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Vascular smooth muscle cell (VSMC) migration plays a critical role in the pathogenesis of many cardiovascular diseases. We recently showed that TMEM16A is involved in hypertension-induced cerebrovascular remodeling. However, it is unclear whether this effect is related to the regulation of VSMC migration. Here, we investigated whether and how TMEM16A contributes to migration in basilar artery smooth muscle cells (BASMCs). We observed that AngII increased the migration of cultured BASMCs, which was markedly inhibited by overexpression of TMEM16A. TMEM16A overexpression inhibited AngII-induced RhoA/ROCK2 activation, and myosin light chain phosphatase (MLCP) and myosin light chain (MLC20) phosphorylation. But AngII-induced myosin light chain kinase (MLCK) activation was not affected by TMEM16A. Furthermore, a suppressed activation of integrinβ3/FAK pathway, determined by reduced integrinβ3 expression, FAK phosphorylation and F-actin rearrangement, was observed in TMEM16A-overexpressing BASMCs upon AngII stimulation. Contrary to the results of TMEM16A overexpression, silencing of TMEM16A showed the opposite effects. These in vitro results were further demonstrated in vivo in basilar arteries from VSMC-specific TMEM16A transgenic mice during AngII-induced hypertension. Moreover, we observed that the inhibitory effect of TMEM16A on BASMC migration was mediated by decreasing the activation of WNK1, a Cl−-sensitive serine/threonine kinase. In conclusion, this study demonstrated that TMEM16A suppressed AngII-induced BASMC migration, thus contributing to the protection against cerebrovascular remodeling during AngII-infused hypertension. TMEM16A may exert this effect by suppressing the RhoA/ROCK2/MLCP/MLC20 and integrinβ3/FAK signaling pathways via inhibiting WNK1. Our results suggest that TMEM16A may serve as a novel therapeutic target for VSMC migration-related diseases, such as vascular remodeling., Graphical abstract This study suggests that modulation of TMEM16A expression and/or activity might be a novel strategy to prevent hypertension-induced vascular remodeling.Image 1

Insufficiency of oocyte activation impairs the subsequent embryo development in assisted reproductive technology (ART). Intracellular Ca2+ concentration ([Ca2+]i) oscillations switch the oocytes to resume the second meiosis and initiate embryonic development. However, the [Ca2+]i oscillation patterns in oocytes are poorly characterized. In this study, we investigated the effects of various factors, such as the oocytes age, pH, cumulus cells, in vitro or in vivo maturation, and ER stress on [Ca2+]i oscillation patterns and pronuclear formation after parthenogenetic activation of mouse oocytes. Our results showed that the oocytes released to the oviduct at 17 h post-human chorionic gonadotrophin (hCG) displayed a significantly stronger [Ca2+]i oscillation, including higher frequency, shorter cycle, and higher peak, compared with oocytes collected at earlier or later time points. [Ca2+]i oscillations in acidic conditions (pH 6.4 and 6.6) were significantly weaker than those in neutral and mildly alkaline conditions (pH from 6.8 to 7.6). In vitro-matured oocytes showed reduced frequency and peak of [Ca2+]i oscillations compared with those matured in vivo. In vitro-matured oocytes from the cumulus-oocyte complexes (COCs) showed a significantly higher frequency, shorter cycle, and higher peak compared with the denuded oocytes (DOs). Finally, endoplasmic reticulum stress (ER stress) severely affected the parameters of [Ca2+]i oscillations, including elongated cycles and lower frequency. The pronuclear (PN) rate of oocytes after parthenogenetic activation was correlated with [Ca2+]i oscillation pattern, decreasing with oocyte aging, cumulus removal, acidic pH, and increasing ER stress. These results provide fundamental but critical information for the mechanism of how these factors affect oocyte activation.

Arsenic can be biomethylated to form a variety of organic arsenicals differing in toxicity and environmental mobility. Trivalent methylarsenite (MAs(III)) produced in the methylation process is more toxic than inorganic arsenite (As(III)). MAs(III) also serves as a primitive antibiotic and, consequently, some environmental microorganisms have evolved mechanisms to detoxify MAs(III). However, the mechanisms of MAs(III) detoxification are not well understood. In this study, we identified an arsenic resistance (ars) operon consisting of three genes, arsRVK, that contribute to MAs(III) resistance in Ensifer adhaerens ST2. ArsV is annotated as an NADPH-dependent flavin monooxygenase with unknown function. Expression of arsV in the arsenic hypersensitive Escherichia coli strain AW3110Δars conferred resistance to MAs(III) and the ability to oxidize MAs(III) to MAs(V). In the presence of NADPH and either FAD or FMN, purified ArsV protein was able to oxidize both MAs(III) to MAs(V) and Sb(III) to Sb(V). Genes with arsV-like sequences are widely present in soils and environmental bacteria. Metagenomic analysis of five paddy soils showed the abundance of arsV-like sequences of 0.12-0.25 ppm. These results demonstrate that ArsV is a novel enzyme for the detoxification of MAs(III) and Sb(III) and the genes encoding ArsV are widely present in soil bacteria.

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key enzymes in the process of lipid transport, is involved in the disease progression of various types of tumors. This article is to study the role of PCSK9 in the progression of hepatocellular carcinoma (HCC). Methods Immunohistochemistry was used to assess the expression of PCSK9 in tumor specimens from 105 HCC patients who underwent curative resection. Western blotting and quantitative real-time PCR were used to test the protein and mRNA expression levels in HCC cell lines. Cell Counting Kit-8 (CCK-8) and clone formation assays were performed to evaluate the proliferation ability of different kinds of cells in vitro. Flow cytometry was used to analyze cell cycle distribution and apoptosis rate. A xenograft model was established to study the effect of PCSK9 on HCC growth in vivo. TUNEL and immunofluorescence assays were used to detect cell apoptosis. Results High expression of PCSK9 in tumor tissues was related to microvascular invasion (p = 0.036) and large tumor size (p = 0.001) in HCC patients. Overall survival and disease-free survival after surgery were poor in patients with high expression of PCSK9 (p = 0.035 and p = 0.007, respectively). In vivo and in vitro experiments showed that PCSK9 promoted the growth of HCC by inhibiting cell apoptosis. A mechanistic study revealed that PCSK9 increases FASN expression, thereby inhibiting apoptosis of HCC cells via the Bax/Bcl-2/Caspase9/Caspase3 pathway. Conclusions PCSK9 expression level in HCC is an indicator of poor prognosis for patients with HCC. FASN-mediated anti-apoptosis plays an important role in PCSK9-induced HCC progression.

A 33 years’ old male complained of excessive salivation with frequent swallowing and spitting, which resulted in communication disturbance, reduced quality of life, and social embarrassment for 19 years. He had been diagnosed as sialorrhea and submandibular gland hyperfunction by stomatologist, then had unilateral submandibular gland resection 13 years ago, but the symptom relief was not satisfactory. After that, he had been treated with glycopyrrolate for less than a year, which was withdrawn because of the short duration of symptomatic control after each tablet take-in and intolerable side effects. With the wish to receive a new treatment with long term effectiveness, low re-operation risk and normal preserved saliva secretion function, the patient was subject to MWA for the right submandibular gland. After systematic clinical evaluation, US-guided percutaneous MWA was successfully performed with an uneventful post-operative course. The volume of the right submandibular gland and ablated area were measured precisely by an ablation planning software system with automatic volume measurement function based on three-dimensional reconstruction of the pre-operative and post-operative enhanced magnetic resonance imaging (MRI) raw data. Finally, the ablated volume was calculated as 62.2% of the whole right submandibular gland. The patient was discharged 1 day after the operation, with symptoms relieved significantly, the mean value of whole saliva flow rate (SFR) decreased from 11 ml to 7.5 ml per 15 minutes. During the follow up by phone three months after operation, the patient reported that the treatment effect was satisfactory, whereas the SFR value became stable as 7 ml per 15 minutes, drooling frequency and drooling severity (DFDS) score decreased from 6 to 5, drooling impact scale (DIS) score decreased from 43 to 26. US-guided percutaneous MWA of submandibular gland seems to be an alternative, minimal invasive, and effective treatment for refractory sialorrhea. We described a patient with refractory sialorrhea treated successfully with ultrasound (US) guided percutaneous microwave ablation (MWA).

Pseudoaneurysm (PSA) formation is the most common arterial complication of endovascular procedures requiring arterial puncture. The present study reported a case of a 72-year-old male patient with iatrogenic femoral artery PSA treated with contrast-enhanced ultrasound (CEUS)-guided thrombin injection. Conventional ultrasound (US) and CEUS were used to diagnose, guide treatment, and evaluate the treatment efficacy. In the case, the PSA was successfully occluded with 1000 IU of thrombin. During the follow-up after 48 hours of thrombin injection, US found that the PSA had complete thrombosis without arterial supply. No complications occurrence in the course of the treatment. CEUS-guided thrombin injection for the treatment of PSA was effective and safety and the associated literatures were also reviewed.

The purpose of this study was to develop, validate and test a prediction model for discriminating malignant from benign breast lesions using conventional ultrasound (US), US elastography of strain elastography and contrast-enhanced ultrasound (CEUS). The study included 454 patients with breast imaging-reporting and data system (BI-RADS) category 4 breast lesions identified on histologic examinations. Firstly, 228 breast lesions (cohort 1) were analyzed by logistic regression analysis to identify the risk factors, and a breast malignancy prediction model was created. Secondly, the prediction model was validated in cohort 2 (84 patients) and tested in cohort 3 (142 patients) by using analysis of the area under the receiver operating characteristic curve (AUC). Univariate regression indicated that age ≥40 y, taller than wide shape on US, early hyperenhancement on CEUS and enlargement of enhancement area on CEUS were independent risk factors for breast malignancy (all p0.05). The logistic regression equation was established as follows: p = 1/1+Exp∑[-5.066 + 3.125 x (if age ≥40 y) + 1.943 x (if taller than wide shape) + 1.479 x (if early hyperenhancement) + 4.167 x (if enlargement of enhancement area). The prediction model showed good discrimination performance with an AUC of 0.967 in cohort 1, 0.948 in cohort 2 and 0.920 in cohort 3. By using the prediction model to selectively downgrade category 4a lesions, the re-rated BI-RADS yield an AUC of 0.880 (95% confidence interval [CI], 0.794-0.965) in cohort 2 and 0.870 (95% CI, 0.801-0.939) in cohort 3. The specificity increased from 0.0% (0/35) to 80.0% (28/35) without loss of sensitivity (from 100.0% to 95.9%, p = 0.153) in cohort 2. Similarly, the specificity increased from 0.0% (0/58) to 77.6% (45/58) without loss of sensitivity (from 100.0% to 96.4%, p = 0.081) in cohort 3. Multimodal US showed good diagnostic performance in predicting breast malignancy of BI-RADS category 4 lesions. Although the loss of sensitivity was existing, the addition of multimodal US to US BI-RADS could improve the specificity in BI-RADS category 4 lesions, which reduced unnecessary biopsies.

AIM: To investigate the influence of unilateral congenital ptosis on the development of the eye and vision in children. METHODS: In this prospective observational study, 41 patients with unilateral congenital ptosis were enrolled (age range 3-15y). The blepharoptosis was divided into 3 subgroups according to the margin reflex distance-1 (MRD-1), including mild group (MRD-1≥2 mm), moderate group (0≤MRD-1

BACKGROUND Minimal-fat angiomyolipoma (mf-AML) is often misdiagnosed as renal cell carcinoma before surgery. AIM To analyze the magnetic resonance imaging (MRI) features of mf-AML and the causes of misdiagnosis by MRI before operation. METHODS A retrospective analysis was performed on ten patients with mf-AML confirmed by surgical pathology, all of whom underwent preoperative MRI examination to analyze the morphological characteristics and MRI signals of the tumor. RESULTS MRI revealed a circular-like mass in 4/10 (40%) patients, an oval mass in 6/10 patients (60%), a mass with a capsule in 9/10 patients (90%), and a mass with a lipid component in 7/10 patients (70%). The diameter of the masses in all ten patients was from 11 to 47 mm; the diameter was between 11 mm and 40 mm in 8/10 (80%) patients and between 40 mm and 47 mm in 2/10 (20%) patients. CONCLUSION An oval morphological characteristic is strong evidence for the diagnosis of mf-AML, while a capsule and lipids are atypical manifestations of mf-AML.

Most hepatocellular carcinoma (HCC) patients are diagnosed at an advanced stage; however, the effect of systemic therapy on advanced HCC remains undetermined. Therefore, new treatment targets must be identified. We analyzed Gene Expression Omnibus datasets from two HCC patient cohorts and found that NT5DC2 was associated with vascular invasion and poor survival. In two hepatoma cell lines, NT5DC2 overexpression promoted HCC cell proliferation and clone formation in vitro and promoted tumor growth in vivo. Coimmunoprecipitation assays and liquid chromatography with tandem mass spectrometry analysis revealed that NT5DC2 bound directly to epidermal growth factor receptor (EGFR). NT5DC2 upregulated EGFR expression by downregulating EGFR ubiquitination and preventing its degradation via the ubiquitin-proteasome pathway but did not upregulate its transcription. EGFR upregulation activated downstream signal transduction, which played a critical role in the protumor effects of NT5DC2. Erlotinib, a small-molecule inhibitor of EGFR, blocked the effect of NT5DC2 in promoting HCC cell proliferation. In a cohort of 79 patients who underwent curative resection for HCC, NT5DC2 expression in the tumors was associated with larger tumors and microvascular invasion. NT5DC2 expression was also independently associated with recurrence-free survival. The present study demonstrated for the first time that NT5DC2 promotes tumor cell proliferation in HCC and may serve as a potential molecular target for treating HCC. EGFR blockage could be used to treat selected patients with NT5DC2 upregulation.

Objectives To compare the imaging findings of Bowen's disease (BD) between ultrasound biomicroscopy (UBM) and conventional high-frequency ultrasound (HFUS). Methods A total of 29 pathologically proven BD lesions in 28 patients were retrospectively enrolled in the study, and all were after surgery. All the lesions were imaged with both UBM and HFUS. The imaging features on HFUS and UBM were analyzed and compared. The diagnostic results of ultrasound for BD were referenced with pathology results. Results All the 29 (100%) BD lesions appeared hypoechogenicity, solid component, and superficial hyperechoic layer (ie, keratinization) on both UBM and HFUS. The typical imaging feature of BD lesions, that was, infiltration depth confined to the epidermis, was visualized in 25 (86.2%, 25/29) lesions on UBM whereas 15 (51.7%, 15/29) on HFUS (P = .002). A "wave sign," which corresponds to the surface keratinization of BD lesion, was visualized in 17 (58.6%, 17/29) of BD lesions on UBM whereas 6 (20.7%, 6/29) on HFUS (P = .001). UBM and HFUS correctly diagnosed 25 (86.2%, 25/29) and 15 (51.7%, 15/29) BD lesions, respectively (P = .002). Conclusions Bowen's disease has some typical imaging features on US. The "wave sign" of the superficial hyperechoic layer and the clear borderline between the tumor in epidermis and the slightly hyperechoic dermis layer are better depicted by UBM in comparison with HFUS, which leads to a more accurate diagnosis of BD. UBM has potential to be used as a diagnostic tool for characterization of BD on account of its high resolution.

Purpose:Exploration of novel strategies to extend the benefit of PARP inhibitors beyond BRCA-mutant cancers is of great interest in personalized medicine. Here, we identified EGFR amplification as a potential biomarker to predict sensitivity to PARP inhibition, providing selection for the glioblastoma (GBM) patient population who will benefit from PARP inhibition therapy.Experimental Design:Selective sensitivity to the PARP inhibitor talazoparib was screened and validated in two sets [test set (n = 14) and validation set (n = 13)] of well-characterized patient-derived glioma sphere-forming cells (GSC). FISH was used to detect EGFR copy number. DNA damage response following talazoparib treatment was evaluated by γH2AX and 53BP1 staining and neutral comet assay. PARP–DNA trapping was analyzed by subcellular fractionation. The selective monotherapy of talazoparib was confirmed using in vivo glioma models.Results:EGFR-amplified GSCs showed remarkable sensitivity to talazoparib treatment. EGFR amplification was associated with increased reactive oxygen species (ROS) and subsequent increased basal expression of DNA-repair pathways to counterelevated oxidative stress, and thus rendered vulnerability to PARP inhibition. Following talazoparib treatment, EGFR-amplified GSCs showed enhanced DNA damage and increased PARP–DNA trapping, which augmented the cytotoxicity. EGFR amplification–associated selective sensitivity was further supported by the in vivo experimental results showing that talazoparib significantly suppressed tumor growth in EGFR-amplified subcutaneous models but not in nonamplified models.Conclusions:EGFR-amplified cells are highly sensitive to talazoparib. Our data provide insight into the potential of using EGFR amplification as a selection biomarker for the development of personalized therapy.

Background Tranexamic acid (TXA) has been demonstrated to reduce blood loss following primary total knee and hip arthroplasty. This study aimed to compare the efficacy and safety of oral and intravenous tranexamic acid for primary total knee and hip arthroplasty. Methods The PubMed, Embase, and Cochrane Library databases were searched for relevant studies published before June 20, 2019. Studies clearly reporting a comparison of oral and intravenous TXA were selected, and total blood loss (TBL), the decline in hemoglobin (DHB), deep vein thrombosis (DVT), intramuscular venous thrombosis (IVT), the length of hospital stay, and the transfusion rate were evaluated. The weighted mean differences and relative risks were calculated using a fixed-effects or random-effects model. Results Ten studies involving 1140 (oral 557; intravenous 583) patients were included in this meta-analysis. There was no significant difference in terms of total blood loss, the decline in hemoglobin, the length of hospital stay, the incidence of DVT or IVT, or the transfusion rate between the oral and intravenous groups, and five studies reported that oral TXA was associated with a lower cost. Conclusion Our research suggests that compared with intravenous use of TXA, the oral approach has similar clinical outcomes and is less expensive for total joint replacement patients.

PI3K-targeting therapy represents one of the most sought-after therapies for glioblastoma (GBM). Several small-molecule inhibitors have been evaluated in clinical trials, however, the emergence of resistance limits treatment potential. Here, we generated a patient-derived glioma sphere–forming cell (GSC) xenograft model resistant to the PI3K-specific inhibitor BKM-120. Integrated RNA sequencing and high-throughput drug screening revealed that the Aurora A kinase (Aurora A)/Polo-like kinase 1 (PLK1)/cyclin-dependent kinase 1 (CDK1) signaling pathway was the main driver of PI3K inhibitor resistance in the resistant xenografts. Aurora kinase was upregulated and pCDK1 was downregulated in resistant tumors from both xenografts and tumor tissues from patients treated with the PI3K inhibitor. Mechanistically, the tyrosine kinase receptor Tie2 physically interacted with FGFR1, promoting STAT3 phosphorylation and binding to the AURKA promoter, which increased Aurora A expression in resistant GSCs. Concurrent inhibition of Aurora A and PI3K signaling overcame PI3K inhibitor–induced resistance. This study offers a proof of concept to target PI3K and the collateral-activated pathway to improve GBM therapy.Significance:These findings provide novel insights into the mechanisms of PI3K inhibitor resistance in glioblastoma.

Previously, we demonstrated that death-associated protein-3 (DAP3) loss drives chemoresistance in gastric cancer cells. In the present study, we aimed to determine the underlying molecular mechanism. The effect of DAP3 silencing on β-catenin signaling was assessed. The direct mediator of DAP3 silencing-induced chemoresistance was identified. Depletion of DAP3 stimulates nuclear accumulation of β-catenin and enhances β-catenin-dependent transcriptional activity in gastric cancer cells. However, the protein kinase B,, extracellular regulated protein kinase and signal transducer and activator of transcription 3 signaling pathways remain unaffected by DAP3 loss. We found that the downstream target gene LGR5 (leucine-rich G-protein coupled receptor 5) is upregulated in DAP3-depleted gastric cancer cells. Moreover, knockdown of LGR5 resensitizes DAP3-depleted gastric cancer cells to 5-fluorouracil (5-FU) and oxaliplatin. We also observed that ectopic expression of LGR5 reduces apoptosis in gastric cancer cells on treatment with 5-FU and oxaliplatin, which is accompanied by prevention of caspase-3 cleavage. The antiapoptotic protein Bcl-2 is identified as a key mediator of LGR5-induced apoptosis resistance in gastric cancer cells. The present findings indicate that DAP3 deficiency-induced chemoresistance in gastric cancer is at least partially mediated through the β-catenin/LGR5/Bcl-2 axis. Targeting LGR5 may provide a novel strategy to overcome chemoresistance in DAP3-deficient gastric cancer cells.

Background Pistachio (Pistacia vera), one of the most important commercial nut crops worldwide, is highly adaptable to abiotic stresses and is tolerant to drought and salt stresses. Results Here, we provide a draft de novo genome of pistachio as well as large-scale genome resequencing. Comparative genomic analyses reveal stress adaptation of pistachio is likely attributable to the expanded cytochrome P450 and chitinase gene families. Particularly, a comparative transcriptomic analysis shows that the jasmonic acid (JA) biosynthetic pathway plays an important role in salt tolerance in pistachio. Moreover, we resequence 93 cultivars and 14 wild P. vera genomes and 35 closely related wild Pistacia genomes, to provide insights into population structure, genetic diversity, and domestication. We find that frequent genetic admixture occurred among the different wild Pistacia species. Comparative population genomic analyses reveal that pistachio was domesticated about 8000 years ago and suggest that key genes for domestication related to tree and seed size experienced artificial selection. Conclusions Our study provides insight into genetic underpinning of local adaptation and domestication of pistachio. The Pistacia genome sequences should facilitate future studies to understand the genetic basis of agronomically and environmentally related traits of desert crops. Electronic supplementary material The online version of this article (10.1186/s13059-019-1686-3) contains supplementary material, which is available to authorized users.

The sterility of hormone-sensitive lipase (HSL) knockout mice clearly shows the link between lipid metabolism and spermatogenesis. However, which substrate or product of this multifunctional lipase affects spermatogenesis is unclear. We found that an HSL protein with a His-tag at the N-terminus preserved the normal hydrolase activity of cholesteryl ester (CE) but the triglyceride lipase (TG) activity significantly decreased in vitro. Therefore, mice with this functionally incomplete HSL (His-HSL) were produced on a background of HSL deficiency (HSL-/- h). As a result, HSL-/- h testis has an 8.65-fold higher CE activity than wild-type testis but a twofold higher TG activity than wild-type testis. To compare His-HSL and wild-type HSL in vitro and in vivo, we confirmed that the His-tag significantly suppressed HSL TG activity. From our results, we believe that TG activity was affected by the His-tag insertion, but CE activity was not influenced. Furthermore, the His-tag protected HSL from binding to the inhibitor BAY. From our study, TG activity and BAY binding sites were affected by N-terminal His-tag insertion.

Alfalfa (Medicago sativa) is a highly valuable perennial forage legume that suffers from autotoxicity, which decreases plant resistance, reduces soil fertility, causes serious soil-borne diseases, and promotes ecological imbalance. We evaluated the effects of autotoxicity on the seed germination of 22 alfalfa varieties, and then elucidated the oxidative damage and lipid peroxidation in two alfalfa varieties with contrasting autotoxicity tolerances. The technique for order of preference by similarity to ideal solution (TOPSIS) method was used to rank the germination of the 22 alfalfa varieties when exposed to six autotoxic concentrations (0, 0.025, 0.075, 0.125, 0.175, and 0.225 g∙mL−1). We found WL656HQ and 3105C to be autotoxicity-tolerant and autotoxicity-sensitive varieties, respectively. The germination index mainly affects the comprehensive allelopathic index of WL656HQ and 3105C, which were the simple vigor index and radicle length according to the random forest model, respectively. 3105C eliminates reactive oxygen species (ROS) via antioxidant enzymes and antioxidants under T1 (0.025 g∙mL−1), but the oxidative stress system and the oxidative scavenging system cannot maintain the balance under T2 (0.125 g∙mL−1), causing oxidative bursts. In comparison, WL656HQ used its oxidative scavenging system (peroxidase (POD), ascorbate peroxidase (APX), and glutathione reductase (GR)) to maintain its redox dynamic balance by removing excess ROS at all concentrations. In conclusion, the positive and negative indicators of autotoxicity for the two varieties were ascorbate (ASA) and hydroxyl free radicals (OH•), and proline (Pro) and dehydroascrobate (DHA), respectively. The most sensitive autotoxic concentrations of 3105C and WL656HQ were T2 (0.125 g∙mL−1) and T1 (0.025 g∙mL−1), respectively.

Glioblastoma (GBM), the most aggressive primary brain tumor, has a dismal prognosis. Despite our growing knowledge of genomic and epigenomic alterations in GBM, standard therapies and outcomes have not changed significantly in the past two decades. There is therefore an urgent unmet need to develop novel therapies for GBM. The inter- and intratumoral heterogeneity of GBM, inadequate drug concentrations in the tumor owing to the blood–brain barrier, redundant signaling pathways contributing to resistance to conventional therapies, and an immunosuppressive tumor microenvironment, have all hindered the development of novel therapies for GBM. Given the high frequency of DNA damage pathway alterations in GBM, researchers have focused their efforts on pharmacologically targeting key enzymes, including poly(ADP-ribose) polymerase (PARP), DNA-dependent protein kinase, ataxia telangiectasia-mutated, and ataxia telangiectasia and Rad3-related. The mainstays of GBM treatment, ionizing radiation and alkylating chemotherapy, generate DNA damage that is repaired through the upregulation and activation of DNA damage response (DDR) enzymes. Therefore, the use of PARP and other DDR inhibitors to render GBM cells more vulnerable to conventional treatments is an area of intense investigation. In this review, we highlight the growing body of data behind DDR inhibitors in GBM, with a focus on putative predictive biomarkers of response. We also discuss the challenges involved in the successful development of DDR inhibitors for GBM, including the intracranial location and predicted overlapping toxicities of DDR agents with current standards of care, and propose promising strategies to overcome these hurdles.

Tourette syndrome (TS) is a developmental neuropsychiatric disorder with onset during childhood. Because of its complex spectrum of phenotypes, the underlying pathophysiology of TS is still unclear. Resting-state functional magnetic resonance imaging demonstrated aberrant spontaneous neural synchronization in conventional frequency band (0.01–0.08 Hz) in TS. No published studies have reported abnormalities of local synchronization across different frequency bands. We estimated the alterations of local synchronization across five bands ranging from 0 to 0.25 Hz. Seventy-nine children with TS and 63 age-, sex-, and handedness-matched healthy children were recruited. Frequency-specific regional homogeneity (ReHo) and independent component analysis were used to identify functional alterations between TS and healthy children. TS patients showed significantly increased ReHo in the left precentral gyrus and decreased ReHo in the right operculum. Abnormal ReHo alterations of the superior frontal gyrus, superior parietal gyrus, anterior cingulate gyrus, putamen, superior temporal gyrus, and operculum were observed in different frequency bands. TS patients showed increased connectivity of the right superior frontal gyrus within the left executive control network. In addition, a significantly negative correlation was found between Yale Global Tic Severity Scale (YGTSS) vocal score and ReHo values of the right operculum in the highest frequency bands (0.198–0.25 Hz), while a significant positive correlation was found between YGTSS motor score and altered connectivity of the right superior frontal gyrus. The present study revealed frequency-specific abnormal alterations of ReHo in the whole brain and altered connectivity within the executive control network of TS children. Its neural importance and clinical practicability require further investigation.

We described a patient with symptomatic giant hepatic hemangioma (GHH) treated with laparoscopic guided percutaneous microwave ablation (MWA). A 58 years’ old woman was referred to our hospital who presented with upper abdominal distension and appetite loss for more than 1 year. The medical history included untreated multiple hepatic hemangiomas (HH) that had been detected 13 years ago and hypertension for more than 12 years. Initial laboratory tests revealed D-dimer mild increase and negative tumor markers. Magnetic resonance (MR) imaging demonstrated multiple nodules of different sizes in the liver and the largest lesion was located on the left lobe (longest diameter 12.8 cm), which replaced the whole enlarged left lobe and compressed the gastric body and inferior vena cava. Contrast-enhanced ultrasound (CEUS) and contrast-enhanced MR imaging both showed the typical enhancement pattern of hemangioma and abnormal perfusion was seen in the surrounding liver parenchyma. With the laparoscopy guidance, we performed microwave ablation till the whole tumor was seen atrophy. The total operation duration was 2 hours, with intra-operative blood loss less than 20 ml. The post-operative course was uneventful. The patient was discharged 3 days after the operation. Abdominal distension decreased, appetite improved, blood pressure controlled at normal level after the operation. MR revealed significant volume reduction of the tumor after the operation.

BACKGROUND: Liver injury is common and also can be fatal, particularly in severe or critical patients with coronavirus disease 2019 (COVID-19). AIM: To conduct an in-depth investigation into the risk factors for liver injury and into the effective measures to prevent subsequent mortality risk. METHODS: A retrospective cohort study was performed on 440 consecutive patients with relatively severe COVID-19 between January 28 and March 9, 2020 at Tongji Hospital, Wuhan, China. Data on clinical features, laboratory parameters, medications, and prognosis were collected. RESULTS: COVID-19-associated liver injury more frequently occurred in patients aged ≥ 65 years, female patients, or those with other comorbidities, decreased lymphocyte count, or elevated D-dimer or serum ferritin (P < 0.05). The disease severity of COVID-19 was an independent risk factor for liver injury (severe patients: Odds ratio [OR] = 2.86, 95% confidence interval [CI]: 1.78-4.59; critical patients: OR = 13.44, 95%CI: 7.21-25.97). The elevated levels of on-admission aspartate aminotransferase and total bilirubin indicated an increased mortality risk (P < 0.001). Using intravenous nutrition or antibiotics increased the risk of COVID-19-associated liver injury. Hepatoprotective drugs tended to be of assistance to treat the liver injury and improve the prognosis of patients with COVID-19-associated liver injury. CONCLUSION: More intensive monitoring of aspartate aminotransferase or total bilirubin is recommended for COVID-19 patients, especially patients aged ≥ 65 years, female patients, or those with other comorbidities. Drug hepatotoxicity of antibiotics and intravenous nutrition should be alert for COVID-19 patients.

Background Oral tranexamic acid (TXA) has been demonstrated to reduce the blood loss in primary total knee and hip arthroplasty, but the optimal regimen of oral TXA administration is still unknown. This study aimed to find the best number of administrations of oral TXA for primary total knee and hip arthroplasty. Methods The PubMed, Embase, and Cochrane Library databases were searched for relevant studies published before March 20, 2020. Studies clearly reporting a comparison of multiple administrations of oral TXA for total hip/knee replacement were included, and the total blood loss (TBL), intraoperative blood loss (IBL), decline in hemoglobin (DHB), deep vein thrombosis (DVT), intramuscular venous thrombosis (IVT), length of hospital stay (LOS), and transfusion rate were evaluated. The weighted mean differences and relative risks were calculated using a fixed effects or random effects model. Results Nine studies involving 1678 patients were included in this meta-analysis (TXA 1363 (one administration, 201; two administrations, 496; three administrations, 215; four administrations, 336; five administrations, 115); placebo 315); the results show that compared with placebo groups, oral TXA could significantly reduce the TBL, IBL, DHB, LOS, and transfusion rate. In addition, the incidences of IVT and DVT were similar between the TXA and placebo groups. Moreover, two administrations of oral TXA significantly reduced the TBL and DHB compared with one administration, three administrations of oral TXA were better than two administrations, and four administrations of oral TXA were better than three administrations. Conclusion Our results suggested that oral TXA could significantly reduce the blood loss and the length of hospital stay but could not increase the incidence of DVT and IVT for total joint replacement patients; additionally, the effectiveness of oral TXA administration increased as the number of administrations increased.

Aim: To compare the value of predictive power of the models for central cervical lymph node metastasis (CLNM) in papillary thyroid carcinomas (PTCs). Patients & methods: 220 PTCs were prospectively enrolled into the study with pathological examination. We established a new risk model with univariate and multivariate analyses and receiver-operating characteristic curves were plotted. Z-test was performed to compare the area under two curves and validated the predictive model for central CLNM in PTCs. The comparison of previous and new predictive model was analyzed. Results: Microcalcification, capsule contact or involvement, internal flow and BRAFV600E mutation were four independent risk factors for PTCs with central CLNMs. The area under the curves for the new and the previous model were 0.948 and 0.934 (p = 0.572), respectively. Conclusion: Two predictive models showed strong consistency in predicting central CLNM in PTCs. The predictive model may be helpful in selecting appropriate treatment method in PTCs.

To explore the role of protease nexin-1 (PN-1) in Alzheimer's disease (AD)PN-1 lentiviral activation particles were injected into APP/PS1 transgenic AD and wild-type (WT) mice; these mice were subjected to the Morris water maze test, followed by ELISA, thioflavin S staining and NeuN-TUNEL dual staining. HT22 cells were induced with AβThe escape latency of the APP/PS1 transgenic AD mice was extended with a decreased number of platform crossings; in addition, increased Aβ deposits, AβPN-1, by blocking SHH pathway, reduced apoptosis of hippocampal neurons to improve spatial learning and memory ability, thereby playing a protective role in AD.

Background Post-hepatectomy liver failure (PHLF) is an important cause of mortality and morbidity. Whether Child–Pugh A Patients with varying degrees of cirrhosis are good candidates for hepatectomy is disputed. The purpose of this study was to analyse the impact of portal venous pressure gradient (PVPG) variation during surgery on PHLF. Methods PVPG, the pressure gradient between the portal vein and central vein, was measured in consecutive patients before and after liver resection. The optimal cut-off of PVGP to predict PHLF was determined by receiver operating characteristic (ROC) curve analysis. Risk factors for PHLF were subjected to univariable and multivariable analysis. Results Sixty Child-Pugh A patients were recruited. The mean PVPG was increased from 5.17 ± 4.78 millimeters of Mercury (mmHg) to 6.37 ± 4.44 mmHg after liver resection. The optimal cut-off value of PVPG increments to predict PHLF was 1.5 mmHg. Multivariable analysis showed prothrombin time (PT), post-hepatectomy PVPG increments of 1.5 mmHg or greater, and resected liver segments of 3 or more to be independent predictors of PHLF. Conclusions Acute PVPG increase after hepatectomy is associated with a higher risk of PHLF in Child-Pugh A patients.

OBJECTIVE With the fast development of artificial intelligence techniques, we proposed a novel two-stage multi-view learning framework for the contrast-enhanced ultrasound (CEUS) based computer-aided diagnosis for liver tumors, which adopted only three typical CEUS images selected from the arterial phase, portal venous phase and late phase. MATERIALS AND METHODS In the first stage, the deep canonical correlation analysis (DCCA) was performed on three image pairs between the arterial and portal venous phases, arterial and delayed phases, and portal venous and delayed phases respectively, which then generated total six-view features. While in the second stage, these multi-view features were then fed to a multiple kernel learning (MKL) based classifier to further promote the diagnosis result. Two MKL classification algorithms were evaluated in this MKL-based classification framework. We evaluated proposed DCCA-MKL framework on 93 lesions (47 malignant cancers vs. 46 benign tumors). RESULTS The proposed DCCA-MKL framework achieved the mean classification accuracy, sensitivity, specificity, Youden index, false positive rate, and false negative rate of 90.41 ± 5.80%, 93.56 ± 5.90%, 86.89 ± 9.38%, 79.44 ± 11.83%, 13.11 ± 9.38% and 6.44 ± 5.90%, respectively, by soft margin MKL classifier. CONCLUSION The experimental results indicate that the proposed DCCA-MKL framework achieves best performance for discriminating benign liver tumors from malignant liver cancers. Moreover, it is also proved that the three-phase CEUS image based CAD is feasible for liver tumors with the proposed DCCA-MKL framework.

OBJECTIVE To assess the performance of conventional high frequency ultrasound (US) and US elastography in diagnosis of complex cystic and solid breast lesions. METHODS Ninety three lesions in 93 patients underwent conventional US and US elastography, including strain elastography, acoustic radiation force impulse (ARFI) imaging, and point shear wave speed (SWS) measurement. RESULTS Pathological examination revealed 31 (33.3%) of the 93 lesions were malignant and the remaining 62 (66.7%) were benign. Multivariate analysis showed that elder patient (OR: 25.301), internal vascularity (OR: 4.518), and not circumscribed margin (OR: 3.813) were independent predictors for malignancy, while predominately cystic lesions (OR: 0.178) was a predictor for benign lesions (all p

To evaluate the value of ultrasound (US) in differentiating the acute phase of gout from the intercritical phase, particularly using shear wave elastography (SWE). 57 gout patients were prospectively enrolled and divided into acute phase and intercritical phase groups. The patients underwent US and SWE examinations for the first metatarsophalangeal joints with the same protocol. Maximum synovial thickness was measured. US features were reviewed by two radiologists independently. The maximum (Emax) and mean (Emean) elastic moduli of synovium were calculated. Diagnostic performances of US, SWE and combined US and SWE were evaluated. US findings demonstrated that the colour Doppler flow signal grade in the acute phase was higher than that in the intercritical phase (p = 0.001), whereas no differences were found for B-mode US features between the two groups (all p > 0.05). For SWE, Emax and Emean were significantly higher in the intercritical phase than in the acute phase (both p < 0.001). The areas under the receiver operating characteristic curve (AUROCs) were 0.494–0.553 for B-mode US, 0.735 for colour Doppler US (CDUS), 0.887 for Emax and 0.882 for Emean. The combination of CDUS and SWE increased the AUROC, sensitivity and accuracy significantly in comparison with CDUS alone (all p < 0.001). However, the combined set did not show stronger diagnostic performance in comparison with SWE alone. SWE increases the diagnostic performance in differentiating the acute phase of gout from the intercritical phase in comparison with conventional US. • Colour Doppler flow signal grade is higher in acute phase of gout than in intercritical phase. • SWE demonstrates that synovium stiffness is higher in intercritical phase of gout than in acute phase. • SWE increases diagnostic performance in differentiating acute phase of gout from intercritical phase in comparison with conventional US.

To propose a risk stratification system for intermediate-risk thyroid nodules (TNs) according to American Association of Clinical Endocrinologists, American College of Endocrinology and Associazione Medici Endocrinologi Medical (AACE/ACE/AME) Guideline with ultrasound (US) features. 1000 patients with 1000 nodules (902 benign nodules and 98 malignant nodules) were included. All the nodules were confirmed with either fine needle aspiration (FNA) cytology and follow-up or histology results after surgery. Univariate analysis and binary multivariate logic regression analysis were applied to analyze the possible risk US features associated with malignancy. Receiver operating characteristic curves (ROC) were drew and compared. Univariate analysis and binary multivariate logistic regression analysis showed that indeterminate hyper-echoic spot (OR = 4.544), slightly ill-defined margin (OR = 2.559), slight hyper-echogenicity (OR = 1.992) and no macro-calcification (OR = 1.921) were risk factors for the intermediate-risk thyroid nodules (TNs). A predicting model was established based on the 4 risk factors. The risk rates of malignancy were 5.7% (26/455) in Stage I, 11.0% (49/445) in Stage II, 23.1% (21/91) in Stage III, 33.3% (3/9) in Stage IV. In conclusion, for the intermediate-risk TNs, special attention should be paid to the TNs with indeterminate hyper-echoic spot, slightly ill-defined margin, slight hyper-echogenicity, or no macro-calcification. The probability of malignancy increased with the number of risk factors increasing.

Recent studies have shown that radiofrequency (RF) ablation therapy is a safe, feasible, and effective procedure for hepatic hemangiomas, even huge hepatic hemangiomas. RF ablation has the following advantages in the treatment of hepatic hemangiomas: minimal invasiveness, definite efficacy, high safety, fast recovery, relatively simple operation, and wide applicability. It is necessary to formulate a widely accepted consensus among the experts in China who have extensive expertise and experience in the treatment of hepatic hemangiomas using RF ablation, which is important to standardize the application of RF ablation for the management of hepatic hemangiomas, regarding the selection of patients with suitable indications to receive RF ablation treatment, the technical details of the techniques, therapeutic effect evaluations, management of complications, etc. A final consensus by a Chinese panel of experts who have the expertise of using RF ablation to treat hepatic hemangiomas was reached by means of literature review, comprehensive discussion, and draft approval.

This study aimed to identify the associated factors for quality measurement (QM) of shear wave speed (SWS) imaging and to validate the additional value of QM in the diagnosis of breast lesions. From September 2014 to February 2015, conventional ultrasound and SWS imaging were performed in 338 women with 361 breast lesions. Binary logistic regression was used to identify associated factors for QM. Sensitivity, specificity and the area under receiver operating characteristic (ROC) curve (AUC) among maximum SWS (SWS max ), QM and SWS max plus QM (SWS max +QM) were compared to validate additional value of QM. Pathology confirmed 263 (72.9%) benign lesions and 98 (27.1%) malignancies. Maximum depth (Odds ratio [OR]: 1.398) and posterior features (OR: 1.206) were identified as independent associated factors for QM. Compared with SWS max and QM, the sensitivity of SWS max +QM increased from 67.3%, 64.3% to 83.7% whereas the specificity decreased from 90.5%, 72.6% to 65.4% (all P max had the highest AUC in comparison with QM and SWS max +QM (0.849 vs. 0.685 vs. 0.745; P max is useful for breast cancer screening and SWS max alone is useful for breast cancer differentiation.

To assess the association between BRAF V600E mutation and ultrasound (US) features in papillary thyroid carcinoma (PTC) patients with and without Hashimoto’s thyroiditis (HT). We retrospectively reviewed the US features and status of BRAF V600E mutation in 438 consecutive patients with surgically confirmed PTCs. The association between BRAF mutation and US features were analyzed. In addition, we conducted subgroup analyses in terms of coexistent HT. The BRAF mutation was found in 86.5% of patients (379 of 438). Patient age (OR: 1.028, P = 0.010), age ≥ 50 y (OR: 1.904, P = 0.030), and microcalcification (OR: 2.262, P = 0.015) on US were significantly associated with BRAF mutation in PTC patients. Solid component (OR: 5.739, P = 0.019) on US was the significant predictor for BRAF mutation in patients with HT, while age (OR: 1.036, P = 0.017) and microcalcification (OR: 3.093, P = 0.017) were significantly associated with BRAF mutation in patients without HT. In conclusion, older age and microcalcification are risk factors for BRAF mutation in PTC patients, especially in those without HT. For those with HT, however, PTCs with BRAF mutation tend to be solid on ultrasound. These factors might be considered when making treatment planning or prognosis evaluation.

The aim of this study was to compare the diagnostic performance of two different 2D shear wave speed imaging techniques of Virtual Touch Tissue ImagingQuantification (VTIQ) and Toshiba shear wave elastography (T-SWE) in predicting malignant thyroid nodules (TNs).75 TNs in 75 patients which were subject to both VTIQ and T-SWE examinations were enrolled and analyzed. Shear wave speed (SWS) values on VTIQ and T-SWE were computed (SWS_max, min, mean and median). Area under the receiver operating characteristic (AUROC) curve was obtained to assess the diagnostic performance.The AUROC for VTIQ was the highest with SWS_min whereas for T-SWE was SWS_max (0.774 versus 0.851; p 0.05). The AUROC, sensitivity and negative predictive value (NPV) corresponding to SWS_max for VTIQ were significantly lower than those for T-SWE (0.717 versus 0.851, 61.5% versus 92.3% and 78.7% versus 94.3%; all p 0.05). However, no significant differences were found between AUROC with SWS_min, SWS_mean, or SWS_median for VTIQ and SWS_max for T-SWE (all p 0.05).In general, VTIQ is equal to T-SWE for diagnosis of TNs. In the clinical practice, the selection of SWS_max should be avoided in VTIQ whereas should be selected in T-SWE.

To compare the sampling efficiency and diagnostic performance of ultrasound (US)-guided fine-needle aspiration cytology (FNAC) and fine-needle non-aspiration cytology (FNNAC) for thyroid nodules.629 thyroid nodules in 629 cases (477 females, 152 males) were randomly subjected to FNAC or FNNAC from Jun 2014 to Feb 2015. Diagnostic performance was calculated in reference to the histological findings or follow-up results.629 patients (152 men, 477 women) with 629 thyroid nodules were enrolled in the study. Pathological results were obtained in 173 nodules and benign nodules at FNA with more than six months' follow-up were found in 65 nodules. Tumor size for FNAC ranges from 3.0 to 51.0 mm (mean±SD; 10.2±6.9 mm); whereas FNNAC (2.0-43.0 mm; 11.9±7.7 mm). Non-diagnostic results were found in 7.59% (24/316) of FNNAC procedures and 7.59% (25/313) of FNAC (P 0.05). Determinate and indeterminate results were found in 50.63% (160/316) and 41.77% (132/316) of FNNAC procedures, whereas 58.15% (182/313) and 33.87% (106/313) of FNAC (P 0.05). In order to obtain determinate cytological results, FNAC might be more suitable than FNNAC for diagnosis of nodules with hypovascularity (51.38% vs. 41.78%, P 0.05) and macrocalcifications (9.72% vs. 6.50%, P 0.05). No US and Color-Doppler US characteristics, such as the presence of hypervascularity (P 0.05), microcalcifications (P 0.05), internal component (P 0.05), or size(P 0.05), were significantly different to obtain determinate cytological results between the FNAC and FNNAC groups. The sensitivity, specificity, positive predictive value, negative predictive value, accuracy of FNAC and FNNAC were as follows: 96.67% vs. 100%, 89.74% vs. 96.5%, 87.88% vs. 96.97%, 97.22% vs. 100%, 92.75% vs.98.36%, respectively (all P 0.05).Both FNAC and FNNAC are effective for diagnosis of thyroid nodules. However, FNAC is more effective than FNNAC to acquire determinate cytological results for nodules which US present hypovascularity and macrocalcifications.

To evaluate the diagnostic performance of two different shear wave elastography (SWE) techniques in distinguishing malignant breast lesions from benign ones.From March 2016 to May 2016, a total of 153 breast lesions (mean diameter, 16.8 mm±10.5; range 4.1-90.0 mm) in 153 patients (mean age, 46.4 years±15.1; age range 20-86 years) were separately performed by two different SWE techniques (i.e. T-SWE, Aplio500, Toshiba Medical System, Tochigi, Japan; and S-SWE, the Aixplorer US system, SuperSonic Imagine, Provence, France). The maximum (Emax), mean (Emean) and standard deviation (ESD) of elasticity modulus values in T-SWE and S-SWE were analyzed. All the lesions were confirmed by ultrasound (US)-guided core needle biopsy (n = 26), surgery (n = 122), or both (n = 5), with pathological results as the gold standard. The areas under the receiver operating characteristic curves (AUROCs) were calculated. Sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV) were calculated to assess the diagnostic performance between T-SWE and S-SWE. Operator consistency was also evaluated.Among the 153 lesions, 41 (26.8%) were malignant and 112 (73.2%) were benign. Emax (T-SWE: 40.10±37.14 kPa vs. 118.78±34.41 kPa; S-SWE: 41.22±22.54 kPa vs. 134.77±60.51 kPa), Emean (T-SWE: 19.75±16.31 kPa vs. 52.93±25.75 kPa; S-SWE: 20.95±10.98 kPa vs. 55.95±22.42 kPa) and ESD (T-SWE: 9.00±8.55 kPa vs. 38.44±12.30 kPa; S-SWE: 8.17±6.14 kPa vs. 29.34±13.88 kPa) showed statistical differences in distinguishing malignant lesions from benign ones both in T-SWE and S-SWE (all p 0.05). In T-SWE, the diagnostic performance of ESD was the highest (AUROC = 0.958), followed by Emax (AUROC = 0.909; p = 0.001 in comparison with ESD) and Emean (AUROC = 0.892; p 0.001 in comparison with ESD), while in S-SWE, the diagnostic performance of Emax was the highest (AUROC = 0.967), followed by ESD (AUROC = 0.962, p 0.05 in comparison with Emax) and Emean (AUROC = 0.930, p = 0.034 in comparison with Emax). AUROC-max (T-SWE: 0.909 vs.0.967), AUROC-mean (T-SWE: 0.892 vs.0.930) and AUROC-SD (T-SWE: 0.958 vs.0.962) showed no significant difference between T-SWE and S-SWE (all p 0.05). The intra-class correlation coefficients (ICC) of the intra-operator consistency and inter-operator consistency respectively were 0.961 and 0.898 in T-SWE, while 0.954 and 0.897 in S-SWE.T-SWE and S-SWE are equivalent for distinguishing the breast lesions. In T-SWE, ESD had the best diagnostic performance, while in S-SWE, Emax had the best diagnostic performance.

To assess the factors associated with initial incomplete ablation (ICA) after radiofrequency ablation for benign thyroid nodules (BTNs).69 BTNs (mean volume 6.35±5.66 ml, range 1.00-25.04 ml) confirmed by fine-needle aspiration cytology (FNAC) in fifty-four patients were treated with ultrasound-guided percutaneous radiofrequency ablation (RFA) and the local treatment efficacy was immediately assessed by intra-procedural contrast-enhanced ultrasound (CEUS). The RFA was performed with a bipolar electrode (CelonProSurge 150-T20, output power: 20 W). CEUS was performed with a second generation contrast agent under low acoustic power (i.e. coded phase inversion, CPI). Characteristics of clinical factors, findings on conventional gray-scale ultrasound, color-Doppler ultrasound, and CEUS were evaluated preoperatively. Factors associated with initial ICA and initial ICA patterns on CEUS were assessed. Volume reduction ratios (VRRs) of ICA nodules were compared with those with complete ablation (CA).The RFA procedures were accomplished with a mean ablation time and mean total energy deposition of 11.13±3.39 min (range, 5.38-22.13 min) and 12612±4466 J (range, 6310-26130 J) respectively. CEUS detected initial ICA in 21 of 69 (30.8%) BTNs and 16 (76.2%) of the 21 BTNs with initial ICA achieved CA after additional RFA, leading to a final CA rate of 92.8% (64/69). The factors associated with initial ICA were predominantly solid nodule, nodule close to danger triangle area, nodule close to carotid artery, and peripheral blood flow on color-Doppler ultrasound (all P 0.05). The mean VRRs of all BTNs were 23.4%, 54.4% and 81.9% at the 1-, 3- and 6-month follow-up, respectively. All BTNs achieved therapeutic success in this series in that all had VRRs of50% at the 6-month follow-up, among which 7 nodules (10.1%) had VRRs of90%. There were significant differences in VRRs between ICA nodules and CA nodules at the 3- and 6-month follow-up (all P 0.05).The factors associated with initial ICA after RFA for BTNs were predominantly solid nodules, nodule close to danger triangle area, nodule close to carotid artery, and peripheral blood flow on color-Doppler ultrasound. CEUS assists quick treatment response evaluation and facilitates subsequent additional RFA and final CA of the nodules. Nodules with CA achieve a better outcome in terms of VRR in comparison with those with ICA.

Functional magnetic resonance imaging (fMRI) studies have shown that the effect of repetitive transcranial magnetic stimulation (rTMS) can induce changes in remote brain regions. In the stimulated regions, low-frequency (≤1 Hz) rTMS induces inhibitory effects, while high-frequency (≥5 Hz) stimulation induces excitatory effects. However, these stereotypical effects arising from low- and high-frequency stimulation are based on measurements of motor evoked potentials (MEPs) induced by pulsed stimulation. To test the effects of rTMS on remote brain regions, the current study recruited 31 young healthy adults who participated in three rTMS sessions (10 Hz high frequency, 1 Hz low frequency, and sham) on three separate days. The stimulation target was based on individual fMRI activation in the motor cortex evoked by a finger movement task. Pre- and post-rTMS resting-state fMRI (RS-fMRI) were acquired. Regional homogeneity (ReHo) and degree centrality (DC) were calculated to measure the local and global connectivity, respectively. Compared with the sham session, high-frequency (10 Hz) rTMS significantly increased ReHo and DC in the right cerebellum, while low-frequency (1 Hz) stimulation did not significantly alter ReHo or DC. Then, using a newly developed PAIR support vector machine (SVM) method, we achieved accuracy of 93.18–97.24% by split-half validation for pairwise comparisons between conditions for ReHo or DC. While the univariate analyses suggest that high-frequency rTMS of the left motor cortex could affect distant brain activity in the right cerebellum, the multivariate SVM results suggest that both high- and low-frequency rTMS significantly modulated widespread brain activity. The current findings are useful for increasing the understanding of the mechanisms of rTMS, as well as guiding precise individualized rTMS treatment of movement disorders.

Objectives: The aim of this study was to develop an ultrasound consolidated score (UCS) in determining the activity of Crohn’s disease (CD) and evaluate it with reference to simple endoscopic score (SES). Methods: From June 2014 to June 2017, 66 patients with CD were retrospectively enrolled in this study. Each patient underwent endoscopy and transabdominal ultrasound (US) examination. The morphological symmetry, echogenicity of bowel wall, bowel wall layer structure, echogenicity of peri-bowel fat, bowel wall thickness (BWT), and Limberg type on power Doppler US were assessed with transabdominal US, and an UCS scoring system was developed based on these characteristics. Endoscopic results were used as the reference standard and SES was calculated to determine the CD activity. Receiver operating characteristic curve analysis was performed to assess the diagnostic performance for determining CD activity and the correlation between UCS and SES was assessed using Spearman correlation analysis. Results: 330 intestinal segments in 66 patients were included. The UCS of the segments in the remission phase ranged from 3.0 to 9.0 (mean, 3.6 ± 0.9) whereas in the active phase from 3.0 to 20.0 (mean, 10.6 ± 4.0) (p < 0.001). The cut-off value of UCS was 6. The associated area under ROC curve, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 0.980, 88.3%, 95.5%, 93.8%, 91.3%, and 92.3%, respectively. The correlation coefficient between UCS and SES was 0.90, which was higher than the correlation coefficient of 0.83 between BWT and SES. Conclusions: The newly developed UCS with transabdominal US has a good performance and potentially provides an effective alternative for evaluating the activity of CD. Advances in knowledge: UCS is an effective method to evaluate the activity of CD because it provides comprehensive information of the disease. Therefore, it could be employed as an alternative for diagnosis of CD.

The incidence of combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma (cHCC-ICC) is relatively low, and the knowledge about the prognosis of cHCC-ICC remains obscure. In the study, we aimed to screen existing primary liver cancer staging systems and shed light on the prognosis and risk factors for cHCC-ICC.We retrospectively reviewed 206 cHCC-ICC patients who received curative surgical resection from April 1999 to March 2017. The correlation of survival measures with the histological types or with tumor staging systems was determined and predictive values of tumor staging systems with cHCC-ICC prognosis were compared.The histological type was not associated with overall survival (OS) (P = 0.338) or disease-free survival (DFS) (P = 0.843) of patients after curative surgical resection. BCLC, TNM for HCC, and TNM for ICC stages correlated with both OS and DFS in cHCC-ICC (all P 0.05). The predictive values of TNM for HCC and TNM for ICC stages were similar in terms of predicting postoperative OS (P = 0.798) and DFS (P = 0.191) in cHCC-ICC. TNM for HCC was superior to BCLC for predicting postoperative OS (P = 0.022) in cHCC-ICC.The TNM for HCC staging system should be prioritized for clinical applications in predicting cHCC-ICC prognosis.

Objectives The purpose of this study was to establish a scoring system for predicting axillary lymph node metastasis (ALNM) in patients with breast invasive ductal carcinoma with negative axillary ultrasound (US) results. Methods In this retrospective study, 156 breast invasive ductal carcinoma lesions from 156 women were retrospectively enrolled. The features of conventional US and contrast-enhanced ultrasound (CEUS) qualitative enhancement patterns and quantitative enhancement parameters were analyzed. Subsequently, a scoring system was created by a multivariate logistic regression analysis. Results The results found that 60 patients (38%) showed ALNM. A scoring system was defined as risk score = 1.75 × (if lesion size ≥20 mm) + 1.93 × (if uncircumscribed margin shown on conventional US) + 1.77 × (if coarse or twisting penetrating vessels shown on CEUS). When the risk scores were less than 1.75, 1.75 to 1.93, 1.94 to 3.70, and 3.70 or higher, the risk rates of ALNM were 0% (0 of 9), 10.7% (5 of 46), 29.2% (14 of 48) and 77.4% (41 of 53), respectively. In comparison with conventional US alone, the scoring system using the combination of conventional US and CEUS showed better discrimination ability in terms of the area under the curve (0.830 versus 0.777; P = .037). Conclusions A scoring system based on conventional US and CEUS may improve the prediction of ALNM.

Portal hypertension after hepatectomy is associated with impaired postoperative recovery. Terlipressin decreased portal vein pressure in patients with variceal bleeding and improved patient survival, but the role of postoperative terlipressin treatment for patients who underwent liver resection is not clear.We determined the effect of terlipressin on portal vein pressure in patients with portal vein pressure12 mmHg after hepatectomy. If portal vein pressure was decreased (ie, Responders), a continuous infusion of terlipressin at 2 mg/day for 4 days was given. The incidence of posthepatectomy liver failure, abdominal drainage, acute kidney injury, operative complications, and side-effects of terlipressin in the Responders were compared with those whose portal vein pressure did not decrease (ie, non-Responders) and patients whose portal vein pressure was ≤12 mmHg after hepatectomy (low portal vein pressure group).We recruited 110 patients, 65 of whom were eligible for terlipressin administration. Portal vein pressure decreased in 46 patients (71%) with the mean portal vein pressure decreasing from 15.8 ± 2.6 mmHg to 14.3 ± 2.9 mmHg (P.001). The median [interquartile range] postoperative abdominal drainage for the first 3 postoperative days was less in the Responders than in the non-Responders (350 mL [228-573] vs 730 mL [330-980]; P = .004). Incidence of posthepatectomy liver failure in the Responders was less than the non-Responders (26% vs 53%, P = .04). Acute kidney injury, operative complications, and side-effects of terlipressin were not different between groups.Terlipressin decreased posthepatectomy portal vein pressure and may decrease the incidence of posthepatectomy liver failure and postoperative abdominal drainage (NCT03352349).

Objective To assess the usefulness of thyroid imaging reporting and data system (TI-RADS) for cytological Bethesda Category III thyroid nodules (TNs). Methods This retrospective study included 121 patients with 121 TNs classified as Bethesda Category III at fine needle aspiration (FNA) cytology and thereafter underwent surgery. The TNs were classified according to US TI-RADS category and the malignancy risk of each category was calculated. Results Surgical pathology confirmed 43 (35.5%) malignant and 78 (64.5%) benign TNs. The malignancy risks of categories 3, 4a, 4b, 4c, and 5 TNs were 0%, 4.0%, 12.5%, 62.2%, and 100%, respectively. For those >10 mm (n = 55), the malignancy risks were 0%, 6.2%, 12.5%, 73.3%, and 100%, respectively, whereas for those ≤10 mm (n = 66), the risks were 0%, 0%, 12.5%, 56.7%, and 100%, respectively. Conclusion Bethesda Category III TNs without suspicious US features or those ≤10 mm with only one suspicious US feature can be followed up with US.

Although appropriate exercise is beneficial for enhancing brain functions, high-intensity exercise (HIE)-induced cognitive dysfunction is causing more and more concerns nowadays. In the present study, we observed the effects of high-intensity treadmill running on the spatial learning of the adult Sprague Dawley male rats in Y-maze (n = 16 per group), and investigated its possible electrophysiological and molecular mechanisms by examining in vivo hippocampal long-term potentiation (LTP), central inflammatory responses, and JNK/p38/ERK signal pathway. The Y-maze active avoidance test showed that high-intensity treadmill running impaired spatial learning ability of rats, with increased error times and prolonged training time in recognizing safety condition. Associated with the cognitive dysfunction, the induction and maintenance of hippocampal LTP were also impaired by the HIE. Furthermore, accompanied by elevated levels of inflammatory factors IL-1β, TNF-α, and iNOS, overactivation of microglia and astrocytes was also found in the CA1 region of hippocampus in the excessive exercise group, indicating an inflammatory response induced by HIE. In addition, Western blot assay showed that the phosphorylation of JNK/p38/ERK proteins was enhanced in the exercise group. These results suggest that exercise stress–induced neuronal inflammatory responses in the hippocampus are associated with HIE-induced cognitive deficits, which may be involved in the upregulation of the JNK/p38/ERK pathway. © 2016 Wiley Periodicals, Inc.

Objectives To investigate the diagnostic performance of a 2-dimensional shear wave elastographic technique (Virtual Touch tissue imaging and quantification [VTIQ]; Siemens Medical Solutions, Mountain View, CA) for predicting thyroid malignancy. Methods A total of 302 thyroid nodules underwent conventional sonography and VTIQ before fine-needle aspiration examination or surgery. Compared with histopathologic or cytologic results in combination with follow-up, the diagnostic performance of various shear wave speed (SWS) indices (minimum [SWSmin], maximum [SWSmax], and mean [SWSmean]) on VTIQ as well as conventional sonographic features for predicting thyroid malignancy was evaluated in all of the nodules. Results Sixty-five malignant and 237 benign thyroid nodules were histopathologically or cytologically confirmed. All SWS indices on VTIQ were lower in benign nodules than thyroid malignancy (all P

// Bo-Ji Liu 1, 2, * , Chong-Ke Zhao 1, 2, * , Hui-Xiong Xu 1, 2 , Yi-Feng Zhang 1, 2 , Jun-Mei Xu 1, 2 , Dan-Dan Li 1, 2 , Xiao-Wan Bo 1, 2 , Xiao-Long Li 1, 2 1 Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Ultrasound Research and Education Institute, Tongji University School of Medicine, Shanghai 200072, China 2 Thyroid Institute, Tongji University School of Medicine, Shanghai Center for Thyroid Diseases, Shanghai 200072, China * These authors contributed equally to this work Correspondence to: Hui-Xiong Xu, email: xuhuixiong@126.com Keywords: shear wave elastography, shear wave speed imaging, thyroid nodule, quality measurement Received: September 26, 2016 Accepted: December 01, 2016 Published: December 16, 2016 ABSTRACT To evaluate the associated factors for quality measurement (QM) on shear wave speed (SWS) imaging and the additional value of QM for differentiation of thyroid nodules. A consecutive series of 238 patients with 254 thyroid nodules were enrolled. They were all evaluated by conventional ultrasound and SWS imaging and were finally proven pathologically. QM was used to assess whether SWS propagation was authentic and was classified as high QM and Low QM. Twelve variables were analyzed to evaluate the associated factors for QM using binary logistic regression. Receiver operating characteristic (ROC) curve was plotted on SWS and SWS+QM. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy and area under ROC curve (AUC) were calculated. The study included 170 benign thyroid nodules (160 high QM and 10 low QM) and 84 malignant thyroid nodules (56 high QM and 28 low QM) ( P < 0.001). The mean SWS of benign and malignant nodules were 2.51 ± 0.47 m/s and 3.43 ± 1.21 m/s respectively ( P < 0.001). The sensitivities, specificities, PPVs, NPVs, accuracies and AUCs were 77.4%, 80.0%, 65.7%, 87.7%, 79.1%, 0.82 for SWS alone with SWS ≥ 2.78 m/s; 33.3–34.5%, 91.2–94.1%, 65.9–73.7%, 73.8–74.1%, 72.4–74.0%, 0.63–0.64 for QM alone and 84.5–85.7%, 72.4–75.9%, 60.5–63.4%, 90.8–91.0%, 76.8–78.7%, 0.79–0.80 for SWS+QM. Nodule depth was identified to be the strongest associated factor for QM of SWS, followed by malignancy and SWS. In conclusion, QM for thyroid nodule is associated with nodule depth, malignancy, and SWS. QM improves the specificity in comparison with SWS alone, whereas SWS+QM does not improve the overall diagnostic performance.

Aim To evaluate the diagnostic performance of parametric imaging with contrast-enhanced ultrasound(CEUS) for differentiating hepatocellular carcinoma(HCC) from metastatic liver cancer(MLC). Methods 30 HCCs (mean diameter, 3.6±1.3 cm; range, 2.1-5.0 cm) and 30 MLCs (mean diameter, 2.8±1.5 cm; range, 1.2-5.0 cm) pathologically diagnosed or confirmed by clinical criteria that underwent CEUS were randomly included. CEUS was carried out using a multifrequency transducer (2-4 MHz) and a bolus injection of 2.4 mL SonoVue. The CEUS clips of the targeted lesion were recorded continuously for 6 minutes. By analyzing CEUS clips, parametric image could be obtained using the SonoLiver® software automatically. Quantitative parameters were compared between HCC and MLC groups. Receiver operating characteristic (ROC) curve analysis was further performed on parameters with significant difference between two groups. Results On parametric imaging, the maximum intensity, rise time, time to peak, mean transit time and washout time for HCC and MLC were 185.6±148.0 vs. 95.2±58.6 (P = 0.003), 25.7±6.3 s vs. 23.8±8.8 s (P = 0.341), 30.7±7.9 s vs. 27.8±10.5 s (P = 0.246), 90.2±45.7 s vs. 89.3±40.3 s (P = 0.805), 63.4±29.5 s vs. 37.2±33.8 s (P = 0.005), respectively. ROC analysis was further performed for washout time and it showed a cut-off point of 43.765 s for the differentiation between HCC and MLC, with the AUC value of 0.780 (95% CI: 0.646-0.914). The corresponding diagnostic specificity, sensitivity and accuracy were 72.0%, 84.6% and 78.4% respectively. Conclusions Parametric imaging of CEUS can display perfusion effects of HCC and MLC objectively and visually and washout time may serve as a useful parameter on the differential diagnosis between HCC and MLC.

The purpose of the study was to evaluate the value of 2-D shear wave elastography (SWE) of virtual touch tissue imaging quantification (VTIQ) for ultrasound (US) Breast Imaging-Reporting and Data System (BI-RADS) category 4 lesions. One hundred sixteen lesions were subject to conventional US, conventional strain elastography (SE) of elasticity imaging (EI), acoustic radiation force impulse (ARFI)-induced SE of virtual touch tissue imaging (VTI) and VTIQ before biopsies. Of the 116 lesions, 69 (59.5%) were benign and 47 (40.5%) were malignant. Significant differences were found between benign and malignant lesions in EI score, VTI score and shear wave speed (SWS) on VTIQ (both p

// Bao-Ding Chen 1,2,3,4,5 , Hui-Xiong Xu 1,2,3,4 , Yi-Feng Zhang 1,2,3,4 , Bo-Ji Liu 1,2,3,4 , Le-Hang Guo 1,2,3,4 , Dan-Dan Li 1,2,3,4 , Chong-Ke Zhao 1,2,3,4 , Xiao-Long Li 1,2,3,4 , Dan Wang 1,2,3,4 and Shuang-Shuang Zhao 5 1 Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Ultrasound Research and Educational Institute, Tongji University School of Medicine, Shanghai, China 2 Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Clinical College of Nanjing Medical University, Shanghai, China 3 Thyroid Institute, Tongji University School of Medicine, Shanghai, China 4 Shanghai Center of Thyroid Diseases, Shanghai, China 5 Department of Medical Ultrasound, Affiliated Hospital of Jiangsu University, Zhenjiang, China Correspondence to: Hui-Xiong Xu, email: // Keywords : thyroid nodule, calcification, ultrasound, shear-wave elastography, point shear-wave measurement Received : June 30, 2016 Accepted : August 26, 2016 Published : August 31, 2016 Abstract Conventional ultrasound cannot satisfactorily distinguish malignant and benign thyroid nodules. Shear-wave elastography (SWE) can evaluate tissue stiffness and complement conventional ultrasound in diagnosing malignant nodules. However, calcification of nodules may affect the results of SWE. The purposes of this study are to compare the differences of shear-wave speed (SWS) measurement among different calcification groups and compare the diagnostic performance between using a single uniform SWS cutoff value and multiple individual calcification-specific cutoff values using technique of point SWS measurement. We retrospectively identified 517 thyroid nodules (346 benign and 171 malignant nodules) examined by conventional ultrasound and point SWS measurement. There were 177 non-calcified, 159 micro-calcified and 181 macro-calcified nodules. The diagnostic performance was evaluated by receiver operating characteristic (ROC) curve and area under the curve (AUC) was computed. The mean SWS in malignant nodules more than doubled that of benign nodules (4.81±2.03 m/s vs. 2.29±0.99 m/s, p 2.42 m/s), micro- (SWS >2.88 m/s) and macro-calcification (SWS >3.59 m/s) nodules in the whole group, the AUC was 0.859 (95% confidence interval [CI], 0.826-0.888), which was significantly better than the AUC of 0.816 (95% CI, 0.780-0.848) if a single uniform cutoff value (SWS >2.72 m/s) was applied to all the nodules regardless of calcification status (p=0.011). The cutoff values of SWS for different calcified nodules warrant future prospective validation.

Background and Aims Post-hepatectomy liver failure (PHLF) is a severe complication and main cause of death in patients undergoing hepatectomy. The aim of this study was to build a predictive model of PHLF in patients undergoing hepatectomy. Methods We retrospectively analyzed patients undergoing hepatectomy at Zhongshan Hospital, Fudan University from July 2015 to June 2018, and randomly divided them into development and internal validation cohorts. External validation was performed in an independent cohort. Least absolute shrinkage and selection operator (commonly referred to as LASSO) logistic regression was applied to identify predictors of PHLF, and multivariate binary logistic regression analysis was performed to establish the predictive model, which was visualized with a nomogram. Results A total of 492 eligible patients were analyzed. LASSO and multivariate analysis identified three preoperative variables, total bilirubin (p=0.001), international normalized ratio (p