PDZK1 confers sensitivity to sunitinib in clear cell renal cell carcinoma by suppressing the PDGFR-ß pathway.

BACKGROUND: Sunitinib has emerged as the primary treatment for advanced or metastatic clear cell renal cell carcinoma (ccRCC) due to its significant improvement in patients' average survival time. However, drug resistance and adverse effects of sunitinib pose challenges to its clinical benefits. METHODS: The differentially expressed genes (DEGs) associated with sunitinib sensitivity and resistance in ccRCC were investigated. Cell counting kit-8, plate colony formation, flow cytometry and subcutaneous xenograft tumor model assays were employed to explore the effects of PDZK1 on ccRCC. Further research on the molecular mechanism was conducted through western blot, co-immunoprecipitation, immunofluorescence co-localization and immunohistochemical staining. RESULTS: We elucidated that PDZK1 is significantly downregulated in sunitinib-resistant ccRCC specimens, and PDZK1 negatively regulates the phosphorylation of PDGFR-ß and the activation of its downstream pathways through interaction with PDGFR-ß. The dysregulated low levels of PDZK1 contribute to inadequate inhibition of cell proliferation, tumor growth, and insensitivity to sunitinib treatment. Notably, our preclinical investigations showed that miR-15b antagomirs enhance sunitinib cytotoxic effects against ccRCC cells by upregulating PDZK1 levels, suggesting their potential in overcoming sunitinib resistance. CONCLUSIONS: Our findings establish the miR-15b/PDZK1/PDGFR-ß axis as a promising therapeutic target and a novel predictor for ccRCC patients' response to sunitinib treatment.

E3 ubiquitin ligase MAGI3 degrades c-Myc and acts as a predictor for chemotherapy response in colorectal cancer.

BACKGROUND: Recurrence and chemoresistance constitute the leading cause of death in colorectal cancer (CRC). Thus, it is of great significance to clarify the underlying mechanisms and identify predictors for tailoring adjuvant chemotherapy to improve the outcome of CRC. METHODS: By screening differentially expressed genes (DEGs), constructing random forest classification and ranking the importance of DEGs, we identified membrane associated guanylate kinase, WW and PDZ domain containing 3 (MAGI3) as an important gene in CRC recurrence. Immunohistochemical and western blot assays were employed to further detect MAGI3 expression in CRC tissues and cell lines. Cell counting kit-8, plate colony formation, flow cytometry, sub-cutaneous injection and azoxymethane plus dextran sulfate sodium induced mice CRC assays were employed to explore the effects of MAGI3 on proliferation, growth, cell cycle, apoptosis, xenograft formation and chemotherapy resistance of CRC. The underlying molecular mechanisms were further investigated through gene set enrichment analysis, quantitative real-time PCR, western blot, co-immunoprecipitation, ubiquitination, GST fusion protein pull-down and immunohistochemical staining assays. RESULTS: Our results showed that dysregulated low level of MAGI3 was correlated with recurrence and poor prognosis of CRC. MAGI3 was identified as a novel substrate-binding subunit of SKP1-Cullin E3 ligase to recognize c-Myc, and process c-Myc ubiquitination and degradation. Expression of MAGI3 in CRC cells inhibited cell growth, promoted apoptosis and chemosensitivity to fluoropyrimidine-based chemotherapy by suppressing activation of c-Myc in vitro and in vivo. In clinic, the stage II/III CRC patients with MAGI3-high had a significantly good recurrence-free survival (~ 80%, 5-year), and were not necessary for further adjuvant chemotherapy. The patients with MAGI3-medium had a robustly good response rate or recurrence-free survival with fluoropyrimidine-based chemotherapy, and were recommended to undergo fluoropyrimidine-based adjuvant chemotherapy. CONCLUSIONS: MAGI3 is a novel E3 ubiquitin ligase by degradation of c-Myc to regulate CRC development and may act as a potential predictor of adjuvant chemotherapy for CRC patients.

Late recurrence of hepatocellular carcinoma after radiofrequency ablation: a multicenter study of risk factors, patterns, and survival.

OBJECTIVE: This study aims to determine the risk factors, patterns, and long-term survival outcomes of late recurrence after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) within the Milan criteria and develop a nomogram to predict the recurrence-free survival (RFS). MATERIALS AND METHODS: This retrospective study included patients with HCC within the Milan criteria, who received RFA at three hospitals in China from January 2011 to December 2016. The clinical variables were assessed by univariate and multivariate Cox regression analyses. RESULTS: A total of 398 patients were included. The median follow-up was 58.7 months (range: 24.1-96.0). Ninety-eight patients had late recurrence. Furthermore, 14 patients (14.29%) had local tumor progression (LTP) alone, 43 patients (43.88%) had intrahepatic distant recurrence (IDR) alone, 15 patients (15.31%) had extrahepatic recurrence (ER) alone, three patients (3.06%) had both LTP and IDR, six patients (6.12%) had both LTP and ER, and 17 patients (17.35%) had both IDR and ER. Patients without late recurrence had better long-term overall survival (OS) compared to those with late recurrence (p < 0.001). Male gender, multiple tumors, and cirrhosis were the independent risk factors of late recurrence. A well-discriminated and calibrated nomogram was constructed to predict the probability of RFS. CONCLUSION: Male gender, multiple tumors, and cirrhosis are the independent risk factors of late recurrence after RFA for HCC within the Milan criteria. Late recurrence might mainly occur from de novo HCC under the background of cirrhosis. An individualized surveillance and prevention strategy for HCC patients after RFA should be developed. KEY POINTS: • In the present retrospective study of 398 patients, male gender, multiple tumors, and cirrhosis were the independent risk factors of late recurrence (> 2 years) of HCC after RFA. • The most common pattern of late recurrence was intrahepatic distant recurrence alone (n = 43, 43.88%). Late recurrence might mainly occur from de novo HCC under the background of cirrhosis. • A prognostic nomogram was built to predict the individualized recurrence-free survival after RFA, which achieved good calibration and discriminatory ability with a concordance index of 0.763.

HPV16 E6 promotes cervical cancer cell migration and invasion by downregulation of NHERF1.

HPV16 is the predominant type of HPV causing invasive cervical cancer. However, the underlying molecular mechanism of the unparalleled carcinogenic power of HPV16 compared to other types of high-risk (HR)-HPV including HPV18 remains elusive. The PDZ binding motif (PBM) of high-risk HPV E6 plays an important role in neoplasia and progression of cervical cancer. HPV16 E6 rather than HPV18 E6, interacted with NHERF1 by its PBM region, and induced degradation of NHERF1. NHERF1 retarded the assembly of cytoskeleton by downregulation of ACTN4, thereby inhibited the migration and invasion of cervical cancer cells in both cell and mouse model. HPV16 E6 was confirmed to enhance actin polymerization with increased ACTN4 level by downregulation of NHERF1, and result in enhanced migration and invasion of cervical cancer cells. GSEA analysis of cervical cancer specimens also showed that HPV16 E6 rather than HPV18 E6, was significantly associated with actin cytoskeleton assembly. That downregulation of NHERF1 by HPV16 E6 promoted cytoskeleton assembly and cell invasion, was an important cause in cervical cancer carcinogenesis. These findings provided the differential mechanism between HPV16 E6 and HPV18 E6 in the development and progression of cervical cancer, which may partially explain the differences of carcinogenic power between these two types of HR-HPVs.

SERPINH1 overexpression in clear cell renal cell carcinoma: association with poor clinical outcome and its potential as a novel prognostic marker.

Precision therapy for clear cell renal cell carcinoma (ccRCC) requires molecular biomarkers ascertaining disease prognosis. In this study, we performed integrated proteomic and transcriptomic screening in all four tumour-node-metastasis stages of ccRCC and adjacent normal tissues (n = 18) to investigate differentially expressed genes. Most identified differentially expressed genes revealed a strong association with transforming growth factor-ß level and the epithelial-to-mesenchymal transition process. Of them, Serpin peptidase inhibitor clade H member 1 (SERPINH1) revealed the strongest association with poor prognosis and regulation on the expression levels of epithelial-to-mesenchymal transition markers. Subsequently, two independent sets (n = 532 and 105) verified the high level of SERPINH1 in ccRCC tissues and its association with reduced overall survival and disease-free survival in all tumour-node-metastasis stages and patients with von Hippel-Lindau wild-type (VHL-WT). SERPINH1 was an independent predictor of poor overall survival (hazard ratio 0.696 for all patients) and disease-free survival (hazard ratio 0.433 for all patients and 0.362 for patients with VHL-WT) in ccRCC. We have thus shown for the first time that SERPINH1 is an independent precision predictor for unfavourable prognosis in ccRCC. This could assist in identifying patients who need early aggressive management and deepen our understanding of the pathogenesis of VHL-WT ccRCC.

Impacts of Related Risk Factors on the Efficacy of Interventional Treatment Towards Intractable Postpartum Hemorrhage.

Objective: To investigate the risk factors that impact the efficacy of interventional treatment of intractable postpartum hemorrhage (IPH). Study Design: A total of 64 IPH patients were admitted and received interventional treatment at First Hospital of Shanxi Medical University from January 2012 to September 2014, among whom 57 cases were successfully treated (bleeding stopped), while 7 cases failed. The clinical data of the success group and the failure group were observed for the multivariate analysis of the possible reasons that might cause hemostatic failure. Results: The univariate analysis of each suspected factor of hemostatic failure showed that history of uterine scar, combined use of uterotonics, uterine inertia, and placenta exhibited statistically significant differences between the 2 groups (p<0.05); the multivariate logistic regression analysis showed that history of uterine scar and combined use of uterotonics were the risk factors for the interventional treatment failure of IPH, with OR values of 11.23 (95% CI 1.26~100.22) and 12.83 (95% CI 1.05-156.34), respectively. Conclusion: History of uterine scar and combined use of uterotonics were the risk factors for interventional treatment failure of IPH.

Clinical efficacy of percutaneous transluminal renal artery stenting for the treatment of renovascular hypertension associated with Takayasu arteritis.

BACKGROUND: This study aims to observe and analyze the clinical efficacy of interventional therapy for patients with Takayasu arteritis (TA) experiencing renovascular hypertension (RH). METHODS: Eight TA patients with RH underwent percutaneous transluminal renal artery stenting (PTRAS). Patients were followed up 1, 6, 12, and 24 months postoperatively for levels of blood pressure, number of antihypertensive drugs being taken, levels of serum creatinine, and the presence of renal artery restenosis. RESULTS: All 8 patients were successfully followed up 1, 6, and 12 months postoperatively, but 1 was lost to follow-up at 24 months. All patients had significantly lower average blood pressure levels compared with those at baseline (P < 0.05); treatment efficacy rates (recovery or improvement) at 1, 6, 12, and 24 months were 94%, 90%, 80%, and 80%, respectively. The average number of antihypertensive drugs being taken was 3.5 at baseline, 1.0 at 1 month, 0.5 at 6 months, 1.0 at 12 months, and 1.5 at 24 months. Serum creatinine levels during the follow-up period were not significantly different from those at the baseline. No patient developed renal artery restenosis during the follow-up period. CONCLUSIONS: PTRAS is a safe and effective treatment for TA-associated RH, with a high technical success rate and a low complication rate. This interventional therapy can effectively control TA-related hypertension and can also preserve and even improve kidney function.

Stabilization of the angiotensin-(1-7) receptor Mas through interaction with PSD95.

The functions and signalling mechanisms of the Ang-(1-7) [angiotensin-(1-7)] receptor Mas have been studied extensively. However, less attention has been paid to the intracellular regulation of Mas protein. In the present study, PSD95 (postsynaptic density 95), a novel binding protein of Mas receptor, was identified, and their association was characterized further. Mas specifically interacts with PDZ1-2, but not the PDZ3, domain of PSD95 via Mas-CT (Mas C-terminus), and the last four amino acids [ETVV (Glu-Thr-Val-Val)] of Mas-CT were determined to be essential for this interaction, as shown by GST pull-down, co-immunoprecipitation and confocal co-localization experiments. Gain-of-function and loss-of-function studies indicated that PSD95 enhanced Mas protein expression by increasing the stabilization of the receptor. Mas degradation was robustly inhibited by the proteasome inhibitor MG132 in time- and dose-dependent manners, and the expression of PSD95 impaired Mas ubiquitination, indicating that the PSD95-Mas association inhibits Mas receptor degradation via the ubiquitin-proteasome proteolytic pathway. These findings reveal a novel mechanism of Mas receptor regulation by which its expression is modulated at the post-translational level by ubiquitination, and clarify the role of PSD95, which binds directly to Mas, blocking the ubiquitination and subsequent degradation of the receptor via the ubiquitin-proteasome proteolytic pathway.

Lipiodol emulsion as a dual chemoradiation-sensitizer for pancreatic cancer treatment.

Pancreatic ductal adenocarcinoma (PDAC) has a low survival rate and limited treatment options. Concurrent chemoradiotherapy is considered beneficial to improve tumor control, but the low drug bioavailability at tumor site and the low radiation tolerance of surrounding healthy organs greatly limits its effectiveness. Lipiodol, a natural drug carrier used in clinical transarterial chemoembolization, has shown potential as a radiosensitizer due to its high Z element iodine composition. Thus, this study aims to repurpose lipiodol as a sensitizer to simultaneously enhance chemo- and radiotherapy for PDAC. To this end, a stable lipiodol emulsion (IOE) loaded with gemcitabine is designed using clinically approved surfactants. At in vivo level, IOE demonstrates better radiotherapeutic effect than existing nanoradiosensitizers and enhanced drug bioavailability over free drug, leading to significant tumor inhibition and improved survival rates under concurrent chemo-radiotherapy. This may due to the sustained drug release, homogenous spatial distribution, and long-term retention ability of IOE in solid PDAC tumor. Furthermore, to better understand the functioning mechanism of drug-loaded IOE, in vitro study is conducted to reveal the ROS- and DNA damage-related therapeutic pathways. Lastly, a comprehensive toxicity assessment also proves the good biocompatibility and safety of as-prepared IOE. This study offers a clinically feasible sensitizer for simultaneous chemoradiotherapy and holds potential for other types of cancer treatment in clinics.

Transarterial chemoembolization combined with lenvatinib plus tislelizumab for unresectable hepatocellular carcinoma: a multicenter cohort study.

Objective: Comparing the efficacy of transarterial chemoembolization (TACE) combined with lenvatinib plus tislelizumab (TLT) with TACE combined with lenvatinib (TL) for unresectable hepatocellular carcinoma, particularly in determining which patients can benefit more from the TLT treatment. Methods: From March 2021 to September 2023, a total of 169 patients from three centers were included in this study, with 103 patients receiving TLT and 66 patients receiving TL. The Kaplan-Meier method was utilized to evaluate the cumulative overall survival (OS) and progression-free survival (PFS) between the two groups and were assessed using the log-rank test. Subgroup analysis on tumor number, maximum tumor diameter, presence of portal vein thrombosis, AFP level, and Child-Pugh class were conducted. Results: The median OS was 26 months in the TLT group, and 20 months in the TL group. The median PFS was 14 months in the TLT group and 9 months in the TL group. The Kaplan-Meier curve demonstrated a significantly superior OS and PFS in the TLT group compared to the TL group. Subgroup analysis showed that for patients with a maximum tumor diameter greater than 7 cm, AFP > 400 ng/ml and accompanied by portal vein tumor thrombus, and Child-Pugh class A, there was a statistically significant difference in OS between TLT and TL groups. Conclusions: OS and PFS were significantly improved in patients who received TLT compared to those who received TL, patients with a largest tumor diameter greater than 7 cm, AFP > 400 ng/ml, Child-Pugh class A and PVTT appeared to derive more benefit.

Color-coded parametric imaging support display of vessel hemorrhage-an in vitro experiment and clinical validation study.

Background: Digital Subtraction Angiography (DSA) is currently the most effective diagnostic method for vascular diseases, but it is still subject to various factors, resulting in uncertain diagnosis. Therefore, a new technology is needed to help clinical doctors improve diagnostic accuracy and efficiency. Purpose: The objective of the study was to investigate the effect of utilizing color-coded parametric imaging techniques on the accuracy of identifying active bleeding through DSA, the widely accepted standard for diagnosing vascular disorders. Methods: Several variables can delay the diagnosis and treatment of active bleeding with DSA. To resolve this, we carried out an in vitro simulation experiment to simulate vascular hemorrhage and utilized five color-coded parameters (area under curve, time to peak, time-of-arrival, transit time, and flow rate of contrast agent) to determine the optimal color coding parameters. We then verified it in a clinical study. Results: Five different color-coded parametric imaging methods were compared and the time-of-arrival color coding was the most efficient technique for diagnosing active hemorrhage, with a statistically significant advantage (P < 0.001). In clinical study, 135 patients (101 with confirmed bleeding and 34 with confirmed no bleeding) were collected. For patients whose bleeding could not be determined using DSA alone (55/101) and whose no bleeding could not be diagnosed by DSA alone (35/55), the combination of time-of-arrival color parametric imaging was helpful for diagnosis, with a statistically significant difference (P < 0.01 and P = 0.01). Conclusions: The time-of-arrival color coding imaging method is a valuable tool for detecting active bleeding. When combined with DSA, it improves the visual representation of active hemorrhage and improves the efficiency of diagnosis.

Spleen volume is associated with overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with portal hypertension.

BACKGROUND: Portal shunt and immune status related to the spleen are related to the occurrence of hepatic encephalopathy (HE). It is unknown whether spleen volume before transjugular intrahepatic portosystemic shunt (TIPS) is related to postoperative HE. AIM: To investigate the relationship between spleen volume and the occurrence of HE. METHODS: This study included 135 patients with liver cirrhosis who underwent TIPS, and liver and spleen volumes were elevated upon computed tomography imaging. The Kaplan-Meier curve was used to compare the difference in the incidence rate of HE among patients with different spleen volumes. Univariate and multivariate Cox regression analyses were performed to identify the factors affecting overt HE (OHE). Restricted cubic spline was used to examine the shapes of the dose-response association between spleen volumes and OHE risk. RESULTS: The results showed that 37 (27.2%) of 135 patients experienced OHE during a 1-year follow-up period. Compared with preoperative spleen volume (901.30 ± 471.90 cm3), there was a significant decrease in spleen volume after TIPS (697.60 ± 281.0 cm3) in OHE patients. As the severity of OHE increased, the spleen volume significantly decreased (P < 0.05). Compared with patients with a spleen volume ≥ 782.4 cm3, those with a spleen volume < 782.4 cm3 had a higher incidence of HE (P < 0.05). Cox regression analysis showed that spleen volume was an independent risk factor for post-TIPS OHE (hazard ratio = 0.494, P < 0.05). Restricted cubic spline model showed that with an increasing spleen volume, OHE risk showed an initial increase and then decrease (P < 0.05). CONCLUSION: Spleen volume is related to the occurrence of OHE after TIPS. Preoperative spleen volume is an independent risk factor for post-TIPS OHE.

Impressive recompensation in transjugular intrahepatic portosystemic shunt-treated individuals with complications of decompensated cirrhosis based on Baveno VII criteria.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is the standard second-line treatment option for individuals with complications of decompensated cirrhosis, such as variceal bleeding and refractory ascites. AIM: To investigate whether recompensation existed in TIPS-treated patients with decompensated cirrhosis according to Baveno VII criteria. METHODS: This retrospective analysis was performed on 64 patients who received TIPS for variceal bleeding or refractory ascites. The definition of recompensation referred to Baveno VII criteria and previous study. Clinical events, laboratory tests, and radiological examinations were regularly conducted during a preset follow-up period. The recompensation ratio in this cohort was calculated. Beyond that, univariate and multivariate regression models were conducted to identify the predictors of recompensation. RESULTS: Of the 64 patients with a 12-mo follow-up, 20 (31%) achieved recompensation. Age [odds ratio (OR): 1.124; 95% confidence interval (CI): 1.034-1.222] and post-TIPS portal pressure gradient < 12 mmHg (OR: 0.119; 95%CI: 0.024-0.584) were identified as independent predictors of recompensation in patients with decompensated cirrhosis after TIPS. CONCLUSION: The present study demonstrated that nearly one-third of the TIPS-treated patients achieved recompensation within this cohort. According to our findings, recompensation is more likely to be achieved in younger patients. In addition, postoperative portal pressure gradient reduction below 12 mmHg contributes to the occurrence of recompensation.

Association of preoperative IL-6 levels with overt HE in patients with cirrhosis after TIPS.

BACKGROUND: HE is a common and dangerous complication after TIPS. The relationship between IL-6 levels and overt HE (OHE) after TIPS is rarely reported.We aimed to explore the relationship between the preoperative serum IL-6 levels and OHE risk after TIPS, and to evaluate its value in predicting the OHE risk. METHODS: This prospective cohort study included 125 participants with cirrhosis who received TIPS. Logistics regression analyses were performed to explore the relationship between IL-6 and OHE risk, and the receiver operating characteristic analysis was used to compare the predictive power of IL-6 and other indexes. RESULTS: Among 125 participants, 44 (35.2%) participants developed OHE after TIPS. Logistics regression showed preoperative IL-6 was associated with a higher OHE risk after TIPS in different models (all p < 0.05). Participants with IL-6 > 10.5 pg/mL had a higher cumulative incidence of OHE after TIPS than those with IL-6 ≤ 10.5 pg/mL (log-rank = 0.0124). The predictive power of IL-6 (AUC = 0.83) for the OHE risk after TIPS was higher than that of other indexes. Age (RR = 1.069, p = 0.002) and IL-6 (RR = 1.154, p < 0.001) were independent risk factors for OHE after TIPS. IL-6 was also a risk factor for the occurrence of coma in patients with OHE (RR = 1.051, p = 0.019). CONCLUSION: Preoperative serum IL-6 levels are closely related to the occurrence of OHE in patients with cirrhosis after TIPS. Patients with cirrhosis with high serum IL-6 levels following TIPS were at a higher risk of developing severe HE.

Prostate arterial chemoembolization for treatment of refractory hematuria and urinary retention in patients with localized advanced prostate cancer.

OBJECTIVES: To evaluate the safety and efficacy transcatheter arterial chemoembolization (TACE) for the treatment of refractory gross hematuria (RGH) and urinary retention (UR) secondary to localized advanced prostate cancer (PCa). PATIENTS AND METHODS: Thirty-two patients (mean age 72.5 years, range 60-89) with advanced PCa-related RGH that failed conventional therapy were included. Twenty-two of these patients had catheter-dependent due to PCa-related UR. TACE was performed with epirubicin (EPI)-eluting HepaSpheres (HS) plus intra-arterial (IA) infusion of docetaxel. Technical success, adverse events (AEs), overall survival (OS), control of RGH, removal of indwelling catheters, and local disease control, were evaluated. RESULTS: Technical success was achieved in 100% without major AEs. Mean follow up post-TACE was 27 months (range 8-56 months) with a mean OS of 30 months. GRH stopped within 5 days after TACE in all patients, 26 (86.7%) of these patients exhibited good bleeding control during a mean follow-up of 24 months; 17 (77.3%) of the 22 patients with UR had recovered spontaneous urination, 15 (88.2%) patients were catheter-free at their last follow-up with a mean of 24 months. BS was obtained in 73.3% (22/30) of patients at a mean follow-up of 29 months. At the last visit, 22 patients had a mean of 36 months follow-up and the mean percentage reduction in prostate volume was 55.5%, with a statistically different from baseline (P = 0.022). Negative biopsy results were obtained in 84.2% (16/19) of the patients at 12-47 months after TACE. Compared with baseline values, there was a significant improvements in IPSS, QoL, Qmax, and PVR (all P < 0.05). CONCLUSIONS: TACE using EPI-eluting HS plus IA infusion of docetaxel is a safe and effective treatment option for the advanced PCa patients with GRH and UR, and it could be considered as an alternative if there was no other therapeutic choice.

EBP50 inhibits EGF-induced breast cancer cell proliferation by blocking EGFR phosphorylation.

Ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50) suppresses breast cancer cell proliferation, potentially through its regulatory effect on epidermal growth factor receptor (EGFR) signaling, although the mechanism by which this occurs remains unknown. Thus in our studies, we aimed to determine the effect of EBP50 expression on EGF-induced cell proliferation and activation of EGFR signaling in the breast cancer cell lines, MDA-MB-231 and MCF-7. In MDA-MB-231 cells, which express low levels of EBP50, EBP50 overexpression inhibited EGF-induced cell proliferation, ERK1/2 and AKT phosphorylation. In MCF-7 cells, which express high levels of EBP50, EBP50 knockdown promoted EGF-induced cell proliferation, ERK1/2 and AKT phosphorylation. Knockdown of EBP50 in EBP50-overexpressed MDA-MB-231 cells abrogated the inhibitory effect of EBP50 on EGF-stimulated ERK1/2 phosphorylation and restoration of EBP50 expression in EBP50-knockdown MCF-7 cells rescued the inhibition of EBP50 on EGF-stimulated ERK1/2 phosphorylation, further confirming that the activation of EGF-induced downstream molecules could be specifically inhibited by EBP50 expression. Since EGFR signaling was triggered by EGF ligands via EGFR phosphorylation, we further detected the phosphorylation status of EGFR in the presence or absence of EBP50 expression. Overexpression of EBP50 in MDA-MB-231 cells inhibited EGF-stimulated EGFR phosphorylation, whereas knockdown of EBP50 in MCF-7 cells enhanced EGF-stimulated EGFR phosphorylation. Meanwhile, total expression levels of EGFR were unaffected during EGF stimulation. Taken together, our data shows that EBP50 can suppress EGF-induced proliferation of breast cancer cells by inhibiting EGFR phosphorylation and blocking EGFR downstream signaling in breast cancer cells. These results provide further insight into the molecular mechanism by which EBP50 regulates the development and progression of breast cancer.

Association of systemic inflammation index with survival in patients with advanced perihilar cholangiocarcinoma treated with interventional therapy.

Objective: Immunity and inflammation are key mediators of carcinoma development, invasion and metastasis. However, it remains unknown whether the systemic immune-inflammation index (SII) can be used as a prognostic indicator for cholangiocarcinoma. In this study, we investigated the association and predictive value of the SII with the prognosis of advanced perihilar cholangiocarcinoma (pCCA) after interventional therapy. Methods: A retrospective cohort of patients with advanced pCCA treated with interventional therapy at the First Hospital of Shanxi Medical University enrolled in this study from January 2019 through January 2021 was examined. Cox regression models were used to analyze the relationship between the SII and overall survival (OS) of patients with advanced pCCA. Receiver operating characteristic (ROC) analysis was used to evaluate the predictive power of SII. Results: Preoperative SII was positively associated with poor OS of pCCA after interventional therapy, with corresponding hazard ratios (HR) of 1.57 (95% CI: 1.17 - 2.10) for an inter-quartile range increase. The predictive power of SII was higher than that of other inflammation indexes based on ROC analysis (AUC = 0.835 [95% CI (0.731 - 0.940)]). The optimal cut-off values, sensitivity, and specificity with SII were 700, 0.774 and 0.846, respectively. An SII ≥ 700 was significantly associated with lymph node metastasis and high carbohydrate antigen199 (CA199) level. In multivariate analyses, total bilirubin, carbohydrate antigen 199, vascular invasion, and SII independently predicted overall survival (P < 0.05). Conclusion: This is the first study demonstrating that an increase in the SII is associated with poor advanced pCCA prognosis, and could serve as a reliable prognostic indicator of pCCA after interventional therapy.

The Relationship and Changes of Liver Blood Supply, Portal Pressure Gradient, and Liver Volume following TIPS in Cirrhosis.

Aim: Transjugular intrahepatic portosystemic shunt (TIPS) alters the liver blood supply and reduces portal pressure. This study was to investigate the changes and associations of the hepatic blood flow, liver volume, and portal pressure gradient (PPG) after TIPS in liver cirrhosis. Methods: Twenty-one patients with liver cirrhosis who received TIPS were recruited. The contrast CT images were used to assess the iodine density (ID) of liver parenchymal and liver volume. The ID of the liver parenchyma was used to reflect hepatic blood flow. We used a paired t-test and regression analysis to investigate the effect of TIPS on hepatic blood flow, liver volume, and PPG in individuals with cirrhosis and the factors that affect changes in liver volume. Results: After TIPS, there was a significant improvement in the ID of liver parenchyma at arterial phase (AP) and PPG in individuals with cirrhosis (P < 0.05). Each 1 unit increase in the ID change of whole liver parenchyma at the venous phase (VP) was significantly associated with a 269.44 cm3 increase in the liver volume after TIPS (b = 269.44, P = 0.012). With an increasing ID change of whole liver parenchyma at VP, the change in liver volume followed an increasing trend (P for overall association = 0.005). Conclusions: Our data indicate that there was a significant improvement in hepatic blood flow, especially at AP, after TIPS and the change in hepatic blood supply from the portal vein is positively associated with the change in liver volume after TIPS. Increasing the blood supply to the liver from the portal vein may improve the reduction of liver volume.

Controlling nutritional status score as a new indicator of overt hepatic encephalopathy in cirrhotic patients following transjugular intrahepatic portosystemic shunt.

BACKGROUND & AIMS: The Controlling Nutritional Status (CONUT) score is designed to assess the immune-nutritional status of patients. Poor nutritional status and inflammation may facilitate the development of hepatic encephalopathy (HE) in cirrhotic patients. However, it remains unknown whether the CONUT score is related to and can be used as a predictive marker for HE. The aim of this study was to investigate the association and predictive value of the CONUT score for overt hepatic encephalopathy (OHE) in cirrhotic patients following transjugular intrahepatic portosystemic shunt (TIPS). METHODS: A retrospective study of 77 patients with cirrhosis having undergone TIPS was performed at The First Hospital of Shanxi Medical University. Relevant patient data were collected from the medical records, and logistics regression analyses were performed to estimate the association between CONUT score and OHE. Restricted cubic spline models were further used to examine the shapes of the dose-response association. The area under curve (AUC) represented the test discriminative power of CONUT score and relevant clinical parameters. The Kaplan-Meier curve was used to compare the patient risk of OHE according to the cut-off CONUT score. RESULTS: During a median follow-up of 13 months, 41 patients (53.2%) experienced OHE events. The optimal cut-off value for the CONUT score of OHE was 5, with sensitivity and specificity values of 0.927 and 0.528, respectively (AUC = 0.815). The predictive power of CONUT score was higher than that of neutrophil lymphocyte ratio (NLR), Model for End-Stage Liver Disease (MELD) score, and Child-Pugh score based on time-dependent receiver operating characteristic (ROC) analysis. The high CONUT group (CONUT score ≥ 5) had significantly higher OHE prevalence (P < 0.001) than the low CONUT group (CONUT score < 5). The CONUT score was an independent predictor of OHE following TIPS (Odds Ratio (OR) = 7.3; 95% CI: 2.1-25.6; P = 0.002). Restricted cubic spline models showed that with an increasing CONUT score, the ln-transformed OR of OHE risk followed an increasing trend (P for overall association < 0.05). Meanwhile, logistic regression analysis with step method showed that history of OHE, blood ammonia, CONUT score, international normalised ratio (INR) and bilirubin were independent predictors of OHE following TIPS. CONCLUSION: To our knowledge, this is the first study demonstrating that the CONUT score was directly correlated with OHE risk, and could serve as a reliable prognostic marker of OHE risk in cirrhotic patients following TIPS. The results suggest it could be beneficial in the evaluation and management of OHE.

The Efficacy of TACE Combined With Lenvatinib Plus Sintilimab in Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Study.

OBJECTIVE: To assess the efficacy and safety of transarterial Chemoembolization (TACE) combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: The data of patients with unresectable HCC administered a combination therapy with TACE and lenvatinib plus sintilimab were retrospectively assessed. Patients received lenvatinib orally once daily 2 weeks before TACE, followed by sintilimab administration at 200 mg intravenously on day 1 of a 21-day therapeutic cycle after TACE. The primary endpoints were objective response rate (ORR) and duration of response (DOR) by the modified RECIST criteria. RESULTS: Median duration of follow-up was 12.5 months (95%CI 9.1 to 14.8 months). ORR was 46.7% (28/60). Median DOR in confirmed responders was 10.0 months (95%CI 9.0-11.0 months). Median progression-free survival (PFS) was 13.3 months (95%CI 11.9-14.7 months). Median overall survival (OS) was 23.6 months (95%CI 22.2-25.0 months). CONCLUSIONS: TACE combined with lenvatinib plus sintilimab is a promising therapeutic regimen in unresectable hepatocellular carcinoma.