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1.
Diabetes Care ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139380

RESUMO

OBJECTIVE: No study has reported global disability burden estimates for individual diabetes-related lower-extremity complications (DRLECs). The Global Burden of Disease (GBD) study presents a robust opportunity to address this gap. RESEARCH DESIGN AND METHODS: GBD 2016 data, including prevalence and years lived with disability (YLDs), for the DRLECs of diabetic neuropathy, foot ulcer, and amputation with and without prosthesis were used. The GBD estimated prevalence using data from systematic reviews and DisMod-MR 2.1, a Bayesian meta-regression tool. YLDs were estimated as the product of prevalence estimates and disability weights for each DRLEC. We reported global and sex-, age-, region-, and country-specific estimates for each DRLEC for 1990 and 2016. RESULTS: In 2016, an estimated 131 million (1.8% of the global population) had DRLECs. An estimated 16.8 million YLDs (2.1% global YLDs) were caused by DRLECs, including 12.9 million (95% uncertainty interval 8.30-18.8) from neuropathy only, 2.5 million (1.7-3.6) from foot ulcers, 1.1 million (0.7-1.4) from amputation without prosthesis, and 0.4 million (0.3-0.5) from amputation with prosthesis. Age-standardized YLD rates of all DRLECs increased by between 14.6% and 31.0% from 1990 estimates. Male-to-female YLD ratios ranged from 0.96 for neuropathy only to 1.93 for foot ulcers. The 50-69-year age-group accounted for 47.8% of all YLDs from DRLECs. CONCLUSIONS: These first-ever global estimates suggest that DRLECs are a large and growing contributor to the disability burden worldwide and disproportionately affect males and middle- to older-aged populations. These findings should facilitate policymakers worldwide to target strategies at populations disproportionately affected by DRLECs.

2.
Nanoscale ; 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32191787

RESUMO

Developing novel small-molecule-based probes with both deep tissue imaging and therapeutic functions is highly significant in cancer diagnosis and treatment. Herein, we report a novel second near-infrared (NIR-II) fluorescent probe QT-RGD constructed with a NIR-II emissive organic fluorophore and two cyclic-(arginine-glycine-aspartic acid) (cRGD) peptides that can specifically bind to the tumor-associated αvß3 integrin for accurate tumor diagnosis and targeting therapy. The isotopic 125I-labeled probe exhibited great tumor targeting ability and emitted intensive NIR-II/photoacoustic (PA)/single-photon emission computed tomography (SPECT) signals, which allows specific and sensitive multimodal visualization of tumors in vivo. More notably, this probe could also be applied for effective imaging-guided photothermal therapy (PTT) of tumors in mouse models owing to its prominent photothermal conversion efficiency and excellent photothermal stability. We thus envision that our work which unveils a combination of NIR-II/PA/SPECT imaging and PTT would offer a valuable means of improving tumor diagnostic accuracy as well as therapeutic efficacy.

3.
J Thromb Haemost ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32017367

RESUMO

BACKGROUND: Activated protein C (APC) is an important homeostatic blood coagulation protease that conveys anticoagulant and cytoprotective activities. Proteolytic inactivation of factors Va and VIIIa facilitated by cofactor protein S is responsible for APC's anticoagulant effects, whereas cytoprotective effects of APC involve primarily the endothelial protein C receptor (EPCR), protease activated receptor (PAR)1 and PAR3. OBJECTIVE: To date, several binding exosites in the protease domain of APC have been identified that contribute to APC's interaction with its substrates but potential contributions of the C-terminus of the light chain have not been studied in detail. METHODS: Site-directed Ala-scanning mutagenesis of six positively charged residues within G142-L155 was used to characterize their contributions to APC's anticoagulant and cytoprotective activities. RESULTS AND CONCLUSIONS: K151 was involved in protein S dependent-anticoagulant activity of APC with some contribution of K150. 3D structural analysis supported that these two residues were exposed in an extended protein S binding site on one face of APC. Both K150 and K151 were important for PAR1 and PAR3 cleavage by APC, suggesting that this region may also mediate interactions with PARs. Accordingly, APC's cytoprotective activity as determined by endothelial barrier protection was impaired by Ala substitutions of these residues. Thus, both K150 and K151 are involved in APC's anticoagulant and cytoprotective activities. The differential contribution of K150 relative to K151 for protein S-dependent anticoagulant activity and PAR cleavage highlights that binding exosites for protein S binding and for PAR cleavage in the C-terminal region of APC's light chain overlap.

4.
Biosci Rep ; 40(2)2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32016349

RESUMO

The present study investigated the role of abnormally expressed mRNA and long noncoding RNA (lncRNA) in the development of colorectal cancer (CRC). We used lncRNA sequencing to analyze the transcriptome (mRNA and lncRNA) of five pairs of CRC tissues and adjacent normal tissues. The total expression of mRNAs and lncRNAs in each sample was determined using the R package and the gene expression was calculated using normalized FPKM. The structural features and expression of all detected lncRNAs were compared with those of mRNAs. Differentially expressed mRNAs were selected to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The functional analysis of differentially expressed lncRNAs was performed by analyzing the GO and KEGG enrichment of predicted cis-regulated target genes. A total of 18.2 × 108 reads were obtained by sequencing, in which the clean reads reached ≥ 94.67%, with a total of 245.2 G bases. The number of mRNAs and lncRNAs differentially expressed in CRC tissues and normal tissues were 113 and 6, respectively. Further predictive analysis of target genes of lncRNAs revealed that six lncRNA genes had potential cis-regulatory effects on 13 differentially expressed mRNA genes and co-expressed with 53 mRNAs. Up-regulated CTD-2256P15.4 and RP11-229P13.23 were the most important lncRNAs in these CRC tissues and involved in cell proliferation and pathway in cancer. In conclusion, our study provides evidence regarding the mRNA and lncRNA transcription in CRC tissues, as well as new insights into the lncRNAs and mRNAs involved in the development of CRC.

5.
BMC Musculoskelet Disord ; 21(1): 69, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013950

RESUMO

BACKGROUND: En bloc excision has been increasingly used for the management of giant cell tumors (GCTs) in the distal radius. An osteoarticular allograft has been used extensively for decades, and custom-made prosthesis reconstruction has been more recently applied. We aimed to compare the clinical outcomes of the two procedures. METHODS: We retrospectively analyzed 30 patients with Campanacci III or recurrent GCTs of the distal radius for follow-up at a mean of 33.2 months. In total, 15 underwent osteoarticular allograft reconstruction (allograft group) and 15 received cementless three-dimensional (3D)-printed prosthesis reconstruction (prosthesis group) between March 18, 2013, and May 20, 2018. All patients underwent by clinical and radiological examinations, including pre- and postoperative active range of motion (ROM) of the wrist, VAS score, grip strength, degenerative change of wrist, Mayo wrist score and Musculoskeletal Tumor Society (MSTS) score. Complications were evaluated using the Henderson classification. RESULTS: Both groups showed significantly increased ROM, grip strength, Mayo score and MSTS score postoperatively. Furthermore, the extension, flexion, MSTS, and Mayo score were significantly higher in the prosthesis group. There was no significant difference in grip strength and VAS between the groups. In allograft group, one patient had a late infection one had resorption of allograft without allograft bone fracture. and four had wrist subluxation. All patients had degenerative changes (mean 9 months). In the prosthesis group, three patients developed wrist subluxation, three had separation of the distal radioulnar joint, and none of the patients developed wrist degeneration. CONCLUSIONS: Our study compared the objective functional outcomes and complications of two reconstructive methods for Campanacci III or recurrent GCT in the distal radius. 3D-printed prosthesis replacement can partially preserve wrist function better than allograft reconstruction in the short-term. During the design of 3D-printed prosthesis, preoperative morphological assessment of the affected proximal row carpal is helpful to control postoperative dislocation. After allograft reconstruction, wrist degeneration, which has been demonstrated in all patients, severely influence their wrist function. Therefore, compared to allograft reconstruction, 3D-printed prosthesis reconstruction has irreplaceable advantages at early-stage application, especially in wrist function, however, further studied with a larger number of cases and longer follow-up.

6.
Analyst ; 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32103211

RESUMO

In this work, a new kind of dendritically amplified fluorescent signal probe on SiO2 microspheres was controllably fabricated by the terminal deoxynucleotidyl transferase (TdT)-catalyzed incorporation of nucleotides combined with bio-barcode (BBC) amplification for the ultrasensitive detection of Hg2+. A thymine T-Hg2+-T hairpin structure was first formed and further initiated the strand displacement amplification (SDA) reaction, generating a mimic target (MT). MT hybridized with a capture probe 1 (C1) on SiO2 microspheres, and the 3'-hydroxyl (OH) termini of MT initiated TdT-based DNA extension, producing abundant poly-guanine sequences (G1). Then, G1 hybridized with a capture probe 2 (C2) with abundant cytosine (C) species to assemble multiple C2/reporter probe-AuNPs onto the SiO2 microspheres. The reporter DNA further initiated TdT-based extension with a poly-T sequence (T1) to link large numbers of signal probes, which generated a very high fluorescence signal for the ultrasensitive detection of target Hg2+. This TdT-based signal amplification method coupled with SDA exhibits extraordinary sensitivity for Hg2+ assay with a limit down to 1.0 aM. The proposed highly sensitive fluorescence strategy holds great potential for detecting targets in environmental and biological fields.

7.
Nat Biomed Eng ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015407

RESUMO

Glucose-responsive insulin delivery systems that mimic pancreatic endocrine function could enhance health and improve quality of life for people with type 1 and type 2 diabetes with reduced ß-cell function. However, insulin delivery systems with rapid in vivo glucose-responsive behaviour typically have limited insulin-loading capacities and cannot be manufactured easily. Here, we show that a single removable transdermal patch, bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix, and fabricated via in situ photopolymerization, regulated blood glucose in insulin-deficient diabetic mice and minipigs (for minipigs >25 kg, glucose regulation lasted >20 h with patches of ~5 cm2). Under hyperglycaemic conditions, phenylboronic acid units within the polymeric matrix reversibly form glucose-boronate complexes that-owing to their increased negative charge-induce the swelling of the polymeric matrix and weaken the electrostatic interactions between the negatively charged insulin and polymers, promoting the rapid release of insulin. This proof-of-concept demonstration may aid the development of other translational stimuli-responsive microneedle patches for drug delivery.

8.
J Am Chem Soc ; 142(4): 2023-2030, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31910008

RESUMO

Upconversion nanoparticles (UCNPs), typically converting near-infrared (NIR) light into visible luminescence, are promising for bioimaging applications. However, optical multiplexed in vivo upconversion experiments have long been hampered by the exceptional rarity of available luminescence bands in UCNPs that can penetrate deep in tissues. Herein, we describe an approach to accomplish multiplexed upconversion in vivo imaging through time-domain discrimination of tissue-penetrating NIR luminescence at 808 nm (from thulium ions) with a multitude of distinct lifetimes. A tetradomain nanostructure design enables one to regulate energy migration and upconverting processes within confined nanoscopic domains in defined ways, thus yielding high quantum yield upconversion luminescence (maximum ≈ 6.1%, 0.11 W/cm2) with precisely controlled lifetimes that span 2 orders of magnitude (from 78 to 2157 µs). Importantly, intravenous and subcutaneous administration of aqueous form UCNPs into a Kunming mouse demonstrates high-contrast lifetime-colored imaging of them in liver and two abdomen subcutis. Moreover, optical patterns of these UCNPs allow multicolour presentation of a series of deciphered images that are hued with precisely defined lifetimes. The described temporal multiplexed upconversion approach, demonstrated in in vivo imaging and multilevel anticounterfeiting, has implications for high-throughput biosensing, volumetric displays, and diagnosis and therapy.

9.
Spectrochim Acta A Mol Biomol Spectrosc ; 230: 118050, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-31955119

RESUMO

Effective and simultaneous detection of multi-metal ions has been achieved by a colorimetric and fluorometric probe (REHBA) synthesized from rhodamine hydrazide and polyhydroxyl aromatic aldehyde. REHBA can serve as a colorimetric detector for Cu2+ and Co2+, and a fluorometric probe for Pb2+. The colorless solution of REHBA changes to pink for Cu2+/Co2+ and shows a remarkable fluorescence for Pb2+. The further differentiation of Cu2+ and Co2+ depends on whether the colorimetric response of REHBA is reversible upon addition of ethylene diamine tetraacetic acid. The response is reversible for Cu2+, while it is not for Co2+. The spirolactam ring-opening in REHBA and the formation of REHBA-metal complexes with binding stoichiometric ratio of 1:1 are responsible for the UV-visible and fluorescence behaviors. REHBA shows excellent selectivity, anti-interference and good sensitivity. The limit of detection of Cu2+, Co2+ and Pb2+ is 0.11 µM, 0.88 µM and 0.73 µM, respectively. In addition, REHBA has been applied to recognize Pb2+ in living cells by fluorescence image and Cu2+, Co2+ and Pb2+ in real water samples, indicating that REHBA is a potential candidate for multi-metal-ions detection.

10.
J Colloid Interface Sci ; 560: 260-272, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31670099

RESUMO

Micron-sized zero-valent aluminum (ZVAl), a heterogeneous Fenton-like catalyst in organic wastewater treatment, whose catalytic activity is limited by the dense and stable oxide layer coating on its surface. In this paper, a simple method of ball milling was exploited to pretreat inert aluminum particles with the addition of low-cost and non-toxic sodium chloride (NaCl) grains. Then the pretreated ZVAl (marked as ZVAlbm) was employed to activate molecular oxygen catalytically for phenol oxidative degradation. No induction period was observed in ZVAlbm/Air system. Meanwhile, the reaction rate and mineralization efficiency of phenol degradation had improved in contrast with the original ZVAl. The characterization results of SEM-EDS, BET, XRD and XPS revealed that the native oxide layer of ZVAlbm was destroyed and became rougher, where its surface was embedded in NaCl grains. Thus the dissolution of NaCl in aqueous solution was imagined to expose the fresh surface of ZVAlbm, facilitating the electron transfer at the interface of ZVAlbm/H2O. Moreover, the specific surface area of ZVAlbm increased for ball milling improved its surface roughness, resulting in the enhanced reactivity of ZVAlbm. The interfacial reaction mechanism was revealed that more dissolved oxygen (DO) was activated by the exposed surface of ZVAlbm to form large amounts of hydrogen peroxide (H2O2). Then in-situ production of H2O2 was catalyzed by the active-surface of ZVAlbm via a Fenton-like process to generate massive OH, which was detected as the predominant active species for phenol degradation. Finally, the reusability experiment indicated that ball milling could rejuvenate the main catalytic activity of used ZVAlbm easily. In summary, ball milling provides a green and easily-operated method to promote the reactivity of inert ZVAl for its application in organic wastewater treatment.

11.
Cell Rep ; 29(6): 1579-1593.e6, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31693897

RESUMO

Pain involves an intrinsically dynamic connectome characterized by fluctuating spontaneous brain activity and continuous neuroplastic changes of relevant circuits. Activity in the hippocampus-medial prefrontal cortex (mPFC) pathway has been suggested to correlate with spontaneous pain and pain chronicity, but causal evidence is lacking. Here we combine longitudinal in vivo electrophysiological recording with behavioral testing and show that persistent spontaneous pain disrupts ventral hippocampal CA1-infralimbic cortex (vCA1-IL) connectivity and hippocampal modulation of IL neuronal activity in rats with peripheral inflammation. Chemo- and optogenetic rescue of vCA1-IL dysfunction relieves spontaneous pain. Circuit-specific overexpression of brain-derived neurotrophic factor (BDNF) in vCA1-IL reverses electrophysiological changes, relieves spontaneous pain, and accelerates overall recovery from inflammatory pain. Our work identifies a neural pathway that specifically correlates with spontaneous pain and supports the significance of using a circuit dynamics-based strategy for more comprehensive understanding of circuitry mechanisms underlying chronic pain.

12.
J Cell Biol ; 218(12): 4093-4111, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31690619

RESUMO

Cells migrate in vivo through complex confining microenvironments, which induce significant nuclear deformation that may lead to nuclear blebbing and nuclear envelope rupture. While actomyosin contractility has been implicated in regulating nuclear envelope integrity, the exact mechanism remains unknown. Here, we argue that confinement-induced activation of RhoA/myosin-II contractility, coupled with LINC complex-dependent nuclear anchoring at the cell posterior, locally increases cytoplasmic pressure and promotes passive influx of cytoplasmic constituents into the nucleus without altering nuclear efflux. Elevated nuclear influx is accompanied by nuclear volume expansion, blebbing, and rupture, ultimately resulting in reduced cell motility. Moreover, inhibition of nuclear efflux is sufficient to increase nuclear volume and blebbing on two-dimensional surfaces, and acts synergistically with RhoA/myosin-II contractility to further augment blebbing in confinement. Cumulatively, confinement regulates nuclear size, nuclear integrity, and cell motility by perturbing nuclear flux homeostasis via a RhoA-dependent pathway.

13.
J Orthop Surg Res ; 14(1): 389, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31775805

RESUMO

BACKGROUND: This study is to describe the detailed design and surgical techniques of three-dimensional (3D)-printed custom-made endoprosthesis for hemipelvic tumorous bone defect. METHODS: According to the pelvic tumor resection classification by Enneking and Dunham, the hemipelvis is divided into three zones including the ilium (P1), acetabulum (P2), and pubis and ischium (P3). Thirteen patients were included in this study. Of these, P1 and P2 were involved in three cases, while P1, P2, and P3 were involved in 10. Based on radiography data, 3D pelvic model was rebuilt, and virtual surgery was simulated. Different fixation methods were applied according to residual bone volume. Parameters of the first sacral (S1) vestibule, second sacral (S2) vestibule, the narrowest zone of superior pubic medullary cavity (NPSPMC), and the resected surface of superior pubic medullary cavity (RSSPMC) were selectively measured in various fixation methods. Model overlapping, feature simplifying, and size controlling were three basic steps during design procedure. Volume proportion of porous structure was determined according to estimated weight of resected specimen. Acetabular location, anteversion, and inclination were modulated. Screw diameter, direction, and combination were considered. The osteotomy guides and plastic models were used during surgery. RESULTS: Of 13 cases, after P1 resection, endoprostheses were fixed to sacra (8; 61.5%), ilia (3; 23.1%), and both (2; 15.4%). After P3 resection, endoprostheses were fixed to residual acetabulum (3; 23.1%), and residual pubis by stem (8; 61.5%) or "cap-like" structure (2; 15.4%). Mean area of the S1 vestibule, S2 vestibule, RSSPMC, and PSPMC were 327.9 (222.2 to 400), 131.7 (102.6 to 163.6), 200.5 (103.8 to 333.2), and 79.8 mm2 (40.4 to 126.2), respectively. Porous structure with 600 µm pore size and 70% porosity accounted for 68.8% (53.0 to 86.0) of the whole endoprosthesis on average. Mean acetabular anteversion and inclination were designed as 23.2° (20 to 25) and 42.4° (40 to 45). Median numbers of screws designed in the S1 vestibule was 5 (IQR, 4 to 6), in the S2 vestibule was 1 (IQR, 1 to 2), in the ilium was 5 (IQR, 2 to 6), and in the pubis was 1 (IQR, 1 to 1), while screws designed in the ischium was all 2. Median number of screws inserted in the S1 vestibule was 4 (IQR, 3 to 4), in the S2 vestibule was 1 (IQR, 1 to 1), in the ilium was 3 (IQR, 1 to 5), in the pubis was 1 (IQR, 0 to 1), and in the ischium was 1 (IQR, 1 to 1). CONCLUSIONS: This study firstly presents detailed design and related surgical techniques of 3D-printed custom-made hemipelvic endoprosthesis reconstruction. Osseointegration is critical for long-term outcome and requires three design elements including interface connection, porous structure, and initial stability achieved by precise matching and proper fixation methods.

14.
ACS Chem Biol ; 14(12): 2691-2700, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31589399

RESUMO

While the opportunities available for targeting RNA with small molecules have been widely appreciated, the challenges associated with achieving specific RNA recognition in biological systems have hindered progress and prevented many researchers from entering the field. To facilitate the discovery of RNA-targeted chemical probes and their subsequent applications, we curated the RNA-targeted BIoactive ligaNd Database (R-BIND). This collection contains an array of information on reported chemical probes that target non-rRNA and have biological activity, and analysis has led to the discovery of RNA-privileged properties. Herein, we developed an online platform to make this information freely available to the community, offering search options, a suite of tools for probe development, and an updated R-BIND data set with detailed experimental information for each probe. We repeated the previous cheminformatics analysis on the updated R-BIND list and found that the distinguishing physicochemical, structural, and spatial properties remained unchanged, despite an almost 50% increase in the database size. Further, we developed several user-friendly tools, including queries based on cheminformatic parameters, experimental details, functional groups, and substructures. In addition, a nearest neighbor algorithm can assess the similarity of user-uploaded molecules to R-BIND ligands. These tools and resources can be used to design small molecule libraries, optimize lead ligands, or select targets, probes, assays, and control experiments. Chemical probes are critical to the study and discovery of novel functions for RNA, and we expect this resource to greatly assist researchers in exploring and developing successful RNA-targeted probes.

15.
Biomolecules ; 9(10)2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591300

RESUMO

Nanobodies are one-tenth the size of conventional antibodies and are naturally obtained from the atypical heavy-chain-only antibodies present in camelids. Their small size, high solubility, high stability, and strong resilience to organic solvents facilitate their use as novel analytical reagents in immunochemistry. In this study, specific nanobodies against pesticide carbofuran were isolated and characterized from an immunized library via phage display platform. We further established an indirect competitive enzyme-linked immunosorbent assay (ELISA) using nanobody Nb316 to detect carbofuran in vegetable and fruit samples. The results showed a half-maximal inhibitory concentration (IC50) of 7.27 ng/mL and a detection limit of 0.65 ng/mL. A simplified sample pretreatment procedure omitting the evaporation of organic solvent was used. The averaged recovery rate of spiked samples ranged between 82.3% and 103.9%, which correlated with that of standard UPLC-MS/MS method. In conclusion, a nanobody with high specificity for carbofuran was characterized, and a nanobody-based sensitive immunoassay for simple and rapid detection of carbofuran in real samples was validated.

16.
PeerJ ; 7: e7414, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576231

RESUMO

Background: Engrailed 1 (EN1), as a member of homeobox-containing transcription factors, participates in the development of the brain. High expressions of EN1 exist in various tumors. However, the role of EN1 in lower grade glioma (LGG) is still unknown. Methods: Coefficients of Cox regression were examined by data mining among 13 cancer types using OncoLnc to validate EN1 expressions in LGG patients from The Cancer Genome Atlas database (TCGA). Bioinformatic analysis was performed by using R2 and the UCSC Xena browser based on the data from 273 glioma cases in GSE16011 from GEO datasets and 530 cases of LGG patients in TCGA. Cases in GSE16011 were divided into two groups according to IDH1 mutation status. Cases in TCGA-LGG were classified to subtypes according to histopathological results, IDH1 mutation status and 1p19q status. The Kaplan-Meier survival curves were performed to analyze the relationship between EN1 expressions and clinicopathological characteristics and survival time respectively. Results: Cox regression results showed that LGG was ranked statistically first among 13 different cancer types according to the false discovery rate (FDR) correction. Results from GSE16011 showed that: glioma, LGG and LGG with IDH1 mutation patients with high EN1 expressions had significantly shorter 5, 10, and 15-year overall survival time (OS) (p < 0.001). Similar results from TCGA-LGG showed that LGG patients with high EN1 expressions had significantly shorter 15-year OS, irrespective of IDH1 mutation and 1p19q co-deletion (p < 0.001). The astrocytoma subgroup showed highest levels of EN1 expression and shortest 5, 10 and 15-year OS compared with oligoastrocytoma and oligodendroglioma (p < 0.05). Conclusion: EN1 can be used as a prognostic marker in LGG patients, combined with IDH1 mutation and 1p19q co-deletion.

17.
Biomater Sci ; 7(11): 4508-4513, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31608343

RESUMO

Insulin administration for the management of diabetes is accompanied by hypoglycemia, which is expected to be mitigated by glucose-responsive smart insulin that has self-regulation ability in response to blood glucose level (BGL) fluctuation. Here, we have prepared a new insulin analog by modifying insulin with forskolin (designated as insulin-F), a glucose-transporter (Glut) inhibitor. In vitro, insulin-F is capable of binding to Glut on erythrocyte ghosts, which can be inhibited by glucose and cytochalasin B. Upon subcutaneous injection in type 1 diabetic mice, insulin-F maintains BGLs below 200 mg mL-1 for up to 10 h, and achieves 20 h with two sequential injections. Moreover, insulin-F also binds to endogenous Gluts. Upon a glucose challenge, the elevated level of glucose competitively replaces and liberates insulin-F that binds to Glut, rapidly restoring BGLs to the normal range.

18.
Neurosurg Rev ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31502029

RESUMO

The use of the internal maxillary artery (IMA) in intracranial artery bypass or subcranial-intracranial (SC-IC) bypass has recently been described as an alternative to traditional bypass. This study explores cerebral glucose metabolism characteristics of SC-IC bypass. Ten crescendo transient ischemic attack (TIA) patients with chronic occlusion of the middle cerebral artery (MCA) received bypass surgery of IMA with the radial artery graft (RAG) to the branch of MCA. The graft's flow volume (FV) was measured by operative intraoperative duplex ultrasonography. Positron emission tomography (PET)/computed tomography (CT) was used to calculate the preoperational and postoperational average of the standard uptake value (SUVavg) of the 18-fluoro-2-deoxy-D-glucose (18F-FDG) in the region of interest (ROI). The asymmetric index (AI) is recommended to reflect the SUVavg changes, and subsequently, cerebral glucose metabolism changes are supposedly clarified. Patent IMA-RAG-MCA bypass in ten chronic ischemia patients was confirmed by angiography after surgery. The intraoperative FV measurement value was 65.64 ± 10.52 (58.11-73.17) ml/min. Before the operation, the SUVavg of the ROI in the ischemic hemisphere (4.76 ± 2.35 (3.08-6.04)) clearly decreased compared to the one (5.99 ± 2.63 (4.11-7.87)) in the contralateral mirror region (P = 0.003). The result of AI of preoperation minus AI of postoperation was more than 10% (P = 0.031), which indicated suspicious significant changes in cerebral metabolism. All symptoms of study patients having crescendo ischemia were resolved in 1 month after the operation. In the cerebral hypoperfusion territory, uptake of 18F-FDG deceased. Improving the flow volume via SC-IC bypass makes available an elevated uptake of 18F-FDG.

19.
J Chem Theory Comput ; 15(10): 5161-5168, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31505931

RESUMO

While a new therapeutic cyclic peptide is approved nearly every year, docking large macrocycles has remained challenging. Here, we present a new version of our peptide docking software AutoDock CrankPep (ADCP), extended to dock peptides cyclized through their backbone and/or side chain disulfide bonds. We show that within the top 10 solutions, ADCP identifies the proper interactions for 71% of a data set of 38 complexes, thus making it a useful tool for rational peptide-based drug design.


Assuntos
Desenho de Drogas , Simulação de Acoplamento Molecular , Peptídeos Cíclicos/química , Software , Dissulfetos/química , Peptídeos Cíclicos/síntese química
20.
Environ Res ; 178: 108714, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520832

RESUMO

BACKGROUND: Available data on the effects of heatwaves on hospitalizations and postdischarge status of Alzheimer's disease patients are very scarce. METHODS: We used data from a retrospective cohort study which included Alzheimer's disease patients who were hospitalized from 1st January 2005 to 31st December 2013 in Brisbane, Australia, and died within two months after they were discharged. A time-stratified case-crossover design using conditional logistic regression was employed to quantify the effects of heatwaves on hospitalizations and postdischarge deaths due to Alzheimer's disease. A case-only design was used to assess the modification effects of age, sex, and community-level vegetation and Socio-Economic Indexes for Areas (SEIFA) on heatwave effects. RESULTS: There were 907 hospitalizations in the study period, and 307 patients died within two months after discharge. Hospitalizations and postdischarge deaths due to Alzheimer's disease increased by 51% (95% confidence interval (CI): 2%, 126%) and 269% (95% CI: 76%, 665%), respectively, during middle-intensity heatwaves (i.e., 95th percentile & ≥2 days). The magnitude of heatwave effect on postdischarge deaths increased dramatically when heatwave intensity increased from 95th percentile to 97th percentile. People who lived in communities with low-level vegetation were more vulnerable to heatwave effect on hospitalizations for Alzheimer's disease than those who lived in communities with high-level vegetation (relative risk: 3.05, 95% CI: 1.16, 7.98). CONCLUSION: Heatwaves increased the risk of hospitalizations for those living with Alzheimer's disease, and increased the risk of postdischarge deaths of Alzheimer's disease patients. Increasing urban greenness may ease heat-related Alzheimer's disease burden.

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