Targeting tumor­associated macrophages: Critical players in tumor progression and therapeutic strategies (Review).

Tumor­associated macrophages (TAMs) are essential components of the tumor microenvironment (TME) and display phenotypic heterogeneity and plasticity associated with the stimulation of bioactive molecules within the TME. TAMs predominantly exhibit tumor­promoting phenotypes involved in tumor progression, such as tumor angiogenesis, metastasis, immunosuppression and resistance to therapies. In addition, TAMs have the potential to regulate the cytotoxic elimination and phagocytosis of cancer cells and interact with other immune cells to engage in the innate and adaptive immune systems. In this context, targeting TAMs has been a popular area of research in cancer therapy, and a comprehensive understanding of the complex role of TAMs in tumor progression and exploration of macrophage­based therapeutic approaches are essential for future therapeutics against cancers. The present review provided a comprehensive and updated overview of the function of TAMs in tumor progression, summarized recent advances in TAM­targeting therapeutic strategies and discussed the obstacles and perspectives of TAM­targeting therapies for cancers.

How the ecological structure affects the aesthetic atmosphere of the landscape: Evaluation of the landscape Beauty of Xingqing Palace Park in Xi'an.

In landscape appreciation, what tourists directly perceive is the atmosphere of the landscape. This paper introduces the concept of "Ecological Structure" from Gernot Böhme's theory of atmospheric aesthetics into the assessment of landscapes, utilizing atmosphere as a bridge between horticultural ecology, aesthetics, and culture. It examines the relationship between the objective environment and subjective perception. This study conducted a field survey of Xingqing Palace Park and selected the waterside plant landscape that directly reflects the atmosphere of the royal garden as the research object. In the first stage of this study, Scenic Beauty Estimation was used to evaluate the overall beauty of 32 landscape units; in the second stage, the Delphi method and Analytic Hierarchy Process were used to evaluate the ecological structures that affect the garden landscape atmosphere; in the third stage, the two evaluation results of the Kendall's W concord coefficient test Analytic Hierarchy Process and Scenic Beauty Estimation have high consistency, which shows that the atmosphere is great value to the beauty of the landscape. This study provides designers with a means to create a garden atmosphere using ecological structures and provides new ideas for landscape design.

Photoinduced Catalyst-Free Deuterodefunctionalization of Aryltriazenes with CDCl3.

A photoinduced deuterodetriazenation of aryltriazenes with CDCl3 under catalyst-free conditions is reported. The reactions featured simple operation, ecofriendly conditions, readily available reagents, inexpensive D sources, precise site selectivity, and a wide range of substrates. Since aryltriazenes could be readily synthesized from arylamine, this protocol can be used as a general method for easily and accurately incorporating deuterium into aromatic systems by using CDCl3 as a D source.

Visible-Light-Driven Bifunctional Photocatalytic Radical-Cascade Selenocyanation/Cyclization of Acrylamides with KSeCN.

A visible-light-induced radical-cascade selenocyanation/cyclization of N-alkyl-N-methacryloyl benzamides, 2-aryl-N-acryloyl indoles, and N-methacryloyl-2-phenylbenzimidazoles with potassium isoselenocyanate (KSeCN) was developed. The reactions were carried out with inexpensive KSeCN as a selenocyanation reagent, potassium persulfate as an oxidant, 2,4,6-triphenylpyrylium tetrafluoroborate as a bifunctional catalyst for phase-transfer catalysis, and photocatalysis. A library of selenocyanate-containing isoquinoline-1,3(2H,4H)-diones, indolo[2,1-a]isoquinoline-6(5H)-ones, and benzimidazo[2,1-a]isoquinolin-6(5H)-ones were achieved in moderate to excellent yields at room temperature under visible-light and ambient conditions. Importantly, the present protocol features mild reaction conditions, large-scale synthesis, simple manipulation, product derivatization, good functional group, and heterocycle tolerance.

Visible-Light-Promoted and EDA Complex-Driven [4 + 2] Annulation for the Construction of Naphtho[1',2':4,5]imidazo[1,2-a]pyridines.

A green visible-light-promoted and electron donor-acceptor (EDA) complex-driven synthetic strategy for the construction of value-added naphtho[1',2':4,5]imidazo[1,2-a]pyridines from 2-arylimidazo[1,2-a]pyridines with Z-α-bromocinnamaldehydes has been accomplished under photocatalyst- and transition-metal-free conditions. This efficient annulation approach provides a new and straightforward pathway for the annulative π-extension of imidazo[1,2-a]pyridine-based aromatics. Moreover, the sustainable methodology exhibits simple operation, a wide range of substrates, benign conditions, and good functional group compatibility.

Pig-eRNAdb: a comprehensive enhancer and eRNA dataset of pigs.

Enhancers and the enhancer RNAs (eRNAs) have been strongly implicated in regulations of transcriptions. Based the multi-omics data (ATAC-seq, ChIP-seq and RNA-seq) from public databases, Pig-eRNAdb is a dataset that comprehensively integrates enhancers and eRNAs for pigs using the machine learning strategy, which incorporates 82,399 enhancers and 37,803 eRNAs from 607 samples across 15 tissues of pigs. This user-friendly dataset covers a comprehensive depth of enhancers and eRNAs annotation for pigs. The coordinates of enhancers and the expression patterns of eRNAs are downloadable. Besides, thousands of regulators on eRNAs, the target genes of eRNAs, the tissue-specific eRNAs, and the housekeeping eRNAs are also accessible as well as the sequence similarity of eRNAs with humans. Moreover, the tissue-specific eRNA-trait associations encompass 652 traits are also provided. It will crucially facilitate investigations on enhancers and eRNAs with Pig-eRNAdb as a reference dataset in pigs.

Pd-Catalyzed Direct C7 Trifluoromethylation of Indolines with Umemoto's Reagent.

An efficient palladium-catalyzed region-selective C7-trifluoromethylation of indolines using commercially available Umemoto's reagent was reported. The reaction utilizing Umemoto's reagent as CF3 radical precursor, pyrimidine as a removable directing group, Pd(II) as a catalyst, and Cu(II) as an oxidant furnished the required products with excellent regioselectivities and good yields. The present strategy has good region-selectivity, broad substrate scope, and scale-up application. Additionally, the present method was underlined by the direct C-1 trifluoromethylation of carbazoles. Furthermore, C7 trifluoromethylated indole can also be easily obtained via Pd-catalyzed direct C-7 trifluoromethylation/oxidation/deprotection sequential reactions.

Comparison of manual sutures and laparoscopic stapler for pancreatic stump closure techniques in robotic distal pancreatectomy: a single-center experience.

BACKGROUND: Postoperative pancreatic fistulas (POPFs) are prevalent and major postoperative complications of distal pancreatectomy (DP). There are numerous ways to manage the pancreatic stump. However, no single approach has been shown to be consistently superior. Moreover, the potential role of robotic systems in reducing POPFs has received little attention. METHODS: The clinical data of 119 patients who had consecutively received robotic distal pancreatectomy between January 2019 and December 2022 were retrospectively analyzed. Patients were divided into two groups according to the method of handling the pancreatic stump. The attributes of the patients and the variables during the perioperative period were compared. RESULTS: The analysis included 72 manual sutures and 47 stapler procedures. The manual suture group had a shorter operative time (removing installation time) than the stapler group (125.25 ± 63.04 min vs 153.30 ± 62.03 min, p = 0.019). Additionally, the manual suture group had lower estimated blood loss (50 mL vs 100 mL, p = 0.009) and a shorter postoperative hospital stay. There were no significant differences in the incidence of clinically relevant POPFs between the two groups (18.1% vs 23.4%, P > 0.05). No perioperative death occurred in either group. CONCLUSION: The manual suturing technique was shown to have an incidence of POPFs similar to the stapler technique in robotic distal pancreatectomy and to be safe and feasible.

Striking a growth-defense balance: Stress regulators that function in maize development.

Maize (Zea mays) cultivation is strongly affected by both abiotic and biotic stress, leading to reduced growth and productivity. It has recently become clear that regulators of plant stress responses, including the phytohormones abscisic acid (ABA), ethylene (ET), and jasmonic acid (JA), together with reactive oxygen species (ROS), shape plant growth and development. Beyond their well established functions in stress responses, these molecules play crucial roles in balancing growth and defense, which must be finely tuned to achieve high yields in crops while maintaining some level of defense. In this review, we provide an in-depth analysis of recent research on the developmental functions of stress regulators, focusing specifically on maize. By unraveling the contributions of these regulators to maize development, we present new avenues for enhancing maize cultivation and growth while highlighting the potential risks associated with manipulating stress regulators to enhance grain yields in the face of environmental challenges.

The conservation of allelic DNA methylation and its relationship with imprinting in maize.

Genomic imprinting refers to allele-specific expression of genes depending on parental origin, and it is regulated by epigenetic modifications. Intraspecific allelic variation for imprinting has been detected; however, the intraspecific genome-wide allelic epigenetic variation in maize and its correlation with imprinting variants remain unclear. Here, three reciprocal hybrids were generated by crossing Zea mays inbred lines CAU5, B73, and Mo17 in order to examine the intraspecific conservation of the imprinted genes in the kernel. The majority of imprinted genes exhibited intraspecific conservation, and these genes also exhibited interspecific conservation (rice, sorghum, and Arabidopsis) and were enriched in some specific pathways. By comparing intraspecific allelic DNA methylation in the endosperm, we found that nearly 15% of DNA methylation existed as allelic variants. The intraspecific whole-genome correlation between DNA methylation and imprinted genes indicated that DNA methylation variants play an important role in imprinting variants. Disruption of two conserved imprinted genes using CRISPR/Cas9 editing resulted in a smaller kernel phenotype. Our results shed light on the intraspecific correlation of DNA methylation variants and variation for imprinting in maize, and show that imprinted genes play an important role in kernel development.

Protocadherin-1 serves as a prognostic biomarker and promotes pancreatic cancer progression by suppressing CD8+ T cell infiltration through CCL5-CCR5 axis.

Previous studies have shown that Protocadherins (PCDHs) enhance tumor proliferation, invasion, and metastasis; yet their role in pancreatic cancer (PC) progression and the tumor immune microenvironment remains unclear. This study aims to elucidate the role of PCDH1 in different cancer types, with a particular focus on its impact on immune suppression in PC. Utilizing data from TCGA, GTEx, and Gent2 databases, we assessed the expression of PCDH1 across various cancer types. The prognostic value of PCDH1 was demonstrated through Cox regression, Kaplan-Meier analysis, and ROC curve, while its relationship with gene mutations, tumor mutational burden (TMB), immune cell infiltration, and other clinical factors was investigated using Spearman correlation. Furthermore, the effect of PCDH1 on PC malignancy was experimentally validated by a series of in vitro and in vivo assays. Our results show a significant upregulation of PCDH1 in various tumor types, which is associated with poor prognosis, suggesting its potential application as an independent prognostic biomarker. Notably, in PC, PCDH1 exhibited significant associations with gene mutations, TMB, and immune cell infiltration. Clinical validations revealed a correlation between high PCDH1 expression and poor prognosis, coupled with a low level of CD8+ T cell infiltration. Furthermore, both in vitro and in vivo experiments confirmed the role of PCDH1 in promoting PC cell proliferation and migration while inhibiting CD8+ T cell recruitment through its modulation of CCL5-CCR5 axis. In conclusion, PCDH1 regulates the proliferation and migration of PC cells as well as CD8+ T cell infiltration in PC. PCDH1 may serve as a prognostic biomarker in multiple tumor types.

Diosbulbin C, a novel active ingredient in Dioscorea bulbifera L. extract, inhibits lung cancer cell proliferation by inducing G0/G1 phase cell cycle arrest.

BACKGROUND: Despite the critical progress of non-small cell lung cancer (NSCLC) therapeutic approaches, the clinical outcomes remain considerably poor. The requirement of developing novel therapeutic interventions is still urgent. In this study, we showed for the first time that diosbulbin C, a natural diterpene lactone component extracted from traditional Chinese medicine Dioscorea bulbifera L., possesses high anticancer activity in NSCLC. METHODS: A549 and NCI-H1299 cells were used. The inhibitory effects of the diosbulbin C on NSCLC cell proliferation were evaluated using cytotoxicity, clone formation, EdU assay, and flow cytometry. Network pharmacology methods were used to explore the targets through which the diosbulbin C inhibited NSCLC cell proliferation. Molecular docking, qRT-PCR, and western blotting were used to validate the molecular targets and regulated molecules of diosbulbin C in NSCLC. RESULTS: Diosbulbin C treatment in NSCLC cells results in a remarkable reduction in cell proliferation and induces significant G0/G1 phase cell cycle arrest. AKT1, DHFR, and TYMS were identified as the potential targets of diosbulbin C. Diosbulbin C may inhibit NSCLC cell proliferation by downregulating the expression/activation of AKT, DHFR, and TYMS. In addition, diosbulbin C was predicted to exhibit high drug-likeness properties with good water solubility and intestinal absorption, highlighting its potential value in the discovery and development of anti-lung cancer drugs. CONCLUSIONS: Diosbulbin C induces cell cycle arrest and inhibits the proliferation of NSCLC cells, possibly by downregulating the expression/activation of AKT, DHFR, and TYMS.

Electrochemical Synthesis of α-Thiocyanated/Methoxylated Ketones Using Enol Acetates.

We have developed the synthesis of α-substituted ketone compounds with enol acetates in an electrochemical way. By using cheap NH4SCN and MeOH as the radical sources, a series of valuable α-thiocyanates/methoxy ketones were synthesized under mild electrolysis conditions in acceptable yields with diverse functional group compatibility. Additionally, the scale-up experiment and synthetic transformations reveal potential applications in organic synthesis.

Causal effect between gut microbiota and pancreatic cancer: a two-sample Mendelian randomization study.

BACKGROUND: Gut microbiota (GM) comprises a vast and diverse community of microorganisms, and recent studies have highlighted the crucial regulatory roles of various GM and their secreted metabolites in pancreatic cancer (PC). However, the causal relationship between GM and PC has yet to be confirmed. METHODS: In the present study, we used two-sample Mendelian randomization (MR) analysis to investigate the causal effect between GM and PC, with genome-wide association study (GWAS) from MiBioGen consortium as an exposure factor and PC GWAS data from FinnGen as an outcome factor. Inverse variance weighted (IVW) was used as the primary method for this study. RESULTS: At the genus level, we observed that Senegalimassilia (OR: 0.635, 95% CI: 0.403-0.998, P = 0.049) exhibited a protective effect against PC, while Odoribacter (OR:1.899, 95%CI:1.157-3.116, P = 0.011), Ruminiclostridium 9(OR:1.976,95%CI:1.128-3.461, P = 0.017), Ruminococcaceae (UCG011)(OR:1.433, 95%CI:1.072-1.916, P = 0.015), and Streptococcus(OR:1.712, 95%CI:1.071-1.736, P = 0.025) were identified as causative factors for PC. Additionally, sensitivity analysis, Cochran's Q test, the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger regression indicated no heterogeneity, horizontal pleiotropy, or reverse causality between GM and PC. CONCLUSIONS: Our analysis establishes a causal effect between specific GM and PC, which may provide new insights into the potential pathogenic mechanisms of GM in PC and the assignment of effective therapeutic strategies.

Designing the pressure-dependent shear modulus using tessellated granular metamaterials.

Jammed packings of granular materials display complex mechanical response. For example, the ensemble-averaged shear modulus 〈G〉 increases as a power law in pressure p for static packings of soft spherical particles that can rearrange during compression. We seek to design granular materials with shear moduli that can either increase or decrease with pressure without particle rearrangements even in the large-system limit. To do this, we construct tessellated granular metamaterials by joining multiple particle-filled cells together. We focus on cells that contain a small number of bidisperse disks in two dimensions. We first study the mechanical properties of individual disk-filled cells with three types of boundaries: periodic boundary conditions (PBC), fixed-length walls (FXW), and flexible walls (FLW). Hypostatic jammed packings are found for cells with FLW, but not in cells with PBC and FXW, and they are stabilized by quartic modes of the dynamical matrix. The shear modulus of a single cell depends linearly on p. We find that the slope of the shear modulus with pressure λ_{c}<0 for all packings in single cells with PBC where the number of particles per cell N≥6. In contrast, single cells with FXW and FLW can possess λ_{c}>0, as well as λ_{c}<0, for N≤16. We show that we can force the mechanical properties of multicell granular metamaterials to possess those of single cells by constraining the end points of the outer walls and enforcing an affine shear response. These studies demonstrate that tessellated granular metamaterials provide a platform for the design of soft materials with specified mechanical properties.

Electrooxidative Hofmann Rearrangement of Phthalimides to Access Anthranilate Derivatives.

A simple and efficient electrooxidative Hofmann rearrangement reaction of phthalimides was developed. Anthranilate derivatives were synthesized in moderate to good yields under green and mild conditions using phthalimides as a rearrangement precursor. This approach not only provides a strategy for synthesizing anthranilates and deuterated anthranilate derivatives with high deuteration efficiency but also realizes efficient conversion at the gram scale. A possible reaction mechanism is proposed.

Genomic Sequencing as a First-Tier Screening Test and Outcomes of Newborn Screening.

Importance: Newborn screening via biochemical tests is in use worldwide. The availability of genetic sequencing has allowed rapid screening for a substantial number of monogenic disorders. However, the outcomes of this strategy have not been evaluated in a general newborn population. Objective: To evaluate the outcomes of applying gene panel sequencing as a first-tier newborn screening test. Design, Setting, and Participants: This cohort study included newborns who were prospectively recruited from 8 screening centers in China between February 21 and December 31, 2021. Neonates with positive results were followed up before July 5, 2022. Exposures: All participants were concurrently screened using dried blood spots. The screen consisted of biochemical screening tests and a targeted gene panel sequencing test for 128 conditions. The biochemical and genomic tests could both detect 43 of the conditions, whereas the other 85 conditions were screened solely by the gene panel. Main Outcomes and Measures: The primary outcomes were the number of patients detected by gene panel sequencing but undetected by the biochemical test. Results: This study prospectively recruited 29 601 newborns (15 357 [51.2%] male). The mean (SD) gestational age was 39.0 (1.5) weeks, and the mean (SD) birth weight was 3273 (457) g. The gene panel sequencing screened 813 infants (2.7%; 95% CI, 2.6%-2.9%) as positive. By the date of follow-up, 402 infants (1.4%; 95% CI, 1.2%-1.5%) had been diagnosed, indicating the positive predictive value was 50.4% (95% CI, 50.0%-53.9%). The gene panel sequencing identified 59 patients undetected by biochemical tests, including 20 patients affected by biochemically and genetically screened disorders and 39 patients affected by solely genetically screened disorders, which translates into 1 out of every 500 newborns (95% CI, 1/385-1/625) benefiting from the implementation of gene panels as a first-tier screening test. Conclusions and Relevance: In this cohort study, the use of gene panel sequencing in a general newborn population as a first-tier screening test improved the detection capability of traditional screening, providing an evidence-based suggestion that it could be considered as a crucial method for first-tier screening.

Biological characteristics of pancreatic ductal adenocarcinoma: Initiation to malignancy, intracellular to extracellular.

Pancreatic ductal adenocarcinoma (PDAC) is a highly life-threatening tumour with a low early-detection rate, rapid progression and a tendency to develop resistance to chemotherapy. Therefore, understanding the regulatory mechanisms underlying the initiation, development and metastasis of pancreatic cancer is necessary for enhancing therapeutic effectiveness. In this review, we summarised single-gene mutations (including KRAS, CDKN2A, TP53, SMAD4 and some other less prevalent mutations), epigenetic changes (including DNA methylation, histone modifications and RNA interference) and large chromosome alterations (such as copy number variations, chromosome rearrangements and chromothripsis) associated with PDAC. In addition, we discussed variations in signalling pathways that act as intermediate oncogenic factors in PDAC, including PI3K/AKT, MAPK/ERK, Hippo and TGF-ß signalling pathways. The focus of this review was to investigate alterations in the microenvironment of PDAC, particularly the role of immunosuppressive cells, cancer-associated fibroblasts, lymphocytes, other para-cancerous cells and tumour extracellular matrix in tumour progression. Peripheral axons innervating the pancreas have been reported to play a crucial role in the development of cancer. In addition, tumour cells can influence the behaviour of neighbouring non-tumour cells by secreting certain factors, both locally and at a distance. In this review, we elucidated the alterations in intracellular molecules and the extracellular environment that occur during the progression of PDAC. Altogether, this review may enhance the understanding of the biological characteristics of PDAC and guide the development of more precise treatment strategies.

Integrating ferroptosis-related genes (FRGs) and prognostic models to enhance UCEC outcome prediction and therapeutic insights.

Ferroptosis is closely associated with uterine corpus endometrial carcinoma (UCEC) development. This project aimed to identify new potential biomarkers to predict the prognosis of UCEC. In this work, UCEC transcriptome data along with clinical information was retrieved from the TCGA database including a total of 382 FRGs. We performed univariate Cox regression analysis to evaluate ferroptosis-related genes (FRGs) for prognostic significance. The genes with prognostic significance were then analyzed using LASSO-Cox to construct a prognosis model. The model genes were further characterized through various proteomic analyses and expression detection in clinical samples. A multivariate Cox regression model was constructed containing four FRGs (CDKN1A, CDKN2A, CEBPG, NOS2). Among four FRGs, higher expressions of CDKN2A, CEBPG, and NOS2 were associated with poorer overall survival probability, while higher expression of CDKN1A was associated with better overall survival probability. The area under the receiver operating characteristic curve of the risk model was 0.617, 0.688, and 0.693 for 1 year, 3 years, and 5 years, respectively. Moreover, proteomic analysis showed that the protein expression of CDKN1A, CDKN2A, and CEBPG was higher in tumor tissues than that in normal tissues. Higher protein expression of CDKN1A and CDKN2A predicted poorer survival probability. Besides, CDKN1A protein had an interaction relationship with CDKN2A protein or NOS2 protein. In clinical samples, all four FRGs were upregulated in UCEC tissues, regardless of gene expression or protein expression. Our four FRGs risk model provides new insights for predicting the prognosis of UCEC patients.