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Background: Microcirculatory changes in congenital heart disease (CHD) patients undergoing cardiac surgery are not fully understood. We aimed to investigate the changes of retinal microcirculation in CHD patients after cardiac surgery by optical coherence tomography angiography (OCTA) and explore the association between retinal microcirculation and surgical outcome.Methods: This prospective observational study consisted of 71 CHD patients aged ≥6 years undergoing cardiac surgery including 19 cyanotic CHD (CCHD) and 52 acyanotic CHD (ACHD). Optical coherence tomography angiography (OCTA) was used to measure vessel density (VD) and capillary density (CD) of radial peripapillary capillary (RPC) and peripapillary, VD of superficial capillary plexus (SCP) and deep capillary plexus (DCP), thickness of retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) preoperatively and 1 month postoperatively. Transthoracic echocardiography was conducted to measure macrocirculation.Results: In CCHD patients, VD and CD of RPC and peripapillary increased postoperatively (all P < 0.05). In ACHD patients, VD of peripapillary, CD of RPC and peripapillary, and RNFL thickness increased postoperatively (all P < 0.05). VD of SCP and DCP, and GCC thickness did not change significantly in CHD patients after surgery. Lower preoperative retinal microvascular density was associated with longer cardiopulmonary bypass (CPB) time and postoperative length of stay (PLOS). No correlation was found between microcirculatory and macrohemodynamic parameters (all P > 0.05).Conclusions: Improved retinal microcirculation was observed after congenital cardiac surgery and impaired preoperative retinal microvasculature was associated with prolonged CPB time and PLOS, which might provide potential information about the outcome of congenital cardiac surgery.

Background: Evaluating clinical outcome prior to concurrent chemoradiotherapy remains challenging for oesophageal squamous cell carcinoma (OSCC) as traditional prognostic markers are assessed at the completion of treatment. Herein, we investigated the potential of using sub-region radiomics as a novel tumour biomarker in predicting overall survival of OSCC patients treated by concurrent chemoradiotherapy. Methods: Independent patient cohorts from two hospitals were included for training (n = 87) and validation (n = 46). Radiomics features were extracted from sub-regions clustered from patients' tumour regions using K-means method. The LASSO regression for ‘Cox’ method was used for feature selection. The survival prediction model was constructed based on the sub-region radiomics features using the Cox proportional hazards model. The clinical and biological significance of radiomics features were assessed by correlation analysis of clinical characteristics and copy number alterations(CNAs) in the validation dataset. Findings: The overall survival prediction model combining with seven sub-regional radiomics features was constructed. The C-indexes of the proposed model were 0.729 (0.656–0.801, 95% CI) and 0.705 (0.628–0.782, 95%CI) in the training and validation cohorts, respectively. The 3-year survival receiver operating characteristic (ROC) curve showed an area under the ROC curve of 0.811 (0.670–0.952, 95%CI) in training and 0.805 (0.638–0.973, 95%CI) in validation. The correlation analysis showed a significant correlation between radiomics features and CNAs. Interpretation: The proposed sub-regional radiomics model could predict the overall survival risk for patients with OSCC treated by definitive concurrent chemoradiotherapy. Fund: This work was supported by the Zhejiang Provincial Foundation for Natural Sciences, National Natural Science Foundation of China. Keywords: Oesophageal cancer, Radiomics, Prognostic model, Radiation therapy, Imaging

Abstract Background Seasonal patterns of influenza A subtypes and B lineages in tropical/subtropical regions across age have remained to be explored. The impact of the 2009 H1N1 pandemic on seasonal influenza activity have not been well understood. Methods Based on a national sentinel hospital-based influenza surveillance system, the epidemiology of influenza virus during 2006/07–2015/16 was characterized in the subtropical city, Chengdu. Chengdu is one of the most populous cities in southwestern China, where the first reported case of A/H1N1pdm09 in mainland China was identified. Wavelet analysis was applied to identify the periodicities of A/H3N2, seasonal A/H1N1, A/H1N1pdm09, Victoria, and Yamagata across age, respectively. The persistence and age distribution patterns were described during the pre-pandemic (2006/07–2008/09), pandemic (2009/10), and post-pandemic (2010/11–2015/16) seasons. Results A total of 10,981 respiratory specimens were collected, of which 2516 influenza cases were identified. Periodicity transition from semi-annual cycles to an annual cycle was observed for composite influenza virus as well as A/H3N2 along in Chengdu since the 2009 H1N1 pandemic. Semi-annual cycles of composite influenza virus and A/H3N2 along were observed again during 2014/15–2015/16, coinciding with the emergence and predominance of A/H3N2 significant antigenic drift groups. However, A/H1N1pdm09, Victoria, and Yamagata generally demonstrated an annual winter-spring peak in non-pandemic seasons. Along with periodicity transitions, age groups with higher positive rates shifted from school-aged children and adults to adults and the elderly for A/H1N1pdm09 during 2009/10–2010/11 and for A/H3N2 during 2014/15–2015/16. Conclusions Differences in periodicity and age distribution by subtype/lineage and by season highlight the importance of increasing year-round influenza surveillance and developing subtype/lineage- and age-specific prevention and control measures. Changes of periodicity and age shifts should be considered in public health response to influenza pandemics and epidemics. In addition, it is suggested to use quadrivalent influenza vaccines to provide protection against both influenza B lineages.

Canine malignant mammary tumor is a dangerously fatal neoplastic disease with poor survival in female dogs. The aim of this study was to preliminary characterize a novel canine mammary cancer cell line, B-CMT, from canine primary mammary gland tumor, and to utilize it as a cell model for in vitro screening of possible therapeutic drugs. The successfully established cell line, B-CMT, was cultured over 50 passages. B-CMT has a fast proliferation rate, and a population doubling time (PDT) of 33.6 h. The B-CMT cell line lacked human epidermal growth factor receptor-2 (HER-2), estrogen receptors (ER) and progesterone receptors (PR) expression by qRT-PCR. Compared with MDCK cells, CDH1 expression of CMT cell line was significantly decreased or even absent, but GATA3 expression dramatically increased, while TGF-β expression was at a similar level. Interestingly, the B-CMT cell line from canine primary tumor also showed positive hypoxia inducible factor-1α (HIF-1α) results in immunofluorescence (IF), western blot, and qRT-PCR analysis. Ten days post inoculation with EGFP-B-CMT (B-CMT cells stably expressing EGFP), the experimental mice developed palpable soft tissue masses which histologically resembled the canine primary tumor, and was approved to be derived from B-CMT cell line through detection of EGFP by immunohistochemical (IHC) analysis. Moreover, we investigated the cytotoxicity of five drugs to B-CMT cells, and the results showed that rapamycin and imatinib significantly inhibited the proliferation of the cells in vitro within a certain range of concentration. They also induced cell cycle arrest of B-CMT cells at G1 and G2 phase, respectively. In summary, the results of this report showed that B-CMT cell line might serve as a tool for future studies on tumor microenvironment and drug resistance.

Background/AimsExenatide is a glucagon-like polypeptide-1 analog, whose main clinical use is to treat type 2 diabetes. However, the mechanism of exenatide in mitigating non-alcoholic steatohepatitis (NASH) remains unclear. This study aimed to investigate the in vitro and in vivo effect of exenatide on NASH.MethodsLeptin receptor-deficient C57BL/KsJ- db/db male mice were fed with methionine-choline-deficient (MCD) diet for 4 weeks to induce NASH, while oleic acid/LPS-treated HepG2 cells were used as an in vitro cell model. Exenatide (20 µg/kg/day, subcutaneous) and specific exenatide inhibitors (20 µg/kg/day, intraperitoneal) were used to determine the effects of exenatide on NASH.ResultsExenatide treatment inhibited the pyroptosis signaling pathway to attenuate NASH.ConclusionTo the best of our knowledge, this report provides the first evidence showing that exenatide attenuated NASH by inhibiting the pyroptosis signaling pathway. Exenatide thus has important pathophysiological functions in NASH and may represent a useful new therapeutic target.

Background: The herbs Rhizoma Curcumae and Rhizoma Sparganii (RCRS) are often used in traditional Chinese medicine for the treatment of uterine leiomyoma (UL). The effectiveness of RCRS for the treatment of UL has been confirmed in our previous studies.Purpose: This study aimed to investigate the molecular mechanism by which RCRS inhibits the activation of fibroblast activation protein (FAP) and prevents UL in rats.Study Design and Methods: A Sprague Dawley (SD) rat model of UL was established via estrogen and progesterone load combined with external stimulation. Histological analyses, enzyme-linked immunosorbent assays, and western blotting were performed to evaluate the effect of RCRS on UL and elucidate its mechanism of action.Results: Our data showed that the treatment of SD rats with RCRS significantly reduced the expression of extracellular matrix component collagen, FAP, and transforming growth factor beta (a FAP-activating factor) and the phosphorylation of the cell proliferation pathway-related signaling factors AKT/MEK/ERK.Conclusion: Our results suggest that RCRS is effective in the prevention and treatment of UL in rats, and RCRS may exert its functions by inhibiting the activation of tumor-associated fibroblasts and cell proliferation and by improving the tumor extracellular matrix.

GLP-1 analogs have been widely used to treat patients with type 2 diabetes in recent years and studies have found that GLP-1 analogs have multiple organ benefits. However, the role of GLP-1 analogs in diabetic retinopathy (DR), a common complication of diabetes mellitus (DM), remains controversial. Retinal ganglion cells (RGCs) are the only afferent neurons responsible for transmitting visual information to the visual center and are vulnerable in the early stage of DR. Protection of RGC is vital for visual function. The incretin glucagon-like peptide-1 (GLP-1), which is secreted by L-cells after food ingestion, could lower blood glucose level through stimulating the release of insulin. In the present study, we evaluated the effects of GLP-1 analog on RGCs both in vitro and in vivo. We established diabetic rat models in vivo and applied an RGC-5 cell line in vitro. The results showed that in high glucose conditions, GLP-1 analog alleviated the damage of RGCs. In addition, GLP-1 analog prevented mitophagy through the PINK1/Parkin pathway. Here we demonstrated the neuroprotective effect of GLP-1 analog, which may be beneficial for retinal function, and we further elucidated a novel mechanism in GLP-1 analog-regulated protection of the retina. These findings may expand the multi-organ benefits of GLP-1 analogs and provide new insights for the prevention of DR.

The purpose of this study was to develop a mechanical critical thinking scale for high school students. A stratified random sampling method was used to establish the norms. After pre-tests and item analysis, the scale was determined to have five subtest sections (i.e., recognition of assumptions, induction, deduction, interpretation, and evaluation of arguments) consisting of 25 items. In addition, using 1,954 high school students as participants, this study established a norm and investigated the differences among genders and ages. The results showed that male students had better mechanical critical thinking skills than did female students in terms of induction aptitude, while female students were better in evaluation aptitude. In addition, the mechanical critical thinking performance of 12th-grade students was superior to that of 10th- and 11th-grade students.

STEM-oriented engineering design practice has become recognized increasingly by technology education professionals in Taiwan. This study sought to examine the effectiveness of the application of an integrative STEM approach within engineering design practices in high school technology education in Taiwan. A quasi-experimental study was conducted to investigate the respective learning performance of students studying a STEM engineering module compared to students studying the technology education module. The student performances for conceptual knowledge, higher-order thinking skills and engineering design project were assessed. The data were analyzed using quantitative ("t" test, ANOVA, ANCOVA, correlation analysis) approaches. The findings showed that the participants in the STEM engineering module outperformed significantly the participants studying the technology education module in the areas of conceptual knowledge, higher-order thinking skills, and the design project activity. A further analysis showed that the key differences in the application of design practice between the two groups were (a) their respective problem prediction and (b) their analysis capabilities. The results supported the positive effect of the use of an integrative STEM approach in high school technology education in Taiwan.

This study explored the effects of cloud-based m-learning on students' creative processes and products in engineering design. A nonequivalent pretest-posttest design was adopted, and 62 university students from Taipei City, Taiwan, were recruited as research participants in the study. The results showed that cloud-based m-learning had a positive effect on creative performance in engineering design. It also improved the creative process in terms of presenting problems and of generating and validating responses. Additionally, cloud-based m-learning effectively improved overall performance, novelty, value and elaboration in designing creative products.

Ammonia is one of the most important environmental factors in aquatic ecosystems. However, there are limited studies on the effects of chronic or long-term ammonia stress and its potential molecular mechanism in fish. This study aimed to investigate the immune response and molecular mechanisms in the spleen and head-kidney of fish following chronic ammonia exposure. Megalobrama amblycephala (9.98 ± 0.48 g) were exposed to different concentrations of total ammonia nitrogen (0–30 mg/L) for 30 days. Ammonia exposure caused significant increases in cortisol levels and decreases in lysozyme and complement 3/4 concentrations in the serum, indicating inhibitory effects of ammonia stress on innate immune responses. Ammonia exposure also induced concentration-dependent increases in ammonia concentrations in tissue, pathological damage and indexes of spleen and head-kidney. Additionally, the contents of immunoglobulin M (IgM), interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) as well as mRNA levels of toll-like receptors (TLRs)/Myeloid differentiation factor 88 (MyD88)-independent signaling molecules in the spleen and head-kidney were significantly downregulated after ammonia exposure. Our findings suggested that chronic ammonia exposure caused the suppression of innate and adaptive immune responses through downregulating TLR/MyD88-independent signaling. Adverse influences of chronic ammonia stress were more severe in the spleen than in the head-kidney.

Fibroblast-like synoviocytes (FLSs) are critical to joint inflammation and destruction in rheumatoid arthritis (RA). Increased glycolysis in RA FLSs contributes to persistent joint damage. SUMOylation, a posttranslational modification of proteins, plays an important role in initiation and development of many diseases. However, the role of small ubiquitin-like modifier–activating (SUMO-activating) enzyme 1 (SAE1)/ubiquitin like modifier activating enzyme 2 (UBA2) in regulating the pathogenic FLS behaviors is unknown. Here, we found an increased expression of SAE1 and UBA2 in FLSs and synovial tissues from patients with RA. SAE1 or UBA2 knockdown by siRNA and treatment with GA, an inhibitor of SAE1/UBA2-mediated SUMOylation, resulted in reduced glycolysis, aggressive phenotype, and inflammation. SAE1/UBA2-mediated SUMOylation of pyruvate kinase M2 (PKM2) promoted its phosphorylation and nuclear translocation and decreased PK activity. Moreover, inhibition of PKM2 phosphorylation increased PK activity and suppressed glycolysis, aggressive phenotype, and inflammation. We further demonstrated that STAT5A mediated SUMOylated PKM2-induced glycolysis and biological behaviors. Interestingly, GA treatment attenuated the severity of arthritis in mice with collagen-induced arthritis and human TNF-α transgenic mice. These findings suggest that an increase in synovial SAE1/UBA2 may contribute to synovial glycolysis and joint inflammation in RA and that targeting SAE1/UBA2 may have therapeutic potential in patients with RA.

X-linked Alport syndrome (XLAS) is a rare form of hereditary nephritis caused by mutations in the COL4A5 gene encoding the type IV collagen α5 chain. A skin biopsy was performed on one female patient with XLAS who carried a heterozygous p.G409S (c. 1225 G > A) mutation in the COL4A5 gene. A human-induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts using the integrating free Sendai virus technique. The generated iPSC line SHCDNRi001-A offers an efficient resource to research pathogenic mechanisms in XLAS, as well as a cell-based disease model for drug testing or other treatments.

Abstract The efficiency of single treatment of conventional chemotherapy drugs is unpleasantly reduced by the physiological barriers of tumors. In this regard, nanoparticles have become attractive for achieving such medical purpose of targeted cancer therapy by delivering anti-tumor agents to the needed area. A novel drug deliverer, poly (ethylene glycol) carboxyl-poly (ε-caprolactone) (PEG-PCCL), has been reported to be highly hydrophilic and stable, while little is known about its organic toxicity. This study focused on systemic toxicity assessments of PEG-PCCL. The pharmacokinetics of PTX-loaded PEG-PCCL (PEG-PCCL/PTX) and its anti-tumor effect were preliminarily investigated. In the present work, PEG-PCCL was characterized by laser particle size analyzer and transmission electron microscopy. The cytotoxicity was investigated by MTT test, LDH leakage assay, immunofluorescence, and transmission electron microscopy. Hemolysis, phlebitis, and organ toxicity tests were performed to demonstrate the biocompatibility and acute biotoxicity. H22 tumor-bearing mice were used to evaluate the pharmacokinetics of the micells of PEG-PCCL/PTX and its anti-tumor effect. The results showed that the size of PEG-PCCL nanospheres was 97 ± 2.6 nm. PEG-PCCL treatment showed little cytotoxicity and good biocompatibility, and did not exhibit organ toxicity. PTX-loading efficiency was 49.98%. The pharmacokinetic study on H22 tumor-bearing mice revealed that PEG-PCCL/PTX has higher stability and slower release than PTX alone. Together, these results suggest that PEG-PCCL nanosphere has little toxicity to organisms and is a potential candidate of biocompatible drug vehicle for hydrophobic drugs.

Abstract Dirhenium halide dianions received considerable attention in past decades due to the unusual metal–metal quadruple bond. The systematic structural evolution of dirhenium halide clusters has not been sufficiently studied and hence is not well-understood. In this work, we report an in-depth investigation on the structures and electronic properties of doubly charged dirhenium halide clusters Re2X8 2− (X = F, Cl, Br, I). Our computational efforts rely on the well-tested unbiased CALYPSO (Crystal structure AnaLYsis by Particle Swarm Optimization) method combined with density functional theory calculations. We find that all ground-state Re2X8 2− clusters have cube-like structures of D 4h symmetry with two Re atoms encapsulated in halogen framework. The reasonable agreement between the simulated and experimental photoelectron spectrum of the Re2Cl8 2− cluster supports strongly the reliability of our computational strategy. The chemical bonding analysis reveals that the δ bond is the pivotal factor for the ground-state Re2X8 2− (X = F, Cl, Br, I) clusters to maintain D 4h symmetric cube-like structures, and the enhanced stability of Re2Cl8 2− is mainly attributed to the chemical bonding of 5d orbital of Re atoms and 3p orbital of Cl atoms.

Abstract Background The principle aim of this study is to incorporate 4DCT ventilation imaging into functional treatment planning that preserves high-functioning lung with both double scattering and scanning beam techniques in proton therapy. Methods Eight patients with locally advanced non-small-cell lung cancer were included in this study. Deformable image registration was performed for each patient on their planning 4DCTs and the resultant displacement vector field with Jacobian analysis was used to identify the high-, medium- and low-functional lung regions. Five plans were designed for each patient: a regular photon IMRT vs. anatomic proton plans without consideration of functional ventilation information using double scattering proton therapy (DSPT) and intensity modulated proton therapy (IMPT) vs. functional proton plans with avoidance of high-functional lung using both DSPT and IMPT. Dosimetric parameters were compared in terms of tumor coverage, plan heterogeneity, and avoidance of normal tissues. Results Our results showed that both DSPT and IMPT plans gave superior dose advantage to photon IMRTs in sparing low dose regions of the total lung in terms of V5 (volume receiving 5Gy). The functional DSPT only showed marginal benefit in sparing high-functioning lung in terms of V5 or V20 (volume receiving 20Gy) compared to anatomical plans. Yet, the functional planning in IMPT delivery, can further reduce the low dose in high-functioning lung without degrading the PTV dosimetric coverages, compared to anatomical proton planning. Although the doses to some critical organs might increase during functional planning, the necessary constraints were all met. Conclusions Incorporating 4DCT ventilation imaging into functional proton therapy is feasible. The functional proton plans, in intensity modulated proton delivery, are effective to further preserve high-functioning lung regions without degrading the PTV coverage.

Abstract Background Chylopericardium effusion is characterized by the accumulation of milky effusion in the pericardium. It is often idiopathic but it can be secondary to trauma, chest radiation, tuberculosis and malignancy. If cardiac tamponade ensues, it becomes life-threatening. Herein we describe chylopericardium tamponade in a child with IgA nephropathy. To the best of our knowledge, this is the first reported case of chylopericardium tamponade in IgA nephropathy. Case presentation A 6 years old boy with IgA nephropathy presented with dyspnea, orthopnea, pretibial pitting edema, ascites and fever. Muffled heart sounds and hepatomegaly were also noted. Echocardiography and thoracic CT revealed that there was a large volume of hydropericardium. Moreover, the pericardial milky fluid by pericardiocentesis was analyzed and chylopericardium effusion was eventually confirmed. Pericardial drainage was continued and his diet was modified to low fat, rich MCT and high protein. Complete remission was achieved after 3 weeks of this combined treatment. Conclusion Chylopericardial tamponade could be a rare and life-threatening complication of IgA nephropathy. Etiological analysis is critical for determining the therapeutic approach in patients with pericardial effusion.

In this paper, we study the reliability of a novel deep learning framework for internal gross target volume (IGTV) delineation from 4-D computed tomography (4DCT), which is applied to patients with lung cancer treated by stereotactic body radiation therapy (SBRT). Seventy seven patients who underwent SBRT followed by 4DCT scans were incorporated in this retrospective study. The IGTV_DL was delineated using a novel deep machine learning algorithm with a linear exhaustive optimal combination framework. For the purpose of comparison, three other IGTVs based on common methods was also delineated. We compared the relative volume difference (RVI), matching index (MI), and encompassment index (EI) for the above IGTVs. Then, multiple parameter regression analysis was performed to assess the tumor volume and motion range as clinical influencing factors in the MI variation. The results demonstrated that the deep learning algorithm with linear exhaustive optimal combination framework has a higher probability of achieving optimal MI compared with other currently widely used methods. For patients after simple breathing training by keeping the respiratory frequency in 10 breath per minute (BPM), the four phase combinations of 0%, 30%, 50% and 90% can be considered as a potential solution for an optimal combination to synthesize IGTV in all respiration amplitudes.

Astragaloside IV is the main active compound of Astragalus membranaceus. Astragaloside IV has strong anti-oxidative activities and protective effects against progression of peripheral neuropathy. In this study, we determined whether astragaloside IV protects retinal ganglion cells (RGC) from oxidative stress injury using the rat RGC-5 cell line. Hydrogen peroxide (H2O2) was used to induce oxidative stress injury, with the protective effect of astragaloside IV examined. Cell Counting Kit-8 and 4′,6-diamidino-2-phenylindole staining showed that astragaloside IV increased cell survival rate and decreased apoptotic cell number. Flow cytometry showed that astragaloside IV decreased H2O2-induced reactive oxygen species levels. While laser confocal microscopy showed that astragaloside IV inhibited the H2O2-induced decrease of mitochondrial membrane potential. Western blot assay showed that astragaloside IV reduced cytochrome c release induced by H2O2, inhibited Bax and caspase-3 expression, and increased Bcl-2 expression. Altogether, these results indicate that astragaloside IV has potential protective effects against H2O2-induced oxidative stress in retinal ganglion cells.