乳腺癌中miR-141表达与临床病理特征、Keap1/Nrf2通路及预后的关系

目的研究乳腺癌中miR-141表达与临床病理特征、KELCH样ECH关联蛋白1(Keap1)/核因子E2相关因子2(Nrf2)通路及预后的关系。方法选择2014年3月至2015年3月期间在本院接受手术治疗的乳腺癌患者作为研究对象,检测乳腺癌组织和癌旁组织中miR-141、Keap1、Nrf2的表达水平,随访乳腺癌患者的总生存期和无病生存期。结果乳腺癌组织中miR-141的表达水平低于癌旁组织(P<0.05);不同肿瘤直径、TNM分期的乳腺癌组织比较,miR-141表达水平比较,差异有统计学意义(P<0.05);与miR-141表达水平<中位数的乳腺癌组织比较,miR-141表达水平≥中位数的乳腺癌组织中Keap1的表达水平明显降低、Nrf2的表达水平明显增加(P<0.05);与miR-141表达水平<中位数的乳腺癌患者比较,miR-141表达水平≥中位数的乳腺癌患者总生存期及无病生存期均明显延长(P<0.05)。结论乳腺癌中miR-141表达降低与病理特征恶化、Keap1/Nrf2通路改变、预后变差有关。     

miR-141 is negatively correlated with TLR4 in neonatal sepsis and regulates LPS-induced inflammatory responses in monocytes

Neonatal sepsis is an inflammatory system syndrome and a main cause of neonatal mortality. However, there is a lack of ideal biomarkers for early neonatal sepsis diagnosis. The aim of this study was to evaluate the clinical significance of miR-141 in sepsis in neonates, and explore the regulatory effects of miR-141 on inflammation in monocytes. This study used qRT-PCR to calculate the expression of miR-141 in the serum of septic neonates. The diagnostic values of procalcitonin (PCT) and serum miR-141 were evaluated by receiver operating characteristic (ROC) curves. The relationship between miR-141 and TLR4 was determined using luciferase reporter assay. An inflammation model was established using monocytes with lipopolysaccharide (LPS) treatment. ELISA assay was used to analyze the levels of pro-inflammatory cytokines. The expression of miR-141 in neonatal sepsis was significantly lower than healthy controls. ROC curves showed that miR-141 had diagnostic accuracy. LPS stimulation in monocytes led to a decrease in the expression of miR-141. A luciferase reporter assay proved that miR-141 targeted TLR4, and a negative correlation of miR-141 with TLR4 was found in septic neonates. ELISA results demonstrated that the overexpression of miR-141 inhibited LPS-induced inflammation in monocytes. In conclusion, serum decreased miR-141 expression served as a candidate diagnostic biomarker of neonatal sepsis. TLR4 is a target gene of miR-141, which may mediate the inhibitory effects of miR-141 overexpression on LPS-induced inflammation in monocytes. Therefore, miR-141 is expected to be a potential diagnostic biomarker and a therapeutic target in neonatal sepsis.     

MiR-188-5p and MiR-141-3p influence prognosis of bladder cancer and promote bladder cancer synergistically

MicroRNA (miRNA) plays a significant role in suppressing the occurrence and development of tumor by inhibiting the translation of target proteins. Although previous researches have verified many miRNAs’ functions in bladder cancer (BC), the function of miR-188-5p and miR-141-3p in BC still remains unknown. Our experiment manifested that miR-188-5p and miR-141-3p were highly expressed in BC tissues and cells, which indicated a poor prognosis. In vitro functional assays suggested that down-regulated miR-188-5p and miR-141-3p inhibited the proliferation, migration and invasion of BC cells, while a combination of half dose down-regulated miR-188-5p and half dose down-regulated miR-141-3p demonstrated a more obvious inhibition effect. All results indicated that miR-188-5p and miR-141-3p promoted BC respectively and synergistically. Therefore, miR-188-5p and miR-141-3p will not only assist the diagnosis of BC, but also serve as more effective joint markers to predict the progression of BC.     

Aberrant Brain Functional Connectivity Dynamic Responses to the Valsalva Maneuver in Heart Failure

BackgroundPatients with heart failure (HF) show abnormal autonomic activities, which may stem from altered functional connectivity (FC) between different brain sites.Methods and ResultsWe evaluate insular and cerebellar FC with other brain areas, before, during, and after the Valsalva challenge, with functional magnetic resonance imaging in 35 HF and 35 control subjects. Significant insular FC emerged with striatum, thalamus, and anterior cingulate. While left and right cerebellar cortices showed significant FC with each other constituting the cerebellum network, the insula and cerebellum networks showed significant negative FC with each other at baseline, challenge, and recovery phases. The challenge induced increased FC within the insula and the cerebellum networks in both HF and controls. However, patients with HF showed more increased insular network FC, but less enhanced cerebellar FC. During the recovery phase, the negative FC between the insular network and cerebellum enhanced significantly in controls, but not in HF. Lower left ventricle ejection fraction was correlated with lower insula network FC, and impaired negative FC between cerebellum and the insula network in HF.ConclusionsIncreased insular FC in patients with HF might contribute to exaggerated sympathetic tone. While impaired cerebellar FC and diminished negative interactions between cerebellum and insular systems may indicate impaired parasympathetic functions in HF.     

Effects of DRD2/ANKK1 gene variations and clinical factors on aripiprazole efficacy in schizophrenic patients

OBJECTIVES: Aripiprazole, a novel antipsychotic agent, acts as a partial agonist at dopamine D2 receptors (DRD2). We investigate whether its efficacy is predictable by DRD2/ANKK1 gene polymorphisms and clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. METHOD: After hospitalization, the patients (n=128) were given aripiprazole for up to 4 weeks. They were genotyped for four functional DRD2/ANKK1 polymorphisms: -141 Ins/Del, Ser311Cys, C957T, and TaqIA. Clinical factors such as gender, age, illness duration, education level, diagnostic subtype, and medication dosage were also recorded. Psychopathology was measured biweekly with the positive and negative syndrome scale (PANSS). The effects of genetic and clinical factors on PANSS performance upon aripiprazole treatment were analyzed by a mixed modeling approach (SAS Proc MIXED). RESULTS: Compared to the patients with TaqI A2/A2 genotype, A1 carriers are associated with superior therapeutic response on positive symptoms after 4-week aripiprazole treatment. Regarding the C957T polymorphism, patients with C/C genotype were associated with poor aripiprazole response for excitement symptoms when compared with T/T patients. The other two polymorphisms, -141 Ins/Del, and Ser311Cys, have no significant effects on PANSS performance. The clinical factors including medication dosage, illness duration, and diagnostic subtype could influence PANSS performance upon aripiprazole treatment. CONCLUSION: This study suggests that DRD2/ANKK1 gene variations and some clinical factors may predict individual response to aripiprazole.     

Measurement of neutron capture cross sections for Pr from 0.5 to 1.6 MeV

Cross sections of ¹⁴¹Pr$(n,\gamma )$¹⁴²Pr reaction are measured at neutron energies of 0.54, 1.09 and 1.59 MeV using the activation method. The activities of the products are counted with a high resolution HPGe detector $\gamma$-ray spectrometer. The neutron fluence is determined by ¹⁹⁷Au$(n,\gamma )$¹⁹⁸Au reaction cross sections. The errors of the measured results are $\pm 6–7\%$. The neutron capture cross sections for this reaction are also calculated with the NUNF code. Our results are compared with those of other authors. Recommendations for inclusion of data in the energy region $0.05–3.90\mathrm{MeV}$ are made, these being in good agreement with the ENDF/B-VI data.     

Development of the Thyroid Hormone Receptor β‐Subtype Agonist KB‐141 : A Strategy for Body Weight Reduction and Lipid Lowering with Minimal Cardiac Side Effects

Few treatments for obesity exist and improvements for treatment of hyperlipidemia are still desirable. Thyroid hormone receptors (TRs) regulate body weight, adiposity, and cholesterol levels. However, thyroid hormones can have deleterious effects, particularly cardiac acceleration, that limits the use of hormones in the treatment of obesity. There is evidence that the TRβ subtype mediates lowering of blood cholesterol levels and possibly elevation of metabolic rate, whereas TRα appears to control heart rate. In studies, described in this review article, we examined the effects of selective TRβ activation on metabolic rate and heart rate in mice, rats and monkeys. T₃ had a greater effect on increasing heart rate in wild type (WT) than in TRα‐/‐ mice (ED₁₅ values of 34 and 469 nmol/kg/day, respectively). T₃ increased metabolic rate (MVO₂) in both WT and TRα‐/‐ mice, but the effect on TRα‐/‐ mice was less pronounced compared to WT mice. Stimulation of MVO₂ is mediated by both TRα and TRβ, but with different profiles. In cholesterol‐fed rats, KB‐141, a selective TRβ agonist, increased MVO₂ with a 10‐fold selectivity and lowered cholesterol with a 27‐fold selectivity vs. tachycardia. In primates, KB‐141 caused significant, cholesterol, Lp(a) and body weight reduction after 1 week of treatment with no effect on heart rate. These data suggest that selective TRβ agonists may represent a novel class of drugs for the treatment of obesity, hypercholesterolemia and elevated Lp(a), which may make them useful therapeutics for patients with metabolic syndrome.     

Ankylosing spondylitis: An important cause of severe disturbances of the cardiac conduction system: Prevalence among 223 pacemaker-treated men

The cause of severe disturbances of the cardiac conduction system is seldom possible to establish clinically at pacemaker implantation, apart from cases of acute myocardial infarction or digitalis intoxication and in relatively rare cases of inflammatory disorders such as sarcoidosis and systemic sclerosis. Since cardiac manifestations, mainly conduction disturbances, occur in patients with ankylosing spondylitis, the prevalence of this disease was determined using radiologie screening for sacroillitis in a population of 223 men who had permanently implanted pacemakers. Sacroillitis was found in 19 men (8.5 percent), 15 of whom fulfilled the diagnostic criteria for ankylosing spondylitis. In six patients, sacroillitis was asymptomatic and two of the patients were completely free of symptoms other than those originating from their heart manifestations. In seven of the 15 patients with ankylosing spondylitis and in the four patients with sacroillitis without clinical criteria of ankylosing spondylitis, the diagnosis was previously unknown. Uveltis and aortic regurgitation occurred in five patients each, while peripheral arthritis was twice as common. The prevalence of sacroillitis and ankylosing spondylitis of 8.5 and 6.7 percent, respectively, differ significantly (p < 0.01) from the frequencies found in general Caucasian populations of 1 to 2 and 0.1 to 0.5 percent, respectively. HLA B27 was present in more than 80 percent of the patients with sacrolilltis and/or ankylosing spondylitis, compared with 8 to 10 percent in the general population. This strong association is in accordance with previous studies of patients with symptomatic sacroillitis and/or ankylosing spondylitis. Thus sacroillitis, diagnosed by x-ray, can be considered a marker for this relatively common rheumatic cause of severe disturbances of the cardiac conduction system.     

Adjuvant for vaccine immunotherapy of cancer – focusing on Toll‐like receptor 2 and 3 agonists for safely enhancing antitumor immunity

Immune‐enhancing adjuvants usually targets antigen (Ag)‐presenting cells to tune up cellular and humoral immunity. CD141⁺ dendritic cells (DC) represent the professional Ag‐presenting cells in humans. In response to microbial pattern molecules, these DCs upgrade the maturation stage sufficient to improve cross‐presentation of exogenous Ag, and upregulation of MHC and costimulators, allowing CD4/CD8 T cells to proliferate and liberating cytokines/chemokines that support lymphocyte attraction and survival. These DCs also facilitate natural killer‐mediated cell damage. Toll‐like receptors (TLRs) and their signaling pathways in DCs play a pivotal role in DC maturation. Therefore, providing adjuvants in addition to Ag is indispensable for successful vaccine immunotherapy for cancer, which has been approved in comparison with antimicrobial vaccines. Mouse CD8α⁺ DCs express TLR7 and TLR9 in addition to the TLR2 family (TLR1, 2, and 6) and TLR3, whereas human CD141⁺ DCs exclusively express the TLR2 family and TLR3. Although human and mouse plasmacytoid DCs commonly express TLR7/9 to respond to their agonists, the results on mouse adjuvant studies using TLR7/9 agonists cannot be simply extrapolated to human adjuvant immunotherapy. In contrast, TLR2 and TLR3 are similarly expressed in both human and mouse Ag‐presenting DCs. Bacillus Calmette–Guerin peptidoglycan and polyinosinic–polycytidylic acid are representative agonists for TLR2 and TLR3, respectively, although they additionally stimulate cytoplasmic sensors: their functional specificities may not be limited to the relevant TLRs. These adjuvants have been posted up to a certain achievement in immunotherapy in some cancers. We herein summarize the history and perspectives of TLR2 and TLR3 agonists in vaccine‐adjuvant immunotherapy for cancer.