Background:Bortezomib results in peripheral neuropathy(PN)in approximately 50%of patients,during multiple myeloma(MM)treatment,a complication known as Bortezomib-induced peripheral neuropathy(BIPN).The drug response v...Background:Bortezomib results in peripheral neuropathy(PN)in approximately 50%of patients,during multiple myeloma(MM)treatment,a complication known as Bortezomib-induced peripheral neuropathy(BIPN).The drug response varies among individuals.Genetic factor may play an important role in BIPN.Methods:A nextgeneration sequencing(NGS)panel containing 1659 targets from 233 genes was used to identify risk variants for developing BIPN in 204 MM patients who received bortezomib therapy.mRNA expression of MTHFR and ALDH1A1 in 62 peripheral blood samples was detected by real-time quantitative PCR(RT-qPCR).Serum homocysteine(Hcy)levels were detected in 40 samples by chemiluminescent microparticle immunoassay(CMIA).Results:Compared with the non-BIPN group(n=89),a total of 8 significantly associated single nucleotide polymorphisms(SNPs)were identified in the BIPN group(n=115):MTHFR(rs1801131,rs1801133,rs17421511),EPHX1(rs1051740),MME(rs2016848),ALDH1A1(rs6151031),HTR7(rs1935349)and CYP2A6(rs8192720).The mRNA expression level of MTHFR in newly diagnosed patients with peripheral neuritis after treatment(NP group)was lower than that of newly diagnosed patients without peripheral neuritis after treatment(NnP group)(1.70±0.77 vs.2.81±0.97,p=0.009).Serum Hcy levels were significantly higher in BIPN group than in non-BIPN group(11.66±1.79μmol/L vs.8.52±3.29μmol/L,p=0.016)and healthy controls(11.66±1.79μmol/L vs.8.55±2.13μmol/L,p≤0.001).Conclusion:CYP2A6,EPHX1,MTHFR,ALDH1A1,HTR7,MME and BIPN are linked in Chinese MM patients.BIPN is more likely to occur in patients with lower MTHFR mRNA expression,which might result in higher serum Hcy levels.展开更多
Background:Buyang Huanwu decoction(BHD)is a traditional Chinese medicine herbal formula used for treating hypertension,particularly in the later stages of hypertension when it is associated with intracerebral hemorrha...Background:Buyang Huanwu decoction(BHD)is a traditional Chinese medicine herbal formula used for treating hypertension,particularly in the later stages of hypertension when it is associated with intracerebral hemorrhage.This study aims to investigate the treatment mechanism of BHD to provide a basis for its clinical application in hypertension treatment.Methods:Network pharmacology analysis and cell culture experiments were performed to explore the potential proteins and mechanisms of action of BHD against hypertension.Bioactive compounds related to BHD were screened,and relevant targets associated with hypertension and BHD were retrieved.Molecular docking technology was used to identify the effective signaling pathway based on the Kyoto Encyclopedia of Genes and Genomes and protein-protein interaction network cores.Lastly,the effects and mechanisms of BHD on salt-sensitive hypertensive endothelial cells were investigated.Results:Ninety-three potential therapeutic targets for BHD and salt-sensitive hypertension were found to be closely associated with the PI3K/Akt/eNOS signaling pathway and oxidative stress.Cell experiments further indicated the pivotal role of endothelial cells in hypertension,and validation analysis showed that BHD significantly preserved cell morphology,suppressed oxidative stress reactions,activated the PI3K/Akt/eNOS signaling pathways,preserved normal endothelial cell function,and reduced cell apoptosis.Conclusion:BHD effectively activates the PI3K/Akt/VEGF signaling pathway,attenuates oxidative stress-induced injury in endothelial cells exposed to high salt levels,and mitigates apoptosis,supporting the use of traditional Chinese medicine BHD in the treatment of salt-sensitive hypertension.展开更多
BACKGROUND:Previous studies have demonstrated that aquaporin-4 (AQP4) plays a key role in the formation and resolution of brain edema.However,the molecular mechanisms and role of AQP4 in hypoxia-ischemia-induced br...BACKGROUND:Previous studies have demonstrated that aquaporin-4 (AQP4) plays a key role in the formation and resolution of brain edema.However,the molecular mechanisms and role of AQP4 in hypoxia-ischemia-induced brain edema remain poorly understood.OBJECTIVE:To establish a newborn animal model of astrocytic oxygen-glucose deprivation and reintroduction,to observe the correlation between AQP4 and cellular volume,and to investigate the role of AQP4 in the development of brain edema following oxygen deprivation and reintroduction.DESIGN,TIME AND SETTING:A comparative experiment was performed at the Experimental Center of West China Second University Hospital between October 2007 and April 2009.MATERIALS:Astrocytes were derived from the neocortex of Sprague Dawley rats aged 3 days.METHODS:Astrocytes were incubated in glucose/serum-free Dulbecco's modified Eagle's medium,followed by 1% oxygen for 6 hours.Finally,oxygen-glucose deprivation and reintroduction models were successfully established.MAIN OUTCOME MEASURES:Real-time polymerase chain reaction and Western blot analysis were used to measure expression of AQP4 mRNA and protein in cultured rat astrocytes following oxygen-glucose deprivation and reintroduction.Astrocytic cellular volume,as determined by [3H]-3-O-methyl-D-glucose,was used to represent the extent of astrocytic swelling.RESULTS:During oxygen-glucose deprivation,AQP4 mRNA and protein expression gradually decreased in astrocytes,whereas cellular volume increased in a time-dependent manner (P〈 0.01).Following oxygen-glucose reintroduction,AQP4 mRNAand protein expression was upregulated,peaked at day 7,and then gradually decreased,but still higher than normal levels (P 〈 0.05).However,cellular volume gradually decreased (P 〈 0.01),and then reached normal levels at day 7.CONCLUSION:AQP4 expression highly correlated with cellular volume changes,suggesting that AQP4 played an important role in modulating brain water transport in an astrocytic oxygen-glucose deprivation and reintroduction model.展开更多
BACKGROUND Bicuspid aortic valve(BAV)is the most common congenital heart disease.However,the prevalence,clinical characteristics,and current management of BAV associated with inherited cardiomyopathy,including hypertr...BACKGROUND Bicuspid aortic valve(BAV)is the most common congenital heart disease.However,the prevalence,clinical characteristics,and current management of BAV associated with inherited cardiomyopathy,including hypertrophic cardiomy-opathy(HCM),dilated cardiomyopathy(DCM),and left ventricular noncompaction(LVNC)have not been well described.METHODS Consecutive patients diagnosed with BAV at a large tertiary cardiovascular referral center between 2009 and 2018 were retrospectively assessed for HCM,DCM,and LVNC based on clinical and echocardiographic criteria.Patients with coexist-ent conditions were investigated further.RESULTS Of 3533 patients with BAV screened,57(1.6%)had concomitant cardiomyopathy.BAV was combined with HCM in 30 of these patients,with DCM in 19,and with LVNC in eight.Forty-six patients(80.7%)were male,and the mean age at first dia-gnosis was 47 years for BAV with HCM,49 years for BAV with DCM,and 35 years for BAV with LVNC.Heart failure and aortic valve dysfunction were common in these patients,and the prevalence of coexisting aortopathy was 43.3%,26.3%and 25.0%,re-spectively,for BAV with HCM,DCM and LVNC.During the index hospitalization,24 of the 57 patients(42.1%)underwent sur-gery,16(28%)underwent aortic valve and/or aortic surgery,and 16 of the 30 patients with HCM had a Morrow procedure.There were no deaths or other major adverse cardiovascular events.CONCLUSIONS The prevalence of inherited cardiomyopathy was higher in our patients with BAV than in the general popula-tion.Aortopathy and heart failure were common,with almost half of patients requiring surgery at diagnosis.展开更多
<div style="text-align:justify;"> An intracavity frequency doubling acousto-optically Q-switched Neodymium-doped Yttrium Orthvanadate (Nd:YVO<sub>4</sub>) 457 nm blue laser by employing a t...<div style="text-align:justify;"> An intracavity frequency doubling acousto-optically Q-switched Neodymium-doped Yttrium Orthvanadate (Nd:YVO<sub>4</sub>) 457 nm blue laser by employing a three-mirror folded cavity was demonstrated. With the incident pump power of 40.4 W, the maximum average output power of 439 mW 457 nm laser, and the minimum pulse duration of 86.14 ns and the maximum peak power of 510 W were achieved at 10 kHz. The M<sup>2</sup> factors are 1.23 and 1.61 in X and Y directions, respectively. The power stability in two hours is better than 2%. </div>展开更多
<div style="text-align:justify;"> The basic principle of sensing is the combination of F-P cavity interference and fiber grating reflection. A hybrid structure sensor probe has been designed based on t...<div style="text-align:justify;"> The basic principle of sensing is the combination of F-P cavity interference and fiber grating reflection. A hybrid structure sensor probe has been designed based on the combination of an F-P cavity of liquid-filled thermometer structure, and a fiber grating with an elastic diaphragm, herein F-P cavity is used for temperature sensing, and the fiber grating is used for pressure sensing. By adopting the dual optical path structure, the dual-parameter detection of temperature and depth is realized, which solves the problem of low accuracy caused by the cross response of temperature and pressure of a single sensor device and the calculation of the depth information of the ocean with empirical formulas. Compared with traditional sensors, the sensitivity is effectively improved. Theoretical analysis shows that the sensitivity of the F-P cavity with a thermometer structure filled with kerosene reaches 1.334 nm/?C, and the depth sensitivity of the fiber grating is 284.6 pm/Mpa within the ocean depth range of 0 - 400 m. </div>展开更多
AIMTo compare the effects of intravitreal injection of bevacizumab (IVB) with intravitreal triamcinolone acetonide (IVTA) on the treatment of cystoid macular edema (CME) secondary to retinal vein occlusion (RVO).METHO...AIMTo compare the effects of intravitreal injection of bevacizumab (IVB) with intravitreal triamcinolone acetonide (IVTA) on the treatment of cystoid macular edema (CME) secondary to retinal vein occlusion (RVO).METHODSA literature search was conducted using PubMed, the Cochrane Central Register of Controlled Trials, Web of Science and the Chinese Biomedical Database. The comparison was divided into two groups, group 1 conducted comparison in branch RVO (BRVO) or central RVO (CRVO), group 2 conducted comparison in ischemic-RVO or nonischemic-RVO. Pooled mean differences (MDs) for changes in visual acuity (VA), central macular thickness (CMT) and intraocular pressure (IOP) were calculated in groups at 4, 12 and 24wk after treatment respectively.RESULTSEight studies comparing the efficacy of IVB with IVTA were included in the Meta-analysis. In group 1, in BRVO, significant difference was shown on the comparison of CMT at 24wk (MD, -45.66; 95% CI, -76.03 to -15.28; P=0.003), IVB was effective on BRVO for at least 24wk; no significant differences were found in the comparison of VA at each time points (P>0.05 respectively). In CRVO, no significant differences were found in the comparison of VA or CMT between IVB and IVTA at each time points (P>0.05, respectively). In group 2, in ischemic-RVO, significant differences were shown in the comparison of VA (MD, -0.28; 95% CI, -0.42 to -0.14; P<0.0001) and CMT (MD, -86.50; 95% CI, -151.18 to -22.43; P=0.008) at 24wk; In nonischemic-RVO, no significant differences were demonstrated in the comparison of VA or CMT between IVB and IVTA at each time points (P>0.05, respectively). The occurrence of high IOP was much lower in IVB group.CONCLUSIONThis Meta-analysis suggested that IVB was effective in decreasing CMT in BRVO for at least 24wk, IVB is more effective on improving VA and reducing CMT in ischemic-RVO. IVB is more promising on RVO than IVTA.展开更多
In this study, 16 patients (19 eyes) with nonarteritic anterior ischemic optic neuropathy in the acute stage (within 4 weeks) and resolving stage (after 12 weeks) were diagnosed by a series of complete ophthalmi...In this study, 16 patients (19 eyes) with nonarteritic anterior ischemic optic neuropathy in the acute stage (within 4 weeks) and resolving stage (after 12 weeks) were diagnosed by a series of complete ophthalmic examinations, including fundus examination, optical coherence tomography and fluorescein fundus angiography, and visual field defects were measured with standard automated perimetry. The contralateral uninvolved eyes were used as controls. The retinal nerve fiber layer thickness was determined by optical coherence tomography which showed that the mean retinal nerve fiber layer thickness and the retinal nerve fiber layer thickness from temporal, superior, nasal and inferior quadrants were significantly higher for all measurements in the acute stage than the corresponding normal values. In comparison, the retinal nerve fiber layer thickness from each optic disc quadrant was found to be significantly lower when measured at the resolving stages, than in the control group. Statistical analysis on the correlation between optic disc nerve fiber layer thickness and visual defects demonstrated a positive correlation in the acute stage and a negative correlation in the resolving stage. Our experimental findings indicate that optical coherence tomography is a useful diagnostic method for nonarteritic anterior ischemic optic neuropathy and can be used to evaluate the effect of treatment.展开更多
Cerebral hypoxia or ischemia results in cell death and cerebral edema, as well as other cellular reactions such as angiogenesis and the reestablishment of functional microvasculature to promote recovery from brain inj...Cerebral hypoxia or ischemia results in cell death and cerebral edema, as well as other cellular reactions such as angiogenesis and the reestablishment of functional microvasculature to promote recovery from brain injury. Vascular endothelial growth factor is expressed in the central nervous system after hypoxic/ischemic brain injury, and is involved in the process of brain repair via the regulation of angiogenesis, neurogenesis, neurite outgrowth, and cerebral edema, which all require vascular endothelial growth factor signaling. In this review, we focus on the role of the vascular endothelial growth factor signaling pathway in the response to hypoxic/ischemic brain injury, and discuss potential therapeutic interventions.展开更多
Background Anemia is a common comorbidity of patients with Takayasu arteritis(TA). This study evaluated the prevalence, clinical characteristics, and treatment in Chinese TA patients with anemia. Methods This retrospe...Background Anemia is a common comorbidity of patients with Takayasu arteritis(TA). This study evaluated the prevalence, clinical characteristics, and treatment in Chinese TA patients with anemia. Methods This retrospective study included 533 consecutive patients hospitalized for TA from January 2009 to April 2018. Anemia was diagnosed on the basis of hemoglobin level, according to World Health Organization criteria. Results A total of 194 patients(36.4%) were diagnosed with anemia. Most had mild anemia(177, 91.2%). Female patients were predominant(92.8% of anemic patients). Normocytic anemia(62.9%) was the most common pattern. Anemic patients were more likely than non-anemic patients to have dizziness(29.4% vs. 21.2%), low body mass index(22.0 ± 3.6 vs. 22.9 ± 3.4 kg/m2), and active disease stage(64.9% vs. 50.1%);pulmonary involvement(12.4% vs. 26.8%), pulmonary hypertension(12.9% vs. 20.1%) and pulmonary hypertensive-target drugs(2.8% vs. 11.6%) were less common among anemic than non-anemic patients(all P < 0.05). Larger left ventricular end-diastolic diameter and lower left ventricular ejection fraction were observed in anemic patients. Over a median follow-up of four months, the increase of hemoglobin in anemic patients was associated with the use of iron supplementation. Conclusions Anemia is a very common concurrent condition in TA, especially in young, female patients. Patients with anemia are more likely to be in the active disease stage. Iron supplementation helps increase hemoglobin.展开更多
BACKGROUND: In addition to neuroprotective genes, the targeted genes of hypoxia-inducible factor 1α (HIF-1α) include pro-apoptotic genes. However, the influence of HIF-1α on neuronal apoptosis in hypoxia-ischemi...BACKGROUND: In addition to neuroprotective genes, the targeted genes of hypoxia-inducible factor 1α (HIF-1α) include pro-apoptotic genes. However, the influence of HIF-1α on neuronal apoptosis in hypoxia-ischemia remains poorly understood. OBJECTIVE: To investigate the relationship between HIF-1α expression and neuronal apoptosis in hypoxia or hypoxia-ischemia brain injury and to determine the role of HIF-1α in regulating neuronal apoptosis. DESIGN, TIME AND SETTING: A randomized, controlled animal experiment was performed at the Laboratory of Children Neurology of Sichuan University between May 2006 and May 2007. MATERIALS: In situ cell death detected kit was provided by Roche, USA; rabbit anti-mouse HIF-1α polyclonal antibody was purchased from Santa Cruz Biotechnologies, USA; rabbit anti-mouse cleaved caspase-3 polyclonal antibody was purchased from Chemicon, USA. METHODS: A total of 36 Sprague Dawley rats aged 10 days were randomly assigned to 3 groups: sham-surgery, hypoxia, and hypoxia-ischemia, with 12 rats per group. The rats were treated at 3 time points: 4, 8, and 24 hours, with 4 rats per time point. In the hypoxia-ischemia group, the right common carotid artery was exposed and permanently ligated through a midline cervical incision. A 2.5-hour exposure to hypoxia (8% O2/92% N2) was used to induce hypoxia-ischemia injury. In the hypoxia group, rats were exposed to hypoxia without ligation of the common carotid artery. In the sham-surgery group, the common carotid artery was exposed without ligation or hypoxia. MAIN OUTCOME MEASURES: Histopathological changes, HIF-1α and activated caspase-3 protein expression, integrated optical density of positive cells, and apoptosis-positive cells. RESULTS: Hematoxylin and eosin staining showed that neuronal degeneration and edema was most prominent at 24 hours after hypoxia-ischemia. HIF-1α protein expression was significantly upregulated at 4 hours, peaked at 8 hours, and decreased at 24 hours after hypoxia or hypoxia-ischemia. HIF-1α protein expression was significant greater in the hypoxia and hypoxia-ischemia groups compared with the sham-surgery group (P 〈 0.01). Activated caspase-3 protein expression began to increase at 4 and 8 hours following hypoxia or hypoxia-ischemia and was significantly upregulated at 24 hours. Activated caspase-3 protein expression remained at low levels in the sham controls compared with the hypoxia and hypoxia-ischemia groups (P〈 0.01). TUNEL staining showed that the number of apoptotic cells significantly increased at 24 hours after hypoxia or hypoxia-ischemia. In addition, HIF-1α protein expression was greater in the hypoxia group compared with the hypoxia-ischemia group at the same time point (P 〈 0.05). However, activated caspase-3 expression and the number of TUNEL-positive cells were less in the hypoxia group compared with the hypoxia-ischemia group at the same time point (P〈 0.05). CONCLUSION: HIF-1α played a neuroprotective role following hypoxia-ischemia brain injury.展开更多
The semiconductor laser array with single-mode emission is presented in this paper.The 6-μm-wide ridge waveguides(RWGs)are fabricated to select the lateral mode.Thus the fundamental mode of laser array can be obtaine...The semiconductor laser array with single-mode emission is presented in this paper.The 6-μm-wide ridge waveguides(RWGs)are fabricated to select the lateral mode.Thus the fundamental mode of laser array can be obtained by the RWGs.And the maximum output power of single-mode emission can reach 36 W at an injection current of 43 A,after that,a kink will appear.The slow axis(SA)far-field divergence angle of the unit is 13.65.The beam quality factor M;of the units determined by the second-order moment(SOM)method,is 1.2.This single-mode emission laser array can be used for laser processing.展开更多
AIM:To evaluate the efficacy and safety of subconjunctival triamcinolone acetonide(TA)injections for treating uveitic macular edema(UME).METHODS:This retrospective case series study included patients with UME who rece...AIM:To evaluate the efficacy and safety of subconjunctival triamcinolone acetonide(TA)injections for treating uveitic macular edema(UME).METHODS:This retrospective case series study included patients with UME who received subconjunctival TA injections with a minimum follow-up period of 6 mo.The main outcome measure was central macular thickness(CMT).The secondary outcome measures included best-corrected visual acuity(BCVA),recurrence rate and intraocular pressure(IOP).RESULTS:In total,65 patients(80 eyes),mainly including idiopathic uveitis in 33 patients(50.77%)and VogtKoyanagi-Harada(VKH)syndrome in 19 patients(29.23%),were enrolled in this study.The mean CMT decreased from 457.6±173.0μm at baseline to 325.9±176.8,302.7±148.2,332.2±177.3 and 270.6±121.6μm at 1-,2-,3-and 6-months postinjection,respectively(all P<0.001).BCVA increased from log MAR 0.5±0.3 at baseline to log MAR 0.4±0.3,0.4±0.3,0.4±0.4 and 0.4±0.3 at the 1-,2-,3-and 6-months postinjection visits,respectively(all P<0.001).Twenty-one(21/80,26.25%)eyes underwent relapse of UME within 6 mo.A total of 20/80(25%)eyes exhibited elevated IOPs,of which 13 eyes were controlled with topical IOP-lowering agents and 7 eyes underwent surgical removal of subconjunctival TA deposit.CONCLUSION:Subconjunctival TA injections appear to be safe and effective for UME.展开更多
BACKGROUND Mutation in the titin gene(TTN)in left ventricular noncompaction(LVNC)has been reported with a highly heterogeneous prevalence,and the molecular mechanisms underlying the pathogenesis of TTN gene mutation a...BACKGROUND Mutation in the titin gene(TTN)in left ventricular noncompaction(LVNC)has been reported with a highly heterogeneous prevalence,and the molecular mechanisms underlying the pathogenesis of TTN gene mutation are uncharacteri-zed.In the present study,we identified a novel TTN mutation in a pedigree with LVNC and investigated the potential pathogenic mechanism by functional studies.METHODS The whole-genome sequencing with linkage analysis was performed in a 3-generation family affected by autoso-mal dominant LVNC cardiomyopathy.The clustered regularly interspaced short palindromic repeats associated protein 9(CRISPR/Cas9)technology was used to establish novel truncating mutation in TTN in a rat cardiomyoblast H9C2 cell line in vitro,in which functional studies were carried out and characterized in comparison to its wild-type counterpart.RESULTS A novel truncating mutation TTN p.R2021X was identified as the only plausible disease-causing variant that segreg-ated with disease among the five surviving affected individuals,with an interrogation of the entire genome excluding other po-tential causes.Quantitative reverse transcription-polymerase chain reaction and cellular immunofluorescence supported a haplo-insufficient disease mechanism in titin truncation mutation cardiomyocytes.Further functional studies suggested mitochondrial abnormities in the presence of mutation,including decreased oxygen consumption rate,reduced adenosine triphosphate produc-tion,impaired activity of electron translation chain,and abnormal mitochondrial structure on electron microscopy.Impaired aut-ophagy under electron microscopy accompanied with activation of the Akt-mTORC1 signaling pathway was observed in TTN p.R2021X truncation mutation cardiomyocytes.CONCLUSIONS The TTN p.R2021X mutation has a function in the cause of a highly penetrant familial LVNC.These findings expand the spectrum of titin’s roles in cardiomyopathies and provide novel insight into the molecular basis of titin-truncating variants-associated LVNC.展开更多
BACKGROUND Left ventricular noncompaction(LVNC) is an increasingly recognised cardiomyopathy of which a significant percentage are genetic in origin. The purpose of the present study was to identify potential pathogen...BACKGROUND Left ventricular noncompaction(LVNC) is an increasingly recognised cardiomyopathy of which a significant percentage are genetic in origin. The purpose of the present study was to identify potential pathogenic mutation leading to disease in a Chinese LVNC family.METHODS A 3-generation family affected by LVNC was recruited. Clinical assessments were performed on available family members, with clinical examination, ECG, echocardiography and cardiac MRI. The proband(Ⅰ-2), the proband’s daughter(Ⅱ-1, affected) and mother(Ⅲ-1, unaffected) were selected for WGS. Sanger sequencing were performed in all of the 4 surviving family members.RESULTS Combined whole genome sequencing with linkage analysis identified a novel missense mutation in the giant protein obscurin(OBSCN NM_001098623, c.C19063T), as the only plausible disease-causing variant that segregates with disease among the four surviving individuals, with interrogation of the entire genome excluding other potential causes. This c.C19063T missense mutation resulted in p.R6355W in the encoded OBSCN protein. It affected a highly conserved residue in the C terminus of the obscurin-B-like isoform between the PH and STKc domains, which was predicted to affect the function of the protein by different bioinformatics tools.CONCLUSIONS Here we present clinical and genetic evidence implicating the novel R6355W missense mutation in obscurin as the cause of familial LVNC. This expands the spectrum of obscurin’s roles in cardiomyopathies. It furthermore highlights that rare obscurin missense variants, currently often ignored or left uninterpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here. This study also provided new insights into the molecular basis of OBSCN mutation positive LVNC.展开更多
Although NPM1 mutations are frequently found in acute myeloid leukemia patients,therapeutic strategies are scarce and unsuitable for those who cannot tolerate intensive chemotherapy.Here we demonstrated that heliangin...Although NPM1 mutations are frequently found in acute myeloid leukemia patients,therapeutic strategies are scarce and unsuitable for those who cannot tolerate intensive chemotherapy.Here we demonstrated that heliangin,a natural sesquiterpene lactone,exerts favorable therapeutic responses in NPM1 mutant acute myeloid leukemia cells,with no apparent toxicity to normal hematogenous cells,by inhibiting their proliferation,inducing apoptosis,causing cell cycle arrest,and promoting differentiation.In-depth studies on its mode of action using quantitative thiol reactivity platform screening and subsequent molecular biology validation showed that the ribosomal protein S2(RPS2)is the main target of heliangin in treating NPM1 mutant AML.Upon covalent binding to the C222 site of RPS2,the electrophilic moieties of heliangin disrupt pre-rRNA metabolic processes,leading to nucleolar stress,which in turn regulates the ribosomal proteins-MDM2-p53 pathway and stabilizes p53.Clinical data shows that the pre-rRNA metabolic pathway is dysregulated in acute myeloid leukemia patients with the NPM1 mutation,leading to a poor prognosis.We found that RPS2 plays a critical role in regulating this pathway and may be a novel treatment target.Our findings suggest a novel treatment strategy and lead compound for acute myeloid leukemia patients,especially those with NPM1 mutations.展开更多
Dust aerosols profoundly influence the radiative balance of the earth–atmosphere system and hence the global and regional climates.In this study,using multi-source satellite and ground-level observations combined wit...Dust aerosols profoundly influence the radiative balance of the earth–atmosphere system and hence the global and regional climates.In this study,using multi-source satellite and ground-level observations combined with meteorological data,we investigated the three-dimensional evolution and transport characteristics of aerosols during a dust event that occurred in Xinjiang,China from 19 to 21 March 2019.Analysis of the meteorological data reveals that the dust air mass initially appeared in the northwest of Xinjiang and was subsequently transported to the Hami and Turpan areas due to the prevailing northwesterly winds,after which the direction of the airflow shifted due to topography,and the dust air masses were transported into southern Xinjiang.The air quality in the affected areas decreased rapidly,accompanied by a significant increase in aerosol optical depth (AOD),with the maximum value exceeding 3.5 in some areas.In addition,the Cloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations(CALIPSO) data reveal that the aerosol particles in the dust-affected areas were mainly dust aerosols,with small amounts of pollutant dust aerosols.A reduction in the attenuated backscatter coefficient (β532||) was found with increasing altitude,with the dust aerosol pollution mainly distributed in the lower troposphere.The size of dust particles in the lower troposphere was relatively small and irregular.The depolarization ratio (PDR) values at altitudes of 8–10 km were relatively lower than those recorded in the lower troposphere,whereas the color ratio (CR)values were higher,which may have been influenced by the sparse vegetation coverage and poor subsurface conditions in Xinjiang,and attributable to the fact that regular large particles of dust are more likely to be dispersed to altitudes between 8 and 10 km within a short period of time.As a consequence of the meteorological conditions and topography,the dusting process in Xinjiang persisted for a relatively long period.These findings will contribute to enhanced understanding of the vertical distribution of aerosols in Northwest China.展开更多
Background:Sepsis,a serious condition with high mortality,usually causes sepsis associated encephalopathy(SAE)that involves neuronal cell death.However,the cell death programs involved and their underlying mechanisms ...Background:Sepsis,a serious condition with high mortality,usually causes sepsis associated encephalopathy(SAE)that involves neuronal cell death.However,the cell death programs involved and their underlying mechanisms are not clear.This study aimed to explore the regulatory mechanisms of different cell death programs in SAE.Methods:A neonatal rat model of SAE was established by cecal ligation and perforation.Survival rate and vital signs(mean arterial pressure and heart rate)were monitored,nerve reflexes were evaluated,and cortical pathological changes were observed by hematoxylin and eosin staining.The expression of pyroptosis,apoptosis,and necroptosis(PANoptosis)-related proteins,mitogen-activated protein kinase(MAPK),and its upstream regulator toll-like receptor 9(TLR9)were detected.The expression of TLR9 in neurons was observed by immunofluorescence staining.The ultrastructure of neurons was observed by transmission electron microscope.Results:First,PANoptosis was found in cortical nerve cells of the SAE rats.Meanwhile,the subunits of MAPKs,p38 MAPK,Jun N-terminal kinase,and extracellular signal-regulated kinase(ERK)were activated.After pharmacologically inhibiting each of the subunits,only p38 MAPK was found to be associated with PANoptosis.Furthermore,blocking the p38 MAPK signaling pathway activated necroptosis but inhibited apoptosis and pyroptosis.When necroptosis was pharmacologically inhibited,apoptosis and pyroptosis were reactivated.Finally,we found that the expression of TLR9,a regulator of MAPKs,was significantly increased in this model.After down-regulation of TLR9,p38 MAPK,and ERK signaling pathways were inhibited,which led to the inhibition of PANoptosis.Further analysis found that down-regulation of TLR9 improved the survival rate and reduced the pathological changes in SAE rats.Conclusions:Our study showed that the programs comprising PANoptosis are activated simultaneously in SAE rats.TLR9 activated PANoptosis through the p38 MAPK signaling pathway.TLR9 may work as a potential target for SAE treatment.展开更多
基金supported by the“GZ Hematologic Malignancy MARKER GHROMOS of Education Department of Liaoning Province”Grant(Grant Number:07102).
文摘Background:Bortezomib results in peripheral neuropathy(PN)in approximately 50%of patients,during multiple myeloma(MM)treatment,a complication known as Bortezomib-induced peripheral neuropathy(BIPN).The drug response varies among individuals.Genetic factor may play an important role in BIPN.Methods:A nextgeneration sequencing(NGS)panel containing 1659 targets from 233 genes was used to identify risk variants for developing BIPN in 204 MM patients who received bortezomib therapy.mRNA expression of MTHFR and ALDH1A1 in 62 peripheral blood samples was detected by real-time quantitative PCR(RT-qPCR).Serum homocysteine(Hcy)levels were detected in 40 samples by chemiluminescent microparticle immunoassay(CMIA).Results:Compared with the non-BIPN group(n=89),a total of 8 significantly associated single nucleotide polymorphisms(SNPs)were identified in the BIPN group(n=115):MTHFR(rs1801131,rs1801133,rs17421511),EPHX1(rs1051740),MME(rs2016848),ALDH1A1(rs6151031),HTR7(rs1935349)and CYP2A6(rs8192720).The mRNA expression level of MTHFR in newly diagnosed patients with peripheral neuritis after treatment(NP group)was lower than that of newly diagnosed patients without peripheral neuritis after treatment(NnP group)(1.70±0.77 vs.2.81±0.97,p=0.009).Serum Hcy levels were significantly higher in BIPN group than in non-BIPN group(11.66±1.79μmol/L vs.8.52±3.29μmol/L,p=0.016)and healthy controls(11.66±1.79μmol/L vs.8.55±2.13μmol/L,p≤0.001).Conclusion:CYP2A6,EPHX1,MTHFR,ALDH1A1,HTR7,MME and BIPN are linked in Chinese MM patients.BIPN is more likely to occur in patients with lower MTHFR mRNA expression,which might result in higher serum Hcy levels.
基金the Liaoning Provincial Science and Technology Plan Project(2023-MSLH-178)the Project Fund of Liaoning Provincial Department of Education(LJKMZ20221315,L202025)+1 种基金the Special Fund of Liaoning Provincial Department of Science and Technology for Central Guidance of Local Science and Technology Development(2018416016)the Project Fund of Liaoning Provincial Department of Human Resources and Social Security"Millions of Talents Program"(2020921097).
文摘Background:Buyang Huanwu decoction(BHD)is a traditional Chinese medicine herbal formula used for treating hypertension,particularly in the later stages of hypertension when it is associated with intracerebral hemorrhage.This study aims to investigate the treatment mechanism of BHD to provide a basis for its clinical application in hypertension treatment.Methods:Network pharmacology analysis and cell culture experiments were performed to explore the potential proteins and mechanisms of action of BHD against hypertension.Bioactive compounds related to BHD were screened,and relevant targets associated with hypertension and BHD were retrieved.Molecular docking technology was used to identify the effective signaling pathway based on the Kyoto Encyclopedia of Genes and Genomes and protein-protein interaction network cores.Lastly,the effects and mechanisms of BHD on salt-sensitive hypertensive endothelial cells were investigated.Results:Ninety-three potential therapeutic targets for BHD and salt-sensitive hypertension were found to be closely associated with the PI3K/Akt/eNOS signaling pathway and oxidative stress.Cell experiments further indicated the pivotal role of endothelial cells in hypertension,and validation analysis showed that BHD significantly preserved cell morphology,suppressed oxidative stress reactions,activated the PI3K/Akt/eNOS signaling pathways,preserved normal endothelial cell function,and reduced cell apoptosis.Conclusion:BHD effectively activates the PI3K/Akt/VEGF signaling pathway,attenuates oxidative stress-induced injury in endothelial cells exposed to high salt levels,and mitigates apoptosis,supporting the use of traditional Chinese medicine BHD in the treatment of salt-sensitive hypertension.
基金the National Natural Science Foundation of China,No.30825039,30973236,30872346,30770748Chinese Postdoctoral Training Grant,No. 20070420575+1 种基金Application Basic Research Foundation of Sichuan Province,No. 2008JY0131Youth Science and Technology Foundation of Sichuan Province,No. 07zq026-135
文摘BACKGROUND:Previous studies have demonstrated that aquaporin-4 (AQP4) plays a key role in the formation and resolution of brain edema.However,the molecular mechanisms and role of AQP4 in hypoxia-ischemia-induced brain edema remain poorly understood.OBJECTIVE:To establish a newborn animal model of astrocytic oxygen-glucose deprivation and reintroduction,to observe the correlation between AQP4 and cellular volume,and to investigate the role of AQP4 in the development of brain edema following oxygen deprivation and reintroduction.DESIGN,TIME AND SETTING:A comparative experiment was performed at the Experimental Center of West China Second University Hospital between October 2007 and April 2009.MATERIALS:Astrocytes were derived from the neocortex of Sprague Dawley rats aged 3 days.METHODS:Astrocytes were incubated in glucose/serum-free Dulbecco's modified Eagle's medium,followed by 1% oxygen for 6 hours.Finally,oxygen-glucose deprivation and reintroduction models were successfully established.MAIN OUTCOME MEASURES:Real-time polymerase chain reaction and Western blot analysis were used to measure expression of AQP4 mRNA and protein in cultured rat astrocytes following oxygen-glucose deprivation and reintroduction.Astrocytic cellular volume,as determined by [3H]-3-O-methyl-D-glucose,was used to represent the extent of astrocytic swelling.RESULTS:During oxygen-glucose deprivation,AQP4 mRNA and protein expression gradually decreased in astrocytes,whereas cellular volume increased in a time-dependent manner (P〈 0.01).Following oxygen-glucose reintroduction,AQP4 mRNAand protein expression was upregulated,peaked at day 7,and then gradually decreased,but still higher than normal levels (P 〈 0.05).However,cellular volume gradually decreased (P 〈 0.01),and then reached normal levels at day 7.CONCLUSION:AQP4 expression highly correlated with cellular volume changes,suggesting that AQP4 played an important role in modulating brain water transport in an astrocytic oxygen-glucose deprivation and reintroduction model.
基金supported by grants from the National Key Research and Development Program of China(2016YFC1300100)National Natural Science Foundation of China(81974042)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019XK320058 and 2019XK320057).
文摘BACKGROUND Bicuspid aortic valve(BAV)is the most common congenital heart disease.However,the prevalence,clinical characteristics,and current management of BAV associated with inherited cardiomyopathy,including hypertrophic cardiomy-opathy(HCM),dilated cardiomyopathy(DCM),and left ventricular noncompaction(LVNC)have not been well described.METHODS Consecutive patients diagnosed with BAV at a large tertiary cardiovascular referral center between 2009 and 2018 were retrospectively assessed for HCM,DCM,and LVNC based on clinical and echocardiographic criteria.Patients with coexist-ent conditions were investigated further.RESULTS Of 3533 patients with BAV screened,57(1.6%)had concomitant cardiomyopathy.BAV was combined with HCM in 30 of these patients,with DCM in 19,and with LVNC in eight.Forty-six patients(80.7%)were male,and the mean age at first dia-gnosis was 47 years for BAV with HCM,49 years for BAV with DCM,and 35 years for BAV with LVNC.Heart failure and aortic valve dysfunction were common in these patients,and the prevalence of coexisting aortopathy was 43.3%,26.3%and 25.0%,re-spectively,for BAV with HCM,DCM and LVNC.During the index hospitalization,24 of the 57 patients(42.1%)underwent sur-gery,16(28%)underwent aortic valve and/or aortic surgery,and 16 of the 30 patients with HCM had a Morrow procedure.There were no deaths or other major adverse cardiovascular events.CONCLUSIONS The prevalence of inherited cardiomyopathy was higher in our patients with BAV than in the general popula-tion.Aortopathy and heart failure were common,with almost half of patients requiring surgery at diagnosis.
文摘<div style="text-align:justify;"> An intracavity frequency doubling acousto-optically Q-switched Neodymium-doped Yttrium Orthvanadate (Nd:YVO<sub>4</sub>) 457 nm blue laser by employing a three-mirror folded cavity was demonstrated. With the incident pump power of 40.4 W, the maximum average output power of 439 mW 457 nm laser, and the minimum pulse duration of 86.14 ns and the maximum peak power of 510 W were achieved at 10 kHz. The M<sup>2</sup> factors are 1.23 and 1.61 in X and Y directions, respectively. The power stability in two hours is better than 2%. </div>
文摘<div style="text-align:justify;"> The basic principle of sensing is the combination of F-P cavity interference and fiber grating reflection. A hybrid structure sensor probe has been designed based on the combination of an F-P cavity of liquid-filled thermometer structure, and a fiber grating with an elastic diaphragm, herein F-P cavity is used for temperature sensing, and the fiber grating is used for pressure sensing. By adopting the dual optical path structure, the dual-parameter detection of temperature and depth is realized, which solves the problem of low accuracy caused by the cross response of temperature and pressure of a single sensor device and the calculation of the depth information of the ocean with empirical formulas. Compared with traditional sensors, the sensitivity is effectively improved. Theoretical analysis shows that the sensitivity of the F-P cavity with a thermometer structure filled with kerosene reaches 1.334 nm/?C, and the depth sensitivity of the fiber grating is 284.6 pm/Mpa within the ocean depth range of 0 - 400 m. </div>
文摘AIMTo compare the effects of intravitreal injection of bevacizumab (IVB) with intravitreal triamcinolone acetonide (IVTA) on the treatment of cystoid macular edema (CME) secondary to retinal vein occlusion (RVO).METHODSA literature search was conducted using PubMed, the Cochrane Central Register of Controlled Trials, Web of Science and the Chinese Biomedical Database. The comparison was divided into two groups, group 1 conducted comparison in branch RVO (BRVO) or central RVO (CRVO), group 2 conducted comparison in ischemic-RVO or nonischemic-RVO. Pooled mean differences (MDs) for changes in visual acuity (VA), central macular thickness (CMT) and intraocular pressure (IOP) were calculated in groups at 4, 12 and 24wk after treatment respectively.RESULTSEight studies comparing the efficacy of IVB with IVTA were included in the Meta-analysis. In group 1, in BRVO, significant difference was shown on the comparison of CMT at 24wk (MD, -45.66; 95% CI, -76.03 to -15.28; P=0.003), IVB was effective on BRVO for at least 24wk; no significant differences were found in the comparison of VA at each time points (P>0.05 respectively). In CRVO, no significant differences were found in the comparison of VA or CMT between IVB and IVTA at each time points (P>0.05, respectively). In group 2, in ischemic-RVO, significant differences were shown in the comparison of VA (MD, -0.28; 95% CI, -0.42 to -0.14; P<0.0001) and CMT (MD, -86.50; 95% CI, -151.18 to -22.43; P=0.008) at 24wk; In nonischemic-RVO, no significant differences were demonstrated in the comparison of VA or CMT between IVB and IVTA at each time points (P>0.05, respectively). The occurrence of high IOP was much lower in IVB group.CONCLUSIONThis Meta-analysis suggested that IVB was effective in decreasing CMT in BRVO for at least 24wk, IVB is more effective on improving VA and reducing CMT in ischemic-RVO. IVB is more promising on RVO than IVTA.
基金supported by the National Natural Science Foundation of China,No.81173440the Natural Science Foundation of Shandong Province,No.ZR2009CL038
文摘In this study, 16 patients (19 eyes) with nonarteritic anterior ischemic optic neuropathy in the acute stage (within 4 weeks) and resolving stage (after 12 weeks) were diagnosed by a series of complete ophthalmic examinations, including fundus examination, optical coherence tomography and fluorescein fundus angiography, and visual field defects were measured with standard automated perimetry. The contralateral uninvolved eyes were used as controls. The retinal nerve fiber layer thickness was determined by optical coherence tomography which showed that the mean retinal nerve fiber layer thickness and the retinal nerve fiber layer thickness from temporal, superior, nasal and inferior quadrants were significantly higher for all measurements in the acute stage than the corresponding normal values. In comparison, the retinal nerve fiber layer thickness from each optic disc quadrant was found to be significantly lower when measured at the resolving stages, than in the control group. Statistical analysis on the correlation between optic disc nerve fiber layer thickness and visual defects demonstrated a positive correlation in the acute stage and a negative correlation in the resolving stage. Our experimental findings indicate that optical coherence tomography is a useful diagnostic method for nonarteritic anterior ischemic optic neuropathy and can be used to evaluate the effect of treatment.
基金supported by the National Natural Science Foundation of China,No.81401238,81330016,31171020,81172174 and 81270724the grants from Ministry of Education of China,No.313037,20110181130002+2 种基金a grant from State Commission of Science Technology of China,No.2012BAI04B04the grants from Science and Technology Bureau of Sichuan Province of China,No.2012SZ0010,2014FZ0113,2014SZ0149a grant from Clinical Discipline Program(Neonatology)from the Ministry of Health of China,No.1311200003303
文摘Cerebral hypoxia or ischemia results in cell death and cerebral edema, as well as other cellular reactions such as angiogenesis and the reestablishment of functional microvasculature to promote recovery from brain injury. Vascular endothelial growth factor is expressed in the central nervous system after hypoxic/ischemic brain injury, and is involved in the process of brain repair via the regulation of angiogenesis, neurogenesis, neurite outgrowth, and cerebral edema, which all require vascular endothelial growth factor signaling. In this review, we focus on the role of the vascular endothelial growth factor signaling pathway in the response to hypoxic/ischemic brain injury, and discuss potential therapeutic interventions.
基金funded by the National Key Research and Development Program of China (2016YFC1300100)CAMS Innovation Fund for Medical Sciences (2016-I2M1-002)
文摘Background Anemia is a common comorbidity of patients with Takayasu arteritis(TA). This study evaluated the prevalence, clinical characteristics, and treatment in Chinese TA patients with anemia. Methods This retrospective study included 533 consecutive patients hospitalized for TA from January 2009 to April 2018. Anemia was diagnosed on the basis of hemoglobin level, according to World Health Organization criteria. Results A total of 194 patients(36.4%) were diagnosed with anemia. Most had mild anemia(177, 91.2%). Female patients were predominant(92.8% of anemic patients). Normocytic anemia(62.9%) was the most common pattern. Anemic patients were more likely than non-anemic patients to have dizziness(29.4% vs. 21.2%), low body mass index(22.0 ± 3.6 vs. 22.9 ± 3.4 kg/m2), and active disease stage(64.9% vs. 50.1%);pulmonary involvement(12.4% vs. 26.8%), pulmonary hypertension(12.9% vs. 20.1%) and pulmonary hypertensive-target drugs(2.8% vs. 11.6%) were less common among anemic than non-anemic patients(all P < 0.05). Larger left ventricular end-diastolic diameter and lower left ventricular ejection fraction were observed in anemic patients. Over a median follow-up of four months, the increase of hemoglobin in anemic patients was associated with the use of iron supplementation. Conclusions Anemia is a very common concurrent condition in TA, especially in young, female patients. Patients with anemia are more likely to be in the active disease stage. Iron supplementation helps increase hemoglobin.
基金Supported by: the National Natural Science Foundation of China, No. 30825039, 30973236, 30770748Outstanding Young Scientist Foundation of Sichuan Province, China, No. 08ZQ026-069
文摘BACKGROUND: In addition to neuroprotective genes, the targeted genes of hypoxia-inducible factor 1α (HIF-1α) include pro-apoptotic genes. However, the influence of HIF-1α on neuronal apoptosis in hypoxia-ischemia remains poorly understood. OBJECTIVE: To investigate the relationship between HIF-1α expression and neuronal apoptosis in hypoxia or hypoxia-ischemia brain injury and to determine the role of HIF-1α in regulating neuronal apoptosis. DESIGN, TIME AND SETTING: A randomized, controlled animal experiment was performed at the Laboratory of Children Neurology of Sichuan University between May 2006 and May 2007. MATERIALS: In situ cell death detected kit was provided by Roche, USA; rabbit anti-mouse HIF-1α polyclonal antibody was purchased from Santa Cruz Biotechnologies, USA; rabbit anti-mouse cleaved caspase-3 polyclonal antibody was purchased from Chemicon, USA. METHODS: A total of 36 Sprague Dawley rats aged 10 days were randomly assigned to 3 groups: sham-surgery, hypoxia, and hypoxia-ischemia, with 12 rats per group. The rats were treated at 3 time points: 4, 8, and 24 hours, with 4 rats per time point. In the hypoxia-ischemia group, the right common carotid artery was exposed and permanently ligated through a midline cervical incision. A 2.5-hour exposure to hypoxia (8% O2/92% N2) was used to induce hypoxia-ischemia injury. In the hypoxia group, rats were exposed to hypoxia without ligation of the common carotid artery. In the sham-surgery group, the common carotid artery was exposed without ligation or hypoxia. MAIN OUTCOME MEASURES: Histopathological changes, HIF-1α and activated caspase-3 protein expression, integrated optical density of positive cells, and apoptosis-positive cells. RESULTS: Hematoxylin and eosin staining showed that neuronal degeneration and edema was most prominent at 24 hours after hypoxia-ischemia. HIF-1α protein expression was significantly upregulated at 4 hours, peaked at 8 hours, and decreased at 24 hours after hypoxia or hypoxia-ischemia. HIF-1α protein expression was significant greater in the hypoxia and hypoxia-ischemia groups compared with the sham-surgery group (P 〈 0.01). Activated caspase-3 protein expression began to increase at 4 and 8 hours following hypoxia or hypoxia-ischemia and was significantly upregulated at 24 hours. Activated caspase-3 protein expression remained at low levels in the sham controls compared with the hypoxia and hypoxia-ischemia groups (P〈 0.01). TUNEL staining showed that the number of apoptotic cells significantly increased at 24 hours after hypoxia or hypoxia-ischemia. In addition, HIF-1α protein expression was greater in the hypoxia group compared with the hypoxia-ischemia group at the same time point (P 〈 0.05). However, activated caspase-3 expression and the number of TUNEL-positive cells were less in the hypoxia group compared with the hypoxia-ischemia group at the same time point (P〈 0.05). CONCLUSION: HIF-1α played a neuroprotective role following hypoxia-ischemia brain injury.
基金Project supported by the National Science and Technology Major Project of China(Grant Nos.2018YFB0504600and 2017YFB0405102)the Frontier Science Key Program of the President of the Chinese Academy of Sciences(Grant No.QYZDY-SSW-JSC006)+7 种基金the Pilot Project of the Chinese Academy of Sciences(Grant No.XDB43030302)the National Natural Science Foundation of China(Grant Nos.62090051,62090052,62090054,11874353,61935009,61934003,61904179,61727822,61805236,62004194,and 61991433)the Science and Technology Development Project of Jilin Province,China(Grant Nos.20200401062GX,202001069GX,20200501006GX,20200501007GX,20200501008GX,and 20190302042GX)the Key Research and Development Project of Guangdong Province,China(Grant No.2020B090922003)the Equipment Pre-researchChina(Grant No.2006ZYGG0304)the Special Scientific Research Project of the Academician Innovation Platform in Hainan Province,China(Grant No.YSPTZX202034)the Dawn Talent Training Program of CIOMP,China。
文摘The semiconductor laser array with single-mode emission is presented in this paper.The 6-μm-wide ridge waveguides(RWGs)are fabricated to select the lateral mode.Thus the fundamental mode of laser array can be obtained by the RWGs.And the maximum output power of single-mode emission can reach 36 W at an injection current of 43 A,after that,a kink will appear.The slow axis(SA)far-field divergence angle of the unit is 13.65.The beam quality factor M;of the units determined by the second-order moment(SOM)method,is 1.2.This single-mode emission laser array can be used for laser processing.
文摘AIM:To evaluate the efficacy and safety of subconjunctival triamcinolone acetonide(TA)injections for treating uveitic macular edema(UME).METHODS:This retrospective case series study included patients with UME who received subconjunctival TA injections with a minimum follow-up period of 6 mo.The main outcome measure was central macular thickness(CMT).The secondary outcome measures included best-corrected visual acuity(BCVA),recurrence rate and intraocular pressure(IOP).RESULTS:In total,65 patients(80 eyes),mainly including idiopathic uveitis in 33 patients(50.77%)and VogtKoyanagi-Harada(VKH)syndrome in 19 patients(29.23%),were enrolled in this study.The mean CMT decreased from 457.6±173.0μm at baseline to 325.9±176.8,302.7±148.2,332.2±177.3 and 270.6±121.6μm at 1-,2-,3-and 6-months postinjection,respectively(all P<0.001).BCVA increased from log MAR 0.5±0.3 at baseline to log MAR 0.4±0.3,0.4±0.3,0.4±0.4 and 0.4±0.3 at the 1-,2-,3-and 6-months postinjection visits,respectively(all P<0.001).Twenty-one(21/80,26.25%)eyes underwent relapse of UME within 6 mo.A total of 20/80(25%)eyes exhibited elevated IOPs,of which 13 eyes were controlled with topical IOP-lowering agents and 7 eyes underwent surgical removal of subconjunctival TA deposit.CONCLUSION:Subconjunctival TA injections appear to be safe and effective for UME.
基金supported by the National Key Research and Development Program of China(2016 YFC1300100)the National Natural Science Foundation of China(No.81974042)+1 种基金the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019XK320058)the Peking Union Medical College Youth Fund(No.3332018058).
文摘BACKGROUND Mutation in the titin gene(TTN)in left ventricular noncompaction(LVNC)has been reported with a highly heterogeneous prevalence,and the molecular mechanisms underlying the pathogenesis of TTN gene mutation are uncharacteri-zed.In the present study,we identified a novel TTN mutation in a pedigree with LVNC and investigated the potential pathogenic mechanism by functional studies.METHODS The whole-genome sequencing with linkage analysis was performed in a 3-generation family affected by autoso-mal dominant LVNC cardiomyopathy.The clustered regularly interspaced short palindromic repeats associated protein 9(CRISPR/Cas9)technology was used to establish novel truncating mutation in TTN in a rat cardiomyoblast H9C2 cell line in vitro,in which functional studies were carried out and characterized in comparison to its wild-type counterpart.RESULTS A novel truncating mutation TTN p.R2021X was identified as the only plausible disease-causing variant that segreg-ated with disease among the five surviving affected individuals,with an interrogation of the entire genome excluding other po-tential causes.Quantitative reverse transcription-polymerase chain reaction and cellular immunofluorescence supported a haplo-insufficient disease mechanism in titin truncation mutation cardiomyocytes.Further functional studies suggested mitochondrial abnormities in the presence of mutation,including decreased oxygen consumption rate,reduced adenosine triphosphate produc-tion,impaired activity of electron translation chain,and abnormal mitochondrial structure on electron microscopy.Impaired aut-ophagy under electron microscopy accompanied with activation of the Akt-mTORC1 signaling pathway was observed in TTN p.R2021X truncation mutation cardiomyocytes.CONCLUSIONS The TTN p.R2021X mutation has a function in the cause of a highly penetrant familial LVNC.These findings expand the spectrum of titin’s roles in cardiomyopathies and provide novel insight into the molecular basis of titin-truncating variants-associated LVNC.
基金supported by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019XK320057)the National Key Research and Development Program of China (2016YFC1300100)+1 种基金the Clinical Transformation and Transformation Fund of the Chinese Academy of Medical Sciences (2019XK320058)the National Natural Science Foundation of China (81974042)
文摘BACKGROUND Left ventricular noncompaction(LVNC) is an increasingly recognised cardiomyopathy of which a significant percentage are genetic in origin. The purpose of the present study was to identify potential pathogenic mutation leading to disease in a Chinese LVNC family.METHODS A 3-generation family affected by LVNC was recruited. Clinical assessments were performed on available family members, with clinical examination, ECG, echocardiography and cardiac MRI. The proband(Ⅰ-2), the proband’s daughter(Ⅱ-1, affected) and mother(Ⅲ-1, unaffected) were selected for WGS. Sanger sequencing were performed in all of the 4 surviving family members.RESULTS Combined whole genome sequencing with linkage analysis identified a novel missense mutation in the giant protein obscurin(OBSCN NM_001098623, c.C19063T), as the only plausible disease-causing variant that segregates with disease among the four surviving individuals, with interrogation of the entire genome excluding other potential causes. This c.C19063T missense mutation resulted in p.R6355W in the encoded OBSCN protein. It affected a highly conserved residue in the C terminus of the obscurin-B-like isoform between the PH and STKc domains, which was predicted to affect the function of the protein by different bioinformatics tools.CONCLUSIONS Here we present clinical and genetic evidence implicating the novel R6355W missense mutation in obscurin as the cause of familial LVNC. This expands the spectrum of obscurin’s roles in cardiomyopathies. It furthermore highlights that rare obscurin missense variants, currently often ignored or left uninterpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here. This study also provided new insights into the molecular basis of OBSCN mutation positive LVNC.
基金supported by grants from the National Natural Science Foundation of China(82074067)Natural Science Foundation of Jiangsu Province China(BK20181419,China)Natural Foundation of Jiangsu Higher Education Institutions of China(19KJA310006)。
文摘Although NPM1 mutations are frequently found in acute myeloid leukemia patients,therapeutic strategies are scarce and unsuitable for those who cannot tolerate intensive chemotherapy.Here we demonstrated that heliangin,a natural sesquiterpene lactone,exerts favorable therapeutic responses in NPM1 mutant acute myeloid leukemia cells,with no apparent toxicity to normal hematogenous cells,by inhibiting their proliferation,inducing apoptosis,causing cell cycle arrest,and promoting differentiation.In-depth studies on its mode of action using quantitative thiol reactivity platform screening and subsequent molecular biology validation showed that the ribosomal protein S2(RPS2)is the main target of heliangin in treating NPM1 mutant AML.Upon covalent binding to the C222 site of RPS2,the electrophilic moieties of heliangin disrupt pre-rRNA metabolic processes,leading to nucleolar stress,which in turn regulates the ribosomal proteins-MDM2-p53 pathway and stabilizes p53.Clinical data shows that the pre-rRNA metabolic pathway is dysregulated in acute myeloid leukemia patients with the NPM1 mutation,leading to a poor prognosis.We found that RPS2 plays a critical role in regulating this pathway and may be a novel treatment target.Our findings suggest a novel treatment strategy and lead compound for acute myeloid leukemia patients,especially those with NPM1 mutations.
基金supported by the National Key Research and Development Program of China(2016YFC1300100)the National Natural Science Foundation of China(81974042)+1 种基金the CAMS Innovation Fund for Medical Sciences(2022-I2M-C&T-A-010,2022I2M-C&T-A-011,and 2022-I2M-C&T-B-041)the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019XK320057 and 2019XK320058)。
基金Supported by the National Natural Science Foundation of China(41771470).
文摘Dust aerosols profoundly influence the radiative balance of the earth–atmosphere system and hence the global and regional climates.In this study,using multi-source satellite and ground-level observations combined with meteorological data,we investigated the three-dimensional evolution and transport characteristics of aerosols during a dust event that occurred in Xinjiang,China from 19 to 21 March 2019.Analysis of the meteorological data reveals that the dust air mass initially appeared in the northwest of Xinjiang and was subsequently transported to the Hami and Turpan areas due to the prevailing northwesterly winds,after which the direction of the airflow shifted due to topography,and the dust air masses were transported into southern Xinjiang.The air quality in the affected areas decreased rapidly,accompanied by a significant increase in aerosol optical depth (AOD),with the maximum value exceeding 3.5 in some areas.In addition,the Cloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations(CALIPSO) data reveal that the aerosol particles in the dust-affected areas were mainly dust aerosols,with small amounts of pollutant dust aerosols.A reduction in the attenuated backscatter coefficient (β532||) was found with increasing altitude,with the dust aerosol pollution mainly distributed in the lower troposphere.The size of dust particles in the lower troposphere was relatively small and irregular.The depolarization ratio (PDR) values at altitudes of 8–10 km were relatively lower than those recorded in the lower troposphere,whereas the color ratio (CR)values were higher,which may have been influenced by the sparse vegetation coverage and poor subsurface conditions in Xinjiang,and attributable to the fact that regular large particles of dust are more likely to be dispersed to altitudes between 8 and 10 km within a short period of time.As a consequence of the meteorological conditions and topography,the dusting process in Xinjiang persisted for a relatively long period.These findings will contribute to enhanced understanding of the vertical distribution of aerosols in Northwest China.
基金This work was supported by grants from the National Natural Science Foundation of China(Nos.81630038,81771634,81842011,81801629,81971433,81971428,and 82071353)the National Key Research and Development Program(Nos.2017YFA0104200 and 2017YFA0104201)+2 种基金the grants from the Science and Technology Bureau of Sichuan Province(Nos.2021YJ0017 and 2020YFS0041)the Fundamental Research Funds for the Central University(No.SCU2020D006)the National Key Project of Neonatal Children(No.1311200003303).
文摘Background:Sepsis,a serious condition with high mortality,usually causes sepsis associated encephalopathy(SAE)that involves neuronal cell death.However,the cell death programs involved and their underlying mechanisms are not clear.This study aimed to explore the regulatory mechanisms of different cell death programs in SAE.Methods:A neonatal rat model of SAE was established by cecal ligation and perforation.Survival rate and vital signs(mean arterial pressure and heart rate)were monitored,nerve reflexes were evaluated,and cortical pathological changes were observed by hematoxylin and eosin staining.The expression of pyroptosis,apoptosis,and necroptosis(PANoptosis)-related proteins,mitogen-activated protein kinase(MAPK),and its upstream regulator toll-like receptor 9(TLR9)were detected.The expression of TLR9 in neurons was observed by immunofluorescence staining.The ultrastructure of neurons was observed by transmission electron microscope.Results:First,PANoptosis was found in cortical nerve cells of the SAE rats.Meanwhile,the subunits of MAPKs,p38 MAPK,Jun N-terminal kinase,and extracellular signal-regulated kinase(ERK)were activated.After pharmacologically inhibiting each of the subunits,only p38 MAPK was found to be associated with PANoptosis.Furthermore,blocking the p38 MAPK signaling pathway activated necroptosis but inhibited apoptosis and pyroptosis.When necroptosis was pharmacologically inhibited,apoptosis and pyroptosis were reactivated.Finally,we found that the expression of TLR9,a regulator of MAPKs,was significantly increased in this model.After down-regulation of TLR9,p38 MAPK,and ERK signaling pathways were inhibited,which led to the inhibition of PANoptosis.Further analysis found that down-regulation of TLR9 improved the survival rate and reduced the pathological changes in SAE rats.Conclusions:Our study showed that the programs comprising PANoptosis are activated simultaneously in SAE rats.TLR9 activated PANoptosis through the p38 MAPK signaling pathway.TLR9 may work as a potential target for SAE treatment.