Posttransplant complications: molecular mechanisms and therapeutic interventions.

Posttransplantation complications pose a major challenge to the long-term survival and quality of life of organ transplant recipients. These complications encompass immune-mediated complications, infectious complications, metabolic complications, and malignancies, with each type influenced by various risk factors and pathological mechanisms. The molecular mechanisms underlying posttransplantation complications involve a complex interplay of immunological, metabolic, and oncogenic processes, including innate and adaptive immune activation, immunosuppressant side effects, and viral reactivation. Here, we provide a comprehensive overview of the clinical features, risk factors, and molecular mechanisms of major posttransplantation complications. We systematically summarize the current understanding of the immunological basis of allograft rejection and graft-versus-host disease, the metabolic dysregulation associated with immunosuppressive agents, and the role of oncogenic viruses in posttransplantation malignancies. Furthermore, we discuss potential prevention and intervention strategies based on these mechanistic insights, highlighting the importance of optimizing immunosuppressive regimens, enhancing infection prophylaxis, and implementing targeted therapies. We also emphasize the need for future research to develop individualized complication control strategies under the guidance of precision medicine, ultimately improving the prognosis and quality of life of transplant recipients.

Dopamine Receptor 1 Treatment Promotes Epithelial Repair of Corneal Injury by Inhibiting NOD-Like Receptor Protein 3-Associated Inflammation.

Purpose: To elucidate the influence of dopamine receptor 1 (DRD1) on the proliferation of mouse corneal epithelial cells (MCECs) under inflammatory conditions. Methods: In vitro, immortalized MCECs (iMCECs) were treated with IL-1ß, with and without pcDNA3.1_DRD1. Primary MCECs (pMCECs) were exposed to IL-1ß, with and without DRD1 agonist (A68930). Cell proliferation was quantified using the Cell Counting Kit-8 (CCK-8) assay and immunofluorescence staining for Ki-67 and p63. Expression levels of NOD-like receptor protein 3 (NLRP3), IL-1ß, and IL-6 were assessed. To establish a corneal injury model in mice, a 2-mm superficial keratectomy was performed. Either 0.1% A68930 or PBS was topically administered three times daily to the injured eyes for up to 5 days post-injury. Immunofluorescence analysis was employed to evaluate the expression of Ki-67, p63, and CD45 in mouse corneas. Western blotting and real-time quantitative PCR were utilized for quantitative analysis of DRD1, NLRP3, IL-1ß, and IL-6 in mouse corneas. Corneal epithelial regeneration was monitored through fluorescein sodium staining for a duration of up to 5 days following the injury. Results: Overexpression of DRD1 and A68930 promoted MCEC proliferation and suppressed the expression of NLRP3, IL-1ß, and IL-6 in vitro. Topical application of the 0.1% A68930 following mechanical corneal injury in mice led to increased Ki-67 and p63 expression compared to PBS treatment. Furthermore, topical administration of the 0.1% A68930 reduced the expression of CD45, NLRP3, IL-1ß, and IL-6. Analysis with fluorescein sodium indicated accelerated corneal epithelial regeneration in the 0.1% A68930 treatment group. Conclusions: DRD1 treatment counteracts NLRP3-associated inflammation and facilitates epithelial repair of corneal injury.

Taurine alleviates high-fat-high-glucose-induced pancreatic islet ß-cell oxidative stress and apoptosis in rat.

The effect of taurine (TAU) as a specific regulatory mediator on pancreatic function in obese rats induced by a high-fat-high-glucose (HFHG) diet was investigated. We fed male Sprague-Dawley rats under different conditions, namely the control, HFHG, TAU, and HFHG + TAU treatment groups for 4 months. Compared with the HFHG group, TAU supplementation significantly reduced malondialdehyde levels and increased superoxide dismutase, total antioxidant capacity, and glutathione levels in the rat pancreas. In addition, TAU significantly decreased the level of reactive oxygen species, and markedly increased the activity of heme oxygenase 1 (HO-1), Kelch-like ECH-associated protein 1 (KEAP-1), and nuclear factor erythrocyte-2-related factor 2 (Nrf2) in the rat pancreas. Notably, HFHG diet could induce pancreatic injury in the rats through the Nrf2/HO-1 signaling pathway and activate the mitochondrial channel-mediated apoptotic signaling pathway. The addition of TAU significantly improved the pancreatic tissue injury induced by the HFHG diet in the rats and reduced the protein expression of Caspase-3, Cleaved-caspase-3, Caspase-9 and Bcl-2 associated protein X (BAX), and increased the protein expression of B-cell lymphoma-2 (Bcl-2). In conclusion, this experiment confirmed that TAU could alleviate the oxidative stress and apoptosis induced by the HFHG diet in rat pancreatic ß-cells.

HES1 deficiency impairs development of human intestinal mesenchyme by suppressing WNT5A expression.

Serious intestinal side-effects that target the NOTCH-HES1 pathway in human cancer differentiation therapy make it necessary to understand the pathway at the human organ level. Herein, we endogenously introduced HES1-/- mutations into human embryonic stem cells (hESCs) and differentiated them into human intestinal organoids (HIO). The HES1-/- hESCs retained ES cell properties and showed gene expression patterns similar to those of wild-type hESCs when they differentiated into definitive endoderm and hindgut. During the formation of the HES1-/- lumen we noted an impaired development of mesenchymal cells in addition to the increased differentiation of secretory epithelium. RNA-Seq revealed that inhibited development of the mesenchymal cells may have been due to a downregulation of WNT5A signaling. Overexpression of HES1 and silencing of WNT5A in the intestinal fibroblast cell line CCD-18Co indicated that HES1 was involved in the activation of WNT5A-induced fibroblast growth and migration, suggesting the likelihood of the Notch pathway in epithelial-mesenchymal crosstalk. Our results facilitated the identification of more precise underlying molecular mechanisms displaying distinct roles in HES1 signaling in stromal and epithelial development in human intestinal mucosa.

Genetic association of PRKCD and CARD9 polymorphisms with Vogt-Koyanagi-Harada disease in the Chinese Han population.

BACKGROUND: Protein kinase C delta (PRKCD) and caspase recruitment domain family member 9 (CARD9) are genes involved in B and T cell activation, and cytokine production, which are vital mechanisms underlying autoimmune disease development. This study aimed to explore the association of the PRKCD and CARD9 genes with Vogt-Koyanagi-Harada disease (VKH) disease. The case-control study was performed to in 912 patients with VKH and 878 normal controls. MassARRAY system, SHEsis online platform, real-time PCR, and enzyme-linked immunosorbent assay were used to detect genotyping, haplotyping, mRNA expression, and cytokine levels, respectively. RESULTS: We found that rs74437127 C allele of PRKCD, rs3812555 CC genotype, and C allele of CARD9 were associated with increased susceptibility of VKH (Pc = 0.020, OR = 1.624; Pc = 2.04 × 10-5, OR = 1.810; Pc = 2.76 × 10-5, OR = 1.698, respectively). However, the rs74437127 T allele, and rs3812555 TC genotype and T allele were linked with decreased susceptibility to VKH (Pc = 0.020, OR = 0.616; Pc = 7.85 × 10-5, OR = 0.559; Pc = 2.76 × 10-5, OR = 0.589, respectively). PRKCD ATG and CARD9 GCTTA haplotypes decreased susceptibility to VKH (Pc = 3.11 × 10-3, OR = 0.594; Pc = 5.00 × 10-3, OR = 0.639, respectively). Functional studies on rs3812555 genotyped individuals revealed that CC carriers had significantly higher CARD9 mRNA expression and tumour necrosis factor-α production than TC/TT carriers (P = 1.00 × 10-4; P = 2.00 × 10-3, respectively). CONCLUSIONS: We found an association between PRKCD rs74437127 and CARD9 rs3812555 polymorphisms and VKH susceptibility and revealed that the increased susceptibility of rs3812555 for VKH may be mediated by regulating CARD9 gene expression and the production of pro-inflammatory cytokines, such as TNF-α.

A radiomics-based model can predict recurrence-free survival of hepatocellular carcinoma after curative ablation.

BACKGROUND: Prediction of early recurrence (ER) of HCC after radical treatment is of great significance for follow-up and subsequent treatment, and there is a lot of unmet needs. Here, our goal is to develop and validate a radiomics nomogram that can predict ER after curative ablation. OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of regorafenib after disease progression with sorafenib in Chinese patients with advanced HCC through this retrospective analysis. METHODS: 149 HCC patients treated between November 2008 and February 2018 were enrolled and randomly divided into training cohort (n = 105) and validation cohort (n = 44). The survival endpoint was recurrence-free survival (RFS). A total of 16908 radiomics features were extracted from the contrast-enhanced MR images of each patient. The minimum redundancy maximum relevance algorithm (mRMR) and random survival forest (RSF) were used for feature selection. Twelve kinds of support vector machine (SVM) models, a Cox regression model (Cox PH), a random survival forest (RSF) model and a gradient boosting model (GBoost) were used to build a radiomics signature. These models were trained after adjusting the model parameters using 5-fold cross-validation. The best models were selected according to the C-index. RESULTS: Using the machine learning (ML) framework, 40 features were identified that demonstrated good prediction of HCC recurrence across all cohorts. The random survival forest (RSF) model showed higher prognostic value, with a C-index of 0.733-0.801 and an integrated Brier score of 0.147-0.165, compared with other SVM models, Cox regression models, etc. (all P < 0.05). Time-dependent receiver operating characteristic (ROC) curve analysis, survival analysis, and decision curve analysis (DCA) were used to verify the performance of the RSF model in predicting tumor recurrence. CONCLUSION: We successfully built a radiomics-based RSF model with integrated radiomics and clinicopathological features that can potentially be used to predict ER after curative ablation in HCC patients.

CARARIME: Interactive web server for comprehensive analysis of renal allograft rejection in immune microenvironment.

Background: Renal transplantation is a very effective treatment for renal failure patients following kidney transplant. However, the clinical benefit is restricted by the high incidence of organ rejection. Therefore, there exists a wealth of literature regarding the mechanism of renal transplant rejection, including a large library of expression data. In recent years, research has shown the immune microenvironment to play an important role in renal transplant rejection. Nephrology web analysis tools currently exist to address chronic nephropathy, renal tumors and children's kidneys, but no such tool exists that analyses the impact of immune microenvironment in renal transplantation rejection. Methods: To fill this gap, we have developed a web page analysis tool called Comprehensive Analysis of Renal Allograft Rerejction in Immune Microenvironment (CARARIME). Results: CARARIME analyzes the gene expression and immune microenvironment of published renal transplant rejection cohorts, including differential analysis (gene expression and immune cells), prognosis analysis (logistics regression, Univariable Cox Regression and Kaplan Meier), correlation analysis, enrichment analysis (GSEA and ssGSEA), and ROC analysis. Conclusions: Using this tool, researchers can easily analyze the immune microenvironment in the context of renal transplant rejection by clicking on the available options, helping to further the development of approaches to renal transplant rejection in the immune microenvironment field. CARARIME can be found in http://www.cararime.com.

Taurine Alleviates LPS-Induced Acute Lung Injury by Suppressing TLR-4/NF-κB Pathway.

Taurine has the function of immune regulation, relieving acute and chronic inflammation caused by various agents, and maintaining cell homeostasis. This investigation focused on the protective functions of taurine targeting acute lung injury (ALI) induced by LPS. Sixty male SD rats aged 6-7 weeks were segregated at random: blank control group (C group), taurine control group (T group), ALI model group (LPS group), and taurine prevention groups (LPST1, LPST, LPST3 Groups). C group and LPS group were given normal drinking water, while T group and LPST group were given 2% taurine in drinking water. LPST1 group was given 1% taurine in drinking water while. LPST3 group was given 3% taurine in drinking water. On the 14th and 28th day, LPS group and LPST1, LPST, and LPST3 groups were subjected to injection of LPS (25 mg/kg) into the trachea of rats. Serum, peripheral blood, lung tissue, and bronchoalveolar lavage fluid (BALF) were collected at 6 h post-LPS injection. The wet/dry ratio (W/D) of lung was measured by hot drying method. The population of white blood cells and the abundance of inflammatory-related cells within peripheral blood were counted by an automatic blood cell analyzer. The population of white blood cells within BALF was counted by a white blood cell counting plate combined with Swiss Giemsa staining, while the proportion of related white blood cells was calculated. BCA reagent was used to determine the protein concentration in BALF. The levels of pro-inflammatory factors (IL-1 ß, IL-6, IL-18, TNF - α), anti-inflammation factors (IL-10, IL-4), and taurine within serum and lung tissue were detected by ELISA. Lung structural tissue alterations were observed through HE staining techniques. Myeloperoxidase (MPO) activities within lung tissue were detected through colorimetry. Protein expression levels of TLR4, MyD88, NF-κ Bp65, NF-κ Bp-p65, MCP-1, together with CD68 within lung tissue, were analyzed by Western blot (WB) and immunohistochemistry (IHC). The taurine pretreatment group contained significantly reduced W/D, MPO activity, and the number of inflammatory cells in BALF induced by LPS. In addition, compared with ALI model group, the taurine pretreatment group contained significantly reduced levels of pro-inflammatory factors in lung tissue, increased levels of anti-inflammatory factors, and decreased expression levels of key proteins in TLR-4/NF-κ B pathway. Taurine can protect rats from ALI by inhibiting the activation of neutrophils, macrophages, and TLR-4/NF-κ B signaling pathway.

Antioxidant Effect of Taurine on Chronic Heat-Stressed Broilers.

The purpose of this study was to investigate the effects of taurine on blood indices of broilers with chronic heat stress and to provide theoretical basis for the application of taurine in the anti-chronic heat stress of broilers. In the test, 240 AA + broilers at 7 days of age were randomly divided into five groups: the normal temperature control group (24 ± 2 °C) in group C, the heat stress control group (34 ± 2 °C) in HS group, and the LTau, MTau, and HTau groups in heat under stress conditions, 0.5 g/L, 2 g/L, and 8 g/L taurine, were added to the drinking water, and each group was repeated three times. After 2 weeks of feeding at normal temperature, heat stress began. The test period was 4 weeks. Blood was collected at 6 h, 12 h, 7 d, 14 d, 21 d, and 28 d after heat stress, and serum was separated. The results showed that compared with the HS group, MTau significantly increased the total serum protein content (P < 0.05), but the other groups were not significantly different (P > 0.05). The MTau and HTau groups contained significantly lowered serum uric acid levels than the HS group (P < 0.05). At 7d and 14d, the LTau, MTau, and HTau groups all exhibited significantly increased T3 and T4 concentrations (P < 0.05). There was no significant difference between the groups at other times (P > 0.05). Compared with the HS group, the MTau group contained significantly reduced serum CK activity, LDH activity, AST activity, and ALT activity (P < 0.05). Compared with the LTau, MTau, and HTau groups, serum MDA content was significantly increased in the heat-stressed broilers (P < 0.05). MTau group contained significantly increased T-AOC, SOD, CAT, and GSH-PX levels (P < 0.05). The other groups were not significantly different (P > 0.05). Compared with group C, serum HSP60 and HSP70 levels were significantly elevated in the HS group (P < 0.05). Compared with the HS group, the LTau and MTau groups contained significantly increased serum HSP60 and HSP70 concentrations (P < 0.05), but the other groups were not significantly different (P > 0.05). In conclusion, taurine can alleviate the symptoms of chronic heat stress of broilers, regulate the metabolism of the body, and improve the antioxidant activity of the body.

Taurine Prevents AFB1-Induced Renal Injury by Inhibiting Oxidative Stress and Apoptosis.

Aflatoxin B1 (AFB1) is one of the most toxic mycotoxins, which can cause serious kidney damage after ingestion. Taurine protects the kidney, an effect related to its antioxidation and anti-apoptotic actions. In the present study, taurine was administered to detect the protective effect and mechanism of taurine on AFB1-induced renal injury in rats. The results show that taurine ameliorated the increase in serum blood urea nitrogen (BUN), blood creatinine (CRE), blood uric acid (UA), cystatin c (Cys-c), and urinary protein and AKP levels. Taurine also inhibits the content of superoxide dismutase (SOD), total antioxidant capacity (T-AOC), catalase (CAT), glutathione (GSH), glutathione peroxidase (GSH-Px), succinate dehydrogenase (SDH), and the mRNA expression of SOD, nicotinamide adenine dinucleotide phosphate-quinine oxidoreductase 1 (NQO1), γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), and glutamate cysteine ligase catalytic (GCLC) in rat kidney tissue. The apoptotic rate of renal cells was decreased by taurine through inhibition of a mitochondrial mechanism. In summary, we found that taurine prevents AFB1-induced renal injury via enhanced antioxidant ability and mitochondrial-dependent apoptosis.

Erratum: Targeting Epstein-Barr virus oncoprotein LMP1-mediated high oxidative stress suppresses EBV lytic reactivation and sensitizes tumors to radiation therapy: Erratum.

[This corrects the article DOI: 10.7150/thno.46006.].

Low Nuclear Magnetic Resonance Experimental Study on Gas Adsorption of High-Rank Coals with Different Beddings.

In order to deeply study the influence of the coal bedding structure on coal gas adsorption, low nuclear magnetic resonance (LNMR) and a confining pressure loading system were used to carry out the LNMR experiment of gas adsorption of high-rank coals with different beddings under different confining pressures. The results showed that the amount of gas adsorption of high-rank coals with different beddings increases with time and decreases with the increase of confining pressure. In the process from low confining pressure to high confining pressure, the coal sample with oblique bedding (bedding angles 30°, 45°, and 60°) has the largest average increment of gas adsorption, followed by the coal sample with vertical bedding (bedding angle 90°), and the coal sample with parallel bedding has the smallest increment of gas adsorption (bedding angle 0°). The linear function relation between the different-bedding high-rank coal gas adsorption state and the confining pressure is y = a - bx. The relation between the free peak area and the confining pressure conforms to the exponential function y = a + bexp(cx). Different-bedding high-rank coal adsorption peaks and the peak area decrease with the increase of confining pressure, and the free peak continues to move to the left; that is, the large pores gradually shrink. With the increase of angle and bedding, the area of the adsorption peak increases first and then decreases, presenting an "inverted V" shape on the whole. The area of the free peak decreases first and then increases, presenting a "V" shape on the whole.

Taurine attenuates AFB1-induced liver injury by alleviating oxidative stress and regulating mitochondria-mediated apoptosis.

Aflatoxin B1 (AFB1), which widely exists in soil and crops, is the most toxic aflatoxin and a carcinogen to humans and animals. The liver is the main organ that processes AFB1 and other mycotoxins and is also the main target of AFB1 toxicity. Taurine is known to exhibit a variety of physiological and pharmacological functions. In the present study, taurine was administered to detect the protective effect and mechanism of taurine in AFB1-induced liver injury in rats. The results showed that taurine inhibited the increase in hepatic injury indices, hepatic apoptosis and hepatic malondialdehyde (MDA) contents while significantly enhanced the hepatic activities of antioxidant enzymes and mitochondrial function-related indices in AFB1-poisoned rats. Meanwhile, the expression levels of key factors in the Nrf2 signalling pathway were upregulated while the expression levels of key proteins in the mitochondria-mediated apoptotic pathway were downregulated after taurine administration. The results showed that taurine can reverse AFB1-induced liver injury and abnormal apoptosis through activation of the Nrf2 signalling pathway and its downstream antioxidant enzymes, which further protects mitochondria from oxidative stress and the subsequent apoptotic pathway.

Changes in best-corrected visual acuity in patients with dry age-related macular degeneration after stem cell transplantation: systematic review and meta-analysis.

BACKGROUND: Stem cell transplantation may improve visual acuity in patients with dry age-related macular degeneration. Herein, we aimed to summarise the evidence on the risks and benefits of stem cell transplantation for improving visual acuity, including the risk of adverse events. METHODS: Data were obtained from the PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials databases, and each database was interrogated from the date of inception until 19 March 2022. The rates of visual acuity outcomes and adverse events associated with stem cell transplantation were examined. All statistical analyses were conducted using Review Manager 5.4. The study was registered with PROSPERO (CRD 42022322902). RESULTS: The analysis examined 10 studies (102 patients), including one and three, randomised and non-randomised clinical trials, and one and five, multicentre prospective and prospective clinical trials, respectively. Meta-analysis showed changes in best-corrected visual acuity in the study eyes after stem cell transplantation (6 months: risk ratio [RR] = 17.00, 95% confidence interval [CI] 6.08-47.56, P < 0.00001; 12 months: RR = 11.00, 95% CI 2.36-51.36, P = 0.002). Subgroup analysis showed that different stem cell types achieved better best-corrected visual acuity at post-operative 6 months, compared to that observed at baseline. Four cases of related ocular adverse events and no related systemic adverse events were reported. CONCLUSION: This meta-analysis suggests that stem cell transplantation may improve best-corrected visual acuity in dry age-related macular degeneration, based on small sample sizes and fewer randomised controlled trials.

CPT1A-mediated fatty acid oxidation promotes cell proliferation via nucleoside metabolism in nasopharyngeal carcinoma.

As the first rate-limiting enzyme in fatty acid oxidation (FAO), CPT1 plays a significant role in metabolic adaptation in cancer pathogenesis. FAO provides an alternative energy supply for cancer cells and is required for cancer cell survival. Given the high proliferation rate of cancer cells, nucleotide synthesis gains prominence in rapidly proliferating cells. In the present study, we found that CPT1A is a determining factor for the abnormal activation of FAO in nasopharyngeal carcinoma (NPC) cells. CPT1A is highly expressed in NPC cells and biopsies. CPT1A dramatically affects the malignant phenotypes in NPC, including proliferation, anchorage-independent growth, and tumor formation ability in nude mice. Moreover, an increased level of CPT1A promotes core metabolic pathways to generate ATP, inducing equivalents and the main precursors for nucleotide biosynthesis. Knockdown of CPT1A markedly lowers the fraction of 13C-palmitate-derived carbons into pyrimidine. Periodic activation of CPT1A increases the content of nucleoside metabolic intermediates promoting cell cycle progression in NPC cells. Targeting CPT1A-mediated FAO hinders the cell cycle G1/S transition. Our work verified that CPT1A links FAO to cell cycle progression in NPC cellular proliferation, which supplements additional experimental evidence for developing a therapeutic mechanism based on manipulating lipid metabolism.

Update of application of olfactory ensheathing cells and stem cells/exosomes in the treatment of retinal disorders.

Age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa and other retinal disorders are the main causes of visual impairment worldwide. In the past, these retinal diseases, especially dry age-related macular degeneration, proliferative diabetic retinopathy and retinitis pigmentosa, were treated with traditional surgery and drugs. However, the effect was moderate. In recent years, researchers have used embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, olfactory ensheathing cells and other stem cells to conduct experiments and found that stem cells can inhibit inflammation, regulate immune response, secrete neurotrophic factors, and differentiate into retinal cells to replace and promote restoration of the damaged parts. These stem cells have the potential to treat retinal diseases. Whether it is in animal experiments or clinical trials, the increase in the number of retinal cells, maintenance of function and improvement of visual function all reflect the advanced of stem cells to treat retinal diseases, but its risk preserves the donor's hidden pathogenic genes, immune rejection and tumorigenicity. With the development of exosomes study, researchers have discovered that exosomes come from a wide range of sources and can be secreted by almost all types of cells. Using exosomes with stem cell to treat retinal diseases is more effective than using stem cells alone. This review article summarizes the recent advances in the application of olfactory ensheathing cells and stem cells/exosomes in the treatment of retinal disorders.

Conformational change of adenine nucleotide translocase-1 mediates cisplatin resistance induced by EBV-LMP1.

Adenine nucleotide translocase-1 (ANT1) is an ADP/ATP transporter protein located in the inner mitochondrial membrane. ANT1 is involved not only in the processes of ADP/ATP exchange but also in the composition of the mitochondrial membrane permeability transition pore (mPTP); and the function of ANT1 is closely related to its own conformational changes. Notably, various viral proteins can interact directly with ANT1 to influence mitochondrial membrane potential by regulating the opening of mPTP, thereby affecting tumor cell fate. The Epstein-Barr virus (EBV) encodes the key tumorigenic protein, latent membrane protein 1 (LMP1), which plays a pivotal role in promoting therapeutic resistance in related tumors. In our study, we identified a novel mechanism for EBV-LMP1-induced alteration of ANT1 conformation in cisplatin resistance in nasopharyngeal carcinoma. Here, we found that EBV-LMP1 localizes to the inner mitochondrial membrane and inhibits the opening of mPTP by binding to ANT1, thereby favoring tumor cell survival and drug resistance. The ANT1 conformational inhibitor carboxyatractyloside (CATR) in combination with cisplatin improved the chemosensitivity of EBV-LMP1-positive cells. This finding confirms that ANT1 is a novel therapeutic target for overcoming cisplatin resistance in the future.

Erratum: Analysis of the In Vivo and In Vitro Effects of Photodynamic Therapy on Breast Cancer by Using a Sensitizer, Sinoporphyrin Sodium: Erratum.

[This corrects the article DOI: 10.7150/thno.10853.].

Stabilization of p18 by deubiquitylase CYLD is pivotal for cell cycle progression and viral replication.

p18 is a key negative regulator of cell cycle progression and mediates cell cycle arrest at the G1/S phase. Ubiquitination is the prime mechanism in regulating p18 protein abundance. However, so far no post- translational regulator, especially DUBs, has been identified to regulate the protein stability of p18. In this paper, we identified CYLD as a deubiquitinase of p18, which binds to and removes the K48-linked polyubiquitylation chains conjugated onto p18, thus stabilizing the p18 protein. Loss of CYLD causes the degradation of p18 and induces the G1/S transition. Epstein-Barr virus (EBV), is the human oncovirus etiologically linked to nasopharyngeal carcinoma (NPC). Here we found that EBV drives a replication passive environment by deregulating the CYLD-p18 axis. Functionally, CYLD inhibits cell proliferation and tumorigenesis through p18 in vivo. Restoring CYLD prevents EBV induced viral replication and tumor growth. Collectively, our results identify CYLD directly stabilizes p18 to regulate the cellular G1/S transition. The reconstitution of CYLD-p18 axis could be a promising approach for EBV-positive cancer therapy.