Adipose tissue (fat) is a heterogeneous organ, both in function and histology, distributed throughout the body. White adipose tissue, responsible for energy storage and more recently found to have ...endocrine and inflammation-modulatory activities, was historically thought to be the only type of fat present in adult humans. The recent demonstration of functional brown adipose tissue in adults, which is highly metabolic, shifted this paradigm. Additionally, recent studies demonstrate the ability of white adipose tissue to be induced toward the brown adipose phenotype – “beige” or “brite” adipose tissue – in a process referred to as “browning.” While these adipose tissue depots are under investigation in the context of obesity, new evidence suggests a maladaptive role in other metabolic disturbances including cancer-associated cachexia, which is the topic of this review. This syndrome is multifactorial in nature and is an independent factor associated with poor prognosis. Here, we review the contributions of all three adipose depots – white, brown, and beige – to the development and progression of cancer-associated cachexia. Specifically, we focus on the local and systemic processes involving these adipose tissues that lead to increased energy expenditure and sustained negative energy balance. We highlight key findings from both animal and human studies and discuss areas within the field that need further exploration.
Impact statement
Cancer-associated cachexia (CAC) is a complex, multifactorial syndrome that negatively impacts patient quality of live and prognosis. This work reviews a component of CAC that lacks prior discussion: adipose tissue contributions. Uniquely, it discusses all three types of adipose tissue, white, beige, and brown, their interactions, and their contributions to the development and progression of CAC. Summarizing key bench and clinical studies, it provides information that will be useful to both basic and clinical researchers in designing experiments, studies, and clinical trials.
Thyroid hormone (TH) has diverse effects on mitochondria and energy expenditure (EE), generating great interest and research effort into understanding and harnessing these actions for the ...amelioration and treatment of metabolic disorders, such as obesity and diabetes. Direct effects on ATP utilization are a result of TH's actions on metabolic cycles and increased cell membrane ion permeability. However, the majority of TH induced EE is thought to be a result of indirect effects, which, in turn, increase capacity for EE. This review discusses the direct actions of TH on EE, and places special emphasis on the indirect actions of TH, which include mitochondrial biogenesis and reduced metabolic efficiency through mitochondrial uncoupling mechanisms. TH analogs and the metabolic actions of T2 are also discussed in the context of targeted modulation of EE. Finally, clinical correlates of TH actions on metabolism are briefly presented.
Migraine is a common neurological disease and is listed second among the most disabling health conditions worldwide. Refractory migraine (RM) is a term used to emphasize the unresponsiveness of ...migraine to various treatment options, encompassing both episodic refractory and chronic refractory migraine. In this paper we discuss various known and possible mechanisms of pharmacological refractoriness in RM, such as possible involvement of the gut microbiome, the blood-brain barrier, migraine genetics and various mechanisms of pharmacokinetic and pharmacodynamic tolerance. Development of medication-overuse headache as a secondary disorder following migraine is also considered. We argue that the available literature is insufficient to fully explain the mechanisms of refractoriness and we present our hypothesis.
HYPOTHESIS. Refractoriness to drugs in migraine may be the result of developing anti-drug antibodies. Most migraine drugs are small molecules, which cannot elicit an immune response on their own due to their size. However, such molecules can bind to peptide carriers in their vicinity, greatly increasing their immunogenicity. A small molecule possessing this binding ability is called a hapten. Haptens form hapten-carrier complexes (HCCs), which can evoke powerful immune responses. Immune reactions to HCCs are known to be predominantly ‘drug allergies’ or type 1 drug hypersensitivity reactions’, usually resulting from IgE or non-IgE mediated mast cell degranulation. We argue that the immune reaction to HCCs can take shape in developing neutralizing anti-drug antibodies (ADA) in the form of IgG and IgA class antibodies. Since biological therapeutics, such as various monoclonal antibodies, face the issue of ADA-induced drug tolerance, HCCs, being similar in the sense that they carry peptide antigens, are of sufficient size and may be considerably immunogenic, can be responded to in a similar way by producing neutralizing ADA. Furthermore, we argue that such responses are expected to happen more frequently than is thought, due to IgG and IgA being prevalent antibodies, which utilize their neutralizing capabilities on regular basis. Finally, it is important to consider that neutralization reactions in normal immune responses are typically asymptomatic, with the only clinical expression being progressive drug tolerance. These cases may be overshadowed by the life-threatening cases of drug allergy induced anaphylaxis, possibly leading to neutralization reactions being underrecognized.
This hypothesis aims to stimulate more research regarding drug resistance, and if it receives support from empirical evidence, it may help further elucidate the mechanisms underlying refractory diseases and contribute to the development of more effective treatment of many disorders.
The performance and bearing capacity of the flexible pavement structure is ensured by providing necessary foundation comprised of unbound granular material (UGM) layers and subgrade. Whin this paper ...the compaction level parameters and deformation modulus relations determined for UGM layers and subgrade in construction site. The experimental data were tested applied standardized and improved test methods, such as an alternative falling weight deflectometer (FWD) test method with repetitive load, the plate load tester, lightweight deflectometer, dynamic cone penetrometer, and density Proctor tests. The data were analyzed based on statistical comparison of the compaction parameters, pairwise multiple comparison of test methods, clustering procedure for setting a level of compaction evidence and variance determination. Results proved capabilities of the alternative FWD test method under repetitive load to assess the relative compactness rate and the resilient responses, and provided the regression models of the dynamic modulus of the UGM layers and subgrade.
Recent reports reveal a close relationship between migraine and gastrointestinal disorders (GI), such as celiac disease (CD) and non-celiac gluten sensitivity (NCGS). CD is a genetic autoimmune ...disorder, which affects the mucosa of the small intestine. Gluten, found in various grains, not only plays a major role in the pathophysiology of CD and NCGS, but also aggravates migraine attacks. Another common food component, which can induce migraine headaches, is histamine. Diamine oxidase (DAO) is an enzyme, which degrades histamine. Reduced activity of DAO means reduced histamine degradation, which can cause histamine build-up and lead to various symptoms, including headaches and migraine. In this paper we propose a hypothesis, that in pathogenesis of migraine, low serum DAO activity is related to CD and NCGS. We also conducted our own pilot study of 44 patients with severe migraine in efforts to evaluate the co-presence of decreased serum DAO activity and celiac disease/NCGS in patients. 44 consecutive migraine patients were divided into 2 groups: decreased DAO activity (group 1; n = 26) and normal DAO activity (group 2; n = 18). All patients were screened for celiac disease. The diagnosis of NCGS was made after exclusion of CD, food allergies and other GI disorders in the presence of gluten sensitivity symptoms. Furthermore, dietary recommendations were given to all participants and their effects were assessed 3 months after the initial evaluation via the MIDAS (Migraine Disability Assessment) questionnaire.
Only 1 patient fit the criteria for celiac disease, rendering this result inconclusive. Pathological findings of the remainder of patients were attributed to NCGS (n = 10). 9 of 10 patients with NCGS belonged to the decreased serum DAO activity group (group 1; n = 26), suggesting a strong relationship between reduced serum DAO activity and NCGS. MIDAS questionnaire revealed, that patients with decreased serum DAO activity were more severely impacted by migraine than those with normal DAO activity, and this remained so after our interventions. Dietary adjustments significantly reduced the impact of migraine on patients’ daily activities after 3 months in both groups. We argue, that migraine, celiac disease and NCGS may benefit from treatment with a multidisciplinary approach, involving neurologists, gastroenterologists and dietitians.
Cement concrete modular pavements, also known as precast concrete pavements, designed for pedestrian and bicycle paths is the advanced next-generation technology characterised as high quality, ...durable, quickly built and easily maintained. Polypropylene fibre reinforced concrete mixture is more frequently used to improve the properties of concrete slabs and to reduce thickness. The thickness of the slab could be reduced to 8-10 cm using the appropriate fibre. This paper focuses on the selection of slab dimensions and verification of fibre reinforced concrete mixture production method when fibres are added to the factory-made concrete mixture (available from the concrete plant) and evaluation of different surface texture of concrete slabs produced by using special texture mats. Seven different combinations of concrete slabs have been developed, constructed and tested in 21 m length pedestrian pathway in Vilnius city. The analysis of mechanical and surface characteristics of these slabs are presented in this paper. The research revealed that the most suitable (pendulum test values ≥ 55) surface texture for the pedestrian pathway is formed by using texture mats.
Production of hot mix asphalt (HMA) requires a lot of consumption of energy, exhaustion of CO(2) and other environment unfriendly materials. The fumes of HMA are injurious for roadmen and asphalt ...plant workers. The use of warm mix asphalt (WMA) allows reducing the HMA production temperatures at which the material is mixed and laid on the road. WMA helps to reduce the working temperature of asphalt up to 30 'C. This article presents the overview of different technologies of WMA production, advantages and disadvantages of these technologies. The laboratory research includes research of physical and mechanical properties of WMA produced with different technologies and different amount of additives for temperature lowering. Two different kinds of asphalt where tested in the laboratory. The chemical additives and chemical and natural zeolite were used for WMA production in the laboratory.
As a result of increasing geogrid reinforcement applications in the road subgrade, there are number of projects where geogrid reinforcement is used to control road pavement evenness when there are ...small layers of peat or mud deeper under road construction. For this task geogrid reinforcement application is not documented but widely used in Lithuania for over a decade. This paper evaluates the long term influence of the geogrid reinforced soil influence on the road surface evenness, when the organic soils stratify in the deeper layers of the subgrade. The geological conditions of the investigated sections are reviewed. The experiment methodology and test results are described, which leads to the conclusions and insights how the pavement evenness depend on the geological conditions and its enhancement. The question is raised about the need for including this geogrid application to the normative documentation. Explanation of the problems that are encountered and the need for further research is given.
Fibroblast growth factor (FGF)-21, a member of the FGF family, is a novel hormone involved in the control of metabolism by modulating glucose homeostasis, insulin sensitivity, ketogenesis, and ...promoting adipose tissue "browning." Recent studies demonstrated that brown adipose tissue is not only a target for FGF-21, but is also a potentially important source of systemic FGF-21. These findings support the hypothesis that FGF-21 plays a physiologic role in thermogenesis and thermogenic recruitment of white adipose tissue by an autocrine-paracrine axis. This review examines the role of FGF-21 in thermogenesis from the perspective of cell-based, animal model, and human studies. We also present recent advances in the characterization of FGF-21's regulation of metabolism.
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