Project description:Statin therapy is generally well tolerated and very effective in the prevention and treatment of cardiovascular disease, regardless of cholesterol levels; however, it can be associated with various adverse events (myalgia, myopathy, rhabdomyolysis, and diabetes mellitus, among others). Patients frequently discontinue statin therapy without medical advice because of perceived side effects and consequently increase their risk for cardiovascular events. In patients with statin intolerance, it may be advisable to change the dose, switch to a different statin, or try an alternate-day regimen. If intolerance is associated with all statins-even at the lowest dose-non-statin drugs and certain nutraceuticals can be considered. This review focuses on the definition of statin intolerance and on the development of clinical and therapeutic strategies for its management, including emerging alternative therapies.
Project description:BackgroundCCAAT/Enhancer Binding Protein D (CEBPD), a pleiotropic glucocorticoid-responsive transcription factor, modulates inflammatory responses. Of relevance to asthma, expression of CEBPD in airway smooth muscle (ASM) increases with glucocorticoid exposure. We sought to characterize CEBPD-mediated transcriptomic responses to glucocorticoid exposure in ASM by measuring changes observed after knockdown of CEBPD and its impact on asthma-related ASM function.MethodsPrimary ASM cells derived from four donors were transfected with CEBPD or non-targeting (NT) siRNA and exposed to vehicle control, budesonide (100 nM, 18 h), TNFα (10 ng/ml, 18 h), or both budesonide and TNFα. Subsequently, RNA-Seq was used to measure gene expression levels, and pairwise differential expression results were obtained for exposures versus vehicle and knockdown versus control conditions. Weighted gene co-expression analysis was performed to identify groups of genes with similar expression patterns across the various experimental conditions (i.e., CEBPD knockdown status, exposures).ResultsCEBPD knockdown altered expression of 3037 genes under at least one exposure (q-value < 0.05). Co-expression analysis identified sets of 197, 152 and 290 genes that were correlated with CEBPD knockdown status, TNFα exposure status, and both, respectively. JAK-STAT signaling pathway genes, including IL6R and SOCS3, were among those influenced by both TNFα and CEBPD knockdown. Immunoblot assays revealed that budesonide-induced IL-6R protein expression and augmented IL-6-induced STAT3 phosphorylation levels were attenuated by CEBPD knockdown in ASM.ConclusionsCEBPD modulates glucocorticoid responses in ASM, in part via modulation of IL-6 receptor signaling.
Project description:Pentraxin-3 (PTX3) is a multifunctional protein involved in both innate and adaptive immunity. Glucocorticoid (GC) is the first-line therapy to mitigate airway inflammation in asthma. Previous pieces of evidence showed that GC has divergent effects on PTX3 production in various cell types. The molecular mechanisms controlling PTX3 expression in HASMC are, however, not yet characterized. In this study, we demonstrate that the synthetic GC, dexamethasone (DEX) increases the expression of PTX3 both at the protein and mRNA levels. We also found that such an effect of DEX was dependent on de novo protein synthesis and the GC receptor (GR). While DEX increases PTX3 mRNA stability, it did not affect its promoter activity. Interestingly, HASMC pre-treated with p42/p44 ERK inhibitor, but not with p38 or JNK-MAPK inhibitors, significantly interfered with DEX-induced PTX3 secretion. Taken together, our data suggest that GC regulates PTX3 expression in HASMC through transcriptional and post-transcriptional mechanisms in a GR and ERK-dependent manner.
Project description:In the past years, human papilloma virus (HPV) has been proved to be an important risk factor for head and neck squamous cell carcinomas (HNSCCs), especially in the oropharynx (OPCCS). The aim of this study was to assess the level of knowledge about HPV among students and to raise their awareness on the issue. A 22-question questionnaire was uploaded to an online service. Information about the project was sent out to students from three Universities in Lodz, Poland. All data were collected via questionnaire website tools. A total of 1710 students participated in this study. The group was divided into medical (MS) and non-medical (non-MS) students. Merely 59.38% of the non-MS had ever heard about HPV. Only 44.74% of the non-MS knew about vaccines against HPV. The oncogenic potential of HPV was evident for 81.17% of the MS and only 55.92% of the non-MS. Very similar numbers of respondents from both groups (39.21% vs. 36.47%) knew that HPV may cause cancers other than cervical. Nearly half of the respondents from both groups (46.28% vs. 48.32%) did not know about the risk of developing oral or oropharyngeal cancer. The level of knowledge about the consequences of HPV infection in head and neck cancers in young adults remains insufficient.
Project description:Systemic juvenile idiopathic arthritis (sJIA) has long been recognized as unique among childhood arthritides, because of its distinctive clinical and epidemiological features, including an association with macrophage activation syndrome. Here, we summarize research into sJIA pathogenesis. The triggers of disease are unknown, although infections are suspects. Once initiated, sJIA seems to be driven by innate proinflammatory cytokines. Endogenous Toll-like receptor ligands, including S100 proteins, probably synergize with cytokines to perpetuate inflammation. These and other findings support the hypothesis that sJIA is an autoinflammatory condition. Indeed, IL-1 is implicated as a pivotal cytokine, but the source of excess IL-1 activity remains obscure and the role of IL-1 in chronic arthritis is less clear. Another hypothesis is that a form of hemophagocytic lymphohistiocytosis underlies sJIA, with varying degrees of its expression across the spectrum of disease. Alternatively, sJIA with MAS might be a genetically distinct subtype. Yet another hypothesis proposes that inadequate downregulation of immune activation is central to sJIA, supporting evidence for which includes 'alternative activation' of monocyte and macrophages and possible deficiencies in IL-10 and T regulatory cells. Some altered immune phenotypes persist during clinically inactive disease, which suggests that this stage might represent compensated inflammation. Despite much progress being made, many questions remain, providing fertile ground for future research.
Project description:The acute respiratory illnesses caused by severe acquired respiratory syndrome corona Virus-2 (SARS-CoV-2) is a global health emergency, involving more than 8.6 million people worldwide with more than 450,000 deaths. Among the clinical manifestations of COVID-19, the disease that results from SARS-CoV-2 infection in humans, a prominent feature is a pro-thrombotic derangement of the hemostatic system, possibly representing a peculiar clinicopathologic manifestation of viral sepsis. The severity of the derangement of coagulation parameters in COVID-19 patients has been associated with a poor prognosis, and the use of low molecular weight heparin (LMWH) at doses registered for prevention of venous thromboembolism (VTE) has been endorsed by the World Health Organization and by Several Scientific societies. However, some relevant issues on the relationships between COVID-19, coagulopathy and VTE have yet to be fully elucidated. This review is particularly focused on four clinical questions: What is the incidence of VTE in COVID-19 patients? How do we frame the COVID-19 associated coagulopathy? Which role, if any, do antiphospolipid antibodies have? How do we tackle COVID-19 coagulopathy? In the complex scenario of an overwhelming pandemic, most everyday clinical decisions have to be taken without delay, although not yet supported by a sound scientific evidence. This review discusses the most recent findings of basic and clinical research about the COVID-associated coagulopathy, to foster a more thorough knowledge of the mechanisms underlying this compelling disease.
Project description:Scientific advances over the last four decades have steadily infused the Alzheimer's disease (AD) field with great optimism that therapies targeting Aβ, amyloid, tau, and innate immune activation states in the brain would provide disease modification. Unfortunately, this optimistic scenario has not yet played out. Though a recent approval of the anti-Aβ aggregate binding antibody, Aduhelm (aducanumab), as a "disease-modifying therapy for AD" is viewed by some as a breakthrough, many remain unconvinced by the data underlying this approval. Collectively, we have not succeeded in changing AD from a largely untreatable, inevitable, and incurable disease to a treatable, preventable, and curable one. Here, I will review the major foci of the AD "disease-modifying" therapeutic pipeline and some of the "open questions" that remain in terms of these therapeutic approaches. I will conclude the review by discussing how we, as a field, might adjust our approach, learning from our past failures to ensure future success.
Project description:Ethnic disparities in health outcomes exist among multiple complex diseases especially cardiovascular disease, hypertension, and kidney disease. Recent discoveries in genetics have taught us that these disparities go beyond environmental and socioeconomic factors. The discovery of ethnic-specific risk variants in the Apolipoprotein L1 (APOL1) gene on chromosome 22 seen only in individuals of recent African ancestry explains a large proportion of kidney disease disparities. In addition, recent large-scale genotype-phenotype association studies have identified associations with cardiovascular disease and hypertension. This review aims to review the recent literature in this field and point toward future directions for research.