Publications by authors named "Jiayi Huang"

138 Publications

Optical Coherence Tomography and Microdialysis for Microneedle-Mediated Penetration Enhancement Study of Paeoniflorin-Loaded Ethosomes.

Skin Pharmacol Physiol 2021 May 6:1-11. Epub 2021 May 6.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.

Background: To understand the cumulative effect of topical formulations after medication, evaluate the therapeutic effect of microneedle-assisted (MN-assisted) paeoniflorin-loaded ethosomes (TGP-E), and explore the potential for deep penetration of drugs, this paper uses microdialysis to systematically study the percutaneous pharmacokinetics of TGP-E.

Methods: First, optical coherence tomography (OCT) was used to study the effectiveness of microneedle puncture. Second, a microdialysis method and a UPLC-MS method for determining the amount of paeoniflorin (Pae) in dialysate were established. Finally, the transdermal pharmacokinetics of TGP-E was studied using in vivo microdialysis in rats under the above MN-assisted conditions.

Results: The optimal MN-assisted conditions were obtained at a microneedle length of 500 μm, a pressure of 3 N, and an action time of 3 min. The pharmacokinetic results demonstrated that the maximum drug concentration (Cmax) and the area under the curve (AUC) of the TGP-E gel were higher than the TGP-saline solution gel, and the mean retention time was lower. These indicated that microneedle can promote the entry of the ethosomes into the skin for in vivo experiments and greatly improve the possibility of deep penetration of the water-soluble Pae.

Conclusion: Therefore, the microneedle-ethosomes delivery system is a more ideal means for promoting the deep penetration of Pae. These findings may provide a reference for the combination of multiple penetration-enhancement ways to promote drug absorption, and also provide a new insight to realize the development of novel, safe, and more effective dosage forms and administration routes of drugs.
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http://dx.doi.org/10.1159/000514321DOI Listing
May 2021

NLK suppresses MAVS-mediated signaling in black carp antiviral innate immunity.

Dev Comp Immunol 2021 Apr 17;122:104105. Epub 2021 Apr 17.

State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, 410081, China. Electronic address:

Mammalian Nemo-like kinase (NLK) plays important roles in multiple biological processes including immune response; however, the roles of teleost NLK remain largely unknown. In the present study, the NLK homolog (bcNLK) of black carp (Mylopharyngodon piceus) has been cloned and characterized. The coding region of bcNLK consists of 1427 nucleotides and encodes 476 amino acid, including two low complexity region (LCR) domains at the N-terminus and a serine/threonine protein kinase catalytic (S-TKc) domain in the middle region. The transcription of bcNLK are promoted after spring viremia of carp virus (SVCV) infection and poly (I:C) stimulation in host cells, but not post LPS treatment. bcNLK exhibits weak impact on the transcription of interferon (IFN) promoter in the reporter assay, however, black carp MAVS (bcMAVS)-mediated IFN promoter transcription is remarkably dampened by bcNLK. The interaction between bcNLK and bcMAVS is detected through the co-immunoprecipitation assay. Accordingly, the plaque assay results show that bcMAVS-mediated antiviral ability is impaired by bcNLK. Moreover, knockdown of bcNLK in host cells leads to the enhanced antiviral ability against SVCV. All these data support the conclusion that black carp NLK associates with MAVS and inhibited MAVS-mediated antiviral signaling.
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http://dx.doi.org/10.1016/j.dci.2021.104105DOI Listing
April 2021

Mechanism of the inhibition and detoxification effects of the interaction between nanoplastics and microalgae Chlorella pyrenoidosa.

Sci Total Environ 2021 Apr 6;783:146919. Epub 2021 Apr 6.

School of Resource and Environmental Sciences, Hubei Biomass-Resource Chemistry and Environmental Biotechnology Key Laboratory, Wuhan University, Wuhan, Hubei 430079, China. Electronic address:

Most previous studies have focused on the toxicity of microplastics on aquatic organisms. However, research on nanoplastics is still limited and poses significant threat to aquatic organisms than microplastics. Therefore, this study investigated the effects of nanoplastics (80 nm) on the microalgae Chlorella pyrenoidosa. One unanticipated finding was that inhibition and detoxification effects existed in the interaction between nanoplastics and C. pyrenoidosa. Nanoplastics contributed the maximum inhibition rates of 27.73%, 29.64%, and 11.76% on algal growth, chlorophyll a, and Fv/Fm, respectively, which were much higher than those of microplastics. However, the inhibitory effect of nanoplastics gradually decreased with prolonged exposure time after reaching a maximum. The transcriptomic analysis explained that the inhibition effect of nanoplastics was due to the blockage of the gene expression of aminoacyl tRNA synthetase and the synthesis of related enzymes and proteins at low concentrations (10 mg·L). Moreover, it affected DNA damage repair and hindered photosynthesis at high concentrations (50 mg·L). The detoxification phenomenon is attributed to the promotion of cell proliferation, the acceleration of the degradation of damaged proteins and organs, and the regulation of intracellular osmotic pressure in algae. The results of this study provide an understanding of the mechanism underlying the interaction between nanoplastics and microalgae.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146919DOI Listing
April 2021

A comparison of the mechanisms and performances of Acorus calamus, Pontederia cordata and Alisma plantagoaquatica in removing nitrogen from farmland wastewater.

Bioresour Technol 2021 Jul 6;332:125105. Epub 2021 Apr 6.

College of Resources and Environment, Hunan Agricultural University, Changsha 410128, PR China; Hunan Provincial Key Laboratory of Farmland Pollution Control and Agricultural Resources Use, Hunan Provincial Key Laboratory of Nutrition in Common University, National Engineering Laboratory on Soil and Fertilizer Resources Efficient Utilization, Changsha 410128, PR China. Electronic address:

This study examined the performances of Acorus calamus, Pontederia cordata, and Alisma plantagoaquatica in removing nitrogen (N) from farmland wastewater. P. cordata showed the fastest rate of N removal, followed by A. plantagoaquatica, whereas that of A. calamus was slowest. P. cordata and A. plantagoaquatica achieving a greater rate of TN reduction in soil than that by A. calamus. A. plantagoaquatica demonstrated the highest N adsorption capacity, 32.6% and 392.1% higher than that of P. cordata and A. calamus, respectively. The higher potential nitrification and denitrification rate, and abundance of functional genes in the P. cordata microcosm resulted in a stronger process of nitrification-denitrification, which accounted for 65.99% of TN loss. Plant uptake and nitrification-denitrification were responsible for 50.06% and 49.94% of TN removed within the A. plantagoaquatica. Nitrification-denitrification accounted for 86.35% of TN loss in A. calamus. These findings helped to insight into N removal mechanisms in different plants.
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http://dx.doi.org/10.1016/j.biortech.2021.125105DOI Listing
July 2021

The predictive value of absolute lymphocyte counts on tumor progression and pseudoprogression in patients with glioblastoma.

BMC Cancer 2021 Mar 16;21(1):285. Epub 2021 Mar 16.

Department of Medicine Division of Oncology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8056, St Louis, MO, 63110, USA.

Background: Differentiating true glioblastoma multiforme (GBM) from pseudoprogression (PsP) remains a challenge with current standard magnetic resonance imaging (MRI). The objective of this study was to explore whether patients' absolute lymphocyte count (ALC) levels can be utilized to predict true tumor progression and PsP.

Methods: Patients were considered eligible for the study if they had 1) GBM diagnosis, 2) a series of blood cell counts and clinical follow-ups, and 3) tumor progression documented by both MRI and pathology. Data analysis results include descriptive statistics, median (IQR) for continuous variables and count (%) for categorical variables, p values from Wilcoxon rank sum test or Fisher's exact test for comparison, respectively, and Kaplan-Meier analysis for overall survival (OS). OS was defined as the time from patients' second surgery to their time of death or last follow up if patients were still alive.

Results: 78 patients were included in this study. The median age was 56 years. Median ALC dropped 34.5% from baseline 1400 cells/mm to 917 cells/mm after completion of radiation therapy (RT) and temozolomide (TMZ). All study patients had undergone surgical biopsy upon MRI-documented progression. 37 had true tumor progression (47.44%) and 41 had pseudoprogression (52.56%). ALC before RT/TMZ, post RT/TMZ and at the time of MRI-documented progression did not show significant difference between patients with true progression and PsP. Although not statistically significant, this study found that patients with true progression had worse OS compared to those with PsP (Hazard Ratio [HR] 1.44, 95% CI 0.86-2.43, P = 0.178). This study also found that patients with high ALC (dichotomized by median) post-radiation had longer OS.

Conclusion: Our results indicate that ALC level in GBM patients before or after treatment does not have predictive value for true disease progression or pseudoprogression. Patients with true progression had worse OS compared to those who had pseudoprogression. A larger sample size that includes CD4 cell counts may be needed to evaluate the PsP predictive value of peripheral blood biomarkers.
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http://dx.doi.org/10.1186/s12885-021-08004-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968315PMC
March 2021

Identification and characterization of a wolfberry carboxypeptidase inhibitor from Lycium barbarum.

Food Chem 2021 Jul 19;351:129338. Epub 2021 Feb 19.

School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore. Electronic address:

Hyperstable cysteine-rich peptides (CRPs) represent an underexplored superfamily of bioactives in functional foods. An example is wolfberry of the Lycium barbarum family. Previously, we discovered a CRP, designated α-lybatide, from L. barbarum bark. Herein, we report the discovery of β-lybatide, a novel carboxypeptidase inhibitor belonging to a different CRP family from the wolfberry plant. Proteomic and transcriptomic analyses showed that β-lybatide contains 36 amino acids with six cysteine residues. NMR spectroscopy revealed that β-lybatide displays a knottin-like structure that renders it highly resistant to thermal, chemical and enzymatic degradation, conditions important for keeping its structural integrity in gastrointestinal tract. Biochemical assays showed that β-lybatide is a potent carboxypeptidase inhibitor which could contribute to the wolfberry biological activities. Bioinformatics analysis revealed an additional 49 β-lybatide-like plant carboxypeptidase inhibitors. Together, our results show that β-lybatide is the first and the smallest plant-derived hyperstable carboxypeptidase inhibitor discovered from a functional food.
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http://dx.doi.org/10.1016/j.foodchem.2021.129338DOI Listing
July 2021

Evaluation of interim MRI changes during limited-field radiation therapy for glioblastoma and implications for treatment planning.

Radiother Oncol 2021 May 13;158:237-243. Epub 2021 Feb 13.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, United States. Electronic address:

Background And Purpose: Consensus for defining gross tumor volume (GTV) and clinical target volume (CTV) for limited-field radiation therapy (LFRT) of GBM are not well established. We leveraged a department MRI simulator to image patients before and during LFRT to address these questions.

Materials And Methods: Supratentorial GBM patients receiving LFRT (46 Gy + boost to 60 Gy) underwent baseline MRI (MRI1) and interim MRI during RT (MRI2). GTV1 was defined as T1 enhancement + surgical cavity on MRI1 without routine inclusion of T2 abnormality (unless tumor did not enhance). The initial CTV margin was 15 mm from GTV1, and the boost CTV margin was 5-7 mm. The GTV1 characteristics were categorized into three groups: identical T1 and T2 abnormality (Group A), T1 only with larger T2 abnormality not included (Group B), and T2 abnormality when tumor lacked enhancement (Group C). GTV2 was contoured on MRI2 and compared with GTV1 plus 5-15 mm expansions.

Results: Among 120 patients treated from 2014-2019, 29 patients (24%) underwent replanning based on MRI2. On MRI2, 84% of GTV2 were covered by GTV1 + 5 mm, 93% by GTV1 + 7 mm, and 98% by GTV1 + 15 mm. On MRI1, 43% of GTV1 could be categorized into Group A, 39% Group B, and 18% Group C. Group B's patterns of failure, local control, or progression-free survival were similar to Group A/C.

Conclusions: Initial CTV margin of 15 mm followed by a boost CTV margin of 7 mm is a reasonable approach for LFRT of GBM. Omitting routine inclusion of T2 abnormality from GTV delineation may not jeopardize disease control.
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http://dx.doi.org/10.1016/j.radonc.2021.01.040DOI Listing
May 2021

Stattic alleviates acute hepatic damage induced by LPS/d-galactosamine in mice.

Innate Immun 2021 Feb;27(2):201-209

Department of Pathophysiology, Chongqing Medical University, China.

Increasing evidence indicates that signal transducer and activator of transcription 3 (STAT3), a vital transcription factor, plays crucial roles in the regulation of inflammation. STAT3 has become a novel therapeutic target for intervention in inflammation-related disorders. However, it remains unclear whether STAT3 plays a part in acute hepatic damage. To investigate the effects of STAT3 here, LPS/d-GalN-induced hepatic damage was induced in mice, the STAT3 inhibitor Stattic was administered, and the degree of liver injury, inflammation, and hepatocyte apoptosis were investigated. The results showed that Stattic mitigated the hepatic morphologic abnormalities and decreased the level of aminotransferase in LPS/D-GalN-insulted mice. The results also indicated that Stattic decreased the levels of TNF-α and IL-6, prevented the activation of the caspase cascade, suppressed cleavage of PARP, and decreased the quantity of TUNEL-positive cells. These results suggest that Stattic provided protective benefits in LPS/d-GalN-induced hepatic damage, and the protective effects might be associated with its anti-inflammatory and anti-apoptotic effects. Therefore, STAT3 might become a novel target for intervening in inflammation-based and apoptosis-based hepatic disorders.
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http://dx.doi.org/10.1177/1753425920988330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882804PMC
February 2021

Successful administration of sequential TVEC and pembrolizumab followed by Temozolomide in immunotherapy refractory intracranial metastatic melanoma with acquired B2M mutation.

Oncotarget 2020 Dec 29;11(52):4836-4844. Epub 2020 Dec 29.

Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.

Despite the substantial advances in the management of metastatic melanoma with the introduction of immune checkpoint inhibitors (ICI), many patients develop disease progression during treatment with immunotherapy. This has been suggested to be mediated by several mechanisms that contribute to acquired resistance to ICI, one of which is acquired beta-2 microgloubulin (B2M) mutation. Talimogene laherparepvec (TVEC) is a genetically modified oncolytic virus that can enhance antitumor immunity. Temozolomide (TMZ) is an oral alkylating agent that has been suggested to augment anti-tumor immune response. The clinical significance of TVEC and TMZ in metastatic melanoma patients who are refractory to immunotherapy is unknown. We report a case of a patient with immunotherapy refractory intracranial metastatic melanoma after initial response to ICI who had acquired B2M mutation. The patient received TVEC and pembrolizumab followed by TMZ. The patient maintained durable response of her visceral and intracranial disease for 19 months and ongoing. More research is essential to delineate whether TVEC or TMZ has efficacy in immunotherapy refractory metastatic melanoma with acquired B2M mutation.
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http://dx.doi.org/10.18632/oncotarget.27848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779252PMC
December 2020

Dosimetric predictors of symptomatic radiation necrosis after five-fraction radiosurgery for brain metastases.

Radiother Oncol 2021 03 11;156:181-187. Epub 2020 Dec 11.

Department of Radiation Oncology, Washington University School of Medicine, St Louis, USA. Electronic address:

Background: To identify factors predictive of developing symptomatic radiation necrosis (sRN) among patients with either intact or resected brain metastases undergoing five-fraction stereotactic radiosurgery (5fSRS).

Methods: Multi-institutional retrospective review of 117 brain metastases from 83 patients treated with 5fSRS. The cumulative incidence of sRN and predictors of sRN were calculated using Gray's competing risks and Cox regression.

Results: The median dose of 5fSRS was 30 Gy (range: 25-40), and 21 lesions (18%) had prior SRS. After a median follow-up of 10.3 months (range: 3-52), the cumulative sRN incidence was 15%, with a median time to sRN of 6.9 months (range: 1.8-31.7). sRN incidence was significantly higher among the lesions treated with prior SRS: hazard ratio (HR): 7.48 [95% confidence interval: 2.57-21.8]. Among lesions without prior SRS, higher volume of uninvolved brain receiving 25 Gy (BrainV25; HR: 1.07 [1.02-1.12]) and 30 Gy (BrainV30; HR: 1.07 [1.01-1.33]) were the most significant factors associated with sRN. Similar results were also observed among the patients with prior SRS. For lesions without prior SRS, BrainV25 > 16 cm (HR: 11.7 [1.47-93.3]) and BrainV30 > 10 cm (HR: 7.08 [1.52-33.0]) were associated with significantly higher risk of sRN. At two years, the sRN incidence was 21% if violating either dosimetric threshold and 2% if violating neither (p = .007).

Conclusion: BrainV25 and BrainV30 are significant dosimetric predictors of sRN of brain metastases treated with 5fSRS. In the absence of prior SRS, maintaining BrainV25Gy < 16 cm and BrainV30Gy < 10 cm may minimize sRN risk.
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http://dx.doi.org/10.1016/j.radonc.2020.12.011DOI Listing
March 2021

Internal dose escalation associated with increased local control for melanoma brain metastases treated with stereotactic radiosurgery.

J Neurosurg 2020 Dec 11:1-7. Epub 2020 Dec 11.

Departments of1Radiation Oncology and.

Objective: The internal high-dose volume varies widely for a given prescribed dose during stereotactic radiosurgery (SRS) to treat brain metastases (BMs). This may be altered during treatment planning, and the authors have previously shown that this improves local control (LC) for non-small cell lung cancer BMs without increasing toxicity. Here, they seek to identify potentially actionable dosimetric predictors of LC after SRS for melanoma BM.

Methods: The records of patients with unresected melanoma BM treated with single-fraction Gamma Knife RS between 2006 and 2017 were reviewed. LC was assessed on a per-lesion basis, defined as stability or a decrease in lesion size. Outcome-oriented approaches were utilized to determine optimal dichotomization for dosimetric variables relative to LC. Univariable and multivariable Cox regression analysis was implemented to evaluate the impact of collected parameters on LC.

Results: Two hundred eighty-seven melanoma BMs in 79 patients were identified. The median age was 56 years (range 31-86 years). The median follow-up was 7.6 months (range 0.5-81.6 months), and the median survival was 9.3 months (range 1.3-81.6 months). Lesions were optimally stratified by volume receiving at least 30 Gy (V30) greater than or equal to versus less than 25%. V30 was ≥ and < 25% in 147 and 140 lesions, respectively. For all patients, 1-year LC was 83% versus 66% for V30 ≥ and < 25%, respectively (p = 0.001). Stratifying by volume, lesions 2 cm or less (n = 215) had 1-year LC of 82% versus 70% (p = 0.013) for V30 ≥ and < 25%, respectively. Lesions > 2 to 3 cm (n = 32) had 1-year LC of 100% versus 43% (p = 0.214) for V30 ≥ and < 25%, respectively. V30 was still predictive of LC even after controlling for the use of immunotherapy and targeted therapy. Radionecrosis occurred in 2.8% of lesions and was not significantly associated with V30.

Conclusions: For a given prescription dose, an increased internal high-dose volume, as indicated by measures such as V30 ≥ 25%, is associated with improved LC but not increased toxicity in single-fraction SRS for melanoma BM. Internal dose escalation is an independent predictor of improved LC even in patients receiving immunotherapy and/or targeted therapy. This represents a dosimetric parameter that is actionable at the time of treatment planning and warrants further evaluation.
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http://dx.doi.org/10.3171/2020.7.JNS192210DOI Listing
December 2020

Successful Use of BRAF/MEK Inhibitors as a Neoadjuvant Approach in the Definitive Treatment of Papillary Craniopharyngioma.

J Natl Compr Canc Netw 2020 12 2;18(12):1590-1595. Epub 2020 Dec 2.

1Division of Medical Oncology, Department of Medicine.

Craniopharyngiomas are rare tumors that arise in the suprasellar region of the brain and are known for their aggressive nature despite their WHO grade I. This is due to the complex neuroanatomy of the sellar/suprasellar region and their proximity to the optic nerve apparatus, hypothalamic-pituitary tract, and other critical neuroanatomical structures. Definitive treatment is based on a multidisciplinary approach and often involves a combination of surgical, radiation, and medical therapy. However, there is high morbidity associated with surgery and RT due to the complex neuroanatomy of this region. Recently, BRAFV600E somatic mutation has been identified in most papillary craniopharyngiomas. This discovery has led to the novel use of RAF pathway inhibitors to treat these tumors. We report the successful use of dabrafenib (BRAF inhibitor) and trametinib (mitogen-activated protein kinase kinase inhibitor) in the neoadjuvant setting followed by definitive stereotactic radiosurgery. We propose an algorithm based on available literature on the integration of targeted therapy in the management of papillary craniopharyngiomas. Our observations, together with prior case reports, advocate the incorporation of targeted therapy for unresectable craniopharyngiomas and reinforce that treatment with dual-targeted therapy is safe and effective.
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http://dx.doi.org/10.6004/jnccn.2020.7624DOI Listing
December 2020

Can proton therapy reduce radiation-related lymphopenia in glioblastoma?

Neuro Oncol 2021 02;23(2):179-181

Miami Cancer Institute and Florida International University, Miami, Florida.

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http://dx.doi.org/10.1093/neuonc/noaa273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906054PMC
February 2021

Prognostic impact of CDKN2A/B deletion, TERT mutation, and EGFR amplification on histological and molecular IDH-wildtype glioblastoma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa126. Epub 2020 Sep 18.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.

Background: We aimed to evaluate the clinical outcomes of molecular glioblastoma (mGBM) as compared to histological GBM (hGBM) and to determine the prognostic impact of mutation, amplification, and deletion on isocitrate dehydrogenase (IDH)-wildtype GBM.

Methods: IDH-wildtype GBM patients treated with radiation therapy (RT) between 2012 and 2019 were retrospectively analyzed. mGBM was defined as grade II-III IDH-wildtype astrocytoma without histological features of GBM but with one of the following molecular alterations: mutation, amplification, or combination of whole chromosome 7 gain and whole chromosome 10 loss. Overall survival (OS) and progression-free survival (PFS) were calculated from RT and analyzed using the Kaplan-Meier method. Multivariable analysis (MVA) was performed using Cox regression to identify independent predictors of OS and PFS.

Results: Of the 367 eligible patients, the median follow-up was 11.7 months. mGBM and hGBM did not have significantly different OS (median: 16.6 vs 13.5 months, respectively, = .16), nor PFS (median: 11.7 vs 7.3 months, respectively, = .08). However, mGBM was associated with better OS (hazard ratio [HR] 0.50, 95% CI 0.29-0.88) and PFS (HR 0.43, 95% CI 0.26-0.72) than hGBM after adjusting for known prognostic factors on MVA. deletion was associated with worse OS (HR 1.57, 95% CI 1.003-2.46) and PFS (HR 1.57, 95% CI 1.04-2.36) on MVA, but mutation and amplification were not.

Conclusion: Criteria for mGBM may require further refinement and validation. deletion, but not mutation or amplification, may be an independent prognostic biomarker for IDH-wildtype GBM patients.
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http://dx.doi.org/10.1093/noajnl/vdaa126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668466PMC
September 2020

Doping Lanthanide Nanocrystals With Non-lanthanide Ions to Simultaneously Enhance Up- and Down-Conversion Luminescence.

Front Chem 2020 23;8:832. Epub 2020 Sep 23.

Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China.

The rare-earth nanocrystals containing Er emitters offer very promising tools for imaging applications, as they can not only exhibit up-conversion luminescence but also down-conversion luminescence in the second near-infrared window (NIR II). Doping non-lanthanide cations into host matrix was demonstrated to be an effective measure for improving the luminescence efficiency of Er ions, while still awaiting in-depth investigations on the effects of dopants especially those with high valence states on the optical properties of lanthanide nanocrystals. To address this issue, tetravalent Zr doped hexagonal NaGdF:Yb,Er nanocrystals were prepared, and the enhancement effects of the Zr doping level on both up-conversion luminescence in the visible window and down-conversion luminescence in NIR II window were investigated, with steady-state and transient luminescence spectroscopies. The key role of the local crystal field distortions around Er emitters was elucidated in combination with the results based on both of Zr and its lower valence counterparts, e.g., Sc, Mg, Mn. Univalent ions such as Li was utilized to substitute Na ion rather than Gd, and the synergistic effects of Zr and Li ions by co-doping them into NaGdF:Yb,Er nanocrystals were investigated toward optimal enhancement. Upon optimization, the up-conversion emission of co-doped NaGdF:Yb,Er nanocrystals was enhanced by more than one order of magnitude compared with undoped nanocrystals. The current studies thus demonstrate that the local crystal field surrounding emitters is an effective parameter for manipulating the luminescence of lanthanide emitters.
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http://dx.doi.org/10.3389/fchem.2020.00832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538674PMC
September 2020

A feasibility study to evaluate early treatment response of brain metastases one week after stereotactic radiosurgery using perfusion weighted imaging.

PLoS One 2020 3;15(11):e0241835. Epub 2020 Nov 3.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.

Background: To explore if early perfusion-weighted magnetic resonance imaging (PWI) may be a promising imaging biomarker to predict local recurrence (LR) of brain metastases after stereotactic radiosurgery (SRS).

Methods: This is a prospective pilot study of adult brain metastasis patients who were treated with SRS and imaged with PWI before and 1 week later. Relative cerebral blood volume (rCBV) parameter maps were calculated by normalizing to the mean value of the contralateral white matter on PWI. Cox regression was conducted to explore factors associated with time to LR, with Bonferroni adjusted p<0.0006 for multiple testing correction. LR rates were estimated with the Kaplan-Meier method and compared using the log-rank test.

Results: Twenty-three patients were enrolled from 2013 through 2016, with 22 evaluable lesions from 16 patients. After a median follow-up of 13.1 months (range: 3.0-53.7), 5 lesions (21%) developed LR after a median of 3.4 months (range: 2.3-5.7). On univariable analysis, larger tumor volume (HR 1.48, 95% CI 1.02-2.15, p = 0.04), lower SRS dose (HR 0.45, 95% CI 0.21-0.97, p = 0.04), and higher rCBV at week 1 (HR 1.07, 95% CI 1.003-1.14, p = 0.04) had borderline association with shorter time to LR. Tumors >2.0cm3 had significantly higher LR than if ≤2.0cm3: 54% vs 0% at 1 year, respectively, p = 0.008. A future study to confirm the association of early PWI and LR of the high-risk cohort of lesions >2.0cm3 is estimated to require 258 patients.

Conclusions: PWI at week 1 after SRS may have borderline association with LR. Tumors <2.0cm3 have low risk of LR after SRS and may be low-yield for predictive biomarker studies. Information regarding sample size and potential challenges for future imaging biomarker studies may be gleaned from this pilot study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241835PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608872PMC
January 2021

Chemical- and species-specific toxicity of nonylphenol and octylphenol to microalgae Chlorella pyrenoidosa and Scenedesmus obliquus.

Environ Toxicol Pharmacol 2021 Jan 17;81:103517. Epub 2020 Oct 17.

College of Resource and Environmental Science, Wuhan University, Wuhan, 430072, PR China; School of Resource and Environmental Sciences, Hubei Biomass-Resource Chemistry and Environmental Biotechnology Key Laboratory, Wuhan University, Wuhan, Hubei, 430079, PR China. Electronic address:

As typical endocrine disrupters, nonylphenol (NP) and octylphenol (OP) are emerging pollutants that have attracted wide attention. This study investigated the toxicity effects of NP and OP on microalgae Chlorella pyrenoidosa and Scenedesmus obliquus, particularly on their growth inhibition, photosynthetic pigment, chlorophyll fluorescence, and superoxide dismutase and malondialdehyde levels. Results showed that the 96 h EC of NP and OP was 2.89 and 5.21 mg/L on C. pyrenoidosa, respectively, and 1.54 and 8.48 mg/L on S. obliquus, respectively. NP exerted a stronger inhibitory effect on cell growth, photosynthesis, and PSII activity, and it contributed more oxidative stress on C. pyrenoidosa than on S. obliquus. By contrast, OP exerted a stronger inhibitory effect on S. obliquus than on C. pyrenoidosa. Furthermore, the toxicity of OP to the tested microalgae was lower than that of NP. Principal component analysis (PCA) and Pearson's correlation indicate that the accumulation of reactive oxygen species is the dominant mechanism of NP and OP cellular toxicity. The principal components of NP and OP affecting microalgae are distinct in the PCA plot, and different endocrine disrupters have varying chemical-specific influences on algal cells. This study confirmed that the toxicity of NP and OP to microalgae C. pyrenoidosa and S. obliquus is chemical- and species-specific. These findings should be considered when assessing the health risk of environmental pollution.
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http://dx.doi.org/10.1016/j.etap.2020.103517DOI Listing
January 2021

Radiation and Checkpoint Inhibitor Immunotherapy Lead to Long Term Disease Control in a Metastatic RCC patient With Brain Metastases.

Front Oncol 2020 23;10:566070. Epub 2020 Sep 23.

Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States.

Renal cell carcinoma (RCC) comprises 4.2% of all new cancer cases in the United States and 30% of cases are metastatic (mRCC) at diagnosis. Brain metastatic RCC historically has poor prognosis, but the development of immune checkpoint inhibitors has revolutionized their care and may be successfully combined with SBRT to improve prognosis. Here, we present a case of a patient with mRCC who had brain metastases treated with concurrent immune checkpoint inhibitors and SBRT. He continues to survive with good functional status years following his initial diagnosis. We discuss the relevant history regarding treatment approach in patients with brain metastatic RCC, ongoing trials focusing on the combination of immunotherapy and radiation, and the potential and promise of the abscopal effect.
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http://dx.doi.org/10.3389/fonc.2020.566070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539115PMC
September 2020

Exosome: A Review of Its Classification, Isolation Techniques, Storage, Diagnostic and Targeted Therapy Applications.

Int J Nanomedicine 2020 22;15:6917-6934. Epub 2020 Sep 22.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China.

Exosomes are nano-sized small extracellular vesicles secreted by cells, carrying nucleic acids, proteins, lipids and other bioactive substances to play a role in the body's physiological and pathological processes. Compared to synthetic carriers such as liposomes and nanoparticles, the endogeneity and heterogeneity of exosomes give them extensive and unique advantages in the field of disease diagnosis and treatment. However, the storage stability, low yield, low purity, and weak targeting of exosomes limit its clinical application. For this reason, further exploration is needed to optimize the above problems and facilitate future functional studies of exosomes. In this paper, the origin, classification, preparation and characterization, storage stability and applications of exosome delivery system are summarized and discussed by searching a large number of literatures.
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http://dx.doi.org/10.2147/IJN.S264498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519827PMC
November 2020

Evaluation of the Metastatic Spine Disease Multidisciplinary Working Group Algorithms as Part of a Multidisciplinary Spine Tumor Conference.

Global Spine J 2020 Oct 16;10(7):888-895. Epub 2019 Oct 16.

7548Washington University, St Louis, MO, USA.

Study Design: Retrospective cohort study.

Objective: The Metastatic Spine Disease Multidisciplinary Working Group Algorithms are evidence and expert opinion-based strategies for utilizing radiation therapy, interventional radiology procedures, and surgery to treat 5 types of spine metastases: asymptomatic spinal metastases, uncomplicated spinal metastases, stable vertebral compression fractures (VCF), unstable VCF, and metastatic epidural spinal cord compression (MESCC). Evaluation of this set of algorithms in a clinical setting is lacking. The authors aimed to identify rate of treatment adherence to the Working Group Algorithms and, subsequently, update these algorithms based on actual patient management decisions made at a single-institution, multidisciplinary, spine tumor conference.

Methods: Patients with metastatic spine disease from primary non-hematologic malignancies discussed at an institutional spine tumor conference from 2013 to 2016 were evaluated. Rates of Working Group Algorithms adherence were calculated for each type of metastasis. Based on the reasons for algorithm nonadherence, and patient outcomes in such cases, updated Working Group Algorithms recommendations were proposed.

Results: In total, 154 eligible patients with 171 spine metastases were evaluated. Rates of algorithm adherence were as follows: asymptomatic (67%), uncomplicated (73%), stable VCF (20%), unstable VCF (32%), and MESCC (41%). The most common deviation from the Working Group Algorithms was surgery for MESCC despite poor prognostic factors, but this treatment strategy was supported based on median survival surpassing 6 months in these patients.

Conclusions: Adherence to the Working Group Algorithm was lowest for MESCC and VCF patients, but many nonadherent treatments were supported by patient survival outcomes. We proposed updates to the Working Group Algorithm based on these findings.
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http://dx.doi.org/10.1177/2192568219882649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485068PMC
October 2020

Sleep deprivation aggravated lipopolysaccharide/D-galactosamine-induced acute liver injury by suppressing melatonin production.

Inflamm Res 2020 Nov 18;69(11):1133-1142. Epub 2020 Aug 18.

Department of Neurology, University-Town Hospital of Chongqing Medical University, 55 Middle Road, University City, Shapingba District, Chongqing, 401331, China.

Objective: Sleep loss is common in patients with liver injury, but the effects of sleep deprivation (SD) on liver injury remain unclear. In the present study, the potential effects of SD on acute liver injury and the underlying mechanisms have been investigated.

Methods: The sleep of male BALB/c mice has been deprived by using a modified multiple platform water bath for 3 days and acute liver injury was induced by intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (D-Gal). The degree of liver injury was detected by aminotransferase determination, histopathology and survival rate analysis. Inflammatory response and melatonin (MT) were measured by enzyme-linked immunosorbent assay (ELISA). In addition, hepatocyte apoptosis was determined by caspase activity measurement and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay.

Results: We observed that SD increased plasma aminotransferases, TUNEL-positive hepatocytes, histological abnormalities and mortality rates in mice with LPS/D-Gal treatment. SD also promoted LPS/D-Gal-induced production of TNF-α and upregulated hepatic caspase-8, caspase-9, and caspase-3 activities in LPS/D-Gal-exposed mice. In addition, SD significantly decreased MT contents in plasma of mice with acute liver injury, but supplementation with MT reversed these SD-promoted changes.

Conclusion: Our data suggested that SD exacerbated LPS/D-Gal-induced liver injury via decreasing melatonin production.
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http://dx.doi.org/10.1007/s00011-020-01393-3DOI Listing
November 2020

Association of systolic blood pressure with atrial fibrillation among treated hypertensive patients.

Ann Palliat Med 2020 Jul 4;9(4):1752-1763. Epub 2020 Jun 4.

Department of Cardiology, Hypertension Research Laboratory, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.

Background: Although many studies have suggested the association between elevated blood pressure and atrial fibrillation (AF), how the relationship between systolic blood pressure (SBP) and AF differ by antihypertensive treatment has been unclear. Therefore, this study aimed to explore the relationship between SBP and AF in hypertensive patients with or without antihypertensive treatment.

Methods: This was a cross-sectional study that enrolled 7,808 hypertensive patients aged ≥18 years old in 2013 in Guangdong, China. AF was screened and diagnosed by rest 12-lead electrocardiogram (ECG) or by self-reported. Patients were categorized into 5 groups according to a 10 mmHg increment in SBP. We then performed logistic regression and restricted cubic spline regression to evaluate the relationship between SBP and AF.

Results: Out of 7,808 participants (women 52.9%, mean age 62.3 years), 78 cases of AF were identified. Both univariate and multivariate logistic regression illustrated that SBP associated with a lower chance of AF in all participants when SBP was treated as a continuous variable (P<0.05) or as a categorical variable (P for trend <0.001). Similar trend was found in patients with antihypertensive therapy (P for trend <0.001) but not for those without antihypertensive medications.

Conclusions: Our findings suggested that higher SBP is associated with lower likelihood of AF among all hypertensive patients and participants with antihypertensive treatment.
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http://dx.doi.org/10.21037/apm-19-649DOI Listing
July 2020

Clinical performance of non-invasive prenatal served as a first-tier screening test for trisomy 21, 18, 13 and sex chromosome aneuploidy in a pilot city in China.

Hum Genomics 2020 06 5;14(1):21. Epub 2020 Jun 5.

Department of Prenatal Diagnosis Center, Dongguan Maternal and Child Health Hospital, Dongguan, 523112, Guangdong, China.

Background: Cell-free fetal DNA (cffDNA) has opened up new approaches for non-invasive prenatal testing (NIPT), and it is often used as the second-tier test for high-risk pregnant women in detecting trisomy (T) 21, T18, and T13 after serum biochemistry screening. This study aims to discuss the clinical performance of NIPT as an alternative first-tier screening test for pregnant women in detecting T21, T18, T13, and sex chromosome aneuploidies (SCAs) in China.

Methods: A total of 42,924 samples were recruited. The cell-free plasma DNA was directly sequenced. Each of the chromosome aneuploidies of PPV was analyzed. A total of 22 placental samples were acquired, including 14 FP and 8 TP samples. The placental verification of FP NIPT results was performed.

Results: Among 42,924 samples, 281 (0.65%) positive cases, including 87 of T21, 31 of T18, 22 of T13, and 141 of SCAs were detected. For the detection of T21, the positive predictive value (PPV) was 78.46%, for trisomy 18, 62.96%, for trisomy 13, 10.00%, for SCAs, 47.22% in the total samples. For trisomy 21, the PPV was 86.67%, for trisomy 18, 80.00%, for trisomy 13, 20.00%, for SCAs, 56.52% in advanced maternal age (AMA) women. The PPV of T21 increased with age. For T18, the PPV showed an overall upward trend. For T13 and SCAs, PPV was raised first and then lowered. Placental verification of false positive (FP) NIPT results confirmed confined placental mosaicism(CPM) was the reason for false positives.

Conclusions: This study represents the first time that NIPT has been used as a first-tier screening test for fetal aneuploidies in a pilot city with large clinical samples in China. We propose that NIPT could replace serum biochemistry screening as a first-tier test.
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http://dx.doi.org/10.1186/s40246-020-00268-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275506PMC
June 2020

Hodgkin Lymphoma, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 06;18(6):755-781

28Huntsman Cancer Institute at the University of Utah.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.
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http://dx.doi.org/10.6004/jnccn.2020.0026DOI Listing
June 2020

Association of mean arterial pressure with all-cause and cardiovascular mortality in young adults.

Postgrad Med J 2020 Aug 13;96(1138):455-460. Epub 2020 May 13.

Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Academy of Medical Sciences, Guangzhou, China

Background: Mean arterial pressure (MAP) is a predictor of all-cause and cardiovascular disease (CVD) mortality in middle-aged population and elderly, but less evidence has been shown in young adults.

Objectives: We examined the associations of MAP with all-cause and CVD mortality in young adults aged between 18 and 40 years.

Methods: Data were from the National Health and Nutrition Examination Survey (1999-2006) and participants were followed up to 31 December 2015. MAP was categorised by quartiles. Multivariable Cox proportional hazards models and Kaplan-Meier survival curves were performed to estimate the association between MAP, all-cause and CVD mortality.

Results: There were a total of 8356 (4598 women (55.03%)) participants with the mean age of 26.63±7.01 years, of which 265 (3.17%) and 10 (0.12%) cases of all-cause and cardiovascular mortality occurred during a median follow-up duration of 152.96±30.45 months, respectively. There was no significant difference in the survival rate by MAP quartiles (p=0.058). When MAP was treated as a continuous variable, the multivariable adjusted HRs for all-cause and CVD mortality were 1.00 (95% CI 0.96 to 1.04; p=0.910) and 0.94 (95% CI 0.77 to 1.14; p=0.529), respectively. When using the lowest quartile (Q1) as referent, the adjusted HRs for all-cause mortality from Q2 to Q4 were 1.16 (95% CI 0.56 to 2.42), 1.06 (95% CI 0.48 to 2.32) and 0.91 (95% CI 0.37 to 2.24; p for tend was 0.749) after adjusting for potential confounders.

Conclusion: There was no significant association of MAP with all-cause and CVD mortality in young adults with a relatively short follow-up time.
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http://dx.doi.org/10.1136/postgradmedj-2019-137354DOI Listing
August 2020

Association between systolic blood pressure and first ischemic stroke in the Chinese older hypertensive population.

J Int Med Res 2020 Apr;48(4):300060520920091

Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

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http://dx.doi.org/10.1177/0300060520920091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177990PMC
April 2020

Association between pulse pressure and ischaemic stroke in elderly patients with hypertension.

Postgrad Med J 2021 Apr 16;97(1146):222-226. Epub 2020 Apr 16.

Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Hypertension Research Laboratory, Guangdong Academy of Medical Sciences, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China

Background: The association between pulse pressure (PP) and the risk of first ischaemic stroke (IS) is inconsistent. Therefore, we evaluated the association between PP and the risk of first IS among elderly hypertensive population in China.

Methods: This was a retrospective cohort study. Patients with hypertension and aged ≥60 years were recruited. Multivariate Cox regression was performed to evaluate the association between PP and the risk of IS. We further stratified the regression models into subgroups and test for interaction to assess whether the associations were modified by other covariates.

Results: A total of 3315 patients with hypertension (44.49% male; mean age 71.41±7.20 years) were included, and 206 cases of IS occurred with a median follow-up of 5.5 years. The results showed that per SD mm Hg increment in PP was associated with a 17% (95% CI 1.05 to 1.40, p=0.0172) increased risk of IS. Moreover, the HR of IS for the highest quartile of PP was 1.46 (95% CI 1.18 to 1.73, p=0.0011, p for trend <0.001) comparing with the lowest quartile of PP. Subgroup analysis showed that population aged ≥70 years, male, patients with smoking or drinking habit, diabetes at baseline, being overweight, with uncontrolled blood pressure or did not take antihypertensive drugs have a higher risk for IS.

Conclusions: We found that PP was significantly associated with IS and was an independent risk factor for IS.
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http://dx.doi.org/10.1136/postgradmedj-2019-137357DOI Listing
April 2021

Ultrasonic-accelerated metallurgical reaction of Sn/Ni composite solder: Principle, kinetics, microstructure, and joint properties.

Ultrason Sonochem 2020 Sep 25;66:105090. Epub 2020 Mar 25.

State Key Laboratory of Advanced Welding and Joining, Harbin Institute of Technology at Shenzhen, Shenzhen 518055, Guangdong, China; Flexible Printing Electronic Technology Center, Harbin Institute of Technology at Shenzhen, Shenzhen 518055, China. Electronic address:

The high-melting-point joints by transient-liquid-phase are increasingly playing a crucial role in the die bonding for the high temperature electronic components. In this study, three kinds of Sn/Ni composite solder pastes composed of different sizes of Ni particles were synthesized to accelerate metallurgical reaction among Sn/Ni interfaces under the ultrasonic-assisted transient liquid phase (U-TLP) soldering. The temperature evolution, microstructure and mechanical property in joints composed by these composite solder pastes with or without ultrasonic energy were systemically investigated. The intermetallic joint consisted of high-melting-point sole NiSn intermetallic compound with a little residual Ni was obtained under the conditions of no pressure and lower power (200 W) in a high-temperature duration of only 10 s, its shear strength was up to 45.3 MPa. Ultrasonic effects significantly accelerated the reaction among the interfaces of liquid Sn and solid Ni, which attributed to the temperature rise caused by acoustic cavitation because of large number of liquid/solid interfaces during U-TLP, resulting in accelerated solid/liquid interfacial diffusion and growth of intermetallic compounds. This intermetallic joint formed by U-TLP soldering has a promising potential for applications in high-power device packaging.
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http://dx.doi.org/10.1016/j.ultsonch.2020.105090DOI Listing
September 2020

Relationship between body mass index and ischaemic stroke in Chinese elderly hypertensive patients.

Postgrad Med J 2021 Apr 27;97(1146):217-221. Epub 2020 Mar 27.

Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Hypertension Research Laboratory, Guangdong Academy of Medical Sciences, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, School of Medicine, South China University of Technology, Guangzhou, China

Background: Despite obesity being a major risk factor for ischaemic stroke (IS), the association between body mass index (BMI) and IS in patients with hypertension remains uncertain.

Objective: To assess the association between BMI and IS among elderly hypertensive patients in China.

Methods And Results: We recruited 3500 hypertensive patients aged ≥60 between 1 January 2010 and 31 December 2011 in China and ascertained their stroke status until December 2016. Multivariate Cox regression was used to evaluate the association between BMI and IS with interaction tests for exposure and covariates. A total of 3315 subjects (mean age 71.41±7.20 years, 44.5% were men) were included for data analysis. During an average follow-up period of 5.5 years, there were 206 onset cases (6.21%) of IS. When BMI was treated as a continuous variable, it was positively associated with the incidence of new onset IS (HR=1.14; 95% CI: 1.05 to 1.34; p=0.005) after adjusting for potential confounders. Meanwhile, when BMI was treated as a categorical variable, the highest category (≥28 kg/m) was strongly associated with an increased risk for IS compared with normal BMI category (18.5 to 24 kg/m) (HR=1.36, 95% CI: 1.09 to 1.80; p<0.001) in the fully adjusted model. Subgroup and interaction analysis also demonstrated that BMI independently associated with IS among males, smokers, alcohol drinkers, diabetic patients, people with uncontrolled blood pressure, decreased estimated glomerular filtration rate and those aged ≥70 years.

Conclusion: BMI was significantly associated with IS and was an independent risk of IS in Chinese elderly hypertensive patients.
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http://dx.doi.org/10.1136/postgradmedj-2019-137457DOI Listing
April 2021

Therapeutic benefits of apocynin in mice with lipopolysaccharide/D-galactosamine-induced acute liver injury via suppression of the late stage pro-apoptotic AMPK/JNK pathway.

Biomed Pharmacother 2020 May 25;125:110020. Epub 2020 Feb 25.

Department of Pathophysiology, Chongqing Medical University, Chongqing, China; Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, China. Electronic address:

The excessive generation of reactive oxygen species (ROS) plays crucial roles in the development of acute liver injury. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is responsible for the robust production of ROS under inflammatory circumstance, but the pathological roles of NOX and the pharmacological significance of NOX inhibitor in acute liver injury remains unclear. In the present study, the potential roles of NOX in acute liver injury were investigated in a mouse model with lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced acute liver injury. The results indicated that LPS/D-Gal exposure time-dependently increased the level of ROS in liver tissue. Pretreatment with the NOX inhibitor apocynin suppressed LPS/D-Gal induced upregulation of ROS, 8-hydroxy-2-deoxyguanosine (8-OH-dG), protein carbonyl content and thiobarbituric acid reactive substances (TBARS). Pretreatment with apocynin also suppressed LPS/D-Gal-induced elevation of aminotransferase, alleviated histological abnormalities, inhibited the production of pro-inflammatory cytokine tumor necrosis factor α (TNF-α), blocked the activation of caspase cascade, reduced the count of TUNEL-positive cells and prevented LPS/D-Gal-induced mortality. Interestingly, post insult treatment with apocynin also suppressed LPS/D-Gal-induced oxidative stress, hepatocyte apoptosis, liver damage but improved the survival rate. Mechanistically, posttreatment with apocynin prohibited LPS/D-Gal-induced activation of the late stage pro-apoptotic AMP-activated protein kinase (AMPK)/c-Jun N-terminal kinase (JNK) pathway. Post-insult treatment with the antioxidant N-acetylcysteine also resulted in suppressed activation of AMPK/JNK, mitigated apoptosis and alleviated liver injury. These data suggest that NOX-derived ROS might be a crucial late stage detrimental factor in LPS/D-Gal-induced acute liver injury via promoting the activation of the pro-apoptotic AMPK/JNK pathway, and the NOX inhibitor might have important value in the pharmacological intervention of inflammation-base liver damage.
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http://dx.doi.org/10.1016/j.biopha.2020.110020DOI Listing
May 2020