Unveiling the link between lactate metabolism and rheumatoid arthritis through integration of bioinformatics and machine learning.

Rheumatoid arthritis (RA) is a persistent autoimmune condition characterized by synovitis and joint damage. Recent findings suggest a potential link to abnormal lactate metabolism. This study aims to identify lactate metabolism-related genes (LMRGs) in RA and investigate their correlation with the molecular mechanisms of RA immunity. Data on the gene expression profiles of RA synovial tissue samples were acquired from the gene expression omnibus (GEO) database. The RA database was acquired by obtaining the common LMRDEGs, and selecting the gene collection through an SVM model. Conducting the functional enrichment analysis, followed by immuno-infiltration analysis and protein-protein interaction networks. The results revealed that as possible markers associated with lactate metabolism in RA, KCNN4 and SLC25A4 may be involved in regulating macrophage function in the immune response to RA, whereas GATA2 is involved in the immune mechanism of DC cells. In conclusion, this study utilized bioinformatics analysis and machine learning to identify biomarkers associated with lactate metabolism in RA and examined their relationship with immune cell infiltration. These findings offer novel perspectives on potential diagnostic and therapeutic targets for RA.

Development of a screening system of gene sets for estimating the time of early skeletal muscle injury based on second-generation sequencing technology.

The present study is aimed to address the challenge of wound age estimation in forensic science by identifying reliable genetic markers using low-cost and high-precision second-generation sequencing technology. A total of 54 Sprague-Dawley rats were randomly assigned to a control group or injury groups, with injury groups being further divided into time points (4 h, 8 h, 12 h, 16 h, 20 h, 24 h, 28 h, and 32 h after injury, n = 6) to establish rat skeletal muscle contusion models. Gene expression data were obtained using second-generation sequencing technology, and differential gene expression analysis, weighted gene co-expression network analysis (WGCNA) and time-dependent expression trend analysis were performed. A total of six sets of biomarkers were obtained: differentially expressed genes at adjacent time points (127 genes), co-expressed genes most associated with wound age (213 genes), hub genes exhibiting time-dependent expression (264 genes), and sets of transcription factors (TF) corresponding to the above sets of genes (74, 87, and 99 genes, respectively). Then, random forest (RF), support vector machine (SVM) and multilayer perceptron (MLP), were constructed for wound age estimation from the above gene sets. The results estimated by transcription factors were all superior to the corresponding hub genes, with the transcription factor group of WGCNA performed the best, with average accuracy rates of 96% for three models' internal testing, and 91.7% for the highest external validation. This study demonstrates the advantages of the indicator screening system based on second-generation sequencing technology and transcription factor level for wound age estimation.

[Spatial Constraints of Rectangular Hydrogel Microgrooves Regulate the Morphology and Arrangement of Human Umbilical Vein Endothelial Cells]. / çŸ©å½¢æ°´å‡èƒ¶å¾®å‡¹æ§½çš„ç©ºé—´çº¦æŸè°ƒæŽ§äººè„é™è„‰å† çš®ç»†èƒžçš„å½¢æ€å’ŒæŽ’åˆ—.

Objective: To construct microscale rectangular hydrogel grooves and to investigate the morphology and alignment of human umbilical vein endothelial cells (HUVECs) under spatial constraints. Vascular endothelial cell morphology and alignment are important factors in vascular development and the maintenance of homeostasis. Methods: A 4-arm polyethylene glycol-acrylate (PEG-acrylate) hydrogel was used to fabricate rectangular microgrooves of the widths of 60 µm, 100 µm, and 140 µm. The sizes and the fibronectin (FN) adhesion of these hydrogel microgrooves were measured. HUVECs were seeded onto the FN-coated microgrooves, while the flat surface without micropatterns was used as the control. After 48 hours of incubation, the morphology and orientation of the cells were examined. The cytoskeleton was labelled with phalloidine and the orientation of the cytoskeleton in the hydrogel microgrooves was observed by laser confocal microscopy. Results: The hydrogel microgrooves constructed exhibited uniform and well-defined morphology, a complete structure, and clear edges, with the width deviation being less than 3.5%. The depth differences between the hydrogel microgrooves of different widths were small and the FN adhesion is uniform, providing a micro-patterned growth interface for cells. In the control group, the cells were arranged haphazardly in random orientations and the cell orientation angle was (46.9±1.8)°. In contrast, the cell orientation angle in the hydrogel microgrooves was significantly reduced (P<0.001). However, the cell orientation angles increased with the increase in hydrogel microgroove width. For the 60 µm, 100 µm, and 140 µm hydrogel microgrooves, the cell orientation angles were (16.4±2.8)°, (24.5±3.2)°, and (30.3±3.5)°, respectively. Compared to that of the control group (35.7%), the number of cells with orientation angles <30° increased significantly in the hydrogel microgrooves of different widths (P<0.001). However, as the width of the hydrogel microgrooves increased, the number of cells with orientation angles <30° gradually decreased (79.9%, 62.3%, 54.7%, respectively), while the number of cells with orientation angles between 60°-90° increased (P<0.001). The cell bodies in the microgrooves were smaller and more rounded in shape. The cells were aligned along the direction of the microgrooves and corresponding changes occurred in the arrangement of the cell cytoskeleton. In the control group, cytoskeletal filaments were aligned in random directions, presenting an orientation angle of (45.5±3.7)°. Cytoskeletal filaments were distributed evenly within various orientation angles. However, in the 60 µm, 100 µm, and 140 µm hydrogel microgrooves, the orientation angles of the cytoskeletal filaments were significantly decreased, measuring (14.4±3.1)°, (24.7±3.5)°, and (31.9±3.3)°, respectively. The number of cytoskeletal filaments with orientation angles <30° significantly increased in hydrogel microgrooves of different widths (P<0.001). However, as the width of the hydrogel microgrooves increased, the number of cytoskeletal filaments with orientation angles <30° gradually decreased, while the number of cytoskeletal filaments with orientation angles between 60°-90° gradually increased (P<0.001). Conclusion: Hydrogel microgrooves can regulate the morphology and orientation of HUVECs and mimic to a certain extent the in vivo microenvironment of vascular endothelial cells, providing an experimental model that bears better resemblance to human physiology for the study of the unique physiological functions of vascular endothelial cells. Nonetheless, the molecular mechanism of spatial constraints on the morphology and the assembly of vascular endothelial cell needs to be further investigated.

Exploration of a hypoxia-immune-related microenvironment gene signature and prediction model for hepatitis C-induced early-stage fibrosis.

BACKGROUND: Liver fibrosis contributes to significant morbidity and mortality in Western nations, primarily attributed to chronic hepatitis C virus (HCV) infection. Hypoxia and immune status have been reported to be significantly correlated with the progression of liver fibrosis. The current research aimed to investigate the gene signature related to the hypoxia-immune-related microenvironment and identify potential targets for liver fibrosis. METHOD: Sequencing data obtained from GEO were employed to assess the hypoxia and immune status of the discovery set utilizing UMAP and ESTIMATE methods. The prognostic genes were screened utilizing the LASSO model. The infiltration level of 22 types of immune cells was quantified utilizing CIBERSORT, and a prognosis-predictive model was established based on the selected genes. The model was also verified using qRT-PCR with surgical resection samples and liver failure samples RNA-sequencing data. RESULTS: Elevated hypoxia and immune status were linked to an unfavorable prognosis in HCV-induced early-stage liver fibrosis. Increased plasma and resting NK cell infiltration were identified as a risk factor for liver fibrosis progression. Additionally, CYP1A2, CBS, GSTZ1, FOXA1, WDR72 and UHMK1 were determined as hypoxia-immune-related protective genes. The combined model effectively predicted patient prognosis. Furthermore, the preliminary validation of clinical samples supported most of the conclusions drawn from this study. CONCLUSION: The prognosis-predictive model developed using six hypoxia-immune-related genes effectively predicts the prognosis and progression of liver fibrosis. The current study opens new avenues for the future prediction and treatment of liver fibrosis.

Correlation between second and first primary cancer: systematic review and meta-analysis of 9 million cancer patients.

BACKGROUND: Many survivors of a first primary cancer (FPCs) are at risk of developing a second primary cancer (SPC), with effects on patient prognosis. Primary cancers have different frequencies of specific SPC development and the development of SPCs may be closely related to the FPC. The aim of this study was to explore possible correlations between SPCs and FPCs. METHODS: Relevant literature on SPCs was retrospectively searched and screened from four databases, namely, PubMed, EMBASE, Web of Science, and PMC. Data on the number of patients with SPC in 28 different organ sites were also collected from The Surveillance, Epidemiology, and End Results (SEER) 8 Registry and NHANES database. RESULTS: A total of 9 617 643 patients with an FPC and 677 430 patients with an SPC were included in the meta-analysis. Patients with a first primary gynaecological cancer and thyroid cancer frequently developed a second primary breast cancer and colorectal cancer. Moreover, those with a first primary head and neck cancer, anal cancer and oesophageal cancer developed a second primary lung cancer more frequently. A second primary lung cancer and prostate cancer was also common among patients with first primary bladder cancer and penile cancer. Patients with second primary bladder cancer accounted for 56% of first primary ureteral cancer patients with SPCs. CONCLUSIONS: This study recommends close clinical follow-up, monitoring and appropriate interventions in patients with relevant FPCs for better screening and early diagnosis of SPCs.

Exploring the boost of steaming with wine on Ligustri Lucidi Fructus in treating postmenopausal osteoporosis based on superior "multi-component structure" and iron/bone metabolism coregulation.

BACKGROUND: Clinical studies indicated that postmenopausal osteoporosis (PMOP) often accompanied by iron overload risk factor, which exacerbated bone metabolism disorders and accelerated PMOP. Previous research found that multicomponent in Ligustri Lucidi Fructus (FLL) or wine-steamed FLL (WFLL) acted on the common targets of iron overload and PMOP simultaneously, which indicated that FLL and WFLL probably regulated iron/bone metabolism dually. Additionally, WFLL had more superior effect according to the theory of Chinese medicine for thousands of years. PURPOSE: To reveal the "superior multi-component structure (SMCS)" and its molecular mechanisms in parallelly down-regulating iron overload and rescuing bone metabolism by WFLL. DESIGNS AND METHODS: HPLC fingerprinting was established to compare the chemical profiles of FLL and WFLL; Then, the chemical compositions and quality markers of FLL and WFLL were analyzed by UPLC-Orbitrap-MS/MS coupled with OPLS-DA; the dynamic contents of quality markers and the multi-component structure at different wine steaming times (WST) were simultaneously determined by HPLC-DAD. Meanwhile, the dynamic efficacy of FLL at different WST were hunt by systematic zebrafish model. Subsequently, potential mechanism of WFLL in treating PMOP accompanied with iron overload was obtained from network pharmacology (NP) and molecular docking (MD). Finally, zebrafish and ovariectomy rat model were carried out to validate this potential mechanism. RESULTS: HPLC fingerprints similarity of 15 batches in FLL and WFLL were among 0.9-1.0. 126 compositions were identified, including 58 iridoids, 25 terpenes, 30 phenylethanoids, 7 flavonoids and 6 others. 20 quality markers associated with WFLL was revealed, and the ratio of phenylethanols: Iridoids: Triterpenes (P/I/T) was converted from 1: 15: 4.5 to 1: 0.8: 0.9 during steaming (0 - 24 h) calculated by the quantification of 11 quality markers; the bone mineralization and motor performance of zebrafish larvae indicated that the optimum efficacy of WFLL at 12 h (p < 0.05) in which the SMCS of P/I/T was converted to 1: 4: 1.8. NP discovered that BMP-Smad pathway is one of the potential mechanisms of FLL in anti PMOP and then regulated bone formation and iron overload simultaneously. MD revealed that 17 active ingredients and 10 core targets genes could spontaneously bind with appropriate affinity. Rats model verified that FLL and WFLL significantly reversed PMOP, based on the improvement in bone formation indexes (ALP, OPG, OGN), iron metabolism indicators (hepcidin, ferritin), bone microstructure (BMD, BV/TV, Tb. Th, Tb. N); Moreover, WFLL significant enhanced reversal effect in anti-PMOP compared to FLL (p < 0.05). FLL and WFLL increased genes and proteins expression (Hep, BMP-6, p-Smad1/5, Smad4) related to BMP-Smad pathway compared with model group, and WFLL was more superior than FLL (p< 0.05). CONCLUSION: The SMCS of FLL was optimized by wine-steam, WFLL represented a dual effect in downregulating iron overload and promoting bone formation, and the BMP-Smad pathway is one of the potential molecular mechanisms.

Multisensory stimulation bundles on sleep and neurobehavioral development in the first year after birth in very preterm infants: a randomized crossover controlled study protocol.

BACKGROUND: Disrupted sleep is believed to contribute to short- and long-term neurodevelopmental problems in very preterm infants (VPIs). This study presents a protocol for an evaluator-blinded, randomized crossover trial. It aims to assess the sleep efficiency of hospitalized VPIs by providing multisensory stimulation bundles. Furthermore, it aims to observe the intervention impacts on sleep during hospitalization of the VPIs and their sleep and neurodevelopmental outcomes during the first year of post-discharge follow-up. METHODS: The study will be conducted in the neonatology department of a tertiary pediatric teaching hospital. All the eligible VPIs will undergo two types of care in random order: "standard care" (2 weeks) and "standard care plus multisensory stimulation bundles," each lasting 2 weeks. A generated list of random numbers will be used for case sequence allocation. Sleep outcomes will be evaluated using the Actiwatch-2 Actigraph. Moreover, the amplitude-integrated electroencephalography and the Griffiths Mental Development Scales will be used to measure the neurodevelopmental outcomes during hospitalization and in the first year of follow-up of the VPIs. DISCUSSION: The intervention protocol of this study differs from that of other traditional interventions by producing precise and consistent supportive stimulations, similar to maternal tactile, auditory, posture, and visual effects for hospitalized VPIs. This protocol could be an effective measure to facilitate sleep and early neurodevelopment of VPIs. The expected outcomes will help confirm the implementation and generalization of the multisensory stimulation bundles' care protocol in neonatology departments. We expect that the study will positively impact hospitalized VPIs, especially in their sleep and early neurodevelopmental outcomes. It will also provide a new perspective regarding parent and infant interaction strategies, particularly for newborn intensive care units that limit visits because of the global spread of COVID-19. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR 2200059099. Registered on 25 April 2022, https://www.chictr.org.cn/showproj.html?proj=166980 ; the Hospital Research Ethics Committee (approval number: SCMCIRB-K2021086-1, Version 01), approved on 21 January 2022.

Robot occupations affect the categorization border between human and robot faces.

The Uncanny Valley hypothesis implies that people perceive a subjective border between human and robot faces. The robot-human border refers to the level of human-like features that distinguishes humans from robots. However, whether people's perceived anthropomorphism and robot-human borders are consistent across different robot occupations remains to be explored. This study examined the robot-human border by analyzing the human photo proportion represented by the point of subjective equality in three image classification tasks. Stimulus images were generated by morphing a robot face photo and one each of four human photos in systematically changed proportions. Participants classified these morphed images in three different robot occupational conditions to explore the effect of changing robot jobs on the robot-human border. The results indicated that robot occupation and participant age and gender influenced people's perceived anthropomorphism of robots. These can be explained by the implicit link between robot job and appearance, especially in a stereotyped context. The study suggests that giving an expected appearance to a robot may reproduce and strengthen a stereotype that associates a certain appearance with a certain job.

[Research progress on vascularization of organoids].

Organoids are three-dimensional structures formed by self-organizing growth of cells in vitro, which own many structures and functions similar with those of corresponding in vivo organs. Although the organoid culture technologies are rapidly developed and the original cells are abundant, the organoid cultured by current technologies are rather different with the real organs, which limits their application. The major challenges of organoid cultures are the immature tissue structure and restricted growth, both of which are caused by poor functional vasculature. Therefore, how to develop the vascularization of organoids has become an urgent problem. We presently reviewed the progresses on the original cells of organoids and the current methods to develop organoids vascularization, which provide clues to solve the above-mentioned problems.

Prognosis after splenectomy plus pericardial devascularization vs transjugular intrahepatic portosystemic shunt for esophagogastric variceal bleeding.

BACKGROUND: Portal hypertension combined with esophagogastric variceal bleeding (EGVB) is a serious complication in patients with hepatitis B virus (HBV)-related cirrhosis in China. Splenectomy plus pericardial devascularization (SPD) and transjugular intrahepatic portosystemic shunt (TIPS) are effective treatments for EGVB. However, a comparison of the effectiveness and safety of those methods is lacking. AIM: To compare the prognosis after SPD vs TIPS for acute EGVB after failure of endoscopic therapy or secondary prophylaxis of variceal rebleeding (VRB) in patients with HBV-related cirrhosis combined with portal hypertension. METHODS: This retrospective cohort study included 318 patients with HBV-related cirrhosis and EGVB who underwent SPD or TIPS at West China Hospital of Sichuan University during 2009-2013. Propensity score-matched analysis (PSM), the Kaplan-Meier method, and multivariate Cox regression analysis were used to compare overall survival, VRB rate, liver function abnormality rate, and hepatocellular carcinoma (HCC) incidence between the two patient groups. RESULTS: The median age was 45.0 years (n = 318; 226 (71.1%) males). During a median follow-up duration of 43.0 mo, 18 (11.1%) and 33 (21.2%) patients died in the SPD and TIPS groups, respectively. After PSM, SPD was significantly associated with better overall survival (OS) (P = 0.01), lower rates of abnormal liver function (P < 0.001), and a lower incidence of HCC (P = 0.02) than TIPS. The VRB rate did not differ significantly between the two groups (P = 0.09). CONCLUSION: Compared with TIPS, SPD is associated with higher postoperative OS rates, lower rates of abnormal liver function and HCC, and better quality of survival as acute EGVB treatment after failed endoscopic therapy or as secondary prophylaxis of VRB in patients with HBV-related cirrhosis combined with portal hypertension. There is no significant between-group difference in VRB rates.

Mapping knowledge landscapes and emerging trends of the biomarkers in melanoma: a bibliometric analysis from 2004 to 2022.

Background: Melanoma is a skin tumor with a high mortality rate, and early diagnosis and effective treatment are the key to reduce its mortality rate. Therefore, more and more attention has been paid for biomarker identification for early diagnosis, prognosis prediction and prognosis evaluation of melanoma. However, there is still a lack of a report that comprehensively and objectively evaluates the research status of melanoma biomarkers. Therefore, this study aims to intuitively analyze the research status and trend of melanoma biomarkers through the methods of bibliometrics and knowledge graph. Objective: This study uses bibliometrics to analyze research in biomarkers in melanoma, summarize the field's history and current status of research, and predict future research directions. Method: Articles and Reviews related to melanoma biomarkers were retrieved by using Web of Science core collection subject search. Bibliometric analysis was performed in Excel 365, CiteSpace, VOSviewer and Bibliometrix (R-Tool of R-Studio). Result: A total of 5584 documents from 2004 to 2022 were included in the bibliometric analysis. The results show that the number of publications and the frequency of citations in this field are increasing year by year, and the frequency of citations has increased rapidly after 2018. The United States is the most productive and influential country in this field, with the largest number of publications and institutions with high citation frequency. Caroline Robert, F. Stephen Hodi, Suzanne L. Topalian and others are authoritative authors in this field, and The New England Journal of Medicine, Journal of Clinical Oncology and Clinical Cancer Research are the most authoritative journals in this field. Biomarkers related to the diagnosis, treatment and prognosis of melanoma are hot topics and cutting-edge hotspots in this field. Conclusion: For the first time, this study used the bibliometric method to visualize the research in the field of melanoma biomarkers, revealing the trends and frontiers of melanoma biomarkers research, which provides a useful reference for scholars to find key research issues and partners.

Multi-scale representation attention based deep multiple instance learning for gigapixel whole slide image analysis.

Recently, convolutional neural networks (CNNs) directly using whole slide images (WSIs) for tumor diagnosis and analysis have attracted considerable attention, because they only utilize the slide-level label for model training without any additional annotations. However, it is still a challenging task to directly handle gigapixel WSIs, due to the billions of pixels and intra-variations in each WSI. To overcome this problem, in this paper, we propose a novel end-to-end interpretable deep MIL framework for WSI analysis, by using a two-branch deep neural network and a multi-scale representation attention mechanism to directly extract features from all patches of each WSI. Specifically, we first divide each WSI into bag-, patch- and cell-level images, and then assign the slide-level label to its corresponding bag-level images, so that WSI classification becomes a MIL problem. Additionally, we design a novel multi-scale representation attention mechanism, and embed it into a two-branch deep network to simultaneously mine the bag with a correct label, the significant patches and their cell-level information. Extensive experiments demonstrate the superior performance of the proposed framework over recent state-of-the-art methods, in term of classification accuracy and model interpretability. All source codes are released at: https://github.com/xhangchen/MRAN/.

The efficacy and safety of lenvatinib plus transarterial chemoembolization in combination with PD-1 antibody in treatment of unresectable recurrent hepatocellular carcinoma: a case series report.

Purpose: To explore the safety and efficacy of lenvatinib in combination with trans-arterial chemoembolization (TACE) and programmed death receptor 1 (PD-1) antibody in the treatment of unresectable recurrent hepatocellular carcinoma (urHCC). Patients and methods: The clinical data of 16 patients with unresectable recurrent hepatocellular carcinoma admitted to the Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, and received the conversion therapy of lenvatinib + TACE + PD-1 antibody between January 2019 and January 2022 were retrospectively analyzed. Results: There were 25% (4/16) patients suffering from grade 3 adverse events and no patients suffering from grade 4 or higher adverse events. After 4 months of treatment of 16 patients, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), two, five, three, and six cases were in complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), respectively, and the objective response rate (ORR) was 43.8% (7/16). The 1-year overall survival (OS) rate and 1-year progression-free survival (PFS) rate were 86.2% and 46.9%, respectively. In our subgroup analysis, the ORR of patients with multiple lesions reached up to 60%, which was higher than that of patients with single lesions. Conclusions: Lenvatinib in combination with TACE and PD-1 antibody is safe and effective in the treatment of unresectable recurrent hepatocellular carcinoma.

The cell origins of foam cell and lipid metabolism regulated by mechanical stress in atherosclerosis.

Atherosclerosis is an inflammatory disease initiated by endothelial activation, in which lipoprotein, cholesterol, extracellular matrix, and various types of immune and non-immune cells are accumulated and formed into plaques on the arterial wall suffering from disturbed flow, characterized by low and oscillating shear stress. Foam cells are a major cellular component in atherosclerotic plaques, which play an indispensable role in the occurrence, development and rupture of atherosclerotic plaques. It was previously believed that foam cells were derived from macrophages or smooth muscle cells, but recent studies have suggested that there are other sources of foam cells. Many studies have found that the distribution of atherosclerotic plaques is not random but distributed at the bend and bifurcation of the arterial tree. The development and rupture of atherosclerotic plaque are affected by mechanical stress. In this review, we reviewed the advances in foam cell formation in atherosclerosis and the regulation of atherosclerotic plaque and lipid metabolism by mechanical forces. These findings provide new clues for investigating the mechanisms of atherosclerotic plaque formation and progression.

Glutamine synthetase-negative hepatocellular carcinoma has better prognosis and response to sorafenib treatment after hepatectomy.

BACKGROUND: Glutamine synthetase (GS) and arginase 1 (Arg1) are widely used pathological markers that discriminate hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma; however, their clinical significance in HCC remains unclear. METHODS: We retrospectively analyzed 431 HCC patients: 251 received hepatectomy alone, and the other 180 received sorafenib as adjuvant treatment after hepatectomy. Expression of GS and Arg1 in tumor specimens was evaluated using immunostaining. mRNA sequencing and immunostaining to detect progenitor markers (cytokeratin 19 [CK19] and epithelial cell adhesion molecule [EpCAM]) and mutant TP53 were also conducted. RESULTS: Up to 72.4% (312/431) of HCC tumors were GS positive (GS+). Of the patients receiving hepatectomy alone, GS negative (GS-) patients had significantly better overall survival (OS) and recurrence-free survival (RFS) than GS+ patients; negative expression of Arg1, which is exclusively expressed in GS- hepatocytes in the healthy liver, had a negative effect on prognosis. Of the patients with a high risk of recurrence who received additional sorafenib treatment, GS- patients tended to have better RFS than GS+ patients, regardless of the expression status of Arg1. GS+ HCC tumors exhibit many features of the established proliferation molecular stratification subtype, including poor differentiation, high alpha-fetoprotein levels, increased progenitor tumor cells, TP53 mutation, and upregulation of multiple tumor-related signaling pathways. CONCLUSIONS: GS- HCC patients have a better prognosis and are more likely to benefit from sorafenib treatment after hepatectomy. Immunostaining of GS may provide a simple and applicable approach for HCC molecular stratification to predict prognosis and guide targeted therapy.

FOXA2 plays a critical role in hepatocellular carcinoma progression and lenvatinib-associated drug resistance.

Hepatic forkhead box protein A2 (FOXA2) is a crucial transcription factor for liver development and metabolic homeostasis. However, its role in hepatocellular carcinoma (HCC) progression and lenvatinib-related drug resistance remains unknown. In this study, the level of FOXA2 expression was found to be lower in HCC tissues than in paired adjacent tumor tissues. A low level of FOXA2 expression was associated with aggressive tumor characteristics (vascular invasion and poor differentiation). A low level of FOXA2 expression was found to be an independent risk factor for tumor recurrence (hazard ratio (HR): 1.899, P < 0.001) and long-term survival (HR: 2.011, P = 0.003) in HCC patients after hepatectomy. In xenograft animal models, FOXA2 overexpression significantly inhibited tumor growth. Moreover, FOXA2 overexpression was found to enhance the inhibitory effect of lenvatinib on HCC cells by upregulating the adenosine monophosphate-activated protein kinase-mechanistic target of rapamycin (AMPK-mTOR) pathway. Conversely, inhibition of adenosine monophosphate-activated protein kinase (AMPK) or stimulation of mechanistic target of rapamycin (mTOR) attenuated the sensitization of cells overexpressing FOXA2 to lenvatinib. Similarly, FOXA2 overexpression augmented the antitumor effect of lenvatinib in animal models with xenograft tumors. FOXA2 overexpression increased autophagy in HCC cells treated with lenvatinib. Lenvatinib treatment activated the platelet-derived growth factor receptor-extracellular regulated protein kinase (PDGFR-ERK) pathway in HCC. FOXA2 overexpression further downregulated the PDGFR-ERK pathway through the activation of the AMPK-mTOR axis. In conclusion, FOXA2 was identified as an independent risk factor for HCC after hepatectomy. FOXA2 was found to be closely associated with the biological progression of HCC. By modulating the AMPK-mTOR-autophagy signaling pathway, FOX2 significantly augmented antitumor effect of lenvatinib in HCC.

Prognostic nomograms for HBV-related BCLC 0-a stage hepatocellular carcinoma incorporating aspartate aminotransferase to albumin ratio.

BACKGROUND: Curative hepatectomy is currently the first-line treatment for hepatocellular carcinoma (HCC), but the prognosis is still not optimistic. The prediction model for prognosis of hepatitis B virus (HBV)-related BCLC 0-A stage HCC has not been well established. Therefore, we aimed to develop new nomograms to predict recurrence and survival in these patients. METHODS: A total of 982 patients with HBV-related BCLC 0-A stage HCC who underwent curative hepatectomy at West China Hospital from February 2007 to February 2016 were retrospectively collected and randomly allocated to a training set and a validation set in a ratio of 4:1. Prognostic nomograms using data from the training set were developed using a Cox regression model and validated on the validation set. RESULTS: We constructed nomograms based on independent factors for recurrence-free survival (RFS) (tumor size, satellite, microvascular invasion, capsular invasion, differentiation and aspartate aminotransferase to albumin ratio (ASAR)) and overall survival (OS) (gender, tumor size, satellite, microvascular invasion, differentiation, lymphocyte count, and ASAR). Compared with conventional HCC staging systems and other nomograms reported by previous literature, our ASAR integrated nomograms predicted RFS and OS with the highest C-indexes (0.682 (95%CI: 0.646-0.709), 0.729 (95%CI: 0.691-0.766), respectively) and had well-fitted calibration curves in the training set. Concurrently, the nomograms also obtained consistent results in the validation set. DCA revealed that our nomograms provided the largest clinical net benefits. CONCLUSION: We first constructed ASAR integrated nomograms to predict the prognosis of HBV-related BCLC 0-A stage HCC patients after curative hepatectomy with good performance.

How seasonality affects the environmental performance of fresh appetite: Insights from cherry consumption in China.

Urbanization and globalization are changing the conventional constraints of seasonality and geography on food consumption, such as that of fresh cherries. The rising demand for year-round cherry consumption in China is currently satisfied by open-field, greenhouse-produced, and imported products. This study conducted a spatial-temporal life cycle evaluation of the environmental performance of cherry consumption behaviors during different seasons of the year. Moreover, based on the definitions of global and local seasonality, the additional environmental costs of out-of-season cherry consumption were estimated. Results show that seasonality was an important factor affecting the environmental burdens of cherry consumption. Eating cherries imported from Chile by air in October resulted in the highest greenhouse gas (GHG) emissions of 6.38 kg CO2-eq/kg, while eating domestic open-field cherries during May to July (the natural harvest season) was a relatively environmentally beneficial option. The total cherry consumption in China in 2019 generated GHG emissions of 126.99 × 104 t CO2-eq. Under the definitions of global and local seasonality, the out-of-season consumption led to additional environmental costs of 57.59 × 104 and 85.67 × 104 t CO2-eq, accounting for 45.35% and 67.46% of total emissions, respectively. Furthermore, the time-environment trade-off effect of cherry consumption illustrates the higher environmental costs are exchanged for satisfying the appetite for out-of-season fresh foods. Our findings emphasize the meaningful implications for developing a sustainable consumption pattern for all stakeholders involved in the entire food chain.