The relationship between innate/adaptive immunity and gastrointestinal cancer : a multi-omics Mendelian randomization study.

BACKGROUND: Innate/adaptive immunity is the key to anti-tumor therapy. However, its causal relationship to Gastrointestinal (GI) cancer remains unclear. METHODS: Immunity genes were extracted from the MSigDB database. The Genome-wide association studies (GWAS) summary data of GI cancer were integrated with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) associated with genes. Summary-data-based Mendelian randomization (SMR) and co-localization analysis were used to reveal causal relationships between genes and GI cancer. Two-sample MR analysis was used for sensitivity analysis. Single cell analysis clarified the enrichment of genes. RESULTS: Three-step SMR analysis showed that a putative mechanism, cg17294865 CpG site regulating HLA-DRA expression was negatively associated with gastric cancer risk. HLA-DRA was significantly differentially expressed in monocyte/macrophage and myeloid cells in gastric cancer. CONCLUSION: This study provides evidence that upregulating the expression level of HLA-DRA can reduce the risk of gastric cancer.

Harnessing genetic interactions for prediction of immune checkpoint inhibitors response signature in cancer cells.

Genetic interactions (GIs) refer to two altered genes having a combined effect that is not seen individually. They play a crucial role in influencing drug efficacy. We utilized CGIdb 2.0 (http://www.medsysbio.org/CGIdb2/), an updated database of comprehensively published GIs information, encompassing synthetic lethality (SL), synthetic viability (SV), and chemical-genetic interactions. CGIdb 2.0 elucidates GIs relationships between or within protein complex models by integrating protein-protein physical interactions. Additionally, we introduced GENIUS (GENetic Interactions mediated drUg Signature) to leverage GIs for identifying the response signature of immune checkpoint inhibitors (ICIs). GENIUS identified high MAP4K4 expression as a resistant signature and high HERC4 expression as a sensitive signature for ICIs treatment. Melanoma patients with high expression of MAP4K4 were associated with decreased efficacy and poorer survival following ICIs treatment. Conversely, overexpression of HERC4 in melanoma patients correlated with a positive response to ICIs. Notably, HERC4 enhances sensitivity to immunotherapy by facilitating antigen presentation. Analyses of immune cell infiltration and single-cell data revealed that B cells expressing MAP4K4 may contribute to resistance to ICIs in melanoma. Overall, CGIdb 2.0, provides integrated GIs data, thus serving as a crucial tool for exploring drug effects.

Unraveling Immune Heterogeneity across Pan-Cancer and Deep Insights in Lung Adenocarcinoma based on Alternative Splicing.

Alternative splicing (AS) participates in tumor development and tumor microenvironment formation. However, the landscape of immune infiltrating AS events (IIASE) in pan-cancer and mechanisms of AS in lung adenocarcinoma (LUAD) have not been comprehensively characterized. We systematically profiled the IIASE landscape of pan-cancer using data from The Cancer Genome Atlas (TCGA), analyzing both commonalities and specific characteristics among different cancer types. We found that AS events tend to occur specifically in one cancer type rather than in multiple cancer types. AS events were used to classify 512 LUAD samples into two subtypes by unsupervised clustering: aberrant splicing subtype (ABS) and immune infiltrating subtype (IIS). The two subtypes showed significant differences in clinicopathology, prognosis, transcriptomics, genomics and immune microenvironment. We constructed a classification signature comprising 10 genes involved in 14 AS events using Logistic regression. The robustness of the signature was validated in three independent datasets using survival analysis. To explore AS mechanisms in LUAD, we constructed subtype-specific co-expression networks using Pearson correlation analysis. AS event of AKT3 regulated by splicing factor ENOX1 was associated with poor prognosis in LUAD. Overall, we outline AS events associated with immune infiltration in pan-cancer and this study provides insights into AS mechanisms in LUAD patient classification.

The safety and efficacy of neoadjuvant immunochemotherapy following laparoscopic gastrectomy for gastric cancer: a multicenter Real-world clinical study.

BACKGROUND: The safety and efficacy of neoadjuvant immunochemotherapy (nICT) for locally advanced gastric cancer (LAGC) remain controversial. METHODS: Patients with LAGC who received either nICT or neoadjuvant chemotherapy (nCT) at 3 tertiary referral teaching hospitals in China between January 2016 and October 2022 were analysed. After propensity-score matching (PSM), comparing the radiological response, pathological response rate, perioperative outcomes, and early recurrence between the two groups. RESULTS: After PSM, 585 patients were included, with 195 and 390 patients comprising the nICT and nCT groups, respectively. The nICT group exhibited a higher objective response rate (79.5% versus [vs.] 59.0%; P<0.001), pathological complete response rate (14.36% vs. 6.41%; P=0.002) and major pathological response rate (39.49% vs. 26.15%; P=0.001) compared with the nCT group. The incidence of surgical complications (17.44% vs. 16.15%, P=0.694) and proportion of perioperative textbook outcomes (80.0% vs. 81.0%; P=0.767) were similar in both groups. The nICT group had a significantly lower proportion of early recurrence than the nCT group (29.7% vs. 40.8%; P=0.047). Furthermore, the multivariable logistic analysis revealed that immunotherapy was an independent protective factor against early recurrence (odds ratio 0.62 [95% CI 0.41-0.92]; P=0.018). No significant difference was found in neoadjuvant therapy drug toxicity between the two groups (51.79% vs. 45.38%; P=0.143). CONCLUSIONS: Compared with nCT, nICT is safe and effective, which significantly enhanced objective and pathological response rates, and reduced the risk for early recurrence among patients with LAGC. TRIAL REGISTRATION: Clinical Trials.gov.

Evaluation Method of Fatigue Life for Asphalt Pavement on the Steel Bridge Deck Based on the Inhomogeneous Poisson Stochastic Process.

The paving layer on the steel box girder bridge deck is widely used when constructing pavements for steel bridges. Owing to the orthotropic feature of steel decks, a transverse clapboard and rib can lead to a concentration of stress. Consequently, fatigue cracks are often identified in asphalt concrete pavement layers due to re-compaction caused by heavy vehicles. This study aims to derive an evaluation method of fatigue life for asphalt pavement based on the inhomogeneous Poisson stochastic process in view of the highly random and uncertain working conditions of layered composite structures. According to the inhomogeneous Poisson stochastic process, along with Miner's fatigue damage accumulation theory and the linear elastic fracture mechanics theory, the fatigue life formula could be deduced. Meanwhile, fatigue experiments for asphalt concrete are designed to investigate the correlation between the theoretical formula and the actual fatigue damage life of the material. Compared with the test, the accuracy error is within 10%, which is better than other traditional methods. Therefore, the fatigue life prediction model could better reflect the loading order effect and the interaction between loads, providing a new path for the fatigue reliability design of steel bridge deck asphalt pavement.

Development and Validation of a Prognostic Model for Postoperative Anastomotic Recurrence in Siewert II or III Adenocarcinomas Without Neoadjuvant Therapy in an East Asian Population.

PURPOSE: Anastomotic recurrence leads to poor prognosis in patients with Siewert II or III adenocarcinoma who undergo radical gastrectomy and do not receive neoadjuvant therapy. We aimed to establish a prognostic model to evaluate the risk of postoperative anastomotic recurrence in patients with Siewert II or III adenocarcinoma who did not receive neoadjuvant therapy. METHODS: We included 366 patients with Siewert II or III adenocarcinoma who were treated with radical gastrectomy without neoadjuvant therapy at Fujian Provincial Hospital (FPH) between 2012 and 2018 as the development cohort. Cox regression was used to verify prognostic factors for anastomotic recurrence, and a nomogram was established. The nomogram was externally validated using a combined cohort of two external centers. Patients were classified into high- or low-risk groups according to the diagnostic threshold and nomogram scores, and recurrence-related survival analysis was analyzed. RESULTS: The average age was 64.6 years, and 285 patients were male. All surgeries were successfully performed (185 open vs 181 laparoscopic). The 3-year anastomotic recurrence rate was significantly lower in the low-risk group (3.5% vs 18.8%, P < 0.001). The predictive performance was verified in the external validation cohort. This model better stratified patient survival than the American Joint Committee on Cancer (AJCC) TNM staging system. CONCLUSIONS: This novel nomogram with surgical margin, postoperative tumor node metastasis (pTNM) stage, and neural invasion as prognostic factors has a significant predictive performance for the risk of anastomotic recurrence after radical gastrectomy in patients with Siewert II or III adenocarcinoma.

LncRNA TYMSOS is a novel prognostic biomarker associated with immune infiltration in prostate cancer.

The long noncoding RNA thymidylate synthetase opposite strand (lncRNA TYMSOS) plays an important role in cancers; however, its impact on prostate cancer (PCa) is still unclear. By analyzing the online data, we found that lncRNA TYMSOS was highly expressed in PCa and associated with T stage, Gleason score, age, and primary therapy outcome. The results of the ROC curve showed that lncRNA TYMSOS has a significant diagnostic ability. Furthermore, Kaplan-Meier analyses suggested that lncRNA TYMSOS plays an important role in progression-free survival (PFS). Increased lncRNA TYMSOS expression was an independent risk factor correlated with PFS in PCa patients. GSEA and GSVA indicated that the lncRNA TYMSOS was involved in the cell cycle, neurodegenerative diseases, oxidative phosphorylation, spliceosomes, and adaptive immune system pathways. Additionally, lncRNA TYMSOS expression was also associated with immune cell infiltrates and tumor mutational burden in PCa. Functional experiments were further conducted, and we verified that lncRNA TYMSOS played an oncogenic role in regulating PCa aggressiveness. Specifically, silencing of lncRNA TYMSOS suppressed cell proliferation, division and epithelial-mesenchymal transition (EMT) but promoted cell apoptosis in PCa cells, and conversely, lncRNA TYMSOS overexpression had the opposite effects. In summary, our study revealed that the lncRNA TYMSOS could be a biomarker and therapeutic target in PCa and participate in tumor-immune cell infiltration.

EXOSC2 Mediates the Pro-tumor Role of WTAP in Breast Cancer Cells via Activating the Wnt/ß-Catenin Signal.

BC (breast cancer) is the leading cause of cancer death in women. Exosome component 2 (EXOSC2), an RNA exosome component, is elevated in BC tissues and may relate to BC carcinogenesis. In this work, the high EXOSC2 expression was correlated with TNM (Tumor Node Metastasis) stage. Moreover, overexpression of EXOSC2 enhanced tumorigenic capacity of BC cells via facilitating cell proliferation and cell cycle progression, increasing migration and angiogenesis, as well as exacerbating xenograft formation in vivo. Whereas, EXOSC2 knockdown showed anti-cancer effects, including inhibition of cell proliferation and angiogenesis. Mechanistically, EXOSC2 activated the wnt/ß-catenin pathway, which was also abolished by EXOSC2 knockdown. In addition, there were m6A methylation modification sites in the mRNA of EXOSC2. WTAP (Wilms tumor 1-associated protein) bound to EXOSC2 mRNA and increased its m6A methylation, resulting in extending the half-life of EXOSC2 mRNA. Luciferase data also confirmed that WTAP enhanced EXOSC2 mRNA stability through binding with the 3'-UTR containing m6A sites. Furthermore, WTAP silencing exhibited cancer-inhibiting effects on cell viability, cell cycle progression and tube formation, which was effectively reversed by EXOSC2 overexpression. In conclusion, our results demonstrate that EXOSC2 promotes the malignant behaviors of BC cells via activating the wnt/ß-catenin pathway. In addition, EXOSC2 mediates the function of WTAP which contributes to the m6A modification of EXOSC2. Totally, this study suggested that EXOSC2 mediated the pro-tumor role of WTAP via activating the wnt/ß-catenin signal.

Inhibition characteristics research of aluminum alloy polishing dust explosion through addition of ultrafine Al(OH)3 inerting agent.

Investigations into the deactivation of explosion sensitivity and reduction of flame propagation for aluminium alloy polishing wastes were carried out by the addition of ultrafine Al(OH)3 inerting agent. Meanwhile, high-purity aluminium powders with similar mean diameters were also used as a comparative study. The explosion propagation characteristics of high-purity aluminium dust and aluminium alloy polishing waste dust under different inerting ratios (ε) were tested and investigated using a standardised Hartmann tester and a developed experimental platform. The results show that the minimum ignition energy of high-purity aluminium powder is between 40 and 45 mJ, and the minimum ignition energy of aluminium alloy polishing waste is between 500 and 550 mJ, which is one order of magnitude higher than that of high-purity aluminium powder. The lower explosion limit concentration of aluminium alloy polishing waste dust is 150 g/m3, which is 53.33% of that of high-purity aluminium powder. According to the analysis of the SEM image, the main reason is that the spherical particles of high-purity aluminium dust have a folded surface and good dispersion. Compared with the smooth fibre surface of aluminium alloy polishing waste dust, the former is easier to contact with air and the contact area is larger. Therefore, in engineering practice, it is not appropriate to use high-purity aluminium dust-related explosion parameters as the basis for the risk assessment of combustion and explosion at aluminium alloy polishing work sites. In addition, as the dust concentration decreases, the combustion intensity of high-purity aluminium dust and aluminium alloy polishing waste dust also decreases, and the flame propagation appears to be a discontinuous phenomenon. The peak flame propagation velocity of aluminium alloy polishing waste is 7.368 m/s at a concentration of 300 g/m3, which is 56.85% of that of high-purity aluminium powder. As the inerting ratio increases, the propagation velocity of the explosion flame slows down. When the inerting ratio reaches 30%, the minimum ignition energy of aluminium alloy polishing waste is inerted to 1 J, and self-sustained flame propagation cannot be formed. The results show that the ultra-fine Al(OH)3 powder has a significant inerting effect and is a realistic possibility in the production of aluminium alloy polishing.

Predictive value of acoustic radiation force impulse imaging in breast cancer after neoadjuvant chemotherapy.

To investigate the predictive value of acoustic radiation force impulse imaging for neoadjuvant chemotherapy in breast cancer. Seventy-eight breast cancer patients treated in our hospital from March 2019 to March 2022 were recruited. They received neoadjuvant chemotherapy and were examined by conventional ultrasound and acoustic radiation force impulse imaging before chemotherapy and after two cycles of chemotherapy. The lesion diameter, intralesional blood flow pulsatility index (PI), resistance index (RI), shear wave velocity (SWV), and change rate (Δlesion diameter, ΔPI, ΔRI, ΔSWV) were compared between the two groups before and after chemotherapy. The receiver operating characteristic curve was drawn to evaluate the predictive power of related parameters on the efficacy of neoadjuvant chemotherapy in breast cancer. After two cycles of neoadjuvant chemotherapy, according to the Miller-Payne grading, 57 cases (73.08%) with significant neoadjuvant chemotherapy response were classified as the response group, and 21 cases (26.92%) with non-significant response were classified as the non-response group. Before and after chemotherapy, the difference in lesion diameter, PI, RI, SWV, and change rate (Δlesion diameter, ΔPI, ΔRI, and ΔSWV) was statistically significant between the two groups (P < 0.05). The area under the curve of ΔSWV in predicting the efficacy of neoadjuvant chemotherapy 0.876 (95%CI 0.781 ~ 0.939) was significantly higher than that of Δlesion diameter 0.652 (95%CI 0.535 ~ 0.756), that of ΔPI 0.712 (95%CI 0.599 ~ 0.809), and that of ΔRI 0.678 (95%CI 0.563 ~ 0.780) (P < 0.05). The change rate of tissue stiffness has a relatively high predictive value for the effect of neoadjuvant chemotherapy in breast cancer.

Infection and co-infection patterns of community-acquired pneumonia in patients of different ages in China from 2009 to 2020: a national surveillance study.

BACKGROUND: Severe community-acquired pneumonia (SCAP) is associated with a substantial number of hospitalisations and deaths worldwide. Infection or co-infection patterns, along with their age dependence and clinical effects are poorly understood. We aimed to explore the causal and epidemiological characteristics by age, to better describe patterns of community-acquired pneumonia (CAP) and their association with severe disease. METHODS: National surveillance of CAP was conducted through a network of hospitals in 30 provinces in China from 2009-20 inclusive. Patients with CAP were included if they had evidence of acute respiratory tract, had evidence of pneumonia by chest radiography, diagnosis of pneumonia within 24 h of hospital admission, and resided in the study catchment area. For the enrolled patients with CAP, nasopharyngeal and oral swabs were taken and tested for eight viral pathogens; and blood, urine, or expectorated sputum was tested for six bacterial pathogens. Clinical outcomes, including SCAP, were investigated with respect to age and patterns of infections or co-infections by performing binary logistic regression and multivariate analysis. FINDINGS: Between January, 2009, and December, 2020, 18 807 patients with CAP (3771 [20·05%] with SCAP) were enrolled. For both children (aged ≤5 years) and older adults (aged >60 years), a higher overall rate of viral and bacterial infections, as well as viral-bacterial co-infections were seen in patients with SCAP than in patients with non-SCAP. For adults (aged 18-60 years), however, only a higher rate of bacterial-bacterial co-infection was observed. The most frequent pathogens associated with SCAP were respiratory syncytial virus (RSV; 21·30%) and Streptococcus pneumoniae (12·61%) among children, and influenza virus (10·94%) and Pseudomonas aeruginosa (15·37%) among older adults. Positive rates of detection of most of the tested pathogens decreased during 2020 compared with the 2009-19 period, except for RSV, P aeruginosa, and Klebsiella pneumoniae. Multivariate analyses showed SCAP was significantly associated with infection with human adenovirus, human rhinovirus, K pneumoniae, or co-infection of RSV and Haemophilus influenzae or RSV and Staphylococcus aureus in children and adolescents (aged <18 years), and significantly associated with infection with P aeruginosa, K pneumoniae, or S pneumoniae, or co-infection with P aeruginosa and K pneumoniae in adults (aged ≥18 years). INTERPRETATION: Both prevalence and infection pattern of respiratory pathogens differed between patients with SCAP and patients with non-SCAP in an age-dependent manner. These findings suggest potential advantages to age-related strategies for vaccine schedules, as well as clinical diagnosis, treatment, and therapy. FUNDING: China Mega-Project on Infectious Disease Prevention and The National Natural Science Funds of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

BML-111 inhibits osteoclast differentiation by suppressing the MAPK and NF-κB pathways, alleviating deterioration of the knee joints in a CIA rat model.

Irreversible destruction of joints is the hallmark of rheumatoid arthritis (RA). Osteoclasts are the only bone-resorbing cells and play an important role in joint rebuilding. BML-111 (5(S),6(R),7-trihydroxyheptanoic acid methyl ester, C8 H16 O5 ) is a synthetic lipoxin A4 agonist with antioxidant and anti-inflammatory properties. The present study aimed to investigate the effect of BML-111 on osteoclasts in vivo and in vitro, to investigate its therapeutic effect on joint destruction in RA. Cell Counting Kit-8 assay and flow cytometry were used to exclude cytotoxic effects of BML-111 to bone marrow-derived macrophages (BMMs). Then, osteoclasts were differentiated in vitro from BMMs by used macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand, and osteoclasts were observed following tartrate-resistant acid phosphatase staining with or without BML-111 treatment. Meanwhile, absorption pit assay and immunofluorescence staining of the fibrous actin ring were used to observe osteoclast function. Moreover, we examined mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) activation. We established collagen-induced arthritis in a rat model and, after treatment with BML-111, joint swelling was measured and the knee joints were processed for histology. We also examined serum and tissue for osteoclastogenesis-related markers. BML-111 inhibited osteoclast formation and differentiation in a time- and concentration-dependent manner, and downregulated the expression levels of MAPK and NF-κB in vitro. Meanwhile, BML-111 effectively alleviated joint structural damage and inhibited osteoclast formation in vivo. BML-111 inhibited osteoclast formation and differentiation in vitro and in vivo, and delayed the progression of joint destruction.

Prevalence of human infection with respiratory adenovirus in China: A systematic review and meta-analysis.

BACKGROUND: Human adenovirus (HAdV) is a major pathogen that causes acute respiratory tract infections (ARTI) and is frequently associated with outbreaks. The HAdV prevalence and the predominant types responsible for ARTI outbreaks remains obscure in China. METHODS: A systematic review was performed to retrieve literature that reported outbreaks or etiological surveillance of HAdV among ARTI patients in China from 2009 to 2020. Patient information was extracted from the literature to explore the epidemiological characteristics and clinical manifestations of the infection of various HAdV types. The study is registered with PROSPERO, CRD42022303015. RESULTS: A total of 950 articles (91 about outbreaks and 859 about etiological surveillance) meeting the selection criteria were included. Predominant HAdV types from etiological surveillance studies differed from those in outbreak events. Among 859 hospital-based etiological surveillance studies, positive detection rates of HAdV-3 (32.73%) and HAdV-7 (27.48%) were significantly higher than other virus types. While nearly half (45.71%) of outbreaks were caused by HAdV-7 with an overall attack rate of 22.32% among the 70 outbreaks for which the HAdVs were typed by the meta-analysis. Military camp and school were main outbreak settings with significantly different seasonal pattern and attack rate, where HAdV-55 and HAdV-7 were identified as the leading type, respectively. Clinical manifestations mainly depended on the HAdV types and patient's age. HAdV-55 infection tends to develop into pneumonia with poorer prognosis, especially in children <5 years old. CONCLUSIONS: This study improves the understanding of epidemiological and clinical features of HAdV infections and outbreaks with different virus types, and helps to inform future surveillance and control efforts in different settings.

Survey and analysis of willingness to use mobile medical services and influencing factors of TB patients treated at home.

INTRODUCTION: The objective of this study was to investigate the willingness of patients with tuberculosis (TB) to use mobile medical services (mHealth) and its influencing factors, so as to provide theoretical guidance for optimizing the TB mobile medical platform and improve the willingness of patients to use mHealth. METHODOLOGY: In this cross-sectional study, convenience sampling method was used to investigate patients with TB from the outpatient clinics of two TB specialized hospitals (Beijing Thoracic Tumor and Tuberculosis Hospital and Tuberculosis Prevention and Treatment Hospital of Shaanxi Province) from January to June 2021 using a self-designed questionnaire. RESULTS: Out of 231 patients, only 90 (38.96%) were aware of mHealth services, and 63 (27.27%) had used mHealth services. Among the 63 patients who had used mHealth services, the proportion of mobile medical forms based on WeChat platform was 74.89%. Patients' willingness to use mHealth was scored (11.49 ± 2.53). Univariate analysis showed that the scores of patients' willingness to use mHealth differed by gender and the different ways of affording healthcare (p < 0.05). Regression analysis showed that the influencing factors of willingness to use mHealth in patients with TB included attitude towards use (0.750), health beliefs (0.091) and social impact (0.169) (adjusted R2 = 0.781, p < 0.001). CONCLUSIONS: Patients' awareness of the advantages of the new medical model needs to be improved. Optimized design can improve the willingness of patients to use mHealth services and improve the role of mHealth in patient management.

Pulmonary sarcoidosis: A novel sequelae of drug reaction with eosinophilia and systemic symptoms: A case report.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an uncommon yet serious adverse drug hypersensitivity reaction with the presentations including rash, fever, lymphadenopathy, and internal organ involvement. Sarcoidosis is a systematic granulomatous disease with unknown etiology. We herein report a case of pulmonary sarcoidosis secondary to allopurinol-induced DRESS. CASE SUMMARY: A 37-year-old man with a history of hyperuricemia was treated with allopurinol for three weeks at a total dose of 7000 milligrams before developing symptoms including anorexia, fever, erythematous rash, and elevated transaminase. The patient was diagnosed with DRESS and was treated with prednisone for 6 mo until all the symptoms completely resolved. Three months later, the patient presented again because of a progressively worsening dry cough. His chest computed tomography images showed bilateral lung parenchyma involvement with lymph node enlargement, which was confirmed to be nonnecrotizing granuloma by pathological examination. Based on radiologic and pathological findings, he was diagnosed with sarcoidosis and was restarted on treatment with prednisone, which was continued for another 6 mo. Reexamination of chest imaging revealed complete resolution of parenchymal lung lesions and a significant reduction in the size of the mediastinal and hilar lymph nodes. Following a 6-month follow-up of completion of treatment, the patient's clinical condition remained stable with no clinical evidence of relapse. CONCLUSION: This is the first case in which pulmonary sarcoidosis developed as a late complication of allopurinol-induced DRESS. The case indicated that the autoimmune reaction of DRESS may play an important role in the pathogenesis of sarcoidosis.

Connective tissue growth factor-targeting DNA aptamer suppresses pannus formation as diagnostics and therapeutics for rheumatoid arthritis.

Connective tissue growth factor (CTGF) has been recently acknowledged as an ideal biomarker in the early disease course, participating in the pathogenesis of pannus formation in rheumatoid arthritis (RA). However, existing approaches for the detection of or antagonist targeting CTGF are either lacking or unsatisfactory in the diagnosis and treatment of RA. To address this, we synthesized and screened high-affinity single-stranded DNA aptamers targeting CTGF through a protein-based SELEX procedure. The structurally optimized variant AptW2-1-39-PEG was characterized thoroughly for its high-affinity (KD 7.86 nM), sensitivity (minimum protein binding concentration, 2 ng), specificity (negative binding to other biomarkers of RA), and stability (viability-maintaining duration in human serum, 48 h) properties using various biochemical and biophysical assays. Importantly, we showed the antiproliferative and antiangiogenic activities of the aptamers obtained using functional experiments and further verified the therapeutic effect of the aptamers on joint injury and inflammatory response in collagen-induced arthritis (CIA) mice, thus advancing this study into actual therapeutic application. Furthermore, we revealed that the binding within AptW2-1-39-PEG/CTGF was mediated by the thrombospondin 1 (TSP1) domain of CTGF using robust bioinformatics tools together with immunofluorescence. In conclusion, our results revealed a novel aptamer that holds promise as an additive or alternative approach for CTGF-targeting diagnostics and therapeutics for RA.

Regulatory role of melatonin on epidermal growth factor receptor, Type I collagen α1 chain, and caveolin 1 in granulosa cells of sheep antral follicles.

We investigated the expression of epidermal growth factor receptor (EGFR), Type I collagen α1 chain (COL1A1), and caveolin 1 (CAV1) during follicular development and examined the regulatory role of melatonin (MLT) on EGFR, COL1A1, and CAV1 in sheep antral ovaries. The expression was detected in granulosa and theca cells by immunohistochemistry. Quantitative real-time polymerase chain reaction and Western blotting were used to examine the expression levels of EGFR, COL1A1, and CAV1 in small (≤2 mm), medium (2-5 mm), and large (≥5 mm) follicles. The mRNA and protein levels of EGFR, COL1A1, and CAV1 were found to be the highest in large follicles. Furthermore, cultured granulosa cells were treated with MLT (10-7 -10-11  M), luzindole (nonselective MT1 and MT2 receptor antagonist, 10-7  M), and 4-phenyl-2-propanamide tetraldehyde (4P-PDOT, MT2 selective antagonist, 10-7  M) to detect the regulatory role of MLT on EGFR, COL1A1, and CAV1. Results indicated COL1A1 and CAV1 were at least partially regulated by MLT through MT1 and MT2 pathways, whereas EGFR was not. This study provided a reference for further studies on MLT regulatory role on EGFR, COL1A1, and CAV1 during sheep follicular development and elucidated the physiological mechanism of MLT regulator production.

Radiographical Evaluation of Tumor Immunosuppressive Microenvironment and Treatment Outcomes in Gastric Cancer: A Retrospective, Multicohort Study.

BACKGROUND: The tumor immunosuppressive microenvironment can influence treatment response and outcomes. A previously validated immunosuppression scoring system (ISS) assesses multiple immune checkpoints in gastric cancer (GC) using tissue-based assays. We aimed to develop a radiological signature for non-invasive assessment of ISS and treatment outcomes. METHODS: A total of 642 patients with resectable GC from three centers were divided into four cohorts. Radiomic features were extracted from portal venous-phase CT images of GC. A radiomic signature for predicting ISS (RISS) was constructed using the least absolute shrinkage and selection operator (LASSO) regression method. Moreover, we investigated the value of the RISS in predicting survival and chemotherapy response. RESULTS: The RISS, which consisted of 10 selected features, showed good discrimination of immunosuppressive status in three independent cohorts (area under the curve = 0.840, 0.809, and 0.843, respectively). Multivariate analysis revealed that the RISS was an independent prognostic factor for both disease-free survival (DFS) and overall survival (OS) in all cohorts (all p < 0.05). Further analysis revealed that stage II and III GC patients with low RISS exhibited a favorable response to adjuvant chemotherapy (OS: hazard ratio [HR] 0.407, 95% confidence interval [CI] 0.284-0.584); DFS: HR 0.395, 95% CI 0.275-0.568). Furthermore, the RISS could predict prognosis and select stage II and III GC patients who could benefit from adjuvant chemotherapy independent of microsatellite instability status and Epstein-Barr virus status. CONCLUSION: The new, non-invasive radiomic signature could effectively predict the immunosuppressive status and prognosis of GC. Moreover, the RISS could help identify stage II and III GC patients most likely to benefit from adjuvant chemotherapy and avoid overtreatment.

Management of retroperitoneal sarcoma involving the iliac artery: Single-center surgical experience.

BACKGROUND: Management of retroperitoneal sarcoma (RPS) involving the iliac artery is challenging and requires the concerted efforts of multidisciplinary team (MDT) members during surgical treatment. AIM: To summarize the clinicopathologic features of RPS involving the iliac artery and our retroperitoneal soft tissue tumor MDT surgical experience. METHODS: In this retrospective study, 15 patients with RPS involving the iliac artery who underwent surgery at our retroperitoneal soft tissue tumor center from July 2004 to June 2020 were analyzed. Statistical analyses were performed by Student's t-test with SPSS 16.0. RESULTS: Complete tumor resection (R0/R1) and iliac artery reconstruction were achieved in all 15 patients. All the operations were successful, with no serious complications or perioperative death. Resection with bilateral iliac artery reconstruction required a higher intraoperative blood transfusion volume than resection with unilateral iliac artery reconstruction. Recurrent cases were more likely to bleed and required a higher blood transfusion volume than primary cases. As of January 2021, 11 patients were alive, and 4 had died. Local recurrence occurred in two patients, one of whom developed liver metastasis. CONCLUSION: Resection of RPS involving iliac vessels is feasible and effective when performed by MDT members. Iliac artery oncovascular resection and reconstruction are key to a successful operation. Adequate blood preparation is important for successful completion of surgery.