scholarly journals Cell stress increases ATP release in NLRP3 inflammasome-mediated autoinflammatory diseases, resulting in cytokine imbalance

2015 ◽  
Vol 112 (9) ◽  
pp. 2835-2840 ◽  
Author(s):  
Sonia Carta ◽  
Federica Penco ◽  
Rosa Lavieri ◽  
Alberto Martini ◽  
Charles Anthony Dinarello ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Atp Release ◽  
Treatment Strategies ◽  
Antioxidant Response ◽  
Cell Stress ◽  
Blood Monocytes ◽  
Negative Effect ◽  
P2x Purinoceptor ◽  
Novel Treatment Strategies ◽  
The Individual

Cell stress is implicated in triggering bouts of systemic inflammation in patients with autoinflammatory disorders. Blood monocytes from patients affected by NLRP3-mediated cryopyrin-associated periodic syndromes (CAPS) release greater amounts of IL-1β than monocytes from unaffected subjects. Here we show that stress lowers the threshold of activation; blood monocytes from CAPS patients maintain the high levels of secreted IL-1β (fivefold) and IL-18 (10-fold) when stimulated with 1,000-fold less LPS than that required for full IL-1β secretion in control subjects. Unexpectedly, IL-1α secretion is increased 10-fold, indicating that inflammatory episodes in CAPS may not be entirely a result of IL-1β but may also involve IL-1α. In CAPS monocytes, LPS induces the externalization of copious amounts of ATP (10-fold), which drive IL-1β, IL-18, and IL-1α release via activation of the P2X purinoceptor 7. This enhanced ATP release appears to be the link between cell stress and increased cytokine secretion in CAPS. In the later phase after LPS stimulation, CAPS monocytes undergo oxidative stress, which impairs production of the anti-inflammatory IL-1 receptor antagonist (IL-1Ra). Remarkably, IL-1Ra secretion is fully restored by treatment with antioxidants. In two patients with the same NLRP3 mutation, but different disease severity, monocytes from the mildly affected patient exhibited more efficient redox response, lower ATP secretion, and more balanced cytokine production. Thus, the robustness of the individual antioxidant response increases the tolerance to stress and reduces the negative effect of the disease. Pharmacologic block of P2X purinoceptor 7 and improved stress tolerance may represent novel treatment strategies in stress-associated inflammatory diseases.

scholarly journals FRI0632-HPR PSYCHOLOGICAL PARTICULIARITIES OF PATIENTS SUFFERING FROM MONOGENIC AUTO-INFLAMMATORY DISEASES.

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 920.1-921
Author(s):  
N. Stepanenko ◽  
E. Fedorov ◽  
S. Salugina ◽  
S. Feoktistova
Keyword(s):  
Inflammatory Diseases ◽  
Life Quality ◽  
Information Storage ◽  
Social Adaptation ◽  
Long Term Memory ◽  
Short Term ◽  
Sequence Of Events ◽  
Communicative Disorders ◽  
Negative Effect ◽  
High Level

Background:Monogenic auto-inflammatory diseases (mAID) are a group of severe chronic multisystemic diseases with recurring episodes of fever and other manifestations that significantly affect the patients’ life quality. Moreover, the hyper expression of pro-inflammatory cytokines (IL1β, etc.) observed in these patients may have a negative effect on the central nervous system.Objectives:to study the state of the cognitive and emotional spheres in children suffering from monogenic auto-inflammatory diseases.Methods:there were examined 22 children at the age of 7 to 17 years old diagnosed with CAPS-9, TRAPS-8, FMF-5. Among them there were 12 boys and 10 girls. The diagnosis in all the patients was confirmed through detection of pathogenic mutations in the NLRP3, TNFRSF1A and MEFV genes. The following methods were used: a clinical conversation; memory diagnostics (learning by heart of 10 words, a pictogram using cues taking into account the patients’ age); attention diagnostics (Schulte tables); thinking diagnostics (establishing a sequence of events, “four is a crwod”, simple analogies, interpretation of proverbs); emotional and communicative fields (the Eight-Color Luscher Test; CMAS (adaptation by A. Prikhozhan); STAI test, a drawing called “an animal that does not exist” and “a house-a tree-a man”).Results:The memory study revealed in all patients with TRAPS and FMF high and medium values of short-term and long-term memory, in patients with CAPS - a low level of short-term auditory-speech memory, information storage and indirect memorization in 1/3 of patients. In 100% of the examined patients with TRAPS, a significant decrease in all processes of attention and distribution of attention. In 1/3 of patients with CAPS, an increased exhaustion of attention was registered and in 11% - a decrease in its stability. In patients with FMF, attention disorders were not detected. In 44% of patients with CAPS, a decrease in the level of generalization and difficulties in establishing causal relationships were registered. In 25% of patients with TRAPS a decrease in the level of generalization, in 12.5%- difficulties in establishing cause-effect relationships, inertia of thinking in 37.5%. In 60% of patients with FMF: a decrease in the level of generalization, in 80%: difficulties in establishing cause-effect relationships, inertia of thinking in 20%. In the emotional sphere, patients with CAPS, TRAPS, and FMF demonstrated signs of aggression (11.1%, 20% and 20% of patients, respectively), communicative disorders (77.8% -80% - 80%), and reduced social adaptation (55.5% - 80% - 80%), a tendency to form neurotic fears (22% - 40% - 40%). A high level of personal anxiety was noted in 1/3 of patients with CAPS and 40% of patients with FMF.Conclusion:various psychological disorders in the cognitive and emotional fields were noted in the majority of the examined patients with monogenic auto-inflammatory diseases. In patients with TRAPS, attention processes are most significantly affected; in patients with CAPS, memory is more often affected. In patients with FMF, disorders in thinking processes are revealed more often. In the emotional sphere, most patients with all the three forms of AID note communicative disorders and social adaptation.Disclosure of Interests:None declared

scholarly journals Novel Treatments and Technologies Applied to the Cure of Neuroblastoma

Children ◽  
2021 ◽  
Vol 8 (6) ◽  
pp. 482
Author(s):  
Irene Paraboschi ◽  
Laura Privitera ◽  
Gabriela Kramer-Marek ◽  
John Anderson ◽  
Stefano Giuliani
Keyword(s):  
Research Effort ◽  
Treatment Strategies ◽  
Adverse Outcomes ◽  
Treatment Protocols ◽  
Ongoing Research ◽  
Hematopoietic Stem ◽  
Novel Treatments ◽  
Therapeutic Modalities ◽  
High Risk Disease ◽  
Novel Treatment Strategies

Neuroblastoma (NB) is the most common extracranial solid tumour in childhood, accounting for approximately 15% of all cancer-related deaths in the paediatric population1. It is characterised by heterogeneous clinical behaviour in neonates and often adverse outcomes in toddlers. The overall survival of children with high-risk disease is around 40–50% despite the aggressive treatment protocols consisting of intensive chemotherapy, surgery, radiation therapy and hematopoietic stem cell transplantation2,3. There is an ongoing research effort to increase NB’s cellular and molecular biology knowledge to translate essential findings into novel treatment strategies. This review aims to address new therapeutic modalities emerging from preclinical studies offering a unique translational opportunity for NB treatment.

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.

scholarly journals Current Insights into Immunology and Novel Therapeutics of Atopic Dermatitis

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1392
Author(s):  
Hidaya A. Kader ◽  
Muhammad Azeem ◽  
Suhib A. Jwayed ◽  
Aaesha Al-Shehhi ◽  
Attia Tabassum ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Skin Diseases ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
Developed Countries ◽  
Food Allergies ◽  
Th2 Response ◽  
Therapeutic Outcomes ◽  
Environmental Agents ◽  
Novel Treatment Strategies

Atopic dermatitis (AD) is one of the most prevalent inflammatory disease among non-fatal skin diseases, affecting up to one fifth of the population in developed countries. AD is characterized by recurrent pruritic and localized eczema with seasonal fluctuations. AD initializes the phenomenon of atopic march, during which infant AD patients are predisposed to progressive secondary allergies such as allergic rhinitis, asthma, and food allergies. The pathophysiology of AD is complex; onset of the disease is caused by several factors, including strong genetic predisposition, disrupted epidermal barrier, and immune dysregulation. AD was initially characterized by defects in the innate immune system and a vigorous skewed adaptive Th2 response to environmental agents; there are compelling evidences that the disorder involves multiple immune pathways. Symptomatic palliative treatment is the only strategy to manage the disease and restore skin integrity. Researchers are trying to more precisely define the contribution of different AD genotypes and elucidate the role of various immune axes. In this review, we have summarized the current knowledge about the roles of innate and adaptive immune responsive cells in AD. In addition, current and novel treatment strategies for the management of AD are comprehensively described, including some ongoing clinical trials and promising therapeutic agents. This information will provide an asset towards identifying personalized targets for better therapeutic outcomes.

scholarly journals Therapeutic Antibodies for the Treatment of Respiratory Tract Infections—Current Overview and Perspectives

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 151
Author(s):  
Alexie Mayor ◽  
Adélaïde Chesnay ◽  
Guillaume Desoubeaux ◽  
David Ternant ◽  
Nathalie Heuzé-Vourc’h ◽  
...  
Keyword(s):  
Respiratory Tract Infections ◽  
Inflammatory Diseases ◽  
Treatment Strategies ◽  
Candida Spp ◽  
Medical Needs ◽  
Life Threatening ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Tract Infections ◽  
Unmet Medical Needs

Respiratorytract infections (RTIs) are frequent and life-threatening diseases, accounting for several millions of deaths worldwide. RTIs implicate microorganisms, including viruses (influenza virus, coronavirus, respiratory syncytial virus (RSV)), bacteria (Pseudomonas aeruginosa, Streptococcus pneumoniae, Staphylococcus aureus and Bacillus anthracis) and fungi (Pneumocystis spp., Aspergillus spp. and very occasionally Candida spp.). The emergence of new pathogens, like the coronavirus SARS-CoV-2, and the substantial increase in drug resistance have highlighted the critical necessity to develop novel anti-infective molecules. In this context, antibodies (Abs) are becoming increasingly important in respiratory medicine and may fulfill the unmet medical needs of RTIs. However, development of Abs for treating infectious diseases is less advanced than for cancer and inflammatory diseases. Currently, only three Abs have been marketed for RTIs, namely, against pulmonary anthrax and RSV infection, while several clinical and preclinical studies are in progress. This article gives an overview of the advances in the use of Abs for the treatment of RTIs, based on the analysis of clinical studies in this field. It describes the Ab structure, function and pharmacokinetics, and discusses the opportunities offered by the various Ab formats, Ab engineering and co-treatment strategies. Including the most recent literature, it finally highlights the strengths, weaknesses and likely future trends of a novel anti-RTI Ab armamentarium.

scholarly journals Weighing in on heart failure: the potential impact of bariatric surgery

2021 ◽  
Author(s):  
Tanuka Datta ◽  
Andrew J. Lee ◽  
Rachel Cain ◽  
Melissa McCarey ◽  
David J. Whellan
Keyword(s):  
Heart Failure ◽  
Bariatric Surgery ◽  
Weight Loss ◽  
Cardiovascular System ◽  
Economic Burden ◽  
Treatment Strategies ◽  
It Impacts ◽  
Potential Impact ◽  
The Individual ◽  
Physiologic System

AbstractObesity is a growing worldwide epidemic with significant economic burden that carries with it impacts on every physiologic system including the cardiovascular system. Specifically, the risk of heart failure has been shown to increase dramatically in obese individuals. The purpose of this review is to provide background on the individual burdens of heart failure and obesity, followed by exploring proposed physiologic mechanisms that interconnect these conditions, and furthermore introduce treatment strategies for weight loss focusing on bariatric surgery. Review of the existing literature on patients with obesity and heart failure who have undergone bariatric surgery is presented, compared, and contrasted.

scholarly journals Molecular mechanisms underpinning sarcomas and implications for current and future therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Victoria Damerell ◽  
Michael S. Pepper ◽  
Sharon Prince
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Strategies ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Cells Of Origin ◽  
Novel Treatment Strategies ◽  
Future Therapy

AbstractSarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

scholarly journals Unique Genomic Landscape of High-Grade Neuroendocrine Cervical Carcinoma: Implications for Rethinking Current Treatment Paradigms

2020 ◽  
pp. 972-987
Author(s):  
Ramez N. Eskander ◽  
Julia Elvin ◽  
Laurie Gay ◽  
Jeffrey S. Ross ◽  
Vincent A. Miller ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Current Treatment ◽  
High Grade ◽  
Novel Treatment ◽  
Sample Average ◽  
Genomic Landscape ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Sample Range ◽  
Novel Treatment Strategies

PURPOSE High-grade neuroendocrine cervical cancer (HGNECC) is an uncommon malignancy with limited therapeutic options; treatment is patterned after the histologically similar small-cell lung cancer (SCLC). To better understand HGNECC biology, we report its genomic landscape. PATIENTS AND METHODS Ninety-seven patients with HGNECC underwent comprehensive genomic profiling (182-315 genes). These results were subsequently compared with a cohort of 1,800 SCLCs. RESULTS The median age of patients with HGNECC was 40.5 years; 83 patients (85.6%) harbored high-risk human papillomavirus (HPV). Overall, 294 genomic alterations (GAs) were identified (median, 2 GAs/sample; average, 3.0 GAs/sample, range, 0-25 GAs/sample) in 109 distinct genes. The most frequently altered genes were PIK3CA (19.6% of cohort), MYC (15.5%), TP53 (15.5%), and PTEN (14.4%). RB1 GAs occurred in 4% versus 32% of HPV-positive versus HPV-negative tumors ( P < .0001). GAs in HGNECC involved the following pathways: PI3K/AKT/mTOR (41.2%); RAS/MEK (11.3%); homologous recombination (9.3%); and ERBB (7.2%). Two tumors (2.1%) had high tumor mutational burden (TMB; both with MSH2 alterations); 16 (16.5%) had intermediate TMB. Seventy-one patients (73%) had ≥ 1 alteration that was theoretically druggable. Comparing HGNECC with SCLC, significant differences in TMB, microsatellite instability, HPV-positive status, and in PIK3CA, MYC, PTEN, TP53, ARID1A, and RB1 alteration rates were found. CONCLUSION This large cohort of patients with HGNECC demonstrated a genomic landscape distinct from SCLC, calling into question the biologic and therapeutic relevance of the histologic similarities between the entities. Furthermore, 73% of HGNECC tumors had potentially actionable alterations, suggesting novel treatment strategies for this aggressive malignancy.

scholarly journals Responsiveness of the Scripps Neurologic Rating Scale During a Multiple Sclerosis Clinical Trial

1999 ◽  
Vol 26 (4) ◽  
pp. 283-289 ◽  
Author(s):  
James A. Koziol ◽  
Adriana Lucero ◽  
Jack C. Sipe ◽  
John S. Romine ◽  
Ernest Beutler
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trial ◽  
Rating Scale ◽  
Effect Sizes ◽  
Active Therapy ◽  
Double Blind ◽  
Treatment Groups ◽  
Negative Effect ◽  
The Individual ◽  
Positive Effect

Objective:The Scripps neurologic rating scale (SNRS) is a summary measure of individual components comprising a neurological examination, designed for use in multiple sclerosis (MS). Our objective is to evaluate the responsiveness of the SNRS, within the context of a 2-year, randomized, double-blind crossover study of the efficacy of cladribine for treatment of secondary progressive MS.Methods:Effect sizes were determined for the SNRS and its components, separately for each treatment group (initial placebo, and initial cladribine) over both years of the clinical trial, using a standard random effects model.Results:Individual components tended to show positive effect sizes (improvement) during periods of active therapy in both treatment groups, and negative effect sizes (deterioration) during periods of no active therapy. Summation indices derived from the individual components of the SNRS seemed somewhat more stable than the individual components. The two components mentation and mood, and bladder, bowel, or sexual dysfunction, were rather unresponsive in our clinical trial.Conclusion:Changes in the components of the SNRS over the course of our clinical trial were consistent between the two treatment groups. Most components were moderately responsive; and, the summary SNRS score appropriately summarized the moderate magnitudes of change evinced in the individual components.

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