[Neurodevelopment and cerebral blood flow in children aged 2-6 years with autism spectrum disorder]. / 2~6å²å­¤ç‹¬ç—‡è°±ç³»éšœç¢å„¿ç«¥ç¥žç»å‘è‚²ä¸Žè„‘è¡€æµé‡çš„ç ”ç©¶.

OBJECTIVES: To investigate the neurodevelopmental characteristics of children with autism spectrum disorder (ASD), analyze the correlation between neurodevelopmental indicators and cerebral blood flow (CBF), and explore the potential mechanisms of neurodevelopment in ASD children. METHODS: A retrospective study was conducted on 145 children aged 2-6 years with newly-diagnosed ASD. Scores from the Gesell Developmental Diagnosis Scale and the Autism Behavior Checklist (ABC) and CBF results were collected to compare gender differences in the development of children with ASD and analyze the correlation between CBF and neurodevelopmental indicators. RESULTS: Fine motor and personal-social development quotient in boys with ASD were lower than those in girls with ASD (P<0.05). Gross motor development quotient in ASD children was negatively correlated with CBF in the left frontal lobe (r=-0.200, P=0.016), right frontal lobe (r=-0.279, P=0.001), left parietal lobe (r=-0.208, P=0.012), and right parietal lobe (r=-0.187, P=0.025). The total ABC score was positively correlated with CBF in the left amygdala (r=0.295, P<0.001). CONCLUSIONS: Early intervention training should pay attention to gender and developmental structural characteristics for precise intervention in ASD children. CBF has the potential to become a biological marker for assessing the severity of ASD.

Survival Benefit and Genetic Profile of Pemetrexed as Initial Chemotherapy in Selected Chinese Patients With Advanced Lung Adenocarcinoma.

Objective: This study investigated survival in selected Chinese patients with advanced lung adenocarcinoma who received initial chemotherapy with pemetrexed. We also explored the relationship between genetic biomarkers and pemetrexed efficacy. Methods: We retrospectively collected patients (n = 1,047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed. Results: The median DOT was 9.1 months (95% CI: 8.5-9.8), and the median OS was 26.2 months (95% CI: 24.2-28.1). OS was positively correlated with DOT (r = 0.403, P < 0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), and PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT > 6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤ 6.9 months set. Conclusion: This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

Toward an Expert Level of Lung Cancer Detection and Classification Using a Deep Convolutional Neural Network.

BACKGROUND: Computed tomography (CT) is essential for pulmonary nodule detection in diagnosing lung cancer. As deep learning algorithms have recently been regarded as a promising technique in medical fields, we attempt to integrate a well-trained deep learning algorithm to detect and classify pulmonary nodules derived from clinical CT images. MATERIALS AND METHODS: Open-source data sets and multicenter data sets have been used in this study. A three-dimensional convolutional neural network (CNN) was designed to detect pulmonary nodules and classify them into malignant or benign diseases based on pathologically and laboratory proven results. RESULTS: The sensitivity and specificity of this well-trained model were found to be 84.4% (95% confidence interval [CI], 80.5%-88.3%) and 83.0% (95% CI, 79.5%-86.5%), respectively. Subgroup analysis of smaller nodules (<10 mm) have demonstrated remarkable sensitivity and specificity, similar to that of larger nodules (10-30 mm). Additional model validation was implemented by comparing manual assessments done by different ranks of doctors with those performed by three-dimensional CNN. The results show that the performance of the CNN model was superior to manual assessment. CONCLUSION: Under the companion diagnostics, the three-dimensional CNN with a deep learning algorithm may assist radiologists in the future by providing accurate and timely information for diagnosing pulmonary nodules in regular clinical practices. IMPLICATIONS FOR PRACTICE: The three-dimensional convolutional neural network described in this article demonstrated both high sensitivity and high specificity in classifying pulmonary nodules regardless of diameters as well as superiority compared with manual assessment. Although it still warrants further improvement and validation in larger screening cohorts, its clinical application could definitely facilitate and assist doctors in clinical practice.

A consensus on immunotherapy from the 2017 Chinese Lung Cancer Summit expert panel.

The notable clinical success of cancer immunotherapy using checkpoint blockade suggests that it is likely to form the foundation of curative therapy for many malignancies. However, checkpoint blockades do not achieve sustained clinical response in most patients and thus amounts of problems needed to be figured out. Regarding these challenges, the 2017 Chinese Lung Cancer Summit expert panel organized a forum on the 14th Chinese Lung Cancer Summit to formally discuss these controversies. Five consensuses finally were reached to guide the application of checkpoint blockades.

A consensus on liquid biopsy from the 2016 Chinese Lung Cancer Summit expert panel.

The diagnosis and treatment of lung cancer have evolved into the era of precision medicine. Liquid biopsy, a minimally invasive approach, has emerged as a promising practice in genetic profiling and monitoring of lung cancer. Translating liquid biopsy from bench to bedside has encountered various challenges, including technique selection, protocol standardisation, data analysis and cost management. Regarding these challenges, the 2016 Chinese Lung Cancer Summit expert panel organised a trilateral forum involving oncologists, clinicians, clinical researchers, and industrial expertise on the 13th Chinese Lung Cancer Summit to formally discuss these controversies. Six consensuses were reached to guide the use of liquid biopsy and perform precision medicine in both clinic and research.

Sodium butyrate ameliorates S100/FCA-induced autoimmune hepatitis through regulation of intestinal tight junction and toll-like receptor 4 signaling pathway.

BACKGROUND AND AIM: Recent investigation revealed that dysbiosis in the gut flora and disruption of permeability of intestinal barrier are possible causes for the development of autoimmune hepatitis. Supplementation of sodium butyrate has been suggested to protect liver injury from disrupted permeability of small intestine. In current study, we employed S100/Freund's complete adjuvant induced autoimmune hepatitis to investigate therapeutic efficacy of sodium butyrate and its mechanism in the liver and upper small intestine. METHODS: C57BL/6 mice were employed and divided into three groups - control group (n=8), autoimmune hepatitis group (n=12) and autoimmune hepatitis with treatment of sodium butyrate group (n=12). Histological staining and western blot analyses were employed to evaluate liver and upper small intestine morphology and gene expression respectively. RESULTS: The findings revealed that S100/Freund's complete adjuvant caused liver injury and disruption of upper small intestine villi. Sodium butyrate attenuated the injuries and prevented migration of Escherichia coli into the liver. Moreover, the effect of sodium butyrate on protection of injuries of the liver and upper small intestine could be due to inhibition of toll-like receptor 4 signaling pathway, as well as its down-regulation of inflammatory cytokines - interleukin-6 and tumor necrosis factor-a. CONCLUSIONS: Sodium butyrate can prevent liver injury by maintaining the integrity of small intestine and inhibiting inflammatory response in S100/Freund's complete adjuvant induced autoimmune hepatitis.

Early initiation of fluorouracil-based adjuvant chemotherapy improves survival in patients with resectable gastric cancer.

PURPOSE: Several clinical trials have suggested that adjuvant chemotherapy improves the survival of patients with resected gastric cancer, but the optimal time at which to initiate post-operative adjuvant chemotherapy has not been studied. This study investigated the association between time to adjuvant chemotherapy and survival in gastric cancer. METHODS: We retrospectively identified 266 patients with stage IB-IIIC gastric cancer who received fluorouracil-based adjuvant chemotherapy after radical gastrectomy. Overall survival (OS) was compared between patients grouped according to time from surgery to adjuvant chemotherapy (<45 and ≥45 days). The Cox proportional hazards model was used to analyze the effects of time to initiation of chemotherapy and other clinical covariates on survival. RESULTS: Of 266 patients, 141 (53%) started adjuvant chemotherapy within 45 days after surgery and 125 (47%) started adjuvant chemotherapy more than 45 days after surgery. The 3-year OS rates were 81.2 and 65.8% for patients starting chemotherapy within 45 days and after 45 days, respectively (p=0.006). Multivariate analysis identified early initiation of adjuvant chemotherapy, completion of the planned chemotherapy, and early-stage disease as favorable prognostic factors in terms of OS (p<0.05). Subgroup analysis suggested that starting chemotherapy within 45 days after surgery was associated with significant OS benefit compared with initiation of chemotherapy after 45 days from surgery in most subgroups. CONCLUSIONS: This retrospective analysis suggests that delaying adjuvant chemotherapy for longer than 45 days after surgery may be associated with poorer survival in patients with resected gastric cancer.

Prognostic Model Based on Systemic Inflammatory Response and Clinicopathological Factors to Predict Outcome of Patients with Node-Negative Gastric Cancer.

Prognostic models are generally used to predict gastric cancer outcomes. However, no model combining patient-, tumor- and host-related factors has been established to predict outcomes after radical gastrectomy, especially outcomes of patients without nodal involvement. The aim of this study was to develop a prognostic model based on the systemic inflammatory response and clinicopathological factors of resectable gastric cancer and determine whether the model can improve prognostic accuracy in node-negative patients. We reviewed the clinical, laboratory, histopathological and survival data of 1397 patients who underwent radical gastrectomy between 2007 and 2013. Patients were split into development and validation sets of 1123 and 274 patients, respectively. Among all 1397 patients, 545 had node-negative gastric cancer; 440 were included in the development set, 105 were included in the validation set. A prognostic model was constructed from the development set. The scoring system was based on hazard ratios in a Cox proportional hazard model. In the multivariate analysis, age, tumor size, Lauren type, depth of invasion, lymph node metastasis, and the neutrophil--lymphocyte ratio were independent prognostic indicators of overall survival. A prognostic model was then established based on the significant factors. Patients were categorized into five groups according to their scores. The 3-year survival rates for the low- to high-risk groups were 98.9%, 92.8%, 82.4%, 58.4%, and 36.9%, respectively (P < 0.001). The prognostic model clearly discriminated patients with stage pT1-4N0M0 tumor into four risk groups with significant differences in the 3-year survival rates (P < 0.001). Compared with the pathological T stage, the model improved the predictive accuracy of the 3-year survival rate by 5% for node-negative patients. The prognostic scores also stratified the patients with stage pT4aN0M0 tumor into significantly different risk groups (P = 0.004). Furthermore, the predictive value of this model was validated in an independent set of 274 patients. This model, which included the systemic inflammatory markers and clinicopathological factors, is more effective in predicting the prognosis of node-negative gastric cancer than traditional staging systems. Patients in the high-risk group might be good candidates for adjuvant chemotherapy.

The role of E3 ubiquitin ligase Cbl proteins in interleukin-2-induced Jurkat T-cell activation.

Interleukin- (IL-) 2 is the major growth factor for T-cell activation and proliferation. IL-2 has multiple functions in the regulation of immunological processes. Although most studies focus on T-cell immunomodulation, T-cell activation by IL-2 is the foundation of priming the feedback loop. Here, we investigated the effect of MAPK/ERK and PI3K/Akt signaling pathways on IL-2-induced cell activation and the regulatory mechanisms of upstream ubiquitin ligase Cbl-b and c-Cbl. Morphological analysis of Jurkat T cells was performed by cytospin preparations with Wright-Giemsa stain. CD25 expression on Jurkat T cells was determined by flow cytometry. Changes in cell activation proteins such as p-ERK, ERK, p-Akt, Akt, and ubiquitin ligase Casitas B-cell Lymphoma (Cbl) proteins were analyzed by western blot. Following IL-2-induced activation of Jurkat T cells, p-ERK expression was upregulated, while there was no change in p-Akt, ERK, or Akt expression. Thus, the MAPK/ERK signaling pathway, but not PI3K/Akt, was involved in IL-2-induced T-cell activation. Either using PD98059 (a specific inhibitor for p-ERK) or depletion of ERK with small interfering RNA (siRNA) reduced the expression of CD25. This study also showed that ubiquitin ligase proteins Cbl-b and c-Cbl might be involved in IL-2-induced Jurkat T-cell activation by negatively regulating the MAPK/ERK signaling pathway.

Optimal duration of fluorouracil-based adjuvant chemotherapy for patients with resectable gastric cancer.

BACKGROUND: Although several clinical trials have suggested that postoperative adjuvant chemotherapy can improve survival of patients with gastric cancer, the optimal treatment duration has not been studied. This retrospective analysis evaluated the outcomes of patients with gastric cancer treated with six cycles of fluorouracil-based treatment compared with a cohort treated with four or eight cycles. METHODS: We retrospectively identified 237 patients with stage IB-IIIC gastric cancer who received four, six, or eight cycles of fluorouracil-based adjuvant chemotherapy administered every 3 weeks after radical gastrectomy. The endpoint was overall survival (OS). Factors associated with prognosis were also analyzed. RESULTS: The estimated 3-year OS rates for the four-, six-, and eight-cycle cohorts were 54.4%, 76.1%, and 68.9%, respectively; and the estimated 5-year OS rates were 41.2%, 74.0%, and 65.8%, respectively. Patients who received six cycles were more likely to have a better OS than those who received four cycles (P = 0.002). Eight cycles failed to show an additional survival benefit (P = 0.454). In the multivariate analysis, the number of chemotherapy cycles was associated with OS independent of clinical covariates (P<0.05). Subgroup analysis suggested that among patients in all age groups examined, male patients, and subgroups of fluorouracil plus oxaliplatin combined chemotherapy, stage III, poor differentiation, and gastrectomy with D2 lymphadenectomy, six cycles of adjuvant chemotherapy were associated with a statistically significant benefit of OS compared with four cycles (P<0.05). CONCLUSIONS: Six cycles of adjuvant chemotherapy might lead to a favorable outcome for patients with gastric cancer, and two further cycles could not provide an additional clinical benefit.

The role of cbl family of ubiquitin ligases in gastric cancer exosome-induced apoptosis of Jurkat T cells.

BACKGROUND. Exosomes are nanometer-sized vesicles with immunomodulatory functions, which are released by a diverse range of living cells. Although recent studies have shown that tumor-derived exosomes can suppress the function of T cells, the molecular mechanisms are not well understood. In the present study, we investigated the role of the Casitas B lineage lymphoma (cbl) family of ubiquitin ligases in gastric cancer exosome-induced apoptosis of Jurkat T cells. MATERIALS AND METHODS. By serial centrifugation and sucrose gradient ultracentrifugation, we isolated and purified the exosomes from gastric cancer SGC7901 cells, and identified them by electron microscopy and Western blotting. Cell apoptosis was detected using propidium iodide staining. Western blotting and RT-PCR was exploited to evaluate the expression of proteins and mRNA, respectively. RESULTS. Gastric cancer exosomes induced Jurkat T cell apoptosis in a time- and dose-dependent manner and activated caspases 3, 8 and 9. The expression of Cbl-b and c-Cbl was up-regulated during exosome-induced apoptosis of cells. Meanwhile, exosomes induced ubiquitination of the p85 subunit of phosphoinositide 3-kinase (PI3K) and reduced downstream Akt activity. Inhibition of proteasome led to partial restoration of Akt activity and cell apoptosis. DISCUSSION AND CONCLUSIONS. The Cbl family of ubiquitin ligases might be involved in regulation of exosome-induced apoptosis of Jurkat T cells by increasing PI3K proteasome degradation, inactivation of PI3K/Akt signaling, thus mediating some effects of caspase activation.

[Effects of Bufalin on SYK and CBL family proteins in induction of HL-60 cell apoptosis].

The study was aimed to explore the mechanism of SYK and CBL family of ubiquitin ligases in Bufalin-induced HL-60 cells apoptosis. Cell viability was tested by trypan blue staining and apoptosis was detected by using flow cytometry. The expressions of CBL and CBL-b and the phosphorylation of SYK were detected by using immunoprecipitation and Western blot. The results showed that Bufalin inhibited HL-60 cell proliferation in time- and dose-dependent manners. IC(50) of suppressing cell viability at 24, 48 and 72 hours were about 26.3, 7.8 and 2.0 nmol/L respectively. The high dose of bufalin already induced apoptosis of HL-60 cells at 8 hours. SYK was quickly phosphorylated, and the expressions of CBL and CBL-b were down-regulated after treatment with Bufalin. It is concluded that SYK activation and CBL protein down-regulation may be involved in Bufalin-induced HL-60 cell apoptosis.