Primate anterior insular cortex represents economic decision variables proposed by prospect theory.

In humans, risk attitude is highly context-dependent, varying with wealth levels or for different potential outcomes, such as gains or losses. These behavioral effects have been modelled using prospect theory, with the key assumption that humans represent the value of each available option asymmetrically as a gain or loss relative to a reference point. It remains unknown how these computations are implemented at the neuronal level. Here we show that macaques, like humans, change their risk attitude across wealth levels and gain/loss contexts using a token gambling task. Neurons in the anterior insular cortex (AIC) encode the 'reference point' (i.e., the current wealth level of the monkey) and reflect 'loss aversion' (i.e., option value signals are more sensitive to change in the loss than in the gain context) as postulated by prospect theory. In addition, changes in the activity of a subgroup of AIC neurons correlate with the inter-trial fluctuations in choice and risk attitude. Taken together, we show that the primate AIC in risky decision-making may be involved in monitoring contextual information used to guide the animal's willingness to accept risk.

An Autism-Related, Nonsense Foxp1 Mutant Induces Autophagy and Delays Radial Migration of the Cortical Neurons.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that has a strong genetic component. Disruptions of FOXP1, a transcription factor expressed in the developing cerebral cortex, were associated with ASD. FOXP1(R525X) is a de novo heterozygous mutation found in patients with autism and severe mental retardation. To explore the neuronal basis of FOXP1(R525X) in ASD, we created Foxp1(R521X), a mouse homolog of the human variant. Ectopic expression of Foxp1(R521X) led to cytoplasmic aggregates and activated macroautophagy in neuroblastoma N2a cells and the developing neuronal cells. Cortical neurons expressing Foxp1(R521X) exhibited delayed migration and altered dendritic morphology. As a control, mutant Y435X that was expressed diffusively in the cytoplasm did not induce autophagy and migration delay in the cortex. The embryonic cortical cells had a minimal activity of nonsense-mediated mRNA decay (NMD) as assayed by a splicing-dependent NMD reporter. We hypothesize that the developing neuronal cells use autophagy but not NMD as a safeguard mechanism against nonsense mutant aggregates, resulting in impairment of the cortical development. This study suggests a novel mechanism other than heterozygous loss of FOXP1 for the development of ASD and may advance our understanding of the complex relationships between gene mutation and the related psychiatric disorders.

Inhibition of EZH2 and EGFR produces a synergistic effect on cell apoptosis by increasing autophagy in gastric cancer cells.

BACKGROUND: Numerous reports have shown that a combination of two or more drugs leads to better cancer treatment. Inhibitors of zeste homology 2 and epidermal growth factor receptor have been widely used in cancer treatments. However, the mechanisms of the combined use of these two drugs remain elusive. METHODS: Sulforhodamine B assays and Alexa Fluor®-488 Annexin V/Dead Cell Apoptosis Kit were used to detect the cell proliferation and cell apoptosis in vitro, respectively. Western blotting analysis was used to detect the relative protein expression, and xenografted tumor was generated in nude mice to evaluate the effect in vivo. RESULTS: Treatment with either Gefitinib ranging from 0 to 12.5 µM or GSK126 ranging from 0 to 8.3 µM caused a dose-dependent decrease in the cell survival fraction, and the combination of Gefitinib at 12.5 µM and GSK126 at 8.3 µM caused further significant decrease. The combination indexes were 0.061, 0.591, 0.713, and 0.371 for MGC803, A549, PC-3, and MDB-MA-231, respectively. In MGC803 cells, the combination of GSK126 and Gefitinib synergistically induced cell apoptosis (56.2%), which was markedly higher as compared to either drug alone (7.6% and 10.6%, P<0.05). Treatment with either Gefitinib or GSK126 alone induced a significant increase in cell apoptosis in LC3-II and p-ULK, whereas the combination of the two induced a further increase. Pretreatment with an autophagy inhibitor, 3-methyladenine, prevented the apoptosis induced by the combined use of Gefitinib and GSK126. In addition, the combined use of Gefitinib and GSK126 also inhibited the activation of mammalian target of rapamycin signaling pathway. Furthermore, the combined use of GSK126 and Gefitinib synergistically inhibited xenografted tumor proliferation. CONCLUSION: The combined use of GSK126 and Gefitinib exerts a synergic effect on tumor growth inhibition both in vitro and in vivo through inducing autophagy and promoting apoptosis. Therefore, GSK126 and Gefitinib in combination may be considered as a potential strategy in treating solid tumor clinically.

Environmental barriers, functioning and quality of life in 2008 Wenchuan earthquake victims with spinal cord injury eight years after the disaster: A cross-sectional study.

OBJECTIVE: To examine environmental barriers, func-tioning, and quality of life in Wenchuan earthquake survivors with spinal cord injury. DESIGN: Cross-sectional study. SUBJECTS: Thirty-two adult Wenchuan earthquake survivors with spinal cord injury. METHODS: Data were collected on environmental factors with the Nottwil Environmental Factors Inventory Short Form (NEFI-SF), physical and mental functioning with the 36-item Short-Form Health Survey (SF-36), and quality of life with the World Health Organization Quality of Life-BREF (WHOQOL-BREF). Descriptive analysis of environmental barriers and comparisons of SF-36 and WHOQOL-BREF domain scores with normative data were performed. Variations in outcomes across demographic and lesion characteristics were examined using Mann-Whitney U test. Associations of NEFI-SF with SF-36 and WHOQOL-BREF domain scores were explored using Spearman's correlation. RESULTS: Wenchuan earthquake survivors with spinal cord injury were affected by a large number of environmental barriers. Their functioning and quality of life were considerably reduced in comparison with respective reference populations. Neither environmental barriers nor functioning or quality of life varied systematically by demographic and lesion characteristics. Increased numbers of perceived environmental barriers were strongly associated with decreased scores across SF-36 and WHOQOL-BREF sub-domains. CONCLUSION: Wenchuan earthquake survivors with SCI faced a considerable number of environmental barriers and showed decreased functioning and quality of life. Environmental barriers were strongly related to functioning and quality of life.

Global Dynamics of an Avian Influenza A(H7N9) Epidemic Model with Latent Period and Nonlinear Recovery Rate.

An SEIR type of compartmental model with nonlinear incidence and recovery rates was formulated to study the combined impacts of psychological effect and available resources of public health system especially the number of hospital beds on the transmission and control of A(H7N9) virus. Global stability of the disease-free and endemic equilibria is determined by the basic reproduction number as a threshold parameter and is obtained by constructing Lyapunov function and second additive compound matrix. The results obtained reveal that psychological effect and available resources do not change the stability of the steady states but can indeed diminish the peak and the final sizes of the infected. Our studies have practical implications for the transmission and control of A(H7N9) virus.

Notch Signaling: Linking Embryonic Lung Development and Asthmatic Airway Remodeling.

Lung development is mediated by assorted signaling proteins and orchestrated by complex mesenchymal-epithelial interactions. Notch signaling is an evolutionarily conserved cell-cell communication mechanism that exhibits a pivotal role in lung development. Notably, both aberrant expression and loss of regulation of Notch signaling are critically linked to the pathogenesis of various lung diseases, in particular, pulmonary fibrosis, lung cancer, pulmonary arterial hypertension, and asthmatic airway remodeling; implying that precise regulation of intensity and duration of Notch signaling is imperative for appropriate lung development. Moreover, evidence suggests that Notch signaling links embryonic lung development and asthmatic airway remodeling. Herein, we summarized all-recent advances associated with the mechanistic role of Notch signaling in lung development, consequences of aberrant expression or deletion of Notch signaling in linking early-impaired lung development and asthmatic airway remodeling, and all recently investigated potential therapeutic strategies to treat asthmatic airway remodeling.

The novel EZH2 inhibitor, GSK126, suppresses cell migration and angiogenesis via down-regulating VEGF-A.

PURPOSE: To explore the effects and mechanisms of GSK126, a novel inhibitor of histone methyltransferase enhancer of zeste homologue 2, on cancer cell migration. METHODS: Gastric cancer cell line MGC803 and human lung adenocarcinoma cell line A549 were treated with GSK126 at three doses. Transwell and wound healing assays were conducted to detect cell migration. Human umbilical vein endothelial cells tube formation assay and chick embryo chorioallantoic membrane assay were performed to assess the effects of GSK126 on angiogenesis in vitro and in vivo, respectively. The mRNA level of VEGF-A was detected by quantitative PCR, and the protein levels of VEGF-A were detected both by western blot analysis and immunohistochemistry. Epi-fluorescent intensity was obtained by in vivo imaging. RESULTS: GSK126 inhibited cell migration in both MGC803 and A549 in a dose-dependent manner, as revealed by transwell and wound healing assays. The effects of GSK 126 were similar to those of gefitinib at the same doses. Moreover, GSK126 at doses of 20 and 50 µM inhibited angiogenesis both in vitro and in vivo. GSK126 reduced both the mRNA and protein expression of VEGF-A in a dose-dependent manner. Finally, in vivo imaging assay revealed that GSK126 at 200 mg/kg significantly inhibited cancer cell migration. CONCLUSIONS: GSK126 inhibits cell migration and angiogenesis in solid tumor cell lines through down-regulation of VEGF-A expression. Thus, it may be considered as a novel anticancer drug candidate for solid tumor.

Clinicopathological analysis of two cases with pelvis villous adenoma and review of relevant literature.

Villous adenoma is a rare primary tumor of the urinary system, especially the bladder and kidneys. This study presents two cases of right pelvis villous adenoma, including that of a 61-year-old patient who had experienced hematuria for more than 1 year and was diagnosed with bladder and ureteral stones via B-ultrasound examination, and the other one involving a 65-year-old patient who was hospitalized for 6 days due to a right upper quadrant mass and diagnosed with right renal pelvis stones and hydrops via B-ultrasound examination. Both patients underwent nephrectomy, and their histological analysis demonstrated papillary projections covered by columnar cells and goblet cells. The first patient had a large amount of renal pelvis mucus accumulation with obvious microscopic intestinal metaplasia and mild-moderate nuclear atypia. Immunohistochemical studies revealed positive carcinoembryonic antigen and the caudal type homeobox 2 staining with varying degrees of cytokeratin (CK)-7 and CK20 expression in both patients. Recurrences or metastasis was not observed during the follow-up period of 3-4 years.

Role of p38 MAPK in enhanced human cancer cells killing by the combination of aspirin and ABT-737.

Regular use of aspirin after diagnosis is associated with longer survival among patients with mutated-PIK3CA colorectal cancer, but not among patients with wild-type PIK3CA cancer. In this study, we showed that clinically achievable concentrations of aspirin and ABT-737 in combination could induce a synergistic growth arrest in several human PIK3CA wild-type cancer cells. In addition, our results also demonstrated that long-term combination treatment with aspirin and ABT-737 could synergistically induce apoptosis both in A549 and H1299 cells. In the meanwhile, short-term aspirin plus ABT-737 combination treatment induced a greater autophagic response than did either drug alone and the combination-induced autophagy switched from a cytoprotective signal to a death-promoting signal. Furthermore, we showed that p38 acted as a switch between two different types of cell death (autophagy and apoptosis) induced by aspirin plus ABT-737. Moreover, the increased anti-cancer efficacy of aspirin combined with ABT-737 was further validated in a human lung cancer A549 xenograft model. We hope that this synergy may contribute to failure of aspirin cancer therapy and ultimately lead to efficacious regimens for cancer therapy.

[Construction and identification of lentiviral vector containing human ILK-shRNA and mda7 gene].

OBJECTIVE: To construct and identify lentiviral vector containing human ILK-shRNA and mda7 gene. METHODS: Based on the human ILK gene sequences, RNAi target sequences were designed and cloned into the lentiviral vector pSicoR-eGFP by restriction endonuclease HpaI and XhoI double digestion and T4 DNA ligase ligation. Based on the human mda7 gene sequences, PCR primers were designed to clone the full-length mda7, and were cloned into the lentiviral vector pLVX-Puro. After the candidate clones were identified by DNA sequencing, the recombinant plasmid and the three packaging plasmids were co-transfected into the human embryonic kidney 293T cells by lipofectamine 2000 to produce the lentiviral particles. Human prostate cancer PC-3 cells were infected with the constructed lentiviral vector. The ILK and mda7 expression levels in PC-3 cells were quantified by qPCR and Western blot, respectively. The effect of ILK and mda7 on proliferation and migration of PC-3 cells were assessed by MTT method and Transwell assay, respectively. RESULTS: ILK-pSicoR-eGFP and mda7-pLVX-Puro lentiviral vectors were successfully constructed. Strong green fluorescence was observed in the 293T cells under the fluorescent microscope after co-transfection of 293T cells with 4 plasmids of lentiviral vector. The transfection efficiency of the collected virus exceeded 90% in the 293T cells and the PC-3 cells were infected with the lentiviral particles with high efficiency. The A and B lentiviral vector inhibited the expression of ILK at both the mRNA and protein levels in PC-3 cells significantly. The mda7-pLVX-Puro lentiviral vector increased the expression of mda7 in PC-3 cells, and the ability was maintained for one month. Within 96 h, ILK and mad7 significantly inhibited the proliferation and migration of PC-3 cells (Ps<0.05). CONCLUSION: The lentiviral vectors of ILK knockdown and mda7 over-expression have been successfully constructed and identified. The recombinant lentivirus can efficiently infect human prostate cancer PC-3 cells, in which ILK expression is inhibited and mda7 is over-expressed.

Pulse HIV vaccination: feasibility for virus eradication and optimal vaccination schedule.

We modify the classical virus dynamics model by incorporating an immune response with fixed or fluctuating vaccination frequencies and dosages to obtain a system of impulsive differential equations for the virus dynamics of both the wild-type and mutant strains. This model framework permits us to obtain precise conditions for the virus elimination, which are much more feasible compared with existing results, which require frequent vaccine administration with large dosage. We also consider the corresponding impulsive optimal control problem to describe when and how much of the vaccine should be administered in order to maximize levels of healthy CD4(+) T cells and immune response cells. A gradient-based optimization method is applied to obtain the optimal schedule numerically. For a case study when the CTL vaccine is administered in a period of one year, our numerical studies support the optimal vaccination schedule consisting of vaccine administration three times, with the first dosage strong (to boost the immune system), followed by a second dosage shortly after (to strengthen the immune response) and then the third and final dosage long after (to ensure the immune system can handle viruses rebound).

RET proto-oncogene genetic screening of families with multiple endocrine neoplasia type 2 optimizes diagnostic and clinical management in China.

BACKGROUND: Genetic screening for germline mutations in the RET proto-oncogene has been extensively exploited worldwide to optimize the diagnostic and clinical management of multiple endocrine neoplasia type 2 (MEN2) patients and their relatives. However, a distinct lag period exists not only in the recognition but also in the medical treatment of patients with MEN2. Here we present a comprehensive genetic and clinical analysis of MEN2 among Chinese families followed from 1975 to 2011. Our series comprises 36 index cases and 134 relatives from 11 independent families. METHODS: Genetic diagnosis was performed in all participants by direct sequencing all relevant RET exons. Thyroidectomy was performed in 50 patients with varying cervical neck dissection procedures. Patients with pheochromocytoma (PHEO) underwent specific surgery. Demographic, clinical profiles, mutation types, tumor histopathologic features, and follow-up records were systematically analyzed. RESULTS: The RET mutations p.C634Y (n=34), p.C634R (n=6), p.C618S (n=13), p.V292M/R67H/R982C (n=7), p.L790F (n=2), and p.C634Y/V292M/R67H/R982C (n=1) were confirmed in 31 index cases and then identified in 32 at-risk relatives (mutation carriers), with MEN2A as the most common clinical subtype. The overall penetrance of PHEO in patients with MEN2A was 46.7%. A total of 50 patients underwent thyroidectomy, and there was a significant lowering of their mean age at thyroidectomy and the tumor diameter of the mutation carriers that were detected and operated on compared with the index cases (age at first surgery: 29.3 vs. 39.3 years, p<0.05; maximum size: 1.1 vs. 3.3 cm, p<0.001). There was also a decrease in the TNM staging and the proportion of patients who underwent inappropriate initial thyroid surgery (pN1: 31.6% vs. 100%, p<0.001; inappropriate surgery: 0% vs. 29%). Meanwhile, disease-free survival (DFS) increased (DFS: 100% vs. 58.1%, p<0.05). Both medullary thyroid carcinoma-specific (n=1) and PHEO-specific (n=5) deaths were reported during the study period. CONCLUSIONS: Our results further substantiate that gene scanning of all relevant RET exons is a powerful tool in the management of MEN2 patients, especially in asymptomatic carriers, and has led to earlier diagnosis and more complete initial treatment of patients with MEN2 in China.

Optimal control of drug therapy: melding pharmacokinetics with viral dynamics.

Pharmacokinetics were melded with a viral dynamical model to design an optimal drug administration regimen such that the basic reproductive number for the virus was minimized. One-compartmental models with two kinds of drug delivery routes, intravenous and extravascular with multiple dosages, and two drug elimination rates, first order and Michaelis-Menten rates, were considered. We defined explicitly the basic reproductive number for the viral dynamical model melded with pharmacokinetics. When the average plasma drug concentration was constant, intravenous administration of the drug with small dosages applied frequently minimized the basic reproductive number. For extravascular administration, the basic reproductive number initially decreases to a trough point and then increases as the drug dosage increases. When a therapeutic window is considered, numerical studies indicate that the wider the window, the smaller the basic reproductive number. Once the width of the therapeutic window is fixed, the basic reproductive number monotonously declines as the minimum therapeutic level increases. The findings suggest that the existence of drug dosage and drug administration interval that minimize the basic reproductive number could help design the optimal drug administration regimen.

Community-based measures for mitigating the 2009 H1N1 pandemic in China.

Since the emergence of influenza A/H1N1 pandemic virus in March-April 2009, very stringent interventions including Fengxiao were implemented to prevent importation of infected cases and decelerate the disease spread in mainland China. The extent to which these measures have been effective remains elusive. We sought to investigate the effectiveness of Fengxiao that may inform policy decisions on improving community-based interventions for management of on-going outbreaks in China, in particular during the Spring Festival in mid-February 2010 when nationwide traveling will be substantially increased. We obtained data on initial laboratory-confirmed cases of H1N1 in the province of Shaanxi and used Markov-chain Monte-Carlo (MCMC) simulations to estimate the reproduction number. Given the estimates for the exposed and infectious periods of the novel H1N1 virus, we estimated a mean reproduction number of 1.68 (95% CI 1.45-1.92) and other A/H1N1 epidemiological parameters. Our results based on a spatially stratified population dynamical model show that the early implementation of Fengxiao can delay the epidemic peak significantly and prevent the disease spread to the general population but may also, if not implemented appropriately, cause more severe outbreak within universities/colleges, while late implementation of Fengxiao can achieve nothing more than no implementation. Strengthening local control strategies (quarantine and hygiene precaution) is much more effective in mitigating outbreaks and inhibiting the successive waves than implementing Fengxiao. Either strong mobility or high transport-related transmission rate during the Spring Festival holiday will not reverse the ongoing outbreak, but both will result in a large new wave. The findings suggest that Fengxiao and travel precautions should not be relaxed unless strict measures of quarantine, isolation, and hygiene precaution practices are put in place. Integration and prompt implementation of these interventions can significantly reduce the overall attack rate of pandemic outbreaks.

[Clinicopathologic study of parvovirus B19 infection in perinatal period].

OBJECTIVE: To characterize the risks and histopathological features of parvovirus B19 infection of infants in perinatal period. METHODS: Routine pathological examination was performed on 1 neonate, 2 dead fetuses and 2 placentas using either autopsy or biopsy materials. RESULTS: The diagnostic intranuclear inclusions were found in erythroblasts in the bone marrow, liver, spleen and lungs in one case, in the spleen and liver in one case, in the spleen in one case, and in the placentas in two cases. CONCLUSIONS: Severe hemolytic anemia or fetal hydrop or hemophagocytosis caused by the infection of parvovirus B19 can lead to death of infected neonates and fetus. Pathological confirmation of parvovirus B19 infection relies on the identification of erythroblasts containing the diagnostic intranuclear inclusions.

[Perivascular epithelioid cell tumor of uterus: report of 5 cases and literature review].

OBJECTIVE: To study the pathologic features, diagnosis, differential diagnosis and biologic behavior of uterine perivascular epithelioid tumor. METHODS: Five cases of uterine perivascular epithelioid cell tumor were studied by light microscopy and immunohistochemistry. Follow-up information was reviewed. RESULTS: All the five tumors were composed by clear or eosinophilic cells arranged in nests and cords, associated with abundant small vessels and hyalinization in the stroma. Immunohistochemically, the tumor cells demonstrated positive staining for melanocytic markers (HMB45 and/or Melan-A), desmin and smooth muscle actin. The staining for cytokeratin and CD10 was negative. All the patients followed for a certain period are still alive, with no evidence of disease recurrence. CONCLUSIONS: Perivascular epithelioid cell tumor is a rare mesenchymal tumor of uterus, with distinctive histologic and immunohistochemical features. It should be distinguished from clear cell carcinoma and epithelioid leiomyoma of uterus. Positivity for melanocytic markers (especially HMB45) plays an important role in the diagnosis of this tumor. In general, the tumor is categorized as benign, with uncertain malignant potential and malignant.