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Abstract Background This study explored the influence of type 2 diabetes and impaired glucose tolerance (IGT) on the risk of the multimorbidity cluster of cardiovascular disease (CVD) and cancer. Methods A total of 1629 participants in the Da Qing Diabetes Prevention Outcome Study were recruited in the present analysis, including normal glucose tolerance (NGT, N = 492), IGT (N = 540), and newly diagnosed type 2 diabetes (N = 597) groups. Cox proportional hazards analyses were performed to assess the relationship between NGT, IGT, and newly diagnosed type 2 diabetes and the risk of the multimorbidity cluster of CVD and cancer. Results The incidence rates for multimorbidity cluster CVD and cancer were 1.25, 3.17, and 3.23 per 1000 person-years in people with NGT, IGT, and the newly diagnosed type 2 diabetes groups, respectively, over 34-year follow-up. Cox analysis revealed that diabetes status (as time-dependent variable) was significantly associated with the subsequent increased risk of multimorbidity cluster of CVD and cancer compared with non-diabetes (hazard ratios [HR] = 2.55, 95% confidence interval [CI] 1.51–4.31) after adjustment of potential confounders. Similar analysis showed that this risk was significantly higher in the IGT and newly diagnosed type 2 diabetes groups compared with NGT, with HR of 3.28 (95% CI 1.83–5.87) and HR of 3.90 (95% CI 2.14–7.09), respectively. Whereas compared diabetes with IGT group, this risk was not significantly different. Conclusions Similar to newly diagnosed type 2 diabetes, IGT is significantly associated with an increased risk of the multimorbidity cluster of CVD and cancer compared with NGT. This finding highlights the urgent need for an active detection of IGT and effective prevention and management of diabetes.

Abstract Background CircRNAs have been demonstrated to play a crucial role in regulating the growth and progression of various cancers, including hepatocellular carcinoma (HCC). Nevertheless, the circRNA's expression pattern and function in HCC need more investigation. Methods Bioinformatics techniques were used to identify differentially expressed circRNAs in HCC. CircASH2L expression in HCC tissues was assessed through qRT-PCR and ISH analysis. To assess circASH2L's impact on HCC progression, a variety of experiments were carried out both in vitro and in vivo, such as CCK8, colony formation, EdU assay, flow cytometry, transwell assay, and xenograft mouse model. Various experimental techniques including qRT-PCR, dual luciferase reporter assay, FISH, RNA pull-down, and RIP experiments were utilized to evaluate the relationship between circASH2L, miR-525-3p, and MTUS2. Additionally, experiments were conducted to explore the impact of m6A modification on circASH2L expression, including RNA stability assay, m6A RNA immunoprecipitation assay (MeRIP), and Co-IP experiments. Results We found that circASH2L was downregulated in HCC tissues and the downregulation of circASH2L was significantly correlated with malignant characteristics as well as poor overall survival of patients with HCC. CircASH2L was found to inhibit cells growth, migration and invasion as well as tumorigenesis and metastasis in vivo. Mechanistically, we established that circASH2L directly interacted with miR-525-3p to enhance MTUS2 expression, subsequently leading to tumor suppression. Moreover, the influence of circASH2L on tumor suppression was attenuated by increasing miR-525-3p levels, and MTUS2 was recognized as an essential intermediary in circASH2L-induced tumor suppression. Additionally, N6−methyladenosine (m6A) modification was identified in circASH2L. Our data suggested that METTL3 was responsible for mediating m6A methylation of circASH2L, ultimately regulating circASH2L expression through the promotion of its degradation. These findings collectively highlight the role of circASH2L as a tumor suppressor through a unique circASH2L/miR-525-3p/MTUS2 axis, shedding light on the significance of m6A modification in regulating circASH2L function. Conclusion The work emphasizes circASH2L as a promising therapeutic target for treating HCC, offering new insights into the role of circRNAs in HCC development.

Abstract In many noise scenarios, ventilation is necessary. The practical realization of noise attenuation under the premise of ensuring ventilation is an urgent problem to be solved. In this paper, a ventilated acoustic metamaterial labyrinth (VAML) is proposed, and the corresponding analytical and numerical computational models are developed considering the thermal viscous effect (TVE). The loss in sound transmission of the VAML is quantitatively obtained and experimentally verified. The theoretical results are compared with the experimental results with an error of 0.6%. By comparing the transmission coefficient and the impedance at the entrance of the side branches, the mechanism of the TVE on the performance of VAML is analyzed, and it is clarified that the TVE is responsible for the sound absorption coefficient. The effects of structure parameters on the transmission coefficient of the VAML are analyzed individually. The results show that the resonant frequency of the system decreases as the length of channel 1 $$l_1$$ l 1 , the length of channel 2 $$l_2$$ l 2 , and the width of channel d increase. By adjusting the magnitude of these three parameters, the control of the resonant frequency can be realized. Meanwhile, as $$l_1$$ l 1 , $$l_2$$ l 2 and ventilation radius R decrease the valley of transmission coefficient decreases which means better noise reduction. Finally, the effect of flow velocity on the transmission coefficient is analyzed, revealing the mechanism of fluid action on macroscopic acoustic properties.

Abstract The incidence of Early-Onset Colorectal Cancer (EOCRC) is increasing. However, the prognosis of EOCRC compared to Late-Onset Colorectal Cancer (LOCRC), and the ideal age for initial colorectal cancer (CRC) screening are not clear. In this study, we identified the pathological differences between the groups and determined the optimal screening age for CRC patients. We included 10,172 patients diagnosed with CRC from January 2011 to December 2021 in this study. Survival differences were compared by plotting Kaplan–Meier survival curves and conducting landmark analysis. Additionally, the diagnostic age of CRC patients was analyzed using age cumulative curves. Compared to LOCRC patients, EOCRC patients had a higher proportion of deficient mismatch repair (dMMR) and more advanced TNM staging (P

Abstract Cardiovascular diseases have been the leading cause of global mortality and disability. In addition to traditional drug and surgical treatment, more and more studies investigate tissue engineering therapeutic strategies in cardiovascular medicine. Collagen interweaves in the form of trimeric chains to form the physiological network framework of the extracellular matrix of cardiac and vascular cells, possessing excellent biological properties (such as low immunogenicity and good biocompatibility) and adjustable mechanical properties, which renders it a vital tissue engineering biomaterial for the treatment of cardiovascular diseases. In recent years, promising advances have been made in the application of collagen materials in blood vessel prostheses, injectable cardiac hydrogels, cardiac patches, and hemostatic materials, although their clinical translation still faces some obstacles. Thus, we reviewed these findings and systematically summarizes the application progress as well as problems of clinical translation of collagen biomaterials in the cardiovascular field. The present review contributes to a comprehensive understanding of the application of collagen biomaterials in cardiovascular medicine. Graphical abstract

Abstract Liver fibrosis, a chronic and long-term disease, can develop into hepatocellular carcinoma (HCC) and ultimately lead to liver failure. Early diagnosis and effective treatment still face significant challenges. Liver inflammation leads to liver fibrosis through continuous activation of hepatic stellate cells (HSCs) and the accumulation of immune cells. Intracellular communication among various immune cells is important for mediating the inflammatory response during fibrogenesis. Extracellular vesicles (EVs), which are lipid bilayer membrane-enclosed particles naturally secreted by cells, make great contributions to cell-cell communication and the transport of bioactive molecules. Nearly all the cells that participate in liver fibrosis release EVs loaded with lipids, proteins, and nucleic acids. EVs from hepatocytes, immune cells and stem cells are involved in mediating the inflammatory microenvironment of liver fibrosis. Recently, an increasing number of extracellular vesicle-based clinical applications have emerged, providing promising cell-free diagnostic and therapeutic tools for liver fibrosis because of their crucial role in immunomodulation during pathogenesis. The advantages of extracellular vesicle-based therapies include stability, biocompatibility, low cytotoxicity, and minimal immunogenicity, which highlight their great potential for drug delivery and specific treatments for liver fibrosis. In this review, we summarize the complex biological functions of EVs in the inflammatory response in the pathogenesis of liver fibrosis and evaluate the potential of EVs in the diagnosis and treatment of liver fibrosis.

Abstract Background N4‐acetylcytidine (ac4C) represents a novel messenger RNA (mRNA) modification, and its associated acetyltransferase N‐acetyltransferase 10 (NAT10) plays a crucial role in the initiation and progression of tumors by regulating mRNA functionality. However, its role in hepatocellular carcinoma (HCC) development and prognosis is largely unknown. This study aimed to elucidate the role of NAT10‐mediated ac4C in HCC progression and provide a promising therapeutic approach. Methods The ac4C levels were evaluated by dot blot and ultra‐performance liquid chromatography‐tandem mass spectrometry with harvested HCC tissues. The expression of NAT10 was investigated using quantitative real‐time polymerase chain reaction, western blotting, and immunohistochemical staining across 91 cohorts of HCC patients. To explore the underlying mechanisms of NAT10‐ac4C in HCC, we employed a comprehensive approach integrating acetylated RNA immunoprecipitation and sequencing, RNA sequencing and ribosome profiling analyses, along with RNA immunoprecipitation, RNA pull‐down, mass spectrometry, and site‐specific mutation analyses. The drug affinity responsive targets stability, cellular thermal shift assay, and surface plasmon resonance assays were performed to assess the specific binding of NAT10 and Panobinostat. Furthermore, the efficacy of targeting NAT10‐ac4C for HCC treatment was elucidated through in vitro experiments using HCC cells and in vivo HCC mouse models. Results Our investigation revealed a significant increase in both the ac4C RNA level and NAT10 expression in HCC. Notably, elevated NAT10 expression was associated with poor outcomes in HCC patients. Functionally, silencing NAT10 suppressed HCC proliferation and metastasis in vitro and in vivo. Mechanistically, NAT10 stimulates the ac4C modification within the coding sequence (CDS) of high mobility group protein B2 (HMGB2), which subsequently enhances HMGB2 translation by facilitating eukaryotic elongation factor 2 (eEF2) binding to the ac4C sites on HMGB2 mRNA's CDS. Additionally, high‐throughput compound library screening revealed Panobinostat as a potent inhibitor of NAT10‐mediated ac4C modification. This inhibition significantly attenuated HCC growth and metastasis in both in vitro experiments using HCC cells and in vivo HCC mouse models. Conclusions Our study identified a novel oncogenic epi‐transcriptome axis involving NAT10‐ac4C/eEF2‐HMGB2, which plays a pivotal role in regulating HCC growth and metastasis. The drug Panobinostat validates the therapeutic potential of targeting this axis for HCC treatment.

Abstract Purpose To investigate the role of Actin like 6 A (ACTL6A) in cancer and explore the potential mechanism of its function. Methods Differential expression of ACTL6A was analyzed using Oncomine and TIMER database. Then, we downloaded data sets from TCGA database. The correlation between ACTL6A expression and survival in pan-cancer were analyzed by “survival”, “survminer” R package and PrognoScan database. STRING (v 11.0) and stringAPP for Cytoscape v3.7.2 were used to predict ACTL6A associated genes. Copy number and methylation alterations of ACTL6A were analyzed using cBioPortal and GSCALite. Transcription factors were downloaded from The Human Transcription Factors Database and analyzed using “limma” R package, JASPAR and PROMO database. Correlations analysis between ACTL6A and immune cells were performed using TIMER and GEPIA database. Results In our studies, we found that ACTL6A was widely upregulated in cancers, which might be attributed to its gene amplifications. Moreover, ACTL6A might regulated by transcription factors (TFs), including E2F1, YY1, CDX2 and HOXD10. In addition, high ACTL6A expression was associated with poor prognosis in most cancers. Meanwhile, ACTL6A was associated with the infiltration of immune cells, especially in liver hepatocellular carcinoma and brain lower grade glioma. Conclusion Amplification of ACTL6A is correlated with poor prognosis and contribute to immune cells infiltration in LIHC and LGG, which may provide immune-related therapeutic targets to guide clinical strategies.

Abstract Background The updated status of hypertension and its risk factors are poorly evaluated in Tibetan highland areas. We initiated a large-scale cross-sectional survey to provide updated status of hypertension and its risk factors (especially salt intake) in the Ganzi Tibetan Plateau, China. Methods Stratified multistage random sampling was performed to obtain a representative sample of 4,036 adult residents from 4 counties in the Ganzi Tibetan area. The whole survey population was used to present the epidemiology and risk factors of hypertension. The participants with blood and urine biochemistry data were used to analyze the relationship between salt intake parameters and hypertension. Results Stratified multistage random sampling was performed to obtain a representative sample of 4,036 adult residents. The overall prevalence rate of hypertension was 33.5% (the age-adjusted prevalence rate was 28.9%). A total of 50.9% of the hypertensive patients knew their conditions; 30.1% of them received antihypertensive treatment; and 11.2% of them had their blood pressure controlled. Age, male sex, living altitude ≥ 3500 m, overweight and abdominal obesity were positively correlated with hypertension. In addition, the adjusted odds ratio (OR) for hypertension was 1.33 (95% CI: 1.01–1.74) for drinking tea with salt, and 1.51 (95% CI: 1.32–1.72) for per SD increase in the estimation of 24-hour urinary sodium excretion (e24hUSE). Furthermore, per 100mmol/day increase in e24hUSE was associated with elevation of blood pressure (+ 10.16, 95% CI: 8.45–11.87 mmHg for SBP; +3.83, 95% CI: 2.74–4.93 mmHg for DBP) in this population. Conclusions Our survey suggests a heavy disease burden of hypertension in the Ganzi Tibetan Plateau. Age, male sex, altitude of residence ≥ 3500 m, overweight, abdominal obesity, and excessive salt intake (shown as drinking tea with adding salt and a higher level of e24hUSE) all increased the risk of hypertension in this highland area.

Abstract High-precision 3D point cloud data have various analyses and application use cases. This study aimed to achieve a more precise noise reduction of the raw 3D point cloud data of asphalt pavements obtained using 3D laser scanning. Hence, a noise-reduction algorithm integrating improved Gaussian filtering and coefficient of variation was developed. A portable laser scanner was used to collect raw, high-precision 3D point cloud data of surface textures from pavement slab samples prepared with three different types of asphalt mixtures: AC-13, SMA-13, and OGFC-13, as well as asphalt from the test sections of the Yakang Expressway. An improved Gaussian filtering and Gaussian filtering that extracts noise using the coefficient of variation were used to filter out the obvious outlier noise and small-scale burr noise, respectively. Finally, the filtering effect of the proposed algorithm, Gaussian filtering, median filtering, and mean filtering on raw 3D point cloud data of pavement textures was evaluated through subjective visual quality and objective index evaluations. The results showed that the proposed algorithm filters out noise while preserving the micro-texture structure information, outperforming Gaussian filtering, median filtering, and mean filtering.

Abstract Advanced metastasis of hepatocellular carcinoma (HCC) significantly contributes to high death rates among patients. The efficiency of targeted therapies and chemotherapeutic agents shows individual variability. Therefore, there is no effective treatment for advanced HCC. Zinc finger proteins (ZFPs) are known to be crucial in various tumors, especially on HCC. In our study, we verified that ZFP41 could suppress the progression and metastasis of HCC through in vitro and in vivo experiments. During the past years, N6‐methyladenine (m6A) regulation has also been increasingly reported in HCC. To investigate whether ZFP41 could be regulated via m6A methylation, our results showed that YTHDF3 bound to the mRNA of ZFP41 and degrade it. Subsequently, to further elucidate the function of ZFP41, we identified Snail, a well‐known oncogenic molecule, through RNA‐seq. As a canonical component in the epithelial‐to‐mesenchymal transition (EMT) pathway, Snail plays a pivotal role and is a critical marker for tumor invasion and metastasis. Our results showed ZFP41 could inhibit Snail and the EMT pathway through its transcriptional repression. In conclusion, our study revealed that ZFP41 is a potential prognostic element for patients with HCC, and targeting ZFP41 might be used for translational clinical applications as a promising therapeutic target.

Abstract Both the transforming growth factor beta (TGF‐β) signaling pathway and N6‐methyladenosine (m6A) modification for mRNA play an important role in hepatocellular carcinoma (HCC) progression. However, the relationship between TGF‐β and m6A in hepatocellular carcinoma (HCC) remains unclear. Here, it is found that TGF‐β can promote the liquid phase separation of METTL3, which further leads to the reduction of mRNA stability of ITIH1. As a secreted protein, ITIH1 can act as a ligand of integrin α5β1 to antagonize fibronectin, induce the inhibition of focal adhesion kinase signaling pathway, and inhibit the progression of HCC. In the preclinical model (mouse model, patient‐derived organoid, patient‐derived xenografts), purified recombinant ITIH1 (r‐ITIH1) protein can be targeted for HCC. More importantly, r‐ITIH1 can play a synergistic role in targeting HCC with TGF‐β inhibitor. The downstream ITIH1 regulatory mechanism of TGF‐β and m6A modification is revealed, and ITIH1 can be translational as a potential target for HCC.

Objectives Ascending aorta dilatation (AAD) has been suggested as a surrogate marker for vascular organ damage in the hypertensive population. However, limited data are available on AAD in normotensive individuals. This study aims to preliminarily explore the correlation between ascending aorta (AAO) and other established clinically significant target organ damage parameters and to investigate the possible risk factors of AAD in the non-diabetic normotensive individuals.Design Our study has a cross-sectional design.Setting All participants were recruited from the inpatient and outpatient departments of our hospital.Participants We recruited 634 normotensive participants (52.26±16.22 years, 39.43% male) who underwent both ambulatory blood pressure monitoring (ABPM) and echocardiography. The whole study population was divided into AAD and non-AAD groups according to age-gender-specific criteria. The baseline mean blood pressure (BP) of the two groups was 126.92/77.72 and 124.16/77.61 mm Hg, respectively.Primary and secondary outcome measures The relationship between AAO and other acknowledged cardiac damage indicators, as well as the associations of AAD with ABPM indexes in the non-diabetic normotensive individuals.Results We observed that AAO exhibited a significant correlation with left ventricular mass index (β=1.905, p

BackgroundThe green alga Chlamydomonas reinhardtii is an accepted food ingredient in the United States of America (United States), the European Union, Singapore, and China. It can be consumed in unlimited quantities. As this alga is rich in nutrients, proteins, and rough polysaccharides and contains a balanced proportion of various amino acids, it is an excellent raw material for food production. Although various edible brown and green algae are available on the market, their color and strong grassy flavor have constrained their popularity among consumers, thereby limiting their application in food additives and animal feed.MethodsChlorophyll-deficient C. reinhardtii mutants were developed using atmospheric and room temperature plasma (ARTP) technology.ResultsA yellow-colored C. reinhardtii variant (A7S80) cultivated in dark conditions was isolated. This light-sensitive variant has a mutation in the chlM gene, and it can grow heterotrophically using acetate as a carbon source.ConclusionCompared to wild-type C. reinhardtii, A7S80 has significantly lower chlorophyll levels, reduced grassy flavor, and more diverse pigments, with considerable potential for commercial application in human and animal food production, as well as in pharmaceutical and cosmetic industries.

Abstract Despite the success of immunotherapy in treating hepatocellular carcinoma (HCC), HCC remains a severe threat to health. Here, a crucial transcription factor, SOX12, is revealed that induces the immunosuppression of liver tumor microenvironment. Overexpressing SOX12 in HCC syngeneic models increases intratumoral regulatory T‐cell (Treg) infiltration, decreases CD8+T‐cell infiltration, and hastens HCC metastasis. Hepatocyte‐specific SOX12 knockout attenuates DEN/CCl4‐induced HCC progression and metastasis, whereas hepatocyte‐specific SOX12 knock‐in accelerates these effects. Mechanistically, SOX12 transcriptionally activates C‐C motif chemokine ligand 22 (CCL22) expression to promote the recruitment and suppressive activity of Tregs. Moreover, SOX12 transcriptionally upregulates CD274 expression to suppress CD8+T‐cell infiltration. Either knockdown of CCL22 or PD‐L1 dampens SOX12‐mediated HCC metastasis. Blocking of CC chemokine receptor 4 (CCR4), a receptor for CCL22, by inhibitor C‐021 or Treg‐specific knockout of CCR4 inhibits SOX12‐mediated HCC metastasis. Transforming growth factor‐β1 (TGF‐β1)/TGFβR1‐Smad2/3/4 is identified as a key upstream signaling for SOX12 overexpression in HCC cells. Combining C‐021 or TGFβR1 inhibitor galunisertib with anti‐PD‐L1 exhibits an enhanced antitumor effect in two HCC models. Collectively, the findings demonstrate that SOX12 contributes to HCC immunosuppression through the CCL22/CCR4‐Treg and PD‐L1‐CD8+T axes. Blocking of CCR4 or TGFβR1 improves the efficacy of anti‐PD‐L1 in SOX12‐mediated HCC.

IntroductionThis study aimed to assess the diagnostic values of bronchoalveolar lavage fluid (BALF) real-time polymerase chain reaction (PCR) and BALF metagenomic next-generation sequencing (mNGS) for Pneumocystis jirovecii pneumonia (PJP) in patients infected with human immunodeficiency virus (HIV).MethodsA total of 99 HIV-infected PJP patients and 61 HIV-infected patients diagnosed with non-PJP pneumonia between March 2019 and December 2022 were enrolled. P. jirovecii and multiple other co-pathogens detected in BALF by mNGS were analyzed. The clinical final diagnosis was employed as a benchmark. We compared the diagnostic performance of mNGS in PJP with serum BDG and BALF real-time PCR. The mixed infections detected by mNGS and modifications of antimicrobial treatment were also analyzed.ResultsThe sensitivity of mNGS test of BALF samples reached 85.86%, which was significantly higher than serum BDG (39.39%, P < 0.001). The sensitivity of BALF P. jirovecii PCR (84.85%) was similar with mNGS (P > 0.05). The specificity of mNGS (100%) was also same as PCR (100.0%), and superior to serum BDG (88.52%, P < 0.001). Besides, mNGS performs remarkably well in identifying co-pathogens of PJP patients infected with HIV. In addition to P. jirovecii, 82 cases (82.83%) of other co-pathogens were identified based on mNGS. Moreover, thirty-four patients (34.34%) increased therapeutic dose of trimethoprim-sulfamethoxazole (TMP-SMZ) based on BALF P. jirovecii PCR. Based on the mNGS results, initial antimicrobial treatment was modified in 86.87% (86/99) of PJP patients.ConclusionBALF mNGS and real-time PCR are two powerful techniques for rapid diagnosis of PJP with high specificity and sensitivity. Moreover, the benefit of mNGS is that it may identify other organisms besides PJP and it may benefit proper and prompt treatment.

ObjectiveThis study aimed to evaluate the relationship between the weight-adjusted waist circumference index (WWI) and the frailty in American adults aged over 60 years.MethodsWe utilized data from the National Health and Nutrition Examination Surveys (NHANES) spanning from 2007 to 2018. WWI was calculated using the square root of waist circumference (cm) divided by body weight (kg). The frailty index ≥ 0.25 was employed to assess frailty. Weighted multivariate logistic regression was conducted to explore the association between WWI and frailty. Generalized Additive Modeling (GAM) was used to explore potential non-linear relationships. Receiver operating characteristic curve (ROC) analysis was used to assess the predictive ability of WWI for frailty.ResultsThe study encompassed 7765 participants. Higher WWI was significantly associated with higher odds of frailty. In the fully adjusted model, each unit increase of WWI was associated with an 82% increased odds of frailty (OR: 1.82, 95% CI: 1.61 – 2.06; P < 0.001). GAM found significant nonlinear relationships and threshold effects.ConclusionThe study presented a robust correlation between elevated WWI and increased odds of frailty among American older adults. However, these findings require further validation in large-scale, prospective studies.

Abstract Background Studies have shown that RASGRP1 was potently associated with the onset of type 2 diabetes mellitus (T2DM), and RASGRP1 rs7403531 was significantly correlated with islet function in T2DM patients. However, the effect of RASGRP1 polymorphism on blood glucose and blood pressure in T2DM patients after continuous treatment has yet to be fully elucidated. Objective This study aimed to explore the association between RASGRP1 genetic polymorphism and cardiovascular complications in T2DM patients, so as to provide more evidence for the individualized treatment of T2DM patients. Methods We retrospectively analyzed a large-scale multicenter drug clinical study cohort that based on a 2 × 2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled design, with follow-up for 5 years. The major vascular endpoint events included cardiovascular death, non-fatal stroke, coronary heart disease, new-onset or worsening renal disease, and diabetic retinopathy. RASGRP1 rs12593201, rs56254815 and rs7403531 were finally selected as candidate single nucleotide polymorphisms. Mixed linear model and Cox hazard ratio (HR) model were used for data analysis with IBM SPSS (version 20.0 for windows; Chicago, IL). Results Our study enrolled 1357 patients with high-risk diabetes, with a mean follow-up duration of 4.8 years. RASGRP1 rs7403531 was associated with vascular events in hypoglycemic and antihypertensive therapy. Specifically, compared with CC carriers, patients with CT/TT genotype had fewer major microvascular events (HR = 0.41, 95% confidence interval (CI) 0.21–0.80, P = 0.009), and reduced the risk of major eye disease events (HR = 0.44, 95% CI 0.20–0.94, P = 0.03). For glucose lowering axis, CT/TT carriers had a lower risk of secondary nephropathy (HR = 0.48, 95% CI 0.25–0.92, P = 0.03) in patients with standard glycemic control. For blood pressure lowering axis, all cerebrovascular events (HR = 2.24, 95% CI 1.11–4.51, P = 0.025) and stroke events (HR = 2.07, 95% CI 1.03–4.15, P = 0.04) were increased in patients with CC genotype compared to those with CT/TT genotype in the placebo group, respectively. Furthermore, patients with CC genotype showed a reduced risk of major cerebrovascular events in antihypertensive group (HR = 0.36, 95% CI 0.15–0.86, P = 0.021). For RASGRP1 rs56254815, compared with the AA genotype carriers, the systolic blood pressure of AG/GG carriers in the antihypertensive group decreased by 1.5mmhg on average (P = 0.04). In the placebo group, the blood pressure of AG/GG carriers was 1.7mmHg higher than that of AA carriers (P = 0.02). Conclusion We found that patients with G allele of RASGRP1 (rs56254815) showed a better antihypertensive therapy efficacy in T2DM patients. The rs7403531 T allele could reduce the risk of major microvascular events and major eye diseases in T2DM patients receiving either hypoglycemic or antihypertensive therapy. Our findings suggest that RASGRP1 genetic polymorphism might predict the cardiovascular complications in T2DM patients.

Abstract Background β-1,3-Xylooligosaccharides (XOS-3) extracted from Caulerpa lentillifera have shown potential antioxidative and anti-tumor properties, but research on their biological activities, particularly their anti-osteoarthritis effects, is still in early stages. Results XOS-3 were produced by eco-friendly enzymatic hydrolysis, displaying a semi-crystalline structure with predominant xylose, xylobiose, xylotriose, and xylotetraose components which were confirmed by IC, SEM, FT-IR, and XRD analysis. Compared with β-1,4-xylooligosaccharides, XOS-3 had stronger antioxidant properties, and the scavenging rate of O2 •− and DPPH• radicals was 82.31% and 58.44% at 2.0 mg/mL respectively. In vitro studies, XOS-3 significantly improved cell viability in IL-1β-induced rat chondrocytes from 43.41 to 73.5% at 100 μg/mL, demonstrating anti-inflammatory and cartilage-protective effects by modulating MMP13 and COL2A1 expression. Conclusions The study displayed the potential antioxidative and anti-osteoarthritis effects of XOS-3, offering new visuals for the development of marine polysaccharides in the treatment of osteoarthritis. Graphical Abstract

Abstract Paradoxically, tumor development and progression can be inhibited and promoted by the immune system. After three stages of immune editing, namely, elimination, homeostasis and escape, tumor cells are no longer restricted by immune surveillance and thus develop into clinical tumors. The mechanisms of immune escape include abnormalities in antitumor-associated immune cells, selection for immune resistance to tumor cells, impaired transport of T cells, and the formation of an immunosuppressive tumor microenvironment. A population of distinct immature myeloid cells, myeloid-derived suppressor cells (MDSCs), mediate immune escape primarily by exerting immunosuppressive effects and participating in the constitution of an immunosuppressive microtumor environment. Clinical trials have found that the levels of MDSCs in the peripheral blood of cancer patients are strongly correlated with tumor stage, metastasis and prognosis. Moreover, animal experiments have confirmed that elimination of MDSCs inhibits tumor growth and metastasis to some extent. Therefore, MDSCs may become the target of immunotherapy for many cancers, and eliminating MDSCs can help improve the response rate to cancer treatment and patient survival. However, a clear definition of MDSCs and the specific mechanism involved in immune escape are lacking. In this paper, we review the role of the MDSCs population in tumor development and the mechanisms involved in immune escape in different tumor contexts. In addition, we discuss the use of these cells as targets for tumor immunotherapy. This review not only contributes to a systematic and comprehensive understanding of the essential role of MDSCs in immune system reactions against tumors but also provides information to guide the development of cancer therapies targeting MDSCs.

Abstract Background Circular RNAs (circRNAs) belong to a class of covalently closed single stranded RNAs that have been implicated in cancer progression. Former investigations showed that hsa-circ-0013561 is abnormally expressed in head and neck squamous cell carcinoma (HNSCC). Nevertheless, the role of hsa-circ-0013561 during the progress of HNSCC still unclear. Methods Present study applied FISH and qRT-PCR to examine hsa-circ-0013561 expression in HNSCC cells and tissue samples. Dual-luciferase reporter assay was employed to identify downstream targets of hsa-circ-0013561. Transwell migration, 5-ethynyl-2′-deoxyuridine incorporation, CCK8 and colony formation assays were utilized to test cell migration and proliferation. A mouse tumor xenograft model was utilized to determine the hsa-circ-0013561 roles in HNSCC progression and metastasis in vivo. Results We found that hsa-circ-0013561 was upregulated in HNSCC tissue samples. hsa-circ-0013561 downregulation inhibited HNSCC cell proliferation and migration to promote apoptosis and G1 cell cycle arrest. The dual-luciferase reporter assay revealed that miR-7-5p and PDK3 are hsa-circ-0013561 downstream targets. PDK3 overexpression or miR-7-5p suppression reversed the hsa-circ-0013561-induced silencing effects on HNSCC cell proliferation and migration. PDK3 overexpression reversed miR-7-5p-induced effects on HNSCC cell proliferation and migration. Conclusion The findings suggest that hsa-circ-0013561 downregulation inhibits HNSCC metastasis and progression through PDK3 expression and miR-7-5p binding modulation.

BackgroundThe association between years of non-diabetes status after diagnosis of impaired glucose tolerance (IGT) and the risk of long-term death and cardiovascular outcomes needed to be clarified.Methods and findingsIn this post hoc analysis, we included 540 individuals with IGT who participated in the original Da Qing Diabetes Prevention Study (DQDPS). In the DQDPS, all participants were diagnosed with IGT by a 75 g oral glucose tolerance test and randomized to intervention or control groups with a 6-year lifestyle intervention trial. After the completion of the trial, death, cardiovascular events, and microvascular complications were monitored over a 30-year follow-up. In this post hoc analysis, the Cox analysis assessed the extended risk of these outcomes in individuals who either remained non-diabetes status or progressed to diabetes at the end of 2, 4, and 6 years after diagnosis of IGT. In all participants, the difference in the cumulative incidence rate of the outcomes between the diabetes and non-diabetes group gradually increased over 30 years. Compared with the diabetes group, a significantly lower risk of all-cause death (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.57 to 0.97, p = 0.026), cardiovascular events (HR: 0.63; 95% CI: 0.49 to 0.82, p < 0.001), and microvascular complications (HR: 0.62; 95% CI: 0.45 to 0.86, p = 0.004) first emerged in individuals who remained non-diabetes at the 4 years visit, whereas the significant risk reduction in cardiovascular death was first observed at the end of 6 years (HR: 0.56; 95% CI: 0.39 to 0.81, p = 0.002) after adjustment for age, sex, smoking status, BMI, systolic blood pressure, blood glucose, total cholesterol, intervention, and medications (including insulin plus oral hypoglycaemics, antihypertensives, and lipid-lowering agents). The results in the original intervention group alone were similar to the whole group. The main limitations of our study are the limited number of participants and the sole ethnicity of the Chinese population.ConclusionsIn this study, we observed that maintaining several years of non-diabetes status after IGT diagnosis was associated with a significant reduction in long-term risk of death and vascular complications, and for most of these outcomes, maintaining at least 4 years of non-diabetes status may be needed to achieve a significant risk reduction.

Abstract Syringa oblata is an important garden plant whose leaf colour turns from green to red in autumn when air temperature and daylength decrease. This study explored the reasons for leaf reddening by detecting phenotypic characteristics and pigment types and contents. With leaf reddening, luminance L* increased and chrominance a* decreased significantly. Chlorophyll and carotenoid contents significantly decreased in accordance with the distribution change of green pigment in leaf cells. Conversely, the red pigment distribution increased and the total polyphenol, total flavonoid and total anthocyanin contents evidently increased. Anthocyanin accumulation was the important reason for leaf reddening. Of the anthocyanins detected in leaves, cyanidin and delphinidin-3-O-rutinoside contents gradually increased with leaf reddening and were negatively correlated with L*. They were considered key anthocyanins influencing leaf colour. Apigenin and syringic acid were correlated with delphinidin-3-O-rutinoside and cyanidin, and they could be the anthocyanin co-pigments. Cyanidin-3-O-arabinoside and taxifolin were more abundant polyphenols in leaves. In summary, anthocyanin accumulation and chlorophyll degradation occurred along with leaf reddening. Temperature, light, and other co-pigments influenced the anthocyanin and chlorophyll contents. This study provides evidence for applications of S. oblata as a coloured-leaf plant in gardens and as a source of active ingredients in the commercial market.

Crop yields are related to N fertilizer management, and also depend on local precipitation. Varying precipitation levels with long-term meteorological data have not been considered to optimize nitrogen (N) strategies in previous studies on the Loess Plateau of China. In this study, Root Zone Water Quality Model 2 (RZWQM2) was calibrated and validated using data from multi-year experiments and used to assess and optimize N management strategies for winter wheat cultivation. Results showed that the basal dressing fertilizer with 120 kg N ha-1 together with the topdressing of 67–77 kg N ha-1 was recommended in regions with 443 mm average annual precipitation. For those with 364 mm and 290 mm average annual precipitation, the basal dressing fertilizer with 90 kg N ha-1 together with the topdressing of 67–77 kg N ha-1 and the basal dressing with 90 kg N ha-1 together with the topdressing fertilizer of 13–23 kg N ha-1 were recommended, respectively. Compared with farmers’ practice (i.e., the single basal dressing), although decreasing the total rate by 12–18 kg N ha-1, the optimized N strategies (i.e., the basal fertilizer together with one-time topdressing) can effectively promote grain N uptake, nitrogen harvest index, and agronomic efficiency of N. It also maintained similar grain yield, evapotranspiration, and crop water productivity. The minimum precipitation threshold was around 300 mm, where the topdressing N fertilizer had little influence on grain yield, evapotranspiration, and grain N uptake. Additionally, the largest advantage of optimized N strategies was saving N fertilizer and reducing the environment footprint of wheat production. However, the crop production under the optimized N strategies was more sensitive to the precipitation variation than that under farmers’ practice. Thus, if climate continues to change following historical data, greater harvest fluctuations are expected under optimized N strategies. To cope with the evolving climate change, optimized N strategies should be integrated with other management measures for smallholder farming households on the Loess Plateau.

Triggering receptor expressed on myeloid cells 1 (TREM1) is a cell surface receptor expressed on neutrophils, monocytes and some tissue macrophages, where it functions as an immunoregulator that controls myeloid cell responses. The activation of TREM1 is suggested to be an upregulation-based, ligands-induced and structural multimerization-mediated process, in which damage- and pathogen-associated molecular patterns play important roles. Activated TREM1 initiates an array of downstream signaling pathways that ultimately result in the production of pro-inflammatory cytokines and chemokines, whereby it functions as an amplifier of inflammation and is implicated in the pathogenesis of many inflammation-associated diseases. Over the past decade, there has been growing evidence for the involvement of TREM1 overactivation in tumor stroma inflammation and cancer progression. Indeed, it was shown that TREM1 promotes tumor progression, immunosuppression, and resistance to therapy by activating tumor-infiltrating myeloid cells. TREM1-deficiency or blockade provide protection against tumors and reverse the resistance to anti-PD-1/PD-L1 therapy and arginine-deprivation therapy in preclinical models. Here, we first review the structure, activation modes and signaling pathways of TREM1 and emphasize the role of soluble TREM1 as a biomarker of infection and cancer. We then focus on the role of TREM1 in cancer and systematically summarize its expression patterns, upregulation mechanisms and functions in tumor development and progression. Lastly, we discuss the therapeutic prospects of TREM1 inhibition, via effective pharmacological inhibitors, in treating cancer and other diseases.

Abstract The sex-determining region Y (SRY)-related high-mobility group (HMG) box (SOX) family, composed of 20 transcription factors, is a conserved family with a highly homologous HMG domain. Due to their crucial role in determining cell fate, the dysregulation of SOX family members is closely associated with tumorigenesis, including tumor invasion, metastasis, proliferation, apoptosis, epithelial-mesenchymal transition, stemness and drug resistance. Despite considerable research to investigate the mechanisms and functions of the SOX family, confusion remains regarding aspects such as the role of the SOX family in tumor immune microenvironment (TIME) and contradictory impacts the SOX family exerts on tumors. This review summarizes the physiological function of the SOX family and their multiple roles in tumors, with a focus on the relationship between the SOX family and TIME, aiming to propose their potential role in cancer and promising methods for treatment.

Abstract Objective This study aimed to investigate the clinical characteristics of severe fever with thrombocytopenia syndrome complicated by viral myocarditis (SFTS-VM) and analyze relevant influencing factors. Methods Retrospective analysis was conducted on clinical data from 79 SFTS-VM patients, categorized into common (SFTS-CVM, n = 40) and severe groups (SFTS-SVM, n = 39). Clinical manifestations, laboratory results, cardiac ultrasonography, and electrocardiogram features were analyzed. Univariate and multivariate analyses identified significant indicators, which were further assessed using ROC curves to predict SFTS-SVM. Results SFTS-SVM group exhibited higher rates of hypotension, shock, abdominal pain, cough with sputum, and consciousness disorders compared to SFTS-CVM group. Laboratory findings showed elevated platelet count, ALT, AST, amylase, lipase, LDH, D-dimer, procalcitonin, TNI, and NT-proBNP in SFTS-SVM. Abnormal electrocardiograms, especially atrial fibrillation, were more prevalent in SFTS-SVM (P 978.5U/L) and NT-proBNP (> 857.5pg/ml)) indicated increased likelihood of SFTS progression into SVM. Conclusion Elevated LDH, NT-proBNP, and consciousness disorders independently correlate with SFTS-SVM. LDH and NT-proBNP can aid in early identification of SFTS-SVM development when above specified thresholds.

Abstract Lipids play crucial roles in many biological processes. Mapping spatial distributions and examining the metabolic dynamics of different lipid subtypes in cells and tissues are critical to better understanding their roles in aging and diseases. Commonly used imaging methods (such as mass spectrometry-based, fluorescence labeling, conventional optical imaging) can disrupt the native environment of cells/tissues, have limited spatial or spectral resolution, or cannot distinguish different lipid subtypes. Here we present a hyperspectral imaging platform that integrates a Penalized Reference Matching algorithm with Stimulated Raman Scattering (PRM-SRS) microscopy. Using this platform, we visualize and identify high density lipoprotein particles in human kidney, a high cholesterol to phosphatidylethanolamine ratio inside granule cells of mouse hippocampus, and subcellular distributions of sphingosine and cardiolipin in human brain. Our PRM-SRS displays unique advantages of enhanced chemical specificity, subcellular resolution, and fast data processing in distinguishing lipid subtypes in different organs and species.

Abstract Transcription factor BTB domain and CNC homology 1 (BACH1) belongs to the Cap ‘n’ Collar and basic region Leucine Zipper (CNC-bZIP) family. BACH1 is widely expressed in mammalian tissues, where it regulates epigenetic modifications, heme homeostasis, and oxidative stress. Additionally, it is involved in immune system development. More importantly, BACH1 is highly expressed in and plays a key role in numerous malignant tumors, affecting cellular metabolism, tumor invasion and metastasis, proliferation, different cell death pathways, drug resistance, and the tumor microenvironment. However, few articles systematically summarized the roles of BACH1 in cancer. This review aims to highlight the research status of BACH1 in malignant tumor behaviors, and summarize its role in immune regulation in cancer. Moreover, this review focuses on the potential of BACH1 as a novel therapeutic target and prognostic biomarker. Notably, the mechanisms underlying the roles of BACH1 in ferroptosis, oxidative stress and tumor microenvironment remain to be explored. BACH1 has a dual impact on cancer, which affects the accuracy and efficiency of targeted drug delivery. Finally, the promising directions of future BACH1 research are prospected. A systematical and clear understanding of BACH1 would undoubtedly take us one step closer to facilitating its translation from basic research into the clinic.

Abstract Objective To delineate the metabolomic differences in plasma samples between patients with coronary artery disease (CAD) and those with concomitant CAD and type 2 diabetes mellitus (T2DM), and to pinpoint distinctive metabolites indicative of T2DM risk. Method Plasma samples from CAD and CAD-T2DM patients across three centers underwent comprehensive metabolomic and lipidomic analyses. Multivariate logistic regression was employed to discern the relationship between the identified metabolites and T2DM risk. Characteristic metabolites' metabolic impacts were further probed through hepatocyte cellular experiments. Subsequent transcriptomic analyses elucidated the potential target sites explaining the metabolic actions of these metabolites. Results Metabolomic analysis revealed 192 and 95 significantly altered profiles in the discovery (FDR

Background: Immune checkpoint inhibitor (ICI)-based combination therapy modalities for hepatocellular carcinoma (HCC) have achieved significant efficacy in clinical research and practice and have become the mainstay for the treatment of unresectable HCC. Summary: To better help clinicians use combination immunotherapy drugs and regimens rationally, effectively, and safely, the editorial board facilitated a discussion with multidisciplinary experts in the field, adopted the “Delphi” consensus formation method, and finally revised and completed the “Chinese Multidisciplinary Expert Consensus on the Immune Checkpoint Inhibitors (ICIs)-Based Combination Therapy for Hepatocellular Carcinoma (2023 Edition)” on the basis of the 2021 edition. Key Messages: This consensus primarily focuses on the principles and methods of clinical practice of combination therapy based on ICIs, aiming to summarize the recommendations for clinical application based on the latest research and expert experience and provide application guidance for clinicians.

Abstract There lacks real‐world study with a large sample size assessing olmesartan medoxomil‐amlodipine besylate (OM‐AML) tablet. Therefore, this study aimed to evaluate the efficacy and safety of OM‐AML tablet in patients with essential hypertension. Totally, 1341 patients from 36 medical centers with essential hypertension who took OM‐AML (20/5 mg) tablet were analyzed in the current prospective, single‐arm, multi‐center, real‐world study (SVK study). Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, week (W)4 and W8 were measured. The mean (±SE) change of SeSBP/SeDBP was ‐10.8 ± 0.4/‐6.6 ± 0.3 mmHg at W4 and ‐12.7 ± 0.5/‐7.6 ± 0.3 mmHg at W8, respectively. At W4, 78.8% and 29.0% patients achieved BP target by China and American Heart Association (AHA) criteria; at W8, 84.7% and 36.5% patients reached blood pressure (BP) target by China and AHA criteria, accordingly. Meanwhile, 80.2% and 86.4% patients achieved BP response at W4 and W8, respectively. Home‐measured SeSBP and SeDBP decreased from W1 to W8 (both p

Abstract Previous studies examining the association between hemoglobin concentration and hypertension have yielded inconsistent results. There is still a lack of evidence regarding the association between hemoglobin concentration and hypertension risk in native Tibetans at high altitude. We performed this cross‐sectional study in Luhuo County of Ganzi Tibetan Autonomous Prefecture (average altitude of 3500 m). In this study, we enrolled 1547 native Tibetans. The association between hemoglobin concentration and hypertension risk was examined by multivariate binary logistic regression and smooth curve fitting. Native Tibetans with hypertension had significantly higher hemoglobin concentrations than those without hypertension (165.9 ± 21.5 g/L vs. 157.7 ± 19.2 g/L, P

Abstract Bioisosteric design has become an essential approach in the development of drug molecules. Recent advancements in synthetic methodologies have enabled the rapid adoption of this strategy into drug discovery programs. Consequently, conceptionally innovative practices would be appreciated by the medicinal chemistry community. Here we report an expeditous synthetic method for synthesizing aryl difluoromethyl bicyclopentane (ADB) as a bioisostere of the benzophenone core. This approach involves the merger of light-driven C−F bond activation and strain-release chemistry under the catalysis of a newly designed N-anionic-based organic photocatalyst. This defluorinative coupling methodology enables the direct conversion of a wide variety of commercially available trifluoromethylaromatic C−F bonds (more than 70 examples) into the corresponding difluoromethyl bicyclo[1.1.1]pentanes (BCP) arenes/difluoromethyl BCP boronates in a single step. The strategy can also be applied to [3.1.1]and [4.1.1]propellane systems, providing access to analogues with different geometries. Moreover, we have successfully used this protocol to rapidly prepare ADB-substituted analogues of the bioactive molecule Adiporon. Biological testing has shown that the ADB scaffold has the potential to enhance the pharmacological properties of benzophenone-type drug candidates.

Abstract Long noncoding RNAs (lncRNAs) play important roles in regulating HIV-1 infection and virus-host interactions. However, it is unclear whether and how ART alters lncRNAs in HIV-infected patients. In the present study, we investigated changes of lncRNAs in PBMCs from HIV-1 patients pre- and post-ART. We identified a total of 974 lncRNAs whose expression was restored to normal levels after ART. Cis-acting analysis showed that six lncRNAs have cis-regulated target genes, among which RP11-290F5.1 and interferon regulatory factor 2 (IRF2) were reported to promote HIV replication. Furthermore, we found that lncRNA CTB-119C2.1, which regulates most mRNAs with differential expression in PBMCs from HIV-1 infected patients after ART, was significantly upregulated by RNA-seq and qRT-PCR assays. KEGG analysis of CTB-119C2.1-associated genes revealed that most of the genes are involved in the p53 signaling pathway and pathways related to cell cycle and DNA replication. Our findings thus reveal the dynamic change of lncRNAs in people living with HIV-1 pre- and post-ART and warrant further investigation of the role of lncRNAs in HIV-1 pathogenesis and treatment.

Background: This study aimed to investigate the effect of tolvaptan on metabolism and electrolyte homeostasis in patients with heart failure (HF). Methods: Literature databases, such as PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, VIP, and WanFang Data, were systematically searched for relevant trials from inception to November 4, 2023. We used the fixed effect model to combine the effect sizes and used I2 to test heterogeneity. Funnel plots were plotted to assess publication bias. Results: 16 studies were eligible for further analysis. No significant differences were identified in the incidence of hyperuricemia between the tolvaptan group and the placebo group (odds ratio (OR) = 1.23, 95% confidence interval (CI) = 0.97 to 1.55, p = 0.09). Tolvaptan decreased the levels of blood uric acid compared to traditional diuretics (mean difference (MD) = –82.8, 95% CI = –96.48 to –69.13, p < 0.00001). There was no significant difference in hypernatremia (OR = 1.62, 95% CI = 0.66 to 3.96, p = 0.29) and hyperkalemia (OR = 1.17, 95% CI = 0.93 to 1.48, p = 0.18) between the tolvaptan and control groups. Conclusions: Tolvaptan reduced the level of blood uric acid compared to conventional diuretics, and could be used as a substitute for traditional diuretics for HF patients with a high risk of gout.

Abstract Cholangiocarcinoma (CCA) is characterized by rapid onset and high chance of metastasis. Therefore, identification of novel therapeutic targets is imperative. E26 transformation‐specific homologous factor (EHF), a member of the E26 transformation‐specific transcription factor family, plays a pivotal role in epithelial cell differentiation and cancer progression. However, its precise role in CCA remains unclear. In this study, through in vitro and in vivo experiments, we demonstrated that EHF plays a profound role in promoting CCA by transcriptional activation of glioma‐associated oncogene homolog 1 (GLI1). Moreover, EHF significantly recruited and activated tumor‐associated macrophages (TAMs) through the C‐C motif chemokine 2/C‐C chemokine receptor type 2 (CCL2/CCR2) axis, thereby remodeling the tumor microenvironment. In human CCA tissues, EHF expression was positively correlated with GLI1 and CCL2 expression, and patients with co‐expression of EHF/GLI1 or EHF/CCL2 had the most adverse prognosis. Furthermore, the combination of the GLI1 inhibitor, GANT58, and CCR2 inhibitor, INCB3344, substantially reduced the occurrence of EHF‐mediated CCA. In summary, our findings suggest that EHF is a potential prognostic biomarker for patients with CCA, while also advocating the therapeutic approach of combined targeting of GLI1 and CCL2/CCR2‐TAMs to inhibit EHF‐driven CCA development.

ObjectivesThere is no theory to quantitatively describe the complex tumor ecosystem. At the same time, cancer immunotherapy is considered a revolution in oncology, but the methods used to describe tumors and the criteria used to evaluate efficacy are not keeping pace. The purpose of this study is to establish a new theory for quantitatively describing the tumor ecosystem, innovating the methods of tumor characterization, and establishing new efficacy evaluation criteria for cancer immunotherapy.MethodsBased on the mathematization of immune equilibrium theory and the establishment of immunodynamics in a previous study, the method of reverse immunodynamics was used, namely, the immune braking force was regarded as the tumor ecological force and the immune force was regarded as the tumor ecological braking force, and the concept of momentum in physics was applied to the tumor ecosystem to establish a series of tumor ecodynamic equations. These equations were used to solve the fundamental and applied problems of the complex tumor ecosystem.ResultsA series of tumor ecodynamic equations were established. The tumor ecological momentum equations and their component factors could be used to distinguish disease progression, pseudoprogression, and hyperprogression in cancer immunotherapy. On this basis, the adjusted tumor momentum equations were established to achieve the equivalence of tumor activity (including immunosuppressive activity and metabolic activity) and tumor volume, which could be used to calculate individual disease remission rate and establish new efficacy evaluation criteria (ieRECIST) for immunotherapy of solid tumor based on tumor ecodynamics. At the same time, the concept of moving cube-to-force square ratio and its expression were proposed to calculate the area under the curve of tumor ecological braking force of blood required to achieve an individual disease remission rate when the adjusted tumor ecological momentum was known.ConclusionsA new theory termed tumor ecodynamics emphasizing both tumor activity and tumor volume is established to solve a series of basic and applied problems in the complex tumor ecosystem. It can be predicted that the future will be the era of cancer immune ecotherapy that targets the entire tumor ecosystem.

Crop sap flow is a critical indicator of crop water demand, and predicting its variation trend is essential for adjusting agricultural planting structure and managing water resource in hyper-arid areas. Presently, research on crop sap flow in hyper-arid areas faces limitations due to inadequate meteorological data and restricted monitoring duration, leading to imprecise assessments of environmental impacts on future crop sap flow. Consequently, this hinders effective irrigation scheduling and oasis sustainable development policy. This study analyzed the sap flow changes characteristics of two economic crops (red jujube and walnut) at different time scales in the oasis in the south of Tarim Basin from 2017 to 2021 and the relationship between four environmental factors (solar radiation, temperature, relative humidity and vapor pressure deficit) and the sap flow of red jujube and walnut. By using the Random Forest (RF) model and the future climate data, the sap flow of the two economic crops from 2020 to 2100 was predicted. The results showed that: (1) walnut had a longer daily peak sap flow duration compared to red jujube, whereas red jujube showed a longer monthly peak sap flow duration; (2) in hyper-arid areas, the moisture and temperature directly influenced crop sap flow, while other environmental factor affected these two factors; (3) with the temperature increases, the water demand of red jujube and walnut in Cele Oasis will exceed local water resources carrying capacity. To achieve sustainable development of oasis, it is vital to consider future climatic changes in planning the expansion and crop structure.

Abstract N6‐methyladenosine (m6A) modification orchestrates cancer formation and progression by affecting the tumor microenvironment (TME). For hepatocellular carcinoma (HCC), immune evasion and angiogenesis are characteristic features of its TME. The role of YTH N6‐methyladenosine RNA binding protein 2 (YTHDF2), as an m6A reader, in regulating HCC TME are not fully understood. Herein, it is discovered that trimethylated histone H3 lysine 4 and H3 lysine 27 acetylation modification in the promoter region of YTHDF2 enhanced its expression in HCC, and upregulated YTHDF2 in HCC predicted a worse prognosis. Animal experiments demonstrated that Ythdf2 depletion inhibited spontaneous HCC formation, while its overexpression promoted xenografted HCC progression. Mechanistically, YTHDF2 recognized the m6A modification in the 5′‐untranslational region of ETS variant transcription factor 5 (ETV5) mRNA and recruited eukaryotic translation initiation factor 3 subunit B to facilitate its translation. Elevated ETV5 expression induced the transcription of programmed death ligand‐1 and vascular endothelial growth factor A, thereby promoting HCC immune evasion and angiogenesis. Targeting YTHDF2 via small interference RNA‐containing aptamer/liposomes successfully both inhibited HCC immune evasion and angiogenesis. Together, this findings reveal the potential application of YTHDF2 in HCC prognosis and targeted treatment.

Hepatocellular carcinoma (HCC) has a poor prognosis, and the efficacy of current therapeutic strategies is extremely limited in advanced diseases. Our previous study reported that protein tyrosine phosphatase receptor epsilon (PTPRE) is a promoting factor in HCC progression. In this study, our objective was to evaluate the treatment effect of PTPRE inhibitors in different HCC preclinical models. Our results indicated that the PTPRE inhibitory compound 63 (Cpd-63) inhibited tumor cell proliferation, migration, and HCC organoid growth. Mechanism research revealed that Cpd-63 could inhibit the expression of MYC and MYC targets by inhibiting the activation of SRC. Additionally, we found that Cpd-63 could improve the response of sorafenib in HCC cells. In conclusion, we demonstrated that the PTPRE inhibitors represented a potential therapeutic agent for HCC management.

Objective: Diets rich in live microbes can bring various health benefits. However, the association between dietary live microbe intake and frailty has not been studied. Methods: The study utilized data from the National Health and Nutrition Examination Survey (NHANES) 2007–2018. A total of 11,529 participants were included. Sanders et al. classified the level of live microbes in foods into low (107 CFU/g). With the methodology of Sanders et al. and dietary questionnaire data, participants were divided into three groups: (1) low dietary live microbe intake group (only low-level foods), (2) medium dietary live microbe intake group (medium but not high-level foods), and (3) high dietary live microbe intake group (any high-level foods). Additionally, foods with medium and high live microbe content were aggravated as MedHi. Frailty index ≥0.25 is defined as frailty. The weighted logistic regression analysis was conducted to examine the relationship between the intake of dietary live microbe and frailty. The restricted cubic splines (RCS) were employed to detect the nonlinear relationships. Results: In the fully adjusted model, participants with high dietary intake of live microbe had a significantly lower risk of frailty than those with low dietary intake of live microbe (OR = 0.67, 95% CI: 0.56, 0.79). For every 100 grams of MedHi food consumed, the risk of frailty decreased by 11% (OR = 0.89, 95% CI: 0.85, 0.92) after adjusting all covariates. The RCS indicated the existence of non-linear relationships. For those who consumed less than 100 grams of MedHi, increasing MedHi intake may significantly reduce the risk of frailty, but after exceeding 100 grams, the curve gradually levels off. Conclusions: Our results suggested that increasing dietary live microbe intake was associated with a lower risk of frailty. However, more research is needed to verify this.

Objective Early detection, diagnosis, treatment and management of chronic obstructive pulmonary disease can lower morbidity and perhaps mortality. This study aimed to evaluate the effect of the application of standardized management against the background of the rapid development of the big data center of modern internet of things technology. Methods Participants ≥40 years of age with chronic obstructive pulmonary disease presenting at Xiamen Medical College Affiliated Haicang Hospital from October 2019 to October 2020 were selected as the observation patients based on the Internet of Things big data center for chronic obstructive pulmonary disease standardized management, and control patients from the community were selected for without down to the chronic obstructive pulmonary disease standardized management. Follow-up after 2 years of patient health records and acute episodes using the World Health Organization Quality of Life Questionnaire-Brief version to evaluate the quality of life of the two groups revealed differences. Results The results of comparative analysis of the number of acute attacks before and after follow-up in the observation and control groups after propensity score matching showed that the decrease in acute episodes before and after in the observation group was significant compared with that in the control group ( t = −3.664, P

Abstract Introduction Hypertension increases the risk of cardiovascular disease. Uncontrolled nocturnal blood pressure is prevalent in patients taking antihypertensive medication, with an incidence rate of 30–60%. Although chronotherapy with antihypertensive agents may provide a new direction for effective control of nocturnal blood pressure, the clinical evidence base remains controversial. This research is presently underway to compare the effects of morning and bedtime administration of antihypertensive medication on nocturnal reduction and circadian rhythm of blood pressure in patients with hypertension. Methods and analysis This study is being performed as a randomized, multicenter, open-label, parallel-group, clinical trial in which 720 participants are to undergo 24-h ambulatory blood pressure measurement (ABPM) and office blood pressure measurement (OBPM) at baseline before being randomly assigned to a morning (6–10 am) or a bedtime (6–10 pm) administration group. Each participant receives one 20/5-mg tablet of olmesartan/amlodipine (OA) daily for 4 weeks and is then followed up at 4-week intervals for a total of 12 weeks. During follow-up, the OA dosage is adjusted according to the ABPM and OBPM results. Patients with uncontrolled hypertension at the first follow-up visit will receive an increase in OA dosage to 1.5 tablets/day. For patients with blood pressure that is still uncontrolled after a further 4 weeks, the dosage of OA can be increased to 2 tablets/day. The primary objective is the reduction in mean nocturnal systolic blood pressure between baseline and week 12. The secondary objectives are the reduction in ambulatory blood pressure at weeks 4 and 12 and the blood pressure control rate at weeks 4, 8, and 12. Discussion Antihypertensive chronotherapy remains controversial. A superiority test hypothesis design has been adopted for this trial, in which all participants will be taking the same antihypertensive medication. We anticipate that our findings will determine if nocturnal blood pressure control in Chinese patients with essential hypertension varies according to whether antihypertensive medication is taken in the morning or at bedtime. This study may provide scientific evidence for the application of chronotherapy in clinical practice. Trial registration ChiCTR2200059719. Registered on 10 May 2022 ( http://www.chictr.org.cn/edit.aspx?pid=169782&htm=4 ) {2a,2b}

The purpose of this study was to compare the effects of different load intensities with rest intervals between sets on heart rate, rating of perceived exertion (RPE), power output, and blood lactate concentration during a squat strength endurance training protocol. A total of 4 sets of strength endurance tests were performed on 15 national Level 2 or above athletes with different load intensities (30% of 1 repetition maximum (1RM), 50% 1RM) and different rest intervals between sets (1 min, 2 min), 20 reps per set. Mean power (P-mean), mean heart-rate (HRmean) and RPE variations during the exercise were collected by using a linear position transducer, heart rate monitor, and Borg 6–20 scale. Besides, finger blood was collected before and after the exercise, and analyzed by using a blood lactate analyzer. HRmean, P-mean and RPE values were significantly higher at 50% 1RM load intensity than at 30% 1RM (p < 0.01), HRmean was significantly higher at 1 min rest interval than at 2 min between sets, while P-mean was significantly higher at 2 min rest interval than at 1 min between sets (p < 0.05); at 30% 1RM loading intensity, blood lactate concentrations were significantly higher at the completion of exercise for the 1 min rest interval between sets than for the 2 min (p < 0.01). However, at 50% 1RM loading intensity, blood lactate increased similarly at the completion of training in multiple sets, independent of the rest interval between sets. From a practical point of view, the results suggest that a 1 min rest interval between sets may be sufficient in a strength endurance training protocol when the load intensity is 30% 1RM. However, when the load intensity is 50% 1RM, we suggest that a 2 min rest interval between sets is required for optimal recovery and maintenance of power output.

Abstract Robotic 3D bin packing (R‐3dBPP), aiming to place deformed cases in various sizes in the container without fences, is a comprehensive application that includes perception, planning, execution, and hardware design. Traditional studies assume that the context of the real space must be accurately perceived and represented. However, disjunctions between the planner and reality are unavoidable in R‐3dBPP, especially with low‐cost sensors. As far as the author knows, there is no practical solution. In this paper, the above assumption is discarded and the typical types of uncertainties prevalent to guide the design of the algorithms are formulated. A new online bin‐packing algorithm is proposed, keeping deformed boxes stacked in close contact with each other, so that the whole pallet is kept stable by friction between the boxes and the container. In order to meet the requirement of close contact under the non‐negligible errors from sensors and planners, a compliant‐based motion planning system is introduced. It replaces the precision‐based feedback with a compliant end‐effector and accompanying motion strategies. Last but not least, a complete online bin‐packing robot system is developed and the system's performance under the influence of the uncertainties mentioned above through simulation and physical experiments is evaluated.