scholarly journals Identification of TNFR2 and IL-33 as therapeutic targets in localized fibrosis

2019 ◽  
Vol 5 (12) ◽  
pp. eaay0370 ◽  
Author(s):  
David Izadi ◽  
Thomas B. Layton ◽  
Lynn Williams ◽  
Fiona McCann ◽  
Marisa Cabrita ◽  
...  
Keyword(s):  
Immune Cells ◽  
Single Cell Analysis ◽  
Unmet Need ◽  
Therapeutic Targets ◽  
Treatment Strategies ◽  
Low Grade ◽  
Interleukin 33 ◽  
Target Disease ◽  
Novel Treatment Strategies ◽  
Molecular Landscape

Dissecting the molecular landscape of fibrotic disease, a major unmet need, will inform the development of novel treatment strategies to target disease progression and identify desperately needed therapeutic targets. Here, we provide a detailed single-cell analysis of the immune landscape in Dupuytren’s disease, a localized fibrotic condition of the hand, and identify a pathogenic signaling circuit between stromal and immune cells. We demonstrate M2 macrophages and mast cells as key cellular sources of tumor necrosis factor (TNF) that promotes myofibroblast development. TNF acts via the inducible TNFR2 receptor and stimulates interleukin-33 (IL-33) secretion by myofibroblasts. In turn, stromal cell IL-33 acts as a potent stimulus for TNF production from immune cells. Targeting this reciprocal signaling pathway represents a novel therapeutic strategy to inhibit the low-grade inflammation in fibrosis and the mechanism that drives chronicity.

scholarly journals Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 901
Author(s):  
Ramiz S. Ahmad ◽  
Timothy D. Eubank ◽  
Slawomir Lukomski ◽  
Brian A. Boone
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Cellular Mechanisms ◽  
Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

Reward Circuits and Apathy in Schizophrenia: Neuroimaging and Treatment Strategies

2017 ◽  
Vol 41 (S1) ◽  
pp. S58-S58
Author(s):  
A. Aleman
Keyword(s):  
Behavioral Treatment ◽  
Negative Symptoms ◽  
Meta Analysis ◽  
Critical Role ◽  
Unmet Need ◽  
Treatment Strategies ◽  
Reward Processing ◽  
Motivated Behavior ◽  
Novel Treatment Strategies ◽  
Quantitative Integration

Approximately 50% of patients with schizophrenia shows deficits in motivation and initiation of goal-directed behavior, which are suggestive of reward system dysfunction. We conducted a meta-analysis of neuroimaging studies reporting on the neural correlates of reward processing and negative symptoms in schizophrenia. A significant mean weighted correlation was observerd, revealing deficits in activation of reward neurocircuitry. A more specific findings is comprised activation of the ventral striatum, involved in anticipation of reward, and structures that play a critical role in the ability to represent the value of outcomes and plans. In a study of VTA connectivity in the resting state in a large group of patients with schizophrenia, we found reduced connectivity with lateral prefrontal, temporal and parietal regions to be associated with higher degrees of apathy. Apathy belongs to the most debilitating symptoms of schizophrenia and represents a significant unmet need in its treatment. Quantitative integration of published findings suggests that treatment with noninvasive magnetic brain stimulation can improve negative symptoms. Previous PET-studies have shown that such stimulation may target circuits with dopaminergic innervation. A behavioral treatment approach that may also target reward-related circuits will also be discussed briefly. It can be concluded that recent results regarding reward and motivated behavior in schizophrenia have clinical implications and may help develop novel treatment strategies.Disclosure of interestAA received speaker fees from Lundbeck.

scholarly journals Translational Research Studies Unraveling the Origins of Psoriatic Arthritis: Moving Beyond Skin and Joints

2021 ◽  
Vol 8 ◽  
Author(s):  
Janne W. Bolt ◽  
Chaja M. J. van Ansenwoude ◽  
Ihsan Hammoura ◽  
Marleen G. van de Sande ◽  
Lisa G. M. van Baarsen
Keyword(s):  
Psoriatic Arthritis ◽  
Translational Research ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Treatment Strategies ◽  
Continuous Treatment ◽  
Adaptive Immune Cells ◽  
Novel Treatment Strategies

Patients with psoriatic arthritis (PsA) are suffering from a decreased quality of life despite currently available treatments. In the latest years, novel therapies targeting the IL-17/IL-23 and TNF pathways improved clinical outcome. Despite this, remission of disease is not achieved in a considerable group of patients, continuous treatment is very often required to reach clinical remission, and prevention of PsA in patients with psoriasis (PsO) is currently impossible. A better understanding of PsA pathogenesis is required to develop novel treatment strategies that target inflammation and destruction more effectively and at an early stage of the disease, or even before clinically manifest disease. The skin is considered as one of the sites of onset of immune activation, triggering the inflammatory cascade in PsA. PsO develops into PsA in 30% of the PsO patients. Influenced by environmental and genetic factors, the inflammatory process in the skin, entheses, and/or gut may evolve into synovial tissue inflammation, characterized by influx of immune cells. The exact role of the innate and adaptive immune cells in disease pathogenesis is not completely known. The involvement of activated IL-17A+ T cells could implicate early immunomodulatory events generated in lymphoid organs thereby shaping the pathogenic inflammatory response leading to disease. In this perspective article, we provide the reader with an overview of the current literature regarding the immunological changes observed during the earliest stages of PsA. Moreover, we will postulate future areas of translational research aimed at increasing our knowledge on the molecular mechanisms driving disease development, which will aid the identification of novel potential therapeutic targets to limit the progression of PsA.

scholarly journals Discovering the Molecular Landscape of Meningioma: The Struggle to Find New Therapeutic Targets

Diagnostics ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1852
Author(s):  
Ilaria Maggio ◽  
Enrico Franceschi ◽  
Vincenzo Di Nunno ◽  
Lidia Gatto ◽  
Alicia Tosoni ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Aggressive Behavior ◽  
Prognostic Value ◽  
Therapeutic Targets ◽  
Genetic Alterations ◽  
Cns Tumors ◽  
Low Grade ◽  
Therapeutic Implications ◽  
Genetic Landscape ◽  
Molecular Landscape

Meningiomas are the most common primary CNS tumors. They are usually benign but can present aggressive behavior in about 20% of cases. The genetic landscape of meningioma is characterized by the presence (in about 60% of cases) or absence of NF2 mutation. Low-grade meningiomas can also present other genetic alterations, particularly affecting SMO, TRAF7, KLF4 AKT1 and PI3KCA. In higher grade meningiomas, mutations of TERT promoter and deletion of CDKN2A/B seem to have a prognostic value. Furthermore, other genetic alterations have been identified, such as BAP1, DMD and PBRM1. Different subgroups of DNA methylation appear to be correlated with prognosis. In this review, we explored the genetic landscape of meningiomas and the possible therapeutic implications.

scholarly journals Novel Treatment Strategies for Glioblastoma

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2883
Author(s):  
Stanley S. Stylli
Keyword(s):  
Median Survival ◽  
Treatment Strategies ◽  
Drug Repurposing ◽  
Standard Of Care ◽  
Invasive Disease ◽  
Central Nervous System Tumor ◽  
Current Standard ◽  
Novel Treatment ◽  
Novel Treatment Strategies ◽  
Molecular Landscape

Glioblastoma (GBM) is the most common primary central nervous system tumor in adults. It is a highly invasive disease, making it difficult to achieve a complete surgical resection, resulting in poor prognosis with a median survival of 12–15 months after diagnosis, and less than 5% of patients survive more than 5 years. Surgical, instrument technology, diagnostic and radio/chemotherapeutic strategies have slowly evolved over time, but this has not translated into significant increases in patient survival. The current standard of care for GBM patients involving surgery, radiotherapy, and concomitant chemotherapy temozolomide (known as the Stupp protocol), has only provided a modest increase of 2.5 months in median survival, since the landmark publication in 2005. There has been considerable effort in recent years to increase our knowledge of the molecular landscape of GBM through advances in technology such as next-generation sequencing, which has led to the stratification of the disease into several genetic subtypes. Current treatments are far from satisfactory, and studies investigating acquired/inherent resistance to current therapies, restricted drug delivery, inter/intra-tumoral heterogeneity, drug repurposing and a tumor immune-evasive environment have been the focus of intense research over recent years. While the clinical advancement of GBM therapeutics has seen limited progression compared to other cancers, developments in novel treatment strategies that are being investigated are displaying encouraging signs for combating this disease. This aim of this editorial is to provide a brief overview of a select number of these novel therapeutic approaches.

scholarly journals Role of subnetworks mediated by $$\hbox {TNF}\alpha$$, IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rakesh Pandey ◽  
Yusur Al-Nuaimi ◽  
Rajiv Kumar Mishra ◽  
Sarah K. Spurgeon ◽  
Marc Goodfellow
Keyword(s):  
Complex Network ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Tnf Alpha ◽  
Cell Network ◽  
Novel Treatment ◽  
Future Drug ◽  
Novel Treatment Strategies

AbstractPsoriasis is a chronic inflammatory skin disease clinically characterized by the appearance of red colored, well-demarcated plaques with thickened skin and with silvery scales. Recent studies have established the involvement of a complex signalling network of interactions between cytokines, immune cells and skin cells called keratinocytes. Keratinocytes form the cells of the outermost layer of the skin (epidermis). Visible plaques in psoriasis are developed due to the fast proliferation and unusual differentiation of keratinocyte cells. Despite that, the exact mechanism of the appearance of these plaques in the cytokine-immune cell network is not clear. A mathematical model embodying interactions between key immune cells believed to be involved in psoriasis, keratinocytes and relevant cytokines has been developed. The complex network formed of these interactions poses several challenges. Here, we choose to study subnetworks of this complex network and initially focus on interactions involving $$\hbox {TNF}_{\alpha }$$ TNF α , IL-23/IL-17, and IL-15. These are chosen based on known evidence of their therapeutic efficacy. In addition, we explore the role of IL-15 in the pathogenesis of psoriasis and its potential as a future drug target for a novel treatment option. We perform steady state analyses for these subnetworks and demonstrate that the interactions between cells, driven by cytokines could cause the emergence of a psoriasis state (hyper-proliferation of keratinocytes) when levels of $$\hbox {TNF}_{\alpha }$$ TNF α , IL-23/IL-17 or IL-15 are increased. The model results explain and support the clinical potentiality of anti-cytokine treatments. Interestingly, our results suggest different dynamic scenarios underpin the pathogenesis of psoriasis, depending upon the dominant cytokines of subnetworks. We observed that the increase in the level of IL-23/IL-17 and IL-15 could lead to psoriasis via a bistable route, whereas an increase in the level of $$\hbox {TNF}_{\alpha }$$ TNF α would lead to a monotonic and gradual disease progression. Further, we demonstrate how this insight, bistability, could be exploited to improve the current therapies and develop novel treatment strategies for psoriasis.

scholarly journals Recent Developments in Treating Cognitive Impairment Associated with Schizophrenia

2021 ◽  
Author(s):  
Robert A Bittner ◽  
Catherine V Barnes-Scheufler ◽  
Meike D Hettwer ◽  
Andreas Reif ◽  
Mishal Qubad
Keyword(s):  
Cognitive Impairment ◽  
Neural Plasticity ◽  
Clinical Symptoms ◽  
Therapeutic Potential ◽  
Cognitive Impairments ◽  
Unmet Need ◽  
Treatment Strategies ◽  
Potential Effect ◽  
Current Evidence ◽  
Novel Treatment Strategies

Pervasive and wide-ranging cognitive deficits are a core feature of schizophrenia and an important determinant of long-term functional outcome. The lack of sufficiently effective treatments for cognitive impairment associated with schizophrenia (CIAS) represents a major unmet need and a central roadblock towards recovery. This is partly due to the current therapeutic focus on clinical symptoms, and the relative neglect of cognitive impairments despite their functionally disabling effects. Furthermore, effective treatment is impeded by our limited knowledge of the complex pathophysiology, which gives rise to perturbed information processing. Here, we review mechanisms and effectiveness of available pharmacological and non-pharmacological treatments for CIAS. Current evidence indicates, that while techniques which broadly enhance neural plasticity show the greatest therapeutic potential, effect sizes are at best moderate. Among other reasons, this is due to a considerable heterogeneity of responses to individual interventions. Furthermore, we discuss how recent conceptual advances in operationalizing cognitive impairments based on cognitive neuroscience have the potential to address these issues and facilitate the development of novel treatment strategies for CIAS. This includes more clearly elucidating pathophysiological mechanisms in both humans and animal models, identifying new treatment targets as well as establishing biomarkers for a better prediction of treatment responses.

scholarly journals PATH-55. MUTATIONS OF H3.3 AND H3.1 IN A LARGE COHORT OF GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi155-vi156
Author(s):  
Ashley Sumrall ◽  
Sandeep Mittal ◽  
Surasak Phuphanich ◽  
Amy Heimberger ◽  
Jenny Eschbacher ◽  
...  
Keyword(s):  
Brain Stem ◽  
Treatment Strategies ◽  
Large Cohort ◽  
Molecular Entity ◽  
Low Grade ◽  
Pediatric Tumors ◽  
Heterogeneous Distribution ◽  
Molecular Alterations ◽  
Dismal Prognosis ◽  
Novel Treatment Strategies

Abstract Mutations in the histone genes H3.3 and H3.1 are driver events in pediatric and adult gliomas and carry diagnostic and prognostic importance for tumors originating from midline structures. Patients with tumors affected by these mutations are difficult to treat. We surveyed a large cohort of gliomas for H3-mutations, including H3K27m. Consecutive gliomas submitted for tumor profiling at Caris Life Sciences from 2015- 2019 were analyzed. NextGen sequencing was done on 592 genes; MGMT promoter methylation was tested by pyrosequencing; and EGFRvIII and gene fusions were tested by RNA-sequencing. Of nearly 1800 tumors analyzed, 41 harbored H3F3A alterations, including 33 with the K27M mutation (4 arose from the spinal cord, 1 from cerebellum, 1 from brain stem, 4 from thalamus, and 23 from brain, NOS). Eight G34R mutations were identified. A HIST1H3B-K27M was detected in a tumor from the brain stem. H3 mutations were more prevalent in pediatric tumors, and all H3 mutations seen in pediatric tumors were from grade IV tumors. Among the H3-mutated adult tumors, histology differed. There were 2 grade II tumors, 1 low grade glioma, 1 anaplastic ganglioglioma, and 2 anaplastic astrocytomas. In the investigated cohort, H3-mutations were mutually exclusive of IDH1/2 mutations and EGFR alterations. Significantly higher mutation rates were seen in H3-mutated tumors for TP53, ATRX, NF1, PDGFRA, FGFR1, FBXW7, BLM, and TSC2 compared with H3-WT. The H3-WT tumors were more enriched for MGMT-methylation and PTEN mutation. In H3-mutated tumors that were MGMT-methylated, most H3-mutations seen were G34R while K27M was largely exclusive. There was a heterogeneous distribution of H3 mutations, and the co-occurring molecular alterations seen in H3-mutated tumors further support the hypothesis that these tumors are a distinct molecular entity. By better characterizing these associations, we can develop insight into novel treatment strategies for a class of tumors with historically dismal prognosis.

scholarly journals Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas

Gut ◽  
2019 ◽  
Vol 68 (11) ◽  
pp. 2019-2031 ◽  
Author(s):  
Qi Zhang ◽  
Yu Lou ◽  
Jiaqi Yang ◽  
Junli Wang ◽  
Jie Feng ◽  
...  
Keyword(s):  
Single Cell Analysis ◽  
Treatment Strategies ◽  
Tumour Heterogeneity ◽  
Local Immunity ◽  
Expression Levels ◽  
Chain Reactions ◽  
Polymerase Chain Reactions ◽  
Novel Treatment Strategies ◽  
Prognostic Prediction

ObjectiveHepatocellular carcinoma (HCC) is heterogeneous, especially in multifocal tumours, which decreases the efficacy of clinical treatments. Understanding tumour heterogeneity is critical when developing novel treatment strategies. However, a comprehensive investigation of tumour heterogeneity in HCC is lacking, and the available evidence regarding tumour heterogeneity has not led to improvements in clinical practice.DesignWe harvested 42 samples from eight HCC patients and evaluated tumour heterogeneity using whole-exome sequencing, RNA sequencing, mass spectrometry-based proteomics and metabolomics, cytometry by time-of-flight, and single-cell analysis. Immunohistochemistry and quantitative polymerase chain reactions were performed to confirm the expression levels of genes. Three independent cohorts were further used to validate the findings.ResultsTumour heterogeneity is considerable with regard to the genomes, transcriptomes, proteomes, and metabolomes of lesions and tumours. The immune status of the HCC microenvironment was relatively less heterogenous. Targeting local immunity could be a suitable intervention with balanced precision and practicability. By clustering immune cells in the HCC microenvironment, we identified three distinctive HCC subtypes with immunocompetent, immunodeficient, and immunosuppressive features. We further revealed the specific metabolic features and cytokine/chemokine expression levels of the different subtypes. Determining the expression levels of CD45 and Foxp3 using immunohistochemistry facilitated the correct classification of HCC patients and the prediction of their prognosis.ConclusionThere is comprehensive intratumoral and intertumoral heterogeneity in all dimensions of HCC. Based on the results, we propose a novel immunophenotypic classification of HCCs that facilitates prognostic prediction and may support decision making with regard to the choice of therapy.

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