The combined application of electromagnetic navigation and porcine fibrin sealant in microwave ablation of lung tumors.

Purpose: This retrospective study aims to assess the efficacy of the combined application of electromagnetic navigation (EMN) and porcine fibrin sealant (PFS) in the microwave ablation (MWA) treatment of lung tumors. Material and methods: In our department from January 2022 to August 2023, 73 patients underwent MWA under standard computed tomography (CT) guidance (CT group) or CT guidance with additional application of EMN and PFS (CT-EMN-PFS group), respectively. The basic data of patients were recorded and analyzed using the Student's t-test and Chi-square test between the two groups, and single factor and multi-factors binary logistic regression analyses were conducted to determine the risk factors of pneumothorax; meanwhile the incidence of complications, the number of CT scans and dose length product (DLP) were calculated and compared between the two guidance modes. Results: Forty-seven patients underwent standard CT-guided MWA, meanwhile the remaining 26 patients underwent CT-guided MWA with combined application of EMN and PFS. The patients with lesions close to the bronchi or interlobar fissures, and underlying emphysema had a higher risk of pneumothorax, the corresponding odds ratio (OR) was 23.290 (p = 0.004), 33.300 (p = 0.019), and 8.007 (p = 0.012), respectively; the combined use of EMN and PFS could reduce the incidence of pneumothorax, with an OR of 0.094 (95 % confidence interval [CI]: 0.015-0.602, p = 0.013). The incidence rates of pneumothorax, pneumorrhagia and pleural effusion were 59.57 %, 61.70 %, and 19.15 % respectively in the CT group, and 30.77 %, 50.00 % and 7.69 % respectively in the CT-EMN-PFS group. The incidence rate of pneumothorax in the CT-EMN-PFS group was significantly lower than that in the CT group (p = 0.017). The median number of CT scans was 9 in the CT group and 5 in the CT-EMN-PFS group, respectively, meanwhile the median DLP was 1060.69 mGy*cm in the CT group and 600.04 mGy*cm in the CT-EMN-PFS group, respectively, which indicated there was a statistical difference in the amount of radiation exposure between the two groups (p < 0.001). Conclusion: The combined application of EMN and PFS demonstrates for the first time that there is a lower incidence rate of pneumothorax and significantly less radiation exposure during the MWA of the lung tumors.

DITTO: A Visual Digital Twin for Interventions and Temporal Treatment Outcomes in Head and Neck Cancer.

Digital twin models are of high interest to Head and Neck Cancer (HNC) oncologists, who have to navigate a series of complex treatment decisions that weigh the efficacy of tumor control against toxicity and mortality risks. Evaluating individual risk profiles necessitates a deeper understanding of the interplay between different factors such as patient health, spatial tumor location and spread, and risk of subsequent toxicities that can not be adequately captured through simple heuristics. To support clinicians in better understanding tradeoffs when deciding on treatment courses, we developed DITTO, a digital-twin and visual computing system that allows clinicians to analyze detailed risk profiles for each patient, and decide on a treatment plan. DITTO relies on a sequential Deep Reinforcement Learning digital twin (DT) to deliver personalized risk of both long-term and short-term disease outcome and toxicity risk for HNC patients. Based on a participatory collaborative design alongside oncologists, we also implement several visual explainability methods to promote clinical trust and encourage healthy skepticism when using our system. We evaluate the efficacy of DITTO through quantitative evaluation of performance and case studies with qualitative feedback. Finally, we discuss design lessons for developing clinical visual XAI applications for clinical end users.

Clinical value of prognostic nutritional index combined with C-reactive protein and albumin in early prediction of anastomotic leakage after radical gastric cancer surgery.

OBJECTIVE: To evaluate the predictive value of the Prognostic Nutritional Index (PNI) combined with C-reactive protein (CRP) and albumin (ALB) for anastomotic leakage following radical gastric cancer surgery. METHODS: A retrospective case-control study was conducted with 275 gastric cancer patients at the Second People's Hospital of Lanzhou City from September 2019 to October 2022. Patients were categorized into an anastomotic leakage group (n=31) or a non-leakage group. Clinical, surgical, and pathological data were analyzed using logistic regression to develop two risk models: a combined clinical-laboratory index (RISK1) and a separate laboratory index (RISK2). Model effectiveness was compared using Receiver Operating Characteristic (ROC) curves. RESULTS: Anastomotic leakage occurred in 11.27% of patients, predominantly in those with advanced TNM stages (P=0.006). Notably, higher operative times (P=0.049) and increased intraoperative bleeding (P=0.027) were associated with the leakage group. Significant differences in ALB, PNI, and CRP levels were observed between the groups. Both RISK1 and RISK2 identified ALB, CRP, PNI, operative time, and intraoperative bleeding as independent predictors of leakage, demonstrating high predictive accuracy (RISK1 AUC=0.937, RISK2 AUC=0.911), with no significant difference in performance between the models (P=0.245). CONCLUSION: The combination of ALB, CRP, and PNI effectively predicts the risk of anastomotic leakage in patients undergoing gastric cancer surgery. These biomarkers can significantly enhance postoperative management and improve patient outcomes.

Predictive performance of [18F]F-fibroblast activation protein inhibitor (FAPI)-42 positron emission tomography/computed tomography (PET/CT) in evaluating response of recurrent or metastatic gastrointestinal stromal tumors: complementary or alternative to [18F]fluorodeoxyglucose (FDG) PET/CT?

Background: Accurately and promptly predicting the response of gastrointestinal stromal tumors (GISTs) to targeted therapy is essential for optimizing treatment strategies. However, some fractions of recurrent or metastatic GISTs present as non-FDG-avid lesions, limiting the value of [18F]fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) in treatment evaluation. This study evaluated the efficacy of [18F]F-fibroblast activation protein inhibitor (FAPI)-42 [18F]FAPI-42) PET/CT for assessing the treatment response in recurrent or metastatic GISTs, in comparison to [18F]FDG PET/CT and explores a model integrating PET/CT imaging and clinical parameters to optimize the clinical use of these diagnostic tools. Methods: Our retrospective analysis included 27 patients with recurrent or metastatic GISTs who underwent [18F]FAPI-42 PET/CT and [18F]FDG PET/CT at baseline before switching targeted therapy. Treatment response status was divided into a progression group (PG) and a non-progression group (NPG) based on the Response Criteria in Solid Tumors (RECIST) 1.1, according to the contrast-enhanced computed tomography (CT) scan at six months. [18F]FAPI-42 and [18F]FDG PET/CT parameters including the mean standardized uptake value (SUVmean), the standard uptake value corrected for lean body mass (SULpeak), the maximum standardized uptake value (SUVmax), tumor-to-blood pool SUV ratio (TBR), tumor-to-liver SUV ratio (TLR), metabolic tumor volume (MTV)/FAPI-positive tumor volume (GTV-FAPI), total lesion glycolysis (TLG)/FAPI-positive total lesion accumulation (TLF) were correlated with the response status to identify indicative of treatment response. The predictive performance of them was quantified by generating receiver operating characteristic curves (ROC), calibration curves, and cross-validation. Results: A total of 110 lesions were identified in 27 patients. Compared with PG, NPG was associated with lower levels of TBR and SUVmean in FDG PET/CT (TBR-FDG, SUVmean-FDG; P=0.033 and P=0.038, respectively), with higher SULpeak and TLF in FAPI PET/CT (SULpeak-FAPI, TLF-FAPI; P=0.10 and P=0.049, respectively). The predictive power of a composite-parameter model, including TBR-FDG, SULpeak-FAPI, gene mutation, and type of targeted therapy [area under the curve (AUC) =0.865], was superior to the few-parameter models incorporating TBR-FDG (AUC =0.637, P<0.001), SULpeak-FAPI (AUC =0.665, P<0.001) or both (AUC =0.721, P<0.001). Conclusions: Both [18F]FAPI-42 PET/CT and [18F]FDG PET/CT have value in predicting the treatment response of recurrent or metastatic GISTs. And [18F]FAPI-42 PET/CT offers synergistic value when used in combination with [18F]FDG PET/CT. Notably, the nomogram generated from the model incorporating [18F]FAPI-42 PET/CT, [18F]FDG PET/CT parameters, gene mutation, and type of targeted therapy could yield more precise predictions of the response of recurrent metastatic GISTs.

Nanoparticles targeting OPN loaded with BY1 inhibits vascular restenosis by inducing FTH1-dependent ferroptosis in vascular smooth muscle cells.

Vascular restenosis following angioplasty continues to pose a significant challenge. The heterocyclic trioxirane compound [1, 3, 5-tris((oxiran-2-yl)methyl)-1, 3, 5-triazinane-2, 4, 6-trione (TGIC)], known for its anticancer activity, was utilized as the parent ring to conjugate with a non-steroidal anti-inflammatory drug, resulting in the creation of the spliced conjugated compound BY1. We found that BY1 induced ferroptosis in VSMCs as well as in neointima hyperplasia. Furthermore, ferroptosis inducers amplified BY1-induced cell death, while inhibitors mitigated it, indicating the contribution of ferroptosis to BY1-induced cell death. Additionally, we established that ferritin heavy chain1 (FTH1) played a pivotal role in BY1-induced ferroptosis, as evidenced by the fact that FTH1 overexpression abrogated BY1-induced ferroptosis, while FTH1 knockdown exacerbated it. Further study found that BY1 induced ferroptosis by enhancing the NCOA4-FTH1 interaction and increasing the amount of intracellular ferrous. We compared the effectiveness of various administration routes for BY1, including BY1-coated balloons, hydrogel-based BY1 delivery, and nanoparticles targeting OPN loaded with BY1 (TOP@MPDA@BY1) for targeting proliferated VSMCs, for prevention and treatment of the restenosis. Our results indicated that TOP@MPDA@BY1 was the most effective among the three administration routes, positioning BY1 as a highly promising candidate for the development of drug-eluting stents or treatments for restenosis.

Interactions between corn starch and lingonberry polyphenols and their effects on starch digestion and glucose transport.

This study investigated the interaction mechanism between corn starch (CS) and lingonberry polyphenols (LBP) during starch gelatinization, focusing on their effects on starch structure and physicochemical properties. Moreover, it explored the effect of this interaction on starch digestion and glucose transport. The results indicated that LBP interacted non-covalently with CS during starch gelatinization, disrupted the short-range ordered structure of starch, decreased gelatinization enthalpy of starch, and formed a dense network structure. Furthermore, the incorporation of LBP remarkably reduced the digestibility of CS. In particular, the addition of 10 % LBP decreased the terminal digestibility (C∞) from 77.87 % to 60.43 % and increased the amount of resistant starch (RS) by 21.63 %. LBP was found to inhibit α-amylase and α-glucosidase in a mixed manner. Additionally, LBP inhibited glucose transport in Caco-2 cells following starch digestion. When 10 % LBP was added, there was a 34.17 % decrease in glucose transport compared with starch digestion without LBP. This study helps establish the foundation for the development of LBP-containing starch or starch-based healthy foods and provides new insights into the mechanism by which LBP lowers blood glucose.

The long-term efficacy of imatinib with hepatic resection or other local treatment for gastrointestinal stromal tumours liver metastases: a retrospective cohort study.

BACKGROUND: The liver is the most common site of metastasis from gastrointestinal stromal tumors (GISTs). The authors aimed to evaluate imatinib (IM) combined with hepatic resection (HR) or other local treatments such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE), compared to IM monotherapy in long-term survival benefits in patients suffering from GIST liver metastases. METHODS: Our research encompassed 238 patients diagnosed with liver metastases of GISTs from January 2002 to April 2022 at the First Affiliated Hospital of Sun Yat-Sen University. The oncological outcomes of concern included overall survival (OS), progression-free survival (PFS), and liver-specific PFS. RESULTS: Of all 238 patients, 126 were treated with IM alone (IM group), 81 with IM combined with HR (IM+HR group), and 31 with IM combined with RFA/TACE (IM+RFA/TACE group). The median follow-up time was 44.83 months. The median OS in the IM group was 132.60 months and was not reached in either the IM+HR group or the IM+RFA/TACE group. The 10-year OS rate in the IM+HR group was significantly superior to the IM group and the IM+RFA/TACE group (91.9% vs. 61.1% vs. 55.2%, respectively, P =0.015), and the liver-specific PFS ( P =0.642) and PFS ( P =0.369) in the three groups showed a beneficial trend in the combined treatment group. Multivariate analyses showed that age less than or equal to 60 years (HR 0.280, P< 0.001) and IM+HR (HR 0.361, P =0.047) were independently associated with better OS. Achieving no evidence of disease through surgical intervention was independently correlated with enhanced OS (HR 0.099, P =0.034), liver-specific PFS (HR 0.388, P =0.014), and PFS (HR 0.402, P =0.004). CONCLUSIONS: In patients with GIST liver metastases, IM combined with HR might improve OS in selected patients compared with IM alone and IM combined with RFA/TACE. Achieving no evidence of disease status with surgical treatment of patients results in significant prolonging of OS, liver-specific PFS, and PFS.

Association between Body Mass Index and Medication-Overuse Headache among Individuals with Migraine: A Cross-Sectional Study.

INTRODUCTION: Medication-overuse headache (MOH) is a secondary chronic headache disorder that occurs in individuals with a pre-existing primary headache disorder, particularly migraine disorder. Obesity is often combined with chronic daily headaches and is considered a risk factor for the transformation of episodic headaches into chronic headaches. However, the association between obesity and MOH among individuals with migraine has rarely been studied. The present study explored the association between body mass index (BMI) and MOH in people living with migraine. METHODS: This cross-sectional study is a secondary analysis of data from the Survey of Fibromyalgia Comorbidity with Headache study. Migraine and MOH were diagnosed using the criteria of the International Classification of Headache Disorders, 3rd Edition. BMI (kg/m2) is calculated by dividing the weight (kg) by the square of the height (m). Multivariable logistic regression analysis was used to evaluate the association between BMI and MOH. RESULTS: A total of 2,251 individuals with migraine were included, of whom 8.7% (195/2,251) had a concomitant MOH. Multivariable logistic regression analysis, adjusted for age, sex, education level, headache duration, pain intensity, headache family history, chronic migraine, depression, anxiety, insomnia, and fibromyalgia, demonstrated there was an association between BMI (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.11; p = 0.031) and MOH. The results remained when the BMI was transformed into a category. Compared to individuals with Q2 (18.5 kg/m2 ≤ BMI ≤23.9 kg/m2), those with Q4 (BMI ≥28 kg/m2) had an adjusted OR for MOH of 1.81 (95% CI, 1.04-3.17; p = 0.037). In the subgroup analyses, BMI was associated with MOH among aged more than 50 years (OR, 1.13; 95%, 1.03-1.24), less than high school (OR, 1.08; 95%, 1.01-1.15), without depression (OR, 1.06; 95%, 1.01-1.12), and without anxiety (OR, 1.06; 95%, 1.01-1.12). An association between BMI and MOH was found in a sensitivity analysis that BMI was classified into four categories according to the World Health Organization guidelines. CONCLUSION: In this cross-sectional study, BMI was associated with MOH in Chinese individuals with migraine.

Identification and functional activity of Nik related kinase (NRK) in benign hyperplastic prostate.

OBJECTIVE: Benign prostatic hyperplasia (BPH) is common in elder men. The current study aims to identify differentially expressed genes (DEGs) in hyperplastic prostate and to explore the role of Nik related kinase (NRK) in BPH. METHODS: Four datasets including three bulk and one single cell RNA-seq (scRNA-seq) were obtained to perform integrated bioinformatics. Cell clusters and specific metabolism pathways were analyzed. The localization, expression and functional activity of NRK was investigated via RT-PCR, western-blot, immunohistochemical staining, flow cytometry, wound healing assay, transwell assay and CCK-8 assay. RESULTS: A total of 17 DEGs were identified by merging three bulk RNA-seq datasets. The findings of integrated single-cell analysis showed that NRK remarkably upregulated in fibroblasts and SM cells of hyperplasia prostate. Meanwhile, NRK was upregulated in BPH samples and localized almost in stroma. The expression level of NRK was significantly correlated with IPSS and Qmax of BPH patients. Silencing of NRK inhibited stromal cell proliferation, migration, fibrosis and EMT process, promoted apoptosis and induced cell cycle arrest, while overexpression of NRK in prostate epithelial cells showed opposite results. Meanwhile, induced fibrosis and EMT process were rescued by knockdown of NRK. Furthermore, expression level of NRK was positively correlated with that of α-SMA, collagen-I and N-cadherin, negatively correlated with that of E-cadherin. CONCLUSION: Our novel data identified NRK was upregulated in hyperplastic prostate and associated with prostatic stromal cell proliferation, apoptosis, cell cycle, migration, fibrosis and EMT process. NRK may play important roles in the development of BPH and may be a promising therapeutic target for BPH/LUTS.

S100A4 modulates cell proliferation, apoptosis and fibrosis in the hyperplastic prostate.

Benign prostatic hyperplasia (BPH) is one of the most common diseases in elderly men worldwide that may result in lower urinary tract symptoms (LUTS). At present, the specific pathophysiological mechanism for BPH/LUTS LUTS remains unclear. S100 calcium binding protein A4 (S100A4), a member of the calcium binding protein family, regulates a variety of biological processes including cell proliferation, apoptosis and fibrosis. The aim of the current study was to explore and clarify the possible role of S100A4 in BPH/LUTS. The human prostate stromal cell line (WPMY-1), rat prostate epithelial cells, human prostate tissues and two BPH rat models were employed in this study. The expression and localization of S100A4 were detected by quantitative real time PCR (qRT-PCR), immunofluorescence microscopy, Western blotting and immunohistochemistry analysis. Also, S100A4 knockdown or overexpression cell models were constructed and a BPH rat model was induced with testosterone propionate (T) or phenylephrine (PE). The BPH animals were treated with Niclosamide, a S100A4 transcription inhibitor. Results demonstrated that S100A4 was mainly localized in human prostatic stroma and rat prostatic epithelium, and showed a higher expression in BPH. Knockdown of S100A4 induced cell apoptosis, cell proliferation arrest and a reduction of tissue fibrosis markers. Overexpression of S100A4 reversed the aforementioned changes. We also demonstrated that S100A4 regulated proliferation and apoptosis mainly through the ERK pathway and modulated fibrosis via Wnt/ß-catenin signaling. In conclusion, our novel data demonstrate that S100A4 could play a crucial role in BPH development and may be explored as a new therapeutic target of BPH.

Development of starch-based films reinforced with curcumin-loaded nanocomplexes: Characterization and application in the preservation of blueberries.

In current study, curcumin-loaded bioactive nanocomplexes (Cur NCs) (2 %, 5 %, 8 %, and 11 %) were used to prepare corn starch (CS)-based composite films (CS-Cur NCs). Fourier-transform infrared spectroscopy, X-ray diffraction and scanning electron microscopy revealed that Cur NCs were uniformly dispersed in the polymer matrix via physical interaction. Moreover, the mechanical, gas barrier, hydrophobicity, optical, and thermal properties and the antioxidant activity of composite films were potentially improved with the addition of Cur NCs. Subsequently, CS-based film with 11 % Cur NCs exhibited high antioxidant activity (the scavenging rates of DPPH and ABTS are 50.07 % ± 0.82 % and 65.26 % ± 1.60 %, respectively) and was used for packaging blueberries. Compared with the control, the CS-Cur NCs packaging treatment effectively improved the appearance and nutrition of blueberries, and maintained the high activity of several antioxidant enzymes. Furthermore, CS-Cur NCs packaging treatment significantly improved the ascorbic acid (AsA) and glutathione (GSH) levels, thus regulating the AsA-GSH cycle system and suppressing the accumulation of reactive oxygen species (ROS). In summary, the CS-Cur NCs packaging could effectively conserve the postharvest quality of blueberries by improving antioxidant enzyme activity and suppressing excessive accumulation of ROS, which contributes to the development of bioactive packaging and provides novel insights into the preservation of blueberries. This work demonstrates that the development of active packaging is promising to absorb the oxidative radicals from food, and protect the food from inherent and external factors, thus enhancing the quality, security, and shelf-life of the food during storage.

Efficacy and safety of ripretinib vs. sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: A phase 2, multicenter, randomized, open-label study in China.

AIM: A bridging study of INTRIGUE study to assess the efficacy and safety of ripretinib versus sunitinib as second-line treatment in Chinese GIST patients. METHODS: This was a phase 2, multicenter, randomized, open-label study in China. GIST patients previously treated with imatinib were randomized (1:1) to receive ripretinib 150 mg once daily (QD) by continuous dosing in 42-day cycles or sunitinib 50 mg QD in 42-day cycles (four weeks on/two weeks off). Primary endpoint was progression-free survival (PFS) by independent radiological review (IRR). RESULTS: Between 6 December 2020 and 15 September 2021, 108 patients were randomized to receive ripretinib (n = 54) or sunitinib (n = 54) (all-patient [AP] intention-to-treat [ITT] population). Seventy patients had primary KIT exon 11 mutations (ripretinib, n = 35; sunitinib, n = 35; Ex11 ITT population). By data cut-off (20 July 2022), in AP ITT population, PFS by IRR was comparable between ripretinib and sunitinib arms (HR 0·99, 95 % CI 0·57, 1·69; nominal p = 0·92; median PFS [mPFS] 10·3 vs 8·3 months). In Ex11 ITT population, PFS by IRR was longer for ripretinib than sunitinib (HR 0·46, 95 % CI 0·23, 0·92; nominal p = 0·03; mPFS not reached in ripretinib arm and 4·9 months in sunitinib arm). Fewer patients experienced grade 3/4 treatment-related treatment-emergent adverse events with ripretinib (17%) versus sunitinib (56%). CONCLUSIONS: Ripretinib demonstrated similar efficacy and a favorable safety profile versus sunitinib as second-line treatment in Chinese GIST patients. Furthermore, ripretinib provided greater clinically meaningful benefit versus sunitinib in patients with KIT exon 11 mutation.

Clinical Benefit of Avapritinib in KIT-Mutant Gastrointestinal Stromal Tumors: A Post Hoc Analysis of the Phase I NAVIGATOR and Phase I/II CS3007-001 Studies.

PURPOSE: The efficacy of the selective KIT/PDGFRA inhibitor avapritinib (300 mg once daily) was explored in patients with non-PDGFRA-mutant gastrointestinal stromal tumors (GISTs) from the phase I NAVIGATOR and phase I/II CS3007-001 trials. PATIENTS AND METHODS: Adults with unresectable/metastatic, KIT-only-mutant GISTs and progression following ≥1 tyrosine kinase inhibitors (TKIs) were included in this post hoc analysis. Baseline mutational status was identified in tumor and plasma. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent radiology review per modified RECIST v1.1 in patients harboring KIT activation-loop mutations (KIT exons 17 or 18) without ATP binding-pocket mutations (KIT exons 13 or 14; ALposABPneg), and other KIT mutations (OTHERS). RESULTS: Sixty KIT ALposABPneg and 100 KIT OTHERS predominantly heavily pretreated patients (61.3% with ≥3 prior TKIs) were included. ORR was significantly higher in KIT ALposABPneg than KIT OTHERS patients (unadjusted: 26.7% vs. 12.0%; P = 0.0852; adjusted: 31.4% vs. 12.1%; P = 0.0047). Median PFS (mPFS) was significantly longer in KIT ALposABPneg patients compared with KIT OTHERS patients (unadjusted: 9.1 vs. 3.5 months; P = 0.0002; adjusted: 9.1 vs. 3.4 months; P < 0.0001), and longer in second- versus later-line settings (19.3 vs. 5.6-10.6 months). Benefit with avapritinib was observed in patients with KIT exon 9 mutations in the ≥4 line settings (mPFS: 5.6 and 3.7 months for 4 line and >4 line, respectively). CONCLUSIONS: Avapritinib showed greater antitumor activity in patients with GISTs harboring KIT ALposABPneg mutations versus KIT OTHERS, and may be considered in the former subpopulation. Patients with KIT exon 9 mutations may also benefit in ≥4 line settings.

STEAP4 modulates cell proliferation and oxidative stress in benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a quite common chronic disease plagued elderly men and its etiology remains unclear. It was reported that the six-transmembrane epithelial antigen of prostate 4 (STEAP4) could modulate cell proliferation/apoptosis ratio and oxidative stress in cancers. Our current study aimed to explore the expression, biological function, and underlying mechanism of STEAP4 in BPH progress. Human prostate tissues and cell lines were utilized. qRT-PCR and immunofluorescence staining were employed. STEAP4 knockdown (STEAP4-KD) or STEAP4 overexpression (STEAP4-OE) cell models were established. Cell proliferation, cell cycle, apoptosis, and reactive oxygen species (ROS) were determined by cell counting kit-8 (CCK-8) assay and flow cytometry. Apoptosis-related proteins and antioxidant enzymes were identified by Western Blot. In addition, the epithelial-mesenchymal transition (EMT) process and fibrosis biomarker (collagen I and α-SMA) were analyzed. It was indicated that STEAP4 was mainly located in the prostate epithelium and upregulated in BPH tissues. STEAP4 deficiency induced apoptosis and inhibited cell survival, but had no effect on the cell cycle, fibrosis, and EMT process. In addition, ROS changes were observed in the STEAP4-KD model. Consistently, overproduction of STEAP4 suppressed apoptosis and promoted cell proliferation, as well as facilitated ROS production. We further examined AKT / mTOR, p38MAPK / p-p38MAPK, and WNT/ ß-Catenin signaling pathway and demonstrated that STEAP4 regulated the proliferation and apoptosis of prostate cells through AKT / mTOR signaling, rather than p38MAPK / p-p38MAPK and WNT/ ß-Catenin pathways. Furthermore, activating AKT / mTOR signaling with SC79 significantly reversed apoptosis triggered by STEAP4 deficiency, whereas suppressing AKT / mTOR signaling with MK2206 reduced the increase of cell viability triggered by STEAP4 overproduction. Our original data demonstrated that STEAP4 is crucial in the onset and progression of prostate hyperplasia and may become a new target for the treatment of BPH.

Comment on Golcic et al. Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours. Cancers 2023, 15, 4081.

We carefully read the article written by Golcic et al. "Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours" [...].

CT features combined with RECIST 1.1 criteria improve progression assessments of sunitinib-treated gastrointestinal stromal tumors.

OBJECTIVES: To explore the auxiliary value of combining CT features with existing response evaluation criteria in the prediction of progressive disease (PD) in gastrointestinal stromal tumors (GIST) patients treated with sunitinib. MATERIAL AND METHODS: Eighty-one patients with GISTs who received sunitinib were included in this retrospective multicenter study and divided into training and external validation cohorts. Progression at six months was determined as a reference standard. The predictive performance of the RECIST 1.1 and Choi criteria was compared. CT features at baseline and the first follow-up were analyzed. Logistic regression analyses were used to determine the most significant predictors and develop modified criteria. RESULTS: A total of 216 lesions showed a good response and 107 showed a poor response in 81 patients. The RECIST 1.1 criteria performed better than the Choi criteria in predicting progression (AUC, 0.75 vs. 0.69, p = 0.04). The expanded/intensified high-enhancement area, blurred tumor-tissue interface, and progressive enlarged vessels feeding or draining the mass (EVFDM) differed significantly between lesions with good and poor responses in the training cohort (p = 0.001, 0.003, and 0.000, respectively). Multivariate analysis revealed that the expanded/intensified high-enhancement area (p = 0.001), progressive EVFDM (p = 0.000), and RECIST PD (p = 0.000) were independent predictive factors. Modified RECIST (mRECIST) criteria were developed and showed significantly higher AUCs in the training and external validation cohorts than the RECIST 1.1 criteria (training: 0.81 vs. 0.73, p = 0.002; validation: 0.82 vs. 0.77, p = 0.04). CONCLUSION: The mRECIST criteria, combining CT features with the RECIST 1.1 criteria, demonstrated superior performance in the prediction of early progression in GIST patients receiving sunitinib. CLINICAL RELEVANCE STATEMENT: The mRECIST criteria, which combine CT features with the RECIST 1.1 criteria, may facilitate the early detection of progressive disease in GIST patients treated with sunitinib, thereby potentially guiding the timely switch to late-line medications or combination with surgical excision. KEY POINTS: • The RECIST 1.1 criteria outperformed the Choi criteria in identifying progression of GISTs in patients treated with sunitinib. • GISTs displayed different morphologic features on CT depending on how they responded to sunitinib. • Combining CT morphologic features with the RECIST 1.1 criteria allowed for the prompt and accurate identification of progressing GIST lesions.

miR-6076 targets BCL6 in SH-SY5Y cells to regulate amyloid-ß-induced neuronal damage.

Amyloid-ß1-42 (Aß1-42 ) is strongly associated with Alzheimer's disease (AD). The aim of this study is to elucidate whether and how miR-6076 participates in the modulation of amyloid-ß (Aß)-induced neuronal damage. To construct the neuronal damage model, SH-SY5Y cells were treated with Aß1-42 . By qRT-PCR, we found that miR-6076 is significantly upregulated in Aß1-42 -treated SH-SY5Y cells. After miR-6076 inhibition, p-Tau and apoptosis levels were downregulated, and cell viability was increased. Through online bioinformatics analysis, we found that B-cell lymphoma 6 (BCL6) was a directly target of miR-6076 via dual-luciferase reporter assay. BCL6 overexpression mediated the decrease in elevated p-Tau levels and increased viability in SH-SY5Y cells following Aß1-42 treatment. Our results suggest that down-regulation of miR-6076 could attenuate Aß1-42 -induced neuronal damage by targeting BCL6, which provided a possible target to pursue for prevention and treatment of Aß-induced neuronal damage in AD.

Mechanism of RhoA regulating benign prostatic hyperplasia: RhoA-ROCK-ß-catenin signaling axis and static & dynamic dual roles.

BACKGROUND: The pathogenesis of benign prostatic hyperplasia (BPH) has not been fully elucidated. Ras homology family member A (RhoA) plays an important role in regulating cell cytoskeleton, growth and fibrosis. The role of RhoA in BPH remains unclear. METHODS: This study aimed to clarify the expression, functional activity and mechanism of RhoA in BPH. Human prostate tissues, human prostate cell lines, BPH rat model were used. Cell models of RhoA knockdown and overexpression were generated. Immunofluorescence staining, quantitative real time PCR (qRT-PCR), Western blotting, cell counting kit-8 (CCK-8), flow cytometry, phalloidine staining, organ bath study, gel contraction assay, protein stability analysis, isolation and extraction of nuclear protein and cytoplasmic protein were performed. RESULTS: In this study we found that RhoA was localized in prostate stroma and epithelial compartments and was up-regulated in both BPH patients and BPH rats. Functionally, RhoA knockdown induced cell apoptosis and inhibited cell proliferation, fibrosis, epithelial-mesenchymal transformation (EMT) and contraction. Consistently, overexpression of RhoA reversed all aforementioned processes. More importantly, we found that ß-catenin and the downstream of Wnt/ß-catenin signaling, including C-MYC, Survivin and Snail were up-regulated in BPH rats. Downregulation of RhoA significantly reduced the expression of these proteins. Rho kinase inhibitor Y-27632 also down-regulated ß-catenin protein in a concentration-dependent manner. However, overexpression of ß-catenin did not affect RhoA-ROCK levels, suggesting that ß-catenin was the downstream of RhoA-ROCK regulation. Further data suggested that RhoA increased nuclear translocation of ß-catenin and up-regulated ß-catenin expression by inhibiting its proteasomal degradation, thereby activating Wnt/ß-catenin signaling. Overexpression of ß-catenin partially reversed the changes in cell growth, fibrosis and EMT except cell contraction caused by RhoA downregulation. Finally, Y-27632 partially reversed prostatic hyperplasia in vivo, further suggesting the potential of RhoA-ROCK signaling in BPH treatment. CONCLUSION: Our novel data demonstrated that RhoA regulated both static and dynamic factors of BPH, RhoA-ROCK-ß-catenin signaling axis played an important role in the development of BPH and might provide more possibilities for the formulation of subsequent clinical treatment strategies.