Tumor and peritumor radiomics analysis based on contrast-enhanced CT for predicting early and late recurrence of hepatocellular carcinoma after liver resection.

BACKGROUND: In China, liver resection has been proven to be one of the most important strategies for hepatocellular carcinoma patients, but the recurrence rate is high. This study sought to investigate the prognostic value of pretreatment tumor and peritumor contrast-enhanced CT radiomics features for early and late recurrence of BCLC stage 0-B hepatocellular carcinoma after liver resection. METHODS: This study involved 329 hepatocellular carcinoma patients after liver resection. A radiomics model was built by using Lasso-Cox regression model. Association between radiomics model and recurrence-free survival was explored by using Harrell's concordance index (C-Index) and receiver operating characteristic (ROC) curves. Then, we combined the radiomics model and clinical factors to establish a nomogram whose calibration and discriminatory ability were revealed. RESULTS: Ten significant tumor and peritumor features were screened to build the radiomics model whose C-indices were 0.743 [95% CI, 0.707 to 0.778] and 0.69 [95% CI, 0.629 to 0.751] in the training and validation cohorts. Moreover, the discriminative accuracy of the radiomics model improved with peritumor features entry. The C-indices of the combined model were 0.773 [95% CI, 0.739 to 0.806] and 0.727 [95% CI, 0.667 to 0.787] in the training and validation cohorts, outperforming the radiomics model. CONCLUSIONS: The tumor and peritumor contrast-enhanced CT radiomic signature is a quantitative imaging biomarker that could improve the prediction of early and late recurrence after liver resection for hepatocellular carcinoma patients when used in addition to clinical predictors.

MiR-1246 regulates the PI3K/AKT signaling pathway by targeting PIK3AP1 and inhibits thyroid cancer cell proliferation and tumor growth.

One of the most prevalent forms of endocrine malignancies is thyroid cancer. Herein, we explored the mechanisms whereby miR-1246 is involved in thyroid cancer. Phosphoinositide 3-kinase adapter protein 1 (PIK3AP1) was identified as a potential miR-1246 target, with the online Gene Expression Omnibus (GEO) database. The binding between miR-1246 and PIK3AP1 and the dynamic role of these two molecules in downstream PI3K/AKT signaling were evaluated. Analysis of GEO data demonstrated significant miR-1246 downregulation in thyroid cancer, and we confirmed that overexpression of miR-1246 can inhibit migratory, invasive, and proliferative activity in vitro and tumor growth in vivo. Subsequent studies indicated that miR-1246 overexpression decreased the protein level of PIK3AP1 and the phosphorylation of PI3K and AKT, which were reversed by PIK3AP1 overexpression. At the same time, overexpression of PIK3AP1 also reversed the miR-1246 mimics-induced inhibition proliferative, migratory, and invasive activity, while promoting increases in apoptotic death, confirming that miR-1246 function was negatively correlated with that of PIK3AP1. Subsequently, we found that the miR-1246 mimics-induced inhibition of PI3K/AKT phosphorylation was reversed by the PI3K/AKT activator IGF-1. miR-1246 mimics inhibited proliferative, migratory, and invasive activity while promoting increases in apoptotic death, which were reversed by IGF-1. Furthermore, miR-1246 agomir can inhibit tumor growth in vivo. We confirmed that miR-1246 affects the signaling pathway of PI3K/AKT via targeting PIK3AP1 and inhibits the development of thyroid cancer. Thus, miR-1246 is a new therapeutic target for thyroid cancer.

Brachytherapy with Iodine-125 seeds for treatment of portal vein-branch tumor thrombus in patients with hepatocellular carcinoma.

BACKGROUND: There is currently no widely-accepted consensus for the management of hepatocellular carcinoma with portal vein tumor thrombus. We evaluate the safety and efficacy of ultrasound-guided percutaneous brachytherapy with iodine-125 seeds for the treatment of hepatocellular carcinoma with portal vein-branch tumor thrombus (PVBTT). METHODS: Sixty-nine hepatocellular carcinoma patients with PVBTT were enrolled; 34 received transarterial chemoembolization (TACE) combined with iodine-125 seeds implanted in the PVBTT; 35 were treated with TACE alone. Adverse events, objective response rate, disease control rate, progression-free survival, and overall survival were compared between the two groups. Tumor responses of PVBTT and intrahepatic tumor were correlated. Multivariate and subgroup analyses were conducted for overall survival. RESULTS: No grade 3 or 4 adverse events were recorded, and there was no difference in grade 1 or 2 adverse events between the two groups. Objective response rate and disease control rate for PVBTT were 58.9 and 91.2%, respectively, in the combined treatment group, which were significantly greater than the 5.7 and 54.3% rates, respectively, in the TACE-alone group (both p's ≤ 0.001). Intrahepatic tumor response was positively correlated with the PVBTT response (γ = 0.782, p < 0.01). Survival outcomes were better in the combined treatment group than in the TACE-alone group: the median progression-free survival for PVBTT was 9 months versus 3 months (HR = 0.187 [95% CI: 0.101, 0.345], p < 0.001), and the median overall survival was 11 months versus 7 months (HR = 0.448 [95% CI: 0.265, 0.758], p = 0.003). Multivariate analysis revealed that application of brachytherapy and lower grade PVBTT (Vp1 + Vp2 vs. Vp3) were protective predictors of overall survival. In stratified analysis, the benefit of overall survival was more significant in the subgroup of PVBTT Vp1 + Vp2 rather than in Vp3. CONCLUSIONS: The combination of iodine-125 seed brachytherapy guided by ultrasound and TACE is a convenient, safe, and effective treatment for patients with HCC and PVBTT, conferring a better survival benefit than TACE alone.

Transcriptome-based analysis of key functional genes in the triterpenoid saponin synthesis pathway of Platycodon grandiflorum.

BACKGROUND: Platycodon grandiflorum (P. grandiflorum) is a commonly used medicinal plant in China. Transcriptome sequencing studies of different tissues of P. grandiflorum have been widely conducted. However, studies on transcriptome sequencing and expression patterns of key genes in the saponin synthesis pathway of Tongcheng P. grandiflorum, a high-quality medicinal resource of different years, are relatively limited. RESULTS: This study involved transcriptome sequencing and bioinformatics analysis of the roots from annual, biennial, and triennial P. grandiflorum in the Tongcheng area. After data filtering and assembly, we obtained 111.44 Gb of clean base data, including 742,880616 clean reads. We identified 5,156 differential expression unigenes between at least two sample groups, with differences noted among annual, biennial, and triennial P. grandiflorum plants. GO enrichment analysis annotated 3509, 1819, and 1393 DEGs in comparison TC1vsTC2, TC1vsTC3, and TC2vsTC3, respectively. Furthermore, KEGG enrichment analysis identified 16 genes encoding key enzymes in the terpene skeleton biosynthesis, sesquiterpene and triterpene biosynthesis pathways, including SE, AACT, FPPS, DXR, HMGR, HMGS, and DXS. The results of qRT-PCR experiments showed that most of the genes were most highly expressed in annual P. grandiflorum. CONCLUSIONS: The present study provided transcriptomic data from the roots of Tongcheng P. grandiflorum of different years, which provides critical bioinformatics data on the growth and development of P. grandiflorum, laying a foundation for further research on saponins and identifying key enzymes involved in this process across different growth stages.

Characterization of two phosphatase 2C domain-containing proteins PPM2A and PPM2B in Toxoplasma gondii.

Protein phosphatases Mg2+/Mn2+ dependent (PPMs), serine/threonine phosphatases, are widely distributed in apicomplexan parasites, and Toxoplasma gondii possesses the largest number of PPMs in the apicomplexan parasites. Though the function of some PPMs has been characterized in T. gondii, much less is known about two phosphatase 2C domain-containing proteins, PPM2A and PPM2B. PPM2A was identified as one of Toxoplasma Calmodulin's interacting proteins through proximity-based protein interaction BioID technology in the previous study, and PPM2B was the homolog of PPM2A in T. gondii. In this study, PPM2A was distributed in the whole tachyzoite of T. gondii, and PPM2B was mainly distributed in the cytoplasm by inserting a 10HA tag in the C-terminus of the two genes in the RH∆ku80 strain. PPM2A knockout (Δppm2a), PPM2B knockout (Δppm2b), and double knockout (ΔΔ) in RHΔhxgprt type I strain under CRISPR-Cas9 system did not result in intracellular replication defect. Besides, mouse experiments demonstrated that PPM2A, PPM2B, and double knockout did not reduce the pathogenicity of T. gondii compared with the RH∆hxgprt strain. However, the plaque size of these single knockout and double knockout strains were smaller than that in the control RH∆hxgprt strain. Our results provide new insight into the function of PPMs in the pathogenesis of T. gondii.

Comparative metabolic profiling of the mycelium and fermentation broth of Penicillium restrictum from Peucedanum praeruptorum rhizosphere.

Microorganisms in the rhizosphere, particularly arbuscular mycorrhiza, have a broad symbiotic relationship with their host plants. One of the major fungi isolated from the rhizosphere of Peucedanum praeruptorum is Penicillium restrictum. The relationship between the metabolites of P. restrictum and the root exudates of P. praeruptorum is being investigated. The accumulation of metabolites in the mycelium and fermentation broth of P. restrictum was analysed over different fermentation periods. Non-targeted metabolomics was used to compare the differences in intracellular and extracellular metabolites over six periods. There were significant differences in the content and types of mycelial metabolites during the incubation. Marmesin, an important intermediate in the biosynthesis of coumarins, was found in the highest amount on the fourth day of incubation. The differential metabolites were screened to obtain 799 intracellular and 468 extracellular differential metabolites. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the highly enriched extracellular metabolic pathways were alanine, aspartate and glutamate metabolism, glyoxylate and dicarboxylate metabolism, and terpenoid backbone biosynthesis. In addition, the enrichment analysis associated with intracellular and extracellular ATP-binding cassette transporter proteins revealed that some ATP-binding cassette transporters may be involved in the transportation of certain amino acids and carbohydrates. Our results provide some theoretical basis for the regulatory mechanisms between the rhizosphere and the host plant and pave the way for the heterologous production of furanocoumarin.

Trigeminal nerve stimulation for prolonged disorders of consciousness: A randomized double-blind sham-controlled study.

BACKGROUND: Trigeminal nerve stimulation (TNS) has been proposed as a promising intervention for coma awakening. However, the effect of TNS on patients with prolonged disorders of consciousness (pDoC) is still unclear. OBJECTIVE: This study aimed to investigate the therapeutic effects of TNS in pDoC caused by stroke, trauma, and anoxia. METHODS: A total of 60 patients (male =25, female =35) aged over 18 who were in a vegetative state or minimally conscious state were randomly assigned to the TNS (N = 30) or sham TNS (N = 30) groups. 4 weeks of intervention and a followed up for 8 weeks were performed. The Glasgow Coma Scale (GCS) and Coma Recovery Scale-Revised (CRS-R) scores as primary outcomes were assessed at baseline and at 2, 4, 8, and 12 weeks. RESULTS: The score changes in the TNS group over time for CRS-R (2-week: mean difference = 0.9, 95% CI = [0.3, 1.5], P = 0.006; 4-week: 1.6, 95% CI = [0.8, 2.5], P < 0.001; 8-week: mean difference = 2.4, 95% CI = [1.3, 3.5], P < 0.001; 12-week: mean difference = 2.3, 95% CI = [1.1, 3.4], P < 0.001) and GCS (4-week: mean difference = 0.7, 95% CI = [0.3, 1.2], P = 0.002; 8-week: mean difference = 1.1, 95% CI = [0.6, 1.7], P < 0.001; 12-week: 1.1, 95% CI = [0.5, 1.7], P = 0.003) were higher than those in the sham group. 18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) revealed that the metabolism of the right parahippocampal cortex, right precuneus, and bilateral middle cingulate cortex was significantly increased in TNS group. CONCLUSION: The results of this study indicate that TNS could increase local brain metabolism and may promote functional recovery in patients with prolonged disorders of consciousness. REGISTRATION INFORMATION: Name of the registry: Chinese Clinical Trial Registry. REGISTRATION NUMBER: ChiCTR1900025573. The date that the study was submitted to a registry: 2019-09-01. The date when the first patient was enrolled was 2021-01-20.

Quality of life evaluation in juveniles with disorders of sexual development.

PURPOSE: To evaluate the quality of life of 6-11-year-old children and 12-17-year-old adolescents with disorders of sexual development (DSDs) following reparative surgery. METHODS: Fifty pediatric patients with DSDs, including 32 cases of congenital adrenal hyperplasia, 2 cases of complete androgen insensitivity syndrome, 1 case of partial androgen insensitivity syndrome, 6 cases of complete testicular dysgenesis, 7 cases of partial testicular dysgenesis, and 2 cases of ovotesticular DSD, with complete follow-up data, were recruited. Healthy control subjects (matched for age, gender, and living environment) served as controls. Physical, socio-emotional, and psychological evaluations were performed. RESULT: Among 50 patients, eight boys and two girls (designated by social gender) were unsatisfied with the morphology of their external genitalia. Social limitations were observed in 4/8 (50 %) of the boys and in 12/42 (28.6 %) of the girls. Psychological problems were significantly more prevalent in the DSD group than in the control group (p < 0.05). CONCLUSIONS: The quality of life of pediatric patients with DSDs was impaired to varying degrees following reparative surgery.

Prognostic Value of Pre-Treatment CT Radiomics and Clinical Factors for the Overall Survival of Advanced (IIIB-IV) Lung Adenocarcinoma Patients.

PURPOSE: The purpose of this study was to investigate the prognostic value of pre-treatment CT radiomics and clinical factors for the overall survival (OS) of advanced (IIIB-IV) lung adenocarcinoma patients. METHODS: This study involved 165 patients with advanced lung adenocarcinoma. The Lasso-Cox regression model was used for feature selection and radiomics signature building. Then a clinical model was built based on clinical factors; a combined model in the form of nomogram was constructed with both clinical factors and the radiomics signature. Harrell's concordance index (C-Index) and Receiver operating characteristic (ROC) curves at cut-off time points of 1-, 2-, and 3- year were used to estimate and compare the predictive ability of all three models. Finally, the discriminatory ability and calibration of the nomogram were analyzed. RESULTS: Thirteen significant features were selected to build the radiomics signature whose C-indexes were 0.746 (95% CI, 0.699 to 0.792) in the training cohort and 0.677 (95% CI, 0.597 to 0.766) in the validation cohort. The C-indexes of combined model achieved 0.799 (95% CI, 0.757 to 0.84) in the training cohort and 0.733 (95% CI, 0.656 to 0.81) in the validation cohort, which outperformed the clinical model and radiomics signature. Moreover, the areas under the curve (AUCs) of the radiomic signature for 2-year prediction was superior to that of the clinical model. The combined model had the best AUCs for 2- and 3-year predictions. CONCLUSIONS: Radiomic signatures and clinical factors have prognostic value for OS in advanced (IIIB-IV) lung adenocarcinoma patients. The optimal model should be selected according to different cut-off time points in clinical application.

Is 18F-FDG PET/CT Beneficial for Newly Diagnosed Breast Cancer Patients With Low Proportion of ER Expression?

OBJECTIVE: It is unclear whether the receptor status of breast malignancy or the proportion of receptors expression is useful in the interpretation of 18F-FDG PET/CT. This study's purpose was to analyze whether 18F-FDG PET/CT was valuable for helping newly diagnosed breast cancer patients find suspected or unsuspected metastasis lesions based on the proportion of receptors expression. MATERIALS AND METHODS: Eighty newly diagnosed breast cancer patients were divided into six groups, containing N0 (no extraaxillary lymph node metastasis), N1 (extraaxillary lymph node metastasis), M0 (no distant metastasis), and M1 (distant metastasis) groups, C0 (no unsuspected metastasis), and C1 (unsuspected metastasis and treatment plan changed) detected by PET/CT. The main data, including the proportion of receptors ER (estrogen receptor), PR (progesterone receptor), and Her-2 (human epidermal growth factor receptor 2) status, were extracted. Simple correlation and logistic regression were preformed to analyze the association between them. RESULTS: Patients in N1 group had lower proportion of ER (%) and PR (%) than that in N0 group (ER: 2 [0-80] vs. 80 [15-95]; PR: 1 [0-10] vs. 20 [0-45], p<0.001). Moreover, the proportions of ER and PR were negatively correlated with N1 (ER: [r= -0.339, p= 0.002], PR: [r= -0.247, p= 0.011]) by simple correlation. Also, patients in C1 group had lower proportion of ER (%) and PR (%) than those in C0 group (ER: 10 [0-85] vs. 80 [15-90], p=0.026; PR: 1 [0-10] vs. 20 [0-70], p=0.041), while the distribution of ER and PR between M1 and M0 group had no significant difference. After the adjustment of traditional factors, the negative correlation between the proportion of ER (OR=0.986, 95% CI of OR [0.972-0.999], p=0.016) and C1 was found by logistic regression, cutoff value was 25% (ER) calculated by ROC (Receiver Operating Characteristic) curve (AUC [Area Under Curve]= 0.647, p=0.024). CONCLUSION: The proportion of ER in newly diagnosed breast cancer was negatively correlated with unsuspected metastasis detected by 18F-FDG PET/CT. 18F-FDG PET/CT might be recommended for newly diagnosed breast cancer patients with single lesions when the ER expression proportion is less than 25% to find unsuspected metastasis lesions and to modify treatment plan contrasted with conventional imaging and clinical examination.

Radiomics Signature as a Predictive Factor for EGFR Mutations in Advanced Lung Adenocarcinoma.

Purpose: To develop and validate a radiomic signature to identify EGFR mutations in patients with advanced lung adenocarcinoma. Methods: This study involved 201 patients with advanced lung adenocarcinoma (140 in the training cohort and 61 in the validation cohort). A total of 396 features were extracted from manual segmentation based on enhanced and non-enhance CT imaging after image preprocessing. The Lasso algorithm was used for feature selection, 6 machine learning methods were used to construct radiomics models. Receiver operating characteristic (ROC) curve analysis was applied to evaluate the performance of the radiomic signature between different data and methods. A nomogram was developed using clinical factors and the radiomics signature, then it was analyzed based on its discriminatory ability and calibration. Decision curve analysis (DCA) was implemented to evaluate the clinical utility. Results: Ten features for contrast data and eleven features for non-contrast data were selected through LASSO algorithm. The performance of the radiomics signature for contrast images was better than that for non-contrast images in all of the 6 different machine learning methods. Finally, the best radiomics signature was built with logistic regression method based on enhanced CT imaging with an area under the curve (AUC) of 0.851 (95% CI, 0.750 to 0.951) in the validation cohort. A nomogram was developed using the radiomics signature and sex with a C-index of 0.908 (95%CI, 0.862 to 0.954) in the training cohort and 0.835 (95% CI, 0.825 to 0.845) in the validation cohort. It showed good discrimination and calibration (Hosmer-Lemeshow test, P = 0.621 for the training cohort and P = 0.605 for the validation cohort). Conclusion: Radiomics signature can help to distinguish between EGFR positive and wild type advanced lung adenocarcinomas.

Role of daily anal stimulation for intractable functional constipation in infants.

Objective: Functional constipation is one of the most common problems in pediatric gastroenterology. The aim of the present study was to evaluate the effectiveness of daily anal stimulation in infants with intractable functional constipation (IFC). Our evaluation was based on clinical improvement and on changes in manometric parameters through time. Methods: Infants with IFC treated between January 2018 and December 2019 were included in this retrospective study. Treatment processing included daily anal stimulation for infants and psychological counseling for parents. All cases underwent a complete intervention program and were evaluated for improvement in symptoms and for changes in anorectal manometry within 1 year of follow-up. Results: A total of 161 patients were included in this study. Positive response was achieved in all patients. Frequency of defecation, change in stool form and decrease in the defecatory pain were significantly relieved in all infants after intervention. On anorectal manometry, no significant difference was found in the peristaltic frequency of distal rectum before and after treatment. There was a significant increase in the mean amplitude of peristalsis and improvement in the rhythm after intervention. In the 1 year of follow-up, three patients had recurrence of constipation requiring colectomy. Conclusion: In terms of the high clinical efficacy and limited side effects, daily anal stimulation may be included in the initial part of an intervention program for IFC in infants.

A Comparison of Transcriptional Diversity of Swine Macrophages Infected With TgHB1 Strain of Toxoplasma gondii Isolated in China.

Toxoplasma gondii is an apicomplexan parasite infecting human and animals, causing huge public health concerns and economic losses. Swine alveolar macrophage plays an important role in controlling T. gondii infection. However, the mechanism by which macrophages infected with T. gondii function in the immunity to the infection is unclear, especially for local isolates such as TgHB1 isolated in China. RNA-seq as a valuable tool was applied to simultaneously analyze transcriptional changes of pig alveolar macrophages infected with TgRH (typeI), TgME49 (typeII) or TgHB1 at different time points post infection (6, 12, and 24 h). Paired-end clean reads were aligned to the Sscrofa10.2 pig genome and T. gondii ME49 genome. The differentially expressed genes of macrophages and T. gondii were enriched through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, respectively. Compared to the TgRH and TgME49 infection groups, 307 down-regulated macrophage genes (mainly enriched for development and metabolism) and 419 up-regulated genes (mainly enriched for immune pathways) were uniquely expressed in the TgHB1 infection group. Additionally, 557 down-regulated and 674 up-regulated T. gondii genes (mainly enriched in metabolism and biosynthesis) were uniquely expressed in the TgHB1 infection group. For validation purposes, some of the differentially expressed genes of macrophages involved in immune-related signaling pathways were used for further analysis via real time quantitative reverse-transcription polymerase-chain reaction (qRT-PCR). This work provides important insights into the temporal immune responses of swine alveolar macrophages to infection by the strain TgHB1 isolated from China, and is helpful for better understanding of the T. gondii genotype-associated activation of macrophages during early phase of the infection.