Reduction of the HIV Protease Inhibitor-Induced ER Stress and Inflammatory Response by Raltegravir in Macrophages

Background HIV protease inhibitor (PI), the core component of highly active antiretroviral treatment (HAART) for HIV infection, has been implicated in HAART-associated cardiovascular complications. Our previous studies have demonstrated that activation of endoplasmic reticulum (ER) stress is linked to HIV PI-induced inflammation and foam cell formation in macrophages. Raltegravir is a first-in-its-class HIV integrase inhibitor, the newest class of anti-HIV agents. We have recently reported that raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of hepatic lipid metabolism by inhibiting ER stress. However, little information is available as to whether raltegravir would also prevent HIV PI-induced inflammatory response and foam cell formation in macrophages. Methodology and Principal Findings In this study, we examined the effect of raltegravir on ER stress activation and lipid accumulation in cultured mouse macrophages (J774A.1), primary mouse macrophages, and human THP-1-derived macrophages, and further determined whether the combination of raltegravir with existing HIV PIs would potentially exacerbate or prevent the previously observed activation of inflammatory response and foam cell formation. The results indicated that raltegravir did not induce ER stress and inflammatory response in macrophages. Even more interestingly, HIV PI-induced ER stress, oxidative stress, inflammatory response and foam cell formation were significantly reduced by raltegravir. High performance liquid chromatography (HPLC) analysis further demonstrated that raltegravir did not affect the uptake of HIV PIs in macrophages. Conclusion and Significance Raltegravir could prevent HIV PI-induced inflammatory response and foam cell formation by inhibiting ER stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the cardiovascular complications associated with current HAART

The adoption intention of travel-related app: A framework integrating perceived characteristics of innovation and software quality

This thesis aims to analyze the views of customers who have great appetite for tourism on the tourism application. According to the perception characteristics of technology acceptance model, innovation diffusion theory and software quality model, the thesis sets up the research model and puts forward the corresponding research hypothesis on the combination of current research results. In the manner of questionnaire design and collection and data processing, data analysis and hypothesis verification will be conducted by the use of structural equation model. The research result implies that application design attributes and application performance features are key to promote the adoption of mobile travel application. In addition, this research broadens our horizons on the accidental impact of application attributes on adoption behavior through adding user gender as a variable to the model, and increases an awesome theoretical basis for future research in this field.Esta tese tem como objetivo analisar as visões de potenciais turistas com grande interesse por aplicações turísticas. De acordo com as características de percepção do modelo de aceitação de tecnologia, teoria da difusão da inovação e modelo de qualidade de software, a tese estabelece o modelo de investigação e propõe hipóteses de investigação correspondentes, sobre a combinação de resultados da pesquisa atual. Uma vez realizado o desenho do questionário e feita a recolha e processamento de dados, a análise de dados e a verificação de hipóteses foram conduzidas pelo uso do modelo de equações estruturais. O resultado da pesquisa implica que os atributos de design do aplicativo e os recursos de desempenho do aplicativo são fundamentais para promover a adoção do aplicativo móvel de viagem. Além disso, esta pesquisa amplia os horizontes sobre o impacto acidental de atributos de aplicação no comportamento de adoção, adicionando o gênero do usuário como uma variável ao modelo, e aumenta uma importante base teórica para pesquisas futuras neste campo

The adoption intention of travel-related app: a framework integrating perceived characteristics of innovation and software quality

This thesis aims to analyze the views of customers who have great appetite for tourism on the tourism application. According to the perception characteristics of technology acceptance model, innovation diffusion theory and software quality model, the thesis sets up the research model and puts forward the corresponding research hypothesis on the combination of current research results. In the manner of questionnaire design and collection and data processing, data analysis and hypothesis verification will be conducted by the use of structural equation model. The research result implies that application design attributes and application performance features are key to promote the adoption of mobile travel application. In addition, this research broadens our horizons on the accidental impact of application attributes on adoption behavior through adding user gender as a variable to the model, and increases an awesome theoretical basis for future research in this field.Esta tese tem como objetivo analisar as visões de potenciais turistas com grande interesse por aplicações turísticas. De acordo com as características de percepção do modelo de aceitação de tecnologia, teoria da difusão da inovação e modelo de qualidade de software, a tese estabelece o modelo de investigação e propõe hipóteses de investigação correspondentes, sobre a combinação de resultados da pesquisa atual. Uma vez realizado o desenho do questionário e feita a recolha e processamento de dados, a análise de dados e a verificação de hipóteses foram conduzidas pelo uso do modelo de equações estruturais. O resultado da pesquisa implica que os atributos de design do aplicativo e os recursos de desempenho do aplicativo são fundamentais para promover a adoção do aplicativo móvel de viagem. Além disso, esta pesquisa amplia os horizontes sobre o impacto acidental de atributos de aplicação no comportamento de adoção, adicionando o gênero do usuário como uma variável ao modelo, e aumenta uma importante base teórica para pesquisas futuras neste campo

A Case Study of Processes Impacting Precipitation Phase and Intensity during the Vancouver 2010 Winter Olympics

Accurate forecasting of precipitation phase and intensity was critical information for many of the Olympic venue managers during the Vancouver 2010 Olympic and Paralympic Winter Games. Precipitation forecasting was complicated because of the complex terrain and warm coastal weather conditions in the Whistler area of British Columbia, Canada. The goal of this study is to analyze the processes impacting precipitation phase and intensity during a winter weather storm associated with rain and snow over complex terrain. The storm occurred during the second day of the Olympics when the downhill ski event was scheduled. At 0000 UTC 14 February, 2 h after the onset of precipitation, a rapid cooling was observed at the surface instrumentation sites. Precipitation was reported for 8 h, which coincided with the creation of a nearly 0°C isothermal layer, as well as a shift of the valley flow from up valley to down valley. Widespread snow was reported on Whistler Mountain with periods of rain at the mountain base despite the expectation derived from synoptic-scale models (15-km grid spacing) that the strong warm advection would maintain temperatures above freezing. Various model predictions are compared with observations, and the processes influencing the temperature, wind, and precipitation types are discussed. Overall, this case study provided a well-observed scenario of winter storms associated with rain and snow over complex terrain

Ethanol inhibits LPS-induced signaling and modulates cytokine production in peritoneal macrophages in vivo in a model for binge drinking

<p>Abstract</p> <p>Background</p> <p>Previous reports indicate that ethanol, in a binge drinking model in mice, inhibits the production of pro-inflammatory cytokines in vivo. However, the inhibition of signaling through TLR4 has not been investigated in this experimental model in vivo. Considering evidence that signaling can be very different in vitro and in vivo, the present study was conducted to determine if effects of ethanol on TLR4 signaling reported for cells in culture or cells removed from ethanol treated mice and stimulated in culture also occur when ethanol treatment and TLR4 activation occur in vivo.</p> <p>Results</p> <p>Phosphorylated p38, ERK, and c-Jun (nuclear) were quantified with kits or by western blot using samples taken 15, 30, and 60 min after stimulation of peritoneal macrophages with lipopolysaccharide in vivo. Effects of ethanol were assessed by administering ethanol by gavage at 6 g/kg 30 min before administration of lipopolysaccharide (LPS). Cytokine concentrations in the samples of peritoneal lavage fluid and in serum were determined at 1, 2, and 6 hr after lipopolysaccharide administration. All of these data were used to measure the area under the concentration vs time curve, which provided an indication of the overall effects of ethanol in this system. Ethanol suppressed production of most pro-inflammatory cytokines to a similar degree as it inhibited key TLR4 signaling events. However, NF-κB (p65) translocation to the nucleus was not inhibited by ethanol. To determine if NF-κB composed of other subunits was inhibited, transgenic mice with a luciferase reporter were used. This revealed a reproducible inhibition of NF-κB activity, which is consistent with the observed inhibition of cytokines whose expression is known to be NF-κB dependent.</p> <p>Conclusion</p> <p>Overall, the effects of ethanol on signalling in vivo were similar to those reported for in vitro exposure to ethanol and/or lipopolysaccharide. However, inhibition of the activation of NF-κB was not detected as translocation of p65 to the nucleus but was detected using transgenic reporter mice. The observation that ethanol given 24 hr before dosing with LPS modulated production of some cytokines indicates a persistent effect which does not require continued presence of ethanol.</p

Current status and future prospects of clinical trials for radioiodine-refractory thyroid cancer

Radioiodine-refractory thyroid cancer (RAIR-TC) refers to thyroid cancer that is unable to or difficult to benefit from 131I treatment. The type of RAIR-TC we commonly encounter is differentiated thyroid cancer (DTC), which is originally well-differentiated but gradually loses its ability to take up iodine during disease progression or after 131I treatment. Compared to DTC that can still take up 131I, RAIR-TC is more malignant, progresses more rapidly, and carries a higher risk of death. Therefore, the subsequent treatment of RAIR-TC has become a hotspot and a challenge in the field of international thyroid cancer research. The treatment of RAIR-TC has evolved through several stages, from initial radioactive iodine therapy to the introduction of targeted drugs in recent years, followed by attempts at immunotherapy, diversifying treatment options. Molecular targeted therapy, especially tyrosine kinase inhibitors (TKIs), has provided new treatment choices for RAIR-TC patients. However, resistance to single-agent targeted therapy has quickly emerged as a bottleneck in treatment efficacy. Studies have shown that the activation of the phosphoinositide3-kinase (PI3K)/protein kinase (AKT)/mammalian target of rapamycin (mTOR) pathway and epidermal growth factor receptor (EGFR) pathway is the main mechanism by which tumors evade targeted therapy. As a result, combination therapy strategies have emerged, aiming to target multiple signaling pathways and optimize the use of combined drugs to overcome single-drug resistance. Additionally, designing personalized treatment plans based on patients’ molecular features (such as BRAF mutations and tumor immune phenotypes) has become a research focus. Immunotherapy, especially immune checkpoint inhibitors (ICIs) such as pembrolizumab, has shown some clinical effect in RAIR-TC patients with high level of programmed death ligand-1 (PD-L1) expression. However, due to the low immunogenicity of RAIR-TC, the overall response rate to immunotherapy remains relatively low, typically ranging from 10% to 15%. In recent years, combination strategies involving targeted therapy and immunotherapy, such as the triplet therapy of BRAF inhibitors, vascular endothelial growth factor receptor (VEGFR) inhibitors, and programmed death-1 (PD-1) inhibitors, have shown significant efficacy in some patients, even achieving complete remission. This offers new directions for improving the efficacy of immunotherapy, however optimizing combination therapy, overcoming resistance, and managing side effects remain key challenges for future research. Moreover, epigenetics and metabolism studies have provided new insights into the treatment of RAIR-TC. Research has shown that epigenetic mechanisms, such as DNA methylation and histone deacetylation, play important roles in the progression and resistance of RAIR-TC. Inhibitors targeting these mechanisms may restore the ability of tumor to take up radioactive iodine, thus enhancing sensitivity to 131I therapy. Although progress has been made in epigenetic research, clinical trials are still in the early stages, and further verification of their potential is needed. Tumor metabolic abnormalities, particularly changes in lactate and glutamine metabolism, play crucial roles in tumor growth and resistance. Studies have found that glutamine synthetase (GLS) inhibitors and lactate dehydrogenase A (LDHA) inhibitors can effectively suppress tumor growth and potentially reverse resistance. Thus, the development of innovative drugs targeting these metabolic pathways is becoming an important direction for future RAIR-TC treatments. Although current therapies have improved the survival of RAIR-TC patients to some extent, challenges such as resistance, toxic reactions and tumor heterogeneity remain. Future research should focus on optimizing combination treatment strategies, developing new targeted drugs, and improving the adaptability of immunotherapy in clinical trials. With the advancement of multidisciplinary collaboration and technological innovation, breakthroughs in RAIR-TC treatment are expected in the future, ultimately improving patient prognosis and quality of life

An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors

Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear, however, whether these phenotypic similarities reflect the activity of common molecular pathways. Here, we analyze the enrichment patterns of gene sets associated with embryonic stem (ES) cell identity in the expression profiles of various human tumor types. We find that histologically poorly differentiated tumors show preferential overexpression of genes normally enriched in ES cells, combined with preferential repression of Polycomb-regulated genes. Moreover, activation targets of Nanog, Oct4, Sox2 and c-Myc are more frequently overexpressed in poorly differentiated tumors than in well-differentiated tumors. In breast cancers, this ES-like signature is associated with high-grade estrogen receptor (ER)-negative tumors, often of the basal-like subtype, and with poor clinical outcome. The ES signature is also present in poorly differentiated glioblastomas and bladder carcinomas. We identify a subset of ES cell-associated transcription regulators that are highly expressed in poorly differentiated tumors. Our results reveal a previously unknown link between genes associated with ES cell identity and the histopathological traits of tumors and support the possibility that these genes contribute to stem cell–like phenotypes shown by many tumors

Global gene expression analysis reveals reduced abundance of putative microRNA targets in human prostate tumours

<p>Abstract</p> <p>Background</p> <p>Recently, microRNAs (miRNAs) have taken centre stage in the field of human molecular oncology. Several studies have shown that miRNA profiling analyses offer new possibilities in cancer classification, diagnosis and prognosis. However, the function of miRNAs that are dysregulated in tumours remains largely a mystery. Global analysis of miRNA-target gene expression has helped illuminate the role of miRNAs in developmental gene expression programs, but such an approach has not been reported in cancer transcriptomics.</p> <p>Results</p> <p>In this study, we globally analysed the expression patterns of miRNA target genes in prostate cancer by using several public microarray datasets. Intriguingly, we found that, in contrast to global mRNA transcript levels, putative miRNA targets showed a reduced abundance in prostate tumours relative to benign prostate tissue. Additionally, the down-regulation of these miRNA targets positively correlated with the number of types of miRNA target-sites in the 3' untranslated regions of these targets. Further investigation revealed that the globally low expression was mainly driven by the targets of 36 specific miRNAs that were reported to be up-regulated in prostate cancer by a miRNA expression profiling study. We also found that the transcript levels of miRNA targets were lower in androgen-independent prostate cancer than in androgen-dependent prostate cancer. Moreover, when the global analysis was extended to four other cancers, significant differences in transcript levels between miRNA targets and total mRNA backgrounds were found.</p> <p>Conclusion</p> <p>Global gene expression analysis, along with further investigation, suggests that miRNA targets have a significantly reduced transcript abundance in prostate cancer, when compared with the combined pool of all mRNAs. The abnormal expression pattern of miRNA targets in human cancer could be a common feature of the human cancer transcriptome. Our study may help to shed new light on the functional roles of miRNAs in cancer transcriptomics.</p