Systematic proteome-wide Mendelian randomization using the human plasma proteome to identify therapeutic targets for lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the predominant histological subtype of lung cancer and the leading cause of cancer-related mortality. Identifying effective drug targets is crucial for advancing LUAD treatment strategies. METHODS: This study employed proteome-wide Mendelian randomization (MR) and colocalization analyses. We collected data on 1394 plasma proteins from a protein quantitative trait loci (pQTL) study involving 4907 individuals. Genetic associations with LUAD were derived from the Transdisciplinary Research in Cancer of the Lung (TRICL) study, including 11,245 cases and 54,619 controls. We integrated pQTL and LUAD genome-wide association studies (GWASs) data to identify candidate proteins. MR utilizes single nucleotide polymorphisms (SNPs) as genetic instruments to estimate the causal effect of exposure on outcome, while Bayesian colocalization analysis determines the probability of shared causal genetic variants between traits. Our study applied these methods to assess causality between plasma proteins and LUAD. Furthermore, we employed a two-step MR to quantify the proportion of risk factors mediated by proteins on LUAD. Finally, protein-protein interaction (PPI) analysis elucidated potential links between proteins and current LUAD medications. RESULTS: We identified nine plasma proteins significantly associated with LUAD. Increased levels of ALAD, FLT1, ICAM5, and VWC2 exhibited protective effects, with odds ratios of 0.79 (95% CI 0.72-0.87), 0.39 (95% CI 0.28-0.55), 0.91 (95% CI 0.72-0.87), and 0.85 (95% CI 0.79-0.92), respectively. Conversely, MDGA2 (OR, 1.13; 95% CI 1.08-1.19), NTM (OR, 1.12; 95% CI 1.09-1.16), PMM2 (OR, 1.35; 95% CI 1.18-1.53), RNASET2 (OR, 1.15; 95% CI 1.08-1.21), and TFPI (OR, 4.58; 95% CI 3.02-6.94) increased LUAD risk. Notably, none of the nine proteins showed evidence of reverse causality. Bayesian colocalization indicated that RNASET2, TFPI, and VWC2 shared the same variant with LUAD. Furthermore, NTM and FLT1 demonstrated interactions with targets of current LUAD medications. Additionally, FLT1 and TFPI are currently under evaluation as therapeutic targets, while NTM, RNASET2, and VWC2 are potentially druggable. These findings shed light on LUAD pathogenesis, highlighting the tumor-promoting effects of RNASET2, TFPI, and NTM, along with the protective effects of VWC2 and FLT1, providing a significant biological foundation for future LUAD therapeutic targets. CONCLUSIONS: Our proteome-wide MR analysis highlighted RNASET2, TFPI, VWC2, NTM, and FLT1 as potential drug targets for further clinical investigation in LUAD. However, the specific mechanisms by which these proteins influence LUAD remain elusive. Targeting these proteins in drug development holds the potential for successful clinical trials, providing a pathway to prioritize and reduce costs in LUAD therapeutics.

IL20Rb aggravates pulmonary fibrosis through enhancing bone marrow derived profibrotic macrophage activation.

Idiopathic pulmonary fibrosis (IPF) is one of the most fatal chronic interstitial lung diseases with unknown pathogenesis, current treatments cannot truly reverse the progression of the disease. Pulmonary macrophages, especially bone marrow derived pro-fibrotic macrophages, secrete multiple kinds of profibrotic mediators (SPP1, CD206, CD163, IL-10, CCL18…), thus further promote myofibroblast activation and fibrosis procession. IL20Rb is a cell-surface receptor that belongs to IL-20 family. The role of IL20Rb in macrophage activation and pulmonary fibrosis remains unclear. In this study, we established a bleomycin-induced pulmonary fibrosis model, used IL4/13-inducing THP1 cells to induce profibrotic macrophage (M2-like phenotype) polarization models. We found that IL20Rb is upregulated in the progression of pulmonary fibrosis, and its absence can alleviate the progression of pulmonary fibrosis. In addition, we demonstrated that IL20Rb promote the activation of bone marrow derived profibrotic macrophages by regulating the Jak2/Stat3 and Pi3k/Akt signaling pathways. In terms of therapeutic strategy, we used IL20Rb neutralizing antibodies for animal administration, which was found to alleviate the progression of IPF. Our results suggest that IL20Rb plays a profibrotic role by promoting profibrotic macrophage polarization, and IL20Rb may become a potential therapeutic target for IPF. Neutralizing antibodies against IL20Rb may become a potential drug for the clinical treatment of IPF.

Zafirlukast ameliorates lipopolysaccharide and bleomycin-induced lung inflammation in mice.

Acute lung injury (ALI) is the result of damage to the capillary endothelia and the alveolar epithelial cell caused by various direct and indirect factors, leading to significant pulmonary interstitial and alveolar edema and acute hypoxic respiratory insufficiency. A subset of ALI cases progresses to irreversible pulmonary fibrosis, a condition with fatal implications. Zafirlukast is a leukotriene receptor antagonist licensed for asthma prevention and long-term treatment. This study demonstrated a significant improvement in lung tissue pathology and a reduction in inflammatory cell infiltration in models of lipopolysaccharide (LPS)-induced ALI and bleomycin (BLM)-induced lung inflammation following zafirlukast administration, both in vivo and in vitro. Moreover, zafirlukast was found to suppress the inflammatory response of alveolar epithelial cells in vitro and lung inflammation in vivo by reducing the activation of the TLR4/NF-κB/NLRP3 inflammasome pathway. In conclusion, zafirlukast relieved lung injury and the infiltration of inflammatory cells in the lung by regulating the TLR4/NF-κB/NLRP3 pathway.

Establishment of Reference Intervals for SII, NLR, PLR, and LMR in Healthy Adults in Jiangsu Region in Eastern China.

BACKGROUND: We preliminarily established the reference intervals for the systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR) in healthy adults in Jiangsu region in Eastern China to guide the interpretation and application of these indicators in clinical practice. METHODS: In total, 29,947 ostensibly healthy subjects from December 2020 to March 2021 were included in this study. The distributions of the SII, NLR, PLR, and LMR were analyzed using the Kolmogorov-Smirnov test. According to the C28-A3 guidelines, the 2.5th and 97.5th percentiles (P2.5 to P97.5) of the SII, NLR, PLR, and LMR were used to establish the reference intervals based on nonparametric methods. RESULTS: All SII, NLR, PLR, and LMR data were non-normally distributed. The levels of the SII, NLR, PLR, and LMR in healthy adults were significantly different between males and females (all p < 0.05). However, there were no significant differences in the SII, NLR, PLR or LMR among the different age groups, regardless of gender (all p > 0.05). Therefore, the reference intervals for the SII, NLR, PLR, and LMR were established based on the Sysmex testing platform for males (162 × 109/L - 811 × 109/L; 0.89 - 3.26; 63.15 - 191.34; 3.18 - 9.61) and females (165 × 109/L - 792 × 109/L; 0.87 - 3.16; 69.04 - 205.62; 3.46 - 10.96). CONCLUSIONS: We have established the reference intervals for SII, NLR, PLR, and LMR in healthy adults based on the Sysmex detection platform and large sample size, which may provide important guidance for its clinical application.

Circ_0006006 facilitates non-small cell lung cancer progression by modulating miR-924/SRSF7 axis.

BACKGROUND: Non-small cell lung cancer (NSCLC) is an aggressive tumor with high mortality. Circular RNAs played crucial roles in the development of cancers, including NSCLC. In the present study, the action of circ_0006006 in NSCLC was investigated. METHODS: Using a real-time quantitative polymerase chain reaction, the relative gene expression was detected. The structure of circ_0006006 was identified using RNase R digestion and actinomycin D treatment. The functional role of circ_0006006 in cell proliferation, migration, invasion, apoptosis and angiogenesis was explored using cell counting kit-8, 5-ethynyl-2'-deoxyuridine, colony formation, wound healing, transwell, flow cytometry and tube formation assays, respectively. Using western blotting, the relative proteins expression was measured. Dual-luciferase reporter and RNA immunoprecipitation assays were employed to verify the correlation between microRNA-924 (miR-924) and circ_0006006 or serine/arginine-rich splicing factor 7 (SRSF7). Xenograft tumor experiment was used to investigate the effect of circ_0006006 on tumor growth in vivo. An immunohistochemistry assay was performed to detect Ki-67, Bax, Bcl-2 and SRSF7 expression in tissues of mice. RESULTS: Circ_0006006 was increased in NSCLC tissues and cells. Loss-of-function assays demonstrated that circ_0006006 silencing repressed proliferative ability, cell migration and invasion, and angiogenesis, as well as promoted cell apoptosis, in A549 and H1299 cells. Follow-up mechanism experiments depicted that circ_0006006 sponged miR-924 and miR-924 inhibitor rescued the circ_0006006 knockdown-mediated inhibition effect on the progression of NSCLC. Additionally, the inhibition effect of circ_0006006 knockdown on SRSF7 expression was reversed by miR-924 inhibitor. Moreover, the suppressive effect of miR-924 on NSCLC progression was reversed by SRSF7 overexpression. Xenograft tumor experiment unveiled that circ_0006006 knockdown inhibited tumor growth in vivo. CONCLUSIONS: Circ_0006006 stimulated NSCLC progression by targeting miR-924 to regulate SRSF7 expression.

Knudsen Number Effects on Two-Dimensional Rayleigh-Taylor Instability in Compressible Fluid: Based on a Discrete Boltzmann Method.

Based on the framework of our previous work [H.L. Lai et al., Phys. Rev. E, 94, 023106 (2016)], we continue to study the effects of Knudsen number on two-dimensional Rayleigh-Taylor (RT) instability in compressible fluid via the discrete Boltzmann method. It is found that the Knudsen number effects strongly inhibit the RT instability but always enormously strengthen both the global hydrodynamic non-equilibrium (HNE) and thermodynamic non-equilibrium (TNE) effects. Moreover, when Knudsen number increases, the Kelvin-Helmholtz instability induced by the development of the RT instability is difficult to sufficiently develop in the later stage. Different from the traditional computational fluid dynamics, the discrete Boltzmann method further presents a wealth of non-equilibrium information. Specifically, the two-dimensional TNE quantities demonstrate that, far from the disturbance interface, the value of TNE strength is basically zero; the TNE effects are mainly concentrated on both sides of the interface, which is closely related to the gradient of macroscopic quantities. The global TNE first decreases then increases with evolution. The relevant physical mechanisms are analyzed and discussed.

Entropy production in thermal phase separation: a kinetic-theory approach.

Entropy production during the process of thermal phase-separation of multiphase flows is investigated by means of a discrete Boltzmann kinetic model. The entropy production rate is found to increase during the spinodal decomposition stage and to decrease during the domain growth stage, attaining its maximum at the crossover between the two. Such behaviour provides a natural criterion to identify and discriminate between the two regimes. Furthermore, the effects of heat conductivity, viscosity and surface tension on the entropy production rate are investigated by systematically probing the interplay between non-equilibrium energy and momentum fluxes. It is found that the entropy production rate due to energy fluxes is an increasing function of the Prandtl number, while the momentum fluxes exhibit an opposite trend. On the other hand, both contributions show an increasing trend with surface tension. The present analysis inscribes within the general framework of non-equilibrium thermodynamics and consequently it is expected to be relevant to a broad class of soft-flowing systems far from mechanical and thermal equilibrium.

Distribution of serum neuron-specific enolase and the establishment of a population reference interval in healthy adults.

BACKGROUND: Neuron-specific enolase (NSE) is an important tumor marker in the serum of patients with lung cancer. Elevated serum NSE levels are also associated with many other diseases. However, there is no unified population reference interval for serum NSE. This study aimed to investigate the distribution of serum NSE in healthy Chinese adults aged 20-79 years and to establish its reference interval in Chinese population. METHODS: A total of 10 575 healthy subjects were in line with the requirements of this study. The concentration of serum NSE was detected by a fully automated Cobas e602 analyzer with matching reagents. The population reference interval for serum NSE was established using the unilateral 95th percentile (P95 ) according to standard guidelines. RESULTS: The distributions of serum NSE were not significantly different between males and females (P > 0.05) and also did not differ by age (P > 0.05). Therefore, the population reference interval for serum NSE was established as upper limit 25.4 ng/mL (90% confidence interval: 24.5-26.2 ng/mL). CONCLUSIONS: We established the first population reference interval for serum NSE in a large healthy Chinese adult cohort, which was higher than that recommended by Roche Diagnostics GmbH. This new reference interval is more practical and applicable in Chinese adults.

Comparison of surgical exposure and maneuverability associated with microscopy and endoscopy in the retrolabyrinthine and transcrusal approaches to the retrochiasmatic region: a cadaveric study.

BACKGROUND: The retrolabyrinthine and transcrusal approaches (RLA and TCA, respectively) are the two most often used posterior transpetrosal approaches that are used to treat lesions in the retrochiasmatic region. Endoscopes are increasingly used in neurosurgical practice. To determine whether a difference exists between the two transpetrosal approaches in the retrochiasmatic region, we evaluated and compared the exposure and maneuverability associated with the microscope and the endoscope in these approaches. METHODS: Seven formalin-fixed cadaveric heads were dissected bilaterally through the two approaches: four for evaluation and three injected with colored latex for photography. The retrochiasmatic region was divided into four sub-compartments: the compartment before the infundibulum, which was further divided into two parts, (1) the ipsilateral and (2) the contralateral compartments; (3) the retroinfundibulum compartment; (4) the third ventricle. After each approach, exposure and maneuverability of the structures in these four compartments obtained by microscopy and endoscopy were scored under a guidance of a numerical grading system for further comparison. RESULTS: The TCA provided better exposure and maneuverability at the retrochiasmatic region than the RLA in both the microscopy model [scores of 39.75 ± 2.12 and 32.38 ± 2.56 respectively (p < 0.05)] and the endoscopy model [scores of 82.13 ± 3.40 and 43.75 ± 1.67 respectively (p < 0.05)]. CONCLUSIONS: The TCA is better than the RLA at offering exposure and manipulation to structures in the retrochiasmatic region, especially in patients whose lesion is located high into the third ventricle and/or expanded into the contralateral part. Endoscopes may be helpful in TCA in terms of exposing and maneuvering structures in the contralateral and interpeduncle fossa areas. However, in RLA, not enough room is available for simultaneously maneuvering an endoscope and a surgical instrument.

Discrete Boltzmann modeling of multiphase flows: hydrodynamic and thermodynamic non-equilibrium effects.

A discrete Boltzmann model (DBM) is developed to investigate the hydrodynamic and thermodynamic non-equilibrium (TNE) effects in phase separation processes. The interparticle force drives changes and the gradient force, induced by gradients of macroscopic quantities, opposes them. In this paper, we investigate the interplay between them by providing a detailed inspection of various non-equilibrium observables. Based on the TNE features, we define TNE strength which roughly estimates the deviation amplitude from the thermodynamic equilibrium. The time evolution of the TNE intensity provides a convenient and efficient physical criterion to discriminate the stages of the spinodal decomposition and domain growth. Via the DBM simulation and this criterion, we quantitatively study the effects of latent heat and surface tension on phase separation. It is found that the TNE strength attains its maximum at the end of the spinodal decomposition stage, and it decreases when the latent heat increases from zero. The surface tension effects are threefold, prolong the duration of the spinodal decomposition stage, decrease the maximum TNE intensity, and accelerate the speed of the domain growth stage.

Emodin enhances cholesterol efflux by activating peroxisome proliferator-activated receptor-γ in oxidized low density lipoprotein-loaded THP1 macrophages.

Peroxisome proliferator-activated receptor (PPAR) γ is a nuclear receptor involved in the regulation of lipid metabolism. In the present study, we sought to investigate the effects of emodin, an anthraquinone derivative isolated from the roots of Rheum palmatum, on PPARγ signalling and cholesterol efflux in macrophage foam cells. Oxidized low-density lipoprotein (oxLDL)-stimulated THP1 macrophages were incubated with different concentrations of emodin (0-10 µmol/L) for 18 h. Western blot analysis and semiquantitative reverse transcription-polymerase chain reaction were used to assess the expression of key genes involved in cholesterol efflux, namely PPARγ, liver X receptor (LXR) α, ATP-binding cassette transporter (ABC) A1 and ABCG1. In addition, apolipoprotein (apo) A-I-mediated cholesterol efflux in emodin-treated cells was measured. Expresssion of PPARγ mRNA and protein was increased in emodin-treated cells in a time- and dose-dependent manner. Emodin treatment also concentration-dependently induced LXRα, ABCA1 and ABCG1 expression. Moreover, emodin promoted apoA-I-mediated cholesterol efflux from oxLDL-loaded THP1 macrophages, which was significantly abolished by pretreatment with the PPARγ-selective antagonist GW9662 or the specific small interfering RNA for PPARγ. Together, the results demonstrate that emodin promotes cholesterol efflux from THP1 macrophages via activation of the PPARγ signalling pathway and may represent a potential anti-atherosclerotic drug.

Causal relationship between gut microbiota and gynecological tumor: a two-sample Mendelian randomization study.

Introduction: Previous research has established associations between alterations in gut microbiota composition and various gynecologic tumors. However, establishing a causal relationship between gut microbiota and these tumors remains necessary. This study employs a two-sample Mendelian randomization (MR) approach to investigate causality, aiming to identify pathogenic bacterial communities potentially involved in gynecologic tumor development. Methods: Data from the MiBioGen consortium's Genome-Wide Association Study (GWAS) on gut microbiota were used as the exposure variable. Four common gynecologic neoplasms, including uterine fibroids (UF), endometrial cancer (EC), ovarian cancer (OC), and cervical cancer (CC), were selected as outcome variables. Single-nucleotide polymorphisms (SNPs) significantly associated with gut microbiota were chosen as instrumental variables (IVs). The inverse variance-weighted (IVW) method was used as the primary MR analysis to assess the causal relationship. External validation An was conducted using an independent. Sensitivity analyses were performed to ensure robustness. Reverse MR analysis was also conducted to assess potential reverse causation. Results: Combining discovery and validation cohorts, we found that higher relative abundance of Lachnospiraceae is associated with lower UF risk (OR: 0.882, 95% CI: 0.793-0.982, P = 0.022). Conversely, higher OC incidence is associated with increased relative abundance of Lachnospiraceae (OR: 1.329, 95% CI: 1.019-1.732, P = 0.036). Sensitivity analyses confirmed these findings' reliability. Reverse MR analysis showed no evidence of reverse causation between UF, OC, and Lachnospiraceae. Discussion: This study establishes a causal relationship between Lachnospiraceae relative abundance and both UF and OC. These findings provide new insights into the potential role of gut microbiota in mechanisms underlying gynecological tumors development.

[Oscillation-static cycle cultivation enhances the synthesis of triterpenes and mycelium activity in Ganoderma lucidum].

Ganoderma lucidum is a precious fungus with both edible and medicinal values and has a long history of medical use. Triterpenes as the main active components endow G. lucidum with anti-tumor, antioxidant, and other pharmacological activities. The present study endeavors to establish a proficient liquid-state fermentation technology for the enhanced production of triterpenes. In view of the limitations inherent in conventional submerged fermentation and oscillation-static two-stage cultivation, this study established an oscillation-static cycle cultivation process and optimized the cultivation conditions by building an artificial neural network model based on genetic algorithms. The cultivation conditions for the high-yield production of triterpenes were optimized as follows: 2.8 days of oscillation, 7.3 days of static cultivation, 0.2 day of oscillation, and 0.3 day of static cultivation. Under these conditions, the content of triterpenes reached 20.82 mg/g. The yield of triterpenes reached 129.09 mg/L, showing a remarkable increase of 324.78% compared with that of the Z10J0 method. Moreover, the established method shortened the cultivation cycle by 10.6 days. The mycelia cultivated under this regimen exhibited commendable anti-tumor and antioxidant activities. This study not only presents an economical liquid-state fermentation approach but also streamlines the fermentation flow, reduces fermentation duration, and effectively ameliorates drawbacks associated with conventional cultivation methods. In addition, this study gives valuable insights into the scaled application of liquid-state fermentation in the high-yield production of triterpenes, which showcases broad prospects.

MICAL2 implies immunosuppressive features and acts as an independent and adverse prognostic biomarker in pancreatic cancer.

At present, clinical outcomes of pancreatic cancer patients are still poor. New therapeutic targets for pancreatic cancer are urgently needed. Previous studies have indicated that Microtubule Associated Monooxygenase, Calponin and LIM Domain Containing 2 (MICAL2) is highly expressed in many tumors and promotes tumor progression. However, the role played by MICAL2 in pancreatic cancer remains unclear. Based on gene expression and clinical information from multiple datasets, we used comprehensive bioinformatics analysis in combination with tissue microarray to explore the function and clinical value of MICAL2. The results showed that MICAL2 was highly expressed in pancreatic cancer tissue and exhibited potential diagnostic capability. High expression of MICAL2 was also associated with poor prognosis and acted as an independent prognostic factor. MICAL2, mainly expressed in fibroblasts of pancreatic cancer, was closely related to metastasis and immune-related features, such as epithelial-mesenchymal transformation, extracellular cell matrix degradation, and inflammatory response. Furthermore, higher MICAL2 expression in pancreatic cancer was also associated with an increase in cancer-associated fibroblasts as well as M2 macrophage infiltration, and a reduction in CD8 + T cell infiltration, thereby facilitating the formation of an immunosuppressive microenvironment. Our results helped elucidate the clinical value and function in metastasis and immunity of MICAL2 in pancreatic cancer. These findings provided potential clinical strategies for diagnosis, targeted therapy combination immunotherapy, and prognosis in patients with pancreatic cancer.

Widely targeted metabolomics analysis of Sanghuangporus vaninii mycelia and fruiting bodies at different harvest stages.

Sanghuangprous vaninii is a medicinal macrofungus cultivated extensively in China. Both the mycelia and fruiting bodies of S. vaninii have remarkable therapeutic properties, but it remains unclear whether the mycelia may serve as a substitute for the fruiting bodies. Furthermore, S. vaninii is a perennial fungus with therapeutic components that vary significantly depending on the growing year of the fruiting bodies. Hence, it is critical to select an appropriate harvest stage for S. vaninii fruiting bodies for a specific purpose. With the aid of Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), metabolomics based on ultra-high performance liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-QQQ-MS) was used to preliminarily determine 81 key active metabolites and 157 active pharmaceutical metabolites in S. vaninii responsible for resistance to the six major diseases. To evaluate the substitutability of the mycelia and fruiting bodies of S. vaninii and to select an appropriate harvest stage for the fruiting bodies of S. vaninii, we analyzed the metabolite differences, especially active metabolite differences, among the mycelia and fruiting bodies during three different harvest stages (1-year-old, 2-year-old, and 3-year-old). Moreover, we also determined the most prominent and crucial metabolites in each sample of S. vaninii. These results suggested that the mycelia show promise as a substitute for the fruiting bodies of S. vaninii and that extending the growth year does not necessarily lead to higher accumulation levels of active metabolites in the S. vaninii fruiting bodies. This study provided a theoretical basis for developing and using S. vaninii.

Exploring the optimal indicator of short-term peridiagnosis weight dynamics to predict cancer survival: A multicentre cohort study.

BACKGROUND: Body weight and its changes have been associated with cancer outcomes. However, the associations of short-term peridiagnosis weight dynamics in standardized, clinically operational time frames with cancer survival remain largely unknown. This study aimed to screen for and evaluate the optimal indicator of short-term peridiagnosis weight dynamics to predict overall survival (OS) in patients with cancer. METHODS: This multicentre cohort study prospectively collected data from 7460 patients pathologically diagnosed with cancer between 2013 and 2019. Body weight data were recorded 1 month before, at the time of and 1 month following diagnosis. By permuting different types (point value in kg, point height-adjusted value in kg/m2, absolute change in kg or relative change in percentage) and time frames (prediagnosis, postdiagnosis or peridiagnosis), we generated 12 different weight-related indicators and compared their prognostic performance using Harrell's C-index, integrated discrimination improvement, continuous net reclassification improvement and time-dependent C-index. We analysed associations of peridiagnosis relative weight change (RWC) with OS using restricted cubic spine (RCS), Kaplan-Meier analysis and multivariable-adjusted Cox regression models. RESULTS: The study enrolled 5012 males and 2448 females, with a median age of 59 years. During a median follow-up of 37 months, 1026 deaths occurred. Peridiagnosis (1 month before diagnosis to 1 month following diagnosis) RWC showed higher prognostic performance (Harrell's C-index = 0.601, 95% confidence interval [CI] = [0.583, 0.619]) than other types of indicators including body mass index (BMI), absolute weight change, absolute BMI change, prediagnosis RWC and postdiagnosis RWC in the study population (all P < 0.05). Time-dependent C-index analysis also indicated that peridiagnosis RWC was optimal for predicting OS. The multivariable-adjusted RCS analysis revealed an N-shaped non-linear association between peridiagnosis RWC and OS (PRWC < 0.001, Pnon-linear < 0.001). Univariate survival analysis showed that the peridiagnosis RWC groups could represent distinct mortality risk stratifications (P < 0.001). Multivariable survival analysis showed that, compared with the maintenance group (weight change < 5%), the significant (gain >10%, hazard ratio [HR] = 0.530, 95% CI = [0.413, 0.680]) and moderate (gain 5-10%, HR = 0.588, 95% CI = [0.422, 0.819]) weight gain groups were both associated with improved OS. In contrast, the moderate (loss 5-10%, HR = 1.219, 95% CI = [1.029, 1.443]) and significant (loss >10%, HR = 1.280, 95% CI = [1.095, 1.497]) weight loss groups were both associated with poorer OS. CONCLUSIONS: The prognostic performance of peridiagnosis RWC is superior to other weight-related indicators in patients with cancer. The findings underscore the importance of expanding the surveillance of body weight from at diagnosis to both past and future, and conducting it within clinically operational time frames, in order to identify and intervene with patients who are at risk of weight change-related premature deaths.

[A Prognostic Model of Elderly Patients with Non-small Cell Lung Cancer 
Based on Geriatric Nutritional Risk Index].

BACKGROUND: The relationship between nutritional status and prognosis of cancer patients has emerged as a hotspot for research. The aim of this study is to explore the application value of the geriatric nutritional risk index (GNRI) in assessing the prognosis of elderly patients with non-small cell lung cancer (NSCLC), and establish a Nomogram to predict the prognosis of elderly patients with NSCLC. METHODS: The data of patients with NSCLC aged ≥65 years who were initially treated in the First Affiliated Hospital of Zhengzhou University from January 2016 to December 2019 were retrospectively analyzed. To determine the optimal cut-off value for GNRI, receiver operating characteristic (ROC) curve was constructed, and the patients were divided into high and low GNRI groups. Kaplan-Meier curve and Log-rank test were used to compare overall survival (OS) of the two groups. Univariate and multivariate Cox regression was used to analyze the risk factors for poor prognosis in elderly patients with NSCLC. Nomogram predicting survival in elderly patients with NSCLC was constructed and validated by using R software. RESULTS: Statistically significant differences in age, gender, body mass index (BMI), histological type, albumin, treatment methods, neutrophil to lymphocyte ratio (NLR), prognostic nutritional index (PNI), systemic immune-inflammation index (SII) and cytokeratin 19 fragment (CYFRA21-1) were observed between the high and low GNRI groups (P<0.05). The Kaplan-Meier curve showed a shorter OS in the low-GNRI group. Multivariate Cox regression analysis showed that CYFRA21-1>3.3 ng/mL was an independent risk factor for the development of OS in patients with NSCLC, and GNRI>97.09 was a protective factor [hazard ratio (HR)=0.52, 95% confidence interval (CI): 0.34-0.79, P<0.05]. Patients in the stage IV had a 1.98-fold increased risk of death compared with patients in the stage I (95%CI: 1.02-3.86, P<0.05). The risk of death was 3.58 times higher in patients receiving chemotherapy alone compared with those receiving combination therapy (95%CI: 2.03-6.32, P<0.05). A Nomogram constructed on the basis of GNRI, which predicted the OS of elderly patients with NSCLC with a concordance index (C-index) of 0.70 (95%CI: 0.65-0.76), and the area under the curve (AUC) for 1 and 2-year survival rates to be 0.93 (95%CI: 0.87-0.98) and 0.72 (95%CI: 0.63-0.80), respectively, and the calibration curve has a good coincidence of prediction. CONCLUSIONS: High GNRI scores are significantly associated with improved survival in elderly patients with NSCLC, and reliance on cut-off values may provide the appropriate timing for nutritional support. The Nomogram constructed in this study can be used as an effective tool to predict the survival rate of elderly patients with NSCLC, which has strong clinical practicability.

PIEZO2 promotes cell proliferation and metastasis in colon carcinoma through the SLIT2/ROBO1/VEGFC pathway.

BACKGROUND: The PIEZO2 may be involved in the occurrence and development of tumors. OBJECTIVES: To explore the potential mechanism and effect of PIEZO2 on colon cancer. MATERIAL AND METHODS: We assessed the expression and prognostic role of PIEZO2 in patients with colon cancer. The role of PIEZO2 in SW480 cell proliferation, migration and invasion in vitro was investigated using cell counting kit-8 (CCK-8), wound healing, and transwell and cell invasion assays, respectively. The effect of PIEZO2 on SW480 cells in vivo was also explored. The potential mechanisms of PIEZO2 in SW480 cells were detected using quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blot. RESULTS: The PIEZO2 was significantly increased in colon cancer tissues and the PIEZO2 high expression group was associated with a lower overall survival (OS) rate. Furthermore, PIEZO2 knockdown weakened the proliferation, migration and invasion of SW480 cells. The PIEZO2 knockdown was related to a lower expression of SLIT2, ROBO1, HIF-1α, and VEGFC. Finally, the tumors in control SW480 cells grew faster and larger than those in mice inoculated with si-PIEZO2 SW480 cells. Moreover, the si-PIEZO2 SW480 cell group showed a reduced expression of Ki67 and VEGFC and, at the same time, a significantly higher apoptosis index of tumor cells compared to the control group. The expression of PIEZO2 was higher in cancer-associated fibroblasts (CAFs) of colon cancer. CONCLUSIONS: The PIEZO2 was increased in colon cancer tissues and was an unfavorable gene in patients with colon cancer, promoting colon cell proliferation, migration and invasion through the SLIT2/ROBO1/VEGFC pathway.

Predicting anticancer drug sensitivity on distributed data sources using federated deep learning.

Drug sensitivity prediction plays a crucial role in precision cancer therapy. Collaboration among medical institutions can lead to better performance in drug sensitivity prediction. However, patient privacy and data protection regulation remain a severe impediment to centralized prediction studies. For the first time, we proposed a federated drug sensitivity prediction model with high generalization, combining distributed data sources while protecting private data. Cell lines are first classified into three categories using the waterfall method. Focal loss for solving class imbalance is then embedded into the horizontal federated deep learning framework, i.e., HFDL-fl is presented. Applying HFDL-fl to homogeneous and heterogeneous data, we obtained HFDL-Cross and HFDL-Within. Our comprehensive experiments demonstrated that (i) collaboration by HFDL-fl outperforms private model on local data, (ii) focal loss function can effectively improve model performance to classify cell lines in sensitive and resistant categories, and (iii) HFDL-fl is not significantly affected by data heterogeneity. To summarize, HFDL-fl provides a valuable solution to break down the barriers between medical institutions for privacy-preserving drug sensitivity prediction and therefore facilitates the development of cancer precision medicine and other privacy-related biomedical research.

Genomic characterization of two carbapenem-resistant Serratia marcescens isolates causing bacteremia: Emergence of KPC-2-encoding IncR plasmids.

The occurrence and transmission of carbapenemase-producing-Enterobacterales (CPE) on a global scale has become a major issue. Clinical reports are rarely providing information on the genomic and plasmid features of carbapenem-resistant Serratia marcescens. Our objective was to investigate the resistance and transmission dynamics of two carbapenem-resistant S. marcescens that are resistant to carbapenem and have caused bacteremia in China. Blood specimens were taken from two individuals with bacteremia. Multiplex PCR was employed to identify genes that code for carbapenemase. Antimicrobial susceptibility tests and plasmid analysis were conducted on S. marcescens isolates SM768 and SM4145. The genome of SM768 and SM4145 were completely sequenced using NovaSeq 6000-PE150 and PacBio RS II platforms. Antimicrobial resistance genes (ARGs) were predicted using the ResFinder tool. S1 nuclease pulsed-field gel electrophoresis (S1-PFGE) and southern blotting were employed to analyze plasmids. Two S. marcescens that produced KPC-2 were identified from bloodstream infections. The antimicrobial susceptibility testing demonstrated that both of the isolates had a resistance to various antibiotics. The whole-genome sequence (WGS) and plasmid analysis revealed the presence of bla KPC-2-bearing IncR plasmids and multiple plasmid-borne antimicrobial resistance genes in the isolates. Our comparative plasmid analysis suggested that the two IncR plasmids identified in this study could be derived from a common ancestor. Our findings revealed the emergence of bla KPC-2-bearing IncR plasmid in China, which could be a hindrance to the transmission of KPC-2-producing S. marcescens in clinical settings.