Liver Transplantation for Hepatocellular Carcinoma: A Narrative Review and A Glimpse into The Future.

Liver transplantation (LT) is a highly effective treatment for carefully selected patients with hepatocellular carcinoma (HCC). In this review, we explored the development of LT selection criteria and organ allocation policies, comparing original data to underscore their historical progression into the intricate task of quantitatively estimating pre- and post-LT survivals. We emphasized the role of biomarkers such as serum alpha-fetoprotein, Des-gamma-carboxy-prothrombin, circulating tumor cells, and circulating tumor DNA in predicting patient outcomes. Additionally, we examined the transplant-associated survival benefits and the difficulties in accurately calculating these benefits. We also reviewed recent advancements in targeted therapy and checkpoint inhibitors for advanced, inoperable HCC and projected their integration into LT for HCC. We further discussed the growing use of living donor liver transplants in the United States and compared its outcomes with those of deceased donor liver transplants. Furthermore, we examined the progress in machine perfusion techniques, which have shown potential in improving patient outcomes and enlarging the donor pool. These advancements present opportunities to enhance LT patient survivals, refine selection criteria, establish new priority metrics, develop innovative bridging and downstaging strategies, and formulate redesigned LT strategies for HCC treatments.

Ex-situ machine perfusion in clinical liver transplantation: Current practices and future directions.

Ex-situ machine perfusion of the liver has surmounted traditional limitations associated with static cold storage in the context of organ preservation. This innovative technology has changed the landscape of liver transplantation by mitigating ischemia perfusion injury, offering a platform for continuous assessment of organ quality, and providing an avenue for optimizing use of traditionally marginal allografts. This review summarizes the contemporary clinical applications of machine perfusion devices, and discusses potential future strategies for real-time viability assessment, therapeutic interventions, and modulation of organ function after recovery.

Intestinal dysbiosis exacerbates susceptibility to the anti-NMDA receptor encephalitis-like phenotype by changing blood brain barrier permeability and immune homeostasis.

Changes in the intestinal microbiota have been observed in patients with anti-N-methyl-D-aspartate receptor encephalitis (NMDARE). However, whether and how the intestinal microbiota is involved in the pathogenesis of NMDARE susceptibility needs to be demonstrated. Here, we first showed that germ-free (GF) mice that underwent fecal microbiota transplantation (FMT) from NMDARE patients, whose fecal microbiota exhibited low short-chain fatty acid content, decreased abundance of Lachnospiraceae, and increased abundance of Verrucomicrobiota, Akkermansia, Parabacteroides, Oscillospirales, showed significant behavioral deficits. Then, these FMT mice were actively immunized with an amino terminal domain peptide from the GluN1 subunit (GluN1356-385) to mimic the pathogenic process of NMDARE. We found that FMT mice showed an increased susceptibility to an encephalitis-like phenotype characterized by more clinical symptoms, greater pentazole (PTZ)-induced susceptibility to seizures, and higher levels of T2 weighted image (T2WI) hyperintensities following immunization. Furthermore, mice with dysbiotic microbiota had impaired blood-brain barrier integrity and a proinflammatory condition. In NMDARE-microbiota recipient mice, the levels of Evan's blue (EB) dye extravasation increased, ZO-1 and claudin-5 expression decreased, and the levels of proinflammatory cytokines (IL-1, IL-6, IL-17, TNF-α and LPS) increased. Finally, significant brain inflammation, mainly in hippocampal and cortical regions, with modest neuroinflammation, immune cell infiltration, and reduced expression of NMDA receptors were observed in NMDARE microbiota recipient mice following immunization. Overall, our findings demonstrated that intestinal dysbiosis increased NMDARE susceptibility, suggesting a new target for limiting the occurrence of the severe phenotype of NMDARE.

Limitations on knowledge of autoimmune encephalitis and barriers to its treatment among neurologists: a survey from western China.

BACKGROUND: Autoimmune encephalitis (AE) is a group of severe antibody-mediated brain diseases. The understanding of clinical management of AE has developed rapidly. However, the knowledge level of AE and barriers to effective treatment among neurologists remains unstudied. METHODS: We conducted a questionnaire survey among neurologist in western China on knowledge of AE, treatment practices, and perspectives on barriers to treatment. RESULTS: A total of 1113 neurologists were invited and 690 neurologists from 103 hospitals completed the questionnaire with a response rate of 61.9%. Respondents correctly answered 68.3% of medical questions about AE. Some respondents (12.4%) never assayed for diagnostic antibodies if patients had suspected AE. Half (52.3%) never prescribed immunosuppressants for AE patients, while another 7.6% did not know whether they should do so. Neurologists who never prescribed immunosuppressants were more likely to have less education, a less senior job title, and to practice in a smaller setting. Neurologists who did not know whether to prescribe immunosuppressants were associated with less AE knowledge. The most frequent barrier to treatment, according to respondents, was financial cost. Other barriers to treatment included patient refusal, insufficient AE knowledge, lack of access to AE guidelines, drugs or diagnostic test, etc. CONCLUSION: Neurologists in western China lack AE knowledge. Medical education around AE is urgent needed and should be more targeted to individuals with less educated level or working in non-academic hospitals. Policies should be developed to increase the availability of AE related antibody testing or drugs and reduce the economic burden of disease.

Influenza Virus Neuraminidase Engages CD83 and Promotes Pulmonary Injury.

Influenza A viruses cause severe respiratory illnesses in humans and animals. Overreaction of the innate immune response to influenza virus infection results in hypercytokinemia, which is responsible for mortality and morbidity. However, the mechanism by which influenza induces hypercytokinemia is not fully understood. In this study, we established a mouse-adapted H9N2 virus, MA01, to evaluate the innate immune response to influenza in the lung. MA01 infection caused high levels of cytokine release, enhanced pulmonary injury in mice, and upregulated CD83 protein in dendritic cells and macrophages in the lung. Influenza virus neuraminidase (NA) unmasked CD83 protein and contributed to high cytokine levels. Furthermore, we provide evidence that CD83 is a sialylated glycoprotein. Neuraminidase treatment enhanced lipopolysaccharide (LPS)-stimulated NF-κB activation in RAW264.7 cells. Anti-CD83 treatment alleviated influenza virus-induced lung injury in mice. Our study indicates that influenza virus neuraminidase modulates CD83 status and contributes to the "cytokine storm," which may suggest a new approach to curb this immune injury.IMPORTANCE The massive release of circulating mediators of inflammation is responsible for lung injury during influenza A virus infection. This phenomenon is referred to as the "cytokine storm." However, the mechanism by which influenza induces the cytokine storm is not fully understood. In this study, we have shown that neuraminidase unmasked CD83 protein in the lung and contributed to high cytokine levels. Anti-CD83 treatment could diminish immune damage to lung tissue. The NA-CD83 axis may represent a target for an interruption of influenza-induced lung damage.

The bile acid-activated retinoic acid response in dendritic cells is involved in food allergen sensitization.

BACKGROUND: Alteration of commensal microbiota is highly correlated with the prevalence of allergic reactions to food in the gastrointestinal tract. The mechanisms by which microbiota modulate food allergen sensitization in the mucosal site are not fully understood. METHODS: We generate DCs specific knockout of retinoic acid receptor α (Rara) gene mice (DC KO Rara) to evaluate food sensitization. The bile acid-activated retinoic acid response was evaluated by flow cytometry, real-time RT-PCR and Illumina transcriptome sequencing. The global effect of Abx treatment on BA profiles in the mucosal lymph tissue mLN in mice was examined by UPLC-MS analysis. RESULTS: In this study, we demonstrate that depletion of commensal gut bacteria leads to enhanced retinoic acid (RA) signaling in mucosal dendritic cells (DCs). RA signaling in DCs is required for the production of food allergen-specific IgE and IgG1. Antibiotics induced an enlarged bile acid (BA) pool, and dysregulated BA profiles contributed to enhanced RA signaling in mucosal DCs. BA-activated RA signaling promoted DC upregulation of interferon I signature, RA signature, OX40L, and PDL2, which may lead to T helper 2 differentiation of CD4+ T cells. BA-activated RA signaling involved the farnesoid X receptor and RA receptor α (RARa) interaction. Depletion of bile acid reduces food allergen specific IgE and IgG1 levels in mice. CONCLUSION: Our research unveils a mechanism of food sensitization modulated by BA-RA signaling in DCs, which suggests a potential new approach for the intervention of food allergic reactions.

Deciphering the bacterial microbiome in response to long-term mercury contaminated soil.

Hg contaminated soils are of concern due to the toxic effects on soil microbes. Currently, the adaptation of bacterial community to long-term Hg contamination remains largely unknown. Here, we assessed the effects of Hg contaminated soils on the bacterial communities under controlled conditions using 16S rRNA gene amplicon sequencing. The results showed that the bacterial α-diversity and richness were significant positively correlated with total Hg (p < 0.05). Land-use type, pH, EC, TK, and nitrate-N played important roles in shaping the bacterial communities. Long-term Hg-contaminated soils can be divided into three types based on land use types: slag type, farmland type, and mining area type. The dominant phyla include Proteobacteria, Actinobacteriota, Acidobacteriota, Chloroflexi, and Firmicutes. The dominant genera identified were Pseudomonas, Gaiella, Sphingomonas, Bacillus, Arthrobacter, Nocardioides. Network analysis showed that dominant taxa had non-random co-occurrence patterns and module 1 had an important role in responding Hg stress. Keystone genera identified were Bauldia, Phycicoccus, Sphingomonas, Gaiella, Nitrospira. The above results further our understanding of the adaptation of the bacterial community in long-term Hg-contaminated soil. This study has important guiding significance for the use of bacterial consortia to remediate Hg-contaminated soil.

Physicochemical and structural properties of dietary fiber from Rosa roxburghii pomace by steam explosion.

Rosa roxburghii pomace was treated by steam explosion (SE) at 0.87 MPa for 97 s. After SE treatment, the Insoluble dietary fiber (IDF) content of Rosa roxburghii pomace decreased from 45.13 ± 0.23 to 30.01 ± 0.15%, and the soluble dietary fiber (SDF) content increased from 9.31 ± 0.07 to 15.82 ± 0.31%. The structure of IDF and SDF after SE showed that the original compact structures were destroyed, and the specific surface areas increased. Thermal analysis showed that the thermal stability of the modified SDF was improved. However, SE did not change the crystal structure and functional group composition of IDF and SDF. Physicochemical analysis indicated that IDF had better hydration capacity after SE treatment, and the oil-holding capacities of IDF and SDF were also significantly improved. SE is an effective method to improve the utilization of Rosa roxburghii pomace and a feasible method for modification of dietary fiber.

The association between ECG criteria and Echo criteria for left ventricular hypertrophy in a general Chinese population.

BACKGROUND: Several ECG criteria have been widely used for diagnosis of left ventricular hypertrophy (LVH) in clinical practice. However, their performance in a general Chinese population is limited. METHODS AND RESULTS: A multi-stage, stratified cluster sampling across China was performed and 7415 representative Chinese adults aged 18-85 years were analyzed. ECG was collected by using GE MAC 5500 machine. The association between five ECG-LVH criteria (i.e., Peguero-Lo Presti, Cornell, Cornell product, Sokolow-Lyon and Sokolow-Lyon product) and echocardiographic LVH (Echo-LVH) was assessed by Pearson's correlation, diagnostic statistics like predictive values, and receiver operating characteristics (ROC) curve. We found that the prevalence of the Echo-LVH was 11% while ECG-LVH ranged from 3% to 27%. All ECG-LVH criteria had high negative predictive value (NPV) (89%) and specificity (73-96%) but low positive predictive value (PPV) (12-24%) and sensitivity (4-29%). The newly Peguero-Lo Presti criteria had higher sensitivity (29%) but lower specificity (73%) and accuracy (68%) compared with other criteria. Cornell product had the best diagnostic performance (AUC: 0.59), as well as the highest specificity (96%) and accuracy (86%) but lowest sensitivity (4%). Among single-lead components of ECG criteria, RaVL voltage and QRS duration performed relatively better than others. Hypertensive and older individuals had higher sensitivity but lower specificity and accuracy than their counterparts. CONCLUSION: ECG-LVH criteria had high NPV to detect Echo-LVH. Though with higher sensitivity, Peguero-Lo Presti criteria did not have better diagnostic performance to detect Echo-LVH. RaVL and QRS duration had stronger association with Echo-LVH among all single-lead components.

Bisphenol A induces apoptosis through GPER-dependent activation of the ROS/Ca2+-ASK1-JNK pathway in human granulosa cell line KGN.

Bisphenol A (BPA) is widely distributed in the environment and human surroundings and is closely related to the occurrence of many chronic diseases including female infertility. Although BPA-induced granulosa cell apoptosis has been widely reported, the underlying mechanisms remain unknown. In this study, we evaluated the induction effect of BPA exposure on apoptosis and mechanisms of regulation in KGN cells (a human granulosa-like tumor cell line). Our results indicated that BPA induced apoptosis of KGN cells in a dose- and time-dependent manner. BPA exposure significantly promoted the expression of pro-apoptotic proteins and decreased mitochondrial membrane potential. We also observed that high concentrations of BPA significantly promoted the generation of reactive oxygen species (ROS) and calcium ion (Ca2+) accumulation. The involvement of ROS and Ca2+ in BPA-induced KGN cell apoptosis was confirmed by pretreatment with NAC (an antioxidant) and BAPTA-AM (a calcium chelator). After inhibitors pretreatment to block the corresponding signaling pathways, it was found that BPA-induced phosphorylation of JNK and ASK1 proteins and apoptosis of KGN cells were significantly inhibited. We pretreated with G15 (a GPER inhibitor) and found that BPA-induced ROS generation and Ca2+ accumulation and apoptosis were significantly inhibited. These results suggest that BPA exposure induces KGN cell apoptosis through GPER-dependent activation of the ROS/Ca2+-ASK1-JNK signaling pathway. Our study provides mechanisms by which BPA induced apoptosis of granulosa cells and ovarian dysfunction.

Preamble Design and Collision Resolution in a Massive Access IoT System.

How to support massive access efficiently is one of the challenges in the future Internet of Things (IoT) systems. To address such challenge, this paper proposes an effective preamble collision resolution scheme to sustain massive random access (RA) for an IoT system. Specifically, a new sub-preamble structure is first proposed to reduce the preamble collision probability. To identify different devices that send the same preamble to the gNB on the same physical random access channel (PRACH), a multiple timing advance (TA) capturing scheme is then proposed. Thereafter, an RA scheme is designed to sustain massive access and the performance of the scheme is studied analytically. Finally, the effectiveness of the proposed RA scheme is validated by extensive simulation experiments in terms of preamble detection probability, preamble collision probability, RA success probability, resource efficiency and TA capturing.

Stochastic Latency Guarantee in Wireless Powered Virtualized Sensor Networks.

How to guarantee the data rate and latency requirement for an application with limited energy is an open issue in wireless virtualized sensor networks. In this paper, we integrate the wireless energy transfer technology into the wireless virtualized sensor network and focus on the stochastic performance guarantee. Firstly, a joint task and resource allocation optimization problem are formulated. In order to characterize the stochastic latency of data transmission, effective capacity theory is resorted to study the relationship between network latency violation probability and the transmission capability of each node. The performance under the FDMA mode and that under the TDMA mode are first proved to be identical. We then propose a bisection search approach to ascertain the optimal task allocation with the objective to minimize the application latency violation probability. Furthermore, a one-dimensional searching scheme is proposed to find out the optimal energy harvesting time in each time block. The effectiveness of the proposed scheme is finally validated by extensive numerical simulations. Particularly, the proposed scheme is able to lower the latency violation probability by 11.6 times and 4600 times while comparing with the proportional task allocation scheme and the equal task allocation scheme, respectively.

Complete response to the combination of Lenvatinib and Pembrolizumab in an advanced hepatocellular carcinoma patient: a case report.

BACKGROUND: The majority of patients diagnosed with hepatocellular carcinoma (HCC) have advanced diseases and many are not eligible for curative therapies. CASE PRESENTATION: We report a rare case of HCC from a patient who had a complete response (CR) with the use of combination of Lenvatinib and Pembrolizumab. A 63-year-old man presented at the hospital with serious abdominal pain and was found to have a mass with heterogeneous enhancement and with hemorrhage in segment III of the liver after the examination of abdominal computerized tomography (CT) scan. The patient's history of viral hepatitis B infection, liver cirrhosis and the ɑ-fetoprotein (AFP) level of 14,429.3 ng/ml supported the clinical diagnosis of HCC and laboratory results demonstrated liver function damage status (Child-Pugh class B, Score 8). The patient first received hepatic arterial embolization treatment on 28th November 2017. At this stage supportive care was recommended for poor liver function. In February 2018, combined immunotherapy of Pembrolizumab (2 mg/kg, q3w) and Lenvatinib (8 mg-4 mg, qd) were performed. Nine months following the treatment he had a CR and now, 22 months since the initial treatment, there is no clinical evidence of disease progression. The current overall survival is 22 months. CONCLUSIONS: HCC is a potentially lethal malignant tumor and the combination of immunotherapy plus anti-angiogenic inhibitors shows promising outcome for advanced diseases.

Effects of Pseudomonas alkylphenolica KL28 on immobilization of Hg in soil and accumulation of Hg in cultivated plant.

OBJECTIVE: The available content of mercury (Hg) in farmland soil is directly related to the safety of agricultural products. Meanwhile, humans may accumulate high concentrations of Hg through the food chain, resulting in health damage. Regarding the remediation technologies of Hg-contaminated soil, research and development is mainly concentrated on the immobilisation of Hg in soil and efficient extraction by accumulators. Therefore, in this work, the highly Hg-tolerant strain Pseudomonas alkylphenolica KL28 was used to study the removal effect of Hg in a solution, immobilization effect of Hg in soil, and its effect on growth, Hg accumulation and photosynthetic characteristics of Brassica campestris L. RESULTS: KL28 could effectively remove Hg2+ in the solution, with the removal ratio of 96.0% at 24 h. This strain could reduce decreases in shoots' and roots' dry weights by 31% and 16%, respectively, at a Hg concentration of 20 mg/L. The available Hg in the soil decreased to 4.7-9.4% in 8 days treated with KL28 bacterial solution at a dosage of 100 L/hm2. Meanwhile, with increases in Hg concentrations, Fv/Fm, Y(II), Y(I) and Y(NPQ) in the leaves of B. campestris showed a downward trend while Y(ND) and Y(NO) displayed an upward trend. Under the stress of 20 mg/L Hg2+, KL28 could reduce the Fv/Fm from 11.2 to 6.1%. CONCLUSIONS: KL28 could effectively remove Hg in the solution, immobilize Hg in soil, promote growth, decrease Hg accumulation and affect photosynthetic characteristics of B. campestris, indicating its potential use in Hg contaminated soils.

Characterization of cadmium-resistant rhizobacteria and their promotion effects on Brassica napus growth and cadmium uptake.

Excessive cadmium (Cd) accumulation in soil can adversely affect plants, animals, microbes, and humans; therefore, novel and uncharacterized Cd-resistant plant-growth-promoting rhizobacteria (PGPR) are required to address this issue. In the paper, 13 bacteria were screened, their partial 16S rRNA sequences determined, and the isolates, respectively, clustered into Curtobacterium (7), Chryseobacterium (4), Cupriavidus (1), and Sphingomonas (1). Evaluation of PGP traits, including indole-3-acetic acid (IAA) production, 1-aminocyclopropane-1-carboxylate (ACC) deaminase activity, siderophore secretion, and cyanhydric acid production, identified Cupriavidus necator GX_5, Sphingomonas sp. GX_15, and Curtobacterium sp. GX_31 as promising candidates for PGPR based on high IAA or ACC deaminase production. Additionally, root-elongation assays indicated that inoculating GX_5, _15, or _31 increased Brassica napus root length both in the presence and absence of Cd by 19.75-29.96% and 19.15-31.69%, respectively. Pot experiments indicated that inoculating B. napus with GX_5, _15, and _31 significantly increased the dry weight of above-ground tissues and root biomass by 40.97-85.55% and 18.99-103.13%, respectively. Moreover, these isolates significantly increased Cd uptake in the aerial parts and root tissue of B. napus by 7.38-11.98% and 48.09-79.73%, respectively. These results identified GX_5, _15, or _31 as excellent promoters of metal remediation by using microorganism-associated phytoremediation.

Sarcopenia in cirrhotic patients: Does frailty matter while waiting for a liver transplant?

Sarcopenia reflects patient frailty and should be routinely assessed due to its high prevalence in cirrhotic patients awaiting liver transplants. Pre-transplant nutritional optimization should be tailored for patients with a definitive diagnosis of sarcopenia, therefore improving functional status at transplant and reducing post-transplant mortality. Hepatologists and transplant surgeons should have raised awareness regarding sarcopenia and the reflected frailty that hinder posttransplant outcomes. The policymakers should also take into account when modifying the organ allocation model that sarcopenia or frailty might become a decisive factor in allocating organs for cirrhotic patients, in order to ensure post-transplant survival and quality of life.

Pomegranate juice-containing serum inhibits migration of hepatocellular carcinoma cells and promotes apoptosis by induction of mitochondrial dysfunction.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with an insidious onset and poor prognosis. Pomegranate is a fruit rich in many natural products with anti-cancer potential; however, its direct biological effects are difficult to evaluate in vitro because of changes in its active components after absorption and metabolism. This study was conducted to prepare pomegranate juice-containing serum (PJ serum) by gavage of pomegranate juice (PJ) in rats and to collect serum. The aim was to investigate the components and the effects of PJ serum on HCC cells by serum pharmacology. 56 compounds were identified in the PJ serum, including 6 prototype components. PJ serum selectively inhibited HCC cells proliferation and migration, and it promoted apoptosis of HCC cells without affecting LO2 cells activity. Furthermore, PJ serum reduced the mitochondrial membrane potential and increased the calcium ion concentration in HCC cells. Mechanistically, PJ serum up-regulated the expression of the Bax family, Caspases and TIMP2/MMP2, and down-regulated the expression of MMP9. This study revealed that PJ serum inhibited HCC cell migration by regulating the TIMP2/MMP2 balance and MMP9 expression and promoted HCC cell apoptosis by inducing mitochondrial dysfunction and causing a Caspase cascade. The polyphenols and flavonoids in PJ may be important components responsible for its anti-HCC activity after metabolism.

Differentiation between viral and autoimmune limbic encephalitis: a prospective cohort study with development and validation of a diagnostic model.

BACKGROUND: Distinguishing between viral encephalitis (VE) and autoimmune limbic encephalitis (ALE) presents a clinical challenge due to the overlap in symptoms. We aimed to develop and validate a diagnostic prediction model to differentiate VE and ALE. METHODS: A prospective observational multicentre cohort study, which continuously enrolled patients diagnosed with either ALE or VE from October 2011 to April 2023. The demographic data, clinical features, and laboratory test results were collected and subjected to logistic regression analyses. The model was displayed as a web-based nomogram and then modified into a scored prediction tool. Model performance was assessed in both derivation and external validation cohorts. RESULTS: A total of 2423 individuals were recruited, and 1001 (496 VE, 505 ALE) patients were included. Based on the derivation cohort (389 VE, 388 ALE), the model was developed with eight variables including age at onset, acuity, fever, headache, nausea/vomiting, psychiatric or memory complaints, status epilepticus, and CSF white blood cell count. The model showed good discrimination and calibration in both derivation (AUC 0.890; 0.868-0.913) and external validation (107 VE, 117 ALE, AUC 0.872; 0.827-0.917) cohorts. The scored prediction tool had a total point that ranged from - 4 to 10 also showing good discrimination and calibration in both derivation (AUC 0.885, 0.863-0.908) and external validation (AUC 0.868, 0.823-0.913) cohorts. CONCLUSIONS: The prediction model provides a reliable and user-friendly tool for differentiating between the VE and ALE, which would benefit early diagnosis and appropriate treatment and alleviate economic burdens on both patients and society.