Heat stress (HS) influences the growth and development of organisms. Thus, a comprehensive understanding of how organisms sense HS and respond to it is required. Ganoderma lucidum, a higher basidiomycete with bioactive secondary metabolites, has become a potential model system due to the complete sequencing of its genome, transgenic systems, and reliable reverse genetic tools. In this study, we found that HS inhibited mycelium growth, reduced hyphal branching, and induced the accumulation of ganoderic acid biosynthesis and heat shock proteins (HSPs) in G. lucidum. Our data showed that HS induced a significant increase in cytosolic Ca2+ concentration. Further evidence showed that Ca2+ might be a factor in the HS-mediated regulation of hyphal branching, ganoderic acid (GA) biosynthesis, and the accumulation of HSPs. Our results further showed that the calcium-permeable channel gene (cch)-silenced and phosphoinositide-specific phospholipase gene (plc)-silenced strains reduced the HS-induced increase in HSP expression compared with that observed for the wild type (WT). This study demonstrates that cytosolic Ca2+ participates in heat shock signal transduction and regulates downstream events in filamentous fungi.
Ganoderma lucidum, a higher basidiomycete with bioactive secondary metabolites, has become a potential model system for evaluating how environmental factors regulate the development and secondary metabolism of basidiomycetes. Heat stress (HS) is an important environmental challenge. In this study, we found that HS inhibited mycelium growth, reduced hyphal branching, and induced HSP expression and ganoderic acid biosynthesis in G. lucidum. Further evidence showed that Ca2+ might be a factor in the HS-mediated regulation of hyphal branching, GA biosynthesis, and the accumulation of HSPs. This study demonstrates that cytosolic Ca2+ participates in heat shock signal transduction and regulates downstream events in filamentous fungi. Our research offers a new way to understand the mechanism underlying the physiological and metabolic responses to other environmental factors in G. lucidum. This research may also provide the basis for heat shock signal transduction studies of other fungi.
Cancer predisposition genes (CPGs) are a class of cancer genes in which germline variants lead to increased risk of cancer. Research has revealed that copy number variation (CNV) may be linked to cancer susceptibility in CPGs. In this pan-cancer analysis, we explored the relationship between somatic CNV and gene expression changes in CPGs. Based on curated 827 human CPGs from literature, we firstly identified 729 CPGs with precise CNV information from 5067 tumor samples using TCGA CNV data. Among them, 128 CPGs tended to have more frequent copy number losses (CNLs) compared with copy number gains (CNGs). Then by correlating these CNV data with TCGA gene expression data, we obtained 49 CPGs with concordant CNLs and gene down-regulation. Intriguingly, five CPGs showed concordance between CNL and down-regulation in 50 or more tumor samples: MTAP (216 samples), PTEN (143), MCPH1 (86), SMAD4 (63), and MINPP1 (51), which may represent the recurrent driving force for gene expression change during oncogenesis. Moreover, network analysis revealed that these 49 CPGs were tightly connected. In summary, this study provides the first observation of concordance between CNLs and down-regulation of CPGs in pan-cancer, which may help better understand the CPG biology in tumorigenesis and cancer progression.
To assess the role of time-intensity curves (TICs) of the normal peripheral zone (PZ) in the identification of biopsy-proven prostate nodules using contrast-enhanced transrectal ultrasound (CETRUS). This study included 132 patients with 134 prostate PZ nodules. Arrival time (AT), peak intensity (PI), mean transit time (MTT), area under the curve (AUC), time from peak to one half (TPH), wash in slope (WIS) and time to peak (TTP) were analyzed using multivariate linear logistic regression and receiver operating characteristic (ROC) curves to assess whether combining nodule TICs with normal PZ TICs improved the prediction of prostate cancer (PCa) aggressiveness. The PI, AUC (p < 0.001 for both), MTT and TPH (p = 0.011 and 0.040 respectively) values of the malignant nodules were significantly higher than those of the benign nodules. Incorporating the PI and AUC values (both, p < 0.001) of the normal PZ TIC, but not the MTT and TPH values (p = 0.076 and 0.159 respectively), significantly improved the AUC for prediction of malignancy (PI: 0.784–0.923; AUC: 0.758–0.891) and assessment of cancer aggressiveness (p < 0.001). Thus, all these findings indicate that incorporating normal PZ TICs with nodule TICs in CETRUS readings can improve the diagnostic accuracy for PCa and cancer aggressiveness assessment.
Background and Purpose
The activation of M
3 cholinoceptors (M
3 receptors) by choline reduces cardiovascular risk, but it is unclear whether these receptors can regulate ischaemia/reperfusion (I/R)‐induced vascular injury. Thus, the primary goal of the present study was to explore the effects of choline on the function of mesenteric arteries following I/R, with a major focus on Ca2+/calmodulin‐dependent protein kinase II (CaMKII) regulation.
Rats were given choline (10 mg·kg−1, i.v.) and then the superior mesenteric artery was occluded for 60 min (ischaemia), followed by 90 min of reperfusion. The M
3 receptor antagonist, 4‐diphenylacetoxy‐N‐methylpiperidine methiodide (4‐DAMP), was injected (0.12 μg·kg−1, i.v.) 5 min prior to choline treatment. Vascular function was examined in rings of mesenteric arteries isolated after the reperfusion procedure. Vascular superoxide anion production, CaMKII and the levels of Ca2+‐cycling proteins were also assessed.
Choline treatment attenuated I/R‐induced vascular dysfunction, blocked elevations in the levels of reactive oxygen species (ROS) and decreased the up‐regulated expression of oxidised CaMKII and phosphorylated CaMKII. In addition, choline reversed the abnormal expression of Ca2+‐cycling proteins, including Na+/Ca2+ exchanger, inositol 1,4,5‐trisphosphate receptor, sarcoplasmic reticulum Ca2+‐ATPase and phospholamban. All of these cholinergic effects of choline were abolished by 4‐DAMP.
Conclusions and Implications
Our data suggest that inhibition of the ROS‐mediated CaMKII pathway and modulation of Ca2+‐cycling proteins may be novel mechanisms underlying choline‐induced vascular protection. These results represent a significant addition to the understanding of the pharmacological roles of M
3 receptors in the vasculature, providing a new therapeutic strategy for I/R‐induced vascular injury.
This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23
Cardiovascular disease remains a major cause of disability and death worldwide. Autonomic imbalance, characterized by suppressed vagal (parasympathetic) activity and increased sympathetic activity, correlates with various pathological conditions, including heart failure, arrhythmia, ischaemia/reperfusion injury and hypertension. Conventionally, pharmacological interventions, such as β‐blocker treatment, have primarily targeted suppressing sympathetic over‐activation, while vagal modulation has always been neglected. Emerging evidence has documented the improvement of cardiac and vascular function mediated by the vagal nerve. Many investigators have tried to explore the effective ways to enhance vagal tone and normalize the autonomic nervous system. In this review, we attempt to give an overview of these therapeutic strategies, including direct vagal activation (electrical vagal stimulation, ACh administration and ACh receptor activation), pharmacological modulation (adenosine, cholinesterase inhibitors, statins) and exercise training. This overview provides valuable information for combination therapy, contributing to establishment of a comprehensive system on vagal modulation from the aspects of clinical application and lifestyle improvement. In addition, the mechanisms contributing to the benefits of enhancing vagal tone are diverse and have not yet been fully defined. We endeavour to outline the recent findings that advance our knowledge regarding the many favourable effects exerted by vagal activation: anti‐inflammatory pathways, modulation of NOS and NO signalling, regulation of redox state, improvement of mitochondrial biogenesis and function, and potential calcium regulation. This review may help to develop novel therapeutic strategies targeting enhancing vagal activity for the treatment of cardiovascular diseases.
This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23
In the treatment of cancer patients, cisplatin (CDDP) exhibits serious cardiac and renal toxicities, while classical combinations related to CDDP are unable to solve these problems and may result in worse prognosis. Alternately, this study covalently conjugated 6-mercaptopurine (6MP) onto the surface of mercapto-modified mesoporous silica nanoparticles (MSNS) to form MSNS-6MP and loaded CDDP into the holes on the surface of MSNS-6MP to form MSNS-6MP/CDDP, a tumor-targeting nano-releasing regime for CDDP and 6MP specifically. In the S180 mouse model, the anti-tumor activity and overall survival of MSNS-6MP/CDDP (50 mg·kg−1·day−1, corresponding to 1 mg·kg−1·day−1 of 6MP and 5 mg·kg−1·day−1 of CDDP) were significantly higher than those of CDDP alone (5 mg·kg−1·day−1) or CDDP (5 mg·kg−1·day−1) plus 6MP (1 mg·kg−1·day−1). The assays of serum alanine aminotransferase, aspartate aminotransferase and creatinine, as well as the images of myocardium and kidney histology, support that MSNS-6MP/CDDP is able to completely eliminate liver, kidney and heart toxicities induced by CDDP alone or CDDP plus 6MP.
6-mercaptopurine; cisplatin; mesoporous silica nanoparticles; cancer therapy; nanomedicine
Radix Puerariae and hawthorn fruit have been demonstrated to treat diabetes. They offer potential benefits for preventing depression in diabetes.
The aim of this study was to investigate whether the combination of Radix Puerariae and hawthorn fruit (CRPHF) could prevent depression in a diabetic rat model generated by feeding the rats with a high-fat diet and a low-dose streptozotocin (STZ).
The CRPHF was provided by the Shanghai Chinese Traditional Medical University. Twenty-four rats were randomly divided into four groups: normal control, normal-given-CRPHF (NC), diabetic control, and diabetic-given-CRPHF (DC) groups. The type 2 diabetic model was created by feeding the rats with a high-fat diet for 4 weeks followed by injection of 25 mg/kg STZ. CRPHF was given at 2 g/kg/d to the rats of NC and DC groups by intragastric gavage daily for 4 weeks after the type 2 diabetic model was successfully created. Body weight, random blood glucose (RBG), oral glucose tolerance test, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured during the study. Depressive-like behavior was evaluated at the end of the treatment by using the open field test (OFT), the elevated plus-maze test (EPMT), locomotor activity test (LAT), and forced swimming test (FST). Levels of extracellular signal-regulated protein kinase (ERK) and brain-derived neurotrophic factor (BDNF) in the prefrontal cortex were evaluated by using Western blot.
1) CRPHF reduced RBG and improved glucose tolerance in diabetic rats; 2) CRPHF reduced TC and TG but did not significantly change HDL-C or LDL-C in diabetic rats; 3) CRPHF reversed the loss in body weights observed in diabetic rats; 4) CRPHF reduced depressive-like behavior as measured by OFT, EPMT, LAT, and FST; 5) BDNF was upregulated, and ERK was activated in the prefrontal cortex of diabetic rats treated with CRPHF.
CRPHF has the potential of preventing depression in patients with diabetes.
Puerarin; Crataegus; diabetes mellitus; depression; BDNF
New 17-nor-pimaranes (1, 2), (9βH)-pimaranes (3, 4), and 17-nor-(9βH)-pimarane (5) were isolated from the tuber of Icacina trichantha. The structures were elucidated based on spectroscopic and HRMS data. The absolute configurations of 3 and 5 were determined by single-crystal X-ray diffraction. Compound 5 possesses a unique 19,20-δ-lactone moiety. Compound 3 showed cytotoxicity against MDA-MB-435 (human melanoma cancer) cells with an IC50 value of 7.04 μM. A plausible biogenetic pathway for compounds 1 – 5 is proposed.
Prolonged ischemia can result in apoptotic death of vascular endothelial cells and lead to ischemic vascular diseases including vascular dementia, arteriosclerosis and brain oedema. Finding protective strategies to prevent this is therefore an urgent mission. Recent studies have shown that dysregulation of microRNAs (miRNAs) can lead to imbalance of Bcl-2 family proteins and mitochondrial dysfunction, leading to further damage of vascular cells under ischemic conditions. However, whether miRNAs can be used as a drug target for treating vascular diseases is not fully understood. In this study, we observed that the natural product 2,4,5-trihydroxybenzaldehyde (TDB) could effectively inhibit vascular cell apoptosis following oxygen-glucose deprivation/reperfusion (OGD/R) by maintaining mitochondrial membrane potential (MMP) and suppressing activation of the mitochondria-dependent caspase-9/3 apoptosis pathway. Furthermore, we identified miR-34a, a crucial negative regulator of Bcl-2, as a target for the protective effect of TDB on vascular cells. TDB-induced suppression of miR-34a resulted in a significant upregulation of Bcl-2 protein, MMP maintenance, and the survival of vascular cells following OGD/R. Our findings suggest that targeting miR-34a with the natural product TDB may provide a novel strategy for the treatment of ischemic vascular injuries, and demonstrate the therapeutic potential in targeting miRNAs using appropriate small molecules.
Up-regulated cyclic adenosine 5'-monophosphate response element modulator α (CREMα) which can inhibit IL-2 and induce IL-17A in T cells plays a critical role in the pathogenesis of systemic lupus erythematosus (SLE). This research aimed to investigate the mechanisms regulating CREMα expression in SLE.
From the chromatin immunoprecipitation (ChIP) microarray data, we found a sharply increased H3 lysine 4 trimethylation (H3K4me3) amount at the CREMα promoter in SLE CD4+ T cells compared to controls. Then, by ChIP and real-time PCR, we confirmed this result. Moreover, H3K4me3 amount at the promoter was positively correlated with CREMα mRNA level in SLE CD4+ T cells. In addition, a striking increase was observed in SET domain containing 1 (Set1) enrichment, but no marked change in mixed-lineage leukemia 1 (MLL1) enrichment at the CREMα promoter in SLE CD4+ T cells. We also proved Set1 enrichment was positively correlated with both H3K4me3 amount at the CREMα promoter and CREMα mRNA level in SLE CD4+ T cells. Knocking down Set1 with siRNA in SLE CD4+ T cells decreased Set1 and H3K4me3 enrichments, and elevated the levels of DNMT3a and DNA methylation, while the amounts of H3 acetylation (H3ac) and H4 acetylation (H4ac) didn’t alter greatly at the CREMα promoter. All these changes inhibited the expression of CREMα, then augmented IL-2 and down-modulated IL-17A productions. Subsequently, we observed that DNA methyltransferase (DNMT) 3a enrichment at the CREMα promoter was down-regulated significantly in SLE CD4+ T cells, and H3K4me3 amount was negatively correlated with both DNA methylation level and DNMT3a enrichment at the CREMα promoter in SLE CD4+ T cells.
In SLE CD4+ T cells, increased Set1 enrichment up-regulates H3K4me3 amount at the CREMα promoter, which antagonizes DNMT3a and suppresses DNA methylation within this region. All these factors induce CREMα overexpression, consequently result in IL-2 under-expression and IL-17A overproduction, and contribute to SLE at last. Our findings provide a novel approach in SLE treatment.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-016-0294-2) contains supplementary material, which is available to authorized users.
Systemic lupus erythematosus; CREMα; H3K4me3; Set1; DNA methylation; DNMT3a
Stressful life leads to mood disorders. Chronic mild stress is presumably major etiology for depression, and acute severe stress leads to anxiety. These stressful situations may impair hypothalamus-pituitary-adrenal axis and in turn induce synapse dysfunction. However, it remains elusive how the stress hormones mess up subcellular compartments and interactions between excitatory and inhibitory neurons, which we have investigated in mouse amygdala, a structure related to emotional states.
Methods and Results
Dexamethasone was chronically given by intraperitoneal injection once a day for one week or was acutely washed into the brain slices. The neuronal spikes and synaptic transmission were recorded by whole-cell patching in amygdala neurons of brain slices. The chronic or acute administration of dexamethasone downregulates glutamate release as well as upregulates GABA release and GABAergic neuron spiking. The chronic administration of dexamethasone also enhances the responsiveness of GABA receptors.
The upregulation of GABAergic neurons and the downregulation of glutamatergic neurons by glucocorticoid impair their balance in the amygdala, which leads to emotional disorders during stress.
Intestinal bacterial communities are highly relevant to the digestion, nutrition, growth, reproduction, and a range of fitness in fish, but little is known about the gut microbial community in Antarctic fish. In this study, the composition of intestinal microbial community in four species of Antarctic fish was detected based on 16S rRNA gene sequencing. As a result, 1 004 639 sequences were obtained from 13 samples identified into 36 phyla and 804 genera, in which Proteobacteria, Actinobacteria, Firmicutes, Thermi, and Bacteroidetes were the dominant phyla, and Rhodococcus, Thermus, Acinetobacter, Propionibacterium, Streptococcus, and Mycoplasma were the dominant genera. The number of common OTUs (operational taxonomic units) varied from 346 to 768, while unique OTUs varied from 84 to 694 in the four species of Antarctic fish. Moreover, intestinal bacterial communities in individuals of each species were not really similar, and those in the four species were not absolutely different, suggesting that bacterial communities might influence the physiological characteristics of Antarctic fish, and the common bacterial communities might contribute to the fish survival ability in extreme Antarctic environment, while the different ones were related to the living habits. All of these results could offer certain information for the future study of Antarctic fish physiological characteristics.
Polypoidal choroidal vasculopathy (PCV) is characterized by the presence of polyps with or without a branching vascular network and more prevalent among Asians. The aim of this study was to compare the outcomes of conbercept therapy between two different angiographic subtypes of PCV.
Fifty-eight patients of PCV were classified into two phenotypes according to indocyanine green angiography (ICGA). In Type 1, both feeder and draining vessels are visible on ICGA and network vessels are numerous. In Type 2, neither feeder nor draining vessels are detectable, and the number of network vessels is small. The patients were treated with intravitreal conbercept (IVC) for 3 months. Additional IVC was given at subsequent monthly visits, if needed. The patients were followed up for 12 months, and changes in mean best-corrected visual acuity (BCVA), central retinal thickness (CRT), subretinal fluid (SRF) thickness, pigmented epithelial detachment (PED), hemorrhage, and number of polypoidal lesions were evaluated.
The mean BCVA in Type 2 PCV (15.92 ± 9.76 letters) achieved a significantly greater improvement than that in the Type 1 (14.10 ± 9.07 letters) at month 12 (t = 2.37, P < 0.01). Moreover, the mean CRT decrease was numerically greater in Type 2 (120.44 ± 73.81 μm) compared with Type 1 (106.48 ± 72.33 μm) at month 6 (t = 4.31, P < 0.01), and greater in Type 2 (130.21 ± 76.28 μm) compared with Type 1 (111.67 ± 79.57 μm) at month 9 (t = 1.87, P < 0.01). There was no significant difference between the two types for the decrease in SRF thickness, PED height, and regression of polyps from month 3 to 12 (t = 2.97, P > 0.05).
Classification systems for PCV will show differences in presentation, natural history, or response to anti-vascular endothelial growth factor treatment and might, therefore, provide a new key to the choice of treatment for the disease.
Angiographic Subtypes; Anti-vascular Endothelial Growth Factor; Conbercept; Polypoidal Choroidal Vasculopathy
Six new pimarane derivatives, including two dinor-pimaranes (1, 2), two 17-nor-pimaranes (3, 4), and two 17-nor-(9β-H)-pimaranes (5, 6) were isolated from the tuber of Icacina trichantha. Their structures were elucidated based on spectroscopic and HRMS data. The absolute configurations of 1 and 5 were determined by single-crystal X-ray diffraction, and that of 2 was established by electronic circular dichroism data analysis. Compound 3 possesses a unique C-20 acetal moiety. It is the first report of the isolation of dinor-(9β-H)-pimarane derivatives from Icacina plants. Compounds 5 and 6 showed moderate cytotoxicity against MDA-MB-435, MDA-MB-231, and OVCAR3 cell lines, with IC50 values of 2.91–7.60 µM and 1.48–3.23 µM, respectively.
Vibration signals measured in the run-up/coast-down (R/C) processes usually carry rich information about the health status of machinery. However, a major challenge in R/C signals analysis lies in how to exploit more diagnostic information, and how this information could be properly integrated to achieve a more reliable maintenance decision. Aiming at this problem, a framework of R/C signals analysis is presented for the health assessment of gearbox. In the proposed methodology, we first investigate the data preprocessing and feature selection issues for R/C signals. Based on that, a sparsity-guided feature enhancement scheme is then proposed to extract the weak phase jitter associated with gear defect. In order for an effective feature mining and integration under R/C, a generalized phase demodulation technique is further established to reveal the evolution of modulation feature with operating speed and rotation angle. The experimental results indicate that the proposed methodology could not only detect the presence of gear damage, but also offer a novel insight into the dynamic behavior of gearbox.
generalized phase demodulation; run-up/coast-down analysis; feature mining and integration; gearbox health assessment; phasogram
Mineral and bone disorder (MBD), especially hyperphosphatemia, is an independently risk factor for adverse prognosis in patients with chronic kidney disease (CKD). However, CKD-MBD among Chinese population was poorly studied. This study aimed to investigate the status of MBD and its association with cardiovascular parameters in Chinese patients with predialysis CKD.
Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE) is a prospective multicenter cohort study involving predialysis CKD patients in China. Markers of MBD, including serum phosphorus, calcium, and intact parathyroid hormone, were measured in baseline samples at the patients’ entry. The association between serum phosphorus and abdominal aortic calcification (AAC), left ventricular hypertrophy (LVH) were examined by logistic regression models.
Altogether 3194 predialysis patients with mean estimated glomerular filtration of 51.8 ± 33.1 ml·min−1.1.73 m−2 were included. The proportion of patients with hyperphosphatemia were 2.6%, 2.9%, 6.8%, and 27.1% in CKD Stages 3a, 3b, 4, and 5, respectively. Moreover, 71.6% of the patients with hyperphosphatemia did not receive any phosphate-binder (PB). Lateral abdominal X-rays were obtained in 2280 patients, 9.8% of the patients were diagnosed as having AAC. Altogether 2219 patients had data of echocardiography, and 13.2% of them were diagnosed with LVH. Multivariate logistic regression analysis showed that serum phosphorus was independently associated with the presence of AAC and LVH.
In Chinese patients with CKD, the percentage of hyperphosphatemia is comparable to that of other countries while the usage of PBs is suboptimal. The prevalence of vascular calcification in Chinese patients is relatively lower compared with the Caucasian population.
Chronic Kidney Disease; Hyperphosphatemia; Left Ventricular Hypertrophy; Mineral and Bone Disorder; Vascular Calcification
Chemical stimulation of white adipose tissue (WAT) causes adipose afferent reflex (AAR) and sympathetic activation. This study is to investigate the effects of AAR on lipolysis and the mechanisms of attenuated lipolysis response to enhanced AAR in obesity. Obesity was caused by high-fat diet for 12 weeks in rats. AAR was induced by injection of capsaicin into inguinal WAT or electrical stimulation of epididymal WAT afferent nerve. AAR caused sympathetic activation, which was enhanced in obesity rats. AAR increased cAMP levels and PKA activity, promoted hormone sensitive lipase (HSL) and perilipin phosphorylation, and increased lipolysis in WAT, which were attenuated in obesity rats. PKA activity, cAMP, perilipin and β-adrenoceptor levels were reduced, while HSL was upregulated in adipocytes from obesity rats. In primary adipocytes, isoproterenol increased cAMP levels and PKA activity, promoted HSL and perilipin phosphorylation, and increased lipolysis, which were attenuated in obesity rats. The attenuated effects of isoproterenol in adipocytes from obesity rats were prevented by a cAMP analogue dbcAMP. The results indicate that reduced lipolysis response to enhanced AAR in obesity is attributed to the impaired activation of β-adrenoceptor-cAMP-PKA-HSL pathway. Increased cAMP level in adipocytes rectifies the attenuated lipolysis in obesity.
Recent studies suggest that uromodulin plays an important role in chronic kidney diseases. It can interact with several complement components, various cytokines and immune system cells. Complement factor H (CFH), as a regulator of the complement alternative pathway, is also associated with various renal diseases. Thus, we have been suggested that uromodulin regulates complement activation by interacting with CFH during tubulointerstitial injury. We detected co‐localization of uromodulin and CFH in the renal tubules by using immunofluorescence. Next, we confirmed the binding of uromodulin with CFH
in vitro and found that the affinity constant (KD) of uromodulin binding to CFH was 4.07 × 10−6M based on surface plasmon resonance results. The binding sites on CFH were defined as the short consensus repeat (SCR) units SCR1–4, SCR7 and SCR19–20. The uromodulin‐CFH interaction enhanced the cofactor activity of CFH for factor I‐mediated cleavage of C3b to iC3b. These results indicate that uromodulin plays a role via binding and enhancing the function of CFH.
uromodulin; Tamm‐Horsfall protein; complement factor H; chronic kidney disease
Besides the phase and group velocities, the amplitude of guided wave mode is also frequency dependent. This amplitude dispersion also influences the performance of guided wave methods in nondestructive evaluation (NDE) and structural health monitoring (SHM). In this paper, the effects of amplitude dispersion to the spectrum and waveform of a propagating wave-packet are investigated. It is shown that the amplitude dispersion results in distortion in the spectrum of guided wave response, and thus influences the waveform of the wave-packet. To remove these effects, an amplitude dispersion compensation method is established on the basis of Vold–Kalman filter and Taylor series expansion. The performance of that method is then investigated by experimental examples. The results show that with the application of the amplitude dispersion compensation, the time reversibility could be preserved, which ensures the applicability of the time reversal method for damage detection. Besides, through amplitude dispersion compensation, the testing resolution of guided waves could be improved, so that the structural features located in the close proximity may be separately identified.
guided wave; dispersion; time reversibility; testing resolution
Circulating tumor DNA (ctDNA) in peripheral blood is a “liquid biopsy” that contains representative tumor information including gene mutations. Additionally, repeated ctDNA samples can be easily obtained to monitor response to treatment and disease progression, which may be especially valuable to lung cancer patients with tumors that cannot be easily biopsied or removed. To investigate the changes in ctDNA after surgical tumor resection, tumor and blood samples obtained before and after surgery were collected prospectively from 41 non-small lung cancer (NSCLC) patients. Somatic driver mutations in tumor DNA (tDNA) and pre- and post-op plasma ctDNA sample pairs were identified by targeted sequencing in several genes including EGFR, KRAS, and TP53 with an overall study concordance of 78.1% and sensitivity and specificity of 69.2% and 93.3%, respectively. Importantly, the frequency of 91.7% of ctDNA mutations decreased after surgery and these changes were observed as little as 2 days post-op. Moreover, the presence of ctDNA had a higher positive predictive value than that of six tumor biomarkers in current clinical use. This study demonstrates the use of targeted sequencing to reliably identify ctDNA changes in response to treatment, indicating a potential utility of this approach in the clinical management of NSCLC.
Cancer pain, especially the one caused by metastasis in bones, is a severe type of pain. Pain becomes chronic unless its causes and consequences are resolved. With improvements in cancer detection and survival among patients, pain has been considered as a great challenge because traditional therapies are partially effective in terms of providing relief. Cancer pain mechanisms are more poorly understood than neuropathic and inflammatory pain states. Chronic inflammatory pain and neuropathic pain are influenced by NB001, an adenylyl cyclase 1 (AC1)-specific inhibitor with analgesic effects. In this study, the analgesic effects of NB001 on cancer pain were evaluated.
Pain was induced by injecting osteolytic murine sarcoma cell NCTC 2472 into the intramedullary cavity of the femur of mice. The mice injected with sarcoma cells for four weeks exhibited significant spontaneous pain behavior and mechanical allodynia. The continuous systemic application of NB001 (30 mg/kg, intraperitoneally, twice daily for three days) markedly decreased the number of spontaneous lifting but increased the mechanical paw withdrawal threshold. NB001 decreased the concentrations of cAMP and the levels of GluN2A, GluN2B, p-GluA1 (831), and p-GluA1 (845) in the anterior cingulate cortex, and inhibited the frequency of presynaptic neurotransmitter release in the anterior cingulate cortex of the mouse models.
NB001 may serve as a novel analgesic to treat bone cancer pain. Its analgesic effect is at least partially due to the inhibition of AC1 in anterior cingulate cortex.
NB001; bone cancer pain; adenylyl cyclase 1; anterior cingulate cortex
Urine output (UO) is an essential criterion of the Kidney Disease Improving Global Outcomes (KDIGO) definition and classification system for acute kidney injury (AKI), of which the diagnostic value has not been extensively studied. We aimed to determine whether AKI based on KDIGO UO criteria (KDIGOUO) could improve the diagnostic and prognostic accuracy, compared with KDIGO serum creatinine criteria (KDIGOSCr).
We conducted a secondary analysis of the database of a previous study conducted by China Critical Care Clinical Trial Group (CCCCTG), which was a 2-month prospective cohort study (July 1, 2009 to August 31, 2009) involving 3063 patients in 22 tertiary Intensive Care Units in Mainland of China. AKI was diagnosed and classified separately based on KDIGOUO and KDIGOSCr. Hospital mortality of patients with more severe AKI classification based on KDIGOUO was compared with other patients by univariate and multivariate regression analyses.
The prevalence of AKI increased from 52.4% based on KDIGOSCr to 55.4% based on KDIGOSCr combined with KDIGOUO. KDIGOUO also resulted in an upgrade of AKI classification in 7.3% of patients, representing those with more severe AKI classification based on KDIGOUO. Compared with non-AKI patients or those with maximum AKI classification by KDIGOSCr, those with maximum AKI classification by KDIGOUO had a significantly higher hospital mortality of 58.4% (odds ratio [OR]: 7.580, 95% confidence interval [CI]: 4.141–13.873, P < 0.001). In a multivariate logistic regression analysis, AKI based on KDIGOUO (OR: 2.891, 95% CI: 1.964–4.254, P < 0.001), but not based on KDIGOSCr (OR: 1.322, 95% CI: 0.902–1.939, P = 0.152), was an independent risk factor for hospital mortality.
UO was a criterion with additional value beyond creatinine criterion for AKI diagnosis and classification, which can help identify a group of patients with high risk of death.
Acute Kidney Injury; Critically Ill; Mortality; Serum Creatinine; Urine Output
In spite of the usual combination form of methotrexate (MTX)/mitoxantrone (MIT) and various complex combination regimens of MTX/MIT with other anticancer drugs, the survival period, cure rate, and systemic toxicity still need to be improved. For this purpose, a nanostructured amino group-modified mesoporous silica nanoparticles (MSNN)−MTX/MIT was designed. In the preparation, the surface of mesoporous silica nanoparticles (MSNs) was modified with amino groups to form MSNN. The covalent modification of the amino groups on the surface of MSNN with MTX resulted in MSNN−MTX. The loading of MIT into the surface pores of MSNN−MTX produced nanostructured MSNN−MTX/MIT. Compared with the usual combination form (MTX/MIT), nanostructured MSNN−MTX/MIT increased the survival period greatly, heightened the cure rate to a great extent, and lowered the systemic toxicity of the treated S180 mice, significantly. These superior in vivo properties of nanostructured MSNN−MTX/MIT over the usual combination form (MTX/MIT) were correlated with the former selectively releasing MTX and MIT in tumor tissue and inside cancer cells in vitro. The chemical structure and the nanostructure of MSNN−MTX/MIT were characterized using infrared and differential scanning calorimeter spectra as well as transmission electron microscope images, respectively.
mitoxantrone; methotrexate; mesoporous silica nanoparticles; cancer therapy; nanomedicine
Circulating tumor DNA (ctDNA) isolated from peripheral blood has recently been shown to be an alternative source to detect gene mutations in primary tumors; however, most previous studies have focused on advanced stage cancers, and few have evaluated ctDNA detection in early-stage lung cancer. In the present study, blood and tumor samples were collected prospectively from 58 early-stage non-small lung cancer (NSCLC) patients (stages IA, IB, and IIA) and a targeted sequencing approach was used to detect somatic driver mutations in matched tumor DNA (tDNA) and plasma ctDNA. We identified frequent driver mutations in plasma ctDNA and tDNA in EGFR, KRAS, PIK3CA, and TP53, and less frequent mutations in other genes, with an overall study concordance of 50.4% and sensitivity and specificity of 53.8% and 47.3%, respectively. Cell-free (cfDNA) concentrations were found to be significantly associated with some clinical features, including tumor stage and subtype. Importantly, the presence of cfDNA had a higher positive predictive value than that of currently used protein tumor biomarkers. This study demonstrates the feasibility of identifying plasma ctDNA mutations in the earliest stage lung cancer patients via targeted sequencing, demonstrating a potential utility of targeted sequencing of ctDNA in the clinical management of NSCLC.
MicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNA target sites (poly-miRTS)-centric multistage meta-analysis for lumbar spine (LS)-, total hip (HIP)- and femoral neck (FN)-bone mineral density (BMD). In stage I, 41 102 poly-miRTSs were meta-analyzed in seven cohorts with a genome-wide significance (GWS) α = 0.05/41 102 = 1.22 × 10−6. By applying α = 5 × 10−5 (suggestive significance), 11 poly-miRTSs were selected, with FGFRL1 rs4647940 and PRR5 rs3213550 as top signals for FN-BMD (P = 7.67 × 10−6 and 1.58 × 10−5) in gender-combined sample. In stage II in silico replication (two cohorts), FGFRL1 rs4647940 was the only signal marginally replicated for FN-BMD (P = 5.08 × 10−3) at α = 0.10/11 = 9.09 × 10-3. PRR5 rs3213550 was also selected based on biological significance. In stage III de novo genotyping replication (two cohorts), FGFRL1 rs4647940 was the only signal significantly replicated for FN-BMD (P = 7.55 × 10−6) at α = 0.05/2 = 0.025 in gender-combined sample. Aggregating three stages, FGFRL1 rs4647940 was the single stage I-discovered and stages II- and III-replicated signal attaining GWS for FN-BMD (P = 8.87 × 10−12). Dual-luciferase reporter assays demonstrated that FGFRL1 3′ untranslated region harboring rs4647940 appears to be hsa-miR-140-5p's target site. In a zebrafish microinjection experiment, dre-miR-140-5p is shown to exert a dramatic impact on craniofacial skeleton formation. Taken together, we provided functional evidence for a novel FGFRL1 poly-miRTS rs4647940 in a previously known 4p16.3 locus, and experimental and clinical genetics studies have shown both FGFRL1 and hsa-miR-140-5p are important for bone formation.