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1.
Pharm Biol ; 58(1): 16-24, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31854225

RESUMO

Context: XingNaoJing injection (XNJ), extracted from a traditional compound Chinese medicine Angong niuhuang pill, is well known for treating stroke in the clinic, but the specific effects and mechanisms remain unclear.Objective: We investigated the mechanistic basis for the protective effect of XNJ on cerebral ischaemia/reperfusion (I/R) injury.Materials and methods: Five groups of 10 SD rats underwent 2 h of middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. XNJ at 10 and 15 mL/kg was intraperitoneally administered 24 h before ischaemia and at the onset of reperfusion respectively. The silent information regulator 1 (SIRT1) inhibitor EX527 was intracerebroventricularly injected 0.5 h before reperfusion. Cerebral infarction size, neurological scores, morphological changes, and expression levels of inflammatory mediators and SIRT1 were measured. Furthermore, human brain microvascular endothelial cells (HBMECs) were subjected to 3 h oxygen and glucose deprivation (OGD) followed by 24 h reoxygenation to mimic cerebral I/R in vitro. EX527 pre-treatment occurred 1 h before OGD. SIRT1 and inflammatory mediator levels were analyzed.Results: Both XNJ doses significantly decreased cerebral infarct area (40.11% vs. 19.66% and 9.87%) and improved neurological scores and morphological changes. Inflammatory mediator levels were remarkably decreased in both model systems after XNJ treatment. XNJ also enhanced SIRT1 expression. Notably, the SIRT1 inhibitor EX527 attenuated the XNJ-mediated decrease in inflammation in vivo and in vitro.Conclusions: XNJ improved cerebral I/R injury through inhibiting the inflammatory response via the SIRT1 pathway, which may be a useful target in treating cerebral I/R injury.

2.
Biomed Pharmacother ; 122: 109677, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31810012

RESUMO

Acetylshikonin, a natural naphthoquinone derivative compound from Lithospermum erythrorhyzon, has been reported to kill bacteria, suppress inflammation, and inhibit tumor growth. However, the effect of acetylshikonin on human chronic myelocytic leukemia (CML) cells apoptosis and its detailed mechanisms remains unknown. The purpose of the present study was to investigate whether acetylshikonin could inhibit proliferation or induce apoptosis of the K562 cells, and whether by regulating the NF-κB signaling pathway to suppress the development of CML. K562 cells were treated with serial diluted acetylshikonin at different concentrations. Our data showed that K562 cell growth was significantly inhibited by acetylshikonin with an IC50 of 2.03 µM at 24 h and 1.13 µM at 48 h, with increased cell cycle arrest in S-phase. The results of annexin V-FITC/PI and AO/EB staining showed that acetylshikonin induced cell apoptosis in a dose-dependent manner. K562 cells treated with acetylshikonin underwent massive apoptosis accompanied by a rapid generation of reactive oxygen species (ROS). Scavenging the ROS completely blocked the induction of apoptosis following acetylshikonin treatment. The levels of the pro-apoptotic proteins Bax, cleaved caspase-9, cleaved PARP and cleaved caspase-3 increased with increased concentrations of acetylshikonin, while the level of the anti-apoptotic protein Bcl-2 was downregulated. The levels of Cyt C and AIF, which are characteristic proteins of the mitochondria-regulated intrinsic apoptotic pathway, also increased in the cytosol after acetylshikonin treatment. However, the mitochondrial fraction of Cyt C and AIF were decreased under acetylshikonin treatment. In addition, acetylshikonin decreased Bcr-Abl expression and inhibited its downstream signaling. Acetylshikonin could lead to a blockage of the NF-κB signaling pathway via decreasing nuclear NF-κB P65 and increasing cytoplasmic NF-κB P65. Moreover, acetylshikonin significantly inhibited the phosphorylation of IkBα and IKKα/ß in K562 cells. These results demonstrated that acetylshikonin significantly inhibited K562 cell growth and induced cell apoptosis through the mitochondria-regulated intrinsic apoptotic pathway. The mechanisms may involve the modulating ROS accumulation, inhibition of NF-κB and BCR-ABL expression. The inhibition of BCR-ABL expression and the inactivation of the NF-κB signaling pathway caused by acetylshikonin treatment resulted in K562 cell apoptosis. Together, our results indicate that acetylshikonin could serve as a potential therapeutic agent for the future treatment of CML.

3.
J Biomed Nanotechnol ; 15(12): 2376-2392, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31748018

RESUMO

Busulfan and other chemotherapeutic drugs used in the treatment of cancer may result in temporary or even permanent damage to spermatogenesis. During spermatogenesis, the rapidly dividing spermatogonia are highly susceptible to chemotherapy. Consequently, there is significant interest in developing an approach that could provide stimulation and regenerate spermatogenesis after chemotherapy. In a previous study, we suggested the potential application for vascular endothelial growth factor C (VEGFC) because of its key role in stimulating the proliferation of spermatogonia. However, methods to facilitate the recovery of spermatogenesis in such patients using VEGFC, or other regulatory factors, are sorely lacking because of the rapid degradation of these proteins and restrictions created by the blood-testis-barrier. To this end, we loaded VEGFC into polyanion dextran sulfate incorporated in a polycation chitosan shell to produce VEGFC sustained-release ultrafine particles (UFPs, CS-DS-VEGFC). We tested such particles in an azoospermic mouse model, created using busulfan. For each mouse, CS-DS-VEGFC was injected into the seminiferous tubules of one testis, while unloaded UFPs (CS-DS), or the VEGFC protein alone, was injected into the opposite testis as a control. All mice were sacrificed and evaluated 5 weeks later. Spermatogenesis in the tubules that were injected with CS-DS-VEGFC was clearly better than those injected with controls, and contained more spermatogonia and spermatocytes, along with Ki67 and PCNA positive-cells per tubule. In addition, the phosphorylation levels of AKT and MAPK in these tubules were also higher than in controls, indicating that CS-DS-VEGFC could induce the sustained activation of these pathways. In conclusion, CS-DS-VEGFC, combined with the efferent tubule injection technique, is a feasible approach with which to improve the regeneration of spermatogenesis in busulfan-induced azoospermic mice.


Assuntos
Espermatogênese , Animais , Preparações de Ação Retardada , Humanos , Masculino , Camundongos , Regeneração , Espermatogônias , Fator C de Crescimento do Endotélio Vascular
4.
Cytojournal ; 16: 21, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31741668

RESUMO

Background: The Paris System (TPS) acknowledges the need for more standardized terminology for reporting urine cytopathology results and minimizing the use of equivocal terms. We apply TPS diagnostic terminologies to assess interobserver agreement, compare TPS with the traditional method (TM) of reporting urine cytopathology, and evaluate the rate and positive predictive value (PPV) of each TPS diagnostic category. A survey is conducted at the end of the study. Materials and Methods: One hundred urine samples were reviewed independently by six cytopathologists. The diagnosis was rendered according to TPS categories: negative for high-grade urothelial carcinoma (NHGUC), atypical urothelial cells (AUC), low-grade urothelial neoplasm (LGUN), suspicious for high-grade urothelial carcinoma (SHGUC), and high-grade urothelial carcinoma (HGUC). The agreement was assessed using kappa. Disagreements were classified as high and low impacts. Statistical analysis was performed. Results: Perfect consensus agreement was 31%, with an overall kappa of 0.362. Kappa by diagnostic category was 0.483, 0.178, 0.258, and 0.520 for NHGUC, AUC, SHGUC, and HGUC, respectively. Both TM and TPS showed 100% specificity and PPV. TPS showed 43% sensitivity (38% by TM) and 70% accuracy (66% by TM). Disagreements with high clinical impact were 27%. Of the 100 cases, 52 were concurrent biopsy-proven HGUC. The detection rate of biopsy-proven HGUC was 43% by TPS (57% by TM). The rate of NHGUC was 54% by TPS versus 26% by TM. AUC rate was 23% by TPS (44% by TM). The PPV of the AUC category by TPS was 61% versus 43% by TM. The survey showed 33% overall satisfaction. Conclusions: TPS shows adequate precision for NHGUC and HGUC, with low interobserver agreement for other categories. TPS significantly increased the clinical significance of AUC category. Refinement and widespread application of TPS diagnostic criteria may further improve interobserver agreement and the detection rate of HGUC.

5.
Complement Ther Med ; 46: 180-188, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31519276

RESUMO

BACKGROUND: N-of-1 trial is a desired and appropriate approach to assessing the efficacy and safety of traditional Chinese medicine (TCM) interventions. There have been an increasing number of N-of-1 trials for TCM published. However, a lack of preferred reporting guidance led in the general poor reporting quality of these trials. Due to the unique characteristics of TCM, the working group developed this CONSORT Extension for reporting N-of-1 Trials for Traditional Chinese Medicine (CENT for TCM) to assist TCM researchers in reporting N-of-1 trials for TCM. METHODS: We registered CENT for TCM at the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network (available at equator-network.org). The development was a comprehensive process through collection of the initial reporting items, two-round scientific Delphi consensus survey with 17 panelists, revision and formation of the final reporting checklist. RESULTS: The checklist includes 25 items within six domains, eight items in which were extended and elaborated on the items of the CENT 2015 checklist. Explanation of the items were listed adequately considering the nature of TCM, introducing the concept of TCM syndrome differentiation and TCM interventions. CONCLUSIONS: CENT for TCM can be used to assess the completeness of the reporting of N-of-1 trials for TCM. The working group expect that CENT for TCM could be a practical tool to enhance the comprehensiveness and transparency of the design, implementation and reporting of N-of-1 trials for TCM.

6.
Chin J Nat Med ; 17(7): 498-505, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31514981

RESUMO

The aim of this study was to explore the neuroprotective effect and mechanism of XingNaoJing injections (XNJ) on cerebral ischemia injury and blood-brain barrier (BBB) disruption. Middle cerebral artery occlusion (MCAO) method was applicated to establish the model of cerebral ischemia/reperfusion (I/R) injury in rats. BBB permeability after I/R injury was assessed with the leaking amount of Evans Blue and the expression of occludin and ZO-1. The expression of NOD-like receptor family, pyrin domain containing (NLRP3) was checked to explore the inhibition of inflammation by XNJ. The results showed that XNJ could significantly increase the survival percent, decrease the infarct area and ameliorate neurological deficits and brain damage after I/R injury. Leaking amount of Evans Blue was reduced by XNJ, and the expression of tight junction protein, occludin and ZO-1 was also up-regulated by XNJ, which showed a role of protection on BBB disruption. The expression of NLRP3 was inhibited after exposure of XNJ, which was associated with inhibition of the inflammatory response. In summary, XNJ could suppress NLRP3 inflammasomes and improve BBB disruption and brain damage in rats after cerebral I/R injury, which provided a beneficial insight to further explore XNJ.

7.
Zhongguo Zhong Yao Za Zhi ; 44(11): 2390-2396, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359668

RESUMO

To systematically review the efficacy and safety of Tongmai Yangxin Pills in treatment for angina pectoris of coronary heart disease. CNKI, WanFang, VIP, SinoMed, PubMed, EMbase and the Cochrane Library databases were retrieved online to collect randomized controlled trials(RCTs) of Tongmai Yangxin Pills for angina pectoris of coronary heart disease since the establishment to November 2018. Two investigators screened out literatures independently, extracted data and assessed the risk of bias of included studies. The risk assessment of included references was made according to criteria recommended by Cochrane Handbook 5.3. Meta-analysis was then performed by RevMan 5.3 software. A total of 9 RCTs were included. The results of Meta-analysis showed that compared with the single application of chemotherapy, the combined administration with Tongmai Yangxin Pills and Western medicine could significantly improve the clinical efficacy of angina(RR=1.22, 95%CI[1.13, 1.31]), the improvement rate of electrocardiogram(RR=1.31, 95%CI[1.21, 1.42]), and the clinical efficacy of traditional Chinese medicine(TCM) syndrome(RR=1.17, 95%CI[1.02, 1.35]). Only one study reported adverse events, while 5 studies reported no adverse event. According to current evidences, in the treatment of angina pectoris of coronary heart disease, Tongmai Yangxin Pills has a better clinical efficacy in the treatment of angina pectoris of coronary heart disease in terms of the improvement rate of electrocardiogram and the clinical efficacy of TCM syndrome. Due to the limited quality and quantity of the included studies, more high-quality studies are required to verify the above conclusions.


Assuntos
Angina Pectoris/tratamento farmacológico , Doença das Coronárias/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Eletrocardiografia , Humanos , Medicina Tradicional Chinesa , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Postgrad Med J ; 95(1121): 162-168, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31109934

RESUMO

Elevated levels of proinflammatory markers are evident in patients with diabetic retinopathy (DR) and are associated with disease progression and prognosis. Intercellular adhesion molecule-1 (ICAM-1) is involved in inflammation and acts as a local intensifying signal in the pathological processes associated with chronic eye inflammation. The aim of this systematic review and meta-analysis was to investigate the relationship between ICAM-1 level and DR. Online electronic databases were searched to retrieve all relevant articles published before December 2017. The standard mean difference (SMD) and their 95% CI were included and then pooled with a random effects model. Subgroup analysis and metaregression analysis were applied to explore the sources of heterogeneity, and publication bias was calculated to assess the quality of pooled studies. A total of 11 articles, containing 428 patients with DR and 789 healthy controls, were included in this meta-analysis. The results indicated a significant increase in ICAM-1 level in the DR group compared with the control group (SMD: 1.20, 95%CI 0.83 to 1.57, p<0.001). Subgroup analyses and metaregression analysis indicated that publication year, region, study method, diabetes mellitus type, Newcastle-Ottawa Scale and sample size were not the potential sources of heterogeneity. The results of this current meta-analysis indicated that the increased level of ICAM-1 generally exists in the patients with DR and it may associated with the severity of DR. However, large-scale and high-quality studies are required to confirm this finding in the future.


Assuntos
Retinopatia Diabética/sangue , Molécula 1 de Adesão Intercelular/sangue , Biomarcadores/sangue , Progressão da Doença , Humanos , Prognóstico
9.
Oncol Lett ; 17(5): 4655-4660, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30988822

RESUMO

Recently, interleukin (IL)-32 has been demonstrated to represent a novel biomarker for evaluating the prognosis of patients with gastric and lung cancer; however, its clinical significance in colon cancer remains unknown. In the present study, the IL-32 expression in 60 patients with colon cancer was examined with an immunohistochemistry assay. IL-32 expression was determined in 37 (61.67%) patients with colon cancer. Additionally, IL-32 was associated with tumor size and Dukes' stage. By using the Kaplan-Meier method, patients with positive IL-32 expression had shorter overall survival time, compared with those with negative IL-32 expression. Multivariate analysis indicated that IL-32 could be an independent prognostic factor in patients with colon cancer; therefore, IL-32 may be a novel prognostic biomarker and therapeutic target for colon cancer.

10.
Cancer Lett ; 454: 37-43, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-30978440

RESUMO

Chemoresistance remains the major obstacle to achieve optimal prognosis in gastric cancer patients, and the underlying molecular mechanisms of cancer-associated fibroblasts (CAFs) in gastric cancer chemoresistance remain poorly understood. We identified the high pretherapeutical serum IL-8 level in gastric cancer patients was associated with poor response to platinum-based therapy, and it increased gradually during neoadjuvant chemotherapy and it decreased after radical surgery. Immunohistochemistry assays showed that IL-8 was highly expressed in gastric cancer tissues in chemoresistant patients, and located in CAFs. Primary CAFs produced more IL-8 than the corresponding normal fibroblasts, and human stomach fibroblast line Hs738 secreted more IL-8 after co-cultured with conditioned media from AGS or MGC-803 cells. IL-8 increased the IC50 of cisplatin (CDDP) in AGS or MGC-803 in vitro. Simultaneously, IL-8 treatment enhanced the expression of PI3K, phosphorylated-AKT (p-AKT), phosphorylated-IKb (p-IKb), phosphorylated-p65 (p-p65) and ABCB1, and ABCB1 and p-p65 were overexpressed in tumor tissues of chemoresistant patients. Collectively, CAFs derived IL-8 promotes chemoresistance in human gastric cancer via NF-κB activation and ABCB1 up-regulation. Our study provides a novel strategy to improve the chemotherapeutical efficacy and the prognosis of gastric cancer.

11.
Zhongguo Gu Shang ; 32(4): 327-334, 2019 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-31027408

RESUMO

OBJECTIVE: To investigate multilineage-differentiating stress-enduring (Muse) by immunomagnetic bead screening from Wharton's jelly mesenchymal stromal cells(WJ-MSCs), and explore transplantation of Muse cell for safety and effectivensess of sub acute cord injury in rats. METHODS: Donated Wharton's Jelly-mesenchymal stromal cells (WJ-MSCs) were successfully derived from a human umbilical cord by a series of procedures namely physical isolation of Wharton's Jelly from cord membrane, collagenase and trypsin treatment and density gradient centrifugation. Magnetic activated cell sorting was performed to specifically select SSEA3+ Muse cells, and flow cytometry and immunocytochemistry were used to identify further. In vivo, spinal cord contusion injury model in rats was induced by NYU-III impactor, and were randomly divided and equally into four groups, namely group A (sham), group B (control), group C (Non-Muse cells transplantation) and group D (Muse cells transplantation). Laminectomy was conducted in group A but no spinal cord contusion injury. Laminectomy and cord injury were performed in group B, C and D, 10 g trip rod was freely falling down from 12.5 mm. Two weeks later, group B, C and D were received PBS injection, Non-Muse cells transplantation and Muse cells transplantation respectively, four-point injection were performed in each cord with totally 4×105 cells. BBB scores were evaluated on 1 day, 1, 2, 3, 4, 5 and 6 week after injury. Four weeks after cell transplantation, the rats were sacrificed, and immunohistochemistry were carried out to observe survival, migration and differentiation of the injected cells. RESULTS: The expression of CD105, CD90 and CD73 were over 99.5% in the derived WJ-MSCs population, but CD45 and CD14 were lower than 0.5%, positive rate of SSEA3+ was 1.46% under flow cytometer, However, after MACS sorting, the percentage of 92.0% Muse cells expressed SSEA3 and CD105, and immunohistochemistry results of SSEA3 showed typically membrane morphology with special processes. In vivo, BBB scores was 21 in group A at different time points. One-way ANOVA and LSD analysis showed that BBB scores in group C and D were significantly higher than that in group B (P=0.004, 0.002), but there was no significantly difference between group C and D. Further intra-group paired t test showed that BBB score was significantly higher at 4 weeks than that 3 weeks in group C (P=0.005). However, in group D, BBB scores were significantly higher at 4 and 6 week than those at 3 and 5 weeks, P values were 0.005 and 0.016 respectively. Immunohistochemistry results showed that both Muse cells and Non-Muse cells could survive for 4 weeks in rats and they migrated from the four-point injection to injury site. But there showed more Muse cells survival than Non-Muse cells in the cord. CONCLUSIONS: Immunomagnetic bead screening is efficient to select large number of purified SSEA3+ Muse cells. Muse cells could survive and target-migrate in injured cord to improve BBB scores continuously. Muse cells are a novel kind of seed cells in the spinal cord injury treatment.


Assuntos
Células-Tronco Mesenquimais , Traumatismos da Medula Espinal , Geleia de Wharton , Alprostadil , Animais , Diferenciação Celular , Células Cultivadas , Humanos , Ratos , Cordão Umbilical
12.
PLoS One ; 14(3): e0214282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30913233

RESUMO

Firefighters are exposed to carcinogens and have elevated cancer rates. We hypothesized that occupational exposures in firefighters would lead to DNA methylation changes associated with activation of cancer pathways and increased cancer risk. To address this hypothesis, we collected peripheral blood samples from 45 incumbent and 41 new recruit non-smoking male firefighters and analyzed the samples for DNA methylation using an Illumina Methylation EPIC 850k chip. Adjusting for age and ethnicity, we performed: 1) genome-wide differential methylation analysis; 2) genome-wide prediction for firefighter status (incumbent or new recruit) and years of service; and 3) Ingenuity Pathway Analysis (IPA). Four CpGs, including three in the YIPF6, MPST, and PCED1B genes, demonstrated above 1.5-fold statistically significant differential methylation after Bonferroni correction. Genome-wide methylation predicted with high accuracy incumbent and new recruit status as well as years of service among incumbent firefighters. Using IPA, the top pathways with more than 5 gene members annotated from differentially methylated probes included Sirtuin signaling pathway, p53 signaling, and 5' AMP-activated protein kinase (AMPK) signaling. These DNA methylation findings suggest potential cellular mechanisms associated with increased cancer risk in firefighters.

13.
Hum Genet ; 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30915546

RESUMO

Statistical methods for genome-wide association studies (GWAS) continue to improve. However, the increasing volume and variety of genetic and genomic data make computational speed and ease of data manipulation mandatory in future software. In our view, a collaborative effort of statistical geneticists is required to develop open source software targeted to genetic epidemiology. Our attempt to meet this need is called the OPENMENDEL project ( https://openmendel.github.io ). It aims to (1) enable interactive and reproducible analyses with informative intermediate results, (2) scale to big data analytics, (3) embrace parallel and distributed computing, (4) adapt to rapid hardware evolution, (5) allow cloud computing, (6) allow integration of varied genetic data types, and (7) foster easy communication between clinicians, geneticists, statisticians, and computer scientists. This article reviews and makes recommendations to the genetic epidemiology community in the context of the OPENMENDEL project.

14.
Am J Respir Crit Care Med ; 200(5): 600-607, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30789752

RESUMO

Rationale: Lung function and growth are adversely associated with nitrogen dioxide (NO2) exposure. Lower levels of circulating club cell secretory protein (CC16) in childhood are also associated with subsequent decreased lung function. NO2 exposure may induce epithelial damage in lungs and alter club cell proliferation and morphology.Objectives: To determine if increased ambient NO2 levels at participants' home addresses in early life were associated with decreased levels of CC16 from age 6 to 32 years.Methods: Participants were enrolled at birth in the Tucson Children's Respiratory Study and had circulating CC16 measured at least once between age 6 and 32. Linear mixed models were used to determine the association between estimated ambient NO2 exposure at participants' home address at birth or age 6 with CC16 levels from age 6 to 32.Measurements and Main Results: NO2 exposures at birth or age 6 were available for 777 children with one or more CC16 measurement. We found a negative association between NO2 exposure and CC16 levels, with a 4.7% (95% confidence interval, -8.6 to -0.7) decrease in CC16 levels from age 6 to 32 per interquartile range increase in NO2 exposure (6.0 ppb) at the participants' birth address. We observed modification by race (p interaction = 0.04), with stronger associations among participants with at least one black parent (-29.6% [95% confidence interval, -42.9% to -13.2%] per interquartile range). NO2 at participant's age 6 address was not significantly associated with CC16 levels (-1.9%; 95% confidence interval, -6.3 to 2.6).Conclusions: Higher exposure to NO2 at birth is associated with persistently low levels of CC16 from 6 to 32 years.

15.
Genet Epidemiol ; 43(3): 250-262, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30623484

RESUMO

In metagenomic studies, testing the association between microbiome composition and clinical outcomes translates to testing the nullity of variance components. Motivated by a lung human immunodeficiency virus (HIV) microbiome project, we study longitudinal microbiome data by using variance component models with more than two variance components. Current testing strategies only apply to models with exactly two variance components and when sample sizes are large. Therefore, they are not applicable to longitudinal microbiome studies. In this paper, we propose exact tests (score test, likelihood ratio test, and restricted likelihood ratio test) to (a) test the association of the overall microbiome composition in a longitudinal design and (b) detect the association of one specific microbiome cluster while adjusting for the effects from related clusters. Our approach combines the exact tests for null hypothesis with a single variance component with a strategy of reducing multiple variance components to a single one. Simulation studies demonstrate that our method has a correct type I error rate and superior power compared to existing methods at small sample sizes and weak signals. Finally, we apply our method to a longitudinal pulmonary microbiome study of HIV-infected patients and reveal two interesting genera Prevotella and Veillonella associated with forced vital capacity. Our findings shed light on the impact of the lung microbiome on HIV complexities. The method is implemented in the open-source, high-performance computing language Julia and is freely available at https://github.com/JingZhai63/VCmicrobiome.


Assuntos
Microbiota , Modelos Genéticos , Simulação por Computador , Humanos , Estudos Longitudinais , Pulmão/microbiologia
16.
Chin J Integr Med ; 25(3): 175-181, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30109589

RESUMO

BACKGROUND: Syndrome is one of the most important concepts in Chinese medicine (CM) theory. However, it was not well accounted in most of randomized controlled trials (RCTs). OBJECTIVES: To determine whether CM syndrome differentiation affects the treatment results, functional constipation (FC) was selected as a target disease, and MaZiRenWan (, MZRW), a classic CM formula commonly used for constipation with excessive heat syndrome, was selected for study. METHODS: It is an 18-week prospective double-blinded, doubledummy RCT, including 2-week run-in, 8-week treatment and 8-week post treatment follow-up. A total of 120 FC patients diagnosed as excessive heat syndrome will be recruited from the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine and the Baokang Affiliated Hospital of Tianjin University of Traditional Chinese Medicine. Patients will be randomly allocated into fixed MZRW (f_MZRW) granule group, modified MZRW (m_MZRW) granule group or bisacodyl group. For m_MZRW group, no more than two herbal granules can be added according to the syndrome differentiation for individual participants. The primary end point is the mean of complete spontaneous bowel movements (CSBMs) per week during the treatment period. Secondary end points include mean of CSBMs per week during follow-up, stool form, global symptom improvement, constipation and constipation-related symptoms assessment, CM syndrome change, and reported adverse events. DISCUSSION: This trial is designed to evaluate the effectiveness of these three interventions for FC patients with the CM syndrome of excessive heat, and to determine the change of CM syndrome and the progress of disease during the treatment course. The results are important to explore whether syndrome differentiation is important for the therapeutic effect of a formula on a disease. [Trial registration: Chinese Clinical Trial Registry (Reg No. ChiCTR-TRC-13003742); protocol version: MZRW/NSFC-81173363 (2015.05.04)].


Assuntos
Constipação Intestinal/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Ensaios Clínicos Controlados Aleatórios como Assunto , Constipação Intestinal/diagnóstico , Método Duplo-Cego , Humanos , Estudos Prospectivos
17.
J Ultrasound Med ; 38(4): 929-934, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30294797

RESUMO

OBJECTIVE: This study explored the use of 2-dimensional (2D) ultrasound scans for the quantitative assessment of the fetal conus medullaris (CM) position and its correlation with gestational age (GA). METHODS: This was a prospective study. We identified the first sacral vertebra (S1) by intersection of 2 lines in 2D scans, then counted upward from S1 to determine the CM level and recorded the number of ossified sacral vertebral bodies. A quantitative assessment of the CM position was performed by measuring the distance between the CM and the midpoint of the S1 (CM-S1). The correlation between the CM-S1 distance and GA was evaluated. RESULTS: We determined the CM level by identifying S1 first in 521 fetuses (GA, 20-38 weeks). The CM position in 70% of cases was at the L2 and L2-3 level, and at the L2 level or above after 37 weeks. The number of ossified sacral veterbral bodies was not consistent. CM-S1 measurements were easy to perform. A significant positive correlation between CM-S1 distance and GA was observed (R2 = .89, P < .05). The best-fit formula was: CM-S1 distance = 1.57 × GA - 16.43. The normal reference range was established and the fifth percentile was calculated for each GA. CONCLUSIONS: S1 was easily identified, and the CM position relative to S1 was useful. There was a substantial correlation between CM-S1 and GA. Below the fifth percentile it was suggested that tethered cord may exist.


Assuntos
Idade Gestacional , Medula Espinal/diagnóstico por imagem , Medula Espinal/embriologia , Ultrassonografia Pré-Natal/métodos , Adulto , Fatores Etários , Estudos de Avaliação como Assunto , Feminino , Humanos , Gravidez , Estudos Prospectivos
18.
Am J Respir Crit Care Med ; 199(3): 302-312, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30543455

RESUMO

RATIONALE: CC16 (club cell secretory protein-16), a member of the secretoglobin family, is one of the most abundant proteins in normal airway secretions and has been described as a serum biomarker for obstructive lung diseases. OBJECTIVES: To determine whether low CC16 is a marker for airway pathology or is implicated in the pathophysiology of progressive airway damage in these conditions. METHODS: Using human data from the birth cohort of the Tucson Children's Respiratory Study, we examined the relation of circulating CC16 levels with pulmonary function and responses to bronchial methacholine challenge from childhood up to age 32 years. In wild-type and CC16-/- mice, we set out to comprehensively examine pulmonary physiology, inflammation, and remodeling in the naive airway. MEASUREMENTS AND MAIN RESULTS: We observed that Tucson Children's Respiratory Study participants in the lowest tertile of serum CC16 had significant deficits in their lung function and enhanced airway hyperresponsiveness to methacholine challenge from 11 years throughout young adult life. Similarly, CC16-/- mice had significant deficits in lung function and enhanced airway hyperresponsiveness to methacholine as compared with wild-type mice, which were independent of inflammation and mucin production. As compared with wild-type mice, CC16-/- mice had significantly elevated gene expression of procollagen type I, procollagen type III, and α-smooth muscle actin, areas of pronounced collagen deposition and significantly enhanced smooth muscle thickness. CONCLUSIONS: Our findings support clinical observations by providing evidence that lack of CC16 in the lung results in dramatically altered pulmonary function and structural alterations consistent with enhanced remodeling.


Assuntos
Pneumopatias Obstrutivas/complicações , Pneumopatias Obstrutivas/genética , Deficiência de Proteína/complicações , Deficiência de Proteína/genética , Uteroglobina/deficiência , Uteroglobina/genética , Adolescente , Adulto , Animais , Biomarcadores , Criança , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/fisiopatologia , Pneumopatias Obstrutivas/fisiopatologia , Masculino , Camundongos , Deficiência de Proteína/fisiopatologia , Adulto Jovem
19.
Hum Pathol ; 86: 85-92, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30537493

RESUMO

Metaplastic breast carcinoma (MBC) is a rare subtype of breast cancer with variable morphology. MBC is more often triple negative (ER-, PR-, HER2-) and is associated with poorer clinical outcome when compared with infiltrating ductal carcinoma. The purpose of our study is to identify molecular alterations in MBC using next-generation sequencing (NGS), which may aid chemotherapy selection and use of targeted therapy. A cohort of 18 patients with MBC yielded adequate DNA from microdissected formalin-fixed and paraffin-embedded tumor blocks. NGS was performed using the Ion AmpliSeq cancer hotspot mutation panel version 2 kit, which targets hotspot regions in 50 genes. Immunohistochemical stains for androgen receptor (AR), and programmed cell death ligand-1 were performed. A total of 23 genetic alterations were identified in 15 (83.3%) of 18 patients. Eleven genetic alterations in the PI3K signaling pathway were identified in 9 (50.0%) of 18 patients, including 7 PIK3CA mutations (38.9%), 3 PTEN genetic alterations (16.7%), and 1 AKT1 mutation (5.6%). Ten (55.6%) of 18 patients each harbored 1 TP53 genetic alteration. Additional genetic alterations identified were 1 HRAS mutation and 1 ATM mutation. AR immunoreactivity was identified in 2 (11.1%) of 18 patients. Programmed cell death ligand-1 was negative in all patients. NGS analysis demonstrated that PI3K pathway-related genetic alterations were detected in a high percentage of MBCs, suggesting that targeting the PI3K/mTOR pathway may be promising in patients with MBC. In addition, patients with AR expressing MBC may benefit from androgen antagonist treatment.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Mutação , PTEN Fosfo-Hidrolase/genética , Receptores Androgênicos/genética , Neoplasias de Mama Triplo Negativas/patologia
20.
Nat Commun ; 9(1): 3879, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30250029

RESUMO

Eosinophil infiltration, a hallmark of allergic asthma, is essential for type 2 immune responses. How the initial eosinophil recruitment is regulated by lung dendritic cell (DC) subsets during the memory stage after allergen challenge is unclear. Here, we show that the initial eosinophil infiltration is dependent on lung cDC1s, which require nitric oxide (NO) produced by inducible NO synthase from lung CD24-CD11b+ DC2s for inducing CCL17 and CCL22 to attract eosinophils. During late phase responses after allergen challenge, lung CD24+ cDC2s inhibit eosinophil recruitment through secretion of TGF-ß1, which impairs the expression of CCL17 and CCL22. Our data suggest that different lung antigen-presenting cells modulate lung cDC1-mediated eosinophil recruitment dynamically, through secreting distinct soluble factors during the memory stage of chronic asthma after allergen challenge in the mouse.


Assuntos
Asma/imunologia , Células Dendríticas/imunologia , Eosinófilos/imunologia , Alérgenos/imunologia , Animais , Quimiocina CCL17/imunologia , Quimiocina CCL17/metabolismo , Quimiocina CCL22/imunologia , Quimiocina CCL22/metabolismo , Doença Crônica , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/citologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Papaína/imunologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
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