Blocking MARCO+ tumor-associated macrophages improves anti-PD-L1 therapy of hepatocellular carcinoma by promoting the activation of STING-IFN type I pathway.

The PD-L1/PD-1 axis is a classic immunotherapy target. However, anti-PD-L1/PD-1 therapy alone can not achieve satisfactory results in solid tumors, especially liver cancer. Among the several factors involved in tumor anti-PD-L1/PD-1 treatment resistance, tumor-associated macrophages (TAMs) have attracted attention because of their immunosuppressive ability. TAMs with a macrophage receptor with a collagenous structure (MARCO) are a macrophage subset group with strong immunosuppressive abilities. Clinical specimens and animal experiments revealed a negative correlation between MARCO + TAMs and patient prognosis with liver cancer. Transcriptional data and in vitro and in vivo experiments revealed that MARCO + TAM immunosuppressive ability was related to secretion. MARCO suppressed IFN-ß secretion from TAMs, reducing antigen presentation molecule expression, infiltration, and CD8+T cell dysfunction, thus producing an immunosuppressive microenvironment in liver cancer. MARCO can promote dying tumor cell clearance by macrophages, reducing tumor-derived cGAMP and ATP accumulation in the tumor microenvironment and inhibiting sting-IFN-ß pathway activation mediated by P2X7R in MARCO+TAMs. Animal experiments revealed that the MARCO and PD-L1 monoclonal antibody combination could significantly inhibit liver cancer growth. Conclusively, targeting MARCO+TAMs can significantly improve anti-PD-L1 resistance in liver cancer, making it a potential novel immune target for liver cancer therapy.

Nanosecond pulsed electric field stimulates CD103+ DC accumulation in tumor microenvironment via NK-CD103+ DC crosstalk.

CD103+ DC is crucial for antitumor immune response. As a promising local therapy on cancers, nanosecond pulsed electric field (nsPEF) has been widely reported to stimulate anti-tumor immune response, but the underlying relationship between intratumoral CD103+ DC and nsPEF treatment remains enigmatic. Here, we focused on the behavior of CD103+ DC in response to nsPEF treatment and explored the underlying mechanism. We found that the nsPEF treatment led to the activation and accumulation of CD103+ DC in tumor. Depletion of CD103+ DC via Batf3-/- mice demonstrated CD103+ DC was necessary for intratumoral CD8+ T cell infiltration and activation in response to nsPEF treatment. Notably, NK cells recruited CD103+ DC into nsPEF-treated tumor through CCL5. Inflammatory array revealed CD103+ DC-derived IL-12 mediated the CCL5 secretion in NK cells. In addition, the boosted activation and infiltration of intratumoral CD103+ DC were abolished by cGAS-STING pathway inhibition, following IL-12 and CCL5 decreasing. Furthermore, nsPEF treatment promoting CD103+ DC-mediated antitumor response enhanced the effects of CD47 blockade strategy. Together, this study uncovers an unprecedented role for CD103+ DC in nsPEF treatment-elicited antitumor immune response and elucidates the underlying mechanisms.

Correction: Ding et al. Full-Right Full-Left Split Liver Transplantation for Two Adult Recipients: A Single-Center Experience in China. J. Clin. Med. 2023, 12, 3782.

Error in Figure/Table [...].

Full-Right Full-Left Split Liver Transplantation for Two Adult Recipients: A Single-Center Experience in China.

BACKGROUND: The most effective treatment for end-stage liver diseases is liver transplantation, which is impeded by the shortage of donor livers. Split liver transplantation (SLT) is important for addressing the donor liver shortage. However, full-right full-left SLT for two adult recipients is globally rarely conducted. This study aimed to investigate the clinical outcomes of this technique. METHODS: We retrospectively analyzed the clinical data of 22 recipients who underwent full-right full-left SLT at Shulan (Hangzhou) Hospital between January, 2021 and September, 2022. The graft-to-recipient weight ratio (GRWR), cold ischemia time, operation time, length of the anhepatic phase, intraoperative blood loss, and red blood cell transfusion amount were all analyzed. The differences in liver function recovery after transplantation were compared between the left and right hemiliver groups. The postoperative complications and prognosis of the recipients were also analyzed. RESULTS: The livers of 11 donors were transplanted into 22 adult recipients. The GRWR ranged from 1.16-1.65%, the cold ischemia time was 282.86 ± 134.87 min, the operation time was 371.32 ± 75.36 min, the anhepatic phase lasted 60.73 ± 19.00 min, the intraoperative blood loss was 759.09 ± 316.84 mL, and the red blood cell transfusion amount was 695.45 ± 393.67 mL. No significant difference in the levels of liver function markers, total bilirubin, aspartate aminotransferase, or alanine aminotransferase between left and right hemiliver groups at 1, 3, 5, 7, 14, and 28 d postoperatively was observed (both p > 0.05). One recipient developed bile leakage 10 d after transplantation, which improved with endoscopic retrograde cholangiopancreatography-guided nasobiliary drainage and stent placement. Another developed portal vein thrombosis 12 d after transplantation and underwent portal vein thrombectomy and stenting to restore portal vein blood flow. A color Doppler ultrasound performed 2 d after transplantation revealed hepatic artery thrombosis in one patient, and thrombolytic therapy was administered to restore hepatic artery blood flow. The liver function of other patients recovered quickly after transplantation. CONCLUSIONS: Full-right full-left SLT for two adult patients is an efficient way to increase the donor pool. It is safe and feasible with careful donor and recipient selection. Transplant hospitals with highly experienced surgeons in SLT are recommended to promote using full-right full-left SLT for two adult recipients.

Galectin-1: A Traditionally Immunosuppressive Protein Displays Context-Dependent Capacities.

Galectin-Carbohydrate interactions are indispensable to pathogen recognition and immune response. Galectin-1, a ubiquitously expressed 14-kDa protein with an evolutionarily conserved ß-galactoside binding site, translates glycoconjugate recognition into function. That galectin-1 is demonstrated to induce T cell apoptosis has led to substantial attention to the immunosuppressive properties of this protein, such as inducing naive immune cells to suppressive phenotypes, promoting recruitment of immunosuppressing cells as well as impairing functions of cytotoxic leukocytes. However, only in recent years have studies shown that galectin-1 appears to perform a pro-inflammatory role in certain diseases. In this review, we describe the anti-inflammatory function of galectin-1 and its possible mechanisms and summarize the existing therapies and preclinical efficacy relating to these agents. In the meantime, we also discuss the potential causal factors by which galectin-1 promotes the progression of inflammation.

Targeting neuropilin-1 abolishes anti-PD-1-upregulated regulatory T cells and synergizes with 4-1BB agonist for liver cancer treatment.

BACKGROUND AIMS: Regulatory T cells (Tregs) are an obstacle to PD-1 blockade-mediated antitumor efficacy. However, the behaviors of Tregs response to anti-PD-1 in HCC and the characteristics of Tregs tissue adaptation from peripheral lymphoid tissues to the tumor are still unclear. APPROACH RESULTS: Here, we determine that PD-1 monotherapy potentially augments the accumulation of tumor CD4 + Tregs. Mechanistically, anti-PD-1 mediates Tregs proliferation in lymphoid tissues rather than in the tumor. Increased peripheral Tregs burden replenishes intratumoral Tregs, raising the ratio of intratumoral CD4 + Tregs to CD8 + T cells. Subsequently, single-cell transcriptomics revealed that neuropilin-1 (Nrp-1) supports Tregs migration behavior, and the genes of Crem and Tnfrsf9 regulate the behaviors of the terminal suppressive Tregs. Nrp-1 + 4-1BB - Tregs stepwise develop to the Nrp-1 - 4-1BB + Tregs from lymphoid tissues into the tumor. Moreover, Treg-restricted Nrp1 depletion abolishes anti-PD-1-upregulated intratumoral Tregs burden and synergizes with the 4-1BB agonist to enhance the antitumor response. Finally, a combination of the Nrp-1 inhibitor and the 4-1BB agonist in humanized HCC models showed a favorable and safe outcome and evoked the antitumor effect of the PD-1 blockade. CONCLUSION: Our findings elucidate the potential mechanism of anti-PD-1-mediated intratumoral Tregs accumulation in HCC and uncover the tissue adaptation characteristics of Tregs and identify the therapeutic potential of targeting Nrp-1 and 4-1BB for reprogramming the HCC microenvironment.

Association between fluoride exposure and blood pressure in children and adolescents aged 6 to19 years in the United States: NHANES, 2013-2016.

To examine the association between fluoride exposure and childhood blood pressure (BP), we used data involving 3260 subjects participating in the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2016. Both plasma and water fluoride concentrations were measured using the ion-specific electrode. Outcome variables were systolic blood pressure (SBP) and diastolic blood pressure (DBP). For a 1-mg/L increase in water fluoride concentration, the participants' SBP decreased by 0.473 mm Hg (95% CI: -0.860, -0.087). Specifically, inverse associations were found between water fluoride and SBP in girls (ß= -0.423, 95% CI: -0.886, -0.021), adolescents (ß= -0.623, 95% CI: -0.975, -0.272), and non-Hispanic whites (ß= -0.694, 95% CI: -1.237, -0.151). Also, every 1-µmol/L increase in plasma fluoride concentration was associated with a 1.183 mm Hg decrease in SBP among other races (95% CI: -2.258, -0.108). This study suggested that fluoride exposure may affect childhood blood pressure.

An Acid-triggered Reactive and Enhanced Fluorescent Probe for Selective Detection of Al3+/H+ and its Application in Real Water Samples and Living Cells.

A reactive fluorescent "turn-on" probe (di-PIP) with imine-linked dual phenanthro[9,10-d]imidazole luminophore have been conveniently prepared as an Al3+ and H+ dual functional receptor. di-PIP displayed high selectivity and sensitivity towards Al3+ ion in DMF/HEPES accompanied by fluorescence blue-shift and a good linear relationship as well as a low detection limit of 30.5 nmol·L-1, which can root from the synergetic functions of the decomposition reaction of di-PIP promoted by acidic Al3+ and the coordination effect between decomposition product and Al3+. Intriguingly, it was found that hydrogen ion H+ can be sufficient for simulating the fluorescence enhancing of di-PIP. 1H NMR titration and MS analyses for elucidation of the intermediate structure further revealed that the acid-triggered decomposition reaction resulted in the rapid, and sensitive sensing to Al3+ and H+. In addition, the probe di-PIP could be successfully applied to the detection of Al3+ in real water samples, and also utilized to visualize Al3+ and H+ in the living cells.

Clinical analysis of Wernicke encephalopathy after liver transplantation.

BACKGROUND: Wernicke encephalopathy (WE) is an acute neurological disease resulting from vitamin B1 deficiency, and there are only very few case reports of WE after liver transplantation. The present study aimed to investigate the clinical characteristics, etiology, magnetic resonance imaging (MRI) features, treatment and prognosis of patients with WE after liver transplantation. METHODS: Twenty-three patients with WE after liver transplantation from the First Affiliated Hospital, Zhejiang University School of Medicine and Jiangxi Provincial People's Hospital between January 2011 and December 2021 were retrospectively analyzed. RESULTS: Among the 23 patients diagnosed with WE after liver transplantation, 6 (26%) had a classic triad of impaired consciousness, oculomotor palsy and ataxia, and 17 (74%) had two features. The misdiagnosis rate was 65%. After treatment with high-dose vitamin B1, 19 (83%) patients showed improvement, whereas 4 (17%) showed no improvement, including 3 with residual short-term memory impairments and 1 with residual spatial and temporal disorientation and ataxia. CONCLUSIONS: The misdiagnosis rate is high in the early stage of WE, and the prognosis is closely associated with whether WE is diagnosed early and treated timely. High-dose glucose or glucocorticoids can trigger WE and cannot be administered before vitamin B1 treatment. Vitamin B1 is suggested to be used as a prophylactic treatment for patients with WE after liver transplantation.

Suppression of flavivirus transmission from animal hosts to mosquitoes with a mosquito-delivered vaccine.

Zoonotic viruses circulate in the natural reservoir and sporadically spill over into human populations, resulting in endemics or pandemics. We previously found that the Chaoyang virus (CYV), an insect-specific flavivirus (ISF), is replication-defective in vertebrate cells. Here, we develope a proof-of-concept mosquito-delivered vaccine to control the Zika virus (ZIKV) within inaccessible wildlife hosts using CYV as the vector. The vaccine is constructed by replacing the pre-membrane and envelope (prME) proteins of CYV with those of ZIKV, assigned as CYV-ZIKV. CYV-ZIKV replicates efficiently in Aedes mosquitoes and disseminates to the saliva, with no venereal or transovarial transmission observed. To reduce the risk of CYV-ZIKV leaking into the environment, mosquitoes are X-ray irradiated to ensure 100% infertility, which does not affect the titer of CYV-ZIKV in the saliva. Immunization of mice via CYV-ZIKV-carrying mosquito bites elicites robust and persistent ZIKV-specific immune responses and confers complete protection against ZIKV challenge. Correspondingly, the immunized mice could no longer transmit the challenged ZIKV to naïve mosquitoes. Therefore, immunization with an ISF-vectored vaccine via mosquito bites is feasible to induce herd immunity in wildlife hosts of ZIKV. Our study provides a future avenue for developing a mosquito-delivered vaccine to eliminate zoonotic viruses in the sylvatic cycle.

What is the best anthropometry index to evaluate the risk of metabolic abnormalities in Chinese adults?

AIMS: Obesity, defined by body mass index (BMI), is a heterogeneous condition with varying metabolic manifestations, and the best index for predicting metabolic abnormalities remains unclear. This study aimed to explore the most suitable anthropometry index for predicting metabolic abnormalities in Chinese adults. METHODS: A cross-sectional study was conducted using the data obtained from 9517 Chinese adults who underwent physical examination, bioelectrical impedance analysis, and laboratory examinations between March 2018 and March 2022. Participants were further divided into eight subgroups according to age, BMI, and sex. Descriptive statistics were calculated, and the area under the receiver operating characteristic curve and Youden index values were calculated to identify the best predictor of metabolic abnormalities in Chinese adults. RESULTS: The waist-to-height ratio (WHtR) had the largest area under the curve for predicting metabolic abnormalities in men of any age and women aged 18-49 years. However, BMI showed the highest accuracy in predicting metabolic abnormalities in women aged 50 years and older. Based on the highest Youden index, the optimal WHtR threshold was 0.51 in women and 0.53 in men. CONCLUSIONS: The WHtR was the most effective index for predicting metabolic abnormalities in most Chinese adults, whereas BMI showed a higher accuracy only in elderly women. This observation supports WHtR as a novel adiposity marker for screening metabolic abnormalities and shows value for public health practice.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

Effects of SNPs in SOD2 and SOD3 interacted with fluoride exposure on the susceptibility of dental fluorosis.

A total of 649 children aged 7-13 years of age were recruited in a cross-sectional study in Tongxu County, China (2017) to assess the effects of interaction between single nucleotide polymorphisms (SNPs) in SOD2 and SOD3 gene and fluoride exposure on dental fluorosis (DF) status. Associations between biomarkers and DF status were evaluated. Logistic regression suggested that the risk of DF in children with rs10370 GG genotype and rs5746136 TT genotype was 1.89-fold and 1.72-fold than that in children with TT/CC genotype, respectively. Increased T-SOD activity was associated with a lower risk of DF (OR = 0.99). The rs2855262*rs10370*UF model was regarded as the optimal interaction model in generalized multifactor dimensionality reduction analyses. Our findings suggested that rs4880 and rs10370 might be useful genetic markers for DF, and there might be interactions among rs10370 in SOD2, rs2855262 in SOD3, and fluoride exposure on DF status.

Optical properties of mountain primary and secondary brown carbon aerosols in summertime.

Brown carbon (BrC) can affect atmospheric radiation due to its strong absorption ability from the near ultraviolet to the visible range, thereby influencing global climate. However, given the complexity of BrC's chemical composition, its optical properties are still poorly understood, especially in mountainous areas. In this study, the black carbon (BC) tracer method is used to explore the light-absorbing properties of primary and secondary BrC at Mount Hua, China during the 2018 summer period. The primary BrC absorption contributes to 10-15% of the total BrC absorption at a wavelength of 370 nm. From the positive matrix factorization analysis, traffic emissions are found to be a major source of primary BrC absorption (44%), followed by industry and biomass-burning emissions (29%). The secondary BrC accounts for 87% of the total BrC absorption at a wavelength of 370 nm, indicating that BrC is dominated by secondary formation. The observation of a higher secondary BrC absorption diurnal pattern at Mount Hua can be affected by secondary BrC in the residual layer after sunrise and the formation of light-absorbing chromophores by photochemical oxidation in the afternoon. The estimated average mass absorption efficiencies of primary and secondary BrC (MAE_pri and MAE_sec, respectively) are 0.4 m2/g and 2.1 m2/g at wavelengths of 370 nm, respectively, indicating a stronger light-absorbing ability for secondary BrC than for primary BrC. There is no significant difference in MAE_pri within a daily variation, but the daytime MAE_sec value is higher than that during the night. Our study shows that secondary BrC is important to light absorption in mountainous areas.

Fluoride Stimulates Anxiety- and Depression-like Behaviors Associated with SIK2-CRTC1 Signaling Dysfunction.

Using Sprague-Dawley rats and rat PC12 cells treated with sodium fluoride (NaF), we investigated the effects of SIK2-CRTC1 signaling on the neurobehavioral toxicity induced by fluoride. The in vivo results demonstrated that NaF treatment induced anxiety- and depression-like behaviors in juvenile rats, resulting in histological and ultrastructural abnormalities in the rat hippocampus and medial prefrontal cortex. Moreover, NaF exposure induced neuronal loss and excessive apoptosis. We also found that NaF elevated the expression of SIK2 and reduced the expression of CRTC1, brain-derived neurotrophic factor (BDNF), and VGF. The in vitro results showed that NaF suppressed cell viability, induced SIK2-CRTC1 signaling dysfunction, and caused excessive apoptosis in PC12 cells. Notably, targeted knockout of SIK2 with SIK2-siRNA or blocking of SIK2-CRTC1 signaling with 7,8-dihydroxyflavone (7,8-DHF) (as well as venlafaxine) can reduce apoptosis and increase cell viability in vitro. These findings suggest that neuronal death resulting from abnormal SIK2-CRTC1 signaling contributes to neurobehavioral toxicity induced by fluoride.

Circ_0030235 knockdown protects H9c2 cells against OGD/R-induced injury via regulation of miR-526b.

BACKGROUNDS: Acute myocardial infarction (MI) is the common clinical manifestation of coronary heart disease. Circular RNAs (circRNAs) act key roles in cardiomyocytes growth and angiogenesis. However, their functions in MI are not entirely clear. This research intended to investigate the role and underlying mechanisms of circ_0030235 in H9c2 cells. METHODS: H9c2 cells were conducted to oxygen glucose deprivation/reperfusion (OGD/R) inducement to establish the MI model. Circ_0030235 and miR-526b expression was tested and altered by qRT-PCR and transfection. Cell viability, apoptosis and reactive oxygen species (ROS) injury were tested by CCK-8 assay, TUNEL assay kit, and ROS Detection Assay Kit, respectively. Assessment of cell injury-related factors was performed by employing ELISA, Mitochondrial Viability Staining and the JC-1-Mitochondrial Membrane Potential Assay Kit. The relationship between circ_0030235 and miR-526b was analyzed by dual luciferase reporter assay. The expression of key proteins was analyzed by western blot. RESULTS: Circ_0030235 was highly expressed in OGD/R-induced H9c2 cells. OGD/R inducement cell viability, while accelerated apoptosis. Besides, the level ROS, cell injury-related factors, mitochondrial membrane potential were notably elevated by OGD/R inducement, while mitochondrial viability was remarkably declined. Whereas, these impacts were all noticeably remitted by circ_0030235 knockdown. miR-526b was a target of circ_0030235. Circ_0030235 knockdown-induced impacts were all notably abrogated by miR-526b inhibition, including the activating impacts on PI3K/AKT and MEK/ERK pathways. CONCLUSIONS: This research implied that circ_0030235 knockdown might remit OGD/R-induced impacts via activation of PI3K/AKT and MEK/ERK pathways and regulation of miR-526b.

The Fecal Microbiota of Dogs Switching to a Raw Diet Only Partially Converges to That of Wolves.

The genomic signature of dog domestication reveals adaptation to a starch-rich diet compared with their ancestor wolves. Diet is a key element to shape gut microbial populations in a direct way as well as through coevolution with the host. We investigated the dynamics in the gut microbiota of dogs when shifting from a starch-rich, processed kibble diet to a nature-like raw meat diet, using wolves as a wild reference. Six healthy wolves from a local zoo and six healthy American Staffordshire Terriers were included. Dogs were fed the same commercial kibble diet for at least 3 months before sampling at day 0 (DC), and then switched to a raw meat diet (the same diet as the wolves) for 28 days. Samples from the dogs were collected at day 1 (DR1), week 1 (DR7), 2 (DR14), 3 (DR21), and 4 (DR28). The data showed that the microbial population of dogs switched from kibble diet to raw diet shifts the gut microbiota closer to that of wolves, yet still showing distinct differences. At phylum level, raw meat consumption increased the relative abundance of Fusobacteria and Bacteroidetes at DR1, DR7, DR14, and DR21 (q < 0.05) compared with DC, whereas no differences in these two phyla were observed between DC and DR28. At genus level, Faecalibacterium, Catenibacterium, Allisonella, and Megamonas were significantly lower in dogs consuming the raw diet from the first week onward and in wolves compared with dogs on the kibble diet. Linear discriminant analysis effect size (LEfSe) showed a higher abundance of Stenotrophomonas, Faecalibacterium, Megamonas, and Lactobacillus in dogs fed kibble diet compared with dogs fed raw diet for 28 days and wolves. In addition, wolves had greater unidentified Lachnospiraceae compared with dogs irrespective of the diets. These results suggested that carbohydrate-fermenting bacteria give way to protein fermenters when the diet is shifted from kibble to raw diet. In conclusion, some microbial phyla, families, and genera in dogs showed only temporary change upon dietary shift, whereas some microbial groups moved toward the microbial profile of wolves. These findings open the discussion on the extent of coevolution of the core microbiota of dogs throughout domestication.

Upregulation of miR­126 inhibits podocyte injury in sepsis via EGFL6/DKC1 signaling pathway.

Sepsis­induced cardiorenal syndrome is one of the multiple organ dysfunctions observed in sepsis. It is determined by a primary dysfunction in one organ that leads to secondary injury to another organ. Studies have shown the involvement of microRNAs (miRs) in the diagnosis and prognosis of several pathologies. However, the implication of miR­126 in the podocyte damage associated with sepsis has not been evaluated until now. In the current study, the miR­126 expression was downregulated in a podocyte injury model together with downregulation of nephrin expression. The transfection of podocytes from podocyte injury group with miR­126 mimics demonstrated an increase in cell proliferation and a decrease in cell apoptosis. Bioinformatics analysis predicted that the target of miR­126 was epidermal growth factor­like domain multiple 6 (EGFL6) and dyskeratosis congenita 1 (DKC1) and these were confirmed by dual­luciferase reporter assay. miR­126 upregulation determined EGFL6 and DKC1 upregulation and prevented podocyte injury. The current study demonstrated that overexpression of miR­126 could protect podocytes from sepsis­induced injury through an EGFL6/DKC1 signaling pathway.

Growth, Antigenicity, and Immunogenicity of SARS-CoV-2 Spike Variants Revealed by a Live rVSV-SARS-CoV-2 Virus.

SARS-CoV-2 is an emerging coronavirus threatening human health and the economy worldwide. As an RNA virus, variants emerge during the pandemic and potentially influence the efficacy of the anti-viral drugs and vaccines. Eight spike variants harboring highly recurrent mutations were selected and introduced into a replication-competent recombinant VSV in place of the original G protein (rVSV-SARS-CoV-2). The resulting mutant viruses displayed similar growth curves in vitro as the wild-type virus and could be neutralized by sera from convalescent COVID-19 patients. Several variants, especially Beta strain, showed resistance to human neutralizing monoclonal antibodies targeting the receptor-binding domain (RBD). A single dose of rVSV-SARS-CoV-2 Beta variant could elicit enhanced and broad-spectrum neutralizing antibody responses in human ACE2 knock-in mice and golden Syrian hamsters, while other mutants generated antibody levels comparable to the wild-type. Therefore, our results will be of value to the development of next-generation vaccines and therapeutic antibodies.

Adult liver transplantation using pediatric donor livers after cardiac or brain death: A report of three cases.

The present study reports on the experience at Jiangxi Provincial People's Hospital (Nanchang, China) with liver transplantation in adults using pediatric donor livers, including indications, technique and results. A total of three cases of liver transplantation performed between April 2008 and May 2016 were retrospectively reviewed. Liver procurement and trimming, recipient selection, surgical tips, prevention and treatment of small-for-size syndrome, selection of immunosuppressive regimens, prevention and treatment of vascular complications and anticoagulant therapy were discussed. The three pediatric donors were 8, 8 and 10 years old. The three recipients were confirmed to have primary liver cancer. In recipient 1 (female; age, 39 years), jaundice persisted in the recipient after the liver transplantation. A reduced dose of FK506 was then given to gradually decrease the total bilirubin level to the normal range. Recipient 1 recovered and was discharged from hospital; however, the patient died of liver cancer recurrence and bone metastasis 6 years post-transplantation. In recipient 2 (male; age, 56 years), the recipient experienced sudden abdominal distension on postoperative day 7. The patient's clotting time was prolonged and the transaminase level was sharply increased, peaking on day 9. The patient was suspected of having small-for-size syndrome and was treated symptomatically. The patient experienced a significant improvement in symptoms on postoperative day 13 and regular postoperative follow-ups were performed until now and the patient is now in remission. In recipient 3 (male; age, 48 years), the recipient recovered well and the liver function returned to normal on postoperative day 3. The patient was discharged from hospital and has been in remission thus far. Adult liver transplantations from pediatric donors are feasible treatments. Systematic donor and recipient assessments, sound surgical skills and optimal postoperative treatments are essential for success in the transplantation of livers from pediatric donors into adult recipients. Considering the condition of the donor liver, the selection of recipients and appropriate surgical methods are particularly important in these cases.