: A total of 273 primary BC patients who underwent a 18F-FDG PET/CT imaging prior to any treatment were included in this retrospective study, and the values of five conventional PET parameters were calculated, including the maximum standardized uptake value (SUVmax), SUVmean, SUVpeak, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The ImageJ 1.50i software and METLAB package were used to delineate the contour of BC lesions and extract PET/CT derived radiomic features reflecting heterogeneity. Then, the least absolute shrinkage and selection operator (LASSO) algorithm was used to select optimal subsets of radiomic features and establish several corresponding radiomic signature models. The predictive powers of individual PET parameters and developed PET/CT derived radiomic signature models in molecular subtype classification of BC were evaluated by using receiver operating curves (ROCs) analyses with areas under the curve (AUCs) as the main outcomes. Results: All of the three SUV parameters but not MTV nor TLG were found to be significantly underrepresented in luminal and non-triple (TN) subgroups in comparison with corresponding non-luminal and TN subgroups. Whereas, no significant differences existed in all the five conventional PET parameters between human epidermal growth factor receptor 2+ (HER2+) and HER2– subgroups. Furthermore, all of the developed radiomic signature models correspondingly exhibited much more better performances than all the individual PET parameters in molecular subtype classification of BC, including luminal vs. non-luminal, HER2+ vs. HER2–, and TN vs. non-TN classification, with a mean value of 0.856, 0.818, and 0.888 for AUC. Conclusions: PET/CT derived radiomic signature models outperformed individual significant PET parameters in molecular subtype classification of BC.

Abstract Background Immunotherapy has shown promising efficacy in patients with nasopharyngeal carcinoma (NPC). Lymphocyte activating 3 gene (LAG-3) represents a significant immune target, however, its relationship with NPC remains unclear. This study aimed to evaluate LAG-3 expression in NPC and its association with CD3+ tumor-infiltrating lymphocytes (TILs), Granzyme B (GZMB), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) expression. Methods A total of 182 patients with NPC from Sun Yat-sen University Cancer Center, China, were included in this retrospective study. LAG-3 expression in 15 NPC cell lines and LAG-3, CD3+ TILs, GZMB, PD-L1 and PD-1 in clinical samples were estimated using immunohistochemistry. The Chi-square test was used to estimate the association between LAG-3, other biomarkers, and clinical characteristics. Survival analysis was performed using the Kaplan–Meier method and the Cox regression model. Results LAG-3 was negatively expressed in all of the 15 NPC cell lines, whereas, 147 patients with NPC (80.8%) exhibited high LAG-3 expression on TILs from tumor tissues. Male patients and those who were EBV-positive presented higher LAG-3 expression. Correlation analyses showed that LAG-3 expression was related to PD-1 expression on TILs, as well as, PD-L1 expression on tumor cells (TCs) and TILs. Both the univariate and multivariate Cox models indicated that pathological type III (P = 0.036), higher LAG-3 on TILs (P

Abstract Background This study aimed to describe the incidence, clinical characteristics, and prognosis of lung cancer patients with synchronous bone metastasis (SBM) and to analyze the prognostic factors of the lung cancer patients with SBM. Methods A total of 15,716 lung cancer patients who were diagnosed between 2009 to 2018 in the Tianjin Medical University Cancer Institute and Hospital were retrospectively reviewed. Among them, patients with SBM were checked. Both the demographic and clinical characteristics were included as follows: age, gender, marital status, history of smoking, alcohol consumption, family history of tumor, Karnofsky score, lymph node metastasis, histological type. Besides, laboratory data such as alkaline phosphatase, lactate dehydrogenase, carcinoembryonic antigen, squamous cell carcinoma antigen, cytokeratin-19 fragment, and neuron specific enolase were also included. The log-rank test and multivariate Cox regression analysis were employed to reveal the potential prognostic predictors. A further analysis using the Kaplan–Meier was employed to demonstrate the difference on the prognosis of LC patients between adenocarcinoma and non-adenocarcinoma. Results Among the included patients, 2738 patients (17.42%) were diagnosed with SBM. A total of 938 patients (34.3%) with SBM were successfully followed and the median survival was 11.53 months (95%CI: 10.57–12.49 months), and the 1-, 2-, and 5-year overall survival rate was 51, 17, and 8%, respectively. Multivariable Cox regression results showed history of smoking and high level of NSE were associated with the poor prognosis, while adenocarcinoma histological type was associated with better survival. Conclusion The prevalence of SBM in lung cancer is relatively high with poor survival. The lung cancer patients with SBM showed diverse prognosis. Among all the pathological types, the division of adenocarcinoma suggested different prognosis of the lung cancer patients with SBM. The present study emphasized the importance of pathological diagnosis on prognostic determinants in lung cancer patients with SBM.

Objective: The immunoscore, which is used to quantify immune infiltrates, has greater relative prognostic value than tumor, node, and metastasis (TNM) stage and might serve as a new system for classification of colorectal cancer. However, a comparable immunoscore for predicting lung adenocarcinoma (LUAD) prognosis is currently lacking. Methods: We analyzed the expression of 18 immune features by immunohistochemistry in 171 specimens. The relationship of immune marker expression and clinicopathologic factors to the overall survival (OS) was analyzed with the Kaplan-Meier method. A nomogram was developed by using the optimal features selected by least absolute shrinkage and selection operator (LASSO) regression in the training cohort (n = 111) and evaluated in the validation cohort (n = 60). Results: The indicators integrated in the nomogram were TNM stage, neuron-specific enolase, carcino-embryonic antigen, CD8center of tumor (CT), CD8invasive margin (IM), FoxP3CT, and CD45ROCT. The calibration curve showed prominent agreement between the observed 2- and 5-year OS and that predicted by the nomogram. To simplify the nomogram, we developed a new immune-serum scoring system (I-SSS) based on the points awarded for each factor in the nomogram. Our I-SSS was able to stratify same-stage patients into different risk subgroups. The combination of I-SSS and TNM stage had better prognostic value than the TNM stage alone. Conclusions: Our new I-SSS can accurately and individually predict LUAD prognosis and may be used to supplement prognostication based on the TNM stage.

Abstract Background Colorectal cancer (CRC) is a major cancer burden, and prognosis is determined by many demographic and clinicopathologic factors. The present study aimed to construct a prognostic nomogram for colorectal cancer patients with distant metastasis. Methods Colorectal cancer patients with distant metastasis diagnosed between 2010 and 2016 were selected from the Surveillance, Epidemiology, and End Results database. Cox proportional hazards regression was used to identify independent prognostic factors. A nomogram was constructed to predict survival, and validation was performed. Results A total of 7099 stage IV colorectal cancer patients were enrolled in the construction cohort. The median overall survival was 20.0 (95% CI 19.3–20.7) months. Age at diagnosis, marital status, race, primary tumour site, tumour grade, CEA level, T stage, N stage, presence of bone, brain, liver and lung metastasis, surgery for primary site and performance of chemotherapy were independent prognostic factors. The nomogram was constructed and the calibration curve showed satisfactory agreement. The C-index was 0.742 (95% CI 0.726–0.758). In the validation cohort (7098 patients), the nomogram showed satisfactory discrimination and calibration with a C-index of 0.746 (95% CI 0.730–0.762). Conclusion A series of factors associated with the survival of CRC patients with distant metastasis were found. Based on the identified factors, a nomogram was generated to predict the survival of stage IV colorectal cancer patients. The predictive model showed satisfactory discrimination and calibration, which can provide a reference for survival estimation and individualized treatment decisions.

PurposeTo investigate the non-cancer causes of death (COD) in cancer patients with synchronous bone metastasis (BM) that is based on the Surveillance, Epidemiology, and End Results (SEER) database.MethodsThe retrospective cohort study included malignant cancer patients with synchronous BM diagnosed from 2010 to 2018 in the SEER database. The frequencies and proportion of non-cancer COD were calculated and analyzed in different genders, ages, and races subgroups.ResultsA total of 97,997 patients were deceased and included into the current study and 6,782 patients were died of non-cancer causes with a male predominance (N = 4,515, 66.6%). Around half of deaths (N = 3,254, 48.0%) occurred within 6 months after diagnosis while 721 patients were deceased after 3 years. Lung and bronchus cancer, prostate cancer, breast cancer, kidney and renal pelvis cancer, and liver cancer were proved to be the top five cancer types resulting in non-cancer caused death. Cardiovascular and cerebrovascular diseases were the leading non-cancer cause of death (N = 2,618), followed by COPD and associated conditions (N = 553) and septicemia, infectious and parasitic diseases (N = 544). Sub-analyses stratified by gender, age and race were performed and the similar results with slightly difference were observed.ConclusionsCardiovascular and cerebrovascular diseases were the main non-cancer cause of death in cancer patients with synchronous BM. Other non-cancer causes included COPD, septicemia, infectious and parasitic diseases, and so on. These findings should be considered by physicians. Physicians can counsel cancer patients with BM regarding survivorship with death causes screening and focus on prevention of non-cancer deaths.

Abstract Wound dressing with the capacities of antioxidation, antiinflammation, and efficient angiogenesis induction is expected for effectively promoting wound healing. Herein, a novel core‐shell hyaluronic acid (HA) microneedle (MN) patch with ferrum‐mesenchymal stem cell‐derived artificial nanovesicles (Fe‐MSC‐NVs) and polydopamine nanoparticles (PDA NPs) encapsulated in the needle tips is presented for wound healing. Fe‐MSC‐NVs containing multifunctional therapeutic cytokines are encapsulated in the inner HA core of the MN tips for accelerating angiogenesis. The PDA NPs are encapsulated in the outer methacrylated hyaluronic acid (HAMA) shell of the MN tips to overcome the adverse impacts from reactive oxygen species (ROS)‐derived oxidative stress. With the gradual degradation of HAMA patch tips in the skin, the PDA NPs are sustainably released at the lesion to suppress the ROS‐induced inflammation reaction, while the Fe‐MSC‐NVs significantly increase the migration, proliferation, and tube formation of human umbilical vein endothelial cells (HUVEC). More attractively, the combination of PDA NPs and Fe‐MSC‐NVs further promotes M2 macrophage polarization, thereby suppressing wound inflammation. Through in vivo experiment, the Fe‐MSC‐NVs/PDA MN patch shows an excellent effect for diabetic wound healing. These features of antioxidation, antiinflammation, and pro‐angiogenesis indicate the proposed composite core‐shell MN patch is valuable for clinical wound healing applications.

Abstract Biofilm formation is responsible for numerous chronic infections and represents a serious health challenge. Bacteria and the extracellular polysaccharides (EPS) cause biofilms to become adherent, toxic, resistant to antibiotics, and ultimately difficult to remove. Inhibition of EPS synthesis can prevent the formation of bacterial biofilms, reduce their robustness, and promote removal. Here, we have developed a framework nucleic acid delivery system with a tetrahedral configuration. It can easily access bacterial cells and functions by delivering antisense oligonucleotides that target specific genes. We designed antisense oligonucleotide sequences with multiple targets based on conserved regions of the VicK protein-binding site. Once delivered to bacterial cells, they significantly decreased EPS synthesis and biofilm thickness. Compared to existing approaches, this system is highly efficacious because it simultaneously reduces the expression of all targeted genes (gtfBCD, gbpB, ftf). We demonstrate a novel nucleic acid-based nanomaterial with multi-targeted inhibition that has great potential for the treatment of chronic infections caused by biofilms.