Miracle-dz/UniFAR-FTUs huggingface dataset:
miR‐495 Enhances the Sensitivity of Non‐Small Cell Lung Cancer Cells to Platinum by Modulation of Copper‐Transporting P‐type Adenosine Triphosphatase A (ATP7A)

Copper‐transporting P‐type adenosine triphosphatase A (ATP7A) is associated with platinum drug resistance in non‐small cell lung cancer (NSCLC). microRNAs (miRNAs) are a class of small non‐coding RNA molecules that regulate gene expression at post‐transcriptional level. In this study, the aim is to explore which miRNAs might participate in the platinum resistance by targeting ATP7A in NSCLC. Using real‐time PCR‐based miRNA expression profiling and bioinformatics, we selected miR‐495 as a candidate miRNA. EGFP reporter assay, real‐time PCR, and Western blot validated that ATP7A was a direct target for miR‐495. The drug sensitivity assay indicated that miR‐495 enhanced the cell response to cisplatin (CDDP) in NSCLC cells, while inhibition of miR‐495 led to the opposite effects. Importantly, either overexpression or knockdown of ATP7A could override the effect of miR‐495 on chemosensitivity. We also demonstrated that miR‐495 increased the intracellular CDDP accumulation and overexpression of ATP7A can reduce the increased drug concentration induced by miR‐495. Finally, we discovered that there was a converse relationship between miR‐495 and ATP7A levels in NSCLC tissues sensitive or resistant to CDDP. In conclusion, our data demonstrate that miR‐495 regulates the multi‐drug resistance by modulation of ATP7A expression in NSCLC and suggest that miR‐495 may serve as a potential biomarker for the treatment of multi‐drug resistant NSCLC patients with high ATP7A levels. J. Cell. Biochem. 115: 1234–1242, 2014. © 2013 Wiley Periodicals, Inc.
CCR5 blockade in rheumatoid arthritis: a randomised, double-blind, placebo-controlled clinical trial

Objective C-C chemokine receptor type 5 (CCR5), a chemokine receptor expressed on T cells and macrophages, and its ligands are found in inflamed synovial tissue (ST) of patients with rheumatoid arthritis (RA). The rationale for testing CCR5 blockade in patients with RA was supported by the effects of a CCR5 antagonist in collagen-induced arthritis in rhesus monkeys. The effects of CCR5 blockade in patients with active RA were explored. Methods In this phase Ib randomised, placebo-controlled trial, treatment with an oral CCR5 inhibitor (SCH351125) in patients with active RA was evaluated. Clinical efficacy was assessed using European League Against Rheumatism and American College of Rheumatology response criteria. ST biopsies were taken before and after 28 days of treatment, and analysed for CCR5+ cells. In a subset of patients, MRIs of an inflamed joint were obtained before and after treatment. Results In all, 32 patients were included; 20 received SCH351125 and 12 placebo. Three patients who received SCH351125 did not complete the study due to adverse events; none of these were serious. No improvement was observed in the active treatment group compared to placebo. Results were consistent for clinical evaluation, ST analysis and MRI. Conclusion This proof of concept study does not support the use of CCR5 blockade as a therapeutic strategy in patients with active RA.
Antibiofilm Activity and Mechanism of Action of the Disinfectant Chloramine T on Candida spp., and Its Toxicity against Human Cells

We evaluated the antifungal and anti-biofilm activity, mechanism of action and cytotoxicity of chloramine T trihydrate (CAT) against Candida spp. The Minimum Inhibitory and Fungicidal Concentrations (MIC/MFC) of CAT were determined. Changes in CAT-treated C. albicans growth kinetics and micromorphology were evaluated, as well as the mechanism of action, and its effects on biofilm. Cytotoxicity was assessed by the hemolysis method. The data were analyzed by inferential statistics (p ≤ 0.05). CAT showed antifungal activity against all strains, with MIC values ranging between 1.38 and 5.54 mmol/L (MIC75%: 2.77 mmol/L). CAT demonstrated an immediate and sustained action on C. albicans growth kinetics, particularly at 2 × MIC. This compound likely acts on the cell wall and membrane permeability simultaneously and was found to cause changes in C. albicans micromorphology. Tha antibiofilm activity of CAT was similar to that of sodium hypochlorite (p > 0.05) against mature biofilms. CAT was more effective than NaOCl in reducing mature biofilm upon 1-min exposure at 2 × MIC (24 h) and 4 × MIC (48 h) (p < 0.05). Toxicological analysis revealed that CAT had hemolytic activity between 61 and 67.7% as compared to 100% by NaOCl. CAT has antifungal and anti-biofilm properties, probably acting on both cell wall and membrane permeability, and showed low toxicity in vitro.
The Long-Term Functional Outcome of Operatively Treated Tibial Plateau Fractures

Objectives To review the long-term functional results of the surgical treatment of tibial plateau fractures using standard techniques of open reduction and internal fixation. Design Retrospective study. Setting University hospital. Methods Forty-seven displaced fractures of the tibial plateau in forty-six patients were treated with open reduction, interfragmental screw fixation of the articular fragments, and buttress plate fixation and had a minimum of five years of follow-up. All aspects of their care, including tibial plateau fracture type, operative management and associated injuries, were documented. Preoperative and postoperative follow-up radiographs were analyzed for fracture classification and adequacy of reduction. All patients were contacted and given functional outcome questionnaires using both a generic health status scale (Short Form 36 [SF-36]) (18) and a disability scale relating to knee osteoarthritis (Western Ontario and McMaster Universities Osteoarthritis index [WOMAC]) (1). Data were also collected regarding return to work and sporting activities. Assessment scores were analyzed with respect to age, fracture type and severity, and were compared to standardized age and sex-matched scores for the healthy population. The average age of the patients at the time of injury was forty years and the average follow-up period was 8.3 years. Of the forty-seven fractures studied, twenty-five were classified as Schatzker types I, II, or III, and the remaining twenty-two were types IV, V, or VI (15). All fractures received operative treatment within forty-eight hours and all but five fractures were acceptably reduced. Results Compared to the standardized SF-36 categorical and aggregate scores, there was no statistically significant difference between the healthy age-matched population and twenty-four of twenty-six of the under-age-forty group regardless of fracture type. With regard to the over-age-forty group, scores statistically similar to the control population were found in only twelve of twenty-one patients. Although there was a large variance in WOMAC scores for all groups resulting in no statistically significant difference being found, a trend toward higher categorical and aggregate scores was seen with increasing age at presentation. There was no correlation between WOMAC scores and fracture type. Multiple-classifications analysis of all data revealed that presentation age was the most significant source of variation with respect to functional outcome. Fracture type had much less influence and adequacy of reduction had no significant influence on outcome, although the group of patients having an inadequate reduction by the authors' criteria was too small in number to reasonably comment upon. Conclusions Open reduction and internal fixation is a satisfactory technique for the treatment of displaced fractures of the tibial plateau, particularly for patients younger than forty years.
Mitigation deterrence and the “moral hazard” of solar radiation management

Fears of a moral hazard effect deterring mitigation have dogged solar radiation management (SRM) research since before 2006. Researchers have debated the significance and relevance of this concern from multiple disciplines and perspectives. This article explores this debate, highlighting the significance of policy goals and the actual and perceived substitutability of SRM for mitigation. The continuing problems in detecting mitigation deterrence in practice are noted. Different forms of moral hazard effect are distinguished, and the plausibility of mitigation galvanization considered. It is predicted that attention will turn to the situated, contingent expressions of mitigation deterrence and mitigation galvanization among different actors and at different scales; and to more sophisticated practical means to minimize the incidence and impacts of mitigation deterrence.
Persistent Activation of ERK Contributes to Glutamate-induced Oxidative Toxicity in a Neuronal Cell Line and Primary Cortical Neuron Cultures*

Oxidative stress can trigger neuronal cell death and has been implicated in several chronic neurological diseases and in acute neurological injury. Oxidative toxicity can be induced by glutamate treatment in cells that lack ionotrophic glutamate receptors, such as the immortalized HT22 hippocampal cell line and immature primary cortical neurons. Previously, we found that neuroprotective effects of geldanamycin, a benzoquinone ansamycin, in HT22 cells were associated with a down-regulation of c-Raf-1, an upstream activator of the extracellular signal-regulated protein kinases (ERKs). ERK activation, although often attributed strictly to neuronal cell survival and proliferation, can also be associated with neuronal cell death that occurs in response to specific insults. In this report we show that delayed and persistent activation of ERKs is associated with glutamate-induced oxidative toxicity in HT22 cells and immature primary cortical neuron cultures. Furthermore, we find that U0126, a specific inhibitor of the ERK-activating kinase, MEK-1/2, protects both HT22 cells and immature primary cortical neuron cultures from glutamate toxicity. Glutamate-induced ERK activation requires the production of specific arachidonic acid metabolites and appears to be downstream of a burst of reactive oxygen species (ROS) accumulation characteristic of oxidative stress in HT22 cells. However, inhibition of ERK activation reduces glutamate-induced intracellular Ca2+accumulation. We hypothesize that the precise kinetics and duration of ERK activation may determine whether downstream targets are mobilized to enhance neuronal cell survival or ensure cellular demise.
The Val66Met polymorphism of the brain‐derived neurotrophic factor gene is associated with psychotic feature and suicidal behavior in Japanese major depressive patients

Recent researches have suggested that brain‐derived neurotrophic factor (BDNF) may be implicated in the pathophysiology of mood disorder. This study examined the association between the BDNF Val66Met polymorphism and major depressive disorder (MDD) in a Japanese population. We genotyped the BDNF Val66Met polymorphism in 154 major depressive patients and 154 age‐ and sex‐matched control subjects. The genotypic distributions and allele frequencies were similar among the patients and control subjects. When the relationships of the polymorphism with several clinical variables (i.e., age, sex, age of onset, number of episode, presence of psychotic features, suicidal behavior, and family history) were examined, the dose of Met allele had significant effects on psychotic feature and suicidal behavior and family history. These results suggest that the BDNF Val66Met polymorphism is not related to the development of MDD but related to clinical features of MDD in a Japanese population. © 2007 Wiley‐Liss, Inc.
IT innovation and firm's sustainable performance: The mediating role of organizational agility

During the last ten years, the business environment has become complex and turbulent. Companies should thus innovate in order to gain competitive advantage. By proposing new IT innovations or adopting new ways to use existing IT innovations, firms are able to sense customers' needs and to design rapidly new products and services. In this article, an original framework is proposed. It links IT innovations and company's sustainable performance and highlights the intermediary role of firm's organizational agility. An inductive/deductive methodology was adopted by formulating general findings and a research question based on observations of both large corporate and SMEs in banking and telecommunications sectors.
Sitagliptin compared with thiazolidinediones as a third-line oral antihyperglycemic agent in type 2 diabetes mellitus.

OBJECTIVE To compare sitagliptin and thiazolidinediones as third-line oral antihyperglycemic agents among ethnic minority patients with poorly controlled type 2 diabetes mellitus. METHODS In an open-label, single-arm design, we treated type 2 diabetic patients who had suboptimal diabetes control on maximum tolerated dosages of metformin plus sulfonylureas with the addition of sitagliptin, 100 mg daily, and compared their responses with findings from a historical control group of similar patients treated with rosiglitazone, 8 mg daily, or pioglitazone, 45 mg daily, as their third-line oral agent. Patients were assessed bimonthly, and those who achieved hemoglobin A1c levels less than 7.5% at 4 months continued through 1 year of follow-up. RESULTS One hundred eight patients were treated with sitagliptin, and 104 patients constituted the historical control group treated with rosiglitazone or pioglitazone. At baseline, sitagliptin- and thiazolidinedione-treated patients had identical hemoglobin A1c levels (mean ± SD) (9.4 ± 1.8% and 9.4 ± 1.9%, respectively) and similar known diabetes duration (6.7 ± 5.0 years and 7.6 ± 5.8 years, respectively). Hemoglobin A1c was reduced in both groups at 4 months (P<.001), but the reduction was greater with thiazolidinediones than with sitagliptin (-2.0 ± 1.7% vs -1.3 ± 1.8%; P = .006), as was the proportion of patients achieving a hemoglobin A1c level less than 7.5% (62% vs 46%; P = .026). Of all patients achieving a hemoglobin A1c level less than 7.5% at 4 months, the same proportions in each group sustained their hemoglobin A1c level less than 7.5% by 12 months (59% vs 58%). Sitagliptin was well tolerated. CONCLUSIONS Among ethnic minority patients with poorly controlled type 2 diabetes while taking maximum tolerated dosages of metformin and sulfonylureas, third-line add-on therapy with a thiazolidinedione controlled hyperglycemia more effectively than sitagliptin after 4 months.
Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment

Background Neuroinflammation and mitochondrial impairment play important roles in the neuropathogenesis of Parkinson’s disease (PD). The activation of NLRP3 inflammasome and the accumulation of α-synuclein (α-Syn) are strictly correlated to neuroinflammation. Therefore, the regulation of NLRP3 inflammasome activation and α-Syn aggregation might have therapeutic potential. It has been indicated that Dl-3-n-butylphthalide (NBP) produces neuroprotection against some neurological diseases such as ischemic stroke. We here intended to explore whether NBP suppressed NLRP3 inflammasome activation and reduced α-Syn aggregation, thus protecting dopaminergic neurons against neuroinflammation. Methods In our study, we established a MPTP-induced mouse model and 6-OHDA-induced SH-SY5Y cell model to examine the neuroprotective actions of NBP. We then performed behavioral tests to examine motor dysfunction in MPTP-exposed mice after NBP treatment. Western blotting, immunofluorescence staining, flow cytometry and RT-qPCR were conducted to investigate the expression of NLRP3 inflammasomes, neuroinflammatory cytokines, PARP1, p-α-Syn, and markers of microgliosis and astrogliosis. Results The results showed that NBP exerts a neuroprotective effect on experimental PD models. In vivo, NBP ameliorated behavioral impairments and reduced dopaminergic neuron loss in MPTP-induced mice. In vitro, treatment of SH-SY5Y cells with 6-OHDA (100uM,24 h) significantly decreased cell viability, increased intracellular ROS production, and induced apoptosis, while pretreatment with 5uM NBP could alleviated 6-OHDA-induced cytotoxicity, ROS production and cell apoptosis to some extent. Importantly, both in vivo and in vitro, NBP suppressed the activation of the NLRP3 inflammasome and the aggregation of α-Syn, thus inhibited neuroinflammation ameliorated mitochondrial impairments. Conclusions In summary, NBP rescued dopaminergic neurons by reducing NLRP3 inflammasome activation and ameliorating mitochondrial impairments and increases in p-α-Syn levels. This current study may provide novel neuroprotective mechanisms of NBP as a potential therapeutic agent.
Psychosocial outcomes in a weight loss camp for overweight youth.

OBJECTIVE There is good evidence that youth attending weight loss camps in the UK and US are successful at achieving weight loss. Limited research suggests improvement in body image and self-esteem as well. This study evaluated changes in eight psychosocial variables following participation in a weight loss camp and examined the role of gender, age, length of stay, and body mass index (BMI) in these changes. METHODS This was an observational and self-report study of 130 participants (mean age = 12.8; mean BMI = 33.5; 70% female; 77% Caucasian). The program consisted of an 1800 kcal/day diet, daily supervised physical activities, cooking/nutrition classes, and weekly psycho-educational/support groups led by psychology staff. Participants completed measures of anti-fat attitudes, values (e.g., value placed on appearance, athletic ability, popularity), body- and self-esteem, weight- and health-related quality of life, self-efficacy, and depressive symptoms. RESULTS Participants experienced significant BMI reduction (average decrease of 7.5 kg [standard deviation, SD = 4.2] and 2.9 BMI points [SD = 1.4]). Participants also exhibited significant improvements in body esteem, self-esteem, self-efficacy, generic and weight-related quality of life, anti-fat attitudes, and the importance placed on appearance. Changes in self-efficacy, physical functioning and social functioning remained significant even after adjusting for initial zBMI, BMI change, and length of stay. Gender differences were found on changes in self-efficacy, depressive symptoms, and social functioning. CONCLUSION Participation in weight loss programs in a group setting, such as a camp, may have added benefit beyond BMI reduction. Greater attention to changes in psychosocial variables may be warranted when designing such programs for youth.
Prenatal diagnosis of congenital toxoplasmosis

Ninety‐three pregnant women with Toxoplasma gondii seroconversion during pregnancy underwent prenatal diagnosis of fetal toxoplasmosis. The following tests were used: (1) amniocentesis for mouse inoculation (93 subjects), (2) amplification of T. gondii DNA by polymerase chain reaction (PCR) (79 subjects), and (3) cordocentesis for the detection of T. gondii‐specific IgM antibodies (13 subjects). All patients had serial ultrasonographic scans to detect those fetuses with abnormalities that could be associated with congenital toxoplasmosis. Eighteen pregnancies (19.4%) had evidence of vertical transmission. A total of 11/18 (61.1%) had positive amniotic mouse inoculation test, while 10/12 (83.3%) had positive PCR results. The combination of both tests allowed the prenatal diagnosis in 17/18 infected fetuses (94.4%). All patients who underwent cordocentesis for the detection of T. gondii‐specific IgM antibodies had negative results. However, in two of the above cases fetal toxoplasmosis was detected by amniotic fluid studies. In five of the infected fetuses there were abnormal ultrasonographic findings. All pregnancies with evidence of vertical transmission were terminated, whereas the remaining pregnancies proceeded normally to term. The present data showed that amniotic fluid studies, preferably PCR amplification of T. gondii DNA, are the best diagnostic tools for the detection of vertical transmission in pregnancies with seroconversion during pregnancy. Copyright © 2002 John Wiley & Sons, Ltd.
Calcium Mobilization Triggered by the Chemokine CXCL12 Regulates Migration in Wounded Intestinal Epithelial Monolayers*

Restitution of intestinal epithelial barrier damage involves the coordinated remodeling of focal adhesions in actively migrating enterocytes. Defining the extracellular mediators and the intracellular signaling pathways regulating those dynamic processes is a key step in developing restitution-targeted therapies. Previously we have determined that activation of the chemokine receptor CXCR4 by the cognate ligand CXCL12 enhances intestinal epithelial restitution through reorganization of the actin cytoskeleton. The aim of these studies was to investigate the role of calcium effectors in CXCL12-mediated restitution. CXCL12 stimulated release of intracellular calcium in a dose-dependent manner. Inhibition of intracellular calcium flux impaired CXCL12-mediated migration of IEC-6 and CaCo2 cells. Pharmacological blockade and specific shRNA depletion of the phospholipase-C (PLCβ3) isoform attenuated CXCL12-enhanced migration, linking receptor activation with intracellular calcium flux. Immunoblot analyses demonstrated CXCL12 activated the calcium-regulated focal adhesion protein proline-rich tyrosine kinase-2 (Pyk2) and the effector proteins paxillin and p130Cas. Interruption of Pyk2 signaling potently blocked CXCL12-induced wound closure. CXCL12-stimulated epithelial cell migration was enhanced on laminin and abrogated by intracellular calcium chelation. These results suggest CXCL12 regulates restitution through calcium-activated Pyk2 localized to active focal adhesions. Calcium signaling pathways may therefore provide a novel avenue for enhancing barrier repair.
The Panel Study of Income Dynamics.

The Panel Study of Income Dynamics (PSID) offers much useful information for life course analysis because it follows the same people for a long period of time and it also follows individuals (called splitoffs) who leave their original families to form new families of their own. It includes an increasingly large sample of children for whose parents the PSID has both past and current information. Cumulative records of illnesses or unemployment in the same individuals or families allow new ways of studying their incidence. Since 1968 the PSID has interviewed annually a representative sample of about 5000 US families. A least 1 member of each family in the sample was in 1 of the original families interviewed in 1968. The study has followed both the original intact families and all members who have left the family since 1968. The 13th wave of data included about 6500 families. The PSID originally oversampled low-income and minority households. PSID data allows analysis on many different levels--households individuals divorced spouses and male heads for example. The PSID differs from the census in that it codes long-term cohabitors as families. Splitoffs who return to their original families continue to be treated as independent units. Sample members who die are replaced by their own children. The cumulative response rate after 14 years is 47% but if this rate is based only on the families interviewed in 1968 it becomes 67%. The PSID asks questions about income sources; family composition; employment; earnings; time spent working commuting and doing housework; food expenditures; housing; and migration. Its findings contradict many of the stereotypes built up from years of cross-sectional analysis. Peoples economic environment is not stable but volatile. Large numbers of workers or families are occasionally poor on welfare or in certain sectors of the labor market; fairly small numbers are persistently in these states. Frequent changes in family composition play a role in much of this volatility; these changes also create havoc in cross-sectional analyses of groups based on their family relationships.