Huazhong University of Science and Technology Hospital

BACKGROUND: Recently, the potential role of gut microbiome in metabolic diseases has been revealed, especially in cardiovascular diseases. Hypertension is one of the most prevalent cardiovascular diseases worldwide, yet whether gut microbiota dysbiosis participates in the development of hypertension remains largely unknown. To investigate this issue, we carried out comprehensive metagenomic and metabolomic analyses in a cohort of 41 healthy controls, 56 subjects with pre-hypertension, 99 individuals with primary hypertension, and performed fecal microbiota transplantation from patients to germ-free mice. RESULTS: Compared to the healthy controls, we found dramatically decreased microbial richness and diversity, Prevotella-dominated gut enterotype, distinct metagenomic composition with reduced bacteria associated with healthy status and overgrowth of bacteria such as Prevotella and Klebsiella, and disease-linked microbial function in both pre-hypertensive and hypertensive populations. Unexpectedly, the microbiome characteristic in pre-hypertension group was quite similar to that in hypertension. The metabolism changes of host with pre-hypertension or hypertension were identified to be closely linked to gut microbiome dysbiosis. And a disease classifier based on microbiota and metabolites was constructed to discriminate pre-hypertensive and hypertensive individuals from controls accurately. Furthermore, by fecal transplantation from hypertensive human donors to germ-free mice, elevated blood pressure was observed to be transferrable through microbiota, and the direct influence of gut microbiota on blood pressure of the host was demonstrated. CONCLUSIONS: Overall, our results describe a novel causal role of aberrant gut microbiota in contributing to the pathogenesis of hypertension. And the significance of early intervention for pre-hypertension was emphasized.

OBJECTIVE. The objective of our study was to determine the misdiagnosis rate of radiologists for coronavirus disease 2019 (COVID-19) and evaluate the performance of chest CT in the diagnosis and management of COVID-19. The CT features of COVID-19 are reported and compared with the CT features of other viruses to familiarize radiologists with possible CT patterns.

Introduction Initial and Boundary Conditions for Lattice Boltzmann Method Improved Lattice Boltzmann Models Sample Applications of LBE for Isothermal Flows LBE for Low Speed Flows with Heat Transfer LBE for Compressible Flows LBE for Multiphase and Multi-component Flows LBE for Microscale Gas Flows Other Applications of LBE.

Clinical and experimental evidence has shown that tumor-associated macrophages promote cancer initiation and progression. However, the macrophage-derived molecular determinants that regulate colorectal cancer metastasis have not been fully characterized. Here, we demonstrate that M2 macrophage-regulated colorectal cancer cells' migration and invasion is dependent upon M2 macrophage-derived exosomes (MDE). MDE displayed a high expression level of miR-21-5p and miR-155-5p, and MDE-mediated colorectal cancer cells' migration and invasion depended on these two miRNAs. Mechanistically, miR-21-5p and miR-155-5p were transferred to colorectal cancer cells by MDE and bound to the BRG1 coding sequence, downregulating expression of BRG1, which has been identified as a key factor promoting the colorectal cancer metastasis, yet is downregulated in metastatic colorectal cancer cells. Collectively, these findings show that M2 macrophages induce colorectal cancer cells' migration and invasion and provide significant plasticity of BRG1 expression in response to tumor microenvironments during malignant progression. This dynamic and reciprocal cross-talk between colorectal cancer cells and M2 macrophages provides a new opportunity for the treatment of metastatic colorectal cancer. SIGNIFICANCE: These findings report a functional role for miRNA-containing exosomes derived from M2 macrophages in regulating migration and invasion of colorectal cancer cells.

UNLABELLED: Innate immunity plays a crucial role in the response to sterile inflammation such as liver ischemia/reperfusion (I/R) injury. The initiation of liver I/R injury results in the release of damage-associated molecular patterns, which trigger an innate immune and inflammatory cascade through pattern recognition receptors. Neutrophils are recruited to the liver after I/R and contribute to organ damage and innate immune and inflammatory responses. Formation of neutrophil extracellular traps (NETs) has been recently found in response to various stimuli. However, the role of NETs during liver I/R injury remains unknown. We show that NETs form in the sinusoids of ischemic liver lobes in vivo. This was associated with increased NET markers, serum level of myeloperoxidase-DNA complexes, and tissue level of citrullinated-histone H3 compared to control mice. Treatment with peptidyl-arginine-deiminase 4 inhibitor or DNase I significantly protected hepatocytes and reduced inflammation after liver I/R as evidenced by inhibition of NET formation, indicating the pathophysiological role of NETs in liver I/R injury. In vitro, NETs increase hepatocyte death and induce Kupffer cells to release proinflammatory cytokines. Damage-associated molecular patterns, such as High Mobility Group Box 1 and histones, released by injured hepatocytes stimulate NET formation through Toll-like receptor (TLR4)- and TLR9-MyD88 signaling pathways. After neutrophil depletion in mice, the adoptive transfer of TLR4 knockout or TLR9 knockout neutrophils confers significant protection from liver I/R injury with a significant decrease in NET formation. In addition, we found inhibition of NET formation by the peptidyl-arginine-deiminase 4 inhibitor and that DNase I reduces High Mobility Group Box 1 and histone-mediated liver I/R injury. CONCLUSION: Damage-associated molecular patterns released during liver I/R promote NET formation through the TLR signaling pathway. Development of NETs subsequently exacerbates organ damage and initiates inflammatory responses during liver I/R.

Abstract The main challenges for programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) checkpoint blockade lie in a lack of sufficient T cell infiltration, tumor immunosuppressive microenvironment, and the inadequate tumor accumulation and penetration of anti-PD-1/PD-L1 antibody. Resetting tumor-associated macrophages (TAMs) is a promising strategy to enhance T-cell antitumor immunity and ameliorate tumor immunosuppression. Here, mannose-modified macrophage-derived microparticles (Man-MPs) loading metformin (Met@Man-MPs) are developed to efficiently target to M2-like TAMs to repolarize into M1-like phenotype. Met@Man-MPs-reset TAMs remodel the tumor immune microenvironment by increasing the recruitment of CD8 + T cells into tumor tissues and decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells. More importantly, the collagen-degrading capacity of Man-MPs contributes to the infiltration of CD8 + T cells into tumor interiors and enhances tumor accumulation and penetration of anti-PD-1 antibody. These unique features of Met@Man-MPs contribute to boost anti-PD-1 antibody therapy, improving anticancer efficacy and long-term memory immunity after combination treatment. Our results support Met@Man-MPs as a potential drug to improve tumor resistance to anti-PD-1 therapy.

Abstract Because of their exotic electronic properties and abundant active sites, two-dimensional (2D) materials have potential in various fields. Pursuing a general synthesis methodology of 2D materials and advancing it from the laboratory to industry is of great importance. This type of method should be low cost, rapid and highly efficient. Here, we report the high-yield synthesis of 2D metal oxides and hydroxides via a molten salts method. We obtained a high-yield of 2D ion-intercalated metal oxides and hydroxides, such as cation-intercalated manganese oxides (Na 0.55 Mn 2 O 4 ·1.5H 2 O and K 0.27 MnO 2 ·0.54H 2 O), cation-intercalated tungsten oxides (Li 2 WO 4 and Na 2 W 4 O 13 ), and anion-intercalated metal hydroxides (Zn 5 (OH) 8 (NO 3 ) 2 ·2H 2 O and Cu 2 (OH) 3 NO 3 ), with a large lateral size and nanometre thickness in a short time. Using 2D Na 2 W 4 O 13 as an electrode, a high performance electrochemical supercapacitor is achieved. We anticipate that our method will enable new path to the high-yield synthesis of 2D materials for applications in energy-related fields and beyond.

Background: Fundc1 (FUN14 domain containing 1), an outer mitochondrial membrane protein, is important for mitophagy and mitochondria-associated endoplasmic reticulum membranes (MAMs). The roles of Fundc1 and MAMs in diabetic hearts remain unknown. The aims of this study, therefore, were to determine whether the diabetes mellitus–induced Fundc1 expression could increase MAM formation, and whether disruption of MAM formation improves diabetic cardiac function. Methods: Levels of FUNDC1 were examined in the hearts from diabetic patients and nondiabetic donors. Levels of Fundc1-induced MAMs and mitochondrial and heart function were examined in mouse neonatal cardiomyocytes exposed to high glucose (HG, 30 mmol/L d -glucose for 48 hours), and in streptozotocin-treated cardiac-specific Fundc1 knockout mice and cardiac-specific Fundc1 knockout diabetic Akita mice, as well. Results: FUNDC1 levels were significantly elevated in cardiac tissues from diabetic patients in comparison with those from nondiabetic donors. In cultured mouse neonatal cardiomyocytes, HG conditions increased levels of Fundc1, the inositol 1,4,5-trisphosphate type 2 receptor (Ip 3 r2), and MAMs. Genetic downregulation of either Fundc1 or Ip 3 r2 inhibited MAM formation, reduced endoplasmic reticulum-mitochondrial Ca 2+ flux, and improved mitochondrial function in HG-treated cardiomyocytes. Consistently, adenoviral overexpression of Fundc1 promoted MAM formation, mitochondrial Ca 2+ increase, and mitochondrial dysfunction in cardiomyocytes exposed to normal glucose (5.5 mmol/L d -glucose). In comparison with nondiabetic controls, levels of Fundc1, Ip 3 r2, and MAMs were significantly increased in hearts from streptozotocin-treated mice and Akita mice. Furthermore, in comparison with control hearts, diabetes mellitus markedly increased coimmunoprecipitation of Fundc1 and Ip 3 r2. The binding of Fundc1 to Ip 3 r2 inhibits Ip 3 r2 ubiquitination and proteasome-mediated degradation. Cardiomyocyte-specific Fundc1 deletion ablated diabetes mellitus–induced MAM formation, prevented mitochondrial Ca 2+ increase, mitochondrial fragmentation, and apoptosis with improved mitochondrial functional capacity and cardiac function. In mouse neonatal cardiomyocytes, HG suppressed AMP-activated protein kinase activity. Furthermore, in cardiomyocytes of Prkaa2 knockout mice, expression of Fundc1, MAM formation, and mitochondrial Ca 2+ levels were significantly increased. Finally, adenoviral overexpression of a constitutively active mutant AMP-activated protein kinase ablated HG-induced MAM formation and mitochondrial dysfunction. Conclusions: We conclude that diabetes mellitus suppresses AMP-activated protein kinase, initiating Fundc1-mediated MAM formation, mitochondrial dysfunction, and cardiomyopathy, suggesting that AMP-activated protein kinase–induced Fundc1 suppression is a valid target to treat diabetic cardiomyopathy.

COVID-19 has a significant impact on public health and poses a challenge to medical staffs, especially to front-line medical staffs who are exposed to and in direct contact with patients. To understand the psychological stress status of medical staffs during the outbreak of COVID-19, random sample questionnaire survey was conducted among 2110 medical staffs and 2158 college students in all provinces of China through a questionnaire, which was compiled and completed through the Questionnaire Star platform relying on Wechat, QQ, and other social software. The differences in psychological stress status of different groups were compared through the analysis of the questionnaire. Results revealed that in all provinces of China, medical staffs scored significantly higher on all items of psychological stress than college students (P < .001). In Wuhan, medical staffs scored significantly higher than college students in all items of psychological stress (P < .001). While among medical staffs, the group in Wuhan area scored significantly higher than the group outside Wuhan on the following items: "Thought of being in danger," "The possibility of self-illness," "Worrying about family infection" (P < .05), "Poor sleep quality," "Needing psychological guidance," and "Worrying about being infected" (P < .01) in the Psychological Stress Questionnaire, but on the item "Confidence in the victory of the epidemic," the group in Wuhan area scored significantly lower than the group outside Wuhan (P < .05). The emotion, cognition, physical, and mental response of front-line medical staff showed obvious "exposure effect", which calls for a psychological crisis intervention strategy that can be helpful.

SUMMARY This study proposes a new uncertain analysis method for multibody dynamics of mechanical systems based on Chebyshev inclusion functions The interval model accounts for the uncertainties in multibody mechanical systems comprising uncertain‐but‐bounded parameters, which only requires lower and upper bounds of uncertain parameters, without having to know probability distributions. A Chebyshev inclusion function based on the truncated Chebyshev series, rather than the Taylor inclusion function, is proposed to achieve sharper and tighter bounds for meaningful solutions of interval functions, to effectively handle the overestimation caused by the wrapping effect, intrinsic to interval computations. The Mehler integral is used to evaluate the coefficients of Chebyshev polynomials in the numerical implementation. The multibody dynamics of mechanical systems are governed by index‐3 differential algebraic equations (DAEs), including a combination of differential equations and algebraic equations, responsible for the dynamics of the system subject to certain constraints. The proposed interval method with Chebyshev inclusion functions is applied to solve the DAEs in association with appropriate numerical solvers. This study employs HHT‐I3 as the numerical solver to transform the DAEs into a series of nonlinear algebraic equations at each integration time step, which are solved further by using the Newton–Raphson iterative method at the current time step. Two typical multibody dynamic systems with interval parameters, the slider crank and double pendulum mechanisms, are employed to demonstrate the effectiveness of the proposed methodology. The results show that the proposed methodology can supply sufficient numerical accuracy with a reasonable computational cost and is able to effectively handle the wrapping effect, as cosine functions are incorporated to sharpen the range of non‐monotonic interval functions. Copyright © 2013 John Wiley &amp; Sons, Ltd.

OBJECTIVE: To demonstrate whether abnormal glucose metabolism (diabetes and prediabetes) is associated with increased risk for cancer in the Chinese population and to identify factors that modify the risk of cancer among individuals with abnormal glucose metabolism. METHODS: Between 2011 and 2012, 259 657 community-dwelling adults, aged 40 years and older, were recruited from 25 centers across mainland China to participant in the baseline survey of the REACTION study, with follow-up investigations performed 3, 5, and 10 years later. Detailed questionnaires about lifestyles, physical and biochemical measurement, bio-samples including serum, urine, and whole blood for DNA extraction were collected for all the participants. RESULTS: The mean ± standard deviation (SD) age of this cohort was 57 ± 10 years. And the prevalence of pre-existing and newly diagnosed diabetes was 10.32% and 10.57%, respectively. A total of 4511 prevalent cancer cases (988 men and 3523 women) were identified, the prevalence was 1.79. Compared to those with normal glucose metabolism, men with diabetes had a significantly lower adjusted prevalence ratio (PR) of stomach cancer (PR: 0.38, 95% CI: 0.16-0.89), and women with diabetes had significantly higher adjusted PRs of cancer of all sites (PR: 1.36, 95% CI: 1.20-1.56), and cancer of the breast (PR: 1.56, 95% CI: 1.21-2.00), the endometrium (PR: 1.58, 95% CI: 1.16-2.15), and the thyroid (PR: 1.53, 95% CI: 1.03-2.27). CONCLUSION: The multi-center REACTION study has captured a broad range of data on physical, psychological and metabolic function as well as health status, biochemical and lifestyle information in 259 657 adults from the general population across the China.

Although alginate hydrogels have been extensively studied for tissue engineering applications, their utilization is limited by poor mechanical strength, rapid drug release, and a lack of cell adhesive ability. Aiming to improve these properties, we employ the interpenetrating hydrogel design rationale. Using alginate and sericin (a natural protein with many unique properties and a major component of silkworm silk), we develop an interpenetrating polymer network (IPN) hydrogel comprising interwoven sericin and alginate double networks. By adjusting the sericin-to-alginate ratios, IPNs' mechanical strength can be adjusted to meet stiffness requirements for various tissue repairs. The IPNs with high sericin content show increased stability during degradation, avoiding pure alginate's early collapse. These IPNs have high swelling ratios, benefiting various applications such as drug delivery. The IPNs sustain controlled drug release with the adjustable rates. Furthermore, these IPNs are adhesive to cells, supporting cell proliferation, long-term survival and migration. Notably, the IPNs inherit sericin's photoluminescent property, enabling bioimaging in vivo. Together, our study indicates that the sericin-alginate IPN hydrogels may serve as a versatile platform for delivering cells and drugs, and suggests that sericin may be a building block broadly applicable for generating IPN networks with other biomaterials for diverse tissue engineering applications.

Accumulation evidence shows that β-amyloid (Aβ) is a neurotoxic and accumulation of Aβ is responsible for the pathology of Alzheimer's disease (AD). However, it is currently not fully understood what makes Aβ toxic and accumulated. Previous studies demonstrate that Aβ is a suitable substrate for glycation, producing one form of the advanced glycation endproducts (AGEs). We speculated that Aβ-AGE formation may exacerbate the neurotoxicity. To explore whether the Aβ-AGE is more toxic than the authentic Aβ and to understand the molecular mechanisms, we synthesized glycated Aβ by incubating Aβ with methylglyoxal (MG) in vitro and identified the formation of glycated Aβ by fluorescence spectrophotometer. Then, we treated the primary hippocampal neurons cultured 8 days in vitro with Aβ-AGE or Aβ for 24 h. We observed that glycation exacerbated neurotoxicity of Aβ with upregulation of receptor for AGE (RAGE) and activation of glycogen synthase kinase-3 (GSK-3), whereas simultaneous application of RAGE antibody or GSK-3 inhibitor reversed the neuronal damages aggravated by glycated Aβ. Thereafter, we found that Aβ is also glycated with an age-dependent elevation of AGEs in Tg2576 mice, whereas inhibition of Aβ-AGE formation by subcutaneously infusion of aminoguanidine for 3 months significantly rescued the early cognitive deficit in mice. Our data reveal for the first time that the glycated Aβ is more toxic. We propose that the glycated Aβ with the altered secondary structure may be a more suitable ligand than Aβ for RAGE and subsequent activation of GSK-3 that can lead to cascade pathologies of AD, therefore glycated Aβ may be a new therapeutic target for AD.

UNLABELLED: (18)F-FPPRGD2, which was approved for clinical study recently, has favorable properties for integrin targeting and showed potential for antiangiogenic therapy and early response monitoring. However, the time-consuming multiple-step synthesis may limit its widespread applications in the clinic. In this study, we developed a simple lyophilized kit for labeling PRGD2 peptide ((18)F-AlF-NOTA-PRGD2, denoted as (18)F-alfatide) using a fluoride-aluminum complex that significantly simplified the labeling procedure. METHODS: Nine patients with a primary diagnosis of lung cancer were examined by both static and dynamic PET imaging with (18)F-alfatide, and 1 tuberculosis patient was investigated using both (18)F-alfatide and (18)F-FDG imaging. Standardized uptake values were measured in tumors and other main organs at 30 min and 1 h after injection. Kinetic parameters were calculated by Logan graphical analysis. Immunohistochemistry and staining intensity quantification were performed to confirm the expression of integrin α(v)β(3). RESULTS: Under the optimal conditions, the whole radiosynthesis including purification was accomplished within 20 min with a decay-corrected yield of 42.1% ± 2.0% and radiochemical purity of more than 95%. (18)F-alfatide PET imaging identified all tumors, with mean standardized uptake values of 2.90 ± 0.10. Tumor-to-muscle and tumor-to-blood ratios were 5.87 ± 2.02 and 2.71 ± 0.92, respectively. CONCLUSION: (18)F-alfatide can be produced with excellent radiochemical yield and purity via a simple, 1-step, lyophilized kit. PET scanning with (18)F-alfatide allows specific imaging of αvβ3 expression with good contrast in lung cancer patients. This technique might be used for the assessment of angiogenesis and for planning and response evaluation of cancer therapies that would affect angiogenesis status and integrin expression levels.

Abstract With the recent advent of immunotherapy, there is a critical need to understand immune cell interactions in the tumor microenvironment in both pan-cancer and tissue-specific contexts. Multidimensional datasets have enabled systematic approaches to dissect these interactions in large numbers of patients, furthering our understanding of the patient immune response to solid tumors. Using an integrated approach, we inferred the infiltration levels of distinct immune cell subsets in 23 tumor types from The Cancer Genome Atlas. From these quantities, we constructed a coinfiltration network, revealing interactions between cytolytic cells and myeloid cells in the tumor microenvironment. By integrating patient mutation data, we found that while mutation burden was associated with immune infiltration differences between distinct tumor types, additional factors likely explained differences between tumors originating from the same tissue. We concluded this analysis by examining the prognostic value of individual immune cell subsets as well as how coinfiltration of functionally discordant cell types associated with patient survival. In multiple tumor types, we found that the protective effect of CD8+ T cell infiltration was heavily modulated by coinfiltration of macrophages and other myeloid cell types, suggesting the involvement of myeloid-derived suppressor cells in tumor development. Our findings illustrate complex interactions between different immune cell types in the tumor microenvironment and indicate these interactions play meaningful roles in patient survival. These results demonstrate the importance of personalized immune response profiles when studying the factors underlying tumor immunogenicity and immunotherapy response. Cancer Res; 77(6); 1271–82. ©2017 AACR.

Abstract Surgical removal of malignant tumors is a mainstay in controlling most solid cancers. However, surgical insult also increases the risk of tumor recurrence and metastasis. Tissue trauma activates the innate immune system locally and systemically, mounting an inflammatory response. Platelets and neutrophils are two crucial players in the early innate immune response that heals tissues, but their actions may also contribute to cancer cell dissemination and distant metastasis. Here we report that surgical stress–activated platelets enhance the formation of platelet-tumor cell aggregates, facilitating their entrapment by neutrophil extracellular traps (NET) and subsequent distant metastasis. A murine hepatic ischemia/reperfusion (I/R) injury model of localized surgical stress showed that I/R promotes capturing of aggregated circulating tumor cells (CTC) by NETs and eventual metastasis to the lungs, which are abrogated when platelets are depleted. Hepatic I/R also increased deposition of NETs within the lung microvasculature, but depletion of platelets had no effect. TLR4 was essential for platelet activation and platelet-tumor cell aggregate formation in an ERK5-GPIIb/IIIa integrin-dependent manner. Such aggregation facilitated NET-mediated capture of CTCs in vitro under static and dynamic conditions. Blocking platelet activation or knocking out TLR4 protected mice from hepatic I/R-induced metastasis with no CTC entrapment by NETs. These results uncover a novel mechanism where platelets and neutrophils contribute to metastasis in the setting of acute inflammation. Targeted disruption of the interaction between platelets and NETs holds therapeutic promise to prevent postoperative distant metastasis. Significance: Targeting platelet activation via TLR4/ERK5/integrin GPIIb/IIIa signaling shows potential for preventing NET-driven distant metastasis in patients post-resection.

Developing potent adjuvants for the stimulation of robust immune response is central for effective cancer immunotherapy. Double-shelled dendritic mesoporous organosilica hollow spheres are an excellent adjuvant and provide superior immunity in cancer immunotherapy, and better than their counterparts either with a pure silica composition or a single-walled architecture. This study provides new insights in the rational design of effective nanostructured adjuvants for vaccine developments.

CD4(+)Foxp3(+) regulatory T (Treg) cells were shown to control all aspects of immune responses. How these Treg cells develop is not fully defined, especially in neonates during development of the immune system. We studied the induction of Treg cells from neonatal T cells with various TCR stimulatory conditions, because TCR stimulation is required for Treg cell generation. Independent of the types of TCR stimulus and without the addition of exogenous TGF-beta, up to 70% of neonatal CD4(+)Foxp3(-) T cells became CD4(+)Foxp3(+) Treg cells, whereas generally <10% of adult CD4(+)Foxp3(-) T cells became CD4(+)Foxp3(+) Treg cells under the same conditions. These neonatal Treg cells exert suppressive function and display relatively stable Foxp3 expression. Importantly, this ability of Treg cell generation gradually diminishes within 2 wk of birth. Consistent with in vitro findings, the in vivo i.p. injection of anti-CD3 mAb to stimulate T cells also resulted in a >3-fold increase in Treg cells in neonates but not in adults. Furthermore, neonatal or adult Foxp3(-) T cells were adoptively transferred into Rag1(-/-) mice. Twelve days later, the frequency of CD4(+)Foxp3(+) T cells converted from neonatal cells was 6-fold higher than that converted from adult cells. Taken together, neonatal CD4(+) T cells have an intrinsic "default" mechanism to become Treg cells in response to TCR stimulations. This finding provides intriguing implications about neonatal immunity, Treg cell generation, and tolerance establishment early in life.

BACKGROUND: Many studies assessed the impact of marine omega-3 fatty acids on glycemic homeostasis and lipid profiles in patients with type 2 diabetes (T2DM), but reported controversial results. Our goal was to systematically evaluate the effects of omega-3 on glucose control and lipid levels. METHODS: Medline, Pubmed, Cochrane Library, Embase, the National Research Register, and SIGLE were searched to identify eligible randomized clinical trials (RCTs). Extracted data from RCTs were analyzed using STATA 11.0 statistical software with fixed or random effects model. Effect sizes were presented as weighted mean differences (WMD) with 95% confidence intervals (95% CI). Heterogeneity was assessed using the Chi-square test with significance level set at p < 0.1. RESULTS: 20 RCT trials were included into this meta-analysis. Among patients with omega-3 supplementation, triglyceride (TG) levels were significantly decreased by 0.24 mmol/L. No marked change in total cholesterol (TC), HbA1c, fasting plasma glucose, postprandial plasma glucose, BMI or body weight was observed. High ratio of EPA/DHA contributed to a greater decreasing tendency in plasma insulin, HbAc1, TC, TG, and BMI measures, although no statistical significance was identified (except TG). FPG levels were increased by 0.42 mmol/L in Asians. No evidence of publication bias was observed in this meta-analysis. CONCLUSIONS: The ratio of EPA/DHA and early intervention with omega 3 fatty acids may affect their effects on glucose control and lipid levels, which may serve as a dietary reference for clinicians or nutritionists who manage diabetic patients.

Neoadjuvant chemoimmunotherapy (NACI) has shown promise in the treatment of resectable esophageal squamous cell carcinoma (ESCC). The microbiomes of patients can impact therapy response, and previous studies have demonstrated that intestinal microbiota influences cancer immunotherapy by activating gut immunity. Here, we investigated the effects of intratumoral microbiota on the response of patients with ESCC to NACI. Intratumoral microbiota signatures of β-diversity were disparate and predicted the treatment efficiency of NACI. The enrichment of Streptococcus positively correlated with GrzB+ and CD8+ T-cell infiltration in tumor tissues. The abundance of Streptococcus could predict prolonged disease-free survival in ESCC. Single-cell RNA sequencing demonstrated that responders displayed a higher proportion of CD8+ effector memory T cells but a lower proportion of CD4+ regulatory T cells. Mice that underwent fecal microbial transplantation or intestinal colonization with Streptococcus from responders showed enrichment of Streptococcus in tumor tissues, elevated tumor-infiltrating CD8+ T cells, and a favorable response to anti-PD-1 treatment. Collectively, this study suggests that intratumoral Streptococcus signatures could predict NACI response and sheds light on the potential clinical utility of intratumoral microbiota for cancer immunotherapy. SIGNIFICANCE: Analysis of intratumoral microbiota in patients with esophageal cancer identifies a microbiota signature that is associated with chemoimmunotherapy response and reveals that Streptococcus induces a favorable response by stimulating CD8+ T-cell infiltration. See related commentary by Sfanos, p. 2985.