The First Case of Ischemia-Free Kidney Transplantation in Humans

Background: Ischemia-reperfusion injury (IRI) has been considered an inevitable event in organ transplantation since the first successful kidney transplant was performed in 1954. To avoid IRI, we have established a novel procedure called ischemia-free organ transplantation. Here, we describe the first case of ischemia-free kidney transplantation (IFKT). Materials and Methods: The kidney graft was donated by a 19-year-old brain-dead donor. The recipient was a 47-year-old man with end-stage diabetic nephropathy. The graft was procured, preserved, and implanted without cessation of blood supply using normothermic machine perfusion. Results: The graft appearance, perfusion flow, and urine production suggested that the kidney was functioning well-during the whole procedure. The creatinine dropped rapidly to normal range within 3 days post-transplantation. The levels of serum renal injury markers were low post-transplantation. No rejection or vascular or infectious complications occurred. The patient had an uneventful recovery. Conclusion: This paper marks the first case of IFKT in humans. This innovation may offer a unique solution to optimizing transplant outcomes in kidney transplantation

Genome-wide CRISPR/Cas9 screening for drug resistance in tumors

Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated nuclease 9 (Cas9) screening is a simple screening method for locating loci under specific conditions, and it has been utilized in tumor drug resistance research for finding potential drug resistance-associated genes. This screening strategy has significant implications for further treatment of malignancies with acquired drug resistance. In recent years, studies involving genome-wide CRISPR/Cas9 screening have gradually increased. Here we review the recent application of genome-wide CRISPR/Cas9 screening for drug resistance, involving mitogen-activated protein kinase (MAPK) pathway inhibitors, poly (ADP-ribose) polymerase inhibitors (PARPi), alkylating agents, mitotic inhibitors, antimetabolites, immune checkpoint inhibitors (ICIs), and cyclin-dependent kinase inhibitors (CDKI). We summarize drug resistance pathways such as the KEAP1/Nrf2 pathway MAPK pathway, and NF-κB pathway. Also, we analyze the limitations and conditions for the application of genome-wide CRISPR/Cas9 screening techniques

Identification of SPRYD4 as a tumour suppressor predicts prognosis and correlates with immune infiltration in cholangiocarcinoma

Abstract Cholangiocarcinoma (CCA) is an aggressive solid tumour with a 5-year survival rate ranging from 7% to 20%. It is, therefore, urgent to identify novel biomarkers and therapeutic targets to improve the outcomes of patients with CCA. SPRY-domain containing protein 4 (SPRYD4) contains SPRY domains that modulate protein–protein interaction in various biological processes; however, its role in cancer development is insufficiently explored. This study is the first to identify that SPRYD4 is downregulated in CCA tissues using multiple public datasets and a CCA cohort. Furthermore, the low expression of SPRYD4 was significantly associated with unfavourable clinicopathological characteristics and poor prognosis in patients with CCA, indicating that SPRYD4 could be a prognosis indicator of CCA. In vitro experiments revealed that SPRYD4 overexpression inhibited CCA cells proliferation and migration, whereas the proliferative and migratory capacity of CCA cells was enhanced after SPRYD4 deletion. Moreover, flow cytometry showed that SPRYD4 overexpression triggered the S/G2 cell phase arrest and promoted apoptosis in CCA cells. Furthermore, the tumour-inhibitory effect of SPRYD4 was validated in vivo using xenograft mouse models. SPRYD4 also showed a close association with tumour-infiltrating lymphocytes and important immune checkpoints including PD1, PD-L1 and CTLA4 in CCA. In conclusion, this study elucidated the role of SPRYD4 during CCA development and highlighted SPRYD4 as a novel biomarker and tumour suppressor in CCA

Mechanisms underlying low-clinical responses to PD-1/PD-L1 blocking antibodies in immunotherapy of cancer: a key role of exosomal PD-L1

Exosomes, as the main group of extracellular vesicles, are biologically active lipid-bilayer vesicles that are naturally released from different types of normal or tumor cells. These vesicles play an important role in intercellular communication and influence the extracellular environment and the immune system. Emerging evidence demonstrates that cancer-derived exosomes are enriched in immunosuppressive proteins, such as the programmed death-ligand 1 (PD-L1). PD-L1 and its receptor programmed cell death protein 1 (PD-1) are the key immune checkpoint molecules that promote tumor progression via negative regulation of immune responses. PDL-1 is highly expressed on the surface of tumor cells and binds to PD-1 on the surface of activated T cells, leading to suppression of T cells, which consequently enables cancer cells to escape antitumor immunity. Currently, there are several Food and Drug Administration-approved monoclonal antibodies blocking PD-1/PD-L1 interaction, which are clinically used for cancer treatment. However, despite impressive treatment outcomes, some patients show poor response to PD-1/PD-L1 blockade. Of note, tumor-derived exosomes containing PD-L1 can recapitulate the effect of cell-surface PD-L1. There is evidence that reveals a significant association between levels of circulating exosomal PD-L1 and rate of response to anti-PD-1/PD-L1 antibody therapy. The present article reviews the role of exosomal PDL-1 in the therapeutic resistance to anti-PD-1/PD-L1 treatment. Importantly, it is suggested that the removal of exosomal PDL-1 could serve as a therapeutic adjuvant for enhancing the efficacy of anti-PD-1/PD-L1 therapy in patients with cancer

Dynamic positron emission tomography image restoration via a kinetics-induced bilateral filter.

Dynamic positron emission tomography (PET) imaging is a powerful tool that provides useful quantitative information on physiological and biochemical processes. However, low signal-to-noise ratio in short dynamic frames makes accurate kinetic parameter estimation from noisy voxel-wise time activity curves (TAC) a challenging task. To address this problem, several spatial filters have been investigated to reduce the noise of each frame with noticeable gains. These filters include the Gaussian filter, bilateral filter, and wavelet-based filter. These filters usually consider only the local properties of each frame without exploring potential kinetic information from entire frames. Thus, in this work, to improve PET parametric imaging accuracy, we present a kinetics-induced bilateral filter (KIBF) to reduce the noise of dynamic image frames by incorporating the similarity between the voxel-wise TACs using the framework of bilateral filter. The aim of the proposed KIBF algorithm is to reduce the noise in homogeneous areas while preserving the distinct kinetics of regions of interest. Experimental results on digital brain phantom and in vivo rat study with typical (18)F-FDG kinetics have shown that the present KIBF algorithm can achieve notable gains over other existing algorithms in terms of quantitative accuracy measures and visual inspection

Lysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase

Abstract To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity

Identification of Prognostic and Therapeutic Biomarkers among FAM83 Family Members for Pancreatic Ductal Adenocarcinoma

Family with sequence similarity 83 (FAM83) members were shown recently to have oncogenic effect in a variety of cancer types, but the biological roles and prognostic value of FAM83 family in pancreatic ductal adenocarcinoma remain unknown. In the current study, the clinical significance and molecular function of the FAM83 family were assessed by multiple bioinformatics analysis. Besides, potential associations between differentially expressed genes (DEGs) of FAM83 family and antitumor immunity were evaluated using TIMER and TISIDB analyses. As the results show, FAM83A, FAM83D, FAM83E, and FAM83H were significantly upregulated in PDAC and were identified as DEGs. Higher expression of FAM83A, FAM83B, FAM83D, FAM83E, and FAM83H were associated with advanced tumor stage or worse patient prognosis. Importantly, the overexpression of DEGs was found to be significantly correlated with activated KRAS and loss of SMAD4, which are important drivers for PDAC. Further, FAM83A, FAM83D, and FAM83H were associated with CD8+ T cell, Gamma Delta T cell, and CD4+ T cell infiltration in PDAC and FAM83H was found closely correlated with some immunomodulators including immunoinhibitors, immunostimulators, and MHC molecules. In conclusion, FAM83A, FAM83D, FAM83E, and FAM83H have significant prognostic value in PDAC and they may play important roles in regulating tumor progression and the immune cell infiltration

A Novel Prognostic Nomogram for Gallbladder Cancer after Surgical Resection: A Single-Center Experience

Background. Gallbladder cancer (GBC), which accounts for more than 80% of biliary tract malignancies, has a poor prognosis with an overall 5-year survival less than 10%. The study aimed to identify risk factors and develop a predictive model for GBC following surgical resection. Methods. 98 GBC patients who underwent surgical resection from Guangdong Provincial People’s Hospital were enrolled in the study. Cox-regression analysis was performed to identify significant prognostic factors. A nomogram was constructed and Harrell’s concordance index, calibration plot, and decision cure analysis were used to evaluate the discrimination and calibration of the nomogram. Results. Liver resection, tumor size, perineural invasion, surgical margin, and liver invasion were identified as independent risk factors for overall survival (OS) in GBC patients who underwent surgical resection. Based on the selected risk factors, a novel nomogram was constructed. The C-index of the nomogram was 0.777, which was higher than the American Joint Committee on Cancer (AJCC) staging system (0.724) and Nevin staging system (0.659). Decision cure analysis revealed that the nomogram had a better net benefit and the calibration curves for the 1-, 3-, and 5-year survival probabilities were also well matched with the actual survival rates. Lastly, high-risk GBC were stratified based on the scores of the nomogram and we found high-risk GBC were associated with both worse OS and disease-free survival (DFS). Conclusion. We developed a nomogram showing a better predictive capacity for patients’ survival of resected GBC than the AJCC staging systems. The established model may help to stratify high-risk GBC and facilitate decision-making in the clinic

Prognostic Nomogram for Patients With Pancreatic Ductal Adenocarcinoma of Pancreatic Head After Pancreaticoduodenectomy

Background: The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) of pancreatic head remains poor, even after potentially curative R0 resection. The aim of this study was to develop an accurate model to predict patients’ prognosis for PDAC of pancreatic head following pancreaticoduodenectomy. Methods: We retrospectively reviewed 112 patients with PDAC of pancreatic head after pancreaticoduodenectomy in Guangdong Provincial People’s Hospital between 2014 and 2018. Results: Five prognostic factors were identified using univariate Cox regression analysis, including age, histologic grade, American Joint Committee on Cancer (AJCC) Stage 8th, total bilirubin (TBIL), CA19-9. Using all subset analysis and multivariate Cox regression analysis, we developed a nomogram consisted of age, AJCC Stage 8th, perineural invasion, TBIL, and CA19-9, which had higher C-indexes for OS (0.73) and RFS (0.69) compared with AJCC Stage 8th alone (OS: 0.66; RFS: 0.67). The area under the curve (AUC) values of the receiver operating characteristic (ROC) curve for the nomogram for OS and RFS were significantly higher than other single parameter, which are AJCC Stage 8th, age, perineural invasion, TBIL, and CA19-9. Importantly, our nomogram displayed higher C-index for OS than previous reported models, indicating a better predictive value of our model. Conclusions: A simple and practical nomogram for patient prognosis in PDAC of pancreatic head following pancreaticoduodenectomy was established, which shows satisfactory predictive efficacy and deserves further evaluation in the future