Causal association of sarcopenia with hepatocellular carcinoma risk in European population: a Mendelian randomization study.

Background: The causal association of sarcopenia with the incidence risk of hepatocellular carcinoma (HCC) in the European population, and the potential mediating role of C-reactive protein (CRP), remains unclear. This study employed a bidirectional two-sample, two-step Mendelian randomization (MR) analysis to investigate the causality and identify the mediator. Methods: Summary statistics for HCC, CRP, and sarcopenia-related traits, including appendicular lean mass (ALM), hand grip strength (HGS), and walking pace (WP), were acquired from publicly available databases. We conducted bidirectional MR and Steiger tests of directionality to check the presence of reverse causality. Additionally, a two-step MR analysis was used to assess the mediating effect of CRP in the causality between sarcopenia and HCC. Tests for heterogeneity and horizontal pleiotropy were performed. Results: As ALM increases, the risk of HCC occurrence decreases [odds ratio (OR), 95% confidence interval (CI): 0.703, 0.524-0.943; P = 0.019]. And, genetically predicted low-HGS (OR, 95%CI: 2.287, 1.013-5.164; P = 0.047) was associated with an increased incidence risk of HCC, with no reverse causality. However, we found no evidence supporting a causality between WP and HCC. CRP was identified as the mediator of the causal effect of ALM and low-HGS on HCC, with corresponding mediating effects of 9.1% and 7.4%. Conclusions: This MR study effectively demonstrates that lower ALM and low-HGS are linked to an elevated risk of HCC within the European population, and the causality was not bidirectional. Furthermore, CRP serves as a mediator in the associations. These findings may help mitigate HCC risk among individuals with sarcopenia.

Nanofiber-Reinforced MXene/rGO Composite Aerogel for a High-Performance Piezoresistive Sensor and an All-Solid-State Supercapacitor Electrode Material.

The assembly of two-dimensional (2D) nanomaterials into a three-dimensional (3D) aerogel can effectively prevent the problem of restacking. Here, nanofiber-reinforced MXene/reduced graphene oxide (rGO) conductive aerogel is prepared via the hydrothermal reduction of GO using pyrrole and in situ composite with MXene. Combined with low-content 2D conductive nanosheets (MXene and rGO) as "brick", conductive polypyrrole as "mortar", and one-dimensional (1D) nanofiber as "rebar", a strong interfacial cross-linking of MXene and rGO nanosheets is realized through covalent and noncovalent bonds to synergistically improve its mechanical performance. Based on the prepared MXene/rGO aerogel, a high-performance piezoresistive sensor with a sensitivity of up to 20.80 kPa-1 in a wide pressure range of 15.6 kPa is obtained, and it can withstand more than 5000 cyclic compressions. Besides, the sensor shows a stable output and can be applied to monitor various human motion signals. In addition, an all-solid-state supercapacitor electrode is also fabricated, which shows a high area-specific capacitance of up to 274 mF/cm2 at a current density of 1 mA/cm2.

Anterior segment optical coherence tomography for superficial keratectomy.

PURPOSE: To report the use of anterior segment optical coherence tomography (AS-OCT) for superficial keratectomy (SK) in anterior corneal opacity. METHODS: The characteristics of 43 eyes (39 patients) with various lesions responsible for anterior corneal opacity were included in this retrospective non-comparative study. AS-OCT was performed on all eyes before surgery. The thickness of corneal opacity and the underlying healthy stroma were measured. SK was performed on each individual. RESULTS: Four types of anterior corneal opacity were evaluated, including corneal degeneration (26/43), Reis-Bücklers corneal dystrophy (8/43), alkali burn (1/43) and corneal tumors (8/43). Based on AS-OCT images, all eyes showed abnormal hyper-reflective signals in the superficial cornea to less than one-third of the normal corneal thickness in the deepest corneal opacity. All 43 eyes underwent an SK procedure. In addition, 1 eye with alkali burns and 7 eyes with corneal tumors were combined with amniotic membrane transplantation. All eyes restored transparency without significant complications. CONCLUSION: AS-OCT is a valuable method for objective preoperative and noninvasive assessments of anterior corneal opacities and is useful for guiding SK.

[Screening for Characteristic Genes of Different Traditional Chinese Medicine Syndromes of Psoriasis Vulgaris: A Study Based on Bioinformatics and Machine Learning]. / ç”Ÿç‰©ä¿¡æ¯å­¦å’Œæœºå™¨å­¦ä¹ ç­›é€‰é“¶å±‘ç— ä¸­åŒ»è¯åž‹ç‰¹å¾åŸºå› .

Objective: To screen for the key characteristic genes of the psoriasis vulgaris (PV) patients with different Traditional Chinese Medicine (TCM) syndromes, including blood-heat syndrome (BHS), blood stasis syndrome (BSS), and blood-dryness syndrome (BDS), through bioinformatics and machine learning and to provide a scientific basis for the clinical diagnosis and treatment of PV of different TCM syndrome types. Methods: The GSE192867 dataset was downloaded from Gene Expression Omnibus (GEO). The limma package was used to screen for the differentially expressed genes (DEGs) of PV, BHS, BSS, and BDS in PV patients and healthy populations. In addition, KEGG (Kyoto Encyclopedia of Genes and Genes) pathway enrichment analysis was performed. The DEGs associated with PV, BHS, BSS, and BDS were identified in the screening and were intersected separately to obtain differentially characterized genes. Out of two algorithms, the support vector machine (SVM) and random forest (RF), the one that produced the optimal performance was used to analyze the characteristic genes and the top 5 genes were identified as the key characteristic genes. The receiver operating characteristic (ROC) curves of the key characteristic genes were plotted by using the pROC package, the area under curve (AUC) was calculated, and the diagnostic performance was evaluated, accordingly. Results: The numbers of DEGs associated with PV, BHS, BSS, and BDS were 7699, 7291, 7654, and 6578, respectively. KEGG enrichment analysis was focused on Janus kinase (JAK)/signal transducer and activator of transcription (STAT), cyclic adenosine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), apoptosis, and other pathways. A total of 13 key characteristic genes were identified in the screening by machine learning. Among the 13 key characteristic genes, malectin (MLEC), TUB like protein 3 (TULP3), SET domain containing 9 (SETD9), nuclear envelope integral membrane protein 2 (NEMP2), and BTG anti-proliferation factor 3 (BTG3) were the key characteristic genes of BHS; phosphatase 15 (DUSP15), C1q and tumor necrosis factor related protein 7 (C1QTNF7), solute carrier family 12 member 5 (SLC12A5), tripartite motif containing 63 (TRIM63), and ubiquitin associated protein 1 like (UBAP1L) were the key characteristic genes of BSS; recombinant mouse protein (RRNAD1), GTPase-activating protein ASAP3 Protein (ASAP3), and human myomesin 2 (MYOM2) were the key characteristic genes of BDS. Moreover, all of them showed high diagnostic efficacy. Conclusion: There are significant differences in the characteristic genes of different PV syndromes and they may be potential biomarkers for diagnosing TCM syndromes of PV.

Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability.

Tumor cells must rewire nucleotide synthesis to satisfy the demands of unbridled proliferation. Meanwhile, they exhibit augmented reactive oxygen species (ROS) production which paradoxically damages DNA and free deoxy-ribonucleoside triphosphates (dNTPs). How these metabolic processes are integrated to fuel tumorigenesis remains to be investigated. MYC family oncoproteins coordinate nucleotide synthesis and ROS generation to drive the development of numerous cancers. We herein perform a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based functional screen targeting metabolic genes and identified nudix hydrolase 1 (NUDT1) as a MYC-driven dependency. Mechanistically, MYC orchestrates the balance of two metabolic pathways that act in parallel, the NADPH oxidase 4 (NOX4)-ROS pathway and the Polo like kinase 1 (PLK1)-NUDT1 nucleotide-sanitizing pathway. We describe LC-1-40 as a potent, on-target degrader that depletes NUDT1 in vivo. Administration of LC-1-40 elicits excessive nucleotide oxidation, cytotoxicity and therapeutic responses in patient-derived xenografts. Thus, pharmacological targeting of NUDT1 represents an actionable MYC-driven metabolic liability.

Biomimetic-Membrane-Protected Plasmonic Nanostructures as Dual-Modality Contrast Agents for Correlated Surface-Enhanced Raman Scattering and Photoacoustic Detection of Hidden Tumor Lesions.

Optical imaging and spectroscopic modalities are of considerable current interest for in vivo cancer detection and image-guided surgery, but the turbid or scattering nature of biomedical tissues has severely limited their abilities to detect buried or occluded tumor lesions. Here we report the development of a dual-modality plasmonic nanostructure based on colloidal gold nanostars (AuNSs) for simultaneous surface-enhanced Raman scattering (SERS) and photoacoustic (PA) detection of tumor phantoms embedded (hidden) in ex vivo animal tissues. By using red blood cell membranes as a naturally derived biomimetic coating, we show that this class of dual-modality contrast agents can provide both Raman spectroscopic and PA signals for the detection and differentiation of hidden solid tumors with greatly improved depths of tissue penetration. Compared to previous polymer-coated AuNSs, the biomimetic coatings are also able to minimize protein adsorption and cellular uptake when exposed to human plasma without compromising their SERS or PA signals. We further show that tumor-targeting peptides (such as cyclic RGD) can be noncovalently inserted for targeting the ανß3-integrin receptors expressed on metastatic cancer cells and tracked via both SERS and PA imaging (PAI). Finally, we demonstrate image-guided resections of tumor-mimicking phantoms comprising metastatic tumor cells buried under layers of skin and fat tissues (6 mm in thickness). Specifically, PAI was used to determine the precise tumor location, while SERS spectroscopic signals were used for tumor identification and differentiation. This work opens the possibility of using these biomimetic dual-modality nanoparticles with superior signal and biological stability for intraoperative cancer detection and resection.

Geriatric Nutritional Risk Index Combined with Calf Circumference Can be a Good Predictor of Prognosis in Patients Undergoing Surgery for Gastric or Colorectal Cancer.

OBJECTIVES: To explore the effect of combined hematological and physical measurement indicators on the prognosis of patients undergoing surgery for gastric or colorectal cancer and to screen for the best prognostic indicators. INTRODUCTION: Gastric and colorectal cancer is a widespread health concern worldwide and one of the major contributors to cancer-related death. The hematological and physical measurement indicators have been shown to associate with the prognosis of patients undergoing surgery for gastric or colorectal cancer, respectively, but it is still unclear whether the combination of the two can reflect the prognosis more effectively. METHODS: Thirteen hematological indicators and 5 physical measurement indicators were selected in this study, and the most promising ones were screened using LASSO regression. Then, the best prognostic indicators were selected by time-ROC curves. Survival curves were constructed using the Kaplan-Meier method, and the effects of hematological and physical measurement indicators on the prognosis of patients undergoing surgery for gastric or colorectal cancers were evaluated by Cox proportional risk regression analysis. In addition, the relationship between hematological and physical measurement indicators on secondary outcomes, including length of stay, hospitalization costs, intensive care unit (ICU) admission, and patients' subjective global assessment scores (PGSGA), was explored. RESULTS: After initial screening, among the hematological indicators, the geriatric nutritional risk index (GNRI) showed the highest mean area under the curve (AUC) values. Among body measures, calf circumference (CC) showed the highest mean AUC value. Further analyses showed that the combination of combined nutritional prognostic index (GNRI) and calf circumference (CC) (GNRI-CC) had the best performance in predicting the prognosis of patients undergoing surgery for gastric or colorectal cancers. Low GNRI, low CC, and low GNRI-low CC increased the risk of death by 44%, 48%, and 104%, respectively. Sensitivity analyses showed the same trend. In addition, low GNRI-low CC increased the risk of malnutrition by 17%. CONCLUSION: This study emphasizes that a combination of blood measures and body measures is essential to accurately assess the prognosis of patients undergoing surgery for gastric or colorectal cancers. The GNRI-CC is a good prognostic indicator and can also assess the risk of possible malnutrition.

Temporal relationship between inflammation and metabolic disorders and their impact on cancer risk.

Background: Inflammation and metabolic disorders are closely associated with cancer. Whether inflammation leads to metabolic disorders or vice versa during cancer initiation remains unclear. In this study, we explored this temporal relationship and the co-exposure effect on cancer risk. Methods: This prospective study had two phases. Initially, we examined the temporal relationship between inflammation (high-sensitivity C-reactive protein (CRP)) and metabolic disorders (metabolic syndrome severity Z-score (MetS-Z)) using a 3.98-year survey and cross-lagged analysis. Subsequently, we assessed the connection of co-exposure to inflammation and metabolic disorders, and the risks of overall cancer, as well as specific obesity-related, non-obesity-related, digestive system, lung, and other cancers using an 11.04-year survey and Cox proportional hazard models. Results: The cross-lagged analysis revealed that the path coefficient from baseline CRP to follow-up MetS-Z (ß2 = 0.032; 95% confidence interval (CI) = 0.026, 0.046) was more significant than the path coefficient from baseline MetS-Z to follow-up CRP (ß1 = 0.009; 95% CI = -0.001, 0.019). During the follow-up, 2304 cases of cancer occurred. Compared with the risk of cancer of patients with low average cumulative CRP and MetS-Z, patients with high value had a significantly increased risk (hazard ratio = 1.54, 95% CI = 1.30, 1.83). The mediation analysis showed that MetS-Z mediated the association between CRP levels and overall cancer (12.67%), digestive system cancer (10.16%), and obesity-related cancer risk (13.87%). Conclusions: Inflammation had a greater impact on metabolic disorders than vice versa. Co-exposure to inflammation and metabolic disorders significantly increased the risk of cancer, particularly digestive system and obesity-related cancers. Registration: Chinese Clinical Trial Registry: ChiCTR-TNRC-11001489.

Evaluation and validation of neutrophil to albumin ratio as a promising prognostic marker for all-cause mortality in patients with cancer: a multicenter cohort study.

OBJECTIVES: The practicality and effectiveness of using the prognostic value of the neutrophil-to-albumin ratio (NAR) in evaluating patients with cancer remain unclear, and research is needed to fully understand its potential application in the cancer population. METHODS: The Kaplan-Meier method was used for survival analysis, and the log-rank test was employed for comparison. Univariate and multivariate Cox proportional hazards models were used to determine the prognostic biomarkers, and Logistic regression analysis was conducted to investigate the relationship between NAR and 90-day outcomes and cachexia. RESULTS: The study included 14 682 patients with cancer, divided into discovery (6592 patients), internal validation (2820 patients), and external validation groups (5270 patients). Patients with high NAR had higher all-cause mortality than those with low NAR in the discovery (50.15% versus 69.29%, P < 0.001), internal validation (54.18% versus 70.91%, P < 0.001), and external validation cohorts (40.60% versus 66.68%, P < 0.001). In the discovery cohort, high NAR was observed to be independently associated with all-cause mortality in patients (HR 1.16, 95% CI 1.12-1.19; P < 0.001). Moreover, we validated the promising prognostic value of NAR as a predictor of survival in patients with cancer through internal validation (HR 1.21, 95% CI 1.16-1.27, P < 0.001) and external validation cohorts (HR 1.27, 95% CI 1.21-1.34, P < 0.001). Additionally, in the subgroup analysis by tumor type, high NAR was identified as a risk factor for most cancers, except for breast cancer. CONCLUSIONS: This study showed that NAR is a feasible and promising biomarker for predicting prognosis and cancer cachexia in cancer patients.

Design, Synthesis, and Biological Activities of Novel Coumarin Derivatives as Pesticide Candidates.

Food security is an important issue in the 21st century; preventing and controlling crop diseases and pests are the key to solve this problem. The creation of new pesticides based on natural products is an important and effective method. Herein, coumarins were selected as parent structures, and a series of their derivatives were designed, synthesized, and evaluated for their antiviral activities, fungicidal activities, and insecticidal activities. We found that coumarin derivatives exhibited good to excellent antiviral activities against tobacco mosaic virus (TMV). The antiviral activities of I-1, I-2a, I-4b, II-2c, II-2g, II-3, and II-3b are better than that of ribavirin at 500 µg/mL. Molecular docking research showed that these compounds had a strong interaction with TMV CP. These compounds also showed broad-spectrum fungicidal activities against 14 plant pathogenic fungi. The EC50 values of I-1, I-2a, I-3c, and II-2d are in the range of 1.56-8.65 µg/mL against Rhizoctonia cerealis, Physalospora piricola, Sclerotinia sclerotiorum, and Pyricularia grisea. Most of the compounds also displayed good insecticidal activities against Mythimna separata. Pesticide-likeness analysis showed that these compounds are following pesticide-likeness and have the potential to be developed as pesticide candidates. The present work lays a foundation for the discovery of novel pesticide lead compounds based on coumarin derivatives.

Predicted lean body mass trajectories, and cancer risk and cancer-specific and all-cause mortality: A prospective cohort study.

BACKGROUND: Although many studies have investigated the association between body composition, cancer risk and mortality, predicting these risks through a single body composition measurement undoubtedly increases the limitations of the study. Few studies have explored the association between the trajectory of changes in body composition and the risk of cancer and death. We aimed to explore the association of predicted lean mass trajectories with cancer risk, cancer-specific mortality and all-cause mortality. METHODS: The participants in this study were all from the Kailuan cohort, a prospective, periodic, resurvey cohort study initiated in 2006. Latent mixture modelling was used to identify predicted lean mass trajectories for 2006-2010. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of the Cox proportional hazard models were used to describe the association between predicted lean mass trajectories and cancer risk and cancer-specific and all-cause mortality during follow-up (2010-2021). RESULTS: A total of 44 374 participants (average age, 53.01 ± 11.41 years, 78.99% men and 21.01% women) were enrolled in this study. Five distinct trajectories were identified: low-stable (n = 12 060), low-increasing (n = 8027), moderately stable-decreasing (n = 4725), moderately stable-increasing (n = 8053) and high-stable (n = 11 509). During the 11-year follow-up period, 2183 cancer events were recorded. After adjusting for age, predicted fat mass in 2010, sex, BMI, sedentary, physical activity, smoke, alcohol use, salt consumption, high-fat diet, high-sensitivity C-reactive protein, serum creatinine, family history of tumour, hypertension, diabetes mellitus, compared with the low-stable group, participants in the low-increasing group (HR = 0.851, 95% CI, 0.748-0.969), moderately stable-increasing group (HR = 0.803, 95% CI, 0.697-0.925) and high-stable group (HR = 0.770, 95% CI, 0.659-0.901) had a lower cancer risk, but not in the moderately stable-decreasing group (HR = 0.864, 95% CI, 0.735-1.015). Compared with the low-stable group, the risk of cancer-specific mortality was reduced by 25.4% (8.8-38.9%), 36.5% (20.3-49.4%) and 35.4% (17.9-49.2%), and the risk of all-cause mortality was reduced by 24.2% (16.9-30.8%), 37.0% (30.0-43.2%) and 47.4% (41.0-53.1%) in the low-increasing, moderately stable-increasing group and high-stable groups, respectively. CONCLUSIONS: Predicted lean mass trajectories may be closely associated with cancer risk and cancer-specific and all-cause mortality. Regular monitoring of body composition is necessary.

Bioinspired, vertically stacked, and perovskite nanocrystal-enhanced CMOS imaging sensors for resolving UV spectral signatures.

Imaging and identifying target signatures and biomedical markers in the ultraviolet (UV) spectrum is broadly important to medical imaging, military target tracking, remote sensing, and industrial automation. However, current silicon-based imaging sensors are fundamentally limited because of the rapid absorption and attenuation of UV light, hindering their ability to resolve UV spectral signatures. Here, we present a bioinspired imaging sensor capable of wavelength-resolved imaging in the UV range. Inspired by the UV-sensitive visual system of the Papilio xuthus butterfly, the sensor monolithically combines vertically stacked photodiodes and perovskite nanocrystals. This imaging design combines two complementary UV detection mechanisms: The nanocrystal layer converts a portion of UV signals into visible fluorescence, detected by the photodiode array, while the remaining UV light is detected by the top photodiode. Our label-free UV fluorescence imaging data from aromatic amino acids and cancer/normal cells enables real-time differentiation of these biomedical materials with 99% confidence.

Identification and validation of INHBE and P4HA1 as hub genes in non-alcoholic fatty liver disease.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent type of liver disease and a worldwide disease threatening human health. This study aims to identify the novel diagnostic biomarkers of NAFLD by comprehensive bioinformatics and machine learning, and to validate our results in hepatocyte and animal models. METHODS: We used Gene Expression Omnibus (GEO) databases on NAFLD patients for differential gene expression analyses. Intersections were taken with genes from the key modules of WGCNA and differentially expressed genes (DEGs). Machine learning algorithms like LASSO regression analysis, SVM-RFE, and RandomForest were used to screen hub genes. In addition, a nomogram model and calibration curves were built in order to forecast the probability of NAFLD occurrence. Then, the relationship between hub genes and immune cells was verified using Spearman analysis. Finally, we further verified the expression of key genes by constructing a steatosis hepatocyte model and animal model. RESULTS: Key genes (INHBE and P4HA1) were identified by comprehensive bioinformatics analysis and machine learning. INHBE and P4HA1 were up-regulated and down-regulated in the steatosis hepatocyte model, respectively. Animal experiments also showed that INHBE was up-regulated in the liver of mice fed with high fat diet (HFD). CONCLUSION: INHBE and P4HA1 are the hub genes of NAFLD. Our findings may contribute to a greater understanding of the occurrence and development of NAFLD and provide potential biomarkers and possible therapeutic targets for future clinical diagnosis and treatment.

Individualized threshold of the involuntary weight loss in prognostic assessment of cancer.

BACKGROUND: Involuntary weight loss (WL) is a common symptom in cancer patients and is associated with poor outcomes. However, there is no standardized definition of WL, and it is unclear what magnitude of weight loss should be considered significant for prognostic purposes. This study aimed to determine an individualized threshold for WL that can be used for prognostic assessment in cancer patients. METHODS: Univariate and multivariate analyses of overall survival (OS) were performed using Cox proportional hazard models. The Kaplan-Meier method was performed to estimate the survival distribution of different WL levels. Logistic regression analysis was used to determine the relationship between WL and 90-day outcomes. Restricted cubic splines with three knots were used to examine the effects of WL on survival under different body mass index (BMI) conditions. RESULTS: Among the 8806 enrolled patients with cancer, median survival time declined as WL increased, from 25.1 to 20.1, 17.8 and 16.4 months at <2%, 2-5%, 5-10% and ≥10% WL, respectively (P < 0.001). Multivariate adjusted Cox regression analysis showed that the risk of adverse prognosis increased by 18.1% based on the SD of WL (5.45 U) (HR: 1.181, 95% CI: 1.144-1.219, P < 0.001). Similarly, categorical WL was independently associated with OS in patients with cancer. With the worsening of WL, the risk of a poor prognosis in patients increases stepwise. Compared with <2% WL, all-cause mortalities were 15.1%, 37% and 64.2% higher in 2-5%, 5-10%, and ≥10% WL, respectively. WL can effectively stratify the prognosis of both overall and site-specific cancers. The clinical prognostic thresholds for WL based on different BMI levels were 4.21% (underweight), 5.03% (normal), 6.33% (overweight), and 7.60% (obese). Multivariate logistic regression analysis showed that WL was independently associated with 90-day outcomes in patients with cancer. Compared with patients with <2% WL, those with ≥10% WL had more than twice the risk of 90-day outcomes (OR: 3.277, 95% CI: 2.287-4.694, P < 0.001). Systemic inflammation was a cause of WL deterioration. WL mediates 6.3-10.3% of the overall association between systemic inflammation and poor prognoses in patients with cancer. CONCLUSIONS: An individualized threshold for WL based on baseline BMI can be used for prognostic assessment in cancer patients. WL and BMI should be evaluated simultaneously in treatment decision-making, nutritional intervention, and prognosis discussions of patients with cancer.

Estimating causal effects in observational studies for survival data with a cure fraction using propensity score adjustment.

In observational studies, covariates are often confounding factors for treatment assignment. Such covariates need to be adjusted to estimate the causal treatment effect. For observational studies with survival outcomes, it is usually more challenging to adjust for the confounding covariates for causal effect estimation because of censoring. The challenge becomes even thornier when there exists a nonignorable cure fraction in the population. In this paper, we propose a causal effect estimation approach in observational studies for survival data with a cure fraction. We extend the absolute treatment effects on survival outcomes-including the restricted average causal effect and SPCE-to survival outcomes with cure fractions, and construct the corresponding causal effect estimators based on propensity score stratification. We prove the asymptotic properties of the proposed estimators and conduct simulation studies to evaluate their performances. As an illustration, the method is applied to a stomach cancer study.

Improving the assessment of malnutrition in cancer: Using systemic inflammation markers as a supplement to the inflammation items of the GLIM criteria.

BACKGROUND & AIMS: Systemic inflammation is a key pathogenic criterion for diagnosing malnutrition using the Global Leadership Initiative on Malnutrition (GLIM) criteria. Although cancer is commonly considered as a chronic inflammation-related disease, the inflammatory burden may vary depending on the type and stage of cancer. Therefore, a more precise definition of inflammation criteria could facilitate the identification of malnutrition in cancer. METHODS: This prospective multicenter study included 1683 cancer patients screened via NRS2002 for malnutrition risk. The inflammatory burden index (IBI), C-reactive protein (CRP) level, neutrophil-to-lymphocyte ratio (NLR), and albumin (ALB) level were used to assess the inflammatory burden. Kaplan-Meier and Cox regression analyses were used to determine the relationship between the GLIM criteria and overall survival. Harrell's concordance index (C-index) was used to compare the discriminative performance of the original, IBI-based, CRP-based, NLR-based, and ALB-based GLIM criteria for survival. Logistic regression models were used to assess the association between GLIM criteria and short-term outcomes, length of hospital stay, and hospitalization costs. RESULTS: Compared to the original GLIM criteria, the IBI/CRP/NLR/ALB-based GLIM criteria better predicted the long-term outcomes of patients with cancer (chi-square: 1.316 vs. 78.321 vs. 74.740 vs. 88.719 vs. 100.921). The C-index revealed that the inflammation marker-based GLIM criteria showed significantly better prognostic accuracy than the original GLIM criteria. The ALB-based GLIM criteria exhibited the best prognostic accuracy. The inflammation marker-based GLIM criteria were independent predictive factors for the long-term prognosis of cancer. Patients with malnutrition had a 45% higher risk of adverse long-term prognoses than those without malnutrition. The inflammation marker-based GLIM criteria had good prognostic ability to predict outcomes at 3, 6, and 12 months. The stepwise effect of the grading of severity via the IBI-based GLIM criteria and CRP-based GLIM criteria was notable. The inflammation marker-based GLIM criteria are useful for predicting short-term outcomes, length of hospitalization, and hospitalization costs. CONCLUSION: The inflammation marker-based GLIM criteria have a stronger predictive value than the original GLIM criteria in evaluating both the short- and long-term prognoses of cancer patients. It is recommended to use the inflammation marker-based GLIM criteria for nutritional evaluation of cancer patients.

IGF2BP3 mediates the mRNA degradation of NF1 to promote triple-negative breast cancer progression via an m6A-dependent manner.

BACKGROUND: N6-methyladenosine (m6A) is an abundant reversible modification in eukaryotic mRNAs. Emerging evidences indicate that m6A modification plays a vital role in tumourigenesis. As a crucial reader of m6A, IGF2BP3 usually mediates the stabilisation of mRNAs via an m6A-dependent manner. But the underlying mechanism of IGF2BP3 in the tumourigenesis of triple-negative breast cancer (TNBC) is unclear. METHODS: TCGA cohorts were analysed for IGF2BP3 expression and IGF2BP3 promoter methylation levels in different breast cancer subtypes. Colony formation, flow cytometry assays and subcutaneous xenograft were performed to identify the phenotype of IGF2BP3 in TNBC. RNA/RNA immunoprecipitation (RIP)/methylated RNA immunoprecipitation (MeRIP) sequencing and luciferase assays were used to certify the target of IGF2BP3 in TNBC cells. RESULTS: IGF2BP3 was highly expressed in TNBC cell lines and tissues. TET3-mediated IGF2BP3 promoter hypomethylation led to the upregulation of IGF2BP3. Knocking down IGF2BP3 markedly reduced the proliferation of TNBC in vitro and in vivo. Intersection co-assays revealed that IGF2BP3 decreased neurofibromin 1 (NF1) stabilisation via an m6A-dependent manner. NF1 knockdown could rescue the phenotypes of IGF2BP3 knockdown cells partially. CONCLUSION: TET3-mediated IGF2BP3 accelerated the proliferation of TNBC by destabilising NF1 mRNA via an m6A-dependent manner. This suggests that IGF2BP3 could be a potential therapeutic target for TNBC.

Design, Synthesis, and Biological Evaluation of Novel Derivatives of the Marine Natural Product Laurene.

Plant pathogenic fungi and viruses are seriously threatening agricultural production. There is an urgent need to develop novel fungicides and antiviral agents with low toxicity and high efficiency. In this study, we designed and synthesized 32 thiazole-, hydrazone-, and amide-containing derivatives of laurene and systematically evaluated their antiviral activities and fungicidal activities. Structure-simplified compounds 5a-5c, 5i, 5k, 5l, 11a, 11j, and 12c displayed higher antiviral activities than that of ningnanmycin. Compound 11a with a simple chemical structure, convenient synthetic route, and excellent antiviral activity emerged as a secondary lead compound. The docking results show that compounds 5i, 5k, and 11a have strong interactions with the tobacco mosaic virus coat protein (TMV CP). These compounds also exhibited significant fungicidal activities. Compounds 5g, 5k, 11j, and 11l displayed 9.15-17.45 µg/mL EC50 values against Pyricularia grisea, and compounds 5h (EC50: 8.01 µg/mL) and 11i (EC50: 15.23 µg/mL) exhibited a similar level of EC50 values with chlorothalonil (EC50: 7.33 µg/mL) against Physalospora piricola. Preliminary fungicidal mechanism research indicated that compound 5h has a certain destructive effect on the hyphae of P. piricola. This work lays a foundation for the application of laurene derivatives in plant protection.

New-Onset Age of Nonalcoholic Fatty Liver Disease and Cancer Risk.

Importance: The onset age of nonalcoholic fatty liver disease (NAFLD) is decreasing, and whether earlier ages of NAFLD onset are associated with increased cancer risk is currently unclear. Objective: To explore the association between NAFLD new-onset age and cancer risk. Design, Setting, and Participants: This cohort study was conducted among 179 328 participants included in the Kailuan Cohort Study between 2006 and 2021. In total, 46 100 incident NAFLD cases were identified. For each case, a participant matched by age (older or younger by 1 year) and sex was randomly selected to create a new matched study cohort. Data were analyzed from December 2022 through April 2023. Exposure: Onset of NAFLD. Main Outcomes and Measures: The association between the onset age of NAFLD and the risk of different cancer types was evaluated using weighted Cox regression models. Population-attributable fractions (PAFs) were used to quantify the association of NAFLD with cancer risk at different ages. Results: Among 63 696 participants (mean [SD] age, 51.37 [12.43] years; ‭10 932 females [17.2%] and ‭52 764 males [82.8%]), 31 848 individuals had NAFLD and 31 848 individuals were in the control group. During a median (IQR) follow-up of 10.16 (7.89-11.67) years, 2415 patients were diagnosed with cancer. Compared with the matched group, patients aged less than 45 years at NAFLD onset exhibited a higher risk of cancer (average hazard ratio [AHR], 1.52; 95% CI, 1.09-2.12), and as the onset age of NAFLD increased, the cancer risk decreased (ages 45-54 years: AHR, 1.50; 95% CI, 1.15-1.97; ages 55-64 years: AHR, 1.13; 95% CI, 0.97-1.33; ages >65 years: AHR, 0.75; 95% CI, 0.45-1.27; P for interaction < .001). Among patients aged less than 45 years at NAFLD onset, cancers were mainly digestive system and lung cancers, with AHR values of 2.00 (95% CI, 1.08-3.47) and 2.14 (95% CI, 1.05-4.36), respectively. PAFs also showed that in patients aged less than 45 years at NAFLD onset, 17.83% (95% CI, 4.92%-29.86%) of cancer risk was attributable to NAFLD.‬‬‬‬. Conclusions and Relevance: This study found that NAFLD was associated with increased cancer risk and there was an interaction with onset age, such that the younger the onset age of NAFLD, the greater the cancer risk.

Development and applicability of modified weight loss grading system in cancer: a real-world cohort study.

BACKGROUND: The original weight loss grading system (WLGS) was developed in western population, which did not perform effectively in cancer patients from China. This study aimed to develop and validate the modified WLGS (mWLGS) in the prognostic assessment of cancer patients in China. METHODS: A prospective multicentre real-world cohort study involving 16 842 patients diagnosed with cancer was conducted. Cox regression was used to calculate the hazard ratios for overall survival. Logistic linear regression was used to assess the odds ratio for 90-day outcomes. RESULTS: We calculated survival risks for the 25 mWLGS groups and clustered the approximate survival risks. Finally, we revised the prognostic grading system for mWLGS to include five grades of 0-4. Compared with the original WLGS, the mWLGS had a better prognostic differentiation effect in predicting the prognosis of patients with cancer. The survival rate gradually deteriorated with increasing grade of mWLGS, with the survival rate of grade 0 decreasing from 76.4% to 48.2% for grade 4 (76.4 vs. 72.8 vs. 66.1 vs. 57.0 vs. 48.2%, respectively). The mWLGS provides effective prognostic stratification for most site-specific cancers, especially lung and gastrointestinal cancers. High-grade mWLGS is independently associated with an increased risk of poor quality of life and adverse 90-day outcomes. Multivariate Cox regression analysis showed that the mWLGS was an independent prognostic factor for cancer patients in the validation cohorts. CONCLUSIONS: Compared with the original WLGS, the mWLGS can better stratify the prognosis of cancer patients. mWLGS is a useful tool for predicting survival, 90-day outcomes, and quality of life in patients with cancer. These analyses may provide new insights into the application of WLGS in cancer patients in China.