Twist Promotes Tumor Metastasis in Basal-Like Breast Cancer by Transcriptionally Upregulating ROR1

Rationale: Twist is a key transcription factor for induction of epithelial-mesenchymal transition (EMT), which promotes cell migration, invasion, and cancer metastasis, confers cancer cells with stem cell-like characteristics, and provides therapeutic resistance. However, the functional roles and targeted genes of Twist in EMT and cancer progression remain elusive. Methods: The potential targeted genes of Twist were identified from the global transcriptomes of T47D/Twist cells by microarray analysis. EMT phenotype was detected by western blotting and immunofluorescence of marker proteins. The dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the direct transcriptional induction of ROR1 by Twist. A lung metastasis model was used to study the pro-metastatic role of Twist and ROR1 by injecting MDA-MB-231 cells into tail vein of nude mice. Bio-informatics analysis was utilized to measure the metastasis-free survival of breast cancer patients. Results: Twist protein was proved to directly activate the transcription of ROR1 gene, a receptor of Wnt5a in non-canonical WNT signaling pathway. Silencing of ROR1 inhibited EMT process, cell migration, invasion, and cancer metastasis of basal-like breast cancer (BLBC) cells. Knockdown of ROR1 also ameliorated the pro-metastatic effect of Twist. Furthermore, analyses of clinical specimens indicated that high expression of both ROR1 and Twist tightly correlates with poor metastasis-free survival of breast cancer patients. Conclusion: ROR1 is a targeted gene of Twist. Twist/ROR1 signaling is critical for invasion and metastasis of BLBC cells

Early Non-Response as a Predictor of Later Non-Response to Antipsychotics in Schizophrenia: A Randomized Trial

BACKGROUND: It remains a challenge to predict the long-term response to antipsychotics in patients with schizophrenia who do not respond at an early stage. This study aimed to investigate the optimal predictive cut-off value for early non-response that would better predict later non-response to antipsychotics in patients with schizophrenia. METHODS: This multicenter, 8-week, open-label, randomized trial was conducted at 19 psychiatric centers throughout China. All enrolled participants were assigned to olanzapine, risperidone, amisulpride, or aripiprazole monotherapy for 8 weeks. The positive and negative syndrome scale (PANSS) was evaluated at baseline, week 2, week 4, and week 8. The main outcome was the prediction of nonresponse. Nonresponse is defined as a \u3c 20% reduction in the total scores of PANSS from baseline to endpoint. Severity ratings of mild, moderate, and severe illness corresponded to baseline PANSS total scores of 58, 75, and 95, respectively. RESULTS: At week 2, a reduction of \u3c 5% in the PANSS total score showed the highest total accuracy in the severe and mild schizophrenia patients (total accuracy, 75.0% and 80.8%, respectively), and patients who were treated with the risperidone and amisulpride groups (total accuracy, 82.4%, and 78.2%, respectively). A 10% decrease exhibited the best overall accuracy in the moderate schizophrenia patients (total accuracy, 84.0%), olanzapine (total accuracy, 79.2%), and aripiprazole group (total accuracy, 77.4%). At week 4, the best predictive cut-off value was \u3c 20%, regardless of the antipsychotic or severity of illness (total accuracy ranging from 89.8 to 92.1%). CONCLUSIONS: Symptom reduction at week 2 has acceptable discrimination in predicting later non-response to antipsychotics in schizophrenia, and a more accurate predictive cut-off value should be determined according to the medication regimen and baseline illness severity. The response to treatment during the next 2 weeks after week 2 could be further assessed to determine whether there is a need to change antipsychotic medication during the first four weeks. TRIAL REGISTRATION: This study was registered on Clinicaltrials.gov (NCT03451734)

Childhood Sexual Abuse and the Development of Recurrent Major Depression in Chinese Women

Background Our prior study in Han Chinese women has shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in our whole data set? Method Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 6017 clinically ascertained with recurrent MD and 5983 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression. Results We confirmed earlier results by replicating prior analyses in 3,950 new recurrent MD cases. There were no significant differences between the two data sets. Any form of CSA was significantly associated with recurrent MD (OR 4.06, 95% confidence interval (CI) [3.19–5.24]). This association strengthened with increasing CSA severity: non-genital (OR 2.21, 95% CI 1.58–3.15), genital (OR 5.24, 95% CI 3.52–8.15) and intercourse (OR 10.65, 95% CI 5.56–23.71). Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes. Recurrent MD patients those with CSA had an increased risk for dysthymia (OR 1.60, 95%CI 1.11–2.27) and phobia (OR 1.41, 95%CI 1.09–1.80). Any form of CSA was significantly associated with suicidal ideation or attempt (OR 1.50, 95% CI 1.20–1.89) and feelings of worthlessness or guilt (OR 1.41, 95% CI 1.02–2.02). Intercourse (OR 3.47, 95%CI 1.66–8.22), use of force and threats (OR 1.95, 95%CI 1.05–3.82) and how strongly the victims were affected at the time (OR 1.39, 95%CI 1.20–1.64) were significantly associated with recurrent MD

Associations of Educational Attainment, Occupation, Social Class and Major Depressive Disorder among Han Chinese Women

Background The prevalence of major depressive disorder (MDD) is higher in those with low levels of educational attainment, the unemployed and those with low social status. However the extent to which these factors cause MDD is unclear. Most of the available data comes from studies in developed countries, and these findings may not extrapolate to developing countries. Examining the relationship between MDD and socio economic status in China is likely to add to the debate because of the radical economic and social changes occurring in China over the last 30 years. Principal findings We report results from 3,639 Chinese women with recurrent MDD and 3,800 controls. Highly significant odds ratios (ORs) were observed between MDD and full time employment (OR = 0.36, 95% CI = 0.25–0.46, logP = 78), social status (OR = 0.83, 95% CI = 0.77–0.87, logP = 13.3) and education attainment (OR = 0.90, 95% CI = 0.86–0.90, logP = 6.8). We found a monotonic relationship between increasing age and increasing levels of educational attainment. Those with only primary school education have significantly more episodes of MDD (mean 6.5, P-value = 0.009) and have a clinically more severe disorder, while those with higher educational attainment are likely to manifest more comorbid anxiety disorders. Conclusions In China lower socioeconomic position is associated with increased rates of MDD, as it is elsewhere in the world. Significantly more episodes of MDD occur among those with lower educational attainment (rather than longer episodes of disease), consistent with the hypothesis that the lower socioeconomic position increases the likelihood of developing MDD. The phenomenology of MDD varies according to the degree of educational attainment: higher educational attainment not only appears to protect against MDD but alters its presentation, to a more anxious phenotype

Minicircle-oriP-IFNγ: A Novel Targeted Gene Therapeutic System for EBV Positive Human Nasopharyngeal Carcinoma

) in which the transgene expression was under the transcriptional regulation of oriP promoter.. Immunohistochemistry was used to detect the expression and the activity of the IFNγ in tumor sections. Our results demonstrated that mc-oriP vectors mediated comparable gene expression and anti-proliferative effect in the EBV-positive NPC cell line C666-1 compared to mc-CMV vectors. Furthermore, mc-oriP vectors exhibited much lower killing effects on EBV-negative cell lines compared to mc-CMV vectors. The targeted expression of mc-oriP vectors was inhibited by EBNA1-siRNA in C666-1. This selective expression was corroborated in EBV-positive and -negative tumor models. as a safe and highly effective targeted gene therapeutic system for the treatment of EBV positive NPC

Microstructure Sensitivity on Environmental Embrittlement of a High Nb Containing TiAl Alloy under Different Atmospheres

Mechanical properties in different atmospheres, including oxygen, vacuum, air and H2, of high Nb containing TiAl alloys with the compositions of Ti–45Al–8.5Nb–(0.2W, 0.2B, 0.02Y) have been investigated in this work. Three different microstructure types, nearly lamellar, gamma phase increased nearly lamellar and fully lamellar are selected for revealing the microstructure sensitivity of environmental embrittlement. The results show that the three types of microstructures are all affected by the hydrogen–induced environmental embrittlement. Although the fracture mode of the experimental alloy is cleavage fracture in all atmospheres, the proportions of transgranular and intergranular fractures are different, especially comparing the fracture surfaces in oxygen and hydrogen. Performance comparison results show that the nearly lamellar microstructure is the most susceptible to the hydrogen–induced environmental embrittlement, while the gamma phase increased microstructure is the most stable one; the fully lamellar microstructure results in moderate susceptibility to the atmospheres. Combined with the hydrogen absorption kinetic analysis, it indicates that γ phase at the interface of lamellar colony significantly inhibits the hydrogen–induced environmental embrittlement, while the effect of β phase is just the opposite. In addition, the correlation between microstructure and hydrogen–induced environmental embrittlement is revealed and the corresponding mechanism is also discussed in this work

Hydrogen absorption/desorption cycling performance of Mg-based alloys with in-situ formed Mg2Ni and LaHx (x = 2, 3) nanocrystallines

Aiming to elucidate the hydrogen absorption/desorption cycling properties of Mg-based alloys with in-situ formed Mg2Ni and LaHx (x = 2, 3) nanocrystallines, the hydrogen storage cycle stability, hydriding/dehydriding cycling kinetics and thermodynamic stability of the experimental alloys have been investigated in detail. The results show that the Mg-Ni-La alloys exhibit improved hydrogen storage cycling properties and can remain storage hydrogen above 5.5 wt% after 200 cycles. With the increase of cycling numbers, the dehydrogenation rates of the experimental samples increase firstly and then gradually decrease, and eventually maintain relative stable state. Microstructure observation reveals that powders sintering and hydrogen decrepitation both exist during hydrogen absorption/desorption cycles due to repeated volume expansion and contraction. Meanwhile, the in-situ formed LaHx (x = 2, 3) and Mg2Ni nanocrystallines stabilize the microstructures of the particles and hinder the powders sintering. After 200 cycles, the average particle size of the experimental samples decreases and the specific surface area apparently increases, which leads to the decomposition temperatures of MgH2 and Mg2NiH4 slightly shift to lower temperatures. Moreover, Mg2Ni and LaHx (x = 2, 3) have been proven to be stable catalysts during long-term cycling, which can still uniformly distribute within the powders after 200 cycles

Microstructure and phase transformations of ωo_o-Ti4_4Al3_3Nb based alloys after quenching and subsequent aging at intermediate temperatures

The existence of ω$_o$ (ordered ω) phase in TiAl alloys in different compositions at intermediate temperatures has been widely reported. In this study, the phase transformation behaviors of ω$_o$-based alloys at 750–900 °C were studied by electron microscopy. It is found that fine-grained microstructures mainly composed of $γ$+ω$_o$ and a tiny amount of $α_2$ phase precipitated in the alloys quenched from high temperature during aging. Twins form in $α_2$ phase after aging, which is analogous to observations reported in deformed TiAl alloys. The $γ$ phase precipitates originate from the stacking faults of $α_2$ laths and grow up by coarsening at 750 °C. Semi-coherent interfaces between $γ$ and ω$_o$ phases are formed and a high density of stacking faults can be observed inside the $α_2$ laths. At higher temperatures, the direct nucleation of $γ$ phase from the ω$_o$/β$_o$ matrix becomes active. Various orientation relationships are found between ω$_o$, $γ$ and $α_2$ phases, leading to a number of grain clusters having smooth interfaces in between. In addition, the effects of Ta, V and Zr on the microstructure are investigated. The effect of these elements on the stability of the ω$_o$ phase is not as obvious as reported for some other elements