A bibliometric and knowledge-map study on the treatment of hematological malignancies with CAR-T cells from 2012 to 2023.

Recently, CAR-T cell therapy in hematological malignancies has received extensive attention. The objective of this study is to gain a comprehensive understanding of the current research status, development trends, research hotspots, and emerging topics pertaining to CAR-T cells in the treatment of hematological malignancies. Articles pertaining to CAR-T cell therapy for hematological malignancies from the years 2012 to 2023 were obtained and assessed from the Web of Science Core Collection (WoSCC). A bibliometric approach was employed to conduct a scientific, comprehensive, and objective quantitative analysis, as well as a visual analysis, of this particular research domain. A comprehensive analysis was conducted on a corpus of 3643 articles, which were collaboratively authored by 72 countries and various research institutions. CAR-T cell research in treating hematological malignancies shows an increasing trend each year. Notably, the study identified the countries and institutions displaying the highest level of activity, the journals with the most citations and output, as well as the authors who garnered the highest frequency of citations and co-citations. Furthermore, the analysis successfully identified the research hotspots and highlighted six emerging topics within this domain. This study conducted a comprehensive exploration and analysis of the research status, development trends, research hotspots, and emerging topics about CAR-T cells in the treatment of hematological malignancies from 2012 to 2023. The findings of this study will serve as a valuable reference and guide for researchers seeking to delve deeper into this field and determine the future direction of their research.

Discovery of L15 as a novel Vif PROTAC degrader with antiviral activity against HIV-1.

Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin-proteasome system to degrade target proteins, which is well established in the field of cancer, but the antiviral PROTAC molecules are rarely reported. In order to explore the effectiveness of PROTAC in the antiviral area, we designed and synthesized a series of degrader of HIV-1 Vif based on 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold. Among them, L15 can degrade Vif protein obviously in a dose-dependent manner and shows certain antivirus activity. Meanwhile, molecular dynamics simulation indicated that the ternary complex formed by L15 Vif, and E3 ligase adopted a reasonable binding mode and maintained a stable interaction. This provided a molecular basis and prerequisite for the selective degradation of the Vif protein by L15. This study reports the HIV-1 Vif PROTAC for the first time and represents the proof-of-concept of PROTACs-based antiviral drug discovery in the field of HIV/ acquired immune deficiency syndrome (AIDS).

Constructing Functional Radiation-Resistant Thorium Clusters for Catalytic Redox Reactions.

When catalytic reactions are interfered with by radiation sources, thorium clusters are promising as potential catalysts due to their superior radiation resistance. However, there is currently very little research on the design synthesis and catalytic application of radiation-stable thorium clusters. In this work, we have elaborately engineered and fabricated three high-nuclear thorium cluster catalysts denoted as Th12L3-MA12, Th12L3-MA6-BF6, and Th12L3-Fcc12, which did not undergo any significant alterations in their molecular structures and compositions after irradiation with 690 kGy γ-rays. We systematically investigated the photocatalytic/thermocatalytic properties of these radiation-resistant thorium clusters for the first time and found that γ-rays could not alter their catalytic activities. In addition, it was found that ligand engineering could modulate the catalytic activity of thorium clusters, thus expanding the range of catalytic applications of thorium clusters, including reduction reactions (nitroarene reduction) and some oxidation reactions (N-heterocyclic oxidative dehydrogenation and diphenylmethane oxidation). Meanwhile, all of these organic transformation reactions achieved a >80% conversion and nearly 100% product selectivity. Radiation experiments combined with DFT calculations showed that the synergistic catalysis of thorium-oxo core and ligands led to the generation of specific active species (H+, O2•-, or tBuO/tBuOO•) and activation of substrate molecules, thus achieving superior catalytic performance. This work is not only the first to develop radiation-resistant thorium cluster catalysts to perform efficient redox reactions but also provides design ideas for the construction of high-nuclearity thorium clusters under mild conditions.

Effects of 6PPD-Quinone on Human Liver Cell Lines as Revealed with Cell Viability Assay and Metabolomics Analysis.

N-(1,3-Dimethyl butyl)-N'-phenyl-phenylenediamine-quinone (6PPD-Q) is a derivative of the widely used rubber tire antioxidant 6PPD, which was first found to be acutely toxic to coho salmon. Subsequent studies showed that 6PPD-Q had species-specific acute toxicity in fishes and potential hepatotoxicity in mice. In addition, 6PPD-Q has been reported in human urine, demonstrating the potential widespread exposure of humans to this chemical. However, whether 6PPD-Q poses a higher risk to humans than its parent compound, 6PPD, and could cause adverse effects in humans is still unclear. In this study, we utilized two human liver cell models (the human proto-hepatocyte model L02 and the human hepatocellular carcinoma cell line HepG2) to investigate the potentially differential effects of these two chemicals. Cell viability curve analysis showed that 6PPD-Q had lower IC50 values than 6PPD for both liver cell lines, suggesting higher toxicity of 6PPD-Q to human liver cells than 6PPD. In addition, L02 cells are more sensitive to 6PPD-Q exposure, which might be derived from its weaker metabolic transformation of 6PPD-Q, since significantly lower levels of phase I and phase II metabolites were detected in 6PPD-Q-exposed L02 cell culture medium. Furthermore, pathway analysis showed that 6PPD-Q exposure induced changes in phenylalanine, tyrosine, and tryptophan biosynthesis and tyrosine metabolism pathways in L02 cells, which might be the mechanism underlying its liver cell toxicity. Gene expression analysis revealed that exposure to 6PPD-Q induced excessive ROS production in L02 cells. Our results further supported the higher risk of 6PPD-Q than 6PPD and provided insights for understanding the effects of 6PPD-Q on human health.

Study on the anti-skin aging effect and mechanism of Sijunzi Tang based on network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Si Jun Zi Tang (SJZT) is a famous traditional Chinese medicine formula composing of 4 herbal medicines (Ginseng Radix et Rhizoma, Atractylodis macrocephalae Rhizoma, Poria, and Glycyrrhizae Radix et Rhizoma) with tonifying spleen and anti-aging effects. It is also known that SJZT can be used to tone, nourish the skin and accelerate wound healing. However, due to the complexity of the formulation, the anti-aging especially anti-skin aging mechanisms as well as the key components of SJZT have not been fully investigated. Therefore, further in vitro and in vivo experimental studies are particularly needed to investigate the anti-skin ageing efficacy of SJZT. AIM OF THE STUDY: The purpose of this article was to explore the therapeutic effect and possible pharmacological mechanism of SJZT in the treatment of skin aging by topical application using network pharmacology and to validate the findings using in vitro and in vivo tests. MATERIALS AND METHODS: Network pharmacology method was applied to predict the underlying biological function and mechanism involved in the anti-skin aging effect of SJZT. Molecular docking was used to preliminarily predict the active components of SJZT-Skin Aging. UPLC QTOF MS/MS was carried out to analyze the chemical compounds. Finally, to confirm the anti-skin aging effort of SJZT, a mouse skin-aging model and UVB-induced EpiSCs (epidermal stem cells) senescence model were established. RESULTS: PPI network analysis and KEGG studies indicated that TP53, CDKN2A, TNF, IL6, and IL1B might be parts of the core targets associated with EpiSCs senescence. Furthermore, molecular docking suggested the top active components, glycyrrhizin, ginsenoside Rg5, ginsenoside Rh2, liquiritin, polyporenic acid C and atractylenolide II showed strong affinity to the key proteins involved in cellular senescence signaling. UPLC QTOF MS/MS analysis of SJZT confirmed the presence of these key components. In-vivo experiments revealed that SJZT could improve UVB-induced skin thickening, increase the number of collagen fibers, strengthen the structure of elastin fibers, and decrease the expression of MDA, as well as increase the expression of CAT and T-SOD in the skin tissue of mouse. And, in-vitro experiments indicated that SJZT could reduce ROS generation and oxidative stress, increase mitochondrial membrane potential, and upregulate the expression of stem cell markers. Moreover, SJZT could suppress the expression of p53, p-p53 and p21, downregulated p38 phosphorylation. Furthermore, the anti-cellular senescence effect of SJZT on EpiSCs disappeared after treatment with the p38 inhibitor adesmapimod. Taken all together, the regulation of senescence signaling in EpiSCs is an important mechanism of SJZT in combating skin aging. CONCLUSION: The research results indicate that SJZT has anti-skin aging effects on UVB-induced skin-aging model, possibly by mediating p38/p53 signaling pathway. These findings strongly demonstrate the great potential of SJZT as an active composite for anti-skin aging and cosmeceutical applications.

Comparison of SOX and CAPOX in patients with advanced gastric cancer after laparoscopic D2 gastrectomy: A randomized controlled trial.

BACKGROUND: Optimal adjuvant chemotherapy after laparoscopic surgery in gastric cancer (GC) patients is still undefined. We aimed to evaluate the efficacy of S-1 plus oxaliplatin (SOX) and capecitabine plus oxaliplatin (CAPOX) in patients with GC after laparoscopic gastrectomy. METHODS: A non-inferiority randomized controlled clinical trial was performed in China. Patients with advanced GC who underwent laparoscopic D2 gastrectomy were randomly assigned to receive SOX and CAPOX regimens. RESULTS: In total, 191 patients were screened between May 2018 and June 2019, and 140 (73.3%) were included in the modified intent-to-treat analysis (mITT), of whom 69 and 71 were assigned to the SOX and CAPOX groups, respectively. The SOX group had similar 3-year overall survival (OS) and disease-free survival to the CAPOX group. Subgroup analysis revealed significantly better OS in the SOX group for male patients ([HR] = 0.395; 95% [CI], 0.153-1.019; p = 0.045), age >60 (HR = 0.219; 95% [CI], 0.064-0.753; p = 0.016), tumors in the gastric antrum (HR = 0.273; 95% [CI], 0.076-0.981; p = 0.047), and moderately differentiated tumors (HR = 0.338; 95% [CI], 0.110-1.041; p = 0.041). There were no significant differences observed in terms of adverse events and recurrence patterns between the two groups. CONCLUSION: Adjuvant SOX was non-inferior to CAPOX treatments for patients with GC who underwent curative laparoscopic D2 gastrectomy. For male patients, aged >60 years, tumors in the gastric antrum, and moderately differentiated tumors, adjuvant SOX may achieve an improvement compared with CAPOX.

Association between arsenic exposure and melanoma: a meta-analysis.

BACKGROUND: Melanoma is a highly malignant tumor. Moreover, its prevalence is increasing at a rapid rate year after year. Currently, UV light is the leading cause of melanoma, although numerous other risk factors exist, including arsenic. The link between arsenic and the likelihood of developing melanoma has long been debated. As a result, we conducted a meta-analysis of the available data to investigate the association between arsenic exposure and melanoma. METHODS: We identified seven non-randomized controlled studies with 41,949 participants by searching the Chinese CNKI, Embase, PubMed, and Cochrane Library databases. We then used random-effects or fixed-effects models to evaluate the pooled odds ratios (OR) and their 95% confidence intervals (CI). Subgroup analyses were also carried out with different included regions. RESULTS: Participants in the study who were exposed to arsenic had a somewhat higher chance of developing melanoma than those who were not (OR = 1.47, 95% CI 1.01-2.13). A subgroup analysis was also carried out for the US region, and the findings were not statistically significant (OR = 1.40, 95% CI 0.94-2.07). CONCLUSION: This meta-analysis shows that arsenic exposure relates to an increased risk of melanoma.

Diagnostic value of combined detection of plasma cfDNA concentration and integrity in NSCLC.

Aim: To evaluate the value of combined detection of plasma cfDNA concentration and integrity in the early diagnosis of NSCLC. Methods: Real-time fluorescence quantitative PCR was used to determine the concentration and integrity of plasma cfDNA in 71 NSCLC patients and 53 healthy people. Results: Combined detection of plasma cfDNA concentration and integrity had higher diagnostic power in differentiating NSCLC patients with stage I/II from healthy people than detection of plasma cfDNA concentration alone or integrity alone. The AUC, sensitivity and specificity of the combined detection of plasma cfDNA concentration and integrity were 0.781, 0.62 and 0.85. Conclusion: Combined detection of plasma cfDNA concentration and integrity could improve the diagnostic value in NSCLC detection.

The discovery of cfDNA has opened up a wide range of new possibilities for the diagnosis of cancer. CfDNA provides a noninvasive diagnostic approach for early screening, early detection and monitoring of patients with cancer. Currently, the application of cfDNA in clinical practice for NSCLC patients has been widely reported, which mainly focused on DNA methylation detection, oncogenic driver gene mutation detection. However, few studies have evaluated the diagnostic value of combined detection of plasma cfDNA concentration and integrity for NSCLC patients. Our study suggests that the combination of plasma cfDNA concentration and integrity has higher AUC value in differentiating NSCLC patients from healthy individuals than plasma cfDNA concentration alone or integrity alone.

Electrochemical protein biosensors for disease marker detection: progress and opportunities.

The development of artificial intelligence-enabled medical health care has created both opportunities and challenges for next-generation biosensor technology. Proteins are extensively used as biological macromolecular markers in disease diagnosis and the analysis of therapeutic effects. Electrochemical protein biosensors have achieved desirable specificity by using the specific antibody-antigen binding principle in immunology. However, the active centers of protein biomarkers are surrounded by a peptide matrix, which hinders charge transfer and results in insufficient sensor sensitivity. Therefore, electrode-modified materials and transducer devices have been designed to increase the sensitivity and improve the practical application prospects of electrochemical protein sensors. In this review, we summarize recent reports of electrochemical biosensors for protein biomarker detection. We highlight the latest research on electrochemical protein biosensors for the detection of cancer, viral infectious diseases, inflammation, and other diseases. The corresponding sensitive materials, transducer structures, and detection principles associated with such biosensors are also addressed generally. Finally, we present an outlook on the use of electrochemical protein biosensors for disease marker detection for the next few years.

Luteolin alleviates cadmium-induced metabolism disorder through antioxidant and anti-inflammatory mechanisms in chicken kidney.

Cadmium (Cd) is a common environmental pollutant associated with an increased incidence of renal metabolic diseases. Luteolin (Lut), a natural flavonoid, is widely used for its multifaceted therapeutic properties in inflammatory diseases. However, whether Lut protects against Cd-induced nephrotoxicity is still equivocal. The present study investigated the effects of Lut supplementation on renal oxidative stress, inflammation and metabolism and their related mechanisms. Therefore, 40 chickens were treated with Cd and/or Lut with automatic water and free food intake for 1 mo and then the kidney tissues were collected to explore this issue. In this study, Cd exposure induced renal glycolipid metabolism disorders and resultant kidney damage by periodic acid Schiff (PAS) staining, Oil Red O staining, total cholesterol (TC), triglyceride (TG), and glucose (Glu) levels in kidney, which were significantly ameliorated by Lut. Moreover, Lut also normalized the expression levels of factors related to Cd-disturbed glycolipid metabolism, improving metabolic homeostasis, and contributing to alleviating kidney damage. Furthermore, Lut demonstrated therapeutic potential against Cd-induced renal oxidative stress and inflammation by enhancing antioxidant capacity and inhibiting cytokine production in the kidney tissues. Mechanistically, Lut activated the AMPK/SIRT1/FOXO1 signaling pathway, attenuating oxidative stress and inflammatory responses, ameliorating the metabolic disturbance. In conclusion, these observations demonstrate that Lut treatment activates AMPK/SIRT1/FOXO1 signaling pathway, decreases oxidative stress and inflammation response, which may contribute to prevent Cd-induced metabolism disorder and consequent kidney damage.

Implicit theories of health predict HPV vaccination intention among young adult Chinese women: The mediating effect of consideration of future consequences and future self-continuity.

This study investigated the predicting effect of implicit theories of health on HPV vaccination intention among young adult Chinese women and its underlying mechanisms. Four-hundred and eighty-three young Chinese women adults (18-26 years old) participated this study by completing measures on implicit theories of health, consideration of future consequences, future self-continuity, and reported their HPV vaccination intention. The results demonstrated that age, whether they knew someone being diagnosed with cancer, implicit (incremental) theories of health, consideration of future consequences (CFC-Future), and future self-continuity significantly predicted young adult Chinese women's HPV vaccination intention. The predicting effect of implicit theories of health was mediated by consideration of future consequences and future self-continuity. Implications of the current research for promoting HPV vaccination among young adult women and directions for future research are discussed.

Luteolin Alleviates Cadmium-Induced Kidney Injury by Inhibiting Oxidative DNA Damage and Repairing Autophagic Flux Blockade in Chickens.

Chickens are a major source of meat and eggs in human food and have significant economic value. Cadmium (Cd) is a common environmental pollutant that can contaminate feed and drinking water, leading to kidney injury in livestock and poultry, primarily by inducing the generation of free radicals. It is necessary to develop potential medicines to prevent and treat Cd-induced nephrotoxicity in poultry. Luteolin (Lut) is a natural flavonoid compound mainly extracted from peanut shells and has a variety of biological functions to defend against oxidative damage. In this study, we aimed to demonstrate whether Lut can alleviate kidney injury under Cd exposure and elucidate the underlying molecular mechanisms. Renal histopathology and cell morphology were observed. The indicators of renal function, oxidative stress, DNA damage and repair, NAD+ content, SIRT1 activity, and autophagy were analyzed. In vitro data showed that Cd exposure increased ROS levels and induced oxidative DNA damage and repair, as indicated by increased 8-OHdG content, increased γ-H2AX protein expression, and the over-activation of the DNA repair enzyme PARP-1. Cd exposure decreased NAD+ content and SIRT1 activity and increased LC3 II, ATG5, and particularly p62 protein expression. In addition, Cd-induced oxidative DNA damage resulted in PARP-1 over-activation, reduced SIRT1 activity, and autophagic flux blockade, as evidenced by reactive oxygen species scavenger NAC application. The inhibition of PARP-1 activation with the pharmacological inhibitor PJ34 restored NAD+ content and SIRT1 activity. The activation of SIRT1 with the pharmacological activator RSV reversed Cd-induced autophagic flux blockade and cell injury. In vivo data demonstrated that Cd treatment caused the microstructural disruption of renal tissues, reduced creatinine, and urea nitrogen clearance, raised MDA content, and decreased the activities or contents of antioxidants (GSH, T-SOD, CAT, and T-AOC). Cd treatment caused oxidative DNA damage and PARP-1 activation, decreased NAD+ content, decreased SIRT1 activity, and impaired autophagic flux. Notably, the dietary Lut supplement observably alleviated these alterations in chicken kidney tissues induced by Cd. In conclusion, the dietary Lut supplement alleviated Cd-induced chicken kidney injury through its potent antioxidant properties by relieving the oxidative DNA damage-activated PARP-1-mediated reduction in SIRT1 activity and repairing autophagic flux blockade.

FTIR spectroscopy for assessment of hair from lung cancer patients and its application in monitoring the chemotherapy treatment effect.

Lung cancer is the most common cancer and the leading cause of death in China. The current gold standard for clinical lung cancer diagnosis is based on histopathological examination of tumors, but it has the limitation for easy operation and convenient applications. Therefore, researchers are still striving to develop other tools and methods for non-invasive and rapid assessment of the health conditions of lung cancer patients. Hair, as a reflection of the metabolism of the body, is closely related to human health conditions. In principle, Fourier-transform infrared (FTIR) spectroscopy can probe the major chemical compositions in the hair. However, as indicated by previous studies, there is still the challenge to make good use of FTIR spectroscopy for achieving reliable analysis of hair from cancer patients. In this study, hair samples from 82 lung cancer patients were collected and subjected to FTIR measurements and analysis, which showed the protein content in the hair is closely related to the protein content in the blood serum of patients, and the contents of protein and lipid are statistically lower in the lung cancer patients. Furthermore, we demonstrated that FTIR spectroscopy could be employed to monitor the hair of lung cancer patients undergoing chemotherapy, and confirmed that the FTIR spectra of the hair may reflect the resultant effect of the chemotherapy. As such, this work validates the way of using FTIR spectroscopy in hair analysis for the assistance of medical diagnosis of lung cancer as well as monitoring the conditions of the patients under the medical treatment.

Colorimetric and SERS dual-mode detection of GSH in human serum based on AuNPs@Cu-porphyrin MOF nanozyme.

BACKGROUND: Rapid and accurate detection of glutathione content in human blood plays an important role in real-time tracking of related diseases. Currently, surface-enhanced Raman scattering/spectroscopy (SERS) combined with nanozyme material has been proven to have excellent properties in the detection applications compared to many other methods because of it combines the advantages of trace detection capability of SERS and efficient catalytic activity of nanozymes. However, there are still existing problems in real sample detection, and to achieve quantitative detection is still challenging. RESULTS: In this study, gold nanoparticles (AuNPs) were synthesized in situ on the surface of two-dimensional Cu-porphyrin metal-organic framework (MOF) nanosheets to produce the AuNPs@Cu-porphyrin MOF nanozyme, which exhibited both oxidase-like activity and SERS detection ability. On one hand, the intrinsic oxidase-like activity of the nanozyme could be inhibited due to the chelation of glutathione (GSH) and Cu, which thus led to the visual color change of the solution. On the other hand, the abundant Raman "hot spots" at the nanogap generated by Au NPs and the internal standard (IS) signal provided by Cu-meso-tetra (4-carboxyphenyl) porphine (Cu-TCPP) MOF improved the sensitivity and quantitative accuracy of detection. SIGNIFICANCE AND NOVELTY: A dual-mode signal output sensor based on the nanozyme was thus established, which could be used in the trace detection of GSH. Such a dual-mode sensor possesses excellent detection performance, with the advantage of both wide detection range from 1 to 300 µM in the colorimetric detection mode and high sensitivity with LOD of 5 nM in the SERS detection mode, and can be applied to GSH detection in actual serum samples with reliable results.

Antithrombin deficiency caused by SERPINC1 gene mutation in white matter lesions: A case report.

RATIONALE: White matter lesions (WMLs) are structural changes in the brain that manifest as demyelination in the central nervous system pathologically. Vasogenic WMLs are the most prevalent type, primarily associated with advanced age and cerebrovascular risk factors. Conversely, immunogenic WMLs, typified by multiple sclerosis (MS), are more frequently observed in younger patients. It is crucial to distinguish between these 2 etiologies. Furthermore, in cases where multiple individuals exhibit WMLs within 1 family, genetic testing may offer a significant diagnostic perspective. PATIENT CONCERNS: A 25-year-old male presented to the Department of Neurology with recurrent headaches. He was healthy previously and the neurological examination was negative. Brain magnetic resonance imaging (MRI) showed widespread white matter hyperintensity lesions surrounding the ventricles and subcortical regions on T2-weighted and T2 fluid-attenuated inversion recovery images, mimicking immunogenic disease-MS. DIAGNOSES: The patient was diagnosed with a patent foramen ovale, which could explain his headache syndrome. Genetic testing unveiled a previously unidentified missense mutation in the SERPINC1 gene in the patient and his father. The specific abnormal laboratory finding was a reduction in antithrombin III activity, and the decrease may serve as the underlying cause for the presence of multiple intracranial WMLs observed in both the patient and his father. INTERVENTIONS: The patient received percutaneous patent foramen ovale closure surgery and took antiplatelet drug recommended by cardiologists and was followed up for 1 month and 6 months after operation. OUTCOMES: While the lesions on MRI remain unchanging during follow-up, the patient reported a significant relief in headaches compared to the initial presentation. LESSONS: This case introduces a novel perspective on the etiology of cerebral WMLs, suggesting that hereditary antithrombin deficiency (ATD) could contribute to altered blood composition and may serve as an underlying cause in certain individuals with asymptomatic WMLs.

Cyclic guanosine monophosphate-adenosine monophosphate synthetase/stimulator of interferon genes signaling aggravated corneal allograft rejection through neutrophil extracellular traps.

The activation of innate immunity following transplantation has been identified as a crucial factor in allograft inflammation and rejection. However, the role of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signaling-mediated innate immunity in the pathogenesis of allograft rejection remains unclear. Utilizing a well-established murine model of corneal transplantation, we demonstrated increased expression of cGAS and STING in rejected-corneal allografts compared with syngeneic (Syn) and normal (Nor) corneas, along with significant activation of the cGAS/STING pathway, as evidenced by the enhanced phosphorylation of TANK-binding kinase 1and interferon regulatory factor 3. Pharmacological and genetic inhibition of cGAS/STING signaling markedly delayed corneal transplantation rejection, resulting in prolonged survival time and reduced inflammatory infiltration. Furthermore, we observed an increase in the formation of neutrophil extracellular traps (NETs) in rejected allografts, and the inhibition of NET formation through targeting peptidylarginine deiminase 4 and DNase I treatment significantly alleviated immune rejection and reduced cGAS/STING signaling activity. Conversely, subconjunctival injection of NETs accelerated corneal transplantation rejection and enhanced the activation of the cGAS/STING pathway. Collectively, these findings demonstrate that NETs contribute to the exacerbation of allograft rejection via cGAS/STING signaling, highlighting the targeting of the NETs/cGAS/STING signaling pathway as a potential strategy for prolonging allograft survival.

Transcriptomic and intervention evidence reveals domestic dogs as a promising model for anti-inflammatory investigation.

Domestic dogs have great potential to expand our understanding of the determinants of aging. To understand the aging pattern of domestic dogs and evaluate whether they can be used as an aging model, we performed RNA sequencing on white blood cells from domestic dogs aged 1-9 years and treated aged dogs with classical antiaging approaches. We obtained 30 RNA sequencing libraries and identified 61 age-associated genes with dynamic changes, the majority of which were related to metabolism and immune function, which may be predominant biomarkers for aging in dogs. We next treated aged dogs with canine mesenchymal stem cells (cMSCs), nicotinamide mononucleotide, and rapamycin to determine whether and how they responded to the antiaging interventions. The results showed that these treatments can significantly reduce the level of inflammatory factors (IL-6 and TNF-α). MSCs effectively improved the heart functions of aged dogs. Three key potential age-related genes (PYCR1, CCRL2, and TOX) were reversed by MSC treatment, two of which (CCRL2 and TOX) are implicated in immunity. Overall, we profiled the transcriptomic pattern of domestic dogs and revealed that they may be a good model of aging, especially in anti-inflammatory investigations.

TPP (totally preperitoneal) making single incision laparoscopic inguinal hernia repair more feasible: a comparison with single incision laparoscopic totally extraperitoneal hernioplasty (SIL-TEP).

BACKGROUND: Totally preperitoneal hernioplasty (TPP) is a concept which was introduced for distinguishing with totally extraperitoneal (TEP). There is few evidence reflecting the single incision laparoscopic totally preperitoneal (SIL-TPP) characteristic. The aim of study is to demonstrate the feasibility of single incision laparoscopic totally preperitoneal hernioplasty (SIL-TPP) and compare the outcomes with the single incision laparoscopic totally extraperitoneal hernioplasty (SIL-TEP) technique. METHODS: During August 2018 and July 2022, 200 inguinal hernia patients received SIL-TPP and 56 patients received SIL-TEP in the First hospital of Ningbo university. The demographics, clinical characteristics, intraoperative and postoperative parameters were retrospectively analysed. RESULTS: SIL-TPP and SIL-TEP hernia repair were successfully conducted in all patients. There was no conversation happened in two group. Patients' demographics were comparable when compared between the two groups adding the comparison initial 52 cases analysis (P > 0.05). The mean unilateral hernia operative time was significant shorter in the SIL-TPP group than SIL-TEP group (unilateral: 81.38 ± 25.32 vs. 95.96 ± 28.54, P: 0.001). Further study of unilateral hernia operative time revealed the mean indirect hernia operative time was significant shorter in the SIL-TPP group than SIL-TEP group (indirect: 81.38 ± 25.33 vs. 95.87 ± 28.54, P: 0.001). The unilateral hernia operation time trend of initial 52 cases of two group analysis revealed the operation time of SIL-TPP reduced faster than SIL-TEP along with treating number increasing (Figs. 2 and 3). The comparison of initial equal quantity unilateral hernia patient mean operative time revealed the SIL-TPP group was significant shorter than SIL-TEP group (85.77 ± 22.76 vs. 95.87 ± 28.54, P: 0.049). The rate of peritoneum tearing of SIL-TPP group was significant high than SIL-TEP (P = 0.005). CONCLUSION: SIL-TPP hernia repair is a superior procedure and possess its own distinguished advantages. We recommend it rather than SIL-TEP for treating inguinal hernia, especially for indirect hernia. However, large-scale randomized controlled trials comparing SIL-TPP and SIL-TEP are needed to confirm these results.

Seed and Soil: Consensus Molecular Subgroups (CMS) and Tumor Microenvironment Features Between Primary Lesions and Metastases of Different Organ Sites in Colorectal Cancer.

Purpose: Consensus molecular subtypes (CMS) are mainly used for biological interpretability and clinical stratification of colorectal cancer (CRC) in primary tumors (PT) but few in metastases. The heterogeneity of CMS distribution in metastases and the concordance of CMS between PT and metastases still lack sufficient study. We used CMS to classify CRC metastases and combine it with histopathological analysis to explore differences between PT and distant metastases. Patients and Methods: We obtained gene expression profiles for 942 PT samples from TCGA database (n=376) and GEO database (n=566), as well as 442 metastasis samples from GEO database. Among these, 765 PT samples and 442 metastasis samples were confidently identified with CMS using the "CMS classifier" and enrolled for analysis. Clinicopathological manifestation and CMS classification of CRC metastases were assessed with data from GEO, TCGA, and cBioPortal. Overall, 105 PT-metastasis pairs were extracted from 10 GEO datasets to assess CMS concordance. Tumor microenvironment (TME) features between PT and metastases were analyzed by immune-stromal infiltration with ESTIMATE and xCell algorithms. Finally, TME features were validated with multiplex immunohistochemistry in 27 PT-metastasis pairs we retrospectively collected. Results: Up to 64% of CRC metastases exhibited concordant CMS groups with matched PT, and the TME of metastases was similar to that of PT. For most common distant metastases, liver metastases were predominantly CMS2 and lung and peritoneal metastases were mainly CMS4, highlighting "seed" of tumor cells of different CMS groups had a preference for metastasis to "soil" of specific organs. Compared with PT, cancer-associated fibroblasts (CAF) reduced in liver metastases, CD4+T cells and M2-like macrophages increased in lung metastases, and M2-like macrophages and CAF increased in peritoneal metastases. Conclusion: Our findings underscore the importance of CMS-guided specific organ monitoring and treatment post-primary tumor surgery for patients. Differences in immune-stromal infiltration among different metastases provide targeted therapeutic opportunities for metastatic CRC.

Insight on ecDNA-mediated tumorigenesis and drug resistance.

Extrachromosomal DNAs (ecDNAs) are a pervasive feature found in cancer and contain oncogenes and their corresponding regulatory elements. Their unique structural properties allow a rapid amplification of oncogenes and alter chromatin accessibility, leading to tumorigenesis and malignant development. The uneven segregation of ecDNA during cell division enhances intercellular genetic heterogeneity, which contributes to tumor evolution that might trigger drug resistance and chemotherapy tolerance. In addition, ecDNA has the ability to integrate into or detach from chromosomal DNA, such progress results into structural alterations and genomic rearrangements within cancer cells. Recent advances in multi-omics analysis revealing the genomic and epigenetic characteristics of ecDNA are anticipated to make valuable contributions to the development of precision cancer therapy. Herein, we conclud the mechanisms of ecDNA generation and the homeostasis of its dynamic structure. In addition to the latest techniques in ecDNA research including multi-omics analysis and biochemical validation methods, we also discuss the role of ecDNA in tumor development and treatment, especially in drug resistance, and future challenges of ecDNA in cancer therapy.