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1.
J Hematol Oncol ; 13(1): 9, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005272

RESUMO

BACKGROUND: PARP inhibitors have been the most promising target drugs with widely proven benefits among ovarian cancer patients. Although platinum-response, HR-related genes, or HRD genomic scar detection are acceptably used in assessment of Olaparib response, there are still evident limitations in the present approaches. Therefore, we aim to investigate more accurate approaches to predict Olaparib sensitivity and effective synergistic treatment strategies. METHODS: We probed two databases (TCGA and Qilu Hospital) in order to quest novel miRNAs associated with platinum-sensitivity or HR-related genes. Cellular experiments in vitro or in vivo and PDX models were utilized to validate their role in tumor suppression and Olaparib sensitizing. Furthermore, HR gene mutation was analyzed through WES to explore the relation between HR gene mutation and Olaparib response. RESULTS: High miR-509-3 expression indicated better response to platinum and longer progression-free and overall survival in two independent ovarian cancer patient cohorts (high vs. low miR-509-3 expression; PFS: TCGA P < 0.05, Qilu P < 0.05; OS: TCGA P < 0.05, Qilu P < 0.01). MiR-509-3 could impair the proliferation, migration, and invasion ability but enhance the sensitivity to Olaparib of ovarian cancer cell in vitro and in vivo by directly targeting HMGA2 and RAD51. In two PDX cases (PDX1 and PDX9), miR-509-3 could significantly increase the sensitivity to Olaparib along with the decrease of RAD51 positive rate (mean tumor weight NC + Olaparib vs. miR-509 + Olaparib; PDX1 P < 0.05, PDX9 P < 0.05). Additionally, in PDX8, miR-509-3 treatment dramatically reversed the Olaparib insensitivity (P < 0.05) by downregulating RAD51 expression. RAD51 functional detection revealed that all Olaparib sensitive cases exhibited low RAD51 positive rate (lesser than 50%) in treated groups. Furthermore, among the four HR gene mutation patients, three harbored HR core gene mutation and were sensitive to Olaparib while the remaining one with non-HR core gene mutation did not respond well to Olaparib. CONCLUSIONS: MiR-509-3 can sensitize ovarian cancer cells to Olaparib by impeding HR, which makes it a potential target in PARPi synergistic treatment. HR core gene analysis and RAD51 functional detection are prospectively feasible in prediction of PARPi response.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32019208

RESUMO

Groundwater quality degradation has raised widespread concerns about water supplies and ecological crises in China. In this study, hydrogeochemistry, environmental stable isotopes (δ18O, δD), and principal component analysis were conducted together to reveal the mechanism's response to the hydrogeochemical and quality degradation of groundwater in Yuncheng Basin, Northern China, so that reasonable water resource management strategies can be developed. The study reveals that groundwater faces a tremendous risk of quality decrease during the past decade: (1) the hydrochemical facies of groundwater shows that the bicarbonate and chloride type water was replaced with sulfate type water and the occupying area of SO4·Cl-Na, SO4·HCO3-Na type water expanded dramatically in shallow and intermediate-deep aquifers. (2) Major ion chemistry and hydrogen and oxygen isotope compositions indicate that the major hydrogeochemical processes responsible for groundwater quality deterioration include the dissolution of evaporates (i.e., halite, gypsum, and mirabilite), ion exchange, and evaporation process. Additionally, (3) anthropogenic activities (overutilization of fertilizer) have resulted in nitrate contamination, and have thereby led to groundwater quality degradation.

3.
Pituitary ; 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32062801

RESUMO

PURPOSE: This study was designed to develop a computer-aided diagnosis (CAD) system based on a convolutional neural network (CNN) to diagnose patients with pituitary tumors. METHODS: We included adult patients clinically diagnosed with pituitary adenoma (pituitary adenoma group), or adult individuals without pituitary adenoma (control group). After pre-processing, all the MRI data were randomly divided into training or testing datasets in a ratio of 8:2 to create or evaluate the CNN model. Multiple CNNs with the same structure were applied for different types of MR images respectively, and a comprehensive diagnosis was performed based on the classification results of different types of MR images using an equal-weighted majority voting strategy. Finally, we assessed the diagnostic performance of the CAD system by accuracy, sensitivity, specificity, positive predictive value, and F1 score. RESULTS: We enrolled 149 participants with 796 MR images and adopted the data augmentation technology to create 7960 new images. The proposed CAD method showed remarkable diagnostic performance with an overall accuracy of 91.02%, sensitivity of 92.27%, specificity of 75.70%, positive predictive value of 93.45%, and F1-score of 92.67% in separate MRI type. In the comprehensive diagnosis, the CAD achieved better performance with accuracy, sensitivity, and specificity of 96.97%, 94.44%, and 100%, respectively. CONCLUSION: The CAD system could accurately diagnose patients with pituitary tumors based on MR images. Further, we will improve this CAD system by augmenting the amount of dataset and evaluate its performance by external dataset.

6.
CNS Neurosci Ther ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31943833

RESUMO

AIMS: Hypertension is a leading cause of cerebral small vessel disease (CSVD). Currently, treatments for CSVD are limited. Nicotinamide riboside (NR) can protect against vascular injury and cognitive impairment in neurodegenerative diseases. In this study, the protective effects of NR against angiotensin - (Ang -)-induced CSVD were evaluated. METHODS: To explore the effects of NR in CSVD, C57BL/6 mice were infused with Ang -, and NR was added to the food of the mice for 28 days. Then, short-term memory, blood-brain barrier (BBB) integrity, and endothelial function were detected. Arteriole injury and glial activation were also evaluated. RESULTS: Our data showed that mice infused with Ang - exhibited decreased short-term memory function and BBB leakage due to decreased claudin-5 expression and increased caveolae-mediated endocytosis after 28 days. Furthermore, Ang - decreased the expression of α-smooth muscle actin (α-SMA) and increased the expression of proliferating cell nuclear antigen (PCNA) in arterioles and decreased the expression of neurofilament 200 (NF200) and myelin basic protein (MBP) in the white matter. These CSVD-related damages induced by Ang - were inhibited by NR administration. Moreover, NR administration significantly reduced glial activation around the vessels. CONCLUSION: Our results indicated that NR administration alleviated Ang --induced CSVD by protecting BBB integrity, vascular remodeling, neuroinflammation, and white matter injury (WMI)-associated cognitive impairment.

7.
Oxid Med Cell Longev ; 2020: 8285065, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998445

RESUMO

White matter injury (WMI) is an important cause of high disability after intracerebral haemorrhage (ICH). It is widely accepted that reactive oxygen species (ROS) contributes to WMI, but there is still no evidence-based treatment. Here, mitoquinone (MitoQ), a newly developed selective mitochondrial ROS scavenger, was used to test its neuroprotective potential. The data showed that MitoQ attenuated motor function deficits and motor-evoked potential (MEP) latency prolongation. Further research found that MitoQ blunted the loss of oligodendrocytes and oligodendrocyte precursor cells, therefore reduced demyelination and axon swelling after ICH. In the in vitro experiments, MitoQ, but not the nonselective antioxidant, almost completely attenuated the iron-induced membrane potential decrease and cell death. Mechanistically, MitoQ blocked the ATP deletion and mitochondrial ROS overproduction. The present study demonstrates that the selective mitochondrial ROS scavenger MitoQ may improve the efficacy of antioxidant treatment of ICH by white matter injury alleviation.

8.
J Mater Chem B ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31904075

RESUMO

Biomedical devices that involved continuous and real-time health-care monitoring have drawn much attention in modern medicine, of which skin electronics and implantable devices are widely investigated. Skin electronics are characterized for their non-invasive access to the physiological signals, and implantable devices are superior at the diagnosis and therapy integration. Despite the significant progress achieved, many gaps remain to be explored to provide a more comprehensive overview of human health. As the connecting point of the outer environment and human systems, the oral cavity contains many unique biomarkers that are absent in skin or inner organs, and hence, this could become a promising alternative locus for designing health-care monitoring devices. In this review, we outline the status of the oral cavity during the communication of the environment and human systems and compare the intraoral devices with skin electronics and implantable devices from the biophysical and biochemical aspects. We further summarize the established diagnosis database and technologies that could be adopted to design intraoral biosensors. Finally, the challenges and potential opportunities for intraoral biosensors are discussed. Intraoral biosensors could become an important complement for existing biomedical devices to constitute a more reliable health-care monitoring system.

9.
World J Microbiol Biotechnol ; 36(1): 14, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31897771

RESUMO

Glycogen is conventionally considered as a transient energy reserve that can be rapidly synthesized for glucose accumulation and mobilized for ATP production. However, this conception is not completely applicable to prokaryotes due to glycogen structural heterogeneity. A number of studies noticed that glycogen with small average chain length gc in bacteria has the potential to degrade slowly, which might prolong bacterial environment survival. This phenomenon was previously examined and later formulated as the durable energy storage mechanism hypothesis. Although recent research has been warming to the hypothesis, experimental validation is still missing at current stage. In this review, we summarized recent progress of the hypothesis, provided a supporting mathematical model, and explored the technical pitfalls that shall be avoided in glycogen study.


Assuntos
Bactérias/crescimento & desenvolvimento , Glucose/metabolismo , Glicogênio/química , Trifosfato de Adenosina/metabolismo , Bactérias/química , Bactérias/metabolismo , Sequência de Carboidratos , Metabolismo Energético , Viabilidade Microbiana , Modelos Teóricos
10.
Int J Radiat Biol ; : 1-10, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-31900034

RESUMO

Background: Radiation is a mode of treatment for many pelvic malignancies, most of which originate in the gynecologic, gastrointestinal, and genitourinary systems. However, the healthy gut is unavoidably included in the irradiation volume, resulting in undesirable results that manifest as radiation-induced diarrhea (RID), which is the most common side effect of radiation therapy and significantly affects the patients' quality of life. This study aimed to investigate the potential mechanism of diarrhea after pelvic radiotherapy in rats based on the effect of radiation on bile acid homeostasis and sodium-dependent bile acid transporter (Asbt).Methods: In this experimental study, male Sprague-Dawley rats were divided into the following groups - pelvic irradiation, cholestyramine-concurrent radiation, and control groups. The rats in the pelvic irradiation group were irradiated in the pelvic region with 2 Gy per day for five consecutive days. The total bile acid (TBA) levels in the ileum, colon, and feces were measured using automatic biochemical analyzer, and the levels of individual bile acids were evaluated by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). The mRNA and protein expression of Asbt in ileum were assessed by qRT-PCR and Western blot assay. The rats in the cholestyramine-concurrent radiation group were administered with cholestyramine, a bile acid-chelating resin, and concurrent radiation for 5 days. The body weight of rats was monitored daily, and the degree of diarrhea was scored.Results: Diarrhea was observed at 2 and 3 days post-pelvic radiation. The TBA levels were significantly decreased at 4 and 5 days post-radiation in the ileum (p < .01, p < .01) and increased at 4 and 5 days post-radiation in the colon (p < .05, p < .05). The fecal excretions of TBA were significantly increased at 3, 4, and 5 days post-radiation (p < .05). The levels of individual bile acids were significantly decreased in the ileum and increased in the colon and feces, post-radiation. The mRNA and protein expression of Asbt in the ileum gradually decreased with increasing days of pelvic radiation and significantly decreased at 3 and 5 days post-radiation, respectively. Furthermore, a significant decrease in body weight was observed post-pelvic radiation, and cholestyramine administration did not reverse the weight loss. However, the incidence of RID was decreased after administration of cholestyramine.Conclusions: Bile acid malabsorption is partially responsible for RID post-pelvic radiation in rats, and the potential mechanism is related to the downregulation of the ileal Asbt.

11.
Biomaterials ; 232: 119668, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31927179

RESUMO

Mitophagy is a specific self-protective autophagic process that degrades damaged or dysfunctional mitochondria, and is generally considered to reduce the effectiveness of mitochondria-targeted therapies. Here, we report an energy depletion-based anticancer strategy by selectively activating excessive mitophagy in cancer cells. We fabricate a type of mitochondria-targeting nanomicelles via the self-assembly of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and dc-IR825 (a near-infrared cyanine dye and a photothermal agent). The TPGS/dc-IR825 nanomicelles enable mitochondrial damage in cancer cells, which, for self-protection, activate two autophagic pathways, (1) mitophagy and (2) adenosine triphosphate (ATP) shortage-triggered autophagy. However, the excessive mitophagy/autophagy activities far surpass the degradative capacity of autolysosomes, leading to the formation of micrometer-sized vacuoles and degradation blockage. Immunofluorescence staining and Western blot analysis reveal that the nanomicelle-treated cancer cells are under severe ATP shortage, which eventually causes substantial cell death. Moreover, the nanomicelles intravenously injected into tumor-bearing mice show high tumor accumulation, long tumor retention, and inhibit the tumor growth by inducing excessive mitophagy/autophagy and energy depletion in tumor cells. Additional near-infrared laser irradiation treatment further enhances the in vitro and in vivo anticancer efficiencies of the nanomicelles, due to the excellent photothermal and photodynamic effects of dc-IR825. We believe that this work highlights the important role of mitophagy/autophagy in treating cancers.

14.
Transl Res ; 217: 61-74, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31951826

RESUMO

Intracerebral hemorrhage (ICH), a subtype of stroke with high morbidity and mortality, occurs mainly in the basal ganglia and causes white matter injury (WMI), resulting in severe motor dysfunction and poor prognosis in patients. The preservation of the white matter around the hematoma is crucial for motor function recovery, but there is currently no effective treatment for WMI following ICH. Lithium has been widely used for the treatment of bipolar disorder for decades. Although the protective effects of lithium on neurodegenerative diseases and cerebral trauma have been studied in recent years, whether it can be used to alleviate WMI after ICH remains to be researched. The results of this study revealed that ICH caused significant functional and pathological abnormalities in mice. After LiCl was administered to mice with ICH, behavioural performance and electrophysiological functions were improved and ICH-induced white matter pathological injury, including myelin sheath and axonal degeneration, was ameliorated. Furthermore, LiCl treatment decreased the death of mature oligodendrocytes (OLGs) in ICH mice, which may have been attributed to the enhanced expression of brain-derived neurotrophic factor (BDNF) regulated by the LiCl-induced inhibition of glycogen synthase kinase-3ß (GSK-3ß). The decreased death of OLGs was closely associated with decreased destruction of the myelin sheath and alleviated degradation of the axons. In summary, this study suggests that the protective effect of lithium on WMI after ICH might be related to an increased level of BDNF and that LiCl treatment may be a potential therapeutic method to palliate WMI after ICH.

15.
J Immunother Cancer ; 7(1): 341, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801636

RESUMO

BACKGROUND: Deciphering the correlation between immune-related adverse events (irAEs) categorized by organ system class and clinical benefit of immunotherapy is critical for clinical practice. The aim of this study is to investigate the incidence rates of irAEs and their correlations with objective response rate (ORR) in patients with advanced solid tumours treated with nivolumab (NIVO) or nivolumab plus ipilimumab (NIVO+IPI). METHODS: PubMed, Embase and Cochrane library were searched for eligible studies from January 1st, 2000 to May 1st 2019. Published clinical trials on NIVO or NIVO+IPI with reported irAEs were included. Logit transformation of the irAE incidences was applied for the generation of pooled estimate and Pearson correlation coefficient was calculated to evaluate the correlation between irAE and ORR. RESULTS: 48 clinical trials involving 7936 patients treated with NIVO or NIVO+IPI were included. Compared to NIVO, NIVO+IPI led to more all-grade and grade 3 or higher irAEs categorized by system organ class (P < 0.05). The ORR of NIVO was positively correlated with the incidence rate of skin (r = 0.79, P < 0.001), gastrointestinal (r = 0.56, P = 0.006) and endocrine irAEs (r = 0.44, P = 0.05), but not hepatic, pulmonary and renal irAEs. The ORR of NIVO+IPI was positively correlated with the incidence rate of skin (r = 0.54, P = 0.04), and gastrointestinal irAEs (r = 0.60, P = 0.02), but not endocrine, hepatic, pulmonary and renal irAEs. CONCLUSION: This meta-analysis summarizes the incidence rates of irAEs in patients with advanced solid tumours treated with NIVO or NIVO+IPI, and uncovers their correlations with ORR across multiple neoplasms. These findings highlight the potential of irAE to reflect response to NIVO or NIVO+IPI.

18.
Plast Reconstr Surg ; 144(6): 1116e-1117e, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31764691
19.
Viruses ; 11(11)2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31752437

RESUMO

The coastal sediments were considered to contain diverse phages playing important roles in driving biogeochemical cycles based on genetic analysis. However, till now, benthic phages in coastal sediments were very rarely isolated, which largely limits our understanding of their biological characteristics. Here, we describe a novel lytic phage (named Shewanella phage S0112) isolated from the coastal sediments of the Yellow Sea infecting a sediment bacterium of the genus Shewanella. The phage has a very high replication capability, with the burst size of ca. 1170 phage particles per infected cell, which is 5-10 times higher than that of most phages isolated before. Meanwhile, the latent period of this phage is relatively longer, which might ensure adequate time for phage replication. The phage has a double-stranded DNA genome comprising 62,286 bp with 102 ORFs, ca. 60% of which are functionally unknown. The expression products of 16 ORF genes, mainly structural proteins, were identified by LC-MS/MS analysis. Besides the general DNA metabolism and structure assembly genes in the phage genome, there is a cluster of auxiliary metabolic genes that may be involved in 7-cyano-7-deazaguanine (preQ0) biosynthesis. Meanwhile, a pyrophosphohydrolase (MazG) gene being considered as a regulator of programmed cell death or involving in host stringer responses is inserted in this gene cluster. Comparative genomic and phylogenetic analysis both revealed a great novelty of phage S0112. This study represents the first report of a benthic phage infecting Shewanella, which also sheds light on the phage-host interactions in coastal sediments.

20.
Sci Rep ; 9(1): 16958, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31740745

RESUMO

Motor function deficit induced by white matter injury (WMI) is one of the most severe complications of intracerebral haemorrhage (ICH). The degree of WMI is closely related to the prognosis of patients after ICH. However, the current behavioural assessment of motor function used in the ICH mouse model is mainly based on that for ischaemic stroke and lacks the behavioural methods that accurately respond to WMI. Here, a series of easy-to-implement behavioural tests were performed to detect motor deficits in mice after ICH. The results showed that the grip strength test and the modified pole test not only can better distinguish the degree of motor dysfunction between different volumes of blood ICH models than the Basso Mouse Scale and the beam walking test but can also accurately reflect the severity of WMI characterized by demyelination, axonal swelling and the latency of motor-evoked potential delay induced by ICH. In addition, after ICH, the results of grip tests and modified pole tests, rather than the Basso Mouse Scale and the beam walking test, were worse than those observed after intraventricular haemorrhage (IVH), which was used as a model of brain haemorrhage in non-white matter areas. These results indicate that the grip strength test and the modified pole test have advantages in detecting the degree of motor deficit induced by white matter injury after ICH in mice.

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