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BMC Palliative Care Dec 2019Despite improvements in medical care, patients with advanced cancer still experience substantial symptom distress. There is increasing interest in the use of medicinal... (Randomized Controlled Trial)
Randomized Controlled Trial
Oral medicinal cannabinoids to relieve symptom burden in the palliative care of patients with advanced cancer: a double-blind, placebo controlled, randomised clinical trial of efficacy and safety of cannabidiol (CBD).
BACKGROUND
Despite improvements in medical care, patients with advanced cancer still experience substantial symptom distress. There is increasing interest in the use of medicinal cannabinoids, but there is little high quality evidence to guide clinicians. This study aims to define the role of cannabidiol (CBD) in the management of symptom burden in patients with advanced cancer undergoing standard palliative care.
METHODS AND DESIGN
This study is a multicentre, randomised, placebo controlled, two arm, parallel trial of escalating doses of oral CBD. It will compare efficacy and safety outcomes of a titrated dose of CBD (100 mg/mL formulation, dose range 50 mg to 600 mg per day) against placebo. There is a 2-week patient determined titration phase, using escalating doses of CBD or placebo to reach a dose that achieves symptom relief with tolerable side effects. This is then followed by a further 2-week assessment period on the stable dose determined in collaboration with clinicians.
DISCUSSION
A major strength of this study is that it will target symptom burden as a whole, rather than just individual symptoms, in an attempt to describe the general improvement in wellbeing previously reported by some patients in open label, non controlled trials of medicinal cannabis. Randomisation with placebo is essential because of the well-documented over reporting of benefit in uncontrolled trials and high placebo response rates in cancer pain trials. This will be the first placebo controlled clinical trial to evaluate rigorously the efficacy, safety and acceptability of CBD for symptom relief in advanced cancer patients. This study will provide the medical community with evidence to present to patients wishing to access medicinal cannabis for their cancer related symptoms.
TRIAL REGISTRATION NUMBER
ALCTRN12618001220257 Registered 20/07/2018.
Topics: Administration, Oral; Adult; Cannabidiol; Double-Blind Method; Female; Humans; Medical Marijuana; Middle Aged; Neoplasms; Palliative Care; Placebos; Syndrome
PubMed: 31810437
DOI: 10.1186/s12904-019-0494-6 -
Frontiers in Immunology 2023Sepsis is a hyper-heterogeneous syndrome in which the systemic inflammatory response persists throughout the course of the disease and the inflammatory and immune... (Review)
Review
Sepsis is a hyper-heterogeneous syndrome in which the systemic inflammatory response persists throughout the course of the disease and the inflammatory and immune responses are dynamically altered at different pathogenic stages. Gasdermins (GSDMs) proteins are pore-forming executors in the membrane, subsequently mediating the release of pro-inflammatory mediators and inflammatory cell death. With the increasing research on GSDMs proteins and sepsis, it is believed that GSDMs protein are one of the most promising therapeutic targets in sepsis in the future. A more comprehensive and in-depth understanding of the functions of GSDMs proteins in sepsis is important to alleviate the multi-organ dysfunction and reduce sepsis-induced mortality. In this review, we focus on the function of GSDMs proteins, the molecular mechanism of GSDMs involved in sepsis, and the regulatory mechanism of GSDMs-mediated signaling pathways, aiming to provide novel ideas and therapeutic strategies for the diagnosis and treatment of sepsis.
Topics: Humans; Gasdermins; Sepsis; Cell Death; Inflammation Mediators; Syndrome
PubMed: 38022612
DOI: 10.3389/fimmu.2023.1203687 -
Clinical Immunology (Orlando, Fla.) Sep 2020The interleukin (IL)-2 - IL-2 receptor (IL-2R) pathway is important in immunity, but is also involved in maintenance of self-tolerance. This paradox is further... (Review)
Review
The interleukin (IL)-2 - IL-2 receptor (IL-2R) pathway is important in immunity, but is also involved in maintenance of self-tolerance. This paradox is further complicated by shedding of the IL-2Rα chain, revealing soluble (s)IL-2R. Binding of IL-2 to sIL-2R may either reduce or enhance responses depending on the target cell being involved in immunity or self-tolerance. Since sIL-2R levels are increasingly measured in clinical practice, it is detrimental for clinical interpretation to understand the possible functional impact of IL-2R shedding. In this review the role of the IL-2 - IL-2R pathway is explored and the conflicting results on the function of sIL-2R are summarized. Finally, the added value of measuring sIL-2R in different types of diseases is being elaborated upon in terms of diagnosis, follow-up, and prognosis. Adequate interpretation of results is hampered by the apparent gap in our knowledge about the functional role of sIL-2R in immunity and tolerance.
Topics: Animals; Disease; Health; Humans; Interleukin-2; Receptors, Interleukin-2; Signal Transduction
PubMed: 32619646
DOI: 10.1016/j.clim.2020.108515 -
The Journal of Clinical Investigation Feb 2021Severe insulin resistance syndromes are a heterogeneous group of rare disorders characterized by profound insulin resistance, substantial metabolic abnormalities, and a... (Review)
Review
Severe insulin resistance syndromes are a heterogeneous group of rare disorders characterized by profound insulin resistance, substantial metabolic abnormalities, and a variety of clinical manifestations and complications. The etiology of these syndromes may be hereditary or acquired, due to defects in insulin potency and action, cellular responsiveness to insulin, and/or aberrations in adipose tissue function or development. Over the past decades, advances in medical technology, particularly in genomic technologies and genetic analyses, have provided insights into the underlying pathophysiological pathways and facilitated the more precise identification of several of these conditions. However, the exact cellular and molecular mechanisms of insulin resistance have not yet been fully elucidated for all syndromes. Moreover, in clinical practice, many of the syndromes are often misdiagnosed or underdiagnosed. The majority of these disorders associate with an increased risk of severe complications and mortality; thus, early identification and personalized clinical management are of the essence. This Review aims to categorize severe insulin resistance syndromes by disease process, including insulin receptor defects, signaling defects, and lipodystrophies. We also highlight several complex syndromes and emphasize the need to identify patients, investigate underlying disease mechanisms, and develop specific treatment regimens.
Topics: Adipose Tissue; Animals; Humans; Insulin; Insulin Resistance; Lipodystrophy; Receptor, Insulin; Severity of Illness Index; Signal Transduction; Syndrome
PubMed: 33586681
DOI: 10.1172/JCI142245 -
Cells May 2020Mitochondria are subcellular organelles evolved by endosymbiosis of bacteria with eukaryotic cells characteristics. They are the main source of ATP in the cell and play...
Mitochondria are subcellular organelles evolved by endosymbiosis of bacteria with eukaryotic cells characteristics. They are the main source of ATP in the cell and play a pivotal role in cell life and cell death. Mitochondria are engaged in the pathogenesis of human diseases and aging directly or indirectly through a broad range of signaling pathways. However, despite an increased interest in mitochondria over the past decades, the mechanisms of mitochondria-mediated cell/organ dysfunction in response to pathological stimuli remain unknown. The Special Issue, "Mitochondria in Health and Diseases," organized by includes 24 review and original articles that highlight the latest achievements in elucidating the role of mitochondria under physiological (healthy) conditions and, in various cell/animal models of human diseases and, in patients. Altogether, the Special Issue summarizes and discusses different aspects of mitochondrial metabolism and function that open new avenues in understanding mitochondrial biology.
Topics: Animals; Disease; Health; Humans; Mitochondria; Models, Biological; Molecular Targeted Therapy
PubMed: 32397376
DOI: 10.3390/cells9051177 -
Molecular Medicine Reports Jan 2022Efferocytosis, the phagocytosis of apoptotic cells performed by both specialized phagocytes (such as macrophages) and non‑specialized phagocytes (such as epithelial... (Review)
Review
Efferocytosis, the phagocytosis of apoptotic cells performed by both specialized phagocytes (such as macrophages) and non‑specialized phagocytes (such as epithelial cells), is involved in tissue repair and homeostasis. Effective efferocytosis prevents secondary necrosis, terminates inflammatory responses, promotes self‑tolerance and activates pro‑resolving pathways to maintain homeostasis. When efferocytosis is impaired, apoptotic cells that could not be cleared in time aggregate, resulting in the necrosis of apoptotic cells and release of pro‑inflammatory factors. In addition, defective efferocytosis inhibits the intracellular cholesterol reverse transportation pathways, which may lead to atherosclerosis, lung damage, non‑alcoholic fatty liver disease and neurodegenerative diseases. The uncleared apoptotic cells can also release autoantigens, which can cause autoimmune diseases. Cancer cells escape from phagocytosis via efferocytosis. Therefore, new treatment strategies for diseases related to defective efferocytosis are proposed. This review illustrated the mechanisms of efferocytosis in multisystem diseases and organismal homeostasis and the pathophysiological consequences of defective efferocytosis. Several drugs and treatments available to enhance efferocytosis are also mentioned in the review, serving as new evidence for clinical application.
Topics: Animals; Apoptosis; Cytophagocytosis; Disease; Epithelial Cells; Extracellular Vesicles; Homeostasis; Humans; Immunity; Inflammation; Macrophages; Necrosis; Pathology; Phagocytes
PubMed: 34779503
DOI: 10.3892/mmr.2021.12529 -
Clinical Immunology (Orlando, Fla.) Jul 2023Meniere Disease (MD) is an inner ear syndrome, characterized by episodes of vertigo, tinnitus and fluctuating sensorineural hearing loss. The pathological mechanism...
BACKGROUND
Meniere Disease (MD) is an inner ear syndrome, characterized by episodes of vertigo, tinnitus and fluctuating sensorineural hearing loss. The pathological mechanism leading to sporadic MD is still poorly understood, however an allergic inflammatory response seems to be involved in some patients with MD.
OBJECTIVE
Decipher an immune signature associated with the syndrome.
METHODS
We performed mass cytometry immune profiling on peripheral blood from MD patients and controls. We analyzed differences in state and differences in abundance of the different cellular subsets. IgE levels were quantified through ELISA on supernatant of cultured whole blood.
RESULTS
We have identified two clusters of individuals according to the single cell cytokine profile. These clusters presented differences in IgE levels, immune cell population abundance, including a reduction of CD56 NK-cells, and changes in cytokine expression with a different response to bacterial and fungal antigens.
CONCLUSION
Our results support a systemic inflammatory response in some MD patients that show a type 2 response with allergic phenotype, which could benefit from personalized IL-4 blockers.
Topics: Humans; Meniere Disease; Vertigo; Cytokines; Hearing Loss, Sensorineural; Syndrome; Immunoglobulin E
PubMed: 37178857
DOI: 10.1016/j.clim.2023.109632 -
International Journal of Molecular... Nov 2020Autophagy refers to the process involving the decomposition of intracellular components via lysosomes. Autophagy plays an important role in maintaining and regulating... (Review)
Review
Autophagy refers to the process involving the decomposition of intracellular components via lysosomes. Autophagy plays an important role in maintaining and regulating cell homeostasis by degrading intracellular components and providing degradation products to cells. In vivo, autophagy has been shown to be involved in the starvation response, intracellular quality control, early development, and cell differentiation. Recent studies have revealed that autophagy dysfunction is implicated in neurodegenerative diseases and tumorigenesis. In addition to the discovery of certain disease-causing autophagy-related mutations and elucidation of the pathogenesis of conditions resulting from the abnormal degradation of selective autophagy substrates, the activation of autophagy is essential for prolonging life and suppressing aging. This article provides a comprehensive review of the role of autophagy in health, physiological function, and autophagy-related disease.
Topics: Animals; Autophagy; Disease; Health; Humans; Mechanistic Target of Rapamycin Complex 1; Models, Biological
PubMed: 33255983
DOI: 10.3390/ijms21238974 -
Ageing Research Reviews Aug 2023Autophagy plays a key role in cellular, tissue and organismal homeostasis and in the production of the energy load needed at critical times during development and in... (Review)
Review
Autophagy plays a key role in cellular, tissue and organismal homeostasis and in the production of the energy load needed at critical times during development and in response to nutrient shortage. Autophagy is generally considered as a pro-survival mechanism, although its deregulation has been linked to non-apoptotic cell death. Autophagy efficiency declines with age, thus contributing to many different pathophysiological conditions, such as cancer, cardiomyopathy, diabetes, liver disease, autoimmune diseases, infections, and neurodegeneration. Accordingly, it has been proposed that the maintenance of a proper autophagic activity contributes to the extension of the lifespan in different organisms. A better understanding of the interplay between autophagy and risk of age-related pathologies is important to propose nutritional and life-style habits favouring disease prevention as well as possible clinical applications aimed at promoting long-term health.
Topics: Aging; Autophagy-Related Proteins; Humans; Biomarkers; Autophagy; Longevity; Disease; Neurodegenerative Diseases; Neoplasms; Cardiovascular Diseases; Metabolic Syndrome
PubMed: 37270146
DOI: 10.1016/j.arr.2023.101967 -
Cells Oct 2021The SEA complex was described for the first time in yeast ten years ago, and its human homologue GATOR complex two years later. During the past decade, many advances on... (Review)
Review
The SEA complex was described for the first time in yeast ten years ago, and its human homologue GATOR complex two years later. During the past decade, many advances on the SEA/GATOR biology in different organisms have been made that allowed its role as an essential upstream regulator of the mTORC1 pathway to be defined. In this review, we describe these advances in relation to the identification of multiple functions of the SEA/GATOR complex in nutrient response and beyond and highlight the consequence of GATOR mutations in cancer and neurodegenerative diseases.
Topics: Animals; Disease; Humans; Multiprotein Complexes; Nutrients; Phenotype; Signal Transduction; Terminology as Topic
PubMed: 34685669
DOI: 10.3390/cells10102689