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Quickly and accurately segmenting the left ventricular (LV) myocardium from ultrasound images and measuring the thickness of the interventricular septum and LV wall play an important role in hypertrophic cardiomyopathy. However, the segmentation of the LV myocardium is a challenging task due to image blurring and individual differences. We attempted to perform LV segmentation in ultrasound images using the encoder–decoder architecture of U-Net and other networks and found it to be not accurate enough. Therefore, we propose a novel multi-task cascaded convolutional neural network (called MTC-Net) to segment the LV myocardium from echocardiography. MTC-Net contains two parts: One is pre-trained Resnet-34 followed by two decoder branches for mask and boundary detection, and the other module is pre-trained with many improved novel encoder–decoder architectures for extracting more detailed features. Both parts of the network use the atrous spatial pyramid pooling module to capture high-level text information. A hybrid loss function is engaged for mask and contour prediction. The network is trained and evaluated with echocardiographic images, which are labeled manually by doctors. The comparison study with other networks shows that MTC-Net has better accuracy and performance. MTC-Net achieves state-of-the-art performance on the test set. The mean value of the dice coefficient is 0.9442 and the mean value of intersection over union is 0.8951.

Objective. The purpose of this study was to evaluate the feasibility and safety of myocardial biopsy using a new approach, the Liwen procedure. Background. Myocardial biopsy is essential when other methods could not differentiate other etiologies from hypertrophic obstructive cardiomyopathy (HOCM). Our previous work using intramyocardial radiofrequency ablation for hypertrophic obstructive cardiomyopathy (Liwen procedure) may provide another approach to obtain the myocardial samples. Method. Seventeen patients with HOCM were enrolled for biopsies through percutaneously accessed intramyocardial septum and evaluated possible complications. Results. We obtained 31 specimens from 17 patients with a success rate of sample acquisition 100.0%. The number of myocardial samples taken per patient was 1.8 ± 0.8, and the average length of all samples was 16.7 ± 5.6 mm which could be used for pathological diagnosis. The complications included pericardial effusion with and without tamponade in one patient (5.9%), and no incidence of nonsustained and sustained ventricular tachycardia, conduction abnormity, perforation, stroke, and pneumothorax. The inhospital and 30-day mortality was 0%. Conclusion. This study has shown that myocardial biopsy of the Liwen procedure is relatively safe and technically feasible with adequate tissue sampling, which may help pathological diagnosis and further research of HOCM of diverse etiologies. This trial is registered with NCT04355260.

Background To investigate relationship between glycated hemoglobin (HbA1c) level and coronary artery disease (CAD) severity Methods Observational study was conducted and 573 participants were enrolled and baseline characteristics were collected. Clinical presentations in terms of stable angina, unstable angina or acute myocardial infarction were diagnosed. All participants were performed coronary angiography to figure out the numbers of coronary artery stenosis in terms of none-stenosis (< 50% stenosis), single or multiple vessels stenoses (≥ 50% stenosis). All participants were divided into subgroups according to two categories in terms of severity of clinical presentation (stable angina, unstable angina, or acute myocardial infarction) and the number of coronary artery stenosis (none, single, and multiple vessels). Primary endpoint was to evaluate relationship between baseline HbA1c value and CAD severity. Results Consistent to previous studies, participants with CAD had more risk factors such as elderly, smoking, low HDL-C and high CRP levels. Notably, HbA1c level was more prominent in CAD group than that without CAD. As compared to stable angina subgroup, HbA1c levels were gradually increased in unstable angina and acute myocardial infarction groups. Similar trend was identified in another category in terms of higher HbA1c level corresponding to more vessels stenoses. Multivariate regression analyses showed that after adjusted for traditional risk factors as well as fasting blood glucose, HbA1c remained strongly associated with the severity of CAD. Nonetheless, there was no significant association when CRP was accounted for. Conclusion HbA1c may be a useful indicator for CAD risk evaluation in non-diabetic adults. [ABSTRACT FROM AUTHOR]

Background: Nocturnal awakening is the most frequent insomnia complaint in the general population. In contrast to a growing knowledge based on adults, little is known about its prevalence, correlated factors, and associations with subjective sleep perception and daytime sleepiness in children. This study was designed to assess the prevalence and the correlate factors of frequent nocturnal awakening (FNA) among Chinese school-aged children. Furthermore, the associations of FNA with subjective sleep perception and daytime sleepiness were examined. Methods: A random sample of 20,505 children aged 5.00 to 11.92 years old (boys: 49.5% vs. girls: 50.5%) participated in a cross-sectional survey, which was conducted in eight cities of China. Parent-administered questionnaires were used to collect information on children’s sleep behaviors, sleep perception, and potential influential factors of FNA from six domains. Univariate and multivariate logistic regression models were performed. Results: The prevalence of FNA was 9.8% (10.0% for boys vs. 8.9% for girls) in our sampled children. The prominent FNA-related factors inclued biological health problems, such as overweight/obesity (OR = 1.70), chronic pain during night (OR = 2.47), and chronic respiratory condition (OR = 1.23), poor psychosocial condition, such as poor mental and emotional functioning (OR = 1.34), poor sleep hygiene, such as frequently doing exciting activities before bedtime (OR = 1.24) and bedtime resistance (OR = 1.42), and parents’ history of insomnia (OR = 1.31). FNA was associated with subjective poor sleep quality (OR = 1.24), subjective insufficient sleep (OR = 1.21), and daytime sleepiness (OR = 1.35). Conclusion: FNA was associated with poor sleep and daytime sleepiness. Compared to sleep environment and family susceptibility, chronic health problems, poor psychosocial condition, and poor sleep hygiene had greater impact on FNA, indicating childhood FNA could be partly prevented by health promotion, by psychological intervention, and by improving sleep hygiene routine. [ABSTRACT FROM AUTHOR]

Background Immunoglobulin-like transcript 4 (ILT4) is an inhibitory molecule involved in immune response and has recently been identified to be strongly inducible by IL-10. The aim of the present study was to examine the associations of ILT4 expression with clinicopathological characteristics and IL-10 expression in primary ductal and lobular breast cancer. Methods We studied the expression of ILT4 in 4 cancer cell lines, 117 primary tumor tissues and 97 metastatic lymph nodes from patients with primary ductal and lobular breast cancer by reverse transcription-polymerase chain reaction, western blot or immunohistochemistry analysis. Additionally, IL-10 expression was also investigated using immunohistochemistry in primary tumor tissues. Then the relationship between ILT4 expression and clinicopathological characteristics/IL-10 expression was evaluated. Results ILT4 was over expressed in all 4 human breast cancer cell lines on both mRNA and protein levels. In primary tumor tissues, ILT4 or IL-10 was expressed in the cell membrane, cytoplasm, or both; the positive rate of ILT4 and IL-10 expression was 60.7% (71/117) and 80.34% (94/117), respectively. ILT4 level was significantly correlated with IL-10 (r =0.577; p < 0.01). Furthermore, the expression of ILT4 or IL-10 was associated with less number of Tumor Infiltrating Lymphocytes (TILs) (p = 0.004 and 0.018, respectively) and more lymph node metastasis (p = 0.046 and 0.035, respectively). Conclusion Our data demonstrated the association of ILT4 and IL-10 expression in human breast cancer, suggesting their important roles in immune dysfunction and lymph node metastases. Virtual slides The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1692652692107916. [ABSTRACT FROM AUTHOR]

Glycogen metabolism plays a key role in tumorigenesis. High expression levels of glycogen phosphorylase B (PYGB) were reported in several cancers and might be served as a prognostic biomarker for cancer from precancerous lesions. Previous studies indicated the high expression of PYGB in hepatocellular carcinoma (HCC) tissues. However, the detailed roles of PYGB in HCC, as well as the regulatory mechanisms, are still unclear. In this study, we confirmed that PYGB was overexpressed in HCC tissues. PYGB overexpression was significantly associated with an aggressive tumor phenotype and poor prognosis of HCC patients. Functionally, PYGB knockdown suppressed HCC cell proliferation, migration and invasion in vitro, as well as tumorigenesis and metastasis in vivo. Bioinformatics analysis indicated that PYGB overexpression might enhance epithelial to mesenchymal transition (EMT) in HCC. Moreover, miR-101-3p was identified to post-transcriptionally inhibit the expression of PYGB via binding to 3′-UTR of PYGB. Overexpression of PYGB antagonized the regulatory effect of miR-101-3p on cell proliferation, migration and invasion in HCC cells. In summary, our results suggest that miR-101-3p/PYGB axis has an important role in HCC and PYGB could be served as a novel prognostic biomarker and therapeutic target for improving the prognosis of HCC patients.

Abstract Isolated ventricular noncompaction is an unclassified cardiomyopathy due to intrauterine arrest of compaction of the loose interwoven meshwork. Its mortality and morbidity are high, including heart failure, thromboembolic events, and ventricular arrhythmias. Isolated right ventricular noncompaction was reported rarely, especially that causes pulmonary embolism and ventricular tachycardia. We describe a case of isolated noncompaction of the right ventricular causing pulmonary embolism and ventricular tachycardia.

Background: Osteosarcoma (OS) is the most common primary bone tumor. The disease has a poor prognosis due to the delay in the diagnosis and the development of metastasis. N6-Methyladenosine (m6A)-related regulators play an essential role in various tumors. In this study, a comprehensive analysis was conducted to elucidate the relationship between the expression profiles of m6A-related molecules and the clinical outcome of OS patients.Materials and Methods: Public genome datasets and a tissue microarray (TMA) cohort were used to analyze the mRNA and protein expression levels of m6A regulators. Next, immunofluorescence (IF) analysis was used to determine the subcellular localization of m6A-related molecules. Kaplan–Meier and Cox regression analyses were performed to confirm the prognostic value of m6A-related molecules in OS. A comprehensive bioinformatic analysis was conducted to identify the potential molecular mechanisms mediated by m6A modification in OS.Results: We found that m6A-related regulator expression was dysregulated in OS tissues, especially in metastatic tumor tissues. Low expression of METTL3, METTL14, and YTHDF2 and high expression of KIAA1429 and HNRNPA2B1 were significantly associated with poor prognosis in the TMA cohort. Simultaneously, the genome meta-cohort analysis revealed that low expression of FTO and METTL14 and high expression of METTL3, HNRNPA2B1, and YTHDF3 were associated with poor prognosis in OS. Cox regression analysis showed that HNRNPA2B1 might be an independent risk factor for OS. Bioinformatic analysis indicated that m6A regulators might be involved in OS progression through humoral immune response and cell cycle pathways.Conclusion: M6A-related regulators are frequently dysregulated and correlate with metastasis and prognosis in OS. M6A-related regulators may serve as novel therapeutic targets and prognostic biomarkers for OS.

Background: Atherosclerosis is a hyperlipidemia-induced condition affecting the arterial wall that damages healthy endothelial cell (EC) function, leading to enhanced risk of atherothrombotic events. Certain microRNAs regulate EC dysfunction in response to hyperlipidemia and may be suitable therapeutic targets to combat atherosclerosis. Methods: miRNA expression in human ECs was analyzed under various conditions to identify key microRNAs. High-cholesterol diet (HCD)-fed Mir652−/−Apoe−/− (Mir652−/−) mice and matching Mir652+/+Apoe−/− (Mir652+/+) mice were subjected to carotid injury to analyze the effects of miR-652 knockdown on endothelial repair. In silico analysis followed by in vitro and in vivo experiments were applied to identify miR-652's target gene Ccnd2 and investigate the pair's effects on ECs. miR-652-5p and miR-652-3p antagomir therapies were tested in Mir652+/+ mice under normal and HCD diet to assess their effect on endothelial repair. Findings: miR-652-3p, which is upregulated in human and murine atherosclerotic plaques, suppresses expression of the endothelial repair gene Ccnd2, thereby enhancing atherosclerotic lesion formation. Post-denudation recovery of ECs was promoted in Mir652−/− mice due to enhanced EC proliferation attributable to de-repression of miR-652-3p's (but not miR-652-5p's) regulation of Ccnd2 expression. Under hyperlipidemic conditions at non-predilection sites, miR-652-3p produces anti-proliferative effects in ECs, such that Mir652−/− mice display reduced atherosclerotic progression. In contrast, neither miR-652-3p nor Ccnd2 displayed significant effects on the endothelium at predilection sites or under disturbed flow conditions. Administration of a miR-652-3p antagomir rescued the proliferation of ECs in vivo, thereby limiting atherosclerotic development. Interpretation: miR-652-3p blockade may be a potential therapeutic strategy against atherosclerosis. Keywords: Atherosclerosis, Endothelium, Cyclin D2, CCND2, miR-652

Background: Although 21 causative mutations have been associated with PRKAG2 syndrome, our understanding of the syndrome remains incomplete. The aim of this project is to further investigate its unique genetic background, clinical manifestations, and underlying structural changes. Methods: We recruited 885 hypertrophic cardiomyopathy (HCM) probands and their families internationally. Targeted next-generation sequencing of sudden cardiac death (SCD) genes was performed. The role of the identified variants was assessed using histological techniques and computational modeling. Findings: Twelve PRKAG2 syndrome kindreds harboring 5 distinct variants were identified. The clinical penetrance of 25 carriers was 100.0%. Twenty-two family members died of SCD or heart failure (HF). All probands developed bradycardia (HRmin, 36.3 ± 9.8 bpm) and cardiac conduction defects, and 33% had evidence of atrial fibrillation/paroxysmal supraventricular tachycardia (PSVT) and 67% had ventricular preexcitation, respectively. Some carriers presented with apical hypertrophy, hypertension, hyperlipidemia, and renal insufficiency. Histological study revealed reduced AMPK activity and major cardiac channels in the heart tissue with K485E mutation. Computational modelling suggests that K485E disrupts the salt bridge connecting the β and γ subunits of AMPK, R302Q/P decreases the binding affinity for ATP, T400N and H401D alter the orientation of H383 and R531 residues, thus altering nucleotide binding, and N488I and L341S lead to structural instability in the Bateman domain, which disrupts the intramolecular regulation. Interpretation: Including 4 families with 3 new mutations, we describe a cohort of 12 kindreds with PRKAG2 syndrome with novel pathogenic mechanisms by computational modelling. Severe clinical cardiac phenotypes may be developed, including HF, requiring close follow-up. Keywords: Genetics, Arrhythmia, PRKAG2 syndrome, Cardiomyopathy, Heart failure, Sudden cardiac death

Abstract Background Pixatimod (PG545) is a novel clinical-stage immunomodulatory agent capable of inhibiting the infiltration of tumor-associated macrophages (TAMs) yet also stimulate dendritic cells (DCs), leading to activation of natural killer (NK) cells. Preclinically, pixatimod inhibits heparanase (HPSE) which may be associated with its inhibitory effect on TAMs whereas its immunostimulatory activity on DCs is through the MyD88-dependent TLR9 pathway. Pixatimod recently completed a Phase Ia monotherapy trial in advanced cancer patients. Methods To characterize the safety of pixatimod administered by intravenous (IV) infusion, a one month toxicology study was conducted to support a Phase Ia monotherapy clinical trial. The relative exposure (AUC) of pixatimod across relevant species was determined and the influence of route of administration on the immunomodulatory activity was also evaluated. Finally, the potential utility of pixatimod in combination with PD-1 inhibition was also investigated using the syngeneic 4T1.2 breast cancer model. Results The nonclinical safety profile revealed that the main toxicities associated with pixatimod are elevated cholesterol, triglycerides, APTT, decreased platelets and other changes symptomatic of modulating the immune system such as pyrexia, changes in WBC subsets, inflammatory changes in liver, spleen and kidney. Though adverse events such as fever, elevated cholesterol and triglycerides were reported in the Phase Ia trial, none were considered dose limiting toxicities and the compound was well tolerated up to 100 mg via IV infusion. Exposure (AUC) up to 100 mg was considered proportional with some accumulation upon repeated dosing, a phenomenon also noted in the toxicology study. The immunomodulatory activity of pixatimod was independent of the route of administration and it enhanced the effectiveness of PD-1 inhibition in a poorly immunogenic tumor model. Conclusions Pixatimod modulates innate immune cells but also enhances T cell infiltration in combination with anti-PD-1 therapy. The safety and PK profile of the compound supports its ongoing development in a Phase Ib study for advanced cancer/pancreatic adenocarcinoma with the checkpoint inhibitor nivolumab (Opdivo®). Trial registration ClinicalTrials.gov Identifier: NCT02042781. First posted: 23 January, 2014 - Retrospectively registered.

Abstract Background Theranostic perfluorocarbon nanoprobes have recently attracted attention due to their fascinating versatility in integrating diagnostics and therapeutics into a single system. Furthermore, although 17β-estradiol (E2) is a potential anti-hypertrophic drug, it has severe non-specific adverse effects in various organs. Therefore, we have developed cardiomyocyte-targeted theranostic nanoprobes to achieve concurrent targeted imaging and treatment of cardiac hypertrophy. Results We had successfully synthesized E2-loaded, primary cardiomyocyte (PCM) specific peptide-conjugated nanoprobes with perfluorocarbon (PFP) as a core (PCM-E2/PFPs) and demonstrated their stability and homogeneity. In vitro and in vivo studies confirmed that when exposed to low-intensity focused ultrasound (LIFU), these versatile PCM-E2/PFPs can be used as an amplifiable imaging contrast agent. Furthermore, the significantly accelerated release of E2 enhanced the therapeutic efficacy of the drug and prevented systemic side effects. PCM-E2/PFPs + LIFU treatment also significantly increased cardiac targeting and circulation time. Further therapeutic evaluations showed that PCM-E2/PFPs + LIFU suppressed cardiac hypertrophy to a greater extent compared to other treatments, revealing high efficiency in cardiac-targeted delivery and effective cardioprotection. Conclusion Our novel theranostic nanoplatform could serve as a potential theranostic vector for cardiac diseases.

Nanoparticles (NPs) have promising applications in medicine. Immune system is an important protective system to defend organisms fromnon-selfmatters. NPs interact with the immune systemand modulate its function, leading to immunosuppression or immunostimulation. These modulating effects may bring benefits or danger. Compositions, sizes, and surface chemistry, and so forth, affect these immunomodulations. Here we give an overview of the relationship between the physicochemical properties of NPs, which are candidates to be applied in medicine, and their immunomodulation properties. [ABSTRACT FROM AUTHOR]

The article presents a study which focuses on neuron-like cells differentiation from parthenogenetic embryonic stem cells obtained from mice. Among the highlights of the study include karyotype analysis, differentiation potential of fertilized and parthenogenetic embryonic stem cells from mice, and parthenogenetic embryonic stem cells from autologous tissue.

We report a generic approach for identification of target proteins of therapeutic molecules using nanoprobes. Nanoprobes verify the integrity of nanoparticle-bound ligands in live cells and pull down target proteins from the cellular proteome, providing very important information on drug targets and mechanisms of action. As an example, target proteins as αci-tubulin and HSP 90 have been identified and validated. [ABSTRACT FROM AUTHOR]

A significant increase in biomedical applications of nanomaterials and their potential toxicity demands versatile analytical techniques to determine protein–nanoparticle (NP) interactions. These diverse analytical techniques are reviewed. Spectroscopic methods play a significant role in studying binding affinity, binding ratio, and binding mechanisms. To elucidate NP–proteome interactions, chromatography and electrophoresis techniques are applied to separate NP-bound proteins and matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) to identify these proteins. Since NP–protein binding is a dynamic event, surface plasmon resonance (SPR) and quartz crystal microbalance (QCM) are methods of choice to study the kinetics of NP–protein binding. [ABSTRACT FROM AUTHOR]

Background: One major risk factor for cutaneous melanoma is chronic sun-exposure and oxidative stress. Among various oxidative DNA damages, 8-oxoquanine is the most abundant and is potentially mutagenic if not sufficiently repaired. The human 8-oxoquanine DNA glycosylase 1 ( hOGG1) gene specifically repairs 8-oxoguanine, and this gene shows frequent loss of heterozygosity (LOH) in human tumors. In this study, we investigate whether hOGG1 LOH occurs in melanoma in situ (MIS) and adjacent atypical melanocytic hyperplasia (AMH). Methods: Twelve skin biopsies with MIS and adjacent AMH were included. DNA samples derived from manual microdissection of tissues were subjected to polymerase chain reaction amplification using three fluorescent-labeled microsatellite makers, followed by fragment analysis. Results: Five of 12 cases were informative for both telomeric (3S1297) and centromeric (3S1289 or 3S1300) markers, bordering the hOGG1 locus. Among them, four (80%) MIS and three (60%) AMH showed hOGG1 LOH at both markers. Conclusions: These results shows that LOH at hOGG1 gene is associated with MIS and AMH and suggest that the hOGG1 gene may play a role in melanocytic tumor progression. [ABSTRACT FROM AUTHOR]

The kidney is constantly exposed to free radicals due to its active metabolism and processing of toxic metabolites. Among 20 or so free radical-induced DNA lesions, 8-oxoquanine is the most abundant and is potentially mutagenic if not sufficiently removed. The human 8-oxoquanine DNA glycosylase 1 ( hOGG1) gene repairs 8-oxoguanine and resides at 3p25–26, which has frequent loss of heterozygosity (LOH) in clear cell–renal cell carcinoma (CC-RCC). Even though some studies found similar genetic alterations between renal papillary adenomas (PA) and papillary RCC (PRCC), no studies have been conducted to compare the alterations of hOGG1 gene in PA, PRCC and CC-RCC. To further explore the relationship between CC-RCC, PRCC and PA at the genetic level LOH of hOGG1 gene was investigated in these three groups. It was found that 8/8 PRCC (100%) and 8/9 CC-RCC (88%) had evidence of hOGG1 LOH, whereas all four PA (0%) were devoid of hOGG1 LOH. It is concluded that deletion of hOGG1 gene occurs commonly in PRCC and CC-RCC but not in renal cortical PA. Further studies are warranted to further explore the exact roles of hOGG1 gene in the development and progression of RCC. [ABSTRACT FROM AUTHOR]

Many chemoradiation therapies cause DNA damage through oxidative stress. An important cellular mechanism that protects cells against oxidative stress involves DNA repair. One of the primary DNA repair mechanisms for oxidative DNA damage is base excision repair (BER). BER involves the tightly coordinated function of four enzymes (glycosylase, apurinic/apyrimidinic endonuclease, polymerase and ligase), in which 8-oxoguanine DNA glycosylase 1 initiates the cycle. An imbalance in the production of any one of these enzymes may result in the generation of more DNA damage and increased cell killing. In this study, we targeted mitochondrial DNA to enhance cancer chemotherapy by over-expressing a human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene in the mitochondria of human hepatoma cells. Increased hOGG1 transgene expression was achieved at RNA, protein and enzyme activity levels. In parallel, we observed enhanced mitochondrial DNA damage, increased mitochondrial respiration rate, increased membrane potential and elevated free radical production. A greater proportion of the hOGG1-over-expressing hepatoma cells experienced apoptosis. Following exposure to a commonly used chemotherapeutic agent, cisplatin, cancer cells over-expressing hOGG1 displayed much shortened long-term survival when compared with control cells. Our results suggest that over-expression of hOGG1 in mitochondria may promote mitochondrial DNA damage by creating an imbalance in the BER pathway and sensitize cancer cells to cisplatin. These findings support further evaluation of hOGG1 over-expression strategies for cancer therapy. [ABSTRACT FROM PUBLISHER]

Objective To analyze the 3β-hydroxysteroid dehydrogenase (NSDHL) gene in verruciform xanthoma (VX) to elucidate its potential role in the histogenesis of this lesion. Design DNA was extracted from paraffin-embedded tissue, followed by polymerase chain reaction amplification of exons 4 and 6 of the NSDHL gene. The polymerase chain reaction products were then directly sequenced and analyzed for the presence of somatic mutations. Patients Nine lesions of VX from 8 patients and 3 unrelated normal controls were evaluated. Results Two of 9 VXs (22%) demonstrated a novel somatic missense mutation in exon 6 of the NSDHL gene. The mutation was not present in the remaining 7 lesions of VX, nonlesional internal controls, and 3 unrelated normal controls. No mutation of exon 4 was found in any case. Mutations of exons 4 and 6 previously identified in CHILD syndrome were not seen in our cases. Conclusions (1) A novel missense mutation (R199H) in exon 6 of the NSDHL gene was identified in a small subset of sporadic VXs. (2) Known CHILD syndrome mutations in exons 4 and 6 of the NSDHL gene do not contribute to the histogenesis of sporadic VXs. [ABSTRACT FROM AUTHOR]

Abstract Background Percutaneous ablation has quickly arisen as one of the important alternative treatments for hepatocellular carcinoma (HCC). We aimed to compare the therapeutic effects of radiofrequency ablation (RFA) and other ablative techniques on HCCs. Methods Databases were searched to identify literature on complete tumor ablation (CTA), overall survival (OS), local tumor recurrence (LTR), and complications of RFA in the treatment of HCC, compared with those of microwave ablation (MWA), percutaneous ethanol injection (PEI), PEI plus RFA, cryoablation (CRA), laser ablation (LSA), and high-intensity focused ultrasound. Randomized controlled trials and high-quality cohort studies were included in the assessment. Results The effects of MWA and CRA appeared to be similar to those of RFA, but lower rates of LTR and higher rates of CTA in large tumors compared with RFA were reported (P

Several lines of evidence have confirmed the magnitude of crosstalk between HGF/c-Met axis (hepatocyte growth factor and its high-affinity receptor c-mesenchymal-epithelial transition factor) and non-coding RNAs (ncRNAs) in tumorigenesis. Through activating canonical or non-canonical signaling pathways, the HGF/c-Met axis mediates a range of oncogenic processes such as cell proliferation, invasion, apoptosis, and angiogenesis and is increasingly becoming a promising target for cancer therapy. Meanwhile, ncRNAs are a cluster of functional RNA molecules that perform their biological roles at the RNA level and are essential regulators of gene expression. The expression of ncRNAs is cell/tissue/tumor-specific, which makes them excellent candidates for cancer research. Many studies have revealed that ncRNAs play a crucial role in cancer initiation and progression by regulating different downstream genes or signal transduction pathways, including HGF/c-Met axis. In this review, we discuss the regulatory association between ncRNAs and the HGF/c-Met axis by providing a comprehensive understanding of their potential mechanisms and roles in cancer development. These findings could reveal their possible clinical applications as biomarkers for therapeutic interventions.

Hepatoblastoma (HB) is the most common and aggressive malignant hepatic neoplasm in childhood and the therapeutic outcomes remain undesirable due to its recurrence and metastasis. Recently, long non-coding RNA (lncRNA) zinc finger antisense 1 (ZFAS1) has been reported to be an oncogenic gene in multiple cancers. However, the expression status and specific role of ZFAS1 involved in cancer progression of human HB remain unknown. This study aimed to identify the role of ZFAS1/miR-193a-3p/RALY axis in the development of HB. Here we showed that the expression of ZFAS1 was significantly upregulated in both HB tissues and cell lines. High ZFAS1 expression was significantly associated with aggressive tumor phenotypes and poorer overall survival in HB. In vitro and in vivo function assays indicated that silencing of ZFAS1 significantly suppressed HB cell proliferation and invasion. Furthermore, miR-193a-3p was identified to be the target of ZFAS1. Subsequently, RALY was confirmed to be regulated by miR-193a-3p/ZFAS1 axis. Mechanistically, our results indicated that the ZFAS1 participated to the progression of HB via regulating the HGF/c-Met signaling. Collectively, these data demonstrated that ZFAS1 acted as an oncogene to promote initiation and progression of HB by regulating miR-193a-3p/RALY (RALY Heterogeneous Nuclear Ribonucleoprotein) axis via HGF/c-Met Pathway, which provides an efficient marker and new therapeutic target for HB.

Whether complement dysregulation directly contributes to the pathogenesis of peripheral nervous system diseases, including sensory neuropathies, is unclear. We addressed this important question in a mouse model of ocular HSV-1 infection, where sensory nerve damage is a common clinical problem. Through genetic and pharmacologic targeting, we uncovered a central role for C3 in sensory nerve damage at the morphological and functional levels. Interestingly, CD4 T cells were central in facilitating this complement-mediated damage. This same C3/CD4 T cell axis triggered corneal sensory nerve damage in a mouse model of ocular graft-versus-host disease (GVHD). However, this was not the case in a T-dependent allergic eye disease (AED) model, suggesting that this inflammatory neuroimmune pathology is specific to certain disease etiologies. Collectively, these findings uncover a central role for complement in CD4 T cell-dependent corneal nerve damage in multiple disease settings and indicate the possibility for complement-targeted therapeutics to mitigate sensory neuropathies.

Murine tumor models have been critical to advances in our knowledge of tumor physiology and for the development of effective tumor therapies. Essential to these studies is the ability to both track tumor development and quantify tumor burden in vivo. For this purpose, the introduction of genes that confer tumors with bioluminescent properties has been a critical advance for oncologic studies in rodents. Methods of introducing bioluminescent genes, such as firefly luciferase, by viral transduction has allowed for the production of tumor cell lines that can be followed in vivo longitudinally over long periods of time. Here we describe methods for the production of stable luciferase expressing tumor cell lines by lentiviral transduction.

Despite advances in management of immunosuppression, graft rejection remains a significant clinical problem in solid organ transplantation. Non-invasive biomarkers of graft rejection can facilitate earlier diagnosis and treatment of acute rejection. The purpose of this study was to investigate the potential role of heparan sulfate as a novel biomarker for acute cellular rejection. Heparan sulfate is released from the extracellular matrix during T-cell infiltration of graft tissue via the action of the enzyme heparanase. In a murine heart transplant model, serum heparan sulfate is significantly elevated during rejection of cardiac allografts. Moreover, expression of the enzyme heparanase is significantly increased in activated T-cells. In human studies, plasma heparan sulfate is significantly elevated in kidney transplant recipients with biopsy-proven acute cellular rejection compared to healthy controls, recipients with stable graft function, and recipients without acute cellular rejection on biopsy. Taken together, these findings support further investigation of heparan sulfate as a novel biomarker of acute cellular rejection in solid organ transplantation.

Biomimetic design and substrate-based surface modification of medical implants will help to improve the integration of tissue to its material interfaces. Surface energy, composition, roughness, and topography all influence the biological responses of the implants, such as protein adsorption and cell adhesion, proliferation and differentiation. In the current study, different surface structures of Ti implants were constructed using facile surface techniques to create various micro-, nano-, and nano/micro composite scale topography. We have fabricated three types of hierarchical structures of TiO2 coating on Ti implants, including nanotube structure, nano sponge-like structure, and nano/micro nest-like structure. The osteointegration and biomechanical performance of the coated Ti screws were evaluated by histology and removal of torque force test in vivo. We found that the nano/micro nest-like and nanotube structured surface possessed better osteointegration ability. It indicated that the alkaline hydrothermally treated Ti substrate was the best for bone-implant integration in terms of all in vitro and in vivo testing parameters. The alkaline hydrothermally treated surface displayed a hydrophilic (contact angle value 5.92 ± 1.2), higher roughness (Ra value 911.3 ± 33.8 nm), higher specific surface area (8.26 ± 1.051 m2/g), and greater apatite inductivity. The electrochemical surface modification may become a powerful approach to enhance metal implant to bone integration in orthopaedic applications.

The correspondence between five precipitation products, including CMORPH, GPCP-2, TRMM 3B43, GPCC, and ITPCAS, and ground-based measurements of precipitation were evaluated on annual, seasonal, and monthly scales during 2000-2014 in the Qinling-Daba Mountains over China, which is a significant area with vital value of climate and hydrology. Performances of the precipitation products in the relatively arid/humid years were also analyzed. In general, ITPCAS data displayed the highest accuracy, GPCP-2 and CMORPH data showed relatively poor performance, and GPCC and TRMM 3B43 data were average at different temporal scales among the five precipitation products. The Pearson correlation coefficient of each station had minor fluctuations for the five precipitation products. A larger deviation was found at Wudu station, most likely due to the undulating terrain. The performances of the precipitation products from highest to least accuracy are as follows: ITPCAS > TRMM 3B43 > GPCC > GPCP-2 > CMORPH. Except for CMORPH (-20.76%), the percentage precipitation differences (PPDs) of the other four precipitation products fluctuated in the range of 10% during the relatively arid (2001) and humid (2011) years. In addition, all precipitation products and ground gauge observed precipitation did not show an obvious gradient with altitude, which is different from that in other mountainous areas and is perhaps due to complex terrain, lack of observation in high altitudes, and precipitation undercatch. In consideration of the significance of Qinling-Daba Mountains as the geographic and ecological dividing lines, the present study may provide a new perspective for hydrological, climatic, and ecological researches and practices in local and other mountainous areas.

The large dv/dt and di/dt outputs of power devices in wireless charging system (WCS) in electric vehicles (EVs) always introduce conducted electromagnetic interference (EMI) emissions. This paper proposes a mitigation conducted emission strategy based on transfer function from a direct current fed (DC-fed) WCS for EVs. A complete test for the DC-fed WCS is set up to measure the conducted emission of DC power cables in a frequency range of 150 kHz–108 MHz. An equivalent circuit with high-frequency parasitic parameters for WCS for EV is built based on measurement results to obtain the characteristics of conducted emission from WCS. The transfer functions of differential mode (DM) interference and common mode (CM) interference were established. A judgment method of using transfer functions to determine the dominated interference mode responsible for EMI is proposed. From the comparison of simulation results between CM or DM and CM+DM interference, it can be seen that the CM interference is the dominated interference mode which causes the conducted EMI in WCS in EVs. A strategy of giving priority to the dominated interference mode is proposed for designing the CM interference filter. Finally, the conducted voltage experiment is performed to verify the mitigation conducted emission strategy. The conducted voltage of simulation and experiment is decreased respectively by 21.17 and 21.4 dBμV at resonance frequency 30 MHz. The conduced voltage at frequency range of 150 kHz–108 MHz can be mitigated to below the limit level-3 of CISPR25 standard (GB/T 18655-2010) by adding the CM interference filters.

Er3+/Yb3+ codoped tellurite-zinc-niobium (TZNb) glass was prepared by the melt-quenching method and used for the construction of a point all-fiber temperature sensor. The glass thermal stability and network structural properties were studied by differential thermal analysis and Raman spectrum, respectively. High glass transition temperature is beneficial to widen the working temperature range. The dependence of fluorescence intensity ratio (FIR) of green upconversion emissions on the surrounding temperature from 276 to 363 K was experimentally investigated and the maximum temperature sensitivity is 95 × 10−4 K−1 at 363 K. Strong green upconversion emission, broad temperature measurement range and high sensitivity indicate this point temperature sensor is a promising optical device for application on optical temperature sensing.

Bisphenol A (BPA) exposure results in numerous developmental and functional abnormalities in reproductive organs in rodent models, but limited data are available regarding BPA effects in the primate uterus. To determine if maternal oral BPA exposure affects fetal uterine development in a non-human primate model, pregnant rhesus macaques carrying female fetuses were exposed orally to 400 µg/kg BPA or vehicle control daily from gestation day (GD) 50-100 or GD100-165. Fetal uteri were collected at the completion of treatment (GD100 or GD165); tissue histology, cell proliferation, and expression of estrogen receptor alpha (ERα) and progesterone receptor (PR) were compared to that of controls. Gene expression analysis was conducted using rhesus macaque microarrays. There were no significant differences in histology or in the percentage of cells expressing the proliferation marker Ki-67, ERα, or PR in BPA-exposed uteri compared to controls at GD100 or GD165. Minimal differences in gene expression were observed between BPA-exposed and control GD100 uteri. However, at GD165, BPA-exposed uteri had significant differences in gene expression compared to controls. Several of the altered genes, including HOXA13, WNT4, and WNT5A, are critical for reproductive organ development and/or adult function. We conclude that second or third trimester BPA exposure does not significantly affect fetal uterus development based on morphological, proliferation, and steroid hormone receptor assessments. However, differences in expression of key developmental genes after third trimester exposure suggest that BPA could alter transcriptional signals influencing uterine function later in life.

Deficiencies in the ATM gene are the underlying cause for ataxia telangiectasia, a syndrome characterized by neurological, motor and immunological defects, and a predisposition to cancer. MicroRNAs (miRNAs) are useful tools for cancer profiling and prediction of therapeutic responses to clinical regimens. We investigated the consequences of ATM deficiency on miRNA expression and associated gene expression in normal human mammary epithelial cells (HME-CCs). We identified 81 significantly differentially expressed miRNAs in ATM-deficient HME-CCs using small RNA sequencing. Many of these have been implicated in tumorigenesis and proliferation and include down-regulated tumor suppressor miRNAs, such as hsa-miR-29c and hsa-miR-16, as well as over-expressed pro-oncogenic miRNAs, such as hsa-miR-93 and hsa-miR-221. MicroRNA changes were integrated with genome wide gene expression profiles to investigate possible miRNA targets. Predicted mRNA targets of the miRNAs significantly regulated after ATM depletion included many genes associated with cancer formation and progression, such as SOCS1 and the proto-oncogene MAF. While a number of miRNAs have been reported as altered in cancerous cells, there is little understanding as to how these small RNAs might be driving cancer formation or how they might be used as biomarkers for cancer susceptibility. This study provides preliminary data for defining miRNA profiles that may be used as prognostic or predictive biomarkers for breast cancer. Our integrated analysis of miRNA and mRNA expression allows us to gain a better understanding of the signaling involved in breast cancer predisposition and suggests a mechanism for the breast cancer-prone phenotype seen in ATM-deficient patients.

The large dv/dt and di/dt outputs of power devices in DC-fed motor drive systems in electric vehicles (EVs) always introduce conducted electromagnetic interference (EMI) emissions and may lead to motor drive system energy transmission losses. The effect of distributed parameters on conducted EMI from the DC-fed high voltage motor drive systems in EVs is studied. A complete test for conducted EMI from the direct current fed(DC-fed) alternating current (AC) motor drive system in an electric vehicle (EV) under load conditions is set up to measure the conducted EMI of high voltage DC cables and the EMI noise peaks due to resonances in a frequency range of 150 kHz–108 MHz. The distributed parameters of the motor can induce bearing currents under low frequency sine wave operation. However the impedance of the distributed parameters of the motor is very high at resonance frequencies of 500 kHz and 30 MHz, and the effect of the bearing current can be ignored, so the research mainly focuses on the distributed parameters in inverters and cables at 500 kHz and 30 MHz, not the effect of distributed parameters of the motor on resonances. The corresponding equivalent circuits for differential mode (DM) and common mode (CM) EMI at resonance frequencies of 500 kHz and 30 MHz are established to determine the EMI propagation paths and analyze the effect of distributed parameters on conducted EMI. The dominant distributed parameters of elements responsible for the appearing resonances at 500 kHz and 30 MHz are determined. The effect of the dominant distributed parameters on conducted EMI are presented and verified by simulation and experiment. The conduced voltage at frequencies from 150 kHz to 108 MHz can be mitigated to below the limit level-3 of CISPR25 by changing the dominant distributed parameters.

Gene expression quantitative trait loci (eQTL) are useful for identifying single nucleotide polymorphisms (SNPs) associated with diseases. At times, a genetic variant may be associated with a master regulator involved in the manifestation of a disease. The downstream target genes of the master regulator are typically co-expressed and share biological function. Therefore, it is practical to screen for eQTLs by identifying SNPs associated with the targets of a transcript-regulator (TR). We used a multivariate regression with the gene expression of known targets of TRs and SNPs to identify TReQTLs in European (CEU) and African (YRI) HapMap populations. A nominal p-value of

Background In recent years, studies have demonstrated the use of ultrasound speckle tracking techniques for the early evaluation of subclinical left ventricular (LV) systolic function in patients with type 2 diabetes mellitus (T2DM). In addition, long-term exposure to hyperglycemia severely damages the microvascular system. However, the interaction between diabetic microvascular complications and subclinical LV systolic function has not been fully understood. Objective To investigate the relationship between subclinical LV systolic function and diabetic microvascular complications in patients with T2DM. Methods A total of 150 patients with T2DM who were admitted to the Department of Endocrinology, the First Affiliated Hospital of Air Force Medical University from June to December 2021 were selected in the cross-sectional study and all underwent conventional echocardiography, pulsed tissue Doppler echocardiography and two-dimensional speckle tracking echocardiography (2D STE). The 2D global longitudinal strain (GLS) of LV was obtained to assess the subclinical LV systolic function. Diabetic microvascular complications were defined as combined diabetic retinopathy, diabetic kidney disease or peripheral neuropathy. The subjects were divided into the T2DM alone group (T2DM alone group, n=76), the T2DM with 1 complication group〔T2DM+C (1) group, n=37〕 and the T2DM with 2 to 3 complications group〔T2DM+C (2 to 3) group, n=37〕 according to the cumulative number of microvascular complications. The general demographic characteristics and biochemical indices of patients in the three groups were compared. The relationship between microvascular complications and subclinical LV systolic function was assessed by using Spearman correlation analysis and Logistic regression analysis. Results GLS was lower in the T2DM+C (1) and T2DM+C (2 to 3) groups than in the T2DM alone group (P

Haploinsufficiency of Meis homeobox 2 (MEIS2), encoding a transcriptional regulator, is associated with human cleft palate, and Meis2 inactivation leads to abnormal palate development in mice, implicating MEIS2 functions in palate development. However, its functional mechanisms remain unknown. Here we observed widespread MEIS2 expression in the developing palate in mice. Wnt1Cre-mediated Meis2 inactivation in cranial neural crest cells led to a secondary palate cleft. Importantly, about half of the Wnt1Cre;Meis2f/f mice exhibited a submucous cleft, providing a model for studying palatal bone formation and patterning. Consistent with complete absence of palatal bones, the results from integrative analyses of MEIS2 by ChIP sequencing, RNA-Seq, and an assay for transposase-accessible chromatin sequencing identified key osteogenic genes regulated directly by MEIS2, indicating that it plays a fundamental role in palatal osteogenesis. De novo motif analysis uncovered that the MEIS2- bound regions are highly enriched in binding motifs for several key osteogenic transcription factors, particularly short stature homeobox 2 (SHOX2). Comparative ChIP sequencing analyses revealed genome-wide co-occupancy of MEIS2 and SHOX2 in addition to their colocalization in the developing palate and physical interaction, suggesting that SHOX2 and MEIS2 functionally interact. However, although SHOX2 was required for proper palatal bone formation and was a direct downstream target of MEIS2, Shox2 overexpression failed to rescue the palatal bone defects in a Meis2-mutant background. These results, together with the fact that Meis2 expression is associated with high osteogenic potential and required for chromatin accessibility of osteogenic genes, support a vital function of MEIS2 in setting up a ground state for palatal osteogenesis. [ABSTRACT FROM AUTHOR]

Recent studies suggest that high expression of the proinflammatory cytokine IL6 is associated with poor survival of lung cancer patients. Accordingly, IL6 has been a target of great interest for lung cancer therapy. However, the role of IL6 in lung cancer has not been determined yet. Here, we demonstrate that IL6 plays opposite roles in the initiation and growth of lung cancer in a mouse model of lung cancer induced by the K-Ras oncogene. We find that compared with wild-type mice, IL6- deficient mice developed much more lung tumors after an activating mutant of K-Ras was induced in the lungs. However, lung tumors developed in IL6-deficient mice were significantly smaller. Notably, both the lung tumor--suppressing and --promoting functions of IL6 involve its ability in activating the transcription factor STAT3. IL6/STAT3 signaling suppressed lung cancer initiation through maintaining lung homeostasis, regulating lung macrophages, and activating cytotoxic CD8 T cells under K-Ras oncogenic stress, whereas it promoted lung cancer cell growth through inducing the cell proliferation regulator cyclin D1. These studies reveal a previously unexplored role of IL6/STAT3 signaling in maintaining lung homeostasis and suppressing lung cancer induction. These studies also significantly improve our understanding of lung cancer and provide a molecular basis for designing IL6/STAT3-targeted therapies for this deadliest human cancer. [ABSTRACT FROM AUTHOR]

The PAX3 (paired box 3) gene plays an important role in embryonic development, diseases, and cancer formation. Our preliminary studies have shown that PAX3 gene is upregulated in glioma cells, which is associated with a worse prognosis. Moreover, PAX3, by facilitating cell proliferation and invasion and inhibiting cell apoptosis, plays an oncogenic role in glioma. However, the specific molecular mechanism of PAX3 acting as an oncogene in glioma remains unclarified. In the present study, we have found that PAX3 overexpression was observed in high grade glioma and predicted a worse prognosis. PAX3 overexpression did not correlate significantly to IDH1 mutation and MGMT methylation. Moreover, the expression of PAX3 was positively correlated with that of β-catenin. In U87 glioma cells, PAX3 interacted with β-catenin, as was confirmed by CO-IP. Besides, PAX3 overexpression promoted cell proliferation and cell cycle progression, while it inhibited cell apoptosis by altering the expressions of important molecules associated with the Wnt signaling pathway, including β-catenin, Myc, VEGF, cyclinD1, MMP7, and Wnt1. In the meantime, it was also proved that PAX3 correlated to β-catenin through a negative regulatory mechanism with respect to the promotion of U87 glioma cell proliferation and cell cycle progression and inhibition of the cell apoptosis. Our experiment demonstrated the role of PAX3 in promoting glioma growth and development, possibly by interacting directly with β-catenin and regulating the Wnt signaling pathway.

In past decades, growing evidence from basic and clinical researches reveal that small guanosine triphosphate binding protein ras homolog gene family, member A (RhoA) and its main effector Rho-associated kinase (ROCK) play central and complex roles in cardiovascular systems, and increasing RhoA and ROCK activity is associated with a broad range of cardiovascular diseases such as congestive heart failure, atherosclerosis, and hypertension. Favorable outcomes have been observed with ROCK inhibitors treatment. In this review, we briefly summarize the pathophysiological roles of RhoA/ROCK signaling pathway on cardiovascular system, displaying the potential benefits in the cardiovascular system with controlling RhoA/ROCK signaling pathway.