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Medication administration is a critical safety issue in hospitals and the community. Children are especially at risk because of their dependence on adults to safely administer medications. The purpose of this study was to examine non-compliance with state child care medication administration regulations and factors associated with improved compliance. The data included routine, unannounced inspections of child care programs by state licensing specialists collected in two time periods over 10 years. Factors potentially associated with regulatory compliance were included in this secondary analysis. Most child care center medication administration regulations showed decreased non-compliance between the two time periods. However, regulations pertaining to prescriber orders and parent permission revealed a significant increase in non-compliance (58.4%). Factors positively associated with medication administration regulatory compliance included: compliance with annual professional development (p

Biliary atresia (BA) is a devastating inflammatory and fibrosing cholangiopathy of neonates with unknown aetiology. We aim to investigate the relationship between these two main characteristics.Single-cell RNA sequencing and spatial transcriptomics were performed on liver samples from a cohort of 14 objects (BA: n = 6; control: n = 8). We conducted data integration and cell-type annotation based on gene expression profiling. Furthermore, we identified fibrosis-related immune cells according to their spatial locations, GO and KEGG analysis. Finally, SPOTlight and CIBERSORTx were used to deconvolute ST data and microarray data of the GSE46960 cohorts, respectively.Immune subpopulations inhabiting the 'fibrotic niche' (areas of scarring), comprising 'intermediate' CD14Fibrosis is an important feature of BA, in which the immune system plays an important role. Our work reveals the subpopulations of immune cells enriched in the fibrotic niche of BA liver, as well as key related pathways and molecules; some are highlighted for the first time in liver fibrosis. These newly identified interactions might partly explain why the rate of liver fibrosis occurs much faster in BA than in other liver diseases.Our study revealed the molecular, cellular and spatial immune microenvironment of the fibrotic niche of BA.

The distribution of pathogenic

Aims: This study aimed to determine the expression of asparagine synthetase (ASNS) in breast cancer (BC) tissues and estimate its prognostic value for BC patients. Besides, the roles of ASNS in the...

Background Transaxillary access (TAx) has shown promise as an excellent alternative TAVR option, but data on the Edwards SAPIEN 3 in TAx-TAVR is limited. We sought to study the safety and efficacy of TAx-TAVR using this current-generation balloon-expandable valve. Methods A retrospective study of our first 24 TAx and 20 transthoracic (TT) TAVR patients treated with the SAPIEN 3 valve was performed, and the patients’ preoperative characteristics, procedural outcomes, and clinical outcomes were compared to our first 100 transfemoral (TF) patients using the SAPIEN 3 device. Results There were no statistical differences observed for outcomes between the TAx and TF groups, despite the TAx patients having more comorbidities (STS-PROM 11.3 ± 7.6 versus 7.3 ± 5.2, p = 0.042). In addition, no significant difference was found in the fluoroscopy time and contrast amount between the two groups. The patients’ baseline characteristics were similar between the TAx and TT groups. Their procedural and clinical outcomes were comparable, but there was a trend towards lower incidence of acute kidney injury (13.0% versus 23.5%), new-onset atrial fibrillation (5.6% versus 33.3%), shorter median length of stay postoperatively (4 versus 6 days), fewer discharges to rehabilitation (16.7% versus 35.0%), and a lower rate of readmission within 30-days (8.3% versus 35.0%), all favoring TAx access. Conclusions TAx-TAVR with the SAPIEN 3 valve is a safe alternative to TF access. It offers advantages of improved recovery over TT access, and appears to be a superior alternative-access option for TAVR. TAx access could be preferred when TF access is not feasible.

Objective We aimed to evaluate the short-term efficacy and safety of fecal microbiota transplantation (FMT) by washed preparation for moderate to severely active UC. Methods An open-label prospective trial was conducted in an inflammatory bowel disease (IBD) tertiary referral center from April 2016 to March 2018. Patients with moderate to severely active UC were randomly assigned to undergo FMT thrice on day 1, 3 and 5 by nasojejunal tube (NJT) or transendoscopic enteral tubing (TET). The primary end-point was a clinical response at week 2 post-FMT. The secondary end-points were clinical and endoscopic remission at week 12 post-FMT, safety and disease progression. Results Of the nine patients included, 77.8% (7/9) achieved a clinical response at week 2. And 55.6% (5/9) and 33.3% (3/9), respectively, achieved clinical remission and endoscopic remission at week 12. In two patients who had no response to FMT, one switched to anti-tumor necrosis factor-α therapy, and the other underwent a colectomy. FMT was delivered through NJT in 44.4% (4/9) of the patients, while TET was used in 55.6% (5/9). The clinical outcomes did not differ significantly based on the delivery route (P > 0.05). Adverse events, all mild and self-limiting, were observed in 33.3% (3/9) of the patients. Conclusions FMT by washed preparation appears to be a safe and effective adjunct therapy for moderate to severely active UC during a short-term follow-up. The efficacy did not differ significantly between the NJT or TET delivery routes. Further randomized controlled studies are needed to confirm these findings.

The homeostasis of the gut-brain axis has been shown to exert several effects on physiological and psychological health. The gut hormones released by enteroendocrine cells scattered throughout the gastrointestinal tract are important signaling molecules within the gut-brain axis. The interaction between gut microbiota and gut hormones has been greatly appreciated in gut-brain cross-talk. The microbiota plays an essential role in modulating many gut-brain axis-related diseases, ranging from gastrointestinal disorders to psychiatric diseases. Similarly, gut hormones also play pleiotropic and important roles in maintaining health, and are key signals involved in gut-brain axis. More importantly, gut microbiota can affect the release and functions of gut hormones. This review highlights the role of gut microbiota in the gut-brain axis and focuses on how microbiota-related gut hormones modulate various physiological functions. Future studies could target the microbiota-hormones-gut brain axis to develop novel therapeutics for different psychiatric and gastrointestinal disorders, such as obesity, anxiety, and depression.

Background Right transaxillary transcatheter aortic valve replacement (TAx-TAVR) is rarely performed due to challenging vascular tortuosity and unfavorable implantation angles. We explored this procedure using the newer-generation balloon-expandable SAPIEN 3 (Edwards Lifesciences, Irvine, CA) valve and our novel “flip-n-flex” technique. The safety and effectiveness of the procedure and the learning curve of our early experiences were investigated. Methods The first 10 consecutive patients undergoing right TAx-TAVR performed at our center from June 2016 to May 2018 were included in the study. Patients’ preoperative characteristics, procedural outcomes, and clinical outcomes were studied. Intraoperative fluoroscopy times were also reviewed to analyze the procedural learning curve. Results The 10 patients were a mean age of 81.8 ± 8.7 years, and 5 patients (50%) were women. Mean Society of Thoracic Surgeons Predicted Risk of Mortality was 12.0% ± 9.5%. Procedural success was achieved in all cases without vascular complications. Paravalvular leak was absent or mild in all patients. Two patients (20%) required permanent pacemaker implantation. The median postoperative length of stay was 4 days (range, 2-13 days). The 30-day mortality was 0%. Mean transvalvular gradient improved from 38.4 ± 12.6 mm Hg to 9 ± 4.4 mm Hg postoperatively. New York Heart Association Functional Classification improved in all patients. The fluoroscopy time showed marked reduction from 44.1 ± 8.2 minutes to 17.4 ± 2.9 minutes with the use of the flip-n-flex technique. Conclusions Our early experience of right TAx-TAVR with the SAPIEN 3 valve demonstrated satisfactory outcomes and a quick learning as facilitated by the flip-n-flex technique. This could be a beneficial TAVR approach to suitable patients.

Transcarotid transcatheter aortic valve replacement (TAVR) is increasingly accepted as a safe and efficacious alternative when transfemoral access is contraindicated. Technical and anatomic considerations unique to transcarotid access warrant several adaptations to the routine TAVR procedure. This report describes an approach to overcome these challenges and improve efficiency, including adoption of the "flip-n-flex" technique originally developed for right transaxillary TAVR. This technique has been used at Tufts Medical Center (Boston, MA) since 2019 in both left and right transcarotid TAVR approaches with success to ensure coaxial alignment of the transcatheter heart valve to the aortic root.

Background To explore the value of the right hemi-diaphragmatic excursion (DE) and its variation in predicting extubation outcome in mechanically ventilated patients with COPD. Methods All included patients with COPD received mechanical ventilation (MV) and were ready to wean from MV. After patients passed the 30 min spontaneous breathing trail (SBT), extubation was considered to be feasible, and the right DE measured by ultrasound at 0 min, 5 min, and 30 min of SBT were named as DE0, DE5, and DE30, respectively. Results Twenty-five patients succeeded extubation; 12 patients failed. The area under receiver operator characteristic curve (AUCROC) of DE30 and ΔDE30−5 (the variation between 30 and 5 min) were 0.762 and 0.835; a cutoff value of DE30 > 1.72 cm and ΔDE30−5 > 0.16 cm were associated with a successful extubation with a sensitivity of 76% and 84%, a specificity of 75% and 83.3%, respectively. The predictive probability equation of the DE30 plus ∆DE30−5 was P = 1/[1 + e−(−5.625+17.689×∆DE30−5+1.802×DE30)], a cutoff value of P > 0.626 was associated with a successful extubation with the AUCROC of 0.867, a sensitivity of 92%, and a specificity of 83.3%. Conclusion The combination of DE30 and ∆DE30−5 could improve the predictive value and could be used as the predictor of extubation outcome in mechanically ventilated patients with COPD.

Objective To explore the analgesic effects of different concentrations of ropivacaine in transversalis fascia plane (TFP) block during laparotomy. Methods Ninety patients who underwent laparotomy admitted to our hospital from March 2019 to March 2020 were selected as the study subjects and were divided equally into a low concentration group, a medium concentration group, and a high concentration group according to the randomized grouping method. The low concentration group adopted 0.4% ropivacaine 40 ml, the medium concentration group was given 0.5% ropivacaine 40 ml, and the high concentration group was given 0.6% ropivacaine 40 ml. The hemodynamic indexes and the incidence of adverse reactions in the two groups were compared. The Numerical Rating Scale (NRS) was used to assess the postoperative pain in the three groups, the Bruggrmann comfort scale (BCS) was used to assess the comfort level in the three groups, and the Mini-mental State Examination (MMSE) was used to evaluate the postoperative cognitive function of the three groups of patients. Results The mean artery pressure (MAP) and heart rate (HR) levels at T1 and T2 were significantly lower in the medium concentration group than in the other two groups (P P P P P Conclusion The medium concentration group exhibits a better analgesic effect than the low concentration group and higher safety than the high concentration group. Therefore, the use of medium concentration ropivacaine in TFP block may provide a referential basis for clinical treatment.

Ewing sarcoma (EwS) is an aggressive malignant neoplasm composed of small round cells. The heterogeneity and developmental trajectories of EwS are uncertain.Single-cell RNA sequencing was performed on 4 EwS tumor tissue samples, and 3 transcriptional atlases were generated. K-nearest neighbor algorithm was used to predict the origin of tumor cells at single-cell resolution. Monocle2 package was used to perform pseudotime trajectory analysis in tumor cells. Differentially expressed genes were compared against those in all other clusters via the FindMarkers function, and then they were subjected to GO analysis using clusterProfiler package.Combined with the results of k-nearest neighbor algorithm and pseudotime trajectory analysis in tumor cells, we thought meningeal EwS originated from neural crest cells during epithelial to mesenchymal transition and simulated the process of neural crest cell lineage differentiation. But for perirenal EwS and spinal EwS, we hypothesized that after the neural crest cell lineage mutated into them, the tumor cells did not maintain the differentiation trajectory of neural crest cell lineage, and the development trajectory of tumor cells became chaotic. GO analysis results showed that interferon signaling pathway-related biological processes play an essential role in the tumorigenesis and tumor progression process of EwS, and among these biological processes genes, JAK1 gene up-regulated most significantly and highly expressed in all tumor cells. Ruxolitinib was used to explore the function of JAK1. Targeting JAK1 can promote apoptosis of EwS tumor cells, inhibit the migration and invasion of EwS tumor cells, and inhibit cell proliferation by inducing cell cycle S phase arrest.EwS was derived from neural crest cell lineage with variable developmental timing of oncogenic conversion, and the JAK1 might be a candidate for therapeutic targets of EwS.

Impella left ventricular assist devices (LVADs) (Abiomed, Danvers, MA) are implanted in the left ventricle across the aortic valve. Several cases of secondary aortic insufficiency (AI) or mitral regurgitation (MR) after Impella LVAD use have been reported. Secondary valvulopathies can worsen cardiac function. This single center retrospective study sought to characterize the incidence of secondary AI and MR development after Impella LVAD support. One hundred fifty-two patients who underwent Impella LVAD support between April 2014 and August 2019 were included. Patient demographics, implant indications, duration of support, pre- and post-Impella LVAD echocardiograms, and incidence of increased AI/MR were analyzed. Impella 5.0 and Impella CP were subanalyzed. Following exclusion criteria, AI and MR were analyzed in 93 and 78 patients, respectively. An increase in AI and MR was seen in 17.2% and 12.8% of patients with an event per support days of 0.03 and 0.02, respectively. Clinically significant increases in AI and MR were seen in 3.2% (n = 3), 6.4% (n = 5), respectively. The incidences of increased AI (p = 0.33) and MR (p = 0.45) were similar between Impella 5.0 and Impella CP patients. Worsening AI and MR clinically occur at a low incidence with Impella LVAD use. However, careful follow-up is still warranted.

Osteoclast over-activation leads to bone loss and chloride homeostasis is fundamental importance for osteoclast function. The calcium-activated chloride channel Anoctamin 1 (also known as TMEM16A) is an important chloride channel involved in many physiological processes. However, its role in osteoclast remains unresolved. Here, we identified the existence of Anoctamin 1 in osteoclast and show that its expression positively correlates with osteoclast activity. Osteoclast-specific Anoctamin 1 knockout mice exhibit increased bone mass and decreased bone resorption. Mechanistically, Anoctamin 1 deletion increases intracellular Cl

Since the current methods of treatment for malignant glioma, radiotherapy and chemotherapy, are unsatisfactory, the development of novel therapeutic compounds is required. In the present study, the inhibitory effect of tetrandrine citrate (TetC) on the proliferation of human glioma U87 cells, as well as its mechanism of action, were investigated. An MTT assay was used to assess cell viability in vitro, and the production of intracellular reactive oxygen species (ROS) was determined by assessing the fluorescence intensity of 2,7‑-dichlorofluorescein (DCF). Flow cytometry was used to determine the level of apoptosis and cell cycle status, and the protein expression levels of apoptosis‑associated proteins were determined using western blotting. Additionally, the antitumor activity of TetC was assessed in vivo using a nude mouse xenograft model. The results revealed that in vitro, the proliferative rate of U87, U251 and human umbilical vein endothelial cells (HUVECs) was significantly reduced in a dose‑dependent manner following treatment with TetC, although TetC had the greatest inhibitory effect on U87 cells. The vacuolization and apoptosis of U87 cells was induced using 10 and 20 µmol/l TetC, respectively. The overall proliferative inhibition was associated with an increase in the levels of ROS and apoptosis. In TetC‑treated cells, the expression levels of apoptosis‑related proteins, including cleaved (CL) caspase‑3, Fas, phosphorylated (p)‑p38 and p‑JNK, were increased, whereas those of caspase‑3 and Bcl‑2 were decreased. In vivo, TetC was highly effective at inhibiting the growth of human glioma U87 xenografts in BALB/c nude mice, with a percentage growth inhibition of ≥68.7%. These findings indicated that the potent antitumor activity of TetC may be mediated through an increase in ROS levels, the downregulation of Bcl‑2, and the upregulation of CL caspase‑3, Fas, p‑p38 and p‑JNK expression levels.

TMEM16A (also known as anoctamin 1, ANO1) is the molecular basis of the calcium-activated chloride channels, with ten transmembrane segments. Recently, atomic structures of the transmembrane domains of mouse TMEM16A (mTMEM16A) were determined by single-particle electron cryomicroscopy. This gives us a solid ground to discuss the electrophysiological properties and functions of TMEM16A. TMEM16A is reported to be dually regulated by Ca2+ and voltage. In addition, the dysfunction of TMEM16A has been found to be involved in many diseases including cystic fibrosis, various cancers, hypertension, and gastrointestinal motility disorders. TMEM16A is overexpressed in many cancers, including gastrointestinal stromal tumors, gastric cancer, head and neck squamous cell carcinoma (HNSCC), colon cancer, pancreatic ductal adenocarcinoma, and esophageal cancer. Furthermore, overexpression of TMEM16A is related to the occurrence, proliferation, and migration of tumor cells. To date, several studies have shown that many natural compounds and synthetic compounds have regulatory effects on TMEM16A. These small molecule compounds might be novel drugs for the treatment of diseases caused by TMEM16A dysfunction in the future. In addition, recent studies have shown that TMEM16A plays different roles in different diseases through different signal transduction pathways. This review discusses the topology, electrophysiological properties, modulators and functions of TMEM16A in mediates nociception, gastrointestinal dysfunction, hypertension, and cancer and focuses on multiple regulatory mechanisms regarding TMEM16A.

Primary Sjögren's Disease (pSjD) is considered a B cell-mediated disease. Toll-like receptor 10 (TLR10) is highly expressed in human B cells, indicating that TLR10 probably plays a vital role in pSjD. We examined TLR10 expression in peripheral B subsets of pSjD patients and analyzed their association with disease activity. We observed that TLR10 expression in total, naïve, memory, and switched memory B cells was significantly increased in low-activity pSjD patients as compared with healthy controls and high-activity patients. TLR10 expression in the above mentioned B subsets (except naïve B) was negatively correlated with serum levels of anti-SSA antibody and BAFF, respectively. Moreover, a higher proportion of high-activity pSjD patients was observed in TLR10 low- than high-expressed patients. Our study concluded that TLR10 expression in CD19

Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) play critical roles in tumorigenesis. However, the mechanisms underlying MDSC and TAM development and function remain unclear. In this study, we find that myeloid-specific activation of Notch/RBP-J signaling downregulates lactate transporter MCT2 transcription via its downstream molecule Hes1, leading to reduced intracellular lactate levels, blunted granulocytic MDSC (G-MDSC) differentiation, and enhanced TAM maturation. We identify c-Jun as a novel intracellular sensor of lactate in myeloid cells using liquid-chromatography-mass spectrometry (LC-MS) followed by CRISPR-Cas9-mediated gene disruption. Meanwhile, lactate interacts with c-Jun to protect from FBW7 ubiquitin-ligase-mediated degradation. Activation of Notch signaling and blockade of lactate import repress tumor progression by remodeling myeloid development. Consistently, the relationship between the Notch-MCT2/lactate-c-Jun axis in myeloid cells and tumorigenesis is also confirmed in clinical lung cancer biopsies. Taken together, our current study shows that lactate metabolism regulated by activated Notch signaling might participate in MDSC differentiation and TAM maturation.

Left ventricular assist device (LVAD) implantations have traditionally been approached through a full median sternotomy (FS). Recently, a minimally invasive left thoracotomy (LT) approach has been popularized. This study sought to compare the outcomes of FS and LT patients post-primary LVAD implantation and post-subsequent heart transplant (HT). This was a single-center retrospective study. 83 patients who underwent primary centrifugal durable LVAD implantation from January 2014 to June 2018 were included (FS, n = 41; LT, n = 42). 41 patients had a subsequent HT (FS, n = 19; LT, n = 22). Pre-operative patient demographics, intraoperative variables, post-operative 1-year survival, length of hospital stay, complications, and outcomes for LVAD implantation and following HT were analyzed. Intraoperative data showed that the LT group had a 23.4% longer mean LVAD implant surgical time (p 0.01). One-year post-LVAD survival was similar between the two groups (p = 0.05). Complication rates, with the exception of the rate of hemorrhagic stroke (p = 0.04) post-LVAD implant were similar. One-year survival post-HT was similar between groups (p = 0.35). Complication rates and mean length of hospital stay were also similar (p = 1.0) post-HT. Our study demonstrated that LT approach does not negatively affect post-LVAD implantation or post-HT outcomes. Further, larger studies may determine more detailed effects of LT approach.

To dissect the disease heterogeneity and identify the underlying cellular and molecular events related to metastasis of immature ovarian teratoma in children, single-cell RNA sequencing was performed for a 2-year-old patient with liver metastases from immature ovarian teratoma. A total of 5976 cells were obtained for further analysis, with a median unique molecular identifier count of 6011 per cell and a median number of 1741 genes detected per cell. Fourteen clusters were recognized, with the main lineages comprising epithelial cells, macrophages, fibroblasts, glial cells, and dendritic cells. Ten subclusters of epithelial cells were further defined, originating from the urinary tract, esophagus, bronchus, lung, skin, and gastrointestinal tract. An undefined UBE2C + population in an active state of proliferation was also identified and its biological processes were related to meiosis and maturation of oocytes. Pseudotime analysis revealed different distributions of epithelial cells in the development trajectory. In conclusion, a cluster of UBE2C + epithelial cells in an active state of proliferation was identified in an immature ovarian teratoma in a child, and may contribute to metastasis by regulating epithelial–mesenchymal transition. These findings help toward understanding the origin of the malignant behaviors, offer a potential biomarker for early determination of the tumor nature, and provide new ideas for the therapy of immature ovarian teratoma in children.

BACKGROUND SOX7 exerts a repressing effect against tumors and imposes vital influences on malignancies. Our research discussed the importance of SOX7 in breast cancer prognoses. MATERIAL AND METHODS SOX7 mRNA expression in breast cancer tissues samples and matched adjacent normal controls of breast cancer patients was measured by quantitative real-time-polymerase chain reaction (qRT-PCR). The relationship of SOX7 with clinicopathological characteristics were analyzed via chi-square test. The association of SOX7 levels with clinical outcomes was evaluated adopting the Kaplan-Meier method and multivariate Cox proportional hazards regression model. RESULTS SOX7 mRNA degree of expression exhibited a declining tendency in breast cancer tissue compared to paired bordering normal tissue specimens (P

Transmembrane 16A (TMEM16A), also known as anoctamin 1, is the molecular basis of the calcium-activated chloride channels. TMEM16A is present in interstitial cells of Cajal, which are the pacemaker cells that control smooth muscle contraction. TMEM16A is implicated in gastrointestinal disorders. Activation of TMEM16A is believed to promote the gastrointestinal muscle contraction. Here, we report a highly efficient, nontoxic, and selective activator of TMEM16A, canthaxanthin (CX). The study using molecular docking and site-directed mutation revealed that CX-specific binging site in TMEM16A is K769. CX was also found to promote the contraction of smooth muscle cells in gastrointestinal tract through activation of TMEM16A channels, which provides an excellent basis for development of CX as a chemical tool and potential therapeutic for gastrointestinal dysfunction.

Recently, we and other groups revealed that aberrant expression of Kv10.1 channel, a voltage-gated potassium ion channel, contributes to a variety of tumorigenesis process. Potent and selective inhibitor of Kv10.1 is urgently needed, both as pharmacological tools for studying the physiological functions of this enigmatic channel and as potential leads for development of anti-tumor drugs. In this study, Procyanidin B1, a natural compound extracted from the grape seed, was identified as a potent, specific inhibitor, which can inhibit the Kv10.1 channel in a concentration-dependent manner (IC50 = 10.38 ± 0.87 μM), but has negligible effects on other potassium channels, including Kir2.1, HERG or KCNQ1. It was demonstrated that Procyanidin B1 directly binds to Kv10.1 channel and inhibits its currents, without increasing intracellular Ca2+. Further, three amino acids, I550, T552, and Q557 in the C-linker domain of Kv10.1 were found critical for forming the binding pocket of Procyanidin B1 with Kv10.1 channel. In addition, Procyanidin B1 inhibits migration and proliferation of liver cancer cells (HuH-7 cells, HepG2 cells) through inhibiting Kv10.1, but not in Kv10.1 negatively expressed cell lines. Next, we assayed the tumor suppressing effect of Procyanidin B1 on cell line-derived xenograft mouse model. Our data showed that 15 mg/kg Procyanidin B1 can significantly suppress the growth of the tumor (HepG2) with an inhibition rate of about 60.25%. Compared with cisplatin, Procyanidin B1 has no side effect on the normal metabolism of the mice. The present work indicated that Procyanidin B1 is a proming liver cancer anti-tumor drug, and also confirmed that Kv10.1 can serve as a potential, tumor-specific drug target.

Calcium-activated chloride channels (CaCCs) play important roles in a multitude of physiological processes, and in many cells types, TMEM16A was identified as the molecular basis of CaCC. Abnormal CaCC function has been implicated in variety of diseases, which reinforces the need for modulators of CaCCs/TMEM16A. However, there are few specific, clinical modulators of CaCCs. Here, we identified a potent novel activator of TMEM16A from a bank of traditional Chinese medicines (TCM) and explored its mechanism of activation by laser confocal scanning microscopy and patch clamping. Fluorescence data demonstrated that among the 36 tested TCM medicines, one compound, cinnamaldehyde (CA), can activate the TMEM16A channel in a dose-dependent manner. To determine the mechanism by which CA activates the TMEM16A channel, we performed an excised patch clamp experiment and measured the intracellular calcium concentration in fluorescence experiments. Our data show that CA activates TMEM16A channels by elevating the intracellular concentrations of calcium ions. The results of the whole-cell patch clamping showed that CA dose-dependently activates these channels, with an EC50 of 9.73 ± 5.64 µM at + 80 mV, and prolongs the deactivation of TMEM16A. Finally, we found that CA can strengthen contractions of the ileum in guinea pigs by activating TMEM16A. The results demonstrate that CA is a novel, natural activator of TMEM16A.

Previous studies have reported that parameters of dynamic contrast-enhanced ultrasound (DCE-US) could predict prognosis of hepatocellular carcinoma (HCC) patients after antiangiogenic therapies. In this study, we aimed to investigate the correlation of DCE-US parameters and the prognosis of HCC patients after microwave ablation (MWA).Between June 2012 and January 2018, a total of 35 HCC patients who received MWA with a curative intent were enrolled. Pre-ablation DCE-US, liver biopsy, CD34 staining, and vascular endothelial growth factor (VEGF) staining were performed. DCE-US parameters were extracted from time-intensity curves using SonoLiver software. The correlation of DCE-US parameters with histopathology results and overall survival (OS) were investigated.Quantitative analysis showed that IMAX, RT, TTP, and mTT of HCC were statistically different with that of reference liver parenchyma (all p ＜ .001). Microvessel density was shown to be positively correlated with IMAX and negatively correlated with TTP (r = 0.755 and -0.647, both p ＜ .01). Additionally, positive correlations were observed between IMAX and VEGF expression (r = 0.665, p ＜ .01). After a median follow-up of 22 months (range 6-64 months), local recurrence was detected in three patients. Largest diameter and TTP were shown to help predict OS in univariate and multivariate analyses.DCE-US parameter may help predict the outcome of HCC patients after MWA, though further study is still needed.

Rhabdomyosarcoma is the most common soft tissue sarcoma in children, and embryonal rhabdomyosarcoma is the most typical type of rhabdomyosarcoma. The heterogeneity, etiology, and origin of embryonal rhabdomyosarcoma remain unknown. After obtaining the gene expression data of every cell in the tumor tissue by single-cell RNA sequencing, we used the Seurat package in R studio for quality control, analysis, and exploration of the data. All cells are divided into tumor cells and non-tumor cells, and we chose tumor cells by marker genes. Then, we repeated the process to cluster the tumor cells and divided the subgroups by their differentially expressed genes and gene ontology/Kyoto Encyclopedia of Genes and Genomes analysis. Additionally, Monocle 2 was used for pseudo-time analysis to obtain the evolution trajectory of cells in tumor tissues. Tumor cells were divided into 5 subgroups according to their functions, which were characterized by high proliferation, sensing and adaptation to oxygen availability, enhanced epigenetic modification, enhanced nucleoside phosphonic acid metabolism, and ossification. Evolution trajectory of cells in tumor tissues is obtained. We used pseudo-time analysis to distinguish between mesenchymal stem cells and fibroblasts, proved that embryonal rhabdomyosarcoma in the pelvic originated from skeletal muscle progenitor cells, showed the evolutionary trajectory of embryonal rhabdomyosarcoma, and improved the method of evaluating the degree of malignancy of embryonal rhabdomyosarcoma.

Acute aortic dissection is one of the most common life-threatening diseases that affects the aortic vessel. We present a case of acute Stanford type A aortic dissection in a patient with coronavirus disease 2019 (COVID-19) under treatment with angiotensin-converting enzyme inhibitors. A 68-year-old woman complaining of acute chest pain and dyspnea was admitted to the emergency clinic of our hospital on May 6, 2020. She had history of diabetes and hypertension. This is one of the first acute aortic surgery cases among patients with COVID-19.

The alternative access route of choice for transcatheter aortic valve replacement (TAVR) remains to be elucidated due to lack of evidences. We performed a meta‐analysis comparing the outcomes of two common alternative access routes, transaxillary (TAx) and transaortic (TAo) approaches. The PubMed/MEDLINE, Embase, and Cochrane library from inception to December 2018 were searched to identify the articles reporting data on both TAx-TAVR and TAo-TAVR. Patients’ baseline characteristics, procedural outcomes, and clinical outcomes were extracted from the articles and pooled for analysis. Four studies, a total of 750 (374 TAo and 376 TAx) patients were included in the study. The two groups were similar in patients’ baseline characteristics, although the TAx group comprised few female patients. The two groups differ in outcomes including 30-day mortality, rates of pacemaker implant and acute kidney injury, and length of hospital stay. There were no differences between the two groups with regard to device success, paravalvular leak, stroke, vascular complications, and 1-year mortality. Compared with the TAo approach, the TAx approach is associated with favorable short-term mortality, lower incidence of acute kidney injury, and shorter length of hospital stay, but increased pacemaker requirement. TAx could be considered over TAo as the preferred alternative access for TAVR.

Circular RNAs (circRNAs) have recently been shown to play critical roles in tumorigenesis. However, the roles of circRNAs in hepatocellular carcinoma (HCC) remain largely unknown. In the present study, we identified a novel circRNA (hsa_circ_0070269) was significantly decreased in HCC tissues and cell lines, low hsa_circ_0070269 expression was positively associated with advanced tumor stage, lymph node metastasis, and poor overall survival. Hsa_circ_0070269 overexpression suppressed proliferation and invasion of HCC cells in vitro and reduced tumor growth in vivo. Mechanistically, hsa_circ_0070269 increased NPTX1 expression via sponging miR-182 in HCC cells, which inhibited aggressive tumor behavior. Taken together, our findings suggest that hsa_circ_0070269 might play an important role in HCC development via miR-182/NPTX1 axis, therefore could serve as a potential therapeutic target for HCC treatment.

Objective The authors aim to evaluate an automated echocardiography software as compared with computed tomography in measurement of the aortic valve annulus in patients with aortic stenosis. The authors hypothesize that aortic annular measurements by this software and computed tomography will show acceptable correlation. Design This study is an Institutional Review Board-approved, retrospective data collection of patients with aortic stenosis who underwent implantation of a transcatheter heart valve with intraprocedural transesophageal echocardiography, multidetector computed tomography, and use of the Siemens eSie Valves automated aortic valve software. Setting Intraprocedural in a single hospital institution. Participants The participants are 47 patients who underwent implantation of an Edwards SAPIEN 3 transcatheter heart valve. Interventions The authors compared aortic valve annulus measurements by two-dimensional transesophageal echocardiography, computed tomography, and the automated software. Measurements and Main Results Aortic annulus measurements by the software correlated more closely to the computed tomography measurements than two-dimensional measurements. Bland-Altman analysis showed qualitative comparability of measurements performed by the automated software to computed tomography (95% limits of agreement between –4.62 mm and 1.26 mm for area-derived and –4.51 mm and 1.45 mm for perimeter-derived methods). Similarly, there was significant linear correlation with automated software use (r = 0.84, p Conclusions Periprocedural aortic valve measurement by automated echocardiographic software correlates with computed tomography in patients with severe aortic stenosis. This technology is helpful and accurate, but has limitations.

As a discarded byproduct of jujube (Z. jujuba), its seeds contain various biological components. Response surface methodology was used to optimize ultrasound-assisted heating extraction conditions of polysaccharides from Z. jujuba cv. Ruoqiangzao seeds (ZJSPs). The optimal parameters were as follows: temperature 83.1 °C, time 100 min, ultrasonic power 140 W, and water-material ratio 33.5 mL/g, allowed a maximum yield of 1.97%. One main fraction (ZJSPs-1) was successfully purified by ion-exchange and gel-permeation chromatography. With a molecular weight of 342 kDa, ZJSPs-1 was composed of arabinose, glucose, xylose, galactose and rhamnose. The presence of pyranose-form sugars as well as both α- and β-configurations was validated by FT-IR and 1H NMR. TG/DSC indicated that ZJSPs-1 has a favorable thermal stability. XRD suggested that ZJSPs-1 exhibited both crystalline and amorphous portions. ZJSPs-1 was in aggregates of homogenous-dense honeycomb like structures observed by SEM and AFM. ZJSPs-1 possessed antitumor activities against HeLa cells in a dose- and time-dependent manner at 24 and 48 h with IC50 of 164.6 and 87.1 μg/mL, respectively. Fluorescent microscopic and flow cytometry revealed that ZJSPs-1 inhibited the proliferation of HeLa cells through apoptosis. Z. jujuba seeds are good sources for antitumor polysaccharides in pharmaceutical and food industries.

Background: The treatment of abdominal wall metastasis presents a challenge, because resection can be followed by poor healing and external radiotherapy is associated with serious adverse events. This study aimed to evaluate the efficacy and safety of interstitial (125)I seed implantation under ultrasound (US) guidance for treating abdominal wall metastasis. Materials and Methods: The cases of 21 patients with 28 abdominal wall metastases who received brachytherapy with (125)I seeds at the department from August 2010 to March 2015 were retrospectively reviewed. (125)I seeds were implanted in the abdominal wall lesions under US guidance and with the help of a treatment planning system. Follow-up was performed using computed tomography at 1 d and at 3, 6, and 12 months after implantation. The lymphocyte count before the surgery was compared with the 3-month postoperative count. The main indicators observed were changes in tumor size, side effects, and complications. Results: All 21 patients were successfully treated with (125)I seed implantation under US guidance. The median follow-up since (125)I seed implantation was 15 months (range 6–23 months). The response rates and local tumor control after 3, 6, and 12 months were 78.6% and 89.3%, 64.3% and 85.7%, and 52.4% and 71.4%, respectively. The mean preoperative lymphocyte count was 0.262 ± 0.117 × 10(9)/L, which did not differ significantly from the postoperative count, which was 0.259 ± 0.094 × 10(9)/L (p = 0.122). Procedure-related complications included fever, bleeding, and pain, but all these were Grade 1–2. No severe side effects or complications were noted. Conclusions: Percutaneous interstitial implantation of (125)I seeds under US guidance is safe and feasible for abdominal wall metastases. However, its long-term efficacy requires further investigation.

Calcium-activated chloride channels (CaCCs)/TMEM16A control diverse fundamental physiological functions, and abnormal function of TMEM16A will lead to various diseases including asthma, hypertension, gastrointestinal hypomotility and cancers. Therefore, TMEM16A as drug targets for related diseases has been increasingly concerned by researchers. In this work, COS were reported as novel natural activators of TMEM16A. It was demonstrated that COS can activate TMEM16A in a concentration dependent manner, with an EC50 of 74.5 μg/mL. Then, fluorescence experiments and inside-out patch clamp experiments were combined to confirm that COS can directly activate TMEM16A. Further, we compared the activation effects of COS monomers DP2 to DP6, with DP3 the best activator. Molecular simulation was performed to find that the binding sites between DP3 and TMEM16A are E143 and E146 in TMEM16A, and it was speculated that COS and TMEM16A may be combined by electrostatic interaction. Finally, we verified that guinea pig ileum contraction was promoted by COS and the monomers through activating TMEM16A. Collectively, COS are novel efficient natural activators of TMEM16A, with potential to be developed to treatment diseases caused by down-regulation of TMEM16A including gastrointestinal hypomotility.

PARP1 encodes a chromatin-associated enzyme which responsible for post-translational poly(ADP-ribosyl)ation modification (Hsieh et al., 2017). It plays an important role in nucleotide excision repair, non-homologous end joining, DNA mismatch repair and many other DNA repair process. Also, PARP1 participates in inflammation and aging. However, its role in human embryonic stem cell biology has not been fully resolved. To clarify the function of PARP1 in human embryonic stem cells, we reported a PARP1 knockout human embryonic stem cell line, generated by CRISPR/Cas9 mediated gene targeting. This cell line shows normal karyotype, pluripotent stem cell marker expression and differentiation potential in vitro.

Neuroblastoma (NB), which is a subtype of neural-crest-derived malignancy, is the most common extracranial solid tumor occurring in childhood. Despite extensive research, the underlying developmental origin of NB remains unclear. Using single-cell RNA sequencing, we generate transcriptomes of adrenal NB from 160,910 cells of 16 patients and transcriptomes of putative developmental cells of origin of NB from 12,103 cells of early human embryos and fetal adrenal glands at relatively late development stages. We find that most adrenal NB tumor cells transcriptionally mirror noradrenergic chromaffin cells. Malignant states also recapitulate the proliferation/differentiation status of chromaffin cells in the process of normal development. Our findings provide insight into developmental trajectories and cellular states underlying human initiation and progression of NB.

Virulence genes are distinct regions of DNA which are present in the genome of pathogenic bacteria and absent in nonpathogenic strains of the same or related species. Virulence genes are frequently associated with bacterial pathogenicity in genus Legionella. In the present study, an assay was performed to detect ten virulence genes, including iraA, iraB, lvrA, lvrB, lvhD, cpxR, cpxA, dotA, icmC and icmD in different pathogenicity islands of 47 Legionella reference strains, 235 environmental strains isolated from water, and 4 clinical strains isolated from the lung tissue of pneumonia patients. The distribution frequencies of these genes in reference or/and environmental L. pneumophila strains were much higher than those in reference non-L. pneumophila or/and environmental non-L. pneumophila strains, respectively. L. pneumophila clinical strains also maintained higher frequencies of these genes compared to four other types of Legionella strains. Distribution frequencies of these genes in reference L. pneumophila strains were similar to those in environmental L. pneumophila strains. In contrast, environmental non-L. pneumophila maintained higher frequencies of these genes compared to those found in reference non-L. pneumophila strains. This study illustrates the association of virulence genes with Legionella pathogenicity and reveals the possible virulence evolution of non-L. pneumophia strains isolated from environmental water.

TMEM16A is the molecular basis of calcium-activated chloride channels and shows Ca(2+)-dependent gating. It is critical to understand how the Ca(2+) sensors dynamically control the gate of TMEM16A. However, the detailed mechanism by which the calcium ions bind and open the channel is still obscure. In this study, the authors confirmed that there are two Ca(2+) sensors which cooperatively couple together in TMEM16A. Our data show that mutations at both Ca(2+)-sensitive domains, E447Y and E702Q-E705Q, weaken the Ca(2+) affinity for TMEM16A channel. The EC50 for WT, E447Y, and E702Q-E705Q are 0.53 ± 0.11, 14.5 ± 0.3, and 26.5 ± 3.6 μM, respectively. The triple mutation, including both of the Ca(2+) sensors, E447Y-E702Q-E705Q, with EC50 as 55.6 ± 5.1 μM, results in much further right-shifted dose response curve than the single sensor's mutations (E447Y, E702Q-E705Q) do, which indicates that there is a cooperation between the two Ca(2+)-sensitive domains. We also found that the divalent cations, both Ca(2+) and Sr(2+), share common mechanism of gating the TMEM16A.

In previous studies, we demonstrated that rhein lysinate (RHL), the salt of rhein and lysine that is easily dissolved in water, inhibited the growth of tumor cells derived from breast and ovarian cancer, hepatocellular carcinoma, cervical cancer and lung carcinoma. Based on these observations, human glioma U87 cells and a xenograft model in BALB/c nude mice were used to examine the antitumor activity of RHL against human glioma. Notably, RHL statistically significantly suppressed the growth of human glioma U87 xenografts in BALB/c nude mice. In vitro, there was a significant reduction in cell proliferation after treatment with RHL in a dose- and time-dependent manner. The overall growth inhibition was correlated with the increase in reactive oxygen species (ROS) production and cell apoptosis. The apoptosis- and cell cycle-related proteins including BAX and Bim were increased, whereas Bcl-2 and cyclin D were decreased in the RHL-treated cells. The results demonstrated that RHL is highly effective against the growth of human glioma U87 xenografts in BALB/c nude mice. The potent antitumor activity of RHL may be mediated through downregulation of Bcl-2 and cyclin D expression and upregulation of BAX and Bim expression.

To overcome the adverse effects of conventional chemotherapy for cancers, various nanoparticles based drug delivery systems have been developed. However, nanoparticles delivering drugs directly to kill tumor cells still faced with challenges, because tumors possessed adopt complex mechanism to resist damages, which compromised the therapeutic efficacy. TMEM16A/CaCCs (Calcium activates chloride channels) has been identified to be overexpressed in lung adenocarcinoma which can serve as a novel tumor specific drug target in our previous work. Here, we developed a novel dual-targeted antitumor strategy via designing a novel nano-assembled, pH-sensitive drug-delivery system loading with specific inhibitors of TMEM16A against lung adenocarcinoma. For validation, we assayed the novel dual-targeting therapy on xenograft mouse model which exhibited significant antitumor activity and not affect mouse body weight. The dual targeting therapy accomplished in this study will shed light on the development of advanced antitumor strategy.

TMEM16A plays critical roles in physiological process and may serve as drug targets for diverse diseases. Recently, TMEM16A has started to be regarded as potential primary lung adenocarcinoma targets. Here, we identified that arctigenin, a natural compound, is a novel TMEM16A inhibitor, and it can suppress lung adenocarcinoma growth through inhibiting TMEM16A both in vitro and in vivo. Our data also showed that the IC50 of actigenin to TMEM16A whole-cell current was 19.29 ± 4.69 μM, and the putative binding sites of arctigenin in TMEM16A were R515 and R535. Arctigenin concentration-dependently inhibited the proliferation and migration of LA795, however, the inhibition effect can be abolished by knockdown of the endogenous TMEM16A with shRNA. Further, we injected arctigenin on xenograft mouse model which exhibited significant antitumor activity with no adverse effect. At last, western blotting results showed the mechanism of arctigenin inhibiting lung adenocarcinoma was through inhibiting MAPK pathway. In summary, TMEM16A is a novel drug target for lung adenocarcinoma treatment. Arctigenin can be used as a lead compound for the development of lung adenocarcinoma therapy drugs.

In a previous study, it was demonstrated that Rhein lysinate (RHL) inhibited HeLa cell proliferation via a specific mechanism. The aim of the present study was to clarify the mechanism of RHL by investigating its effect on mitochondrial damage and cell apoptosis. The results indicated that RHL inhibited cell growth and proliferation in HeLa cells. HeLa cells treated with RHL developed extensive vacuolization in a dose- and time-dependent manner. Ultrastructure analysis using transmission electron microscopy revealed that the vacuoles observed were damaged mitochondria and endoplasmic reticulum. The effects of RHL on mitochondria were further confirmed by a decrease in mitochondrial membrane potential and increased generation of reactive oxygen species. The mitochondrial proteome was analyzed, and the results demonstrated that the expression of the cytoskeletal protein keratin and dermal papilla derived protein 12 (associated with the oxidation- reduction process), which are associated with mitochondrial structure and function, were decreased compared with the untreated control group. Hoechst staining, flow cytometry and western blotting also revealed that apoptosis was induced at 24 h following RHL treatment. These results confirm that RHL toxicity in HeLa cells is a dynamic process. Vacuolar degeneration appeared in HeLa cells treated with 160 µmol/l RHL during the first 6 h and with the extension of RHL treatment, cell apoptosis was presented at ~24 h in HeLa cells.

The decline in skeletal muscle mass and function with age is referred as sarcopenia. It is characterized by the muscle fiber's quality, strength, muscle endurance and metabolic ability decreasing as well as the fat and connective tissue growing. Previous studies have shown that sarcopenia in itself features decreased number and cross-sectional area of muscle fibers and the net degradation of protein, which results from the joint effects of multiple factors such as the exacerbation of inflammation, oxidative stress injury, mitochondrial dysfunction, abnormal autophagy and dysregulation of muscle quality regulatory factors. In this review, we systematically displayed the molecular mechanism of sarcopenia, which will be helpful to deepen our understanding of sarcopenia and provide potential targets for the prevention and treatment of sarcopenia.

Dysregulation of epidermal growth factor receptor (EGFR) signaling is responsible for the resistance to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, and is thereby associated with the progression of tumors in non‑small cell lung cancers (NSCLCs). Immunoblotting results revealed that geranylgeranyl transferase 1 inhibitor (GGTI)‑298, a geranylgeranyl transferase 1 inhibitor with potential antitumor effects, effectively inhibited the phosphorylation of EGFR and its downstream target protein kinase B (AKT). A combination of gefitinib and GGTI‑298 amplified the inhibition of the EGFR‑AKT signaling pathway. In addition, GGTI‑298 treatment produced a synergistic effect on the inhibition of proliferation as indicated by the combination index values of

Mutant KRAS and BRAF are associated with primary EGFR inhibitor resistance in colorectal cancer (CRC). However, other biomarkers that could predict EGFR inhibitor resistance remain elusive. In the present study, immunoblotting and cell proliferation results revealed that yes‑associated protein (YAP), a downstream effector of the Hippo pathway, was positively associated with primary cetuximab resistance in CRC cells. YAP knockdown enhanced the cytotoxicity of cetuximab in CRC cells. Simvastatin, a 3‑hydroxy‑3‑methylglutaryl‑coenzyme A (HMG‑CoA) reductase inhibitor of the mevalonate pathway that inhibits YAP bioactivity through nuclear translocation and total YAP expression, increased the cytotoxicity of EGFR inhibitors (cetuximab and gefitinib) against CRC cells. The combination of simvastatin and EGFR inhibitors inhibited YAP and EGFR signaling more markedly than each agent alone. Adding back geranylgeranyl pyrophosphate (GGPP), a key product of the mevalonate pathway, reversed the YAP bioactivity inhibition induced by simvastatin and the cell proliferation inhibition induced by the combination of simvastatin and EGFR inhibitors. Collectively, these results revealed that YAP may be useful in identifying cetuximab resistance in CRC and indicated that targeting of both YAP and EGFR signals may present a promising therapeutic approach for CRC.