A comparative analysis of risk factors in taxi-related crashes using XGBoost and SHAP.

Taxis play a crucial role in urban public transportation, but the traffic safety situation of taxi drivers is far from optimistic, especially considering the introduction of ride-hailing services into the taxi industry. This study conducted a comparative analysis of risk factors in crashes between traditional taxi drivers and ride-hailing taxi drivers in China, including their demographic characteristics, working conditions, and risky driving behaviors. The data was collected from 2,039 traditional taxi drivers and 2,182 ride-hailing taxi drivers via self-reported questionnaires. Four XGBoost models were established, taking into account different types of taxi drivers and crash types. All models showed acceptable performance, and SHAP explainer was used to analyze the model results. The results showed that for both taxi drivers, risk factors related to risky driving behaviors are more important in predicting property damage (PD) crashes, while risk factors related to working conditions are more important in predicting person injury (PI) crashes. However, the relative importance of each risk factor varied depending on the type of crashes and the type of taxi drivers involved. Furthermore, the results also validated certain interactions among the risk factors, indicating that the combination of certain factors generated a greater impact on crashes compared to individual factors alone. These findings can provide valuable insights for formulating appropriate measures to enhance road safety for taxi driver.

Assessing the dynamic resilience of Urban Rail Transit Networks during their evolution using a ridership-weighted network.

The assessment of the resilience of Urban Rail Transit Networks (URTNs) and the analysis of their evolutionary characteristics during network growth can help in the design of efficient, safe, and sustainable networks. However, there have been few studies regarding the change of resilience in long-term network development. As for the existing resilience studies, they rarely consider the entire cycle of accident occurrence and repair; furthermore, they ignore the changes in network transportation performance during emergencies. Moreover, the measurement metrics of the important nodes have not been comprehensively considered. Therefore, to remedy these deficiencies, this paper proposes a URTN dynamic resilience assessment model that integrates the entire cycle of incident occurrence and repair, and introduces the network transport effectiveness index E(Gw) to quantitatively assess the network resilience. In addition, a weighted comprehensive identification method of the important nodes (the WH method) is proposed. The application considers the Xi'an urban rail transit network (XURTN) during 2011-2021. The obtained results identify the resilience evolutionary characteristics during network growth. And longer peripheral lines negatively affect the resilience of XURTN during both the attack and the repair processes. The central city network improves the damage index Rdam and the recovery index Rrec by up to 123.46% and 11.65%, respectively, over the overall network. In addition, the WH method can comprehensively and accurately identify the important nodes in the network and their evolutionary characteristics. Compared to the single-factor and topological strategies, the Rdam is 1.17%~178.89% smaller and the Rrec is 1.68%~84.81% larger under the WH strategy. Therefore, this method improves the accuracy of the important node identification. Overall, the insights from this study can provide practical and scientific references for the synergistic development of URTN and urban space, the enhancement of network resilience, and the protection and restoration of important nodes.

Gastrointestinal Talaromyces marneffei infection in a man with AIDS: A case report.

RATIONALE: Reports of intestinal Talaromyces marneffei infection have increased year by year, but those of gastric infection remain rare. Here, we report disseminated talaromycosis with gastric and intestinal ulcers in an AIDS patient who was treated by antifungal agents and a proton pump inhibitor and achieved a satisfactory outcome. PATIENT CONCERNS: A 49-year-old man developed a gastrointestinal illness with main abdominal distension, poor appetite and a positive HIV infection to our AIDS clinical treatment center. DIAGNOSES: Electronic gastrointestinal endoscopy showed that the patient had multiple ulcers in the gastric angle, gastric antrum and large intestine. Gastric Helicobacter pylori infection was ruled out by paraulcerative histopathological analysis and a C14 urea breath test. The diagnosis was confirmed by gastroenteroscopic biopsy and metagenomic next-generation sequencing of gastric ulcer tissue. INTERVENTIONS: Symptomatic and supportive treatments [a proton pump inhibitor and gastrointestinal motility promotion] were initiated. The patient was prescribed sequential antifungal therapy with amphotericin B (0.5 mg/kg·d, 2 weeks) and itraconazole (200 mg, q12h, 10 weeks), and then followed with itraconazole for long-term secondary prevention (200 mg, qd). OUTCOMES: The combined use of antifungal agents and a proton pump inhibitor improved the patient's condition, and he was discharged home 20 days later. He had no gastrointestinal symptom during 1 year of telephone-based follow-up. LESSONS: In endemic areas, clinicians should be alert to the possibility of Talaromyces marneffei infection presenting with gastric ulcers in patients with AIDS, after excluding Helicobacter pylori infection.

Downregulation of phosphoserine phosphatase potentiates tumor immune environments to enhance immune checkpoint blockade therapy.

BACKGROUND: Effects of immune checkpoint blockade (ICB) treatment in hepatocellular carcinoma (HCC) are limited. The current study explored the possibility of exploiting tumor metabolic switches to enhance HCC sensitivity to immune therapies. METHODS: Levels of one-carbon (1C) metabolism and the expression of phosphoserine phosphatase (PSPH), an upstream enzyme of 1C pathway, were evaluated in paired non-tumor and tumor tissues from HCC. Underlying mechanisms mediating the role of PSPH in regulating the infiltration of monocytes/macrophages and CD8+ T lymphocytes were studied through both in vitro and in vivo experiments. RESULTS: PSPH was significantly upregulated in tumor tissues of HCC and its levels were positively correlated with disease progression. PSPH knockdown inhibited tumor growth in immunocompetent mice, but not in those with macrophage or T lymphocyte deficiencies, indicating the pro-tumor effects of PSPH were dependent on both immune components. Mechanistically, PSPH facilitated monocytes/macrophages infiltration by inducing the production of C-C motif chemokine 2 (CCL2), while at the same time reduced CD8+ T lymphocytes recruitment through inhibiting the production of C-X-C Motif Chemokine 10 (CXCL10) in tumor necrosis factor alpha (TNF-α)-conditioned cancer cells. Glutathione and S-adenosyl-methionine were partially involved in regulating the production of CCL2 and CXCL10, respectively. shPSPH (short hairpin RNA) transfection of cancer cells enhanced tumor sensitivity to anti-programmed cell death protein 1 (PD-1) therapy in vivo, and interestingly, metformin could inhibit PSPH expression in cancer cells and mimic the effects of shPSPH in sensitizing tumors to anti-PD-1 treatment. CONCLUSIONS: By tilting the immune balance towards a tumor-friendly composition, PSPH might be useful both as a marker in stratifying patients for ICB therapy, and as an attractive therapeutic target in the treatment of human HCC.

Carbonic anhydrase XII mediates the survival and prometastatic functions of macrophages in human hepatocellular carcinoma.

Macrophages constitute a major immune component in tumor tissues, but how these cells adapt to and survive in the nutrient-depleted and lactic acid-induced acidic tumor microenvironments is not yet fully understood. Here, we found that levels of carbonic anhydrase XII (CA12) expression were significantly and selectively upregulated on macrophages in human hepatocellular carcinoma (HCC). Transient glycolytic activation of peritumoral monocytes induced sustained expression of CA12 on tumor-infiltrating macrophages via autocrine cytokines and HIF1α pathways. On the one hand, CA12 mediated the survival of macrophages in relatively acidic tumor microenvironments, while on the other hand, it induced macrophage production of large amounts of C-C motif chemokine ligand 8 (CCL8), which enhanced cancer cell epithelial-mesenchymal transition (EMT) and facilitated tumor metastasis. Consistently, the accumulation of CA12+ macrophages in tumor tissues was associated with increased tumor metastatic potential and reduced survival of patients with HCC. Selective targeting of tumor-infiltrating macrophages with a CA12 inhibitor reduced tumor growth in mice and was sufficient to synergistically enhance the therapeutic efficacy of immune-checkpoint blockade. We suggest that CA12 activity is a previously unappreciated mechanism regulating the accumulation and functions of macrophages in tumor microenvironments and therefore represents a selective vulnerability that could be exploited in future designs for antitumor immunotherapeutic strategies.

Injury severity analysis of two-vehicle crashes at unsignalized intersections using mixed logit models.

The severity of the two-vehicle crash is closely related to the characteristics of both the struck and striking vehicles. Ignoring vehicle roles may lead to biased results. Thus, this study used mixed logit models to determine the factors that influence injury severity in the two-vehicle crash, taking into account the vehicle characteristics of the different crash roles. The data used is collected from Pennsylvania Department of Transportation (PennDOT) Open Data Portal. First, the synthetic minority oversampling technique and nearest neighbors (SMOTE-ENN) strategy was selected to address the class imbalance problem of crash data. Then, two separated mixed logit models were developed for four- and three-legged unsignalized intersections. The results suggest that the type and movement of vehicles have significant effects on crash severity. For example, right-turn vehicles being struck can lead to more serious crashes than striking other vehicles. Large trucks striking other vehicles are found to increase crash severity, but being struck is found to decrease crash severity. Additionally, several factors were also identified to affect crash severity in both models and effective countermeasures suggestions were proposed to mitigate crash severity.Supplemental data for this article is available online at at .

Neutrophil extracellular traps induce tumor metastasis through dual effects on cancer and endothelial cells.

Neutrophils constitute a major component in human hepatocellular carcinoma (HCC) and can facilitate disease progression via poorly understood mechanisms. Here, we show that neutrophil extracellular traps (NETs) formation was increased in human HCC tumor tissues than in paired non-tumor liver tissues. Mechanism study revealed that tumor-induced metabolic switch toward glycolysis and pentose phosphate pathway in tumor infiltrating neutrophils promoted NETs formation in a reactive oxygen species dependent-manner. NETs subsequently induced the migration of cancer cells and down-regulation of tight junction molecules on adjacent endothelial cells, thus facilitating tumor intravasation and metastasis. Accordingly, NETs depletion could inhibit tumor metastasis in mice in vivo, and the infiltration levels of NETs-releasing neutrophils were negatively associated with patient survival and positively correlated with tumor metastasis potential of HCC patients. Our results unveiled a pro-metastatic role of NETs in the milieu of human HCC, and pointed to the importance of metabolic reprogramming in shaping their characteristics, thus providing an applicable efficient target for anti-cancer therapies.

Characteristics and Prognosis of Talaromyces marneffei Infection in HIV-positive Children in Southern China.

Knowledge about the clinical characteristics and prognostic factors of Talaromyces marneffei infection in children is limited, especially in HIV-positive children. We performed a retrospective study of all HIV-positive pediatric inpatients with T. marneffei infection in a tertiary hospital in Southern China between 2014 and 2019 and analyzed the related risk factors of poor prognosis using logistic regression. Overall, 28 cases were enrolled and the prevalence of talaromycosis in AIDS children was 15.3% (28/183). The median age of the onset was 8 years (range: 1-14 years). The typical manifestation of skin lesion with central umbilication was not common (21.4%). All the children had very low CD4+ cell counts (median 13.5 cells/µL, range: 3-137 cells/µL) on admission. 92.9% children were misdiagnosed and talaromycosis was only noted after positivity for HIV infection. 89.3% diagnoses of T. marneffei infections were based on positive blood cultures, with a long culture time (median 7 days, range from 3-14 days). The sensitivity of fungus 1,3-ß-D-glucan assay was 63.2%. Amphotericin B was superior to itraconazole in the induction antifungal therapy of talaromycosis in HIV-positive children. A six-month follow-up revealed a 28.6% mortality. Lower ratio of CD4+/CD8+ and amphotericin B treatment not over 7 days predicted poor prognosis. Our retrospective study provided an overview and update on the current knowledge of talaromycosis in HIV-positive children. Pediatricians in endemic areas should be aware of mycoses to prevent misdiagnosis. 1,3-ß-D-glucan assay did not show optimal sensitivity. Amphotericin B treatment over 7 days can improve poor prognosis.

The Effects of Hedgehog Signaling Pathway on the Proliferation and Apoptosis of Melanoma Cells.

BACKGROUND: Studies have found that the abnormality of the Hedgehog signaling pathway is related to the occurrence and development of a variety of tumors, but the effect of this signaling pathway on melanoma cells is still unclear. METHODS: This study aimed to discuss the effect of Hedgehog signaling pathway on the proliferation and apoptosis of human malignant melanoma A375 cells and explore its possible mechanism in the proliferation and apoptosis of melanoma cells. Different concentrations of Hedgehog signaling pathway inhibitor cyclopamine (5, 10, 20 and 40 µM) were used to treat human melanoma A375 cells for 24, 48, and 72 h, and set a blank control group (0 µM). Trypan blue cell counting method was used to detect cell viability. MTT method was used to detect the inhibition rate of cell proliferation. Transwell was used to detect cell invasion, and flow cytometry was used to detect cell apoptosis. RESULTS: Through the trypan blue cell counting method and MTT experiment, it was found that the Hedgehog signaling pathway inhibitor cyclopamine has an inhibitory effect on the proliferation and viability of melanoma A375 cells (P < 0.05), and the proliferation inhibitory effect is enhanced with prolonged action time in a dose- and time-dependent manner. Transwell experiment showed that compared with the blank control group, the invasion and migration ability of the treated melanoma A375 cells are significantly reduced, and the difference is statistically significant (P < 0.05). Cell apoptosis experiment showed that compared with the blank control group, the apoptosis rate of A375 cells is significantly higher after treated by 40 µM cyclopamine for 24 h, and the difference is statistically significant (P < 0.05). Gli1 and Bcl-2 protein are highly expressed in melanoma A375 cells, and their expressions show a downward trend (P < 0.05) after being treated by cyclopamine. CONCLUSION: Cyclopamine inhibits cell proliferation and induces cell apoptosis by downregulating Gli1. Hedgehog signaling pathway can be used as a new target for the treatment of malignant melanoma, and multiple measures can be used to inhibit the signaling pathway to achieve a therapeutic effect.

A comparative analysis of factors influencing the injury severity of daytime and nighttime crashes on a mountainous expressway in China.

This study focuses on analyzing the injury severity of crashes occurring at different times of the day and providing insights into crash prevention countermeasures. The data contained 1521 police-reported crashes that occurred on a mountainous expressway between 2012 and 2017, which were divided into two subsamples: the daytime crash sample and the nighttime crash sample. The statistical plausibility of developing separate models for the two subsamples was verified by the likelihood ratio test. Two random thresholds random parameters hierarchical ordered probit models were independently conducted to analyze the relationship between injury severity and risk factors. The results showed that the contributing factors to injury severity were different between the two subsamples. The three factors most likely to cause serious crashes during the daytime were 'not keep a safe distance', 'drunk driving' and 'adverse weather', while during the nighttime, these three factors were 'fatigued driving', 'adverse weather' and 'drunk driving'. The same factors can cause more serious consequences during the nighttime than that during the daytime. After fully identifying the contributing factors related to injury severity, and in particular distinguishing the features of daytime and nighttime crashes, some useful suggestions were proposed to mitigate crash injury severity.

Work-related factors, fatigue, risky behaviours and traffic accidents among taxi drivers: a comparative analysis among age groups.

The main purpose of this study was to investigate the effect of work-related factors, fatigue, risky behaviours on accident involvement among different age groups of taxi drivers in China. A total of 2391 taxi drivers were selected to complete a self-reported questionnaire about their demographic data and information on working conditions, fatigue, risky behaviours, as well as involvement in traffic accidents between 2014 and 2016. The drivers were divided into three categories according to their age. Then, a set of comparative analyses and three structural equation models were used to analyze the samples of specific age groups. The results indicated that taxi drivers in the younger group rest the least with the most dissatisfaction with income while those in the mid-age group worked the longest time and were charged the most management fee, but the older taxi drivers more frequently engaged in risky behaviours and traffic accidents. Furthermore, two mediating chain processes were confirmed (i.e. 'work-related factors - fatigue - accidents' and 'work-related factors - risky behaviours - accidents') across the three age groups. However, the causes of fatigue, risky behaviours and accidents in different age groups are not exactly the same. These findings suggest that the regulation of the taxi industry should be carefully improved. Incentive policy and education aimed at taxi drivers may also hold promise.

Therapeutic Effect of Berberine on Insomnia Rats by ErbB Signaling Pathway.

BACKGROUND Insomnia seriously affects people's health and quality of life. Short-term use of Western drugs may also be harmful. Traditional Chinese medicine has been widely used to treat diseases in world. Therefore, this paper aims to study the therapeutic effect of berberine based on the insomnious rat model. MATERIAL AND METHODS The insomnia rat model was established by intragastric administration of caffeine and parachlorophenylalanine (PCPA). Berberine and diazepam were used to treat the established insomnia rats. Then, the pathological changes of insomnia rats were detected. In addition, transcriptome sequencing and data analysis were carried out using rat hippocampus. The expression of key genes was verified by quantitative polymerase chain reaction and western blot. RESULTS After 7 days of intragastric administration of berberine, the body weight, memory, and sleep quality of insomnia rats were significantly improved. The key roles of Erbb4, Erbb2, Ar, and Grin2a in berberine treatment were identified. Through the analysis of biological functions and signaling pathways, berberine was shown to play a salutary role through nervous system development and ErbB signaling pathway. Gene-set enrichment analysis (GSEA) results showed that berberine treatment affected more metabolic pathways. Compared with diazepam, berberine can play a faster role, and also improve the overall health level of insomnia rats. CONCLUSIONS These results suggest that berberine can alleviate insomnia in rats through a neuroprotective effect and improved metabolic level. Berberine has great potential in treatment of insomnia and might have better clinical significance.

How does financial burden influence the crash rate among taxi drivers? A self-reported questionnaire study in China.

Objective: Taxis play an important role in the transportation system of China, but they have a relatively high accident rate. The current study discusses the driver's financial burden in the Chinese context and explores its correlation with working conditions, risky driving behavior, and other characteristics of taxi drivers who are involved in accidents.Method: A total of 2,391 taxi drivers from 29 companies in four Chinese cities were interviewed and then asked to complete a questionnaire concerning their socio-demographic characteristics, working conditions, risky driving behavior, and accident frequency during the previous two years. Given the increase in the management fee (measured in CNY) charged by taxi companies, the drivers were divided into three groups: the "less than 150" group, the" 150 to 180" group and the "over 180" group, where were named Group 1, Group 2 and Group 3, respectively. Finally, the zero-inflated Poisson model was used to investigate the factors that contributed to the accident rate for each group.Result: The significant factors that lead to accidents differed significantly for drivers with different levels of financial burden. First, most of the factors were weakly correlated with the crash rate among Group 1 drivers. Second, many factors related to working conditions and risky driving behavior were significant for drivers in Groups 2 and 3, while working hours and off-duty days were significant only for drivers in Group 3. Third, working hours were negatively correlated with accident rates for drivers in Group 3, and the drivers who suffered from the heaviest financial burden were most affected by fatigue and sleep problems.Conclusion: Financial burden is the root cause behind the propensity of taxi drivers to be involved in accidents. Taxi companies should find ways to reduce drivers' expenses, and new technologies, such as taxi-calling or location and navigation based on mobile applications, should be introduced into the traditional taxi industry.

Glycolytic activation of monocytes regulates the accumulation and function of neutrophils in human hepatocellular carcinoma.

BACKGROUND & AIMS: Neutrophils are one of the most abundant components in human hepatocellular carcinoma (HCC) and have been shown to play important roles in regulating disease progression. However, neutrophils are very short-lived cells in circulation, and mechanisms regulating their accumulation and functions in HCC are not yet fully understood. METHODS: Monocytes were purified from non-tumor or paired tumor tissues of patients with HCC, and their production of neutrophil-attracting chemokines was evaluated. Mechanisms regulating the expression of CXCL2/8 by tumor monocytes, and the role of tumor monocyte-derived chemokines and cytokines in modulating neutrophil accumulation and functions were studied with both ex vivo analyses and in vitro experiments. RESULTS: Monocyte-derived CXCL2 and CXCL8 were major factors in regulating the recruitment of neutrophils into tumor milieus. These chemokines, in addition to tumor-derived soluble factors, could inhibit apoptosis and sustain survival of neutrophils, thus leading to neutrophil accumulation in tumor tissues. Moreover, monocyte-derived TNF-α acted synergistically with tumor-derived soluble factors to induce the production of the pro-metastasis factor OSM by neutrophils. Further, the glycolytic switch in tumor-infiltrating monocytes mediated their production of CXCL2 and CXCL8 via the PFKFB3-NF-κB signaling pathway. Accordingly, levels of PFKFB3, CXCL2/CXCL8 production in monocytes and infiltration of OSM-producing neutrophils were positively correlated in human HCC tissues. CONCLUSIONS: Our results unveiled a previously unappreciated link between monocytes and neutrophils in human HCC, identifying possible targets that could be therapeutically exploited in the future. LAY SUMMARY: Neutrophils constitute a major but poorly understood component of human hepatocellular carcinoma (HCC). Herein, we unveil a novel mechanism by which metabolic switching in monocytes promotes the accumulation of neutrophils in the tumors of patients with HCC. Both monocyte-produced chemokines and signals from the tumor microenvironment promote the production of the pro-metastatic factor OSM by neutrophils. These data identify potential targets for immune-based anticancer therapies for HCC.

Sedative and Hypnotic Effects and Transcriptome Analysis of Polygala tenuifolia in Aged Insomnia Rats.

OBJECTIVE: To study the sedative and hypnotic effects and underlying mechanisms of Polygala tenuifolia (PT) on treating aged insomnia rats. METHODS: Sixty Sprague-Dawley male rats were divided into 6 groups by a random number table, including control group, model group, diazepam group (0.92 mg/kg), as well as PT low-, medium- and high-dose groups (0.0875, 0.175, 0.35 g/kg, respectively), 10 rats in each group. Aged insomnia rat model was established with subcutaneous injection of D-galactose for 42 days and then intraperitoneal injection of para-chlorophenylalanine for 3 days. PT and diazepam were respectively given to aged insomnia rats by intragastric administration for 7 days after model establishment. Then the rats were investigated by body weight, Morris water maze test, pentobarbital test, enzyme-linked immunosorbent assay, and transcriptome sequencing. RESULTS: Compared with the model group, PT increased the body weight, improved memory ability, and prolonged pentobarbital-induced sleep time of aged insomnia rats (P<0.01 or P<0.05). The medium dose of PT also increased the neurotransmitter levels of 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA), and decreased the level of Glu in the hippocampus of aged insomnia rats (P<0.05 or P<0.01). Twenty-four differentially expressed genes (DEGs) were overlapped among model group, medium-dose PT group, and diazepam group in transcriptome analysis. Fuom and Pcp2 were down-regulated by the treatment of medium-dose PT (P<0.01 or P<0.05). The metabolic pathways of PT were relatively less than diazepam (91 vs. 104). CONCLUSIONS: The sedative and hypnotic effects of PT in aged insomnia rats might be related to neuro, metabolism pathways, especially through GABAergic signaling pathway. It provided more effective herb choice for the treatment of senile insomnia.

Niacin Protects against Butyrate-Induced Apoptosis in Rumen Epithelial Cells.

The effects and underlying mechanisms of butyrate and butyrate+niacin on apoptosis in sheep rumen epithelial cells were investigated. Cells were exposed to butyrate (0-140 mM) for 6 h. A low concentration (20 mM) of butyrate increased cell viability and promoted growth whereas high concentrations (40-140 mM) inhibited proliferation. Cells were then cocultured with 120 mM butyrate and niacin (0-100 mM) for 6 h. Niacin addition attenuated butyrate-induced cellular damage and promoted proliferation at 20-80 mM; 40 mM presented the optimal effect. Higher concentrations (100 mM) of niacin resulted in low cell viability. Subsequent experiments confirmed that 120 mM butyrate increased intracellular reactive oxygen species (ROS) production and reduced the intracellular total antioxidant capacity (T-AOC) versus the untreated control. Compared with 120 mM butyrate, cotreatment with 40 mM niacin significantly reduced the intracellular ROS content and increased the intracellular T-AOC. Flow cytometry analysis revealed that 120 mM butyrate increased the proportion of apoptotic cells by 17.8% versus the untreated control, and 120 mM butyrate+40 mM niacin treatment reduced the proportion of apoptotic cells by 28.6% and 39.4% versus the untreated control and butyrate treatment, respectively. Treatment with 120 mM butyrate increased caspase-9 and p53 mRNA levels and decreased the expression of Bcl-2 and Bax, and the Bcl-2/Bax ratio versus the untreated control. Treatment with 120 mM butyrate+40 mM niacin downregulated the expression of caspase-3 and p53 and increased the expression of Bcl-2 and Bax versus butyrate treatment alone but had no effect on the Bcl-2/Bax ratio. Thus, high concentrations of butyrate may induce rumen epithelial cell apoptosis by increasing oxidative stress and inducing caspase-9 and p53 expression. Cotreatment with niacin regulates apoptosis-related gene expression by reducing intracellular ROS production and DNA damage and downregulating caspase-3 and p53 expressions to protect rumen epithelial cells against butyrate-induced apoptosis.

Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3-PD-L1 axis in human hepatocellular carcinoma.

BACKGROUND & AIMS: Programmed cell death 1 ligand 1 (PD-L1) expression on antigen-presenting cells is essential for T cell impairment, and PD-L1-expressing macrophages may mechanistically shape and therapeutically predict the clinical efficacy of PD-L1 or programmed cell death 1 blockade. We aimed to elucidate the mechanisms underlying PD-L1 upregulation in human tumor microenvironments, which remain poorly understood despite the clinical success of immune checkpoint inhibitors. METHODS: Monocytes/macrophages were purified from peripheral blood, non-tumor, or paired tumor tissues of patients with hepatocellular carcinoma (HCC), and their possible glycolytic switch was evaluated. The underlying regulatory mechanisms and clinical significance of metabolic switching were studied with both ex vivo analyses and in vitro experiments. RESULTS: We found that monocytes significantly enhanced the levels of glycolysis at the peritumoral region of human HCC. The activation of glycolysis induced PD-L1 expression on these cells and subsequently attenuated cytotoxic T lymphocyte responses in tumor tissues. Mechanistically, tumor-derived soluble factors, including hyaluronan fragments, induced the upregulation of a key glycolytic enzyme, PFKFB3, in tumor-associated monocytes. This enzyme not only modulated the cellular metabolic switch but also mediated the increased expression of PD-L1 by activating the nuclear factor kappa B signaling pathway in these cells. Consistently, the levels of PFKFB3+CD68+ cell infiltration in peritumoral tissues were negatively correlated with overall survival and could serve as an independent prognostic factor for survival in patients with HCC. CONCLUSIONS: Our results reveal a mechanism by which the cellular metabolic switch regulates the pro-tumor functions of monocytes in a specific human tumor microenvironment. PFKFB3 in both cancer cells and tumor-associated monocytes is a potential therapeutic target in human HCC. LAY SUMMARY: Programmed cell death 1 ligand 1 (PD-L1) expressed on antigen-presenting cells, rather than tumor cells, has been reported to play an essential role in checkpoint blockade therapy. A fundamental understanding of mechanisms that regulate the expression of PD-L1 on tumor-infiltrating monocytes/macrophages will undoubtedly lead to the possibility of developing novel PD-L1 blockade strategies with high specificity and efficiency. The current study unveils a novel mechanism by which metabolic switching links immune activation responses to immune tolerance in the tumor milieu, identifying potential targets for future immune-based anti-cancer therapies.