Natural background level, source apportionment and health risk assessment of potentially toxic elements in multi-layer aquifers of arid area in Northwest China.

Groundwater contaminated by potentially toxic elements has become an increasing global concern for human health. Therefore, it is crucial to identify the sources and health risks of potentially toxic elements, especially in arid areas. Despite the necessity, there is a notable research gap concerning the sources and risks of these elements within multi-layer aquifers in such regions. To address this gap, 54 phreatic and 24 confined groundwater samples were collected from an arid area in Northwest China. This study aimed to trace the sources and evaluate the human health risks of potentially toxic elements by natural background level (NBL), positive matrix factorization (PMF) model, and health risk model. Findings revealed exceeding levels of potentially toxic elements existed in phreatic and confined aquifers. Source apportionment and NBL results indicated that mineral dissolution, evaporation, redox reactions, and human activities were the main factors for elevated concentrations of potentially toxic elements. High Fe and Mn concentrations were attributed to reduction environments, while F accumulation resulted from slow runoff, and irrigation from the Yellow River. Due to high F levels, more than one-third of groundwater samples (phreatic: 33.14 %, confined: 56.22 %) posed non-carcinogenic health risks to population groups. Adults displayed higher carcinogenic risks (phreatic: 19.47 %, confined: 34.16 %) than infants (phreatic: 0 %, confined: 0 %) and children (phreatic: 1.26 %, confined: 7.97 %) owing to the toxic elements of Cr. The confined aquifer presented greater health risks than the phreatic aquifer. Consequently, controlling the levels of F and Cr in multi-layered aquifers is key to reducing health risks. These findings provide valuable insights into protecting groundwater from contamination by potentially toxic elements in multi-layered aquifers worldwide.

Cellular and Molecular Network Characteristics of TARM1-Related Genes in Mycobacterium tuberculosis Infections.

Tuberculosis (TB) is a global infectious threat, and the emergence of multidrug-resistant TB has become a major challenge in eradicating the disease that requires the discovery of new treatment strategies. This study aimed to elucidate the immune infiltration and molecular regulatory network of T cell-interacting activating receptors on myeloid cell 1 (TARM1)-related genes based on a bioinformatics analysis. The GSE114911 dataset was obtained from the Gene Expression Omnibus (GEO) and screened to identify 17 TARM1-related differentially expressed genes (TRDEGs). Genes interacting with the TRDEGs were analyzed using a Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A gene set enrichment analysis (GSEA) was used to identify the biological pathways significantly associated with a Mycobacterium tuberculosis (Mtb) infection. The key genes were obtained based on Cytoscape's cytoHubba plug-in. Furthermore, protein-protein interaction (PPI) networks were analyzed through STRING, while mRNA-RNA-binding protein (RBP) and mRNA-transcription factor (TF) interaction networks were developed utilizing the StarBase v3.0 and ChIPBase databases. In addition, the diagnostic significance of key genes was evaluated via receiver operating characteristic (ROC) curves, and the immune infiltration was analyzed using an ssGSEA and MCPCounter. The key genes identified in the GSE114911 dataset were confirmed in an independent GSE139825 dataset. A total of seventeen TRDEGs and eight key genes were obtained in a differential expression analysis using the cytoHubba plug-in. Through the GO and KEGG analysis, it was found that these were involved in the NF-κB, PI3K/Akt, MAPK, and other pathways related to inflammation and energy metabolism. Furthermore, the ssGSEA and MCPCounter analysis revealed a significant rise in activated T cells and T helper cells within the Mtb infection group, which were markedly associated with these key genes. This implies their potential significance in the anti-Mtb response. In summary, our results show that TRDEGs are linked to inflammation, energy metabolism, and immune cells, offering fresh insights into the mechanisms underlying TB pathogenesis and supporting further investigation into the possible molecular roles of TARM1 in TB, as well as assisting in the identification of prospective diagnostic biomarkers.

Association between Visceral Adiposity Index and Hyperuricemia among Steelworkers: The Moderating Effects of Drinking Tea.

BACKGROUND/OBJECTIVES: Steelworkers are more likely to have a higher prevalence of hyperuricemia due to their exposure to special occupational factors and dietary habits. The interrelationships of visceral adiposity index (VAI), hyperuricemia, and drinking tea remain uncertain. This study aimed to assess the association between VAI and hyperuricemia among steelworkers, and if drinking tea modified this association. METHODS: A total of 9928 steelworkers from Hunan Hualing Xiangtan Iron and Steel Company participated in this cross-sectional study. All participants completed a questionnaire, received anthropometric measurements, and provided blood samples for biochemical testing. Three logistic regression models were used to analyze the association between VAI and hyperuricemia. RESULTS: In this study, the prevalence of hyperuricemia was approximately 23.74% (males: 24.41%; females: 20.63%), and a positive correlation between VAI and hyperuricemia risk was observed. In multivariate logistic regression analysis, the risk of hyperuricemia increased 1.76 times (95% CI: 1.64-1.89) and 2.13 times (95% CI: 1.76-2.57) with the increase of ln VAI in males and females, respectively. For males, compared to quartile 1, the risk of hyperuricemia in the second, third, and fourth quartile of VAI were 1.75 (95% CI: 1.11-2.71), 2.56 (95% CI: 1.67-3.93) and 4.89 (95% CI: 3.22-7.43). For females, compared to quartile 1, the risk of hyperuricemia in the second, third, and fourth quartile of VAI were 1.99 (95% CI: 1.40-2.82), 2.92 (95% CI: 1.96-4.34) and 4.51 (95% CI: 2.89-7.02). Additionally, our study found that, compared with not consuming tea, drinking tea could reduce uric acid levels by 0.014 in male steelworkers (t = -2.051, p = 0.040), 0.020 in workers consuming smoked food (t = -2.569, p = 0.010), and 0.022 in workers consuming pickled food (t = -2.764, p = 0.006). CONCLUSIONS: In conclusion, VAI is positively correlated with hyperuricemia in steelworkers. Drinking tea may lower uric acid levels in male steelworkers and steelworkers who prefer smoked and pickled foods.

Discovery of a Highly Potent and Selective Inhibitor Targeting Protein Lysine Methyltransferase NSD2.

The histone lysine methyltransferase NSD2 has been recognized as an attractive target for cancer treatment, due to the functional implication of its dysregulation in the initiation and progression of many cancers. Although considerable efforts have been made to develop NSD2 small-molecule inhibitors, highly potent and selective ones are still rarely available till now. Here, we report the discovery of a series of novel NSD2 inhibitors via an extensive SAR exploration of the privileged quinazoline scaffold within compound 8. The most promising compound 42 showed excellent NSD2 enzymatic inhibitory activity and good antiproliferative activity in cells. In addition, it demonstrated favorable pharmacokinetic properties and significantly inhibited the tumor growth in a RS411 tumor xenograft model with good safety. Taken together, compound 42 could be a promising NSD2 inhibitor and deserves further investigation.

Prevalence and genetic diversity of Parechovirus.

Human parechovirus (HPeV) is a common virus that can cause severe infections in newborns. Due to the limited knowledge of the prevalence of HPeV in different cities in China and the unknown association between HPeV infection and clinical characteristics of newborns, this research investigated the epidemiological and clinical characteristics of HPeV infection in hospitalized neonates in Changsha. From August to October 2023, 145 anal swab samples from 96 newborns and 38 pharyngeal swab samples from 33 newborns in the neonatal intensive care unit (NICU) were collected. The prevalence of HPeV was detected by reverse transcription-polymerase chain reaction (RT-PCR). The genomes of HPeV were sequenced and the viral protein 1 (VP1) region was used for genotyping. Phylogenetic analysis and recombination analysis of HPeV genome were performed. Finally, HPeV was detected in 10 out of 44 patients in October, all of them were HPeV-1. The sequenced 4 genomes of HPeV showed high genetic diversity with known strains. Additionally, a HPeV-1 recombinant strain was detected. Compared with HPeV negative patients, HPeV patients had higher prevalence of abdominal pain and diarrhea, intracranial hemorrhage, and purulent meningitis. Compared with HPeV negative patients, HPeV patients had higher peripheral blood lymphocytes, albumin, globulin, pH and lower peripheral blood neutrophils and hemoglobin. HPeV is an important viral cause of newborn infections and appears to be increasing in prevalence in recent years. Characteristic clinical pictures exist in HPeV infections, and further research is needed to accumulate more cases to obtain a comprehensive understanding of HPeV infections.

The coexistence and transition of weak and strong wave turbulences in acoustic broadening.

This study experimentally demonstrates the coexistence and transition between weak and strong wave turbulence during the interaction of acoustic waves and turbulent flows. We identify conditions under which different wave turbulence regimes occur based on the wave number of the turbulent flow and acoustic waves. As the sound frequency increases, strong wave turbulence dominates, requiring a specific scaling factor to reconcile the spectra with the weak turbulence theory. Our analysis using the wave turbulence framework is confirmed by experimental results, providing deep insights into the complex interaction between acoustics and turbulence.

CD4+ Effective Memory T Cell Markers GBP2 and LAG3 Are Risk Factors for PTB and COVID-19 Infection: A Study Integrating Single-Cell Expression Quantitative Trait Locus and Mendelian Randomization Analyses.

Observational studies indicate that variations in peripheral blood mononuclear cell (PBMC) subsets are associated with an increased risk of pulmonary tuberculosis (PTB) and coronavirus disease 2019 (COVID-19), but causal validation is lacking. Here, we combined single-cell expression quantitative trait locus (sc-eQTL) and two-sample mendelian randomization (MR) analyses to elucidate the causal relationship between PBMC subsets and the occurrence of PTB and COVID-19 and verified by RT-qPCR. We observed an increase in the CD4+ Effective Memory T Cell (CD4+ TEM) cluster in both PTB and COVID-19 patients according to the single-cell transcriptional landscape of PBMC. Through MR analysis using an inverse variance weighted (IVW) method, we found strong evidence of positive correlations between CD4+ TEM cell markers (GBP2, TRAV1-2, and ODF2L) and PTB, and between markers (LAG3 and SLFN5) and COVID-19, especially highlighted by lead eQTL-SNPs of GBP2 (rs2256752, p = 4.76321 × 10-15) and LAG3 (rs67706382, p = 6.16× 10-16). Similar results were observed in validation sets, and no pleiotropy was detected in sensitivity analyses including weighted median (WM), MR-Egger, MR-pleiotropy residual sum and outlier, and leave-one-out analyses (all p > 0.05). We visualized the colocalization of marker-eQTLs and markers of PTB and COVID-19 genome-wide association study (GWAS) associations. Based on CellChat analyses, monocytes communicated predominantly with CD4+ TEM cells positively expressing PTB markers (GBP2, TRAV1-2, and ODF2L) and COVID-19 markers (LAG3 and SLFN5) in both PTB and COVID-19. Our data suggest a causal effect between two key CD4+ TEM cell markers (GBP2 and LAG3) and the risk for PTB and COVID-19 infection. Our findings provide novel insights into the biological mechanism for PTB and COVID-19 infection, but future single-cell studies are necessary to further enhance understanding of this find.

Transcatheter Arterial Chemoembolization Combined with Hepatic Arterial Infusion Chemotherapy Versus Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

BACKGROUND/AIMS: In this study, we evaluated the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with hepatic arterial infusion chemotherapy (HAIC) compared to TACE monotherapy for the treatment of unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Relevant studies were systematically searched in PubMed, Embase, Web of Science, and Cochrane Library databases until September 1, 2023. Our analysis included 7 cohort studies encompassing a total of 630 patients. RESULTS: The results demonstrated that the TACE plus HAIC group exhibited significantly improved prognosis compared to the TACE alone group, as evidenced by superior rates of complete response, partial response, progressive disease, objective response rate, and disease control rate. Moreover, the TACE group displayed a lower risk of platelet reduction and vomiting when compared to the TACE plus HAIC group. None of the 7 studies reported any intervention-related mortality. CONCLUSION: In conclusion, the combination of TACE and HAIC may be recommended as a viable option for patients with unresectable HCC, given its evident enhancements in survival and tumor response rates without significant differences in adverse events when compared to TACE monotherapy. Nevertheless, additional randomized controlled trials and studies involving Western cohorts are warranted to further validate these findings.

Transcatheter Arterial Chemoembolization Combined with Hepatic Arterial Infusion Chemotherapy Versus Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

In this study, we evaluated the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with hepatic arterial infusion chemotherapy (HAIC) compared to TACE monotherapy for the treatment of unresectable hepatocellular carcinoma (HCC). Relevant studies were systematically searched in PubMed, Embase, Web of Science, and Cochrane Library databases until September 1, 2023. Our analysis included 7 cohort studies encompassing a total of 630 patients. The results demonstrated that the TACE plus HAIC group exhibited significantly improved prognosis compared to the TACE alone group, as evidenced by superior rates of complete response, partial response, progressive disease, objective response rate, and disease control rate. Moreover, the TACE group displayed a lower risk of platelet reduction and vomiting when compared to the TACE plus HAIC group. None of the 7 studies reported any intervention-related mortality. In conclusion, the combination of TACE and HAIC may be recommended as a viable option for patients with unresectable HCC, given its evident enhancements in survival and tumor response rates without significant differences in adverse events when compared to TACE monotherapy. Nevertheless, additional randomized controlled trials and studies involving Western cohorts are warranted to further validate these findings.

Discovery of a Highly Potent Lysine Methyltransferases G9a/NSD2 Dual Inhibitor to Treat Solid Tumors.

Both G9a and NSD2 have been recognized as promising therapeutic targets for cancer treatment. However, G9a inhibitors only showed moderate inhibitory activity against solid tumors and NSD2 inhibitors were limited to the treatment of hematological malignancies. Inspired by the advantages of dual-target inhibitors that show great potential in enhancing efficiency, we developed a series of highly potent G9a/NSD2 dual inhibitors to treat solid tumors. The candidate 16 demonstrated much enhanced antiproliferative activity compared to the selective G9a inhibitor 3 and NSD2 inhibitor 15. In addition, it exhibited superior potency in inhibiting colony formation, inducing cell apoptosis, and blocking cancer cell metastasis. Furthermore, it effectively inhibited the catalytic functions of both G9a and NSD2 in cells and exhibited significant antitumor efficacy in the PANC-1 xenograft model with good safety. Therefore, compound 16 as a highly potent G9a/NSD2 dual inhibitor presents an attractive anticancer drug candidate for the treatment of solid tumors.

Electrochemical semi-hydrogenation of adiponitrile over copper nanowires as a key step for the green synthesis of nylon-6.

The industrial production of nylon 6 usually includes synthesizing caprolactam through the cyclohexanone-hydroxylamine route. This approach requires complex protocols, elevated temperatures, noble metal catalysts and the use of hazardous strong acids or hydroxylamine. Additionally, a significant quantity of ammonium sulphate is generated during the synthesis procedure. This study aims to develop an electrochemical reduction system for the conversion of ADN generated from the electrolytic dimerization of acrylonitrile (AN) to 6-aminocapronitrile (ACN), a precursor of nylon 6. This system utilizes a cost-effective Cu nanomaterial under eco-friendly conditions, avoiding lengthy and harsh processes, eliminating NH2OH use, and reducing low-value ammonium sulfate generation. This electrosynthesis method maintains approximately 85% ACN selectivity at 40-100 mA cm-2 when passing the charge required for 37% theoretical conversion. When extending the reaction time to achieve an 80% conversion, ACN selectivity still reached 81.6%, exceeding the theoretical value of non-selective hydrogenation by 20%. The pseudo-first-order reaction kinetic modeling proves that the reaction rate constant for ADN hydrogenation is significantly greater than that for ACN hydrogenation, highlighting the selectivity advantage of the system for ACN. This study establishes the foundation for developing a continuous electrolysis process to produce the nylon 6 precursor from AN feedstock.

Effects of N, N-bis (carboxymethyl)-L-glutamic acid and polyaspartic acid on the phytoremediation of cadmium in contaminated soil at the presence of pyrene: Biochemical properties and transcriptome analysis.

Chelator-assisted phytoremediation is an efficacious method for promoting the removal efficiency of heavy metals (HMs). The effects of N, N-bis(carboxymethyl)-L-glutamic acid (GLDA) and polyaspartic acid (PASP) on Cd uptake and pyrene removal by Solanum nigrum L. (S. nigrum) were compared in this study. Using GLDA or PASP, the removal efficiency of pyrene was over 98%. And PASP observably raised the accumulation and transport of Cd by S. nigrum compared with GLDA. Meanwhile, both GLDA and PASP markedly increased soil dehydrogenase activities (DHA) and microbial activities. DHA and microbial activities in the PASP treatment group were 1.05 and 1.06 folds of those in the GLDA treatment group, respectively. Transcriptome analysis revealed that 1206 and 1684 differentially expressed genes (DEGs) were recognized in the GLDA treatment group and PASP treatment group, respectively. Most of the DEGs found in the PASP treatment group were involved in the metabolism of carbohydrates, the biosynthesis of brassinosteroid and flavonoid, and they were up-regulated. The DEGs related to Cd transport were screened, and ABCG3, ABCC4, ABCG9 and Nramp5 were found to be relevant with the reduction of Cd stress in S. nigrum by PASP. Furthermore, with PASP treated, transcription factors (TFs) related to HMs such as WRKY, bHLH, AP2/ERF, MYB were down-regulated, while more MYB and bZIP TFs were up-regulated. These TFs associated with plant stress resistance would work together to induce oxidative stress. The above results indicated that PASP was more conducive for phytoremediation of Cd-pyrene co-contaminated soil than GLDA.

Protocol for observing lipid droplet dynamics in chicken cone cells.

Chicken cone cells are an excellent model for studying the regulation of lipid droplet dynamics. Here, we present a protocol for studying cone cell lipid droplets from in vivo and ex vitro cultured retinas of chicken embryos. We describe steps for dissecting chicken retinas, electroporating retinas, culturing retinas ex vivo and in vitro, and staining lipid droplets with neutral lipid dye. This protocol is also applicable to investigating other organelles in retinas. For complete details on the use and execution of this protocol, please refer to Pan et al.1.

Global prevalence of Borrelia burgdorferi and Anaplasma phagocytophilum coinfection in Ixodes tick populations: protocol for a systematic review and meta-analysis.

INTRODUCTION: Ixodes ticks are pivotal in transmitting diseases like Lyme disease and human granulocytic anaplasmosis, caused by Borrelia burgdorferi and Anaplasma phagocytophilum, respectively. These pathogens not only affect humans through single or multiple tick bites but also pose risks to animal hosts, leading to potential coinfections. Despite regional studies indicating significant prevalence, their global coinfection data remain sparse. This study aims to bridge this gap through a systematic review and meta-analysis of B. burgdorferi and A. phagocytophilum coinfections in Ixodes ticks worldwide. Addressing data limitations and study variability, it seeks to provide a nuanced understanding of coinfection patterns, their epidemiological implications and inform targeted prevention strategies. METHODS AND ANALYSIS: Following Preferred Reporting Items for Systematic Review and Meta-analysis Protocols 2015 guidelines and PROSPERO registration, this study will undertake a thorough database search without constraints on language or publication date, using standardised screening and data extraction protocols. The quality and bias of studies will be evaluated using Joanna Briggs Institute tools. In the statistical analysis phase, conducted in R, we will initially determine the use of fixed or random-effects models based on the assessment of data heterogeneity. This choice will guide the framework for subsequent analyses. Within the selected model's framework, we will perform subgroup analyses and meta-regression to investigate the effects of various factors, ensuring that each step is tailored to the initial model selection to maintain analytical consistency. ETHICS AND DISSEMINATION: As this study does not involve clinical research or data collection from subjects, ethical approval is not required. We will uphold ethical standards in synthesising and reporting data. Study outcomes will be published in peer-reviewed journals, communicating findings to the scientific community and contributing to the understanding of Ixodes tickborne diseases. PROSPERO REGISTRATION NUMBER: CRD42023449735.

An open auscultation dataset for machine learning-based respiratory diagnosis studies.

Machine learning enabled auscultating diagnosis can provide promising solutions especially for prescreening purposes. The bottleneck for its potential success is that high-quality datasets for training are still scarce. An open auscultation dataset that consists of samples and annotations from patients and healthy individuals is established in this work for the respiratory diagnosis studies with machine learning, which is of both scientific importance and practical potential. A machine learning approach is examined to showcase the use of this new dataset for lung sound classifications with different diseases. The open dataset is available to the public online.

Groundwater suitability assessment for irrigation and drinking purposes by integrating spatial analysis, machine learning, water quality index, and health risk model.

An in-depth understanding of nitrate-contaminated surface water and groundwater quality and associated risks is important for groundwater management. Hydrochemical characteristics and driving forces of groundwater quality and non-carcinogenic risks of nitrate were revealed by the integrated approaches of self-organizing map analysis, spatial visualization by geography information system, entropy and irrigation water quality indices, and human health risk model. Groundwater samples were categorized into two clusters by SOM analysis. Cluster I including three samples were Ca-SO4 type and cluster II of remaining 136 samples were Ca-HCO3 type. Hydrochemical compositions of two cluster samples were dominated by water-rock interaction: (1) calcite and gypsum dissolution for cluster I samples and (2) calcite dissolution, silicate weathering, and positive cation exchange for cluster II samples. Nitrate contamination occurred in both cluster I and II samples, primarily induced by agricultural nitrogen fertilizer. The EWQI results showed that 90.97% in total groundwater samples were suitable for drinking purpose, while the IWQI results demonstrated that 65.03% in total groundwater samples were appropriate for irrigation purpose. The HHR model and Monte Carlo simulation indicated that the non-carcinogenic nitrated risk was highest in children. Exposure frequency was the most sensitive factor (86.33% in total) influencing the total non-carcinogenic risk, indicated by sensitivity analysis. Compared with the two clusters of groundwater, surface water has a shorter circulation cycle and lower ion concentrations resulting in better water quality. This study can provide scientific basis for groundwater quality evaluation in other parts of the world.

Natural background levels, source apportionment and health risks of potentially toxic elements in groundwater of highly urbanized area.

Identifying the natural background levels (NBLs), threshold values (TVs), sources and health risks of potentially toxic elements in groundwater is crucial for ensuring the water security of residents in highly urbanized areas. In this study, 96 groundwater samples were collected in urban area of Sichuan Basin, SW China. The concentrations of potentially toxic elements (Li, Fe, Cu, Zn, Al, Pb, B, Ba and Ni) were analyzed for investigating the NBLs, TVs, sources and health risks. The potentially toxic elements followed the concentration order of Fe > Ba > B > Al > Zn > Li > Cu > Ni > Pb. The NBLs and TVs indicated the contamination of potentially toxic elements mainly occurred in the northern and central parts of the study area. The Positive Matrix Factorization (PMF) model identified elevated concentrations of Fe, Al, Li, and B were found to determine groundwater quality. The primary sources of Fe, Al, Pb, and Ni were attributed to the dissolution of oxidation products, with Fe additionally affected by anthropogenic reduction environments. Li and B were determined to be originated from the weathering of tourmaline. High levels of Ni and Cu concentrations were derived from electronic waste leakage, while excessive Ba and Zn were linked to factory emissions and tire wear. The reasonable maximum exposure (RME) of hazard index (HI) was higher than safety standard and reveal the potential health risks in the southwestern study area. Sensitivity analysis demonstrated the Li concentrations possessed the highest weight contributing to health risk. This study provides a valuable information for source-specific risk assessments of potentially toxic elements in groundwater associated with urban areas.

Postoperative leukocyte counts as a surrogate for surgical stress response in matched robot- and video-assisted thoracoscopic surgery cohorts of patients: A preliminary report.

The objective is to preliminary evaluated postoperative leukocyte counts as a surrogate for the surgical stress response in NSCLC patients who underwent RATS or VATS for further prospective analyses with proper assessment of surgical stress response and tissue trauma. We retrospectively analyzed patients with stageI-IIIA NSCLC who underwent RATS or VATS at a hospital between 8 May 2020 and 31 December 2021. Analysis of leukocytes (including neutrophils and lymphocytes) and albumin on postoperative days (PODs) 1 and 3 in patients with NSCLC treated with RATS or VATS after propensity score matching (PSM). In total, 1824 patients (565 RATS and 1259 VATS) were investigated. The two MIS groups differed significantly with regard to operative time (p < 0.001), chronic lung disease (p < 0.001), the type of pulmonary resection (p < 0.001), the excision site of lobectomy (p = 0.004), and histology of the tumor (p = 0.028). After PSM, leukocyte and neutrophil levels in the RATS group were lower than those in the VATS group on PODs 1 and 3, with those on POD 3 (p < 0.001) being particularly notable. While lymphocyte levels in the RATS group were significantly lower than those in the VATS group only at POD 1 (p = 0.016). There was no difference in albumin levels between the RATS and VATS groups on PODs 1 and 3. The surgical stress response and tissue trauma was less severe in NSCLC patients who underwent RATS than in those who underwent VATS, especially reflected in the neutrophils of leukocytes.

Discovery of Novel PROTAC Degraders of p300/CBP as Potential Therapeutics for Hepatocellular Carcinoma.

Adenoviral E1A binding protein 300 kDa (p300) and its closely related paralog CREB binding protein (CBP) are promising therapeutic targets for human cancer. Here, we report the first discovery of novel potent small-molecule PROTAC degraders of p300/CBP against hepatocellular carcinoma (HCC), one of the most common solid tumors. Based upon the clinical p300/CBP bromodomain inhibitor CCS1477, a conformational restriction strategy was used to optimize the linker to generate a series of PROTACs, culminating in the identification of QC-182. This compound effectively induces p300/CBP degradation in the SK-HEP-1 HCC cells in a dose-, time-, and ubiquitin-proteasome system-dependent manner. QC-182 significantly downregulates p300/CBP-associated transcriptome in HCC cells, leading to more potent cell growth inhibition compared to the parental inhibitors and the reported degrader dCBP-1. Notably, QC-182 potently depletes p300/CBP proteins in mouse SK-HEP-1 xenograft tumor tissue. QC-182 is a promising lead compound toward the development of p300/CBP-targeted HCC therapy.