Protein-protein interaction (PPI) is one of the most important functional components of a living cell. Recently, researchers have been interested in investigating the correlation between PPI and microRNA, which has been found to be a regulator at the post-transcriptional level. Studies on miRNA-regulated PPI networks will not only facilitate an understanding of the fine tuning role that miRNAs play in PPI networks, but will also provide potential candidates for tumor diagnosis. This review describes basic studies on the miRNA-regulated PPI network in the way of bioinformatics which includes constructing a miRNA-target protein network, describing the features of miRNA-regulated PPI networks and overviewing previous findings based on analysing miRNA-regulated PPI network features.
miRNA; Regulation; Protein-protein interaction
Brain metastases from solid tumours are associated with poor prognosis despite aggressive treatment. Temozolomide can be used for the treatment of glioblastoma multiforme as well as melanoma. It has also been shown to have activity in patients with brain metastases from various malignancies, since it can cross the blood-brain barrier. To better understand the efficacy of temozolomide in the treatment of brain metastases, we carried out a review of 21 published clinical trials to determine whether temozolomide would benefit patients with brain metastases from solid tumours. Information regarding complete response, partial response, stable disease, objective response and objective response rate were collected to assess clinical outcomes. A modest therapeutic effect was observed when temozolomide was used as a single agent, however, the combination of temozolomide with whole-brain radiotherapy and/or other anticancer drugs exhibited encouraging activity. Thus, future high quality studies are warranted to confirm our findings.
Temozolomide; Solid tumours; Brain metastases; Clinical trials; Clinical outcomes
Behcet’s disease (BD) is a rare and life-long disorder characterized by inflammation of blood vessels throughout the body. BD was originally described in 1937 as a syndrome involving oral and genital ulceration in addition to ocular inflammation. Intestinal BD refers to colonic ulcerative lesions documented by objective measures in patients with BD. Many studies have shown that over 40% of BD patients have gastrointestinal complaints. Symptoms include abdominal pain, diarrhea, nausea, anorexia and abdominal distension. Although gastrointestinal symptoms are common, the demonstration of gastrointestinal ulcers is rare. This so-called intestinal BD accounts for approximately 1% of cases. There is no specific test for BD, and the diagnosis is based on clinical criteria. The manifestations of intestinal BD are similar to those of other colitis conditions such as Crohn’s disease or intestinal tuberculosis, thus, it is challenging for gastroenterologists to accurately diagnose intestinal BD in patients with ileo-colonic ulcers. However, giant ulcers distributed in the esophagus and ileocecal junction with gastrointestinal hemorrhage are rare in intestinal BD. Here, we present a case of untypical intestinal BD. The patient had recurrent aphthous ulceration of the oral mucosa, and esophageal and ileo-colonic ulceration, but no typical extra-intestinal symptoms. During examination, the patient had massive acute lower gastrointestinal bleeding. The patient underwent ileostomy after an emergency right hemicolectomy and partial ileectomy, and was subsequently diagnosed with incomplete-type intestinal BD by pathology. The literature on the evaluation and management of this condition is reviewed.
Intestinal Behcet’s disease; Hemorrhage; Skip ulcers
Schizophrenia (SZ) is a neurodevelopmental disorder in which altered immune function typically plays an important role in mediating the effect of environmental insults and regulation of inflammation. The breast cancer suppressor protein associated protein (BRAP) is suggested to exert vital effects in neurodevelopment by modulating the mitogen-activated protein kinase cascade and inflammation signaling. To explore the possible role of BRAP in SZ, we conducted a two-stage study to examine the association of BRAP polymorphisms with SZ in the Han Chinese population. In stage one, we screened SNPs in BRAP from our GWAS data, which detected three associated SNPs, with rs3782886 being the most significant one (P = 2.31E-6, OR = 0.67). In stage two, we validated these three SNPs in an independently collected population including 1957 patients and 1509 controls, supporting the association of rs3782886 with SZ (P = 1.43E-6, OR = 0.73). Furthermore, cis-eQTL analysis indicates that rs3782886 genotypes are associated with mRNA levels of aldehyde dehydrogenase 2 family (ALDH2) (P = 0.0039) and myosin regulatory light chain 2 (MYL2) (P < 1.0E-4). Our data suggest that the BRAP gene may confer vulnerability for SZ in Han Chinese population, adding further evidence for the involvement of developmental and/or neuroinflammatory cascades in the illness.
The aim of the present study was to investigate human papillomavirus (HPV) infection and p16INK4A and p53 protein expression, to evaluate their roles in the pathological diagnosis and grading for cervical intraepithelial neoplasia (CIN). The detection of HPV DNA and p16INK4A and p53 protein expression were examined in a panel of clinical tissue samples using polymerase chain reaction or immunohistochemistry. In 104 cases, HPV16/18 DNA was identified in 49.0% and HPV6/11 DNA in 9.6% of cases. While in 203 cases, 74.4% positively expressed p16INK4A and 47.3% positively expressed p53. The expression of p16INK4A exhibited a significantly higher rate in the CIN I group than in the squamous metaplasia coupled with hyperplasia group (SMH; P<0.0001) and the CIN II–III group (P=0.005). A marked correlation was revealed between the band-like staining pattern of p16INK4A and HPV16/18 infection. On the contrary, p53 expression was not found to significantly correlate with CIN grade or the HPV16/18 infection status. These results suggested that p16INK4A expression correlates with a higher grade of CIN and may be used as a diagnostic marker to distinguish between CIN I and SMH, as well as between CIN I and CIN II–III.
immuhistochemistry; human papillomavirus; p16INK4A; p53; cervical intraepithelia neoplasia
Mouse testicular experimental models are widely used in the study of andrology, reproductive toxicology and pharmacology. Under physiological conditions, a normal adult mouse is usually considered to have normal testes. However, whether normal adult mouse testes exhibit pathological changes has not been evaluated. The objective of this study was to investigate the pathological changes of testicular tissues in normal adult mice. A retrospective analysis of 720 adult male Kunming mice, used in previous studies as controls, was performed. Bilateral testicular tissues were stained with hematoxylin and eosin for pathological examinations. Among the 720 mice, nine had abnormal testes, an incidence of 1.3%. The nine mice with abnormal testes included two with microrchidia (22.2%) while the others had a normal testicular size. The observed pathological changes associated with microrchidia were seminiferous epithelial vacuolation, spermatogenesis arrest at the spermatocyte stage and the absence of sperm in all tubules. In other abnormal testes, pathological alterations included seminiferous epithelial vacuolation, severe hypospermatogenesis and symplasts composed of collapsed spermatids in tubules. The results demonstrate that normal adult male mice exhibit testicular pathological changes. Therefore, the possibility of abnormal testes in normal adult mice must be considered when using mice to establish a testicular experimental model.
mouse; testis; pathology
With the trend of an increasing aged population worldwide, Alzheimer's disease (AD), an age-related neurodegenerative disorder, as one of the major causes of dementia in elderly people is of growing concern. Despite the many hard efforts attempted during the past several decades in trying to elucidate the pathological mechanisms underlying AD and putting forward potential therapeutic strategies, there is still a lack of effective treatments for AD. The efficacy of many potential therapeutic drugs for AD is of main concern in clinical practice. For example, large bodies of evidence show that the anti-tumor histone deacetylase (HDAC) inhibitor, suberoylanilidehydroxamic acid (SAHA), may be of benefit for the treatment of AD; however, its extensive inhibition of HDACs makes it a poor therapeutic. Moreover, the natural flavonoid, curcumin, may also have a potential therapeutic benefit against AD; however, it is plagued by low bioavailability. Therefore, the integrative effects of SAHA and curcumin were investigated as a protection against amyloid-beta neurotoxicity in vitro. We hypothesized that at low doses their synergistic effect would improve therapeutic selectivity, based on experiments that showed that at low concentrations SAHA and curcumin could provide comprehensive protection against Aβ25–35-induced neuronal damage in PC12 cells, strongly implying potent synergism. Furthermore, network analysis suggested that the possible mechanism underlying their synergistic action might be derived from restoration of the damaged functional link between Akt and the CBP/p300 pathway, which plays a crucial role in the pathological development of AD. Thus, our findings provided a feasible avenue for the application of a synergistic drug combination, SAHA and curcumin, in the treatment of AD.
The MXAN3885 to -3882 gene locus cluster (designated here mcuABCD) of Myxococcus xanthus encodes a member of the archaic chaperone-usher (CU) systems that functions in spore coat formation. We show here that McuD, a putative spore coat protein, affects cellular accumulation and cell surface localization of the spore coat protein McuA. We previously reported that genetic disruption of the putative usher McuC nearly eliminates surface display of McuA and show here that lack of the periplasmic chaperone-like protein McuB, which forms a complex with McuA, has a similar effect. Deletion mutation confirms that the G1 β strand of McuB is absolutely essential for the stability and secretion of McuA. Site-directed mutagenesis identified two additional alternating hydrophobic residues Ile113 and Val115, together with the highly conserved proline within the G1 strand, as critical residues for chaperone function. These findings suggest that the assembly proteins McuB and McuC mediate the transport of McuA onto the cell surface and that McuA may interact with another spore coat protein, McuD, for its secretion. Importantly, although our data argue that the M. xanthus CU system is likely to use the basic principle of donor strand complementation (DSC), as in the cases of classical CU pathways, to promote folding and stabilization of the structural subunit(s), the periplasmic chaperone McuB appears to exhibit structural variation in mediating chaperone-subunit interaction.
Subjective cognitive impairment (SCI) in older persons without
manifest symptomatology is a common condition with a largely unclear
prognosis. We hypothesized that (1) examining outcome for a sufficient
period by using conversion to mild cognitive impairment (MCI) or dementia
would clarify SCI prognosis, and (2) with the aforementioned procedures, the
prognosis of SCI subjects would differ significantly from that of
demographically matched healthy subjects, free of SCI, termed no cognitive
impairment (NCI) subjects.
A consecutive series of healthy subjects, aged ≥40 years,
presenting with NCI or SCI to a brain aging and dementia research center
during a 14-year interval, were studied and followed up during an 18-year
observation window. The study population (60 NCI, 200 SCI, 60%
female) had a mean age of 67.2 ± 9.1 years, was well-educated (mean,
15.5 ± 2.7 years), and cognitively normal (Mini-Mental State
Examination, 29.1 ± 1.2).
A total of 213 subjects (81.9% of the study population) were
followed up. Follow-up occurred during a mean period of 6.8 ± 3.4
years, and subjects had a mean of 2.9 ± 1.6 follow-up visits. Seven
NCI (14.9%) and 90 SCI (54.2%) subjects declined
(P < .0001). Of NCI decliners, five declined to
MCI and two to probable Alzheimer’s disease. Of SCI decliners, 71
declined to MCI and 19 to dementia diagnoses. Controlling for baseline
demographic variables and follow-up time, Weibull proportional hazards model
revealed increased decline in SCI subjects (hazard ratio, 4.5; 95%
confidence interval, 1.9–10.3), whereas the accelerated failure time
model analysis with an underlying Weibull survival function showed that SCI
subjects declined more rapidly, at 60% of the rate of NCI subjects
(95% confidence interval, 0.45–0.80). Furthermore, mean time
to decline was 3.5 years longer for NCI than for SCI subjects
(P = .0003).
These results indicate that SCI in subjects with normal cognition is
a harbinger of further decline in most subjects during a 7-year mean
follow-up interval. Relevance for community populations should be
investigated, and prevention studies in this at-risk population should be
Subjective cognitive impairment; Subjective cognitive complaints; Brain aging; Cognition; Mild cognitive impairment; Outcome studies; Longitudinal studies; Dementia; Risk factors for dementia; Neuropsychological testing
Pituitary adenomas (PAs) are commonly occurring neoplasms with diverse endocrine and neurological effects. Although somatic gene mutations are uncommon in sporadic PAs, recent studies lend support to epigenetic modification as a potential cause of tumorigenesis and tumor progression.
A systematic literature review of the PubMed and Google Scholar databases was conducted to identify abstracts (n=1,082) pertaining to key targets and mechanisms implicated in epigenetic dysregulation of PAs published between 1993-2013. Data regarding histopathological subtype, target genes, mode of epigenetic modification, and clinical correlation were recorded and analyzed.
Of the 47 that studies met inclusion criteria and focused on epigenomic assessment of PAs, only 2 were genome-scale analyses. Current evidence supports epigenetic alteration in at least 24 PA genes, which were categorized into four groups based on function and epigenetic alteration: 1) Sixteen tumor suppressor genes silenced via DNA methylation; 2) Two oncogenes overexpressed via histone acetylation and hypomethylation; 3) Three imprinted genes with selective allelic silencing; and 4) One epigenome writer inducing abnormal genome-scale activity and 5) Two transcription regulators indirectly modifying the genome. Of these, 5 genes (CDKN2A, GADD45y, FGFR2, caspase-8, and PTAG) showed particular susceptibility to epigenetic modification, with abnormal DNA methylation in >50% of PA samples. Several genes displayed correlations between epigenetic modification and clinically relevant parameters, including invasiveness (CDKN2A; DAPK; Rb1), sex (MAGE-A3), tumor size (GNAS1), and histopathological subtype (CDKN2A; MEG3; p27; RASSF1A; Rb1).
Epigenetic modification of selected PA genes may play a key role in tumorigenesis and progression, which may translate into important diagnostic and therapeutic applications.
AIM: To investigate the effect of somatostatin and dexamethasone on early postoperative small bowel obstruction with obliterative peritonitis (EPSBO-OP).
METHODS: This prospective randomized study included 70 patients diagnosed with EPSBO-OP from June 2002 to January 2009. Patients were randomized into two groups: a control group received total parenteral nutrition and nasogastric (NG) tube feeding; and an intervention group received, in addition, somatostatin and dexamethasone treatment. The primary endpoints were time to resolution of bowel obstruction and length of hospital stay, and the secondary endpoints were daily NG output and NG feeding duration, treatment-related complications, postoperative obstruction relapse, and patient satisfaction.
RESULTS: Thirty-six patients were allocated to the intervention group and 34 to the control group. No patient needed to undergo surgery. Patients in the intervention group had an earlier resolution of bowel obstruction (22.4 ± 9.1 vs 29.9 ± 10.1 d, P = 0.002). Lower daily NG output (583 ± 208 vs 922 ± 399 mL/d, P < 0.001), shorter duration of NG tube use (16.7 ± 8.8 vs 27.7 ± 9.9 d, P < 0.001), and shorter length of hospital stay (25.8 vs 34.9 d, P = 0.001) were observed in the intervention group. The rate of treatment-related complications (P = 0.770) and relapse of obstruction (P = 0.357) were comparable between the two groups. There were no significant differences in postoperative satisfaction at 1, 2 and 3 years between the two groups.
CONCLUSION: Somatostatin and dexamethasone for EPSBO-OP promote resolution of obstruction and shorten hospital stay, and are safe for symptom control without increasing obstruction relapse.
Dexamethasone; Intestinal obstruction; Parenteral nutrition; Postoperative period; Somatostatin
Mina is an epigenetic gene regulatory protein known to function in multiple physiological and pathological contexts, including pulmonary inflammation, cell proliferation, cancer and immunity. We showed previously that the level of Mina gene expression is subject to natural genetic variation linked to 21 SNPs occurring in the Mina 5′ region . In order to explore the mechanisms regulating Mina gene expression, we set out to molecularly characterize the Mina promoter in the region encompassing these SNPs. We used three kinds of assays – reporter, gel shift and chromatin immunoprecipitation – to analyze a 2 kb genomic fragment spanning the upstream and intron 1 regions flanking exon 1. Here we discovered a pair of Mina promoters (P1 and P2) and a P1-specific enhancer element (E1). Pharmacologic inhibition and siRNA knockdown experiments suggested that Sp1/3 transcription factors trigger Mina expression through additive activity targeted to a cluster of four Sp1/3 binding sites forming the P1 promoter. These results set the stage for comprehensive analysis of Mina gene regulation from the context of tissue specificity, the impact of inherited genetic variation and the nature of upstream signaling pathways.
We reported recently that apoptosis-stimulating protein of p53 (ASPP) 2, an activator of p53, co-operates with oncogenic RAS to enhance the transcription and apoptotic function of p53. However, the detailed mechanism remains unknown. Here we show that ASPP2 is a novel substrate of mitogen-activated protein kinase (MAPK). Phosphorylation of ASPP2 by MAPK is required for RAS-induced increased binding to p53 and increased transactivation of pro-apoptotic genes. In contrast, an ASPP2 phosphorylation mutant exhibits reduced p53 binding and fails to enhance transactivation and apoptosis. Thus phosphorylation of ASPP2 by RAS/MAPK pathway provides a novel link between RAS and p53 in regulating apoptosis.
Forkhead box O (FOXO) transcriptional protein family members, including FOXO1 and FOXO3, are involved in the modulation of autophagy. However, whether there is redundancy between FOXO1 and FOXO3 in the ability to induce autophagy remains unclear. In this study, we showed that FOXO3 induced a transcription-dependent autophagy, and FOXO1 was required for this process. Overexpression of wild-type FOXO3 (WT) or FOXO3 (3A), which harbors alanine mutations at residues Thr32, Ser253 and Ser315, but not transcription-inactive FOXO3 (∆DB3A), significantly induced autophagy in the human embryonic kidney cell line HEK293T and mouse embryonic fibroblast (MEF) cell lines. Interestingly, depletion of FOXO1 by siRNA attenuated FOXO3-induced autophagy. Our data also showed that FOXO3 overexpression did not increase the expression of FOXO1 at the protein level, although FOXO3 was capable of binding the promoter region of FOXO1 and inducing an increase in the transcription of FOXO1 mRNA. Furthermore, our results showed that FOXO3 promoted the translocation of FOXO1 from the nucleus to the cytoplasm, resulting in an increase in FOXO1-induced autophagy. Moreover, our results supported a mechanism whereby FOXO3 dramatically increased the expression of the class I PtdIns3K catalytic subunit PIK3CA, leading to an increase in AKT1 activity, which resulted in the phosphorylation and nuclear export of FOXO1. To the best of our knowledge, our data are the first to suggest that FOXO1 plays a central role in FOXO3-induced autophagy.
FOXO1; FOXO3; autophagy; PIK3CA; AKT1
The relaxed complex scheme is an in silico drug
screening method that accounts for receptor flexibility by using molecular
dynamics simulations. Here, we used this approach combined with similarity
searches and experimental inhibition assays to identify several low micro-molar,
non-bisphosphonate inhibitors, bisamidines, of farnesyl diphosphate synthase
(FPPS), an enzyme targeted by some anti-cancer and anti-microbial agents and for
the treatment of bone resorption diseases. This novel class of FPPS inhibitors
have more drug-like properties than existing bisphosphonate inhibitors, making
them interesting pharmaceutical leads.
Objective. To examine the biocompatibility of a novel nanohydroxyapatite/poly[lactic-co-glycolic acid] (nHA/PLGA) composite and evaluate its feasibility as a scaffold for cartilage tissue engineering. Methods. Chondrocytes of fetal rabbit were cultured with nHA/PLGA scaffold in vitro and the cell viability was assessed by MTT assay first. Cells adhering to nHA/PLGA scaffold were then observed by inverted microscope and scanning electron microscope (SEM). The cell cycle profile was analyzed by flow cytometry. Results. The viability of the chondrocytes on the scaffold was not affected by nHA/PLGA comparing with the control group as it was shown by MTT assay. Cells on the surface and in the pores of the scaffold increased in a time-dependent manner. Results obtained from flow cytometry showed that there was no significant difference in cell cycle profiles between the coculture group and control (P > 0.05). Conclusion. The porous nHA/PLGA composite scaffold is a biocompatible and good kind of scaffold for cartilage tissue engineering.
The goals of this study were to investigate the effects of hypoxia on cochlear hair cell damage, and to explore the role of sirtuin1 in hypoxia-induced hair cell damage. Cochlear organotypic cultures from postnatal day 4 rats were used in this study. Hypoxia was induced by treating cochlear explants with CoCl2. Cochlear cultures were treated with CoCl2 alone or in combination with the sirtuin1 activator resveratrol and the sirtuin1 inhibitor sirtinol. Hair cell damage was identified by phalloidin staining and imaged using scanning electron microscopy. RT-PCR and Western blot analyses were used to detect the expression of sirtuin1 and acetylated nuclear factor-κB (NF-κB). Low concentrations of CoCl2 (100–200 μM) did not cause an obvious change in the number and morphology of hair cells, whereas higher concentrations of CoCl2 (300–400 μM) induced swelling of hair cells, accompanied by cell loss. Increased sirtuin1 expression was induced by CoCl2 at 100 to 200 μM, but not at 400 μM. NF-κB acetylation was significantly increased in explants treated with 400 μM CoCl2. Pretreatment with resveratrol prevented CoCl2-induced hair cell loss and acetylation of NF-κB. The protective effect of resveratrol was significantly reduced by sirtinol. CoCl2 induces hair cell damage in organotypic cochleae cultures. Resveratrol attenuates CoCl2-induced cochlear hair cell damage possibly via activation of sirtuin1, which deacetylates NF-κB.
Abnormal host-microbe interactions are implicated in the pathogenesis of inflammatory bowel diseases. Previous 16S rRNA sequence analysis of intestinal tissues demonstrated that a subset of Crohn’s disease (CD) and ulcerative colitis (UC) samples exhibited altered intestinal associated microbial compositions characterized by depletion of Bacteroidetes and Firmicutes (particularly Clostridium taxa). We hypothesize that NOD2 and ATG16L1 risk alleles may be associated with these alterations.
To test this hypothesis, we genotyped 178 specimens collected from 35 CD, 35 UC and 54 control patients for the three major NOD2 risk alleles (Leu 1007fs, R702W and G908R) and the ATG16L1T300A risk allele, that had undergone previous 16S rRNA sequence analysis. Our statistical models incorporated the following independent variables:1.) disease phenotype (CD, UC, Non-IBD Control); 2.) NOD2 composite genotype (NOD2R = at least one risk allele, NOD2NR = no risk alleles); 3.) ATG16L1T300A genotype (ATG16L1R/R, ATG16L1R/NR, ATG16L1NR/NR); 4.) patient age at time of surgery and all first order interactions. The dependent variable(s) were the relative frequencies of bacterial taxa classified by applying the RDP 2.1 classifier to previously reported 16S rRNA sequence data.
Disease phenotype, NOD2 composite genotype and ATG16L1 genotype were significantly associated with shifts in microbial compositions by nonparametric MANCOVA. Shifts in the relative frequencies of Faecalibacterium and Escherichia taxa were significantly associated with disease phenotype by nonparametric ANCOVA.
These results support the concept that disease phenotype and genotype are associated with compositional changes in intestinal associated microbiota.
NOD2; ATG16L1; inflammatory bowel diseases; microbiota
We provide optimal treatment allocation schemes when the outcome variance varies across the treatment groups and our objectives are to estimate treatment effects with equal or unequal interest. Unlike other optimal designs, such as A-optimal designs, the proposed designs can be found without an iterative scheme. We evaluate robustness properties of the optimal designs to mis-specification in the expected variance from each group and identify situations when popular allocation schemes have poor efficiencies. An application to design a randomized rheumatoid arthritis trial is discussed, along with a potential application to design a cancer screening trial when the main outcome is a continuous variable.
continuous design; DA-optimal design; efficiency; multiple-objective optimal design
This study was aimed at investigating the functional significance of heparan sulfate (glucosamine) 3-O-sulfotransferase 2 (HS3ST2) hypermethylation in non-small cell lung cancer (NSCLC).
Methodology/ Principal Findings
HS3ST2 hypermethylation was characterized in six lung cancer cell lines, and its clinical significance was analyzed using 298 formalin-fixed paraffin-embedded tissues and 26 fresh-frozen tissues from 324 NSCLC patients. MS-HRM (methylation-specific high-resolution melting) and EpiTYPERTM assays showed substantial hypermethylation of CpG island at the promoter region of HS3ST2 in six lung cancer cell lines. The silenced gene was demethylated and re-expressed by treatment with 5-aza-2′-deoxycytidine (5-Aza-dC). A promoter assay also showed the core promoter activity of HS3ST2 was regulated by methylation. Exogenous expression of HS3ST2 in lung cancer cells H460 and H23 inhibited cell migration, invasion, cell proliferation and whereas knockdown of HS3ST2 in NHBE cells induced cell migration, invasion, and cell proliferation in
vitro. A negative correlation was observed between mRNA and methylation levels of HS3ST2 in 26 fresh-frozen tumors tissues (ρ = -0.51, P = 0.009; Spearman’s rank correlation). HS3ST2 hypermethylation was found in 95 (32%) of 298 primary NSCLCs. Patients with HS3ST2 hypermethylation in 193 node-negative stage I-II NSCLCs with a median follow-up period of 5.8 years had poor overall survival (hazard ratio = 2.12, 95% confidence interval = 1.25–3.58, P = 0.005) compared to those without HS3ST2 hypermethylation, after adjusting for age, sex, tumor size, adjuvant therapy, recurrence, and differentiation.
The present study suggests that HS3ST2 hypermethylation may be an independent prognostic indicator for overall survival in node-negative stage I-II NSCLC.
Traditional Chinese herbal medicines (TCHMs) were tested for their ability of antiquorum sensing. Water extracts of Rhubarb, Fructus gardeniae, and Andrographis paniculata show antiquorumsensing activity when using Chromobacterium violaceum CV12472 as reporter; the sub-MIC concentrations of these TCHMs were tested against AHL-dependent phenotypic expressions of PAO1. Results showed significant reduction in pyocyanin pigment, protease, elastase production, and biofilm formation in PAO1 without inhibiting the bacterial growth, revealing that the QSI by the extracts is not related to static or killing effects on the bacteria. The results indicate a potential modulation of bacterial cell-cell communication, P. aeruginosa biofilm, and virulence factors by traditional Chinese herbal medicine. This study introduces not only a new mode of action for traditional Chinese herbal medicines, but also a potential new therapeutic direction for the treatment of bacterial infections, which have QSI activity and might be important in reducing virulence and pathogenicity of pathogenic bacteria.
The purpose of this study was to analyze the clinical features and prognostic factors of surgical outcome of foot drop caused by lumbar degenerative disease and put forward the clinical stage.
We retrospectively reviewed 135 patients with foot drop due to lumbar degenerative disease. The clinical features and mechanism were analyzed. Age, sex, duration of palsy, preoperative muscle strength of tibialis anterior (TA), sensation defect of affected lower limb, affected foot, diagnosis and compressed nerve roots were recorded and compared with surgical outcome.
Foot drop was observed in 8.1% of all inpatients of lumbar degenerative disease. L5 nerve root compression was observed in 126 of all 135 patients (93.3%). Single, double and triple roots compression was observed respectively in 43, 83, and 9 patients (31.9%, 61.5%, and 6.6%). But there was no significant relationship between preoperative muscle strength of TA and the number of compressed roots. The muscle strength of TA was improved in 113 (83.7%) patients after surgery, but it reached to >=4 in only 21 (15.6%) patients. Improvement of the muscle strength of TA was almost stable at the 6-month follow-up. At the last follow-up, the muscle strength of TA was 1, 2, 3, 4, 5 respectively in 28, 24, 62, 13, 8 patients. Multivariate logistic regression showed duration of palsy (p=0.0360, OR=2.543), preoperative muscle strength of TA (p=0.0064, OR=5.528) and age (p=0.0309, OR=3.208) were factors that influenced recovery following an operation.
L5 nerve root was most frequently affected. The muscle strength of TA improved in most patients after surgery, but few patients can get a good recovery from foot drop. Patients of shorter duration of palsy, better preoperative muscle strength of TA and younger age showed a better surgical outcome.
Depression is one of the most common and debilitating psychiatric illnesses around the world, but the current antidepressants used to treat depression have many limitations. Progressively more studies have shown that neuropeptide systems are potential novel therapeutic targets for depression. However, whether the neuropeptide trefoil factor 3 (TFF3) participates in the development of depression has not been examined. In the current experiments, we assessed the antidepressant effects of TFF3 using the forced swim test (FST), tail suspension test (TST), and chronic mild stress (CMS) paradigm. Furthermore, we determined the mechanism that underlies the antidepressant-like effects of TFF3 in the rat FST. TFF3 dose-dependently reduced immobility time in both FST and TST. CMS elevated plasma TFF3 and decreased basolateral amygdala (BLA) TFF3 levels in rats, and acute TFF3 (0.1 mg/kg, i.p.) treatment reversed the depressive-like behaviors induced by CMS. Furthermore, TFF3 (0.1 mg/kg, i.p.) significantly increased Fos expression in the BLA, medial prefrontal cortex, and hypothalamus in rats subjected to the FST. Intra-BLA infusions of TFF3 (1 ng/side) exerted rapid antidepressant-like effects in the rat FST. Additionally, acute systemic TFF3 administration increased the level of phosphorylated-Akt (p-Akt) in the BLA. Finally, intra-BLA infusions of LY294002 (5 mM/side), a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, significantly blocked the antidepressant-like effect of TFF3. Our results demonstrated that TFF3 exerts antidepressant-like effects that might be mediated by the PI3K/Akt signaling pathway in the BLA. These findings suggest a novel neuropeptide system target in the development of new antidepressants.
depression; neuropeptide; trefoil factor 3; basolateral amygdala; phosphatidylinositol 3-kinase; chronic mild stress; animal models; behavioral science; biological psychiatry; chronic stress; depression; unipolar/bipolar; neuropeptide
RhoB, a member of small GTPases belonging to the Ras protein superfamily, might have a suppressive activity in cancer progression. Here, expression of RhoB gene was evaluated in human benign, borderline and malignant ovary tumors by immunostaining, with normal ovary tissue as control. Malignant tumors were assessed according to Federation Internationale de Gynecologie Obstetrique (FIGO) guidelines and classified in stage I-IV. Revivification of RhoB gene was investigated by analyzing the effect of histone deacetylase (HDAC) inhibitor trichostatin (TSA) and methyltransferase inhibitor 5-azacytidine (5-Aza) on ovarian cancer cells via RT-PCR and western blot. Apoptosis of ovary cancer cells was detected using flowcytometry and fluorescence microscopy. Subsequently, RhoB expression is detected in normal ovary epithelium, borderline tumors, and decreases significantly or lost in the majority of ovarian cancer specimen (P<0.05). RhoB expression decreases significantly from stage II (71.4%) to stage III (43.5%) to stage IV (18.2%, P<0.05). TSA can both significantly revive the RhoB gene and mediate apoptosis of ovarian cancer cells, but 5-Aza couldn’t. Interference into Revivification of RhoB gene results in reduction of ovary carcinoma cell apoptosis. It is proposed that loss of RhoB expression occurs frequently in ovary carcinogenesis and progression and its expression could be regulated by histone deacetylation but not by promoter hypermethylation, which may serve as a prospective gene treatment target for the patients with ovarian malignancy not responding to standard therapies.
A common model of power supply for implantable devices was established to study factors affecting volume conduction energy transfer. Electromagnetic and equivalent circuit models were constructed to study the effect of separation between the source electrode pairs on volume conduction energy transfer. In addition, the parameters of external signal including waveform, amplitude and frequency were analyzed. As the current amplitude did not lead to tissue injury and the current frequency did not cause nerve excitability, the recommended separation between the source electrodes was 3 cm, the proposed waveform of signal source was sinusoidal wave and the optimal frequency was 200 KHz. In agar experiment and swine skin experiment, the current transfer efficiencies were 28.13% and 20.65%, respectively, and the energy transfer efficiencies were 9.86% and 6.90%, respectively. In conclusion, we can achieve optimal efficiency of energy transfer by appropriately setting the separation between the source electrode parameters of the signal source.
volume conduction; implantable device; simulation; energy transfer