Objective: To investigate the association between atherogenic index of plasma (AIP) and risk of incident kidney stones. Methods: A nested case-control study was conducted using data from the Shanghai Kidney Stone Cohort from December 2018 to February 2023. Kidney stones were ascertained by ultrasound. Propensity score matching selected 2,550 patients with incident kidney stones and 5,100 controls from a total of 64,121 adults. Baseline fasting plasma samples were collected to measure the AIP, defined as the logarithm of the ratio triglycerides to high-density lipoprotein cholesterol. A multivariable conditional logistic regression model and restricted cubic spline were applied to examine the association between the AIP and the risk of incident kidney stones. Results: The baseline AIP values of the incident kidney stone patients and controls were 0.98 (0.67) and 0.91 (0.65), respectively. Patients with incident kidney stones had much higher baseline AIP levels than controls (p < 0.001). Participants in the highest AIP quartile had a 29% greater risk of developing kidney stones. Moreover, each increase in the standard deviation of the AIP was associated with a 10% greater risk of nephrolithiasis. A restricted cubic spline showed a significant positive and linear correlation between the AIP and the risk of developing kidney stones (P-overall = 0.040, P-nonlinear = 0.923). These findings remained robust in sensitivity analyses. Conclusions: A higher AIP is associated with a greater risk of incident kidney stones. KEY MESSAGES 1. A higher atherogenic index of plasma (AIP) significantly increases the risk of kidney stones. 1. Each standard deviation increase in AIP is associated with a 10% higher risk of nephrolithiasis. 2. The study suggests incorporating AIP assessment into management strategies for kidney stone prevention.

OBJECTIVE:Kidney stones (KS) are a growing global health concern with significant morbidity. Although individual lifestyle factors have been linked to KS risk, the combined influence of healthy lifestyles and the mediating role of lipid metabolism remains unclear. This study aimed to investigate whether the atherogenic index of plasma (AIP) mediates the link between KS risk and a composite healthy lifestyle score. DESIGN:Cross-sectional study. SETTING:National Health and Nutrition Examination Survey (NHANES) 2007-2016, USA. PARTICIPANTS:7576 US adults (mean age, 47.39 years; 52.57% male). OUTCOME MEASURES:The association between healthy lifestyle scores and KS risk was assessed by multivariable logistic regression. The mediating role of AIP was evaluated through mediation analysis. Dose-response relationships were examined by restricted cubic spline (RCS) analysis. Stratified analyses explored potential effect modifications by age, sex, race/ethnicity and metabolic conditions. RESULTS:Participants in the highest healthy lifestyle score quartile had 0.49 times the odds of KS compared with individuals in the lowest quartile (OR, 0.49; 95% CI, 0.38 to 0.64). A 19% decreased risk of KS was linked to every unit rise in the healthy lifestyle score (OR, 0.81; 95% CI, 0.76 to 0.87). An inverse linear dose-response association was shown by RCS analysis between healthy lifestyle scores and KS risk (P-overall<0.001, P-nonlinearity=0.321). AIP mediated 7.18% (95% CI, 1.07% to 14.40%) of the association between lifestyle and KS. The association remained across sensitivity analyses and subgroups. CONCLUSIONS:A healthier lifestyle is linked to lower odds of KS, with AIP partially mediating this association. These results emphasise the potential importance of composite lifestyle modifications for the prevention of KS.

Kidney stones pose a significant healthcare burden worldwide. Dyslipidemia is a risk factor for kidney stones, but the relationship between remnant cholesterol (RC) and kidney stone risk is unknown. We aimed to investigate the association between RC and the risk of incident kidney stones. We conducted a nested case-control study based on data from Shanghai Kidney Stone Cohort conducted in Shanghai from December 2018 to February 2023. Propensity score matching was used to select 2550 incident kidney stone cases and 7650 controls from a total of 60,158 adults. Baseline fasting plasma samples were collected to measure RC, which was calculated as total cholesterol minus high-density lipoproteins cholesterol and low-density lipoproteins cholesterol. Multivariable conditional logistic regression and a restricted cubic spline were used to estimate the association between tertiles of RC and kidney stone risk. Subgroup and sensitivity analyses were also performed. The baseline RC of incident kidney stone cases and controls were 0.58 (0.57) and 0.54 (0.55), respectively. Incident kidney stones had much higher baseline RC levels than controls (P < 0.001). Higher baseline RC levels were significantly associated with increased kidney stone risk after adjustment for potential confounders (highest vs. lowest tertile: OR 1.16, 95

Background:In renal cell carcinoma (RCC), skin metastases (SMs) occur in only 3.3% of cases and are even rarer as an initial manifestation of the disease. Although combination therapy with immune checkpoint inhibitors (ICIs) and targeted agents is the current standard of care, access to these treatments may be limited in certain regions due to cost constraints. Tislelizumab, a structurally enhanced humanized IgG4 monoclonal antibody developed indigenously in China, has demonstrated substantial efficacy and manageable safety profiles in clinical trials across a variety of solid tumors. Case Description:We report the case of a 46-year-old male who initially presented with painless ulcerative skin nodules on his scalp and the tip of his nose. Surgical removal of the scalp nodules led to a pathological diagnosis of metastatic clear cell RCC (ccRCC). Subsequent positron emission tomography/computed tomography (PET/CT) imaging revealed metastases in the lungs, bones, and brain. Due to financial constraints, the patient opted for combination therapy with tislelizumab and sunitinib. After one treatment cycle, the skin nodules resolved, pulmonary metastases decreased in size, and the left renal mass stabilized. However, disease progression (PD) was observed before the start of the twelfth cycle. Conclusions:Our case demonstrates that tislelizumab combined with sunitinib exhibits potential benefits for patients with advanced RCC, particularly in regions where access to standard combination therapy is limited. However, further clinical evidence is needed to support its widespread adoption in routine clinical practice.

Aldolase B (ALDOB), a glycolytic enzyme, is uniformly depleted in clear cell renal cell carcinoma (ccRCC) tissues. We previously showed that ALDOB inhibited proliferation through a mechanism independent of its enzymatic activity in ccRCC, but the mechanism was not unequivocally identified. We showed that the corepressor C-terminal-binding protein 2 (CtBP2) is a novel ALDOB-interacting protein in ccRCC. The CtBP2-to-ALDOB expression ratio in clinical samples was correlated with the expression of CtBP2 target genes and was associated with shorter survival. ALDOB inhibited CtBP2-mediated repression of multiple cell cycle inhibitor, proapoptotic, and epithelial marker genes. Furthermore, ALDOB overexpression decreased the proliferation and migration of ccRCC cells in an ALDOB-CtBP2 interaction-dependent manner. Mechanistically, our findings showed that ALDOB recruited acireductone dioxygenase 1, which catalyzes the synthesis of an endogenous inhibitor of CtBP2, 4-methylthio 2-oxobutyric acid. ALDOB functions as a scaffold to bring acireductone dioxygenase and CtBP2 in close proximity to potentiate acireductone dioxygenase-mediated inhibition of CtBP2, and this scaffolding effect was independent of ALDOB enzymatic activity. Moreover, increased ALDOB expression inhibited tumor growth in a xenograft model and decreased lung metastasis in vivo. Our findings reveal that ALDOB is a negative regulator of CtBP2 and inhibits tumor growth and metastasis in ccRCC.

PurposeThis study aimed to evaluate the efficacy and safety of same-session flexible ureteroscopy (fURS) for the treatment of bilateral upper urinary tract stones and to examine the influence of stone load on the outcome of same-session fURS, stratifying by total diameter of stones (TDS) ≤30 mm vs. >30 mm.Patients and methodsWe retrospectively reviewed all cases of same-session fURS performed for bilateral upper urinary tract stones at four institutions between January 2017 and September 2020. All patients were divided into two groups based on TDS, ≤30 mm and >30 mm. Data on patient demographics, stone characteristics, surgical results, and complications were collected and analyzed for differences between the two groups. Stone-free rate (SFR) was defined as patients endoscopically stone-free or with radiological fragments <2 mm of each renal unit.ResultsA total of 121 patients with bilateral upper urinary tract stones underwent same-session fURS, consisting of 73 patients in the TDS ≤ 30 mm group and 48 patients in the TDS > 30 mm group. The mean bilateral stone size was 28.2 ± 12.2 mm (range: 9.1–38.4 mm), with a mean operating time of 97.1 ± 39.6 min (range: 19–220 min). The SFR was 54.5% after the first fURS, and SFR increased to 97.5% after re-fURS for residual stones. The operation time for the TDS > 30 mm group was longer than that of the TDS ≤ 30 mm group (85.1 ± 36.5 vs. 115.4 ± 37.4 min, p < 0.001). The SFR after the first fURS was significantly lower in the TDS > 30 mm group than in the TDS ≤ 30 mm group (25.0% vs. 73.9%, p < 0.001). Although there was no statistically significant difference in overall SFR between the two groups (93.7% vs. 100%, p = 0.060), the rate of re-fURS for residual stones was higher in the TDS > 30 mm group than in the TDS ≤ 30 mm group (75% vs. 26%, p < 0.001). There were no significant differences in length of hospital stay (LOS) (2.2 ± 0.7 vs. 2.3 ± 1.0, p = 0.329) or complication rate (10.9% vs. 14.6%, p = 0.582) between the two groups.ConclusionThe results suggested that same-session fURS can be effectively performed with a low complication rate. A higher SFR after the first fURS can be achieved in the case of bilateral upper urinary tract stones with TDS ≤ 30 mm, and priority should be given to same-session fURS.

Background Although the molecular features of pancreatic ductal adenocarcinoma (PDAC) have been well described, the impact of detailed gene mutation subtypes on disease progression remained unclear. This study aimed to evaluate the impact of different TP53 mutation subtypes on clinical characteristics and outcomes of patients with PDAC. Methods We included 639 patients treated with PDAC in Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine between Jan 2019 and Jun 2021. The genomic alterations of PDAC were analyzed, and the association of TP53 mutation subtypes and other core gene pathway alterations with patients’ clinical characteristics were evaluated by Chi-squared test, Kaplan-Meier method and Cox regression model. Results TP53 missense mutation was significantly associated with poor differentiation in KRAS mut PDAC (50.7% vs. 36.1%, P = 0.001). In small-sized (≤ 2 cm) KRAS mut tumors, significantly higher LNs involvement (54.8% vs. 23.5%, P = 0.010) and distal metastic rate (20.5% vs. 2.9%, P = 0.030) were observed in those with TP53 missense mutation instead of truncating mutation. Compared with TP53 truncating mutation, missense mutation was significantly associated with reduced DFS (6.6 [5.6–7.6] vs. 9.2 [5.2–13.3] months, HR 0.368 [0.200–0.677], P = 0.005) and OS (9.6 [8.0-11.1] vs. 18.3 [6.7–30.0] months, HR 0.457 [0.248–0.842], P = 0.012) in patients who failed to receive chemotherapy, while higher OS (24.2 [20.8–27.7] vs. 23.8 [19.0–28.5] months, HR 1.461 [1.005–2.124], P = 0.047) was observed in TP53 missense cases after chemotherapy. Conclusions TP53 missense mutation was associated with poor tumor differentiation, and revealed gain-of-function properties in small-sized KRAS transformed PDAC. Nonetheless, it was not associated with insensitivity to chemotherapy, highlighting the neoadjuvant therapy before surgery as the potential optimized strategy for the treatment of a subset of patients.

Background Thyroid cancer-related deaths mostly result from metastasis. It was reported that the immunometabolism associated enzyme interleukin-4-induced-1 (IL4I1) was related to tumor metastasis. The present study was intended to investigate the effects of IL4I1 on thyroid cancer metastasis and its relationship with the prognosis. Methods Data from Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to find out the different mRNA expressions of IL4I1 between thyroid cancer and normal tissues. And Human Protein Atlas (HPA) was used to assess IL4I1 protein expression. To further differentiate thyroid cancer from normal tissues and estimate the impact of IL4I1 on the prognosis, the receiver operating characteristic curve (ROC) and Kaplan–Meier (KM) method was performed. The protein–protein interaction (PPI) network was established using STRING, and functional enrichment analyses were conducted by “clusterProfiler” package. Then, we assayed the correlation between IL4I1 and some related molecules. The relationship between IL4I1 and immune infiltration was performed using “Gene Set Variation Analysis (GSVA)” package in TCGA and tumor-immune system interaction database (TISIDB). Finally, we did in vitro experiments in order to further prove the bioeffects of IL4I1 on metastasis. Results The expression of IL4I1 mRNA and IL4I1 protein was significantly upregulated in thyroid cancer tissues. The increment of IL4I1 mRNA expression was related to high-grade malignancy, lymph node metastases and extrathyroidal extension. The ROC curve displayed the cutoff value of 0.782, with the sensitivity of 77.5% and the specificity of 77.8%. KM survival analysis showed that there was a worse PFS in patients with high IL4I1 expression than those with low IL4I1 expression ( p = 0.013). Further study indicated that IL4I1 was associated with lactate, body fluid secretion, positive regulation of T cell differentiation, and cellular response to nutrients in Gene Ontology (GO) analysis. Moreover, IL4I1 was found correlated with immune infiltration. Finally, the in vitro experiments revealed the promotion of IL4I1 on cancer cell proliferation, migration and invasion. Conclusions The increased IL4I1 expression is markedly correlated with the immune imbalance in the tumor microenvironment (TME) and predicts poor survival in thyroid cancer. This study reveals the potential clinical biomarker of poor prognosis and the target of immune therapy in thyroid cancer.

Purpose. Grade-dependent decrease of lipid storage in clear cell renal cell carcinoma (ccRCC) leads to morphology changes in HE sections. This study investigated the role of cytoplasmic features in frozen sections of ccRCC on prognosis using the digital pathology approach. Methods. We established an automatic pipeline that performed tumor region selection, stain vector normalization, nuclei segmentation, and feature extraction based on the pathologic data from Shanghai General Hospital and The Cancer Genome Atlas database. Extracted features were subjected to survival analysis. Results. Kurtosis of the cytoplasm in the hematoxylin channel was correlated with progression-free survival (HR 0.10, 95% CI: 0.04–0.24, p=6.52∗10−7) and overall survival (HR 0.11, 95% CI: 0.05–0.31, p=1.72∗10−5) in ccRCC, which outperformed other texture features in this analysis. Multivariate Cox regression analysis revealed that low kurtosis of cytoplasm in the hematoxylin channel was an independent predictor for a shorter progression-free survival time (p=0.044) and overall survival time (p = 0.01). Kaplan–Meier survival analysis of progression-free survival and overall survival also showed a significantly worse prognosis in patients with low kurtosis of the cytoplasm in the hematoxylin channel (both p<0.0001). Lower kurtosis of cytoplasm in the hematoxylin channel was associated with higher pathologic grade, less cholesterol ester, and more mitochondrial DNA content. Conclusion. Kurtosis of the cytoplasm in the hematoxylin channel predicts survival in clear cell renal cell carcinoma.

In some patients, the passage of semi-rigid ureteroscopes up the ureter is impossible due to narrow ureteral lumen. We established a neural network to predict the inability of the ureter to accommodate the semi-rigid ureteroscope and the need for active or passive dilatation using non-contrast computed tomography (CT) images. Data were collected retrospectively from two centers of 1989 eligible patients who underwent ureteroscopic lithotripsy with ureteral stones. Patients were categorized into two groups: control and narrow ureter. The network was designed and trained for predicting a narrow ureter during initial ureteroscopic lithotripsy, which integrated multi-scale features of the ureter. The predictive efficacy of neural networks DenseNet3D, ResNet3D, ResNet3D MC, and TimeSformer was compared. Furthermore, a previous ureteroscopy or a history of double-J stent placement, ureteral wall thickness and Hounsfield unit (HU) density of the ureter under the stone were compared. Model performance was assessed based on the accuracy, area under the receiver operating characteristic curve (AUC ROC), etc. The DenseNet3D-based network achieved an AUC ROC score of 0.884 and an accuracy of 85.29%, followed by the ResNet3D-based network, the ResNet3D MC-based network, and the TimeSformer-based network. The DenseNet3D-based network significantly outperformed other candidate predictors. Furthermore, the networks were validated in an external test set. Decision curve analysis showed the clinical utility of the neural network. The neural network provides an individualized preoperative prediction of narrow ureter based on non-contrast CT images, which could be employed as part of a surgical decision-making support system.

Immune checkpoint inhibitors have emerged as a novel therapeutic strategy for many different tumors, including clear cell renal cell carcinoma (ccRCC). However, these drugs are only effective in some ccRCC patients, and can produce a wide range of immune-related adverse reactions. Previous studies have found that ccRCC is different from other tumors, and common biomarkers such as tumor mutational burden, HLA type, and degree of immunological infiltration cannot predict the response of ccRCC to immunotherapy. Therefore, it is necessary to further research and construct corresponding clinical prediction models to predict the efficacy of Immune checkpoint inhibitors. We integrated PBRM1 mutation data, transcriptome data, endogenous retrovirus data, and gene copy number data from 123 patients with advanced ccRCC who participated in prospective clinical trials of PD-1 inhibitors (including CheckMate 009, CheckMate 010, and CheckMate 025 trials). We used AI to optimize mutation data interpretation and established clinical prediction models for survival (for overall survival AUC: 0.931; for progression-free survival AUC: 0.795) and response (ORR AUC: 0.763) to immunotherapy of ccRCC. The models were internally validated by bootstrap. Well-fitted calibration curves were also generated for the nomogram models. Our models showed good performance in predicting survival and response to immunotherapy of ccRCC.

The researchers aimed to study the correlations of expression of glucose-regulated protein 94 (GRP94) with clinicopathological characteristics and prognosis of patients with non-small cell lung cancer (NSCLC). NSCLC tissue specimens were collected from January 2016 to January 2018. The prognostic factors of NSCLC patients were analyzed. Survival curves were plotted. Logistic multivariate regression analysis was performed to explore the factors influencing prognosis. GRP94 protein was mainly expressed in the nucleus in NSCLC and para-carcinoma tissues. The high expression rates of GRP94 in NSCLC tissues were significantly different in patients with and without tumor metastasis after surgery (P<0.05). GRP94-positive NSCLC patients had significantly longer mean survival time than GRP94-negative ones (P<0.01). Positive GRP94 expression, maximum diameter of tumor, pathological type, lymph node metastasis, T stage and postoperative TNM stage were independent risk factors affecting prognosis. GRP94 is an independent factor influencing the prognosis of NSCLC, as a potential target for treatment.

The histone methyltransferase SET and MYND domain protein 2 (SMYD2) has been implicated in tumorigenesis through methylating histone H3 at lysine36 (H3K36) and some non-histone substrates. Currently, the role of SMYD2 in acute kidney injury (AKI) remains unknown. Here, we investigated the effects of AZ505, a highly selective inhibitor of SMYD2, on the development of AKI and the mechanisms involved in a murine model of cisplatin-induced AKI. SMYD2 and trimethylated histone H3K36 (H3K36Me3) were highly expressed in the kidney following cisplatin treatment; administration of AZ505 remarkedly inhibited their expression, along with improving kidney function and ameliorating kidney damage. AZ505 also attenuated kidney tubular cell injury and apoptosis as evidenced by diminished the expression of neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule (Kim-1), reduced the number of TUNEL positive cells, decreased the expression of cleaved caspase-3 and the BAX/BCL-2 ratio in injured kidneys. Moreover, AZ505 inhibited cisplatin-induced phosphorylation of p53, a key driver of kidney cell apoptosis and reduced expression of p21, a cell cycle inhibitor. Meanwhile, AZ505 promoted expression of proliferating cell nuclear antigen and cyclin D1, two markers of cell proliferation. Furthermore, AZ505 was effective in suppressing the phosphorylation of STAT3 and NF-κB, two transcriptional factors associated with kidney inflammation, attenuating the expression of monocyte chemoattractant protein-1 and intercellular cell adhesion molecule-1 and reducing infiltration of F4/80+ macrophages to the injured kidney. Finally, in cultured HK-2 cells, silencing of SMYD2 by specific siRNA inhibited cisplatin-induced apoptosis of kidney tubular epithelial cells. Collectively, these results suggests that SMYD2 is a key determinant of cisplatin nephrotoxicity and targeting SMYD2 protects against cisplatin-induced AKI by inhibiting apoptosis and inflammation and promoting cell proliferation.

Abstract Background Regulator of cullins 1 (ROC1) is an important catalytic subunit of cullin–RING E3 ligase. Nuclear factor-kappa B (NF-κB) signaling is closely related to tumor invasion and metastasis. Earlier, we reported that ROC1 was associated with a poor prognosis in patients with bladder cancer (BCa). However, it is unclear whether ROC1 is involved in the NF-κB signaling associated with malignant BCa progression. Methods The expression of ROC1 and p65 in bladder cancer and paracancerous tissues were detected by immunohistochemistry (IHC). Pearson correlation was used to assess correlation between ROC1 and p65 protein expressions. The wound-healing and transwell assays were used to monitor cell invasion and migration. The effect of ROC1 on the expression of key proteins in the NF-κB signaling was determined by immunofluorescence and western blot (WB). Cycloheximide (CHX), MG132 and immunoprecipitation assays were used to evaluate the effect of ROC1 on the ubiquitination of phosphorylated inhibitor of kappa B alpha (p-IκBα). A lung metastasis mouse model was generated to detect the role of ROC1 in tumor metastasis. Results We found that ROC1 was up-regulated in BCa tissues and cell lines, and high ROC1 levels were positively correlated with higher tumour grade, lymph node metastasis, distant metastasis and poor prognosis. Linear-regression analysis showed significant a Pearson correlation between ROC1 and nuclear p65 expression in BCa tissue microarray (TMA) samples. Functional studies demonstrated that ROC1 promoted BCa cell invasion and migration. In vitro and in vivo experiments showed that ROC1 activated NF-κB signaling by enhancing the ubiquitination of p-IκBα, which caused p65 nuclear translocation and promoted the transcription of some metastasis-related target genes, such as urokinase-type plasminogen activator receptor (uPAR), intracellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and matrix metalloproteinase 9 (MMP9), resulting in promoting BCa metastasis. Conclusion ROC1 plays an important role in the progression of BCa and serves as a potential diagnostic and therapeutic target for patients with BCa.

Circular RNAs (circRNA) are a class of covalently closed single-stranded RNAs that have been implicated in cancer progression. Here we identify circNDUFB2 to be downregulated in non-small cell lung cancer (NSCLC) tissues, and to negatively correlate with NSCLC malignant features. Elevated circNDUFB2 inhibits growth and metastasis of NSCLC cells. Mechanistically, circNDUFB2 functions as a scaffold to enhance the interaction between TRIM25 and IGF2BPs, a positive regulator of tumor progression and metastasis. This TRIM25/circNDUFB2/IGF2BPs ternary complex facilitates ubiquitination and degradation of IGF2BPs, with this effect enhanced by N 6 -methyladenosine (m 6 A) modification of circNDUFB2 . Moreover, circNDUFB2 is also recognized by RIG-I to activate RIG-I-MAVS signaling cascades and recruit immune cells into the tumor microenvironment (TME). Our data thus provide evidences that circNDUFB2 participates in the degradation of IGF2BPs and activation of anti-tumor immunity during NSCLC progression via the modulation of both protein ubiquitination and degradation, as well as cellular immune responses.

Almost all currently approved systemic therapies for hepatocellular carcinoma (HCC) failed to achieve satisfactory therapeutic effect. Exploring tailored treatment strategies for different individuals provides an approach with the potential to maximize clinical benefit. Previously, multiple studies have reported that hepatoma cell lines belonging to different molecular subtypes respond differently to the same treatment. However, these studies only focused on a small number of typical chemotherapy or targeted drugs across limited cell lines due to time and cost constraints. To compensate for the deficiency of previous experimental researches as well as link molecular classification with therapeutic response, we conducted a comprehensive in silico screening, comprising nearly 2000 compounds, to identify compounds with subclass-specific efficacy. Here, we first identified two transcriptome-based HCC subclasses (AS1 and AS2) and then made comparison of drug response between two subclasses. As a result, we not only found that some agents previously considered to have low efficacy in HCC treatment might have promising therapeutic effects for certain subclass, but also identified novel therapeutic compounds that were not routinely used as anti-tumor drugs in clinic. Discovery of agents with subclass-specific efficacy has potential in changing the status quo of population-based therapies in HCC and providing new insights into precision oncology.

BACKGROUND:T-acute lymphoblastic leukemia (T-ALL) was a hematological malignancy characterized by the accumulation of immature T cells in bone marrow and peripheral blood. In this study, we tried to explore the physiological role of CD59 in T-ALL.METHODS:In this study, we collected the bone marrow samples from 17 T-ALL patients and 38 healthy participants to find differences in CD59 expression patterns. Then, CD59 was over-expressed in T-ALL cell line Jurkat, and its biological functions were detected. In addition, in order to understand the active site of CD59, the Trp40 was mutated. Further, we constructed a mouse model by transplanting Jurkat cells into the nude mice to verify the function of CD59 in vitro. At last, mechanism studies were performed by western blot.RESULTS:We found that the proportion of T lymphocytes expressing CD59 in bone marrow of T-ALL patients was significantly higher than that of healthy individuals. Then, we found that the overexpression of CD59 in Jurkat cells was beneficial to the cell survival by inhibiting apoptosis and promoting IL-2 secretion. In this process, Trp40 of CD59 was a key functional site. Further, the high expression of CD59 inhibited apoptosis of bone marrow and peripheral blood cells, and promoted IL-2 secretion in mouse model. At last, mechanism studies showed that the activation of AKT, STAT5 and Notch1 signaling pathways in Jurkat cells, may be involved in the regulation of apoptosis by CD59; and mutation in the Trp40 affect the interaction of CD59 with these signaling pathways.CONCLUSIONS:In conclusion, CD59 inhibited apoptosis of T-ALL by regulating AKT/Notch1 signaling pathway, providing a new perspective for the treatment of T-ALL.

Hepatocellular carcinoma (HCC), the most common aggressive malignancy of liver, is the third leading cause of cancer death across the world. Laminin gamma 1 (Lamc1), encodes laminin-γ1, an extracellular matrix protein involved in various progresses such as tumor cell proliferation and metabolism. In the present study, high expression of Lamc1 and PKM2 was observed in tumor tissues of HCC patients. In vitro, down-regulation of Lamc1 inhibited proliferation of HCC cells by promoting cell death, reduced glucose consumption and lactate production, accompanied by a decrease in the expression of glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA), and PTEN increased, as well as PTEN S380 and AKT S473/T308 phosphorylation decreased, while Lamc1 up-regulation had the opposite effect. The effects of PKM2 were similar to that of Lamc1 and markedly counteracted the effects of Lamc1 down-regulation. In addition, Lamc1-induced increase in PKM2 expression was strongly attenuated by a PI3K inhibitor, LY294002 or a si-p110 PI3K, with a significant decrease in GLUT1 and LDHA expression, as well as decreased AKT T308 phosphorylation. Thus, we speculated that Lamc1 was implicated in the progression of HCC probably by regulating PKM2 expression through PTEN/AKT pathway.

Clear cell renal cell carcinoma (ccRCC) is characterized by the activation of hypoxia-inducible factors and enhanced aerobic glycolysis. In our previous study, metabolic profiling revealed a threefold increase of fructose 1,6-bisphosphate (FBP) in ccRCC tissue compared with normal kidney tissue. As an important intermediate metabolite, its role in cancer development remains unknown. We found that high levels of FBP were required for cancer growth because of its ability to affect the redox status. Mechanistically, FBP regulated the redox status partially by suppressing NADPH oxidase isoform NOX4 activity in ccRCC cells. ccRCC maintained high levels of FBP through the downregulation of aldolase B (ALDOB). Reduction of FBP levels in cancer cells by the ectopic expression of ALDOB disrupted redox homeostasis, arrested cancer proliferation, and sensitized ccRCC cells to a chemotherapy agent (paclitaxel). Furthermore, low expression of ALDOB portended significantly worse disease-free survival and overall survival in ccRCC patients. In summary, the downregulation of ALDOB and accumulation of FBP promote ccRCC growth by counteracting oxidative stress.

Nuclear receptor binding protein 1 (NRBP1) is an evolutionarily highly conserved adaptor protein with multiple domains. Recently, its role in cancers has received increasing attention. To investigate whether NRBP1 is involved in the development of bladder cancer, we used tissue microarray and analyzed the association between the expression levels of NRBP1 and clinico-pathological features of 56 patients diagnosed with bladder cancer. Subsequently, NRBP1 was silenced using siRNA in bladder cancer cell lines T24 and 5637, and cell phenotype such as proliferation and apoptosis were observed. Further, in vivo tumor formation assay was performed. The expression of apoptosis markers was detected by Western blot. A significant positive correlation between increased NRBP1 expression and tumor stage, and lymph node metastasis was observed in 56 patients. High expression of NRBP1 was associated with poor prognosis and NRBP1 knockdown significantly inhibited cell proliferation and induced intrinsic apoptosis in vitro. Moreover, we also found that NRBP1 knockdown significantly suppress tumor growth in xenograft mouse model. Taken together, these data suggest that NRBP1 plays a critical role in the development of bladder cancer and may represent a potential target for bladder cancer treatment.