Ex vivo liver resection and auto-transplantation as an alternative for the treatment of liver malignancies: Progress and challenges.

Hepatectomy is still the major curative treatment for patients with liver malignancies. However, it is still a big challenge to remove the tumors in the central posterior area, especially if their location involves the retrohepatic inferior vena cava and hepatic veins. Ex vivo liver resection and auto-transplantation (ELRA), a hybrid technique of the traditional liver resection and transplantation, has brought new hope to these patients and therefore becomes a valid alternative to liver transplantation. Due to its technical difficulty, ELRA is still concentrated in a few hepatobiliary centers that have experienced surgeons in both liver resection and liver transplantation. The efficacy and safety of this technique has already been demonstrated in the treatment of benign liver diseases, especially in the advanced alveolar echinococcosis. Recently, the application of ELRA for liver malignances has gained more attention. However, standardization of clinical practice norms and international consensus are still lacking. The prognostic impact in these oncologic patients also needs further evaluation. In this review, we summarized the principles and recent progresses on ELRA.

Short-term postoperative bacteriobilia or fungibilia in liver transplantation patients with donation after circulatory death allografts associated with a longer hospital stay: A single-center retrospective observational study in China.

BACKGROUND: Normal bile is sterile. Studies have shown that cholangitis after liver transplantation (LT) was associated with a relatively poor prognosis. It remains unclear whether the bacteriobilia or fungibilia impact the patient outcomes in LT recipients, especially with donation after circulatory death (DCD) allografts, which was correlated with a higher risk of allograft failure. METHODS: This retrospective study included 139 LT recipients of DCD grafts from 2019 to 2021. All patients were divided into two groups according to the presence or absence of bacteriobilia or fungibilia. The prevalence and microbial spectrum of postoperative bacteriobilia or fungibilia and its possible association with outcomes, especially hospital stay were analyzed. RESULTS: Totally 135 and 171 organisms were isolated at weeks 1 and 2, respectively. Among all patients included in this analysis, 83 (59.7%) developed bacteriobilia or fungibilia within 2 weeks post-transplantation. The occurrence of bacteriobilia or fungibilia (ß = 7.43, 95% CI: 0.02 to 14.82, P = 0.049), particularly the detection of Pseudomonas (ß = 18.84, 95% CI: 6.51 to 31.07, P = 0.003) within 2 weeks post-transplantation was associated with a longer hospital stay. However, it did not affect the graft and patient survival. CONCLUSIONS: The occurrence of bacteriobilia or fungibilia, particularly Pseudomonas within 2 weeks post-transplantation, could influence the recovery of liver function and was associated with prolonged hospital stay but not the graft and patient survival.

Influence of sex on outcomes of liver transplantation for hepatocellular carcinoma: a multicenter cohort study in China.

OBJECTIVE: Sex-specific differences are observed in various liver diseases, but the influence of sex on the outcomes of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains to be determined. This study is the first Chinese nationwide investigation of the role of sex in post-LT outcomes in patients with HCC. METHODS: Data for recipients with HCC registered in the China Liver Transplant Registry between January 2015 and December 2020 were analyzed. The associations between donor, recipient, or donor-recipient transplant patterns by sex and the post-LT outcomes were studied with propensity score matching (PSM). The survival associated with different sex-based donor-recipient transplant patterns was further studied. RESULTS: Among 3,769 patients enrolled in this study, the 1-, 3-, and 5-year overall survival (OS) rates of patients with HCC after LT were 96.1%, 86.4%, and 78.5%, respectively, in female recipients, and 95.8%, 79.0%, and 70.7%, respectively, in male recipients after PSM (P = 0.009). However, the OS was comparable between recipients with female donors and male donors. Multivariate analysis indicated that male recipient sex was a risk factor for post-LT survival (HR = 1.381, P = 0.046). Among the donor-recipient transplant patterns, the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival (P < 0.05). CONCLUSIONS: Our findings highlighted that the post-LT outcomes of female recipients were significantly superior to those of male recipients, and the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival. Livers from male donors may provide the most benefit to female recipients. Our results indicate that sex should be considered as a critical factor in organ allocation.

Super-resolution terahertz imaging based on a meta-waveguide.

A terahertz metamaterial waveguide (meta-waveguide) and a meta-waveguide-based lens-free imaging system are presented. The meta-waveguide not only inherits the low-loss transmission performance of a waveguide but also breaks through the diffraction limit under the action of the metamaterial, achieving subwavelength focusing. The focusing distance is far greater than the Rayleigh length, thus enabling far-field scanning imaging. For verification, a metal ring-based meta-waveguide was fabricated by 3D printing and metal cladding technology. Then, a transmission scanning imaging system working at 0.1 THz was built. High quality terahertz images with a resolution of 1/3 of the wavelength were obtained by placing the imaging targets at the focus and performing two-dimensional scanning. The focusing and transmission of terahertz wave in the meta-waveguide were simulated and analyzed.

A fully Bayesian approach for comprehensive mapping of magnitude and phase brain activation in complex-valued fMRI data.

Functional magnetic resonance imaging (fMRI) plays a crucial role in neuroimaging, enabling the exploration of brain activity through complex-valued signals. These signals, composed of magnitude and phase, offer a rich source of information for understanding brain functions. Traditional fMRI analyses have largely focused on magnitude information, often overlooking the potential insights offered by phase data. In this paper, we propose a novel fully Bayesian model designed for analyzing single-subject complex-valued fMRI (cv-fMRI) data. Our model, which we refer to as the CV-M&P model, is distinctive in its comprehensive utilization of both magnitude and phase information in fMRI signals, allowing for independent prediction of different types of activation maps. We incorporate Gaussian Markov random fields (GMRFs) to capture spatial correlations within the data, and employ image partitioning and parallel computation to enhance computational efficiency. Our model is rigorously tested through simulation studies, and then applied to a real dataset from a unilateral finger-tapping experiment. The results demonstrate the model's effectiveness in accurately identifying brain regions activated in response to specific tasks, distinguishing between magnitude and phase activation.

The Absence of Intra-Tumoral Tertiary Lymphoid Structures is Associated with a Worse Prognosis and mTOR Signaling Activation in Hepatocellular Carcinoma with Liver Transplantation: A Multicenter Retrospective Study.

Tertiary lymphoid structure (TLS) can predict the prognosis and sensitivity of tumors to immune checkpoint inhibitors (ICIs) therapy, whether it can be noninvasively predicted by radiomics in hepatocellular carcinoma with liver transplantation (HCC-LT) has not been explored. In this study, it is found that intra-tumoral TLS abundance is significantly correlated with recurrence-free survival (RFS) and overall survival (OS). Tumor tissues with TLS are characterized by inflammatory signatures and high infiltration of antitumor immune cells, while those without TLS exhibit uncontrolled cell cycle progression and activated mTOR signaling by bulk and single-cell RNA-seq analyses. The regulators involved in mTOR signaling (RHEB and LAMTOR4) and S-phase (RFC2, PSMC2, and ORC5) are highly expressed in HCC with low TLS. In addition, the largest cohort of HCC patients is studied with available radiomics data, and a classifier is built to detect the presence of TLS in a non-invasive manner. The classifier demonstrates remarkable performance in predicting intra-tumoral TLS abundance in both training and test sets, achieving areas under receiver operating characteristic curve (AUCs) of 92.9% and 90.2% respectively. In summary, the absence of intra-tumoral TLS abundance is associated with mTOR signaling activation and uncontrolled cell cycle progression in tumor cells, indicating unfavorable prognosis in HCC-LT.

Evaluation of Profile Control and Oil Displacement Effect of Starch Gel and Nano-MoS2 Combination System in High-Temperature Heterogeneous Reservoir.

The Henan Oilfield's medium-permeability blocks face challenges such as high temperatures and severe heterogeneity, making conventional flooding systems less effective. The starch gel system is an efficient approach for deep profile control in high-temperature reservoirs, while the nano-MoS2 system is a promising enhanced oil recovery (EOR) technology for high-temperature low-permeability reservoirs. Combining these two may achieve the dual effects of profile control and oil displacement, significantly enhancing oil recovery in high-temperature heterogeneous reservoirs. The basic performance evaluation of the combination system was carried out under reservoir temperature. Displacement experiments were conducted in target blocks under different permeabilities and extreme disparity core flooding to evaluate the combination system's oil displacement effect. Additionally, the displacement effects and mechanisms of the starch gel and nano-MoS2 combination system in heterogeneous reservoirs were evaluated by simulating interlayer and intralayer heterogeneity models. The results show that the single nano-MoS2 system's efficiency decreases with increased core permeability, and its effectiveness is limited in triple and quintuple disparity parallel experiments. After injecting the starch gel-nano-MoS2 combination system, the enhanced oil recovery effect was significant. The interlayer and intralayer heterogeneous models demonstrated that the primary water flooding mainly affected the high-permeability layers, while the starch gel effectively blocked the dominant channels, forcing the nano-MoS2 oil displacement system towards unswept areas. This coordination significantly enhanced oil displacement, with the combination system improving recovery by 15.33 and 12.20 percentage points, respectively. This research indicates that the starch gel and nano-MoS2 combination flooding technique holds promise for enhancing oil recovery in high-temperature heterogeneous reservoirs of Henan Oilfield, providing foundational support for field applications.

BATF-mediated regulation of exhausted CD8+ T-cell responses and potential implications for chimeric antigen receptor-T therapy.

Chimeric antigen receptor (CAR) T-cell therapy for malignant tumors has reached a crucial stage, with recent studies underscoring the role of T-cell exhaustion in determining the efficacy of CAR-T therapy. This trailblazing discovery has opened new avenues to augment the potency of CAR-T therapy. Basic leucine zipper ATF-like transcription factor (BATF) is indispensable in alleviating T-cell exhaustion and is pivotal in the early stages of CD8+ T-cell differentiation. In cooperation with other transcription factors, it plays a key role in the differentiation and maturation processes of exhausted T cells. A deeper comprehension of BATF's mechanisms in T-cell biology may yield novel insights into amplifying the efficacy of CAR-T therapy.

Chimeric antigen receptor (CAR) T-cell therapy, a treatment that boosts the body's immune system to fight cancer, has made significant progress. Recent research has shown that T-cell exhaustion, which is when the body's immune cells become less effective, affects how well this therapy works. This finding has opened new possibilities to make CAR-T therapy more effective. There is a specific protein called BATF that plays an important role in reducing T-cell exhaustion and influencing the early development of certain immune cells. This review describes how BATF interacts with exhausted T cells, to improve CAR-T therapy. By understanding how BATF works in the immune system, new ways to enhance CAR-T therapy and its ability to fight cancer may be found.

A novel nomogram for prognosis stratification in salvage liver transplantation: a national-wide study with propensity score matching analysis in China.

Background: Salvage liver transplantation (SLT) has been reported to be an efficient treatment option for patients with recurrent hepatocellular carcinoma (HCC) after liver resection (LR). However, for recipients who underwent liver transplantation (LT) due to recurrent HCC after LR in China, the selection criteria are not well established. Methods: In this study, data from the China Liver Transplant Registry (CLTR) of 4,244 LT performed from January 2015 to December 2019 were examined, including 3,498 primary liver transplantation (PLT) and 746 SLT recipients. Propensity score matching (PSM) analysis was used to minimize between-group imbalances. The overall survival (OS) and disease-free survival (DFS) between PLT and SLT in recipients fulfilling the Milan or Hangzhou criteria were compared based on the multivariate analysis, nomograms were plotted to further classify the SLT group into low- and high-risk groups. Results: In this study, the 1-, 3- and 5-year OS and DFS of SLT recipients fulfilling Milan criteria (OS, P=0.01; DFS, P<0.001) or Hangzhou criteria (OS, P=0.03; DFS, P=0.003) were significantly reduced when compared to that of PLT group after PSM analysis. Independent risk factors, including preoperative transarterial chemoembolization (TACE), alpha fetoprotein (AFP) level, tumor maximum size and tumor total diameter were selected to draw a prognostic nomogram. The low-risk SLT recipients (1-year, 95.34%; 3-year, 84.26%; 5-year, 77.20%) showed a comparable OS with PLT recipients fulfilling Hangzhou criteria (P=0.107). Conclusions: An optimal nomogram model for prognosis stratification and clinical decision guidance of SLT was established. The low-risk SLT recipients based on the nomograms showed comparable survival with those fulfilling Hangzhou criteria in PLT group.

Identification and validation of PCSK9 as a prognostic and immune-related influencing factor in tumorigenesis: a pan-cancer analysis.

Introduction: Proprotein convertase subtilisin/kexin-9 (PCSK9) has been primarily studied in the cardiovascular field however, its role in cancer pathophysiology remains incompletely defined. Recently, a pivotal role for PCSK9 in cancer immunotherapy was proposed based on the finding that PCSK9 inhibition was associated with enhancing the antigen presentation efficacy of target programmed cell death-1 (PD-1). Herein, we provide results of a comprehensive pan-cancer analysis of PCSK9 that assessed its prognostic and immunological functions in cancer. Methods: Using a variety of available online cancer-related databases including TIMER, cBioPortal, and GEPIA, we identified the abnormal expression of PCSK9 and its potential clinical associations in diverse cancer types including liver, brain and lung. We also validated its role in progression-free survival (PFS) and immune infiltration in neuroblastoma. Results: Overall, the pan-cancer survival analysis revealed an association between dysregulated PCSK9 and poor clinical outcomes in various cancer types. Specifically, PCSK9 was extensively genetically altered across most cancer types and was consistently found in different tumor types and substages when compared with adjacent normal tissues. Thus, aberrant DNA methylation may be responsible for PCSK9 expression in many cancer types. Focusing on liver hepatocellular carcinoma (LIHC), we found that PCSK9 expression correlated with clinicopathological characteristics following stratified prognostic analyses. PCSK9 expression was significantly associated with immune infiltrate since specific markers of CD8+ T cells, macrophage polarization, and exhausted T cells exhibited different PCSK9-related immune infiltration patterns in LIHC and lung squamous cell carcinoma. In addition, PCSK9 was connected with resistance of drugs such as erlotinib and docetaxel. Finally, we validated PCSK9 expression in clinical neuroblastoma samples and concluded that PCSK9 appeared to correlate with a poor PFS and natural killer cell infiltration in neuroblastoma patients. Conclusion: PCSK9 could serve as a robust prognostic pan-cancer biomarker given its correlation with immune infiltrates in different cancer types, thus potentially highlighting a new direction for targeted clinical therapy of cancers.

Efficacy and safety of anlotinib as an adjuvant therapy in hepatocellular carcinoma patients with a high risk of postoperative recurrence.

Objective: Hepatocellular carcinoma (HCC) has a high rate of postoperative recurrence and lacks an effective treatment to prevent recurrence. This study aims to investigate the efficacy and safety of anlotinib in postoperative adjuvant therapy for HCC patients with high-risk recurrence factors. Methods: For this multicenter, retrospective study, we recruited 63 HCC patients who received either anlotinib (n=27) or transcatheter arterial chemoembolization (TACE) (n=36) from six research centers in China between March 2019 and October 2020. The primary endpoint was disease-free survival (DFS) and the secondary endpoints were overall survival (OS) and safety. Results: In this study, the median follow-up time was 25.9 and 26.8 months in the anlotinib and TACE groups, respectively. There was no significant difference in the median DFS between the anlotinib [26.8 months, 95% confidence interval (95% CI): 6.8-NE] and TACE groups (20.6 months, 95% CI: 8.4-NE). The 12-month OS rates in the anlotinib and TACE groups were 96.3% and 97.2%, respectively. In the anlotinib group, 19 of 27 patients (70.4%) experienced treatment-emergent adverse events, with the most common events (≥10%) being hypertension (22.2%) and decreased platelet count (22.2%). Conclusions: The results indicate that anlotinib, as a new, orally administered tyrosine kinase inhibitor, has the same efficacy as TACE, and side effects can be well controlled.

The m6A-related gene signature stratifies poor prognosis patients and characterizes immunosuppressive microenvironment in hepatocellular carcinoma.

Background: N6-methyladenosine (m6A) is the most abundant epitranscriptomic modification of RNA, which can affect RNA metabolism and protein translation. The m6A modification plays a critical role in cancer development, including hepatocellular carcinoma (HCC). Despite several m6A-related signatures in HCC, most of them lack the necessary validation and the reliability is still elusive. Methods: Differentially expressed genes (DEGs) in the Cancer Genome Atlas were comprehensively analyzed to identify m6A signature associated with HCC prognosis. Gene set enrichment analysis, tumor mutation burden (TMB), immune infiltration, and therapeutic response were evaluated. Importantly, mass spectrometry proteomics and multiplex immunofluorescence assays were performed for validation. Results: The m6A-related protein-coding gene signature was established, which can divide HCC into high-/low-risk subgroups with markedly different overall survival (OS) and clinical stages. Furthermore, we validated its reliability and robustness in our 101 independent HCC specimens using proteomic detection and confirmed that our signature readily identified high-risk HCC patients with 3-year survival rates of 44.1% vs. 71.8% in the low-risk group. Functional analysis indicated that the high-risk group might stimulate the cell cycle and activate oncogenic pathways such as MAPK, mTOR, and VEGF, whereas the low-risk group mainly regulated amino acid, fatty acid, and drug metabolism. Additionally, the high-risk group had more TMB, upregulated immune checkpoint molecule expression, including PD-1, CTLA4, TIM3, and LAG3, and preferentially formed an immunosuppressive microenvironment. Accordingly, potential therapeutic responses showed that high-risk patients were potentially sensitive to inhibitors targeting the cell cycle and MAPK signaling, with patients possibly benefiting from immunotherapy. Moreover, multiplex immunofluorescence assays indicated that high-risk HCC samples displayed distinct immunosuppressive features, with abundant M2-polarized macrophages and T-regulatory cell infiltration. Conclusion: The m6A signature had a prominent capacity to evaluate OS and characterize the tumor immune microenvironment of HCC, which may serve as a useful approach for risk stratification management and provide a valuable clue to choosing rational therapeutic strategies.

Arouse potential stemness: Intrinsic and acquired stem cell therapeutic strategies for advanced liver diseases.

Liver diseases are a major health issue, and prolonged liver injury always progresses. Advanced liver disorders impair liver regeneration. Millions of patients die yearly worldwide, even with the available treatments of liver transplantation and artificial liver support system. With its abundant cell resources and significant differentiative potential, stem cell therapy is a viable treatment for various disorders and offers hope to patients waiting for orthotopic liver transplantation. Considering such plight, stem cell therapeutic strategies deliver hope to the patients. Moreover, we conclude intrinsic and acquired perspectives based on stem cell sources. The properties and therapeutic uses of these stem cells' specific types or sources were then reviewed. Owing to the recent investigations of the above cells, a safe and effective therapy will emerge for advanced liver diseases soon.

Early warning of tipping in a chemical model with cross-diffusion via spatiotemporal pattern formation and transition.

The spatiotemporal pattern formation and transition driven by cross-diffusion of the Gray-Scott model are investigated for the early warning of tipping in this paper. The mathematical analyses of the corresponding non-spatial model and spatial model are performed first, which enable us to have a comprehensive understanding. Then, the linear stability analysis and the multiple scale analysis method exhibit that cross-diffusion is the key mechanism for the evolution of spatiotemporal patterns. Through selecting a cross-diffusion coefficient as the bifurcation parameter, the amplitude equations that can describe structural transition and determine the stability of different types of Turing patterns are derived. Ultimately, numerical simulations verify the validity of the theoretical results. It is demonstrated that in the absence of cross-diffusion, the spatiotemporal distribution of substances is homogeneous. Nevertheless, when the cross-diffusion coefficient exceeds its threshold value, the spatiotemporal distribution of substances will become inhomogeneous in space. As the cross-diffusion coefficient increases, the Turing instability region will be extended, leading to various types of Turing patterns: spots, stripes, and a mixture of spots and stripes.

Terahertz super-resolution imaging based on a confocal waveguide and a slider-crank scanning mechanism.

Due to the limitation of Abbe diffraction limit, the traditional terahertz (THz) continuous wave imaging methods based on lenses or mirrors are difficult to achieve super-resolution. Here we present a confocal waveguide scanning method for THz reflective super-resolution imaging. In the method, a low loss THz hollow waveguide is used to replace the traditional terahertz lens or parabolic mirror. Through optimizing the size of the waveguide, we can achieve far field subwavelength focusing at 0.1THz and achieve super-resolution terahertz imaging. In addition, a slider-crank high-speed scanning mechanism is used in the scanning system, and the imaging speed is more than 10 times faster than the traditional step scanning system based on linear guides.

When immunotherapy meets liver transplantation for hepatocellular carcinoma: A bumpy but promising road.

Liver transplantation (LT) is a highly curative therapy for patients with hepatocellular carcinoma (HCC). However, due to the shortage of donor livers and rapid progression of HCC, a majority of patients are dropped out from the waitlist. Recently, immunotherapy has shown great promise in the treatment of advanced HCC. However, the use of immunotherapy is limited in LT mainly due to the potentially increasing risk of graft rejection. One of the main challenges for researchers is the protection of donor graft from an immunotherapy-boosted immune response mounted by the host. Besides, the safety, availability, and costs of immunotherapy are other challenges that need to be addressed. Here, we reviewed the literature involving patients who received immunotherapy prior to transplant to avoid waitlist dropouts and following transplantation to prevent the progression of tumor recurrence and metastasis. Statistically, the incidence of rejection was 25.0% pre-transplant and 18.5% post-transplant. Based on the review of these clinical studies, we can conclude that conducting clinical trials on the safety and efficacy of currently available immunotherapy drugs and identifying novel immunotherapy targets through extensive research may be promising for patients who do not meet the selection criteria for LT and who experience post-transplant recurrence. To date, the clinical experience on the use of immunotherapy before or after LT comes from individual case studies. Although some of the reported results are promising, they are not sufficient to support the standardized use of immunotherapy in clinical practice.

Tree-structured neural networks: Spatiotemporal dynamics and optimal control.

How the network topology drives the response dynamic is a basic question that has not yet been fully answered in neural networks. Elucidating the internal relation between topological structures and dynamics is instrumental in our understanding of brain function. Recent studies have revealed that the ring structure and star structure have a great influence on the dynamical behavior of neural networks. In order to further explore the role of topological structures in the response dynamic, we construct a new tree structure that differs from the ring structure and star structure of traditional neural networks. Considering the diffusion effect, we propose a diffusion neural network model with binary tree structure and multiple delays. How to design control strategies to optimize brain function has also been an open question. Thus, we put forward a novel full-dimensional nonlinear state feedback control strategy to optimize relevant neurodynamics. Some conditions about the local stability and Hopf bifurcation are obtained, and it is proved that the Turing instability does not occur. Moreover, for the formation of the spatially homogeneous periodic solution, some diffusion conditions are also fused together. Finally, several numerical examples are carried out to illustrate the results' correctness. Meanwhile, some comparative experiments are rendered to reveal the effectiveness of the proposed control strategy.

Stability and Bifurcation Exploration of Delayed Neural Networks With Radial-Ring Configuration and Bidirectional Coupling.

For decades, studying the dynamic performances of artificial neural networks (ANNs) is widely considered to be a good way to gain a deeper insight into actual neural networks. However, most models of ANNs are focused on a finite number of neurons and a single topology. These studies are inconsistent with actual neural networks composed of thousands of neurons and sophisticated topologies. There is still a discrepancy between theory and practice. In this article, not only a novel construction of a class of delayed neural networks with radial-ring configuration and bidirectional coupling is proposed, but also an effective analytical approach to dynamic performances of large-scale neural networks with a cluster of topologies is developed. First, Coates' flow diagram is applied to acquire the characteristic equation of the system, which contains multiple exponential terms. Second, by means of the idea of the holistic element, the sum of the neuron synapse transmission delays is regarded as the bifurcation argument to investigate the stability of the zero equilibrium point and the beingness of Hopf bifurcation. Finally, multiple sets of computerized simulations are utilized to confirm the conclusions. The simulation results expound that the increase in transmission delay may cause a leading impact on the generation of Hopf bifurcation. Meanwhile, the number and the self-feedback coefficient of neurons are also playing significant roles in the appearance of periodic oscillations.

The metabolites of de novo NAD+ synthesis are a valuable predictor of acute kidney injury.

Background: Acute kidney injury (AKI) is often iatrogenic and potentially preventable. Reduced renal nicotinamide adenine dinucleotide (NAD+) is reported to increase the susceptibility of AKI. The present study explored the predictive value of urinary de novo NAD+ synthetic metabolites for AKI using two independent cohorts. Methods: The expression of de novo NAD+ synthetic enzymes in human kidney was examined by immunohistochemistry and single-cell transcriptomes. Urine samples were collected from two independent cohorts: the methotrexate (MTX) cohort with high-dose MTX treatment for lymphoma (n = 189) and the liver transplantation cohort with orthotopic liver transplantation (n = 49). Urinary metabolomics study of NAD+ de novo synthesis was performed by liquid chromatography with mass spectrometry, screening for AKI predictive biomarkers. Nephroseq database and immunohistochemistry were used to analyze kidney de novo NAD+ synthetic enzymes expression in AKI-susceptible conditions. Results: Human proximal tubule was the main structure in the kidney that expressed the necessary enzymes for NAD+ de novo synthesis. In the MTX cohort, the urinary quinolinic acid (QA)/3-hydroxyanthranilic acid (3-OH AA) ratio before chemotherapy was significantly lower in those who developed AKI after chemotherapy compared with those who did not. This finding was consistent in the liver transplantation cohort. The area under the receiver-operating characteristic curve (AUC) of urinary QA/3-OH AA for AKI prediction was 0.749 and 0.729 in two cohorts, respectively. 3-Hydroxyanthranilic acid dioxygenase (HAAO), the enzyme catalyzing QA synthesis from 3-OH AA, decreased in AKI-susceptible diabetic kidneys. Conclusions: The human proximal tubules were important source of NAD+ from the de novo pathway. Reduced urinary QA/3-OH AA ratio, which possibly suggested decreased HAAO activity, could be a potential AKI predictive biomarker.

Individual dose recommendations for drug interaction between tacrolimus and voriconazole in adult liver transplant recipients: A semiphysiologically based population pharmacokinetic modeling approach.

The magnitude of drug-drug interaction between tacrolimus and voriconazole is highly variable, and individually tailoring the tacrolimus dose when concomitantly administered with voriconazole remains difficult. This study aimed to develop a semiphysiologically based population pharmacokinetic (semi-PBPK) model and a web-based dashboard to identify the dynamic inhibition of tacrolimus metabolism caused by voriconazole and provide individual tacrolimus regimens for Chinese adult liver transplant recipients. A total of 264 tacrolimus concentrations and 146 voriconazole concentrations were prospectively collected from 32 transplant recipients. A semi-PBPK model with physiological compartments including the gut wall, portal vein, and liver was developed using the nonlinear mixed-effects modeling software NONMEM (version 7.4). A web-based dashboard was established in R software (version 3.6.1) to recommend the individual tacrolimus regimens when concomitantly administered with voriconazole. The reversible inhibition of tacrolimus metabolism caused by voriconazole was investigated in both the liver and the gut wall. Moreover, voriconazole could highly inhibit the CYP3A activity in the gut wall more than in the liver. BMI and postoperative days were identified as significant covariates on intrinsic intestinal and hepatic clearance of tacrolimus, respectively. Age and postoperative days were identified as significant covariates on the volume of distribution of voriconazole. The individual tacrolimus regimens when concomitantly administered with voriconazole could be recommended in the dashboard (https://tac-vor-ddi.shinyapps.io/shinyapp3/). In conclusion, the semi-PBPK model successfully described the dynamic inhibition process between tacrolimus and voriconazole, and the web-based dashboard could provide individual tacrolimus regimens when concomitantly administered with voriconazole.