Renal thrombotic microangiopathy is associated with poor renal survival in children with immunoglobulin A nephropathy.

AIM: The aim of this study was to examine the clinical and pathological characteristics as well as the prognosis of immunoglobulin A nephropathy (IgAN) accompanied by renal thrombotic microangiopathy (rTMA) in paediatric patients. METHODS: After balancing epidemiological characteristics and pathological types between groups, 427 patients (rTMA group: 23, non-rTMA group: 46) were included. The clinical and pathological features, prognosis and clinical risk factors of the two groups were analysed. RESULTS: IgAN-rTMA children showed more severe clinical and pathological manifestations. The findings from the logistic regression analysis indicated that hypercellularity 1 (E1) (HR: 0.805, 95% CI: 0.763 ~ 1.452, P = .016), endocapillary proliferation (HR: 1.214, 95% CI: 0.093 ~ 4.815, P = .025) and C3 staining (HR: 7.554, 95% CI: 2.563 ~ 15.729, P = .037) were the risk factors for rTMA in children with IgAN. The renal survival in rTMA group was lower than non-rTMA group (χ2 = 18.467, P = .000). Cox regression analysis showed that E1 (HR: 7.441, 95% CI: 1.095 ~ 10.768, P = .037), C3 disposition (HR: 3.414, 95% CI: 0.834 ~ 11.578, P = .027) and rTMA (HR: 8.918, 95% CI: 1.032 ~ 16.754, P = .041) were identified as independent risk factors for the development of end-stage renal disease (ESRD). CONCLUSION: The presence of rTMA had a significant impact on the severity and prognosis of IgAN. And rTMA has been identified as an independent risk factor for the development of renal failure in children diagnosed with IgAN.

Exploring Novel Genome Instability-associated lncRNAs and their Potential Function in Pan-Renal Cell Carcinoma.

OBJECTIVE: Genomic instability can drive clonal evolution, continuous modification of tumor genomes, and tumor genomic heterogeneity. The molecular mechanism of genomic instability still needs further investigation. This study aims to identify novel genome instabilityassociated lncRNAs (GI-lncRNAs) and investigate the role of genome instability in pan-Renal cell carcinoma (RCC). MATERIALS AND METHODS: A mutator hypothesis was employed, combining the TCGA database of somatic mutation (SM) information, to identify GI-lncRNAs. Subsequently, a training cohort (n = 442) and a testing cohort (n = 439) were formed by randomly dividing all RCC patients. Based on the training cohort dataset, a multivariate Cox regression analysis lncRNAs risk model was created. Further validations were performed in the testing cohort, TCGA cohort, and different RCC subtypes. To confirm the relative expression levels of lncRNAs in HK-2, 786-O, and 769-P cells, qPCR was carried out. Functional pathway enrichment analyses were performed for further investigation. RESULTS: A total of 170 novel GI-lncRNAs were identified. The lncRNA prognostic risk model was constructed based on LINC00460, AC073218.1, AC010789.1, and COLCA1. This risk model successfully differentiated patients into distinct risk groups with significantly different clinical outcomes. The model was further validated in multiple independent patient cohorts. Additionally, functional and pathway enrichment analyses revealed that GI-lncRNAs play a crucial role in GI. Furthermore, the assessments of immune response, drug sensitivity, and cancer stemness revealed a significant relationship between GI-lncRNAs and tumor microenvironment infiltration, mutational burden, microsatellite instability, and drug resistance. CONCLUSIONS: In this study, we discovered four novel GI-lncRNAs and developed a novel signature that effectively predicted clinical outcomes in pan-RCC. The findings provide valuable insights for pan-RCC immunotherapy and shed light on potential underlying mechanisms.

Heterometallic Clusters with Cerium-Transition-Metal Bonding Supported by Nitrogen-Phosphorus Ligands.

Ligands are known to play a crucial role in the construction of complexes with metal-metal bonds. Compared with metal-metal bonds involving d-block transition metals, knowledge of the metal-metal bonds involving f-block rare-earth metals still lags far behind. Herein, we report a series of complexes with cerium-transition-metal bonds, which are supported by two kinds of nitrogen-phosphorus ligands N[CH2CH2NHPiPr2]3 (VI) and PyNHCH2PPh2 (VII). The reactions of zerovalent group 10 metal precursors, Pd(PPh3)4 and Pt(PPh3)4, with the cerium complex supported by VI generate heterometallic clusters [N{CH2CH2NPiPr2}3Ce(µ-M)]2 (M = Pd, 2 and M = Pt, 3) featuring four Ce-M bonds; meanwhile, the bimetallic species [(PyNCH2PPh2)3Ce-M] (M = Ni, 5; M = Pd, 6; and M = Pt, 7) with a single Ce-M bond were isolated from the reactions of the cerium precursor 4 supported by VII with Ni(COD)2, Pd(PPh3)4, or Pt(PPh3)4, respectively. These complexes represent the first example of species with an RE-M bond between Ce and group 10 metals, and 2 and 3 contain the largest number of RE-M donor/acceptor interactions ever to have been observed in a molecule.

Risk factors for lymphorrhea and lymphocele after radical prostatectomy: a retrospective case-control study.

PURPOSE: To investigate the risk factors for postoperative lymphorrhea or/and lymphocele (PLL) in patients undergoing radical prostatectomy (RP). MATERIALS AND METHODS: The clinical data of 606 patients were retrospectively collected. The receiver operating characteristic (ROC) curve was utilized to identify the optimal cutoff value. Multivariable logistic regression analysis was used to screen the independent predictors of PLL. RESULTS: Univariate analysis showed that nine factors differed between the PLL and non-PLL group. Multivariable logistic regression analysis showed that low preoperative fibrinogen level, extraperitoneal surgery, robot-assisted laparoscopic radical prostatectomy (RALRP), and hypoalbuminemia were risk factors and the use of fibrin glue was a protective factor. Correlation analysis showed that the scope of LN dissection (LND) and number of lymph nodes (LNs) dissected were positively correlated with PLL in the extraperitoneal approach, but were not significantly correlated with PLL in the transperitoneal approach. The use of fibrin glue was negatively associated with PLL in the overall procedure and the extraperitoneal approach, but not significantly so in the transperitoneal approach. Comparison of LNs clearance between the two surgical approaches revealed that the extent of LND and number of LNs dissected in the extraperitoneal approach were less than in the transperitoneal approach. CONCLUSION: During RALRP, more attention should be paid to fully clotting the broken end of lymphatic vessels. The use of fibrin glue could reduce the probability of PLL. The extent of LND or number of LNs dissected were positively correlated with PLL in the extraperitoneal approach.

Head-to-head comparisons of [68Ga]Ga-PSMA-11 PET/CT, multiparametric MRI, and prostate-specific antigen for the evaluation of therapeutic responses to neoadjuvant chemohormonal therapy in high-risk non-metastatic prostate cancer patients: a prospective study.

PURPOSE: The optimal tool to evaluate the tumour therapeutic responses to neoadjuvant chemohormonal therapy (NCHT) in patients with high-risk non-metastatic prostate cancer (PCa) remains uncertain. We compared the role of [68Ga]-labeled prostate-specific membrane antigen (PSMA)-11 positron emission tomography/computerized tomography ([68Ga]Ga-PSMA-11 PET/CT), multiparametric MRI (mpMRI), and prostate-specific antigen (PSA) and assessed the practical value of the recent European Association of Urology and European Association of Nuclear Medicine (EAU/EANM) recommended criteria of PSMA PET/CT to evaluate the therapeutic responses to NCHT in patients with high-risk non-metastatic PCa. METHODS: This prospective study included 72 high-risk non-metastatic PCa patients receiving NCHT followed by radical prostatectomy from June 2021 to March 2022. PSA testing, [68Ga]Ga-PSMA-11 PET/CT, and mpMRI scanning were conducted in all patients before and after NCHT. Therapeutic responses to NCHT were evaluated with PSA, RECIST 1.1, PERCIST 1.0, and EAU/EANM recommended criteria. Postoperative pathological results were considered the reference standard. A favourable pathological response was defined as pathologic complete remission (pCR) or minimal residual disease (MRD). Diagnostic accuracy was assessed by sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), positive predictive value (PPV), negative predictive value (NPV), and Cohen's kappa index. Logistic regression analysis was used to determine the independent predictive value of [68Ga]Ga-PSMA-11 PET/CT-derived parameters. RESULTS: All cases experienced a marked decrease in PSA levels after NCHT. Twenty-four (33.33%) cases experienced a favourable pathological response, including five (6.94%) cases of pCR and 19 (26.39%) cases of MRD. According to the results of [68Ga]Ga-PSMA-11 PET/CT, EAU/EANM recommended criteria indicated that 20 (27.78%) cases had a CR, whereas PERCIST 1.0 criteria indicated that 23 (31.94%) cases had a CR. There was a strong association between EAU/EANM recommended criteria and PERCIST 1.0 criteria (Pearson's R=0.857). The sensitivity (75.00%, 79.17% vs. 58.33%, 58.33%), specificity (95.83%, 91.67% vs. 83.33%, 68.75%), PLR (18.00, 9.50 vs. 3.50, 1.87), NLR (0.26, 0.23 vs. 0.50, 0.61), PPV (90.0%, 82.6% vs. 63.6%, 48.3%), and NPV (88.5%, 89.8% vs. 80.0%, 76.7%) of [68Ga]Ga-PSMA-11 PET/CT (including EAU/EANM recommended criteria and PERCIST 1.0 criteria) to predict favourable pathological responses were all superior to those of mpMRI and nadir PSA. The kappa index to predict a favourable pathological response was 0.257 for PSA, 0.426 for RECIST 1.1, 0.716 for PERCIST 1.0, and 0.739 for EAU/EANM recommended criteria. Multivariate logistic analysis revealed that the post-NCHT maximum standardized uptake value (SUVmax) before radical prostatectomy was an independent predictor of a favourable pathological response to NCHT. CONCLUSIONS: [68Ga]Ga-PSMA-11 PET/CT had a better concordance with a favourable pathological response to NCHT compared with nadir PSA and mpMRI. EAU/EANM recommended criteria and PERCIST 1.0 criteria performed equally to identify pathological responders when [68Ga]Ga-PSMA-11 PET/CT was used as a therapeutic response assessment tool.

Low TLR and PSMA-TV predict biochemical response to abiraterone acetate in metastatic prostate cancer patients developing castration resistance after chemohormonal therapy at hormone-sensitive stage.

OBJECTIVE: To explore whether 68Ga-PSMA-11 PET/CT-derived parameters could predict biochemical response to abiraterone acetate (AA) treatment and prognosis in metastatic prostate cancer patients developing castration resistance after chemohormonal therapy at hormone-sensitive stage. METHODS: The clinicopathologic data of 106 mCRPC cases receiving AA treatment were retrospectively analyzed. Logistic regression analysis was used to determine the independent predictors of biochemical response to AA treatment. Cox analyses were applied to investigate the independent prognostic factors for time to biochemical progression (TTBP) and radiological progression-free survival (rPFS). Survival analysis and ROC curve were also used. RESULTS: Multivariable Logistic analysis demonstrated that prior ADT duration ≥ 12 months, low prostate specific membrane antigen receptor-expressing tumor volume (PSMA-TV), low tumor to liver ratio (TLR) were independent predictors of biochemical response to AA treatment. Multivariate Cox analysis demonstrated that low PSMA-TV and low TLR were independent prognostic factors of longer TTBP and rPFS. The TTBP and rPFS of patients with higher PSMA-TV or TLR were significantly decreased compared with that of patients with lower PSMA-TV and TLR. The area under ROC curve (AUC) of combining ADT duration, PSMA-TV and TLR was 0.82 for predicting biochemical response to AA, which was significantly increased compared with that of other 68Ga-PSMA-11 PET/CT-derived parameters alone. CONCLUSIONS: Low PSMA-TV, low TLR were vital independent predictors of biochemical response to AA treatment and were associated with preferable prognosis in mCRPC patients. Combining ADT duration, PSMA-TV and TLR performed well in distinguishing AA responders from non-responders in mCRPC patients.

Recent advances in electrochemical proximity ligation assay.

Proximity ligation assay (PLA) is a vigorously developed homogeneous immunoassay assisted by DNA combining dual recognition of target protein by pairs of proximity probes, in which the detection of protein is tactfully converted to the detection of DNA. The booming developments in PLA have enabled a variety of ultrasensitive assays for the detection of protein and this concept of PLA is also extended to the detection of nucleic acids and some small molecule. The association between PLA and electrochemical method, defined as electrochemical proximity ligation assay (ECPLA), has gained much interests in disease diagnosis, food safety and environmental assays with the advantages, such as broad range of targets, simplicity, low cost and rapid response. In this review, we took a different perspective to present the history of PLA, the classical ECPLA biosensing methodology as well as the developments of ECPLA based on several key parameters, such as sensitivity, selectivity, reusability and generalization. In addition, the developments of PLA with electrochemiluminescence as readout are also presented. Finally, perspective and some unresolved challenges in ECPLA that can potentially be addressed have also been discussed.

A Novel Tumor Mutation Burden Related lncRNA Signature Identified Prognosis and Tumor Immune Microenvironment Features in Clear Cell Renal Cell Carcinoma.

BACKGROUND: Emerging evidence indicates that long noncoding RNA (lncRNA) plays an important biological role in clear cell renal cell carcinoma (ccRCC); however, the clinical value of tumor mutation burden-related lncRNA in ccRCC patients is unknown yet. METHODS: Somatic mutation profiles and lncRNA expression data of ccRCC were downloaded from the TCGA database. We retrospectively analyzed lncRNA expression data and survival information from 116 patients with ccRCC fromJanuary 2013 to January 2014. Univariate and multivariate Cox regression analyses were performed to construct lncRNA signature, and the prognosis value was determined by Kaplan-Mayer and receiver operating characteristic curve (ROC) analysis. RESULTS: Based on 160 differentially expressed TMB-related lncRNAs, two TMB-related molecular clusters with distinct immune checkpoints expression and immune cells infiltration were established for ccRCC patients. Moreover, a novel TMB-related lncRNA signature was constructed based on five lncRNAs for individualized prognosis assessment. High-risk group represents significantly worse overall survival in all cohorts. The area under the ROC curve was 0.716, 0.775 and 0.744 in the training cohort, testing cohort and TCGA cohort, respectively. Results of qRT-PCR successfully validated the expression levels of AP002360.3, LINC00460, AL590094.1, LINC00944 and LINC01843 in HK-2, 786-O, 769-P and ACHN cells. More importantly, the predictive performance of TMB-related lncRNA signature was successfully validated in an independent cohort of 116 ccRCC patients at our institution. CONCLUSION: This study successfully developed and validated a novel TMB-related lncRNA signature for individualized prognosis assessment of ccRCC patients.

Diagnostic accuracy of C-reactive protein and procalcitonin in the early diagnosis of infections after laparoscopic rectal cancer surgery.

BACKGROUND: We aimed to examine the diagnostic accuracy of postoperative procalcitonin (PCT) and C-reactive protein (CRP) in the detection of infectious complications in patients after laparoscopic rectal cancer surgery, as opposed to all colorectal surgery. METHODS: Between December 2018 and December 2020, 204 patients who underwent laparoscopic rectal cancer surgery were enrolled retrospectively. The PCT, CRP and white blood cell (WBC) count were measured before surgery and on postoperative days (PODs) 3 and 5. Diagnostic accuracy was determined by the area under the receiver operating characteristic curve (AUC). Net Reclassification Index (NRI) was used to calculate the ability to correct reclassification. RESULTS: Infectious complications occurred in 36 patients (17.6%), including 17 cases of anastomotic leakage (AL) (8.3%). The AUCs of PCT and CRP in predicting infectious complications on POD 3 were 0.690 and 0.731, respectively, which were better than those on POD 5 (AUC 0.666 and 0.697, respectively). PCT with an optimal cutoff value of 1.10 ng/mL (AUC 0.792, specificity 78.6%, negative predictive value [NPV] 96.6%), CRP with an optimal cutoff value of 109.5 mg/L (AUC 0.760, specificity 78.6%, NPV 96.1%) on POD 3 had superior diagnostic accuracy in predicting AL, both better than WBC (AUC 0.627). The AUC of combining PCT and CRP on POD 3 in predicting AL was 0.851, with a specificity of 79.7% and NPV of 97.4%, and the NRI was estimated to be 7.0%. CONCLUSIONS: Both PCT and CRP on POD 3 are excellent negative predictors for early monitoring of infectious complications, especially AL, in patients undergoing laparoscopic rectal cancer surgery.

A radiation resistance related index for biochemical recurrence and tumor immune environment in prostate cancer patients.

PURPOSE: To establish and verify a novel radiation resistance related index for predicting biochemical recurrence and tumor immune environment in prostate cancer (PCa) patients. MATERIALS AND METHODS: The transcriptome information of PCa were obtained from GEO and TCGA portal. We identified radiation resistance related genes (RRGs) between radioresistant and radiosensitive PCa cells. We conducted multivariate Cox analysis to construct a novel radiation resistance related index for predicting biochemical recurrence (BCR)-free survival (BCRFS). Internal and external validations were conducted. Preliminary experimental verifications were performed. RESULTS: We identified 194 differentially expressed RRGs and three radiation resistance related molecular clusters for PCa. Moreover, we established a novel radiation resistance related index and succeeded in conducting internal and external validations. High-risk populations meant significantly worse BCRFS in training, testing and validating cohort. The area under receiver operating characteristic curve were 0.809, 0.698, and 0.712 in training, testing, and validating cohort. The immune microenvironment was significantly different between high and low-risk score patients. Preliminary experiment identified and validated three potential biomarkers related to radiation resistance (ZNF695, TM4SF19, CCDC3) of PCa. CONCLUSIONS: This study successfully established and verified a novel radiation resistance related index, which had an excellent performance in predicting BCR and tumor immune microenvironment in patients with PCa.

Immune-responsive gene 1 protects against liver injury caused by concanavalin A via the activation Nrf2/HO-1 pathway and inhibition of ROS activation pathways.

Itaconate is produced by an enzyme encoded by the immune-responsive gene 1 (IRG1) and exerts antibacterial, anti-inflammatory, and antioxidant effects via multiple mechanisms. However, the role of IRG1/itaconate in liver injury caused by Concanavalin A (Con A) is not fully understood. In this study, we explored the therapeutic effect of IRG1/four-octyl itaconate (4-OI), a derivative of itaconate, on liver injury caused by Con A and its possible underlying mechanisms. In vivo experiments, we found that Con A promoted IRG1 expression in the liver tissue. Deletion of IRG1 in mice aggravated Con A-induced liver injury. Compared to wild-type (WT) mice, the inflammatory response, hepatocyte apoptosis, and serum cytokine levels were significantly increased, while the antioxidant capacity was significantly attenuated in IRG1-/- mice. In addition, we found that Con A promoted the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome, caspase-1, and gasdermin D activation, and pyroptosis was more obvious in IRG1-/- mice, while 4-OI inhibited pyroptosis. In vivo experiments showed that Con A promoted hepatocyte apoptosis by promoting reactive oxygen species (ROS) expression, and 4-OI reduced ROS-mediate apoptosis in NCTC 1469 cells. In RAW264.7 cells, we demonstrated that 4-OI inhibited the inflammatory response by promoting the nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and inhibiting the nuclear factor-kappa B (NF-κB)/mitogen-activated protein kinases signaling pathway. To further confirm that Nrf2 is the target of itaconate, we pretreated WT mice with ML385, an Nrf2 inhibitor, and found that ML385 could weaken the protection of 4-OI in Con A-induced liver injury mouse model. Furthermore, when we knocked down the Nrf2 gene in NCTC 1469 and RAW264.7 cells, the effect of 4-OI in inhibiting inflammation and apoptosis also decreased. In conclusion, our study shows the importance of IRG1 in inflammation and oxidative stress, and suggests that it plays a vital protective role in Con A-induced liver injury. These findings indicate IRG1/itaconate is a potential therapeutic strategy for immune liver injury, which requires further clinical exploration.

Maresin 1 protects against lipopolysaccharide/d-galactosamine-induced acute liver injury by inhibiting macrophage pyroptosis and inflammatory response.

BACKGROUND: Acute liver injury (ALI) caused by sepsis is a fearful disease with high mortality and poor prognosis. This study aimed to explore the roles and mechanism of Maresin 1 (MaR1) in lipopolysaccharide/d-galactosamine (LPS/D-GalN)-induced ALI. METHODS: We established an ALI mouse model induced by LPS/D-GalN. Each group was treated with or without LPS/D-GalN or MaR1. For the vitro experiments, RAW264.7, NCTC1469 cells, and bone marrow-derived macrophages (BMDMs) were stimulated with LPS. The effects of MaR1 on the reactive oxygen species (ROS), pyroptosis and inflammatory response in macrophages were investigated. RESULTS: MaR1 significantly inhibited an excessive inflammatory response and proinflammatory markers during LPS/D-GalN-induced ALI. MaR1 markedly decreased the levels of ROS, tumor necrosis factor-α, and interleukin-1ß (IL-1ß) in macrophages, and limited hepatocyte apoptosis in vitro. Upon exploring the mechanisms underlying the protective role of MaR1, we found MaR1 markedly upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and considerably reduced the phosphorylation of p38, ERK, and nuclear factor-kappa B (NF-κB)-p65. Knocking down Nrf2 decreased the effect of MaR1. Furthermore, we observed that MaR1 reduced inflammatory injury by inhibiting M1 macrophages and promoting M2 macrophage polarization. Finally, we observed that MaR1 could inhibit the production of gasdermin D N-terminus (GSDMD-N) in vivo. In vitro, MaR1 could significantly suppressed the expression of NLR family pyrin domain containing 3 (NLRP3) inflammasome, GSDMD-N, and IL-1ß caused by LPS and nigericin stimulation in BMDMs. CONCLUSION: MaR1 could ameliorate inflammation during LPS/D-GalN induced ALI by suppressing mitogen-activated protein kinase /NF-κB signaling and NLRP3 inflammasome-induced pyroptosis, activating macrophage M1/M2 polarization and Nrf2/HO-1 signaling. This provides new evidence for the potential of developing MaR1 for ALI treatment.

Preoperative abdominal fat distribution and systemic immune inflammation were associated with response to intravesical Bacillus Calmette-Guerin immunotherapy in patients with non-muscle invasive bladder cancer.

OBJECTIVE: To investigate the predictors of response to intravesical Bacillus Calmette-Guerin (BCG) immunotherapy for intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) patients. MATERIALS AND METHODS: We retrospectively analyzed the clinicopathological data of 184 intermediate and high risk NMIBC cases receiving transurethral resection of bladder tumor (TURBT) and intravesical BCG immunotherapy from December 2014 to April 2021 at our center. All patients were divided into BCG responders and non-responders. Multivariate Logistic regression analysis was performed to identify the independent predictors of response to intravesical BCG immunotherapy. Univariate and multivariate Cox regression analyses were applied to explore the independent prognostic factors of recurrence-free survival (RFS). Receiver operating characteristic (ROC) curve and Kaplan-Meier survival analysis were also utilized. RESULTS: The RFS of BCG responders was significantly increased compared with BCG non-responders. Multivariate Cox regression analysis demonstrated that low grade, pTa stage, non-CIS, lower relative visceral fat area (rVFA) and lower systemic immune inflammation index (SII) were independent prognostic factors of increased RFS after intravesical BCG immunotherapy. Multivariate Logistic regression analysis demonstrated that pTa stage, low grade, non-CIS, low rVFA, and low SII were independent predictors of response to intravesical BCG immunotherapy. Kaplan-Meier survival analysis indicated that the RFS of patients in low rVFA group or low SII group was significantly increased in comparison with those in high rVFA group or high SII group. ROC curve analysis showed that the area under ROC (AUC) of including SII and rVFA was significantly increased, indicating that the inclusion of preoperative SII and rVFA could significantly improve the predictive efficiency. CONCLUSIONS: Low grade, pTa stage, non-CIS, preoperative lower rVFA and lower SII were vital independent predictors of response to intravesical BCG immunotherapy and were associated with preferable prognosis in NMIBC patients. The inclusion of preoperative SII and rVFA could significantly improve the predictive efficiency.

Redox-induced reversible P-P coupling in a uranium complex.

A synthesized redox-active multidentate N-P ligand reacted with UCl4 in the presence of KHMDS or nBuLi, where two novel U(IV) complexes with or without P-P coupling were formed, respectively. The reversible P-P coupling in these complexes was observed in redox-induced reactions.

Risk Factors and Predictive Score Model for Early Recurrence After Curative Surgery in Patients With Poorly Differentiated Gastrointestinal Neuroendocrine Neoplasms.

Purpose: Studies on early recurrence in gastrointestinal neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma (MANEC) are lacking and risk factors related to early recurrence are not clear. We evaluated risk factors for early recurrence in such patients and developed a predictive scoring model. Methods: Patients undergoing curative surgery for GI-NEC or MANEC between January 2010 and January 2019 were included. Early recurrence was defined as recurrence within 12 months after surgery. Risk factors for early recurrence were identified using logistic regression. Results: Of the 80 included patients, 27 developed early recurrence and 53 had no early recurrence. Independent risk factors associated with early recurrence included tumor location in the midgut/hindgut [odds ratio (OR) = 5.077, 95% confidence interval (CI) 1.058-24.352, p = 0.042], alkaline phosphatase (ALP) >80 (OR = 5.331, 95% CI 1.557-18.258, p = 0.008), and lymph node ratio (LNR) >0.25 (OR = 6.578, 95% CI 1.971-21.951, p = 0.002). Risk scores were assigned to tumor location (foregut, 0; midgut/hindgut, 1), ALP (≤80, 0; >80, 1), and LNR (≤0.25, 0; >0.25, 1). Patients with a high risk (score 2-3) for early recurrence had significantly shorter disease-free survival and overall survival than those with low- (score 0) and intermediate risks (score 1) (both p < 0.001). The novel scoring model had superior predictive efficiency for early recurrence over TNM staging (area under the curve 0.795 vs. 0.614, p = 0.003). Conclusion: Tumor location, preoperative ALP, and LNR were independent factors associated with early recurrence after curative surgery for GI-NEC or MANEC. The risk scoring model developed based on these three factors shows superior predictive efficiency.

Regulation of Endoplasmic Reticulum Stress-Autophagy: A Potential Therapeutic Target for Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic nonspecific inflammation that mainly affects the mucosa and submucosa of the rectum and colon. Numerous studies have shown that endoplasmic reticulum stress (ERS)-induced autophagy plays a vital role in the pathogenesis of UC. ERS is the imbalance of internal balance caused by misfolded or unfolded proteins accumulated in the endoplasmic reticulum (ER).Excessive ERS triggers the unfolded protein response (UPR), an increase in inositol-requiring enzyme 1, and a Ca2+ overload, which activates the autophagy pathway. Autophagy is an evolutionarily conserved method of cellular self-degradation. Dysregulated autophagy causes inflammation, disruption of the intestinal barrier, and imbalance of intestinal homeostasis, therefore increasing the risk of colonic diseases. This review summarizes the pathogenesis of ERS, UPR, and ERS-related autophagy in UC, providing potential new targets and more effective treatment options for UC.

Identification of vital prognostic genes related to tumor microenvironment in pheochromocytoma and paraganglioma based on weighted gene co-expression network analysis.

Pheochromocytoma and paraganglioma (PCPG) is a rare neuroendocrine tumor. This study aims to identify vital prognostic genes which were associated with PCPG tumor microenvironment (TME). We downloaded transcriptome data of PCPG from TCGA database and calculated the immune scores and stromal scores by using the ESTIMATE algorithm. DEGs related to TMB were then identified. We conducted WGCNA to further extract the TME-related modules. GO, KEGG pathway analysis, and PPI network were performed. Survival analysis was conducted to identify the hub genes associated with the prognosis of PCPG. A total of 150 PCPG samples were included in this study. We obtained 1507 and 2067 DEGs based on immune scores and stromal scores, respectively. WGCNA analysis identified the red module and brown module were correlated with immune sores while the turquoise module and red module were significantly associated with stromal scores. Functional enrichments analysis revealed that 307 TME-related genes were correlated with the inflammation or immune response. Survival analysis showed that three TME-relate genes (ADGRE1, CCL18, and LILRA6) were associated with PCPG prognosis. These three hub genes including ADGRE1, CCL18, and LILRA6 might be involved in the progression of PCPG and could serve as potential biomarkers and novel therapeutic targets.

Development and Validation of Hub Genes for Adrenal Aldosterone-Producing Adenoma by Integrated Bioinformatics Analysis.

OBJECTIVE: To develop and validate hub genes involving in the development and progression of primary aldosteronism (PA) and adrenal aldosterone-producing adenoma (APA). MATERIALS AND METHODS: A total of four datasets of gene expression profiles related to APA were downloaded from GEO datasets. GSE60042 and GSE8514 were used to identify DEGs. Weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network module analysis were conducted. GO and KEGG enrichment analysis was performed. GSE10927 and GSE33371 were used for further external validation. RESULTS: We identified a total of 892 DEGs from GSE60042 and 1167 DEGs from GSE8514. WGCNA analysis demonstrated that the blue module (255 genes) and turquoise module (303 genes) were significantly correlated with APA. PPI networks were then constructed. GO term enrichment analysis suggested that cellular divalent inorganic cation homeostasis, calcium ion homeostasis, collagen-containing extracellular matrix, transport vesicle and metal ion transmembrane transporter activity were the vital annotations. KEGG pathway analysis found that these genes were significantly enriched in neuroactive ligand-receptor interaction, calcium signaling pathway. Finally, we identified a total of 11 candidate genes involving in the development and progression of APA and PA. Besides, two independent datasets (GSE10927 and GSE33371) were used for external validation, and there were seven hub genes successfully verified, including C3, GRM3, AVPR1A, WFS1, PTGFR, NTSR2, and JUN. CONCLUSION: These newly identified genes could contribute to the understanding of potential mechanism in APA and PA and might be promising targets for the treatment of APA and PA.

Risk factors for intraoperative cyst rupture in partial nephrectomy for cystic renal masses.

PURPOSE: To determine the risk factors of intraoperative cyst rupture in partial nephrectomy (PN) for a cystic renal mass (CRM) and their effect on the prognosis of patients. MATERIALS AND METHODS: Patients who underwent partial nephrectomy for CRMs from January 2009 to January 2015 were included. Uni/multivariate Logistic/Cox analysis and Kaplan-Meier analysis were performed. RESULTS: A total of 174 patients were included in this study. There were 27 (15.5%) intraoperative cyst ruptures. The median follow-up time was 60 months. Multivariate logistic analysis showed that the E component (P = 0.018) and N component (P = 0.022) of the R.E.N.A.L. nephrometry score, Bosniak category III (P = 0.044), and surgeon's experience (P = 0.030) were risk factors associated with intraoperative cyst rupture in PN for CRMs. The 5-year recurrence-free survival (RFS), cancer-free survival (CFS) and overall survival (OS) were 92.7%, 90.32% and 94.4%, respectively, in 124 cases of malignant CRM. Kaplan-Meier analysis demonstrated that 5-year RFS and 5-year CFS in patients with cyst rupture was worse than those without cyst rupture (P = 0.006 and 0.003, respectively). Multivariate Cox analysis revealed that intraoperative cyst rupture was independent risk factor for 5-year RFS and 5-year CFS (P = 0.039 and 0.013, respectively). However, there was no significant difference in OS between the two groups (P = 0.275). CONCLUSIONS: The prevalence of intraoperative cyst rupture is relatively high. Higher E and N scores, Bosniak category III, and lacking surgical experience (<20 cases) increase the risk of occurrence of intraoperative cyst rupture.