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1.
Nat Commun ; 12(1): 5881, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620857

RESUMO

Hydroalkylation, the direct addition of a C(sp3)-H bond across an olefin, is a desirable strategy to produce valuable, complex structural motifs in functional materials, pharmaceuticals, and natural products. Herein, we report a reliable method for accessing α-branched amines via nickel-catalyzed hydroalkylation reactions. Specifically, by using bis(cyclooctadiene)nickel (Ni(cod)2) together with a phosphine ligand, we achieved a formal C(sp3)-H bond insertion reaction between olefins and N-sulfonyl amines without the need for an external hydride source. The amine not only provides the alkyl motif but also delivers hydride to the olefin by means of a nickel-engaged ß-hydride elimination/reductive elimination process. This method provides a platform for constructing chiral α-branched amines by using a P-chiral ligand, demonstrating its potential utility in organic synthesis. Notably, a sulfonamidyl boronate complex formed in situ under basic conditions promotes ring-opening of the azanickellacycle reaction intermediate, leading to a significant improvement of the catalytic efficiency.

2.
Theranostics ; 11(19): 9415-9430, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646378

RESUMO

The feasibility of personalized medicine for cancer treatment is largely hampered by costly, labor-intensive and time-consuming models for drug discovery. Herein, establishing new pre-clinical models to tackle these issues for personalized medicine is urgently demanded. Methods: We established a three-dimensional tumor slice culture (3D-TSC) platform incorporating label-free techniques for time-course experiments to predict anti-cancer drug efficacy and validated the 3D-TSC model by multiphoton fluorescence microscopy, RNA sequence analysis, histochemical and histological analysis. Results: Using time-lapse imaging of the apoptotic reporter sensor C3 (C3), we performed cell-based high-throughput drug screening and shortlisted high-efficacy drugs to screen murine and human 3D-TSCs, which validate effective candidates within 7 days of surgery. Histological and RNA sequence analyses demonstrated that 3D-TSCs accurately preserved immune components of the original tumor, which enables the successful achievement of immune checkpoint blockade assays with antibodies against PD-1 and/or PD-L1. Label-free multiphoton fluorescence imaging revealed that 3D-TSCs exhibit lipofuscin autofluorescence features in the time-course monitoring of drug response and efficacy. Conclusion: This technology accelerates precision anti-cancer therapy by providing a cheap, fast, and easy platform for anti-cancer drug discovery.

3.
Int J Biol Macromol ; 191: 230-242, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34536474

RESUMO

G-quadruplexes have become attractive drug targets in cancer therapy. However, due to the polymorphism of G-quadruplex structures, it is difficult to experimentally verify the relevant structures of multiple intermediates and transition states in dynamic equilibrium. Hence, understanding the mechanism by which structural conversions of G-quadruplexes occur is still challenging. We conducted targeted molecular dynamics simulation with umbrella sampling to investigate how salt affects the conformational conversion of human telomeric G-quadruplex. Our results explore a unique view into the structures and energy barrier of the intermediates and transition states in the interconversion process. The pathway of G-quadruplex conformational interconversion was mapped out by a free energy landscape, consisting of branched parallel pathways with multiple energy basins. We propose a salt-controlled mechanism that as the salt concentration increases, the conformational conversion mechanism switches from multi-pathway folding to sequential folding pathways. The hybrid-I and hybrid-II structures are intermediates in the basket-propeller transformation. In high-salt solutions, the conformational conversion upon K+ binding is more feasible than upon Na+ binding. The free energy barrier for conformational conversions ranges from 1.6 to 4.6 kcal/mol. Our work will be beneficial in developing anticancer agents.

4.
J Formos Med Assoc ; 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34454794

RESUMO

BACKGROUND: Recurrent pneumonia is uncommon in children and few studies investigate the clinical impact of underlying diseases on this issue. This study aimed to explore the difference in clinical manifestations, pathogens, and prognosis of recurrent pneumonia in children with or without underlying diseases. METHODS: We conducted a retrospective study of pediatric recurrent pneumonia from 2007 to 2019 in National Taiwan University Hospital. Patients under the age of 18 who had two or more episodes of pneumonia in a year were included, and the minimum interval of two pneumonia episodes was more than one month. Aspiration pneumonia was excluded. Demographic and clinical characteristics of patients were collected and compared. RESULTS: Among 8508 children with pneumonia, 802 (9.4%) of them had recurrent pneumonia. Among these 802 patients, 655 (81.7%) had underlying diseases including neurological disorders (N = 252, 38.5%), allergy (N = 211, 32.2%), and cardiovascular diseases (N = 193, 29.5%). Children without underlying diseases had more viral bronchopneumonia (p < 0.001). Children with underlying diseases were more likely to acquire Staphylococcus aureus (p = 0.001), and gram-negative bacteriae, more pneumonia episodes (3 vs 2, p < 0.001), a longer hospital stay (median: 7 vs. 4 days, p < 0.001), a higher ICU rate (28.8% vs 3.59%, p < 0.001), and a higher case-fatality rate (5.19% vs 0%, p < 0.001) than those without underlying diseases. CONCLUSION: Children with underlying diseases, prone to have recurrent pneumonia and more susceptible to resistant microorganisms, had more severe diseases and poorer clinical outcomes. Therefore, more attention may be paid on clinical severity and the therapeutic plan.

5.
Transl Vis Sci Technol ; 10(9): 18, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34403475

RESUMO

Purpose: Fundus images are typically used as the sole training input for automated diabetic retinopathy (DR) classification. In this study, we considered several well-known DR risk factors and attempted to improve the accuracy of DR screening. Metphods: Fusing nonimage data (e.g., age, gender, smoking status, International Classification of Disease code, and laboratory tests) with data from fundus images can enable an end-to-end deep learning architecture for DR screening. We propose a neural network that simultaneously trains heterogeneous data and increases the performance of DR classification in terms of sensitivity and specificity. In the current retrospective study, 13,410 fundus images and their corresponding nonimage data were collected from the Chung Shan Medical University Hospital in Taiwan. The images were classified as either nonreferable or referable for DR by a panel of ophthalmologists. Cross-validation was used for the training models and to evaluate the classification performance. Results: The proposed fusion model achieved 97.96% area under the curve with 96.84% sensitivity and 89.44% specificity for determining referable DR from multimodal data, and significantly outperformed the models that used image or nonimage information separately. Conclusions: The fusion model with heterogeneous data has the potential to improve referable DR screening performance for earlier referral decisions. Translational Relevance: Artificial intelligence fused with heterogeneous data from electronic health records could provide earlier referral decisions from DR screening.


Assuntos
Aprendizado Profundo , Diabetes Mellitus , Retinopatia Diabética , Inteligência Artificial , Retinopatia Diabética/diagnóstico , Humanos , Encaminhamento e Consulta , Estudos Retrospectivos
6.
J Formos Med Assoc ; 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34446339

RESUMO

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of childhood pneumonia, but there is limited understanding of whether bacterial co-infections affect clinical severity. METHODS: We conducted a retrospective cohort study at National Taiwan University Hospital from 2010 to 2019 to compare clinical characteristics and outcomes between RSV with and without bacterial co-infection in children without underlying diseases, including length of hospital stay, intensive care unit (ICU) admission, ventilator use, and death. RESULTS: Among 620 inpatients with RSV pneumonia, the median age was 1.33 months (interquartile range, 0.67-2 years); 239 (38.6%) under 1 year old; 366 (59.0%) males; 201 (32.4%) co-infected with bacteria. The three most common bacteria are Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae. The annually seasonal analysis showed that spring and autumn were peak seasons, and September was the peak month. Compared with single RSV infection, children with bacterial co-infection were younger (p = 0.021), had longer hospital stay (p < 0.001), needed more ICU care (p = 0.02), had higher levels of C-reactive protein (p = 0.009) and more frequent hyponatremia (p = 0.013). Overall, younger age, bacterial co-infection (especially S. aureus), thrombocytosis, and lower hemoglobin level were associated with the risk of requiring ICU care. CONCLUSION: RSV related bacterial co-infections were not uncommon and assoicated with ICU admission, especially for young children, and more attention should be given. For empirical antibacterial treatment, high-dose amoxicillin-clavulanic acid or ampicillin-sulbactam was recommended for non-severe cases; vancomycin and third-generation cephalosporins were suggested for critically ill patients requiring ICU care.

7.
J Formos Med Assoc ; 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34332830

RESUMO

BACKGROUND/PURPOSE: Influenza is frequently complicated with bacterial co-infection. This study aimed to disclose the significance of Streptococcus pneumoniae co-infection in children with influenza. METHODS: We retrospectively reviewed medical records of pediatric patients hospitalized for influenza with or without pneumococcal co-infection at the National Taiwan University Hospital from 2007 to 2019. Clinical characteristics and outcomes were compared between patients with and without S. pneumoniae co-infection. RESULTS: There were 558 children hospitalized for influenza: 494 had influenza alone whereas 64 had S. pneumoniae co-infection. Patients with S. pneumoniae co-infection had older ages, lower SpO2, higher C-Reactive Protein (CRP), lower serum sodium, lower platelet counts, more chest radiograph findings of patch and consolidation on admission, longer hospitalization, more intensive care, longer intensive care unit (ICU) stay, more mechanical ventilation, more inotropes/vasopressors use, more surgical interventions including video-assisted thoracoscopic surgery (VATS) and extracorporeal membrane oxygenation (ECMO), and higher case-fatality rate. CONCLUSION: Compared to influenza alone, patients with S. pneumoniae co-infection had more morbidities and mortalities. Pneumococcal co-infection is considered when influenza patients have lower SpO2, lower platelet counts, higher CRP, lower serum sodium, and more radiographic patches and consolidations on admission.

8.
Biomed Opt Express ; 12(5): 2888-2901, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34168906

RESUMO

We have demonstrated widely tunable Yb:fiber-based laser sources, aiming to replace Ti:sapphire lasers for the nJ-level ultrafast applications, especially for the uses of nonlinear light microscopy. We investigated the influence of different input parameters to obtain an expansive spectral broadening, enabled by self-phase modulation and further reshaped by self-steepening, in the normal dispersion regime before the fiber damage. We also discussed the compressibility and intensity fluctuations of the demonstrated pulses, to reach the transform-limited duration with a very low intensity noise. Most importantly, we have demonstrated clear two-photon fluorescence images from UV-absorbing fluorophores to deep red dye stains.

9.
Brain Pathol ; 31(6): e12968, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33960564

RESUMO

Intrauterine growth restriction (IUGR) is a leading cause of perinatal mortality and morbidity, and IUGR survivors are at increased risk of neurodevelopmental deficits. No effective interventions are currently available to improve the structure and function of the IUGR brain before birth. This study investigated the protective effects of low-intensity pulsed ultrasound (LIPUS) on postnatal neurodevelopmental outcomes and brain injury using a rat model of IUGR induced by maternal exposure to dexamethasone (DEX). Pregnant rats were treated with DEX (200 µg/kg, s.c.) and LIPUS daily from gestational day (GD) 14 to 19. Behavioral assessments were performed on the IUGR offspring to examine neurological function. Neuropathology, levels of neurotrophic factors, and CaMKII-Akt-related molecules were assessed in the IUGR brain, and expression of glucose and amino acid transporters and neurotrophic factors were examined in the placenta. Maternal LIPUS treatment increased fetal weight, fetal liver weight, and placental weight following IUGR. LIPUS treatment also increased neuronal number and myelin protein expression in the IUGR brain, and attenuated neurodevelopmental deficits at postnatal day (PND) 18. However, the number of oligodendrocytes or microglia was not affected. These changes were associated with the upregulation of brain-derived neurotrophic factor (BDNF) and placental growth factor (PlGF) protein expression, and enhancement of neuronal CaMKII and Akt activation in the IUGR brain at PND 1. Additionally, LIPUS treatment promoted glucose transporter (GLUT) 1 production and BDNF expression in the placenta, but had no effects on GLUT3 or amino acid transporter expression. Our findings suggest that antenatal LIPUS treatment may reduce IUGR-induced brain injury via enhancing cerebral BDNF/CaMKII/Akt signaling. These data provide new evidence that LIPUS stimulation could be considered for antenatal neuroprotective therapy in IUGR.

10.
J Am Chem Soc ; 143(11): 4154-4161, 2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33691068

RESUMO

Chiral α-branched amines are common structural motifs in functional materials, pharmaceuticals, and chiral catalysts. Therefore, developing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in synthetic chemistry. Herein, we describe an atom-economical, modular method for a nickel-catalyzed enantioselective α-alkenylation of readily available linear N-sulfonyl amines with alkynes to afford a wide variety of allylic amines without the need for exogenous oxidants, reductants, or activating reagents. The method provides a platform for constructing chiral α-branched amines as well as derivatives such as α-amino amides and ß-amino alcohols, which can be conveniently accessed from the newly introduced alkene. Given the generality, versatility, and high atom economy of this method, we anticipate that it will have broad synthetic utility.

11.
ACS Appl Bio Mater ; 4(3): 2523-2533, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35014370

RESUMO

The beneficial effects of Sr- and Mg-doped hydroxyapatite (HAp) on osteoblast proliferation and bone regeneration have been investigated in the past, and the antibacterial ability of Zn ions is well known. However, HAp coatings doped with these three elements via thermal spraying have not yet been investigated. In this study, HAp powder was synthesized at different pH values (4, 6, 8, and 10) and calcined at different temperatures (200, 400, 600, 800, and 1000 °C) to obtain HAp with the highest purity. Subsequently, strontium-, magnesium-, and zinc-doped HAp powders were synthesized at the optimal pH value and calcination temperature. The HAp powder was then coated onto Ti disks using atmospheric plasma spraying (APS) or vapor-induced pore-forming atmospheric plasma spraying (VIPF-APS) techniques at different working currents (350, 400, and 450 A) and spraying distances (10 and 15 cm). X-ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy equipped with energy-dispersive spectroscopy were used for material characterization to determine the optimal parameters. With these optimal coating parameters, HAp, Zn-HAp, SrMg-HAp, and ZnSrMg-HAp powders were deposited onto the Ti disks using VIPF-APS and named HAp-Ti, Zn-HAp-Ti, SrMg-HAp-Ti, and ZnSrMg-HAp-Ti, respectively. The in vitro bioactivity of these four groups was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and alkaline phosphatase (ALPase) activity assay. Besides, the antibacterial activities against Prevotella nigrescens, Porphyromonas gingivalis, and Fusobacterium nucleatum were assessed. The results showed that the purity of HAp synthesized at pH 10 and 800 °C was 98.40%. A porous coating without cracks was obtained at a 10 cm spraying distance and 400 A working current using VIPF-APS. SrMg-HAp-Ti and ZnSrMg-HAp-Ti resulted in higher osteoblast proliferation and ALPase activity than the control. Moreover, both Zn-HAp-Ti and ZnSrMg-HAp-Ti exhibited antibacterial activity against the three bacteria. Therefore, ZnSrMg-HAp has potential as a coating for biomedical materials due to its ability to reduce bacterial infection and enhance osseointegration.

12.
Comput Biol Med ; 122: 103798, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32658724

RESUMO

INTRODUCTION: MRI T2* relaxometry protocols are often used for Liver Iron Quantification in patients with hemochromatosis. Several methods exist to semi-automatically segment parenchyma and exclude vessels for this calculation. PURPOSE: To determine if inclusion of multiple echoes inputs to Convolutional Neural Networks (CNN) improves automated liver and vessel segmentation in MRI T2* relaxometry protocols and to determine if the resultant segmentations agree with manual segmentations for liver iron quantification analysis. METHODS: Multi echo Gradient Recalled Echo (GRE) MRI sequence for T2* relaxometry was performed for 79 exams on 31 patients with hemochromatosis for iron quantification analysis. 275 axial liver slices were manually segmented as ground truth masks. A batch normalized U-Net with variable input width to incorporate multiple echoes is used for segmentation, using DICE as the accuracy metric. ANOVA is used to evaluate significance of channel width changes in segmentation accuracy. Linear regression is used to model the relationship of channel width on segmentation accuracy. Liver segmentations are applied to relaxometry data to calculate liver T2* yielding liver iron concentration(LIC) derived from literature based calibration curves. Manual and CNN based LIC values are compared with Pearson correlation. Bland altman plots are used to visualize differences between manual and CNN based LIC values. RESULTS: Performance metrics are tested on 55 hold out slices. Linear regression indicates that there is a monotonic increase of DICE with increasing channel depth (p = 0.001) with a slope of 3.61e-3. ANOVA indicates a significant increase segmentation accuracy over single channel starting at 3 channels. Incorporation of all channels results in an average DICE of 0.86, an average increase of 0.07 over single channel. The calculated LIC from CNN segmented livers agrees well with manual segmentation (R = 0.998, slope = 0.914, p«0.001), with an average absolute difference 0.27 ± 0.99 mg Fe/g or 1.34 ± 4.3%. CONCLUSION: More input echoes yields higher model accuracy until the noise floor. Echos beyond the first three echo times in GRE based T2* relaxometry do not contribute significant information for segmentation of liver for LIC calculation. Deep learning models with three channel width allow for generalization of model to protocols of more than three echoes, effectively a universal requirement for relaxometry. Deep learning segmentations achieve a good accuracy compared with manual segmentations with minimal preprocessing. Liver iron values calculated from hand segmented liver and Neural network segmented liver were not statistically different from each other.


Assuntos
Ferro , Redes Neurais de Computação , Calibragem , Humanos , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética
13.
Sci Rep ; 10(1): 9157, 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32514011

RESUMO

The high cost and platinum dissolution issues of counter electrodes (CEs) are two core problems for the development of dye-sensitized solar cells (DSSCs). In this work, different CEs based on binary alloy Ru81.09Co18.91, Ru80.55Se19.45 and Co20.85Se79.15 nanostructures for DSSCs were successfully synthesized and investigated by a facile and environmentally friendly approach. Here, we found that the Co20.85Se79.15 alloy CE-based device yields the higher photoelectric conversion efficiency of 7.08% compared with that (5.80%) of the DSSC using a pure Pt CE because of the larger number of active sites with improved charge transferability and reduced interface resistance by matching work function with the I3‒/I‒ redox electrolyte. The inexpensive synthesis method, cost-effectiveness and superior catalytic activity of the Co20.85Se79.15 alloy may open up a new avenue for the development of CEs for DSSCs in the near future.

14.
Cogn Neurodyn ; 14(3): 291-300, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32399072

RESUMO

This study examined brain activation in graphic designers responding to pictorial stimulation during exploration tasks and determined the predictive effects of design exploration on designer creativity through a deep learning approach. The top and bottom 25% (10 each participants) were assigned high-creativity and low-creativity groups, respectively. The results provided the following indications. (i) Shallow architectures had higher prediction accuracy than deeper architectures. (ii) The prediction accuracy of shallow long short-term memory networks was higher than that of convolution neural networks. (iii) Bandpower exhibited increased prediction accuracy, and shallow LSTM networks with differing power spectra among independent components outperformed other deep learning methods. (iv) Direct acyclic graph networks did not improve prediction accuracy. (v) Design exploration could effectively predict designer creativity.

15.
Microb Biotechnol ; 13(4): 1094-1102, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32233071

RESUMO

Transforming petrochemical processes into bioprocesses has become an important goal of sustainable development. The chemical synthesis of 2,5-furandicarboxylic acid (FDCA) from 5-hydroxymethylfurfural (HMF) is expensive and environmentally unfavourable. The study aims to investigate a whole-cell biocatalyst for efficient biotransformation of HMF to FDCA. For the first time, a genetically engineered Pseudomonas putida S12 strain expressing 5-hydroxymethylfurfural oxidase (HMFO) was developed for the biocatalytic conversion of HMF to FDCA. This whole-cell biocatalyst produced 35.7 mM FDCA from 50 mM HMF in 24 h without notable inhibition. However, when the initial HMF concentration was elevated to 100 mM, remarkable inhibition on FDCA production was observed, resulting in a reduction of FDCA yield to 42%. We solve this substrate inhibition difficulty by increasing the inoculum density. Subsequently, we used a fed-batch strategy by maintaining low HMF concentration in the culture to maximize the final FDCA titre. Using this approach, 545 mM of FDCA was accumulatively produced after 72 hs, which is the highest production rate per unit mass of cells to the best of our knowledge.


Assuntos
Pseudomonas putida , Furaldeído/análogos & derivados , Furanos , Oxirredutases , Pseudomonas putida/genética
16.
Br J Cancer ; 122(6): 918-924, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31929517

RESUMO

BACKGROUND: For female adolescent and young adult (AYA), cancer with treatments may affect their children's health. Our aim was to determine reliable risk estimates of adverse birth outcomes in AYA cancer survivors and the differential effects of treatments. METHODS: The study population of 4547 births in the AYA cancer survivor group and 45,463 in the comparison group were identified from two national databases between 2004 and 2014. Detailed maternal health conditions, such as maternal comorbidities, medication use during pregnancy and lifestyles, were adjusted in the statistical analyses. The outcomes included low birth weight, preterm labour, stillbirth, small or large for gestational age, a 5-min Apgar score <7, congenital malformation and foetal distress. RESULTS: The AYA cancer survivor group had a 9% higher risk of overall adverse birth outcomes (adjusted odds ratio, 1.09; 95% confidence interval, 1.02-1.16), especially low birth weight and preterm labour than the comparison group. The radiotherapy-only group additionally had a higher risk of foetal distress, and a 5-min Apgar score <7. CONCLUSION: AYA cancer survivors, especially those who have received radiotherapy, still have higher risks of adverse birth outcomes after adjusting for detailed maternal health conditions. Preconception counselling and additional surveillance may be warranted in this population.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Resultado da Gravidez/genética , Adolescente , Adulto , Feminino , Humanos , Gravidez , Adulto Jovem
17.
Neuroreport ; 31(2): 118-124, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31895744

RESUMO

Isoflurane protects the blood-brain barrier (BBB) against cerebral extravasation of Evans blue dye (EBD), a commonly used serum protein tracer, in animals subjected to BBB disruption. As such, it has been implicated as a therapeutic agent that can prevent brain edema and damage caused by a number of brain insults, including focal ischemia and subarachnoid hemorrhage. Recently, it has been shown that isoflurane inhibits the cerebral extravasation of EBD following ischemic stroke chiefly by inducing hypothermia, raising the intriguing possibility that isoflurane protected against other causes of BBB disruption also through hypothermia. To test this hypothesis, we subjected mice and rats to inhalation of 20-30% carbogen, an inducer of BBB disruption, in the presence or absence of isoflurane while measuring their rectal temperature. In mice, carbogen inhalation on its own decreased rectal temperature from 36.4 ± 0.4 to 26.2 ± 0.6°C over a period of 60 minutes, and under this condition, isoflurane had no additional effect on body temperature. Nevertheless, isoflurane protected against carbogen-induced cerebral extravasation of EBD. In addition, when the body temperature was maintained in the normothermic range using an automated heating pad, isoflurane remained protective against cerebral extravasation of EBD. In rats, isoflurane also protected against cerebral extravasation of EBD, while having no effect on plasma pH, electrolyte concentrations, or osmolarity. In conclusion, isoflurane protected against BBB disruption caused by carbogen inhalation in mice and rats, but unlike isoflurane-mediated protection against ischemic BBB disruption, the effect could not be explained by anesthesia-induced hypothermia.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Edema Encefálico/tratamento farmacológico , Isoflurano/farmacologia , Animais , Barreira Hematoencefálica/metabolismo , Temperatura Corporal/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Edema Encefálico/induzido quimicamente , Edema Encefálico/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Dióxido de Carbono/farmacologia , Hipotermia Induzida/métodos , Masculino , Camundongos Endogâmicos C57BL , Oxigênio/farmacologia , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/metabolismo
18.
Front Oncol ; 9: 1138, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781483

RESUMO

Esophageal squamous cell carcinoma (ESCC) is a deadly disease for which no effective targeted therapeutic agent has been approved. Both AXL and c-MET have been reported to be independent prognostic factors for ESCC. Thus, inhibitors of AXL/c-MET might have great potential as targeted therapy for ESCC. In the current study, we evaluated the therapeutic potential of the AXL/c-MET selective inhibitors, R428 and cabozantinib, in cell and mouse xenograft models. We demonstrated that both R428 and cabozantinib significantly inhibited the growth of CE81T and KYSE-70 ESCC cells and showed by wound-healing assay that they both inhibited ESCC cell migration. In the animal model, ESCC xenograft models were established by injecting KYSE-70 cells with Matrigel into the upper back region of NOD-SCID male mice followed by treatment with vehicle control, R428 (50 mg/kg/day), cisplatin (1.0 mg/kg), or cabozantinib (30 mg/kg/day) for the indicated number of days. R428 alone significantly inhibited ESCC tumor growth compared to the vehicle; however, no synergistic effect with cisplatin was observed. Notably, the dramatic efficacy of cabozantinib alone was observed in the mouse xenograft model. Collectively, our study demonstrated that both cabozantinib and R428 inhibit ESCC growth in cell and xenograft models. The results reveal the great potential of using cabozantinib for targeted therapy of ESCC.

19.
BMC Surg ; 19(1): 88, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291917

RESUMO

BACKGROUND: No data are available to assess the learning curve for transvaginal natural orifice transluminal endoscopic hysterectomy for non-prolapsed uteri in benign gynecologic diseases. The lack of exposure to transvaginal natural orifice transluminal endoscopic hysterectomy during training, in addition to a poorly defined learning curve, further deters interested physicians from applying this technique to daily practice. The aim of this study was to evaluate the learning curve and perioperative outcome of transvaginal natural orifice transluminal endoscopic hysterectomy by an experienced endoscopist. METHODS: A total of 240 cases of transvaginal natural orifice transluminal endoscopic hysterectomies with or without adnexectomy for various benign gynecologic diseases were included. Demographic data and various perioperative parameters were reviewed from the prospectively collected database. Operative time was set as a surrogate marker for surgical competency. The learning curve was evaluated using the cumulative sum method. RESULTS: The overall mean operative time (OT) was 76.5 min ± 22.4. Four unique phases of the learning curve were derived using cumulative sum analysis: the mean OT of phase I (the initial learning curve of 20 cases) was 86.3 ± 23.7 min, phase II (acquisition of competence of 80 cases) was 71.0 ± 21.4 min, phase III (proficiency and plateau of 80 cases) was 76.0 ± 20.4 min, and phase IV (post-learning in which more challenging cases were managed) was 81.3 ± 23.6 min. No major complications were encountered. One case in phase III converted to laparoscopy due to difficulty in performing anterior colpotomy. CONCLUSION: Our data demonstrated four distinct phases of the learning curve of transvaginal natural orifice transluminal endoscopic hysterectomy. In a well-trained endoscopist, surgical competence in transvaginal natural orifice transluminal endoscopic hysterectomy can be reached after 20 cases.


Assuntos
Competência Clínica , Doenças dos Genitais Femininos/cirurgia , Histerectomia/métodos , Curva de Aprendizado , Cirurgia Endoscópica por Orifício Natural , Adulto , Idoso , Feminino , Humanos , Histerectomia/educação , Laparoscopia/métodos , Pessoa de Meia-Idade , Cirurgia Endoscópica por Orifício Natural/educação , Duração da Cirurgia , Estudos Retrospectivos
20.
J Phys Chem B ; 123(32): 6917-6932, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31282162

RESUMO

Hydration water serves as a microscopic manifestation of structural stability and functions of biomolecules. To develop bio-nanomaterials in applications, it is important to study how the surface topography and heterogeneity of biomolecules result in their diversity of the hydration dynamics and energetics. We here performed molecular dynamics simulations combined with the steered molecular dynamics and umbrella sampling to investigate the dynamics and escape process associated with the free energy change of water molecules close to a globular biomolecule, i.e., hemoglobin (Hb) and G-quadruplex DNA (GDNA). The residence time, power of long-time tail, and dipole relaxation time were found to display drastic changes within the averaged hydration shell of 3.0-5.0 Å. Compared with bulk water, in the inner hydration shell, the water dipole moment displays a slower relaxation process and is more oriented toward GDNA than toward Hb, forming a hedgehog-like structure when it surrounds GDNA. In particular, a spine water structure is observed in the GDNA narrow groove. The water isotope effect not only prolongs the dynamic time scales of libration motion in the inner hydration shell and the dipole relaxation processes in the bulk but also strengthens the DNA spine water structure. The potential of the mean force profile reflects the integrity of the hydration shell structure and enables us to obtain detailed insights into the structures formed by water, such as the caged H-bond network and the edge bridge structures; it also reveals that local hydration shell free energy (LHSFE) depends on H-bond rupture processes and ranges from 0.2 to 4.2 kcal/mol. Our results demonstrate that the surface topography of a biomolecule influences the integrity of the hydration shell structure and LHSFE. Our studies are able to identify various further applications in the areas of microfluid devices and nano-dewetting on bioinspired surfaces.


Assuntos
Quadruplex G , Hemoglobinas/química , Água/química , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , Conformação Proteica
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