Project description:The PGC1 family (Peroxisome proliferator-activated receptor γ (PPARγ) coactivators) of transcriptional coactivators are considered master regulators of mitochondrial biogenesis and function. The PGC1α isoform is expressed especially in metabolically active tissues, such as the liver, kidneys and brain, and responds to energy-demanding situations. Given the altered and highly adaptable metabolism of tumor cells, it is of interest to investigate PGC1α in cancer. Both high and low levels of PGC1α expression have been reported to be associated with cancer and worse prognosis, and PGC1α has been attributed with oncogenic as well as tumor suppressive features. Early in carcinogenesis PGC1α may be downregulated due to a protective anticancer role, and low levels likely reflect a glycolytic phenotype. We suggest mechanisms of PGC1α downregulation and how these might be connected to the increased cancer risk that obesity is now known to entail. Later in tumor progression PGC1α is often upregulated and is reported to contribute to increased lipid and fatty acid metabolism and/or a tumor cell phenotype with an overall metabolic plasticity that likely supports drug resistance as well as metastasis. We conclude that in cancer PGC1α is neither friend nor foe, but rather the obedient servant reacting to metabolic and environmental cues to benefit the tumor cell.
Project description:The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies.
Project description:ARID1A belongs to a class of chromatin regulatory proteins that function by maintaining accessibility at most promoters and enhancers, thereby regulating gene expression. The high frequency of ARID1A alterations in human cancers has highlighted its significance in tumorigenesis. The precise role of ARID1A in cancer is highly variable since ARID1A alterations can have a tumor suppressive or oncogenic role, depending on the tumor type and context. ARID1A is mutated in about 10% of all tumor types including endometrial, bladder, gastric, liver, biliopancreatic cancer, some ovarian cancer subtypes, and the extremely aggressive cancers of unknown primary. Its loss is generally associated with disease progression more often than onset. In some cancers, ARID1A loss is associated with worse prognostic features, thus supporting a major tumor suppressive role. However, some exceptions have been reported. Thus, the association of ARID1A genetic alterations with patient prognosis is controversial. However, ARID1A loss of function is considered conducive for the use of inhibitory drugs which are based on synthetic lethality mechanisms. In this review we summarize the current knowledge on the role of ARID1A as tumor suppressor or oncogene in different tumor types and discuss the strategies for treating ARID1A mutated cancers.
Project description:Jun/JUN is a basic leucine zipper (bZIP) protein and a prototypic member of the activator protein-1 (AP-1) family of transcription factors that can act as homo- or heterodimers, interact with DNA elements and co-factors, and regulate gene transcription. Jun is expressed by both immune and inflammatory cells. Jun is traditionally seen as an oncoprotein that regulates processes involved in transformation and oncogenesis in human tumours. This article examines the traditional view that Jun plays a permissive role in cancer development and progression, whilst exploring emerging evidence supporting Jun's potential to prevent immune cell exhaustion and promote anti-tumour efficacy.
Project description:Aggregation of misfolded microtubule associated protein tau into abnormal intracellular inclusions defines a class of neurodegenerative diseases known as tauopathies. The consistent spatiotemporal progression of tau pathology in Alzheimer's disease (AD) led to the hypothesis that tau aggregates spread in the brain via bioactive tau "seeds" underlying advancing disease course. Recent studies implicate microglia, the resident immune cells of the central nervous system, in both negative and positive regulation of tau pathology. Polymorphisms in genes that alter microglial function are associated with the development of AD and other tauopathies. Experimental manipulation of microglia function can alter tau pathology and microglia-mediated neuroinflammatory cascades can exacerbate tau pathology. Microglia also exert protective functions by mitigating tau spread: microglia internalize tau seeds and have the capacity to degrade them. However, when microglia fail to degrade these tau seeds there are deleterious consequences, including secretion of exosomes containing tau that can spread to neurons. This review explores the intersection of microglia and tau from the perspective of neuropathology, neuroimaging, genetics, transcriptomics, and molecular biology. As tau-targeted therapies such as anti-tau antibodies advance through clinical trials, it is critical to understand the interaction between tau and microglia.
Project description:Current evidence strongly suggests that aberrant activation of the NF-κB signalling pathway is associated with carcinogenesis. A number of key cellular processes are governed by the effectors of this pathway, including immune responses and apoptosis, both crucial in the development of cancer. Therefore, it is not surprising that dysregulated and chronic NF-κB signalling can have a profound impact on cellular homeostasis. Here we discuss NFKB1 (p105/p50), one of the five subunits of NF-κB, widely implicated in carcinogenesis, in some cases driving cancer progression and in others acting as a tumour-suppressor. The complexity of the role of this subunit lies in the multiple dimeric combination possibilities as well as the different interacting co-factors, which dictate whether gene transcription is activated or repressed, in a cell and organ-specific manner. This review highlights the multiple roles of NFKB1 in the development and progression of different cancers, and the considerations to make when attempting to manipulate NF-κB as a potential cancer therapy.
Project description:BackgroundA higher chemotherapy completion rate is associated with better outcomes including treatment efficacy and overall survival. Exercise may have the potential to improve relative dose intensity (RDI) by reducing the frequency and severity of chemotherapy-related toxicities. We examined the association between exercise adherence and RDI and possible clinical- and health-related fitness predictors of RDI.MethodsChemotherapy records were extracted from the electronic medical record for patients enrolled in the ENACT trial (n = 105). Chemotherapy completion was assessed using average RDI. A threshold of 85% was established for "high" versus "low" RDI. Logistic regression analyses were used to estimate the associations between the clinical- and health-related fitness predictors of RDI.ResultsPatients with breast cancer (BC) had a significantly higher average RDI (89.8% ± 17.6%) compared with gastrointestinal cancer (GI) (76.8% ± 20.9%, p = 0.004) and pancreatic cancer (PC) (65.2% ± 20.1%, p < 0.001). Only 25% of BC patents required a dose reduction compared to 56.3% of GI and 86.4% of PC patients. Cancer site was significantly associated with RDI. Compared with BC, patients with GI (β = -0.12, p = 0.03) and PC (β = -0.22, p = 0.006) achieved significantly lower RDI. Every 2.72 unit increase in overall exercise adherence led to a significant 7% decrease in RDI (p = 0.001) in GI patients. Metastatic GI patients had a 15% RDI increase for every 2.72 unit increase in exercise adherence (p = 0.04).ConclusionExercise is a supportive therapy that has potential to enhance chemotherapy tolerance and completion. The relationship between exercise adherence and RDI is influenced by factor such as cancer site and treatment type. Special attention must be paid to how exercise is prescribed to ensure that exercise adherence does not negatively affect RDI. Cancer site, exercise dosage, and multimodal interventions to address toxicities are key areas identified for future research.
Project description:The prevalence and incidence of cancers has risen over the last decade. Available treatments have improved outcomes, yet mortality and morbidity remain high, creating an urgent demand for personalized and new therapy targets. Interferon induced transmembrane protein (IFITM3) is highly expressed in cancers and is a marker of poor prognosis. In this review, we discuss recent advances in IFITM3 biology, the regulatory pathways, and its function within cancer as part of immunity and maintaining stemness. Overexpression of IFITM3 is likely an indirect effect of ongoing inflammation, immune and cancer epithelial-to-mesenchymal (EMT) related pathways i.e., interferons, TGF-β, WNT/β-catenin, etc. However, IFITM3 also influences tumorigenic phenotypes, such as cell proliferation, migration and invasion. Furthermore, IFITM3 plays a key role in cancer growth and maintenance. Silencing of IFITM3 reduces these phenotypes. Therefore, targeting of IFITM3 will likely have implications for potential cancer therapies.
Project description:The study aims were to investigate knowledge and attitudes towards antibiotics and antibiotic resistance (ABR), and to assess the extent of practices regarding antibiotic consumption and Internet use among university students in Southern Italy. Data were collected through an anonymous online questionnaire from 1 April to 14 April 2021. The eligibility criteria for the study were: (i) age between 18 and 30 years and (ii) registered as an undergraduate student at the university. Among the 1051 sampled students, only 7.4% gave the correct answer to all 7 knowledge statements about antibiotics and ABR. The main determinants of knowledge were being younger and attending to medical or life sciences majors. Almost two-thirds took an antibiotic in the previous 12 months and 24.6% reported having self-medicated with antibiotics. More than half of the sample used the Internet to seek information about antibiotics and/or ABR, and it was the strongest predictor of self-medication with antibiotics. The study findings highlighted gaps in knowledge, considerable antibiotic consumption, sometimes without prescription, together with an extensive Internet use to seek health-related information. To facilitate the health-promoting use of the Internet in conjunction with health care providers, we could make young adults aware of the rational use of antibiotics.
Project description:Cardiovascular disease (CVD) prevalence at a global level is predicted to increase substantially over the next decade due to the increasing ageing population and incidence of obesity. Hence, there is an urgent requirement to focus on modifiable contributors to CVD risk, including a high dietary intake of saturated fatty acids (SFA). As an important source of SFA in the UK diet, milk and dairy products are often targeted for SFA reduction. The current paper acknowledges that milk is a complex food and that simply focusing on the link between SFA and CVD risk overlooks the other beneficial nutrients of dairy foods. The body of existing prospective evidence exploring the impact of milk and dairy consumption on risk factors for CVD is reviewed. The current paper highlights that high milk consumption may be beneficial to cardiovascular health, while illustrating that the evidence is less clear for cheese and butter intake. The option of manipulating the fatty acid profile of ruminant milk is discussed as a potential dietary strategy for lowering SFA intake at a population level. The review highlights that there is a necessity to perform more well-controlled human intervention-based research that provides a more holistic evaluation of fat-reduced and fat-modified dairy consumption on CVD risk factors including vascular function, arterial stiffness, postprandial lipaemia and markers of inflammation. Additionally, further research is required to investigate the impact of different dairy products and the effect of the specific food matrix on CVD development.