PD-1 blockade plus COX inhibitors in dMMR metastatic colorectal cancer: Clinical, genomic, and immunologic analyses from the PCOX trial.

BACKGROUND: Approximately 20% of patients with DNA mismatch repair deficiency (dMMR) metastatic colorectal cancer do not respond to anti-programmed death-1 (PD-1) ligand therapy, and baseline biomarkers of response are lacking. METHODS: We conducted a phase 2 study to evaluate the efficacy of cyclooxygenase (COX) inhibitors in combination with anti-PD-1 therapy in patients with dMMR metastatic colorectal cancer. The primary endpoint was objective response rate. The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate, duration of response, and safety. FINDINGS: A total of 30 patients were enrolled, and the objective response rate was 73.3%, meeting the predefined endpoint of 68%. The median PFS and median OS were not reached at a median follow-up period of 50.8 months. Disease control was achieved in 28 patients (93.3%). The median duration of response was not reached. The combination was well tolerated. Multiomics analysis revealed that the antigen processing and presentation pathway was positively associated with treatment response and PFS. Higher TAPBP expression was predictive of better PFS (log-rank p = 0.003), and this prognostic significance was confirmed in an immunotherapy validation cohort. CONCLUSIONS: Thus, COX inhibitors combined with PD-1 blockade may be effective and safe treatment options for patients with dMMR metastatic colorectal cancer, and TAPBP may serve as a biomarker for immune checkpoint inhibitor therapy (this study was registered at ClinicalTrials.gov: NCT03638297). FUNDING: Funded by the National Natural Science Foundation of China (81974369) and the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004).

A Review of Traditional Use, Constituent Analysis, Bioactivity, and Application of Volatile Oils from Elsholtzia.

BACKGROUND: Elsholtzia belongs to the Labiatae family, which consists of herbaceous subshrubs and shrubs. Among them, volatile oils are an important chemical component in Elsholtzia, which have various bioactive medicinal and developmental values. METHODS: The references about volatile oils of Elsholtzia in this review were obtained from Web of Science, SciFinder, PubMed, Willy, Elsevier, SpringLink, ACS publications, Google Scholar, Baidu Scholar, Scopus, and CNKI. The other information about Elsholtzia was obtained from classical works or ancient books. RESULTS: Traditionally, the volatile oils from Elsholtzia were used in Chinese medicine to treat cholera, abdominal pain, vomiting, and scattered edema. Relevant research revealed that Elsholtzia contains many different types of volatile oils, and most of them display bioactivities, including anti-oxidant, anti-bacterial, anti-viral, hypolipidemic, insecticidal, and antiinflammatory activities, treating spleen and stomach. Furthermore, the applications of volatile oils were summarized and analyzed in this paper. CONCLUSION: The contents of traditional use, constituent analysis, bioactivity, and application of volatile oils from Elsholtzia were reviewed in this paper. This will provide important research value and a scientific basis for the in-depth study of the plants of Elsholtzia in the future.

An Investigation of the Efficient-Precise Continuous Electrochemical Grinding Process of Ti-6Al-4V.

Titanium alloys have many excellent characteristics, and they are widely used in aerospace, biomedicine, and precision engineering. Meanwhile, titanium alloys are difficult to machine and passivate readily. Electrochemical grinding (ECG) is an ideal technology for the efficient-precise machining of titanium alloys. In the ECG process of titanium alloys, the common approach of applying high voltage and active electrolytes to achieve high efficiency of material removal will lead to serious stray corrosion, and the time utilized for the subsequent finishing will be extended greatly. Therefore, the application of ECG in the field of high efficiency and precision machining of titanium alloys is limited. In order to address the aforementioned issues, the present study proposed an efficient-precise continuous ECG (E-P-C-ECG) process for Ti-6Al-4V applying high-pulsed voltage with an optimized duty cycle and low DC voltage in the efficient ECG stage and precise ECG stage, respectively, without changing the grinding wheel. According to the result of the passivation properties tests, the ideal electrolyte was selected. Optimization of the process parameters was implemented experimentally to improve the processing efficiency and precision of ECG of Ti-6Al-4V. Utilizing the process advantages of the proposed process, a thin-walled structure of Ti-6Al-4V was obtained with high efficiency and precision. Compared to the conventional mechanical grinding process, the compressive residual stress of the machined surface and the processing time were reduced by 90.5% and 63.3% respectively, and both the surface roughness and tool wear were obviously improved.

Phyllanthus emblica Linn: A comprehensive review of botany, traditional uses, phytonutrients, health benefits, quality markers, and applications.

Phyllanthus emblica Linn is not only an edible fruit with high nutritional value, but also a medicinal plant with multiple bioactivities. It is widely used in clinical practice with functions of clearing heat, cooling blood, digesting food, strengthening stomach, promoting fluid production, and relieving cough. This review summarized a wide variety of phytonutrients, including nutritional components (mineral elements, amino acids, vitamins, polysaccharides, unsaturated free fatty acids) and functional components (phenolic acids (1-34), tannins (35-98), flavonoids (99-141), sterols (142-159), triterpenoids (160-175), lignans (176-183), alkaloids (184-197), alkanes (198-212), aromatic micromolecules (213-222), other compounds (223-239)). The isolated compounds and the various extracts of P. emblica Linn presented a diverse spectrum of biological activities such as anti-oxidant, anti-cancer, anti-inflammatory, anti-bacterial, hepatoprotective, hypoglycemic, anti-atherosclerosis, neuroprotective, enhancing immunity, anti-fatigue, anti-myocardial fibrosis. The quality markers of P. emblica Linn were predicted and analyzed based on traditional medicinal properties, traditional efficacy, plant genealogy and chemical component characteristics, biogenic pathway of chemical components, measurability of chemical components, transformation characteristics of polyphenolic components, homologous characteristics of medicine and food, compound compatibility environment, and clinical applications. This review also summarized and prospected applications of P. emblica Linn in beverages, preserved fruits, fermented foods, etc. However, the contents of mechanism, structure-activity relationship, quality control, toxicity, extraction, processing of P. emblica Linn are not clear, and are worth further studies in the future.

Jet Electrochemical Micromilling of Ti-6Al-4V Using NaCl-Ethylene Glycol Electrolyte.

Titanium alloys are widely used in aerospace and biomedicine because of their excellent mechanical characteristics, but these properties also make such alloys difficult to cut. Jet electrochemical micromilling (JEMM) is based on the principle of electrochemical anodic dissolution; it has some inherent advantages for the machining of titanium alloy microstructures. However, titanium oxidizes readily, forming an oxide film that impedes a uniform dissolution during electrochemical machining. Therefore, a high voltage and an aqueous NaCl electrolyte are usually used to break the oxide film, which can lead to severe stray corrosion. To overcome this problem, the present study investigated the JEMM of Ti-6Al-4V using a NaCl-ethylene glycol (NaCl-EG) electrolyte. Electrochemical testing showed that Ti-6Al-4V exhibits a better corrosion resistance in the NaCl-EG electrolyte compared to the aqueous NaCl electrolyte, thereby reducing stray corrosion. The localization and surface quality of the grooves were enhanced significantly when using JEMM with a NaCl-EG electrolyte. A multiple-pass strategy was adopted during JEMM to improve the aspect ratio, and the effects of the feed depth and number of passes on the multiple-pass machining performance were investigated. Ultimately, a square annular microstructure with a high geometric dimensional consistency and a smooth surface was obtained via JEMM with multiple passes using the optimal parameters.

Exploring the topic structure and abuse trends of new psychoactive Substance since the 21st century from a bibliometric perspective.

Nowadays, NPS abuse are continuing to expand in terms of harm and scope, due to its cheap and easy to manufacture anywhere in the world. This study reviewed articles related to seven heavily abused NPS to analyze the structure and trends of NPS abuse. A total of 2476 articles were retrieved based on the search strategy for bibliometric analysis. A significant trend of research in recent years was the increasing number of research on synthetic opioids and designer benzodiazepines, but synthetic cannabinoid and synthetic cathinone still dominate, which were mainly concerned with the development of metabolic models and determining methods as well as their abuse characteristics and reasons. However, with the introduction of class-wide ban on synthetic cannabinoid in China and a series of enhancements in other countries, the abuse of it might decrease to some extent, but more than 20 kinds of synthetic cannabinoid beyond the scope of ban in China still reminded researchers of their potential threats. As for synthetic cathinone, an important phenomenon was some of the drugs first identified during certain period might be more widely distributed in the future. Besides, several problems such as the regulation and prevention mode of emerging NPS, development of testing technologies as well as the interpretation and identification of multiple NPS combinations were also worth paying attention to. This study could help entrants better understand the structure of NPS abuse and provided direction for future research in forensic toxicology.

Application of terahertz Time-Domain spectroscopy and chemometrics-based whale optimization algorithm in PDE5 inhibitor detection.

Combating the illicit use of PDE5 inhibitor drugs is a focal point in forensic science research. In order to achieve rapid identification of such drugs, this study applies terahertz time-domain spectroscopy combined with chemometrics to establish a fast and accurate detection method for PDE5 inhibitors. The optimal detection method is determined by comparing the spectral performance of three optical parameters, namely absorption coefficient, refractive index, and dielectric constant. Linear discriminant models based on different spectral parameters, whale optimization algorithm optimized extreme learning machine models, and whale optimization algorithm optimized random forest models are established. The effectiveness and performance of principal component analysis and competitive adaptive reweighted sampling algorithm for spectral feature data selection are also investigated. The PDE5 inhibitor identification model based on the competitive adaptive reweighted sampling - whale optimization algorithm - random forest (CARS-WOA-RF) model achieves an accuracy of 98.61%, and the identification model for two concentrations of Sildenafil achieves 100% accuracy. The results demonstrate that terahertz time-domain spectroscopy combined with chemometrics can effectively detect various common types of PDE5 inhibitor drugs and different concentrations.

Targeting the NAT10/NPM1 axis abrogates PD-L1 expression and improves the response to immune checkpoint blockade therapy.

BACKGROUND: PD-1/PD-L1 play a crucial role as immune checkpoint inhibitors in various types of cancer. Although our previous study revealed that NPM1 was a novel transcriptional regulator of PD-L1 and stimulated the transcription of PD-L1, the underlying regulatory mechanism remains incompletely characterized. METHODS: Various human cancer cell lines were used to validate the role of NPM1 in regulating the transcription of PD-L1. The acetyltransferase NAT10 was identified as a facilitator of NPM1 acetylation by coimmunoprecipitation and mass spectrometry. The potential application of combined NAT10 inhibitor and anti-CTLA4 treatment was evaluated by an animal model. RESULTS: We demonstrated that NPM1 enhanced the transcription of PD-L1 in various types of cancer, and the acetylation of NPM1 played a vital role in this process. In particular, NAT10 facilitated the acetylation of NPM1, leading to enhanced transcription and increased expression of PD-L1. Moreover, our findings demonstrated that Remodelin, a compound that inhibits NAT10, effectively reduced NPM1 acetylation, leading to a subsequent decrease in PD-L1 expression. In vivo experiments indicated that Remodelin combined with anti-CTLA-4 therapy had a superior therapeutic effect compared with either treatment alone. Ultimately, we verified that the expression of NAT10 exhibited a positive correlation with the expression of PD-L1 in various types of tumors, serving as an indicator of unfavorable prognosis. CONCLUSION: This study suggests that the NAT10/NPM1 axis is a promising therapeutic target in malignant tumors.

Analysis on dynamic changes of etizolam and its metabolites and exploration of its development prospect using UPLC-Q-exactive-MS.

As one of the most widely abused designer benzodiazepines in the world, etizolam has been found in many cases in many countries. In this study, UPLC-Q-Exactive-MS was used for the first time to establish a dynamic change model of etizolam and its metabolites in rats. Compared with previous studies, the detection sensitivity and reproducibility of the instrument were higher. In the experiment, we optimized the traditional pharmacokinetic model based on Gauss function. According to the significant difference of etizolam in the plasma elimination phase of rats, a new pharmacokinetic model based on Lorentz function was established to describe the dynamic changes of etizolam more rigorously, which made the error effects lower and the accuracy of the pharmacokinetic parameters was improved. At the same time, the pharmacokinetic parameters of etizolam were compared with four other designer benzodiazepines reported in previous studies in rats, and we found the direct reason for the popularity of etizolam in the NPS market and explored the future development of etizolam for the first time. In addition, 21 metabolites were found through rat experiments to effectively detect etizolam abuse for a long time, of which 4 metabolites had the longest detection window and could be used as long-acting metabolites for experiments, which greatly prolongs the detection window and extends the time range in which etizolam was detected in real cases. This study is the first to conduct a systematic and comprehensive study on the metabolism and pharmacokinetics of etizolam and find out the direct reason for the prevalence of etizolam abuse, and we also discuss the development trend of etizolam in the future market of new psychoactive substances, which is beneficial for forensic experts to assess the trend of drug abuse and can provide reference for relevant drug control and drug treatment.

Biomarkers of Pathologic Complete Response to Neoadjuvant Immunotherapy in Mismatch Repair-Deficient Colorectal Cancer.

PURPOSE: Immune checkpoint inhibitors (ICI) have become the standard of care for patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer. However, biomarkers of response to ICI are still lacking. EXPERIMENTAL DESIGN: Forty-two patients with dMMR colorectal cancer treated with neoadjuvant PD-1 blockade were prospectively enrolled. To identify biomarkers of pathologic complete response (pCR) to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles based on next-generation sequencing, and immune cell density based on multiplex immunofluorescence (mIF) staining. An integrated analysis of single-cell RNA sequencing from our previous study and GSE178341, as well as mIF was performed to further explore the significance of the tumor microenvironment (TME) on pCR response. RESULTS: The tumor mutation burden of both tumor tissue and plasma blood samples was comparable between the pCR and non-pCR groups, while HLA-DQA1 and HLA-DQB1 were significantly overexpressed in the pCR group. Gene signature enrichment analysis showed that pathways including T-cell receptor pathway, antigen presentation pathway were significantly enriched in the pCR group. In addition, higher pre-existing CD8+ T-cell density was associated with pCR response (767.47 per.mm2 vs. 326.64 per.mm2, P = 0.013 Wilcoxon test). Further integrated analysis showed that CD8+ T cells with low PD-1 expression (PD-1lo CD8+ T cells) expressing high levels of TRGC2, CD160, and KLRB1 and low levels of proliferated and exhausted genes were significantly associated with pCR response. CONCLUSIONS: Immune-associated transcriptomic features, particularly CD8+ T cells were associated with pCR response to ICI in dMMR colorectal cancer. Heterogeneity of TME within dMMR colorectal cancer may help to discriminate patients with complete response to neoadjuvant ICI.

The sources, properties, extraction, biosynthesis, pharmacology, and application of lycopene.

Lycopene is an important pigment with an alkene skeleton from Lycopersicon esculentum, which is also obtained from some red fruits and vegetables. Lycopene is used in the food field with rich functions and serves in the medical field with multiple clinical values because it has dual functions of both medicine and food. It was found that lycopene was mainly isolated by solvent extraction, ultrasonic-assisted extraction, supercritical fluid extraction, high-intensity pulsed electric field-assisted extraction, enzymatic-assisted extraction, and microwave-assisted extraction. Meanwhile, it was also obtained via 2 synthetic pathways: chemical synthesis and biosynthesis. Pharmacological studies revealed that lycopene has anti-oxidant, hypolipidemic, anti-cancer, immunity-enhancing, hepatoprotective, hypoglycemic, cardiovascular-protective, anti-inflammatory, neuroprotective, and osteoporosis-inhibiting effects. The application of lycopene mainly includes food processing, animal breeding, and medical cosmetology fields. It is hoped that this review will provide some useful information and guidance for future study and exploitation of lycopene.

Tumor stroma Siglec15 expression is a poor prognosis predictor in colon adenocarcinoma.

Sialic acid binding Ig-like lectin 15 (Siglec15) is considered a novel immune checkpoint and an emerging target for next-generation cancer immunotherapy. However, the significance of Siglec15 and its relationship with programmed death-ligand 1 (PD-L1) in colon adenocarcinoma (COAD) remain unknown. In this study, we analyzed Siglec15 expression within stromal area (SA) and tumor area (TA), and its relationship with tumor-infiltrating lymphocytes (TILs) in COAD and mismatch repair-proficient (MMR-p) COAD. Siglec15 expression was significantly higher in COAD tissues than in normal tissues, and elevated Siglec15(SA) expression, rather than Siglec15(TA) and Siglec15 (whole) expression, was correlated with poor prognosis and inversely correlated with the density of CD8+ T cell, both in COAD and MMR-p COAD. Moreover, there were no correlations between Siglec15(SA) and PD-L1(SA), and between Siglec15(TA) and PD-L1(TA), whereas there was positive correlation between Siglec15(whole) and PD-L1(whole). A new immune classification based on the Siglec15(SA)/PD-L1(SA) expression, indicated that patients with Siglec15(SA)Low/PD-L1(SA)+ status had the longest survival times in COAD. Our study highlights that Siglec15(SA) is an independent predictor of poor prognosis and has an immunosuppressive role in COAD and MMR-p COAD tissues. These findings may provide insights into improving responses to immunotherapy-included comprehensive treatments for COAD in the future.

Non-destructive recognition of copy paper based on advanced spectral fusion and feature optimization.

In order to provide more clues for ongoing investigations and case handling, as well as achieve fast, non-destructive, and accurate identification of copy paper found at crime scenes, this study aims to utilize advanced spectral fusion technology to characterize and identify the three-dimensional features of the "origin-manufacturer-brand" of copy paper. Confocal Raman Microscopic and Fourier transform infrared spectroscopy were employed to collect spectral data from 200 samples from four regions (Shandong, Henan, Shaanxi, Jiangsu). The effects of different preprocessing methods, such as Hilbert transformation and deconvolution, on the model's ability to distinguish were compared. Feature variables were extracted using principal component analysis, and Bayesian discriminant classification models were constructed based on single infrared spectroscopy, Raman spectroscopy, and three types of spectral fusion datasets. By comparing the classification accuracy of different models, the primary fusion based on the full spectrum dataset was selected as the optimal model for the three-dimensional feature classification of copy paper. The accuracy achieved for origin (96%), manufacturer (100%), and brand (100%) was satisfactory, and the classification results were highly accurate. This study provides valuable insights and serves as a reference for its application in forensic science research.

NLRP9 involved in antiviral innate immunity via binding VIM in IPEC-J2 cells.

BACKGROUND: Nucleotide-binding oligomerization domain (NOD)-like receptors with a pyrin domain (PYD)-containing protein 9 (NLRP9) was the first nucleotide-binding region receptor (NLR) proposed to be expressed and function only in the reproductive system. Recent evidence suggests that NLRP9 is also capable of playing a role in infectious and inflammatory diseases. RESULTS AND CONCLUSIONS: In this study, we examined the expression of NLRP9 in various tissues of piglets and IPEC-J2 cells. The results showed that high expression of NLRP9 mRNA and protein were detected in both intestine of piglets and IPEC-J2 cells. Both LPS and poly I:C significantly up-regulated NLRP9 protein levels in the IPEC-J2 cells. Besides, poly I:C upregulated the level of transcriptional elements NF-κB, IRF3, IRF7, ISG15, ISG56, OAS1, and IFNB1. Furthermore, interference with the NLRP9 gene in the presence of poly I:C strongly downregulated the expression of all the above genes. Moreover, we demonstrated for the first time that NLRP9 acts in combination with VIM (Vimentin). These results suggested that NLRP9 may participate in the antiviral innate immune by binding to VIM in the porcine intestine. The findings provide preliminary insights into the molecular mechanisms involved in the regulation of mucosal immunity in the porcine intestine by NLRP9.

Vicatia thibetica de Boiss: Botany, Traditional Uses, Phytochemistry, Quantitative Analysis, and Pharmacology.

BACKGROUND: Vicatia thibetica de Boiss is a common Tibetan medicine used for both medicine and food, belonging to the family Apiaceae. This plant has the functions of dispelling wind, removing dampness, dispersing cold, and relieving pain. It has great development potential and application prospects in food development and medicinal value. METHODS: The related references on botany, traditional uses, phytochemistry, quantitative analysis, and pharmacology of V. thibetica de Boiss had been retrieved from both online and offline databases, including PubMed, ScienceDirect, Web of Science, Elsevier, Willy, SpringLink, SciFinder, Google Scholar, Baidu Scholar, ACS publications, SciHub, Scopus, and CNKI. RESULTS: V. thibetica de Boiss exerts nourishing, appetizing, and digestive effects according to the theory of Tibetan medicine. Phytochemical reports have revealed that V. thibetica de Boiss contains flavonoids, coumarins, sterols, and organic acids. Meanwhile, the quantitative analysis of the chemical constituents of V. thibetica de Boiss has been done by means of UPLC-Q-TOF-MS. It has also been found that V. thibetica de Boiss possesses multiple pharmacological activities, including anti-fatigue, anti-oxidant, anti-aging, and non-toxic activities. CONCLUSION: This paper has comprehensively summarized botany, traditional uses, phytochemistry, quantitative analysis, and pharmacology of V. thibetica de Boiss. It will not only provide an important clue for further studying V. thibetica de Boiss, but also offer an important theoretical basis and valuable reference for in-depth research and exploitation of this plant in the future.

Metabolic Profile Analysis of Designer Benzodiazepine Etizolam in Zebrafish and Human Liver Microsomes.

As one of the most widely abused designer benzodiazepines worldwide, Etizolam is characterized by its high addiction potential, low production cost, and difficulty in detection. Due to the rapid metabolism of Etizolam in the human body, the probability of detecting the Etizolam parent drug in actual case samples by forensic personnel is low. Therefore, without detecting the parent drug, analysis of Etizolam metabolites can help forensic personnel provide references and suggestions on whether the suspect has taken Etizolam. This study simulates the objective metabolic process of the human body. It establishes a zebrafish in vivo metabolism model and a human liver microsome in vitro metabolism model to analyze the metabolic characteristics of Etizolam. A total of 28 metabolites were detected in the experiment, including 13 produced in zebrafish, 28 produced in zebrafish urine and feces, and 17 produced in human liver microsomes. The UPLC-Q-Exactive-MS technology was used to analyze the structures and related metabolic pathways of Etizolam metabolites in zebrafish and human liver microsomes, and a total of 9 metabolic pathways were identified, including monohydroxylation, dihydroxylation, hydration, desaturation, methylation, oxidative deamination to alcohol, oxidation, reduction acetylation, and glucuronidation. Among them, metabolites involving hydroxylation reactions (including monohydroxylation and dihydroxylation) accounted for 57.1% of the total number of potential metabolites, indicating that hydroxylation may be the major metabolic pathway of Etizolam. Based on the response values of each metabolite, monohydroxylation (M1), desaturation (M19), and hydration (M16) were recommended as potential biomarkers for Etizolam metabolism. The experimental results provide reference and guidance for forensic personnel in identifying Etizolam use in suspects.

Alterations in gene expressions of Caco-2 cell responses to LPS and ploy(I:C) stimulation.

The intestinal epithelium barrier serves as a highly dynamic immunologic frontier in the defense against invading pathogenic bacteria and viruses. Hence, understanding of the complicated underlying relationship between enteric pathogens and the intestinal epithelium barrier is vital for developing strategies to improve the intestinal health of farm animals. To this end, Caco-2 cells were stimulated by 1 µg/ml lipopolysaccharide (LPS) for 24 h and 5 µg/ml polyinosinic-polycytidylic acid (ploy(I:C)) for 4 h to imitate bacterial and viral infection processes, respectively. The specific alterations in gene expression of Caco-2 cells after stimulation were characterized by transcriptome sequencing. Seventy differentially expressed genes (DEGs) were identified under LPS exposure, and 17 DEGs were observed under ploy(I:C) exposure. We found that most DEGs were specific, and only one common DEG SPAG7 was observed. Gene Ontology (GO) annotation analysis indicated that all DEGs identified in the different treatments were mainly derived from GO terms related to the maintenance of cellular homeostasis. Moreover, specific DEGs such as SLC39A10, MT2A, and MT1E regulated by LPS treatment, while IFIT2 and RUNX2 mediated by ploy(I:C) treatment, which are derived from immune function modulation related GO terms, were confirmed by both transcriptome sequencing and qRT-PCR. In addition, both transcriptome sequencing and qRT-PCR results verified that LPS specifically down-regulated the DEGs INHBE and ARF6, which are involved in inflammation responses related to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway including the TGF-beta signaling pathways and the Ras signaling pathway. Ploy(I:C) uniquely suppressed the DEGs GABARAP and LAMTOR3, which participated in viral replication-associated pathways including autophagy and mTOR signaling pathway.

The impact of multi-drug resistant Pseudomonas aeruginosa infections on acute pancreatitis patients.

INTRODUCTION: Acute pancreatitis (AP) accounts for a high proportion of digestive diseases worldwide and has a high risk of infection. Pseudomonas aeruginosa, a common pathogen of hospital infections, has been observed to increase the resistance rate to several antibiotics, causing difficulties in treatments. Our study aims to investigate the impact of the multi-drug resistant Pseudomonas aeruginosa (MDR-PA) infections on AP patients. METHODS: At two Chinese tertiary referral centers for AP patients infected with MDR-PA, a retrospective case-control study with a 1:2 case-control ratio was performed. Comparisons were preformed between with/without MDR-PA infections and different drug-resistance of MDR-PA infections patients, respectively. Independent risk factors of overall mortality were assessed via univariate and multivariate binary logistic regression analyses, and the distribution and antibiotic resistant rates of strains were described. RESULTS: Mortality in AP patients with MDR-PA infections was significantly higher than in those without MDR-PA infections (7 (30.4%) vs. 4 (8.7%), P = 0.048). The rate of prophylactic use of carbapenem for 3 days (0 vs. 50%, P = 0.019) and the incidence rate of multiple organ failure (MOF) (0 vs. 57.1%, P = 0.018) were remarkably higher in the carbapenem-resistant Pseudomonas aeruginosa group compared with the carbapenem-sensitive Pseudomonas aeruginosa group. In the multivariate analysis, the severe categories of AP (OR = 13.624, 95% CIs = 1.567-118.491, P = 0.018) and MDR-PA infections (OR = 4.788, 95% CIs = 1.107-20.709, P = 0.036) were independent risk factors for mortality. The resistance rates of MDR-PA strains were low for amikacin (7.4%), tobramycin (3.7%), and gentamicin (18.5%). The resistance rates of MDR-PA strains to imipenem and meropenem were up to, 51.9% and 55.6%, respectively. CONCLUSION: In AP patients, severe categories of AP and MDR-PA infections were both independent risk factors for mortality. Inappropriate use of carbapenem antibiotics and MOF were related to carbapenem-resistant Pseudomonas aeruginosa infections. Amikacin, tobramycin, and gentamicin are recommended for the treatment of AP patients with MDR-PA infections.

Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer.

Immune checkpoint inhibitor (ICI) therapy can induce complete responses in mismatch repair-deficient and microsatellite instability-high (d-MMR/MSI-H) colorectal cancers (CRCs). However, the underlying mechanism for pathological complete response (pCR) to immunotherapy has not been completely understood. We utilize single-cell RNA sequencing (scRNA-seq) to investigate the dynamics of immune and stromal cells in 19 patients with d-MMR/MSI-H CRC who received neoadjuvant PD-1 blockade. We found that in tumors with pCR, there is a concerted decrease in CD8+ Trm-mitotic, CD4+ Tregs, proinflammatory IL1B+ Mono and CCL2+ Fibroblast following treatment, while the proportions of CD8+ Tem, CD4+ Th, CD20+ B, and HLA-DRA+ Endothelial cells increase. Proinflammatory features in the tumor microenvironment mediate the persistence of residual tumors by modulating CD8+ T cells and other response-associated immune cell populations. Our study provides valuable resources and biological insights into the mechanism of successful ICI therapy and potential targets for improving treatment efficacy.

Hippophae rhamnoides L.: A Comprehensive Review on the Botany, Traditional Uses, Phytonutrients, Health Benefits, Quality Markers, and Applications.

Hippophae rhamnoides L. (sea buckthorn), consumed as a food and health supplement worldwide, has rich nutritional and medicinal properties. Different parts of H. rhamnoides L. were used in traditional Chinese medicines for relieving cough, aiding digestion, invigorating blood circulation, and alleviating pain since ancient times. Phytochemical studies revealed a wide variety of phytonutrients, including nutritional components (proteins, minerals, vitamins, etc.) and functional components like flavonoids (1-99), lignans (100-143), volatile oils (144-207), tannins (208-230), terpenoids (231-260), steroids (261-270), organic acids (271-297), and alkaloids (298-305). The pharmacological studies revealed that some crude extracts or compounds of H. rhamnoides L. demonstrated various health benefits, such as anti-inflammatory, antioxidant, hepatoprotective, anticardiovascular disease, anticancer, hypoglycemic, hypolipidemic, neuroprotective, antibacterial activities, and their effective doses and experimental models were summarized and analyzed in this paper. The quality markers (Q-markers) of H. rhamnoides L. were predicted and analyzed based on protobotanical phylogeny, traditional medicinal properties, expanded efficacy, pharmacokinetics and metabolism, and component testability. The applications of H. rhamnoides L. in juice, wine, oil, ferment, and yogurt were also summarized and future prospects were examined in this review. However, the mechanism and structure-activity relationship of some active compounds are not clear, and quality control and potential toxicity are worth further study in the future.