Miracle-dz/UniFAR-FTUs huggingface dataset:
Frequent epigenetics inactivation of KEAP1 gene in non-small cell lung cancer

The KEAP1/Nrf2 pathway is a master regulator of several redox-sensitive genes implicated in resistance of tumor cells against chemotherapeutic drugs. Recent data suggest that epigenetic mechanisms may play a pivotal role in the regulation of KEAP1 expression. We performed a comprehensive genetic and epigenetic analysis of the KEAP1 gene in 47 non-small cell lung cancer tissues and normal specimens. Promoter methylation analysis was performed using a quantitative methylation specific PCR assay in real time. Methylation at the KEAP1 promoter region was detected in 22 out of the 47 NSCLCs (47%) and in none of the normal tissues analyzed. Somatic mutations were detected in 7 out of the 47 tumors (15%) and loss of heterozygosity (LOH) in 10 out of the 47 (21%) of the cases. Overall, we found at least one molecular alteration in 57% of the cases. Approximately one third of the tumors had two alterations and this feature was associated with higher risk of disease progression in univariate COX regression analysis (HR = 3.62; 95% CI 1.24–10.65, p = 0.02). This result was confirmed by Kaplan-Meier analysis, which demonstrated an association between worst outcome and KEAP1 double alterations (p = 0.01, Log rank test). Our results further suggest that deregulation of the NRF2/KEAP1 system could play a pivotal role in the cancerogenesis of NSCLC. In addition identifying patients with KEAP1 genetic and epigenetic abnormalities may contribute to disease progression prediction and response to therapy in lung cancer patients.
Role for Stearoyl-CoA Desaturase-1 in Leptin-Mediated Weight Loss

Leptin elicits a metabolic response that cannot be explained by its anorectic effects alone. To examine the mechanism underlying leptin's metabolic actions, we used transcription profiling to identify leptin-regulated genes in ob/ob liver. Leptin was found to specifically repress RNA levels and enzymatic activity of hepatic stearoyl–CoA desaturase-1 (SCD-1), which catalyzes the biosynthesis of monounsaturated fatty acids. Mice lacking SCD-1 were lean and hypermetabolic. ob/ob mice with mutations in SCD-1 were significantly less obese than ob/ob controls and had markedly increased energy expenditure. ob/ob mice with mutations in SCD-1 had histologically normal livers with significantly reduced triglyceride storage and VLDL (very low density lipoprotein) production. These findings suggest that down-regulation of SCD-1 is an important component of leptin's metabolic actions.
An implementation intention strategy can improve prospective memory in older adults with very mild Alzheimer's disease.

OBJECTIVES This study tested whether (1) very mild Alzheimer's disease (AD) is associated with impaired prospective memory (PM) for tasks that are supported by either spontaneous retrieval (focal PM) or strategic monitoring (non-focal PM) and (2) implementation intention (II) encoding could improve PM performance in very mild AD. DESIGN Thirty-eight healthy older adults and 34 with very mild AD were randomly assigned to perform two PM tasks in either the standard or the II encoding condition. METHOD All participants performed blocks of category decision in which they were asked to respond to a focal PM target (e.g., the word 'orange') and a non-focal PM target (e.g., words that begin with the letter 'o'). Half of the participants encoded PM instructions in the standard manner, while the other half had a stronger encoding by forming IIs. PM accuracy and category decision accuracy and reaction times were measured. RESULTS Participants with very mild AD showed deficits in both focal and non-focal PM performance compared to the healthy controls, reflecting deficits in both spontaneous retrieval and strategic monitoring. Participants with very mild AD in the II encoding condition showed better focal PM performance relative to those in the standard encoding condition. CONCLUSIONS Deficits in both focal and non-focal PM are associated with very mild AD and IIs may be a helpful behavioural intervention for the focal PM deficits. PRACTITIONER POINTS Multiple deficits in PM are observable in very mild AD. Implementation intentions may enhance focal PM in very mild AD. Future research using larger samples is needed to better understand the effect of II on non-focal PM tasks in healthy older adults and those with very mild AD. The use of simple laboratory PM tasks may limit the generality of our findings. Future research is needed to investigate whether IIs improve PM over a range of more realistic tasks.
Human papillomavirus genotypes among females in Mexico: a study from the Mexican institute for social security.

BACKGROUND The aetiological relationship between human papillomavirus (HPV) infection and cervical cancer (CC) is widely accepted. Our goal was to determine the prevalence of HPV types in Mexican women attending at the Mexican Institute for Social Security from different areas of Mexico. MATERIALS AND METHODS DNAs from 2,956 cervical samples were subjected to HPV genotyping: 1,020 samples with normal cytology, 931 with low-grade squamous intraepithelial lesions (LGSIL), 481 with high grade HGSIL and 524 CC. RESULTS Overall HPV prevalence was 67.1%. A total of 40 HPV types were found; HPV16 was detected in 39.4% of the HPV-positive samples followed by HPV18 at 7.5%, HPV31 at 7.1%, HPV59 at 4.9%, and HPV58 at 3.2%. HPV16 presented the highest prevalence both in women with altered or normal cytology and HPV 18 presented a minor prevalence as reported worldwide. The prevalence ratio (PR) was calculated for the HPV types. The analysis of PR showed that HPV16 presents the highest association with CC, HPV 31, -33, -45, -52 and -58 also demonstrating a high association. CONCLUSIONS The most prevalent HPV types in cervical cancer samples were -16, -18, -31, but it is important to note that we obtained a minor prevalence of HPV18 as reported worldwide, and that HPV58 and -52 also were genotypes with an important prevalence in CC samples. Determination of HPV genotypes is very important in order to evaluate the impact of vaccine introduction and future cervical cancer prevention strategies.
Subregional changes in discharge rate, pattern, and drug sensitivity of putative GABAergic nigral neurons in the kindling model of epilepsy

The substantia nigra pars reticulata (SNr) is thought to act as a seizure‐gating mechanism in kindling and other epilepsy models. We investigated whether the kindling process induces site‐specific (anterior‐posterior) and seizure‐outlasting alterations in the activity of putative GABAergic SNr neurons and in their response to pharmacological manipulation. Female Wistar rats were kindled via the basolateral amygdala by daily stimulation. In vivo extracellular single unit recordings of SNr neurons were performed in kindled rats 1 day after a generalized seizure in order to examine activity changes that outlast the kindled seizures. Sham‐kindled and naive rats served as controls. We found a significant and seizure‐outlasting increase of discharge rates within the posterior but not within the anterior SNr of kindled rats when compared to controls. Furthermore, kindling resulted in seizure‐outlasting burst‐like firing pattern of SNr neurons. The antiepileptic drug valproic acid (VPA; 100 mg/kg i.v.) significantly reduced SNr discharge rates in all animal groups. Interestingly, neurons located in the anterior SNr of kindled rats were significantly less depressed by VPA compared to the reduction obtained in naive controls. The present data disclose kindling induced functional plasticity within basal ganglia regions. The findings are relevant for a better understanding of the mechanisms underlying the seizure‐gating function of the SNr and might provide new targets for rational therapeutic manipulations, which aim to establish a remote control of epileptic seizures.
Effects of palliative treatment with temozolomide in patients with high-grade gliomas.

BACKGROUND AND PURPOSE The aim of the study was to assess the results of treatment with temozolomide in patients with high-grade gliomas who no longer benefit from surgical treatment and radiotherapy. MATERIAL AND METHODS The retrospective analysis included 51 patients treated between 2001 and 2007 in the Centre of Oncology in Kraków. Glioblastoma multiforme was histologically diagnosed in 24 (47%) patients; anaplastic astrocytomas and other grade III gliomas (according to WHO classification) were diagnosed in 27 (53%) patients. Patients received 1-11 cycles of treatment with temozolomide - 210 cycles were given in total. Forty-five patients were eligible for efficacy assessment because 6 patients received only one chemotherapy cycle (due to rapid progression of the glioma). RESULTS According to the radiological assessment, 6 patients (13%) had an objective response and a further 16 patients (36%) had stabilization of the glioma. Subjective improvement was noted in 26 patients (58%), and neurological improvement was observed in 14 patients (31%). The median survival in the whole group was 41 weeks (40 weeks in patients with glioblastoma multiforme and 54 weeks in patients with anaplastic gliomas). One-year overall survival in the above-mentioned groups was 40.7%, 22%, and 50%, respectively. Two-year overall survival was 16%, 8%, and 20.9%, respectively. Adverse events were observed during 73 (35%) cycles of treatment and prompted a dose reduction in 12 (24.5%) patients. The most frequent adverse events were: thrombocytopenia, leukopenia, nausea and vomiting. Adverse events did not lead to treatment withdrawal in any patient. CONCLUSIONS Objective benefit from the temozolomide treatment (stabilization or objective remission) was observed in 49% of patients irrespective of histological diagnosis. Tolerability of treatment with temozolomide in patients with high-grade gliomas is good.
The effect of external partner heterogeneity on open innovation: the moderating role of the technological regime

ABSTRACT There is widespread agreement that open innovation (OI) is strongly influenced by external partner heterogeneity. While previous studies have examined partner heterogeneity using quantitative analysis, the implications of a weighted assignment using an external partner heterogeneity index have received less attention. The purpose of this study is to develop a modified partner heterogeneity model. Specifically, using a questionnaire survey of Chinese firms, we develop a new method to measure partner organisational heterogeneity (POH). Then, the moderating factors of an industry's technological environment, termed the technological regime, are introduced. The empirical analysis shows that the technological regime is positively correlated with POH and OI performance. Hence, an advanced technological regime improves POH and OI performance by incorporating external resources and increasing innovation potential.
Local High-Tech Job Multipliers in Europe

Examining employment growth in local labor markets across Europe, this article finds that each worker in a high-skilled occupation creates up to five extra jobs in local less-skilled-intensive services in the same region. However, it is also shown that there exist persistent differences in the size of this local high-tech job multiplier across regions. In particular, we find that the multiplier is larger in regions with higher immigration, an abundance of less-skilled workers, and lower gross output per capita. At the country level, we also show that this results in local high-tech job multipliers that are larger in Southern European countries than in the rest of Europe.
Enhancement of Adaptive Immunity by the Human Vaccine Adjuvant AS01 Depends on Activated Dendritic Cells

Adjuvant System AS01 is a liposome-based vaccine adjuvant containing 3-O-desacyl-4′-monophosphoryl lipid A and the saponin QS-21. AS01 has been selected for the clinical development of several candidate vaccines including the RTS,S malaria vaccine and the subunit glycoprotein E varicella zoster vaccine (both currently in phase III). Given the known immunostimulatory properties of MPL and QS-21, the objective of this study was to describe the early immune response parameters after immunization with an AS01-adjuvanted vaccine and to identify relationships with the vaccine-specific adaptive immune response. Cytokine production and innate immune cell recruitment occurred rapidly and transiently at the muscle injection site and draining lymph node postinjection, consistent with the rapid drainage of the vaccine components to the draining lymph node. The induction of Ag-specific Ab and T cell responses was dependent on the Ag being injected at the same time or within 24 h after AS01, suggesting that the early events occurring postinjection were required for these elevated adaptive responses. In the draining lymph node, after 24 h, the numbers of activated and Ag-loaded monocytes and MHCIIhigh dendritic cells were higher after the injection of the AS01-adjuvanted vaccine than after Ag alone. However, only MHCIIhigh dendritic cells appeared efficient at and necessary for direct Ag presentation to T cells. These data suggest that the ability of AS01 to improve adaptive immune responses, as has been demonstrated in clinical trials, is linked to a transient stimulation of the innate immune system leading to the generation of high number of efficient Ag-presenting dendritic cells.
Does Age Exacerbate the Gender-Wage Gap? New Method and Evidence From Germany, 1984–2014

ABSTRACT Given theoretical premises, the gender-wage gap adjusted for individual characteristics is likely to vary according to age. This study adapts John DiNardo, Nicole M. Fortin, and Thomas Lemieux's (1996) semi-parametric technique to disentangle year, cohort, and age effects in adjusted gender-wage gaps. The study relies on a long panel of data from the German Socio-Economic Panel (SOEP) covering 1984–2015. The results indicate that, in Germany, the gender-wage gap increases over a birth cohort's lifetime, including in the post-reproductive age for some birth cohorts. The results suggest that age and gender are overlapping handicaps in the labor market and call for a policy intervention.
Effect of alpha‐stat vs. pH‐stat strategies on cerebral oximetry during moderate hypothermic cardiopulmonary bypass

Background and objectives: This study was undertaken to compare the effect of alpha‐stat vs. pH‐stat strategies for acid–base management on regional cerebral oxygen saturation (RsO2) in patients undergoing moderate hypothermic haemodilution cardiopulmonary bypass (CPB). Methods: In 14 adult patients undergoing elective coronary artery bypass grafting, an awake RsO2 baseline value was monitored using a cerebral oximeter (INVOS 5100). Cerebral oximetry was then monitored continuously following anaesthesia and during the whole period of CPB. Mean ± SD of RsO2, CO2, mean arterial pressure and haematocrit were determined before bypass and during the moderate hypothermic phase of the CPB using the alpha‐stat followed by pH‐stat strategies of acid–base management. Alpha‐stat was then maintained throughout the whole period of CPB. Results: The mean baseline RsO2 in the awake patient breathing room air was 59.6 ± 5.3%. Following anaesthesia and ventilation with 100% oxygen, RsO2 increased up to 75.9 ± 6.7%. Going on bypass, RsO2 significantly decreased from a pre‐bypass value of 75.9 ± 6.7% to 62.9 ± 6.3% during the initial phase of alpha‐stat strategy. Shifting to pH‐stat strategy resulted in a significant increase of RsO2 from 62.9 ± 6.3% to 72.1 ± 6.6%. Resuming the alpha‐stat strategy resulted in a significant decrease of RsO2 to 62.9 ± 7.8% which was similar to the RsO2 value during the initial phase of alpha‐stat. Conclusion: During moderate hypothermic haemodilutional CPB, the RsO2 was significantly higher during the pH‐stat than during the alpha‐stat strategy. However, the RsO2 during pH‐stat management was significantly higher than the baseline RsO2 value in the awake patient breathing room air, denoting luxury cerebral perfusion. In contrast, the RsO2 during alpha‐stat was only slightly higher than the baseline RsO2, suggesting that the alpha‐stat strategy avoids luxury perfusion, but can maintain adequate cerebral oxygen supply‐demand balance during moderate hypothermic haemodilutional CPB.
Digital Natives or Digital Immigrants? The Impact of User Characteristics on Online Trust

Abstract Previous research suggests that user characteristics such as web experience and demographics may affect online trust. Drawing on social cognitive theory, we explore the moderating effect of user characteristics on online trust. Based on a survey of German Internet users, we differentiate three groups by age, web experience, and education. We term these groups digital natives, digital immigrants, and naturalized digitals. A multiple-group analysis reveals significant differences in trust formation, particularly in the cues considered in the evaluation of online services. Whereas a large user base inspires confidence in digital natives, naturalized digitals are more geared toward familiar brands and recommendations. Digital immigrants most critically weigh the risks of a transaction against its benefits. We argue that specific user characteristics are associated with distinct cognitive schemata, implying distinct interests and evaluations in online transactions. Online services should differentiate their signaling efforts according to the targeted customer group.
Long-horizon Investing: Pensions and Private Equity

This paper provides the explicit solution to the three-factor diffusion model recently proposed by the Danish Society of Actuaries to the Danish industry of life insurance and pensions. The solution is obtained by use of the known general solution to multidimensional linear stochastic differential equation systems. With offset in the explicit solution, we establish the conditional distribution of the future state variables which allows for exact simulation. Using exact simulation, we illustrate how simulation of the system can be improved compared to a standard Euler scheme. In order to analyze the effect of choosing the exact simulation scheme over the traditional Euler approximation scheme frequently applied by practitioners, we carry out a simulation study. We show that due to its recursive nature, the Euler scheme
HIV‐induced apoptosis of activated primary CD4+ T lymphocytes is not mediated by Fas–Fas ligand

Objective:To investigate the role of the Fas–Fas ligand (FasL) interaction in HIV-1-induced apoptosis of primary CD4+ T lymphocytes. Design:Activated CD4+ T lymphocytes are the main target of HIV, and T-cell activation leads to the expression of Fas–FasL and enhances HIV-mediated apoptosis. Phytohemagglutinin-activated primary CD4+ T cells were infected with HIV; the process of cell death was examined, and whether the dying and dead cells were the productively infected cells. The modulation of Fas and FasL expression and its role in HIV-induced cell death was also investigated. Methods:The number of viable and dead cells was determined by trypan blue exclusion. Apoptosis was quantified using an enzyme-linked immunosorbent assay measuring the release of cytoplasmic histone-associated DNA fragments. The percentage of HIV-infected cells was determined by FACS analysis, and viral production was assessed by a p24 core antigen assay. The following three markers, HIV-gp-120, annexin-V and 7-AAD, were used to monitor the apoptotic process in HIV-negative and positive cells. Fas and FasL expression was analyzed at the RNA level by reverse transcription polymerase chain reaction and at the protein level by flow cytometry. The contribution of Fas–FasL interactions to apoptosis was examined by blocking experiments using the antagonist ZB4 anti-Fas antibody. Results:HIV-induced apoptosis in activated purified CD4+ T lymphocytes required infectious virus and was dose-dependent. Apoptosis in HIV-infected cultures was mostly confined to productively infected cells. The expression of Fas and FasL was not significantly modulated by infection and blocking Fas-FasL interactions did not reduce the extent of apoptosis. Conclusions:HIV-induced apoptosis of activated CD4+ T cells in vitro is confined to productively infected cells and is not mediated by a Fas–FasL interaction.
Role of endotoxemia in cardiovascular dysfunction and lethality: virulent and nonvirulent Escherichia coli challenges in a canine model of septic shock

We investigated whether the severity of septic shock is determined by virulence factors associated with or the levels of endotoxemia produced by two Escherichia coli strains. Canines were challenged intraperitoneally with an E. coli strain (O6:H1:K2) that has virulence factors associated with human disease or with an equal dose of a nonvirulent strain (O86:H8) that lacks these factors. Both strains were administered in viable, heat-killed, and purified endotoxin forms. Median survival times with the virulent strain compared with the nonvirulent strain were shorter with viable bacteria (5 x 10(10) CFU/kg) (144 h versus > 672 h; Wilcoxon, P = 0.03), longer with heat-killed bacteria (5 x 10(9) CFU/kg) ( > 676 h versus 26 h; P = 0.03), and similar with purified endotoxin (15 mg/kg) (28 h versus 48 h; P = 0.71). However, whether the challenge contained viable bacteria, heat-killed bacteria, or purified endotoxin, the virulent strain produced less endotoxemia (P = 0.001). Hence, the changing outcomes with differing forms of the two strains cannot be attributed solely to endotoxin levels. The viable virulent strain caused less endotoxemia but more harm, and this does not appear to be explained by a more potent endotoxin or other heat-stable component. This study suggests that circulating endotoxin levels per se are less important in the outcome of septic shock than virulence factors associated with E. coli strains. Furthermore, the data call into question the significance of the endotoxin concentration in the blood in predicting the severity of shock and the lethality of gram-negative infections.
The role and significance of traditional leadership in the governance of modern democratic South Africa

ABSTRACT The institution of traditional leadership in Africa pre-existed both the colonial and apartheid systems and was the only known system of governance among indigenous people. However, contrary to the current political trend of discrediting traditional leadership, Africans have their own understanding of democracy, which is sharply from the liberal democracy of the west. The institution of traditional rulership was democratic in its own unique way in what we nowadays refer to as ‘consensus’. This article argues that the institution of traditional/indigenous leadership is still relevant as a trusted institution for governance by the majority of people living in rural South Africa. The Basotho adage: mooa khotla ha a tsekisoe is the maxim in which my argument – that traditional rulership is a sine qua non in rural areas – is grounded. The South African democratic government has failed to decisively define and unambiguously clarify the role of traditional leadership in government. The article aims to demonstrate government’s strategy of rendering the institution of traditional leadership obsolete and thus erasing it from South African political landscape. The debate on the role of traditional leadership is mainly founded on two diverse viewpoints: traditionalism and modernism; these viewpoints will form part of this paper. In this paper, I will refer to the legal or political framework of South Africa on the institution of traditional leadership.