Targeted metabolomics study of fatty-acid metabolism in lean metabolic-associated fatty liver disease patients.

BACKGROUND: The annual incidence of metabolic-associated fatty liver disease (MAFLD) in China has been increasing and is often overlooked owing to its insidious characteristics. Approximately 50% of the patients have a normal weight or are not obese. They are said to have lean-type MAFLD, and few studies of such patients are available. Because MAFLD is associated with abnormal lipid metabolism, lipid-targeted metabolomics was used in this study to provide experimental evidence for early diagnosis and pathogenesis. AIM: To investigate the serum fatty-acid metabolic characteristics in lean-type MAFLD patients using targeted serum metabolomic technology. METHODS: Between January and June 2022, serum samples were collected from MAFLD patients and healthy individuals who were treated at Shanghai Putuo District Central Hospital for serum metabolomics analysis. Principal component analysis and orthogonal partial least squares-discriminant analysis models were developed, and univariate analysis was used to screen for biomarkers of lean-type MAFLD and analyze metabolic pathways. UPLC-Q-Orbitrap/MS content determination was used to determine serum palmitic acid (PA), oleic acid (OA), linoleic acid (LA), and arachidonic acid (AA) levels in lean-type MAFLD patients. RESULTS: Urea nitrogen and uric acid levels were higher in lean-type MAFLD patients than in healthy individuals (P < 0.05). Alanine transaminase and cholinesterase levels were higher in lean-type MAFLD patients than in healthy individuals (P < 0.01). The expression of high-density lipoprotein and apolipoprotein A-1 were lower in lean-type MAFLD patients than in healthy individuals (P < 0.05) and the expression of triglycerides and fasting blood glucose were increased (P < 0.01). A total of 65 biomarkers that affected the synthesis and metabolism of fatty acids were found with P < 0.05 and variable importance in projection > 1". The levels of PA, OA, LA, and AA were significantly increased compared with healthy individuals. CONCLUSION: The metabolic profiles of lean-type MAFLD patients and healthy participants differed significantly, yielding 65 identified biomarkers. PA, OA, LA, and AA exhibited the most significant changes, offering valuable clinical guidance for prevention and treatment of lean-type MAFLD.

Influencing factors and risk prediction model for emergence agitation after general anesthesia for primary liver cancer.

BACKGROUND: General anesthesia is commonly used in the surgical management of gastrointestinal tumors; however, it can lead to emergence agitation (EA). EA is a common complication associated with general anesthesia, often characterized by behaviors, such as crying, struggling, and involuntary limb movements in patients. If treatment is delayed, there is a risk of incision cracking and bleeding, which can significantly affect surgical outcomes. Therefore, having a proper understanding of the factors influencing the occurrence of EA and implementing early preventive measures may reduce the incidence of agitation during the recovery phase from general anesthesia, which is beneficial for improving patient prognosis. AIM: To analyze influencing factors and develop a risk prediction model for EA occurrence following general anesthesia for primary liver cancer. METHODS: Retrospective analysis of clinical data from 200 patients who underwent hepatoma resection under general anesthesia at Wenzhou Central Hospital (January 2020 to December 2023) was conducted. Post-surgery, the Richmond Agitation-Sedation Scale was used to evaluate EA presence, noting EA incidence after general anesthesia. Patients were categorized by EA presence postoperatively, and the influencing factors were analyzed using logistic regression. A nomogram-based risk prediction model was constructed and evaluated for differentiation and fit using receiver operating characteristics and calibration curves. RESULTS: EA occurred in 51 (25.5%) patients. Multivariate analysis identified advanced age, American Society of Anesthesiologists (ASA) grade III, indwelling catheter use, and postoperative pain as risk factors for EA (P < 0.05). Conversely, postoperative analgesia was a protective factor against EA (P < 0.05). The area under the curve of the nomogram was 0.972 [95% confidence interval (CI): 0.947-0.997] for the training set and 0.979 (95%CI: 0.951-1.000) for the test set. Hosmer-Lemeshow test showed a good fit (χ 2 = 5.483, P = 0.705), and calibration curves showed agreement between predicted and actual EA incidence. CONCLUSION: Age, ASA grade, catheter use, postoperative pain, and analgesia significantly influence EA occurrence. A nomogram constructed using these factors demonstrates strong predictive accuracy.

Current Role and Future Perspectives of Cardiac Rehabilitation in Heart Disease.

As a comprehensive secondary prevention program, cardiac rehabilitation (CR) is a beneficial and cost-effective intervention for patients with heart disease, but the participation rate of patients in CR is low globally. In recent years, due to the COVID-19 pandemic and scientific and technological advances, an increasing number of alternative CR modes have been developed, such as remote CR, home-based CR, hybrid CR and virtual CR. These alternative CR modes represent changes and new opportunities for patients with heart disease. In this review, we will discuss in detail the impact of CR on patients with different types of heart disease, review the various alternative CR models, and explore some prospects for the future of CR in the field of heart disease.

Clinical efficacy of EUS-guided celiac plexus neurolysis versus EUS-guided celiac ganglion irradiation with iodine-125 seeds for pain relief in advanced pancreatic cancer: A long-term retrospective study.

Background and Objective: To compare the efficacy of EUS-guided celiac plexus neurolysis (CPN) and celiac plexus irradiation with iodine-125 (125I) seeds with absolute ethanol for relieving pain in patients with advanced pancreatic cancer. Methods: We retrospectively analyzed data of 81 patients with advanced pancreatic cancer who underwent EUS-CPN or EUS-125I implantation between January 2017 and December 2020. Postoperative pain was assessed using visual analog scale (VAS) scores; self-assessments of quality of life and the median survival time were compared between the 2 groups. Results: EUS-CPN and 125I implantation were performed in 43 and 38 patients, respectively. Postoperative VAS scores were significantly lower than the preoperative levels in both groups. One week after the operation, 26 patients (60.5%) in the EUS-CPN group achieved partial pain relief, whereas no patients in the EUS-125I seed group experienced pain relief. However, after 4 weeks postoperatively, VAS scores had decreased, and the rate of partial pain relief was higher for EUS-125I seeds than for EUS-CPN. Self-assessments of quality of life were similar in both groups during the first 1 month after the procedure. Conclusions: Both EUS-CPN and EUS-125I seeds can safely and effectively relieve pain in patients with advanced pancreatic cancer. Although EUS-125I seeds take additional time to show effects, the extent and duration of pain relief are better compared with CPN, and interestingly, the median survival time was different.

Ovarian function in patients with systemic lupus erythematosus: Pathogenesis, drug application and prospective therapies.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which multiple organs are damaged that prevails in fertile women. Currently, glucocorticoids and immunosuppressants are widely used to treat SLE patients. However, ovarian dysfunction occurs following the use of these drugs in women with SLE. Here, we summarize recent progress in terms of understanding ovarian injury, the effects of drug application and strategies to improve ovarian function in women with SLE. This review could be helpful to precisely cure SLE in women desiring to have offspring.

Mind the gap in kidney care: Translating what we know into what we do.

Historically, it takes an average of 17 years to move new treatments from clinical evidence to daily practice. Given the highly effective treatments now available to prevent or delay kidney disease onset and progression, this is far too long. The time is now to narrow the gap between what we know and what we do. Clear guidelines exist for the prevention and management of common risk factors for kidney disease, such as hypertension and diabetes, but only a fraction of people with these conditions worldwide are diagnosed, and even fewer are treated to target. Similarly, the vast majority of people living with kidney disease are unaware of their condition because in the early stages, it is often silent. Even among patients who have been diagnosed, many do not receive appropriate treatment for kidney disease. Considering the serious consequences of kidney disease progression, kidney failure, or death, it is imperative that treatments are initiated early and appropriately. Opportunities to diagnose and treat kidney disease early must be maximized beginning at the primary care level. Many systematic barriers exist, ranging from patient to clinician to health systems to societal factors. To preserve and improve kidney health for everyone everywhere, each of these barriers must be acknowledged so that sustainable solutions are developed and implemented without further delay.

Fatigue and physical activity in post-CABG patients: the parallel mediation model of kinesiophobia and self-efficacy : a prospective multicentre and cross-sectional study in China.

OBJECTIVES: The objective of this study was to investigate how kinesiophobia and self-efficacy explain the relationship between fatigue and physical activity (PA) in post-coronary artery bypass grafting (post-CABG) patients over the age of 45. DESIGN: A prospective multicentre and cross-sectional study. SETTING: The study was conducted in four public tertiary hospitals in China. PARTICIPANTS: A total of 1278 patients who underwent CABG surgery were selected from the case pool, with their surgeries occurring between 3 and 19 months prior to selection. Out of 1038 patients who met the inclusion criteria and were invited to participate in the study, 759 patients agreed to participate and complete the questionnaire. Ultimately, 376 questionnaires were deemed eligible and included in the analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: The questionnaire included the following scales: the Chinese version of the Multidimensional Fatigue Inventory (MFI-20), the Tampa Scale for Kinesiophobia Heart (TSK-SV Heart), the Cardiac Exercise Self-Efficacy Instrument (CESEI) and the International Physical Activity Questionnaire-Long (IPAQ-L). A serial mediation model was used to test whether the association between fatigue and PA was mediated by kinesiophobia and self-efficacy, in the overall sample and subsamples defined by age. RESULTS: The results confirmed that fatigue was directly (95% CI (-5.73 to -3.02)) associated with PA. Higher kinesiophobia (95% CI (-0.16 to -0.05)) or lower PA self-efficacy (95% CI (-0.11 to -0.02)) were parallel pathways through which higher fatigue impediment reduced PA levels. In both subgroups, the street pathways of kinesiophobia and self-efficacy were altered. In the age, 45-60 years group, kinesiophobia (Boot 95% CI (-0.19 to-0.05)) was a mediator of fatigue on PA levels, while in the 61-75 years age group, self-efficacy (Boot 95% CI (-0.17 to -0.04)) was a mediator of fatigue on PA levels. CONCLUSIONS: A clear relationship between fatigue and PA was mediated by both kinesiophobia and self-efficacy. Furthermore, our findings highlight the importance of adapting the intervention according to the age of the patients, mainly by reducing patients' kinesiophobia in patients aged 45-60 years and increasing patients' self-efficacy in patients aged 61-75 years. It may be possible to improve PA levels in post-CABG patients over 45 years of age by eliminating kinesiophobia and increasing self-efficacy.

Short-term skin reactions and changes in stratum corneum following different ways of facial sheet mask usage.

BACKGROUND: The global facial mask market grows steadily at 8.5 % annually. However, prolonged use may lead to skin inflammation. OBJECTIVE: To investigate how various mask types and wearing durations impact skin physiology and aquaporins3 (AQP3) expression in healthy subjects. METHODS: We used a randomized controlled design to investigate the effects of three types of facial masks (pure water, hyaluronan, and bifida ferment lysate) and four different duration(5, 15, 25, and 40 min) on various skin parameters in volunteers, assessing moisture content, transepidermal water loss (TEWL), sebum, corneocyte size, and AQP3 expression before and after mask application, while also evaluating adverse reactions, discomfort, and noncompliance. RESULT: Hydration and TEWL increased at first, then decreased. Sebum increased with all types of masks, particularly after 40 min. Vasodilation and AQP3 expression were linked to mask duration. Corneocyte sizes remained constant. The main adverse reactions were redness (10.71 %, n = 28) and dryness (57.14 %, n = 28), especially with pure water masks lasting over 25 min. CONCLUSION: Short-term use of facial sheet masks (<25 min) benefits skin with improved hydration, reduced redness, and AQP3 activation, while prolonged use can lead to increased dryness and redness.

Gastric Cancer Assembloids Derived from Patient-Derived Xenografts: A Preclinical Model for Therapeutic Drug Screening.

The construction of reliable preclinical models is crucial for understanding the molecular mechanisms involved in gastric cancer and for advancing precision medicine. Currently, existing in vitro tumor models often do not accurately replicate the human gastric cancer environment and are unsuitable for high-throughput therapeutic drug screening. In this study, droplet microfluidic technology is employed to create novel gastric cancer assembloids by encapsulating patient-derived xenograft gastric cancer cells and patient stromal cells in Gelatin methacryloyl (GelMA)-Gelatin-Matrigel microgels. The usage of GelMA-Gelatin-Matrigel composite hydrogel effectively alleviated cell aggregation and sedimentation during the assembly process, allowing for the handling of large volumes of cell-laden hydrogel and the uniform generation of assembloids in a high-throughput manner. Notably, the patient-derived xenograft assembloids exhibited high consistency with primary tumors at both transcriptomic and histological levels, and can be efficiently scaled up for preclinical drug screening efforts. Furthermore, the drug screening results clearly demonstrated that the in vitro assembloid model closely mirrored in vivo drug responses. Thus, these findings suggest that gastric cancer assembloids, which effectively replicate the in vivo tumor microenvironment, show promise for enabling more precise high-throughput drug screening and predicting the clinical outcomes of various drugs.

Patient Retention in a Substance Use Disorder Telemedicine Clinic.

OBJECTIVES: Although research has continued to show that substance use disorders (SUDs) can be treated effectively with evidence-based treatment, there continues to be gaps in access, and utilization remains low. Alternative SUD treatment methods, including telemedicine, are increasingly being explored to reach patients where traditional in-person treatment approaches are inaccessible. This cross-sectional study aimed to explore SUD treatment retention, specifically comparing telemedicine-delivered opioid use disorder (OUD) treatment with a traditional in-person treatment delivery approach. METHODS: Patients at Cahaba Medical Care, an FQHC in Birmingham, AL with a diagnosis of OUD and undergoing buprenorphine/naloxone or buprenorphine treatment were categorized into two groups: treatment and control. The dependent variable, retention to SUD treatment, was assessed at four different time periods over 12 months to determine patient SUD consultation appointment attendance. Multiple linear regression was used to examine the relationship between SUD treatment retention and delivery mode. Correlations were obtained to assess associations between frequency of urine drug screens performed and SUD treatment retention. RESULTS: As the number of the urine drug screens patients received increased by 1, the number of SUD treatment program consultations patients attended increased by 0.69 (P < 0.001). There was no significant difference in SUD treatment retention between traditional in-person and telemedicine delivered approaches, however. CONCLUSIONS: The findings of this study suggest that a telemedicine-delivered treatment program equals retention effectiveness when compared with in-person delivery. This suggests that leveraging telemedicine to treat patients with SUD could be an effective alternative for those unable to access treatment or who are less likely to attend or complete traditional in-person treatment sessions.

AI-based digital pathology provides newer insights into lifestyle intervention-induced fibrosis regression in MASLD: An exploratory study.

BACKGROUND AND AIMS: Lifestyle intervention is the mainstay of therapy for metabolic dysfunction-associated steatohepatitis (MASH), and liver fibrosis is a key consequence of MASH that predicts adverse clinical outcomes. The placebo response plays a pivotal role in the outcome of MASH clinical trials. Second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence analyses can provide an automated quantitative assessment of fibrosis features on a continuous scale called qFibrosis. In this exploratory study, we used this approach to gain insight into the effect of lifestyle intervention-induced fibrosis changes in MASH. METHODS: We examined unstained sections from paired liver biopsies (baseline and end-of-intervention) from MASH individuals who had received either routine lifestyle intervention (RLI) (n = 35) or strengthened lifestyle intervention (SLI) (n = 17). We quantified liver fibrosis with qFibrosis in the portal tract, periportal, transitional, pericentral, and central vein regions. RESULTS: About 20% (7/35) and 65% (11/17) of patients had fibrosis regression in the RLI and SLI groups, respectively. Liver fibrosis tended towards no change or regression after each lifestyle intervention, and this phenomenon was more prominent in the SLI group. SLI-induced liver fibrosis regression was concentrated in the periportal region. CONCLUSION: Using digital pathology, we could detect a more pronounced fibrosis regression with SLI, mainly in the periportal region. With changes in fibrosis area in the periportal region, we could differentiate RLI and SLI patients in the placebo group in the MASH clinical trial. Digital pathology provides new insight into lifestyle-induced fibrosis regression and placebo responses, which is not captured by conventional histological staging.

Fermentation biotechnology applied to wheat bran for the degradation of cell wall fiber and its potential health benefits: A review.

Consumption of wheat bran is associated with health benefits. However, the insoluble cell layer fiber and considerable levels of anti-nutritional factors limit bioavailability of wheat bran, which can be effectively improved through fermentation. To comprehensively elucidate the precise biotransformation and health benefits mechanisms underlying wheat bran fermentation. This review investigates current fermentation biotechnology for wheat bran, nutritional effects of fermented wheat bran, mechanisms by which fermented wheat bran induces health benefits, and the application of fermented wheat bran in food systems. The potential strategies to improve fermented wheat bran and existing limitations on its application are also covered. Current findings support that microorganisms produce enzymes that degrade the cell wall fiber of wheat bran during the fermentation, releasing nutrients and producing new active substances while degrading anti-nutrient factors in order to effectively improve nutrient bioavailability, enhance antioxidant activity, and regulate gut microbes for health effects. Fermentation has been an effective way to degrade cell wall fiber, thereby improving nutrition and quality of whole grain or bran-rich food products. Currently, there is a lack of standardization in fermentation and human intervention studies. In conclusion, understanding effects of fermentation on wheat bran should guide the development and application of bran-rich products.

Laboratory animal ethics education improves medical students' awareness of laboratory animal ethics.

OBJECTIVE: In this study, we added laboratory animal ethics education into both didactic sessions and practical sessions the general surgery laboratory course, with the didactic sessions focus on teaching the fundamental principles of laboratory animal ethics, while the practical sessions emphasize the application of these principles in laboratory classes and have assessed the changes in medical students' perception of laboratory animal ethics following medical students exposure to such education. METHODS: One hundred and eighty-nine third-year medical students from Wuhan University's Second Clinical College completed a laboratory animal ethics awareness questionnaire and a laboratory animal ethics written examination before and after laboratory animal ethics education. RESULTS: After receiving laboratory animal ethics education, the percentage of students who supported euthanasia for the execution of animals and humane treatment of laboratory animals were 95.2% and 98.8%, respectively, which did not differ from the 94.9% and 96.4% observed before the education. Moreover, there was a notable increase in the proportion of students who knew about regulations related to laboratory animals (from 39.9% to 57.1%), welfare issues (from 31.9% to 50.0%), and the 3R principle (from 30.4% to 58.9%) post-education, all statistically significant at P < 0.05. Test scores also showed improvement, with students scoring (93.02 ± 11.65) after education compared to (67.83 ± 8.08) before, a statistically significant difference. CONCLUSIONS: This research helps to provide information for the good practices of laboratory animal ethics education. After receiving laboratory animal ethics education, students are better able to treat laboratory animals in a correct animal ethical manner. Laboratory animal ethics education helps improve students' knowledge of laboratory animal ethics. Students' perception towards how the laboratory animal ethics course should be delivered may vary. Still, new courses or better organized courses on laboratory animal ethics education are required in order to provide students an in-depth understanding.

Tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for hepatocellular carcinoma: recent research progress.

Hepatocellular carcinoma (HCC) is one of the cancers that seriously threaten human health. Immunotherapy serves as the mainstay of treatment for HCC patients by targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis. However, the effectiveness of anti-PD-1/PD-L1 treatment is limited when HCC becomes drug-resistant. Tumor-associated macrophages (TAMs) are an important factor in the negative regulation of PD-1 antibody targeted therapy in the tumor microenvironment (TME). Therefore, as an emerging direction in cancer immunotherapy research for the treatment of HCC, it is crucial to elucidate the correlations and mechanisms between TAMs and PD-1/PD-L1-mediated immune tolerance. This paper summarizes the effects of TAMs on the pathogenesis and progression of HCC and their impact on HCC anti-PD-1/PD-L1 immunotherapy, and further explores current potential therapeutic strategies that target TAMs in HCC, including eliminating TAMs in the TME, inhibiting TAMs recruitment to tumors and functionally repolarizing M2-TAMs (tumor-supportive) to M1-TAMs (antitumor type).

A pretreatment-free and eco-friendly rapid detection for mycotoxins in edible oils based on magnetic separation technique.

Pretreatment steps of current rapid detection methods for mycotoxins in edible oils not only restrict detection efficiency, but also produce organic waste liquid to pollute environment. In this work, a pretreatment-free and eco-friendly rapid detection method for edible oil is established. This proposed method does not require pretreatment operation, and automated quantitative detection could be achieved by directly adding oil samples. According to polarity of target molecules, the content of surfactant in reaction solutions could be adjusted to achieve the quantitative detection of AFB1 in peanut oil and ZEN in corn oil. The recoveries are between 96.5%-110.7% with standard deviation <10.4%, and the limit of detection is 0.17 µg/kg for AFB1 and 4.91 µg/kg for ZEN. This method realizes full automation of the whole chain detection, i.e. sample in-result out, and is suitable for the on-site detection of batches of edible oils samples.

Noradrenergic tuning of arousal is coupled to coordinated movements.

Matching arousal level to the motor activity of an animal is important for efficiently allocating cognitive resources and metabolic supply in response to behavioral demands, but how the brain coordinates changes in arousal and wakefulness in response to motor activity remains an unclear phenomenon. We hypothesized that the locus coeruleus (LC), as the primary source of cortical norepinephrine (NE) and promoter of cortical and sympathetic arousal, is well-positioned to mediate movement-arousal coupling. Here, using a combination of physiological recordings, fiber photometry, optogenetics, and behavioral tracking, we show that the LCNE activation is tightly coupled to the return of organized movements during waking from an anesthetized state. Moreover, in an awake animal, movement initiations are coupled to LCNE activation, while movement arrests, to LCNE deactivation. We also report that LCNE activity covaries with the depth of anesthesia and that LCNE photoactivation leads to sympathetic activation, consistent with its role in mediating increased arousal. Together, these studies reveal a more nuanced, modulatory role that LCNE plays in coordinating movement and arousal.

Epigenetic control of skeletal muscle atrophy.

Skeletal muscular atrophy is a complex disease involving a large number of gene expression regulatory networks and various biological processes. Despite extensive research on this topic, its underlying mechanisms remain elusive, and effective therapeutic approaches are yet to be established. Recent studies have shown that epigenetics play an important role in regulating skeletal muscle atrophy, influencing the expression of numerous genes associated with this condition through the addition or removal of certain chemical modifications at the molecular level. This review article comprehensively summarizes the different types of modifications to DNA, histones, RNA, and their known regulators. We also discuss how epigenetic modifications change during the process of skeletal muscle atrophy, the molecular mechanisms by which epigenetic regulatory proteins control skeletal muscle atrophy, and assess their translational potential. The role of epigenetics on muscle stem cells is also highlighted. In addition, we propose that alternative splicing interacts with epigenetic mechanisms to regulate skeletal muscle mass, offering a novel perspective that enhances our understanding of epigenetic inheritance's role and the regulatory network governing skeletal muscle atrophy. Collectively, advancements in the understanding of epigenetic mechanisms provide invaluable insights into the study of skeletal muscle atrophy. Moreover, this knowledge paves the way for identifying new avenues for the development of more effective therapeutic strategies and pharmaceutical interventions.

A personalized prognostic model for long-term survival in patients with intrahepatic cholangiocarcinoma: a retrospective cohort study.

Purpose: This study aimed to determine the optimal cutoff points for age and tumor size of patients with intrahepatic cholangiocarcinoma (ICC) and to establish and verify a predictive nomogram of overall survival at 1, 3, and 5 years. Methods: From the SEER (Surveillance, Epidemiology, and End Results) database, 1,325 ICC patients were selected and randomly divided into training and testing cohorts at a 7:3 ratio. Using the X-tile software, age and tumor size were classified into 3 subgroups: ≤61, 62-74, and ≥75 years and ≤35, 36-55, and ≥56 mm. Subsequently, univariate and multivariate Cox regression analyses were performed using the R software in the training cohort to determine independent risk factors, compile the prediction nomogram, and verify it with the testing cohort findings. Results: The C-indexes of the new prediction nomograms in the training and testing cohorts were 0.738 (95% confidence interval [CI], 0.718-0.758) and 0.750 (95% CI, 0.72-0.78), respectively. Furthermore, the areas under the 1-, 3-, and 5-year receiver operating characteristic (ROC) curves based on the nomogram were 0.792, 0.853, and 0.838, respectively, higher than the ROC based on the 7th and 8th editions of the American Joint Cancer Commission (AJCC) staging system. Conclusion: This study established and verified a prognostic nomogram that improved the accuracy of the 1-, 3-, and 5-year survival predictions for ICC patients, compared with that based on the 7th and 8th editions of the AJCC staging system, and can help clinicians make personalized survival predictions.

The Impact of Proton Pump Inhibitors on the Efficacy of Immune Checkpoint Inhibitor Combinations in Patients with HBV-Associated Advanced Hepatocellular Carcinoma.

Purpose: There is limited research on whether Proton Pump Inhibitors (PPIs) will affect the efficacy of immune checkpoint inhibitors (ICIs) in treating hepatocellular carcinoma (HCC).This study aimed to determine whether PPIs affect the survival outcomes of patients with HBV-associated advanced HCC receiving combination therapy based on ICIs. Methods: We retrospectively analyzed patients with hepatitis B virus (HBV)-associated advanced HCC who underwent ICIs combination therapy from January 1, 2020, to December 30, 2022. Patients were stratified into PPI and non-PPI groups based on whether they received PPI treatment within 30 days before or after ICIs therapy. Patients' survival and the risk of PPI-associated mortality was assessed. Adverse events were also evaluated. Results: A total of 183 patients with HBV-associated HCC treated with ICI combination therapy were included. The median survival time (12.5 months vs 13.7 months, P = 0.285) and incidence of adverse events (P = 0.729) did not significantly differ between the PPI and non-PPI groups. Even after propensity score matching, the difference in median overall survival (OS) between the two groups was not significant (10.7 months vs 11.4 months; P = 0.596) and the patient's OS is not significantly related to the dosage of PPI application (P > 0.05).However, according to our subgroup analysis, among HCC patients with a serum HBV DNA concentration ≥ 200 IU/mL, the use of PPIs significantly increased the risk of mortality in patients receiving ICI combination therapy (P = 0.024). Conclusion: PPIs do not notably influence the survival prognosis of patients receiving ICI combination therapy for HBV-associated advanced HCC. However, among patients with high levels of HBV DNA, PPIs increase the risk of mortality. Therefore, antiviral therapy should be intensified in the patients with HBVDNA > 200 IU/mL. Additionally, PPIs do not impact the incidence of adverse reactions in these patients.

M6A-mediated upregulation of lncRNA TUG1 in liver cancer cells regulates the antitumor response of CD8+ T cells and phagocytosis of macrophages.

Tumor immune evasion relies on the crosstalk between tumor cells and adaptive/innate immune cells. Immune checkpoints play critical roles in the crosstalk, and immune checkpoint inhibitors have achieved promising clinical effects. The long non-coding RNA taurine-upregulated gene 1 (TUG1) is upregulated in hepatocellular carcinoma (HCC). However, how TUG1 is upregulated and the effects on tumor immune evasion are incompletely understood. Here, METTL3-mediated m6A modification led to TUG1 upregulation is demonstrated. Knockdown of TUG1 inhibited tumor growth and metastasis, increased the infiltration of CD8+ T cells and M1-like macrophages in tumors, promoted the activation of CD8+ T cells through PD-L1, and improved the phagocytosis of macrophages through CD47. Mechanistically, TUG1 regulated PD-L1 and CD47 expressions by acting as a sponge of miR-141 and miR-340, respectively. Meanwhile, TUG1 interacted with YBX1 to facilitate the upregulation of PD-L1 and CD47 transcriptionally, which ultimately regulated tumor immune evasion. Clinically, TUG1 positively correlated with PD-L1 and CD47 in HCC tissues. Moreover, the combination of Tug1-siRNA therapy with a Pdl1 antibody effectively suppressed tumor growth. Therefore, the mechanism of TUG1 in regulating tumor immune evasion is revealed and can inform existing strategies targeting TUG1 for enhancing HCC immune therapy and drug development.