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1.
Mol Neurobiol ; 2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33939165

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia, which affects more than 5 million individuals in the USA. Unfortunately, no effective therapies are currently available to prevent development of AD or to halt progression of the disease. It has been proposed that monoacylglycerol lipase (MAGL), the key enzyme degrading the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, is a therapeutic target for AD based on the studies using the APP transgenic models of AD. While inhibition of 2-AG metabolism mitigates ß-amyloid (Aß) neuropathology, it is still not clear whether inactivation of MAGL alleviates tauopathies as accumulation and deposition of intracellular hyperphosphorylated tau protein are the neuropathological hallmark of AD. Here we show that JZL184, a potent MAGL inhibitor, significantly reduced proinflammatory cytokines, astrogliosis, phosphorylated GSK3ß and tau, cleaved caspase-3, and phosphorylated NF-kB while it elevated PPARγ in P301S/PS19 mice, a tau mouse model of AD. Importantly, tau transgenic mice treated with JZL184 displayed improvements in spatial learning and memory retention. In addition, inactivation of MAGL ameliorates deteriorations in expression of synaptic proteins in P301S/PS19 mice. Our results provide further evidence that MAGL is a promising therapeutic target for AD.

2.
J Med Chem ; 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33901402

RESUMO

Tumor hypoxia is a major factor responsible for tumor progression, metastasis, invasion, and treatment resistance, leading to low local tumor control and recurrence after radiotherapy in cancers. Here,18F-positron emission tomography (PET) probes are developed for visualizing viable hypoxic cells in biopsies. Pimonidazole derivatives and nitroimidazole-based agents bearing sulfonyl linkers were evaluated. A small-animal PET study showed that the tumor uptake of [18F]-23 [poly(ethylene glycols) (PEG)-sulfonyl linker] of 3.36 ± 0.29%ID/g was significantly higher (P < 0.01) than that of [18F]-20 (piperazine-linker tracer, 2.55 ± 0.49%ID/g) at 2 h postinjection in UPPL tumors. The tumor-to-muscle uptake ratio of [18F]-23 (2.46 ± 0.48 at 2 h pi) was well improved compared with that of [18F]-FMISO (1.25 ± 0.14 at 2 h pi). A comparable distribution pattern was observed between ex vivo autoradiography of [18F]-23 and pimonidazole staining of the neighboring slice, indicating that [18F]-23 is a promising PET agent for hypoxia imaging.

3.
Subst Use Misuse ; : 1-8, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33882788

RESUMO

BACKGROUND: Mental health issues in individuals with substance use disorders are common and can affect treatment outcomes. OBJECTIVES: Secondary analysis of a multi-center trial of an internet-delivered psychosocial SUD treatment intervention (Therapeutic Education System; TES) to: 1) describe psychological symptoms over time, 2) explore whether treatment assignment was associated with psychological symptoms 3) explore whether psychological symptoms at baseline moderated the effect of TES on abstinence or retention at the end of treatment. METHODS: Psychological symptoms were measured using the Global Severity Index (GSI) from the Brief Symptom Inventory (BSI-18), PHQ-9, and MINI SPIN (social anxiety). Zero-inflated-negative-binomial models given high numbers of "0" GSI scores and multivariate logistic regression models were run to estimate the effect of the interaction between treatment and baseline psychological symptoms. RESULTS: The mean age was 35, 37.9% were female, 56.0% were white. Fifty-four percent had a negative urine drug or breath alcohol screen at baseline. Mean GSI score at baseline was 13.5 (SD = 12.6). GSI scores significantly improved (p<.0001) over time. Treatment was not significantly associated with GSI scores (aIRR = 0.97, 95%CI = 0.85-1.11). Those with social anxiety at baseline had a higher likelihood of achieving abstinence when receiving TES compared to TAU (b = 1.2071, SE = 0.6109, p = 0.0482). CONCLUSIONS: Psychological symptoms may improve over time in individuals seeking treatment for SUD, and for those with social anxiety, technology-based treatments may result in a better response. Examining the effect of SUD treatment on broader psychological outcomes in addition to abstinence may help clinicians provide more individualized care for those with co-occurring conditions.

4.
Arterioscler Thromb Vasc Biol ; : ATVBAHA120315522, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33792349

RESUMO

OBJECTIVE: Atherosclerosis is accumulation of lipids and extracellular matrix in the arterial wall. TIMPs (tissue inhibitor of metalloproteinases) can impact plaque deposition by regulating ECM (extracellular matrix) turnover. TIMP4 also influences lipid metabolism and smooth muscle cell (SMC) proliferation. We investigated the role of TIMP4 in atherosclerosis. Approach and Results: Mice lacking low-density lipoprotein receptor (Ldlr-/-) and Timp4 (Timp4-/-/Ldlr-/-) were fed high-fat diet (HFD) or regular laboratory diet. After 3 or 6 months, HFD-fed male and female Timp4-/-/Ldlr-/- mice exhibited higher plaque density in the abdominal aorta (but not in aortic valves, arch, thoracic aorta) compared with Ldlr-/- mice. Although plasma lipid and cholesterol levels were lower in Timp4-/-/Ldlr-/--HFD, cholesterol content in the abdominal aorta was higher along with elevated inflammatory cytokines, MMP (matrix metalloproteinase) activities, CD68+/calponin+ macrophage-like SMCs in Timp4-/-/Ldlr-/--HFD compared with Ldlr-/--HFD mice. In vitro, oxidized LDL (low-density lipoprotein) markedly increased CD68 expression, reduced SMC markers, increased lipid uptake, and reduced cholesterol efflux protein ABCA1 (ATP-binding cassette transporter A1) in Timp4-/-/Ldlr-/- compared with Ldlr-/- primary SMCs from abdominal, but not thoracic aorta. TIMP4 expression in the abdominal aorta (in vivo) and its corresponding SMCs (in vitro) was ≈2-fold higher than in the thoracic aorta and SMCs; TIMP4 levels decreased following HFD. Timp4-deficiency in bone marrow-derived macrophages did not alter their foam cell formation capacity. CONCLUSIONS: TIMP4 protects against plaque deposition in the abdominal aorta independent of plasma cholesterol levels. TIMP4 prevents proteolytic degradation of ABCA1 in SMCs, hindering cholesterol accumulation and transdifferentiation to macrophage-like foam cells, representing a novel negative regulator of atherosclerosis.

5.
J Surg Oncol ; 123(5): 1253-1262, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33524213

RESUMO

BACKGROUND AND OBJECTIVES: In this retrospective study, we examined the CA17 tissue expression and analyzed its clinical significance in cholangiocarcinoma (CCA). MATERIALS AND METHODS: Immunohistochemistry was performed to assess CA17 expression on tissue microarrays in a training cohort enrolling 120 CCA patients and a validation cohort comprising 60 CCA patients. Image pro plus was applied to score the staining intensity and expression level of CA17 marker. Kaplan-Meier analysis, Cox's proportional hazards regression, and nomogram were applied to evaluate the prognostic significance of CA17. RESULTS: CA17 cancer biomarker over-expression was significantly observed in CCA compared to their non-tumor counterparts, and positively correlated with aggressive tumor phenotypes, like lymph node metastasis. Meanwhile, patients with high expression of CA17 correlated with worse postoperative overall survival (OS) and recurrence-free survival. Besides, multivariate analysis identified that CA17 expression was an independent prognostic factor for cholangiocarcinoma patients, which indicated that the CA17 could be more efficient than serum CA19-9 in predicting the OS of CCA patients. Notably, the nomogram integrating CA17 expression had better prognostic performance as compared with current TNM staging systems. CONCLUSION: CA17 was an independent adverse prognostic factor for CCA patients' survival, which may serve as a promising prognostic biomarker for CCA patients.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Colangiocarcinoma/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
6.
J Alzheimers Dis ; 80(2): 855-864, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33579835

RESUMO

BACKGROUND: Age-related hearing loss (HL) has been associated with dementia, though the neurocognitive profile of individuals with HL is poorly understood. OBJECTIVE: To characterize the neurocognitive profile of HL. METHODS: N = 8,529 participants from the National Alzheimer's Coordinating Center ≥60 years and free of cognitive impairment who were characterized as Untreated-, Treated-, or No HL. Outcomes included executive function (Trail Making Test [TMT] Part B), episodic memory (Immediate/Delayed Recall), language fluency (Vegetables, Boston Naming Test), and conversion to dementia. Regression models were fit to examine associations between HL and neurocognitive performance at baseline. Cox proportional hazards models examined the links between HL, neurocognitive scores, and development of dementia over follow-up. RESULTS: At baseline, those with Untreated HL (versus No HL) had worse neurocognitive performance per standardized difference on executive function (TMT Part B [mean difference = 0.05 (95% CI 0.00, 0.10)]) and language fluency (Vegetables [mean difference = -0.07 (95% CI -0.14, -0.01)], Boston Naming Test [mean difference = -0.07 (95% CI -0.13, -0.01)]). No differences in these neurocognitive performance scores were demonstrated between Treated HL and No HL groups other than MMSE [mean difference = -0.06 (95% CI -0.12, 0.00)]. Through follow-up, executive dysfunction differed by hearing group (χ2(2) = 46.08, p < 0.0001) and was present among 39.12% in No HL, 44.85% in Untreated HL, and 49.40% in Treated HL. Worse performance across all cognitive domains predicted incident dementia. CONCLUSION: The observed association between Untreated HL and lower cognitive ability that improved when hearing aids were worn may reflect an inability to hear the test instructions. Future studies using cognitive assessments validated for use in HL are needed to evaluate the neuropsychological profile of HL and identify individuals at risk for dementia.

7.
J Fungi (Basel) ; 7(2)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33513923

RESUMO

Fusarium solani (Fs) is one of the notorious necrotrophic fungal pathogens that cause root rot and vascular wilt, accounting for the severe loss of Populus production worldwide. The plant-pathogen interactions have a strong molecular basis. As yet, the genomic information and transcriptomic profiling on the attempted infection of Fs remain unavailable in a woody model species, Populus trichocarpa. We used a full RNA-seq transcriptome to investigate the molecular interactions in the roots with a time-course infection at 0, 24, 48, and 72 h post-inoculation (hpi) of Fs. Concomitantly, the invertase and invertase inhibitor-like gene families were further analyzed, followed by the experimental evaluation of their expression patterns using quantitative PCR (qPCR) and enzyme assay. The magnitude profiles of the differentially expressed genes (DEGs) were observed at 72 hpi inoculation. Approximately 839 genes evidenced a reception and transduction of pathogen signals, a large transcriptional reprogramming, induction of hormone signaling, activation of pathogenesis-related genes, and secondary and carbohydrate metabolism changes. Among these, a total of 63 critical genes that consistently appear during the entire interactions of plant-pathogen had substantially altered transcript abundance and potentially constituted suitable candidates as resistant genes in genetic engineering. These data provide essential clues in the developing new strategies of broadening resistance to Fs through transcriptional or translational modifications of the critical responsive genes within various analyzed categories (e.g., carbohydrate metabolism) in Populus.

8.
Eur J Dent Educ ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33471403

RESUMO

Substance use disorders (SUD) are chronic relapsing medical conditions characterised by compulsive substance seeking and use. They constitute a substantial disease burden globally. Labelling of persons with SUD has created barriers to treatment but there are effective management strategies. The dental profession has embraced reforms designed to address the SUD epidemic by promoting continuing education for practitioners and initiating curriculum changes in dental schools. Screening, Brief Intervention and Referral to Treatment (SBIRT) is an evidence-based model for managing patients with SUD. The use of a formative 1-station Objective Structured Clinical Examination (OSCE) for learning and assessment in SBIRT, operationalised with the MD3 rating scale is presented in this study. In 3 years of implementation, the SBIRT OSCE successfully integrated into the curriculum of the College of Dental Medicine, Columbia University. Mean score of total adherent behaviours was 11.80 (SD =4.23) (range: 2 - 24) and Cronbach's coefficient alpha for across-items reliability in adherent behaviours was 0.66. Adherent behaviours correlated with the global ratings (r = 0.66). Mean of global rating scores were 2.90 (SD =1.01) for collaboration and 2.97 (SD =1.00) for empathy and the global rating scores correlated with each other (r = 0.85). Histograms of global rating scores resembled normal distribution. The 1-station OSCE is a good model for learning about SBIRT. Psychometric analysis was useful in understanding the underlying construct of the MD3 rating scale and supported its reliability, validity and utility in dental education.

9.
ACS Nano ; 15(2): 3123-3138, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33470095

RESUMO

Exploring a rational delivery system of integrating chemotherapy with immunotherapy to broaden benefits of cancer immunochemotherapy is still under challenge. Herein, we developed doxorubicin (DOX)-loaded biomimetic hybrid nanovesicles (DOX@LINV) via fusing artificial liposomes (LIPs) with tumor-derived nanovesicles (TNVs) for combinational immunochemotherapy. DOX@LINV with a homologous targeting ability could deliver DOX to tumor tissue and elicit an effective immunogenic cell death response to improve the immunogenicity of a tumor. Meanwhile, the preserved tumor antigens and endogenous danger signals in DOX@LINV activated dendritic cells and induced a subsequent antigen-specific T cell immune response. DOX@LINV displayed a specific antitumor effect on murine melanoma, Lewis lung cancer, and 4T1 breast cancer based on the infiltration of effector immune cells and improvement of the immunosuppressive tumor microenvironment. Furthermore, the combination of DOX@LINV with immune checkpoint inhibitor amplified antitumor efficacy with 33.3% of the mice being tumor-free. Therefore, the hybrid LINV is a promising drug delivery platform with a boosted antitumor immune response for effective immunochemotherapy.

10.
JAMA Netw Open ; 4(1): e2031073, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33410876

RESUMO

Importance: Limited information is available regarding the association between parental and adolescent medical prescription opioid use and misuse in the US. Objective: To examine the associations between parental and adolescent prescription opioid medical use and misuse. Design, Setting, and Participants: This cross-sectional, nationally representative study included 15 200 parent-adolescent dyads from the annual 2015-2017 National Survey on Drug Use and Health. Data were collected from January 6, 2015, to December 20, 2017, and analyzed from October 4, 2019, to October 15, 2020. Exposures: Parental past 12-month exclusive medical prescription opioid use and any misuse (ie, using without a prescription or in any way not directed by a physician). Main Outcomes and Measures: Adolescent past 12-month medical prescription opioid use or misuse. Multivariable regressions estimated associations between parental and offspring medical prescription opioid use or misuse, controlling for sociodemographic and psychosocial variables. Results: Respondents included 9400 mother-child and 5800 father-child dyads in the same household; children were aged 12 to 17 years (52.8% male; mean [SD] age, 14.5 [1.7] years). Controlling for other factors, parental medical prescription opioid use was associated with adolescent prescription opioid medical use (adjusted odds ratio [aOR], 1.28; 95% CI, 1.06-1.53) and misuse (aOR, 1.53; 95% CI, 1.07-2.25), whereas parental misuse was not. Parental medical prescription stimulant use was associated with adolescent medical prescription opioid use (aOR, 1.40; 95% CI, 1.02-1.91). Parental marijuana use (aOR, 1.84; 95% CI, 1.13-2.99), parent-adolescent conflict (aOR, 1.26; 95% CI, 1.05-1.52), and adolescent depression (aOR, 1.75; 95% CI, 1.26-2.44) were associated with adolescent prescription opioid misuse. Adolescent delinquency (aOR, 1.55; 95% CI, 1.38-1.74) and perceived schoolmates' drug use (aOR, 2.87; 95% CI, 1.95-4.23) were also associated with adolescent misuse and more weakly with medical use (aORs, 1.13 [95% CI, 1.05-1.22] and 1.61 [95% CI, 1.32-1.96], respectively). Conclusions and Relevance: Youth use of prescription opioids is in part a structural/environmental issue. The findings of this study suggest that parental medical prescription opioid use is associated with offspring prescription opioid use, whereas parental misuse is not. Restricting physicians' opioid prescribing to parents is a crucial public health goal. In addition, parents could be educated on the risks of their prescription opioid use for offspring and on practices to mitigate risk, including safe medication storage and disposal. Screening for parental prescription opioid use could be part of pediatric practice. Addressing adolescent mental health could also reduce adolescent prescription opioid misuse.


Assuntos
Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Adolescente , Adulto , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/tratamento farmacológico , Pais , Estados Unidos/epidemiologia
11.
Clin Lab ; 67(1)2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33491424

RESUMO

BACKGROUND: The purpose of this study was to analyze the coagulation status of gestational diabetes mellitus (GDM) patients in combination with glucose levels and screen out indicators closely related to the severity of GDM and adverse pregnancy outcome. METHODS: The subjects of 110 GDM patients and 100 normal pregnant women were randomly selected. The results of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), D-dimer (D-D), and plaque level test (PLT) in GDM patients and normal pregnant women (comparison group) were analyzed. The study screened out the coagulation indexes of GDM closely related to FPG and then analyzed the correlation between indexes and adverse prognosis. RESULTS: The results of PT were significantly lower in the GDM group. The PT was related to the severity of GDM and adverse pregnancy outcome. CONCLUSIONS: The PT levels of GDM patients in the third trimester can be used as a reliable index for disease and prognosis evaluation.

12.
Small ; : e2004905, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33206460

RESUMO

Exploring optimal strategies to improve patient outcome postoperatively is still under challenge. Cancer immunotherapy has great potential to prevent the postoperative tumor recurrence and metastasis, which could be further strengthened by re-education of tumor microenvironment (TME). Herein, a local and sustained drug delivery system of liquid crystal formation system (LCFS) co-loaded with doxorubicin (DOX) and resiquimod (R848) (D/R@LCFS) is reported to confer effective chemoimmunotherapy with reduced systematic toxicity. After local administration, D/R@LCFS turns tumor into in situ vaccine via DOX-triggered immunogenic cell death effect accompanied with immunostimulatory effect of R848. Meanwhile, combination treatment of D/R@LCFS facilitates the recruitment of effector CD8+ T cells and the polarization of myeloid-derived suppressor cells and immunosuppressive type 2-polarized macrophages to tumoricidal antigen-presenting cells, favoring antigen-specific T cell immune response and inducing more immunogenic phenotypes in tumors. The generated in situ vaccine as well as reshaped TME by D/R@LCFS elicited systematic immune response and long term immune-memory effect in combination with immune checkpoint blockade to significantly prevent postoperative B16F10 or 4T1 tumor recurrence and metastasis. Therefore, this combination strategy of spatiotemporal TME modulation is expected to provide a clinical available option for effective postoperative chemoimmunotherapy.

13.
Biomed Pharmacother ; 133: 111014, 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33246225

RESUMO

BACKGROUND: Intestinal microbiota is a novel drug target of metabolic diseases, especially for those with poor oral bioavailability. Nuciferine, with poor bioavailability, has an anti-hyperlipidemic effect at low dosages. PURPOSE: In the present study, we aimed to explore the role of intestinal microbiota in the anti-hyperlipidemic function of nuciferine and identify the key bacterial targets that might confer the therapeutic actions. METHODS: The contribution of gut microbes in the anti-hyperlipidemic effect of nuciferine was evaluated by conventional and antibiotic-established pseudo-sterile mice. Whole-metagenome shotgun sequencing was used to characterize the changes in microbial communities by various agents. RESULTS: Nuciferine exhibited potent anti-hyperlipidemic and liver steatosis-alleviating effects at the doses of 7.5-30 mg/kg. The beneficial effects of nuciferine were substantially abolished when combined with antibiotics. Metagenomic analysis showed that nuciferine significantly shifted the microbial structure, and the enrichment of Akkermansia muciniphila was closely related to the therapeutic effect of nuciferine. CONCLUSIONS: Our results revealed that gut microbiota played an essential role in the anti-hyperlipidemic effect of nuciferine, and enrichment of Akkermansia muciniphila represented a key mechanism through which nuciferine exerted its therapeutic effects.

14.
J Pak Med Assoc ; 70 [Special Issue](9): 24-30, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33177724

RESUMO

OBJECTIVE: To explore the clinical application of fast-track rehabilitation nursing in the perioperative period of therapeutic laparoscopy of colon cancer patients. METHODS: Patients with colorectal cancers who were hospitalized in the Department of Oncology and General Surgery of The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University from August 2016 to December 2018 were selected as the research subjects of the study. All the research subjects were divided into the study group 1(n=29), the study group 2(n=29) and the control group (n=24). The control group received routine nursing during the perioperative period, and the research group 1 and 2 received rapid rehabilitation nursing during the perioperative period. Postoperative comparison was made between the two groups on the differences in the time of the first time out of bed, the time of the first anal exhaust, and the time of the first feeding. The differences of pain control in each group after nursing care were evaluated by the pain scale, and the degree of satisfaction of each group was evaluated by the satisfaction scale. RESULTS: In terms of the basic information of patients, the experimental results had indicated no significant statistical difference among the study group 1, the study group 2, and the control group (P>0.05). By analysing the postoperative physical condition indicators of patients, the time of first off-bed activity, the time of first anal exhaust, and the first time of food intake of patients in the observation group 1 and the observation group 2 were significantly different (P<0.05) as compared with the control group. Besides that, the postoperative pain scale and pain satisfaction of patients were observed, in which the difference in pain scales at each 6h, 12h, 24h, and 48h after the surgeries were statistically significant (P<0.05). In terms of the satisfaction of pain control or pain relief, the differences were statistically significant (P<0.05). CONCLUSIONS: Therefore, it was concluded that the fast-track rehabilitation nursing could promote the treatment of colon cancer patients. Despite the deficiencies of the experimental processes, the study has provided the good results on fast-track rehabilitation nursing with a reliable theoretical basis.

15.
Int J Lab Hematol ; 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33068078

RESUMO

INTRODUCTION: Multiple myeloma (MM) is a hematological malignancy. It is of great clinical significance to screen microRNAs (miRNAs) in urine as noninvasive diagnostic biomarkers for MM. METHODS: Urinary miRNAs in MM were performed by Agilent Bioanalyzer 2100 and verified by quantitative real-time PCR (qRT-PCR). Receiver operator characteristic (ROC) was used to evaluate the diagnostic value of abnormal miRNAs for MM. Progression-free survival (PFS) of MM was calculated by Kaplan-Meier. RESULTS: In microarray analysis, twelve down-regulated miRNAs dysregulated in MM. The expression levels of miR-134-5p, miR-6500-5p, miR-548q, and miR-548y were validated. These miRNAs were significantly lower in MM (P < .05), but there was no significant difference between newly diagnosed, relapse, and remission group of MM (P> .05). ROC curve analysis showed that the sensitivity of miR-134-5p, miR-6500-5p, miR-548q, and miR-548y to MM was 91.7%, 100%, 100%, and 91.7%, and the specificity was 66.7%, 75.0%, 75.0%, and 100%, respectively. The four miRNAs were negatively correlated with the total urinary light chain (r = -0.427 P = .030, r = -0.461 P = .018, r = -0.469 P = .016, r = -0.493 P = .011). In addition, miR-134-5p, miR-6500-5p, and miR-548q were positively correlated with serum ALB (r = 0.518 P = .006, r = 0.400 P = .039, r = 0.492 P = .009). The expression level of miRNAs had no significant influence on PFS in MM patients (P> .05). CONCLUSION: The results show that miR-134-5p, miR-6500-5p, miR-548q, and miR-548y are potential noninvasive diagnostic biomarkers for MM.

16.
Front Cell Dev Biol ; 8: 587961, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33117816

RESUMO

The marine bacterium Vibrio vulnificus causes potentially fatal bloodstream infections, typically in patients with chronic liver diseases. The inflammatory response and anti-bacterial function of phagocytes are crucial for limiting bacterial infection in the human hosts. How V. vulnificus affects macrophages after phagocytosis is unclear. In this report, we found that the bactericidal activity of macrophages to internalize V. vulnificus was dependent on mammalian target of rapamycin (mTOR) and NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) interaction. Additionally, the NLRP3 expression was dependent on mTORC1 activation. Inhibited mTORC1 or absence of NLRP3 in macrophages impaired V. vulnificus-induced phagosome acidification and phagolysosome formation, leading to a reduction of intracellular bacterial clearance. mTORC1 signaling overactivation could increase NLRP3 expression and restore insufficient phagosome acidification. Together, these findings indicate that the intracellular bactericidal activity of macrophages responding to V. vulnificus infection is tightly controlled by the crosstalk of NLRP3 and mTOR and provide critical insight into the host bactericidal activity basis of clearance of V. vulnificus through lyso/phagosome.

17.
Front Aging Neurosci ; 12: 571437, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33088272

RESUMO

Background: Aggregation of alpha-synuclein (α-Syn) is considered to be a significant pathological hallmark and a driving force of Parkinson's disease (PD). PD dementia (PDD) occurs in a substantial number of PD patients. Naturally occurring antibody against α-Syn (NAb-α-Syn) exists ubiquitously in human blood and is reported to be altered in PD. However, it is not clear yet whether PDD had similar changes of circulating NAb-α-Syn. Methods: In this study, we recruited 61 PDD patients, 52 patients with Alzheimer's disease (AD), 51 patients with vascular dementia (VaD), and 50 normal controls (NCs). ELISA was used to examine NAb-α-Syn levels in serum. Results: In comparison with NCs, serum levels of NAb-α-Syn were significantly lower in patients with PDD. However, serum levels of NAb-α-Syn were comparable among AD, VaD, and NC groups. Serum levels of NAb-α-Syn were positively correlated with the cognitive function, as reflected by Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Serum levels of NAb-α-Syn were negatively correlated with the severity of PD [as reflected by the Unified Parkinson Disease Rating Scale (UPDRS)] and the duration of PD and PDD. Serum NAb-α-Syn can differentiate PDD patients from AD and VaD patients. Conclusion: These results suggest that circulating NAb-α-Syn might be a potential biomarker of PDD.

18.
Dis Markers ; 2020: 8880034, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32904578

RESUMO

Gestational diabetes mellitus (GDM) is a common disease of pregnant women, which has a higher incidence in recent years. The purpose of this study is to explore urinary biomarkers that could predict and monitor gestational diabetes mellitus (GDM). Urine samples from 30 normal pregnant women and 78 GDM patients were collected and purified by weak cationic exchange magnetic beads (MB-WCX), then analyzed by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS). The urinary peptide signatures of the two groups were compared by BioExplorer software. The potential ability of the differently expressed peptides to distinguish GDM patients from normal pregnant women was evaluated by receiver operating characteristic (ROC) analysis. At last, the differently expressed peptides were identified by liquid chromatography tandem mass spectrometry (LC-MS). There were four differently expressed peptides (m/z 1000.5, 1117.5, 1142.9, and 2022.9) between two groups, which were identified as fragments of urinary albumin, α2-macroglobulin, human hemopexin, and α1-microglobulin, respectively. The diagnostic efficacy of m/z 1142.9 was better than the other peptides. The area under the curve (AUC) of the m/z 1142.9 was 0.690 (95% CI: 0.583-0.796). The discovery of urinary polypeptides provides the possibility for the early prediction of GDM and the monitoring of glucose metabolism in GDM patients by a noninvasive method.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32959064

RESUMO

BACKGROUND: Hearing loss (HL), late-life depression, and dementia are three prevalent and disabling conditions in older adults, but the inter-relationships between these disorders remain poorly understood. METHODS: N=8,529 participants ≥60 years who were free of cognitive impairment at baseline were analyzed from National Alzheimer's Coordinating Center Uniform Data Set. Participants had either No HL, Untreated HL, or Treated HL. Primary outcomes included depression (15-item Geriatric Depression Scale ≥5) and conversion to dementia. A longitudinal logistic model was fit to examine the association between HL and changes in depressive symptoms across time. Two Cox proportional hazards models were used to examine HL and the development of dementia: Model A included only baseline variables and Model B included time-varying depression to evaluate for the direct effect of changes in depression on dementia over time. RESULTS: Treated HL (vs. no HL) had increased risk for depression (OR=1.26, 95% CI 1.04-1.54, p=0.02) and conversion to dementia (HR=1.29, 95% CI 1.03-1.62, p=0.03). Baseline depression was a strong independent predictor of conversion to dementia (HR=2.32, 95% CI 1.77-3.05, p<.0001). Development/persistence of depression over time was also associated with dementia (HR=1.89, 95% CI 1.47-2.42, p<.0001), but only accounted for 6% of the direct hearing-dementia relationship (Model A logHR=0.26 [SE 0.12] to Model B logHR=0.24 [SE 0.12]) suggesting no significant mediation effect of depression. CONCLUSIONS: Both HL and depression are independent risk factors for eventual conversion to dementia. Further understanding the mechanisms linking these later-life disorders may identify targets for early interventions to alter the clinical trajectories of at-risk individuals.

20.
Adv Med Educ Pract ; 11: 455-461, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32636697

RESUMO

Purpose: Screening, Brief Intervention, and Referral to Treatment (SBIRT) is an evidence-based framework for assessing and addressing risky substance use. This study evaluated the substance-related attitudes of medical students who participated in an Enhanced Pre-Clinical SBIRT Curriculum designed to reduce stigma, help students empathize with the experiences of people using alcohol and drugs, understand substance use in-context, and feel more optimistic about efforts to prevent and treat substance use disorders (SUDs). Methods: Students (N=118; 73.8% of eligible) completed the Attitudes and Opinions Survey for alcohol and drugs before and after this 2-year, multi-modality curriculum. The authors classified attitudes as "positive" or "negative" and grouped students by pre-post attitudinal change: persistently negative, persistently positive, negative-to-positive, positive-to-negative. Using chi-square tests, the authors assessed differences by sex, race/ethnicity, and whether students had a family member or friend with an SUD. Results: Most students (>90%) reported persistently positive attitudes regarding physicians in recovery, societal contributions of patients with SUDs; ability to learn from such patients; and general attitudes toward SUD treatment. This skewed distribution precluded the investigation of subgroup differences. Fewer students reported persistently positive attitudes regarding SUD patients' healthcare utilization (alcohol 58.5%; drug 57.8%) and impact on other patients' care (alcohol 73.7%; drug 72.4%), compared to other attitudinal domains (at p-values < 0.0001 in the McNemar's tests). Approximately, 1 in 5 students reported more negative healthcare utilization attitudes on follow-up. There were no demographic differences in these two attitudinal domains. Conclusion: Unlike previous studies of medical student attitudes, most students who participated in the Enhanced Pre-Clinical SBIRT Curriculum reported an enduring appreciation for the educational and societal contributions of patients with SUDs. Attitudes toward healthcare utilization and the impact of patients with SUDs on the care of other patients were more resistant to change, possibly due to the predominance of acute-care inpatient settings in clinical training.

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