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1.
Biomater Sci ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31674634

RESUMO

Gambogic acid (GA) is a natural anti-tumor drug whose application is restricted by its poor aqueous solubility and inefficient bioavailability. Developing nanomaterials with excellent biocompatibility can amplify the therapeutic effects of GA. In this study, a tumor-targeted redox controllable self-assembled nano-system with magnetic enhanced EPR effects (mPEG-HA/CSO-SS-Hex/SPION/GA) was developed to improve the anticancer efficacy of GA. The nano-system is constituted by three layers: the outer layer is mono-aminated poly(ethylene glycol) grafted hyaluronic acid (mPEG-HA), which can target the CD44 receptor in breast cancer cells; the middle layer consists of disulfide linked hexadecanol (Hex) and chitosan oligosaccharide (CSO) to control the drug release by reduction response; the core layer is superparamagnetic iron oxide nanoparticles (SPION), which can enhance the EPR effect by magnetic guidance and contribute to GA entrapment. Different experiments were performed to characterize the complex self-assembly, and the cytotoxicity, pharmacokinetics, and in vivo antitumor activity of the self-assembly were investigated to evaluate its anti-tumor effects. The results revealed that mPEG-HA/CSO-SS-Hex/SPION/GA is an excellent nanosystem with appropriate size and sensitive responsiveness; it can accumulate in tumor sites and achieve excellent therapeutic effects on triple-negative breast cancer (TNBC). In summary, a CD44-targeted redox-triggered self-assembly nanosystem with magnetic enhanced EPR effects was developed for effective amplification of GA; it has potential to act as an effective carrier in drug delivery for chemotherapy of TNBC.

2.
Drug Deliv ; 26(1): 1206-1221, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31746243

RESUMO

As an emerging novel drug carrier, nanoparticles provide a promising way for effective treatment of parasitic diseases by overcoming the shortcomings of low bioavailability, poor cellular permeability, nonspecific distribution and rapid elimination of antiparasitic drugs from the body. In recent years, some kinds of ideal nanocarriers have been developed for antiparasitic drug delivery. In this review, the progress of the enhanced antiparasitic effects of different nanoparticles payload and their influencing factors were firstly summarized. Secondly, the transport and disposition process in the body were reviewed. Finally, the challenges and prospects of nanoparticles for antiparasitic drug delivery were proposed. This review will help scholars to understand the development trend of nanoparticles in the treatment of parasitic diseases and explore strategies in the development of more efficient nanocarriers to overcome the difficulty in the treatment of parasite infections in the future.

3.
BMC Nephrol ; 20(1): 434, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31771550

RESUMO

BACKGROUND: Primary nephrotic syndrome (PNS) is a common glomerular disease in children. T cell dysfunction plays a crucial role in the pathogenesis of PNS. Moreover, dysbiosis of gut microbiota contributes to immunological disorders. Whether the initial therapy of PNS affects gut microbiota remains an important question. Our study investigated compositional changes of gut microbiota after initial therapy. METHODS: Fecal samples of 20 children with PNS were collected before and after 4-week initial therapy. Total bacteria DNA were extracted and the V3-V4 regions of bacteria 16S ribosomal RNA gene were sequenced. The composition of gut microbiota before and after initial therapy was analyzed by bioinformatics methods. The function of altered gut microbiota was predicted with PICRUSt method. RESULTS: The richness and diversity of gut microbiota were similar before and after 4-week initial therapy. Gut microbiota at the phylum level was dominated by four phyla including Firmicutes, Proteobacteria, Bacteroidetes and Actinobacteria, but the increased relative abundance after initial therapy was found in Deinococcus-Thermus and Acidobacteria. At the genus level, the increased abundance of gut microbiota after initial therapy was observed in short chain fat acids (SCFA)-producing bacteria including Romboutsia, Stomatobaculum and Cloacibacillus (p < 0.05). Moreover, the predicted functional profile of gut microbiota showed that selenocompound metabolism, isoflavonoid biosynthesis and phosphatidylinositol signaling system weakened after initial therapy of PNS. CONCLUSIONS: Initial therapy of PNS increased SCFA-producing gut microbiota, but might diminish selenocompound metabolism, isoflavonoid biosynthesis and phosphatidylinositol signaling system in children.

4.
Bioorg Chem ; 93: 103310, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31586704

RESUMO

A series of quinoline-ferulic acid hybrids has been designed, synthesized, and evaluated as cholinesterase inhibitors. Most of the compounds showed good inhibitory activities toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, 10f was found to be the most potent inhibitor against AChE (IC50 = 0.62 ±â€¯0.17 µm), and 14 was the most potent inhibitor against BChE (IC50 = 0.10 ±â€¯0.01 µm). Representative compounds, such as 10f and 12g, act in a competitive manner when they inhibit AChE or BChE. Molecular docking and dynamic simulation revealed that the synthesized compounds bind to the target by simultaneously interacting with the catalytic active site (CAS) and the peripheral anionic site (PAS) of both AChE and BChE. The U-shaped confirmation was preferred when 12g bound to BChE, which was different from the linear conformation of 10f bound to AChE. Cell-based assays have confirmed the moderate neuroprotective effects of compounds 10f and 12g against H2O2-induced oxidative damage towards PC12 cells. Moreover, the hepatotoxicity of 12g was lower than that of tacrine, indicating its potential safety as an anti-Alzheimer's agent. In summary, we report a new chemotype of multifunctional hybrid, which may be further modified to develop new anti-Alzheimer's agents.

5.
Sensors (Basel) ; 19(20)2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31614888

RESUMO

Large-scale urbanization has brought about severe ground subsidence in Kunming (China), threatening the stability of urban infrastructure. Mapping of the spatiotemporal variations of ground deformation is urgently needed, along with summarization of the causes of the subsidence over Kunming with the purpose of disaster prevention and mitigation. In this study, for the first time, a multi-temporal interferometric synthetic aperture radar (InSAR) technique with L-band Advanced Land Observation Satellite (ALOS-1) and X-band Constellation of Small Satellites for Mediterranean basin Observation (COSMO-SkyMed) data was applied to Kunming to derive the time series deformation from 2007 to 2016. The annual deformation velocity revealed two severe subsiding regions in Kunming, with a maximum subsidence of 35 mm/y. The comparison of the deformation between InSAR and leveling showed root-mean-square error (RMSE) values of about 4.5 mm for the L-band and 3.7 mm for the X-band, indicating that our results were reliable. We also found that the L-band illustrated a larger amount of subsidence than the X-band in the tested regions. This difference was mainly caused by the different synthetic aperture radar (SAR)-acquired times and imaging geometries between the L- and X-band SAR images. The vertical time series deformation over two severe subsiding regions presented an approximate linear variation with time, where the cumulative subsidence reached 209 mm during the period of 2007-2016. In view of relevant analyses, we found that the subsidence in Kunming was the result of soft soil consolidation, building load, and groundwater extraction. Our results may provide scientific evidence regarding the sound management of urban construction to mitigate potential damage to infrastructure and the environment.

6.
J Vet Sci ; 20(5): e40, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31565887

RESUMO

Misuse and abuse of veterinary antimicrobial agents have led to an alarming increase in bacterial resistance, clinical treatment failure, and drug residues. To address these problems, consistent and appropriate dosage regimens for veterinary antimicrobial agents are needed. Pharmacokinetics/Pharmacodynamics (PK/PD) models have been widely used to establish rational dosage regimens for veterinary antimicrobial agents that can achieve effective prevention and treatment of bacterial diseases and avoid the development of bacterial resistance. This review introduces building methods for PK/PD models and describes current PK/PD research progress toward rational dosage regimens for veterinary antimicrobial agents. Finally, the challenges and prospects of PK/PD models in the design of dosage regimens for veterinary antimicrobial agents are reviewed. This review will help to increase awareness of PK/PD modeling among veterinarians and hopefully promote its development and future use.

7.
Theranostics ; 9(22): 6532-6549, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588234

RESUMO

Precision medicine has increased the demand for stage-specific cancer chemotherapy. Drugs with different properties are needed for different stages of tumor development, which is, inducing rapid destruction in the early stage and facilitating deep penetration in the advanced stage. Herein, we report a novel reduction-activated charge-conversional core-shell nanoparticle (CS NP) formula based on ring-closing metathesis of the thiamine disulfide system (TDS) to deliver the chemotherapeutic agent-gambogic acid (GA). Methods: The shell consisted of hyaluronic acid-all-trans retinoid acid with a disulfide bond as the linker (HA-SS-ATRA). The core was selected from poly (γ-glutamic acid) with different grafting rates of the functional group (Fx%) of TDS. GA/CF100%S NPs, with the strongest reduction-responsive drug release, and GA/CF60%S NPs with the strongest penetration have been finally screened. On this basis, a stage-specific administration strategy against a two-stage hepatocellular carcinoma was proposed. Results: The developed CS NPs have been confirmed as inducing reduction-activated charge conversion from about -25 to +30 mV with up to 95% drug release within 48 h. The administration strategy, GA/CF100%S NPs for the early-stage tumor, and sequential administration of GA/CF60%S NPs followed by GA/CF100%S NPs for the advanced-stage tumor, achieved excellent tumor inhibition rates of 93.86±2.94% and 90.76±6.43%, respectively. Conclusions: Our CS NPs provide a novel platform for charge conversion activated by reduction. The stage-specific administration strategy showed great promise for cancer therapy.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31650478

RESUMO

Novel adsorbent, diethylenetriamine-grafted Spirodela polyrhiza (DSP), was synthesized via modifying natural S. polyrhiza (SP) with diethylenetriamine by cross-linking with epichlorohydrin and applied to adsorb Ni2+ and Pb2+ from water. The effecting parameters on adsorption of Ni2+ and Pb2+ such as adsorbent dosage, pH, contact time, temperature, and initial concentration were studied through equilibrium experiments. The adsorption of Ni2+ and Pb2+ followed the pseudo-second-order model and the Langmuir isotherm adsorption model. The study discusses thermodynamic parameters, including changes in Gibbs free energy, entropy, and enthalpy, for the adsorption of Ni2+ and Pb2+ on DSP, and revealed that the adsorption process was spontaneous and exothermic under natural conditions. The maximum Ni2+ and Pb2+ adsorption capacities of DSP were 33.02 and 36.50 mg/g, respectively. The newly prepared materials were characterized through scanning electron microscopy (SEM), mapping analysis, and zeta potential analysis. Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) analyses indicated that functional groups (-OH and N-H) were involved in Ni2+ and Pb2+ adsorption. Notably, DSP can be easily regenerated and reused for multiple cycles. Therefore, DSP is a promising adsorbent for effective Ni2+ and Pb2+ removal.

9.
Pain ; 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31651580

RESUMO

Patients with chronic pain often report being sensitive to pain at night before falling asleep, a time when the synchronization of cortical activity is initiated. However, how cortical activity relates to pain sensitivity is still unclear. Since sleep is characterized by enhanced cortical delta power, we hypothesized that enhanced cortical delta power may be an indicator of intensified pain. To test this hypothesis, we used pain thresholds tests, EEG/electromyogram recordings, c-Fos staining and chemogenetic and pharmacological techniques in mice. We found that sleep deprivation or pharmacologic enhancement of EEG delta power by reserpine and scopolamine dramatically decreased mechanical pain thresholds, but not thermal withdrawal latency, in a partial sciatic-nerve ligation model of neuropathic pain mice. On the contrary, suppression of EEG delta power using a wake-promoting agent modafinil significantly attenuated mechanical allodynia. Moreover, when EEG delta power was enhanced, c-Fos expression decreased in most regions of the cortex, except the anterior cingulate cortex (ACC), where c-Fos was increased in the somatostatin and parvalbumin positive GABAergic neurons. Chemogenetic activation of GABAergic neurons in ACC enhanced EEG delta power and lowered mechanical pain thresholds simultaneously in naïve mice. However, chemogenetic inhibition of ACC GABAergic neurons could not block mechanical allodynia. These results provided compelling evidence that elevated EEG delta power is accompanied with aggravated neuropathic pain, whereas decreased delta power attenuated it, suggesting that enhanced delta power can be a specific marker of rising chronic neuropathic pain and that wake-promoting compounds could be used as analgesics in the clinic.

10.
J Org Chem ; 84(21): 14342-14348, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31580081

RESUMO

Herein, an operationally simple and mild strategy to construct sulfenation of oxindoles with a series of thiols in the absence of transition metals was developed. This methodology provides an efficient way to directly form a C-S bond at the C-3 position of oxindoles under mild reaction conditions with a cheap and common solvent and base in moderate to good yields.

11.
Bioorg Chem ; 92: 103258, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520892

RESUMO

Alzheimer disease (AD), a prevalent neurodegenerative disorder, is one of the leading causes of dementia. However, there is no effective drug for this disease to date. Picrasma quassioides (D.Don) Benn, a Chinese traditional medicine, was used mainly for the treatment of inflammation, fever, microbial infection and dysentery. In this paper, we reported that the EtOAc extract of Picrasma quassioides stems showed potential neuroprotective activities in l-glutamate-stimulated PC12 and Aß25-35-stimulated SH-SY5Y cell models, as well as improved memory and cognitive abilities in AD mice induced by amyloid-ß peptide. Moreover, it was revealed that the anti-AD mechanism was related to suppressing neuroinflammatory and reducing Aß1-42 deposition using ELISA assay kits. To clarify the active components of the EtOAc extract of Picrasma quassioides stems, a systematic phytochemistry study led to isolate and identify six ß-carboline alkaloids (1-6), seven canthin-6-one alkaloids (7-13), and five quassinoids (14-18). Among them, four ß-carbolines (1-3, and 6) and six canthin-6-ones (7-11, and 13) exhibited potential neuroprotective activities in vitro. Based on these date, the structure-activity relationships of alkaloids were discussed. Furthermore, molecular docking experiments showed that compounds 2 and 3 have high affinity for both of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYPKIA) and butyrylcholinesterase (BuChE).

12.
Pak J Pharm Sci ; 32(3 Special): 1427-1430, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31551226

RESUMO

This paper aims to investigate the curative effect of carvedilol combined with conventional therapy in treatment of chronic heart failure. 180 patients who have been treated for chronic heart failure were selected as research objects and divided into control group and research group. The control group was given conventional treatment (including oxygen therapy, ACEI, taking digitalis preparations, vasodilators, diuretics, positive inotropic drugs), while research group was given carvedilol combined with conventional therapy. The overall therapeutic effect of the two groups was observed and compared. The research group had significantly higher overall therapeutic efficiency than control group, P<0.05; by comparing the echocardiographic results of the patients between two groups, the results showed LVEF (left ventricular ejection fraction), LVESD (left ventricular end-systolic diameter) and LVEDD (left ventricular end-diastolic diameter) of the research group after treatment were significantly better than that of control group, P<0.05; through recording the quality of life level of the two groups, the results showed that the score advantages of the research group were significant in terms of social function, psychological function and physical function, P<0.05. For patients with chronic heart failure, carvedilol combined with conventional treatment can effectively improve the efficiency of treatment and improve cardiac function, thus improving the quality of life.

13.
Sleep ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31552427

RESUMO

Light has immediate effects on sleep in rodents, but the neural pathways underlying the effect remain to be elucidated. The intergeniculate leaflet (IGL) containing GABAergic neurons receives direct retinal inputs. We hypothesized that IGL GABAergic neurons may mediate light-induced sleep. EEG/electromyogram recording, immunohistochemistry, electrophysiology, optogenetics, fiber photometry, behavioral tests, and cell-specific destruction were employed to investigate the role of IGL GABAergic neurons in the regulation of acute light-induced sleep. Here, EEG/ electromyogram recordings revealed that acute light exposure during the nocturnal active phase in mice induced a significant increase in non-rapid eye movement and rapid eye movement sleep compared with controls. Immunohistochemistry showed that acute light exposure for 2 h in the active phase induced an increase in c-Fos expression in the IGL, whereas lights-off in the rest phase inhibited it. Patch clamp coupled with optogenetics demonstrated that retinal ganglion cells had monosynaptic functional connections to IGL GABAergic neurons. Calcium activity by fiber photometry in freely behaving mice showed that light exposure increased the activity of IGL GABAergic neurons. Furthermore, lesion of IGL GABAergic neurons by caspase-3 virus significantly attenuated the sleep-promoting effect of light exposure during active phases. Collectively, these results clearly indicated that the IGL is one of key nuclei mediating light-induced sleep in mice.

15.
Food Chem Toxicol ; 133: 110780, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31449894

RESUMO

Dietary Apigenin (AP), a natural flavonoid from plants, could alleviate high-fat diet (HFD) induced obesity and its complication. Nonetheless, the direct correlation between dietary AP and their effects in adipose tissues remained unclear. In this study, male C57BL/6 mice were fed with low-fat diet, HFD with or without 0.04% (w/w) AP for 12 weeks. Dietary AP ameliorated HFD induced body weight gain, glucose intolerance, and insulin resistance. Energy expenditure was increased with no influence on energy intake, which indicated us that AP prevented obesity by enhancing energy export. Interestingly, AP activated lipolysis (ATGL/FOXO1/SIRT1) without higher cycling free fatty acids (FFAs). FFAs were consumed by the upregulation of fatty acid oxidation (AMPK/ACC), thermogenesis, and browning (UCP-1, PGC-1α). Additionally, adipose tissue metabolic inflammation (NF-кB, MAPK) was also reduced by AP. Our study proposed that dietary AP could be explored as a new dietary strategy to combat obesity and related insulin resistance.

16.
Eur J Med Chem ; 181: 111581, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400711

RESUMO

Casein kinase (CK) is a type of conserved serine/threonine protein kinase that phosphorylates many important proteins in body. Researchers found that CK is involved in a variety of signaling pathways, and also plays an important role in inflammation, cancer, and nervous system diseases. Thus, it is considered to be a promising target for the treatment of related diseases. Many CK small molecule inhibitors have been reported so far, and most are ATP competitive inhibitors. However, these CK inhibitors lack the basic properties required for in vivo use, such as selectivity, cell permeability, metabolic stability, correct pharmacokinetic characteristics, and cellular environment. But small molecule inhibitors still have an advantage in drug research due to their controllable pharmacological and pharmacokinetic properties. CX-4945 discovered by Cylene Pharmaceutical is the only one CK2 inhibitor entering into Phase II clinical trials till now. In recent years, significant advances have been made in the design of non-competitive inhibitors of CK and in the application of multi-target inhibition strategies. Here, we review the published CK inhibitors and analyze their structure-activity relationships (SAR). We also summarized the eutectic structure with identified hot spots to provide a reference for future drug discovery.


Assuntos
Caseína Quinase II/antagonistas & inibidores , Caseína Quinase I/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Caseína Quinase I/química , Caseína Quinase I/metabolismo , Caseína Quinase II/química , Caseína Quinase II/metabolismo , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular
17.
Environ Pollut ; 254(Pt A): 112960, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31394344

RESUMO

That an alteration of the intestinal permeability is associated with gut barrier function has been increasingly evident, which plays an important role in human and animal health. Bisphenol A (BPA), an industrial compound used worldwide, has recently been classified as an environmental pollutant. One of our earlier studies has demonstrated that BPA disrupts the intestinal barrier function by inducing apoptosis and inhibiting cell proliferation in the human colonic epithelial cells line. In this study, we investigated the effects of dietary BPA uptake on the colonic barrier function in mice, as well as the intestinal permeability. Dietary BPA uptake was observed to destroy the morphology of the colonic epithelium and increase the pathology score. The levels of endotoxin, diamine peroxidase, D-lactate, and zonulin were found to have been significantly elevated in both plasma and colonic mucosa. A decline in the number of intestinal goblet cells and in mucin 2 gene expression was observed in the mice belonging to the BPA group. The results of immunohistochemistry revealed that the expression of tight junction proteins (ZO-1, occludin, and claudin-1) in colonic epithelium of BPA mice decreased significantly, and their gene abundance was also inhibited. Moreover, dietary BPA uptake was also found to have significantly reduced colonic microbial diversity and altered microbial structural composition. The functional profiles of colonic bacterial community exhibited adverse effects of dietary BPA intake on the endocrine and digestive systems, as well as the transport and catabolism functions. Collectively, our study highlighted that dietary BPA increased the colonic permeability, and this effect was closely related to the disruption of intestinal chemistry and physical and biological barrier functions.

18.
BMC Cancer ; 19(1): 716, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324162

RESUMO

BACKGROUND: Assessing the prognostic significance of specific clinicopathological features plays an important role in surgical management after radical cystectomy. This study investigated the association between ten clinicopathological characteristics and cancer-specific survival (CSS) in patients with bladder cancer. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, a literature search was conducted through the PubMed, EMBASE and Web of Science databases using appropriate search terms from the dates of inception until November 2018. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to evaluate the CSS. Fixed- or random-effects models were constructed according to existence of heterogeneity. RESULTS: Thirty-three articles met the eligibility criteria for this systematic review, which included 19,702 patients. The overall results revealed that CSS was associated with advanced age (old vs. young: pooled HR = 1.01; 95% CI:1.00-1.01; P < 0.001), higher tumor grade (3 vs. 1/2: pooled HR = 1.29; 95% CI:1.15-1.45; P < 0.001), higher pathological stage (3/4 vs. 1/2: pooled HR = 1.60; 95% CI:1.37-1.86; P < 0.001), lymph node metastasis (positive vs. negative: pooled HR = 1.51; 95% CI:1.37-1.67; P < 0.001), lymphovascular invasion (positive vs. negative: pooled HR = 1.36; 95% CI:1.28-1.45; P < 0.001), and soft tissue surgical margin (positive vs. negative: pooled HR = 1.42; 95% CI:1.30-1.56; P < 0.001). However, gender (male vs. female: pooled HR = 0.98; 95% CI: 0.96-1.01; P = 0.278), carcinoma in situ (positive vs. negative: pooled HR = 0.98; 95% CI: 0.88-1.10; P = 0.753), histology (transitional cell cancer vs variant: pooled HR = 0.90; 95% CI: 0.79-1.02; P = 0.089) and adjuvant chemotherapy (yes vs. no: pooled HR = 1.16; 95% CI: 1.00-1.34; P = 0.054) did not affect CSS after radical resection of bladder cancer. CONCLUSIONS: Our results revealed that several clinicopathological characteristics can predict CSS risk after radical cystectomy. Prospective studies are needed to further confirm the predictive value of these variables for the prognosis of bladder cancer patients after radical cystectomy.

19.
Nat Genet ; 51(8): 1222-1232, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31332380

RESUMO

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.

20.
Cancer Immunol Immunother ; 68(8): 1369-1378, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31338558

RESUMO

Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy with poor prognosis. The evaluation of recurrence risk after liver resection is of great importance for ICCs. We aimed to assess the prognostic value of intra- and peritumoral immune infiltrations and to establish a novel histopathology-related immunoscore (HRI) associated with ICC recurrence. A total of 280 ICC patients who received curative resection between February 2005 and July 2011 were enrolled in our study. Patients were randomly assigned to the derivation cohort (n = 176) or the validation cohort (n = 104). Sixteen immune biomarkers in both intra- and peritumoral tissues were examined by immunohistochemistry. The least absolute shrinkage and selection operator (LASSO) Cox model was used to establish the HRI score. Cox regression analysis was used for multivariate analysis. Nine recurrence-related immune features were identified and integrated into the HRI score. The HRI score was used to categorize patients into low-risk and high-risk groups using the X-tile software. Kaplan-Meier analysis presented that the HRI score showed good stratification between low-risk and high-risk groups in both the derivation cohort (P < 0.001) and the validation cohort (P = 0.014), respectively. Multivariate analysis demonstrated that serum γ-glutamyl transpeptidase, carbohydrate antigen 19-9, lymphoid metastasis, tumor numbers, and the HRI score were independent risk factors associated with recurrence-free survival (RFS). The combination of Shen's model and HRI score provided better performance in recurrence prediction compared with traditional staging systems. The HRI score might serve as a promising RFS predictor for ICC with prognostic values.


Assuntos
Antígenos Glicosídicos Associados a Tumores/metabolismo , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/diagnóstico , Neoplasias Hepáticas/diagnóstico , Fígado/metabolismo , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Estudos de Coortes , Feminino , Hepatectomia , Humanos , Fígado/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Prognóstico , Projetos de Pesquisa , Análise de Sobrevida , Carga Tumoral , gama-Glutamiltransferase/metabolismo
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