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Objectives: Norovirus is associated with one-fifth of all gastroenteritis cases, but basic epidemiological data is lacking, especially in developing countries. As long-term surveillance on norovirus gastroenteritis is scarce in western China, this study aims to update the epidemiological knowledge of norovirus gastroenteritis and to characterize the genotypes of norovirus strains. Methods: Stool samples were collected from hospitalized children under 5 years old with gastroenteritis in Chengdu, China. All samples were tested for norovirus as well as rotavirus, sapovirus, enteric adenovirus, and astrovirus by real-time RT-PCR. RdRp and VP1 genes were sequenced in norovirus-positive samples to investigate viral phylogenies. Results: Of the 1181 samples collected from 2015 to 2019, 242 (20.5%) were positive for norovirus.Among norovirus-positive cases, 65 cases had co-infection with another virus; norovirus/enteric adenovirus was most frequently detected (50.8%, 33/65). The highest positive rate was observed in children aged 13–18 months (23.7%, 68/287). Norovirus infection peaked in autumn (36.6%, 91/249), followed by summer (20.3%, 70/345). Pearson correlation analysis showed significant correlation between the norovirus-positive rate and humidity (r = 0.773, P

Background Epiregulin (EREG) is an important component of EGF and was demonstrated to promote the osteo/dentinogenic differentiation of stem cells from dental apical papilla (SCAPs). Whether EREG can stimulate the osteo/dentinogenic differentiation of dental pulp stem cells (DPSCs) in inflammatory environment is not clear. The purpose of the present study is to investigate the role of EREG on the osteo/dentinogenic differentiation ability of DPSCs in inflammatory environment. Methods DPSCs were isolated from human third molars. Short hairpin RNAs (shRNAs) were used to knock down EREG expression in DPSCs. Recombinant human EREG (rhEREG) protein was used in the rescue experiment. TNF-α was employed to mimic the inflammatory environment in vitro. Alkaline phosphatase (ALP) staining, Alizarin red staining, quantitative calcium analysis, and real-time RT-PCR were performed to detect osteo/dentinogenic differentiation markers and related signalling pathways under normal and inflammatory conditions. Results EREG depletion promoted the ALP activity and mineralization ability of DPSCs. The expression of BSP, DMP-1, and DSPP was also enhanced. Moreover, 50 ng/mL rhEREG treatment decreased the osteo/dentinogenic differentiation potential of DPSCs, while treatment with 10 ng/mL TNF-α for 4 h increased the expression of EREG in DPSCs. Conversely, EREG knockdown rescued the impaired osteo/dentinogenic differentiation ability caused by TNF-α treatment. Further mechanistic studies showed that EREG depletion activated the p38 MAPK and Erk signalling pathways in DPSCs under normal and inflammatory conditions. Conclusions Our results demonstrated that EREG could inhibit the osteo/dentinogenic differentiation potential of DPSCs via the p38 MAPK and Erk signalling pathways. Under inflammatory environment, EREG depletion enhanced osteo/dentinogenic differentiation potential of DPSCs by improving the expression of p-p38 MAPK and p-Erk.

Objective:The aim of this study was to assess the current status of disease-related knowledge and to analyze the relationship among the general condition, illness perception, and psychological status of patients with coronavirus disease 2019 (COVID-19).Methods:A hospital-based cross-sectional study was conducted on 118 patients using convenience sampling. The general questionnaire, disease-related knowledge questionnaire of COVID-19, Illness Perception Questionnaire (IPQ), and Profile of Mood States (POMS) were used to measure the current status of participants.Results:The overall average score of the disease-related knowledge of patients with COVID-19 was (79.19 ± 14.25), the self-care situation was positively correlated with knowledge of prevention and control (r = 0.265; P = 0.004) and total score of disease-related knowledge (r = 0.206; P = 0.025); the degree of anxiety was negatively correlated with the knowledge of diagnosis and treatment (r = −0.182; P = 0.049). The score of disease-related knowledge was negatively correlated with negative cognition (volatility, consequences, emotional statements) and negative emotions (tension, fatigue, depression) (P < 0.05); positively correlated with positive cognition (disease coherence) and positive emotion (self-esteem) (P < 0.05).Conclusions:It was recommended that we should pay more attention to the elderly and low-income groups, and increase the knowledge about diagnosis and treatment of COVID-19 and self-care in the future health education for patients.

Gastric cancer (GC) is one of the most common cancers around the world. We demonstrate that SPIN1 is upregulated and associated with poor prognosis in GC. SPIN1 sustains GC cell proliferation via activation of MDM2‐p21‐E2F1 signaling pathway by binding to H3K4me3 of the MDM2 promoter. E2F1 could directly bind to the SPIN1 promoter and activate its transcription, forming a positive feedback loop., Gastric cancer (GC) is one of the most common cancers around the world. Searching for specific gene expression changes during the development of GC could help identify potential therapy targets. We previously showed that the histone code reader SPIN1 may act as an oncogene in breast cancer. At present, the biological function and regulation of SPIN1 in GC remain unclear. Here, we demonstrate that SPIN1 is upregulated in GC tissues, compared with nontumorous gastric tissues. Increased expression of SPIN1 is closely associated with poor prognosis for patients with GC. Increased SPIN1 expression enhances GC cell proliferation, migration, and invasion and promotes cell cycle progression. Mechanically, SPIN1 sustains GC cell proliferation via activation of the MDM2‐p21‐E2F1 signaling pathway by binding to H3K4me3 of the MDM2 promoter region. Interestingly, E2F1 could directly bind to the SPIN1 promoter and activate its transcription, thus forming a positive feedback loop. Our data suggest that SPIN1 plays an important role in the development of GC and could be used as a promising prognostic biomarker and therapeutic target for GC.

OBJECTIVE The psychological resilience of postoperative non-small cell lung cancer (NSCLC) patients is influenced by many factors. The purpose of this study is to investigate the current state of psychological resilience and identify its influencing factors in postoperative NSCLC patients. METHODS This descriptive cross-sectional study used a convenience sampling method and recruited 382 inpatients from two Class A hospitals in Hunan, China. The Connor-Davidson Resilience Scale (CD-RISC), Strategies Used by People to Promote Health (SUPHH), Medical Coping Modes Questionnaire (MCMQ), and Multidimensional Scale of Perceived Social Support (MSPSS) were used. RESULTS Postoperative NSCLC patients' psychological resilience was at a low level, with a score of (57.18 ± 8.55). Stepped Linear Regression showed that the related influencing factors of psychological resilience of postoperative NSCLC patients were age (β = -0.313, P

Objective: To investigate the effect of Fuhe decoction on the behavior and levels of monoamine neurotransmitters in different brain regions in a depression rat model induced by chronic unpredictable mild stimulation (CUMS) combined with social isolation. Methods: Fifty male SD rats were randomly divided into a blank group, model group, fluoxetine group, Chaiqinwendan decoction group, and Fuhe decoction group. Chronic unpredictable mild stimulation combined with a social isolation method was used to replicate the depression rat model. After 42 days of administration, a tail suspension test and high-performance liquid electrochemical detection (HPLC-ECD) were used to detect the behavioral changes and changes in the content of monoamine neurotransmitters norepinephrine (NE), dopamine (DA), 5-hydroxytrytamine (5-HT), and metabolites in different brain regions of rats in each group before and after treatment. Results: Compared with the model group, the epinephrine (E) content in the Fuhe decoction group was highly significantly increased (P

Three species of Scheffersomyces were identified during a diversity study of yeasts. All three are associated with insects and rotting wood in China. Phylogenetic analyses of a genomic dataset combining ITS and nrLSU revealed that these new collections are distinct from known species, thus three new species are introduced i.e. S. jinghongensis, S. paraergatensis, and S. anoplophorae. In our phylogenetic analyses, Scheffersomyces jinghongensis possesses a strong independent lineage and is closely related to S. titanus. S. paraergatensis is closely related to S. ergatensis, while S. anoplophorae is related to S. stambukii. Several differences in physiological traits and molecular data indicate that S. jinghongensis, S. paraergatensis, and S. anoplophorae are three newly identified species.

Objective To compare the clinical efficacy and safety of a personalized three‐dimensional (3D) printed dynamic anterior plate–screw system for the quadrilateral area (DAPSQ) titanium plate and a traditional DAPSQ reconstruction plate in the treatment of double‐column acetabular fractures. Methods This was a retrospective case‐control study. From May 2014 to January 2018, 43 patients with double‐column acetabular fractures underwent open reduction and internal fixation. Among these, 20 cases were fixed with a 3D printed DAPSQ plate (3D printed group) and 23 cases were fixed with a DAPSQ reconstruction plate (control group). The 3D printed group comprised 15 men and 5 women, with an average age of 50.1 ± 8.2 years. The control group comprised 16 men and 7 women, with an average age of 51.0 ± 8.6 years. The evaluation index included the surgical data (i.e. blood loss, operating time, duration of hospital stay, and intraoperative and postoperative complications), position and length of implants, reduction quality, hip function, and related complications. The reduction quality was evaluated using the Matta scoring standard and hip function was evaluated using the modified Merle d’Aubigné score. Results A total of 43 patients met the inclusion criteria. The mean postoperative follow up was 35.2 months in the 3D printed group and 36.9 months in the control group. There were no significant group differences in demographic data between the two groups. The position and length of the 3D printed implants were generally in accord with preoperative planning using a 3D pelvic model. Patients in the 3D printed group had significantly shorter operation time (223.2 vs 260.5 min, P 0.05). The general complication rate in the 3D printed group and the control group was 15% and 26.1%, respectively, but the difference between the two groups was not statistically significant. Conclusion Use of a personalized 3D printed DAPSQ plate has potential advantages in reducing the operation time and blood loss during the treatment of double‐column acetabular fractures.

Stroke is a major cause of death and disability in China, and no therapies have proven effective to prevent it. Popular belief holds that the lunar cycle affects human physiology, behavior, and health. The aim of our study is to determine whether the lunar cycle impacts the incidence of stroke subtypes [intracerebral hemorrhage (ICH), transient ischemic attack (TIA) and ischemic stroke (IS)]. We retrospectively extracted the discharge registry data of all patients with first-ever acute stroke hospitalized in the affiliated hospital of Beijing University of Traditional Chinese Medicine during 2002-2015. The onset times of stroke were assigned to four primary lunar phases based on NASA definitions. Chi-square tests and multiple logistic regression analyses were used to estimate the association between the lunar cycle and stroke incidence with adjustment for age, sex and season. A total of 5,965 patients with stroke (4,909 admissions for ischemic stroke IS, 754 admissions for ICH, and 302 admissions for TIA) were evaluated in our study. Subgroup analysis indicated that the admission rates of different sexes for IS tended to have opposite variation during the four moon phases. More female patients were admitted during the new moon than in the first and third quarters, while fewer male patients were admitted during the new moon than in the first and third quarters (χ2 = 15.589, P = .001). Multiple logistic regression analyses revealed that men were more likely to be admitted for IS in the first quarter than during the new moon (odds ratio [OR] = 1.252, 95% confidence interval [CI] = 1.076-1.456) (P = .004), and a corresponding trend was also identified for the third quarter (OR = 1.235, 95% CI = 1.062-1.437) (P = .006). No significant gender differences were shown in ICH or TIA. No sex difference is obvious during the full moon. Moon phases seem to affect both genders, but in very different ways. It seems that the new moon is a protective factor for male ischemic stroke patients and a risk factor for female ones. Woman tends to be more vulnerable than ever at the new moon, so deserves more attention and care. The mechanisms underlying this observation are worth studying further.

To observe the effect of moxibustion at Feishu (BL 13) on related inflammatory cells and inflammatory factors in the bronchoalveolar lavage fluid of asthma model rats, and to explore the mechanism of moxibustion in treating asthma. A total of 48 Sprague-Dawley (SD) rats were randomly divided into a normal group, a model group, a moxibustion group and a medication group, with 12 rats in each group. Except for the normal group, the rats in the other three groups were subjected to ovalbumin sensitization to stimulate the asthma. At the same time, rats in the moxibustion group received moxibustion at bilateral Feishu (BL 13), and rats in the medication group received dexamethasone by intragastric administration. Rats in the normal and the model groups only received the same fixation and normal saline by intragastric administration. After the interventions, the inspiratory resistance, the expiratory resistance, and the pulmonary compliance were measured for rats in each group; the numbers of the inflammatory cells in the bronchoalveolar lavage fluid were counted; the levels of the involved inflammatory factors in bronchoalveolar lavage fluid were detected; the pathological morphologies of the lung tissues were observed under light microscope. After modeling, compared with the normal group, the rats in the model group showed obvious asthma attack-like response, significantly increased inspiratory resistance and expiratory resistance (both P 0.05). Both moxibustion at Feishu (BL 13) and intragastric administration of dexamethasone can improve the asthma attack-like symptoms of ovalbumin-sensitized rats; regulating the inflammatory cell numbers and the inflammatory factor contents in the lung may be one mechanism of moxibustion in treating asthma.

Long noncoding RNAs (lncRNAs) were demonstrated to play important roles in gene regulation and cancer progression. However, the functional roles of lncRNAs and the detailed mechanisms underlying gastric cancer (GC) progression remain largely unclear. Here, we identified a novel cancer-related lncRNA, termed lncRNA GCMA (Gastric Cancer metastasis-associated lncRNA), which was upregulated in GC tissues with lymph node metastasis (LNM) compared with tissues without LNM. High expression of GCMA was significantly associated with poor prognosis of patients with GC. Luciferase assays, bioinformatics analyses and chromatin immunoprecipitation (ChIP) assays indicated that SP1 transcription factor directly bound to the GCMA promoter region and activated its transcription. Functionally, upregulation of GCMA dramatically promoted GC cells proliferation, migration and invasion in vitro, whereas knockdown of GCMA elicited the opposite function. Consistently, stable knockdown of GCMA inhibited tumor proliferation, invasion and metastasis in vivo. Mechanistically, by using bioinformatics analyses, RNA binding protein immunoprecipitation (RIP) assays, luciferase assays and western-blot assays, GCMA was demonstrated to function as a competing endogenous RNA (ceRNA) via competitively absorbing miR-124 and miR-34a to upregulate slug and snail, thereby induced epithelial-mesenchymal transition (EMT) and GC cell metastasis in vitro and in vivo. Collectively, these results demonstrate that GCMA functions as an oncogenic lncRNA that may serve as a potential prognostic biomarker for GC and shed new lights on targeted therapy of GC in the future.

Objective Patients with HER2-positive metastatic breast cancer (MBC) benefit from trastuzumab-based therapy but eventually develop intrinsic or acquired resistance. Whether plasma HER2 gene copy number (GCN) could predict survival after trastuzumab treatment remained controversial. We evaluated the prognostic value of plasma HER2 GCN using low-coverage whole-genome sequencing (LC-WGS). Methods The plasma was collected from HER2-positive MBC patients whose pre-therapeutic samples were available before first-line trastuzumab-based treatment. Plasma DNA was extracted and assessed by LC-WGS for HER2 GCN. The optimal cut-off point for HER2 GCN to shorter survival was determined by receiver operating characteristic (ROC) curve analysis. Results A total of 49 patients were retrieved from 2013 to 2017, among whom 21 had multiple organ involvement (≥3 sites). Variations of HER2 GCN in pre-therapeutic plasma ranged from 1.89 to 23.86 (median = 2.59). ROC analysis identified the optimal cut-off point for HER2 GCN as 2.82 (P = 0.005), with 23 patients had high-level HER2 GCN and 26 in the low-level group. Both progression-free survival (PFS, P = 0.032) and overall survival (OS, P = 0.006) were adversely associated with high-level HER2 GCN. In multivariate analyses, high HER2 GCN was independently associated with shorter PFS [hazard ratio (HR) = 2.042, P = 0.037], while both high HER2 GCN (HR = 4.909, P = 0.004) and more metastatic organs (HR = 4.019, P = 0.011) were negative prognostic factors for OS. Conclusion In this population of patients with HER2-positive MBC, individuals with high HER2 GCNs in plasma had worse prognosis after trastuzumab-based therapy. Plasma HER2 GCN may be a prognostic marker in these patients.

Background Accumulating evidence demonstrated that long noncoding RNAs (lncRNAs) played important regulatory roles in many cancer types. However, the role of lncRNAs in gastric cancer (GC) progression remains unclear. Methods RT-qPCR assay was performed to detect the expression of HNF1A-AS1 in gastric cancer tissues and the non-tumourous gastric mucosa. Overexpression and RNA interference approaches were used to investigate the effects of HNF1A-AS1 on GC cells. Insight into competitive endogenous RNA (ceRNA) mechanisms was gained via bioinformatics analysis, luciferase assays and an RNA-binding protein immunoprecipitation (RIP) assay, RNA-FISH co-localisation analysis combined with microRNA (miRNA)-pulldown assay. Results This study displayed that revealed expression of HNF1A-AS1 was associated with positive lymph node metastasis in GC. Moreover, HNF1A-AS1 significantly promoted gastric cancer invasion, metastasis, angiogenesis and lymphangiogenesis in vitro and in vivo. In addition, HNF1A-AS1 was demonstrated to function as a ceRNA for miR-30b-3p. HNF1A-AS1 abolished the function of the miRNA-30b-3p and resulted in the derepression of its target, PIK3CD, which is a core oncogene involved in the progression of GC. Conclusion This study demonstrated that HNF1A-AS1 worked as a ceRNA and promoted PI3K/AKT signalling pathway-mediated GC metastasis by sponging miR-30b-3p, offering novel insights of the metastasis mechanism in GC.

Objective: Findings on the effect of the lunar cycle on mental illness are conflicting. We investigated the association between the lunar cycle and a number of psychiatric presentations of schizophrenia and determined which subtypes were susceptible to lunar phases.Methods: We evaluated 13,067 patients admitted to Zhumadian Psychiatric Hospital between January 1, 2012, and December 31, 2017 (73 lunar cycles). Patients were retrospectively assigned to lunar phase based on their admission date: new moon +/- 1 day, first quarter +/- 1 day, full moon +/- 1 day, and third quarter +/- 1 day. The International Statistical Classification of Diseases, 10th revision (ICD-10), was used for diagnosis. We used a Chi-squared goodness of fit test to evaluate the distribution of admissions across the lunar phase and R*C Chi-squared tests to compare age, sex, birth season, and clinical subtype distributions by phase. We used multiple logistic regression to further identify the relationship between clinical subtype and lunar phase.Results: Psychiatric admissions for schizophrenia varied significantly across the lunar cycle (χ2 = 36.400, p .05).Conclusions: Psychiatric admissions for schizophrenia show lunar periodicities. People with schizophrenia tend to be stable in the new moon, but their condition is easily aggravated during the first quarter and full moon. Patients with paranoid schizophrenia are more susceptible to deterioration at the full moon, so merit more attention and care from communities, families, and hospitals.

BACKGROUND: Many studies have investigated the association between matrix metalloproteinase polymorphisms and lung cancer susceptibility. However, the results are still controversial. To clarify these associations, we conducted a meta-analysis. METHODS: A systematic search of studies was conducted in PubMed, Embase, and China National Knowledge Infrastructure. Overall and subgroup analysis stratified by ethnicity was conducted. OR with 95% CI was used to assess the strength of the association. Furthermore, false-positive report probability (FPRP) tests were also performed for associations obtained in this meta-analysis. RESULTS: Twenty-four studies, including 10,099 cases and 9,395 controls, were analyzed. Nine polymorphisms were reported. For MMP1 -1607 1G/2G and MMP7 -181 A/G, increased lung cancer risk was found in Asians. For MMP2 -1306 C/T and MMP2 -735 C/T, decreased lung cancer risk was found in both “diverse populations” and Asians. For MMP9 -1562, C/T decreased lung cancer risk was found in both “diverse populations” and Caucasians. For MMP13 -77A/G, the A/G genotype decreased lung cancer risk in Asians. However, only associations between MMP1 -1607 1G/2G, MMP2 -1306 C/T, MMP2 -735 C/T, and MMP7 -181 A/G and lung cancer risk were considered noteworthy according to FPRP tests. There was no association between MMP3 -1171 5A/6A, MMP9 R279Q, and MMP12 -82A/G and lung cancer risk. CONCLUSIONS: Our meta-analysis suggested that MMP1 -1607 1G/2G and MMP7 -181 A/G were risk factors for lung cancer, while MMP2 -1306 C/T, MMP2 -735 C/T, MMP9 -1562 C/T, and MMP13 -77A/G might be protective factors. However, results for MMP9 -1562 C/T and MMP13 -77A/G should be interpreted with caution due to the probability of false-positive reports.

Background: Androgen receptor (AR) blocker has become an increased interest in the treatment of BC, in which about 60-80% patients showed AR positive. However, currently no AR blocker has been approved in mBC. GT0918 is a new chemical entity of AR blocker with possible AR down-regulation. This study is an open-label, single-center, dose escalation phase I trial to assess GT0918 in mBC female patients who have progressed after systemic treatments in China. The primary objectives are to identify the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). The secondary objectives are to assess pharmacokinetics and pharmacodynamics of GT0918 with single and multiple dosage applications. (CTR20170757) Methods: Patients (pts) with historically confirmed mBC who had progressed after either chemotherapy, hormonal or targeted therapy, or could not tolerate currently standard therapies were eligible. With the starting dose at 100 mg of GT0918, the decision of dose escalation in the 3+3 design was based on the safety and tolerability assessments. GT0918 was administered orally once, followed by a 7-day off-treatment period for single dose PK analysis of drug elimination. Then GT0918 oral administration was resumed once daily for 28 consecutive days and multiple dose PK analysis was assessed at the end of first cycle (28 days). The first 28-days on treatment (cycle 1) was defined as DLT period. Pts manifesting an objective response or stable disease and likely to have clinical benefit from continued treatment were continued on GT0918 thereafter until they experienced one of following events of intolerable toxicities, disease progression or withdrew consent. Results: 18 pts were enrolled and treated with GT0918 since 9/6/2017 as defined in protocol at five dose levels: 100 mg (n = 3), 200 mg (n = 4), 300 mg (n = 4), 400 mg (n = 4) and 500 mg (n = 3) (as to 7/2/2019). All pts progressed more than two lines of therapies with 83.3% (15/18) pts were treated ≥3rd lines. Out of 6 confirmed AR positive pts, two (33.3%) at 300 mg cohort had finished 17 and 19 cycles individually and continue treatment (as 7/2/19). No DLT was observed and MTD has not been reached. GT0918 related adverse events (AEs) were grade 1 or 2 as per CTCAE v4.03, including fatigue, hypertriglyceridemia, anemia, hypercholesterolemia, increased LDL, nausea, loss of appetite, increased ALT, increase of weight loss, constipation and thrombocytopenia. PK profile analysis showed that in the single-dose study, GT0918 showed a fast absorption profile. In the multiple-dose study, the steady-state serum concentration level of GT0918 and its main metabolite were attained at 21 days. Conclusions: Proxalutamide (GT0918) administrated orally once a day is well tolerated in late-stage pts. No DLT has occurred at maximum dose 500 mg. Pts with AR positive biomarker could have better clinical outcomes with GT0918 treatment. GT0918 and its main metabolite exhibited a nonlinear pharmacokinetic profile over the dose range from 100mg to 500 mg. An expanded/phase Ib in AR positive mBC pts has launched in China to evaluate the anti-tumor activity and safety of GT0918. 200 mg and 300 mg were selected for dose expansion. Citation Format: Huiping Li, Ran Ran, Guohong Song, Hanfang Jiang, Ruyan Zhang, Yaxin Liu, Luping Meng, Phoebe Zhang, Ke Chen, Qiaoxia Zhou, Karl Zhou, Youzhi Tong. Evaluation of safety, pharmacokinetics and pharmacodynamics of proxalutamide (GT0918), a potent androgen receptor (AR) blocker, in patients with metastatic breast cancer (mBC): Phase I dose escalation trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-17-05.

Epithelial to mesenchymal transition (EMT) is a dynamic process that drives cancer cell plasticity and is thought to play a major role in metastasis. Here we show, using MDA-MB-231 cells as a model, that the plasticity of at least some metastatic breast cancer cells is dependent on the transcriptional co-regulator CBFβ. We demonstrate that CBFβ is essential to maintain the mesenchymal phenotype of triple-negative breast cancer cells and that CBFβ-depleted cells undergo a mesenchymal to epithelial transition (MET) and re-organise into acini-like structures, reminiscent of those formed by epithelial breast cells. We subsequently show, using an inducible CBFβ system, that the MET can be reversed, thus demonstrating the plasticity of CBFβ-mediated EMT. Moreover, the MET can be reversed by expression of the EMT transcription factor Slug whose expression is dependent on CBFβ. Finally, we demonstrate that loss of CBFβ inhibits the ability of metastatic breast cancer cells to invade bone cell cultures and suppresses their ability to form bone metastases in vivo. Together our findings demonstrate that CBFβ can determine the plasticity of the metastatic cancer cell phenotype, suggesting that its regulation in different micro-environments may play a key role in the establishment of metastatic tumours.

Hyperactivity of the hypothalamic-pituitary-adrenal axis and impairment of the central corticotropin-releasing factor system are factors in the pathogenesis of depression. Though several antagonists of the corticotropin-releasing factor 1 receptor were effective in the recognized behavioral tests for antidepressant activity, there is still little information on the potential interactions between corticotropin-releasing factor 1 receptor inhibitors and conventional antidepressant therapy. The aim of our study was to assess the influence of CP154526, a corticotropin-releasing factor 1 receptor blocker, which presented some signs of depression. Our results revealed that CP154526 (5 and 10 mg/kg) or fluoxetine (10 mg/kg) treatment notably improved the sucrose consumption, produced anti-depressive-like behavior in open-field test, as well as immobility time in forced swimming test. The levels of interleukin-6, interleukin-1β, tumor necrosis factor-α, and corticotropin-releasing hormone concentration in the serum were inhibited effectively by CP154526 or fluoxetine administration. Real-time quantitative PCR and western blot analysis showed the upregulated levels of brain-derived neurotrophic factor and growth associated protein 43 (GAP43) in the hypothalamus of the rats exposed to chronic unpredictable mild stress (CUMS), while different degrees of downregulation in their expression were detected after CP154526 (5 and 10 mg/kg) or fluoxetine (10 mg/kg) treatment, respectively. Thus, our data demonstrated that CP154526 exhibited antidepressant effect in CUMS rats, which might be mediated by decreasing the brain-derived neurotrophic factor and GAP43 expression in the hypothalamus.

Objective Fluzoparib (SHR3162) is a novel, potent poly(ADP-ribose) polymerases (PARP)1, 2 inhibitor that showed anti-tumor activity in xenograft models. We conducted a phase I, first-in-human, dose-escalation and expansion (D-Esc and D-Ex) trial in patients with advanced solid cancer. Methods This was a 3+3 phase I D-Esc trial with a 3-level D-Ex at 5 hospitals in China. Eligible patients for D-Esc had advanced solid tumors refractory to standard therapies, and D-Ex enrolled patients with ovarian cancer (OC). Fluzoparib was administered orally once or twice daily (bid) at 11 dose levels from 10 to 400 mg/d. Endpoints included dose-finding, safety, pharmacokinetics, and antitumor activity. Results Seventy-nine patients were enrolled from March, 2015 to January, 2018 [OC (47, 59.5%); breast cancer (BC) (16, 20.3%); colorectal cancer (8, 10.1%), other tumors (8, 10.1%)]; 48 patients were treated in the D-Esc arm and 31 in the D-Ex arm. The maximum tolerated dose (MTD) was 150 mg bid, with a half-life of 9.14 h. Grade 3/4 adverse events included anemia (7.6%) and neutropenia (5.1%). The objective response rate (ORR) was 30% (3/10) in patients with platinum-sensitive OC and 7.7% (1/13) in patients with BC. Among patients treated with fluzoparib ≥120 mg/d, median progression-free survival (mPFS) was 7.2 [95% confidence interval (95% CI), 1.8-9.3] months in OC, 9.3 (95% CI, 7.2-9.3) months in platinum-sensitive OC, and 3.5 (range, 2.0-28.0) months in BC. In patients with germline BC susceptibility gene mutation (gBRCA Mut) (11/43 OC; 2/16 BC), mPFS was 8.9 months for OC (range, 1.0-23.2; 95% CI, 1.0-16.8) and 14 and 28 months for BC (those two patients both also had somaticBRCA Mut). Conclusions The MTD of fluzoparib was 150 mg bid in advanced solid malignancies. Fluzoparib demonstrated single-agent antitumor activity in BC and OC, particularly in BRCA Mut and platinum-sensitive OC.

Background: Fulvestrant 500mg has proved its clinical effectiveness in previous trials as primary or second line treatment of hormone receptor positive, human epidermal receptor 2 negative (HR+/HER2˗) post-menopausal advanced breast cancer. This real-world study aimed to investigate the efficacy and safety of Fulvestrant in HR+/HER2˗ Chinese advanced breast cancer patients. Method: HR+/HER2˗ advanced breast cancer patients who received Fulvestrant 500mg from January 2015 to December 2018 in Beijing Cancer Hospital were enrolled in this retrospective study. Progression free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS) and adverse events (AEs) of Fulvestrant were investigated. Result: In total 303 enrolled patients [median age was 51 years (range: 21-82)], 255 (84.2%) patients were at postmenopausal status at the start of Fulvestrant treatment and 264 patients (87.1%) had advanced breast cancer. The median PFS (95% confidence interval) was 14.1 months (10.1-18.0) for the first-line, 11.2 months (2.2-20.3) for the second-line and 6.7 months (4.8-8.5) for ≥third-line of Fulvestrant. The ORR and CBR were 3.8% and 86.8% for the first-line, 5.5% and 75.4% for the second-line, 1.1% and 61.1% for ≥third-line of Fulvestrant. The multivariate subgroup analyses showed, PFS was significantly longer for the patients with light tumor burden, less palliative chemotherapy before Fulvestrant and long disease-free interval. For patients receiving Fulvestrant after palliative chemotherapy, the median PFS was numerically greater in maintenance treatment group than those who progressed after chemotherapy. Only 5.0% of patients (15/303) experienced adverse events and majority were grade 1-2. The most common adverse event was headache and palpitation, with merely one patient had severe adverse event (pulmonary embolism). Conclusion: Fulvestrant is an effective, safe and well-tolerated treatment regimen in endocrine therapy for HR+/HER2˗ metastatic breast cancer. Light tumor burden, less palliative chemotherapy before Fulvestrant and long disease-free survival (DFS) might be the ideal condition of Fulvestrant treatment. Fulvestrant can be effective for premenopausal patients with drug-induced menopause. Patients of different luminal subtypes can benefit from Fulvestrant. For patients with visceral metastases, presence of liver metastases rather than lung metastases was poor prognostic factor. Fulvestrant may also be considered as a maintenance treatment after first-line palliative chemotherapy.

A novel Gram-stain-negative, strictly aerobic, rod-shaped, gray-pigmented bacterial strain, designated L-25–5 w-1T, was isolated from the water at Baiyang Lake, PR China. Cells of strain L-25–5 w-1T were motile, with a single polar flagellum. L-25–5 w-1T was able to grow at 15–37 °C (optimum 37 °C) and pH 5–8 (optimum pH 6) in R2A medium. 16S rRNA gene sequence analysis and phylogenetic analysis of L-25–5 w-1T showed the highest relationship to Azospirillum doebereinerae GSF71T (97.9 %), Azospirillum . thiophilum DSM 21654T (97.9 %) and Azospirillum . agricola CC-HIH038T (97.0 %), with other species of the genus Azospirillum showing less than 97 % sequence similarity. The predominant polar lipids were phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol, diphosphatidylglycerol and two unidentified aminolipids; the major cellular fatty acids were C16 : 0, C16 : 0 3-OH, C18 : 1 2-OH, iso-C18 : 0, summed feature 2 (C12 : 0 aldehyde and/or unknown 10.9525 and/or iso-C16 : 1I and/or C14 : 0 3-OH), summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c) and summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c); and the major respiratory quinone was ubiquinone 10. The draft genome size of L-25–5 w-1T was 5.8 Mbp, and the DNA G+C content was 66.6 %. The average nucleotide identity value and digital DNA–DNA hybridization relatedness value between L-25–5 w-1T and related type strains were 80.2 and 24.7 % with A. doebereinerae GSF71T and 78.8 and 23.6 % with A. thiophilum DSM 21654T, respectively. According to the phylogenetic, chemotaxonomic and genotypic properties, strain L-25–5 w-1T represents a novel species in the genus Azospirillum , for which the name Azospirillum griseum sp. nov. is proposed. The type strain is L-25–5 w-1T (=CGMCC 1.13672T=KCTC 62777T).

Neuropathic pain is one of the most common and notorious neurological diseases. The changes in cerebral structures after nerve injury and the corresponding contributions to neuropathic pain are not well understood. Here we found that the majority of glutamatergic neurons in the area 2 of midcingulate cortex (MCC Cg2Glu) were inhibited by painful stimulation in male mice. Optogenetic manipulation revealed that these neurons were tonically involved in the inhibitory modulation of multimodal nociception. We further identified the projections to GABAergic neurons in the zona incerta (ZIGABA) mediated the pain inhibitory role. However, MCC Cg2Glubecame hypoactive after nerve injury. Although a brief activation of the MCC Cg2Gluto ZIGABAcircuit was able to relieve the aversiveness associated with spontaneous ongoing pain, consecutive activation of the circuit was required to alleviate neuropathic allodynia. In contrast, glutamatergic neurons in the area 1 of MCC played opposite roles in pain modulation. They became hyperactive after nerve injury and only consecutive inhibition of their activity relieved allodynia. These results demonstrate that MCC Cg2Gluconstitute a component of intrinsic pain inhibitory circuitry and their hypoactivity underlies neuropathic pain. We propose that selective and persistent activation of the MCC Cg2Gluto ZIGABAcircuit may serve as a potential therapeutic strategy for this disease.SIGNIFICANCE STATEMENTGlutamatergic neurons in the area 2 of midcingulate cortex (MCC Cg2Glu) are tonically involved in the intrinsic pain inhibition via projecting to GABAergic neurons in the zona incerta. They are hypoactive after nerve injury. Selective activation of the circuit compensates the reduction of its analgesic strength and relieves neuropathic pain. Therefore, MCC Cg2Gluand the related analgesic circuit may serve as therapeutic targets for neuropathic pain. In contrast, MCC Cg1Gluhave an opposite role in pain modulation and become hyperactive after nerve injury. The present study provides novel evidence for the concept that neuropathic pain is associated with the dysfunction of endogenous pain modulatory system and new perspective on the treatment of neuropathic pain.

OBJECTIVE To improve the clinical understanding of anti-gamma-aminobutyric-acid B receptor encephalitis (anti-GABABR encephalitis) by analyzing 13 cases. METHODS We retrospectively studied demographic and clinical features including clinical symptoms, serum/cerebrospinal fluid (CSF) laboratory findings (including antibody test), brain magnetic resonance imaging (MRI), electroencephalogram (EEG), treatment plan, and treatment effect for 13 patients with a definitive diagnosis of anti-GABABR encephalitis. RESULTS Seven patients (53.8%, 7/13) were complicated with lung cancer. Epileptic seizures were the most common symptoms at onset in 11 patients (84.6%, 11/13). All patients had seizures in the course of the disease. Abnormalities in craniocerebral MRI examination, including hippocampus, occipital lobe, insular lobe, were found in six of nine tested patients, and EEG abnormalities were found in seven out of nine tested patients. Elevated pro-gastrin releasing peptide (ProGRP) levels were found in 70% of patients with a median value of 490.10 pg/ml; and CSF oligoclonal bands were positive for 4 of 10 tested cases. However, there were no significant differences in modified Rankin Scale (mRS) between the ProGRP or CSF oligoclonal band positive and negative groups at admission and follow-up (p > .05). The value between SCLC and non-SCLC subgroup was significantly different (p

Purpose: We investigated the pathogenesis of idiopathic nephrotic syndrome (INS) by measuring the effects two specific miRNAs on Th2 cells in children with this disease.Methods: After informed consent, we enrolled 20 children with active INS before steroid initiation, 20 children with INS in remission after steroid therapy, and 20 age-matched healthy controls. Flow cytometry was used to measure the levels of Th2 cells and a cytometric bead array was used to measure the levels of IgE, interleukin (IL)−4, and IL-13. RT-PCR was used to measure the levels of miR-24 and miR-27 in CD4+TCD25− cells. PBMCs were isolated using Ficoll density gradient centrifugation, and transfected with different mimic or inhibitor miRNAs. RT-PCR was used to measure the expression of different RNAs, and flow cytometry was used to determine the percentage of Th2 cells.Results: Relative to healthy controls, children with active INS had higher percentages of Th2 cells (P < 0.05), but there was no significant difference in controls and children in remission. The plasma levels of IgE, IL-4, and IL-13 were significantly increased in children with active INS (P < 0.05). There were lower levels of miR-24 and miR-27 in children with active non-atopic INS (P < 0.05). Transfection experiments indicated that upregulation of each miRNA decreased the percentage of Th2 cells and the level of IL-4 (P < 0.05), and down-regulation of each miRNA had the opposite effects (P < 0.05).Conclusion: Children with active INS, with or without atopy, had higher levels of IgE, possibly related to their higher levels of IL-13 and IL-4 due to a drift toward Th2 cells. miR-24 and miR-27 suppressed the expression of Th2 cells and have a critical function regulating Th2 cell expression in INS.

Ginsenoside (GS Rg1), which has neuroprotection and anti-inflammation activities, is the main active ingredient of Radix Ginseng. However, its antidepressant-like effect in rats remains unclear. Our study was conducted to investigate whether GS Rg1 confers an antidepressant effect in rats exposed to a chronic unpredictable mild stress model of depression and to explore its possible mechanisms. Our results revealed that GS Rg1 treatments for 3 weeks alleviated the depression-related behaviors of chronic unpredictable mild stress-exposed rats, as indicated by increasing sucrose preference, improving locomotor activity and shortening immobile time in both the forced swimming tests and tail suspension tests. And these ameliorative effects of GS Rg1 treatment were involved with regulating chronic unpredictable mild stress-induced pro-inflammatory cytokine interleukin beta (IL-1β) related neuro-inflammation. In addition, we further found that GS Rg1 reversed chronic unpredictable mild stress-induced IL-1β elevation, possibly by inhibiting nuclear factor kappa B pathway activation and regulating nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome expression. In short, our results suggested that GS Rg1 exerted a potential antidepressant-like effect in chronic unpredictable mild stress rat model of depression, which may provide an insight into the potential of GS Rg1 in therapeutic implications for depression.

The aim of this study was to investigate the effectiveness of cognitive behavioral therapy (CBT) on improving the cognitive function in minor depression (MiD) and major depression (MaD). The study will constitute a placebo-controlled single-blind parallel-group randomized controlled trial. The selected participants will be randomly allocated into one of two parallel groups with a 1:1 ratio: the CBT-based group and the general health education group. CBT significantly alleviated depressive symptoms of MiD and MaD at 12 weeks (p < 0.001), and the treatment effect was maintained for at least 12 months (p < 0.001). Interestingly, CBT significantly promotes more cognitive function of MiD and partial cognitive function of MaD at 12 weeks in the intervention group than in the control group (p < 0.01). CBT can alleviate depressive symptoms of both minor and MaDs. The effectiveness of CBT is different on improving the cognitive function in MiD and MaD.

The modification of the mouse genome by site-specific gene insertion of transgenes and other genetic elements allows the study of gene function in different developmental stages and in the pathogenesis of diseases. Here, we generated a “genomic safe harbor” Hipp11 (H11) locus-specific knock-in transgenic mouse line in which the albumin promoter is used to drive the expression of the reverse tetracycline transactivator (rtTA) in the liver. The newly generated H11-albumin-rtTA transgenic mice were bred with tetracycline-operator-Histone-2B-green fluorescent protein (TetO-H2BGFP) mice to assess inducibility and tissue-specificity. Expression of the H2BGFP fusion protein was observed exclusively upon doxycycline (Dox) induction in the liver of H11-albumin-rtTA/TetO-H2BGFP double transgenic mice. To further analyze the ability of the Dox-inducible H11-albumin-rtTA mice to implement conditional DNA recombination, H11-albumin-rtTA transgenic mice were crossed with TetO-Cre and Ai14 mice to generate H11-albumin-rtTA/TetO-Cre/Ai14 triple transgenic mice. We successfully confirmed that the Cre-mediated recombination efficiency was as strong in Dox-induced H11-albumin-rtTA /TetO-Cre/Ai14 mice as in the control albumin-Cre/A14 mice. Finally, to characterize the expression-inducing effects of Dox in H11-albumin-rtTA/TetO-H2BGFP mice in detail, we examined GFP expression in embryos at different developmental stages and found that newly conceived H11-albumin-rtTA/TetO-H2BGFP embryos of Dox-treated pregnant female mice were expressing reporter GFP by E16.5. Our study demonstrates that these new H11-albumin-rtTA transgenic mice are a powerful and efficient tool for the temporally and spatially conditional manipulation of gene expression in the liver, and illustrates how genetic crosses with these new mice enable the generation of complex multi-locus transgenic animals for mechanistic studies.

Background Transcutaneous electrical acupoint stimulation (TEAS), which is also known as acupuncture-like transcutaneous electrical nerve stimulation (TENS), has been widely used in acute or chronic pain. However, previous research has not demonstrated that TEAS is effective for cancer-related pain. Opioid drugs are strongly recommended for treating cancer-related pain, but opioid-induced immunosuppression is still the most intractable drug-induced medical problem. Evaluating the efficacy and potential advantage of TEAS combined with opioid drugs in moderate and severe cancer-related pain in China is important because such studies are lacking. Methods/Design This trial is a multicenter, prospective randomized controlled clinical trial. In total, 160 patients who were enrolled from two hospitals in the Zhejiang Province (China) will be randomly allocated into two groups: a TEAS group and sham TEAS group without acupoint electrical stimulation. Both groups will receive a 21-day interval of chemotherapy and conventional cancer pain therapy. Fifteen treatment sessions will be performed over a three-week period. The primary outcomes will be measured by changes in the Numerical Rating Scale (NRS) scores and equivalent dosage of morphine at baseline, three weeks of treatment and one two-week follow-up. The secondary outcome measures include cellular immunity function, life quality assessment, opioids side effects assessment, and safety and compliance evaluation. Discussion This trial is expected to clarify whether TEAS is effective for cancer-related pain. These results demonstrate the advantage of TEAS combined with opioid drugs on improving immune function and decreasing opioid induced side effects. Trial registration Chinese Clinical Trial Registry, ChiCTR-13003803. Registered on 27 August 2013. Electronic supplementary material The online version of this article (10.1186/s13063-018-3145-y) contains supplementary material, which is available to authorized users.

Peroxiredoxin 3 (PRX3) is predominantly located in mitochondria and plays a major role in scavenging hydrogen peroxide of mitochondria. In the present study, we detected plasma PRX3 in pregnant women receiving oral glucose tolerance test at 24–28 gestational weeks. Plasma PRX3 was significantly increased about 1 h later than insulin secretion. In vitro detection of PRX3 in mouse islet cells showed up-regulation by more than 2-fold at 1 h and reached its top at 2 h of glucose stimulation, and the PRX3 level in cultured mediums was concomitantly elevated in a glucose concentration-dependent manner. In addition, both fasting plasma insulin and PRX3 were significantly higher in the subjects of term pregnancy as compared to that at 24–28 gestational weeks, and there was a positive correlation between plasma PRX3 and insulin. Our results indicate that PRX3 plays an active role in the response to insulin release. The positive association of plasma PRX3 and insulin suggest PRX3 to be a potential indicator of high insulin resistance.

Long noncoding RNAs (lncRNA) are dysregulated in various human cancers and control tumor development and progression. However, the upstream mechanisms underlying their dysregulation remain unclear. Here, we demonstrate that the expression of hepatocyte nuclear factor 1 homeobox A antisense RNA 1 (HNF1A-AS1) is significantly upregulated in gastric cancer tissues. Overexpression of HNF1A-AS1 enhanced cell proliferation and promoted cell-cycle progression, whereas knockdown of HNF1A-AS1 elicited the opposite effects. Early growth response protein 1 (EGR1) directly bound the HNF1A-AS1 promoter region and activated its transcription. Overexpression of EGR1 enhanced cell proliferation and promoted cell-cycle promotion, similar to the function of HNF1A-AS1. HNF1A-AS1 functioned as competing endogenous RNA (ceRNA) by binding to miR-661, upregulating the expression of cell division cycle 34 (CDC34), which is a direct target of miR-661. EGR1 and HNF1A-AS1 enhanced the expression of cyclin-dependent kinase 2 (CDK2), CDK4, and cyclin E1 but inhibited the expression of p21 by promoting CDC34-mediated ubiquitination and degradation of p21. Taken together, these findings suggest that EGR1-activated HNF1A-AS1 regulates various pro- and antigrowth factors to promote the development of gastric cancer, implicating it as a possible target for therapeutic intervention in this disease. Significance: This study provides novel insights into mechanisms by which the noncoding RNA HNF1A-AS1 contributes to gastric cancer progression through modulation of the cell cycle. Cancer Res; 78(20); 5877–90. ©2018 AACR.

Background: Cognitive impairment is one of the core symptoms of schizophrenia, which is considered to be significantly correlated to prognosis. In recent years, many studies have suggested that metabolic disorders could be related to a higher risk of cognitive defects in a general setting. However, there has been limited evidence on the association between metabolism and cognitive function in patients with early-stage schizophrenia.Methods: In this study, we recruited 172 patients with early-stage schizophrenia. Relevant metabolic parameters were examined and cognitive function was evaluated by using the MATRICS Consensus Cognitive Battery (MCCB) to investigate the relationship between metabolic disorder and cognitive impairment.Results: Generally, the prevalence of cognitive impairment among patients in our study was 84.7% (144/170), which was much higher than that in the general population. Compared with the general Chinese setting, the study population presented a higher proportion of metabolic disturbance. Patients who had metabolic disturbance showed no significant differences on cognitive function compared with the other patients. Correlation analysis showed that metabolic status was significantly correlated with cognitive function as assessed by the cognitive domain scores (p < 0.05), while such association was not found in further multiple regression analysis.Conclusions: Therefore, there may be no association between metabolic disorder and cognitive impairment in patients with early-stage schizophrenia.Trial Registration: Clinicaltrials.gov, NCT02880462. Registered August 26, 2016.

Purpose: Autoimmune encephalitis (AE) is a heterogeneous neurological autoimmune disorder associated with cognitive and psychiatric symptoms. It can be divided into several subtypes based on autoantibodies. Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor encephalitis (AMPAR-E) is one of the recently discovered AE subtypes, usually manifesting limbic encephalitis and with a good prognosis. Considering AMPAR-E has been described for the first time, only a few cases with similar antibodies have been reported clinically. We aimed to clarify the clinical course and prognosis of the disease in the light of previous reports.Patients and Methods: We collected data on the diagnosis and treatment of six cases of AMPAR-E, diagnosed at the Qilu Hospital of Shandong University in the past 5 years. We retrospectively analyzed the clinical characteristics of the patients and performed a follow-up of the disease.Results: The patients often presented with limbic encephalitis, which sometimes coexisted with tumors. In addition, immunotherapy had a significant effect on the disease. The clinical outcome was related to factors such as the age of onset, timing of treatment, and presence of tumors.Conclusion: In conclusion, specific antibody tests should be performed as early as possible in suspected cases. Clinicians should actively administer immunotherapy and the management of the co-tumor. In addition, repeat antibody tests and image examinations following discharge from the hospital guide the maintenance protocol of immunotherapy.

Background Intercostal artery pseudoaneurysm is rare and at the risk of rupture. The aetiology is always reported to be iatrogenic and traumatic injury. Embolisation is the most common therapeutic method. Here, we report a case of spontaneous intercostal artery pseudoaneurysm and cured by combining covered stent grafting and surgical management. Case presentation A 60-year-old man complained of acute right back pain for 5 h. Computed tomography showed right massive hemothorax and a giant mass with distinct feeding vessel originated from the thoracic aorta within the right hemithorax. Thoracocentesis was performed, and then a covered stent was positioned across the origin of the feeding vessel. The patient was diagnosed with intercostal artery pseudoaneurysm. Finally, we successfully resected the pseudoaneurysm and ligated the proximal part of the artery. Histologic examination have proved the diagnosis. The postoperative course was uneventful, and the patient was discharged on postoperative day 10. There is no recurrence reported during follow-up. Conclusions Spontaneous intercostal artery pseudoaneurysm is extremly rare. Delayed hemothorax due to rupture of the pseudoaneurysm may occur years after the formation. Early diagnosis is important and a combined treatment of endovascular intervention and surgical management is feasible, especially for the case of ruptured large tumour-like mass presentation of the pseudoaneurysm.

Shan Qiao,1 Huai-kuan Wu,1 Ling-ling Liu,2 Mei-ling Wang,3 Ran-ran Zhang,4 Tao Han,5 Xue-wu Liu4 1Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province 250014, People’s Republic of China; 2Department of Neurology, Liaocheng People’s Hospital, Liaocheng, Shandong Province 252000, People’s Republic of China; 3Department of Neurology, Binzhou Medical University Hospital, Binzhou, Shandong Province 256603, People’s Republic of China; 4Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, People’s Republic of China; 5Department of Neurology, Shandong Provincial Hospital, Jinan, Shandong Province, People’s Republic of ChinaCorrespondence: Xue-wu LiuDepartment of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wen Hua Xi Road, Jinan 250012, Shan Dong, People’s Republic of ChinaTel + 86 0531-82169114Email snlxw1966@163.comPurpose: To describe the clinical manifestation, immunotherapy, and long-term outcomes of anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis.Patients and Methods: This study was a retrospective analysis of 117 patients with a diagnosis of anti-LGI1 encephalitis identified from the databases of multiple clinical centers between September 2014 and December 2019. The clinical features, ancillary test results, and details of long-term outcomes were evaluated.Results: Among the 117 patients with anti-LGI1 encephalitis, 69.2% (81/117) were male and 30.8% (36/117) were female. The median age of all patients at the onset of the disease was 57 years (interquartile range [IQR], 52– 67). The median time from symptom onset to diagnosis was 8.7 weeks (IQR, 4.2– 25). The main clinical features identified were seizures, cognitive impairment, and mental and behavioral abnormalities. Of the 117 patients, 109 were treated with immunotherapy. Symptoms including memory, mental ability, and behavior improved in all 109 patients after 3– 5 days of treatment. The median time of follow-up for the treated patients was 33 months (IQR, 17– 42). Of the treated patients, 16.2% (19/117) experienced a relapse, with a median delay of 5 months (IQR, 2.1– 17) between onset and the first relapse. There were no mortalities over the follow-up period.Conclusion: The long-term outcome of patients with anti-LGI1 encephalitis was mostly favorable, although some patients continued to experience cognitive dysfunction. Early recognition is important for prompt initiation of immunotherapy that can improve clinical symptoms of anti-LGI1 encephalitis.Keywords: anti-LGI1 encephalitis, autoimmune epilepsy, follow-up, immunotherapy, relapse

Objective To evaluate the efficacy and safety of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) for the treatment of cervical squamous intraepithelial lesion (SIL). Methods We prospectively screened and enrolled patients with cervical SIL and persistent high-risk human papilloma virus (HR-HPV) infection to receive ALA–PDT from March 27, 2019, to January 23, 2020, at Beijing Youan Hospital, China. The primary outcome was the remission rate of SIL and HPV. The secondary outcome was the symptom improvement and adverse events of ALA-PDT in these cases. Results 54 patients with cervical SIL and persistent HR-HPV infection were enrolled and divided these individuals into three groups: high-grade squamous intraepithelial lesion (HSIL) group (10 patients), low-grade squamous intraepithelial lesion (LSIL) group (33 patients), and simple HR-HPV infection group (11 patients). 49 of 54 patients finished six sessions treatment and 46 of 49 patients complete the follow-up. After six sessions’ treatment, HR-HPV remission rates were 71.43 %(5/7)in the simple HR-HPV infection group, 63.64 %(14/22) in the LSIL group, and 50 %(4/8) in the HSIL group. The histology remission rates were 80 %(4/5) in the simple HR-HPV infection group, 69.57 %(16/23)in the LSIL group, and 75 % (6/8) in the HSIL group. Symptoms improvement rates in the simple HR-HPV infection, LSIL group, and HSIL group were 100 %(5/5), 66.67 %(5/15) and 71.43 %(5/7). No severe adverse events or systemic side effects were observed in treatment. Conclusion Topical ALA-PDT is an effective and safe treatment for cervical SIL.

Firsocostat (FIR: previously GS-0976), a highly sensitive OATP substrate, reduces hepatic de novo lipogenesis (DNL) by inhibiting acetyl-CoA carboxylases (ACC). Measuring the pharmacodynamic (PD) efficacy of FIR on DNL provides a unique opportunity to determine optimal dosing strategies for liver-targeted OATP substrates in settings of altered OATP function. A randomized, four-way crossover drug-drug interaction study was conducted. Hepatic DNL, a marker for ACC activity, was measured in 28 healthy volunteers after reference, single dose FIR 10 mg, FIR 10 mg plus the OATP inhibitor rifampin (RIF) 300 mg i.v., or RIF 300 mg i.v. (control for DNL effect of RIF), each separated by a 7-day washout. Samples were collected for pharmacokinetic (PK) and PD assessments through 24 hours after each treatment. Hepatic DNL and its inhibition by FIR were assessed. Twenty-four subjects completed the study. All adverse events were mild. RIF alone increased hepatic DNL area under the effect curve from time of administration up to the time of the last quantifiable concentration (AUEClast ; 35.7%). Despite a 5.2-fold increase in FIR plasma exposure (area under the concentration-time curve from zero to infinity (AUCinf )) when administered with RIF, FIR alone, and FIR + RIF had the same hepatic PD effect, 37.1% and 34.9% reduction in DNL AUEClast , respectively, compared with their respective controls. These findings indicate that large decreases in OATP activity do not alter hepatic intracellular exposure (as inferred by no change in PD) for drugs that are primarily eliminated hepatically and permeability rate-limited, such as FIR. These results support PK theory that has been difficult to test and provide practical guidance on administration of liver-targeted drugs in settings of reduced OATP function.

Invasion and metastasis of gastric cancer after curative resection remain the most common lethal outcomes. However, our current understanding of the molecular mechanism underlying gastric cancer metastasis is far from complete. Herein, we identified TOR signaling pathway regulator (TIPRL) as a novel metastasis suppressor in gastric cancer through genome-wide gene expression profiling analysis using mRNA microarray. Decreased TIPRL expression was detected in clinical gastric cancer specimens, and low TIPRL expression was correlated with more-advanced TNM stage, distant metastasis, and poor clinical outcome. Moreover, TIPRL was identified as a direct target of miR-216a-5p and miR-383-5p. Functional study revealed that re-expression of TIPRL in gastric cancer cell lines suppressed their migratory and invasive capacities, whereas inverse effects were observed in TIPRL-deficient models. Mechanistically, TIPRL downstream effectors and signaling pathways were investigated using mRNA microarray. Gene expression profiling revealed that TIPRL could not modulate the downstream genes at transcriptional levels, thereby implying that the regulation might occur at the post-transcriptional levels. We further demonstrated that TIPRL induced phosphorylation/activation of AMPK, which in turn attenuated phosphorylation of mTOR, p70S6K, and 4E-BP1, thereby leading to inactivation of mTOR signaling and subsequent suppression of cell migration/invasion in gastric cancer. Taken together, TIPRL acts as a novel metastasis suppressor in gastric cancer, at least in part, through regulating AMPK/mTOR signaling, likely representing a promising target for new therapies in gastric cancer.

Global myocardial work (MW) analysis by pressure-strain loops (PSL) allows the non-invasive assessment of left ventricular (LV) function. We aimed to investigate the relationship between LV global MW and the degree of coronary artery stenosis in suspected coronary artery disease (CAD) patients with normal LV ejection fraction and regional wall motion. A total of 164 suspected CAD patients were divided into four groups according to coronary artery angiography. The results showed that global work efficiency (GWE) as the most significant predictor in all MW parameters had the optimal cut-off value of 94.5% for detecting moderate stenosis, and the sensitivity and specificity was 89.7% and 85.8%, respectively. A cut-off value of 94.0% for GWE was the most significant predictor of severe stenosis, and the sensitivity and specificity was 81.4% and 76.1%, respectively. In conclusion, LV global MW is a sensitive tool in detecting the degree of coronary artery stenosis and a potential valuable method to provide early diagnosis for CAD patients.

Background & Aims Preclinical identification of compounds at risk of causing drug induced liver injury (DILI) remains a significant challenge in drug development, highlighting a need for a predictive human system to study complicated DILI mechanism and susceptibility to individual drug. Here, we established a human liver organoid (HLO)–based screening model for analyzing DILI pathology at organoid resolution. Methods We first developed a reproducible method to generate HLO from storable foregut progenitors from pluripotent stem cell (PSC) lines with reproducible bile transport function. The qRT-PCR and single cell RNA-seq determined hepatocyte transcriptomic state in cells of HLO relative to primary hepatocytes. Histological and ultrastructural analyses were performed to evaluate micro-anatomical architecture. HLO based drug-induced liver injury assays were transformed into a 384 well based high-speed live imaging platform. Results HLO, generated from 10 different pluripotent stem cell lines, contain polarized immature hepatocytes with bile canaliculi-like architecture, establishing the unidirectional bile acid transport pathway. Single cell RNA-seq profiling identified diverse and zonal hepatocytic populations that in part emulate primary adult hepatocytes. The accumulation of fluorescent bile acid into organoid was impaired by CRISPR-Cas9–based gene editing and transporter inhibitor treatment with BSEP. Furthermore, we successfully developed an organoid based assay with multiplexed readouts measuring viability, cholestatic and/or mitochondrial toxicity with high predictive values for 238 marketed drugs at 4 different concentrations (Sensitivity: 88.7%, Specificity: 88.9%). LoT positively predicts genomic predisposition (CYP2C9∗2) for Bosentan-induced cholestasis. Conclusions Liver organoid-based Toxicity screen (LoT) is a potential assay system for liver toxicology studies, facilitating compound optimization, mechanistic study, and precision medicine as well as drug screening applications.

Gastric cancer (GC) is one of the most common malignant neoplasms. Invasion and metastasis are the main causes of GC-related deaths. Recently, kinesins were discovered to be involved in tumor development. The aim of this study was to elucidate the roles of kinesin superfamily protein 26A (KIF26A) in GC and its underlying molecular mechanism in regulating tumor invasion and metastasis. Using real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC), we showed that KIF26A expression was lower in GC tissues without lymph node metastasis (LNM) than in nontumorous gastric mucosa, and even lower in GC tissues with LNM than in GC tissues without LNM. Functional experiments showed that KIF26A inhibited migration and invasion of GC cells. We further identified focal-adhesion kinase (FAK), phosphatidylinositol 3-kinase regulatory subunit alpha (PI3KR1), VAV3, Rac1 and p21-activated kinase 2, and β-PAK (PAK3) as downstream effectors of KIF26A in the focal-adhesion pathway, and we found that KIF26A could regulate FAK mRNA expression through inhibiting c-MYC by MAPK pathway. c-MYC could bind to the promoter of FAK and activate FAK transcription. Moreover, we found that KIF26A-mediated inactivation of the focal-adhesion pathway could reduce the occurrence of the epithelial-to-mesenchymal transition (EMT) by increasing expression of E-cadherin and reducing that of Snail. Luciferase assays and Western blotting revealed that miR-19a and miR-96 negatively regulate KIF26A. Finally, we found that decreased expression of KIF26A has been positively correlated with histological differentiation, Lauren classification, LNM, distal metastasis, and clinical stage, as well as poor survival in patients with GC. These data indicate that KIF26A could inhibit GC migration and invasion by regulating the focal-adhesion pathway and repressing the occurrence of EMT.

Background Fatty liver is a high incidence of perinatal disease in dairy cows caused by negative energy balance, which seriously threatens the postpartum health and milk production. It has been reported that lysine acetylation plays an important role in substance and energy metabolism. Predictably, most metabolic processes in the liver, as a vital metabolic organ, are subjected to acetylation. Comparative acetylome study were used to quantify the hepatic tissues from the severe fatty liver group and normal group. Combined with bioinformatics analysis, this study provides new insights for the role of acetylation modification in fatty liver disease of dairy cows. Results We identified 1841 differential acetylation sites on 665 proteins. Among of them, 1072 sites on 393 proteins were quantified. Functional enrichment analysis shows that higher acetylated proteins are significantly enriched in energy metabolic pathways, while lower acetylated proteins are significantly enriched in pathways related to immune response, such as drug metabolism and cancer. Among significantly acetylated proteins, many mitochondrial proteins were identified to be interacting with multiple proteins and involving in lipid metabolism. Furthermore, this study identified potential important proteins, such as HADHA, ACAT1, and EHHADH, which may be important regulatory factors through modification of acetylation in the development of fatty liver disease in dairy cows and possible therapeutic targets for NAFLD in human beings. Conclusion This study provided a comprehensive acetylome profile of fatty liver of dairy cows, and revealed important biological pathways associated with protein acetylation occurred in mitochondria, which were involved in the regulation of the pathogenesis of fatty liver disease. Furthermore, potential important proteins, such as HADHA, ACAT1, EHHADH, were predicted to be essential regulators during the pathogenesis of fatty liver disease. The work would contribute to the understanding the pathogenesis of NAFLD, and inspire in the development of new therapeutic strategies for NAFLD.

Gastric cancer is one of the most common cancers in the world, and long non-coding RNAs (lncRNAs) play a crucial role in proliferation, metastasis, and invasion of gastric cancer. However, there are very few researches focusing on the effects of lncRNAs on metastatic gastric cancer. In this research, we identify one kind of lncRNA, called AK025387, which is highly expressed in metastatic gastric cancer samples compared with non-metastatic gastric cancer samples. The expression of AK025387 is significantly positively correlated with lymph node metastasis. The in situ hybridization demonstrates that AK025387 is located in both nucleus and cytoplasm, but mostly in cytoplasm. AK025387 promotes gastric cancer cells migratory and invasive ability, but it inhibits apoptosis in vitro. Furthermore, AK025387 regulates Raf-1, mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK), and extracellular signal-regulated kinase (ERK) and is involved in mitogen-activated protein kinase (MAPK) signaling pathway to perform its biological functions. We conclude that AK025387 is highly expressed in metastatic gastric cancer, and its biological functions suggest the potential of AK025387 to be a biomarker of metastatic gastric cancer.

Despite significant advances in transplantation, acute cellular rejection (AR) remains a major obstacle that is most prevalent in the first months post heart transplantation (HT). Current treatments require high doses of immunosuppressive drugs followed by maintenance therapies that have systemic side effects including early infection. In this study, we attempted to prevent AR with a myocardial-targeted galectin-7-siRNA delivery method using cationic microbubbles (CMBs) combined with ultrasound targeted microbubble destruction (UTMD) to create local immunosuppression in a rat abdominal heterotopic heart transplantation acute rejection model.Galectin-7-siRNA (siGal-7) bound to CMBs were synthesized and effective ultrasound-targeted delivery of siGal-7 into target cells confirmed in vitro. Based on these observations, three transplant rat models were tested：①isograft (ISO); ② Allograft (ALLO) +UTMD; and ③ALLO + PBS. UTMD treatments were administered at 1, 3, 5, 7 days after HT. Galectin 7 expression was reduced by 50% compared to ALLO + PBS (p 0.005), and this was associated with significant reductions in both galectin 7 and Interleukin-2 protein levels (p 0.001). The ALLO + UTMD group had Grade II or less inflammatory infiltration and myocyte damage in 11/12 rats using International Society For Heart and Lung Transplantation grading, compared to 0/12 rats with this grading in the ALLO + PBS group at 10 days post HT (p 0.001).Ultrasound-targeted galectin-7-siRNA knockdown with UTMD can prevent acute cellular rejection in the early period after allograft heart transplantation without the need for systemic immunosuppression.Microbubble, Acute Rejection, Heart Transplantation, Galectin-7, RNA.

Objectives To evaluate the efficacy and safety of a novel fixation technique referred to as the dynamic anterior plate-screw system for quadrilateral plate (DAPSQ) for complex acetabular fractures with quadrilateral plate involvement through the single ilioinguinal approach. Methods A total of 32 patients with acetabular fractures, selected between January 2009 and March 2016, were managed by DAPSQ with "quadrilateral screws" through single ilioinguinal approach. The primary outcomes measure was the reduction quality evaluated according to the Matta radiological criteria, and the functional outcomes were evaluated by the modified Merle d'Aubigne score at the last follow-up. Secondary outcomes were postoperative complications and intraoperative conditions included, for instance, operation time and blood loss. Results Of these 32 consecutive patients, 19, 9, and 4 were classified as both columns, anterior column posterior hemi-transverse, and T-shaped fractures, respectively, and with an average of 47 months' follow-up. Anatomic reduction was obtained in 19 cases (59%), imperfect reduction in 9 cases (28%), and poor reduction in 4 cases (13%). The modified Merle d'Aubigne scores were excellent in 15 cases (47%), good in 13 cases (41%), fair in 2 cases (6%), and poor in 2 cases (6%). Three cases sustained temporary lateral femoral cutaneous nerve injuries. One patient had a superficial wound infection that resolved after debridement. Five patients had posttraumatic arthritis; one of them underwent total hip arthroplasty at 46 months. No cases had quadrilateral screws entering the hip joint. Conclusion The use of DAPSQ with quadrilateral screws is an effective and safe choice for complex acetabular fractures with quadrilateral plate involvement through the single ilioinguinal approach.

Aim We aimed to clarify tumor features and prognosis of pregnancy‐associated breast cancer (PABC) among Chinese women. Methods PABC was defined as breast cancer diagnosed during pregnancy or within a year after delivery. Patients with PABC were selected from breast cancer cases of women ≤45 years treated at our institution between December 2012 and December 2017, and one non‐PABC control was matched for stage, age, and year of diagnosis for each case. Results Forty‐one women with PABC were identified (22 diagnosed during pregnancy and 19 within 1 year of delivery). There were significantly more progesterone receptor (PR)‐ and triple‐negative tumors in the PABC (56.1% and 24.4%, respectively) than in the non‐PABC group (31.7% and 4.9%, respectively) (P = .045 and .026, respectively). Human epidermal growth factor receptor 2 positivity was the same in both groups (31.7%). Median disease‐free survival (DFS) was 29.0 months (95% confidence interval [CI], 6.5‐51.5 months) in the PABC and 40.9 months (95% CI, 22.8‐58.8 months) in the non‐PABC group (P = .167). Median overall survival (OS) was 82.8 months in the PABC (95% CI, 39.3‐126.5 months) versus 80.1 months (95% CI, 56.7‐103.6 months) in the non‐PABC group (P = .131). Conclusion Histological features were similar in both groups, except that PR‐ and triple‐negative tumors were more frequent in the PABC group. Survival analyses show similar OS for patients with PABC and non‐PABC. DFS tended to be shorter in the PABC group; however, this difference was not statistically significant., After matching PABC cases with non‐PABC cases for stage and age (±1 year), as well as year of diagnosis secondarily (±1 year),on survival analysis, the median DFS tended to be shorter in women with PABC than in non‐PABC; however, this difference was not statistically significant and the median OS of the two groups were almost the same.

Therapies against hepatitis B virus (HBV) have improved in recent decades; however, the development of individualized treatments has been limited by the lack of individualized infection models. In this study, we used human induced pluripotent stem cell (hiPSC) to generate a functional liver organoid (LO) that inherited the genetic background of the donor, and evaluated its application in modeling HBV infection and exploring virus–host interactions. To establish a functional hiPSC-LO, we cultured hiPSC-derived endodermal, mesenchymal, and endothelial cells with a chemically defined medium in a three-dimensional microwell culture system. Based on cell-cell interactions, these cells could organize themselves and gradually differentiate into a functional organoid, which exhibited stronger hepatic functions than hiPSC derived hepatic like cell (HLC). Moreover, the functional LO demonstrated more susceptibility to HBV infection than hiPSC-HLC, and could maintain HBV propagation and produce infectious virus for a prolonged duration. Furthermore, we found that virus infection could cause hepatic dysfunction of hiPSC-LOs, with down-regulation of hepatic gene expression, induced release of early acute liver failure markers, and altered hepatic ultrastructure. Therefore, our study demonstrated that HBV infection in hiPSC-LOs could recapitulate virus life cycle and virus induced hepatic dysfunction, suggesting that hiPSC-LOs may provide a promising individualized infection model for the development of individualized treatment for hepatitis. Keywords: Liver organoid, hiPSC, Hepatitis B virus, Virus-host interactions

Breast cancer is the most common female malignancy worldwide, however its molecular pathogenesis still needs in-depth investigation. Here we first revealed that the olfactory receptor family 2, subfamily T, member 6 (OR2T6) was significantly over-expressed in breast cancer tissues compared with normal breast tissues. OR2T6 expression was tightly correlated with higher TNM staging, positive lymph node metastasis, and associated with poorer patients' overall and disease-free survival. And OR2T6 enhanced the proliferation, invasion, and migration ability of breast cancer cell lines in vitro (MCF-7 and MDA-MD-231). Mechanically, it promoted the expression of mesenchymal markers (Vimentin, N-cadherin, and β-catenin) while inhibited E-cadherin expression, suggesting that OR2T6 played a key role in the regulation of epithelial-mesenchymal transition (EMT) process. Moreover, the human gene expression microarray clarified that MAPK/ERK pathway could be initiated by OR2T6 at mRNA level, which was further confirmed at protein level by western blot analysis. Thus, we concluded that OR2T6, as a novel oncogene, contributed to the progression of breast carcinoma by the initiation of EMT and MAPK/ERK pathway.

Consolidated bioprocessing (CBP) strategy was developed to construct a cell-surface displayed consortium for heterologously expressing functional lignocellulytic enzymes. The reaction system composed of two engineered yeast strains: Y5/XynII-XylA (co-displaying two types of xylanases) and Y5/EG-CBH-BGL (co-displaying three types of cellulases). The immobilization of recombinant fusion proteins and their cell-surface accessibility of were analyzed by flow cytometry and immunofluorescence. The feasibility of consolidated bioprocessing by using pretreated corn stover (CS) as substrate for direct bioconversion was further investigated, and the synergistic activity and proximity effect between cellulases and xylanases on lignocelluloses degradation were also discussed in this work. Without any commercial enzyme addition, the combined yeast consortium produced 1.61 g/L ethanol which achieved 64.7% of the theoretical ethanol yield during 144 h from steam-exploded CS. The results indicated that the assembly of cellulases and xylanases using a synthetic consortium capable of combined displaying lignocellulytic enzymes is a promising approach for simultaneous saccharification and fermentation to ethanol from lignocellulosic biomass.

Objective To evaluate the effectiveness and potential benefits of topical tranexamic acid (TXA) in the management of acute epistaxis. Methods Retrospective review was performed among all patients presenting to the institution's emergency department (ED) with epistaxis between September 2014 and August 2016. Patients achieving hemostasis with standard of care agents, such as oxymetazoline, lidocaine, or epinephrine were excluded. The primary outcome was the ED length of stay (LOS). Secondary outcomes included the incidence of hospital admission, otolaryngologist consultation, nasal packing, prophylactic antibiotic use, and ED visit for rebleeding within seven days of treatment. Results Among 122 patients, 30 received topical TXA (500 mg injectable solution soaked onto packing material and applied to the affected nostril) and 92 were managed with standard care. Nearly half (46.7%) of TXA-treated subjects received TXA either alone or in combination with standard of care agents as their initial treatment strategy. No significant difference was observed in the ED LOS (272 vs 232 min in TXA and standard care arms, respectively, p = 0.26). However, TXA was associated with a significant reduction in otolaryngologist consults (30.0% vs 65.2%, p = 0.002) and nasal packing (16.7% vs 23.9%, p = 0.003). Conclusions This investigation did not demonstrate a significant difference in ED LOS among patients with acute epistaxis treated with topical TXA or standard care. However, this data does add to existing evidence that TXA may be associated with a reduction in resource utilization, suggesting it may provide more effective bleeding control. Overall, more data is needed to confirm the potential benefits of this practice.

Parainfluenza virus infection is a common respiratory illness in children. Although lncRNAs are novel regulators of virus-induced innate immunity, a systemic attempt to characterize the differential expression of lncRNAs upon parainfluenza virus infection is lacking. In this report, we identify 207 lncRNAs and 166 mRNAs differentially expressed in SeV-infected HEK293T cells by microarray. The functional annotation analysis reveals that differentially regulated transcripts are predominantly involved in the host antiviral response pathway. The lncRNAs with the potential to regulate SeV-induced antiviral response are identified by building the lncRNA-mRNA coexpression network. Furthermore, silencing lncRNA ENST00000565297 results in reduced type I IFN signaling upon SeV infection. These catalogs may facilitate future analysis of the functions of lncRNAs in innate immunity and related diseases.