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Platinum-based chemotherapy drugs play a very important role in the treatment of patients with advanced colorectal cancer, but the drug resistance of platinum-based chemotherapy drugs is an important topic that puzzles us. If we can find mechanisms of resistance, it will be revolutionary for us. We analysed the differential genes, core genes and their enrichment pathways in platinum-resistant and non-resistant patients through a public database. Platinum-resistant cell lines were cultured in vitro for in vitro colony and Transwell analysis. Tumorigenesis analysis of nude mice in vivo. Verify the function of core genes. Through differential gene and enrichment analysis, we found that CUL4B was the main factor affecting platinum drug resistance and EMT. Our hypothesis was further verified by in vitro drug-resistant and wild-type cell lines and in vivo tumorigenesis analysis of nude mice. CUL4B leads to platinum drug resistance in colorectal cancer by affecting tumour EMT.

Gastric cancer is one of the most lethal human malignancies in the world. Although great efforts are put in developing novel therapeutic targets, the effective targeting drugs are still limited. Recent studies reveal the abnormality of Hippo/YAP axis play critical role in the oncogenic process of gastric cancer. It is of great importance to demonstrate the regulation of Hippo signaling activity and YAP protein turnover in gastric cancer. Besides, the phosphorylation cascade on YAP function, which has been thoroughly investigated, the ubiquitination of YAP is also important in Hippo signaling status. Here, We utilized the DUB (Deubiquitinase) siRNA library to identify critical DUB for Hippo signaling. We discovered OTUB1 as a critical factor to facilitate gastric cancer cell stemness and progression, which deubiquitinated and stabilized YAP protein. The clinical data analysis implicated OTUB1 was higher expressed in gastric cancer, which correlated with YAP activity and poor survival. OUTB1 interacted with YAP protein via its OTU domain (Ovarian tumor domain) and deubiquitinated YAP at several lysine sites (K90, K280, K343, K494 and K497), which subsequently inhibited YAP degradation. Our study revealed a novel deubiquitinase of Hippo/YAP axis and one possible therapeutic target for YAP-driven gastric cancer.

Glioblastoma has been identified as the most common and aggressive primary brain tumor in adults. Recently, it has been found that cisplatin (DDP) treatment is a common chemotherapeutic method for GBM patients. circ_PTN (ID number: hsa_circ_0003949) is a newly found circular (circRNA) which has been proved to be highly expressed in GBM cells, while its role in GBM remains unclear. Therefore, our study focused on investigating the role of circ_PTN in the DDP resistance of GBM cells. The expression of circ_PTN in DDP-sensitive and DDP-resistant GBM cells was detected in our assay. Functional experiments were utilized to unveil the effects of circ_PTN on the DDP resistance of GBM cells. Moreover, mechanism assays were conducted to confirm the mechanism of how circ_PTN affected the DDP resistance of GBM cells. According to the results, we found that circ_PTN promoted the DDP resistance of GBM cells through activation of the PI3K/AKT pathway. Moreover, circ_PTN silencing inhibited the DDP resistance of GBM tumors in vivo. To conclude, our study unveiled the influence of circ_PTN on the DDP resistance of GBM cells, which might provide a therapeutic target for GBM treatment via DDP., Graphical abstract, Recently, it has been found that DDP treatment is a common chemotherapeutic method for glioblastoma patients. Our study disclosed that circ_PTN could sequester miR-542-3p to boost PIK3R3, so as to stimulate PI3K/AKT signaling, contributing to the cisplatin resistance of glioblastoma cells. Therefore, circ_PTN could be a promising target for glioblastoma treatment.

Background:. Multiple techniques are commonly used for posterior cruciate ligament (PCL) reconstruction. However, the optimum method regarding the fixation of PCL reconstruction after PCL tears remains debatable. The purpose of this study was to compare the biomechanical properties among three different tibial fixation procedures for transtibial single-bundle PCL reconstruction. Methods:. Thirty-six porcine tibias and porcine extensor tendons were randomized into three fixation study groups: the interference screw fixation (IS) group, the transtibial tubercle fixation (TTF) group, and TTF + IS group (n = 12 in each group). The structural properties of the three fixation groups were tested under cyclic loading and load-to-failure. The slippage after the cyclic loading test and the stiffness and ultimate failure load after load-to-failure testing were recorded. Results:. After 1000 cycles of cyclic testing, no significant difference was observed in graft slippage among the three groups. For load-to-failure testing, the TTF + IS group showed a higher ultimate failure load than the TTF group and the IS group (876.34 ± 58.78 N vs. 660.92 ± 77.74 N [P

Background Breast cancer is the most common cancer in women worldwide. More than 70% of breast cancers are estrogen receptor (ER) alpha positive. Compared with ER alpha-negative breast cancer, which is more aggressive and has a shorter survival time, ER alpha-positive breast cancer could benefit from endocrine therapy. Selective estrogen receptor modulators, such as tamoxifen, are widely used in endocrine therapy. Approximately half of ER alpha-positive breast cancer patients will eventually develop endocrine resistance, making it a major clinical challenge in therapy. Thus, decoding the throughput of estrogen signaling, including the control of ER alpha expression and stability, is critical for the improvement of breast cancer therapeutics. Methods TRIM3 and ER alpha protein expression levels were measured by western blotting, while the mRNA levels of ER alpha target genes were measured by RT–PCR. A CCK-8 assay was used to measure cell viability. RNA sequencing data were analyzed by Ingenuity Pathway Analysis. Identification of ER alpha signaling activity was accomplished with luciferase assays, RT–PCR and western blotting. Protein stability assays and ubiquitin assays were used to detect ER alpha protein degradation. Ubiquitin-based immunoprecipitation assays were used to detect the specific ubiquitination modification on the ER alpha protein. Results In our current study, we found that TRIM3, an E3 ligase, can promote ER alpha signaling activity and breast cancer progression. TRIM3 depletion inhibits breast cancer cell proliferation and migration, while unbiased RNA sequencing data indicated that TRIM3 is required for the activity of estrogen signaling on the -genome-wide scale. The immunoprecipitation assays indicated that TRIM3 associates with ER alpha and promotes its stability, possibly by inducing K63-linked polyubiquitination of ER alpha. In conclusion, our data implicate a nongenomic mechanism by which TRIM3 stabilizes the ER alpha protein to control ER alpha target gene expression linked to breast cancer progression. Conclusion Our study provides a novel posttranslational mechanism in estrogen signaling. Modulation of TRIM3 expression or function could be an interesting approach for breast cancer treatment. Graphical abstract

Chemotherapy is widely used in a variety of solid tumors, such as lung cancer, gastric cancer and breast cancer. The genotoxic drugs, such as cisplatin, suppress cancer progression either by inhibition cell proliferation or facilitating apoptosis. However, the chemotherapy resistance remains an urgent challenge in cancer therapy, especially in advanced stages. Several studies showed that the activation of pro-survival pathways, such as PI3K-AKT, participated in mediating chemotherapy resistance. The insights into the molecular mechanisms for underlying chemotherapy resistance are of great importance to improve cancer patient survival in advanced stages. The HOIP protein belongs to the RING family E3 ubiquitin ligases and modulates several atypical ubiquitination processes in cellular signaling. Previous studies showed that HOIP might be an important effector in modulating cancer cell death under genotoxic drugs. Here, we report that HOIP associates with PTEN and facilitates PTEN degradation in cancer cells. Depletion of HOIP causes cell cycle arrest and apoptosis, which effects could be rescued by PTEN silencing. Besides, the survival data from public available database show that HOIP expression correlates with poor survival in several types of chemotherapy-treated cancer patients. In conclusion, our study establishes a novel mechanism by which HOIP modulates PTEN stability and facilitates chemotherapy resistance in malignancies.

Autophagy has been shown to maintain neural system homeostasis during stroke. However, the molecular mechanisms underlying neuronal autophagy in ischemic stroke remain poorly understood. This study aims to investigate the regulatory mechanisms of the pathway consisting of MEG3 (maternally expressed gene 3), microRNA-378 (miR-378), and GRB2 (growth factor receptor-bound protein 2) in neuronal autophagy and neurological functional impairment in ischemic stroke. A mouse model of the middle cerebral artery occluded–induced ischemic stroke and an in vitro model of oxygen-glucose deprivation–induced neuronal injury were developed. To understand the role of the MEG3/miR-378/GRB2 axis in the neuronal regulation, the expression of proteins associated with autophagy in neurons was measured by Western blotting analysis, and neuron death was evaluated using a lactate dehydrogenase leakage rate test. First, it was found that the GRB2 gene, up-regulated in middle cerebral artery occluded–operated mice and oxygen-glucose deprivation–exposed neurons, was a target gene of miR-378. Next, miR-378 inhibited neuronal loss and neurological functional impairment in mice, as well as neuronal autophagy and neuronal death by silencing of GRB2. Confirmatory in vitro experiments showed that MEG3 could specifically bind to miR-378 and subsequently up-regulate the expression of GRB2, which in turn suppressed the activation of Akt/mTOR pathway. Taken together, these findings suggested that miR-378 might protect against neuronal autophagy and neurological functional impairment and proposed that a MEG3/miR-378/GRB2 regulatory axis contributed to better understanding of the pathophysiology of ischemic stroke.

Our aim was to investigate factors predicting blood pressure (BP) variability during diagnostic cerebral angiography and associations between BP variability and clinical outcomes in patients with acute and subacute ischemic stroke and intracranial artery stenosis. 114 patients with ischemic stroke and intracranial artery stenosis (stenosis rate >50%) were recruited. Patients who underwent cerebral angiography within 3 days and 3–14 days of disease onset are referred to be Group A and Group S, respectively. BP variability in Group A was defined as the coefficient of variance (CV) of BP. Univariate and multivariate regression analyses were used to identify predictors of CV of BP and associations between CV of BP and clinical outcomes at discharge. In Group A patients, advanced age was associated with increased CV of SBP and diastolic blood pressure (DBP), and antihypertensive use was associated with lower CV of SBP. Male was associated with lower CV of DBP. In Group S, higher CV of SBP was associated with hypertension and antihypertensive use. Males had lower CV of SBP than females. The calcium channel blocker was associated with lower CV of DBP. Higher scores of the Stroke Scale at admission were significantly associated with poor clinical outcomes for both groups, while BP variability was not. Factors associated with BP variability are significantly different between stroke patients undergoing angiography within 3 days vs. 3–14 days after disease onset. BP variability is not significantly associated with clinical outcomes at discharge.

Background The Hippo pathway functions as a tumor-suppressor pathway in human cancers, while the dys-function of Hippo pathway is frequently observed in malignancies. Although the YAP/TAZ activity is tightly controlled by the phosphorylation cascade of MST-LATS-YAP/TAZ axis, it is still unclear why YAP/TAZ protein is activated in human cancers, even Hippo pathway is still active. Besides phosphorylation, recent studies implicate that several post-translational modifications also play critical roles in modulating TAZ function, including ubiquitination. Methods We work on the ER alpha positive breast cancer cell lines and performed western blots, real-time PCR, immuno-precipitation assay, in vitro ubiquitin assay and xenograft mice studies Results Here, by a DUB (Deubiquitinases) siRNA screening library, we discovered DUB1 as a critical modulator to facilitate gastric cancer stemness and progression, which deubiquitinated and activated TAZ protein. We also identified DUB1 was elevated in gastric cancer, which correlated with TAZ activation and poor survival. DUB1 associated with TAZ protein and deubiquitinated TAZ at several lysine sites, which subsequently stabilized and facilitated TAZ function. Conclusions Our study revealed a novel deubiquitinase of Hippo/TAZ axis and one possible therapeutic target for Hippo-driven gastric cancer.

To observe the effect of electroacupuncture (EA) on skeletal muscle adiponectin receptor (Adipor1) / adenylate activated protein kinase (AMPK) / peroxisome proliferator-activated receptor α (PPARα) signaling pathway and skeletal muscle morphology by the secretion of serum adiponectin in Zucker diabetic obese (ZDF) rats, so as to explore its mechanism underlying regulating glucose and lipid metabolism of type 2 diabetes mellitus (T2DM) and improving skeletal muscle insulin resistance (IR).Twelve male ZDF rats and six Zucker thin (ZL) rats were selected. The rats were fed with Purina#5008 high-fat diet for four weeks to induce T2DM model after adaptive feeding with normal diet for one week. The ZDF rats were randomly divided into model group and EA group according to blood glucose level after modeling and 6 ZL rats were used as the blank control group. Rats in the EA group were treated with "Pishu" (BL20), EA stimulation of "Yishu" (EX-B3), "Zusanli" (ST36) and "Sanyinjiao" (SP6), once a day and 6 times a week for 4 weeks. Rats of the model and blank control groups were grabbed and fixed in the same way as EA group. Fasting blood glucose (FBG) was measured before and after EA intervention. Serum levels of insulin (INS), C-peptide (C-P), adiponectin (APN) were measured by radioimmunoassay, and those of free fatty acid (FFA), low-density lipoprotein (LDL), cholesterol (TC), triglyceride (TG) content determined by enzyme colorimetry and insulin resistance index (HOMA-IR) was calculated. The protein expression levels of AdipoR1, AMPK and PPARα proteins in the quadriceps femoris tissues were detected by Western blot and histopathological changes of quadriceps femoris muscle were observed by H.E. staining.Compared with the blank control group, the levels of FBG, serum INS, C-P, FFA, LDL, TC, TG and HOMA-IR in the model group were significantly increased (EA can reduce blood glucose and lipid levels, and improve IR in ZDF rats, which may be related to its functions in up-regulating AdipoR1/AMPK/PPARα signaling and in promoting APN secretion.

Background: The important effect of regular blood flow surveillance on arteriovenous fistula maintenance is emphasized. The ultrasonic dilution technique for blood flow surveillance can be performed during hemodialysis, but there are some limitations. Blood flow is traditionally measured by duplex Doppler ultrasound during the nondialysis period. However, the surveillance workload for arteriovenous fistula has increased with the rapid increase in the hemodialysis population size. Efficient methods for blood flow surveillance during hemodialysis are needed. Methods: Eighty-four hemodialysis patients with a forearm radiocephalic arteriovenous fistula were enrolled in this cross-sectional study. Each received blood flow measurements using ultrasonic dilution technique and duplex Doppler ultrasound during hemodialysis. Duplex Doppler ultrasound measurements included the blood flow of the brachial artery and radial artery. The correlations between these variables were analyzed. Results: The correlation coefficients ( r) between flow measured by ultrasonic dilution technique and brachial artery flow measured by duplex Doppler ultrasound, between flow measured by ultrasonic dilution technique and radial artery flow measured by duplex Doppler ultrasound, and between brachial artery flow and radial artery flow measured by duplex Doppler ultrasound were 0.724, 0.784, and 0.749, respectively (all p < 0.001). Conclusion: Blood flow measured by ultrasonic dilution technique was positively correlated with blood flow measured by duplex Doppler ultrasound during hemodialysis, suggesting that duplex Doppler ultrasound can be used to monitor the trends in the blood flow of the brachial artery and radial artery for timely intervention to improve patency during hemodialysis.

Breast cancer is the most common malignancy for women worldwide, while Triple Negative Breast Cancer (TNBC) accounts for 20% in all patients. Compared with estrogen receptor positive breast cancer, which could be effectively controlled via endocrine therapy, TNBC is more aggressive and worse in prognosis. It is therefore urgent and necessary to develop a novel therapeutic strategy for TNBC treatment. Recent studies identified Hippo signaling is highly activated in TNBC, which could be a driving pathway for TNBC progression. In our study, we determine RNF187 as a negative regulator for Hippo signaling activation. RNF187 depletion significantly decreases cell migration and invasion capacity in TNBC. These effects could be rescued by further YAP depletion. Depletion of RNF187 increases the YAP protein level and Hippo signaling target genes, such as CTGF and CYR61 in TNBC. Immuno-precipitation assay shows that RNF187 associates with YAP, promoting its degradation possibly via inducing YAP K48-dependent poly-ubiquitination. Interestingly, Our clinical data reveals that RNF187 reversely correlates with YAP protein level and Hippo target genes. RNF187 tends to correlate with good prognosis in TNBC patients. Our study provides evidence to establish a proteolytic mechanism in regulation Hippo signaling activation in TNBC.

Breast cancer is one of the most common malignancies worldwide, while the luminal types (ERα positive) accounts for two third of all breast cancer cases. Although ERα positive breast cancer could be effective controlled by endocrine therapy, most of the patients will develop endocrine resistance, which becomes a headache clinical issue for breast cancer field. Endocrine resistance could be caused by multiple pathway disorders, the dys-regulation of ERα signaling might be a critical factor, which makes it urgent and important to reveal the potential molecular mechanism of ERα signaling. In our current study, we identified a new deubiquitination enzyme USP1 through screening the whole DUB (Deubiquitinases) siRNA library. The expression of USP1 is elevated in human breast cancer compared with normal mammary tissues. Importantly, USP1 expression levels are specially correlated with poor survival in ERα positive patients. USP1 depletion inhibited breast cancer cell progression and ERα signaling activity. Immuno-precipitation assays indicate that USP1 associates with ERα and promotes its stability possibly via inhibiting ERα K48-linked poly-ubiquitination. In conclusion, our data implicate a non-genomic mechanism by USP1 via stabilizing ERα protein controls ERα target gene expression linked to breast cancer progression.

Objective: Esophageal squamous cell carcinoma (ESCC) is one of the most commonly diagnosed cancer types in China. Recent genomic sequencing analysis indicated the over-activation of Hippo/YAP signaling might play important roles for the carcinogenic process and progression for ESCC patients. However, little is known about the molecular mechanisms that controls Hippo signaling activity in ESCC. Our previous studies indicated that PLCE1-an important risk factor for ESCC-linked to ESCC progression through snail signaling, during this period, we found PARK2 was an important downstream target of PLCE1-snail axis. PARK2 was decreased in ESCC human samples, and correlated with good prognosis in ESCC patients. Further research showed that PARK2 could inhibit YAP, which functions as key downstream effectors of the Hippo pathway. Here, we aim to reveal the molecular mechanisms of PARK2 modulated Hippo pathway in ESCC. Methods: To evaluate the function of PARK2 in ESCC, we used a tissue microarray (TMA) of 223 human ESCC patients and immunohistochemistry to analyze the correlation between PARK2 expression and clinicopathologic variables. Depletion of endogenous PARK2 and YAP from ESCC cells using CRISPR/Cas9 technologies. Flow cytometry and EdU cell proliferation assay were used to detect proliferation of ESCC cells. Nude mice subcutaneous injection and Ki-67 staining were used to evaluate tumor growth in vivo. Migration and invasion assays were performed. In addition, lung metastasis models in mice were used to validate the function of PARK2 in vivo. Identification of PARK2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays. The RNA-seq analysis results were validated through quantitative real-time PCR (qRT-PCR) analysis. The protein half-life of YAP was analyzed by Cycloheximide assay, and the TEAD activity was detected by Luciferase reporter assays. Results: Clinical sample of ESCC revealed that low PARK2 expression correlated with late tumor stage (P < 0.001), poor differentiation (P < 0.04), lymph node (P < 0.001) and distant metastasis (P = 0.0087). Multivariate Cox proportional regression analysis further revealed that PARK2 expression (P = 0.032) is an independent prognostic factor for the overall survival of ESCC patients. Besides, the immunohistochemistry results showed that PARK2 negatively correlated with YAP protein level (P < 0.001). PARK2 depletion promotes ESCC progression both through Hippo/YAP axis, while PARK2 overexpression suppresses ESCC tumor progression by Hippo signaling. Co-IP and ubiquitination assays revealed that PARK2 could interact with YAP in the cytosol and promotes YAP K48-linked ubiquitination at K90 sites. Conclusion: Clinical sample analysis and mechanistic study have validated PARK2 as a tumor suppressor for ESCC. Multivariate Cox proportional regression analysis further revealed that PARK2 is an independent prognostic factor for the overall survival of ESCC patients. Cellular and molecular mechanisms in this study showed that PARK2 associated with YAP protein in the cytosol, promoted YAP ubiquitination and proteasome-dependent degradation in ESCC cells. Therefore, as a novel modulator for Hippo signaling, modulation of PARK2 activity or gene expression level could be an appealing strategy to treat esophageal.

Aim: Studies have suggested that genetic and environmental factors do not account for all risks and mechanisms of intracranial atherosclerotic stenosis (ICAS). DNA methylation may play a role in the progression of ICAS. Methods: DNA methylation profiles of peripheral blood leucocytes from 7 patients with early-onset ICAS and 7 perfectly matched controls were interrogated for the first time using the Illumina Infinium Human MethylationEPIC BeadChip. Afterward, functional analysis for differentially methylated genes was conducted. In addition, pyrosequencing verification was performed in an independent cohort comprising 21 patients with earlyonset ICAS and 21 age- and gender-matched controls. Results: A total of 318 cytosine-phosphate-guanine sites were found to be differentially methylated based on the established standards. Functional analysis annotated differentially methylated sites to atherosclerosis-related processes and pathways, such as the negative regulation of hydrolase activity (GO 0051346), type II diabetes mellitus (KEGG hsa04930), and the insulin signaling pathway (KEGG hsa04910). In addition, a differentially methylated site was also validated, cg22443212 in gene Rnf213, which showed significant hypermethylation in patients with early-onset ICAS compared with controls 59.56% (49.77%, 88.55%) vs. 44.65% (25.07%, 53.21%), respectively; P = 0.010). Receiver operating characteristic curve analysis showed that the area under the curve value of cg22443212 was 0.744 (95% confidence interval, 0.586–0.866; P = 0.002). Conclusions: We revealed that altered DNA methylation may play a role in the occurrence and development of ICAS. These results provided new epigenetic insights into ICAS.

Background and aims Circulating microRNAs (miRNAs) have recently emerged as promising biomarkers for acute ischaemic stroke (AIS). However, the expression profiles of miRNAs in AIS patients receiving intravenous thrombolysis, and their associations with outcome have not been investigated. Methods In a prospective cohort study, a total of 84 AIS patients, who received intravenous thrombolysis (21.4% received combined reperfusion therapy) and completed 3 month follow-up visits, were included. Favourable and unfavourable outcomes were defined as modified Rankin Scale (mRS) scores of 0–1 and 2–6, respectively. Plasma samples were collected at 24 h after thrombolysis. We used RNA sequencing to study miRNA profiles in 5 patients with unfavourable outcomes and 5 matched patients with favourable outcomes. Differentially expressed miRNAs were further validated in all cohorts using quantitative real-time polymerase chain reaction assays. Results After identification and validation, we found that miR-124-3p, miR-125b-5p and miR-192-5p levels were higher in patients with unfavourable outcomes than in patients with favourable outcomes. Logistic regressions and receiver-operating characteristic curve analyses demonstrated that these altered miRNAs may function as predictive biomarkers for outcome in AIS patients receiving thrombolysis, whether combined with endovascular thrombectomy or not. In addition, miR-124-3p and miR-125b-5p were closely associated with stroke severity. Conclusions A set of circulating microRNAs (miR-124-3p, miR-125b-5p and miR-192-5p) are associated with unfavourable 3 month outcomes and might have clinical utility in AIS patients receiving thrombolysis.

In this study, a crystal porous organic framework (POF) belonging to ctn topology (POFct-1) is synthesized to selectively scavenge Hg(II) and Cu(II) ions. The maximum adsorption capacities of 167.1...

Background Increasing evidence has suggested that the cerebellum is associated with pain and migraine. In addition, the descending pain system of the brainstem is the major site of trigeminal pain processing and modulation and has been discussed as a main player in the pathophysiology of migraine. Cerebellar and brainstem structural changes associated with migraineurs remain to be further investigated. Methods Voxel-based morphometry (VBM) (50 controls, 50 migraineurs without aura (MWoAs)) and diffusion tensor imaging (DTI) (46 controls, 46 MWoAs) were used to assess cerebellum and brainstem anatomical alterations associated with MWoAs. We utilized a spatially unbiased infratentorial template toolbox (SUIT) to perform cerebellum and brainstem optimized VBM and DTI analysis. We extracted the average diffusion values from a probabilistic cerebellar white matter atlas to investigate whether MWoAs exhibited microstructure alterations in the cerebellar peduncle tracts. Results MWoAs showed decreased fractional anisotropy (FA) in the vermis VI extending to the bilateral lobules V and VI of the cerebellum. We also found higher axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) in the right inferior cerebellum peduncle tract in MWoAs. MWoAs exhibited both reduced gray matter volume and increased AD, MD and RD in the spinal trigeminal nucleus (SpV). Conclusion MWoAs exhibited microstructural changes in the cerebellum and the local brainstem. These structural differences might contribute to dysfunction of the transmission and modulation of noxious information, trigeminal nociception, and conduction and integration of multimodal information in MWoAs. These findings further suggest involvement of the cerebellum and the brainstem in the pathology of migraine without aura. Electronic supplementary material The online version of this article (10.1186/s10194-019-1045-5) contains supplementary material, which is available to authorized users.

Different from conventional ultrasound, contrast-enhanced ultrasound (CEUS) is better in observing microperfusion. For atypical focal adenomyosis and uterine leiomyomas that are difficult to be distinguished by conventional ultrasound, this study aims to further improve the differential diagnosis performance by using CEUS model.After screening the cases with difficulties in identifying focal myometrium lesions through conventional ultrasound, the number of cases covered in the focal adenomyosis group and leiomyomas group were 60 and 30 in derivation cohort, 14 and 7 in validation cohort. The qualitative and quantitative characteristics of CEUS were analyzed according to the surgical pathology. The qualitative characteristics include: the enhancement level based on the myometrium, the contrast enhancement pattern, the enhanced time of the lesion based on the myometrium, post-contrast lesion border, the distribution of the contrast agent, and the wash-out time based on the myometrium. The quantitative characteristics include: arrive time (AT), time to peak (TTP), peak intensity (PI), ΔAT, ΔTTP, ΔPI, |ΔAT|, |ΔTTP|, |ΔPI| and lesion temporal variability. Multiple logistic regression analysis was used to screen the independent risk factors, and a risk prediction model for the differential diagnosis of the two diseases was established. The area under the receiver operating characteristic (ROC) curve (AUC) was used to assess the diagnostic performance of the model. The validation cohort was used to further evaluate the diagnostic performance of the model.Through the multivariate analysis, it concluded that short-term vessels first enhanced enhancement mode, unclear boundary, lesion temporal variability under CEUS9.5 s, uneven contrast agent distribution could be independent risk factors for the diagnosis of adenomyosis [AUC =0.908, 95% confidence interval (CI): 0.833-0.982]. We also determined the sensitivity (98.33%), specificity (70.00%), positive predictive value (PPV) (86.76%), negative predictive value (NPV) (95.45%), and accuracy (87.78%) of this model. Based on pathological diagnosis, the sensitivity and specificity of the model in the validation cohort were both 85.71%, with NPV of 75% and PPV of 92.3%. The area under the ROC curve was 0.898 (95% CI: 0.742-1.000).The establishment of CEUS model has certain clinical application value in differentiating atypical focal adenomyosis from leiomyomas.

Hippo signaling restricts tissue growth by inhibiting the transcriptional effector YAP. Here we uncover a role of Hippo signaling and a tumor suppressor function of YAP in estrogen receptor positive (ER