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Anti- cytokine therapies

Sophie Langdon, Adina Hughes, Molly A Taylor, Elizabeth A Kuczynski, Deanna A Mele, Oona Delpuech, Laura Jarvis, Anna Staniszewska, Sabina Cosulich, Larissa S Carnevalli, Charles Sinclair
mTOR inhibition can promote or inhibit immune responses in a context dependent manner, but whether this will represent a net benefit or be contraindicated in the context of immunooncology therapies is less understood. Here, we report that the mTORC1/2 dual kinase inhibitor vistusertib (AZD2014) potentiates anti-tumour immunity in combination with anti-CTLA-4 (αCTLA-4), αPD-1 or αPD-L1 immune checkpoint blockade. Combination of vistusertib and immune checkpoint blocking antibodies led to tumour growth inhibition and improved survival of MC-38 or CT-26 pre-clinical syngeneic tumour models, whereas monotherapies were less effective...
2018: Oncoimmunology
Brenda J Curtis, Jill A Shults, Devin M Boe, Luis Ramirez, Elizabeth J Kovacs
Cutaneous burn injury is one of the most devastating injuries one can obtain with tissue damage extending beyond the skin wound to distal organs, including the gastrointestinal tract, liver, and lungs. Multiple organ failure is a leading cause of death after burn injury resulting in excessive systemic and localized inflammation directly contributing to end organ damage. We postulated that the gut-liver-lung inflammatory axis underscores multiple organ failure in the context of burn injury and is hyper-activated when ethanol intoxication precedes burn...
September 11, 2018: Alcohol
Dongdong Sun, Feng Zhang, Jie Qian, Weixing Shen, Huisen Fan, Jiani Tan, Liu Li, Changliang Xu, Ye Yang, Haibo Cheng
Angiogenesis is fundamental for solid tumor growth and metastasis, and anti-angiogenic therapy has been an important therapeutic option for cancer treatment. Colorectal cancer (CRC) represents the fourth leading cause of cancer-related death worldwide. The current studies were aimed at investigating the anti-angiogenic effects of the natural compound 4'-hydroxywogonin (4'-HW) on CRC-related angiogenesis. Human CRC cell line SW620 cells and normal human intestinal epithelial HIEC cells were cultured and treated with interleukin-6 to mimic the tumor inflammatory microenvironment...
September 11, 2018: Chemico-biological Interactions
Wei Liu, Lei Zhang, Hui-Jing Xu, Yan Li, Chuan-Min Hu, Jing-Yan Yang, Mei-Yan Sun
In conjunction with the classical functions of regulating intestinal, bone, and kidney calcium and phosphorus absorption, as well as bone mineralization of vitamin D, the population-based association between low vitamin D status and increased cancer risk is now generally accepted. Inflammation is causally related to oncogenesis. It is widely thought that vitamin D plays an important role in the modulation of the inflammation system by regulating the production of inflammatory cytokines and immune cells, which are crucial for the pathogenesis of many immune-related diseases...
September 13, 2018: International Journal of Molecular Sciences
Britta Stapel, Irina Sieve, Christine S Falk, Stefan Bleich, Denise Hilfiker-Kleiner, Kai G Kahl
Schizophrenia and major depression are associated with alterations in peripheral inflammatory markers, and anti-inflammatory therapy has been proposed as a promising add-on approach in the pharmacologic treatment of both disorders. Second-generation atypical antipsychotics are currently first-line drugs in the treatment of schizophrenia and are also used as augmentation strategies in treatment-resistant major depression. Furthermore, these drugs have been reported to exhibit distinct metabolic side effects and to influence inflammatory processes...
September 4, 2018: Journal of Psychiatric Research
Ji-Hoon Jeong, Hae Jin Jang, Sungmin Kwak, Gi-Jun Sung, Seung-Ho Park, Ji-Hye Song, Hyunhee Kim, Younghwa Na, Kyung-Chul Choi
Transforming growth factor β1 (TGF-β1), a multifunctional cytokine, is known to promote tumor invasion and metastasis and induce epithelial-mesenchymal transition (EMT) in various cancer cells. Inhibition of TGF-β1 signaling is a new strategy for cancer therapy. Most cancer cells display altered or nonfunctional TGF-β1 signaling; hence, TGF-β1 inhibitors exert limited effects on these cells. Recent studies have suggested that developing a TGF-β1 inhibitor from natural compounds is a key step to create novel therapeutic agents...
September 14, 2018: Journal of Cellular Biochemistry
Xingbo Dang, Gongliang Du, Wei Hu, Longyang Ma, Pei Wang, Yi Li
Acute lung injury (ALI) interferes with lung function by causing pulmonary inflammation and oxidative stress. Suppressing intracellular reactive oxygen species (ROS) may block intracellular inflammation. Thus, the purpose of the current study was to investigate the roles of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α)/HSF1 axis in an lipopolysaccharide (LPS)-induced ALI murine model and in RAW264.7 macrophages. In the LPS-administrated mouse model, the addition of PGC1α obviously ameliorated secretion of pro-inflammatory mediators tumor necrosis factor-α and Interleukin 6 as well as MCP-1 expression triggered by LPS stimulation, accompanied with reduced infiltration of inflammatory cells...
September 14, 2018: Journal of Cellular Biochemistry
Bhagwat V Alapure, Yan Lu, Mingyu He, Chih-Chang Chu, Hongying Peng, Filipe Muhale, Yue-Liang Brewerton, Bruce A Bunnell, Song Hong
Severe burns are some of the most challenging problems in clinics and still lack ideal modalities. Mesenchymal stem cells (MSCs) incorporated with biomaterial coverage of burn wounds may offer a viable solution. In this report, we seeded MSCs to a biodegradable hybrid hydrogel, namely ACgel, that was synthesized from unsaturated arginine-based poly(ester amide) (UArg-PEA) and chitosan derivative. MSC adhered to ACgels. ACgels maintained a high viability of MSCs in culture for 6 days. MSC seeded to ACgels presented well in third-degree burn wounds of mice at 8 days post-burn (dpb) after the necrotic full-thickness skin of burn wounds was debrided and filled and covered by MSC-carrying ACgels...
September 14, 2018: Stem Cells and Development
Felicitas Rataj, Fabian B T Kraus, Michael Chaloupka, Simon Grassmann, Constanze Heise, Bruno L Cadilha, Peter Duewell, Stefan Endres, Sebastian Kobold
Background: Interaction of the programmed death receptor 1 (PD-1) and its ligand, PD-L1, suppresses T cell activity and permits tumors to evade T cell-mediated immune surveillance. We have recently demonstrated that antigen-specific CD8+ T cells transduced with a PD1-CD28 fusion protein are protected from PD-1-mediated inhibition. We have now investigated the potential of PD1-CD28 fusion protein-transduced CD4+ T cells alone or in combination with CD8+ T cells for immunotherapy of pancreatic cancer and non-Hodgkin lymphoma...
2018: Frontiers in Immunology
Tyler J Peters, Amruta A Jambekar, William S A Brusilow
Background: The glutamine synthetase inhibitor methionine sulfoximine (MSO), shown previously to prevent death caused by an inflammatory liver response in mice, was tested on in vitro production of cytokines by mouse peritoneal macrophages triggered with lipopolysaccharide (LPS). Results: MSO significantly reduced the production of Interleukin 6 (IL-6) and Tumor Necrosis Factor Alpha (TNFα) at 4 and 6 h after LPS-treatment. This reduction did not result from decreased transcription of IL-6 and TNFα genes, and therefore appeared to result from post-transcriptional inhibition of synthesis of these cytokines...
2018: Journal of Inflammation
Iris de Weerdt, Tom Hofland, Roeland Lameris, Sanne Endstra, Aldo Jongejan, Perry Moerland, Renee Cg de Bruin, Ester B M Remmerswaal, Ineke J M Ten Berge, Nora Liu, Mario van der Stelt, Laura M Faber, Mark-David Levin, Eric Eldering, Sanne H Tonino, Tanja D de Gruijl, Hans J van der Vliet, Arnon P Kater
The efficacy of autologous (αβ)-T cell-based treatment strategies in chronic lymphocytic leukemia (CLL) has been modest. The Vγ9Vδ2T-cell subset comprises of cytotoxic T lymphocytes with potent anti-lymphoma activity via a major histocompatibility complex (MHC)-independent mechanism. We studied whether Vγ9Vδ2-T cells can be exploited as autologous effector lymphocytes in CLL. Healthy control (HC) Vγ9Vδ2-T cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived Vγ9Vδ2-T cells proved dysfunctional with respect to effector cytokine production and degranulation, despite an increased frequency of the effector-type subset...
September 13, 2018: Blood
Jinhai Huang, Xinxin Yu, Yanfang Zhou, Renshu Zhang, Qianqian Song, Qinmei Wang, Xingyi Li
In this paper, we presented a simple yet versatile strategy to generate a high drug payload nanoparticles by the combination with small molecular assembly and polymeric assembly for topical suppression of ocular inflammation. Upon physical mixing of the succinated triamcinolone acetonide (TA-SA) supramolecular hydrogel with the poly (ethylene glycol)-poly (ɛ-caprolactone)-poly (ethylene glycol) (PECE) aqueous solution at 37°C, TA-SA/PECE nanoparticles formed spontaneously and characterized thoroughly by transmission electron microscopy (TEM), X-ray diffraction (XRD) and differential scanning calorimetry (DSC)...
September 10, 2018: International Journal of Pharmaceutics
Sara La Manna, Concetta Di Natale, Daniele Florio, Daniela Marasco
Inflammation is a physiological mechanism used by organisms to defend themselves against infection, restoring homeostasis in damaged tissues. It represents the starting point of several chronic diseases such as asthma, skin disorders, cancer, cardiovascular syndrome, arthritis, and neurological diseases. An increasing number of studies highlight the over-expression of inflammatory molecules such as oxidants, cytokines, chemokines, matrix metalloproteinases, and transcription factors into damaged tissues. The treatment of inflammatory disorders is usually linked to the use of unspecific small molecule drugs that can cause undesired side effects...
September 11, 2018: International Journal of Molecular Sciences
Izabela Lasinska, Tomasz Kolenda, Anna Teresiak, Katarzyna M Lamperska, Lukasz Galus, Jacek Mackiewicz
Head and neck squamous cell carcinoma (HNSCC) is the most common malignant cancer occurring in the head and neck area, approximately 90% of the cases. Even in the cases of primary radical treatment (surgical, concomitant chemoradiotherapy or radiotherapy alone), local recurrence or distal metastases are often observed. In patients with recurrent disease who are unable to receive radical treatment, the results of palliative chemotherapy are not satisfactory. The breakthrough in the therapy of advanced HNSCC was the approval of cetuximab in combination with chemotherapy in 2008...
September 9, 2018: Anti-cancer Agents in Medicinal Chemistry
Chen-Yi-Yu Zhang, Min-Jie Zeng, Li-Ping Zhou, Ya-Qin Li, Fan Zhao, Zhi-Yuan Shang, Xue-Yang Deng, Zhan-Qiang Ma, Qiang Fu, Shi-Ping Ma, Rong Qu
Chronic stress can provoke depressive-like behaviors through activation of inflammation and apoptosis, leading to a reduction of neurons. Antidepressant therapy may contribute to inhibiting inflammation responses and have neuroprotective effects. Baicalin (BA) has an antidepressant effect in the chronic unpredictable mild stress (CUMS) animal model and exerts anti-inflammation, anti-apoptosis, as well as neuroprotective effects in many central nervous system (CNS)-related diseases. But the effects of BA on neuroprotection, apoptosis, and neuroinflammation and the potential mechanisms in depression are unclear...
September 5, 2018: International Immunopharmacology
Sihong Song, Yuanqing Lu, Ahmed S Elshikha
Alpha-1-antitrypsin (AAT) is a circulating protein, a serpin, with multiple protective functions. Beside the well-known proteinase inhibitory function, which protects the lungs from chronic obstructive pulmonary disease (COPD), many studies have shown that AAT inhibits pro-inflammatory cytokine gene expression and functions. These anti-inflammatory and immune-regulatory properties have led to studies testing the therapeutic effect of AAT in autoimmune disease models. Initially, a study using recombinant adeno-associated viral (rAAV) vector showed that AAT gene therapy prevented type 1 diabetes (T1D) development in a nonobese diabetic (NOD) mouse model...
2018: Methods in Molecular Biology
Shima Hadifar, Ava Behrouzi, Abolfazl Fateh, Shohreh Khatami, Fatemeh Rahimi Jamnani, Seyed Davar Siadat, Farzam Vaziri
Alveolar epithelial cell (AEC) provides a replication niche for Mycobacterium tuberculosis. Based on the role of AEC in M. tuberculosis pathogenesis and existence of genetic diversity within this bacterium, we investigated interactions between AEC II and two different M. tuberculosis lineages. We have compared the transcriptome and cytokines/chemokines levels of A549 infected by M. tuberculosis lineage three and four using qRT-PCR and ELISA arrays, respectively. We showed different M.  tuberculosis strains induced changes in different effectors that involved in TLRs and NF-κB signaling pathways...
September 7, 2018: Journal of Cellular Physiology
Karen T Mueller, Edward R Waldron, Stephan A Grupp, John E Levine, Theodore W Laetsch, Michael A Pulsipher, Michael W Boyer, Keith August, Jason Hamilton, Rakesh Awasthi, Andrew M Stein, Denise Sickert, Abhijit Chakraborty, Bruce L Levine, Carl H June, Lori Tomassian, Sweta Shah, Mimi Leung, Tetiana Taran, Patricia A Wood, Shannon L Maude
PURPOSE: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). EXPERIMENTAL DESIGN: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across 2 studies in pediatric B-ALL (ELIANA; ENSIGN)...
September 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
John Lynes, Sadhana Jackson, Victoria Sanchez, Gifty Dominah, Xiang Wang, Averie Kuek, Christina Piper Hayes, Sarah Benzo, Gretchen C Scott, Prashant Chittiboina, Kareem A Zaghloul, Deric M Park, Jing Wu, Christopher S Hourigan, Amber J Giles, Tianxia Wu, Dragan Maric, Jinguo Chen, Martha Quezado, John D Heiss, Mark R Gilbert, Edjah K Nduom
BACKGROUND: Glioblastoma is the most common primary malignancy of the brain, with a dismal prognosis. Immunomodulation via checkpoint inhibition has provided encouraging results in non-CNS malignancies, but prediction of responders has proven to be challenging in glioblastoma patients. OBJECTIVE: To determine the proportion of patients who have a measurable increase of interferon gamma levels in brain tumor tissue after their first dose of nivolumab, and to evaluate the safety of using brain tumor microdialysis to monitor for immune response while evaluating the safety of the combination of anti-programmed death 1 (PD-1) and anti-lymphocyte activation gene 3 (LAG-3) checkpoint inhibition...
September 4, 2018: Neurosurgery
Jung-Mo Ahn, Jun Sik Lee, Seul-Gee Um, Beom-Seop Rho, Ki Beom Lee, Sung-Gil Park, Ho-Jin Kim, Yoonjin Lee, Young Min Chi, Ye-Eun Yoon, Sun Hyo Jo, Mi Eun Kim, Kyung-Bae Pi
BACKGROUND: Skin inflammation and dermal injuries are a major clinical problem because current therapies are limited to treating established scars, and there is a poor understanding of healing mechanisms. Mussel adhesive proteins (MAPs) have great potential in many tissue engineering and biomedical applications. It has been successfully demonstrated that the redesigned hybrid type MAP (fp-151) can be utilized as a promising adhesive biomaterial. The aim of this study was to develop a novel recombinant protein using fp-151 and vitronectin (VT) and to elucidate the anti-inflammatory effects of this recombinant protein on macrophages and keratinocytes...
September 6, 2018: Immunological Investigations
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