PD-1 inhibitor combined with chemotherapy for first-line treatment of esophageal squamous cell carcinoma patients with distant metastasis: a real-world retrospective study.

Background: The aim of this study was to evaluate whether the efficacy and safety of PD-1 inhibitors combined with chemotherapy in the treatment of patients with esophageal squamous cell carcinoma (ESCC) with distant metastasis in the real world are as effective and safe as in clinical trials. Patients and methods: From July 2019 to July 2023, a total of 422 patients with distant metastasis of ESCC were included and divided into the PD-1 inhibitor combined chemotherapy group (PC group) and the chemotherapy alone group (C group) according to the treatment regimen. There were 278 patients in the PC group and 144 patients in the C group. The primary endpoint of this study was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: The objective response rate (ORR) and disease control rate (DCR) of the PC group were 44.60% (124/278) and 91.00% (253/278), respectively, which were 18.9% and 3.5% higher than those of the C group. The median PFS and median OS of the PC group were significantly better than those of the C group (median PFS: 6.5 vs. 5.5 months, P < 0.001; median OS: 16.6 vs. 13.9 months, P = 0.002). Further univariate and multivariate Cox analysis showed that the Eastern Cooperative Oncology Group performance status (ECOG PS) score and the number of metastatic sites were potential predictors of PFS in PC patients. The combination of PD-1 inhibitors with cisplatin and paclitaxel (TP) was more beneficial for patients with PFS compared to the combination of cisplatin and fluorouracil (PF). Furthermore, the presence of bone metastasis, body mass index (BMI), and lymphocyte-to-monocyte ratio (LWR) before treatment may be potential predictive factors for patient OS. The adverse reactions that occurred in the PC group can be tolerated or alleviated after both prevention and active treatment. Conclusions: The combination of PD-1 inhibitors and chemotherapy as first-line treatment for ESCC patients with distant metastasis still has good efficacy and safety compared to clinical trials in the real world.

Jiangu formula: A novel osteoclast-osteoblast coupling agent for effective osteoporosis treatment.

BACKGROUND: The discovering of an osteoclast (OC) coupling active agent, capable of suppressing OC-mediated bone resorption while concurrently stimulating osteoblast (OB)-mediated bone formation, presents a promising strategy to overcome limitations associated with existing antiresorptive agents. However, there is a lack of research on active OC coupling agents. PURPOSE: This study aims to investigate the potential of Jiangu Formula (JGF) in inhibiting OCs while maintaining the OCOB coupling function. METHODS: The anti-osteoporosis efficacy of JGF was evaluated in osteoporosis models induced by ovariectomy in C57BL/6 mouse and SD rats. The effect of JGF on OCs was evaluated by detecting its capacity to inhibit OC differentiation and bone resorption in an in vitro osteoclastogenesis model induced by RANKL. The OCOB coupling activity of JGF was evaluated by measuring the secretion levels of OC-derived coupling factors, OB differentiation activity of MC3T3-E1 interfered with conditioned medium, and the effect of JGF on OC inhibition and OB differentiation in a C3H10T1/2-RAW264.7 co-culture system. The mechanism of JGF was studied by network pharmacology and validated using western blot, immunofluorescence (IF), and ELISA. Following that, the active ingredients of JGF were explored through a chemotype-assembly approach, activity evaluation, and LC-MS/MS analysis. RESULTS: JGF inhibited bone resorption in murine osteoporosis without compromising the OCOB coupling effect on bone formation. In vitro assays showed that JGF preserved the coupling effect of OC on OB differentiation by maintaining the secretion of OC-derived coupling factors. Network analysis predicted STAT3 as a key regulation point for JGF to exert anti-osteoporosis effect. Further validation assays confirmed that JGF upregulated p-STAT3(Ser727) and its regulatory factors IL-2 in RANKL-induced RAW264.7 cells. Moreover, 23 components in JGF with anti-OC activity identified by chemotype-assembly approach and verification experiments. Notably, six compounds, including ophiopogonin D, ginsenoside Re, ginsenoside Rf, ginsenoside Rg3, ginsenoside Ro, and ononin were identified as OC-coupling compounds. CONCLUSION: This study first reported JGF as an agent that suppresses bone loss without affecting bone formation. The potential coupling mechanism of JGF involves the upregulation of STAT3 by its regulators IL-2. Additionally, the chemotype-assembly approach elucidated the activity compounds present in JGF, offering a novel strategy for developing an anti-resorption agent that preserves bone formation.

Efficacy and safety of sintilimab combined with apatinib as third-line or above therapy for patients with advanced or metastatic gastric cancer.

This study aimed to evaluate the efficacy and safety of the combination of sintilimab and apatinib for the treatment of patients with advanced or metastatic gastric cancer (GC) and gastroesophageal junction (GEJ) cancer. This retrospective study analyzed data from 34 patients who had advanced or metastatic GC/GEJ cancer and received the combination therapy of sintilimab and apatinib as a third-line or above treatment. The primary endpoint was progression-free survival (PFS), and secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Among the 34 patients, none achieved a complete response (CR), 3 patients (8.8%) achieved a partial response, 23 patients (67.6%) had stable disease, and 8 patients (23.5%) experienced progressive disease. The ORR and DCR were 8.8% and 76.5%, respectively. The median PFS was 6.0 months (95% CI: 3.6-8.4), and the median OS was 11.6 months (95% CI: 8.1-15.1). Subgroup analysis revealed significant differences in OS between patients with high and low Eastern Cooperative Oncology Group Performance Status scores and between patients with and without a history of gastrectomy. Common adverse events (AEs) during treatment included fatigue (52.9%), anemia (47.1%), leukopenia (26.5%), hypothyroidism (23.5%), nausea and vomiting (20.6%), neutropenia (20.6%), and thrombocytopenia (17.6%), most of which were grade 1 and 2 AEs. No deaths occurred due to AEs. These findings indicate that the combination of sintilimab and apatinib has a favorable therapeutic effect in patients with advanced GC. Moreover, the AEs associated with this therapy are generally manageable.

Machine Learning Classification of Body Part, Imaging Axis, and Intravenous Contrast Enhancement on CT Imaging.

Purpose: The development and evaluation of machine learning models that automatically identify the body part(s) imaged, axis of imaging, and the presence of intravenous contrast material of a CT series of images. Methods: This retrospective study included 6955 series from 1198 studies (501 female, 697 males, mean age 56.5 years) obtained between January 2010 and September 2021. Each series was annotated by a trained board-certified radiologist with labels consisting of 16 body parts, 3 imaging axes, and whether an intravenous contrast agent was used. The studies were randomly assigned to the training, validation and testing sets with a proportion of 70%, 20% and 10%, respectively, to develop a 3D deep neural network for each classification task. External validation was conducted with a total of 35,272 series from 7 publicly available datasets. The classification accuracy for each series was independently assessed for each task to evaluate model performance. Results: The accuracies for identifying the body parts, imaging axes, and the presence of intravenous contrast were 96.0% (95% CI: 94.6%, 97.2%), 99.2% (95% CI: 98.5%, 99.7%), and 97.5% (95% CI: 96.4%, 98.5%) respectively. The generalizability of the models was demonstrated through external validation with accuracies of 89.7 - 97.8%, 98.6 - 100%, and 87.8 - 98.6% for the same tasks. Conclusions: The developed models demonstrated high performance on both internal and external testing in identifying key aspects of a CT series.

Regulation of the CB1R/AMPK/PGC-1α signaling pathway in mitochondria of mouse hearts and cardiomyocytes with chronic intermittent hypoxia.

PURPOSE: This study evaluated the effects of chronic intermittent hypoxia (CIH) at different times on the mitochondria of mouse hearts and H9C2 cardiomyocytes to determine the role of the cannabinoid receptor 1 (CB1R)/adenosine 5'-monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) signaling pathway. METHODS: Animal and cellular CIH models were prepared in an intermittent hypoxia chamber at different times. The cardiac function of mice was determined, and heart tissue and ultrastructural changes were observed. Apoptosis, reactive oxygen species (ROS), and mitochondrial membrane potential were detected, and MitoTracker™ staining was performed to observe cardiomyocyte mitochondria. Western blot, immunohistochemistry, and cellular immunofluorescence were also performed. RESULTS: In the short-term CIH group, increases in mouse ejection fraction (EF) and heart rate (HR); mitochondrial division; ROS and mitochondrial membrane potential; and the expression levels of CB1R, AMPK, and PGC-1α were observed in vivo and in vitro. In the long-term CIH group, the EF and HR increased, the myocardial injury and mitochondrial damage were more severe, mitochondrial synthesis decreased, the apoptosis percentage and ROS increased, mitochondrial fragmentation increased, membrane potential decreased, CB1R expression increased, and AMPK and PGC-1α expression levels decreased. Targeted blocking of CB1R can increase AMPK and PGC-1α, reduce damage attributed to long-term CIH in mouse hearts and H9C2 cells, and promote mitochondrial synthesis. CONCLUSION: Short-term CIH can directly activate the AMPK/PGC-1α pathway, promote mitochondrial synthesis in cardiomyocytes, and protect cardiac structure and function. Long-term CIH can increase CB1R expression and inhibit the AMPK/PGC-1α pathway, resulting in structural damage, the disturbance of myocardial mitochondria synthesis, and further alterations in the cardiac structure. After targeted blocking of CB1R, levels of AMPK and PGC-1α increased, alleviating damage to the heart and cardiomyocytes caused by long-term CIH.

Exosomes: New Insights into the Pathogenesis of Metabolic Syndrome.

Exosomes are a subtype of extracellular vesicles (EVs) with a diameter of 30~150 nm (averaging ~100 nm) that are primarily produced through the endosomal pathway, and carry various components such as lipids, proteins, RNA, and other small molecular substances. Exosomes can mediate intercellular communication through the bioactive substances they carry, thus participating in different physiological activities. Metabolic syndrome (MS) is a disease caused by disturbances in the body's metabolism, mainly including insulin resistance (IR), diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), hyperlipidemia, and atherosclerosis (AS). Recent studies have shown that exosomes are closely related to the occurrence and development of MS. Exosomes can act as messengers to mediate signaling transductions between metabolic cells in the organism and play a bidirectional regulatory role in the MS process. This paper mainly reviews the components, biogenesis, biological functions and potential applications of exosomes, and exosomes involved in the pathogenesis of MS as well as their clinical significance in MS diagnosis.

[Research Advances of RAD51AP1 in Tumor Progression and Drug Resistance].

The genomic instability may lead to an initiation of cancer in many organisms. Homologous recombination repair (HRR) is vital in maintaining cellular genomic stability. RAD51 associated protein 1 (RAD51AP1), which plays a crucial role in HRR and primarily participates in forming D-loop, was reported as an essential protein for maintaining cellular genomic stability. However, recent studies showed that RAD51AP1 was significantly overexpressed in various cancer types and correlated with poor prognosis. These results suggested that RAD51AP1 may play a significant pro-cancer effect in multiple cancers. The underlying mechanism is still unclear. Cancer stemness-maintaining effects of RAD51AP1 might be considered as the most reliable mechanism. Meanwhile, RAD51AP1 also promoted resistance to radiation therapy and chemotherapy in many cancers. Thus, researches focused on RAD51AP1, and its regulatory molecules may provide new targets for overcoming cancer progression and treatment resistance. Here, we reviewed the latest research on RAD51AP1 in cancers and summarized its differential expression and prognostic implications. In this review, we also outlined the potential mechanisms of its pro-cancer and drug resistance-promoting effects to provide several potential directions for further research.
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Comparison of the efficacy and safety of third-line treatments for metastatic colorectal cancer: a systematic review and network meta-analysis.

Background: The objective of this study is to evaluate the efficacy and safety of different third-line treatment regimens for metastatic colorectal cancer (mCRC) through a comprehensive analysis and network meta-analysis (NMA). Additionally, the study aims to provide guidance on selecting appropriate third-line systemic treatment regimens for patients with mCRC. Methods: We conducted a search of the PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials databases from January 1, 2005, to May 20, 2023, to include phase II/III randomized clinical trials (RCTs) of third-line treatments for mCRC. The primary outcome assessed in the NMA was median overall survival (mOS), and other outcomes included median progression-free survival (mPFS), disease control rate (DCR), and grade 3 or higher adverse events (≥3AEs). Results: Ultimately, nine phase II/III RCTs involving five treatment regimens were included in this study. Trifluridine/tipiracil (TAS-102) plus bevacizumab (hazard ratio [HR] 0.41, 95% credible interval [CrI] 0.32-0.52) was found to be the most effective treatment for mOS compared to best supportive care (BSC). TAS-102 plus bevacizumab also significantly improved mPFS compared to BSC (HR 0.20, 95% CrI 0.16-0.25). In terms of adverse events (AEs), TAS-102 (RR 0.52, 95% CrI 0.35-0.74) had a lower incidence of ≥3AEs compared to fruquintinib, but fruquintinib (RR 1.79, 95% CrI 1.10-3.11) showed better improvement in DCR than TAS-102. Subgroup analysis using the Bayesian surface under the cumulative ranking curve (SUCRA) ranked the regimens based on the OS benefit. The results indicated that TAS-102 plus bevacizumab ranked first across age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), and time from initial diagnosis of metastatic disease to randomization. Conclusion: TAS-102, fruquintinib, TAS-102 plus bevacizumab, the regorafenib standard dose regimen (regorafenib), and the regorafenib dose-escalation regimen (regorafenib 80+) all demonstrated improved OS and PFS compared to BSC in mCRC patients. However, TAS-102 plus bevacizumab may be the optimal choice for third-line treatment in mCRC patients. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php, CRD42023434929.

Mapping Molecular Hamiltonians into Hamiltonians of Modular cQED Processors.

We introduce a general method based on the operators of the Dyson-Masleev transformation to map the Hamiltonian of an arbitrary model system into the Hamiltonian of a circuit Quantum Electrodynamics (cQED) processor. Furthermore, we introduce a modular approach to programming a cQED processor with components corresponding to the mapping Hamiltonian. The method is illustrated as applied to quantum dynamics simulations of the Fenna-Matthews-Olson (FMO) complex and the spin-boson model of charge transfer. Beyond applications to molecular Hamiltonians, the mapping provides a general approach to implement any unitary operator in terms of a sequence of unitary transformations corresponding to powers of creation and annihilation operators of a single bosonic mode in a cQED processor.

Application of a New Approach for Laparoscopic Resection of Bismuth IIIa Hilar Cholangiocarcinoma.

Background: Hilar cholangiocarcinoma (HCCA) has a high degree of malignancy and poor prognosis, and the best long-term prognosis can only be achieved by radical resection. However, the surgical steps are complicated, and the operating space is limited, making it hard to complete laparoscopically. So our team proposes a new surgical approach for laparoscopic left-liver-first anterior radical modular orthotopic right hemihepatectomy (Lap-Larmorh). In this way, we can simplify the operation steps and reduce the difficulty. Materials and Methods: We recorded and analyzed the clinical data of 26 patients with type IIIa HCCA, who underwent laparoscopic radical resection in our department from December 2018 to January 2023. According to the laparoscopic surgical approach, we divided the patients into the new approach (NA) group (n = 14) using the Lap-Lamorh and the traditional approach (TA) group (n = 12) not using the Lap-Lamorh. Results: All surgeries in this study were completed laparoscopically with no conversion to open surgery. The operation time in the NA group and TA group had statistically significant differences, which was 372.5 (332.8, 420.0) minutes versus 423.5 (385.8, 498.8) minutes (P = .019). The two groups showed no significant difference in other characteristics (P > .05). Only 1 patient suffered from transient liver failure due to portal vein thrombosis. Patients with pleural effusion or ascites were cured by catheter drainage and enhanced nutrition. Conclusion: Lap-Larmorh reduces the difficulty of serving the vessels at the second and third hepatic hilum by splitting the right and left livers early intraoperatively. The new approach is more suitable for the narrow space of laparoscopic surgery and reflects the no-touch principle of oncology.

How to implement minimally invasive duodenum-preserving total pancreatic head resection for patients with pancreatic head lesions: A retrospective study.

Laparoscopic duodenum-preserving pancreatic head resection (LDPPHR) has been widely reported. However, due to the challenges involved in performing total pancreatic head resection during operation, there are few studies reporting it. Between November 2016 and October 2022, we performed laparoscopic duodenum-preserving total pancreatic head resection (LDPPHRt) on 64 patients in the Department of Hepatobiliary Surgery, the Second Hospital of Hebei Medical University. Perioperative data of the patients such as age, gender, body mass index, operation time, blood loss, and postoperative hospital stay were collected and analyzed. This study included 40 women and 24 men aged 41.4 ±â€…15.7 years. All patients completed the surgery, and none of the patients underwent laparotomy. The average operation time was 275 (255, 310) min. The average postoperative hospital stay was 12 (10, 16) days. The rate of occurrence of pancreatic fistula was 10.9% (7/64), and that of the biliary fistula was 9.4% (6/64). One of the patients underwent cholangiojejunostomy 3 months after the operation due to painless jaundice and bile duct dilatation. By dissecting the space between the pancreatic head and duodenum, the posterior pancreatic duodenal arterial arch and the surface vascular network of the common bile duct (CBD) can be preserved. This ensures the success of LDPPHRt and avoids postoperative complications in the absence of intraoperative image guidance.

Simulating Open Quantum System Dynamics on NISQ Computers with Generalized Quantum Master Equations.

We present a quantum algorithm based on the generalized quantum master equation (GQME) approach to simulate open quantum system dynamics on noisy intermediate-scale quantum (NISQ) computers. This approach overcomes the limitations of the Lindblad equation, which assumes weak system-bath coupling and Markovity, by providing a rigorous derivation of the equations of motion for any subset of elements of the reduced density matrix. The memory kernel resulting from the effect of the remaining degrees of freedom is used as input to calculate the corresponding non-unitary propagator. We demonstrate how the Sz.-Nagy dilation theorem can be employed to transform the non-unitary propagator into a unitary one in a higher-dimensional Hilbert space, which can then be implemented on quantum circuits of NISQ computers. We validate our quantum algorithm as applied to the spin-boson benchmark model by analyzing the impact of the quantum circuit depth on the accuracy of the results when the subset is limited to the diagonal elements of the reduced density matrix. Our findings demonstrate that our approach yields reliable results on NISQ IBM computers.

Multiple effects of ZnO nanoparticles on goldfish (Carassius auratus): Skin mucus, gut microbiota and stable isotope composition.

The skin and the gut are direct target tissues for nanoparticles, yet attention to effects of metal-based nanoparticles (MNPs) on these two and the discrepancy in these effects remain inadequate. Here, effects of ZnO nanoparticles (nZnO) on skin mucus and gut microbiota of goldfish (Carassius auratus) were investigated, as well as further elements turnover and metabolic variations. After 14 days of exposure, considerable variations in levels of biomarkers (protein, glucose, lysozyme and immunoglobulin M) in skin mucus demonstrated significant stress responses to nZnO. nZnO exposure significantly reduced the abundance of Cetobacterium in the gut while increased that of multiple pathogens, and further leading to down-regulation of pathways such as carbohydrate metabolism, translation, and replication and repair. Decreased δ15N values indicated declined N turnover in vivo, further demonstrating the negative effect of nZnO on metabolism in the organism. Integration analysis of each biomarker using the biomarker response index version 2 (IBRv2) revealed concentration-dependent effects of nZnO on skin mucus, while effects on physiology in vivo was not, demonstrating the discrepancy in the toxicity pathways and toxic effects of nZnO on different tissues. This work improved our understanding about the comprehensive toxicity of nZnO on aquatic organism.

Deciphering the mechanisms of Yinlan Tiaozhi capsule in treating hyperlipidemia by combining network pharmacology, molecular docking and experimental verification.

Yinlan Tiaozhi capsule (YLTZC) has been widely used to treat hyperlipidemia (HLP). However, its material basis and underlying pharmacological effects remain unclean. The current study aimed to explore the mechanisms involved in the treatment of YLTZC on HLP based on network pharmacology, molecular docking, and experimental verification. Firstly, UPLC-Q-TOF-MS/MS was used to comprehensively analyze and identify the chemical constituents in YLTZC. A total of 66 compounds, mainly including flavonoids, saponins, coumarins, lactones, organic acids, and limonin were characterized and classified. Simultaneously, the mass fragmentation pattern of different types of representative compounds was further explored. By network pharmacology analysis, naringenin and ferulic acid may be the core constituents. The 52 potential targets of YLTZC, including ALB, IL-6, TNF, and VEGFA, were considered potential therapeutic targets. Molecular docking results showed that the core active constituents of YLTZC (naringenin and ferulic acid) have a strong affinity with the core targets of HLP. Lastly, animal experiments confirmed that naringenin and ferulic acid significantly upregulated the mRNA expression of ALB and downregulated the mRNA expression of IL-6, TNF, and VEGFA. In sum, the constituents of YLTZC, such as naringenin and ferulic acid, might treat HLP by regulating the mechanism of angiogenesis and inhibiting inflammatory responses. Furthermore, our data fills the gap in the material basis of YLTZC.

Characterizing quantum circuits with qubit functional configurations.

We develop a systematic framework for characterizing all quantum circuits with qubit functional configurations. The qubit functional configuration is a mathematical structure that can classify the properties and behaviors of quantum circuits collectively. Major benefits of classifying quantum circuits in this way include: 1. All quantum circuits can be classified into corresponding types; 2. Each type characterizes important properties (such as circuit complexity) of the quantum circuits belonging to it; 3. Each type contains a huge collection of possible quantum circuits allowing systematic investigation of their common properties. We demonstrate the theory's application to analyzing the hardware-efficient ansatzes of variational quantum algorithms. For potential applications, the functional configuration theory may allow systematic understanding and development of quantum algorithms based on their functional configuration types.

Quantum Simulation of the Radical Pair Dynamics of the Avian Compass.

The simulation of open quantum dynamics on quantum circuits has attracted wide interests recently with a variety of quantum algorithms developed and demonstrated. Among these, one particular design of a unitary-dilation-based quantum algorithm is capable of simulating general and complex physical systems. In this paper, we apply this quantum algorithm to simulating the dynamics of the radical pair mechanism in the avian compass. This application is demonstrated on the IBM QASM quantum simulator. This work is the first application of any quantum algorithm to simulating the radical pair mechanism in the avian compass, which not only demonstrates the generality of the quantum algorithm but also opens new opportunities for studying the avian compass with quantum computing devices.

Effects of bovine milk and buffalo milk on lipid metabolism in mice.

Buffalo milk contains more polyunsaturated fatty acids than bovine milk. However, it is not clear about the effects of buffalo milk and bovine milk on lipid metabolism. In this study, a mouse model was used to explore the effects of buffalo milk and bovine milk on lipid metabolism in mice. The experiment was divided into three groups: a control group on a normal diet; a bovine milk group infused with bovine milk; a buffalo milk group infused with buffalo milk. We fed three groups of mice (n = 6) for 6 weeks. These results showed that bovine milk and buffalo milk had no effect on body weight gain. Bovine milk increased the content of ApoA1, ApoB and glucose in serum, compared with the control group, but buffalo milk has no profound change in serum ApoB. Remarkably, buffalo milk decreased the content of total cholesterol (TC) and triglyceride (TG) in the liver lipid profile, and also downregulated the expression of the carnitine palmitoyltransferase 2 (Cpt2) gene involved in the fatty acid oxidation in the liver. This study also found that bovine milk and buffalo milk did not cause the expression of pro-inflammatory factors in serum and colon tissues. This experiment proved that buffalo milk has beneficial effects on the regulation of lipid metabolism, and also does not affect the normal growth and pro-inflammatory response of the colon in mice. It provides a theoretical basis for future in-depth research on the special functions of buffalo milk and the development of buffalo milk functional foods.

Neutrophil infiltration associated genes on the prognosis and tumor immune microenvironment of lung adenocarcinoma.

The neutrophils exhibit both anti-tumor and pro-tumor effects in cancers. The correlation between neutrophils and tumor development in lung adenocarcinoma (LUAD) is still uncertain, possibly due to a lack of specific neutrophil infiltration evaluation methods. In this study, we identified 30 hub genes that were significantly associated with neutrophil infiltration in LUAD through data mining, survival analysis, and multiple tumor-infiltrating immune cells (TICs) analysis, including TIMER, CIBERSORT, QUANTISEQ, XCELL, and MCPCOUNTER. Consensus clustering analysis showed that these 30 hub genes were correlated with clinical features in LUAD. We further developed a neutrophil scoring system based on these hub genes. The neutrophil score was significantly correlated with prognosis and tumor immune microenvironment (TIME) in LUAD. It was also positively associated with PD-L1 expression and negatively associated with tumor mutational burden (TMB). When combined with the neutrophil score, the predictive capacity of PD-L1 and TMB for prognosis was significantly improved. Thus, the 30 hub genes might play an essential role in the interaction of neutrophils and LUAD, and the neutrophil scoring system might effectually assess the infiltration of neutrophils. Furthermore, we verified the expression of these 30 genes in the LUAD tumor tissues collected from our department. We further found that overexpressed TNFAIP6 and TLR6 and downregulated P2RY13, SCARF1, DPEP2, PRAM1, CYP27A1, CFP, GPX3, and NCF1 in LUAD tissue might be potentially associated with neutrophils pro-tumor effects. The following in vitro experiments demonstrated that TNFAIP6 and TLR6 were significantly overexpressed, and P2RY13 and CYP27A1 were significantly downregulated in LUAD cell lines, compared to BEAS-2B cells. Knocking down TNFAIP6 in A549 and PC9 resulted in the upregulation of FAS, CCL3, and ICAM-1, and the downregulation of CCL2, CXCR4, and VEGF-A in neutrophils when co-culturing with the conditioned medium (CM) from LUAD cells. Knocking down TNFAIP6 in LUAD also led to an elevated early apoptosis rate of neutrophils. Therefore, overexpressed TNFAIP6 in LUAD cancer cells might lead to neutrophils "N2" polarization, which exhibited pro-tumor effects. Further research based on the genes identified in this pilot study might shed light on neutrophils' effects on LUAD in the future.

Evaluation of left ventricular function in obese patients with obstructive sleep apnea by three-dimensional speckle tracking echocardiography.

Both obstructive sleep apnea(OSA) and obesity can cause myocardial remodeling and cardiac insufficiency via corresponding pathophysiological pathways. Therefore, it is speculated that the superposition of OSA and obesity may cause more severe impairment of cardiac function. The objective of our study was to evaluate the early changes of left ventricular systolic function in obese patients with OSA with three-dimensional speckle tracking echocardiography(3D-STE). This study was conducted with 33 obese OSA, 46 non-obese OSA, and 20 healthy subjects. Demographic, biochemical, and Polysomnography(PSG) data were collected, and their relation with the left ventricular strain was measured and analyzed with 3D-STE. The left ventricular strain was significantly worse in the OSA group compared to the control group(P < 0.05). The global longitudinal strain(GLS) was significantly worse obese group compared to non-obese OSA group (P < 0.05). The GLS value positively correlated with body mass index(BMI)(r = 0.406, P < 0.001), apnea-hypopnea index(AHI)(r = 0.610, P < 0.001)and homeostasis model assessment of insulin resistance(HOME-IR)(r = 0.431, P < 0.001) in patients with OSA, as well as high sensitivity C-reactive protein(hs-CRP)(r = 0.394, P < 0.001). Multiple linear regression analysis showed BMI and AHI were predictors of GLS. In OSA patients, the myocardial strain was impaired before the damages in left ventricular ejection fraction, suggesting that the left ventricular systolic function is damaged early. The coexistence of obesity and OSA can lead to severe impairment of cardiac function through mechanisms such as hypoxia and insulin resistance.