Pan-cancer scRNA-seq analysis reveals immunological and diagnostic significance of the peripheral blood mononuclear cells.

Peripheral blood mononuclear cells (PBMCs) reflect systemic immune response during cancer progression. However, a comprehensive understanding of the composition and function of PBMCs in cancer patients is lacking, and the potential of these features to assist cancer diagnosis is also unclear. Here, the compositional and status differences between cancer patients and healthy donors in PBMCs were investigated by single-cell RNA sequencing (scRNA-seq), involving 262,025 PBMCs from 68 cancer samples and 14 healthy samples. We observed an enhanced activation and differentiation of most immune subsets in cancer patients, along with reduction of naïve T cells, expansion of macrophages, impairment of NK cells and myeloid cells, as well as tumor promotion and immunosuppression. Based on characteristics including differential cell type abundances and/or hub genes identified from weight gene co-expression network analysis (WGCNA) modules of each major cell type, we applied logistic regression to construct cancer diagnosis models. Furthermore, we found that the above models can distinguish cancer patients and healthy donors with high sensitivity. Our study provided new insights into using the features of PBMCs in non-invasive cancer diagnosis.

Assessing base-resolution DNA mechanics on the genome scale.

Intrinsic DNA properties including bending play a crucial role in diverse biological systems. A recent advance in a high-throughput technology called loop-seq makes it possible to determine the bendability of hundred thousand 50-bp DNA duplexes in one experiment. However, it's still challenging to assess base-resolution sequence bendability in large genomes such as human, which requires thousands of such experiments. Here, we introduce 'BendNet'-a deep neural network to predict the intrinsic DNA bending at base-resolution by using loop-seq results in yeast as training data. BendNet can predict the DNA bendability of any given sequence from different species with high accuracy. To explore the utility of BendNet, we applied it to the human genome and observed DNA bendability is associated with chromatin features and disease risk regions involving transcription/enhancer regulation, DNA replication, transcription factor binding and extrachromosomal circular DNA generation. These findings expand our understanding on DNA mechanics and its association with transcription regulation in mammals. Lastly, we built a comprehensive resource of genomic DNA bendability profiles for 307 species by applying BendNet, and provided an online tool to assess the bendability of user-specified DNA sequences (http://www.dnabendnet.com/).

Metal-Ligand Bonds Based Reprogrammable and Re-Processable Supramolecular Liquid Crystal Elastomer Network.

Dynamic covalent bonds endow liquid crystal elastomers (LCEs) with network rearrangeability, facilitating the fixation of mesogen alignment induced by external forces and enabling reversible actuation. In comparison, the bond exchange of supramolecular interactions is typically too significant to stably maintain the programmed alignment, particularly under intensified external stimuli. Nevertheless, remaking and recycling of supramolecular interaction-based polymer networks are more accessible than those based on dynamic covalent bonds, as the latter are difficult to completely dissociate. Thus, preparing an LCE that possesses both supramolecular-like exchangeability and covalent bond-level stability remains a significant challenge. In this work, we addressed this issue by employing metal-ligand bonds as the crosslinking points of LCE networks. As such, mesogen alignment can be repeatedly encoded through metal-ligand bond exchange and stably maintained after programming, since the bond exchange rate is sufficiently slow when the programming and actuation temperatures are below the bond dissociation temperature. More importantly, the metal-ligand bonds can be completely dissociated at high temperatures, allowing the LCE network to be dissolved in a solvent and reshaped into desired geometries via solution casting. Building on these properties, our LCEs can be fabricated into versatile actuators, such as reversible folding origami, artificial muscles, and soft robotics.

CsbD, a Novel Group B Streptococcal Stress Response Factor That Contributes to Bacterial Resistance against Environmental Bile Salts.

Group B Streptococcus (GBS) can cause many serious infections and result in severe symptoms depending on the infected organs. To survive and initiate infection from the gastrointestinal tract, GBS must resist physiochemical factors, such as bile salts, a potent antibacterial compound in the intestine. We found that GBS isolated from diverse sources all possess the capability to defend bile salts and permit survival. By constructing the GBS A909 transposon mutant library (A909Tn), we identified several candidate genes that might participate in the bile salt resistance of GBS. The rodA and csbD genes were validated as relevant to bile salt resistance. The rodA gene was anticipated to be related to peptidoglycan synthesis and influence the bile salt resistance of GBS by cell wall construction. Notably, we found that the csbD gene worked as a bile salt resistance response factor and influenced several ABC transporter genes, specifically at the later growth period of GBS under bile salt stress. We further detected the marked intracellular bile salt accumulation in ΔcsbD by hydrophilic interaction chromatography-liquid chromatography/mass spectrometry (HILIC-LC/MS). Collectively, we showed a novel GBS stress response factor, csbD, contributes to bacterial survival in bile salts by sensing bile salt stress and subsequently induces transcription of transporter genes to excrete bile salts. IMPORTANCE GBS, a conditional pathogenetic colonizer of the human intestinal flora, can cause severe infectious diseases in immunocompromised patients. Therefore, it is critical to understand the factors that contribute to the resistance to bile salts, which are abundant in the intestine but harmful to bacteria. We identified rodA and csbD genes involved in bile salt resistance using a transposon insertion site sequencing (TIS-seq) based screen. The rodA gene products might be involved in peptidoglycan synthesis as important contributors to stress resistance including bile salts. However, the csbD gene conferred bile salt resistance by promoting transporter genes transcription at the later growth period of GBS in response to bile salts. These findings developed a better understanding of the stress response factor csbD on the bile salt resistance of GBS.

Clusterin Is a Prognostic Biomarker of Lower-Grade Gliomas and Is Associated with Immune Cell Infiltration.

Dysregulation of clusterin (CLU) has been demonstrated in many cancers and has been proposed as a regulator of carcinogenesis. However, the roles of CLU in gliomas remain unclear. The expression of CLU was assessed using TIMER2.0, GEPIA2, and R package 4.2.1 software, leveraging data from TCGA and/or GTEx databases. Survival analysis and Cox regression were employed to investigate the prognostic significance of CLU. Immune infiltration was evaluated utilizing TIMER2.0, ESTIMATE, and CIBERSORT. The findings reveal the dysregulated expression of CLU in many cancers, with a marked increase observed in glioblastoma and lower-grade glioma (LGG). High CLU expression indicated worse survival outcomes and was an independent risk factor for the prognosis in LGG patients. CLU was involved in immune status as evidenced by its strong correlations with immune and stromal scores and the infiltration levels of multiple immune cells. Additionally, CLU was co-expressed with multiple immune-related genes, and high CLU expression was associated with the activation of immune-related pathways, such as binding to the antigen/immunoglobulin receptor and aiding the cytokine and cytokine receptor interaction. In conclusion, CLU appears to play crucial roles in tumor immunity within gliomas, highlighting its potential as a biomarker or target in glioma immunotherapy.

Built environment, physical activity, and obesity of adults in Pingshan District, Shenzhen City in Southern China.

BACKGROUND: The relation between neighbourhood built environment and obesity has been described as both nuanced and complex. AIM: The objective of this study was to examine the relationship between the built environment, physical activity, and obesity in a rapidly urbanised area of China. SUBJECTS AND METHODS: This is a cross-sectional study. Descriptive statistics were used to describe the socio-demographic variables, physical activity levels and BMI status. Multivariable logistic regression models were used to examine the association between neighbourhood environment, the likelihood of engaging in different types of physical activity, and BMI. RESULTS: A total of 842 respondents completed the questionnaires and were included (84.1% response rate). Among them, 56.4% reported meeting high physical activity levels, while 40.7% were overweight or obese. Multivariable regression analysis showed that better road conditions (ß = 0.122, t = 2.999, p = 0.003) and access to physical activity facilities (ß = 0.121, t = 3.193, p = 0.001) were significantly associated with higher levels of physical activity. Physical activity levels were inversely associated with the likelihood of being overweight (OR = 0.565, 95%CI: 0.3 4 9-0.917) or obese (OR = 0.614, 95%CI: 0.3 9 0-0.966). CONCLUSION: The built environment has an important impact on physical activity. However, the direct impact of leisure physical activity on BMI is not significant. This research provides a summary of recent evidence in Pingshan District on built environments that are most favourable for physical activity and obesity.

Perioperative Management of Pregnant Women With Idiopathic Pulmonary Arterial Hypertension: An Observational Case Series Study From China.

OBJECTIVES: The mortality of pregnant women with idiopathic pulmonary arterial hypertension (PAH) is very high. There are limited data on the management of idiopathic PAH during pregnancy. The authors aimed to examine systematically the characteristics of parturient women with idiopathic PAH, to explore the adverse effects of idiopathic PAH on pregnancy outcomes, and to report the multidisciplinary perioperative management strategy from the largest comprehensive cardiac hospital in China. DESIGN: Observational case series study. SETTING: Tertiary referral acute care hospital in Beijing, China. PARTICIPANTS: The cases of 17 consecutive pregnant idiopathic PAH patients undergoing abortion or parturition at Anzhen Hospital were reviewed retrospectively. INTERVENTIONS: Preoperative characteristics, anesthesia method, intensive care management, PAH-specific therapy, and maternal and neonatal outcomes were analyzed in this case series study. MEASURES AND MAIN RESULTS: Maternal and neonatal outcomes were the main measures. The mean ages of the 17 parturient women with idiopathic PAH were 28.3 ± 5.4 years, and the mean systolic pulmonary arterial pressure was 97.9 ± 18.6 mmHg. Fifteen patients (88.2%) received PAH-specific therapy before delivery, including sildenafil, iloprost, and treprostinil. All except 1 parturient received epidural anesthesia for surgery due to an emergency Caesarean section. Three patients experienced pulmonary hypertension crisis that necessitated conversion to general anesthesia. Ten parturients underwent Caesarean delivery at a median gestational age of 31 weeks. Three patients developed acute pulmonary hypertensive crisis intraoperatively. Two patients underwent cardiopulmonary resuscitation and extracorporeal membrane oxygenation support. The maternal mortality was 17.6% (3/17). Of the 10 delivered neonates, 9 (90.0%) survived. CONCLUSIONS: The maternal mortality of the idiopathic PAH parturient was high in this case series from China. The authors applied epidural anesthesia, early management with multidisciplinary approaches, PAH-specific therapy, avoidance of oxytocin, and timely delivery or pregnancy termination to improve maternal and neonatal outcomes.

SIRT2-mediated FOXO3a deacetylation drives its nuclear translocation triggering FasL-induced cell apoptosis during renal ischemia reperfusion.

We have found that Fas/FasL-mediated "extrinsic" pathway promoted cell apoptosis induced by renal ischemic injury. This study is to elucidate the upstream mechanism regulating FasL-induced extrinsic pathway during renal ischemia/reperfusion. Results demonstrated that when SIRT2 was activated by renal ischemia/reperfusion, activated SIRT2 could bind to and deacetylate FOXO3a, promoting FOXO3a nuclear translocation which resulted in an increase of nuclear FOXO3a along with FasL expression and activation of caspase8 and caspase3, triggering cell apoptosis during renal ischemia/reperfusion. The administration of SIRT2 inhibitor AGK2 prior to renal ischemia decreased significantly the number of apoptotic renal tubular cells and alleviated ultrastructure injury. These results indicate that inhibition of FOXO3a deacetylation might be a promising therapeutic approach for renal ischemia /reperfusion injury.

How Does Public Service Motivation Affect the Proactive Service Behaviors of Grid Workers? A Study of Survey Evidence from Eastern China.

In China, grid workers have increasingly become an indispensable and important force in basic social governance. They not only undertake several tasks, such as gaining publicity, collecting information, resolving conflicts, and assisting in management, but they also actively serve the grid residents enthusiastically and engage in proactive service behaviors. In order to better cultivate this important force, we hope to have a better understanding of the factors contributing to the behavioral performance of grid workers, especially the impact of organizational and personal factors. In this study, we sought to establish what factors influence the proactive service behaviors of grid workers. Based on a theoretical consideration of factors such as public service motivation, occupational identity, and organizational climate, a multi-factor influence hypothesis model was constructed to explain the proactive service behaviors of these workers. By analyzing data based on 348 paired survey samples received in two stages in eastern China, these hypotheses were then tested. The results reflect that grid workers' public service motivation can stimulate proactive service behaviors. Furthermore, occupational identity plays a mediating role, while organizational support and organizational service climate play a positive moderating role between public service motivation and occupational identity. This finding clarifies the important influencing factors of proactive service behaviors among grassroots workers, such as grid workers, and has important implications for how to effectively motivate these groups to provide more proactive services, promoting their sustainable development and improve the effectiveness of grassroots governance.

Predictive value of blood coagulation and routine blood indices for rebleeding after endoscopic treatment in hepatitis B-related cirrhotic patients with esophagogastric fundal varices: a logistic regression model analysis.

OBJECTIVE: To evaluate the predictive value of blood coagulation and routine blood indices for rebleeding after endoscopic treatment of ruptured esophagogastric fundal varices (EGVB) in cirrhotic patients with hepatitis B infection. METHODS: This retrospective analysis included 248 patients with hepatitis B-related cirrhosis and EGVB who received initial endoscopic treatment from October 2019 to March 2022 and were followed up for 12 months. Patients were divided into rebleeding and non-rebleeding groups. Laboratory indices were analyzed, and univariate and multivariate analyses identified predictors of rebleeding. The efficacy of a logistic regression model was evaluated using Receiver Operating Characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA), and a risk factor nomogram was constructed for assessing the predictive efficiency of those risk factors. RESULTS: Univariate analysis showed significant differences in portal vein diameters and lower Child-Pugh scores in the rebleeding group in contrast to those in the non-rebleeding group. Key laboratory markers such as platelet count (PLT), albumin (ALB), alanine aminotransferase (ALT), lymphocytes (LYM), and prognostic nutritional index (PNI) were lower, while prothrombin time (PT) and lactate levels (LN) were higher in the rebleeding group than those in the non-rebleeding group. Multivariate analysis identified portal vein diameter, PLT, ALT, PT, LYM, and PNI as significant predictors of rebleeding. The logistic model demonstrated high accuracy (AUC=0.986) and clinical value, validated by ROC curves, calibration curves (C-index =0.986), and DCA results. A risk factor predictive nomogram was successfully constructed. CONCLUSION: This study developed a logistic regression model with a nomogram for predicting EGVB-related rebleeding in patients with hepatitis B-related cirrhosis, achieving an AUC of 0.986, indicating high accuracy and significant clinical relevance.

Pluralizing actuation behavior of 3D printable liquid crystal elastomers via polymerization sequence control.

Mechanical stretching is commonly used for mesogen alignment which is essential for the muscle-like actuations of liquid crystal elastomers (LCEs). Despite the simplicity of the method, the mesogens are typically aligned in the stretching direction, limiting exclusively the LCE to an actuation mode of cooling-induced elongation. Here, we design an interpenetrating double network consisting of an LCE network and an elastomer network, with one polymerized network stretched before the polymerization of the other network. Depending on the polymerization sequence of the two networks, the double network shows two opposite actuation modes, namely, the conventional cooling-induced elongation or an unusual cooling-induced contraction. Strategic integration of the two opposite behaviors into the same LCE leads to sophisticated actuation difficult to achieve with a conventional LCE design. Coupled with 3D printing, geometrically complexed LCEs with diverse multimodal four-dimensional actuation behaviors are illustrated. Our work expands the design scope of LCE actuators and their potential device applications.

Multimodal Autonomous Locomotion of Liquid Crystal Elastomer Soft Robot.

Self-oscillation phenomena observed in nature serve as extraordinary inspiration for designing synthetic autonomous moving systems. Converting self-oscillation into designable self-sustained locomotion can lead to a new generation of soft robots that require minimal/no external control. However, such locomotion is typically constrained to a single mode dictated by the constant surrounding environment. In this study, a liquid crystal elastomer (LCE) robot capable of achieving self-sustained multimodal locomotion, with the specific motion mode being controlled via substrate adhesion or remote light stimulation is presented. Specifically, the LCE is mechanically trained to undergo repeated snapping actions to ensure its self-sustained rolling motion in a constant gradient thermal field atop a hotplate. By further fine-tuning the substrate adhesion, the LCE robot exhibits reversible transitions between rolling and jumping modes. In addition, the rolling motion can be manipulated in real time through light stimulation to perform other diverse motions including turning, decelerating, stopping, backing up, and steering around complex obstacles. The principle of introducing an on-demand gate control offers a new venue for designing future autonomous soft robots.

Driving effect of P16 methylation on telomerase reverse transcriptase-mediated immortalization and transformation of normal human fibroblasts.

BACKGROUND: P16 inactivation is frequently accompanied by telomerase reverse transcriptase (TERT) amplification in human cancer genomes. P16 inactivation by DNA methylation often occurs automatically during immortalization of normal cells by TERT. However, direct evidence remains to be obtained to support the causal effect of epigenetic changes, such as P16 methylation, on cancer development. This study aimed to provide experimental evidence that P16 methylation directly drives cancer development. METHODS: A zinc finger protein-based P16-specific DNA methyltransferase (P16-Dnmt) vector containing a "Tet-On" switch was used to induce extensive methylation of P16 CpG islands in normal human fibroblast CCD-18Co cells. Battery assays were used to evaluate cell immortalization and transformation throughout their lifespan. Cell subcloning and DNA barcoding were used to track the diversity of cell evolution. RESULTS: Leaking P16-Dnmt expression (without doxycycline-induction) could specifically inactivate P16 expression by DNA methylation. P16 methylation only promoted proliferation and prolonged lifespan but did not induce immortalization of CCD-18Co cells. Notably, cell immortalization, loss of contact inhibition, and anchorage-independent growth were always prevalent in P16-Dnmt&TERT cells, indicating cell transformation. In contrast, almost all TERT cells died in the replicative crisis. Only a few TERT cells recovered from the crisis, in which spontaneous P16 inactivation by DNA methylation occurred. Furthermore, the subclone formation capacity of P16-Dnmt&TERT cells was two-fold that of TERT cells. DNA barcoding analysis showed that the diversity of the P16-Dnmt&TERT cell population was much greater than that of the TERT cell population. CONCLUSION: P16 methylation drives TERT-mediated immortalization and transformation of normal human cells that may contribute to cancer development.

[An analysis of risk factors for postpartum cardiac events in pregnant women with heart disease].

OBJECTIVE: To investigate the risk factors for postpartum cardiac events in pregnant women with heart diseases and to provide prenatal counseling for them. METHODS: A retrospective analysis was made in cases of pregnant women with heart diseases admitted to the surgical intensive care unit (SICU) of Anzhen Hospital from May 2004 to May 2012. Data were used to identify univariate and multivariate predictors for postpartum cardiac events. RESULTS: A total of 190 patients ( ≥ 20 weeks gestation) were enrolled in the study with 134 (70.5%) of congenital heart disease, 30(15.8%) of rheumatic heart disease, 10 (5.3%) of cardiomyopathy, 2 (1.1%) of peripartum cardiomyopathy and 14 (7.4%) of hypertensive heart disease. Postpartum cardiac events were observed in 42 cases with the incidence of 22.1%. A total of 7 cases resulted in death with the mortality rate of 3.7%. Among them, 5 cases were dead of circulatory collapse and pulmonary hypertensive crisis postpartum, while the other 2 cases with secondary pulmonary infection were died of respiratory and circulatory collapse. The baseline parameters of New York Heart Academy(NYHA)>1, left ventricular ejection fraction(LVEF)<50%, use of cardiac drugs and pulmonary artery hypertension (PAH)>80 mm Hg(1 mm Hg = 0.133 kPa) were the independent predictors for postpartum cardiac events by univariate and multivariate logistic regression analysis. CONCLUSIONS: The incidence of postpartum cardiac events is high in pregnant women with heart diseases. Pulmonary artery hypertension and heart failure are the main causes of death.

Performance of artificial intelligence in diabetic retinopathy screening: a systematic review and meta-analysis of prospective studies.

Aims: To systematically evaluate the diagnostic value of an artificial intelligence (AI) algorithm model for various types of diabetic retinopathy (DR) in prospective studies over the previous five years, and to explore the factors affecting its diagnostic effectiveness. Materials and methods: A search was conducted in Cochrane Library, Embase, Web of Science, PubMed, and IEEE databases to collect prospective studies on AI models for the diagnosis of DR from January 2017 to December 2022. We used QUADAS-2 to evaluate the risk of bias in the included studies. Meta-analysis was performed using MetaDiSc and STATA 14.0 software to calculate the combined sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of various types of DR. Diagnostic odds ratios, summary receiver operating characteristic (SROC) plots, coupled forest plots, and subgroup analysis were performed according to the DR categories, patient source, region of study, and quality of literature, image, and algorithm. Results: Finally, 21 studies were included. Meta-analysis showed that the pooled sensitivity, specificity, pooled positive likelihood ratio, pooled negative likelihood ratio, area under the curve, Cochrane Q index, and pooled diagnostic odds ratio of AI model for the diagnosis of DR were 0.880 (0.875-0.884), 0.912 (0.99-0.913), 13.021 (10.738-15.789), 0.083 (0.061-0.112), 0.9798, 0.9388, and 206.80 (124.82-342.63), respectively. The DR categories, patient source, region of study, sample size, quality of literature, image, and algorithm may affect the diagnostic efficiency of AI for DR. Conclusion: AI model has a clear diagnostic value for DR, but it is influenced by many factors that deserve further study. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023389687.

The dual M protein systems have diverse biological characteristics, but both contribute to M18-type Group A Streptococcus pathogenicity.

M protein is a key surface virulence factor in Group A Streptococcus (GAS), Group C Streptococcus (GCS), and other streptococcal species. GAS encodes M protein using the emm gene, while GCS employs the szm (or sem) gene. In M18-type GAS, dual M protein systems exist, comprising both GAS and GCS M proteins (encoded separately by emm18 and spa18). The spa18 gene in M18-type GAS shares a conserved region highly similar to GCS's szm gene. Our study reveals that spa18 exhibits higher transcription levels than emm18 in M18-type GAS strains. The dual M protein systems defective mutant (Δemm18Δspa18) displays a smooth surface, whereas wild-type and single M protein gene mutants remain rough. M18 and SPA18 proteins possess distinct characteristics, showing varied binding properties and cytotoxicity effects on macrophages (THP-1) and keratinocytes (HaCaT). Both emm18 and spa18 genes contribute to the skin pathogenicity of M18-type GAS. Transcriptome analysis suggests the potential involvement of the mga gene in spa18 transcription regulation, while SpyM18_2047 appears to be specific to spa18 regulation. In summary, this research offers a crucial understanding of the biological characteristics of dual M protein systems in M18-type GAS, highlighting their contributions to virulence and transcriptional regulation.

Programming actuation onset of a liquid crystalline elastomer via isomerization of network topology.

Tuning actuation temperatures of liquid crystalline elastomers (LCEs) achieves control of their actuation onsets, which is generally accomplished in the synthesis step and cannot be altered afterward. Multiple actuation onsets in one LCE can be encoded if the post-synthesis regulation of actuation temperature can be spatiotemporally achieved. This would allow realizing a logical time-evolution of actuation, desired for future soft robots. Nevertheless, this task is challenging given the additional need to ensure mesogen alignment required for actuation. We achieved this goal with a topology isomerizable network (TIN) of LCE containing aromatic and aliphatic esters in the mesogenic and amorphous phases, respectively. These two ester bonds can be distinctly activated for transesterification. The homolytic bond exchange between aliphatic esters allows mechanically induced mesogen alignment without affecting the mesogenic phase. Most importantly, the heterolytic exchange between aromatic and aliphatic esters changes the actuation temperature under different conditions. Spatial control of the two mechanisms via a photo-latent catalyst unleashes the freedom in regulating actuation temperature distribution, yielding unusual controllability in actuation geometries and logical sequence. Our principle is generally applicable to common LCEs containing both aromatic and aliphatic esters.

Birthweight, genetic risk, and gastrointestinal cancer incidence: a prospective cohort study.

BACKGROUND: The epidemiologic studies investigating the association of birthweight and genetic factors with gastrointestinal cancer remain scarce. The study aimed to prospectively assess the interactions and joint effects of birthweight and genetic risk levels on gastrointestinal cancer incidence in adulthood. METHODS: A total of 254,997 participants were included in the UK Biobank study. We used multivariate restricted cubic splines and Cox regression models to estimate the hazard ratios (HRs) and 95% confidential intervals (CI) for the association between birthweight and gastrointestinal cancer risk, then constructed a polygenic risk score (PRS) to assess its interaction and joint effect with birthweight on the development of gastrointestinal cancer. RESULTS: We documented 2512 incident cases during a median follow-up of 8.88 years. Compare with participants reporting a normal birthweight (2.5-4.5 kg), multivariable-adjusted HR of gastrointestinal cancer incidence for participants with high birthweight (≥4.5 kg) was 1.17 (95%CI: 1.01-1.36). Such association was remarkably observed in pancreatic cancer, with an HR of 1.82 (95%CI: 1.26-2.64). No statistically significant association was observed between low birth weight and gastrointestinal cancers. Participants with high birthweight and high PRS had the highest risk of gastrointestinal cancer (HR: 2.95, 95%CI: 2.19-3.96). CONCLUSION: Our findings highlight that high birthweight is associated with a higher incidence of gastrointestinal cancer, especially for pancreatic cancer. Benefits would be obtained from birthweight control, particularly for individuals with a high genetic risk.KEY MESSAGESThe epidemiologic studies investigating the association of birthweight and genetic factors with gastrointestinal cancer remain scarce.This cohort study of 254,997 adults in the United Kingdom found an association of high birthweight with the incidence of gastrointestinal cancer, especially for pancreatic cancer, and also found that participants with high birthweight and high polygenic risk score had the highest risk of gastrointestinal cancer.Our data suggests a possible effect of in utero or early life exposures on adulthood gastrointestinal cancer, especially for those with a high genetic risk.

An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte-tumor cell crosstalk, local immunosuppression and tumor progression.

Dissecting and understanding the cancer ecosystem, especially that around the tumor margins, which have strong implications for tumor cell infiltration and invasion, are essential for exploring the mechanisms of tumor metastasis and developing effective new treatments. Using a novel tumor border scanning and digitization model enabled by nanoscale resolution-SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we identified a 500 µm-wide zone centered around the tumor border in patients with liver cancer, referred to as "the invasive zone". We detected strong immunosuppression, metabolic reprogramming, and severely damaged hepatocytes in this zone. We also identified a subpopulation of damaged hepatocytes with increased expression of serum amyloid A1 and A2 (referred to collectively as SAAs) located close to the border on the paratumor side. Overexpression of CXCL6 in adjacent malignant cells could induce activation of the JAK-STAT3 pathway in nearby hepatocytes, which subsequently caused SAAs' overexpression in these hepatocytes. Furthermore, overexpression and secretion of SAAs by hepatocytes in the invasive zone could lead to the recruitment of macrophages and M2 polarization, further promoting local immunosuppression, potentially resulting in tumor progression. Clinical association analysis in additional five independent cohorts of patients with primary and secondary liver cancer (n = 423) showed that patients with overexpression of SAAs in the invasive zone had a worse prognosis. Further in vivo experiments using mouse liver tumor models in situ confirmed that the knockdown of genes encoding SAAs in hepatocytes decreased macrophage accumulation around the tumor border and delayed tumor growth. The identification and characterization of a novel invasive zone in human cancer patients not only add an important layer of understanding regarding the mechanisms of tumor invasion and metastasis, but may also pave the way for developing novel therapeutic strategies for advanced liver cancer and other solid tumors.