ICBcomb: a comprehensive expression database for immune checkpoint blockade combination therapy.

The success of immune checkpoint blockade (ICB) promotes the immunotherapy to be a new pillar in cancer treatment. However, the low response rate of the ICB therapy limits its application. To increase the response rate and enhance efficacy, the ICB combination therapy has emerged and its clinical trials are increasing. Nevertheless, the gene expression profile and its pattern of ICB combination were not comprehensively studied, which limits the understanding of the ICB combination therapy and the identification of new drugs. Here, we constructed ICBcomb (http://bioinfo.life.hust.edu.cn/ICBcomb/), a comprehensive database, by analyzing the human and mouse expression data of the ICB combination therapy and comparing them between groups treated with ICB, other drugs or their combinations. ICBcomb contains 1399 samples across 29 cancer types involving 52 drugs. It provides a user-friendly web interface for demonstrating the results of the available comparisons in the ICB combination therapy datasets with five functional modules: [1, 2] the 'Dataset/Disease' modules for browsing the expression, enrichment and comparison results in each dataset or disease; [3] the 'Gene' module for inputting a gene symbol and displaying its expression and comparison results across datasets/diseases; [4] the 'Gene Set' module for GSVA/GSEA enrichment analysis on the built-in gene sets and the user-input gene sets in different comparisons; [5] the 'Immune Cell' module for immune cell infiltration comparison between different groups by immune cell abundance analysis. The ICBcomb database provides the first resource for gene expression profile and comparison in ICB combination therapy, which may provide clues for discovering the mechanism of effective combination strategies and new combinatory drugs.

CircTLK1: A novel regulator involved in VSMC phenotypic switching and the developmental process of atherosclerosis.

Phenotypic switching of vascular smooth muscle cells (VSMCs) is essential for atherosclerosis development. Circular RNA (circRNA) is a specific non-coding RNA that is produced as a closed-loop structure in mammals, and its specific expression pattern is closely related to its cell type and tissue. To clarify the roles of circTLK1 in VSMC phenotypic switching, we performed qRT-PCR, immunoblotting, and immunostaining. qRT-PCR revealed that circTLK1 was upregulated in both mouse models of atherosclerosis in vivo and PDGF (platelet-derived growth factor)-BB-induced VSMCs in vitro. Furthermore, the overexpression of circTLK1 promoted PDGF-BB-induced VSMC phenotypic switching. Conversely, experiments performed in vivo demonstrate that the knockdown of SMC-specific circTLK1 led to a reduction in the development of atherosclerosis. The relationship between circTLK1 and miR-513a-3p and Krüppel-like factor 4 (KLF4) was detected by RNA immunoprecipitation (RIP), luciferase reporter assay, RNA pull-down, and RNA fluorescence in situ hybridization (RNA FISH). Mechanistically, circTLK1 acted as a sponge for miR-513a-3p, leading to the upregulation of KLF4, a key transcription factor for phenotypic switching. Targeting the circTLK1/miR-513a-3p/KLF4 axis may provide a potential therapeutic strategy for atherosclerosis.

Novel multidrug resistance genomic islands and transposon carrying blaVEB-1 identified in mcr-positive Aeromonas strains from raw meat in China.

OBJECTIVES: To characterize the genetic environments of ESBL gene blaVEB-1 in mcr-positive Aeromonas strains from raw meat in China. METHODS: Whole genomes of Aeromonas strains were sequenced using the Illumina or Nanopore platforms. Genetic environments of blaVEB-1 were analysed using the BLAST program. RESULTS: The blaVEB-1 gene was detected in five Aeromonas strains carrying the mcr-7-like gene. WGS revealed that all blaVEB-1 genes were located on Aeromonas chromosome, and were carried by two novel different genomic islands named Aeromonas veronii genomic islands AveGI1 and AveGI2, as well as one transposon named Tn7690. AveGI1 is a new member of the Salmonella genomic island 1 family, incorporated into the 3'-end of mnmE (trmE). AveGI2 is a novel genomic island that has a size of 23 180 bp and is incorporated into the 3'-end of syd. The MDR regions of AveGI1 and AveGI2 are two different class 1 integrons containing 10 and five resistance genes, respectively. Tn7690 is a Tn1722 derivative containing In4-type integron and Tn5393, which harbours 10 resistance genes and integrates into different positions on the chromosomes of three strains with the capacity for mobility. CONCLUSIONS: We report chromosomally located novel MDR genomic islands and transposon that carry blaVEB-1 in mcr-positive Aeromonas strains. These genetic elements may mediate the spread of blaVEB-1 in Aeromonas, and may also evolve by capturing new antimicrobial resistance genes or other mobile genetic elements.

Cancer-associated fibroblast-derived extracellular vesicles promote lymph node metastases in oral cavity squamous cell carcinoma by encapsulating ITGB1 and BMI1.

BACKGROUND: Extracellular vesicles (EVs) have been revealed to facilitate the development of oral squamous cavity cell carcinoma (OCSCC), while its supporting role in lymph node metastases is under continuous investigation. This study aimed to examine the function of cancer-associated fibroblasts (CAF)-derived EVs (CAF-EVs) during lymph node metastasis in OCSCC and the mechanisms. METHODS: CAF were isolated from OCSCC tissues of patients, and CAF-EVs were extracted and identified. EdU, colony formation, wound healing, and Transwell assays were performed. The OCSCC cells before and after CAF-EVs treatment were injected into mice to probe the effects of CAF-EVs on tumor growth and lymph node metastasis, respectively. The effect of CAF-EVs treatment on transcriptome changes in OCSCC cells was analyzed. Clinical data of patients with OCSCC were analyzed to determine the prognostic significance of the selected genes. Finally, loss-of-function assays were conducted to corroborate the involvement of polycomb complex protein BMI-1 (BMI1) and integrin beta1 (ITGB1). RESULTS: CAF-EVs promoted the malignant behavior of OCSCC cells and accelerated tumor growth and lymph node metastasis in mice. CAF-EVs significantly increased the expression of BMI1 and ITGB1, and the expression of BMI1 and ITGB1 was negatively correlated with the overall survival and relapse-free survival of OCSCC patients. Knockdown of BMI1 or ITGB1 in OCSCC cells abated the promoting effects of CAF-EVs in vitro and in vivo. CONCLUSION: CAF-EVs elicited the metastasis-promoting properties in OCSCC by elevating BMI1 and ITGB1, suggesting that BMI1 and ITGB1 could be potential biomarkers and therapeutic targets for OCSCC.

Metformin-induced PCSK9 inhibition further decreases LDL-C following statin treatment in patients with coronary artery disease and without diabetes.

In vitro investigations have established metformin's capacity to downregulate PCSK9 expression, suggesting a potential beneficial effect on atherogenic lipoprotein particles when combined with metformin therapy. Our objective was to assess whether metformin could mitigate statin-induced adverse effects on PCSK9, thereby improving lipid profiles in patients with coronary artery disease (CAD) but without diabetes. Employing an open-label, placebo-controlled, randomized trial, we randomized patients with CAD but without diabetes into CLA (Cholesterol-Lowering Agents alone: atorvastatin+/-ezetimibe, n=38) and Met+CLA groups (metformin plus CLA, n=33) at a 1:1 ratio. The primary endpoint was the therapeutic impact of one-month metformin combination treatment on LDL-C and PCSK9 levels. Baseline LDL-C and PCSK9 levels were 76.18 mg·dL-1 and 80.54 ng·mL-1, respectively. After one month, metformin significantly reduced LDL-C (-20.81%, P<0.001), enabling 72% of patients to attain guideline-recommended LDL-C goals. Noteworthy reductions in PCSK9 levels (-15.03%, P<0.001) were observed. Moreover, Met+CLA markedly reduced LDL particle number more than CLA alone (-10.65% vs 1.45%, P=0.009), primarily due to diminished small-dense LDL particle count. Mechanistically, our study demonstrated metformin's inhibition of statin-induced PCSK9 expression in human hepatocellular cells. In summary, a one-month metformin combination regimen reduced LDL-C levels in patients with CAD but without diabetes by inhibiting PCSK9 expression.

Simple and field-adapted species identification of biological specimens combining multiplex multienzyme isothermal rapid amplification, lateral flow dipsticks, and universal primers for initial rapid screening without standard PCR laboratory.

Species identification of biological specimens can provide the valuable clues and accelerate the speed of prosecution material processing for forensic investigation, especially when the case scene is inaccessible and the physical evidence is cumbersome. Thus, establishing a rapid, simple, and field-adapted species identification method is crucial for forensic scientists, particularly as first-line technology at the crime scene for initial rapid screening. In this study, we established a new field-adapted species identification method by combining multiplex multienzyme isothermal rapid amplification (MIRA), lateral flow dipstick (LFD) system, and universal primers. Universal primers targeting COX I and COX II genes were used in multiplex MIRA-LFD system for seven species identification, and a dedicated MIRA-LFD system primer targeting CYT B gene was used to detect the human material. DNA extraction was performed by collecting DNA directly from the centrifuged supernatant. Our study found that the entire amplification process took only 15 min at 37 °C and the results of LFDs could be visually observed after 10 min. The detection sensitivity of human material could reach 10 pg, which is equivalent to the detection of single cell. Different common animal samples mixed at the ratio of 1 ng:1 ng, 10 ng:1 ng, and 1 ng:10 ng could be detected successfully. Furthermore, the damaged and degraded samples could also be detected. Therefore, the convenient, feasible, and rapid approach for species identification is suitable for popularization as first-line technology at the crime scene for initial rapid screening and provides a great convenient for forensic application.

Metabolomics efficiently discriminates monozygotic twins in peripheral blood.

Monozygotic (MZ) twins cannot be distinguished using conventional forensic STR typing because they present identical STR genotypings. However, MZ twins do not always live in the same environment and often have different dietary and other lifestyle habits. Metabolic profiles are deyermined by individual characteristics and are also influenced by the environment in which they live. Therefore, they are potential markers capable of identifying MZ twins. Moreover, the production of proteins varies from organism to organism and is influenced by both the physiological state of the body and the external environment. Hence, we used metabolomics and proteomics to identify metabolites and proteins in peripheral blood to discriminate MZ twins. We identified 1749 known metabolites and 622 proteins in proteomic analysis. The metabolic profiles of four pairs of MZ twins revealed minor differences in intra-MZ twins and major differences in inter-MZ twins. Each pair of MZ twins exhibited distinct characteristics, and four metabolites-methyl picolinate, acesulfame, paraxanthine, and phenylbenzimidazole sulfonic acid-were observed in all four MZ twin pairs. These four differential exogenous metabolites conincidently show that the different external environments and life styles can be well distinguished by metabolites, considering that twins do not all have the same eating habits and living environments. Moreover, MZ twins showed different protein profiles in serum but not in whole blood. Thus, our results indicate that differential metabolites provide potential biomarkers for the personal identification of MZ twins in forensic medicine.

Evolutionary history of the angiosperm flora of China.

High species diversity may result from recent rapid speciation in a 'cradle' and/or the gradual accumulation and preservation of species over time in a 'museum'. China harbours nearly 10% of angiosperm species worldwide and has long been considered as both a museum, owing to the presence of many species with hypothesized ancient origins, and a cradle, as many lineages have originated as recent topographic changes and climatic shifts-such as the formation of the Qinghai-Tibetan Plateau and the development of the monsoon-provided new habitats that promoted remarkable radiation. However, no detailed phylogenetic study has addressed when and how the major components of the Chinese angiosperm flora assembled to form the present-day vegetation. Here we investigate the spatio-temporal divergence patterns of the Chinese flora using a dated phylogeny of 92% of the angiosperm genera for the region, a nearly complete species-level tree comprising 26,978 species and detailed spatial distribution data. We found that 66% of the angiosperm genera in China did not originate until early in the Miocene epoch (23 million years ago (Mya)). The flora of eastern China bears a signature of older divergence (mean divergence times of 22.04-25.39 Mya), phylogenetic overdispersion (spatial co-occurrence of distant relatives) and higher phylogenetic diversity. In western China, the flora shows more recent divergence (mean divergence times of 15.29-18.86 Mya), pronounced phylogenetic clustering (co-occurrence of close relatives) and lower phylogenetic diversity. Analyses of species-level phylogenetic diversity using simulated branch lengths yielded results similar to genus-level patterns. Our analyses indicate that eastern China represents a floristic museum, and western China an evolutionary cradle, for herbaceous genera; eastern China has served as both a museum and a cradle for woody genera. These results identify areas of high species richness and phylogenetic diversity, and provide a foundation on which to build conservation efforts in China.

Microecological characteristics of water bodies/sediments and microbial remediation strategies after 50 years of pollution exposure in ammunition destruction sites in China.

The effects of long-term ammunition pollution on microecological characteristics were analyzed to formulate microbial remediation strategies. Specifically, the response of enzyme systems, N/O stable isotopes, ion networks, and microbial community structure/function levels were analyzed in long-term (50 years) ammunition-contaminated water/sediments from a contamination site, and a compound bacterial agent capable of efficiently degrading trinitrotoluene (TNT) while tolerating many heavy metals was selected to remediate the ammunition-contaminated soil. The basic physical and chemical properties of the water/sediment (pH (up: 0.57-0.64), nitrate (up: 1.31-4.28 times), nitrite (up: 1.51-5.03 times), and ammonium (up: 7.06-70.93 times)) were changed significantly, and the significant differences in stable isotope ratios of N and O (nitrate nitrogen) confirmed the degradability of TNT by indigenous microorganisms exposed to long-term pollution. Heavy metals, such as Pb, Zn, Cu, Cd, Cs, and Sb, have synergistic toxic effects in ammunition-contaminated sites, and significantly decreased the microbial diversity and richness in the core pollution area. However, long-term exposure in the edge pollution area induced microorganisms to use TNT as a carbon and nitrogen sources for life activities and growth and development. The Bacteroidales microbial group was significantly inhibited by ammunition contamination, whereas microorganisms such as Proteobacteria, Acidobacteriota, and Comamonadaceae gradually adapted to this environmental stress by regulating their development and stress responses. Ammunition pollution significantly affected DNA replication and gene regulation in the microecological genetic networks and increased the risk to human health. Mg and K were significantly involved in the internal mechanism of microbial transport, enrichment, and metabolism of TNT. Nine strains of TNT-utilizing microbes were screened for efficient TNT degradation and tolerance to typical heavy metals (copper, zinc and lead) found in contaminated sites, and a compound bacterial agent prepared for effective repair of ammunition-contaminated soil significantly improved the soil ecological environment.

TREM2 promotes cholesterol uptake and foam cell formation in atherosclerosis.

Disordered lipid accumulation in the arterial wall is a hallmark of atherosclerosis. Previous studies found that the expression of triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane receptor of the immunoglobulin family, is increased in mouse atherosclerotic aortic plaques. However, it remains unknown whether TREM2 plays a role in atherosclerosis. Here we investigated the role of TREM2 in atherosclerosis using ApoE knockout (ApoE-/-) mouse models, primary vascular smooth muscle cells (SMCs), and bone marrow-derived macrophages (BMDMs). In ApoE-/- mice, the density of TREM2-positive foam cells in aortic plaques increased in a time-dependent manner after the mice were fed a high-fat diet (HFD). Compared with ApoE-/- mice, the Trem2-/-/ApoE-/- double-knockout mice showed significantly reduced atherosclerotic lesion size, foam cell number, and lipid burden degree in plaques after HFD feeding. Overexpression of TREM2 in cultured vascular SMCs and macrophages exacerbates lipid influx and foam cell formation by upregulating the expression of the scavenger receptor CD36. Mechanistically, TREM2 inhibits the phosphorylation of p38 mitogen-activated protein kinase and peroxisome proliferator activated-receptor gamma (PPARγ), thereby increasing PPARγ nuclear transcriptional activity and subsequently promoting the transcription of CD36. Our results indicate that TREM2 exacerbates atherosclerosis development by promoting SMC- and macrophage-derived foam cell formation by regulating scavenger receptor CD36 expression. Thus, TREM2 may act as a novel therapeutic target for the treatment of atherosclerosis.

Detection of Arsenic(V) by Fluorescence Sensing Based on Chlorin e6-Copper Ion.

The high toxicity of arsenic (As) can cause irreversible harm to the environment and human health. In this study, the chlorin e6 (Ce6), which emits fluorescence in the infrared region, was introduced as the luminescence center, and the addition of copper ion (Cu2+) and As(V) provoked a regular change in fluorescence at 652 nm, whereas that of As(III) was 665 nm, which was used to optionally detect Cu2+, arsenic (As(III), and As(V)). The limit of detection (LOD) values were 0.212 µM, 0.089 ppm, and 1.375 ppb for Cu2+, As(III), and As(V), respectively. The developed method can be used to determine Cu2+ and arsenic in water and soil with good sensitivity and selectivity. The 1:1 stoichiometry of Ce6 with Cu2+ was obtained from the Job plot that was developed from UV-visible spectra. The binding constants for Cu2+ and As(V) were established to be 1.248 × 105 M-1 and 2.35 × 1012 M-2, respectively, using B-H (Benesi-Hildebrand) plots. Fluorescence lifetimes, B-H plots, FT-IR, and 1H-NMR were used to postulate the mechanism of Cu2+ fluorescence quenching and As(V) fluorescence restoration and the interactions of the two ions with the Ce6 molecule.

TCR repertoire landscape reveals macrophage-mediated clone deletion in endotoxin tolerance.

BACKGROUND: Endotoxin tolerance (ET) is a protective mechanism in the process of sepsis, septic shock, and their sequelae including uncontrolled inflammation. Accumulating evidence has shown that peripheral T cells contribute to the induction of ET. However, what and how T-cell development contributes to ET inductions remain unclear. METHODS: Mice were intraperitoneally injected with LPS at a concentration of 5 mg/kg to establish an LPS tolerance model and were divided into two groups: a group examined 72 h after LPS injection (72-h group) and a group examined 8 days after LPS injection (8-day group). Injection of PBS was used as a control. We performed high-throughput sequencing to analyze the characteristics and changes of CD4+SP TCRß CDR3 repertoires with respect to V direct to J rearrangement during the ET induction. Moreover, the proportion and proliferation, as well as surface molecules such as CD80 and CD86, of F4/80+ macrophages were analyzed using FCM. Furthermore, ACT assay was designed and administered by the tail vein into murine LPS-induced mouse model to evaluate the role of F4/80+ macrophages on the development of CD4+SP thymocytes in ET condition. RESULTS: We found that the frequency and characteristics of the TCRß chain CDR3 changed obviously under condition of ET, indicating the occurrence of TCR rearrangement and thymocyte diversification. Moreover, the absolute numbers of F4/80+ macrophages, but not other APCs, were increased in thymic medulla at 72-h group, accompanied by the elevated function-related molecules of F4/80+ macrophages. Furthermore, adoptively transferred OVA332-339 peptide-loaded macrophages into Rag-1-/- mice induced the clone deletion of OVA-specific CD4+SP, thereby ameliorating the pathology in lung tissue in LPS challenge. CONCLUSIONS: These data reveal that the frequency and characteristics of the TCRß chain CDR3 undergo dynamic programming under conditions of LPS tolerance. Furthermore, the peripheral macrophages may be a key factor which carry peripheral antigen to thymic medulla and affect the negative selection of T-cell population, thereby contributing to the formation of ET. These results suggest that the clone selection in thymus in ET may confer protection against microbial sepsis.

Magnetic bead-based separation of sperm cells from semen-vaginal fluid mixed stains using an anti-ACRBP antibody.

Forensic DNA analysis of semen-vaginal fluid mixed stains is essential and necessary in sexual assault cases. Here, we used a magnetic bead conjugated acrosin binding protein (ACRBP) antibody to separate and enrich sperm cells from mixed stains. Previously, western blotting indicated that ACRBP was specifically expressed in sperm cells, but not in female blood and epithelial cells, while immunofluorescence data showed ACRBP was localized to the acrosome in sperm cells. In our study, sperm were separated from mixed samples at three sperm cell/female buccal epithelial cell ratios (103:103; 103:104; and 103:105) using a magnetic bead conjugated ACRBP antibody. Subsequently, 23 autosomal short tandem repeat (STR) loci were amplified using the Huaxia™ Platinum PCR Amplification System and genotyped using capillary electrophoresis. The genotyping success rate for STR loci was 90% when the sperm to female buccal epithelial cell ratio was > 1:100 in mixed samples. Our results suggest that the magnetic bead conjugated ACRBP antibody is effective for isolating sperm cells in sexual assault cases.

Preparation of Alcohol Dehydrogenase-Zinc Phosphate Hybrid Nanoflowers through Biomimetic Mineralization and Its Application in the Inhibitor Screening.

A biomimetic mineralization method was used in the facile and rapid preparation of nanoflowers for immobilizing alcohol dehydrogenase (ADH). The method mainly uses ADH as an organic component and zinc phosphate as an inorganic component to prepare flower-like ADH/Zn3(PO4)2 organic-inorganic hybrid nanoflowers (HNFs) with the high specific surface area through a self-assembly process. The synthesis conditions of the ADH HNFs were optimized and its morphology was characterized. Under the optimum enzymatic reaction conditions, the Michaelis-Menten constant (Km) of ADH HNFs (ß-NAD+ as substrate) was measured to be 3.54 mM, and the half-maximal inhibitory concentration (IC50) of the positive control ranitidine (0.2-0.8 mM) was determined to be 0.49 mM. Subsequently, the inhibitory activity of natural medicine Penthorum chinense Pursh and nine small-molecule compounds on ADH was evaluated using ADH HNFs. The inhibition percentage of the aqueous extract of P. chinense is 57.9%. The vanillic acid, protocatechuic acid, gallic acid, and naringenin have obvious inhibitory effects on ADH, and their percentages of inhibition are 55.1%, 68.3%, 61.9%, and 75.5%, respectively. Moreover, molecular docking analysis was applied to explore the binding modes and sites of the four most active small-molecule compounds to ADH. The results of this study can broaden the application of immobilized enzymes through biomimetic mineralization, and provide a reference for the discovery of ADH inhibitors from natural products.

Engrailed homeobox 1 transcriptional regulation of COL22A1 inhibits nasopharyngeal carcinoma cell senescence through the G1/S phase arrest.

EN1 is well known as a transcription factor in other tumours, but its role in NPC is unclear. In this study, we first used bioinformatics to analyse GEO data to obtain the differentially expressed gene EN1, and subsequently verified that EN1 was highly expressed in nasopharyngeal carcinoma cells by tissue microarrays as well as cell lines. Further, we down-regulated the expression of EN1 in cells for RNA sequencing. The analysis of sequencing results using KEGG and GO revealed significant changes in cell proliferation and cycle function after downregulation of EN1. Meanwhile, we found that cells underwent senescence after inhibition of EN1 under electron microscopy and the SA-ß-gal assays. Based on the sequencing results, we verified that EN1 can promote the proliferation and cycle of NPC cells in cell function experiments and animal experiments. To investigate how EN1 affects cell senescence, we found that EN1 transcriptional regulation of COL22A1 regulated cell proliferation and cycle via CDK4/6-cyclin D1-Rb signalling pathway by dual luciferase reporter, Immunoblotting and rescue experiment. Accordingly, we uncovered that EN1 could serve as a target for the regulation of senescence in NPC.

MicroRNA-7 overexpression positively regulates the CD8+ SP cell development via targeting PIK3R1.

microRNA-7 (miR-7), a distinct miRNA family member, has been reported to be involved in the biological functions of immune cells. However, the potential role of miR-7 in the CD8+ T cell development remains to be elucidated. In this study, we estimated the potential effects of miR-7 overexpression in the thymic CD8+ SP cell development using miR-7 overexpression mice. Our results showed that compared with those in control wild type (WT) mice, the volume, weight and total cell numbers of thymus in miR-7 overexpression (OE) mice increased significantly. The absolute cell number of CD8+ SP cells in miR-7 OE mice increased and its ability of activation and proliferation enhanced. Futhermore, we clarified that miR-7 overexpression had an intrinsic promote role in CD8+ SP cell development by adoptive cell transfer assay. Mechanistically, the expression level of PIK3R1, a target of miR-7, decreased significantly in CD8+ SP cells of miR-7 OE mice. Moreover, the expression level of phosphorylated (p)-AKT and p-ERK changed inversely and indicating that miR-7 overexpression impaired the balance of AKE and ERK pathways. In summary, our work reveals an essential role of miR-7 in promoting CD8+ SP cell development through the regulation of PIK3R1 and balance of AKT and ERK pathways.

An update on the phenotypic switching of vascular smooth muscle cells in the pathogenesis of atherosclerosis.

Vascular smooth muscle cells (VSMCs) are involved in phenotypic switching in atherosclerosis. This switching is characterized by VSMC dedifferentiation, migration, and transdifferentiation into other cell types. VSMC phenotypic transitions have historically been considered bidirectional processes. Cells can adopt a physiological contraction phenotype or an alternative "synthetic" phenotype in response to injury. However, recent studies, including lineage tracing and single-cell sequencing studies, have shown that VSMCs downregulate contraction markers during atherosclerosis while adopting other phenotypes, including macrophage-like, foam cell, mesenchymal stem-like, myofibroblast-like, and osteochondral-like phenotypes. However, the molecular mechanism and processes regulating the switching of VSMCs at the onset of atherosclerosis are still unclear. This systematic review aims to review the critical outstanding challenges and issues that need further investigation and summarize the current knowledge in this field.

The effectiveness of case management for cancer patients: an umbrella review.

BACKGROUND: Case management (CM) is widely utilized to improve health outcomes of cancer patients, enhance their experience of health care, and reduce the cost of care. While numbers of systematic reviews are available on the effectiveness of CM for cancer patients, they often arrive at discordant conclusions that may confuse or mislead the future case management development for cancer patients and relevant policy making. We aimed to summarize the existing systematic reviews on the effectiveness of CM in health-related outcomes and health care utilization outcomes for cancer patient care, and highlight the consistent and contradictory findings. METHODS: An umbrella review was conducted followed the Joanna Briggs Institute (JBI) Umbrella Review methodology. We searched MEDLINE (Ovid), EMBASE (Ovid), PsycINFO, CINAHL, and Scopus for reviews published up to July 8th, 2022. Quality of each review was appraised with the JBI Critical Appraisal Checklist for Systematic Reviews and Research Syntheses. A narrative synthesis was performed, the corrected covered area was calculated as a measure of overlap for the primary studies in each review. The results were reported followed the Preferred reporting items for overviews of systematic reviews checklist. RESULTS: Eight systematic reviews were included. Average quality of the reviews was high. Overall, primary studies had a slight overlap across the eight reviews (corrected covered area = 4.5%). No universal tools were used to measure the effect of CM on each outcome. Summarized results revealed that CM were more likely to improve symptom management, cognitive function, hospital (re)admission, treatment received compliance, and provision of timely treatment for cancer patients. Overall equivocal effect was reported on cancer patients' quality of life, self-efficacy, survivor status, and satisfaction. Rare significant effect was reported on cost and length of stay. CONCLUSIONS: CM showed mixed effects in cancer patient care. Future research should use standard guidelines to clearly describe details of CM intervention and its implementation. More primary studies are needed using high-quality well-powered designs to provide solid evidence on the effectiveness of CM. Case managers should consider applying validated and reliable tools to evaluate effect of CM in multifaced outcomes of cancer patient care.

Microenvironment components and spatially resolved single-cell transcriptome atlas of breast cancer metastatic axillary lymph nodes.

As an indicator of clinical prognosis, lymph node metastasis of breast cancer has drawn great attention. Many reports have revealed the characteristics of metastatic breast cancer cells, however, the effect of breast cancer cells on the microenvironment components of lymph nodes and spatial transcriptome atlas remains unclear. In this study, by integrating single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, we investigate the transcriptional profiling of six surgically excised lymph node samples and the spatial organization of one positive lymph node. We identify the existence of osteoclast-like giant cells (OGC) which have high expressions of CD68 and CD163, the biomarkers of tumor-associated macrophages (TAMs). Through a spatially resolved transcriptomic method, we find that OGCs are scattered among metastatic breast cancer cells. In the lymph node microenvironment with breast cancer cell infiltration, TAMs are enriched in protumoral pathways including NF-κB signaling pathways and NOD-like receptor signaling pathways. Further subclustering demonstrates the potential differentiation trajectory in which macrophages develop from a state of active chemokine production to a state of active lymphocyte activation. This study is the first to integrate scRNA-seq and spatial transcriptomics in the tumor microenvironment of axillary lymph nodes, offering a systematic approach to delve into breast cancer lymph node metastasis.

Colchicine for Secondary Prevention of Coronary Artery Disease: A Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: Colchicine has become prominent as an anti-inflammatory therapy for secondary cardiovascular prevention in patients with coronary artery disease (CAD). This meta-analysis was performed to evaluate the efficacy and safety of colchicine in patients with CAD. METHODS: Randomised controlled trials (RCTs) that compare major adverse cardiovascular events (MACEs) between patients with CAD randomised to colchicine versus placebo (or no colchicine) were included. Random effect risk ratios (RRs) were calculated for clinical outcomes. RESULTS: A total of 12,071 patients in seven RCTs were included in the meta-analysis. Compared with placebo or no colchicine, colchicine was associated with a significantly lower incidence of MACEs (RR 0.64, 95% CI 0.51-0.80, p<0.01). The reduction in MACEs in the colchicine group was driven by statistically significant reductions in the incidence of myocardial ischaemia (RR 0.74, 95% CI 0.58-0.95, p=0.02), coronary revascularisation (RR 0.61, 95% CI 0.42-0.89, p=0.01), and stroke (RR 0.48, 95% CI 0.28-0.83, p=0.01). However, there was no statistically significant difference for cardiovascular death (RR 0.82, 95% CI 0.55-1.22, p=0.33). All-cause and non-cardiovascular mortality, gastrointestinal events, infection, and cancer were not significantly different between the colchicine and control groups. CONCLUSIONS: Colchicine is a reasonably efficacious and safe drug that could be successfully utilised for the secondary prevention of CAD.