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Background Glioma is the most common malignancy of the central nervous system. Fos-like antigen 1 (FOSL1) is overexpressed and acts as a tumor-promoting factor in glioma. However, the regulation of FOSL1 remains unknown. KLF14, a member of Kruppel-like factors that are involved gene transcription, plays an important role in the regulation of cell proliferation, differentiation and apoptosis. Loss of KLF14 triggers spontaneous tumorigenesis of lung, spleen and lymph node, suggesting its potential as biomarker for cancer. However, its role in glioma still needs to be deciphered. Therefore, we explore the interactions between FOSL1 and KLF14, as well as their role in glioma. Methods We first determined that FOSL1 can be transcriptional inhibited by KLF14 using dual-luciferase reporter gene assays and qPCR assays. Then, through immunohistochemistry (IHC)assay and western blotting (WB) assay in glioma tissues, we demonstrated a negative correlation between FOSL1 and KLF14. Next, KLF14 knockdown cells and double knockdown of KLF14 and FOSL1 cells were generated, and cell growth were detected by different experimental methods (MTT assay, crystal violet staining, cell migration assay). We then used qPCR and WB assay to search for and validate how KLF14 affects tumor cell migration through FOSL1. Finally, we confirmed the inhibition of tumor growth by KLF14 using xenograft tumor model. Results In this study, we showed that KLF14 inhibited the transcription of FOSL1.There is a negative correlation between KLF14 and FOSL1 in glioma tissues. Overexpression of KLF14 reversed the effect of FOSL1 in cell invasion, migration and epithelial-mesenchymal transition in glioma cells, and this was accompanied by the down-regulation of Snail2 and CD44. Moreover, KLF14 overexpression inhibits tumor progression in vivo. Conclusions The present results suggest that KLF14 is a new tumor molecular marker and a potential target for the treatment of glioma, providing a new target for anti-tumor drug research.

Relatively little is known about allantois and urachal development in early humans. Serial sagittal histological sections from eight human embryos and fetuses were examined to determine allantois development. At gestational age 6-7 weeks, the primitive allantois consists of an enlarged tube located between the umbilical cord and abdominal cavity, whereas the urachus is not yet developed. At 8 weeks, the allantois gradually withdraws from the distal to the proximal end of the umbilical cord, and both the proximal allantois and the rectum (hindgut) start to develop into the cloaca. At 10 weeks, the allantois was located mostly in the abdominal cavity. The urachus forms from the distal end of the allantois and develops into a closed fibrous cord between the base of the urinary bladder and the umbilicus. The urogenital sinus forms from the proximal end of the allantois.

The sequential occurrence of three layers of smooth muscle layers (SML) in human embryos and fetus is not known. Here, we investigated the process of gut SML development in human embryos and fetuses and compared the morphology of SML in fetuses and neonates. The H&E, Masson trichrome staining, and Immunohistochemistry were conducted on 6–12 gestation week human embryos and fetuses and on normal neonatal intestine. We showed that no lumen was seen in 6–7th gestation week embryonic gut, neither gut wall nor SML was developed in this period. In 8–9th gestation week embryonic and fetal gut, primitive inner circular SML (IC-SML) was identified in a narrow and discontinuous gut lumen with some vacuoles. In 10th gestation week fetal gut, the outer longitudinal SML (OL-SML) in gut wall was clearly identifiable, both the inner and outer SML expressed α-SMA. In 11–12th gestation week fetal gut, in addition to the IC-SML and OL-SML, the muscularis mucosae started to develop as revealed by α-SMA immune-reactivity beneath the developing mucosal epithelial layer. Comparing with the gut of fetuses of 11–12th week of gestation, the muscularis mucosae, IC-SML, and OL-SML of neonatal intestine displayed different morphology, including branching into glands of lamina propria in mucosa and increased thickness. In conclusions, in the human developing gut between week-8 to week-12 of gestation, the IC-SML develops and forms at week-8, followed by the formation of OL-SML at week-10, and the muscularis mucosae develops and forms last at week-12.

Objectives Intestinal failure-associated liver disease (IFALD) is a feared and life-threatening complication in neonates with intestinal failure (IF) receiving long-term total parenteral nutrition (TPN). This study aims to investigate the effect of exogenous secretin on liver pathology and hepatic function in a rat model of PN-associated liver disease (PNALD). Methods Male Sprague-Dawley rats underwent right jugular venous catheterization to receive 14-day continuous TPN therapy. All rats were allocated into 3 groups: the Control group (n = 8) did not have surgery or TPN and was fed standard rat chow ad libitum; the TPN group (n = 8) underwent catheter insertion and TPN treatment; and the TPN/S group (n = 8) also underwent catheter insertion, TPN treatment, and exogenous secretin treatment (2.5 nmol · kg · day) daily. Fourteen days after initial surgery, we collected the animals' liver and blood samples for further test. Results The TPN/S group had diminished direct bilirubin (TPN, 2.1 ± 0.7 μmol/L; TPN/S, 1.5 ± 0.2 μmol/L) and liver total bile acid levels (TPN, 144.5 ± 21.2 μmol/L; TPN/S, 123.4 ± 10.4 μmol/L) and improved histological outcomes compared with those in the TPN group. Exogenous secretin also enhanced the canalicular transporter (BSEP, 0.5-fold, P = 0.011) and inhibited the basolateral transporter (OSTA, -0.48-fold, P = 0.002; OSTB, -0.6-fold, P = 0.013) of liver bile acid. Conclusions In this animal model of PNALD, secretin may improve cholestasis by enhancing canalicular transport, inhibiting the basolateral export of liver bile acid, and eventually decreasing the total bile acid level in the liver. Exogenous secretin treatment may potentially prevent and treat IFALD in IF patients relying on long-term TPN therapy.

A Rho GTPase-activating protein (RhoGAP), deleted in liver cancer 1 (DLC1), is known to function as a tumor suppressor in various cancer types; however, whether DLC1 is a tumor-suppressor gene or an oncogene in melanoma remains to be clarified. Here we revealed that high DLC1 expression was detected in most of the melanoma tissues where it was localized in both the nuclei and the cytoplasm. Functional studies unveiled that DLC1 was both required and sufficient for melanoma growth and metastasis. These tumorigenic events were mediated by nuclear-localized DLC1 in a RhoGAP-independent manner. Mechanistically, mass spectrometry analysis identified a DLC1-associated protein, FOXK1 transcription factor, which mediated oncogenic events in melanoma by translocating and retaining DLC1 into the nucleus. RNA-sequencing profiling studies further revealed MMP9 as a direct target of FOXK1 through DLC1-regulated promoter occupancy for cooperative activation of MMP9 expression to promote melanoma invasion and metastasis. Concerted action of DLC1–FOXK1 in MMP9 gene regulation was further supported by their highly correlated expression in melanoma patients’ samples and cell lines. Together, our results not only unravel a mechanism by which nuclear DLC1 functions as an oncogene in melanoma but also suggest an unexpected role of RhoGAP protein in transcriptional regulation.

Laparoscopic-assisted anorectoplasty (LAARP) is considered to benefit the patients with vesico-prostatic fistula. The aim of this study is to present the details of our LAARP technique for improving the short- and long-term outcomes in the patients with high and intermediate types of anorectal malformations (ARMs). 330 patients with high-type (174 cases) and intermediate-type (156 cases) anorectal malformation (aged 8 days to 15 years) underwent LAARP from 2001 to 2019. LAARP was performed for full mobilization and resection of the dilated rectum, intra-rectal closure of the fistula, visualization, and enlargement of the center of the longitudinal muscle tube (LMT) from pelvic and perineal aspects. LAARP was performed in all patients and no patient was converted to open procedure. The urethral diverticulum was found in three patients (1.02%, 3/294) according to postoperative protocol voiding cystourethrogram but was not associated with any symptoms such as urinary tract infection and dysuria. Rectal prolapse requiring surgical intervention developed in 25 (7.6%) of 330 patients. Anal stricture occurred in three patients and re-do anoplasty was performed 5 months after LAARP. Anal retraction occurred in two patients and re-pull-through was conducted at 5 and 6 days, respectively, after LAARP. 228 patients who were older than 3 years were followed up. The median follow-up period was 5.8 years (range 3–15 years). 217 patients (95.2%) had voluntary bowel movements; 202 patients (88.6%) were free from soiling or with grade 1 soiling; 30 patients (13.6%) and 25 patients (11.3%) suffered from grade 1 and grade 2 constipation, respectively, while no patient had grade 3 constipation. Our experience demonstrates that the LAARP has advantages on rectal mobilization and resection, intra-rectal fistula closure and accurate tunnel formation in the LMT with minimal trauma. The improvement of the short-term and long-term outcomes after LAARP has been shown not only for high-type ARM but also for intermediate-type ARM.

Background Laparoscopic percutaneous extraperitoneal closure (LPEC) with variable devices seems to be one of the most simple and reliable methods. We described our modifications of single-port laparoscopic herniorrhaphy using an inner two-hooked cannula device with preperitoneal hydrodissection. Patients and methods 1568 children with 2114 inguinal hernias were treated by single-port LPEC. Under laparoscopic visualization, the two-hooked cannula device carrying a silk suture was inserted at the point of the internal ring and could be readily kept in an identical path. The hernia orifice was completely lassoed extraperitoneally by the suture with the assistance of hydrodissection. Any huge hernias of more than 1.5 cm were repaired with the incorporation of medial umbilical fold flap as reinforcement. Results All hernia repairs were successfully performed by LPEC. 1022 patients had unilateral inguinal hernia repair, and 546 patients underwent bilateral inguinal hernia repair. Of these, additional medial umbilical flap reinforcement was necessary in 68 cases, and an assisted grasping instrument was used in 19 cases owing to omental adhesion or sliding hernia. Mean operating times for unilateral and bilateral inguinal hernia repairs were 9.8 ± 2.1 min and 13.6 ± 2.2 min, respectively. There were no operative complications. Two recurrences and three hydroceles were observed during 6 to 30 months of follow-up. Conclusions One-puncture LPEC using the two-hooked cannula device with preperitoneal hydrodissection has proved to be a safe and effective procedure with excellent cosmetic results. Level of evidence IV

We compared the cross-sectional areas of the duodenum to the distal small intestine during early gestation to determine if there is a difference in age for recanalization. Serial sagittal sections ...

An infectious disease named "coronavirus disease 2019" (COVID-19) currently has brought a threat to global health security and trends to be more and more severe in many countries. It also has introduced great challenges to the diagnosis and management of children with hepatoblastoma (HB). During the COVID-19 pandemic, pediatric surgeons should not only develop personalized treatment plans for HB therapy, but also emphasize the diagnosis, prevention, and treatment of this virus. Children with both HB and COVID-19 are recommended to undertake multidisciplinary assessment. Anti-SARS-CoV-2 therapy may be a preferred treatment for the infected without presenting a surgical emergency. However, emergent operation may be necessary for HB children with concurrent COVID-19 who developed a life-threatening surgical emergency condition. Otherwise, for children with negative virus examination results, treatment advice should be based on the impact of the epidemic and regional economic considerations. A "wait and see" strategy is recommended for children with resectable tumors after new adjuvant chemotherapy treatment (NACT). Assessment of liver transplantation is recommended for children with HB whose tumors cannot be resected after NACT. Children with HB with pulmonary metastasis may have abnormal findings on chest imaging due to COVID-19. Besides, the detailed therapeutic regimens may vary for children with HB with or without an emergency presentation. Based on previous consensus, current research, and the experiences of our hospital, we aim to offer available management plans for the above-mentioned concerns.

Laparoscopic-assisted anorectoplasty (LAARP) is considered to benefit the male patients with anorectal malformation (ARM). This study evaluates LAARP management for intermediate type rectovestibular fistula (IRVF) in the female patient with ARM. Twelve patients with IRVF (aged 3–5 months) underwent LAARP from 2017 to 2019 in our institute. LAARP was performed for mobilization of the rectum, visualization and enlargement of the center of the sphincter muscle complex (SMC) from pelvic and perineal aspects, intra-fistula mucosectomy and rectal pull-through in the SMC with the fourchette and the perineal body unattached. LARRP was performed in all patients without conversion to open procedure. No patient suffered from wound infection, vaginal injury, recurrent fistula and anal stenosis. The parents were satisfied with the appearance of the wound. Rectal prolapse developed in one patient and needed surgical correction. The patients were followed up for a mean of 19.7 months (ranged from 12 to 35 months). Our preliminary experience shows that LAARP offers an alternative method of correction for the IRVF with good visualization of the SMC and may diminish the risks of wound dehiscence and vaginal injury.

Background:Cholestatic liver disease (CLD) is a common disease of infancy, threatening infants’ health seriously. However, there is no effective drug to treat this disease.It is urgently to develop a new drug to overcome it. Polyamide-amine (PAMAM) dendrimer is a hyperbranched nano polymer, which has been found that has an anti-inflammatory effect recently. For this study, we aim to explore the protective effect and mechanism of PAMAM on CLD.Methods:In this study, a mouse model of cholestatic liver injury was created using ANIT,and TNF-α was utilized to stimulate human hepatocytes to investigate the protective effect and mechanism of 4.5th generation carboxyl-terminated PAMAM dendrimers (G4.5-COOH) in vivo and in vitro.Liver serum biochemistry, inflammatory, oxidative stress(OxS), endoplasmic reticulum(ER) stress and apoptosis indicators were determined.In addition, the effects of G4.5-COOH on PPAR-γ and PI3K/AKT/mTOR signaling pathway were studied. Data were analyzed by using one-way ANOVA. Results:We find the G4.5-COOH may inhibit TNF-α to damage hepatocytes and ameliorate the cholestatic liver injury. We also find that the protective effect of G4.5-COOH might be due to inhibition of P-Akt、P-mTOR expression by a mechanism that might be partly dependent on up-regulated functional expression of PPAR-γ.Conclusions:G4.5-COOH PAMAM dendrimer has a protective effect on CLD.

Dezhong Sun, 1 Li Chen, 2 Huaiqing Lv, 1 Yongli Gao, 3 Xuelai Liu, 4 Xiaoyan Zhang 3 1Department of Otolaryngology, Linyi People’s Hospital, Linyi, Shandong, People’s Republic of China; 2Department of Anesthesiology Operation, Linyi People’s Hospital, Linyi, Shandong, People’s Republic of China; 3Department of Medicine Oncology, Linyi People’s Hospital, Linyi, Shandong, People’s Republic of China; 4Department of Neurosurgery, Linyi Hospital of Traditional Chinese Medicine, Linyi, Shandong, People’s Republic of ChinaCorrespondence: Xiaoyan ZhangDepartment of Medicine Oncology, Linyi People’s Hospital, No. 27, Jiefang Road East Section, Linyi, Shandong 276000, People’s Republic of ChinaTel +86 539 8092120Email vgvlug@163.comBackground: Thyroid cancer (TC) is an endocrine disease, and its progression is regulated by many factors, including circular RNAs (circRNAs). However, as a new circRNA, the role of circ_0058124 in TC is worth further exploration.Methods: The expression levels of circ_0058124, microRNA-940 (miR-940) and mitogen-activated protein kinase 1 (MAPK1) were assessed by quantitative polymerase chain reaction (q-PCR). The circular characteristic of circ_0058124 was identified by oligo (dT) 18 primers, Ribonuclease R (RNase R) and Actinomycin D (ActD), and its localization was determined by nuclear-cytoplasmic separation assay. Also, cell proliferation was detected by colony formation assay, and cell migration and invasion were assessed by transwell assay. Further, Seahorse XF Extracellular Flux Analyzer was used to measure the oxygen consumption rate (OCR) of cells. Besides, dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays were used to identify the mechanism of circ_0058124. Western blot (WB) analysis was used to test the MAPK1 protein level. In addition, mice xenograft models were constructed to test the effect of circ_0058124 on TC tumor growth in vivo.Results: Circ_0058124 was highly expressed in TC and is a stable cyclic transcript, mainly located in the cytoplasm. Circ_0058124 knockdown suppressed proliferation, migration, invasion and metabolic abilities in TC cells. MiR-940 could be absorbed by circ_0058124, and the inhibition effect of its overexpression on TC progression could be reversed by overexpressed-circ_0058124. MAPK1 was a target of miR-940, and the suppression effect of its silencing on TC progression could be inverted by miR-940 inhibitor. Besides, MAPK1 expression was regulated by circ_0058124 and miR-940. Interference of circ_0058124 also reduced TC tumor growth in vivo.Conclusion: Circ_0058124 might play a carcinogenic role in TC progression by regulating the miR-940/MAPK1 axis, which might provide a new idea for the treatment of TC.Keywords: TC, circ_0058124, miR-940, MAPK1

Temozolomide (TMZ)-based chemotherapy is a standard strategy for gliomas, although chemoresistance remains a major therapeutic challenge. The chemical mechanism by which TMZ induces cell death is DNA methylation, leading to double-stranded breaks (DSBs) and thus to apoptosis. However, TMZ-induced N6-meG sites are efficiently repaired and mediated by the DNA repair protein O6-methylguanine-DNA methyl-transferase (MGMT), leading to TMZ resistance. KLF15, a member of the Kruppel-like factors family, mainly functions as transcription factor and potential suppressor gene by inhibiting proliferation, migration, and inducing apoptosis. However, the roles and regulatory mechanisms of KLF15 in glioma tumorigenesis and chemoresistance are poorly understood. In this study, KLF15 expression was upregulated in glioma tissues and cell lines upon TMZ treatment. Knockdown of KLF15 amplified TMZ-induced repression of cell proliferation, while KLF15 overexpression reversed this process. Mechanistically, KLF15 functioned as a transcriptional activator of MGMT. Moreover, KLF15 knockdown sensitized tumors to TMZ treatment in vivo. Taken together, these results suggested that KLF15 up-regulated MGMT through direct binding to the promoter of MGMT, which plays an important role in glioma resistance to TMZ, and which may be a potential target for cancer diagnosis and treatment.

The capillarywall radiationheating system is established. The indoor temperature, speed, PMV and PPD is simulated by the Airpak software. By analysis and comparison, the conclusion is drew: numerical simulation shows that the distance from capillary is less than 0.5m, the temperature, velocity, PMV and PPD are greatly affected by the asymmetric radiation of the capillary. Otherwise, the influence of the asymmetric radiation is weak and can be neglected. The distance from the ground is less than 0.6m and the outer window is less than 0.5m, which is greatly affected by asymmetric cold radiation, while the other locations have less influence.

With the more and more extensive application of jet pump in heating system, the research of jet pump is becoming more and more important. This paper studies the occasions of jet pump in the heating system and takes a heating pipe network of Ji’nan city as an example to analyze the energy saving effect of jet pump, the jet pump has obtained good economic benefit and energy saving application in heating system.

Overexpression of NEDD9 restores the oncogenic properties of SOX10 KD + SOX9 KD melanoma cells. (A) AlamarBlue assay for each cell line treated with the indicated constructs. (B) Representative images of crystal violet stained A375M and WM266–4 clones subjected to different treatments. (C) Quantification of the number of A375M and WM266–4 colonies treated with the indicated constructs. (D) Quantification of the number of invaded cells treated with the indicated constructs. (E) DAPI images of transwell invasion of melanoma cells treated with the indicated constructs. Error bars represent ± SD of three independent experiments. *p

Background In this research, we aimed to resolve contradictory results whether SOX9 plays a positive or negative role in melanoma progression and determine whether SOX9 and its closely related member SOX10 share the same or distinct targets in mediating their functions in melanoma. Methods Immunofluorescence, TCGA database and qPCR were used to analyze the correlation between the expression patterns and levels of SOX9, SOX10 and NEDD9 in melanoma patient samples. AlamarBlue, transwell invasion and colony formation assays in melanoma cell lines were conducted to investigate the epistatic relationship between SOX10 and NEDD9, as well as the effects of graded SOX9 expression levels. Lung metastasis was determined by tail vein injection assay. Live cell imaging was conducted to monitor dynamics of melanoma migratory behavior. RHOA and RAC1 activation assays measured the activity of Rho GTPases. Results High SOX9 expression was predominantly detected in patients with distant melanoma metastases whereas SOX10 was present in the different stages of melanoma. Both SOX9 and SOX10 exhibited distinct but overlapping expression patterns with metastatic marker NEDD9. Accordingly, SOX10 was required for NEDD9 expression, which partly mediated its oncogenic functions in melanoma cells. Compensatory upregulation of SOX9 expression in SOX10-inhibited melanoma cells reduced growth and migratory capacity, partly due to elevated expression of cyclin-dependent kinase inhibitor p21 and lack of NEDD9 induction. Conversely, opposite phenomenon was observed when SOX9 expression was further elevated to a range of high SOX9 expression levels in metastatic melanoma specimens, and that high levels of SOX9 can restore melanoma progression in the absence of SOX10 both in vitro and in vivo. In addition, overexpression of SOX9 can also promote invasiveness of the parental melanoma cells by modulating the expression of various matrix metalloproteinases. SOX10 or high SOX9 expression regulates melanoma mesenchymal migration through the NEDD9-mediated focal adhesion dynamics and Rho GTPase signaling. Conclusions These results unravel NEDD9 as a common target for SOX10 or high SOX9 to partly mediate their oncogenic events, and most importantly, reconcile previous discrepancies that suboptimal level of SOX9 expression is anti-metastatic whereas high level of SOX9 is metastatic in a heterogeneous population of melanoma. Electronic supplementary material The online version of this article (10.1186/s13046-018-0998-6) contains supplementary material, which is available to authorized users.

Background Our previous studies revealed that silver nanoparticles (AgNPs) promoted wound healing in part through their anti-inflammatory actions. As recent reports also suggested anti-inflammatory effects of dendrimers, we therefore undertook this study using dendrimer as the delivery system for AgNP to explore any potential synergistic anti-inflammatory efficacy. Methods Lipopolysaccharide (LPS) was added to cultured RAW264.7 and J774.1 cells to mimic in vitro inflammation condition, followed by the addition of either silver dendrimer nanocomposite (Ag-DNC), AgNPs, or dendrimer. The levels of inflammatory markers TNF-alpha and interleukin-6 were assessed using ELISA assay. Furthermore, in vivo effects such of Ag-DNC, AgNPs, or dendrimer were studied in a burn wound model in mice. Results Our results confirmed that both naked dendrimer and AgNPs had anti-inflammatory properties. In in vitro study, Ag-DNC was shown to have the best anti-inflammatory efficacy than AgNPs or dendrimer alone. In-vivo experiments also indicated that animals in the Ag-DNC group had the fastest healing time with the least inflammation. Conclusion Our study would suggest that dendrimer could provide additional anti-inflammatory benefits and might be an excellent delivery system for silver nanoparticles for future clinical application.

In our previous study, we coated silver nanoparticles (AgNPs) onto the surface of absorbable braided suture using layer-by-layer deposition and demonstrated significant anti-inflammatory property during the early phase of intestinal anastomosis healing in mice. The present study aimed to further investigate the long-term anti-inflammatory efficacy.AgNP-coated suture, antibiotic coated suture, and normal suture were respectively used for single layered, interrupted intestinal anastomosis. The anastomotic segments in each group were harvested on day 14, day 21, and day 28 postoperation and investigated for the degree of inflammation by cell infiltration and expression of cytokines as well as collagen deposition.When compared with the control groups, the AgNP-coated suture group showed better histological appearance in the intestinal anastomotic segments at each time point. Immunohistochemistry staining and quantitative evaluation further indicated less macrophage infiltration and decreased production of IL-6, IL-10, and TNF-α (p0.05). Masson staining showed normal collagen deposition and remodeling at intestinal anastomotic tissue in the AgNP-coated suture group.Our study shows that AgNP-coated suture provides better long-term anti-inflammatory efficacy and ideal tissue remodeling in intestinal anastomosis. Despite these findings, clinical trials are still needed for evaluation before medical application.

Background & Aims Biliary atresia (BA) is a rare and most severe cholestatic disease in neonates, but the pathogenic mechanisms are unknown. Through a previous genome wide association study (GWAS) on Han Chinese, we discovered association of the 10q24.2 region encompassing ADD3 and XPNPEP1 genes, which was replicated in Chinese and Thai populations. This study aims to fully characterize the genetic architecture at 10q24.2 and to reveal the link between the genetic variants and BA. Methods We genotyped 107 single nucleotide polymorphisms (SNPs) in 10q24.2 in 339 Han Chinese patients and 401 matched controls using Sequenom. Exhaustive follow-up studies of the association signals were performed. Results The combined BA-association p -value of the GWAS SNP (rs17095355) achieved 6.06×10 −10 . Further, we revealed the common risk haplotype encompassing 5 tagging-SNPs, capturing the risk-predisposing alleles in 10q24.2 [ p =5.32×10 −11 ; odds ratio, OR: 2.38; confidence interval, CI: (2.14-2.62)]. Through Sanger sequencing, no deleterious rare variants (RVs) residing in the risk haplotype were found, dismissing the theory of "synthetic" association. Moreover, in bioinformatics and in vivo genotype-expression investigations, the BA-associated potentially regulatory SNPs correlated with ADD3 gene expression (n=36; p =0.0030). Remarkably, the risk haplotype frequency coincides with BA incidences in the population, and, positive selection (favoring the derived alleles that arose from mutations) was evident at the ADD3 locus, suggesting a possible role for the BA-associated common variants in shaping the general population diversity. Conclusions Common genetic variants in 10q24.2 can alter BA risk by regulating ADD3 expression levels in the liver, and may exert an effect on disease epidemiology and on the general population.

Background & Aims Hirschsprung disease, or congenital aganglionosis, is believed to be oligogenic—that is, caused by multiple genetic factors. We performed whole-genome sequence analyses of patients with Hirschsprung disease to identify genetic factors that contribute to disease development and analyzed the functional effects of these variants. Methods We performed whole-genome sequence analyses of 443 patients with short-segment disease, recruited from hospitals in China and Vietnam, and 493 ethnically matched individuals without Hirschsprung disease (controls). We performed genome-wide association analyses and gene-based rare-variant burden tests to identify rare and common disease–associated variants and study their interactions. We obtained induced pluripotent stem cell (iPSC) lines from 4 patients with Hirschsprung disease and 2 control individuals, and we used these to generate enteric neural crest cells for transcriptomic analyses. We assessed the neuronal lineage differentiation capability of iPSC-derived enteric neural crest cells using an in vitro differentiation assay. Results We identified 4 susceptibility loci, including 1 in the phospholipase D1 gene (PLD1) (P = 7.4 × 10–7). The patients had a significant excess of rare protein-altering variants in genes previously associated with Hirschsprung disease and in the β-secretase 2 gene (BACE2) (P = 2.9 × 10–6). The epistatic effects of common and rare variants across these loci provided a sensitized background that increased risk for the disease. In studies of the iPSCs, we observed common and distinct pathways associated with variants in RET that affect risk. In functional assays, we found variants in BACE2 to protect enteric neurons from apoptosis. We propose that alterations in BACE1 signaling via amyloid β precursor protein and BACE2 contribute to pathogenesis of Hirschsprung disease. Conclusions In whole-genome sequence analyses of patients with Hirschsprung disease, we identified rare and common variants associated with disease risk. Using iPSC cells, we discovered some functional effects of these variants.

Regenerative medicine is the creation of a tissue or organ with normal structures and functions to replace the lost or impaired ones via biological modulation and tissue engineering. Indeed, many researchers have focused on exploring new techniques or approaches in this field. In recent years, numerous nanotechnologies have been incorporated into the field of regenerative medicine, aiming to replace tissues. The application of nanotechnology is important as many nanomaterials exhibit novel biological properties in the modulation of cellular events. The two main directions in this field are to provide biologically compatible scaffolds as an optimal environment for cell migration and proliferation; as well as to attempt to induce stem cell recruitment and differentiation. Thus, this review will focus on these two aspects, briefly describing the clinical applications.

Data, regarding the use of botulinum toxin (BT-A) in laryngeal dyspnea, are scarce, coming from some cases reports in the literature, including Vocal fold paralysis, laryngeal dystonia, vocal cord dysfunction also called paradoxical motion of the vocal fold (PMVF), and post-neuroleptic laryngeal dyskinesia. There is no consensus regarding the muscles and the doses to inject. The aim of this study is to present a retrospective review of patients treated in our ENT Department by BT-A injection in this indication. This study is a retrospective study describing patients who underwent an injection of botulinum toxin for laryngeal dyspnea in the ENT Department from 2005 to 2015 years. The inclusion criteria were a dyspnea associated with a laryngeal dysfunction, confirmed by flexible fiberoptic nasopharyngolaryngoscopy. Information concerning the causes of the dyspnea, the botulinum toxin BT-A injections procedure, post-injection follow-up, and respiratory outcome were collected for all patients included. In the group of 13 patients included, the main cause identified as principal factor linked with the short breath was: a bilateral VF paralysis (Patel et al., Otolaryngol Head Neck Surg 130:686–689, 7), laryngeal dystonia (Balkissoon and Kenn, Semin Respir Crit Care Med 33:595–605, 2), Anxiety syndrome associated with unilateral vocal fold paralysis or asthma (Marcinow et al., Laryngoscope 124:1425–1430, 3), and an isolated asthma (Zwirner et al., Eur Arch Otorhinolaryngol 254:242–245, 1). Nine out of the thirteen patients were improved by the injections. A BT-A-induced stable benefit for four patients led them to stop the injections in the follow-up. Good outcome was observed in five other patients (main cause: bilateral VP paralysis), allowing a progressive lengthening of the delay between BT-A injections. Four patients did not report a positive risk/benefit ratio after BT-A injections; two of them (with bilateral VF paralysis), because of respiratory side effects and lack of benefit without the side effects for the two others. This failure of effect was not related with BT-A doses injected. This study provides support for using BT-A injections as a symptomatic treatment of periodic laryngeal dyspnea, regardless of the etiologic context. From our data, we suggest that a small starting dose (of around 4 U BT-A Botox®) could be enough for a first injection to obtain a good benefit. The target muscle should be determined by the EMG analysis.

With the development of society and the improvement of people's living standard, the proportion of building energy consumption has increased, energy shortage and environmental pollution problems have become severe increasingly. Based on the importance of energy consumption quota method for public building,in this paper, according to the principle of the total amount control, the statistical quota is determined through sampling investigation and mathematical statistics of building energy consumption. Then compared the statistical quota and the technical quota determined by the building energy consumption simulation software Dest to determine the final building energy consumption quota , exploring the route of determining building energy consumption quota.This is of great significance for the realization of energy-saving emission reduction, reducing building energy consumption.

The advances in science have resulted in the emergence of nanotechnology, which deals with the design and use of tools and devices of size 1-100 nm. The application of nanotechnologies to medicine is thus termed nanomedicine. Significant research has been focused on this new and exciting field and this review article will describe the basics of nanomedicine. This is followed by its experimental and clinical applications in diagnostics, drug therapy and regenerative medicine. Safety issues of in vivo use of nanomaterials are also discussed. In the future, it is foreseen that nanomedicine will facilitate the development of personalized medicine and will have a major impact on the delivery of better healthcare.

PURPOSE: Laparoendoscopic single-site surgery has recently been described in children and regarded as an improved technology leading to less pain and better cosmetic outcome. Compared to the traditional three-port method, it is not known if the single-port method is less invasive. The aim of this study was thus to investigate the post-operative acute inflammatory response in order to evaluate surgical stress in the two surgical approaches in children. METHODS: A prospective, single blinded, case-control study was carried out. Thirteen male patients who presented with unilateral varicocele were divided into two groups. Six children underwent single-port laparoscopic procedure, while the other seven children underwent three-port laparoscopic procedure. Pre-operative and post-operative blood samples were taken for the measurement of tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) using ELISA. Demographics including the operation time, and complications were recorded. Data between the two groups were analyzed using unpaired t-test and a p value of, published_or_final_version, Springer Open Choice, 21 Feb 2012

Objective Long-term total parenteral nutrition (TPN) in children is often complicated by parental nutrition–associated liver disease and may even lead to liver failure. Recently, the addition of ω -3 fatty acids to TPN has been shown to reduce the risk of parental nutrition–associated liver disease. The purpose of this study was to explore the anti-inflammatory effects of ω -3 fatty acids (eicosapentaenoic acid [EPA]) to demonstrate the protection of the liver against hepatic steatosis and damage. Materials and Methods Lipopolysaccharide (LPS) and prostaglandin E 2 (PGE 2 ) were used to stimulate human macrophages and hepatocytes (THLE-3) to induce in vitro inflammatory condition. The cells were then incubated with either ω -3 (EPA) or ω -6 (arachidonic acid) fatty acids. Supernatants were collected at different time points for the measurement of tumor necrosis factor α (TNF- α ), interleukin 6 (IL-6), and interleukin 10 (IL-10) using enzyme-linked immunosorbent assay. Furthermore, pretreated macrophages by LPS stimulation and after incubation with EPA were added to prestimulated hepatocytes for the subsequent measurement of cytokine response. Results Eicosapentaenoic acid effectively reduced LPS-induced or PGE 2 -induced TNF- α and IL-6 expression, and increased IL-10 expression significantly when compared with arachidonic acid. Furthermore, supernatant collected after co-culturing EPA with macrophages also suppressed the levels of TNF- α and IL-6 in hepatocytes. This would suggest that EPA not only had an anti-inflammatory effect on macrophages and hepatocytes directly, it could indirectly reduce hepatocyte inflammation through activated macrophages. Conclusions The addition of ω -3 fatty acids in TPN suppresses the inflammatory response via direct and indirect routes. The findings may help explain the clinical benefits of EPA in pediatric patients receiving long-term TPN.

The potential use of osteo-conducive biomaterials in the promotion of bone fracture healing has attracted wide attention. This study investigated if silver nanoparticles (AgNps) could promote the proliferation and osteogenesis of mesenchymal stem cells (MSCs), and improve bone fracture healing. We showed that AgNps promoted MSCs' proliferation and osteogenic differentiation in vitro . Using a mouse femoral facture model, AgNps encapsulated in collagen promoted the formation of fracture callus, and induced early closure of the fracture gap. AgNps may promote the formation of the callus and the subsequent end joining of the fracture bone via multiple routes: (i) chemo-attraction of MSCs and fibroblasts to migrate to the fracture site; (ii) induction of the proliferation of MSCs; (iii) induction of osteogenic differentiation of MSCs via induction/activation of TGF-β/BMP signaling in MSCs. We concluded that AgNps might be beneficial as an adjunct treatment for bone fracture healing clinically. From the Clinical Editor Silver nanoparticles are widely used in wound management in the clinical setting. In this article, the authors demonstrated a novel application in that these nanoparticles were efficient in promoting osteoblastic differentiation in both in-vitro and in-vivo studies. The findings may provide a new treatment direction for bone fracture in the future.

This study demonstrates a novel method of using silver nanoparticles for Achilles tendon injury healing. In vitro results indicated a stimulatory effect on cell proliferation and collagen synthesis with silver nanoparticles. Biomechanical test on the 42-day post operation Achilles tendon sample exhibited a significant improvement in tensile modulus when compared to the untreated group. Histology suggested that silver nanoparticles promoted cell alignment and proteoglycan synthesis. The collagen deposition was also improved. An alleviation of tumor necrosis factor α, and an increase in fibromodulin and proliferating cell nuclear antigen expression were seen in silver nanoparticles group by immunohistochemistry. This study further corroborates the finding of our previous study that silver nanoparticles help to restore the functionality of injured connective tissues. We believe that the anti-inflammatory nature of silver nanoparticles has an important role in accelerating the healing process and reducing scarring, leading to better functional outcome. From the clinical editor: Tendon healing after surgeries remains a slow and tedious process, typically requiring several weeks of recovery time and gradual introduction of physical therapy. There are no currently utilized methods that could promote tendon healing. In this study, silver nanoparticles are reported to facilitate Achilles tendon repair in a model system, through increased proteoglycan and collagen synthesis, paving the way to potential clinical applications in the future.

Emergence of new materials and technology and their broad application is invariably identified as the symbol of scientific progress in any era. With recent advancement and development of nanotechnology, it has been made possible to engineer many kinds of materials into various shapes and sizes at the nanometer level. The sizes of these nanoparticles usually vary from 1 nm to 100 nm, which is much smaller than the generally targeted cells in the organism (Fig. 21.1), and will exhibit remarkably differential and amazing biological activities due to their unusual physical and chemical properties due to enhanced surface area to volume ratio for a given mass [1, 2]. This means that nano-sized particles are more likely to have increased cell surface interactions and to gain access into internal cell environments, resulting in significant biomedical effect or efficacy. In recent years, burgeoning interest in the medical applications of nanotechnology has led to the emergence of a new scientific field—Nanomedicine [3–8]. Nanomedicine, as the most important cross-link subject between nanoscience and biomedicine, is defined as the process of disease prevention, diagnosis, and therapeutic using nanomaterials or nanotechnology [9, 10].

On the basis of the introduction to household heat metering, this paper explains the function and working principle of weather compensators, and gives the temperature control model as well as its transfer functions. Then, with weather compensators ,we specific analyse and calculate the supply and return water temperature and the heat flow of outdoor pipe networks in different outdoor temperature. Automatic compensation of the system can be realized, and we can also achieve the aim of energy saving.

Development of anticancer drugs is challenging. Indeed, much research effort has been spent in the development of new drugs to improve clinical outcomes with minimal toxicity. We have previously reported that a formulation of lipid gold porphyrin nanoparticles reduced systemic drug toxicity when compared with free gold porphyrin. In this study, we investigated the delivery and treatment efficiency of PEG surface-modified lipid nanoparticles as a carrier platform. We encapsulated antitumor drugs into PEG-modified lipid nanoparticles and these were characterized by size, zeta potential, and encapsulation efficiency. The delivery efficiency into tumor tissue was evaluated using a biodistribution study. To evaluate antitumor efficacy, gold porphyrin or camptothecin (a DNA topoisomerase I inhibitor) were encapsulated and compared using an in vivo neuroblastoma (N2A) model. We showed that drug encapsulation into PEG-modified lipid nanoparticles enhanced the preferential uptake in tumor tissue. Furthermore, higher tumor killing efficiency was observed in response to treatment with PEG-modified lipid nanoparticles encapsulating gold porphyrin or camptothecin when compared with free gold porphyrin or free camptothecin. The in vivo antitumor effect was further confirmed by study of tumor inhibition and positive apoptosis activity. Surface modification of lipophilic nanoparticles with PEG increased the efficiency of drug delivery into tumor tissue and subsequently more effective antitumor activity. This specific design of a chemotherapeutic agent using nanotechnology is important in the development of a safe and effective drug in cancer therapy., published_or_final_version

Hirschsprung disease (HSCR) is a congenital disorder characterized by aganglionosis of the distal intestine. To assess the contribution of copy number variants (CNVs) to HSCR, we analysed the data generated from our previous genome-wide association study on HSCR patients, whereby we identified NRG1 as a new HSCR susceptibility locus. Analysis of 129 Chinese patients and 331 ethnically matched controls showed that HSCR patients have a greater burden of rare CNVs (p = 1.50×10 -5), particularly for those encompassing genes (p = 5.00×10 -6). Our study identified 246 rare-genic CNVs exclusive to patients. Among those, we detected a NRG3 deletion (p = 1.64×10 -3). Subsequent follow-up (96 additional patients and 220 controls) on NRG3 revealed 9 deletions (combined p = 3.36×10 -5) and 2 de novo duplications among patients and two deletions among controls. Importantly, NRG3 is a paralog of NRG1. Stratification of patients by presence/absence of HSCR-associated syndromes showed that while syndromic-HSCR patients carried significantly longer CNVs than the non-syndromic or controls (p = 1.50×10 -5), non-syndromic patients were enriched in CNV number when compared to controls (p = 4.00×10 -6) or the syndromic counterpart. Our results suggest a role for NRG3 in HSCR etiology and provide insights into the relative contribution of structural variants in both syndromic and non-syndromic HSCR. This would be the first genome-wide catalog of copy number variants identified in HSCR. © 2012 Tang et al., published_or_final_version

Hirschsprung disease (HSCR, congenital colon aganglionosis) is a relatively common complex genetic condition caused by abnormal development of the enteric nervous system (ENS). Through a recent genome-wide association study conducted on Chinese HSCR patients, we identified a new HSCR contributing locus, neuregulin 1 (NRG1; 8p12), a gene known to be involved in the development of the ENS. As genes in which disease-associated common variants are found are to be considered as candidates for the search of deleterious rare variants (RVs) in the coding sequences, we sequenced the NRG1 exons of 358 sporadic HSCR patients and 333 controls. We identified a total of 13 different heterozygous RVs including 8 non-synonymous (A28G, E134K, V266L, H347Y, P356L, V486M, A511T, P608A) and 3 synonymous amino acid substitutions (P24P, T169T, L483L), a frameshift (E239fsX10), and a c.503-4insT insertion. Functional analysis of the most conserved non-synonymous substitutions, H347Y and P356L, showed uneven intracellular distribution and aberrant expression of the mutant proteins. Except for T169T and V486M, all variants were exclusive to HSCR patients. Overall, there was a statistically significant over-representation of NRG1 RVs in HSCR patients (p = 0.008). We show here that not only common, but also rare variants of the NRG1 gene contribute to HSCR. This strengthens the role of NRG1.

The space moisture load is mainly from human, open wide water, and plants in office buildings. Based on the pollutants general ventilation equation and energy conservation, considers indoor temperature and humidity ratio dynamic formula in fresh air start-up stage. According to the weather parameter of Jinan, calculated fresh air pre-dehumidification time, considers when fresh air is 1.3 times of meeting personnel and health requirements, it can control on 30 minutes.

Based on elaborating the characteristics of capillary tube air-conditioning system, especially investigated the heat transfer property of this system cooling in summer, and establishes a two-dimensional mathematical model of steady-state heat transfer. In this paper, the Matlab program programmed by a micro-body heat balance method focuses the impact on the ceiling temperature field and the cooling performance of the factors such as temperature of supply water and return water and the pipe space. Then compared the computing results with the experimental results, it turns out that the numerical solutions of the heat transfer per unit area calculated by the model are in good agreement with the measured values, which provides the technical support for the design and promotion of the capillary tube air-conditioning system.