Abstract
Background
Lenabasum is a cannabinoid type 2 receptor (CB2R) reverse agonist that demonstrates anti-inflammatory effects in vivo and in vitro in dermatomyositis (DM) and is currently being ...investigated for therapeutic potential. The purpose of our study is to investigate CB2R distribution as well as the effects of lenabasum in DM.
Methods
Immunohistochemistry staining (IHC) was utilized to examine immune cell and cytokine production changes in lesional DM skin biopsies from lenabasum and placebo-treated patients. CB2R expression in various immune cell populations within DM skin was investigated with image mass cytometry (IMC), whereas flow cytometry elucidated CB2R expression in DM peripheral blood mononuclear cells (PBMCs) as well as cytokine production by CB2R-expressing cell populations.
Results
After 12 weeks of lenabasum treatment, IHC staining showed that CD4+ T cells, CB2R, IL-31, IFN-γ, and IFN-β cytokines were downregulated. IFN-γ and IFN-β mRNA decreased in lesional DM skin but not in PBMCs. IMC findings revealed that CB2R was upregulated in DM lesional skin compared to HC skin and DM PBMCs (
p
<0.05). In DM skin, CB2R was upregulated on dendritic cells, B cells, T cells, and macrophages while dendritic cells had the greatest expression in both DM skin and PBMCs (
p
<0.05). These CB2R+ cells in the skin produce IL-31, IL-4, IFN-γ, and IFN-β.
Conclusion
Our findings of differential CB2R expression based on location and cell type suggest modes by which lenabasum may exert anti-inflammatory effects in DM and highlights dendritic cells as potential therapeutic targets.
mTOR kinase forms the mTORC1 complex by associating with raptor and other proteins and affects a number of key cell functions. mTORC1 activates p70S6kinase 1 (p70S6K1) and inhibits 4E-binding protein ...1 (4E-BP1). In turn, p70S6K1 phosphorylates a S6 protein of the 40S ribosomal subunit (S6rp) and 4E-BP1, with the latter negatively regulating eukaryotic initiation factor 4E (eIF-4E). MNK1 and MNK2 kinases phosphorylate and augment activity of eIF4E. Rapamycin and its analogs are highly specific, potent, and relatively non-toxic inhibitors of mTORC1. Although mTORC1 activation is present in many types of malignancies, rapamycin-type inhibitors shows relatively limited clinical efficacy as single agents. Initially usually indolent, CTCL displays a tendency to progress to the aggressive forms with limited response to therapy and poor prognosis. Our previous study (M. Marzec et al. 2008) has demonstrated that CTCL cells display mTORC1 activation and short-term treatment of CTCL-derived cells with rapamycin suppressed their proliferation and had little effect on the cell survival.
Cells derived from CTCL were treated with mTORC1 inhibitor rapamycin and MNK inhibitor and evaluated for inhibition of the mTORC1 signaling pathway and cell growth and survival.
Whereas the treatment with rapamycin persistently inhibited mTORC1 signaling, it suppressed only partially the cell growth. MNK kinase mediated the eIF4E phosphorylation and inhibition or depletion of MNK markedly suppressed proliferation of the CTCL cells when combined with the rapamycin-mediated inhibition of mTORC1. While MNK inhibition alone mildly suppressed the CTCL cell growth, the combined MNK and mTORC1 inhibition totally abrogated the growth. Similarly, MNK inhibitor alone displayed a minimal pro-apoptotic effect; in combination with rapamycin it triggered profound cell apoptosis.
These findings indicate that the combined inhibition of mTORC1 and MNK may prove beneficial in the treatment of CTCL and other malignancies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Medical cannabis' importance in Poland increased dramatically following its legalization as the 12th country in Europe in 2017. However, no studies have been published to give insight into Polish ...physicians' opinions about medical cannabis.
To investigate physician's opinions about cannabinoids' utility in clinical practice, concerns regarding their safety profile, and their clinical experience with cannabinoids.
The survey using a self-developed tool was conducted online; participants were physicians with or without specialist training. Participation was voluntary. Physicians were recruited through personal networks, palliative care courses, and Medical Chambers.
From June to October 2020, we recruited 173 physicians from 15/16 voivodeships. The largest age group (43.9%;
= 76) was 30-39 year-olds. A similar proportion declared they never used cannabis and did not receive any training regarding cannabinoids (60% for both). Only 15 (8%) ever prescribed medical cannabis, although about 50% declared knowing suitable patients for such therapy, and 53.8% had at least one patient proactively asking for such treatment in the last 6 mo. The most common indication chosen was pain: chronic cancer-related (
= 128), chronic non-cancer (
= 77), and neuropathic (
= 60). Other commonly chosen conditions were alleviation of cancer treatment side-effects (
= 56) and cachexia (
= 57). The overall safety profile of THC was assessed as similar to most commonly used medications, including opioids; NSAIDs and benzodiazepines were, however, perceived as safer.
Polish physicians favored the legalization of medical cannabis. However, it is of concern that a limited number have any experience with prescribing cannabis. The creation of clear guidelines to advise physicians in their routine practice and education about pain management and the risks related to the consumption of recreational cannabis for medical conditions are needed.
The Nationwide Scientific Conference “The principle of unity of the civil law vs cohesion of commercial law and family law regulations,” organised by the Civil and Commercial Law Department of the ...Law and Administration Faculty of the University of Szczecin in cooperation with the Institute of Legal Sciences of the Polish Academy of Sciences, was held in the Senate Hall of the University of Szczecin on 19 October 2018. Held under the patronage of the President of the City of Szczecin, the conference was attended by 50 participants from 16 research centres who presented 10 papers and 8 communiqués.
Endotoxin tolerance, the transient, secondary down-regulation of a subset of endotoxin-driven responses after exposure to bacterial products, is thought to be an adaptive response providing ...protection from pathological hyperactivation of the innate immune system during bacterial infection. However, although protecting from the development of sepsis, endotoxin tolerance also can lead to fatal blunting of immunological responses to subsequent infections in survivors of septic shock. Despite considerable experimental effort aimed at characterizing the molecular mechanisms responsible for a variety of endotoxin tolerance-related phenomena, no consensus has been achieved yet. IL-12 is a macrophage- and dendritic cell (DC)-derived cytokine that plays a key role in pathological responses to endotoxin as well as in the induction of protective responses to pathogens. It recently has been shown that IL-12 production is suppressed in endotoxin tolerance, providing a likely partial mechanism for the increased risk of secondary infections in sepsis survivors. We examined the development of IL-12 suppression during endotoxin tolerance in mice. Decreased IL-12 production in vivo is clearly multifactorial, involving both loss of CD11c(high) DCs as well as alterations in the responsiveness of macrophages and remaining splenic DCs. We find no demonstrable mechanistic role for B or T lymphocytes, the soluble mediators IL-10, TNF-alpha, IFN-alphabeta, or nitric oxide, or the NF-kappaB family members p50, p52, or RelB.
•Little evidence exists on perspectives and knowledge about medical uses of cannabinoids among European healthcare providers.
Since the introduction of the National Medical Cannabis Programme in The ...Netherlands, many other countries in Europe have made medical cannabis (MC) and cannabis-based medicines (CBMs) available. However, each of them has implemented a unique legal framework and reimbursement strategy for these products. Therefore, it is vital to study healthcare professionals’ knowledge level (HCP) and HCPs in-training regarding both medical uses and indications and understand their safety concerns and potential barriers for MC use in clinical practice.
A comprehensive, systematic literature review was performed using PubMed/MEDLINE, EMBASE, and Google Scholar databases, as well as PsychINFO. Grey literature was also included. Due to the high diversity in the questionnaires used in the studies, a narrative synthesis was performed.
From 6995 studies retrieved, ten studies, all of them being quantitative survey-based studies, were included in the review. In most studies, the majority of participants were in favor of MC and CBMs use for medical reasons. Other common findings were: the necessity to provide additional training regarding medical applications of cannabinoids, lack of awareness about the legal status of and regulations regarding MC among both certified physicians, as well as prospective doctors and students of other medicals sciences (e.g., nursing, pharmacy).
For most European countries, we could not identify any studies evaluating HCPs’ knowledge and attitudes towards medicinal cannabis. Therefore, similar investigations are highly encouraged. Available evidence demonstrates a need to provide medical training to the HCPs in Europe regarding medical applications of cannabinoids.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cutaneous T cell lymphomas (CTCLs) are malignancies of skin-trafficking T cells. Patients with advanced CTCL manifest immune dysfunction that predisposes to infection and suppresses the antitumor ...immune response. Therapies that stimulate immunity have produced superior progression-free survival compared with conventional chemotherapy, reinforcing the importance of addressing the immune deficient state in the care of patients with CTCL. Recent research has better defined the pathogenesis of these immune deficits, explaining the mechanisms of disease progression and revealing potential therapeutic targets. The features of the malignant cell in mycosis fungoides and Sézary syndrome are now significantly better understood, including the T helper 2 cell phenotype, regulatory T cell cytokine production, immune checkpoint molecule expression, chemokine receptors, and interactions with the microenvironment. The updated model of CTCL immunopathogenesis provides understanding into clinical progression and therapeutic response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In the past few decades, immunotherapy has emerged as an effective therapeutic option for patients with cutaneous T cell lymphoma (CTCL). CTCL is characterized by progressive impairment of multiple ...arms of the immune system. Immunotherapy targets these deficits to stimulate a more robust antitumor response, thereby both clearing the malignant T cells and repairing the immune dysfunction. By potentiating rather than suppressing the immune system, immunotherapy can result in longer treatment responses than alternatives such as chemotherapy. In recent years, advances in our understanding of the pathogenesis of CTCL have led to the development of several new agents with promising efficacy profiles. The second article in this continuing medical education series describes the current immunotherapeutic options for treatment of CTCL, with a focus on how they interact with the immune system and their treatment outcomes in case studies and clinical trials. We will discuss established CTCL immunotherapies, such as interferons, photopheresis, and retinoids; emerging therapies, such as interleukin-12 and Toll-like receptor agonists; and new approaches to targeting tumor antigens and checkpoint molecules, such as mogamulizumab, anti–programmed cell death protein 1, anti-CD47, and chimeric antigen receptor T cell therapy. We also describe the principles of multimodality immunotherapy and the use of total skin electron beam therapy in such regimens.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tyrosine kinases play a fundamental role in cell proliferation, survival, adhesion, and motility and have also been shown to mediate malignant cell transformation. Here we describe constitutive ...expression of the protein tyrosine kinase Brk in a large proportion of cutaneous T-cell lymphomas and other transformed T- and B-cell populations. The kinase is expressed in the nuclear localization and activated state. Brk expression was also induced in normal T cells on their activation. Introduced expression of the Brk gene resulted in markedly diminished cytokine and growth factor dependence of transfected BaF3 lymphocytes in regard to their
in vitro proliferation and survival. Brk also conferred
in vivo oncogenicity on the BaF3 cells. siRNA-mediated inhibition of the endogenous Brk in malignant T cells diminished their growth and survival capacity. These findings document inducible expression of Brk in normal T lymphocytes and persistent expression of the activated kinase in malignant T and B cells. Furthermore, our results indicate that Brk may play a key role in lymphomagenesis, hence identifying the kinase as a potential therapeutic target in lymphomas.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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