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Background Though BRCA1 mutation is the most susceptible factor of breast cancer, its prognostic value is disputable. Here in this study, we use a novel method which based on whole-genome analysis to evaluate the chromosome instability (CIN) value and identified the potential relationship between CIN and prognosis of breast cancer patients with germline-BRCA1 mutation. Materials and methods Sanger sequencing or a 98-gene panel sequencing assay was used to screen for BRCA1 germline small mutations in 1151 breast cancer patients with high-risk factors. MLPA assay was employed to screen BRCA1 large genomic rearrangements in familial breast cancer patients with BRCA1 negative for small mutations. Thirty-two samples with unique BRCA1 germline mutation patterns were further subjected to CIN evaluation by LPWGS (low-pass whole-genome sequencing) technology. Results Firstly, 113 patients with germline BRCA1 mutations were screened from the cohort. Further CIN analysis by the LPWGS assay indicated that CIN was independent from the mutation location or type of BRCA1. Patients with high CIN status had shorter disease-free survival rates (DFS) (HR = 6.54, 95% CI 1.30–32.98, P = 0.034). The TP53 copy loss was also characterized by LPWGS assay. The rates of TP53 copy loss in CIN high and CIN low groups were 85.71% (12/14) and 16.67% (3/18), respectively. Conclusion CIN-high is a prognostic factor correlated with shorter DFS and was independent with the germline BRCA1 mutation pattern. Higher CIN values were significantly correlated with TP53 copy loss in breast cancer patients with germline BRCA1 mutation. Our results revealed a reliable molecular parameter for distinguishing patients with poor prognosis from the BRCA1-mutated breast cancer patients.

Healthcare workers (HCWs) are considered both a high-risk population regarding infections and effective vaccine recommenders whose willingness to be vaccinated is the key to herd immunity. However, the vaccination status, acceptance, and knowledge of the 2019 coronavirus disease (COVID-19) vaccine among HCWs remain unknown. Therefore, we conducted an online survey regarding the above among HCWs in China after the vaccine was made available. Questionnaires returned by 1,779 HCWs were analyzed. Among these participants, 34.9% were vaccinated, 93.9% expressed their willingness to receive the COVID-19 vaccine, and vaccine knowledge level was high (89.2%). A bivariate analysis found that participants with a college degree, low level of knowledge, non-exposure to COVID-19 status, and those who are females or nurses have a lower vaccination rate, while participants who are married, with a monthly income of more than 5,000 yuan, and low knowledge levels are less willing to be vaccinated. A multivariate analysis found that participants with a high (OR = 7.042, 95% CI = 4.0918-12.120) or medium (OR = 3.709, 95% CI = 2.072-6.640) knowledge level about COVID-19 vaccines were more willing to be vaccinated. Participants were less likely to accept a COVID-19 vaccine if they were married (OR = 0.503, 95% CI = 0.310-0.815). In summary, Chinese HCWs have a strong willingness to be vaccinated and a high level of knowledge. Measures, such as targeted education for HCWs with low willingness and low level of knowledge, open vaccine review procedures, increased government trust, reduced vaccine costs, and provide vaccination guarantee policies, may improve the vaccination coverage of the at-risk group.

Although impaired ability to regulate emotion is commonly reported in schizophrenic patients, the exact pattern of regulation of negative emotions in high-risk individuals remains unclear. In the current study, 26 high-schizotypy individuals paired with 26 controls completed an emotion regulation questionnaire (ERQ) and a laboratory emotion regulation task with electroencephalogram (EEG) recording. Two emotion regulation strategies, namely, reappraisal and expression suppression, were concurrently examined. The late positive potential (LPP) and frontal alpha asymmetry (FAA) were selected as two independent neural indicators of the emotion regulation effect. In the ERQ questionnaire, individuals in the high schizotypy group reported higher habitual use of suppression than the controls. During the emotion regulation task, the high schizotypy group showed no early LPP reduction in reappraisal compared with the control group and exhibited a general negative FAA pattern (left-biased alpha). In conclusion, we found that individuals with high schizotypy exhibited maladaptive regulation of negative emotions, manifested in hindered reappraisal and biased suppression; this may exacerbate the negative affect of such emotions and further serve as a risk factor for psychosis conversion. Early interventions targeting the regulation of negative emotions may be beneficial for individuals with high schizotypal traits.

Glioblastoma (GBM) is the most common primary malignant intracranial tumor. Due to its high morbidity, high mortality, high recurrence rate, and low cure rate, it has brought great difficulty for treatment. Although the current treatment is multimodal, including surgical resection, radiotherapy, and chemotherapy, it does not significantly improve survival time. The dismal prognosis and inevitable recurrence as well as resistance to chemoradiotherapy may be related to its highly cellular heterogeneity and multiple subclonal populations. Traditional Chinese medicine has its own unique advantages in the prevention and treatment of it. A comprehensive literature search of anti-glioblastoma active ingredients and derivatives from traditional Chinese medicine was carried out in literature published in PubMed, Scopus, Web of Science Cochrane library, CNKI, Wanfang, and VIP database. Hence, this article systematically reviews experimental research progress of some traditional Chinese medicine in treatment of glioblastoma from two aspects: strengthening vital qi and eliminating pathogenic qi. Among, strengthening vital qi medicine includes panax ginseng, licorice, lycium barbarum, angelica sinensis; eliminating pathogenic medicine includes salvia miltiorrhiza bunge, scutellaria baicalensis, coptis rhizoma, thunder god vine, and sophora flavescens. We found that the same active ingredient can act on different signaling pathways, such as ginsenoside Rg3 inhibited proliferation and induced apoptosis via the AKT, MEK signal pathway. Hence, this multi-target, multi-level pathway may bring on a new dawn for the treatment of glioblastoma.

Attention bias modification (ABM) is a potential intervention in relieving social anxiety symptoms, while its underlying neural mechanisms are not yet understood. The current study included 63 college students with social anxiety. Participants were assigned to the attention modification program (AMP, n = 20), the attention control condition (ACC, n = 20) and the passive waiting group (PW, n = 23). Questionnaires and the emotional Stroop task with EEG recordings were used to assess whether and how the 4-week ABM period affected emotional symptoms and specific emotional processing. Results showed that the two training groups (AMP and ACC) produced comparable emotional improvements and both showed a decrease in negative bias compared with the PW group. The ERP results indicated that despite no significant ERP changes in the PW group, the ACC group exhibited a greater N1, whereas the AMP group exhibited a reduced VPP at the post-test stage compared to the pre-test stage. Besides, both training groups showed a similar late positive potential (LPP) reduction. Notably, the reduction in LPP was positively correlated with behavioral and symptom improvement. Thus, manipulations unique to ABM (face-target contingency) primarily modulate the early attention distribution of material-related stimuli. However, the clinical benefits of attention training may be due to later cognitive-affective mechanisms.

Individuals have a tendency to show enhanced vigilance to groups of which they themselves are not a member. Stress can up-regulate hypervigilance towards threatening stimuli and was shown to promote the reinstatement of out-group related biases in a previous study conducted in women only. The current study examines how exposure to acute stress affects the retrieval of out-group related extinction biases in male participants. Results showed that men exerted a specific out-group related bias at the beginning of extinction training indexed by higher skin conductance responses (SCRs) towards out-group faces, while stress led to a return of this extinguished out-group bias. Specifically, the stress group showed higher SCRs towards out-group faces during retrieval compared to the control group and the bias index was negatively related to post-stress cardiovascular recovery. These results indicate the important interaction between stress and intergroup bias in fear conditioning, along with a potential modulation of sex.

When memories are reactivated, they enter a period of instability in which they can be affected by a variety of follow-up manipulations. The existence of this type of memory reconsolidation offers the potential for clinical interventions of maladaptive memory. However, such potential cannot be fully exploited until the internal mechanisms of memory changes via reconsolidation are better understood. In the current study, we used a three-day AB-AC paradigm that included self-referential simulation processing and employed electroencephalogram (EEG) techniques to explore how post-retrieval updates of episodic memory come about. Behaviorally, we found that reactivation alongside interference learning (ReI-L, AB-AC, n = 52) can produce much more false memories compared to no reactivation new learning (New-L, AB-DC, n = 31) and reactivation repetitive learning (Rep-L, AB-AB. n = 30). More importantly, ERP results revealed that trials from ReI-L in which memory distortions subsequently occurred showed an observable (compared to the new-learning without memory reactivation) but attenuated (compared to trials associating with later intact memory) amplitude of frontal N400, indicating a moderate level of early conflict reactivation is necessary to trigger crucial memory instability. In addition, to promote optimal distortion of the original memory, a sufficient later constructional processing is also required, reflecting in these intrusive/later false trials showed a larger amplitude of late posterior negativity (LPN). A linear classifier employing neuro features of FN400 and LPN during the reconsolidation phase could predict the original memory retention with 72% accuracy. The present findings indicate that nuance in post-retrieval interference, moderate conflict with protracted construction can lead to optimal alterations of episodic memories.

Schizotypy is associated with poor emotion regulation that is thought to contribute to the development of psychotic symptoms and to indicate a predisposition to schizophrenia. Having focused primarily on the relationship between schizotypy and explicit emotion regulation, existing studies have, until now, neglected to acknowledge the potentially important role of implicit emotion regulation. Our aim in the current study was to investigate implicit emotion regulation deficits in schizotypy. To this end, we used a newly developed Priming-Identification (PI) ERP paradigm, consisting of a priming phase and an emotion identification phase, to test 30 individuals with schizotypy and 30 healthy controls while also acquiring EEG data. During the priming phase, we aimed to manipulate emotion regulation goals (i.e., to bring about an intended emotional state) by presenting a category of words related to emotion regulation alongside a category of control words. Associated brain responses occurring during the subsequent stage were indexed according to three ERP components: N170, early posterior negativity (EPN) and late positive potential (LPP). Results showed that, in the control group, priming words associated with emotion regulation led to enhancements in the early N170 amplitude and the middle EPN during expression identification. The same pattern was not observed in the schizotypy group. In summary, our results suggest the presence of deficits in the early and middle stages of the implicit emotion regulation process among individuals with high schizotypal traits.

Rumination is an important etiological factor of anxiety pathology, with its mechanism related to the deficit of working memory. The current study examined whether working memory training (WM-T) and emotional working memory training (EWM-T) could reduce rumination in anxious individuals. The participants with high trait anxiety underwent 21 days of mobile applications-based WM-T (n = 34), EWM-T (n = 36) or placebo control (n = 36), with questionnaires, cognitive tasks, and resting electroencephalogram (EEG) as the pre-post-test indicators. The results revealed that two training groups obtained comparable operation span increases (WM-T: d = 0.53; EWM-T: d = 0.65), updating improvement (WM-T: d = 0.43; EWM-T: d = 0.60) and shifting improvement (WM-T: d = 0.49; EWM-T: d = 0.72). Furthermore, compared to the control group, the EWM-T showed significant self-reported rumination reduction (d = 0.69), increased inhibition ability (d = 0.72), as well as modification of resting EEG microstate C parameters (Duration C: d = 0.42, Coverage C: d = 0.39), which were closely related to rumination level (r ~ 0.4). The WM-T group also showed the potential to reduced self-reported rumination (d = 0.45), but with the absence of the observable inhibition improvement and resting EEG changes. The correlation analysis suggested that the emotional benefits of WM-T depending more on improved updating and shifting, and that of EWM-T depending more on improved inhibition ability. The advantage to add emotional distractions into general working memory training for targeting rumination related anxiety has been discussed.

e13069 Background: The PI3K/AKT/mTOR pathway is frequently altered in breast cancer. Everolimus is a selective inhibitor of mammalian target of Rapamycin (mTOR).The benefit of everolimus in metastatic breast cancer patients with PI3K/AKT/mTOR mutations remains unclear, especially in TNBC patients. Our study aimed to investigate the efficacy of the everolimus-containing chemotherapy in metastatic breast cancer patients with PI3K/AKT/mTOR mutations. Methods: 13 cases of HER2- metastatic breast cancer with PI3K/AKT/mTOR mutations treated with everolimus-containing chemotherapy were analyzed. The genetic profile in PI3K/AKT/mTOR pathway was studied. Results: Overall, 4 cases were hormone receptor (HR) positive and 9 were TNBC. 7 patients only had PIK3CA mutations, 1 patient had only PIK3R1 mutations, and 5 patients had other mutations in the pathway in addition to PIK3CA, including PTEN, PIK3CB, CTNNB1, FGFR1 and TSC2. 5 cases were treated as first or second line chemotherapy, and 8 were as third line or above. The ORR (CR+PR) was 38.5% (5/13), and DCR (CR+PR+SD) was 84.6% (11/13), including 5 cases of PR, 6 cases of SD, and 2 cases of PD. The median PFS was 5.8 months (95% CI 3.7-9.7), and the median OS was 14.3 months (95% CI 6.47-null). However, the ORR of TNBC patients was higher than that of HR-positive, which were 44.4% (4/9) and 25% (1/4), respectively ( p = 0.070). The mPFS was also longer than that of HR-positive with 5.8 months versus 1.7 months, as well as the mOS with 14.3 versus 3.8 months. We also found that the patients carrying other mutations besides PIK3CA in the PI3K/AKT/mTOR pathway had a longer PFS compared to the patients without other mutations, which was 9.7 months and 4.3 months respectively ( p = 0.272). And the DCR of the two groups were 100% and 75% respectively ( p = 0.451). Conclusions: We found that everolimus-containing chemotherapy was effective in the treatment of HER2- metastatic breast cancer with PI3K/AKT/mTOR pathway activation. TNBC patients had a trend of longer mPFS than HR+ patients. And the patients carrying other mutations besides PIK3CA in the PI3K/AKT/mTOR pathway have a trend of longer PFS and higher DCR compared to the patients without other mutations. However, trails with larger samples are needed for further verification.

Reversion mutations are associated with clinical resistance to poly(ADP-ribose) polymerase inhibitors (PARPi). Here, we describe the detection of a BRCA1 reversion mutation in a 39-year-old woman with metastatic breast cancer harboring a heterozygous germline BRCA1 exons 7–8 deletion who received PARPi olaparib combined with immune checkpoint inhibitor camrelizumab as third-line therapy. During progression from the olaparib and camrelizumab combination therapy, we identified via genomic sequencing a novel 7-base pair somatic deletion in BRCA1 (c.617_623delACAAATC). Sequence analyses indicated that this mutation realigned the reading frame of BRCA1, which potentially led to the reversal of its normal function and conferred resistance to PARPi.

Objective Previous studies have employed self-report measures to investigate emotion regulation (ER) strategy biases in individuals with anxiety. We investigated the neural signatures underlying ER strategy biases. Method Twenty individuals with high trait anxiety (HTA) and twenty individuals with low trait anxiety (LTA) completed both the Emotion Regulation Questionnaire and ER tasks. During the tasks, participants were required to passively view, reappraise, and suppress expression while viewing negative images. Event-related potential (ERP) indexes: P2 (an early positive component of the latency around 200ms) and late positive potential (LPP) were adopted to examine the reliability of ER strategy bias in early and later stages during ER procedure. Results Results of the questionnaire indicated that trait anxiety level was positively correlated with habitual suppression use. ERP results revealed that, in LTA individuals, P2 amplitudes were reduced during both reappraisal and suppression strategy use. HTA individuals, however, showed no significant differences in P2 amplitudes between passive-view and regulation conditions. Furthermore, during the reappraisal block, a reduction of LPP was only observed in the LTA group, while HTA individuals showed a relatively more pronounced reduction in LPP during the application of the suppression strategy. Conclusion Individuals in the HTA group do not demonstrate the application of effectively strategies during the initial stages of ER process, perhaps due to the presence of an automatic negative bias. While during the later stages of ER, HTA individuals demonstrated successful use of suppression but were deficient in voluntarily applying reappraisal techniques. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The present study explored the mechanism of attention bias modification (ABM) on Social Anxiety Disorder (SAD). The participants were assigned into training group (attention modification program, AMP) or attention bias holding group (attention control condition, ACC) randomly. To examine the underlying neural mechanism of ABM training, we used the event-related potentials (ERPs) technology and combined with a Stroop task reflecting the function of cognitive control. The behavioral results showed that after attention training, anxiety symptoms were relieved in both groups. The ERP results showed that, in Stroop task, both AMP and ACC group had an increasing N450 and an increasing SP after training, showing an improvement of cognitive control through this long-term repeated training. We also found the reduced P2 amplitudes after AMP training, but not after ACC training, which suggested that ABM training can reduce the early attention resource allocation of the individual to the relevant stimulus. Therefore, computer-based attention training could generally improve the cognitive control function in anxiety individuals, while manipulative training contingency in ABM mainly modulated the early stage of attention processing.

Thirty-six patients with high anxiety were recruited. The subjects were divided into working memory training group and control group in a voluntary and random manner, with 18 individuals in each group. The training group was trained for 21 days of working memory, and the control group was not trained for working memory. The subjective emotion ratings and the ERP indicator late positive potential (LPP) of the two groups of participants were recorded, under three experimental conditions (watching negative images, cognitive reappraisal, attentional distraction). It was found that the LPP amplitude reduction was significantly higher for training group than control group specifically in the condition of cognitive reappraisal. This study showed that working memory training can improve the ability cognitive reappraisal and can be a potential intervention for promoting the emotional regulation of individuals with high trait anxiety.

Due to the difficulty of trigger automatic emotion processing, the automatic emotion regulation of anger and fear is unclear and to explore. Using a priming procedure and ERP analysis, the current study investigated the time course of automatic emotion regulation and difference between anger and fear. 46 participants were required to finish a word matching task to activate the processing of emotion regulation unconsciously, then to complete angry and fearful facial expression identify task. Subjective self-reports and ERP results verified that: (1) priming procedure could effectively evoke automatic emotion regulation; (2) N170, EPN and LPP components analysis supported that the automatic emotion regulation started at the early stage, continued to the middle stage, and dissolved at the late stage of emotion processing; (3) anger and fear are two difference emotions with same automatic emotion regulation mechanism but distinct emotion processing.

The neural mechanism of emotion regulation had been widely concerned while still unclear. Therefore, the goal of the present study was to investigate and highlight common neural correlates of emotion regulation in healthy populations. During this task, 51 participants were required to down-regulate their emotion when viewing negative images with reappraisal and expressive suppression strategies. Using ERP and source current density analysis, the present study provided precise time frame and construct destiny sources map to show the temporal unfolding of neural events that occur during emotion regulation processes. Results showed that: (1) Emotion regulation processing starts from early attention selection to late emotion experiences processing, represented by decreased P2 and LPP to negative stimulus during emotion regulation. (2) LPP derived from prefrontal gyrus, with different neural circles involving in reappraisal and suppression emotion regulation. (3) There is conflict between the self-reporting and ERP results, indicating the necessary of using objective research methods in study of emotion regulation.

Ethnopharmacological relevance Frankincense (FRA), Ruxiang, is the resin of Boswellia carterii Birdw and Boswellia bhaw-dajiana Birdw which has been used for centuries as formulas to improve the circulation and to relieve pain against carbuncles. Stir-fried Frankincense (SFF) and vinegar processed Frankincense (VPF) are two major processed Frankincense, and the processing procedures reportedly enhance the curative efficacy or reduce the side effects of FRA. This paper describes the comparisons in plasma pharmacokinetic behaviors of 11-keto-β-boswellic acid (KBA) and 3-acetyl-11-keto-β-boswellic acid (AKBA) in FRA and its processed products, and their effects on coagulation factors and blood clotting tetrachoric, using an acute cold blood-stasis animal model after oral administration of FRA, SFF, and VPF. Materials and methods For pharmacokinetic study, Sprague–Dawley (SD) rats were randomly divided into three groups, including group FRA, group SFF and group VPF. And the plasma samples were analyzed by HPLC. For study of anticoagulatory effect, SD rats were randomly divided into six groups, including control, acute cold blood-stasis model, Fu-fang-dan-shen tablet- (0.75 g/kg), FRA-, SFF-, and VPF-treated (2.7 g/kg) groups, respectively. The serum contents of thrombin–antithrombin complex (TAT), D-dimer (D-D), and prostacyclin (PGI 2 ) of each group were measured by ELISA. The values of prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT) and fibrinogen (FIB) were also assessed by hematology analyzer. Results Significantly increased levels of C max , AUC, T 1/2, and MRT were found in rats treated with the processed products. In addition, decreased levels of D-D and TAT and increased contents of PGI 2 were observed in rats given FRA and its processed products, compared with that of the model group. Moreover, VPF improved anticoagulation more than SFF in the animals. Conclusions The observed improvement of anticoagulation by processed FRA may result from the increased absorption and bioavailability of triterpenoids.

Xyloketal B (Xyl-B) is a novel marine compound isolated from mangrove fungus Xylaria sp. We previously demonstrated that pretreatment with Xyl-B exerted neuroprotective effects and attenuated hypoxic-ischemic brain injury in neonatal mice. In the present study we investigated the neuroprotective effects of pre- and post-treatment with Xyl-B in adult mice using a transient middle cerebral artery occlusion (tMCAO) model, and explored the underlying mechanisms. Adult male C57 mice were subjected to tMCAO surgery. For the pre-treatment, Xyl-B was given via multiple injections (12.5, 25, and 50 mg·kg−1·d−1, ip) 48 h, 24 h and 30 min before ischemia. For the post-treatment, a single dose of Xyl-B (50 mg/kg, ip) was injected at 0, 1 or 2 h after the onset of ischemia. The regional cerebral perfusion was monitored using a laser-Doppler flowmeter. TTC staining was performed to determine the brain infarction volume. We found that both pre-treatment with Xyl-B (50 mg/kg) and post-treatment with Xyl-B (50 mg/kg) significantly reduced the infarct volume, but had no significant hemodynamic effects. Treatment with Xyl-B also significantly alleviated the neurological deficits in tMCAO mice. Furthermore, treatment with Xyl-B significantly attenuated ROS overproduction in brain tissues; increased the MnSOD protein levels, suppressed TLR4, NF-κB and iNOS protein levels; and downregulated the mRNA levels of proinflammatory cytokines, including IL-1β, TNF-α, IL-6 and IFN-γ. Moreover, Xyl-B also protected blood-brain barrier integrity in tMCAO mice. In conclusion, Xyl-B administered within 2 h after the onset of stroke effectively protects against focal cerebral ischemia; the underlying mechanism may be related to suppressing the ROS/TLR4/NF-κB inflammatory signaling pathway.

Epothilone B and its derivatives are tested in multiple clinical trials. Epothilone B induces neurotoxic effect in clinical trials; however, low-dose epothilone B regimen can promote neuroprotection and neurogenesis. Thus, the study of new combination chemotherapy regimen incorporating low-dose epothilone B with other chemotherapeutic agents might help to develop epothilone B-based approaches to cancer treatment and avoid the neurotoxicity of epothilone B. Cell proliferation was assessed by SRB cell viability assay. Apoptosis was analyzed by propidium iodide (PI) staining. Mitochondrial membrane depolarization was evaluated using JC-1 staining. The expression of proteins was detected by western blotting. In this study, we demonstrated that the combination of ABT-737 and low-dose epothilone B showed synergistic anti-proliferation effects on human cancer cells. In addition, epothilone B + ABT-737 synergy was through mitochondria-mediated apoptosis pathway. Furthermore, combination treatment markedly induced the activation of caspase-3 and the cleavage of PARP. The activation of PI3K/Akt/mTOR pathway is associated with resistance to epothilone B. Our data showed that epothilone B plus ABT-737 resulted in a blockade of the PI3K/AKT/mTOR signaling pathway. These data indicate that ABT-737 may be a pertinent sensitizer to epothilone B, and the strategy of combining epothilone B with ABT-737 appears to be an attractive option for overcoming the resistance and neurotoxicity of epothilone B.

Erlotinib is effective in NSCLC patients with known drug-sensitizing EGFR mutations, but its clinical efficacy in patients with wild-type EGFR or acquired resistance to erlotinib remains modest. Evodiamine is a chemical extracted from the Evodia rutaecarpa (Juss.) Benth, we showed that evodiamine could induce anti-proliferation and apoptosis in four wild-type EGFR NSCLC cell lines, and combining evodiamine with erlotinib might successfully inhibit cell proliferation and survival in wild-type EGFR NSCLC cells, characterized as erlotinib-resistant. In addition, evodiamine plus erlotinib significantly increased the apoptotic rate of NSCLC cells, as compared to single agent treatment alone. Further investigation of the mechanism underlying these effects revealed that evodiamine plus erlotinib might downregulate Mcl-1 expression through the mTOR/S6K1 control of its translation. Thus, our study has revealed evodiamine as a pertinent sensitizer to erlotinib and the strategy of combining erlotinib with evodiamine appears to be an attractive option for reversing resistance to erlotinib.