Publications by authors named "Ying Zhang"

7,698 Publications

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Myositis specific antibodies are associated with isolated anti-Ro-52 associated interstitial lung disease.

Rheumatology (Oxford) 2021 Jun 15. Epub 2021 Jun 15.

Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Objectives: Anti-Ro-52 antibody positivity might be associated with the presence of interstitial lung disease (ILD) among patients with autoimmune features. However, the clinical significance of isolated anti-Ro-52 positivity (i.e., the presence of anti-Ro52 antibodies but the absence of anti-Ro60 antibodies; anti-Ro52+-Ro60-) in patients with ILD is not clear.

Methods: This is a prospective and observational study of Chinese ILD patients with isolated anti-Ro-52 positivity. According to their myositis-specific antibody (MSA) status, patients were split into groups, and their clinical and radiological features were compared.

Results: Of the 158 enrolled patients with ILD and isolated anti-Ro-52 positivity (isolated anti-Ro-52-ILD), there were 130 patients with a positive MSA status and 28 patients with a negative MSA status. Anti-synthetase antibodies (ASAs) were found in 61.5% of patients with MSA+ ILD, and anti-melanoma differentiated-associated protein 5 (MDA-5) antibodies were found in the remaining 38.5% of patients. The anti-nuclear antibody (ANA) pattern was associated with ASA and anti-MDA-5 positivity (χ2=70.7, P < 0.001; Cramer's value 0.47, P < 0.001): ANA negativity was associated with anti-MDA-5 positivity, and cytoplasmic ANA positivity was associated with ASA positivity. There were statistically significant differences in the high-resolution CT patterns between patients with isolated anti-Ro-52 positivity with different MSA statuses (χ2=29.8, P < 0.001; Cramer's value 0.31, P < 0.001): OP pattern was more common in patients with anti-MDA-5 antibodies than in those without anti-MDA-5 antibodies.

Conclusions: Patients with isolated anti-Ro-52-ILD showed high positivity of MSA. Isolated anti-Ro-52 positivity with cytoplasmic ANA positivity was strongly associated with ASA+-ILD, while ANA negativity was associated with anti-MDA-5+-ILD.
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http://dx.doi.org/10.1093/rheumatology/keab488DOI Listing
June 2021

Cumulative risk assessment of dietary exposure to triazole fungicides from 13 daily-consumed foods in China.

Environ Pollut 2021 Jun 9;286:117550. Epub 2021 Jun 9.

Institute of Plant Protection, Chinese Academy of Agricultural Sciences, State Key Laboratory for Biology of Plant Diseases and Insect Pests, Key Laboratory of Control of Biological Hazard Factors (Plant Origin) for Agricultural product Quality and Safety, Ministry of Agriculture, Beijing, 100193, People's Republic of China.

The agroeconomic benefits of the routine use of triazole fungicides on crops have been evident for more than 40 years. However, increasing evidence shows that residues of triazoles are ubiquitous in various foods and thus could pose a potential health risk to humans. We analyzed 3406 samples of 13 food commodities that were collected from markets in 9 regions across China, and assessed the health risk of both chronic and acute exposure to the triazoles for Chinese children (1-6 years old) and the general population. Among all samples, 55.52% had triazoles in concentrations of 0.10-803.30 μg/kg, and 29.77% of samples contained a combination of 2-7 triazoles. Tebuconazole and difenoconazole were the most commonly found triazoles in the foods, being detected in 33.44% and 30.45% of samples, respectively. Chronic and acute cumulative risk assessment for total triazoles based on a relative potency factor method revealed that exposure to triazoles from these particular commodities was below the levels that might pose a health risk (chronic hazard index range, 5.90×10 to 1.83×10; acute hazard index range, 7.77×10 to 0.39, below 1). Notably, dietary exposure risk for children was greater than that for the general population-particularly for the acute intake of mandarin, grape, and cucumber (acute hazard index values of 0.35-0.39). Despite the low health risk, the potential hazards of exposure to triazoles should raise public concern owing to their ubiquitous presence in common foods and potential cumulative effects.
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http://dx.doi.org/10.1016/j.envpol.2021.117550DOI Listing
June 2021

Transfusion-induced platelet antibodies and regulatory T cells in multiply transfused patients.

J Clin Lab Anal 2021 Jun 14:e23864. Epub 2021 Jun 14.

Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Background: Platelet transfusion refractoriness (PTR) remains a difficult problem in patients requiring long-term platelet supportive care. However, there are little data on the frequency of platelet antibodies in multiply transfused Chinese patients. Moreover, the relationship between peripheral regulatory T cells (Tregs) and PTR remains unclear.

Methods: We retrospectively studied the frequency of alloimmunization against platelet antigens in patients receiving multiple transfusions between 2013 and 2017. Monoclonal antibody solid-phase platelet antibody test (MASPAT) kits were used to screen for platelet antibodies before each platelet transfusion. Peripheral Tregs and CD4 CD25 CD127 T cells were detected by flow cytometry, while transforming growth factor-beta (TGF-β) and interleukin (IL)-17 cytokines were detected by enzyme-linked immunosorbent assay.

Results: A total of 399 patients who met the inclusion criteria were enrolled for the analysis of platelet antibodies and refractoriness. Among these patients, 10 (2.5%) were positive for platelet antibodies before transfusion and 47 (11.8%) became antibody-positive during the study period. The number of alloimmunized patients was significantly higher in patients with hematological disease as compared with other disease groups (p < 0.05). Refractoriness and alloimmunization occurred in 77 (19.3%) and 22 (28.6%) patients, respectively. There were no significant differences in CD4 , CD8 , and CD4 CD25 CD127 T cell numbers and plasma levels of TGF-β1 and IL-17 between patients with PTR and the control group.

Conclusions: Refractoriness was common in patients undergoing multiple platelet transfusions (19.3%), with alloimmunization observed in 28.6% of patients. However, Tregs in peripheral blood may not play a key role in PTR.
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http://dx.doi.org/10.1002/jcla.23864DOI Listing
June 2021

Circadian Rhythms within the Female HPG Axis: From Physiology to Etiology.

Endocrinology 2021 Jun 14. Epub 2021 Jun 14.

Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.

Declining female fertility has become a global health concern. It results partially from an abnormal circadian clock caused by unhealthy diet and sleep habits in modern life. The circadian clock system is a hierarchical network consisting of central and peripheral clocks. It not only controls the sleep-wake and feeding-fasting cycles but also coordinates and maintains the required reproductive activities in the body. Physiologically, the reproductive processes are governed by the hypothalamic-pituitary-gonadal (HPG) axis in a time-dependent manner. The HPG axis releases hormones, generates female characteristics, and achieves fertility. Conversely, an abnormal daily rhythm caused by aberrant clock genes or abnormal environmental stimuli contributes to disorders of the female reproductive system, such as polycystic ovarian syndrome (PCOS) and premature ovarian insufficiency (POI). Therefore, breaking the "time code" of the female reproductive system is crucial. In this paper, we review the interplay between circadian clocks and the female reproductive system and present its regulatory principles, moving from normal physiology regulation to disease etiology.
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http://dx.doi.org/10.1210/endocr/bqab117DOI Listing
June 2021

Exogenous Biological Renal Support Improves Kidney Function in Mice With Rhabdomyolysis-Induced Acute Kidney Injury.

Front Med (Lausanne) 2021 28;8:655787. Epub 2021 May 28.

State Key Laboratory of Kidney Diseases, Department of Nephrology, National Clinical Research Center for Kidney Diseases, Chinese People's Liberation Army (PLA) Institute of Nephrology, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.

Rhabdomyolysis (RM) is a clinical syndrome characterized by breakdown of skeletal muscle fibers and release of their contents into the circulation. Myoglobin-induced acute kidney injury (AKI) is one of the most severe complications of RM. Based on our previous research, exogenous biological renal support alleviates renal ischemia-reperfusion injury in elderly mice. This study aimed to determine whether exogenous biological renal support promotes renal recovery from RM-induced AKI and to preliminarily explore the mechanisms involved. A parabiosis animal model was established to investigate the effects of exogenous biological renal support on RM-induced AKI. Mice were divided into three groups: the control group (in which mice were injected with sterile saline), the RM group (in which mice were injected with 8 mL/kg glycerol), and the parabiosis + RM group (in which recipient mice were injected with glycerol 3 weeks after parabiosis model establishment). Blood samples and kidney tissue were collected for further processing 48 h after RM induction. Bioinformatics analysis was conducted via Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, functional enrichment analysis, and clustering analysis. No mice died within 48 h after the procedure. Exogenous biological renal support attenuated the histological and functional deterioration in mice with RM-induced AKI. Bioinformatics analysis identified key pathways and proteins involved in this process. We further demonstrated that exogenous biological renal support ameliorated AKI through multiple mechanisms, including by suppressing the complement system; attenuating oxidative stress, inflammation, and cell death; and increasing proliferation. Exogenous biological renal support provided by parabiosis can improve renal function in RM-induced AKI by suppressing the complement system; decreasing oxidative stress, inflammation, and cell death; and promoting tubular cell proliferation. Our study provides basic research evidence for the use of bioartificial kidneys to treat RM-induced AKI.
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http://dx.doi.org/10.3389/fmed.2021.655787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193099PMC
May 2021

Immunological Identification and Characterization of the Capsid Scaffold Protein Encoded by UL26.5 of Herpes Simplex Virus Type 2.

Front Cell Infect Microbiol 2021 26;11:649722. Epub 2021 May 26.

Institute of Medical Biology, Chinese Academy of Medicine Sciences & Peking Union Medical College, Yunnan Key Laboratory of Vaccine Research and Development for Severe Infectious Diseases, Kunming, China.

Herpes simplex virus type 2 (HSV2), a pathogen that causes genital herpes lesions, interferes with the host immune system various known and unknown mechanisms. This virus has been used to study viral antigenic composition. Convalescent serum from HSV2-infected patients was used to identify viral antigens 2-D protein electrophoresis and immunoblotting. The serum predominantly recognized several capsid scaffold proteins encoded by gene UL26.5, mainly ICP35. This protein has been primarily reported to function temporarily in viral assembly but is not expressed in mature virus particles. Further immunological studies suggested that this protein elicits specific antibody and cytotoxic T lymphocyte (CTL) responses in mice, but these responses do not result in a clinical protective effect in response to HSV2 challenge. The data suggested that immunodominance of ICP35 might be used to design an integrated antigen with other viral glycoproteins.
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http://dx.doi.org/10.3389/fcimb.2021.649722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187855PMC
May 2021

Immediate Psychosocial Impact on Healthcare Workers During COVID-19 Pandemic in China: A Systematic Review and Meta-Analysis.

Front Psychol 2021 28;12:645460. Epub 2021 May 28.

Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.

The corona virus disease-2019 (COVID-19) pandemic spread globally, and we aimed to investigate the psychosocial impact on healthcare workers (HWs) in China during the pandemic. In this systematic review and meta-analysis, we searched seven electronic databases for cross-sectional studies on psychosocial impact on HWs in relation to COVID-19 from January 1, 2020 to October 7, 2020. We included primary studies involving Chinese HWs during the pandemic, and data were extracted from the published articles. Our primary outcome was prevalence of anxiety, depression, and stress disorders. We pooled prevalence value with their 95% confidence interval using random effect models and assessed study quality on the basis of an 11-item checklist recommended by the Agency for Healthcare Research and Quality. The study protocol was registered in PROSPERO (CRD42020195843). We identified 25 articles comprising a total of 30,841 completed questionnaires and 22 studies for meta-analysis. The prevalence of anxiety, depression, and stress disorders was 34.4% (29.5-39.4%), 31.1% (24.5-37.7%), and 29.1% (24.3-33.8%) for HWs. The pooled prevalence of anxiety disorders for HWs from late January to early February was 46.4% (42.9-49.9%), significantly higher than those in mid-term February (28.0%, 23.9-32.1%) and after late February (27.6%, 16.0-39.2%). The pooled prevalence of depression disorders for HWs from late January to early February was 46.5% (38.8-54.2%), significantly higher than those in mid-term February (27.1%, 19.8-34.5%) and after late February (32.9%, 16.2-49.5%). HWs working in Hubei Province had a higher prevalence of anxiety (37.9 vs. 30.8%) and a lower prevalence of depression (27.5 vs. 34.7%) than those working in other regions. Nurses had a higher prevalence of anxiety (44.1 vs. 29.0%) and depression (34.1 vs. 29.2%) than other HWs. About one-third of HWs in China suffered anxiety, depression, and stress at the early epidemic of COVID-19. HWs in Hubei Province, especially nurses, had a higher prevalence of psychological disorders. During the pandemic, a negative psychological state may persist in a proportion of Chinese HWs, fluctuating with the control of the pandemic. The long-term impact should continue to be observed. Attention should be paid to HWs for their psychological impact due to the pandemic. The study protocol was registered with PROSPERO (CRD42020195843).
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http://dx.doi.org/10.3389/fpsyg.2021.645460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192844PMC
May 2021

CO Electroreduction to Formate at a Partial Current Density up to 590 mA mg via Micrometer-Scale Lateral Structuring of Bismuth Nanosheets.

Small 2021 Jun 13:e2100602. Epub 2021 Jun 13.

School of Chemical and Material Engineering, Jiangnan University, Wuxi, 214122, China.

2D bismuth nanosheets are a promising layered material for formate-producing via electrocatalytic CO conversion. However, the commercial interest of bismuth nanosheets in CO electroreduction is still rare due to the undesirable current density for formate at moderate operation potentials (about 200 mA mg ) and harsh synthesis conditions (high temperature and/or high pressure). This work reports the preparation of Bi nanosheets with a lateral size in micrometer-scale via electrochemical cathodic exfoliation in aqueous solution at normal pressure and temperature. As-prepared Bi LNSs (L indicates large lateral size) possess high Faradaic efficiencies over 90% within a broad potential window from -0.44 to -1.10 V versus RHE and a superior partial current density about 590 mA mg for formate in comparison with state-of-the-art results. Structure analysis, electrochemical results, and density functional theory calculations demonstrate that the increasing tensile lattice strain observed in Bi LNSs leads to less overlap of d orbitals and a narrower d-band width, which tuning the intermediate binding energies, and therefore promotes the intrinsic activity.
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http://dx.doi.org/10.1002/smll.202100602DOI Listing
June 2021

Next generation sequencing in children with unexplained epilepsy: A retrospective cohort study.

Brain Dev 2021 Jun 10. Epub 2021 Jun 10.

Department of Paediatrics, Peking University People's Hospital, Beijing 100044, China.

Objective: To evaluate the clinical utility of next-generation sequencing (NGS) in unexplained pediatric epilepsy, and to identify the potential predictors associated with Mendelian genetic causes.

Methods: Two hundred and ten children with unexplained epilepsy, who underwent NGS test were included. We analyzed the demographic, clinical and genetic characteristics, and executed a Logistic regression analysis for identifying predictors for Mendelian genetic causes. Patients were classified as either with isolated epilepsy or syndromic epilepsy with concurrent neurodevelopmental phenotypes.

Results: The overall diagnostic yield was 29.0% (61/210). A total of 68 variants spanning 39 genes were identified in 58 patients (27.6%, 58/210) from exome sequencing based testing. Of the 68 variants, 33 were novel ones. Besides, STAR and CNTN2 were identified to be a candidate gene for epilepsy. Patients with syndromic epilepsy had a much higher diagnostic yield than that of isolated epilepsy (53/135, 39.3% vs. 8/75, 10.7%, p = 0.000). The odds ratio of detecting genetic cause was 3.939 (95% CI 1.369-11.332) for syndromic epilepsy without epileptic encephalopathy (EE), 5.814 (95% CI 2.208-15.306) for EE, 2.958 (95% CI 1.093-8.000) for patients with seizure onset <12 months, and 2.932 (95%CI 1.414-6.080) for female. Of the 210 patients, 78.4% of patients (145/185) had at least a 50% reduction in seizure frequency and 58.9% (109/185) reached seizure freedom. There was no difference between seizure prognosis and diagnostic outcomes.

Significance: NGS is effective for Mendelian genetic etiological diagnosis for unexplained pediatric epilepsy. Female patients with syndromic epilepsy with onset within the first year of life are most likely to yield a positive test result.
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http://dx.doi.org/10.1016/j.braindev.2021.05.014DOI Listing
June 2021

Developmental consequences of children born from mothers with telbivudine treatment during late pregnancy: A prospective study with 3-year follow-up.

Virulence 2021 Dec;12(1):1527-1537

Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China.

We prospectively investigated the neurological development in infants born from mothers treated with telbivudine (LdT) in the third trimester for prevention of hepatitis B virus (HBV) mother-to-infant transmission. Mothers with high HBV load were assigned to either the LdT group ( = 81, 600 mg of LdT each day from gestational week 28 to delivery) or the Control group ( = 39, untreated). Their infants were followed for 36 months to assess physical and neurological developments with Gesell Developmental Schedule tools. At 12 months after birth, the mean scores in the LdT group for gross motor, fine motor, adaptive, linguistic, and personal social domains were similar to those in the Control group. At 36 months, infants in the LdT group had higher mean scores for gross motor than the Control group (98.42 ± 9.69 vs. 94.54 ± 7.48, = 0.03). In the LdT group, the rates of normal development were higher for gross motor (96.30% vs. 82.05% = 0.01) and lower for adaptive (74.07% vs. 92.31% = 0.02). Multivariate regression analyses showed that exposure to LdT during pregnancy was independently associated with infant's development in gross motor (OR 6.49, 95% CI 1.37-30.20, = 0.02) and adaptive (OR 0.18, 95% CI 0.05-0.71, = 0.01) at 36 months. These results suggest that prenatal LdT exposure might affect neurological development in long-term observation.Abbreviations: LdT: telbivudine; HBV: hepatitis B virus; HBsAg: hepatitis B surface antigen; HBeAg: hepatitis Be antigen; HbsAb: hepatitis B surface antibody; ALT: alanine aminotransferase; NA: nucleoside/nucleotide analog; LAM: lamivudine; MTCT: mother-to-child transmission; GDS: Gesell Developmental Schedule; OR: odds ratio; CI: confidence interval; DQ: developmental quotient; RMB: renminbi; BMI: body mass Index; HBIG: hepatitis B immunoglobulin.
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http://dx.doi.org/10.1080/21505594.2021.1936769DOI Listing
December 2021

Mortality of neuromyelitis optica spectrum disorders in a Chinese population.

Ann Clin Transl Neurol 2021 Jun 13. Epub 2021 Jun 13.

Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.

Objective: Neuromyelitis optica spectrum disorder (NMOSD) is a rapidly disabling disease. Epidemiologic studies have suggested varying NMOSD mortality across ethnic groups. However, NMOSD mortality data in China are scarce. This study's objectives were to explore mortality and causes of death among Chinese NMOSD patients and to identify independent predictors of death.

Methods: We performed a retrospective study with a 10-year follow-up of Chinese NMOSD patients. A Cox proportional hazards model was used to identify independent predictors of death.

Results: Five hundred and sixty-nine patients were included; 24 patients died during follow-up, for overall mortality of 4.2%. In these patients, the median disease duration at the time of death was 3.4 years. The most common cause of death was secondary infection (62.5%), especially respiratory infection (45.8%). The second most common cause of death was extensive cervical myelitis with respiratory failure (16.7%). Other causes included suicide (8.3%), cancer (4.2%), cerebral embolism (4.2%), and unknown causes (4.2%). The multivariate Cox analyses indicated that a short first interattack interval (HR = 0.93, 95% CI 0.89-0.98, p = 0.003), lack of regular immunotherapy (HR = 10.34, 95% CI 4.05-26.37, p < 0.001), and older age at onset were independent predictors of death. Every increasing decade of onset age increased the risk of death 2.59 times (95% CI 1.74-3.86, p < 0.001).

Interpretation: Infections were more common in patients not treated with any immunotherapy, indicating that early and consequent immunotherapy might prevent death by infections, which is of great importance for further treatment of NMOSD patients to avoid undertreatment due to fear of treatment-associated infections.
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http://dx.doi.org/10.1002/acn3.51404DOI Listing
June 2021

Ultrafast in-situ forming halloysite nanotube-doped chitosan/oxidized dextran hydrogels for hemostasis and wound repair.

Carbohydr Polym 2021 Sep 11;267:118155. Epub 2021 May 11.

Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, China; Guangdong Key Lab of Orthopedic Technology and Implant Materials, General Hospital of Southern Theater Command of PLA, The First School of Clinical Medicine of Southern Medical University, Guangzhou 510010, China. Electronic address:

A series of halloysite nanotube (HNT)-doped chitosan (CS)/oxidized dextran (ODEX) adhesive hydrogels were developed through a Schiff base reaction. The resultant CS/ODEX/HNT hydrogels could not only form in situ on wounds within only 1 s when injected, but could also adapt to wounds of different shapes and depths after injection. We established four rat and rabbit hemorrhage models and demonstrated that the hydrogels are better than the clinically used gelatin sponge for reducing hemostatic time and blood loss, particularly in arterial and deep noncompressible bleeding wounds. Moreover, the natural antibacterial features of CS and ODEX provided the hydrogels with strong bacteria-killing effects. Consequently, they significantly promoted methicillin-resistant Staphylococcus aureus -infected-wound repair compared to commercial gelatin sponge and silver-alginate antibacterial wound dressing. Hence, our multifunctional hydrogels with facile preparation process and utilization procedure could potentially be used as first-aid biomaterials for rapid hemostasis and infected-wound repair in emergency injury events.
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http://dx.doi.org/10.1016/j.carbpol.2021.118155DOI Listing
September 2021

miR-1224 contributes to ischemic stroke-mediated natural killer cell dysfunction by targeting Sp1 signaling.

J Neuroinflammation 2021 Jun 12;18(1):133. Epub 2021 Jun 12.

The Third Affiliated Hospital of Zhengzhou University, No. 7 Kangfu front ST, Zhengzhou, Henan, China.

Background: Brain ischemia compromises natural killer (NK) cell-mediated immune defenses by acting on neurogenic and intracellular pathways. Less is known about the posttranscriptional mechanisms that regulate NK cell activation and cytotoxicity after ischemic stroke.

Methods: Using a NanoString nCounter® miRNA array panel, we explored the microRNA (miRNA) profile of splenic NK cells in mice subjected to middle cerebral artery occlusion. Differential gene expression and function/pathway analysis were applied to investigate the main functions of predicted miRNA target genes. miR-1224 inhibitor/mimics transfection and passive transfer of NK cells were performed to confirm the impact of miR-1224 in NK cells after brain ischemia.

Results: We observed striking dysregulation of several miRNAs in response to ischemia. Among those miRNAs, miR-1224 markedly increased 3 days after ischemic stroke. Transfection of miR-1224 mimics into NK cells resulted in suppression of NK cell activity, while an miR-1224 inhibitor enhanced NK cell activity and cytotoxicity, especially in the periphery. Passive transfer of NK cells treated with an miR-1224 inhibitor prevented the accumulation of a bacterial burden in the lungs after ischemic stroke, suggesting an enhanced immune defense of NK cells. The transcription factor Sp1, which controls cytokine/chemokine release by NK cells at the transcriptional level, is a predicted target of miR-1224. The inhibitory effect of miR-1224 on NK cell activity was blocked in Sp1 knockout mice.

Conclusions: These findings indicate that miR-1224 may serve as a negative regulator of NK cell activation in an Sp1-dependent manner; this mechanism may be a novel target to prevent poststroke infection specifically in the periphery and preserve immune defense in the brain.
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http://dx.doi.org/10.1186/s12974-021-02181-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196447PMC
June 2021

Revealing the Mechanism of "Huai Hua San" in the Treatment of Ulcerative Colitis based on Network Pharmacology and Experimental Study.

J Ethnopharmacol 2021 Jun 9:114321. Epub 2021 Jun 9.

Faculty of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, China; Key Laboratory of Traditional Chinese Medicine Resources and Chemistry of Hubei Province, Wuhan, 430065, China; Collaborative Innovation Center of Traditional Chinese Medicine of New Products for Geriatrics Hubei Province, Wuhan, 430065, China. Electronic address:

Ethnopharmacological Relevance: "Huai Hua San" (HHS) is one of the first hundred ancient classic prescriptions drugs, which is commonly used to treat hemorrhoids, colitis, and other symptoms of wind heat in stool. However, the potential molecular mechanism of action of this substance remains unclear.

Aims Of The Study: In this study, we explored the active compounds of HHS for the treatment of ulcerative colitis (UC), predicted the potential targets of the drug, and studied its mechanism of action through network pharmacology via in vitro and in vivo experiments.

Materials And Methods: First, we identified the active compounds and key targets of HHS for treating UC via network pharmacology. The key signaling pathways associated with the anti-inflammatory effect of HHS were analyzed. The anti-inflammatory effects of HHS and its active compounds were studied using the RAW264.7 inflammatory cell model in vitro. Furthermore, we used the dextran sulfate sodium (DSS) mouse model to explore the efficacy and mechanism of HHS in UC in vivo, and the expression level of key proteins were detected by Western blotting.

Results: In all, 23 compounds and 97 targets were obtained from TCMSP database, PharmMapper database, and GeneCards database. After enrichment via Kyoto Encyclopedia of Genes and Genomes (KEGG), HIF-1 signaling pathway, PI3K/AKT signaling pathway, and VEGF signaling pathway were identified to be the top three signaling pathways associated with UC treatment. The results of molecular docking showed that the docking scores of the top 10 active compounds were higher than the threshold values. In vitro, different concentrations of HHS and the four main active compounds could effectively inhibit the release of inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1 β. In vivo, HHS could alleviate UC symptoms.

Conclusion: Taken together, the treatment of UC with HHS may alleviate the inflammatory response of the colon, and HHS mainly inhibits the EGFR/PI3K/AKT/HIF-1/VEGF signaling pathways.
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http://dx.doi.org/10.1016/j.jep.2021.114321DOI Listing
June 2021

Analysis of the genomic landscape of yolk sac tumors reveals mechanisms of evolution and chemoresistance.

Nat Commun 2021 06 11;12(1):3579. Epub 2021 Jun 11.

Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Yolk sac tumors (YSTs) are a major histological subtype of malignant ovarian germ cell tumors with a relatively poor prognosis. The molecular basis of this disease has not been thoroughly characterized at the genomic level. Here we perform whole-exome and RNA sequencing on 41 clinical tumor samples from 30 YST patients, with distinct responses to cisplatin-based chemotherapy. We show that microsatellite instability status and mutational signatures are informative of chemoresistance. We identify somatic driver candidates, including significantly mutated genes KRAS and KIT and copy-number alteration drivers, including deleted ARID1A and PARK2, and amplified ZNF217, CDKN1B, and KRAS. YSTs have very infrequent TP53 mutations, whereas the tumors from patients with abnormal gonadal development contain both KRAS and TP53 mutations. We further reveal a role of OVOL2 overexpression in YST resistance to cisplatin. This study lays a critical foundation for understanding key molecular aberrations in YSTs and developing related therapeutic strategies.
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http://dx.doi.org/10.1038/s41467-021-23681-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196104PMC
June 2021

K63-linked ubiquitination of DYRK1A by TRAF2 alleviates Sprouty 2-mediated degradation of EGFR.

Cell Death Dis 2021 Jun 11;12(6):608. Epub 2021 Jun 11.

Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Dual specificity tyrosine phosphorylation regulated kinase 1A, DYRK1A, functions in multiple cellular pathways, including signaling, endocytosis, synaptic transmission, and transcription. Alterations in dosage of DYRK1A leads to defects in neurogenesis, cell growth, and differentiation, and may increase the risk of certain cancers. DYRK1A localizes to a number of subcellular structures including vesicles where it is known to phosphorylate a number of proteins and regulate vesicle biology. However, the mechanism by which it translocates to vesicles is poorly understood. Here we report the discovery of TRAF2, an E3 ligase, as an interaction partner of DYRK1A. Our data suggest that TRAF2 binds to PVQE motif residing in between the PEST and histidine repeat domain (HRD) of DYRK1A protein, and mediates K63-linked ubiquitination of DYRK1A. This results in translocation of DYRK1A to the vesicle membrane. DYRK1A increases phosphorylation of Sprouty 2 on vesicles, leading to the inhibition of EGFR degradation, and depletion of TRAF2 expression accelerates EGFR degradation. Further, silencing of DYRK1A inhibits the growth of glioma cells mediated by TRAF2. Collectively, these findings suggest that the axis of TRAF2-DYRK1A-Sprouty 2 can be a target for new therapeutic development for EGFR-mediated human pathologies.
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http://dx.doi.org/10.1038/s41419-021-03887-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196033PMC
June 2021

Capturing the grouping and compactness of high-level semantic feature for saliency detection.

Neural Netw 2021 Apr 24;142:351-362. Epub 2021 Apr 24.

School of Physics Electronic Engineering, Nanyang Normal University, Nanyang 473061, China.

Saliency detection is an important and challenging research topic due to the variety and complexity of the background and saliency regions. In this paper, we present a novel unsupervised saliency detection approach by exploiting the grouping and compactness characteristics of the high-level semantic features. First, for the high-level semantic feature, the elastic net based hypergraph model is adopted to discover the group structure relationships of salient regional points, and the calculation of the spatial distribution is constructed to detect the compactness of the saliency regions. Next, the grouping-based and compactness-based saliency maps are improved by a propagation algorithm. The propagation process uses an enhanced similarity matrix, which fuses the low-level deep feature and the high-level semantic feature through cross diffusion. Results on four benchmark datasets with pixel-wise accurate labeling demonstrate the effectiveness of the proposed method. Particularly, the proposed unsupervised method achieves competitive performance with deep learning-based methods.
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http://dx.doi.org/10.1016/j.neunet.2021.04.028DOI Listing
April 2021

The distribution characteristics of β-propeller phytase genes in rhizosphere sediment provide insight into species specialty from phytic mineralization in subtropical and tropical seagrass ecosystems.

Ecotoxicology 2021 Jun 11. Epub 2021 Jun 11.

CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, 510301, Guangzhou, China.

Seagrass meadows have seriously deteriorated in recent years. Seagrass associated phytate-mineralizing rhizobacteria potentially have functions related to seagrass nutrition, health and sustainable growth. The β-propeller phytases (BPPs) are the only phytase family in aquatic environments, but there are few studies on the BPP community structure of seagrass. In this study, clone libraries and quantitative PCR (qPCR) assays were used to compare the diversity and abundances of the BPP communities of Halodule endl, Halophila ovalis and Thalassia hemprichii in Xisha and Sanya, and to investigate the distribution characteristics of BPP genes in the rhizosphere sediment, which provedes insight into species specialty from phytic mineralization in subtropical and tropical seagrass ecosystems. The highest diversity of BPP genes was found for Thalassia hemprichii in Sanya Bay. Thalassia hemprichii in Sanya had higher abundances of BPPs, which were linked to Gammaproteobacteria. The BPP community diversity and OTUs of Thalassia hemprichii in Sanya were much higher than those of Thalassia hemprichii on Yongxing Island and Stone Island. The seagrass BPP communities had higher diversity and evenness from sampling sites with more human activity. The qPCR results showed that the abundance of phytate acid-degradating bacteria was approximately three times larger in Thalassia hemprichii rhizosphere sediment samples than in Halodule endl and Halophila ovalis rhizosphere sediment samples. This study highlighted that the diversity and abundances of bacteria genetically encoding BPP in the rhizosphere of Thalassia hemprichii were clearly higher than those of Halodule endl and Halophila ovalis. Further study of microbial phosphorus cycling will provide new insights into seagrass meadow ecosystems.
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http://dx.doi.org/10.1007/s10646-021-02425-2DOI Listing
June 2021

A Prospective Investigation of Bispecific CD19/22 CAR T Cell Therapy in Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma.

Front Oncol 2021 25;11:664421. Epub 2021 May 25.

Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.

Background: The use of T cells expressing chimeric antigen receptor (CAR T) engineered to target CD19 constitutes breakthrough treatment for relapsed or refractory B cell non-Hodgkin lymphoma (R/R B-NHL). Despite improved outcomes, high relapse rate remains a challenge to overcome. Here, we report the clinical results and the pharmacokinetics of bispecific CD19/22 CAR T in patients with R/R B-NHL.

Methods: We performed a prospective, single-arm study of bispecific CD19/22 CAR T cells in R/R B-NHL. We analyzed the safety and efficacy and investigated the kinetic profiles of the CAR T cells. CAR transgene levels were measured using quantitative polymerase chain reaction, and correlation analyses of pharmacodynamic markers and product characteristics, disease conditions, clinical efficacy and adverse events were performed.

Results: From August 2017 to September 2020, a total of 32 patients with CD19/22 CAR T administration were analyzed. The overall response rate was 79.3%, and the complete response rate was 34.5%. The progression-free survival (PFS) and overall survival (OS) rates at 12 months were 40.0% and 63.3%, respectively. Among patients who had a CR at 3 months, the PFS and OS rates at 12 months were 66.7% and 100%, respectively. Severe cytokine release syndrome (sCRS) (grade 3 and higher) occurred in nine patients (28.1%). Grade 3 or higher neurologic events occurred in four patients (12.5%). One patient died from irreversible severe CRS-associated acute kidney injury. Long-term CAR T cells persistence correlated with clinical efficacy (133 days vs 22 days, P = 0.004). Patients treated with more than three prior therapies and presenting extranodal organ involvement had lower maximal concentration (C) values than other patients. Responders had higher C and area under the curve values than non-responders. Tumour burden and C were potentially associated with the severity of CRS.

Conclusions: This study demonstrates the safety and potential clinical efficacy of bispecific CD19/22 CAR T cells in patients with R/R B-NHL and highlights the importance of measuring kinetic parameters in PB to predict efficacy and safety in clinical applications of CAR T cell therapy.

Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT03196830, identifier NCT03196830.
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http://dx.doi.org/10.3389/fonc.2021.664421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185372PMC
May 2021

Tryptophan Pathway-Targeted Metabolomics Study on the Mechanism and Intervention of Cisplatin-Induced Acute Kidney Injury in Rats.

Chem Res Toxicol 2021 Jun 10. Epub 2021 Jun 10.

Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P.R. China.

Cisplatin is a chemotherapeutic agent widely employed in the treatment of various solid tumors. However, its use is often restricted by acute kidney injury (AKI) which is the dose-limiting adverse effect of cisplatin. While numerous studies aiming to alleviate the AKI have been conducted, there are no effective remedies in clinical practice. In this paper, a targeted metabolomics study was performed to reveal the potential relationship between tryptophan metabolism and cisplatin-induced AKI. A chemical derivatization integrated liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) approach was utilized to quantify 29 metabolites in the tryptophan pathway in rat kidney medulla and cortex after cisplatin administration. Results showed that tryptophan metabolism was remarkably disturbed both in the medulla and cortex after cisplatin administration. We also found that the tryptophan pathway in the medulla was more sensitive to cisplatin exposure compared with the cortex. Among these metabolites, indoxyl sulfate was focused for further study because it accumulated most significantly in the kidney cortex and medulla in a dose-dependent manner. A function verification study proved that chlormethiazole, a widely used CYP2E1 inhibitor, could reduce the production of indoxyl sulfate in the liver and attenuate cisplatin-induced AKI in rats. In conclusion, our study depicted the tryptophan pathway in cisplatin-induced AKI for the first time and demonstrated tryptophan metabolism is closely associated with the renal toxicity caused by cisplatin, which can be of great use for the discovery of renal toxicity attenuating remedies.
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http://dx.doi.org/10.1021/acs.chemrestox.1c00110DOI Listing
June 2021

A Phase I Clinical Trial of HC-1119, a Deuterated Form of Enzalutamide.

Int J Cancer 2021 Jun 10. Epub 2021 Jun 10.

Institute of Clinical Pharmacology, GCP center, West China Hospital, Sichuan University, Chengdu, China.

The purpose of this study was to investigate the safety, pharmacokinetics (PK), and initial anti-tumor efficacy of HC-1119 in patients with metastatic castration-resistant prostate cancer (mCRPC). Eligible mCRPC patients were included in this study (NCT03774056) with two parts. Part A was a dose escalation study in which patients received a dose escalation of HC-1119 (40, 80, 160, and 200 mg/day). Part B was a dose expansion study in which patients received HC-1119 at the dose of 80 and 160 mg. Safety assessment and pharmacokinetic samplings were performed for all patients at the given time points; preliminary tumour response was also assessed.Twenty-four patients were enrolled in part A and nineteen patients in part B, respectively. HC-1119 was safe, well tolerated and no dose-limiting toxicity was observed. Fatigue was the most common treatment-related adverse event and no seizures were observed. At the dose levels of 40, 80, and 160 mg, the AUC and C of HC-1119 in plasma increased almost dose-proportionally at the steady state in mCRPC patients. Maximum prostate-specific antigen (PSA) response rates (≥50% reduction from the baseline) in dose escalation and dose expansion cohorts were 77% and 75%, respectively; the overall disease control rate (22 patients available for imaging analysis) was 72.7%, with PR in 4 patients, SD in 12 patients, and PD in 6 patients; the 2-year overall survival rate in patients from Part B was 56.8%. HC-1119 was safe, well tolerated, and efficacious and HC-1119 at 80 mg/day is recommended for further studies. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ijc.33706DOI Listing
June 2021

[Clinical study of modified posterior dental splint in the treatment of anterior disk displacement without reduction of the temporomandibular joint].

Shanghai Kou Qiang Yi Xue 2021 Apr;30(2):210-213

Department of Temporomandibular Joint Disorders, Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University. Guangzhou 510140, Guangdong Province, China.

Purpose: To investigate the clinical effect of modified posterior dental splint in the treatment of anterior disk displacement without reduction of the temporomandibular joint (TMJ).

Methods: Eight-nine patients with anterior disk displacement without reduction of the TMJ who were treated in Stomatology Hospital of Guangzhou Medical University from October 2016 to October 2017 were selected in the study. 47 patients in the first group were treated by modified posterior dental splint, while 42 patients in the second group were treated by stabilization splint. The patients' pain index, mouth opening degrees were collected before treatment,3 months, 6 months, and 1 year after treatment. Statistical analysis of the data was performed using SPSS 18.0 software package, multivariate test was used to compare the indicators between the two groups.

Results: The effect of modified posterior dental splint on treating limited mouth opening was better than those of stabilization splint(P<0.05). In the treatment of joint pain, the two splints had no significant difference(P>0.05).

Conclusions: Modified posterior dental splint is a new type of splint for the treatment of TMJ disorders. It is suitable for clinical application.
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April 2021

[Efficacy and Relapse Prediction Model of Allogeneic Peripheral Blood Stem Cell Transplantation in Adult Acute Leukemia].

Zhongguo Shi Yan Xue Ye Xue Za Zhi 2021 Jun;29(3):696-702

Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China,E-mail:

Objective: To observe the clinical efficacy of allogeneic peripheral blood stem cell transplantation(allo-HSCT) on the treatment of adult acute leukemia patients, moreover, to establish and evaluate a Logistic model to predict the risk of relapse in adult acute leukemia patients after allo-HSCT.

Methods: The clinical data of 145 adult acute leukemia patients treated by peripheral blood stem cell transplantation in the First Affiliated Hospital of Xi'an Jiaotong University from January 2010 to December 2019 was enrolled and analyzed retrospectively. Complications and survival of patients were observed. The relationship between patients' age, diagnosis, leukocyte count at onset, risk stratification, time of diagnosis to transplantation, HCT-CI, minimal residual disease pre-transplantation, donor-recipient sex relationship, HLA match degree, prophylaxis of graft versus host disease(GVHD), donor age, number of transfused mononuclear cells, CD34 positive cells, engraftment time, acute and chronic GVHD, CMV, EBV infection, and hemorrhagic cystitis and recurrence after transplantation were analyzed by logistic regression. Relapse prediction model was established and evaluated according to the results.

Results: Among 145 acute leukemia patients, 81 with acute myeloid leukemia, 64 with acute lymphocytic leukemia, 18 with EBV infection, 2 with post-transplant lymphoproliferative disorder(PTLD), 85 with CMV, 26 with hemorrhagic cystitis, 65 patients developed acute GVHD, 51 patients developed chronic GVHD and 45 patients relapsed. The overall survival (OS) rates in one and three years were 86.4% and 61.8%, and the progress-free survival (PFS) rates in one and three years were 67.5% and 62.4%, respectively. There were significant differences in OS and PFS between relapsed and non-relapsed patients, as well as AML and ALL patients. Univariate analysis revealed that patient's age, risk stratification, time to transplantation, HCT-CI index, ATG based GVHD prophylaxis, minimal residual disease pre-transplantation, GVHD prophylaxis, and acute and chronic GVHD were associated with the relapse of disease, multivariate logistic regression analysis showed that pre-transplantation minimal residual disease showed positively correlation with relapse of the disease, while chronic GVHD showed negatively correlation.

Conclusion: The relapse rate of adult acute leukemia patients treated with allo-HSCT in our hospital is 31.0%, and OS of AML patients is better than ALL patients'. OS of relapsed patients is significantly lower than non-relapsed patients'. Pre-transplantation minimal residual disease is a risk factor of relapse. The risk of relapse is reduced in patients with chronic GVHD.
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http://dx.doi.org/10.19746/j.cnki.issn.1009-2137.2021.03.007DOI Listing
June 2021

Exogenous Bimodal Cues Attenuate Age-Related Audiovisual Integration.

Iperception 2021 May-Jun;12(3):20416695211020768. Epub 2021 May 27.

Department of Psychology, Faculty of Education, Hubei University, Wuhan, China.

Previous studies have demonstrated that exogenous attention decreases audiovisual integration (AVI); however, whether the AVI is different when exogenous attention is elicited by bimodal and unimodal cues and its aging effect remain unclear. To clarify this matter, 20 older adults and 20 younger adults were recruited to conduct an auditory/visual discrimination task following bimodal audiovisual cues or unimodal auditory/visual cues. The results showed that the response to all stimulus types was faster in younger adults compared with older adults, and the response was faster when responding to audiovisual stimuli compared with auditory or visual stimuli. Analysis using the race model revealed that the AVI was lower in the exogenous-cue conditions compared with the no-cue condition for both older and younger adults. The AVI was observed in all exogenous-cue conditions for the younger adults (visual cue > auditory cue > audiovisual cue); however, for older adults, the AVI was only found in the visual-cue condition. In addition, the AVI was lower in older adults compared to younger adults under no- and visual-cue conditions. These results suggested that exogenous attention decreased the AVI, and the AVI was lower in exogenous attention elicited by bimodal-cue than by unimodal-cue conditions. In addition, the AVI was reduced for older adults compared with younger adults under exogenous attention.
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http://dx.doi.org/10.1177/20416695211020768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165524PMC
May 2021

mPEG-PCL Polymeric Micelles Influence Pharmacokinetics and Hypoglycemic Efficacy of Metformin through Inhibition of Organic Cation Transporters in Rats.

Mol Pharm 2021 Jun 9. Epub 2021 Jun 9.

Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, PR China.

Increasing evidence has shown that nanocarriers have effects on several efflux drug transporters. To date, little is known about whether influx transporters are also modulated. Herein, we investigated the impact of amphiphilic polymer micelles on the uptake function of organic cation transporters (OCTs) and the influence on the pharmacokinetics and pharmacodynamics of metformin, a well-characterized substrate of OCTs. Five types of polymeric micelles (mPEG-PCL, mPEG-PCL, mPEG-PCL, mPEG-PCL, and mPEG-PCL) were prepared to evaluate the inhibition of hOCT1-3-overexpressing Madin-Darby canine kidney cells. The mPEG-PCL micelles played an inhibitory role above the critical micelle concentration. The inhibitory potency could be ranked as mPEG-PCL > mPEG-PCL > mPEG-PCL > mPEG-PCL > mPEG-PCL, which negatively declined with the increase of molecular weight of the hydrophobic segment. The inhibitory effects of polymeric micelles on the hOCT1 isoform were the most pronounced, with the lowest IC values ranging from 0.106 to 0.280 mg/mL. The mPEG-PCL micelles distinctly increased the plasma concentration of metformin and significantly decreased by 35.6% ( < 0.05) after seven consecutive treatments in rats, which was interrelated with the restrained metformin distribution in the liver and kidney. The uptake inhibition of micelles on hepatic and renal rOcts also diminished the glucose-lowering effect of metformin and fasting insulin levels in the oral glucose tolerance test. Consistent with the inhibitory effects, the mRNA and protein levels of rOct1 and rOct2 were decreased in the liver, kidney, and small intestine. The present study demonstrated that mPEG-PCL micelles could inhibit the transport function of OCTs, indicating a potential risk of drug-drug interactions during concomitant medication of nanomedicine with organic cationic drugs.
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http://dx.doi.org/10.1021/acs.molpharmaceut.1c00078DOI Listing
June 2021

Down-regulating Circular RNA Prkcsh suppresses the inflammatory response after spinal cord injury.

Neural Regen Res 2022 Jan;17(1):144-151

Department of Orthopedics, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.

Circular RNAs (circRNAs) are a class of conserved, endogenous non-coding RNAs that are involved in transcriptional and post-transcriptional gene regulation and are highly enriched in the nervous system. They participate in the survival and differentiation of multiple nerve cells, and may even promote the recovery of neurological function after stroke. However, their role in the inflammatory response after spinal cord injury remains unclear. In the present study, we established a mouse model of T9 spinal cord injury using the modified Allen's impact method, and identified 16,013 circRNAs and 960 miRNAs that were differentially expressed after spinal cord injury. Of these, the expression levels of circPrkcsh were significantly different between injured and sham-treated mice. We then treated astrocytes with tumor necrosis factor-α in vitro to simulate the inflammatory response after spinal cord injury. Our results revealed an elevated expression of circPrkcsh with a concurrent decrease in miR-488 expression in injured cells. We also found that circPrkcsh regulated the expression of the inflammation-related gene Ccl2. Furthermore, in tumor necrosis factor-α-treated astrocytes, circPrkcsh knockdown decreased the expression of Ccl2 by upregulating miR-488 expression, and reduced the secretion of inflammatory cytokines in vitro. These findings suggest that differentially expressed circRNAs participate in the inflammatory response after spinal cord injury and act as the regulators of certain microRNAs. Furthermore, circPrkcsh may be used as an miR-488 sponge to regulate Ccl2 expression, which might provide a new potential therapy for SCI. The study was approved by the Animal Ethics Committee of Shandong University of China (approval No. KYLL-20170303) on March 3, 2017.
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http://dx.doi.org/10.4103/1673-5374.314114DOI Listing
January 2022

Cost-effectiveness of Pembrolizumab + Chemotherapy versus Chemotherapy and Pembrolizumab Monotherapy in 1st Line Treatment of NSCLC in the U.S. - .

J Med Econ 2021 Jun 8. Epub 2021 Jun 8.

Merck Sharp & Dohme, HTA Statistics Europe, Brussels, Belgium.

Pembrolizumab + chemotherapy substantially extends life expectancy for metastatic non-small cell lung cancer (NSCLC) patients. Its cost-effectiveness (CE) was previously evaluated based on interim trial analyses (follow-up ∼1 year). The present analysis describes CE incorporating additional follow-up based on protocol-specified final trial analyses (1-1.5 years additional follow-up), from a U.S. healthcare payer perspective. A partitioned survival model is used to compare pembrolizumab + chemotherapy vs. chemotherapy using data from the KN189 (non-squamous patients) and KN407 (squamous patients) clinical trials. An indirect treatment comparison vs. pembrolizumab monotherapy is made for patient subgroups with PD-L1 TPS ≥50% and 1-49% based on data from the KN024 and KN042 trials. Efficacy, treatment utilization, health utility and safety data are derived from trials and projected over 20 years. Costs for drugs, non-drug disease management and adverse events are also incorporated. Overall, versus chemotherapy alone, pembrolizumab + chemotherapy is projected to increase life expectancy by 1.12 years (3.35 vs. 2.23) and 0.67 years (3.17 vs. 2.50) in non-squamous and squamous patients, respectively. Resultant ICERs ($158,030/QALY and $178,387/QALY) are below a U.S. 3 times GDP per capita threshold ($195,000/QALY). ICERs vs. chemotherapy also generally fall below the threshold within PD-L1 sub-groups (except in squamous PD-L1 < 1%, which may have differed due to small sample size) while ICERs vs pembrolizumab monotherapy in PD-L1 ≥ 50% and 1-49% sub-groups, generally exceed it (except in squamous PD-L1 1-49%); largely a result of the higher drug acquisition cost of pembrolizumab + chemotherapy relative to differences in life expectancy. Taken together, with longer-term trial follow-up and in the context of prior literature, in the U.S., one of the two options for pembrolizumab use (either pembrolizumab + chemotherapy or pembrolizumab monotherapy), represents a cost-effective treatment in virtually all non-squamous and squamous metastatic NSCLC patient populations and PD-L1 sub-groups evaluated.
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http://dx.doi.org/10.1080/13696998.2021.1937188DOI Listing
June 2021

The prognosis of epilepsy patients with CACNA1H missense variants: A longitudinal cohort study.

Seizure 2021 May 28;91:52-59. Epub 2021 May 28.

Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China. Electronic address:

Objective: CACNA1H is regarded as a gene conferring susceptibility to generalised epilepsy. However, the prognosis of epilepsy patients carrying the CACNA1H missense variants of uncertain significance (VUS) is unknown. A prospective cohort was generated to determine the deleterious effects of these variants and to check whether the presence of these variants affects the prognosis of epilepsy patients.

Method: This study was conducted at Xijing Hospital in Xian, China. All patients were followed up for at least 1 year. Previous reports were searched for previously reported variants. Ensembl database was searched for variants in the general population. Combined Annotation Dependent Depletion (CADD) was used to evaluate the deleterious effect of variants. Logistic regression and Cox regression were used for data analysis.

Results: The study included 176 epilepsy patients with or without CACNA1H variants. In epilepsy patients with missense variants, we found 35 different variants, including 33 variants with uncertain significance and 2 likely benign variants. No significant difference was observed between the distribution of CADD scores of the variants from this cohort, of the general population, and of those found in previous reports. Among epilepsy patients with missense variants, the number of antiepileptic drugs (AEDs) administered to the patients, a first-degree family history of epilepsy, and possibly the presence of abnormalities in brain radiology findings were correlated with the poorer prognosis. Among the entire cohort, the type of epilepsy, number of AEDs administered, and presence of abnormalities in brain radiology findings were associated with the prognosis of these patients. The deleterious effect of CACNA1H missense variants or their presence was not related to the prognosis of epilepsy patients.

Conclusion: The results of our study suggest that CACNA1H variants are related to multiple epilepsy syndromes. However, there is no strong evidence of the correlation between CACNA1H missense variants and a certain type of epilepsy. In our study cohort, both the deleterious effects and the presence of CACNA1H variants were found to be unrelated to the prognosis of patients with epilepsy. These findings suggest that CACNA1H missense variants that are classified as VUS might not influence the outcome of epilepsy.
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http://dx.doi.org/10.1016/j.seizure.2021.05.019DOI Listing
May 2021

The prevalence and functional characteristics of CrpP-like in Pseudomonas aeruginosa isolates from China.

Eur J Clin Microbiol Infect Dis 2021 Jun 7. Epub 2021 Jun 7.

Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.

Modifying enzyme-CrpP and its variants reduced the MICs of fluoroquinolones in Pseudomonas aeruginosa. This study investigated the dissemination and functional characteristics of CrpP-like in P. aeruginosa from China. The positive rate of crpP-like genes in 228 P. aeruginosa was 25.4% (58/228), and 6 new crpP-like genes were determined. Transformation experiments showed that CrpP-like had a low effect on CIP and LEV susceptibility. The genetic of crpP-positive was diverse. Furthermore, the mean expression level of crpP was no statistical difference between fluoroquinolone-susceptible and -resistant group (P > 0.05). CrpP-like may not play a significant role in fluoroquinolone resistance in P. aeruginosa.
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http://dx.doi.org/10.1007/s10096-021-04287-2DOI Listing
June 2021

Modified lung ultrasound scoring system to evaluate the feasibility of pregnant women with COVID-19 pneumonia.

J Matern Fetal Neonatal Med 2021 Jun 6:1-6. Epub 2021 Jun 6.

Department of Ultrasound Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.

Objective: To investigate whether physicians with short-term training can use a modified lung ultrasound scoring system for coronavirus disease 2019 (COVID-19) pneumonia to assess lung damage in pregnant women.

Methods: Sixteen consecutively hospitalized third-trimester pregnant women with pregnancy-induced hypertension, preeclampsia, rheumatoid arthritis or connective tissue disease were selected as the study subjects for the simulation of COVID-19 pneumonia. Two physicians (imaging and internal medicine) without ultrasonic experience performed lung examinations on pregnant women after six days of lung ultrasound training, and their consistency with examinations by the expert was assessed. In addition, 54 healthy third-trimester pregnant women and 54 healthy nonpregnant women of the same age who were continuously treated in the outpatient clinic of this hospital were selected for comparisons of abnormalities on lung ultrasound.

Results: (1) Third trimester pregnant women with pregnancy-induced hypertension, preeclampsia, rheumatoid arthritis or connective tissue disease had the same lung ultrasound patterns as those associated with COVID-19 pneumonia. (2) There was no statistically significant difference between the scores of the two trained doctors and the expert when the modified ultrasound scoring system was used ( > .05). (3) The evaluations of the two trained doctors and the expert showed good consistency (kappa value = 0.833-0.957). (4) The incidence of abnormal ultrasound manifestations of the pleura and lung parenchyma was higher among healthy third-trimester pregnant women than among healthy women of the same age ( < .001).

Conclusions: After receiving short-term training, imaging and internal medicine physicians can use the modified lung ultrasound scoring system to evaluate pregnant women's pulmonary damage, but caution is needed to avoid false-positive results among pregnant women with suspected COVID-19 pneumonia.
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http://dx.doi.org/10.1080/14767058.2021.1874912DOI Listing
June 2021