Epithelial splicing regulatory protein 1 promotes peritoneal dissemination of ovarian cancer by inducing the formation of circular RNAs modulating epithelial plasticity.

Peritoneal metastases prevalently occur in ovarian cancer, deteriorating patient prognosis. During the metastatic cascade, tumor plasticity enables cells to adapt to environmental changes, thereby facilitating dissemination. We previously found that epithelial splicing regulatory protein 1 (ESRP1) is linked to peritoneal metastasis and epithelial-mesenchymal plasticity in ovarian cancer. This study delves into the underlying mechanism. We found that ESRP1 preserves epithelial plasticity in ovarian cancer cells in vitro and in vivo. Functionally, ESRP1 enhances ovarian cancer cell growth and peritoneal dissemination. High-throughput sequencing revealed several ESRP1-related epithelial RNAs, encompassing both linear and circular forms. Specifically, ESRP1 triggers the cyclization of circPAFAH1B2 and circUBAP2 through binding to the GGU sequences in adjacent introns. The two ESRP1-induced circular RNAs stabilize DKK3 and AHR mRNAs, which are critical for epithelial plasticity, through interaction with IGF2BP2. Collectively, ESRP1 triggers the formation of circPAFAH1B2 and circUBAP2, which in turn stabilizes DKK3 and AHR through IGF2BP2 binding, thereby modulating the epithelial plasticity and aiding the peritoneal spread of ovarian cancer cells. The findings unveiled a biological network, orchestrated by ESRP1, that governs the epithelial-mesenchymal plasticity of ovarian cancer cells, emphasizing the therapeutic potential of ESRP1 and its induced circular RNAs for ovarian cancer treatment.

Clinical outcomes and prognostic factors of parameningeal rhabdomyosarcoma in children and adolescents: results of two consecutive protocols.

Background: Parameningeal rhabdomyosarcoma (PM-RMS) accounts for about 20% of all rhabdomyosarcoma (RMS) cases. At present, most research on PM-RMS has been conducted in Europe and the United States of America, and research in China has been very limited. This study sought to analyze the clinical outcomes and prognostic factors of PM-RMS in children and adolescents from two consecutive protocols at Beijing Children's Hospital (BCH). Methods: A total of 80 patients aged up to 18 years with previously untreated PM-RMS who had received treatment under two consecutive protocols [i.e., either the BCH-RMS-2006 protocol or the Chinese Children Cancer Group (CCCG)-RMS-2016 protocol] were included in the statistical analysis. The Kaplan-Meier method was used for the survival analysis, and Cox regression was used for the univariate and multivariate analyses. Results: Of the 80 patients enrolled in the study, 69 (86.2%) had meningeal invasion (MI). Of these 69 MI patients, 18 (22.5%) had cranial nerve palsy (CNP), 64 (80.0%) had cranial base bone erosion (CBBE), 25 (31.3%) had intracranial extension (ICE), and 2 (2.5%) had positive cerebrospinal fluid (CSF) tumor cells. The median follow-up time was 20.5 months (range, 5-100 months). The 5-year overall survival (OS) and progression-free survival (PFS) rates for the entire cohort were 51.7% and 45.6%, respectively. The 5-year OS rates of the patients who received the BCH-RMS-2006 protocol (18/80, 22.5%) and the CCCG-RMS-2016 protocol (62/80, 77.5%) were 33.3% and 57.0%, respectively (P<0.05), while the PFS rates of these patients were 22.2% and 53.6%, respectively (P<0.05). In relation to the PM-RMS patients with MI, the 5-year OS rates were 21.4% and 52.7%, and the 5-year PFS rates were 14.3% and 51.1% for the patients who received the old and new regimens, respectively (P<0.05). The extent of surgical resection had no significant effect on survival. The multivariate analysis showed that the coexistence of CBBE and ICE, no radiotherapy, a poor response to induction chemotherapy, and the BCH-RMS-2006 protocol were risk factors affecting PFS and OS. Conclusions: Of the patients examined in this study, those with PM-RMS with CBBE accompanied by ICE had the worst prognosis. The patients with MI benefited from intensive chemotherapy combined with radiation therapy, but the effect of surgery was very limited.

Association between body mass index and lymph node metastasis among women with cervical cancer: a systematic review and network meta-analysis.

PURPOSE: Lymph node status is a determinant of survival in patients with early-stage cervical cancer. However, the relationship between obesity and lymph node status remains unclear. Therefore, this systematic review aims to evaluate the correlation between body mass index (BMI) and lymph node metastasis in cervical cancer. METHODS: Cohort studies through six databases were reviewed until December 2021. Odds ratios (ORs) for lymphatic metastasis were estimated using random-effects models and network meta-analysis. BMI groups for lymph node metastasis were ranked. Heterogeneities were assessed using I2. Subgroup analyses were performed to determine possible sources of heterogeneity. RESULTS: No significant difference was found between obese (BMI ≥ 25) and non-obese patients (BMI < 25) (OR = 1.01; 95% CI 0.69-1.47; P = 0.97). In subgroup analyses, obesity was associated with higher risk among the Americans and advanced-stage patients. The grouping analysis based on BMI and the rankogram values revealed that the '35 ≤ BMI' group had the highest risk of lymph node metastasis. CONCLUSION: Although there were no significant differences in lymph node metastasis between obese and non-obese cervical cancer patients in overall analysis, patients with BMI ≥ 35 were at significantly higher risk of lymph node metastasis.

Clinical features and treatment outcomes of liver involvement in paediatric Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder in children, and liver involvement in LCH is rare. This retrospective study reported the clinical features and prognosis of patients with hepatic LCH. Liver involvement was defined by histopathological findings, liver dysfunction or abnormalities, or ultrasound imaging. A total of 130 patients (14.5%) with hepatic LCH out of 899 in the LCH population were enrolled. Patients with liver involvement had greater frequencies of skin, lung, hearing system, and haematologic system involvement, and hemophagocytic lymphohistiocytosis (P<0.001, 0.001, 0.002, 0.009, and <0.001, respectively). Overall survival and progression-free survival were lower in LCH patients with liver involvement than in those without liver involvement (P<0.001 and <0.001). In patients with liver involvement, the overall survival (OS) and progression-free survival (PFS) rates were lower in patients with cholangitis than in those without cholangitis (P<0.020 and 0.030). For the treatment response, the response rate of hepatic LCH patients to initial first-line therapy (n=89) was 22.5%. However, there was no significant difference in the response rate or recurrence rate between patients who shifted from first-line treatment to second-line treatment (n=29) or to targeted therapy (n=13) (P=0.453 and 1.000). The response rate of hepatic LCH patients who received initial second-line therapy (n=13) was 38.5%. Two of these patients subsequently experienced bone recurrence. The response rate of hepatic LCH patients who received initial targeted therapy (n=16) was 75.0%. Three patients subsequently experienced recurrence, including 2 in the bone and 1 in the liver and skin. A total of 39.3% of patients who received second-line treatment had severe myelosuppression (grade III-IV), and 50.8% had varying degrees of gastrointestinal events, whereas there was no severe toxicity in patients who received first-line treatment and targeted therapy. Four patients underwent liver transplantation because of liver cirrhosis. The patients' liver disease improved within a follow-up period of 18-79 months. This study demonstrated that LCH with liver involvement, especially cholangitis, indicates a poor prognosis. Targeted therapy provides a good treatment response and less toxicity. However, it may relapse after withdrawal. Liver transplantation is still a reliable salvage option for patients with end-stage liver disease.

Mitochondrial-Targeted Copper Delivery for Cuproptosis-Based Synergistic Cancer Therapy.

Cuproptosis is dependent on mitochondrial respiration modulation by targeting lipoylated tricarboxylic acid cycle (TCA) cycle proteins, showing great potential in cancer treatment. However, the specific release of copper ions at mitochondrial is highly needed and still a major challenge to trigger cellular cuproptosis. Herein, a metal-organic framework-based nanoplatform (ZCProP) is designed for mitochondrial-targeted and ATP/pH-responsive Cu2+ and prodigiosin release. The released Cu2+ promotes aggregation of lipoylated protein and loss of Fe-S cluster protein, resulting in cell cuproptosis. In the meanwhile, Cu2+ can concert with prodigiosin to induce mitochondrial dysfunction and DNA damage and enhance cell cuproptosis. Furthermore, this nanoplatform has an ability to deplete glutathione, which not only further promotes cuproptosis but also triggers cell ferroptosis by the suppression of glutathione peroxidase 4, an anti-ferroptosis protein. Collectively, the designed ZCProP nanoplatform can responsively release cargos at mitochondrial and realize a conspicuous therapeutic efficacy through a cuproptosis-mediated concerted effect. Along with its excellent biocompatibility, this nanoplatform may provide a novel therapeutic modality paradigm to boost cancer therapeutic strategies based on cuproptosis.

ITGA7 loss drives the differentiation of adipose-derived mesenchymal stem cells to cancer-associated fibroblasts.

Cancer-associated fibroblasts (CAFs) represent a major cellular component of the tumor (pre-)metastatic niche and play an essential role in omental dissemination of ovarian cancer. The omentum is rich in adipose, and adipose-derived mesenchymal stem cells (ADSCs) have been identified as a source of CAFs. However, the molecular events driving the phenotype shift of ADSCs remain largely unexplored. In this research, we focus on integrins, transmembrane receptors that have been widely involved in cellular plasticity. We found that integrin α7 (ITGA7) was the only member of the integrin family that positively correlated with both overall survival and progression-free survival in ovarian cancer through GEPIA2. The immunohistochemistry signal of ITGA7 was apparent in the tumor stroma, and a lower omental ITGA7 level was associated with metastasis. Primary ADSCs were isolated from the omentum of patients with ovarian cancer and identified by cellular morphology, biomarkers, and multilineage differentiation. The conditional medium of ovarian cancer cells induced ITGA7 expression decrease and phenotypic changes in ADSCs. Downregulation of ITGA7 in primary omental ADSCs led to decrease in stemness properties and emerge of characteristic morphology and biomarkers of CAFs. Moreover, the conditioned medium of ADSCs with ITGA7 depletion exhibited enhanced abilities to improve the migration and invasion of ovarian cancer cells in vitro. Overall, these findings indicate that loss of ITGA7 may induce the differentiation of ADSCs to CAFs that contribute to a tumor-supportive niche.

Epidemiology and survival of patients with spinal meningiomas: a large retrospective cohort study.

INTRODUCTION: Spinal meningiomas (SMs) are relatively rare central nervous system tumors that usually trigger neurological symptoms. The prevalence of SMs is increasing with the aging of the global population. This study aimed to perform a systematic epidemiologic and survival prognostic analysis of SMs to evaluate their public health impact and to develop a novel method to estimate the overall survival at 3-year, 5-year, and 10-year in patients with SMs. METHODS: Five thousand one hundred fifty eight patients with SMs were recruited from the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2019. Firstly, descriptive analysis was performed on the epidemiology of SMs. Secondly, these individuals were randomly allocated to the training and validation sets in a ratio of 7:3. Kaplan-Meier method and Cox regression analysis were utilized in the training set to identify independent prognostic factors and to construct a nomogram for survival prognosis. Subsequently, the discriminative power, predictive performance, and clinical utility of the nomogram were evaluated by receiver operating characteristic curve and decision curve analysis. Finally, a mortality risk stratification system and a web-based dynamic nomogram were constructed to quantify the risk of mortality in patients with SMs. RESULTS: The annual age-adjusted incidence rates of SMs increased steadily since 2004, reaching a rate of 0.40 cases per 100 000 population in 2019, with a female-to-male ratio of ~4:1. The age groups of 50-59, 60-69, and 70-79 years old were the most prevalent ages for SMs, accounting for 19.08, 24.93, and 23.32%, respectively. In addition, seven independent prognostic factors were identified to establish a prognostic nomogram for patients with SMs. The decision curve analysis and receiver operating characteristic curve indicated that the nomogram had high clinical utility and favorable accuracy. Moreover, the mortality risk stratification system effectively divided patients into low-risk, middle-risk, and high-risk subgroups. CONCLUSIONS: SMs are relatively rare benign spinal tumors prevalent in the white elderly female population. Clinicians could use the nomogram to personalize the prediction of the overall survival probability of patients with SMs, categorize these patients into different mortality risk subgroups, and develop personalized decision-making plans. Moreover, the web-based dynamic nomogram could help to further promote clinical application and assist clinicians in providing personalized counseling, timely monitoring, and clinical assessment for patients.

Efficacy and safety of Shenqi Dihuang decoction for lupus nephritis: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Lupus Nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE). However, the treatment of lupus nephritis using traditional Chinese medicine remains controversial. AIM OF THE STUDY: To assess the efficacy and safety of Shenqi Dihuang decoction in the treatment of LN and review the clinical guidelines. MATERIALS AND METHODS: Six databases (China National Knowledge Infrastructure, Wanfang, PubMed, China Biology Medicine, the Cochrane Library, and Embase) were searched from their inception to September 10, 2022, for randomized controlled trials on the treatment of lupus nephritis using Shenqi Dihuang decoction. We conducted a meta-analysis of random effects using Review Manager 5.4 and assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: A total of 15,790 citations were identified, from which 14 eligible randomized controlled trials that enrolled 1002 participants were selected for this systematic review. Low-to-moderate certainty of evidence indicated that when compared with Western medicine, Shenqi Dihuang decoction combined with Western medicine was associated with favorable effects on clinical efficacy (risk ratio (RR) = 1.25, 95% confidence interval (CI): 1.15-1.37), vascular endothelial growth factor (mean difference (MD) = -30.90, 95% CI: -40.18 to -21.63), serum level (MD = -4.81 µmol L-1, 95% CI: -17.14 to 7.53), complement C3 (MD = -0.14 g L-1, 95% CI: -0.23 to -0.04), erythrocyte sedimentation rate (MD = -11.87 mm h-1, 95% CI: -22.01 to -1.73), and SLE disease activity score (MD = -3.38, 95% CI: -4.15 to -2.61), and exhibited a lower risk of infection (RR = 0.2, 95% CI: 0.05-0.90), gastrointestinal reaction (RR = 0.47, 95% CI: 0.17-1.28), and insomnia (RR = 0.29, 95% CI: 0.09-0.92). CONCLUSIONS: This systematic review provides a potential reference for understanding the efficacy and safety of Shenqi Dihuang decoction combined with Western medicine for treating patients with lupus nephritis. However, owing to the limited quality of the studies included in this review, lack of mycophenolate mofetil control, and high heterogeneity among the included studies, the current findings should be interpreted with caution. Therefore, the efficacy and safety of Shenqi Dihuang decoction in patients with PN still require further verification through future high-quality clinical studies.

The effect of calcium dobesilate combined with hypoglycemic drugs in the treatment of cataract NPDR and its effect on fundus microcirculation and blood ICAM-1, MCP-1 and MIF levels.

Background: To explore the effect of calcium dobesilate combined with hypoglycemic drugs in the treatment of cataract complicated with non-proliferative diabetic retinopathy (NPDR) and its effects on fundus microcirculation, intercellular adhesion molecule 1 (ICAM-1), mono - cyte chemoattractant protein 1 (MCP-1), and macrophage migration inhibitory factor (MIF). Methods: From March 2019 to January 2021, a total of 114 patients with cataract and NPDR were included, and the patients were assigned into the control and the observation groups by random number table method, with 57 cases/group. The control was given hypoglycemic drugs, and the observation was given calcium dobesilate combined therapy. The therapeutic efficacy, blood glucose and blood lipid levels, fluorescein fundus angiography results, fundus microcirculation indexes, retinal neovascularizationrelated factors, and ICAM-1, MCP-1, and MIF levels before and after treatment were compared between the two groups. Results: The total effective rate of treatment in the observation was higher vs. the control (P < 0.05); Fasting blood glucose (FBG), 2 h postprandial blood glucose (2hPG), glycosylated hemoglobin (HbA1c), triglyceride (TG), total cholesterol (TC) and low density lipoprotein (LDL) in the observation after treatment were reduced vs. the control (P < 0.05); The number of micro-hemangiomas in the observation after treatment was less vs. the control, and the area of hemorrhage, the area of exudation and the thickness of the yellow plate were smaller vs. the control (P < 0.05); The resistance index (RI) value of the observation after treatment was lower than the control, and the end-diastolic blood flow velocity (EDV) and the peak systolic blood flow velocity (PSV) of the observation were higher vs. the control (P < 0.05). ICAM-1, MCP-1, MIF, vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF1) in the observation after treatment were reduced vs. the control, but pigment epithelium-derived factor (PEDF) were higher vs. the control (P < 0.05); one case of gastrointestinal reaction took place in the observation, but no adverse reaction occurred in the control, and no clear difference exhibited in the incidence of adverse reactions between the two groups (P > 0.05). Conclusions: Calcium dobesilate combined with hypoglycemic drugs has good clinical efficacy in the treatment of cataract complicated with NPDR, which can effectively reduce the level of blood glucose and blood lipids, reduce inflammation, and mitigate the microcirculation of branch retinal vein occlusion lesions.

Hypertension and hyperglycaemia are positively correlated with local invasion of early cervical cancer.

Background: Metabolic disorders are involved in the development of numerous cancers, but their association with the progression of cervical cancer is unclear. This study aims to investigate the association between metabolic disorders and the pathological risk factors and survival in patients with early cervical cancer. Methods: Patients with FIGO IB1 (2009) primary cervical cancer who underwent radical hysterectomy and systematic pelvic lymph node dissection at our institution from October 2014 to December 2017 were included retrospectively. Clinical data regarding the metabolic syndrome and surgical pathology of the patient were collected. The correlations between metabolic disorders (hypertension, hyperglycemia, and obesity) and clinicopathological characteristics as well as survival after surgery were analyzed. Results: The study included 246 patients with clinical IB1 cervical cancer, 111 (45.1%) of whom had at least one of the comorbidities of hypertension, obesity, or hyperglycemia. Hypertension was positively correlated with parametrial invasion and poorly differentiated histology; hyperglycemia was positively correlated with stromal invasion; obesity was negatively associated with lymph node metastasis; but arbitrary disorder did not show any correlation with pathologic features. Hypertension was an independent risk factor for parametrial invasion (OR=6.54, 95% CI: 1.60-26.69); hyperglycemia was an independent risk factor for stromal invasion (OR=2.05, 95% CI: 1.07-3.95); and obesity was an independent protective factor for lymph node metastasis (OR=0.07, 95% CI: 0.01-0.60). Moreover, the patients with hypertension had a significantly lower 5-year OS rate (70.0% vs. 95.3%, P<0.0001) and a significantly lower 5-year PFS rate than those without hypertension (70.0% vs. 91.2%, P=0.010). Conclusion: Hypertension and hyperglycemia are positively associated with local invasion of early cervical cancer, which need to be verified in multi-center, large scale studies.

Management of complicated choledochal cyst in children: ultrasound-guided percutaneous external drainage and subsequent definitive operation.

OBJECTIVE: The purpose of this study was to analyze the outcomes of the combination of ultrasound (US)-guided percutaneous external drainage and subsequent definitive operation to manage complicated choledochal cyst in children. METHODS: This retrospective study included 6 children with choledochal cyst who underwent initial US-guided percutaneous external drainage and subsequent cyst excision with Roux-en-Y hepaticojejunostomy between January 2021 and September 2022. Patient characteristics, laboratory findings, imaging data, treatment details, and postoperative outcomes were evaluated. RESULTS: Mean age at presentation was 2.7 ± 2.2 (0.5-6.2) years, and 2 patients (2/6) were boys. Four patients (4/6) had a giant choledochal cyst with the widest diameter of ≥ 10 cm and underwent US-guided percutaneous biliary drainage on admission or after conservative treatments. The other 2 patients (2/6) underwent US-guided percutaneous transhepatic cholangio-drainage and percutaneous transhepatic gallbladder drainage due to coagulopathy, respectively. Five patients (5/6) recovered well after US-guided percutaneous external drainage and underwent the definitive operation, whereas 1 patient (1/6) had liver fibrosis confirmed by Fibroscan and ultimately underwent liver transplantation 2 months after external drainage. The mean time from US-guided percutaneous external drainage to the definitive operation was 12 ± 9 (3-21) days. The average length of hospital stay was 24 ± 9 (16-31) days. No related complications of US-guided percutaneous external drainage occurred during hospitalization. At 10.2 ± 6.8 (1.0-18.0) months follow-up, all patients had a normal liver function and US examination. CONCLUSIONS: Our detailed analysis of this small cohort suggests that US-guided percutaneous external drainage is technically feasible for choledochal cyst with giant cysts or coagulopathy in children, which may provide suitable conditions for subsequent definitive operation with a good prognosis. TRIAL REGISTRATION: Retrospectively registered.

Association of soft drinks and 100% fruit juice consumption with risk of cancer: a systematic review and dose-response meta-analysis of prospective cohort studies.

BACKGROUND: Studies of the associations between soft drinks and the risk of cancer showed inconsistent results. No previous published systematic reviews and meta-analysis has investigated a dose-response association between exposure dose and cancer risk or assessed the certainty of currently available evidence. Therefore, we aim to demonstrate the associations and assessed the certainty of the evidence to show our confidence in the associations. METHODS: We searched Embase, PubMed, Web of Science, and the Cochrane Library from inception to Jun 2022, to include relevant prospective cohort studies. We used a restricted cubic spline model to conduct a dose-response meta-analysis and calculated the absolute effect estimates to present the results. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of the evidence. RESULTS: Forty-two articles including on 37 cohorts enrolled 4,518,547 participants were included. With low certainty evidence, increased consumption of sugar-sweetened beverages (SSBs) per 250 mL/day was significantly associated with a 17% greater risk of breast cancer, a 10% greater risk of colorectal cancer, a 30% greater risk of biliary tract cancer, and a 10% greater risk of prostate cancer; increased consumption of artificially sweetened beverages (ASBs)re per 250 mL/day was significantly associated with a 16% greater risk of leukemia; increased consumption of 100% fruit juice per 250 mL/day was significantly associated with a 31% greater risk of overall cancer, 22% greater risk of melanoma, 2% greater risk of squamous cell carcinoma, and 29% greater risk of thyroid cancer. The associations with other specific cancer were no significant. We found linear dose-response associations between consumption of SSBs and the risk of breast and kidney cancer, and between consumption of ASBs and 100% fruit juices and the risk of pancreatic cancer. CONCLUSIONS: An increment in consumption of SSBs of 250 mL/day was positively associated with increased risk of breast, colorectal, and biliary tract cancer. Fruit juices consumption was also positively associated with the risk of overall cancer, thyroid cancer, and melanoma. The magnitude of absolute effects, however, was small and mainly based on low or very low certainty of evidence. The association of ASBs consumption with specific cancer risk was uncertain. TRIAL REGISTRATION: PROSPERO: CRD42020152223.

Discovery of Targets for Immune-Metabolic Antitumor Drugs Identifies Estrogen-Related Receptor Alpha.

Drugs that kill tumors through multiple mechanisms have the potential for broad clinical benefits. Here, we first developed an in silico multiomics approach (BipotentR) to find cancer cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway and then used it to identify 38 candidate immune-metabolic regulators. We show the tumor activities of these regulators stratify patients with melanoma by their response to anti-PD-1 using machine learning and deep neural approaches, which improve the predictive power of current biomarkers. The topmost identified regulator, ESRRA, is activated in immunotherapy-resistant tumors. Its inhibition killed tumors by suppressing energy metabolism and activating two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization, and (ii) antigen-presentation stimulation, recruiting CD8+ T cells into tumors. We also demonstrate a wide utility of BipotentR by applying it to angiogenesis and growth suppressor evasion pathways. BipotentR (http://bipotentr.dfci.harvard.edu/) provides a resource for evaluating patient response and discovering drug targets that act simultaneously through multiple mechanisms. SIGNIFICANCE: BipotentR presents resources for evaluating patient response and identifying targets for drugs that can kill tumors through multiple mechanisms concurrently. Inhibition of the topmost candidate target killed tumors by suppressing energy metabolism and effects on two immune mechanisms. This article is highlighted in the In This Issue feature, p. 517.

Diagnostic efficacy of high-frequency ultrasound and X-ray contrast enema in colonic strictures after necrotizing enterocolitis: a retrospective study.

OBJECTIVE: To compare the efficacy of high-frequency ultrasound and X-ray contrast enema in the diagnosis of colonic strictures after necrotizing enterocolitis. METHODS: This study included pediatric patients who developed progressive abdominal distension or constipation after conservative treatment for necrotizing enterocolitis at our hospital between June 2012 and April 2020. All patients had high-frequency ultrasounds and X-ray contrast enema, and we used surgery, pathology, and telephone return visits as the reference standard. Patients with colonic strictures were confirmed by surgery and pathology. A patient was considered without colonic stricture if no stricture was reported or did not have related symptoms during telephone return visits. The areas under the Receiver operating characteristic (ROC) curves were used as evaluation indexes to compare the differential efficacy of high-frequency ultrasound and X-ray contrast enema. RESULTS: A total of 81 patients have been included in this study. Among them, 49 patients were diagnosed with colonic strictures after necrotizing enterocolitis. The AUCs for high-frequency ultrasound and X-ray contrast enema were 0.990 vs 0.938, respectively (p > 0.05). CONCLUSION: The diagnostic efficacy of high-frequency ultrasound was similar to that of X-ray contrast enema, furthermore this study also demonstrates the benefits of using high-frequency ultrasound to identify colonic strictures after necrotizing enterocolitis.

GBP2 as a potential prognostic predictor with immune-related characteristics in glioma.

Guanylate binding protein 2 (GBP2) is a member of the guanine binding protein family, and its relationship with prognostic outcomes and tumor immune microenvironments in glioma remains elusive. We found GBP2 were increased in glioma tissues at both mRNA and protein levels. Kaplan-Meier curves revealed that high GBP2 expression was linked with worse survival of glioma patients, and multivariate Cox regression analysis indicated that high GBP2 expression was an independent prognostic factor for glioma. Combined analysis in immune database revealed that the expression of GBP2 was significantly related to the level of immune infiltration and immunomodulators. Single-cell analysis illustrated the high expression of GBP2 in malignant glioma cells showed the high antigen presentation capability, which were confirmed by real-time polymerase chain reaction (qRT-PCR) data. Additionally, the hsa-mir-26b-5p and hsa-mir-335-5p were predicted as GBP2 regulators and were validated in U87 and U251 cells. Our results first decipher immune-related characteristics and noncoding regulators of GBP2 in glioma, which may provide insights into associated immunotherapies and prognostic predictor.

Laparoscopic versus open repair of congenital duodenal obstruction: a systematic review and meta-analysis.

PURPOSE: To assess the safety and efficacy of laparoscopic versus open repair of congenital duodenal obstruction (CDO), we conducted a systematic review and meta-analysis (CDO). METHODS: A literature search was conducted to identify studies that compared laparoscopic surgery (LS) and open surgery (OS) for neonates with CDO. Meta-analysis was used to pool and compare variables such as operative time, time to feeding, length of hospital stay, anastomotic leak or stricture, postoperative ileus, wound infection, and overall postoperative complications. RESULTS: Among the 1348 neonatal participants with CDO in the ten studies, 304 received LS and 1044 received OS. When compared to the OS approach, the LS approach resulted in shorter hospital stays, faster time to initial and full feeding, longer operative time, and less wound infection. However, no significant difference in secondary outcomes such as anastomotic leak or stricture, postoperative ileus, and overall postoperative complications was found between LS and OS. CONCLUSIONS: LS is a safe, feasible and effective surgical procedure for neonatal CDO when compared to OS. Compared with OS, LS has a faster time to feeding, a shorter hospital stay, and less wound infection. Furthermore, in terms of anastomotic leak or stricture, postoperative ileus, and overall postoperative complications, LS is equivalent to OS. We conclude that LS should be considered an acceptable option for CDO.

Structural basis for product specificities of MLL family methyltransferases.

Human mixed-lineage leukemia (MLL) family methyltransferases methylate histone H3 lysine 4 to different methylation states (me1/me2/me3) with distinct functional outputs, but the mechanism underlying the different product specificities of MLL proteins remains unclear. Here, we develop methodologies to quantitatively measure the methylation rate difference between mono-, di-, and tri-methylation steps and demonstrate that MLL proteins possess distinct product specificities in the context of the minimum MLL-RBBP5-ASH2L complex. Comparative structural analyses of MLL complexes by X-ray crystal structures, fluorine-19 nuclear magnetic resonance, and molecular dynamics simulations reveal that the dynamics of two conserved tyrosine residues at the "F/Y (phenylalanine/tyrosine) switch" positions fine-tune the product specificity. The variation in the intramolecular interaction between SET-N and SET-C affects the F/Y switch dynamics, thus determining the product specificities of MLL proteins. These results indicate a modified F/Y switch rule applicable for most SET domain methyltransferases and implicate the functional divergence of MLL proteins.

A pocket-based 3D molecule generative model fueled by experimental electron density.

We report for the first time the use of experimental electron density (ED) as training data for the generation of drug-like three-dimensional molecules based on the structure of a target protein pocket. Similar to a structural biologist building molecules based on their ED, our model functions with two main components: a generative adversarial network (GAN) to generate the ligand ED in the input pocket and an ED interpretation module for molecule generation. The model was tested on three targets: a kinase (hematopoietic progenitor kinase 1), protease (SARS-CoV-2 main protease), and nuclear receptor (vitamin D receptor), and evaluated with a reference dataset composed of over 8000 compounds that have their activities reported in the literature. The evaluation considered the chemical validity, chemical space distribution-based diversity, and similarity with reference active compounds concerning the molecular structure and pocket-binding mode. Our model can generate molecules with similar structures to classical active compounds and novel compounds sharing similar binding modes with active compounds, making it a promising tool for library generation supporting high-throughput virtual screening. The ligand ED generated can also be used to support fragment-based drug design. Our model is available as an online service to academic users via https://edmg.stonewise.cn/#/create .

Contrast-enhanced ultrasonography for assessing histopathology in pediatric immunoglobulin A nephropathy and Henoch-Schönlein purpura nephritis.

BACKGROUND: Glomerular disease, including immunoglobulin A nephropathy (IgAN) and Henoch-Schönlein purpura nephritis, is one of the most common kidney diseases in children. The diagnosis of these diseases depends on pathological biopsy, although this procedure is seriously limited by its invasive and high-risk nature. OBJECTIVE: To investigate the potential of contrast-enhanced ultrasonography (CEUS) for evaluating the histopathological severity of IgAN and Henoch-Schönlein purpura nephritis (HSPN). MATERIALS AND METHODS: We investigated a total of 13 children with IgAN and 12 children with HSPN confirmed by renal histopathology. We reevaluated the pathological lesions of the children according to the Oxford classification and the Lee grading system and then all the children underwent CEUS. Using SonoLiver software, we constructed time-intensity curves of CEUS for regions of interest in the renal cortex. We analyzed CEUS quantitative parameters for IgAN and HSPN and used Spearman correlation analysis to examine the correlation between CEUS parameters and clinicopathological indexes in the study cohort. RESULTS: The CEUS parameters rise time (RT) and time to peak (TTP) were significantly higher in children with Lee grade IV than in those with Lee grades II or III. Spearman correlation analysis revealed a positive correlation between rise time and time to peak with Lee grade in the overall cohort of children, and a positive correlation between rise time and time to peak and severity of crescents in the Oxford classification scoring system. CONCLUSION: Contrast-enhanced US may be used as a noninvasive imaging technique to evaluate the severity of renal pathology and formation of crescents in children with IgAN and HSPN.