Deep learning-enabled classification of kidney allograft rejection on whole slide histopathologic images.

Background: Diagnosis of kidney transplant rejection currently relies on manual histopathological assessment, which is subjective and susceptible to inter-observer variability, leading to limited reproducibility. We aim to develop a deep learning system for automated assessment of whole-slide images (WSIs) from kidney allograft biopsies to enable detection and subtyping of rejection and to predict the prognosis of rejection. Method: We collected H&E-stained WSIs of kidney allograft biopsies at 400x magnification from January 2015 to September 2023 at two hospitals. These biopsy specimens were classified as T cell-mediated rejection, antibody-mediated rejection, and other lesions based on the consensus reached by two experienced transplant pathologists. To achieve feature extraction, feature aggregation, and global classification, we employed multi-instance learning and common convolution neural networks (CNNs). The performance of the developed models was evaluated using various metrics, including confusion matrix, receiver operating characteristic curves, the area under the curve (AUC), classification map, heat map, and pathologist-machine confrontations. Results: In total, 906 WSIs from 302 kidney allograft biopsies were included for analysis. The model based on multi-instance learning enables detection and subtyping of rejection, named renal rejection artificial intelligence model (RRAIM), with the overall 3-category AUC of 0.798 in the independent test set, which is superior to that of three transplant pathologists under nearly routine assessment conditions. Moreover, the prognosis models accurately predicted graft loss within 1 year following rejection and treatment response for rejection, achieving AUC of 0.936 and 0.756, respectively. Conclusion: We first developed deep-learning models utilizing multi-instance learning for the detection and subtyping of rejection and prediction of rejection prognosis in kidney allograft biopsies. These models performed well and may be useful in assisting the pathological diagnosis.

The impact of donor hepatitis B virus infection on transplant outcomes in deceased donor kidney transplantation recipients.

Background: The use of hepatitis B virus (HBV)-positive donor kidneys to expand the donor pool has been implemented, but limited evidence exists regarding their impact on transplant outcomes. This study aimed to investigate the effects of donor HBV infection on transplant outcomes. Methods: Donor and recipient data between 2015 and 2021 were collected. A total of 743 kidney transplant cases were screened, including 94 donor hepatitis B surface antigen (HBsAg)+/recipient HBsAg- (D+R-) and 649 donor HBsAg-/recipient HBsAg- (D-R-) cases. The analysis endpoints included recipient HBV infection, delayed graft function (DGF), peak estimated glomerular filtration rate (eGFR) within 12 months, recipient survival, and death-censored graft survival (DCGS). Results: The D+R- group had a significantly higher risk of HBV infection compared to the D-R- group (6/72 vs. 3/231; relative risk, 6.4; p = 0.007). The risk of HBV transmission decreased significantly with increasing hepatitis B surface antibody (HBsAb) titer (p for trend = 0.003). Furthermore, the D+R- group did not exhibit an increased risk of DGF compared to the D-R- group (odds ratio, 0.70; p = 0.51) in the multivariable mixed model. Both groups had similar peak eGFR within 12 months (ß = 1.01, p = 0.71), and this had no impact on patient survival (hazard ratio [HR], 0.36; p = 0.10) and DCGS (HR, 0.79, p = 0.59) in the shared-frailty Cox model. Conclusion: The use of HBsAg-positive donor kidneys appears relatively safe for HBV-immunized recipients in the short term. D+R- does not negatively affect graft function recovery and provides comparable posttransplant outcomes. Maintaining an HBsAb titer over 100 IU/L before transplantation is critical to reduce the risk of HBV transmission.

Combined Hounsfield units of hepatocellular carcinoma on computed tomography and PET as a noninvasive predictor of early recurrence after living donor liver transplantation: Time-to-recurrence survival analysis.

BACKGROUND: Liver transplantation is an effective treatment for preventing hepatocellular carcinoma (HCC) recurrence. This retrospective study aimed to quantitatively evaluate the attenuation in Hounsfield units (HU) on contrast-enhanced computed tomography (CECT) as a prognostic factor for hepatocellular carcinoma (HCC) following liver transplantation as a treatment. Our goal is to optimize its predictive ability for early tumor recurrence and compare it with the other imaging modality-positron emission tomography (PET). METHODS: In 618 cases of LDLT for HCC, only 131 patients with measurable viable HCC on preoperative CECT and preoperative positron emission tomography (PET) evaluations were included, with a minimum follow-up period of 6 years. Cox regression models were developed to identify predictors of postoperative recurrence. Performance metrics for both CT and PET were assessed. The correlation between these two imaging modalities was also evaluated. Survival analyses were conducted using time-dependent receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) to assess accuracy and determine optimized cut-off points. RESULTS: Univariate and multivariate analyses revealed that both arterial-phase preoperative tumor attenuation (HU) and PET were independent prognostic factors for recurrence-free survival. Both lower arterial tumor enhancement (Cut-off value = 59.2, AUC 0.88) on CT and PET positive (AUC 0.89) increased risk of early tumor recurrence 0.5-year time-dependent ROC. Composites with HU < 59.2 and a positive PET result exhibited significantly higher diagnostic accuracy in detecting early tumor recurrence (AUC = 0.96). CONCLUSION: Relatively low arterial tumor enhancement values on CECT effectively predict early HCC recurrence after LDLT. The integration of CT and PET imaging may serve as imaging markers of early tumor recurrence in HCC patients after LDLT.

Identification of RNA-binding protein genes associated with renal rejection and graft survival.

Rejection is one of the major factors affecting the long-term prognosis of kidney transplantation, and timely recognition and aggressive treatment of rejection is essential to prevent disease progression. RBPs are proteins that bind to RNA to form ribonucleoprotein complexes, thereby affecting RNA stability, processing, splicing, localization, transport, and translation, which play a key role in post-transcriptional gene regulation. However, their role in renal transplant rejection and long-term graft survival is unclear. The aim of this study was to comprehensively analyze the expression of RPBs in renal rejection and use it to construct a robust prediction strategy for long-term graft survival. The microarray expression profiles used in this study were obtained from GEO database. In this study, a total of eight hub RBPs were identified, all of which were upregulated in renal rejection samples. Based on these RBPs, the renal rejection samples could be categorized into two different clusters (cluster A and cluster B). Inflammatory activation in cluster B and functional enrichment analysis showed a strong association with rejection-related pathways. The diagnostic prediction model had a high diagnostic accuracy for T cell mediated rejection (TCMR) in renal grafts (area under the curve = 0.86). The prognostic prediction model effectively predicts the prognosis and survival of renal grafts (p < .001) and applies to both rejection and non-rejection situations. Finally, we validated the expression of hub genes, and patient prognosis in clinical samples, respectively, and the results were consistent with the above analysis.

The Renoprotective and Anti-Inflammatory Effects of Human Urine-Derived Stem Cells on Acute Kidney Injury Animals.

BACKGROUND: Acute Kidney Injury (AKI) is defined as a sudden loss of kidney function, which is often caused by drugs, toxins, and infections. The large spectrum of AKI implies diverse pathophysiological mechanisms. In many cases, AKI can be lethal, and kidney replacement therapy is frequently needed. However, current treatments are not satisfying. Developing novel therapies for AKI is essential. Adult stem cells possess regenerative ability and play an important role in medical research and disease treatment. METHODS: In this study, we isolated and characterized a distinct human urine-derived stem cell, which expressed both proximal tubular cell and mesenchymal stem cell genes as well as certain unique genes. RESULTS: It was found that these cells exhibited robust protective effects on tubular cells and anti- inflammatory effects on macrophages in vitro. In an ischemia-reperfusion-induced acute kidney injury NOD-SCID mouse model, transplantation of USCs significantly protected the kidney morphology and functions in vivo. CONCLUSION: In summary, our results highlighted the effectiveness of USCs in protecting from PTC injury and impeding macrophage polarization, as well as the secretion of pro-inflammatory interleukins, suggesting the potential of USCs as a novel cell therapy in AKI.

Bruton's tyrosine kinase ablation inhibits B cell responses and antibody production for the prevention of chronic rejection in cardiac transplantation.

Chronic rejection is the primary cause of late allograft failure, however, the current treatments for chronic rejection have not yielded desirable therapeutic effects. B cell activation and donor-specific antibody (DSA) production are the primary factors leading to chronic rejection. Bruton's tyrosine kinase (BTK) plays a key role in the activation and differentiation of B cells and in antibody production. This study investigated the efficacy of blocking BTK signalling in the prevention of chronic rejection. BTK signalling was blocked using the BTK inhibitor ibrutinib and gene knockout. In vitro assays were conducted to examine the consequences and underlying mechanisms of BTK blockade in regards to B cell activation, differentiation, and antibody secretion. Additionally, we established a cardiac transplantation mouse model of chronic rejection to explore the preventive effects and mechanisms of BTK ablation on chronic rejection. Ablating BTK signalling in vitro resulted in the inhibition of B cell activation, differentiation, and antibody production. In vivo experiments provided evidence that ablating BTK signalling alleviated chronic rejection, leading to reduced damage in myocardial tissue, neointimal hyperplasia, interstitial fibrosis, inflammatory cell infiltration, and C4d deposition. Allograft survival was prolonged, and B cell responses and DSA production were inhibited as a result. We confirmed that ablation of BTK signalling inhibited B cell response by blocking downstream PLCγ2 phosphorylation and inhibiting the NF-κB, NFAT, and ERK pathways. Our findings demonstrated that ablation of BTK signalling inhibited B cell activation and differentiation, reduced DSA production, and effectively prevented chronic rejection.

Alternative polyadenylation reprogramming of MORC2 induced by NUDT21 loss promotes KIRC carcinogenesis.

Alternative polyadenylation (APA), a posttranscriptional mechanism of gene expression via determination of 3'UTR length, has an emerging role in carcinogenesis. Although abundant APA reprogramming is found in kidney renal clear cell carcinoma (KIRC), which is one of the major malignancies, whether APA functions in KIRC remains unknown. Herein, we found that chromatin modifier MORC2 gained oncogenic potential in KIRC among the genes with APA reprogramming, and moreover, its oncogenic potential was enhanced by 3'UTR shortening through stabilization of MORC2 mRNA. MORC2 was found to function in KIRC by downregulating tumor suppressor DAPK1 via DNA methylation. Mechanistically, MORC2 recruited DNMT3A to facilitate hypermethylation of the DAPK1 promoter, which was strengthened by 3'UTR shortening of MORC2. Furthermore, loss of APA regulator NUDT21, which was induced by DNMT3B-mediated promoter methylation, was identified as responsible for 3'UTR shortening of MORC2 in KIRC. Additionally, NUDT21 was confirmed to act as a tumor suppressor mainly depending on downregulation of MORC2. Finally, we designed an antisense oligonucleotide (ASO) to enhance NUDT21 expression and validated its antitumor effect in vivo and in vitro. This study uncovers the DNMT3B/NUDT21/APA/MORC2/DAPK1 regulatory axis in KIRC, disclosing the role of APA in KIRC and the crosstalk between DNA methylation and APA.

A bibliometric and knowledge-map analysis of antibody-mediated rejection in kidney transplantation.

OBJECTIVES: Antibody-mediated rejection (AMR) is a large obstacle to the long-term survival of allograft kidneys. It is urgent to find novel strategies for its prevention and treatment. Bibliometric analysis is helpful in understanding the directions of one field. Hence, this study aims to analyze the state and emerging trends of AMR in kidney transplantation. METHODS: Literature on AMR in kidney transplantation from 1999 to 2022 was collected from the Web of Science Core Collection. HistCite (version 12.03.17), CiteSpace (version 6.2.R2), Bibliometrix 4.1.0 Package from R language, and Gephi (https://gephi.org) were applied to the bibliometric analysis of the annual publications, leading countries/regions, core journals, references, keywords, and trend topics. RESULTS: A total of 2522 articles related to AMR in kidney transplantation were included in the analysis and the annual publications increased year by year. There were 10874 authors from 118 institutions located in 70 countries/regions contributing to AMR studies, and the United States took the leading position in both articles and citation scores. Halloran PF from Canada made the most contribution to AMR in kidney transplantation. The top 3 productive journals, American Journal of Transplantation, Transplantation, and Transplantation Proceedings, were associated with transplantation. Moreover, the recent trend topics mainly focused on transplant outcomes, survival, and clinical research. CONCLUSIONS: North American and European countries/regions played central roles in AMR of kidney transplantation. Importantly, the prognosis of AMR is the hotspot in the future. Noninvasive strategies like plasma and urine dd-cfDNA may be the most potential direction in the AMR field.

Case report: Application of nonsurgical method in saving transplant renal vein thrombosis caused by acute diarrhea.

Transplant renal vein thrombosis is a rare complication after kidney transplantation, which can seriously threaten graft survival. Though the measures like thrombolytic therapy or operative intervention could be taken to deal with this complication, allograft loss is the most common outcome. Thus, early finding as well as decisive intervention is crucial to saving the graft. Here we present a 46-year-old male patient who underwent kidney transplantation from a cadaveric donor who developed a transplant renal venous thrombosis induced by acute diarrhea more than 1 year after renal transplantation with an initial symptom of sudden anuria and pain in the graft area. Subsequently, serum creatinine levels increased to 810.0 µmol/L. Pelvic CT showed increased vascular density of the transplanted kidney, and contrast-enhanced ultrasound confirmed venous thrombosis. The patient was treated with heparin sodium alone and diuresis gradually resumed. After more than 1 year of follow-up, serum creatinine returned to the baseline level prior to thrombosis. Our case indicates that quick ancillary examination and treatment without hesitation would be indispensable in rescuing allografts with renal vein thrombus. Unfractionated heparin can be recommended as an effective treatment for mid-long-term renal transplantation patients with renal vein thrombosis.

Alternative polyadenylation writer CSTF2 forms a positive loop with FGF2 to promote tubular epithelial-mesenchymal transition and renal fibrosis.

Effective therapies for renal fibrosis, the common endpoint for most kidney diseases, are lacking. We previously reported that alternative polyadenylation (APA) drives transition from acute kidney injury to chronic kidney disease, suggesting a potential role for APA in renal fibrogenesis. Here, we found that among canonical APA writers, CSTF2 expression was upregulated in tubular epithelial cells (TEC) of fibrotic kidneys. CSTF2 was also identified as a TGF-ß-inducible pro-fibrotic gene. Further analysis revealed that CSTF2 promoted epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) overproduction in TEC by inducing 3'UTR shortening and upregulation of the expression of basic fibroblast growth factor 2 (FGF2). Additionally, 3'UTR shortening stabilised FGF2 mRNA through miRNA evasion. Interestingly, FGF2 enhanced CSTF2 expression, leading to the forming of a CSTF2-FGF2 positive loop in TEC. Furthermore, CSTF2 knockdown alleviated unilateral ureteral obstruction-induced renal fibrosis in vivo. Finally, we developed a CSTF2-targeted antisense oligonucleotide (ASO) and validated its effectiveness in vitro. These results indicate that the expression of the APA writer, CSTF2, is upregulated by TGF-ß and CSTF2 facilitates TGF-ß-induced FGF2 overexpression, forming a TGF-ß-CSTF2-FGF2 pro-fibrotic axis in TEC. CSTF2 is a potentially promising target for renal fibrosis that does not directly disrupt TGF-ß.

Inhibition of PLK3 Attenuates Tubular Epithelial Cell Apoptosis after Renal Ischemia-Reperfusion Injury by Blocking the ATM/P53-Mediated DNA Damage Response.

Objective: Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury (AKI) in transplanted kidneys. This study was aimed at exploring the role of PLK3 (polo-like kinase 3) in renal I/R injury, focusing on its relationship with oxidative stress-induced DNA damage and renal tubular epithelial cell (TEC) apoptosis. Methods: TRAP-seq data from the development dataset GSE52004 and the validation dataset GSE121191 were analyzed using GEO2R. PLK3 overexpression plasmids and targeted silencing siRNAs were used in a model of hypoxia/reoxygenation (H/R) injury, and rAAV-9-PLK3-KD were administered to C57BL/6J mice exposed to I/R injury. The ATM-specific inhibitor KU-60019 was used to block the DNA damage response (DDR). Western blotting was performed to measure DDR- and apoptosis-associated protein expression. Cell viability was measured by CCK-8 reagent, and apoptosis was examined by flow cytometry and TUNEL assay. Furthermore, the fluorescent probes H2DCFH-DA and DHE were used to measure ROS production in vitro. The MDA level and SOD activity were measured to assess oxidative stress in vivo. KIM-1 staining and Scr and BUN were used to evaluate kidney injury. Results: The mRNA and protein levels of PLK3 were markedly increased in the H/R injury and I/R injury models. GO terms showed that PLK3 was mainly involved in oxidative stress and DNA damage after renal I/R injury. Overexpression of PLK3 decreased cell viability and increased apoptosis. In contrast, targeted silencing of PLK3 expression decreased the Bax/Bcl-2 ratio by decreasing P53 phosphorylation, thereby reducing TEC apoptosis. Furthermore, KU-60019 reduced PLK3 activation and DDR-induced apoptosis, while overexpression of PLK3 reversed the mitigating effect of KU-60019 on TEC apoptosis. Similarly, rAAV-9-PLK3 KD mice exhibited a lower rate of TEC apoptosis and milder renal damage after I/R injury. Conclusion: We demonstrate for the first time that PLK3 is involved in oxidative stress-induced DNA damage and TEC apoptosis in renal I/R injury. Inhibition of PLK3 attenuates TEC apoptosis after I/R injury by blocking the ATM/P53-mediated DDR. Therefore, PLK3 may serve as a potential therapeutic target for ischemic AKI.

A randomized controlled trial to evaluate efficacy and safety of early conversion to a low-dose calcineurin inhibitor combined with sirolimus in renal transplant patients.

BACKGROUND: The calcineurin inhibitor (CNI)-based immune maintenance regimen that is commonly used after renal transplantation has greatly improved early graft survival after transplantation; however, the long-term prognosis of grafts has not been significantly improved. The nephrotoxicity of CNI drugs is one of the main risk factors for the poor long-term prognosis of grafts. Sirolimus (SRL) has been employed as an immunosuppressant in clinical practice for over 20 years and has been found to have no nephrotoxic effects on grafts. Presently, the regimen and timing of SRL application after renal transplantation vary, and clinical data are scarce. Multicenter prospective randomized controlled studies are particularly rare. This study aims to investigate the effects of early conversion to a low-dose CNI combined with SRL on the long-term prognosis of renal transplantation. METHODS: Patients who receive four weeks of a standard regimen with CNI + mycophenolic acid (MPA) + glucocorticoid after renal transplantation in multiple transplant centers across China will be included in this study. At week 5, after the operation, patients in the experimental group will receive an additional administration of SRL, a reduction in the CNI drug doses, withdrawal of MPA medication, and maintenance of glucocorticoids. In addition, patients in the control group will receive the maintained standard of care. The patients' vital signs, routine blood tests, routine urine tests, blood biochemistry, serum creatinine, BK virus (BKV)/ cytomegalovirus (CMV), and trough concentrations of CNI drugs and SRL at the baseline and weeks 12, 24, 36, 48, 72, and 104 after conversion will be recorded. Patient survival, graft survival, and estimated glomerular filtration rate will be calculated, and concomitant medications and adverse events will also be recorded. CONCLUSION: The study data will be utilized to evaluate the efficacy and safety of early conversion to low-dose CNIs combined with SRL in renal transplant patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800017277.

Identification of Subtypes and a Delayed Graft Function Predictive Signature Based on Ferroptosis in Renal Ischemia-Reperfusion Injury.

Renal ischemia-reperfusion injury (IRI) is an inevitable process in kidney transplantation, leading to acute kidney injury, delayed graft function (DGF), and even graft loss. Ferroptosis is an iron-dependent regulated cell death in various diseases including IRI. We aimed to identify subtypes of renal IRI and construct a robust DGF predictive signature based on ferroptosis-related genes (FRGs). A consensus clustering analysis was applied to identify ferroptosis-associated subtypes of 203 renal IRI samples in the GSE43974 dataset. The FRG-associated DGF predictive signature was constructed using the Least Absolute Shrinkage and Selection Operator (LASSO), and its robustness was further verified in the validation set GSE37838. The present study revealed two ferroptosis-related patient clusters (pBECN1 and pNF2 cluster) in renal IRI samples based on distinct expression patterns of BECN1 and NF2 gene clusters. Cluster pBECN1 was metabolically active and closely correlated with less DGF, while pNF2 was regarded as the metabolic exhausted subtype with higher incidence of DGF. Additionally, a six-gene (ATF3, SLC2A3, CXCL2, DDIT3, and ZFP36) ferroptosis-associated signature was constructed to predict occurrence of DGF in renal IRI patients and exhibited robust efficacy in both the training and validation sets. High-risk patients tended to have more infiltration of dendritic cells, macrophages, and T cells, and they had significantly enriched chemokine-related pathway, WNT/ß-catenin signaling pathway, and allograft rejection. Patients with low risks of DGF were associated with ferroptosis-related pathways such as glutathione and fatty acid metabolism pathways. In conclusion, patient stratification with distinct metabolic activities based on ferroptosis may help distinguish patients who may respond to metabolic therapeutics. Moreover, the DGF predictive signature based on FRGs may guide advanced strategies toward prevention of DGF in the early stage.

Redox Metabolism-Associated Molecular Classification of Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma. Redox metabolism has been recognized as the hallmark of cancer. But the concrete role of redox-related genes in patient stratification of ccRCC remains unknown. Herein, we aimed to characterize the molecular features of ccRCC based on the redox gene expression profiles from The Cancer Genome Atlas. Differentially expressed redox genes (DERGs) and vital genes in metabolism regulation were identified and analyzed in the ccRCC. Consensus clustering was performed to divide patients into three clusters (C1, C2, and C3) based on 139 redox genes with median FPKM value > 1. We analyzed the correlation of clusters with clinicopathological characteristics, immune infiltration, gene mutation, and response to immunotherapy. Subclass C1 was metabolic active with moderate prognosis and associated with glucose, lipid, and protein metabolism. C2 had intermediate metabolic activity with worse prognosis and correlated with more tumor mutation burden, neoantigen, and aneuploidy, indicating possible drug sensitivities towards immune checkpoint inhibitors. Metabolic exhausted subtype C3 showed high cytolytic activity score, suggesting better prognosis than C1 and C2. Moreover, the qRT-PCR was performed to verify the expression of downregulated DERGs including ALDH6A1, ALDH1L1, GLRX5, ALDH1A3, and GSTM3, and upregulated SHMT1 in ccRCC. Overall, our study provides an insight into the characteristics of molecular classification of ccRCC patients based on redox genes, thereby deepening the understanding of heterogeneity of ccRCC and allowing prediction of prognosis of ccRCC patients.

Radiofrequency Ablation a Safe and Effective Treatment for Pediatric Benign Nodular Thyroid Goiter.

Purpose: To evaluate the effectiveness of radiofrequency ablation (RFA) for benign thyroid nodules in pediatric patients. Materials and Methods: Twelve pediatric patients (11 female, 1 male; mean age 15.54 ± 2.8 years, range 10-19 years) with benign thyroid nodules (mean longest diameter 4.1 ± 1.4 cm, range 1.5-5.9 cm) treated by RFA from 2017 to 2020 were evaluated. The inclusion criteria for RFA therapy were (i) age < 20 years; (ii) benign cytological confirmation by 2 separate ultrasound guided fine-needle aspiration cytology (FNAC) or core needle biopsies; (iii) pressure symptoms or cosmetic problems caused by thyroid nodules; (iv) absence of any sonographic suspicious feature; and (v) follow-up for >6 months. Under local anesthesia, RFA was performed with the use of an RF generator and an 18-gauge internally cooled electrode. Volume changes in nodules on follow-up ultrasonography (US), changes in symptomatic and cosmetic scores, and complications arising during or after RFA were evaluated. Results: Mean follow-up period was 24.9 ± 13.9 months (range 6-43 months). At the last follow-up visits, volume of the nodule had decreased significantly (15.34 ± 11.52 mL vs. 4.07 ± 4.99 mL; P < 0.05), whereas volume reduction rate was 74.31% ± 19.59%. Both cosmetic and compressive symptoms were also significantly improved (2.91 ± 0.79 vs. 0.92 ± 0.67 and 1.5 ± 1.93 vs. 0.17 ± 0.39; P < 0.05). The mean number of ablation sessions was 1.4 ± 0.6 (range 1-3 sessions), and one of the patients suffered from transient vocal cord palsy which was spontaneously resolved 53 days later. Conclusions: RFA is a safe and effective treatment for benign thyroid nodules in pediatric patients, and can thus serve as an alternative treatment for thyroidectomy.

Engineering Nano-Therapeutics to Boost Adoptive Cell Therapy for Cancer Treatment.

Although adoptive transfer of therapeutic cells to cancer patients is demonstrated with great success and fortunately approved for the treatment of leukemia and B-cell lymphoma, potential issues, including the unclear mechanism, complicated procedures, unfavorable therapeutic efficacy for solid tumors, and side effects, still hinder its extensive applications. The explosion of nanotechnology recently has led to advanced development of novel strategies to address these challenges, facilitating the design of nano-therapeutics to improve adoptive cell therapy (ACT) for cancer treatment. In this review, the emerging nano-enabled approaches, that design multiscale artificial antigen-presenting cells for cell proliferation and stimulation in vitro, promote the transducing efficiency of tumor-targeting domains, engineer therapeutic cells for in vivo imaging, tumor infiltration, and in vivo functional sustainability, as well as generate tumoricidal T cells in vivo, are summarized. Meanwhile, the current challenges and future perspectives of the nanostrategy-based ACT for cancer treatment are also discussed in the end.

Donor Death Category Is an Effect Modifier Between Cold Ischemia Time and Post-transplant Graft Function in Deceased-Donor Kidney Transplant Recipients.

Objectives: We aimed to analyze the effect of cold ischemia time (CIT) on post-transplant graft function through mixed-effect model analysis to reduce the bias caused by paired mate kidneys. Methods: We reviewed all kidney transplantation records from 2015 to 2019 at our center. After applying the exclusion criteria, 561 cases were included for analysis. All donor characteristics, preservation and matching information, and recipient characteristics were collected. Transplant outcomes included delayed graft function (DGF) and estimated glomerular filtration rate (eGFR). Generalized linear mixed models were applied for analysis. We also explored potential effect modifiers, namely, donor death category, expanded criteria donors, and donor death causes. Results: Among the 561 cases, 79 DGF recipients developed DGF, and 15 recipients who died after surgery were excluded from the eGFR estimation. The median stable eGFR of the 546 recipients was 60.39 (47.63, 76.97) ml/min/1.73 m2. After adjusting for confounding covariates, CIT had a negative impact on DGF incidence [odds ratio = 1.149 (1.006, 1.313), P = 0.041]. In the evaluation of the impact on eGFR, the regression showed that CIT had no significant correlation with eGFR [ß = -0.287 (-0.625, 0.051), P = 0.096]. When exploring potential effect modifiers, only the death category showed a significant interaction with CIT in the effect on eGFR (P interaction = 0.027). In the donation after brain death (DBD) group, CIT had no significant effect on eGFR [ß = 0.135 (-0.433, 0.702), P = 0.642]. In the donation after circulatory death/donation after brain death followed by circulatory death (DCD/DBCD) group, CIT had a significantly negative effect on eGFR [ß= -0.700 (-1.196, -0.204), P = 0.006]. Compared to a CIT of 0-6 h, a CIT of 6-8 or 8-12 h did not decrease the post-transplant eGFR. CIT over 12 h (12-16 h or over 16 h) significantly decreased eGFR. With the increase in CIT, the regenerated eGFR worsened (P trend = 0.011). Conclusion: Considering the effect of paired mate kidneys, the risk of DGF increased with prolonged CIT. The donor death category was an effect modifier between CIT and eGFR. Prolonged CIT did not reduce the eGFR level in recipients from DBDs but significantly decreased the eGFR in recipients from DCDs/DBCDs. This result indicates the potential biological interaction between CIT and donor death category.

Plasma Macrophage Migration Inhibitory Factor Predicts Graft Function Following Kidney Transplantation: A Prospective Cohort Study.

Background: Delayed graft function (DGF) is a common complication after kidney transplantation (KT) with a poor clinical outcome. There are no accurate biomarkers for the early prediction of DGF. Macrophage migration inhibitory factor (MIF) release during surgery plays a key role in protecting the kidney, and may be a potential biomarker for predicting post-transplant renal allograft recovery. Methods: Recipients who underwent KT between July 2020 and December 2020 were enrolled in the study. Plasma MIF levels were tested in recipients at different time points, and the correlation between plasma MIF and DGF in recipients was evaluated. This study was registered in the Chinese Clinical Trial Registry (ChiCTR2000035596). Results: Intraoperative MIF levels were different between immediate, slowed, and delayed graft function groups (7.26 vs. 6.49 and 5.59, P < 0.001). Plasma MIF was an independent protective factor of DGF (odds ratio = 0.447, 95% confidence interval [CI] 0.264-0.754, P = 0.003). Combining plasma MIF level and donor terminal serum creatinine provided the best predictive power for DGF (0.872; 95%CI 0.795-0.949). Furthermore, plasma MIF was significantly associated with allograft function at 1-month post-transplant (R 2 = 0.42, P < 0.001). Conclusion: Intraoperative MIF, as an independent protective factor for DGF, has excellent diagnostic performance for predicting DGF and is worthy of further exploration.