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Annals of the American Thoracic Society Jul 2024
Topics: Humans; Cystic Fibrosis Transmembrane Conductance Regulator; Cystic Fibrosis; Quinolones; Aminophenols; Benzodioxoles; Aminopyridines; Health Services Accessibility; Chloride Channel Agonists
PubMed: 38949605
DOI: 10.1513/AnnalsATS.202404-439ED -
Journal of the American Chemical Society Jul 2024Advanced in vitro diagnosis technologies are highly desirable in early detection, prognosis, and progression monitoring of diseases. Here, we engineer a multiplex...
Advanced in vitro diagnosis technologies are highly desirable in early detection, prognosis, and progression monitoring of diseases. Here, we engineer a multiplex protein biosensing strategy based on the tunable liquid confinement self-assembly of multi-material heterochains, which show improved sensitivity, throughput, and accuracy compared to standard ELISA kits. By controlling the material combination and the number of ligand nanoparticles (NPs), we observe robust near-field enhancement as well as both strong electromagnetic resonance in polymer-semiconductor heterochains. In particular, their optical signals show a linear response to the coordination number of the semiconductor NPs in a wide range. Accordingly, a visible nanophotonic biosensor is developed by functionalizing antibodies on central polymer chains that can identify target proteins attached to semiconductor NPs. This allows for the specific detection of multiple protein biomarkers from healthy people and pancreatic cancer patients in one step with an ultralow detection limit (1 pg/mL). Furthermore, rapid and high-throughput quantification of protein expression levels in diverse clinical samples such as buffer, urine, and serum is achieved by combining a neural network algorithm, with an average accuracy of 97.3%. This work demonstrates that the heterochain-based biosensor is an exemplary candidate for constructing next-generation diagnostic tools and suitable for many clinical settings.
PubMed: 38949598
DOI: 10.1021/jacs.4c04460 -
The Journal of Clinical Investigation Jul 2024Cystic fibrosis is a debilitating disease characterized by a poor medical prognosis due to devastating lung injury. Recent medical advances targeting the major genetic...
Cystic fibrosis is a debilitating disease characterized by a poor medical prognosis due to devastating lung injury. Recent medical advances targeting the major genetic mutation ΔF508 of the cystic fibrosis transmembrane conductance regulator (CFTR) protein have dramatically increased the lifespan of patients with this mutation. This development has led to major changes in the field and has pushed research beyond the ion transport nature of cystic fibrosis and toward multiorgan physiological reprogramming. In this issue of the JCI, Bae, Kim, and colleagues utilized a large animal pig model prior to the onset of disease. They revealed metabolic reprogramming and organ crosstalk that occurred prior to disease progression. These findings provide paradigm-shifting insight into this complex disease.
Topics: Cystic Fibrosis; Animals; Humans; Cystic Fibrosis Transmembrane Conductance Regulator; Swine; Disease Models, Animal
PubMed: 38949023
DOI: 10.1172/JCI182329 -
Frontiers in Genetics 2024The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the...
The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the maturation and homeostasis of multiple organs. Recently, we have shown that inactivation in the mouse pancreas alters growth and immune gene expression networks, antagonizing Kras-mediated pancreatic cancer initiation and promotion. Here, we elucidate the essential role of Ehmt2 in maintaining a transcriptional landscape that protects organs from inflammation. Comparative RNA-seq studies between normal postnatal and young adult pancreatic tissue from conditional knockout animals ( ) targeted to the exocrine pancreatic epithelial cells ( and ), reveal alterations in gene expression networks in the whole organ related to injury-inflammation-repair, suggesting an increased predisposition to damage. Thus, we induced an inflammation repair response in the pancreas and used a data science-based approach to integrate RNA-seq-derived pathways and networks, deconvolution digital cytology, and spatial transcriptomics. We also analyzed the tissue response to damage at the morphological, biochemical, and molecular pathology levels. The pancreas displays an enhanced injury-inflammation-repair response, offering insights into fundamental molecular and cellular mechanisms involved in this process. More importantly, these data show that conditional inactivation in exocrine cells reprograms the local environment to recruit mesenchymal and immunological cells needed to mount an increased inflammatory response. Mechanistically, this response is an enhanced injury-inflammation-repair reaction with a small contribution of specific Ehmt2-regulated transcripts. Thus, this new knowledge extends the mechanisms underlying the role of the Ehmt2-mediated pathway in suppressing pancreatic cancer initiation and modulating inflammatory pancreatic diseases.
PubMed: 38948355
DOI: 10.3389/fgene.2024.1412767 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024To explore the relationship between baseline clinical characteristics and hematological parameters of patients undergoing radical resection for pancreatic ductal...
OBJECTIVE
To explore the relationship between baseline clinical characteristics and hematological parameters of patients undergoing radical resection for pancreatic ductal adenocarcinoma (PDAC) and their prognosis, and to provide references for stratifying the patients' clinical risks.
METHODS
We retrospectively collected clinical data from 445 patients who underwent radical surgical treatment for PDAC at West China Hospital, Sichuan University between January 2010 and February 2019. Then, we conducted retrospective clinical analysis with the collected data. Data on patients' basic clinical characteristics, routine blood test results, and tumor indicators were collected to explore their effects on the postoperative overall survival (OS) of PDAC patients. Cox proportional hazards regression was used to identify factors affecting OS. Statistical analysis was performed using the SPSS 23.0 software package.
RESULTS
The postoperative median overall survival (mOS) was 17.0 months (95% CI: 15.0-19.0). The 1, 2, 3, 4, and 5-year survival rates of the patients included in the study were 60.6%, 33.4%, 19.1%, 12.7%, and 9.6%, respectively. The multivariate Cox proportional hazards model analysis demonstrated that a number of factors independently affect postoperative survival in PDAC patients. These factors include tumor location (hazards ratio [HR]=1.574, 95% CI: 1.233-2.011), degree of tumor cell differentiation (HR=0.687, 95% CI: 0.542-0.870), presence of neural invasion (HR=0.686, 95% CI: 0.538-0.876), TNM staging (HR=1.572, 95% CI: 1.252-1.974), postoperative adjuvant therapy (HR=1.799, 95% CI: 1.390-2.328), preoperative drinking history (HR=0.744, 95% CI: 0.588-0.943), and high serum CA199 levels prior to the surgery (HR=0.742, 95% CI: 0.563-0.977).
CONCLUSION
In PDAC patients, having tumors located in the head of the pancreas, moderate and high degrees of differentiated, being free from local neurovascular invasion, being in TNM stage Ⅰ, undergoing postoperative adjuvant therapy, no history of alcohol consumption prior to the surgery, and preoperative serum CA199 being less than or equal to 37 U/mL are significantly associated with a better prognosis.
Topics: Humans; Pancreatic Neoplasms; Retrospective Studies; Prognosis; Male; Female; Carcinoma, Pancreatic Ductal; Survival Rate; Proportional Hazards Models; Middle Aged; China; Aged
PubMed: 38948268
DOI: 10.12182/20240560604 -
ACS Omega Jun 2024Curcumin has demonstrated promising preclinical antiobesity effects, but its low bioavailability makes it difficult to exert its full effect at a suitable dose. The...
Curcumin has demonstrated promising preclinical antiobesity effects, but its low bioavailability makes it difficult to exert its full effect at a suitable dose. The objective of this study was to screen curcumin derivatives with enhanced bioavailability and lipid-lowering activity under the guidance of computer-aided drug design (CADD). CAAD was used to perform virtual assays on curcumin derivatives to assess their pharmacokinetic properties and effects on pancreatic lipase activity. Subsequently, 19 curcumin derivatives containing 5 skeletons were synthesized to confirm the above virtual assay. The in vitro pancreatic lipase inhibition assay was employed to determine the half-maximal inhibitory concentration (IC) of these 19 curcumin derivatives. Based on CADD analysis and in vitro pancreatic lipase inhibition, 2 curcumin derivatives outperformed curcumin in both aspects. Microscale thermophoresis (MST) experiments were employed to assess the binding equilibrium constants ( ) of the aforementioned 2 curcumin derivatives, curcumin, and the positive control drug with pancreatic lipase. Through virtual screening utilizing a chemoinformatics database and molecular docking, 6 derivatives of curcumin demonstrated superior solubility, absorption, and pancreatic lipase inhibitory activity compared to curcumin. The IC value for 1,7-bis(4-hydroxyphenyl)heptane-3,5-dione (C4), which displayed the most effective inhibitory effect, was 42.83 μM, while the IC value for 1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (C6) was 98.62 μM. On the other hand, the IC value for curcumin was 142.24 μM. The MST experiment results indicated that the values of C4, C6, and curcumin were 2.91, 18.20, and 23.53 μM, respectively. The results of the activity assays exhibited a relatively high degree of concordance with the outcomes yielded by CADD screening. Under the guidance of CADD, the targeted screening of curcumin derivatives with excellent properties in this study exhibited high-efficiency and low-cost benefits.
PubMed: 38947805
DOI: 10.1021/acsomega.4c03596 -
Endoscopic Ultrasound 2024EUS interventions have an increasing role in the treatment for hepatobiliary-pancreatic diseases. However, the procedure itself is not frequently performed, needs... (Review)
Review
EUS interventions have an increasing role in the treatment for hepatobiliary-pancreatic diseases. However, the procedure itself is not frequently performed, needs expertise, and carries a high risk of complications. With these limitations, the hands-on practice model is very important for the endoscopist in training for EUS intervention. There have been various hands-on models for EUS interventions, ranging from living pig model to all-synthetic model. Although a living model provides realistic sensation, the preparation is complex and increases concerns for zoonotic issues. All-synthetic models are easier to prepare and store but not realistic and still need the room for improvement. Hybrid model is more widely available and provides various training procedures but still needs special preparation for the porcine tissue.
PubMed: 38947748
DOI: 10.1097/eus.0000000000000046 -
Journal of Cancer 2024Hepatocellular carcinoma (HCC), the predominant malignancy of the digestive tract, ranks as the third most common cause of cancer-related mortality globally,...
Hepatocellular carcinoma (HCC), the predominant malignancy of the digestive tract, ranks as the third most common cause of cancer-related mortality globally, significantly impeding human health and lifespan. Emerging immunotherapeutic approaches have ignited fresh optimism for patient outcomes. This investigation probes the link between 731 immune cell phenotypes and HCC through Mendelian Randomization and single-cell sequencing, aiming to unearth viable drug targets and dissect HCC's etiology. We conducted an exhaustive two-sample Mendelian Randomization analysis to ascertain the causal links between immune cell features and HCC, utilizing publicly accessible genetic datasets to explore the causal connections of 731 immune cell traits with HCC susceptibility. The integrity, diversity, and potential horizontal pleiotropy of these findings were rigorously assessed through extensive sensitivity analyses. Furthermore, single-cell sequencing was employed to penetrate the pathogenic underpinnings of HCC. Establishing a significance threshold of pval_Inverse.variance.weighted at 0.05, our study pinpointed five immune characteristics potentially elevating HCC risk: B cell % CD3- lymphocyte (TBNK panel), CD25 on IgD+ (B cell panel), HVEM on TD CD4+ (Maturation stages of T cell panel), CD14 on CD14+ CD16- monocyte (Monocyte panel), CD4 on CD39+ activated Treg ( Treg panel). Conversely, various cellular phenotypes tied to BAFF-R expression emerged as protective elements. Single-cell sequencing unveiled profound immune cell phenotype interactions, highlighting marked disparities in cell communication and metabolic activities. Leveraging MR and scRNA-seq techniques, our study elucidates potential associations between 731 immune cell phenotypes and HCC, offering a window into the molecular interplays among cellular phenotypes, and addressing the limitations of mono-antibody therapeutic targets.
PubMed: 38947379
DOI: 10.7150/jca.96744 -
Journal of Cancer 2024Pancreatic cancer continues to pose a significant threat due to its high mortality rate. While MYB family genes have been identified as oncogenes in certain cancer...
Pancreatic cancer continues to pose a significant threat due to its high mortality rate. While MYB family genes have been identified as oncogenes in certain cancer types, their role in pancreatic cancer remains largely unexplored. The mRNA and protein expression of MYB family genes in pancreatic cancer samples was analyzed using TNMplot, HPA, and TISBID online bioinformatics tools, sourced from the TCGA and GETx databases. The relationship between MYB family gene expression and survival time was assessed through Kaplan-Meier analysis, while the prognostic impact of MYB family gene expression was evaluated using the Cox proportional hazards model. Additionally, Spearman's correlation analysis was employed to investigate the correlation between MYB family genes and TMB/MSI. The integration of data from various databases demonstrated that all MYB family genes exhibited dysregulated expression in pancreatic cancer. However, only the expression of the MYBL2 gene displayed a notable association with the grade and stage of pancreatic cancer. Furthermore, the MYBL2 gene exhibited significant variations in both univariate and multivariate factor analyses.Subsequent functional analyses revealed a significant correlation between MYBL2 expression in pancreatic cancers and various biological processes, such as DNA replication, tumor proliferation, G2M checkpoint regulation, pyrimidine metabolism, and the P53 pathway. Additionally, a notable positive association was observed between MYBL2 expression and tumor mutational burden (TMB), a predictive indicator for response to PD1 antibody treatment. MYBL2 may be a double marker for independent diagnosis and PD1 antibody response prediction of pancreatic cancer patients.
PubMed: 38947375
DOI: 10.7150/jca.96320 -
Frontiers in Immunology 2024Type I diabetes is an autoimmune disease mediated by T-cell destruction of β cells in pancreatic islets. Currently, there is no known cure, and treatment consists of...
Type I diabetes is an autoimmune disease mediated by T-cell destruction of β cells in pancreatic islets. Currently, there is no known cure, and treatment consists of daily insulin injections. Genome-wide association studies and twin studies have indicated a strong genetic heritability for type I diabetes and implicated several genes. As most strongly associated variants are noncoding, there is still a lack of identification of functional and, therefore, likely causal variants. Given that many of these genetic variants reside in enhancer elements, we have tested 121 CD4+ T-cell enhancer variants associated with T1D. We found four to be functional through massively parallel reporter assays. Three of the enhancer variants weaken activity, while the fourth strengthens activity. We link these to their cognate genes using 3D genome architecture or eQTL data and validate them using CRISPR editing. Validated target genes include and While these genes have been previously implicated in type 1 diabetes and other autoimmune diseases, we show that enhancers controlling their expression harbor functional variants. These variants, therefore, may act as causal type 1 diabetic variants.
Topics: Diabetes Mellitus, Type 1; Humans; CD4-Positive T-Lymphocytes; Enhancer Elements, Genetic; Genetic Predisposition to Disease; Suppressor of Cytokine Signaling 1 Protein; Genome-Wide Association Study; Lectins, C-Type; Genetic Variation; Polymorphism, Single Nucleotide; Quantitative Trait Loci
PubMed: 38947339
DOI: 10.3389/fimmu.2024.1387253