Computer-assisted three-dimensional individualized extreme liver resection for hepatoblastoma in proximity to the major liver vasculature.

BACKGROUND: The management of hepatoblastoma (HB) becomes challenging when the tumor remains in close proximity to the major liver vasculature (PMV) even after a full course of neoadjuvant chemotherapy (NAC). In such cases, extreme liver resection can be considered a potential option. AIM: To explore whether computer-assisted three-dimensional individualized extreme liver resection is safe and feasible for children with HB who still have PMV after a full course of NAC. METHODS: We retrospectively collected data from children with HB who underwent surgical resection at our center from June 2013 to June 2023. We then analyzed the detailed clinical and three-dimensional characteristics of children with HB who still had PMV after a full course of NAC. RESULTS: Sixty-seven children diagnosed with HB underwent surgical resection. The age at diagnosis was 21.4 ± 18.8 months, and 40 boys and 27 girls were included. Fifty-nine (88.1%) patients had a single tumor, 39 (58.2%) of which was located in the right lobe of the liver. A total of 47 patients (70.1%) had PRE-TEXT III or IV. Thirty-nine patients (58.2%) underwent delayed resection. After a full course of NAC, 16 patients still had close PMV (within 1 cm in two patients, touching in 11 patients, compressing in four patients, and showing tumor thrombus in three patients). There were 6 patients of tumors in the middle lobe of the liver, and four of those patients exhibited liver anatomy variations. These 16 children underwent extreme liver resection after comprehensive preoperative evaluation. Intraoperative procedures were performed according to the preoperative plan, and the operations were successfully performed. Currently, the 3-year event-free survival of 67 children with HB is 88%. Among the 16 children who underwent extreme liver resection, three experienced recurrence, and one died due to multiple metastases. CONCLUSION: Extreme liver resection for HB that is still in close PMV after a full course of NAC is both safe and feasible. This approach not only reduces the necessity for liver transplantation but also results in a favorable prognosis. Individualized three-dimensional surgical planning is beneficial for accurate and complete resection of HB, particularly for assessing vascular involvement, remnant liver volume and anatomical variations.

Associations between R.E.N.A.L. nephrometry score and survival outcomes in renal tumours.

OBJECTIVE: The radius-exophytic/endophytic-nearness-anterior/posterior-location nephrometry score could be used to predict surgical outcomes and renal tumour aggressiveness. We aimed to analyse its associations with survival outcomes. METHODS: We included 1368 patients with sporadic, unilateral and non-metastatic renal tumours who received curative nephrectomy in Zhongshan Hospital from January 2009 to September 2019. Radius-exophytic/endophytic-nearness-anterior/posterior-location nephrometry scores were assigned by three urologists based on preoperative CT/MRI scans. Correlations between parameters or sum of radius-exophytic/endophytic-nearness-anterior/posterior-location nephrometry scores, overall survival and recurrence-free survival were analysed by Kaplan-Meier analyses and the multivariate Cox regression model. We further compared survival outcomes between patients who received partial nephrectomy and patients who received radical nephrectomy. RESULTS: We observed statistically significant associations between all components of radius-exophytic/endophytic-nearness-anterior/posterior-location nephrometry scores and oncologic outcomes, including R (radius) (overall survival, P < 0.001; recurrence-free survival , P < 0.001), E (exophytic/endophytic) (overall survival, P = 0.003; recurrence-free survival, P < 0.001), N (nearness) (overall survival, P = 0.063; recurrence-free survival, P < 0.001), A (anterior/posterior) (overall survival, P < 0.001; recurrence-free survival, P = 0.005), L (location) (overall survival, P = 0.008; recurrence-free survival, P < 0.001) and suffix 'h' (overall survival, P = 0.237; recurrence-free survival, P = 0.034). Kaplan-Meier curves of overall survival and recurrence-free survival rates were significantly different when stratified by radius-exophytic/endophytic-nearness-anterior/posterior-location nephrometry score complexity group (overall survival, P < 0.001; recurrence-free survival, P < 0.001). After adjusting for tumour stage and grade, radius-exophytic/endophytic-nearness-anterior/posterior-location nephrometry score as continuous variables was an adverse independent risk factor for survival outcomes [P = 0.027, hazard ratio (95% confidence interval) = 1.151 (1.016-1.303)] and recurrence-free survival [P < 0.001, hazard ratio (95% confidence interval) = 1.299 (1.125-1.501)]. For tumours with radius-exophytic/endophytic-nearness-anterior/posterior-location nephrometry scores of 4 and 5, partial nephrectomy showed a survival benefit than radical nephrectomy. CONCLUSION: Both components and complexity groups of the radius-exophytic/endophytic-nearness-anterior/posterior-location nephrometry score are associated with survival outcomes in renal tumour patients.

TL-MSE2-Net: Transfer learning based nested model for cerebrovascular segmentation with aneurysms.

Cerebrovascular (i.e., cerebral vessel) segmentation is essential for diagnosing and treating brain diseases. Convolutional neural network models, such as U-Net, are commonly used for this purpose. Unfortunately, such models may not be entirely satisfactory in dealing with cerebrovascular segmentation with tumors due to the following issues: (1) Relatively small number of clinical datasets from patients obtained through different modalities such as computed tomography (CT) and magnetic resonance imaging (MRI), leading to inadequate training and lack of transferability in the modeling; (2) Insufficient feature extraction caused by less attention to both convolution sizes and cerebral vessel edges. Inspired by the existence of similar features on cerebral vessels between normal subjects and patients, we propose a transfer learning strategy based on a pre-trained nested model called TL-MSE2-Net. This model uses one of the publicly available datasets for cerebrovascular segmentation with aneurysms. To address issue (1), our transfer learning strategy leverages a pre-trained model that uses a large number of datasets from normal subjects, providing a potential solution to the lack of sufficient clinical datasets. To tackle issue (2), we structure the pre-trained model based on 3D U-Net, comprising three blocks: ResMul, DeRes, and REAM. The ResMul and DeRes blocks enhance feature extraction by utilizing multiple convolution sizes to capture multiscale features, and the REAM block increases the weight of the voxels on the edges of the given 3D volume. We evaluated the proposed model on one small private clinical dataset and two publicly available datasets. The experimental results demonstrated that our MSE2-Net framework achieved an average Dice score of 70.81 % and 89.08 % on the two publicly available datasets, outperforming other state-of-the-art methods. Ablation studies were also conducted to validate the effectiveness of each block. The proposed TL-MSE2-Net yielded better results than MSE2-Net on a small private clinical dataset, with increases of 5.52 %, 3.37 %, 6.71 %, and 0.85 % for the Dice score, sensitivity, Jaccard index, and precision, respectively.

Clinical Significance of Preoperative Assessment of Intravesical Prostatic Protrusion in Radical Prostatectomy.

Background: Intravesical prostatic protrusion (IPP) is common in prostate-related diseases, whose clinical significance in radical prostatectomy was unknown. Methods: 791 patients underwent robot-assisted or open radical prostatectomy at our institution were enrolled. The transabdominal ultrasound examination of prostate and IPP was carried out preoperatively, by which IPP was classified as no (0-0.5cm, grade 0), slight (0.6-1.0cm, grade 1) and noticeable (>1.0cm, grade 2). Results: 185 (23.4%), 170 (21.5%) and 436 (55.1%) patients had no, slight and noticeable IPP, respectively. Generally, prostate specific antigen (PSA), Gleason score and pT stage increased with IPP grade. In particular, cases with grade 0 IPP had a decreased proportion of seminal vesicles' involvement than those with grade 1 and grade 2 IPP (p=0.035). Reconstruction of the bladder neck (in robot-assisted group), increased surgical bleeding (>200ml), and prolonged postoperative hospital stays (>14 days) happened more in patients with grade 2 IPP. Blood transfusion only happened in patients with noticeable IPP. PSM of bladder neck was only associated with higher IPP grade in open surgery group (p=0.032), not in robot-assisted surgery group. Conclusion: IPP is associated with cancer aggressiveness, surgery difficulty and PSM of bladder neck in prostate cancer. Assessment of it provides more information for operations.

Nomogram predicting overall prognosis for invasive micropapillary carcinoma of the breast: a SEER-based population study.

OBJECTIVES: The prognosis of invasive micropapillary carcinoma (IMPC) of the breast is determined by many clinicopathological factors. This study aims to identify prognostic factors and develop reliable nomogram to predict the overall survival (OS) in patients with IMPC. DESIGN: Log-rank test and Cox proportional hazards analysis were used to identify variables and construct a nomogram based on the training cohort. C-index and calibration curves were performed to evaluate the performance of the model in the training cohort and validation cohorts. SETTING: We collected the patient data from the Surveillance, Epidemiology and End Results (SEER) database. This database holds data related to the cancer incidence from 18 population-based cancer registries in the USA. PARTICIPANTS: The SEER database was used to screen 754 eligible patients as the study cohort. The whole cohort was randomly divided into a training cohort (n=377) and a validation cohort (n=377). RESULTS: Age at diagnosis, hormone receptors, number of positive regional lymph nodes and clinical stage were independent prognostic factors for patients with IMPC. The calibration curves presented excellent consistency between the actual and nomogram-predict survival probabilities in the training and validation cohorts. The C-index values of the nomogram were 0.794 and 0.774 for OS in the training and validation cohorts, respectively. CONCLUSIONS: The novel nomogram provides new insights of the risk of each prognostic factor and can assist doctors in predicting the 1-year, 3-year and 5-year OS in patients with IMPC.

Comparison and validation of different risk models for papillary renal cell carcinoma.

BACKGROUND: Several prognostic algorithms were specifically or nonspecifically used for papillary renal cell carcinoma (PRCC). No consensus was reached upon their efficacy of discrimination. We aim to compare the stratifying ability of current models or systems in predicting the risk of recurrence of PRCC. METHODS: A PRCC cohort consisting of 308 patients from our institution and 279 patients from The Cancer Genome Atlas (TCGA) was generated. With ISUP grade, TNM classification, UCLA Integrated Staging System (UISS), STAGE, SIZE, GRADE AND NECROSIS (SSIGN), Leibovich model and VENUSS system, recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) were studied using Kaplan-Meier method and concordance index (c-index) was compared. Differences between risk groups in gene mutation and infiltration of inhibitory immune cells were studied with TCGA database. RESULTS: All the algorithms were able to stratify patients in RFS as well as DSS and OS (all P < 0.001). VENUSS score and risk group generally had the highest and balanced c-index (0.815 and 0.797 for RFS). ISUP grade, TNM stage and Leibovich model had the lowest c-indexes in all analysis. Among the 25 most frequently mutated genes in PRCC, eight had different mutation frequency between VENUSS low- and intermediate-/high-risk patients and mutated KMT2D and PBRM1 resulted in worsened RFS (P = 0.053 and P = 0.007). Increased Treg cells in tumors of intermediate-/high- risk patients were also identified. CONCLUSIONS: VENUSS system showed better predictive accuracy in RFS, DSS and OS compared with SSIGN, UISS and Leibovich risk models. VENUSS intermediate-/high-risk patients had increased frequency of mutation in KMT2D and PBRM1 and increased infiltration of Treg cells.

[Role and mechanism of platelet-derived growth factor BB in thrombocytosis in Kawasaki disease]. / è¡€å°æ¿è¡ç”Ÿç”Ÿé•¿å› å­BBåœ¨å·å´Žç— è¡€å°æ¿å¢žå¤šä¸­çš„ä½œç”¨åŠæœºåˆ¶ç ”ç©¶.

OBJECTIVES: To study the role and mechanism of platelet-derived growth factor BB (PDGF-BB) on platelet production in Kawasaki disease (KD) mice and human megakaryocytic Dami cells through in vitro and invivo experiments. METHODS: ELISA was used to measure the expression of PDGF in the serum of 40 children with KD and 40 healthy children. C57BL/6 mice were used to establish a model of KD and were then randomly divided into a normal group, a KD group, and an imatinib group (30 mice in each group). Routine blood test was performed for each group, and the expression of PDGF-BB, megakaryocyte colony forming unit (CFU-MK), and the megakaryocyte marker CD41 were measured. CCK-8, flow cytometry, quantitative real-time PCR, and Western blot were used to analyze the role and mechanism of PDGF-BB in platelet production in Dami cells. RESULTS: PDGF-BB was highly expressed in the serum of KD children (P<0.001). The KD group had a higher expression level of PDGF-BB in serum (P<0.05) and significant increases in the expression of CFU-MK and CD41 (P<0.001), and the imatinib group had significant reductions in the expression of CFU-MK and CD41 (P<0.001). In vitro experiments showed that PDGF-BB promoted Dami cell proliferation, platelet production, mRNA expression of PDGFR-ß, and protein expression of p-Akt (P<0.05). Compared with the PDGF-BB group, the combination group (PDGF-BB 25 ng/mL + imatinib 20 µmol/L) had significantly lower levels of platelet production, mRNA expression of PDGFR-ß, and protein expression of p-Akt (P<0.05). CONCLUSIONS: PDGF-BB may promote megakaryocyte proliferation, differentiation, and platelet production by binding to PDGFR-ß and activating the PI3K/Akt pathway, and the PDGFR-ß inhibitor imatinib can reduce platelet production, which provides a new strategy for the treatment of thrombocytosis in KD.

Computer-assisted rescue of the inferior mesenteric artery in a child with a giant ganglioneuroblastoma: A case report.

BACKGROUND: Ganglioneuroblastoma (GNB) is a peripheral neuroblastoma (NB) with malignant degree between highly malignant NB and benign ganglioma (GN). Pathology is the gold standard of diagnosis. Although GNB is not uncommon in children, biopsy alone may lead to an inaccurate diagnosis, especially for giant tumors. However, surgical resection may be associated with significant complications. Here, we report a case of computer-assisted surgical resection of a giant GNB in a child and successful rescue of the inferior mesenteric artery. CASE SUMMARY: A 4-year-old girl was admitted to our department for a giant retroperitoneal lesion, which was considered to be an NB by her local hospital. The symptoms of the girl disappeared spontaneously without treatment. On physical examination, a mass of about 10 cm × 7 cm could be palpated in her abdomen. Ultrasonography and contrast-enhanced computed tomography performed in our hospital also showed an NB, and there was a very thick blood vessel inside the tumor. However, aspiration biopsy revealed GN. Surgical resection is the best treatment option for this giant benign tumor. For precise preoperative evaluation, three-dimensional reconstruction was performed. It was clear that the tumor was close to the abdominal aorta. The superior mesenteric vein was pushed forward, and the inferior mesenteric artery passed through the tumor. Because GN generally does not invade blood vessels, we split the tumor with a CUSA knife during the operation and found that there was indeed a straight and intact vascular sheath. Arterial pulsation was observed in the completely exposed inferior mesenteric artery. The pathologists interpreting the tissue finally diagnosed it as a mixed GNB (GNBi), which is more malignant than GN. However, both GN and GNBi usually have a good prognosis. CONCLUSION: This was a case of successful surgical resection of a giant GNB, and aspiration biopsy underestimated the pathological staging of the tumor. Preoperative three-dimensional reconstruction assisted with the radical resection of the tumor and rescue of the inferior mesenteric artery.

Performance of Artificial Intelligence-Aided Diagnosis System for Clinically Significant Prostate Cancer with MRI: A Diagnostic Comparison Study.

BACKGROUND: The high level of expertise required for accurate interpretation of prostate MRI. PURPOSE: To develop and test an artificial intelligence (AI) system for diagnosis of clinically significant prostate cancer (CsPC) with MRI. STUDY TYPE: Retrospective. SUBJECTS: One thousand two hundred thirty patients from derivation cohort between Jan 2012 and Oct 2019, and 169 patients from a publicly available data (U-Net: 423 for training/validation and 49 for test and TrumpeNet: 820 for training/validation and 579 for test). FIELD STRENGTH/SEQUENCE: 3.0T/scanners, T2 -weighted imaging (T2 WI), diffusion-weighted imaging, and apparent diffusion coefficient map. ASSESSMENT: Close-loop AI system was trained with an Unet for prostate segmentation and a TrumpetNet for CsPC detection. Performance of AI was tested in 410 internal and 169 external sets against 24 radiologists categorizing into junior, general and subspecialist group. Gleason score >6 was identified as CsPC at pathology. STATISTICAL TESTS: Area under the receiver operating characteristic curve (AUC-ROC); Delong test; Meta-regression I2 analysis. RESULTS: In average, for internal test, AI had lower AUC-ROC than subspecialists (0.85 vs. 0.92, P < 0.05), and was comparable to junior (0.84, P = 0.76) and general group (0.86, P = 0.35). For external test, both AI (0.86) and subspecialist (0.86) had higher AUC than junior (0.80, P < 0.05) and general reader (0.83, P < 0.05). In individual, it revealed moderate diagnostic heterogeneity in 24 readers (Mantel-Haenszel I2  = 56.8%, P < 0.01), and AI outperformed 54.2% (13/24) of readers in summary ROC analysis. In multivariate test, Gleason score, zonal location, PI-RADS score and lesion size significantly impacted the accuracy of AI; while effect of data source, MR device and parameter settings on AI performance is insignificant (P > 0.05). DATA CONCLUSION: Our AI system can match and to some case exceed clinicians for the diagnosis of CsPC with prostate MRI. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Simulated weightlessness led to the transformation of glycolipid metabolism in the livers of mice / La antigravedad simulada provocó la transformación del metabolismo de los glicolípidos en el hígado de ratones / Antigravidade simulada levou à transformação do metabolismo de glicolipídios no fígado de camundongos

ABSTRACT Objectives: The effects of weightlessness on the liver were studied using a tail suspension (TS) male mouse model. Methods: The effects of 0-, 2- and 4-week TS (CON, TS2 and TS4 groups) on glycogen and lipid content, as well as on the molecular processes of the synthesis and degradation pathways, were examined. Results: (1) The number of glycogenosomes under ultrastructure and the glycogen content were considerably larger in the TS4 group than in the other two groups. (2) In the TS4 group, glycogen synthase activity remained constant while glycogen phosphorylase activity dropped, indicating that glycogen breakdown was reduced. (3) The livers of the TS2 group had the highest lipid and triglyceride content, indicating lipid buildup in the liver at this time. (4) In the TS2 group, the activities of the fatty acid synthesis-related factors acetyl-CoA carboxylase and fatty acid synthase increased, while hepatic lipase decreased, indicating that lipid synthesis increased, while decomposition decreased. (5) In the TS2 group, the protein expression of glucose transporters 1 and 2 increased. Conclusions: From TS2 weeks to TS4 weeks, the main energy consumption mode in the livers of mice transitioned from glucose metabolism to lipid metabolism as glucose use decreased. Level of evidence II; Comparative prospective study.

RESUMEN Objetivos: Se estudiaron los efectos de la antigravedad en el hígado utilizando un modelo de ratón macho en prueba de suspensión de la cola (TS, tail suspension). Métodos: Se examinaron los efectos de la TS a las 0, 2 y 4 semanas (grupos CON, TS2 y TS4) sobre el contenido de glucógeno y lípidos, así como sobre los procesos moleculares de las vías de síntesis y degradación. Resultados: (1) El número de glucogenosomas ultraestructurales y el contenido de glucógeno fueron expresivamente más altos en el grupo TS4 que en los otros dos grupos. (2) En el grupo TS4, la actividad de la glucógeno sintasa se mantuvo constante, mientras que la actividad de la glucógeno fosforilasa disminuyó, lo que indica que la degradación del glucógeno se redujo. (3) Los hígados del grupo TS2 presentaron el mayor contenido de lípidos y triglicéridos, lo que indica la acumulación de lípidos en el hígado en ese momento. (4) En el grupo TS2, la actividad de los factores relacionados con la síntesis de ácidos grasos acetil-CoA carboxilasa y ácido graso sintasa aumentó, mientras que la lipasa hepática disminuyó, indicando que la síntesis de lípidos aumentó mientras que la descomposición disminuyó. (5) En el grupo TS2, la expresión proteica de los transportadores de glucosa 1 y 2 aumentó. Conclusiones: Desde la semana TS2 hasta la semana TS4, el principal modo de consumo de energía en el hígado de los ratones pasó del metabolismo de la glucosa al metabolismo de los lípidos a medida que disminuía el uso de la glucosa. Nivel de Evidencia II, Estudio retrospectivo comparativo.

RESUMO Objetivos: Os efeitos da antigravidade no fígado foram estudados usando um modelo de camundongo macho com a suspensão pela cauda (TS, tail suspension). Métodos: Foram examinados os efeitos da TS em 0, 2 e 4 semanas (grupos CON, TS2 e TS4) sobre o conteúdo de glicogênio e lipídios, bem como nos processos moleculares das vias de síntese e degradação. Resultados: (1) O número de glicogenossomos ultraestruturais e o teor de glicogênio foram expressivamente maiores no grupo TS4 do que nos outros dois grupos. (2) No grupo TS4, a atividade de glicogênio sintase permaneceu constante, enquanto a atividade de glicogênio fosforilase caiu, indicando que a degradação do glicogênio foi reduzida. (3) Os fígados do grupo TS2 tiveram o maior teor lipídico e de triglicérides, indicando acúmulo de lipídios no fígado no momento. (4) No grupo TS2, a atividade dos fatores relacionados com a síntese de ácidos graxos acetil-CoA carboxilase e ácido graxo sintase aumentaram, enquanto a lipase hepática diminuiu, indicando que a síntese de lipídios aumentou, enquanto a decomposição diminuiu. (5) No grupo TS2, a expressão proteica dos transportadores de glicose 1 e 2 aumentou. Conclusões: De TS2 semanas para TS4 semanas, o principal modo de consumo de energia no fígado de camundongos passou do metabolismo da glicose para o metabolismo lipídico, à medida que o uso de glicose diminuiu. Nível de evidência II, Estudo retrospectivo comparativo.

Effects of Soil Properties on Pb, Cd, and Cu Contents in Tobacco Leaves of Longyan, China, and Their Prediction Models.

Longyan City in Fujian Province is one of China's top-quality tobacco-producing areas and plays an essential role in local economic development. To determine the correlation between heavy metal content in tobacco leaves and soil factors, soil physical and chemical properties and heavy metal contents of lead, cadmium, and copper in tobacco leaves were measured and analyzed by the correlation regression method. The content of lead, cadmium, and copper in soil was determined using hydrochloric acid extraction-AAS and graphite furnace atomic absorption spectrometry. Inductively coupled plasma-mass spectrometry was used to determine heavy metal in tobacco leaf. The findings revealed that the average concentrations of lead, cadmium, and copper in the soil were 12.1, 0.092, and 3.88 mg/kg, respectively. In contrast, the average levels of lead, cadmium, and copper in tobacco leaves were 2.33, 4.89, and 4.35 mg/kg, respectively. The cadmium enrichment coefficient of 54.3 was higher than lead and copper, indicating a greater health risk. Soil pH value was negatively correlated with lead content in tobacco leaf, while potassium and phosphorus nutrient levels were negatively correlated with copper content. In contrast, a positive correlation was established between the presence of organic matter with cadmium content in tobacco leaves. The prediction models of lead, cadmium, and copper in tobacco leaves can be expressed by the regression equation corresponding to each heavy metal as follows: YPb=2.33 - 0.005∗ XK+0.007∗XN - 0.271∗XpH+0.065∗XPb (R2 = 0.787), YCd=1.55+0.012∗XOM - 0.014∗XCu+34.6∗XCd (R2 = 0.891), and YCu=4.64 - 0.029∗XP - 0.007∗XK+0.245∗XCu (R2 = 0.724), respectively. The prediction models above provide an effective predictive tool for assessing heavy metal risk in tobacco leaves using soil properties in the study area.

[Clinical and gastroscopic features of children with cyclic vomiting syndrome: an analysis of 63 cases]. / 儿童周期性呕吐综合征63例临床与胃镜分析.

OBJECTIVES: To study the clinical and gastroscopic features of children with cyclic vomiting syndrome. METHODS: A retrospective analysis was performed on the medical data of 63 children with cyclic vomiting syndrome who were hospitalized and followed up in Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University from August 2019 to March 2022. RESULTS: Among the 63 children, there were 30 boys and 33 girls, with a mean age of 6.11 years, a mean course of disease of 2.57 years, and a mean vomiting period of 4.04 days. The most common accompanying symptom was listlessness or somnolence (55/63, 87%), followed by anorexia (45/63, 71%), abdominal pain or abdominal discomfort (40/63, 63%), constipation (19/63, 30%), salivation (12/63, 19%), nausea (11/63, 17%), headache (11/63, 17%), fever (6/63, 10%), and rash (1/63, 2%). All 63 children underwent gastroscopy, among whom 3 had no marked abnormalities, 22 (35%) had chronic superficial gastritis or chronic non-atrophic gastritis alone, and 38 (60%) had other abnormal changes aside from chronic gastritis (16 children with reflux esophagitis, 12 with bile reflux gastritis, 13 with duodenitis, 10 with erosive gastritis, and 5 with gastric or duodenal ulcer). Among the 63 children, 42 underwent pathological examinations of gastric mucosa, among whom 5 had no marked abnormalities, 34 had mild chronic gastritis, 2 had moderate chronic gastritis, and 1 had severe chronic gastritis. Among the 63 children, 15 received 24-hour dynamic esophageal pH monitoring during the interictal period, among whom 9 children were found to have pathological acid reflux. CONCLUSIONS: In addition to recurrent vomiting, most children with cyclic vomiting syndrome also have the symptoms such as somnolence or listlessness, anorexia, and abdominal pain. The main manifestation on gastroscopy is chronic gastritis, and most children may also have reflux esophagitis, bile reflux gastritis, and erosive gastritis. Mild chronic gastritis is the main pathological change of gastric mucosa.

Unexpected assembly machinery for 4(3H)-quinazolinone scaffold synthesis.

4(3H)-quinazolinone is the core scaffold in more than 200 natural alkaloids and numerous drugs. Many chemosynthetic methodologies have been developed to generate it; however, investigation of its native enzymatic formation mechanism in fungi has been largely limited to fumiquinazolines, where the two nitrogen atoms come from anthranilate (N-1) and the α-NH2 of amino acids (N-3). Here, via biochemical investigation of the chrysogine pathway, unexpected assembly machinery for 4(3H)-quinazolinone is unveiled, which involves a fungal two-module nonribosomal peptide synthase ftChyA with an unusual terminal condensation domain catalysing tripeptide formation; reveals that N-3 originates from the inorganic ammonium ions or the amide of L-Gln; demonstrates an unusual α-ketoglutarate-dependent dioxygenase ftChyM catalysis of the C-N bond oxidative cleavage of a tripeptide to form a dipeptide. Our study uncovers a unique release and tailoring mechanism for nonribosomal peptides and an alternative route for the synthesis of 4(3H)-quinazolinone scaffolds.

Postoperative Curative Effect of Cardiac Surgery Diagnosed by Compressed Sensing Algorithm-Based E-Health CT Image Information and Effect of Baduanjin Exercise on Cardiac Autonomic Nerve Function of Patients.

This research was aimed at exploring the effect of CT images reconstructed by optimized compressed sensing algorithm on postoperative diagnosis of patients with hypertensive heart disease and the influence of Baduanjin on cardiac autonomic nerve function. Based on the compressed sensing algorithm, the maximum likelihood expectation maximization algorithm was introduced to optimize it, and the optimization algorithm was established. The optimized algorithm and filtered back projection algorithm (FBP) were compared regarding the root mean squared error (RMSE), peak signal-to-noise ratio (PSNR), and structural similar image metric (SSIM). A total of 126 patients with hypertensive heart disease who underwent CT examination in the hospital were selected as study subjects. According to whether Baduanjin intervention was adopted, patients were divided into observation group (conventional treatment +Baduanjin) and control group (conventional treatment), with 63 patients in each group. The effect of CT examination on postoperative diagnosis was analyzed. Systolic blood pressure (SBP), diastolic blood pressure (DBP), differential pressure (DP), respiratory rate and heart rate (HR), very low-frequency (VLF) power, low-frequency (LF) power, high-frequency (HF) power, total power (TP) of HR variability, and changes in LF/HF of patients before and after treatment were compared. The RMSE of the compressed sensing optimization algorithm (3.28 ± 0.36) was significantly lower than that of the FBP algorithm (9.25 ± 1.03) (P < 0.05). The SSIM and PNSR of the compressed sensing optimization algorithm were (0.87 ± 0.10) and (21.22 ± 1.60) dB, respectively. The SSIM was significantly higher than the FBP algorithm (P < 0.01), and the PNSR was also higher than the FBP algorithm (P < 0.05). The detection rate of CT for pleural effusion was 16 cases (25.40%) higher than 5 cases (7.94%) with TTE (P < 0.01). After treatment, SBP, DBP, HR, LF, VLF, LF/HF, and DP values in the observation group were lower than those in the control group (P < 0.05), and TP and HF were higher than those in the control group (P < 0.05). It suggested that a novel algorithm was established based on compressed sensing algorithm to improve image quality. CT image had important guiding significance for postoperative diagnosis of heart. Baduanjin intervention could improve the integrated function of patient's autonomic nervous system and the regulation ability of the vagus nerve.

Combined Cyclin-Dependent Kinase Inhibition Overcomes MAPK/Extracellular Signal-Regulated Kinase Kinase Inhibitor Resistance in Plexiform Neurofibroma of Neurofibromatosis Type I.

MAPK/extracellular signal-regulated kinase kinase (MEK) 1/2 inhibitors (MEKis) have recently achieved surprising success in treating unresectable plexiform neurofibromas (PNFs). However, few studies have investigated the mechanisms of MEKi resistance in patients with PNF. We determined the efficacy of six different MEKis for treating PNFs, explored drug resistance mechanisms, and identified potential combination therapies to overcome resistance. By screening drug efficacy among six MEKis in human NF1-deficient PNF cell lines, TAK-733 was found to reduce PNF cell viability the most. We then cultured the TAK-733‒resistant cells and explored the potential targets for further treatment. Both high-throughput drug screening and RNA sequencing analyses of MEKi-resistant PNF cells identified cyclin-dependent kinase inhibitors as potential agents for PNFs. Dinaciclib, a cyclin-dependent kinase inhibitor, showed synergistic effects on MEKi-resistant cells. Coadministration of dinaciclib and TAK-733 significantly reduced cell viability and inhibited sphere formation and colony formation. Dinaciclib did not affect MEK signaling but decreased the expression of several prosurvival proteins, including survivin and cyclin-dependent kinase 1, to induce apoptosis and inhibit mitosis. TAK-733/dinaciclib combination therapy induced tumor reduction in PNF patient‒derived xenografts mouse models. Therefore, the combination of MEKi and cyclin-dependent kinase inhibitor may be promising for treating inoperable PNFs, especially when drug resistance exists. Our findings provide evidence for future clinical trials with MEKi-resistant patients with PNF.

Combination of Tumor Mutational Burden and Specific Gene Mutations Stratifies Outcome to Immunotherapy Across Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma.

Purpose: To investigate the prognostic significance of tumor mutational burden (TMB) combined with specific prognosis-related gene mutations in immunotherapy for recurrent and metastatic head and neck squamous cell carcinoma (r/m HNSCC). Methods: One hundred thirty-two r/m HNSCC patients from the Morris and Allen cohorts had undergone immunotherapy. We constructed the immunotherapy-related gene prognostic index TP-PR combining TMB and PIK3CA, TP53, or ROS1 mutation. And we analyzed the differences in overall survival (OS) and immune cell infiltration between samples in different groups. The association of each signature's single-sample gene set enrichment analysis scores with TP-PR was tested using Spearman's correlation test. Results: The median OS of the patients with high TMB (TMB ≥10 mut/Mb) who received immunotherapy for r/m HNSCC was 2.5 times as long as that of the patients with low TMB (25 vs. 10 months). More importantly, the high TP-PR (TP-PR >0) group had better median OS (25 vs. 8 months) than the low TP-PR (TP-PR ≤0) group. CD8+ T cells and activated memory CD4+ T cells in the tissues of the patients with high TP-PR were higher than those in the patients with low TP-PR. Results showed that TP-PR stratification had a higher area under the curve (AUC) value (0.77, 95% CI 0.86-0.68) compared with TMB stratification (0.56, 95% CI 0.68-0.44). The differential gene expression in the high and low TP-PR groups mainly influenced metabolism-related signaling pathways. Conclusion: TP-PR was an effective predictor of immunotherapy outcome for r/m HNSCC, which might be better than TMB alone. Patients with high TP-PR had a better survival benefit than had the patients with low TP-PR.

Pathological and genomic phenotype of second neuroendocrine carcinoma during long-term follow-up after radical radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: Second head and neck neuroendocrine carcinoma (NEC) after radical radiotherapy for nasopharyngeal carcinoma (NPC) treatment is rarely reported. The prognosis of second cancer is poor, and our research focuses on finding a breakthrough in the treatment. In this study, we aimed to investigate clinicopathological characteristics and to identify the genomic landscape of second head and neck NECs. METHODS: We collected five second head and neck NEC cases in the recent three years from our patient database. Clinicopathological data and images were obtained. Genomic analysis was performed using high-throughput second generation sequencing. KEGG pathway enrichment analyses between high-frequency mutations were performed using the STRING database. RESULTS: All patients had been diagnosed with second NEC, according to the pathological observations. The interval between diagnosis of NPC and NEC ranged from 10 to 18 years. Two patients had brain or liver metastasis at three and nine months, respectively, after the diagnosis of NEC. Three patients died of the disease with the overall survival time ranging from three to nine months. Commonly altered genes (50%) in second head and neck NECs included TP53, RB1, NOTCH2, PTEN, POLG, KMT2C, U2AF1, EPPK1, ELAC2, DAXX, COL22A1, and ABL1. Those genetic lesions might affect p53 signaling, MAPK signaling, PI3K-Akt signaling, sphingolipid signaling, and neurotrophin signaling pathways. CONCLUSIONS: Second head and neck NECs had poor prognosis. We revealed, for the first time, the mutational landscape, high-frequency somatic mutations, and potential signaling pathways of second head and neck NECs. Its optimal treatment model needs to be further studied in future clinical trials.

Impacts of NF1 Gene Mutations and Genetic Modifiers in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a tumor predisposition genetic disorder that directly affects more than 1 in 3,000 individuals worldwide. It results from mutations of the NF1 gene and shows almost complete penetrance. NF1 patients show high phenotypic variabilities, including cafe-au-lait macules, freckling, or other neoplastic or non-neoplastic features. Understanding the underlying mechanisms of the diversities of clinical symptoms might contribute to the development of personalized healthcare for NF1 patients. Currently, studies have shown that the different types of mutations in the NF1 gene might correlate with this phenomenon. In addition, genetic modifiers are responsible for the different clinical features. In this review, we summarize different genetic mutations of the NF1 gene and related genetic modifiers. More importantly, we focus on the genotype-phenotype correlation. This review suggests a novel aspect to explain the underlying mechanisms of phenotypic heterogeneity of NF1 and provides suggestions for possible novel therapeutic targets to prevent or delay the onset and development of different manifestations of NF1.

Analysis of Glomerular IgG Subclasses Switch in Idiopathic Membranous Nephropathy Classified by Glomerular Phospholipase A2 Receptor Antigen and Serum Antibody.

BACKGROUND: The role of IgG subclass in idiopathic membranous nephropathy (IMN) was unclarified. Recent study found IgG subtype switches from IgG1 to IgG4 in the early pathological stage in IMN. The profile of IgG subclass in phospholipase A2 receptor- (PLA2R-) related and PLA2R-unrelated IMN was unrevealed. Our study is aimed at testifying whether IgG subclass switch existed in PLA2R-related and PLA2R-unrelated IMN, respectively. METHODS: Our study retrospectively enrolled 157 Chinese patients with biopsy-confirmed IMN between September 2017 and November 2019. We measured glomerular PLA2R antigen and serum anti-PLA2R antibody to classify the patients into PLA2R-related (n = 132) and PLA2R-unrelated (n = 25) subgroup. We evaluated glomerular IgG subclass by immunofluorescence (IF) predominance. Our study defined IgG subclass deposition as predominant if the IF score was higher than the other three and ≥1 +, or as codominant if the IF intensity was equal to any other and ≥1 +. We explored the relationship between IF predominance of glomerular IgG subtype and electron microscopic (EM) stages of IMN. RESULTS: We did not find statistical difference of predominant or codominant rate (pre/co-rate) among EM stages in any subclass (P > 0.05). Pre/co-rate of IgG3 linearly associated with EM stage in total and PLA2R-related subgroup (P = 0.044, P = 0.013). PLA2R-related subgroup showed higher IgG4 intensity (2.1 ± 0.6 vs. 1.6 ± 0.7, P = 0.001) and pre/co-rate of IgG4 in stage 1 (97% vs. 57%, P = 0.015) than PLA2R-unrelated group. We found no difference of IgG subclass pre/co-rate in different EM stages or linear association between pre/co-rate of IgG1, IgG2, IgG4, and EM stages (P > 0.05). CONCLUSIONS: Pre/co-rate of IgG3 declined with EM stage in total and PLA2R-related subgroup. We did not find IgG subclass switches from IgG1 to IgG4 in either IMN patients or subgroups.

Genetic Features of Plasmid- and Chromosome-Mediated mcr-1 in Escherichia coli Isolates From Animal Organs With Lesions.

The genomic context of the mcr-1 gene in Escherichia coli from animal feces has been widely reported. However, less is known about the mcr-1-carrying plasmid characteristics and other functional regions of Escherichia coli isolates from animal organs with lesions. The present study investigated the antimicrobial resistance, population structure, and genetic features of mcr-1-positive Escherichia coli strains isolated from animal organs with lesions. The antimicrobial susceptibility testing indicated that 24 mcr-1-positive Escherichia coli isolates were resistant to at least three or all antimicrobial categories. MLST analysis suggested that the dominant clone complexes (CC) were mainly CC156, CC448, and CC10. In addition, ST10596, a newly discovered sequence type in swine, failed to be classified. Meanwhile, the mcr-1 gene located on the different plasmids was successfully transferred to the recipients, and whole-genome sequencing indicated the mcr-1 gene was embedded in mcr-1-pap2 cassette but not flanked by ISApl1. The mcr-1 gene is located on the chromosome and embedded in Tn6330. Furthermore, NDM-5 was found on the IncX3-type plasmid of J-8. The virB6 and traI gene of type IV secretion system (T4SS) were truncated by IS2 and IS100 and located on the IncX4- and the IncHI2/HI2A/N-type plasmids, respectively. The multidrug-resistant (MDR) region of IncHI2/HI2A/N-type plasmids contained two class 1 integrons (In0, In640) and four composite transposons (Tn4352, Tn6010, cn_4692_IS26, cn_6354_IS26). Overall, 24 mcr-1-positive Escherichia coli isolates in our study showed MDR, or even extensively drug resistant (XDR), and exhibited population diversity. The T4SS gene truncation by the insertion sequence may affect the efficiency of plasmid conjugative transfer. Furthermore, the class 1 integrons and composite transposons in the MDR region of IncHI2/HI2A/n-type plasmid contributed to the multireplicon plasmid formation, the acquisition, and transfer of antimicrobial resistance genes (ARGs).