Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation.

Efficient clearance of dying cells (efferocytosis) is an evolutionarily conserved process for tissue homeostasis. Genetic enhancement of efferocytosis exhibits therapeutic potential for inflammation resolution and tissue repair. However, pharmacological approaches to enhance efferocytosis remain sparse due to a lack of targets for modulation. Here, we report the identification of columbamine (COL) which enhances macrophage-mediated efferocytosis and attenuates intestinal inflammation in a murine colitis model. COL enhances efferocytosis by promoting LC3-associated phagocytosis (LAP), a non-canonical form of autophagy. Transcriptome analysis and pharmacological characterization revealed that COL is a biased agonist that occupies a part of the ligand binding pocket of formyl peptide receptor 2 (FPR2), a G-protein coupled receptor involved in inflammation regulation. Genetic ablation of the Fpr2 gene or treatment with an FPR2 antagonist abolishes COL-induced efferocytosis, anti-colitis activity and LAP. Taken together, our study identifies FPR2 as a potential target for modulating LC3-associated efferocytosis to alleviate intestinal inflammation and highlights the therapeutic value of COL, a natural and biased agonist of FPR2, in the treatment of inflammatory bowel disease.

Nomogram Models for Distinguishing Intraductal Carcinoma of the Prostate From Prostatic Acinar Adenocarcinoma Based on Multiparametric Magnetic Resonance Imaging.

OBJECTIVE: To compare multiparametric magnetic resonance imaging (MRI) features of intraductal carcinoma of the prostate (IDC-P) with those of prostatic acinar adenocarcinoma (PAC) and develop prediction models to distinguish IDC-P from PAC and IDC-P with a high proportion (IDC ≥ 10%, hpIDC-P) from IDC-P with a low proportion (IDC < 10%, lpIDC-P) and PAC. MATERIALS AND METHODS: One hundred and six patients with hpIDC-P, 105 with lpIDC-P and 168 with PAC, who underwent pretreatment multiparametric MRI between January 2015 and December 2020 were included in this study. Imaging parameters, including invasiveness and metastasis, were evaluated and compared between the PAC and IDC-P groups as well as between the hpIDC-P and lpIDC-P subgroups. Nomograms for distinguishing IDC-P from PAC, and hpIDC-P from lpIDC-P and PAC, were made using multivariable logistic regression analysis. The discrimination performance of the models was assessed using the receiver operating characteristic area under the curve (ROC-AUC) in the sample, where the models were derived from without an independent validation sample. RESULTS: The tumor diameter was larger and invasive and metastatic features were more common in the IDC-P than in the PAC group (P < 0.001). The distribution of extraprostatic extension (EPE) and pelvic lymphadenopathy was even greater, and the apparent diffusion coefficient (ADC) ratio was lower in the hpIDC-P than in the lpIDC-P group (P < 0.05). The ROC-AUCs of the stepwise models based solely on imaging features for distinguishing IDC-P from PAC and hpIDC-P from lpIDC-P and PAC were 0.797 (95% confidence interval, 0.750-0.843) and 0.777 (0.727-0.827), respectively. CONCLUSION: IDC-P was more likely to be larger, more invasive, and more metastatic, with obviously restricted diffusion. EPE, pelvic lymphadenopathy, and a lower ADC ratio were more likely to occur in hpIDC-P, and were also the most useful variables in both nomograms for predicting IDC-P and hpIDC-P.

Current status and temporal trend of disease burden of thyroid cancer in China from 1990 to 2019.

OBJECTIVE: Thyroid cancer has been an increasingly high-profile public health issue. Comprehensive assessment for its disease burden seems particularly important for understanding health priorities and hinting high-risk populations. METHODS: We estimated the age-sex-specific thyroid cancer burden and its temporal trend in China from 1990 to 2019 by following the general methods from the global burden of disease (GBDs) 2019 Study. And Joinpoint regression model, the Cox-Stuart trend test, and Cochran-Armitage test were applied for the analysis of temporal and age trend. The Mantel-Haenszel statistical method was used to compare the gender difference. RESULTS: From 1990 to 2019, the age-standardized incidence rate of thyroid cancer in China has almost doubled to 2.05 per 100,000. Although the mortality rate and DALY rate kept leveling off, they presented a downtrend among females, while an upward trend in males. While the average annual percentage changes of those metrics all became deline since 2010 than the previous years. With age advancing, the rates of incidence, mortality, and DALYs for both sexes all presented linear fashion increases, which was particularly typical among males. CONCLUSION: Given the serious trend and gender-age heterogeneity of Chinese thyroid cancer burden, male gender and advanced age may be related to poor prognosis of thyroid cancer, and strengthening primary prevention and exploring the underlying risk factors should be among the top priorities.

A rare case report of multifocal para-aortic and para-vesical paragangliomas.

Background: Paragangliomas (PGLs) are uncommon tumors of uncertain malignant potential. Multifocal paragangliomas are scarcely reported in the literature. Case summary: A 25-year-old male patient was reported for the first time with multifocal para-aortic and para-vesical PGLs. The diagnosis was identified by blood catecholamine tests and enhanced CT scan and MIBG scintigraphy. A resection surgery was performed for treatment and the immunochemistry test of the tumors presented the features of PGL. Conclusion: A case of multifocal para-aortic and para-vesical PGLs confirmed by the catecholamine test, enhanced CT, and MIBG scintigraphy is presented. The cooperation of experienced surgeons, anesthesiologists, and endocrinologists was critical in treatment.

Association of prostate zonal volume with location and aggressiveness of clinically significant prostate cancer: A multiparametric MRI study according to PI-RADS version 2.1.

BACKGROUND: The relationship between prostate cancer (PCa) and benign prostatic hyperplasia (BPH) remains unclear. This study aimed to determine whether prostate zonal volume was associated with the location and aggressiveness of PCa. METHODS: 412 PCa patients were retrospectively enrolled. The volumes of the whole prostate (V) and transition zone (Vtz) were calculated by the prolate ellipsoid formula, and volume of the peripheral zone (Vpz) was calculated by their subtraction. Locations of PCa were divided into three categories, including peripheral zone (PZ), transition zone (Vtz) and mixed zone group. The mixed zone group was further divided into PZ-dominated, TZ-dominated and equally distributed subgroups. RESULTS: The Vtz of Gleason score (GS) 3 + 4 group was the largest, while the Vpz of GS 9 group was the largest. Tumor diameters of the PZ and TZ groups were weakly correlated with their corresponding zonal volume (r = 0.261, p < 0.001; r = 0.311, p = 0.009, respectively). There was no significant difference in the zonal volumes and GS distribution among the location groups. The proportion of tumors with high-grade GS of 8 and 9 was higher in the PZ than that in the TZ group (38.5 vs 24.3%, p = 0.041). For tumors located in the TZ, the V and Vpz of tumors with high-grade GS were larger than those in the low-grade GS of 7 group (p = 0.033 and 0.039, respectively). Among the subgroups of mixed zone group, the Vtz of the TZ-dominated group was larger than those of PZ-dominated and equally distributed groups (p = 0.016 and 0.001, respectively). CONCLUSION: PCa with high-grade GS is more likely to have a relatively larger Vpz and involve PZ, while PCa with a larger Vtz is more likely to be with low-grade GS, which support the theoretical model that pressure exerted by increasing prostate size/mechanical deformation may inhibit PCa growth from the clinical point. However, the increase in zonal volume might not be the direct cause of tumorigenesis and aggressiveness.

Predictors of efficacy of corticosteroid switching from abiraterone plus prednisone to dexamethasone in patients with metastatic castration-resistant prostate cancer.

Corticosteroid switching can reverse abiraterone resistance in some patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we investigated the potential biomarkers for predicting the efficacy of corticosteroid switching during treatment with abiraterone acetate (AA). We retrospectively analyzed 101 mCRPC patients receiving corticosteroid switching from West China Hospital and Sun Yat-Sen University Cancer Center between January 2016 and December 2018. All cases received AA plus prednisone as first-line therapy during mCRPC. Primary end points were biochemical progression-free survival (bPFS) and overall survival (OS). The risk groups were defined based on multivariate analysis. A total of 42 (41.6%) and 25 (24.8%) patients achieved 30% and 50% decline in prostate-specific antigen (PSA), respectively, after corticosteroid switching. The median bPFS and median OS on AA plus dexamethasone were 4.9 (95% confidence interval [CI]: 3.7-6.0) months and 18.8 (95% CI: 16.2-30.2) months, respectively. Aldo-keto reductase family 1 member C3 (AKR1C3) expression (hazard ratio [HR]: 2.15, 95% Cl: 1.22-3.80, P = 0.008) and baseline serum alkaline phosphatase (ALP; HR: 4.95, 95% Cl: 2.40-10.19, P < 0.001) were independent predictors of efficacy before corticosteroid switching in the multivariate analysis of bPFS. Only baseline serum ALP >160 IU l-1 (HR: 3.41, 95% Cl: 1.57-7.38, P = 0.002) together with PSA level at switch ≥50 ng ml-1 (HR: 2.59, 95% Cl: 1.22-5.47, P = 0.013) independently predicted poorer OS. Based on the predictive factors in multivariate analysis, we developed two risk stratification tools to select candidates for corticosteroid switching. Detection of serum ALP level, PSA level, and tissue AKR1C3 expression in mCRPC patients could help make clinical decisions for corticosteroid switching.

Multidetector CT Characteristics of Fumarate Hydratase-Deficient Renal Cell Carcinoma and Papillary Type II Renal Cell Carcinoma.

OBJECTIVE: To investigate the multidetector computed tomography (MDCT) features of fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) with germline or somatic mutations, and compare them with those of papillary type II RCC (pRCC type II). MATERIALS AND METHODS: A total of 24 patients (mean ± standard deviation, 40.4 ± 14.7 years) with pathologically confirmed FH-deficient RCC (15 with germline and 9 with somatic mutations) and 54 patients (58.6 ± 12.6 years) with pRCC type II were enrolled. The MDCT features were retrospectively reviewed and compared between the two entities and mutation subgroups, and were correlated with the clinicopathological findings. RESULTS: All the lesions were unilateral and single. Compared with pRCC type II, FH-deficient RCC was more prevalent among younger patients (40.4 ± 14.7 vs. 58.6 ± 12.6, p < 0.001) and tended to be larger (8.1 ± 4.1 vs. 5.4 ± 3.2, p = 0.002). Cystic solid patterns were more common in FH-deficient RCC (20/24 vs. 16/54, p < 0.001), with 16 of the 20 (80.0%) cystic solid tumors having showed typical polycystic and thin smooth walls and/or septa, with an eccentric solid component. Lymph node (16/24 vs. 16/54, p = 0.003) and distant (11/24 vs. 3/54, p < 0.001) metastases were more frequent in FH-deficient RCC. FH-deficient RCC and pRCC type II showed similar attenuation in the unenhanced phase. The attenuation in the corticomedullary phase (CMP) (76.3% ± 25.0% vs. 60.2 ± 23.6, p = 0.008) and nephrographic phase (NP) (87.7 ± 20.5, vs. 71.2 ± 23.9, p = 0.004), absolute enhancement in CMP (39.0 ± 24.8 vs. 27.1 ± 22.7, p = 0.001) and NP (50.5 ± 20.5 vs. 38.2 ± 21.9, p = 0.001), and relative enhancement ratio to the renal cortex in CMP (0.35 ± 0.26 vs. 0.24 ± 0.19, p = 0.001) and NP (0.43 ± 0.24 vs. 0.29 ± 0.19, p < 0.001) were significantly higher in FH-deficient RCC. No significant difference was found between the FH germline and somatic mutation subgroups in any of the parameters. CONCLUSION: The MDCT features of FH-deficient RCC were different from those of pRCC type II, whereas there was no statistical difference between the germline and somatic mutation subgroups. A kidney mass with a cystic solid pattern and metastatic tendency, especially in young patients, should be considered for FH-deficient RCC.

Clinical and oncologic findings of extraprostatic extension on needle biopsy in de novo metastatic prostate cancer.

This study aimed to explore the clinical and oncologic findings in patients with de novo metastatic prostate cancer (mPCa) and extraprostatic extension (EPE) on biopsy. We retrospectively evaluated data on 630 patients with de novo mPCa between January 2009 and December 2017 in the West China Hospital (Chengdu, China), including evaluating the relationships between EPE and other variables and the association of EPE with survival outcomes by the Chi-square test, Kaplan-Meier curves, and the Cox proportional-hazards model. EPE was found in 70/630 patients, making a prevalence of 11.1%. The presence of EPE on biopsy was associated with higher Gleason scores and higher incidence of neuroendocrine differentiation (NED), intraductal carcinoma of the prostate (IDC-P), and perineural invasion (PNI). Compared with those without EPE, patients with EPE had shorter castration-resistant prostate cancer-free survival (CFS; median: 14.1 vs 17.1 months, P = 0.015) and overall survival (OS; median: 43.7 vs 68.3 months, P = 0.032). According to multivariate analysis, EPE was not an independent predictor for survival. Subgroup analyses demonstrated that patients with favorable characteristics, including negative NED or IDC-P status, Eastern Cooperative Oncology Group (ECOG) score <2, and prostate-specific antigen (PSA) <50 ng ml-1, had worse prognoses if EPE was detected. In patients with PSA <50 ng ml-1, EPE was a negative independent predictor for OS (hazard ratio [HR]: 4.239, 95% confidence interval [CI]: 1.218-14.756, P = 0.023). EPE was strongly associated with other aggressive clinicopathological features and poorer CFS and OS. These data suggest that EPE may be an indicator of poor prognosis, particularly in patients, otherwise considered likely to have favorable survival outcomes.

Sensing cisplatin-induced permeation of single live human bladder cancer cells by scanning electrochemical microscopy.

Cisplatin is a widely used anti-cancer agent, which was believed to trigger apoptosis of cancer cells by forming DNA adducts. However, recent studies evidenced a cisplatin-induced extrinsic apoptotic pathway through interaction with plasma membranes. We present quantitative time-course imaging of cisplatin-induced permeation of ferrocenemethanol to single live human bladder cancer cells (T24) using scanning electrochemical microscopy (SECM). Simultaneous quantification of cellular topography and membrane permeability was realized by running SECM in the depth scan mode. It was demonstrated that the acute addition of cisplatin to the outer environment of T24 cells immediately induced membrane permeability change in 5 min, which indicated a loosened structure of the cellular membrane upon cisplatin dosage. The cisplatin-induced permeation of T24 cells might be a one-step action, an extrinsic mechanism, since the cell response was quick, and no continuous increase in the membrane permeability was observed. The time-lapse SECM depth scan method provided a simple and facile way of monitoring cisplatin-induced membrane permeability changes. Our study is anticipated to lead to a methodology of screening anti-cancer drugs through their interactions with live cells.

SOX9 was involved in TKIs resistance in renal cell carcinoma via Raf/MEK/ERK signaling pathway.

Renal cell carcinoma (RCC) is common genitourinary malignancy in human, 30-40% of patients with RCC would be diagnosed with metastatic RCC (mRCC). Even in the era of targeted therapy, patients with mRCC would inevitably progress due to drug resistance. Herein, exploration of the mechanisms of resistance is noteworthy to study. In the present study, we firstly reported the expression profile of SOX9 in renal carcinoma cells and tissues, and found that its expression was significantly associated with Fuhrman grading. Dual luciferase analysis confirmed that Raf/MEK/ERK pathway could directly be regulated by SOX9, and sequential experiments demonstrated that, renal carcinoma cells could sensitize to Sorafenib/Sunitinib through Raf/MEK/ERK signaling pathway inhibition regulated by SOX9 down-regulation. In a small cases with mRCC treated with Sorafenib/Sunitinib (n=38), comparative analysis showed that patients with SOX9 (-) had much better therapeutic response to TKIs than those with SOX9 (+) (PD: 9.1% vs. 56.2%, P=0.002, DCR: 90.9% vs. 43.8%, P=0.002). Based on these findings, we concluded that, SOX9 was firstly described to be highly expressed in renal cell carcinoma, and its expression was involved in TKIs drug resistance through activation of Raf/MEK/ERK pathway. In vitro, patients with SOX9 (-) was related to better response to TKIs treatment than those with SOX9 (+). SOX9 could be expected to be a promising biomarker predicting TKIs response and even expected to be another novel target in the treatment of mRCC.