NGEF is a potential prognostic biomarker and could serve as an indicator for immunotherapy and chemotherapy in lung adenocarcinoma.

BACKGROUND: Neuronal guanine nucleotide exchange factor (NGEF) plays a key role in several cancers; however, its role in lung adenocarcinoma (LUAD) remains unclear. The aim of this study was to evaluate the efficacy of NGEF as a prognostic biomarker and potential therapeutic target for LUAD. METHODS: NGEF expression data for multiple cancers and LUAD were downloaded from multiple databases. The high- and low-NGEF expression groups were constructed based on median NGEF expression in LUAD samples, and then performed Kaplan-Meier survival analysis. Differentially expressed genes (DEGs) from the two NGEF expression groups were screened and applied to construct a protein-protein interaction network. The primary pathways were obtained using gene set enrichment analysis. The associations between NGEF expression and clinical characteristics, immune infiltration, immune checkpoint inhibitors (ICIs), sensitivity to chemotherapy, and tumor mutation burden (TMB) were investigated using R. Levels of NGEF expression in the lung tissue was validated using single-cell RNA sequencing, quantitative polymerase chain reaction (qPCR), immunohistochemical staining, and western blot analysis. RESULTS: The expression of NGEF mRNA was upregulated in multiple cancers. mRNA and protein expression levels of NGEF were higher in patients with LUAD than in controls, as validated using qPCR and western blot. High NGEF expression was an independent prognostic factor for LUAD and was associated with advanced tumor stage, large tumor size, more lymph node metastasis, and worse overall survival (OS). A total of 182 overlapping DEGs were screened between The Cancer Genome Atlas and GSE31210, among which the top 20 hub genes were identified. NGEF expression was mainly enriched in the pathways of apoptosis, cell cycle, and DNA replication. Moreover, elevated NGEF expression were associated with a high fraction of activated memory CD4+ T cells and M0 macrophages; elevated expression levels of the ICIs: programmed cell death 1 and programmed cell death 1 ligand 1 expression; higher TMB; and better sensitivity to bortezomib, docetaxel, paclitaxel, and parthenolide, but less sensitivity to axitinib and metformin. CONCLUSION: NGEF expression is upregulated in LUAD and is significantly associated with tumor stages, OS probability, immune infiltration, immunotherapy response, and chemotherapy response. NGEF may be a potential diagnostic and prognostic biomarker and therapeutic target in LUAD.

Tris(1,3-dichloro-2-propyl) phosphate-induced cytotoxicity and its associated mechanisms in human A549 cells.

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used organophosphorus flame retardant and has been detected in various environmental matrices including indoor dust. Inhalation of indoor dust is one of the most important pathways for human exposure to TDCIPP. However, its adverse effects on human lung cells and potential impacts on respiratory toxicity are largely unknown. In the current study, human non-small cell carcinoma (A549) cells were selected as a cell model, and the effects of TDCIPP on cell viability, cell cycle, cell apoptosis, and underlying molecular mechanisms were investigated. Our data indicated a concentration-dependent decrease in the cell viability of A549 cells after exposure to TDCIPP for 48 h, with half lethal concentration (LC50) being 82.6 µM. In addition, TDCIPP caused cell cycle arrest mainly in the G0/G1 phase by down-regulating the mRNA expression of cyclin D1, CDK4, and CDK6, while up-regulating the mRNA expression of p21 and p27. In addition, cell apoptosis was induced via altering the expression levels of Bcl-2, BAX, and BAK. Our study implies that TDCIPP may pose potential health risks to the human respiratory system and its toxicity should not be neglected.

Flavonoids, gut microbiota, and host lipid metabolism.

Flavonoids are widely distributed in nature and have a variety of beneficial biological effects, including antioxidant, anti-inflammatory, and anti-obesity effects. All of these are related to gut microbiota, and flavonoids also serve as a bridge between the host and gut microbiota. Flavonoids are commonly used to modify the composition of the gut microbiota by promoting or inhibiting specific microbial species within the gut, as well as modifying their metabolites. In turn, the gut microbiota extensively metabolizes flavonoids. Hence, this reciprocal relationship between flavonoids and the gut microbiota may play a crucial role in maintaining the balance and functionality of the metabolism system. In this review, we mainly highlighted the biological effects of antioxidant, anti-inflammatory and antiobesity, and discussed the interaction between flavonoids, gut microbiota and lipid metabolism, and elaborated the potential mechanisms on host lipid metabolism.

Extracellular volume fraction derived from dual-energy CT: a potential predictor for acute pancreatitis after pancreatoduodenectomy.

OBJECTIVES: To investigate the value of extracellular volume (ECV) fraction and fat fraction (FF) derived from dual- energy CT (DECT) for predicting postpancreatectomy acute pancreatitis (PPAP) after pancreatoduodenectomy (PD). METHODS: This retrospective study included patients who underwent DECT and PD between April 2022 and September 2022. PPAP was determined according to the International Study Group for Pancreatic Surgery (ISGPS) definition. Iodine concentration (IC) and FF of the pancreatic parenchyma were measured on preoperative DECT. The ECV fraction was calculated from iodine map images of the equilibrium phase. The independent predictors for PPAP were assessed by univariate and multivariable logistic regression analysis and receiver operating characteristic (ROC) curve analysis. RESULTS: Sixty-nine patients were retrospectively enrolled (median age, 60 years; interquartile range, 55-70 years; 47 men). Of these, nine patients (13.0%) developed PPAP. These patients had lower portal venous phase IC, equilibrium phase IC, FF, and ECV fraction, and higher pancreatic parenchymal-to-portal venous phase IC ratio and pancreatic parenchymal-to-equilibrium phase IC ratio, compared with patients without PPAP. After multivariable analysis, ECV fraction was independently associated with PPAP (odd ratio [OR], 0.87; 95% confidence interval [CI]: 0.79, 0.96; p < 0.001), with an area under the curve (AUC) of 0.839 (sensitivity 100.0%, specificity 58.3%). CONCLUSIONS: A lower ECV fraction is independently associated with the occurrence of PPAP after PD. ECV fraction may serve as a potential predictor for PPAP after PD. CLINICAL RELEVANCE STATEMENT: DECT-derived ECV fraction of pancreatic parenchyma is a promising biomarker for surgeons to preoperatively identify patients with higher risk for postpancreatectomy acute pancreatitis after PD and offer selective perioperative management. KEY POINTS: PPAP is a complication of pancreatic surgery, early identification of higher-risk patients allows for risk mitigation. Lower DECT-derived ECV fraction was independently associated with the occurrence of PPAP after PD. DECT aids in preoperative PAPP risk stratification, allowing for appropriate treatment to minimize complications.

Circumventing drug resistance in gastric cancer: A spatial multi-omics exploration of chemo and immuno-therapeutic response dynamics.

BACKGROUND: Gastric Cancer (GC) characteristically exhibits heterogeneous responses to treatment, particularly in relation to immuno plus chemo therapy, necessitating a precision medicine approach. This study is centered around delineating the cellular and molecular underpinnings of drug resistance in this context. METHODS: We undertook a comprehensive multi-omics exploration of postoperative tissues from GC patients undergoing the chemo and immuno-treatment regimen. Concurrently, an image deep learning model was developed to predict treatment responsiveness. RESULTS: Our initial findings associate apical membrane cells with resistance to fluorouracil and oxaliplatin, critical constituents of the therapy. Further investigation into this cell population shed light on substantial interactions with resident macrophages, underscoring the role of intercellular communication in shaping treatment resistance. Subsequent ligand-receptor analysis unveiled specific molecular dialogues, most notably TGFB1-HSPB1 and LTF-S100A14, offering insights into potential signaling pathways implicated in resistance. Our SVM model, incorporating these multi-omics and spatial data, demonstrated significant predictive power, with AUC values of 0.93 and 0.84 in the exploration and validation cohorts respectively. Hence, our results underscore the utility of multi-omics and spatial data in modeling treatment response. CONCLUSION: Our integrative approach, amalgamating mIHC assays, feature extraction, and machine learning, successfully unraveled the complex cellular interplay underlying drug resistance. This robust predictive model may serve as a valuable tool for personalizing therapeutic strategies and enhancing treatment outcomes in gastric cancer.

Efficacy of Flexible Ureteroscopy Lithotripsy and Percutaneous Nephrolithotomy in the Treatment of Patients with Kidney Stones and Their Impact on Inflammatory Response and Renal Function.

BACKGROUND: Kidney stones are one of the most common benign diseases in urology. As technology updates and iterates, more minimally invasive and laparoscopic surgeries with higher safety performance appear. This paper explores the effectiveness of retrograde intrarenal surgery (RIRS) and percutaneous nephrolithotomy (PCNL) in treating kidney stones, focusing on their effects on inflammatory responses and renal function. METHODS: We conducted a retrospective analysis of 200 patients with kidney stones treated in our hospital between June 2019 and June 2023. 100 patients who underwent RIRS were included in the RIRS group. Another 100 patients who underwent PCNL treatment were included in the PCNL group. The intraoperative blood loss, operation duration, and hospitalization time of the two groups of patients were recorded and compared. The enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of inflammatory factors in the serum of the two groups of patients: [serum amyloid A (SAA), interleukin-6 (IL-6) and high-sensitivity C-reactive protein (CRP)] and renal function index [blood urea nitrogen (BUN), creatinine (Scr) and serum cystatin (Cys-c)]. The two groups of patients were recorded separately: Postoperative complications and stone-free rate. RESULTS: Operation duration was longer for the RIRS group than the PCNL group, which exhibited significantly less intraoperative blood loss and shorter hospital stays (p < 0.05). Before surgery, there was no statistically significant difference in the serum levels of SAA, IL-6, and CRP between the two groups of patients (p > 0.05). On the first day after surgery, the serum SAA levels in both groups were lower than before surgery, IL-6 and CRP levels were higher than before surgery, and the serum levels of SAA, IL-6, and CRP in the RIRS group were significantly lower than those in the PCNL group. The difference was statistically significant (p < 0.05). Before surgery, there was no statistically significant difference in the serum BUN, Scr, and Cys-c levels between the two groups of patients (p > 0.05). On the first day after surgery, the serum BUN, Scr, and Cys-c levels of the two groups of patients were significantly higher than those before surgery. The serum BUN, Scr, and Cys-c levels of the RIRS group were significantly lower than those of the PCNL group, and the difference was statistically significant (p < 0.05). Both surgical methods have sound stone-clearing effects regarding long-term stone clearance rates 1 month and 3 months after surgery (p > 0.05). PCNL had a better stone clearance rate on the 2nd postoperative day (p < 0.05). The incidence of postoperative complications in the RIRS group was significantly lower than that in the PCNL group, and the difference was statistically significant (p < 0.05). CONCLUSION: For kidney stones ≤2 cm, PCNL showed higher stone clearance rates on the second postoperative day. However, RIRS and PCNL demonstrated adequate long-term stone clearance at 1 and 3 months post-surgery. Both surgical methods are safe and effective, and RIRS is safer than PCNL. Compared with PCNL, RIRS is a new method of kidney stone operation, which has less trauma to the patient's body and fewer complications after the operation, speeding up the recovery process of the patient.

Treatment of Pauwels III femoral neck fracture in young patients using biplane double support screw internal fixation technology based on X-ray image.

Traditional treatment methods have certain limitations. In recent years, the technique of internal fixation with double-plane double-supported screws based on X-ray images has been proposed to improve the therapeutic effect. The main objective of this research was to examine the effectiveness of the X-ray image-based bi-planar double-braced screw internal fixation technique . During surgery, the procedure was determined based on X-ray images, followed by an open reduction procedure at the fracture site, and finally internal fixation using bi-planar double-support screws. All patients were successfully treated with X-ray image-based bi-planar double support screw fixation. After surgery, X-ray images showed a good reduction of the fracture site without significant loosening or failure of the internal fixation. At the postoperative follow-up, the patient's pain symptoms were significantly relieved, and no significant complications occurred during recovery.

Inhibition of inflammation by berberine: Molecular mechanism and network pharmacology analysis.

BACKGROUND: Traditional Chinese Medicine (TCM), renowned for its holistic approach with a 2000-year history of utilizing natural remedies, offers unique advantages in disease prevention and treatment. Berberine, found in various Chinese herbs, has been employed for many years, primarily for addressing conditions such as diarrhea and dysentery. Berberine has recently become a research focus owing to its pharmacological activities and benefits to human bodies. However, little is known about the anti-inflammatory mechanism of berberine. PURPOSE: To summarize recent findings regarding the pharmacological effects and mechanisms of berberine anti-inflammation and highlight and predict the potential therapeutic effects and systematic mechanism of berberine. METHODS: Recent studies (2013-2023) on the pharmacological effects and mechanisms of berberine anti-inflammation were retrieved from Web of Science, PubMed, Google Scholar, and Scopus up to July 2023 using relevant keywords. Network pharmacology and bioinformatics analysis were employed to predict the therapeutic effects and mechanisms of berberine against potential diseases. RESULTS: The related pharmacological mechanisms of berberine anti-inflammation include the inhibition of inflammatory cytokine production (e.g., IL-1ß, IL-6, TNF-α), thereby attenuating the inflammatory response; Inhibiting the activation of NF-κB signaling pathway and IκBα degradation; Inhibiting the activation of MAPK signaling pathway; Enhancing the activation of the STAT1 signaling pathway; Berberine interacts directly with cell membranes through a variety of pathways, thereby influencing cellular physiological activities. Berberine enhances human immunity and modulates immune system function, which is integral to addressing certain autoimmune and tumour-related health concerns. CONCLUSION: This study expounds on the correlation between berberine and inflammatory diseases, encapsulating the mechanisms through which berberine treats select typical inflammatory ailments. Furthermore, it delves into a deeper understanding of berberine's effectiveness by integrating network pharmacology and molecular docking techniques in the context of treating inflammatory diseases. It provides guidance and reference for berberine's subsequent revelation of the modern scientific connotation of Chinese medicine.

Assessment of risk factors of lymph node metastasis and prognosis of Siewert II/III adenocarcinoma of esophagogastric junction: A retrospective study.

Adenocarcinoma of the esophagogastric junction (AEG) has a high incidence, and the extent of lymph node dissection (LND) and its impact on prognosis remain controversial. This study aimed to explore the risk factors for lymph node metastasis (LNM) and prognosis in Siewert II/III AEG patients. A retrospective review of 239 Siewert II/III AEG patients surgically treated at Beijing Friendship Hospital from July 2013 to December 2022 was conducted. Preoperative staging was conducted via endoscopy, ultrasound gastroscopy, CT, and biopsy. Depending on the stage, patients received radical gastrectomy with LND and chemotherapy. Clinicopathological data were collected, and survival was monitored semiannually until November 2023. Utilizing logistic regression for data analysis and Cox regression for survival studies, multivariate analysis identified infiltration depth (OR = 0.038, 95% CI: 0.011-0.139, P < .001), tumor deposit (OR = 0.101, 95% CI: 0.011-0.904, P = .040), and intravascular cancer embolus (OR = 0.234, 95% CI: 0.108-0.507, P < .001) as independent predictors of LNM. Lymph nodes No. 1, 2, 3, 4, 7, 10, and 11 were more prone to metastasis in the abdominal cavity. Notably, Siewert III AEG patients showed a higher metastatic rate in nodes No. 5 and No. 6 compared to Siewert II. Mediastinal LNM was predominantly found in nodes No. 110 and No. 111 for Siewert II AEG, with rates of 5.45% and 3.64%, respectively. A 3-year survival analysis underscored LNM as a significant prognostic factor (P = .001). Siewert II AEG patients should undergo removal of both celiac and mediastinal lymph nodes, specifically nodes No. 1, 2, 3, 4, 7, 10, 11, 110, and 111. Dissection of nodes No. 5 and No. 6 is not indicated for these patients. In contrast, Siewert III AEG patients do not require mediastinal LND, but pyloric lymphadenectomy for nodes No. 5 and No. 6 is essential. The presence of LNM is associated with poorer long-term prognosis. Perioperative chemotherapy may offer a survival advantage for AEG patients.

Sulfotransferase SULT2B1 facilitates colon cancer metastasis by promoting SCD1-mediated lipid metabolism.

Metastasis is responsible for at least 90% of colon cancer (CC)-related deaths. Lipid metabolism is a critical factor in cancer metastasis, yet the underlying mechanism requires further investigation. Herein, through the utilisation of single-cell sequencing and proteomics, we identified sulfotransferase SULT2B1 as a novel metastatic tumour marker of CC, which was associated with poor prognosis. CC orthotopic model and in vitro assays showed that SULT2B1 promoted lipid metabolism and metastasis. Moreover, SULT2B1 directly interacted with SCD1 to facilitate lipid metabolism and promoted metastasis of CC cells. And the combined application of SCD1 inhibitor CAY with SULT2B1- konockout (KO) demonstrated a more robust inhibitory effect on lipid metabolism and metastasis of CC cells in comparison to sole application of SULT2B1-KO. Notably, we revealed that lovastatin can block the SULT2B1-induced promotion of lipid metabolism and distant metastasis in vivo. Further evidence showed that SMC1A transcriptionally upregulated the expression of SULT2B1. Our findings unveiled the critical role of SULT2B1 in CC metastasis and provided a new perspective for the treatment of CC patients with distant metastasis.

Clinical effect of vein of Marshall ethanol infusion on mitral isthmus ablation.

Purpose: This study aimed to investigate the effect of Marshall ethanol infusion (VOM-Et) in the vein on mitral isthmus (MI) ablation. Methods: Patients with persistent atrial fibrillation (AF) were grouped into vein of VOM-Et combined with radiofrequency (RF) ablation (VOM-Et-RF) and RF groups. The primary outcome was MI block immediate block rate after surgery. Stratified analysis was also performed for factors affecting the outcome measures. Results: A total of 118 consecutive patients underwent AF ablation at Taizhou Hospital of Zhejiang Province from January 2018 to December 2021. Successful bidirectional perimitral block was achieved in 96% of patients in VOM-Et-RF (69 of 72) and in 76% of patients in the RF group (35 of 46) (P < 0.01). In the subgroup analysis, male sex, elder than 60 years, Left atrial diameter <55 mm, and AF duration <3 years were associated with the benefits of VOM-Et in AF Patients. Conclusion: The vein of Marshall ethanol infusion for catheter ablation can improve the MI block rate. Male sex, elder age, smaller Left atrial diameter and shorter AF duration may have significant benefits for VOM-Et.

Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment.

Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect tumor growth under physiological conditions. Here we report that in aging mice factor-inhibiting HIF (FIH), one of the most studied negative regulators of HIF, is a haploinsufficient suppressor of spontaneous B cell lymphomas, particular pulmonary B cell lymphomas. FIH deficiency alters immune composition in aged mice and creates a tumor-supportive immune environment demonstrated in syngeneic mouse tumor models. Mechanistically, FIH-defective myeloid cells acquire tumor-supportive properties in response to signals secreted by cancer cells or produced in the tumor microenvironment with enhanced arginase expression and cytokine-directed migration. Together, these data demonstrate that under physiological conditions, FIH plays a key role in maintaining immune homeostasis and can suppress tumorigenesis through a cell-extrinsic pathway.

Simultaneous targeting of AMPK and mTOR is a novel therapeutic strategy against prostate cancer.

Metastatic colonization by circulating cancer cells is a highly inefficient process. To colonize distant organs, disseminating cancer cells must overcome many obstacles in foreign microenvironments, and only a small fraction of them survives this process. How these disseminating cancer cells cope with stress and initiate metastatic process is not fully understood. In this study, we report that the metastatic onset of prostate cancer cells is associated with the dynamic conversion of metabolism signaling pathways governed by the energy sensors AMPK and mTOR. While in circulation in blood flow, the disseminating cancer cells display decreased mTOR and increased AMPK activities that protect them from stress-induced death. However, after metastatic onset, the mTOR-AMPK activities are reversed, enabling mTOR-dependent tumor growth. Suppression of this dynamic conversion by co-targeting of AMPK and mTOR signaling significantly suppresses prostate cancer cell and tumor organoid growth in vitro and experimental metastasis in vivo, suggesting that this can be a therapeutic approach against metastasizing prostate cancer.

The safety and efficacy of anti-PD-1 inhibitor-based combinational therapy in non-small cell lung cancer patients with oncogenic alterations.

Background: The anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immunotherapy has been extensively used in patients with non-small cell lung cancer (NSCLC) in which the tumors are negative for oncogenic alterations. However, whether PD-1/PD-L1 blockade therapy could be applicable in patients harboring oncogenic mutations is largely unknown. Methods: In this retrospective study, we analyzed the safety and efficacy of anti-PD-1 inhibitor-based combinational therapy in a NSCLC cohort of 84 patients who harbored oncogenic alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), k-Ras, RET, HER2 and BRAF. The patients were followed up till disease progression or death. The adverse effects associated with the treatment were carefully evaluated and timely interrupted. Results: There were 50 patients harboring EGFR mutations, 17 patients with k-Ras mutation, 2 patients with ALK rearrangement, 6 patients with RET rearrangement, 6 patients with HER2 exon20 insertion and 3 patients with BRAF V600E mutation. About 58.8% of the k-Ras mutant patients responded to the combinational treatment. The median progression-free survival (mPFS) of the k-Ras cohort was 14 months, with the 12-month median overall survival (mOS) ratio and the 24-month OS ratio of 86.7% and 75.8%, respectively. Patients with EGFR exon21 L858R mutation or RET rearrangement tended to have a more favorable response, while patients harboring ALK rearrangement, HER2 exon20 insertion and BRAF V600E mutation did not respond well to anti-PD-1 inhibitor-based combinational therapy. The incidence of treatment-related toxicity was 52.3% and the most common immune-related adverse events (irAEs) were PD-1 inhibitors-related hypothyroidism and pneumonitis. The PD-L1 status and lung immune prognostic index (LIPI) could be used as biomarkers dictating therapeutic outcomes of the combinational therapy. Conclusions: The anti-PD-1 inhibitor-based combinational therapy elicited exciting anti-tumor efficacy and prolonged patient survival with manageable adverse effects in NSCLC patients harboring oncogenic alterations. The PD-L1 status and LIPI could be used as a biomarker predicting response to anti-PD-1 inhibitor-based combinational treatment in these patients.

Low-temperature methanation of fermentation gas with Ni-based catalysts in a multicomponent system.

A large amount of greenhouse gases, such as carbon dioxide and methane, are released during the production process of bioethanol and biogas. Converting CO2 into methane is a promising way of capturing CO2 and generating high-value gas. At present, CO2 methanation technology is still in the early stage. It requires high temperature (300-400 â„ƒ) and pressure (> 1 MPa), leading to high cost and energy consumption. In this study, a new catalyst, Ni-Fe/Al-Ti, was developed. Compared with the activity of the common Ni/Al2O3 catalyst, that of the new catalyst was increased by 1/3, and its activation temperature was reduced by 100℃. The selectivity of methane was increased to 99%. In the experiment using simulated fermentation gas, the catalyst showed good catalytic activity and durability at a low temperature and atmospheric pressure. Based on the characterization of catalysts and the study of reaction mechanisms, this article innovatively proposed a Ni-Fe/Al-Ti quaternary catalytic system. Catalytic process was realized through the synergism of Al-Ti composite support and Ni-Fe promotion. The oxygen vacancies on the surface of the composite carrier and the higher activity metals and alloys promoted by Fe accelerate the capture and reduction of CO2. Compared with the existing catalysts, the new Ni-Fe/Al-Ti catalyst can significantly improve the methanation efficiency and has great practical application potential.

Multi-ancestry genome-wide meta-analysis identifies novel basal cell carcinoma loci and shared genetic effects with squamous cell carcinoma.

Basal cell carcinoma (BCC) is one of the most common malignancies worldwide, yet its genetic determinants are incompletely defined. We perform a European ancestry genome-wide association (GWA) meta-analysis and a Hispanic/Latino ancestry GWA meta-analysis and meta-analyze both in a multi-ancestry GWAS meta-analysis of BCC, totaling 50,531 BCC cases and 762,234 controls from four cohorts (GERA, Mass-General Brigham Biobank, UK Biobank, and 23andMe research cohort). Here we identify 122 BCC-associated loci, of which 36 were novel, and subsequently fine-mapped these associations. We also identify an association of the well-known pigment gene SLC45A2 as well as associations at RCC2 and CLPTM1L with BCC in Hispanic/Latinos. We examine these BCC loci for association with cutaneous squamous cell carcinoma (cSCC) in 16,407 SCC cases and 762,486 controls of European ancestry, and 33 SNPs show evidence of association. Our study findings provide important insights into the genetic basis of BCC and cSCC susceptibility.

Dipeniroqueforins A-B and Peniroqueforin D: Eremophilane-Type Sesquiterpenoid Derivatives with Cytotoxic Activity from Penicillium roqueforti.

Guided by the Global Natural Products Social (GNPS) molecular networking strategy, five undescribed eremophilane-type sesquiterpenoid derivatives (1-5) were isolated and identified from fungus Penicillium roqueforti, which was separated from the root soil of plant Hypericum beanii collected in Shennongjia Forestry District, Hubei Province. Dipeniroqueforins A-B (1-2), representing a lactam-type sesquiterpenoid skeleton with a highly symmetrical and homodimeric 5/6/6-6/6/5 hexacyclic system, are reported within the eremophilane-type family for the first time. Peniroqueforin D (5) represents the first example of a 1,2-seco eremophilane-type sesquiterpenoid derivative featuring an undescribed 7/6-fused ring system. The structures of these compounds were elucidated by various spectroscopic analyses, DP4+ probability analyses, ECD calculations, and single-crystal X-ray diffraction experiments. Furthermore, these isolates were evaluated for cytotoxicity, and the result uncovered that compound 1 displayed broad-spectrum activity. Further mechanistic study revealed that compound 1 could significantly upregulate the mRNA expression of genes related to the oxidative induction, leading to the abnormal ROS levels in tumor cells and ultimately causing tumor cell apoptosis.

Artificial intelligence for automatic surgical phase recognition of laparoscopic gastrectomy in gastric cancer.

PURPOSE: This study aimed to classify laparoscopic gastric cancer phases. We also aimed to develop a transformer-based artificial intelligence (AI) model for automatic surgical phase recognition and to evaluate the model's performance using laparoscopic gastric cancer surgical videos. METHODS: One hundred patients who underwent laparoscopic surgery for gastric cancer were included in this study. All surgical videos were labeled and classified into eight phases (P0. Preparation. P1. Separate the greater gastric curvature. P2. Separate the distal stomach. P3. Separate lesser gastric curvature. P4. Dissect the superior margin of the pancreas. P5. Separation of the proximal stomach. P6. Digestive tract reconstruction. P7. End of operation). This study proposed an AI phase recognition model consisting of a convolutional neural network-based visual feature extractor and temporal relational transformer. RESULTS: A visual and temporal relationship network was proposed to automatically perform accurate surgical phase prediction. The average time for all surgical videos in the video set was 9114 ± 2571 s. The longest phase was at P1 (3388 s). The final research accuracy, F1, recall, and precision were 90.128, 87.04, 87.04, and 87.32%, respectively. The phase with the highest recognition accuracy was P1, and that with the lowest accuracy was P2. CONCLUSION: An AI model based on neural and transformer networks was developed in this study. This model can identify the phases of laparoscopic surgery for gastric cancer accurately. AI can be used as an analytical tool for gastric cancer surgical videos.

Luteolin Pretreatment Ameliorates Myocardial Ischemia/Reperfusion Injury by lncRNA-JPX/miR-146b Axis.

Background: In the present study, we aimed to find out whether luteolin (Lut) pretreatment could ameliorate myocardial ischemia/reperfusion (I/R) injury by regulating the lncRNA just proximal to XIST (JPX)/microRNA-146b (miR-146b) axis. Methods: We established the models in vitro (HL-1 cells) and in vivo (C57BL/6J mice) to certify the protection mechanism of Lut pretreatment on myocardial I/R injury. Dual luciferase reporter gene assay was utilized for validating that JPX could bind to miR-146b. JPX and miR-146b expression levels were determined by RT-qPCR. Western blot was utilized to examine apoptosis-related protein expression levels, including cleaved caspase-9, caspase-9, cleaved caspase-3, caspase-3, Bcl-2, Bax, and BAG-1. Apoptosis was analyzed by Annexin V-APC/7-AAD dualstaining, Hoechst 33342 staining, as well as flow cytometry. Animal echocardiography was used to measure cardiac function (ejection fraction (EF) and fractional shortening (FS) indicators). Results: miR-146b was demonstrated to bind and recognize the JPX sequence site by dual luciferase reporter gene assay. The expression level of miR-146b was corroborated to be enhanced by H/R using RT-qPCR (P < 0.001 vs. Con). Moreover, JPX could reduce the expression of miR-146b, whereas inhibiting JPX could reverse the alteration (P < 0.001 vs. H/R, respectively). Western blot analysis demonstrated that Lut pretreatment increased BAG-1 expression level and Bcl-2/Bax ratio, but diminished the ratio of cleaved caspase 9/caspase 9 and cleaved caspase 3/caspase 3 (P < 0.001 vs. H/R, respectively). Moreover, the cell apoptosis change trend, measured by Annexin V-APC/7-AAD dualstaining, Hoechst 33342 staining, along with flow cytometry, was consistent with that of apoptosis-related proteins. Furthermore, pretreatment with Lut improved cardiac function (EF and FS) (P < 0.001 vs. I/R, respectively), as indicated in animal echocardiography. Conclusion: Our results demonstrated that in vitro and in vivo, Lut pretreatment inhibited apoptosis via the JPX/miR-146b axis, ultimately improving myocardial I/R injury.

IER5L is a Prognostic Biomarker in Pan-Cancer Analysis and Correlates with Immune Infiltration and Immune Molecules in Non-Small Cell Lung Cancer.

Purpose: Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases. Immediate early response 5 like (IER5L) plays crucial roles in progression and prognosis for several tumors, but its role in NSCLC remains unclear. Patients and Methods: Gene expression and mutation profiles, DNA methylation data, and clinical information for cancers were downloaded from multiple databases. Relative expression, prognostic value, and correlation with disease progression of IER5L were analyzed in multiple cancers, including NSCLC. Upstream mechanisms were explored using a transcriptional network. Functional enrichment analysis, protein-protein interaction network, and gene set enrichment analysis were applied to study downstream mechanisms. Correlations of IER5L with immune infiltration, immune molecules, methylation status, and tumor mutation burden (TMB) were analyzed using R language. Finally, quantitative polymerase chain reaction (qPCR) and single-cell RNA sequencing (scRNA seq) analysis were performed to validate IER5L expression in NSCLC. Results: Pan-cancer analysis displayed that IER5L expression was upregulated in multiple cancers and was associated with disease prognosis and progression, including NSCLC, which was validated using qPCR. scRNA seq analysis showed that multiple cells had increased IER5L expression. An EGR1-hsa-miR-8075-IER5L network was constructed for NSCLC. A total of 191 DEGs were identified between the two IER5L groups, which were significantly enriched in biological process of action potential, sodium ion transport, and regulation of membrane potential. Increased IER5L expression was primarily enriched in cell cycle, NOTCH signaling pathway, and oxidative phosphorylation pathway, and was correlated with increased regulatory T cells and neutrophils, elevated levels of immune molecules, and higher TMB. Conclusion: Our findings show that increased IER5L expression was correlated with progression and prognosis in multiple cancers as well as with immune infiltration and immune molecules in NSCLC. Thus, IER5L is a prognostic biomarker in multiple cancers and may correlate with immunotherapeutic response in NSCLC.