Upregulation of CYR61 by TGF-ß and YAP signaling exerts a counter-suppression of hepatocellular carcinoma.

Transforming growth factor-ß (TGF-ß) and Hippo signaling are two critical pathways engaged in cancer progression by regulating both oncogenes and tumor suppressors, yet how the two pathways coordinately exert their functions in the development of hepatocellular carcinoma (HCC) remains elusive. In this study, we firstly conducted an integrated analysis of public liver cancer databases and our experimental TGF-ß target genes, identifying CYR61 as a pivotal candidate gene relating to HCC development. The expression of CYR61 is downregulated in clinical HCC tissues and cell lines than that in the normal counterparts. Evidence revealed that CYR61 is a direct target gene of TGF-ß in liver cancer cells. In addition, TGF-ß-stimulated Smad2/3 and the Hippo pathway downstream effectors YAP and TEAD4 can form a protein complex on the promoter of CYR61, thereby activating the promoter activity and stimulating CYR61 gene transcription in a collaborative manner. Functionally, depletion of CYR61 enhanced TGF-ß- or YAP-mediated growth and migration of liver cancer cells. Consistently, ectopic expression of CYR61 was capable of impeding TGF-ß- or YAP-induced malignant transformation of HCC cells in vitro and attenuating HCC xenograft growth in nude mice. Finally, transcriptomic analysis indicates that CYR61 can elicit an antitumor program in liver cancer cells. Together, these results add new evidence for the crosstalk between TGF-ß and Hippo signaling and unveil an important tumor suppressor function of CYR61 in liver cancer.

A novel PIEZO2 mutation in a fetus from a Chinese family with Gordon syndrome.

We describe a fetus from a Chinese family whose parents were both healthy but showed multiple malformations, including clubfoot, camptodactyly, micrognathia, and cleft palate. Genomic DNA was extracted from the peripheral blood of the proband's parents and skeletal muscle tissue from the aborted fetus to determine the diagnosis and underlying cause. Whole-exome sequencing revealed that the fetus was heterozygous for a novel variant of uncertain significance in exon 56 (c.8576G>A; p.Trp2859*) of the Piezo-type mechanosensitive ion channel component 2 gene (PIEZO2) (NM_001378183.1). A diagnosis of Gordon syndrome (GS) was made from the presence of this variant and ultrasonic manifestation. Sanger sequencing of the proband's parents resulted in normal chromatograms, suggesting that this was either a de novo variant in the fetus or, less likely, the result of germline mosaicism in the proband's mother or father. This is the first description of GS caused by a PIEZO2 variant in which the fetus was the proband. A prenatal diagnosis of GS can be established by fetal ultrasound examination combined with genetic testing.

A Bioinspired Atomically Thin Nanodot Supported Single-Atom Nanozyme for Antibacterial Textile Coating.

Surface antibacterial coatings with outstanding antibacterial efficiency have attracted increasing attention in medical protective clothing and cotton surgical clothing. Although nanozymes, as a new generation of antibiotics, are used to combat bacteria, their catalytic performance remains far from satisfactory as alternatives to natural enzymes. Single-atom nanodots provide a solution to the low catalytic activity bottleneck of nanozymes. Here, atomically thin C3 N4 nanodots supported single Cu atom nanozymes (Cu-CNNDs) are developed by a self-tailoring approach, which exhibits catalytic efficiency of 8.09 × 105 M-1 s-1 , similar to that of natural enzyme. Experimental and theoretical calculations show that excellent peroxidase-like activity stems from the size effect of carrier optimizing the coordination structure, leading to full exposure of Cu-N3 active site, which improves the ability of H2 O2 to generate hydroxyl radicals (•OH). Notably, Cu-CNNDs exhibit over 99% superior antibacterial efficacy and are successfully grafted onto cotton fabrics. Thus, Cu-CNNDs blaze an avenue for exquisite biomimetic nanozyme design and have great potential applications in antibacterial textiles.

A Metabolomics-Based Study on the Discriminative Classification Models and Toxicological Mechanism of Estazolam Fatal Intoxication.

Fatal intoxication with sedative-hypnotic drugs is increasing yearly. However, the plasma drug concentration data for fatal intoxication involving these substances are not systematic and even overlap with the intoxication group. Therefore, developing a more precise and trustworthy approach to determining the cause of death is necessary. This study analyzed mice plasma and brainstem samples using the liquid chromatography-high resolution tandem mass spectrometry (LC-HR MS/MS)-based metabolomics method to create discriminative classification models for estazolam fatal intoxication (EFI). The most perturbed metabolic pathway between the EFI and EIND (estazolam intoxication non-death) was examined, Both EIND and EFI groups were administered 500 mg of estazolam per 100 g of body weight. Mice that did not die beyond 8 hours were treated with cervical dislocation and were classified into the EIND groups; the lysine degradation pathway was verified by qPCR (Quantitative Polymerase Chain Reaction), metabolite quantitative and TEM (transmission electron microscopy) analysis. Non-targeted metabolomics analysis with EFI were the experimental group and four hypoxia-related non-drug-related deaths (NDRDs) were the control group. Mass spectrometry data were analyzed with Compound Discoverer (CD) 3.1 software and multivariate statistical analyses were performed using the online software MetaboAnalyst 5.0. After a series of analyses, the results showed the discriminative classification model in plasma was composed of three endogenous metabolites: phenylacetylglycine, creatine and indole-3-lactic acid, and in the brainstem was composed of palmitic acid, creatine, and indole-3-lactic acid. The specificity validation results showed that both classification models distinguished between the other four sedatives-hypnotics, with an area under ROC curve (AUC) of 0.991, and the classification models had an extremely high specificity. When comparing different doses of estazolam, the AUC value of each group was larger than 0.80, and the sensitivity was also high. Moreover, the stability results showed that the AUC value was equal to or very close to 1 in plasma samples stored at 4 °C for 0, 1, 5, 10 and 15 days; the predictive power of the classification model was stable within 15 days. The results of lysine degradation pathway validation revealed that the EFI group had the highest lysine and saccharopine concentrations (mean (ng/mg) = 1.089 and 1.2526, respectively) when compared to the EIND and control group, while the relative expression of SDH (saccharopine dehydrogenase) showed significantly lower in the EFI group (mean = 1.206). Both of these results were statistically significant. Furthermore, TEM analysis showed that the EFI group had the more severely damaged mitochondria. This work gives fresh insights into the toxicological processes of estazolam and a new method for identifying EFI-related causes of mortality.

A novel NOTCH1 missense variant in two fetuses with a non-syndromic conotruncal heart defect from a single family.

AIMS: We describe two fetuses with conotruncal heart defects (CTDs) (persistent truncus arteriosus and pulmonary atresia/ventricular septal defect, respectively) in a Chinese family whose parents were both healthy. Testing was performed to identify any underlying genetic cause. MATERIALS AND METHODS: Genomic DNA was extracted from the peripheral blood of the proband's parents and the skeletal muscle tissue of the two aborted fetuses for genetic testing. RESULTS: A heterozygous likely pathogenic missense variant, c.1724G〉C (:p.Cys575Ser), in the NOTCH1 gene (NM_017617.5) was detected in the two affected fetuses but not in the parents, and the next generation sequencing test of the proband's father showed a normal result. It is therefore presumed to result from germline mosaicism in the proband's mother or, less likely, is a recurrent de novo variant in the fetuses. CONCLUSION: This is the first description of fetal non-syndromic CTD caused by a variant in NOTCH1. This report not only expands the gene variant spectrum of CTDs, but also emphasizes the importance of NOTCH1 testing when a fetal of CTD is detected.

A novel ZIC3 mutation in a Chinese family with heterotaxy and multiple types of congenital heart defect.

AIMS: A couple was referred for prenatal counseling at gestational age 21 weeks for revealed situs inversus with levocardia (HP:0,031,592), atrial situs inversus (HP:0,011,538), congenitally corrected transposition of the great arteries (ccTGA, HP:0,011,540) with ventricular septal defect (HP:0,001,629) and right aortic arch (HP:0,012,020). The couple had multiple prior pregnancies with complex congenital heart defects (CHDs, HP:0,001,627) in male fetuses. Testing was initiated to identify any fetal abnormality. The genetic cause of the observed prenatal defects was investigated. MATERIALS AND METHODS: Whole exome sequencing and Sanger sequencing were performed on DNA extracted from parental blood samples and skeletal muscle tissue of the aborted fetuses. RESULTS: A pathogenic hemizygous missense variant in ZIC3 (NM_003413.4: c.895 T > C) associated with X-linked heterotaxy-1 (HTX1) and multiple types of congenital heart defect-1 (CHTD1) (OMIM #306955) was identified, which was inherited from the mother. CONCLUSION: ZIC3 encodes a highly conserved zinc-finger protein that is highly correlated with CHDs. The present study of a Han Chinese family with CHDs expands the mutation spectrum of ZIC3 and provides further evidence that ZIC3 plays important roles in CHDs.

Novel compound heterozygous variants in EMC1: Overlapping phenotypes of left ventricular noncompaction and long QT syndrome warranting in-depth exploration.

A couple was referred for prenatal counseling at the gestational age of 35 weeks of a male fetus (II-2) with sinus bradycardia and suspected first degree atrioventricular block with left ventricular noncompaction (LVNC). A previous pregnancy for the couple of a female fetus (II-1) was diagnosed prenatally as sinus bradycardia at the gestational age of 30 weeks. Both fetuses were confirmed to have long QT syndrome (LQTS) with LVNC after birth, and died of heart failure during infancy. The genetic cause of the combined cardiovascular disorders was investigated by trio whole-exome sequencing and Sanger sequencing on DNA extracted from parental blood samples and umbilical cord serum of the proband. Compound heterozygous variants were identified in the endoplasmic reticulum membrane protein complex subunit 1 gene (EMC1, NM_015047.3), including paternally inherited c.245C>T (p. Thr82Met) and maternally inherited c.1459delC (p. Arg487Alafs*49). Pathogenic variants in EMC1 have been associated with a recessive neurodevelopmental disorder, whereas Emc10 knockout mice exhibit cardiovascular issues. The present study shows that EMC1 variation potentially causes the overlapping phenotypes of LVNC and LQTS and may expand the spectrum of diseases caused by EMC1 variation.

Dynamic Changes in Plasma Metabolic Profiles Reveal a Potential Metabolite Panel for Interpretation of Fatal Intoxication by Chlorpromazine or Olanzapine in Mice.

Diagnosing the cause of fatal intoxication by antipsychotic agents is an important task in forensic practice. In the 2020 Annual Report of the American Association of Poison Control Centers, among 40 deaths caused by antipsychotics, 21 cases were diagnosed as "probably responsible", thereby indicating that more objective diagnostic tools are needed. We used liquid chromatography-mass spectrometry-based integrated metabolomics analysis to measure changes in metabolic profiles in the plasma of mice that died from fatal intoxication due to chlorpromazine (CPZ) or olanzapine (OLA). These results were used to construct a stable discriminative classification model (DCM) comprising L-acetylcarnitine, succinic acid, and propionylcarnitine between fatal intoxication caused by CPZ/OLA and cervical dislocation (control). Performance evaluation of the classification model in mice that suffered fatal intoxication showed relative specificity for different pharmacodynamic drugs and relative sensitivity in different life states (normal, intoxication, fatal intoxication). A stable level of L-acetylcarnitine and variable levels of succinic acid and propionylcarnitine between fatal-intoxication and intoxication groups revealed procedural perturbations in metabolic pathways related to fatal intoxication by CPZ/OLA. Additional stability studies revealed that decomposition of succinic acid in fatal-intoxication samples (especially in the OLA group) could weaken the prediction performance of the binary-classification model; however, levels of these three potential metabolites measured within 6 days in fresh samples kept at 4 °C revealed a good performance of our model. Our findings suggest that metabolomics analysis can be used to explore metabolic alterations during fatal intoxication due to use of antipsychotic agents and provide evidence for the cause of death.

Case report: Prenatal diagnosis of fetal non-compaction cardiomyopathy with bradycardia accompanied by de novo CALM2 mutation.

We herein report what appears to be the first case of fetal non-compaction cardiomyopathy in both ventricles accompanied by a mutation in the calmodulin gene (CALM2). A 25-year-old woman was referred to our hospital at 25+1 weeks of gestation for evaluation of fetal defects. Prenatal echocardiography showed biventricular non-compaction cardiomyopathy with sinus bradycardia. After termination of the pregnancy, fetal biventricular non-compaction cardiomyopathy was confirmed by autopsy and histopathologic examination. Additionally, whole-exome sequencing of genomic DNA demonstrated a de novo heterozygous mutation (c.389A > G; p.D130G) in CALM2, whereas the parents were normal. In this case report, we highlight the importance of prenatal ultrasound and genetic testing in fetal non-compaction cardiomyopathy with arrhythmia.

Grisel's syndrome associated with mumps: A case report.

Grisel's syndrome (GS) is defined as atlantoaxial rotatory subluxation/fixation not associated with trauma or bone disease, usually following head and neck infection/inflammation or ear, nose, and throat (ENT) surgery. Many conditions could lead to Grisel's syndrome, of which mumps is rarely to be seen. This report discusses a case of GS in children with Type I atlantoaxial joint subluxation and previously diagnosed mumps. A 6-year-old boy who had cervical pain and torticollis for 2 weeks was admitted to our hospital. There was no trauma and he had not had ENT surgery but was diagnosed with mumps 2 weeks previously due to swelling of the left cheek and cervical lymph node. Physical examination and computed tomography confirmed a diagnosis of Grisel's syndrome with an ADI (atlanto-dens interval) of 1.6 mm. The patient then received occipito-mandibular traction for 6 days and recovered. No recurrence was observed at 1 year follow-up. Physicians should raise awareness of this rare complication of mumps to avoid life-threatening neurological impairments owing to Grisel's syndrome.

Prenatal diagnosis of generalized arterial calcification of infancy in the second trimester.

OBJECTIVES: Generalized arterial calcification of infancy (GACI) is a rare autosomal recessive disorder characterized by subintimal fibrous proliferation and deposition of calcium salts in the internal elastic lamina, leading to extensive arterial calcification and stenosis of large and medium-sized arteries. Prenatal diagnosis is usually made in the third trimester by detection of aortic and pulmonary calcification with associated nonimmune hydrops; earlier prenatal diagnosis is rare. This study was performed to examine the prenatal ultrasound and genetic features of fetuses with GACI. METHODS: We retrospectively reviewed the ultrasound findings, their progression in utero, and the clinical features in three fetuses with GACI ascertained using ultrasound in the second trimester. GACI was subsequently confirmed through pathological examination and/or molecular genetic testing. RESULTS: All three fetuses had hyperechogenic valves or annuli as the first detectable manifestation in the second trimester, followed by relatively rapid progression to arterial wall calcification. Three novel mutations of the ENPP1 gene associated with GACI were found in two of the cases (c.26dupG, c.1454A > G, and c.263C > G). CONCLUSIONS: GACI should be suspected when hyperechogenic cardiac valves, annuli, or arterial walls are noted after ruling out other causes of arterial calcification. Genetic testing is important for prenatal and future preimplantation genetic diagnosis.

Can prenatal diagnosis of parachute mitral valve be achieved? A case report of fetal parachute mitral valve.

Parachute mitral valve (PMV) is a common form of congenital mitral stenosis and is difficult to diagnose prenatally. This report describes a fetal case of PMV with coarctation of the aorta that was diagnosed at 25 weeks' gestation by echocardiography and confirmed at autopsy. We describe the ultrasonographic features in this case and present a useful sign for making a prenatal diagnosis of PMV.

Accuracy of flow-void diameters on MR images in diagnosing uterine arteriovenous malformations in patients with pregnancy-related diseases.

To evaluate the "flow void" diameter in patients with pregnancy-related diseases with and without uterine AVMs and assess the diagnostic performance of unenhanced MRI for uterine AVMs. From May 2014 to April 2019, 79 patients with pregnancy-related diseases were included, including 36 with and 43 without uterine AVMs confirmed by DSA. On MRI, the diameter of the most prominent "flow void" (hereinafter referred to as fv-D) was measured and compared between patients with and without uterine AVMs. The diagnostic performance of fv-D was estimated with receiver operating characteristic curves. The "flow void" sign was observed in patients with and without uterine AVMs (P > 0.05). The fv-D was significantly larger in patients with uterine AVMs in the myometrium and parametrium than in patients without uterine AVMs (P < 0.0001). The fv-D achieved a reliable diagnostic performance in the myometrium (sensitivity 80.6%, specificity 60.5%, negative predictive value 78.8%, positive predictive value 63%, AUC 0.727, cut-off: > 1.33 mm) and parametrium (sensitivity 97.2%, specificity 67.4%, negative predictive value 96.7%, positive predictive value 71.4%, AUC 0.881, cut-off > 2.6 mm). On MRI, fv-D could diagnose uterine AVMs. The fv-D had a much higher diagnostic efficiency in the parametrium than in the myometrium. The parametrium fv-D greatly improved the diagnostic sensitivity and provides a more accurate, noninvasive method of investigating possible uterine AVMs.

Anal atresia as the diagnostic clue in VACTERL association: A first-trimester case report.

Anal atresia is the most common malformation occurring in VACTERL association, but it is difficult to diagnose antenatally. We herein present a case of fetal anal atresia in VACTERL association diagnosed by ultrasonography and supported by autopsy. This case emphasizes the clues to ultrasonographic diagnosis of anal atresia at 11-13+6 weeks of gestation, promoting increased awareness of VACTERL association during first-trimester screening.

Coordination-driven interfacial cross-linked graphene oxide-alginate nacre mesh with underwater superoleophobicity for oil-water separation.

Inspired by the seashell nacre and seaweed, a novel GO-Ca2+-SA nacre-inspired hybrid mesh was prepared via an interfacial layer-by-layer self-assembly and cross-linking, using graphene oxide (GO) and sodium alginate (SA) as the building blocks and calcium chloride as the coordination agent, respectively. Hybrid mesh was characterized by FTIR, XPS, XRD, SEM and contact angel instrument, showing superhydrophilic and underwater superoleophobic property and low oil adhesion, due to its wrinkle and rough surface, and high hydration ability of GO-Ca-alginate nanohydrogels. The separation efficiencies of various oil-water mixtures were above 99 %, with a highest flux of 119,426 L m-2 h-1. Hybrid mesh showed an orderly layered "brick and mortar" microstructure with many ultrasmall nanoscaled protuberances. Ca2+ ions could chelate with SA to form the "egg-box" structure, and interact with GO nanosheets. Hybrid mesh possessed high salt/acid/alkaline tolerance, abrasion resistance, mechanical property with Young's modulus of 35.8 ± 4.9 GPa, and excellent cycling stability.

Effects and safety of massage therapy for patients with metatarsal pain: A protocol for systematic review and meta-analysis.

BACKGROUND: Metatarsalgia refers to localized or generalized forefoot pain in the region of the metatarsal heads. Often this pain is plantar, beneath the metatarsal heads, and arises from either mechanical or iatrogenic causes. The treatment of metatarsalgia remains controversial. A thorough understanding of the biomechanics of the forefoot and the underlying pathology of the particular type of metatarsalgia affecting the patient is a prerequisite to selecting the proper treatment. In recent years, massage therapy has been increasingly accepted by patients due to its lower costs, fewer unwanted side effects, and safety for clinical use. In this systematic review, we aim to evaluate the effectiveness and safety of massage therapy for patients with metatarsal pain. METHODS: We will search the following electronic databases for randomized controlled trials to evaluate the effectiveness and safety of massage therapy in treating metatarsal pain: Wanfang and PubMed Database, CNKI, CENTRAL, CINAHL, and EMBASE. Each database will be searched from inception to October 2020. The entire process will include study selection, data extraction, risk of bias assessment, and meta-analyses. RESULTS: This proposed study will evaluate the effectiveness and safety of massage therapy for patients with metatarsal pain. The outcomes will include changes in metatarsal pain relief and adverse effect. CONCLUSIONS: This proposed systematic review will evaluate the existing evidence on the effectiveness and safety of massage therapy for patients with metatarsalgia. DISSEMINATION AND ETHICS: The results of this review will be disseminated through peer-reviewed publication. Because all of the data used in this systematic review and meta-analysis has been published, this review does not require ethical approval. Furthermore, all data will be analyzed anonymously during the review process. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/C6KFJ.

Efficacy and safety of massage therapy for chronic atrophic gastritis: A protocol for systematic review and meta-analysis.

BACKGROUND: Chronic atrophic gastritis (CAG) is an established precursor of gastric carcinoma with high prevalence worldwide. It is a typical complex gastro-intestinal disease with multiple influence factors, of which exact mechanisms remain unelucidated. Therefore, an ideal strategy to relieve CAG is urgently needed. In recent years, massage therapy has been increasingly accepted by CAG patients due to its lower costs, fewer unwanted side effects and safety for clinical use. In this systematic review, we aim to evaluate the effectiveness and safety of massage therapy for patients with chronic atrophic gastritis. METHODS: We will search the following electronic databases for randomized controlled trials to evaluate the effectiveness and safety of massage therapy in treating chronic atrophic gastritis: Wanfang and Pubmed Database, China National Knowledge Infrastructure Database, Cochrane Central register of controlled trials, Cumulative Index of Nursing and Allied Health Literature, and Excerpta Medica database. Each database will be searched from inception to September 2020. The entire process will include study selection, data extraction, risk of bias assessment, and meta-analyses. RESULT: This proposed study will evaluate the effectiveness and safety of massage therapy for patients with chronic atrophic gastritis. The outcomes will include changes in CAG relief and adverse effect. CONCLUSION: This proposed systematic review will evaluate the existing evidence on the effectiveness and safety of massage therapy for patients with chronic atrophic gastritis. DISSEMINATION AND ETHICS: The results of this review will be disseminated through peer-reviewed publication. Because all of the data used in this systematic review and meta-analysis has been published, this review does not require ethical approval. Furthermore, all data will be analyzed anonymously during the review process.

Successful management of Klippel-Trenaunay syndrome in a pregnant Asian woman: A case report.

RATIONALE: Klippel-Trenaunay Syndrome (KTS) is a congenital vascular disease characterized by cutaneous hemangiomas, venous varicosities, and limb hypertrophy. Although extremely rare in pregnant women, the present vascular alterations may be aggravated, consequent to postural and hormonal changes inherent to the pregnancy. Pregnancy is not advised in KTS women due to increased obstetrical risk. PATIENT CONCERNS: A 31-year-old pregnancy woman presented with prominent vascularity in pelvis, right lower limb, spleen, and liver at 28 weeks of gestation. We started administration of anticoagulant therapy and obstetrics management. DIAGNOSIS: MRI and ultrasound revealed that multiple varicosities in her pelvis, right lower limb, spleen, and liver. She was diagnosed with KTS. INTERVENTIONS: At her first visit at 28 weeks of gestation, multidisciplinary evaluation had been done. Blood transfusion and iron supplement had been given for anemia correction. Anticoagulant therapy was performed to prevent potential thrombus risk. She had a vaginal delivery with a healthy newborn in her second visit without any complications at the gestation of 36 weeks due to rupture of preterm membranes. OUTCOMES: After successful management, the patient was discharged without any complications 2 days after vaginal delivery. No symptoms of hemorrhage or thrombus were observed. At 6 months follow-up, her right lower toes enlarged obviously, MRI revealed that no obvious changes of hemangiomas was found compared to those during the pregnancy and ultrasound revealed that there was no thrombus in her right lower limb. LESSONS: Patients with KTS can be pregnant and have healthy babies safely with regularly monitor and reasonable treatment during pregnancy. A careful follow-up and guidance are necessary.