A novel liver-function-indicators-based prognosis signature for patients with hepatocellular carcinoma treated with anti-programmed cell death-1 therapy.

BACKGROUND: The liver function reserve has a significant impact on the therapeutic effects of anti-programmed cell death-1 (PD-1) for hepatocellular carcinoma (HCC). This study aimed to comprehensively evaluate the ability of liver-function-based indicators to predict prognosis and construct a novel prognostic score for HCC patients with anti-PD-1 immunotherapy. METHODS: Between July 2018 and January 2020, patients diagnosed with HCC who received anti-PD-1 treatment were screened for inclusion in the study. The valuable prognostic liver-function-based indicators were selected using Cox proportional hazards regression analysis to build a novel liver-function-indicators-based signature (LFIS). Concordance index (C-index), the area under the receiver operating characteristic (ROC) curve (AUC), and Kaplan-Meier survival curves were utilized to access the predictive performance of LFIS. RESULTS: A total of 434 HCC patients who received anti-PD-1 treatment were included in the study. The LFIS, based on alkaline phosphatase-to-albumin ratio index, Child-Pugh score, platelet-albumin score, aspartate aminotransferase-to-lymphocyte ratio index, and gamma-glutamyl transpeptidase-to-lymphocyte ratio index, was constructed and identified as an independent risk factor for patient survival. The C-index of LFIS for overall survival (OS) was 0.692, which was higher than the other single liver-function-based indicator. The AUC of LFIS at 6-, 12-, 18-, and 24-month were 0.74, 0.714, 0.747, and 0.865 for OS, respectively. Patients in the higher-risk LFIS group were associated with both worse OS and PFS. An online and easy-to-use calculator was further constructed for better application of the LFIS signature. CONCLUSION: The LFIS score had an excellent prognosis prediction ability superior to every single liver-function-based indicator for anti-PD-1 treatment in HCC patients. It is a reliable, easy-to-use tool to stratify risk for OS and PFS in HCC patients who received anti-PD-1 treatment.

Effect of lignin on the structure-property behavior of metal-coordinated and chemically crosslinked ethylene-propylene-diene-monomer composites.

The efficient development and utilization of green biomass-based macromolecule engineering materials are essential for the sustainable development of human civilization. In this study, lignin-based ethylene-propylene-diene-monomer (EPDM) composites with excellent mechanical performance were fabricated using a simple method. The effects of water-insoluble enzymatically hydrolyzed lignin (EL) and alkali lignin (KL) on the mechanical performance of the composites were investigated separately. The results showed that the tensile strength of EPDM reinforced with KL and EL increased to 24.5 MPa and 22.1 MPa, respectively, surpassing that of the carbon black (CB)-reinforced EPDM. After 72 h of thermo-oxidative aging, the retention rates of the tensile strength and elongation at break in the lignin-reinforced EPDM were much better than those formed with pure CB, indicating that lignin significantly improved the thermo-oxidative aging resistance of the composites. In summary, the Zn2+ coordination bonds formed between the interface of EPDM and lignin in lignin/CB/EPDM ternary composites effectively improved the mechanical performance and aging resistance of the composites. This study has significant implications for enhancing the utilization of lignin and green functional polymer materials.

Pan-cancer analysis of CDKN2A alterations identifies a subset of gastric cancer with a cold tumor immune microenvironment.

BACKGROUND: Although CDKN2A alteration has been explored as a favorable factor for tumorigenesis in pan-cancers, the association between CDKN2A point mutation (MUT) and intragenic deletion (DEL) and response to immune checkpoint inhibitors (ICIs) is still disputed. This study aims to determine the associations of CDKN2A MUT and DEL with overall survival (OS) and response to immune checkpoint inhibitors treatment (ICIs) among pan-cancers and the clinical features of CDKN2A-altered gastric cancer. METHODS: This study included 45,000 tumor patients that underwent tumor sequencing across 33 cancer types from four cohorts, the MSK-MetTropism, MSK-IMPACT, OrigiMed2020 and TCGA cohorts. Clinical outcomes and genomic factors associated with response to ICIs, including tumor mutational burden, copy number alteration, neoantigen load, microsatellite instability, tumor immune microenvironment and immune-related gene signatures, were collected in pan-cancer. Clinicopathologic features and outcomes were assessed in gastric cancer. Patients were grouped based on the presence of CDKN2A wild type (WT), CDKN2A MUT, CDKN2A DEL and CDKN2A other alteration (ALT). RESULTS: Our research showed that CDKN2A-MUT patients had shorter survival times than CDKN2A-WT patients in the MSK MetTropism and TCGA cohorts, but longer OS in the MSK-IMPACT cohort with ICIs treatment, particularly in patients having metastatic disease. Similar results were observed among pan-cancer patients with CDKN2A DEL and other ALT. Notably, CDKN2A ALT frequency was positively related to tumor-specific objective response rates to ICIs in MSK MetTropism and OrigiMed 2020. Additionally, individuals with esophageal carcinoma or stomach adenocarcinoma who had CDKN2A MUT had poorer OS than patients from the MSK-IMPACT group, but not those with adenocarcinoma. We also found reduced levels of activated NK cells, T cells CD8 and M2 macrophages in tumor tissue from CDKN2A-MUT or DEL pan-cancer patients compared to CDKN2A-WT patients in TCGA cohort. Gastric cancer scRNA-seq data also showed that CDKN2A-ALT cancer contained less CD8 T cells but more exhausted T cells than CDKN2A-WT cancer. A crucial finding of the pathway analysis was the inhibition of three immune-related pathways in the CDKN2A ALT gastric cancer patients, including the interferon alpha response, inflammatory response, and interferon gamma response. CONCLUSIONS: This study illustrates the CDKN2A MUT and DEL were associated with a poor outcome across cancers. CDKN2A ALT, on the other hand, have the potential to be used as a biomarker for choosing patients for ICI treatment, notably in esophageal carcinoma and stomach adenocarcinoma.

State Responses of Several Classes of Linear Systems Based on Fundamental Matrices.

State responses for several classes of linear systems are investigated in this article. The involved systems include state-delayed linear systems, and high-order linear systems. At first, the single-fundamental-matrix-based approach is extended to these systems, and their state responses are expressed by their fundamental matrices (FMs). In addition, the multiple-FMs-based approach is presented for these systems. Based on a group of FMs, the state responses for the considered time-invariant systems are derived. For the considered time-variant systems, their state responses are explicitly expressed by their transition matrices. As an application of the fundamental-matrix-based approach, a stabilizing control law is designed for a class of high-order fully actuated continuous-time linear systems with a single input-delay.

Associations and attributable burden between risk factors and all-cause and cause-specific mortality at different ages in patients with hypertension.

It remains unclear the age-specific associations of risk factors with deaths and mortality burden attributable across age. In a territory-wide retrospective cohort, 1,012,228 adults with hypertension were identified. Comorbidities including diabetes, chronic kidney disease (CKD), cardiovascular disease (CVD), heart failure, and cancer, and risk factors including current smoking and suboptimal control of blood pressure (BP), glucose and low-density lipoprotein cholesterol were defined. Associations of comorbidities/risk factors with all-cause and cause-specific mortality across age groups (18-54, 55-64, 65-74, and ≥75 years) were assessed. Population attributable fractions were also quantified. During a median follow-up of 10.7 years, 244,268 (24.1%) patients died, with pneumonia (7.2%), cancer (5.1%), and CVD (4.2%) being the leading causes. Despite increasing deaths with age, relative risk of mortality related to comorbidities/risk factors decreased with age; similar patterns were found for cause-specific mortality. The assessed risk factors accounted for 24.0% (95% CI 22.5%, 25.4%) deaths, with highest proportion in the youngest group (33.5% [28.1%, 38.5%] in 18-54 years vs 19.4% [17.0%, 21.6%] in ≥75 years). For mortality burden, CKD was the overall leading risk factor (12.7% [12.4%, 12.9%]) with higher proportions in older patients (11.1-13.1% in ≥65 years), while diabetes was the leading risk factor in younger patients (15.9-13.5% in 18-54 years). The association of comorbidities or risk factors with mortality is stronger in younger patients with hypertension, despite lower absolute mortality in young patients than in the elderly. Leading risk factors differed across age, highlighting the importance of targeted and precise risk management.

Secreted dengue virus NS1 from infection is predominantly dimeric and in complex with high-density lipoprotein.

Severe dengue infections are characterized by endothelial dysfunction shown to be associated with the secreted nonstructural protein 1 (sNS1), making it an attractive vaccine antigen and biotherapeutic target. To uncover the biologically relevant structure of sNS1, we obtained infection-derived sNS1 (isNS1) from dengue virus (DENV)-infected Vero cells through immunoaffinity purification instead of recombinant sNS1 (rsNS1) overexpressed in insect or mammalian cell lines. We found that isNS1 appeared as an approximately 250 kDa complex of NS1 and ApoA1 and further determined the cryoEM structures of isNS1 and its complex with a monoclonal antibody/Fab. Indeed, we found that the major species of isNS1 is a complex of the NS1 dimer partially embedded in a high-density lipoprotein (HDL) particle. Crosslinking mass spectrometry studies confirmed that the isNS1 interacts with the major HDL component ApoA1 through interactions that map to the NS1 wing and hydrophobic domains. Furthermore, our studies demonstrated that the sNS1 in sera from DENV-infected mice and a human patient form a similar complex as isNS1. Our results report the molecular architecture of a biological form of sNS1, which may have implications for the molecular pathogenesis of dengue.

A ternary correlation multi-symptom network strategy based on in vivo chemical profile identification and metabolomics to explore the molecular basis of Ephedra herb against viral pneumonia.

Ephedra herb (EH), an important medicine prescribed in herbal formulas by Traditional Chinese Medicine practitioners, has been widely used in the treatment of viral pneumonia in China. However, the molecular basis of EH in viral pneumonia remains unclear. In this study, a ternary correlation multi-symptom network strategy was established based on in vivo chemical profile identification and metabolomics to explore the molecular basis of EH against viral pneumonia. Results showed that 143 compounds of EH and 70 prototype components were identified in vivo. EH could reduce alveolar-capillary barrier disruption in rats with viral pneumonia and significantly downregulate the expression of inflammatory factors and bronchoalveolar lavage fluid. Plasma metabolomics revealed that EH may be involved in the regulation of arachidonic acid, tryptophan, tyrosine, nicotinate, and nicotinamide metabolism. The multi-symptom network showed that 12 compounds have an integral function in the treatment of viral pneumonia by intervening in many pathways related to viruses, immunity and inflammation, and lung injury. Further verification demonstrated that sinapic acid and frambinone can regulate the expression of related genes. It has been shown to be a promising representative of the pharmacological constituents of ephedra.

The war between the immune system and the tumor - using immune biomarkers as tracers.

Nowadays, immunotherapy is one of the most promising anti-tumor therapeutic strategy. Specifically, immune-related targets can be used to predict the efficacy and side effects of immunotherapy and monitor the tumor immune response. In the past few decades, increasing numbers of novel immune biomarkers have been found to participate in certain links of the tumor immunity to contribute to the formation of immunosuppression and have entered clinical trials. Here, we systematically reviewed the oncogenesis and progression of cancer in the view of anti-tumor immunity, particularly in terms of tumor antigen expression (related to tumor immunogenicity) and tumor innate immunity to complement the cancer-immune cycle. From the perspective of integrated management of chronic cancer, we also appraised emerging factors affecting tumor immunity (including metabolic, microbial, and exercise-related markers). We finally summarized the clinical studies and applications based on immune biomarkers. Overall, immune biomarkers participate in promoting the development of more precise and individualized immunotherapy by predicting, monitoring, and regulating tumor immune response. Therefore, targeting immune biomarkers may lead to the development of innovative clinical applications.

Parametric Analysis of Free Vibration of Functionally Graded Porous Sandwich Rectangular Plates Resting on Elastic Foundation.

Based on the three-dimensional elasticity theory, the free vibration of functionally graded porous (FGP) sandwich rectangular plates is studied, and a unified solution for free vibration of the plates is proposed in this study. The arbitrary boundary conditions of FGP sandwich rectangular plates are simulated by using the Rayleigh-Ritz method combined with artificial spring theory. The calculation performances of the unified solution for FGP sandwich rectangular plates such as convergence speed and computational efficiency are compared extensively under different displacement functions. In addition, three kinds of elastic foundation (Winkler/Pasternak/Kerr foundations) and three porosity distributions are considered. Some benchmark results and accurate values for the free vibration of FGP sandwich rectangular plates resting on elastic foundations are given. Finally, the effects of diverse structural parameters, elastic foundations with different parameters, and boundary conditions on the free vibration of the FGP sandwich rectangular plates are analyzed.

Hepatic Arterial Infusion Chemotherapy vs Transcatheter Arterial Chemoembolization as Adjuvant Therapy Following Surgery for MVI-Positive Hepatocellular Carcinoma: A Multicenter Propensity Score Matching Analysis.

Background: Microvascular invasion (MVI) is a significant pathological feature in hepatocellular carcinoma (HCC), adjuvant hepatic arterial infusion chemotherapy (a-HAIC) and adjuvant transcatheter arterial chemoembolization (a-TACE), are commonly used for HCC patients with MVI. This study aims to evaluate the efficacies of two adjuvant therapies after surgical treatment for HCC, compare them, and identify the significant factors. Methods: Clinical data from two randomized controlled trials involving HCC patients with MVI after surgical treatment were retrospectively reviewed. Propensity score matching (PSM) analysis was performed to balance baseline differences between patients who received a-HAIC or a-TACE, and control groups who underwent hepatectomy alone. Disease-free survival (DFS) and overall survival (OS) rates were compared. Results: In total of 549 patients were collected from two randomized controlled trials. Using the PSM and Kaplan-Meier method, the median DFS of the a-HAIC, a-TACE, and control groups was 63.2, 21.7, and 11.2 months (P<0.05). The a-HAIC group show significantly better 1-, 3-, and 5-year OS rates compared to the a-TACE and control groups (96.3%, 80.0%, 72.8% vs 84.4%, 57.0%, 29.8% vs 84.5%, 62.8%, 53.4%, P<0.05). But the OS rates of a-TACE and control groups showed no significant difference (P=0.279). Multivariate analysis identified a-HAIC (HR=0.449, P=0.000) and a-TACE (HR=0.633, P=0.007) as independent protective factors. For OS, a-HAIC (HR=0.388, P=0.003) was identified as an independent protective factor, too. Conclusion: Compared to a-TACE and the control group, a-HAIC demonstrated greater benefits in preventing tumor recurrence and improving survival in HCC patients with MVI.

L-fucose and fucoidan alleviate high-salt diet-promoted acute inflammation.

Excessive salt intake is a widespread health issue observed in almost every country around the world. A high salt diet (HSD) has a strong correlation with numerous diseases, including hypertension, chronic kidney disease, and autoimmune disorders. However, the mechanisms underlying HSD-promotion of inflammation and exacerbation of these diseases are not fully understood. In this study, we observed that HSD consumption reduced the abundance of the gut microbial metabolite L-fucose, leading to a more substantial inflammatory response in mice. A HSD led to increased peritonitis incidence in mice, as evidenced by the increased accumulation of inflammatory cells and elevated levels of inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and monocyte chemotactic protein-1 (MCP-1, also known as C-C motif chemokine ligand 2 or CCL2), in peritoneal lavage fluid. Following the administration of broad-spectrum antibiotics, HSD-induced inflammation was abolished, indicating that the proinflammatory effects of HSD were not due to the direct effect of sodium, but rather to HSD-induced alterations in the composition of the gut microbiota. By using untargeted metabolomics techniques, we determined that the levels of the gut microbial metabolite L-fucose were reduced by a HSD. Moreover, the administration of L-fucose or fucoidan, a compound derived from brown that is rich in L-fucose, normalized the level of inflammation in mice following HSD induction. In addition, both L-fucose and fucoidan inhibited LPS-induced macrophage activation in vitro. In summary, our research showed that reduced L-fucose levels in the gut contributed to HSD-exacerbated acute inflammation in mice; these results indicate that L-fucose and fucoidan could interfere with HSD-promotion of the inflammatory response.

Large-Area Flexible Carbon Nanofilms with Synergistically Enhanced Transmittance and Conductivity Prepared by Reorganizing Single-Walled Carbon Nanotube Networks.

Large-area flexible transparent conductive films (TCFs) are highly desired for future electronic devices. Nanocarbon TCFs are one of the most promising candidates, but some of their properties are mutually restricted. Here, a novel carbon nanotube network reorganization (CNNR) strategy, that is, the facet-driven CNNR (FD-CNNR) technique, is presented to overcome this intractable contradiction. The FD-CNNR technique introduces an interaction between single-walled carbon nanotube (SWNT) and Cu─-O. Based on the unique FD-CNNR mechanism, large-area flexible reorganized carbon nanofilms (RNC-TCFs) are designed and fabricated with A3-size and even meter-length, including reorganized SWNT (RSWNT) films and graphene and RSWNT (G-RSWNT) hybrid films. Synergistic improvement in strength, transmittance, and conductivity of flexible RNC-TCFs is achieved. The G-RSWNT TCF shows sheet resistance as low as 69 Ω sq-1 at 86% transmittance, FOM value of 35, and Young's modulus of ≈45 MPa. The high strength enables RNC-TCFs to be freestanding on water and easily transferred to any target substrate without contamination. A4-size flexible smart window is fabricated, which manifests controllable dimming and fog removal. The FD-CNNR technique can be extended to large-area or even large-scale fabrication of TCFs and can provide new insights into the design of TCFs and other functional films.

Tumour organoids and assembloids: Patient-derived cancer avatars for immunotherapy.

BACKGROUND: Organoid technology is an emerging and rapidly growing field that shows promise in studying organ development and screening therapeutic regimens. Although organoids have been proposed for a decade, concerns exist, including batch-to-batch variations, lack of the native microenvironment and clinical applicability. MAIN BODY: The concept of organoids has derived patient-derived tumour organoids (PDTOs) for personalized drug screening and new drug discovery, mitigating the risks of medication misuse. The greater the similarity between the PDTOs and the primary tumours, the more influential the model will be. Recently, 'tumour assembloids' inspired by cell-coculture technology have attracted attention to complement the current PDTO technology. High-quality PDTOs must reassemble critical components, including multiple cell types, tumour matrix, paracrine factors, angiogenesis and microorganisms. This review begins with a brief overview of the history of organoids and PDTOs, followed by the current approaches for generating PDTOs and tumour assembloids. Personalized drug screening has been practised; however, it remains unclear whether PDTOs can predict immunotherapies, including immune drugs (e.g. immune checkpoint inhibitors) and immune cells (e.g. tumour-infiltrating lymphocyte, T cell receptor-engineered T cell and chimeric antigen receptor-T cell). PDTOs, as cancer avatars of the patients, can be expanded and stored to form a biobank. CONCLUSION: Fundamental research and clinical trials are ongoing, and the intention is to use these models to replace animals. Pre-clinical immunotherapy screening using PDTOs will be beneficial to cancer patients. KEY POINTS: The current PDTO models have not yet constructed key cellular and non-cellular components. PDTOs should be expandable and editable. PDTOs are promising preclinical models for immunotherapy unless mature PDTOs can be established. PDTO biobanks with consensual standards are urgently needed.

Patients with hepatocellular carcinoma extrahepatic metastases can benefit from hepatic arterial infusion chemotherapy combined with lenvatinib plus programmed Death-1 inhibitors.

BACKGROUND: Lenvatinib plus Programmed Death-1 (PD-1) inhibitors (LEN-P) have been recommended in China for patients with advanced hepatocellular carcinoma (HCC). However, they provide limited survival benefits to patients with extrahepatic metastases. We aimed to investigate whether combining hepatic arterial infusion chemotherapy (HAIC) with LEN-P could improve its efficacy. MATERIALS AND METHODS: This multi-center cohort study included patients with HCC extrahepatic metastases who received HAIC combined with LEN-P (HAIC-LEN-P group, n=127) or LEN-P alone (n=103) as the primary systemic treatment between January 2019 and December 2022. Baseline data were balanced using a one-to-one propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). RESULTS: After PSM, the HAIC-LEN-P group significantly extended the median overall survival (mOS) and median progression-free survival (mPFS), compared with the LEN-P group (mOS: 27.0 months vs. 9.0 months, P<0.001; mPFS: 8.0 months vs. 3.0 months, P=0.001). After IPTW, the mOS (hazard ratio (HR)=0.384, P<0.001) and mPFS (HR=0.507, P<0.001) were significantly higher in the HAIC-LEN-P group than in the LEN-P group. The HAIC-LEN-P group's objective response rate was twice as high as that of the LEN-P group (PSM cohort: 67.3% vs. 29.1%, P<0.001; IPTW cohort: 66.1% vs. 27.8%, P<0.001). Moreover, the HAIC-LEN-P group exhibited no noticeable increase in the percentages of grade 3 and 4 adverse events compared with the LEN-P group (P>0.05). CONCLUSION: HAIC can improve the efficacy of LEN-P in patients with HCC extrahepatic metastases and may be an alternative treatment for advanced HCC management.

A fungal core effector exploits the OsPUX8B.2-OsCDC48-6 module to suppress plant immunity.

Proteins containing a ubiquitin regulatory X (UBX) domain are cofactors of Cell Division Cycle 48 (CDC48) and function in protein quality control. However, whether and how UBX-containing proteins participate in host-microbe interactions remain unclear. Here we show that MoNLE1, an effector from the fungal pathogen Magnaporthe oryzae, is a core virulence factor that suppresses rice immunity by specifically interfering with OsPUX8B.2. The UBX domain of OsPUX8B.2 is required for its binding to OsATG8 and OsCDC48-6 and controls its 26 S proteasome-dependent stability. OsPUX8B.2 and OsCDC48-6 positively regulate plant immunity against blast fungus, while the high-temperature tolerance heat-shock protein OsBHT, a putative cytoplasmic substrate of OsPUX8B.2-OsCDC48-6, negatively regulates defense against blast infection. MoNLE1 promotes the nuclear migration and degradation of OsPUX8B.2 and disturbs its association with OsBHT. Given the high conservation of MoNLE1 among fungal isolates, plants with broad and durable blast resistance might be generated by engineering intracellular proteins resistant to MoNLE1.

B7-H3 is associated with the armored-cold phenotype and predicts poor immune checkpoint blockade response in melanoma.

Melanoma is the most suitable tumor type for immunotherapy, but not all melanoma patients could respond to immunotherapy. B7 homolog 3 (B7-H3) belongs to the B7 family and is overexpressed in a number of malignant tumors, but the expression pattern of B7-H3 in melanoma has not been well summarized. The expression of B7-H3 was investigated in melanoma and its correlations with features of the tumor microenvironment (TME) by using various public databases, including the Cancer Genome Atlas (TCGA), the GEPIA, and the Human Protein Atlas databases. In addition, the in-house melanoma tissue microarray was applied to validate the results from public databases. Based on the public and in-house cohorts, we found that B7-H3 was overexpressed in melanoma tumor tissues and high B7-H3 expression was related to poor clinical outcome. Moreover, B7-H3 was negatively correlated with levels of tumor-infiltrating lymphocytes (TILs) and positively correlated with collagen infiltration. With clinical translational value, the predictive value of B7-H3 for conventional immunotherapy was detected using the Kaplan-Meier plotter tool, and the results showed that melanoma patients with high B7-H3 expression were insensitive to anti-PD-1 and anti-CTLA-4 immunotherapy. In conclusion, we first investigate the expression of B7-H3 in melanoma and its correlations with the TME features, and indicate B7-H3 as a promising therapeutic target in melanoma patients that are insensitive to conventional immunotherapy.

Conserved immuno-collagenic subtypes predict response to immune checkpoint blockade.

BACKGROUND: Immune checkpoint blockade (ICB) has revolutionized the treatment of various cancer types. Despite significant preclinical advancements in understanding mechanisms, identifying the molecular basis and predictive biomarkers for clinical ICB responses remains challenging. Recent evidence, both preclinical and clinical, underscores the pivotal role of the extracellular matrix (ECM) in modulating immune cell infiltration and behaviors. This study aimed to create an innovative classifier that leverages ECM characteristics to enhance the effectiveness of ICB therapy. METHODS: We analyzed transcriptomic collagen activity and immune signatures in 649 patients with cancer undergoing ICB therapy. This analysis led to the identification of three distinct immuno-collagenic subtypes predictive of ICB responses. We validated these subtypes using the transcriptome data from 9,363 cancer patients from The Cancer Genome Atlas (TCGA) dataset and 1,084 in-house samples. Additionally, novel therapeutic targets were identified based on these established immuno-collagenic subtypes. RESULTS: Our categorization divided tumors into three subtypes: "soft & hot" (low collagen activity and high immune infiltration), "armored & cold" (high collagen activity and low immune infiltration), and "quiescent" (low collagen activity and immune infiltration). Notably, "soft & hot" tumors exhibited the most robust response to ICB therapy across various cancer types. Mechanistically, inhibiting collagen augmented the response to ICB in preclinical models. Furthermore, these subtypes demonstrated associations with immune activity and prognostic predictive potential across multiple cancer types. Additionally, an unbiased approach identified B7 homolog 3 (B7-H3), an available drug target, as strongly expressed in "armored & cold" tumors, relating with poor prognosis. CONCLUSION: This study introduces histopathology-based universal immuno-collagenic subtypes capable of predicting ICB responses across diverse cancer types. These findings offer insights that could contribute to tailoring personalized immunotherapeutic strategies for patients with cancer.

A novel mouse model of familial combined hyperlipidemia and atherosclerosis.

Within the context of residual cardiovascular risk in post-statin era, emerging evidence from epidemiologic and human genetic studies have demonstrated that triglyceride (TG)-rich lipoproteins and their remnants are causally related to cardiovascular risk. While, carriers of loss-of-function mutations of ApoC3 have low TG levels and are protected from cardiovascular disease (CVD). Of translational significance, siRNAs/antisense oligonucleotide (ASO) targeting ApoC3 is beneficial for patients with atherosclerotic CVD. Therefore, animal models of atherosclerosis with both hypercholesterolemia and hypertriglyceridemia are important for the discovery of novel therapeutic strategies targeting TG-lowering on top of traditional cholesterol-lowering. In this study, we constructed a novel mouse model of familial combined hyperlipidemia through inserting a human ApoC3 transgene (hApoC3-Tg) into C57BL/6 J mice and injecting a gain-of-function variant of adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-D377Y concurrently with high cholesterol diet (HCD) feeding for 16 weeks. In the last 10 weeks, hApoC3-Tg mice were orally treated with a combination of atorvastatin (10 mg·kg-1·d-1) and fenofibrate (100 mg·kg-1·d-1). HCD-treated hApoC3-Tg mice demonstrated elevated levels of serum TG, total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). Oral administration of atorvastatin and fenofibrate significantly decreased the plaque sizes of en face aorta, aortic sinus and innominate artery accompanied by improved lipid profile and distribution. In summary, this novel mouse model is of considerable clinical relevance for evaluation of anti-atherosclerotic drugs by targeting both hypercholesterolemia and hypertriglyceridemia.

The relationship between duration of infertility and clinical outcomes of intrauterine insemination for younger women: a retrospective clinical study.

BACKGROUND: The objective of this research was to elucidate the association between the length of infertility and the outcomes of intrauterine insemination (IUI) in women of varying ages - a topic that has been the subject of investigation for numerous years, yet lacks a definitive consensus. METHODS: A retrospective cohort investigation involving 5268 IUI cycles was undertaken at the Reproductive Medicine Center of Nanjing Drum Tower Hospital from 2016 to 2022. Utilizing the smooth fitting curve along with threshold and saturation effect analysis, the correlation between infertility duration and IUI clinical pregnancy rates was discerned. Moreover, patients were bifurcated into two cohorts based on their respective infertility durations. A secondary examination was also performed employing propensity-score matching to mitigate the impact of confounding variables. Subsequent threshold and saturation effect analysis was carried out across various subgroups, segmented on the basis of age differentiation. RESULTS: When the duration of infertility was more than 5 years, the clinical pregnancy rate decreased with the increase of infertility duration (aOR: 0.894, 95%CI: 0.817-0.991, p = 0.043). The multivariate regression analysis suggested that longer duration of infertility (≥ 5 years) was significantly correlated with the lower clinical pregnancy rate (aOR: 0.782, 95% CI: 0.643-0.950, p = 0.01). After the propensity-score matching, the clinical pregnancy rate of women with longer infertility duration were also higher. When the duration of infertility was more than 5 years, the clinical pregnancy rate of women younger than 35 years old decreased with the increase of infertility duration (aOR: 0.906, 95%CI: 0.800-0.998, p = 0.043). CONCLUSIONS: The clinical pregnancy rate and live birth rate of IUI in young women (< 35 years old) who have been infertile for more than 5 years significantly decrease with the prolongation of infertility time. Therefore, for young women who have been infertile for more than 5 years, IUI may not be the best choice.

DDOST is associated with tumor immunosuppressive microenvironment in cervical cancer.

Evidence has revealed that DDOST plays an important role in cancer development and progression. However, there are no reports on functions of DDOST in cervical tumorigenesis. Hence, we investigated the relationship of DDOST with prognosis, mutation, promoter methylation, immune cell infiltration, and drug sensitivity using bioinformatics techniques. Our results demonstrated that DDOST was significantly upregulated in a variety of tumor types and correlated with poor prognosis, including cervical cancer. Cox regression analysis dissected that high DDOST expression was associated with poor survival in cervical cancer patients. Immune infiltration analysis defined that DDOST was negatively correlated with CD8 T cells and NK cells. Strikingly, the sensitivity to multiple drugs was negatively correlated with the expression of DDOST. Therefore, our findings uncovered that DDOST could play an essential role in the tumor microenvironment and tumor immune regulation in cervical cancer, which indicated that DDOST could be a useful biomarker for prognosis and a potential therapeutic target for cancer treatment.