Nuclear KRT19 is a transcriptional co-repressor promoting histone deacetylation and liver tumorigenesis.

BACKGROUND AND AIMS: Epigenetic reprogramming and escape from terminal differentiation are poorly understood enabling characteristics of liver cancer. Keratin 19 (KRT19), classically known to form the intermediate filament cytoskeleton, is a marker of stemness and worse prognosis in liver cancer. This study aimed to address the functional roles of KRT19 in liver tumorigenesis and to elucidate the underlying mechanisms. APPROACH AND RESULTS: Using multiplexed genome editing of hepatocytes in vivo, we demonstrated that KRT19 promoted liver tumorigenesis in mice. Cell fractionation revealed a previously unrecognized nuclear fraction of KRT19. Tandem affinity purification identified histone deacetylase 1 (HDAC1) and REST co-repressor 1 (RCOR1), components of the co-repressor of RE-1 silencing transcription factor (CoREST) complex as KRT19-interacting proteins. KRT19 knockout markedly enhanced histone acetylation levels. Mechanistically, KRT19 promotes CoREST complex formation by enhancing HDAC1 and RCOR1 interaction, thus increases the deacetylase activity. ChIP-seq revealed hepatocyte-specific genes, such as hepatocyte nuclear factor 4 alpha (HNF4A), as direct targets of KRT19-CoREST. In addition, we identified forkhead box P4 (FOXP4) as a direct activator of aberrant KRT19 expression in liver cancer. Furthermore, treatment of primary liver tumors and patient-derived xenografts in mice suggest that KRT19 expression has the potential to predict response to HDAC inhibitors especially in combination with Lenvatinib. CONCLUSIONS: Our data show that nuclear KRT19 acts as a transcriptional co-repressor through promoting the deacetylase activity of the CoREST complex, resulting in dedifferentiation of liver cancer. These findings reveal a previously unrecognized function of KRT19 in directly shaping the epigenetic landscape in cancer.

Universal antifungal prophylaxis effectively prevents fungal bloodstream infection in pediatric liver transplant recipients: a retrospective real-world study.

OBJECTIVES: Fungal bloodstream infection (fBSI) following pediatric liver transplantation presents a significant challenge; however, there remains a paucity of guidance regarding antifungal prophylaxis in this population. This study aimed to evaluate the effectiveness of universal antifungal prophylaxis and propose a desirable strategy. METHODS: We enrolled 604 pediatric patients who underwent liver transplantation between 2020 and 2023, including 242 patients with empirical prophylaxis and 362 patients with universal prophylaxis. Univariate and multivariate logistic regression analyses were performed to identify independent factors for fBSI. RESULTS: Eight (2.2%) pediatric recipients in the universal prophylaxis group and 13 (5.4%) in the empirical group developed fBSI (P = 0.038). Universal prophylaxis was a protective factor (P = 0.044), while high-volume intraoperative plasma transfusion and deceased donor liver transplantation were independent risk factors for fBSI (P = 0.035 and 0.008, respectively). Universal antifungal strategy showed an increased overall survival trend after liver transplantation although without significant statistical difference (P = 0.217). Patients with fBSI had poorer survival than those without fBSI (P <0.001). CONCLUSIONS: Universal prophylaxis strategy for fBSI in pediatrics after liver transplantation is desirable as it could markedly decrease the occurrence of fBSI. Pediatric patients with deceased donors and high-volume intraoperative transfusion should be paid more attention to preventing fBSI.

PBX3 as a biomarker for the early diagnosis and prediction of prognosis of glioma.

BACKGROUND: Increasing evidence have elucidated that PBX3 played a crucial role in cancer initiation and progression. PBX3 was differentially expressed in many cancer types. However, PBX3 potential involvement in gliomas remains to be explored. METHODS: The expression level of PBX3 in glioma tissues and glioma cells, and its correlation with clinical features were analyzed by data from TCGA, GEPIA, CGGA and CCLE. Univariable survival and Multivariate Cox analysis was used to compare several clinical characteristics with survival. We also analyzed the correlation between PBX3 expression level and survival outcome and survival time of LGG and GBM patients by using linear regression equation. GSEA was used to generate an ordered list of all genes related to PBX3 expression and screening of genes co-expressed with PBX3 mRNA by "limma" package. RESULTS: The results showed that PBX3 was highly expressed in gliomas and its expression increased with the increase of malignancy. Survival analysis found that PBX3 is more valuable in predicting the OS and PFI of LGG patients than that of GBM. For further study, TCGA and CGGA data were downloaded for univariate Cox analysis and multivariate Cox analysis which showed that the expression of PBX3 was independent influencing factors for poor prognosis of LGG patients. Meanwhile, Receiver operating characteristic (ROC) curve showed that PBX3 was a predictor of overall survival rate and progression-free survival rate of LGG. Linear regression model analysis indicated that the higher expression of PBX3 the higher the risk of death of LGG patients, and the higher expression of PBX3 the higher the risk of disease progression of LGG patients. Next, TCGA data were downloaded for GSEA and Co-expression analyses, which was performed to study the function of PBX3. CONCLUSION: PBX3 may be involved in the occurrence and development of glioma, and has potential reference value for the early diagnosis and prediction of prognosis of glioma.

Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders.

Lysosomal storage disorders (LSDs), which are characterized by genetic and metabolic lysosomal dysfunctions, constitute over 60 degenerative diseases with considerable health and economic burdens. However, the mechanisms driving the progressive death of functional cells due to lysosomal defects remain incompletely understood, and broad-spectrum therapeutics against LSDs are lacking. Here, we found that various gene abnormalities that cause LSDs, including Hexb, Gla, Npc1, Ctsd and Gba, all shared mutual properties to robustly autoactivate neuron-intrinsic cGAS-STING signalling, driving neuronal death and disease progression. This signalling was triggered by excessive cytoplasmic congregation of the dsDNA and DNA sensor cGAS in neurons. Genetic ablation of cGAS or STING, digestion of neuronal cytosolic dsDNA by DNase, and repair of neuronal lysosomal dysfunction alleviated symptoms of Sandhoff disease, Fabry disease and Niemann-Pick disease, with substantially reduced neuronal loss. We therefore identify a ubiquitous mechanism mediating the pathogenesis of a variety of LSDs, unveil an inherent connection between lysosomal defects and innate immunity, and suggest a uniform strategy for curing LSDs.

18F-FAPI-04 Outperforms 18F-FDG PET/CT in Clinical Assessments of Patients with Pancreatic Adenocarcinoma.

Accurate diagnosis and staging are crucial for selecting treatment for patients with pancreatic ductal adenocarcinoma (PDAC). The desmoplastic responses associated with PDAC are often characterized by hypometabolism. Here, we investigated 18F-fibroblast activation protein inhibitor (FAPI)-04 PET/CT in evaluation of PDAC and compared the findings with those obtained using 18F-FDG. Methods: Sixty-two PDAC patients underwent 18F-FAPI-04 PET/CT and 18F-FDG PET/CT. Identification of primary lesions, lymph node (LN) metastasis, and distant metastasis (DM) by these methods was evaluated, and TNM staging was performed. Correlation between SUVmax of the primary lesion and treatment response was explored in patients who received systemic therapy. Results: 18F-FAPI-04 PET/CT identified all patients with PDAC; 18F-FDG PET/CT missed 1 patient. Tracer uptake was higher in 18F-FAPI-04 PET/CT than in 18F-FDG PET/CT in primary tumors (10.63 vs. 2.87, P < 0.0001), LN metastasis (2.90 vs. 1.43, P < 0.0001), and DM (liver, 6.11 vs. 3.10, P = 0.002; peritoneal, 4.70 vs. 2.08, P = 0.015). The methods showed no significant difference in the T staging category, but the N and M values were significantly higher for 18F-FAPI-04 PET/CT than for 18F-FDG PET/CT (P = 0.002 and 0.008, respectively). Thus, 14 patients were upgraded, and only 1 patient was downgraded, by 18F-FAPI-04 PET/CT compared with 18F-FDG PET/CT. A high SUVmax of the primary tumor did not correlate with treatment response for either 18F-FAPI-04 or 18F-FDG. Conclusion: 18F-FAPI-04 PET/CT performed better than 18F-FDG PET/CT in identification of primary tumors, LN metastasis, and DM and in TNM staging of PDAC.

Targeting cancer-associated fibroblast autophagy renders pancreatic cancer eradicable with immunochemotherapy by inhibiting adaptive immune resistance.

Accumulating evidence suggests that cancer-associated fibroblast (CAF) macroautophagy/autophagy is crucial in tumor development and may be a therapeutic target for pancreatic ductal adenocarcinoma (PDAC). However, the role of CAF autophagy during immune surveillance and cancer immunotherapy is unclear. The present study revealed that the inhibition of CAF autophagy suppresses in vivo tumor development in immune-deficient xenografts. This deletion compromises anti-tumor immunity and anti-tumor efficacy both in vitro and in vivo by upregulating CD274/PDL1 levels in an immune-competent mouse model. A block in CAF autophagy reduced the production of IL6 (interleukin 6), disrupting high desmoplastic TME and decreasing USP14 expression at the transcription level in pancreatic cancer cells. We further identify USP14 as the post-translational factor responsible for downregulating CD274 expression by removing K63 linked-ubiquitination at the K280 residue. Finally, chloroquine diphosphate-loaded mesenchymal stem cell (MSC)-liposomes, by accurately targeting CAFs, inhibited CAF autophagy, improving the efficacy of immunochemotherapy to combat pancreatic cancer.Abbreviation: AIR: adaptive immune resistance; ATRA: all-trans-retinoicacid; CAF: cancer-associated fibroblast; CD274/PDL1: CD274 molecule; CM: conditioned medium; CQ: chloroquine diphosphate; CyTOF: Mass cytometry; FGF2/bFGF: fibroblast growth factor 2; ICB: immune checkpoint blockade; IF: immunofluorescence; IHC: immunohistochemistry; IP: immunoprecipitation; MS: mass spectrometer; MSC: mesenchymal stem cell; PDAC: pancreatic ductal adenocarcinoma; TEM: transmission electron microscopy; TILs: tumor infiltrating lymphocytes; TME: tumor microenvironment; USP14: ubiquitin specific peptidase 14.

Position Prior Attention Network for Pancreas Tumor Segmentation.

Segmentation of pancreatic tumors on CT images is essential for the diagnosis and treatment of pancreatic cancer. However, low contrast between the pancreas and the tumor, as well as variable tumor shape and position, makes segmentation challenging. To solve the problem, we propose a Position Prior Attention Network (PPANet) with a pseudo segmentation generation module (PSGM) and a position prior attention module (PPAM). PSGM and PPAM maps pancreatic and tumor pseudo segmentation to latent space to generate position prior attention map and supervises location classification. The proposed method is evaluated on pancreatic patient data collected from local hospital and the experimental results demonstrate that our method can significantly improve the tumor segmentation results by introducing the position information in the training phase.

Hurdle or thruster: Glucose metabolism of T cells in anti-tumour immunity.

Glucose metabolism is essential for the activation, differentiation and function of T cells and proper glucose metabolism is required to maintain effective T cell immunity. Dysregulation of glucose metabolism is a hallmark of cancer, and the tumour microenvironment (TME2) can create metabolic barriers in T cells that inhibit their anti-tumour immune function. Targeting glucose metabolism is a promising approach to improve the capacity of T cells in the TME. The efficacy of common immunotherapies, such as immune checkpoint inhibitors (ICIs3) and adoptive cell transfer (ACT4), can be limited by T-cell function, and the treatment itself can affect T-cell metabolism. Therefore, understanding the relationship between immunotherapy and T cell glucose metabolism helps to achieve more effective anti-tumour therapy. In this review, we provide an overview of T cell glucose metabolism and how T cell metabolic reprogramming in the TME regulates anti-tumour responses, briefly describe the metabolic patterns of T cells during ICI and ACT therapies, which suggest possible synergistic strategies.

Siamese Delta Network with Multimodality Fusion for Systemic Treatment Response Prediction in Pancreatic Cancer.

Systemic treatment is a main way for pancreas cancer patients that are ineligible for surgery. A subgroup of patients showed good response to systemic treatment and the rest received limited benefits. CT images provide a non-invasive way to assess the treatment response. Alternative non-image methods include radiology analysis, tumor marker analysis and combination analysis. To combine the image and non-image data, we propose the Siamese Delta Network with Multimodality Fusion (SDN-MF) to predict systemic treatment response in an end-to-end way. First, a Siamese Delta Network (SDN) is designed to process pre-treatment and pre-surgery CT images and get the image feature changes to predict response. Then, patients' characteristics from EMR and alternative analysis results forms non-image data, which is incorporated into SDN with a multimodality fusion (MF) module. The proposed SDN-MF is evaluated on a private dataset and achieves average AUC value of 0.883 with five cross-validation. Comparison among image-only, non-image-only, and fusion models verifies the superior of multimodality model in predicting systemic treatment response of pancreas cancer patients.

Protocol for isolating single cells from human pancreatic cancer tissues and analyzing major immune cell populations using flow cytometry.

Here, we present a protocol for collecting, dissociating, isolating, staining, and analyzing immune cells from pancreatic cancer tissues for flow cytometry. The isolated cells can also be used for single-cell RNA sequencing and other related procedures. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2023).1.

In vitro and in vivo killing effects of methionine enkephalin on osteosarcoma.

OBJECTIVE: This study aimed to investigate the underlying regulatory effects of methionine enkephalin (MENK) on osteosarcoma. METHODS: The Cell Counting Kit-8 assay, clone formation, wound healing, transwell assay, and flow cytometry were performed to measure the effects of MENK on the proliferation, migration, invasion, and apoptosis of MG-63 and Saos-2 cells. Opiate growth factor receptor expression (OGFr) in cells was stably knocked down using siRNA. A tumor model was established by inoculating MG-63 cells into mice. Flow cytometry was performed to identify alterations in mice bone marrow, spleen, and tumor tissue immune cells. The phenotype of tumor-associated macrophages was determined using immunohistochemistry. After OGFr knockdown or/and treatment with MENK, Bax, Bcl-2, caspase 3, caspase 9, and PARP expression levels were characterized using qRT-PCR, western blot, and WES, respectively. RESULTS: MENK could significantly inhibit the proliferation, invasion, and migration of MG-63 and Saos-2, arrest the cell cycle in the G0/G1 phase, upregulate Bax, caspase 3, caspase 9, and PARP expression, and downregulate Bcl-2 expression. Tumor size and weight were lower in the MENK group than those in the control group. MENK-treated mice exhibited a reduced ratio of CD11b + Gr-1 + myeloid-derived suppressor cells. MENK increased the ratio of M1-type macrophages and decreased the proportion of M2-type macrophages in tumor tissue. Furthermore, the level of TNF-α significantly increased while that of IL-10 decreased in MENK-treated mice. The effect of MENK could be partly reversed by OGFr knockdown. CONCLUSION: MENK reduces the abundance of myeloid-derived suppressor cells, induces M1 polarization of macrophages, and exhibits an inhibitory effect on osteosarcoma.

Improve the prediction of liver transplant mortality based on pre-transplant factors: A multi-center study from China: Mortality prediction of LT.

AIMS: To designed a new model using pre-transplant data to predict post-transplant mortality for Chinese population and compared its performance to that of existing models. METHODS: In this multicenter study, 544 recipients of liver transplants for non-tumor indications were enrolled in the training group and 276 patients in the validation group. The new Simplified Mortality Prediction Scores (SMOPS) model was compared to the MELD and four existing models using the C-statistic. RESULTS: SMOPS model used 6 independent pre-transplantation risk factors screened from the training group (chronic liver failure/organ failure scores, fever > 37.6 â„ƒ, ABO blood-type compatibility, arterial lactate level, leukocyte count and re-transplantation). The SMOPS accurately predicted patients' 30-day, 90-day and 365-day mortality following liver transplantation, and its' scores were more accurate than those of the other models. The SMOPS generated four levels of risk: low risk (<10 points), moderate risk (11-20 points), high risk (21-25 points) and futile risk (≥26 points). The survival within all risk levels was not different between MELD=40 and MELD<40. The survival within moderate-, high- or extreme-risk ALF was not different between ALF and non-ALF. CONCLUSION: The SMOPS model uses pre-transplant risk factors to stratify post-transplant survival and is superior to current models for Chinese population, and has the potential to contribute to improvements in organ-allocation policies.

Integrative analysis identified two subtypes and a taurine-related signature to predict the prognosis and efficacy of immunotherapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent subtypes of primary liver cancer, with high mortality and poor prognosis. Immunotherapy has revolutionized treatment strategies for many cancers. However, only a subset of patients with HCC achieve satisfactory benefits from immunotherapy. Therefore, a reliable biomarker that could predict the prognosis and immunotherapy response in patients with HCC is urgently needed. Taurine plays an important role in many physiological processes. However, its participation in the occurrence and progression of liver cancer and regulation of the composition and function of various components of the immune microenvironment remains elusive. In this study, we identified and validated two heterogeneous subtypes of HCC with different taurine metabolic profiles, presenting distinct genomic features, clinicopathological characteristics, and immune landscapes, using multiple bulk transcriptome datasets. Subsequently, we constructed a risk model based on genes related to taurine metabolism to assess the prognosis, immune cell infiltration, immunotherapy response, and drug sensitivity of patients with HCC. The risk model was validated using several independent external cohorts and showed a robust predictive performance. In addition, we evaluated the expression patterns of taurine metabolism-related genes in the tumor microenvironment and the heterogeneity of taurine metabolism among cancer cells using a single-cell transcriptome. In conclusion, our study provides insights into the important role played by taurine metabolism in tumor progression and immune regulation. Furthermore, the risk model can serve as a biomarker to assess patient prognosis and immunotherapy response, potentially helping clinicians make more precise and personalized clinical decisions.

Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition).

Background: Primary liver cancer, of which around 75-85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer. Key Messages: The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."

Clinical characteristics and outcomes of liver transplant recipients infected by Omicron during the opening up of the dynamic zero-coronavirus disease policy in China: A prospective, observational study.

We analyzed the characteristics, risk factors, outcomes, and post-coronavirus disease 2019 (COVID-19) symptoms in liver transplant recipients in China's late 2022 COVID-19 wave. Recipients with COVID-19 were enrolled from December 1, 2022, to January 31, 2023, and followed up until May 31, 2023. Baseline and characteristic data were collected. A total of 930 recipients were included, with a vaccination rate (non-mRNA) of 40.0%. Among 726 (78.1%) recipients with COVID-19, 641 (88.3%) patients were treated at home, 81 (11.2%) patients required hospitalization in general wards, 4 (0.6%) patients required intensive care, and 1 (0.1%) patient died because of COVID-19. Severe acute respiratory syndrome coronavirus 2 infection was related to close contact with confirmed cases (P < .001) and the condition of end-stage kidney disease (P < .046). Older age, male sex, less vaccination, and hypertension were independent risk factors for hospitalization. Fatigue (36.9%) was the most common symptom post-COVID-19, followed by memory loss (35.7%) and sleep disturbance (23.9%). Two doses of vaccines had a protective effect against these post-COVID-19 symptoms (P < .05). During this Omicron outbreak, liver transplant recipients were susceptible to COVID-19, with frequent hospitalization but low mortality. Two doses of non-mRNA COVID-19 vaccines could protect against liver transplant recipient hospitalization and post-COVID-19 symptoms.

Tumor Radiomic Features on Pretreatment MRI to Predict Response to Lenvatinib plus an Anti-PD-1 Antibody in Advanced Hepatocellular Carcinoma: A Multicenter Study.

Introduction: Lenvatinib plus an anti-PD-1 antibody has shown promising antitumor effects in patients with advanced hepatocellular carcinoma (HCC), but with clinical benefit limited to a subset of patients. We developed and validated a radiomic-based model to predict objective response to this combination therapy in advanced HCC patients. Methods: Patients (N = 170) who received first-line combination therapy with lenvatinib plus an anti-PD-1 antibody were retrospectively enrolled from 9 Chinese centers; 124 and 46 into the training and validation cohorts, respectively. Radiomic features were extracted from pretreatment contrast-enhanced MRI. After feature selection, clinicopathologic, radiomic, and clinicopathologic-radiomic models were built using a neural network. The performance of models, incremental predictive value of radiomic features compared with clinicopathologic features and relationship between radiomic features and survivals were assessed. Results: The clinicopathologic model modestly predicted objective response with an AUC of 0.748 (95% CI: 0.656-0.840) and 0.702 (95% CI: 0.547-0.884) in the training and validation cohorts, respectively. The radiomic model predicted response with an AUC of 0.886 (95% CI: 0.815-0.957) and 0.820 (95% CI: 0.648-0.984), respectively, with good calibration and clinical utility. The incremental predictive value of radiomic features to clinicopathologic features was confirmed with a net reclassification index of 47.9% (p < 0.001) and 41.5% (p = 0.025) in the training and validation cohorts, respectively. Furthermore, radiomic features were associated with overall survival and progression-free survival both in the training and validation cohorts, but modified albumin-bilirubin grade and neutrophil-to-lymphocyte ratio were not. Conclusion: Radiomic features extracted from pretreatment MRI can predict individualized objective response to combination therapy with lenvatinib plus an anti-PD-1 antibody in patients with unresectable or advanced HCC, provide incremental predictive value over clinicopathologic features, and are associated with overall survival and progression-free survival after initiation of this combination regimen.

Dynamic evaluation based on acute-on-chronic liver failure predicts survival of patients after liver transplantation: a cohort study.

BACKGROUND AND AIMS: Dynamic evaluation of critically ill patients is the key to predicting their outcomes. Most scores based on the Model for End-stage Liver Disease (MELD) and acute-on-chronic liver failure (ACLF) utilize point-in-time assessment. This study mainly aimed to investigate the impact of dynamic clinical course change on post-liver transplantation (LT) survival. METHODS: This study included 637 adults (overall cohort) with benign end-stage liver diseases. The authors compared the MELD scores and our ACLF-based dynamic evaluation scores. Patients enrolled or transplanted with ACLF-3 were defined as the ACLF-3 cohort ( n =158). The primary outcome was 1-year mortality. ΔMELD and ΔCLIF-OF (Chronic Liver Failure-Organ Failure) represented the respective dynamic changes in liver transplant function. Discrimination was assessed using the area under the curve. A Cox regression analysis identified independent risk factors for specific organ failure and 1-year mortality. RESULTS: Patients were grouped into three groups: the deterioration group (D), the stable group (S), and the improvement group (I). The deterioration group (ΔCLIF-OF ≥2) was more likely to receive national liver allocation ( P =0.012) but experienced longer cold ischemia time ( P =0.006) than other groups. The area under the curves for ΔCLIF-OF were 0.752 for the entire cohort and 0.767 for ACLF-3 cohorts, both superior to ΔMELD ( P <0.001 for both). Compared to the improvement group, the 1-year mortality hazard ratios (HR) of the deterioration group were 12.57 (6.72-23.48) for the overall cohort and 7.00 (3.73-13.09) for the ACLF-3 cohort. Extrahepatic organs subscore change (HR=1.783 (1.266-2.512) for neurologic; 1.653 (1.205-2.269) for circulation; 1.906 (1.324-2.743) for respiration; 1.473 (1.097-1.976) for renal) were key to transplantation outcomes in the ACLF-3 cohort. CLIF-OF at LT (HR=1.193), ΔCLIF-OF (HR=1.354), and cold ischemia time (HR=1.077) were independent risk factors of mortality for the overall cohort, while ΔCLIF-OF (HR=1.384) was the only independent risk factor for the ACLF-3 cohort. Non-ACLF-3 patients showed a higher survival rate than patients with ACLF-3 in all groups ( P =0.002 for I, P =0.005 for S, and P =0.001 for D). CONCLUSION: This was the first ACLF-based dynamic evaluation study. ΔCLIF-OF was a more powerful predictor of post-LT mortality than ΔMELD. Extrahepatic organ failures were core risk factors for ACLF-3 patients. CLIF-OF at LT, ΔCLIF-OF, and cold ischemia time were independent risk factors for post-LT mortality. Patients with a worse baseline condition and a deteriorating clinical course had the worst prognosis. Dynamic evaluation was important in risk stratification and recipient selection.

Targeting leucine-rich repeat serine/threonine-protein kinase 2 sensitizes pancreatic ductal adenocarcinoma to anti-PD-L1 immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to immune checkpoint blockade therapy, and negative feedback of tumor immune evasion might be partly responsible. We isolated CD8+ T cells and cultured them in vitro. Proteomics analysis was performed to compare changes in Panc02 cell lines cultured with conditioned medium, and leucine-rich repeat kinase 2 (LRRK2) was identified as a differential gene. LRRK2 expression was related to CD8+ T cell spatial distribution in PDAC clinical samples and upregulated by CD8+ T cells via interferon gamma (IFN-γ) simulation in vitro. Knockdown or pharmacological inhibition of LRRK2 activated an anti-pancreatic cancer immune response in mice, which meant that LRRK2 acted as an immunosuppressive gene. Mechanistically, LRRK2 phosphorylated PD-L1 at T210 to inhibit its ubiquitination-mediated proteasomal degradation. LRRK2 inhibition attenuated PD-1/PD-L1 blockade-mediated, T cell-induced upregulation of LRRK2/PD-L1, thus sensitizing the mice to anti-PD-L1 therapy. In addition, adenosylcobalamin, the activated form of vitamin B12, which was found to be a broad-spectrum inhibitor of LRRK2, could inhibit LRRK2 in vivo and sensitize PDAC to immunotherapy as well, which potentially endows LRRK2 inhibition with clinical translational value. Therefore, PD-L1 blockade combined with LRRK2 inhibition could be a novel therapy strategy for PDAC.