scholarly journals Jakinibs of All Trades: Inhibiting Cytokine Signaling in Immune-Mediated Pathologies

2021 ◽  
Vol 15 (1) ◽  
pp. 48
Author(s):  
Madison Alexander ◽  
Yiming Luo ◽  
Giorgio Raimondi ◽  
John J. O’Shea ◽  
Massimo Gadina
Keyword(s):  
Late Phase ◽  
Allergic Diseases ◽  
Allogeneic Transplantation ◽  
Clinical Applications ◽  
Clinical Development ◽  
Cytokine Signaling ◽  
Graft Versus Host ◽  
Immune Mediated ◽  
Potential Benefits ◽  
Multiple Molecules

Over the last 25 years, inhibition of Janus kinases (JAKs) has been pursued as a modality for treating various immune and inflammatory disorders. While the clinical development of JAK inhibitors (jakinibs) began with the investigation of their use in allogeneic transplantation, their widest successful application came in autoimmune and allergic diseases. Multiple molecules have now been approved for diseases ranging from rheumatoid and juvenile arthritis to ulcerative colitis, atopic dermatitis, graft-versus-host-disease (GVHD) and other inflammatory pathologies in 80 countries around the world. Moreover, two jakinibs have also shown surprising efficacy in the treatment of hospitalized coronavirus disease-19 (COVID-19) patients, indicating additional roles for jakinibs in infectious diseases, cytokine storms and other hyperinflammatory syndromes. Jakinibs, as a class of pharmaceutics, continue to expand in clinical applications and with the development of more selective JAK-targeting and organ-selective delivery. Importantly, jakinib safety and pharmacokinetics have been investigated alongside clinical development, further cementing the potential benefits and limits of jakinib use. This review covers jakinibs that are approved or are under late phase investigation, focusing on clinical applications, pharmacokinetic and safety profiles, and future opportunities and challenges.

scholarly journals The exosome journey: from biogenesis to uptake and intracellular signalling

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Sonam Gurung ◽  
Dany Perocheau ◽  
Loukia Touramanidou ◽  
Julien Baruteau
Keyword(s):  
Clinical Trials ◽  
Plasma Membrane ◽  
Scientific Community ◽  
Cell Types ◽  
Clinical Applications ◽  
Clinical Development ◽  
Intracellular Signalling ◽  
Clinical Settings ◽  
Health And Disease ◽  
Adequate Definition

AbstractThe use of exosomes in clinical settings is progressively becoming a reality, as clinical trials testing exosomes for diagnostic and therapeutic applications are generating remarkable interest from the scientific community and investors. Exosomes are small extracellular vesicles secreted by all cell types playing intercellular communication roles in health and disease by transferring cellular cargoes such as functional proteins, metabolites and nucleic acids to recipient cells. An in-depth understanding of exosome biology is therefore essential to ensure clinical development of exosome based investigational therapeutic products. Here we summarise the most up-to-date knowkedge about the complex biological journey of exosomes from biogenesis and secretion, transport and uptake to their intracellular signalling. We delineate the major pathways and molecular players that influence each step of exosome physiology, highlighting the routes of interest, which will be of benefit to exosome manipulation and engineering. We highlight the main controversies in the field of exosome research: their adequate definition, characterisation and biogenesis at plasma membrane. We also delineate the most common identified pitfalls affecting exosome research and development. Unravelling exosome physiology is key to their ultimate progression towards clinical applications.

Immune‐mediated neuromuscular complications of graft‐versus‐host disease

2021 ◽  
Author(s):  
Jacqui‐Lyn Saw ◽  
M. Hasib Sidiqi ◽  
Michelle L. Mauermann ◽  
Hassan Alkhateeb ◽  
Elie Naddaf
Keyword(s):  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Immune Mediated ◽  
Neuromuscular Complications

Clinical Trials and Machine Learning: Regulatory Approach Review

2021 ◽  
Vol 16 ◽  
Author(s):  
Diego Alejandro Dri ◽  
Maurizio Massella ◽  
Donatella Gramaglia ◽  
Carlotta Marianecci ◽  
Sandra Petraglia
Keyword(s):  
Artificial Intelligence ◽  
Machine Learning ◽  
Clinical Trials ◽  
Patient Safety ◽  
Drug Discovery ◽  
Clinical Applications ◽  
Clinical Development ◽  
Regulatory Approach ◽  
National Competent Authorities ◽  
Review Current

: Machine Learning, a fast-growing technology, is an application of Artificial Intelligence that has significantly contributed to drug discovery and clinical development. In the last few years, the number of clinical applications based on Machine Learning has constantly been growing. Moreover, it is now also impacting National Competent Authorities during the assessment of most recently submitted Clinical Trials that are designed, managed, or generating data deriving from the use of Machine Learning or Artificial Intelligence technologies. We review current information available on the regulatory approach to Clinical Trials and Machine Learning. We also provide inputs for further reasoning and potential indications, including six actionable proposals for regulators to proactively drive the upcoming evolution of Clinical Trials within a strong regulatory framework, focusing on patient safety, health protection, and fostering immediate access to effective treatments.

Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study

Blood ◽  
2006 ◽  
Vol 107 (4) ◽  
pp. 1724-1730 ◽  
Author(s):  
Julio Delgado ◽  
Kirsty Thomson ◽  
Nigel Russell ◽  
Joanne Ewing ◽  
Wendy Stewart ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Fungal Infections ◽  
Allogeneic Transplantation ◽  
Lymphocytic Leukemia ◽  
British Society ◽  
Graft Versus Host ◽  
Blood And Marrow Transplantation ◽  
Immunosuppressed Patients ◽  
Related Mortality

We report results in 41 consecutive patients with chronic lymphocytic leukemia (CLL) who underwent allogeneic hematopoietic cell transplantation (HCT) after fludarabine, melphalan, and alemtuzumab conditioning. Donors were 24 HLA-matched siblings and 17 unrelated volunteers, 4 of them mismatched with recipients. All but 3 patients had initial hematologic recovery, but 5 more patients had secondary graft failure. Median intervals to neutrophil (greater than 0.5 × 109/L) and platelet (greater than 20 × 109/L) recovery were 14 days (range, 9-30 days) and 11 days (range, 8-45 days), respectively. Eleven (27%) patients had relapses and received escalated donor lymphocyte infusions, but only 3 of them had sustained responses. Acute and chronic graft-versus-host disease (GVHD) was observed in 17 (41%) and 13 (33%) patients, respectively. Seventeen (41%) patients have died, 5 of progressive disease. The 2-year overall survival and transplantation-related mortality (TRM) rates were 51% (95% confidence interval [CI], 33%-69%) and 26% (95% CI, 14%-46%), respectively. The alemtuzumabbased regimen was feasible and effective in patients with CLL with a relatively low rate of GVHD. However, TRM remains relatively high as a result of a variety of viral and fungal infections. Studies are ongoing to address the efficacy of reduced doses of alemtuzumab in this group of immunosuppressed patients.

scholarly journals Von Willebrand Factor, Factor VIII, and Other Acute Phase Reactants as Biomarkers of Inflammation and Endothelial Dysfunction in Chronic Graft-Versus-Host Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Antonela Lelas ◽  
Hildegard Theresia Greinix ◽  
Daniel Wolff ◽  
Günther Eissner ◽  
Steven Zivko Pavletic ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Factor Viii ◽  
Acute Phase ◽  
Von Willebrand Factor ◽  
Graft Versus Host Disease ◽  
Acute Phase Reactants ◽  
Graft Versus Host ◽  
Immune Mediated ◽  
Von Willebrand ◽  
Willebrand Factor

Chronic graft-versus-host disease (cGvHD) is an immune mediated late complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). Discovery of adequate biomarkers could identify high-risk patients and provide an effective pre-emptive intervention or early modification of therapeutic strategy, thus reducing prevalence and severity of the disease among long-term survivors of alloHSCT. Inflammation, endothelial injury, and endothelial dysfunction are involved in cGvHD development. Altered levels of acute phase reactants have shown a strong correlation with the activity of several immune mediated disorders and are routinely used in clinical practice. Since elevated von Willebrand factor (VWF) and factor VIII (FVIII) levels have been described as acute phase reactants that may indicate endothelial dysfunction and inflammation in different settings, including chronic autoimmune diseases, they could serve as potential candidate biomarkers of cGvHD. In this review we focused on reported data regarding VWF and FVIII as well as other markers of inflammation and endothelial dysfunction, evaluating their potential role in cGvHD.

scholarly journals Assessment of Expression of SOCS Genes in Acquired Immune-Mediated Polyneuropathies

2021 ◽  
Vol 12 ◽  
Author(s):  
Mohammad Taheri ◽  
Somayeh Sangseifid ◽  
Pariya Shahani ◽  
Mohammad Mahdi Eftekharian ◽  
Shahram Arsang-Jang ◽  
...  
Keyword(s):  
Specific Pattern ◽  
Bayesian Regression ◽  
Cytokine Signaling ◽  
Control Group ◽  
Operating Characteristics ◽  
Mean Values ◽  
Immune Mediated ◽  
Male Patients ◽  
Underlying Mechanisms ◽  
And Control

Acquired immune-mediated polyneuropathies are classified to some subtypes among them are acute and chronic inflammatory demyelinating polyradiculoneuropathies (AIDP and CIDP). These two conditions share some common signs and underlying mechanisms. Based on the roles of Suppressor of cytokine signaling (SOCS) genes in the modulation of immune system reactions, these genes might be involved in the pathogenesis of these conditions. We evaluated expression of SOCS1-3 and SOCS5 genes in the leukocytes of 32 cases of CIDP, 19 cases of AIDP and 40 age- and sex-matched controls using real time PCR method. The Bayesian regression model was used to estimate differences in mean values of genes expressions between cases and control group. Expression levels of SOCS1 and SOCS2 were significantly lower in male patients compared with controls. This sex-specific pattern was also observed for SOCS3 down-regulation. Based on the area under curve values in Receiver Operating Characteristics (ROC) curve, diagnostic powers of SOCS1, SOCS2, SOCS3 and SOCS5 genes in the mentioned disorder were 0.61, 0.73, 0.68 and 0.58, respectively. Expression of none of genes was correlated with age of enrolled cases. The current study shows evidences for participation of SOCS genes in the pathophysiology of acquired immune-mediated polyneuropathies.

scholarly journals “Influence of Body Composition Assessed by Computed Tomography on Mortality in Older Adults Undergoing Hematopoietic Stem Cell Transplantation”

2021 ◽  
Author(s):  
Ludmila Koch ◽  
Andrea Z Pereira ◽  
Nelson Hamerschlak ◽  
Adham do Amaral e Castro ◽  
Adriano Tachibana ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Body Composition ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Positive Association ◽  
Allogeneic Transplantation ◽  
Hematopoietic Stem ◽  
Death Risk ◽  
Graft Versus Host

Abstract Aim: The incidence of most hematologic malignancies increases with age. Hematopoietic stem cell transplantation (HSCT) provides a potentially life-prolonging or curative option for many patients in this scenario. Limited data is available on muscle mass and density assessed from CT-images on outcomes after HSCT. We aimed to evaluate the influence of body composition on morbidity and mortality in older adults undergoing (HSCT). Methods: Retrospective longitudinal study conducted with 50 patients ≥ 60 years undergoing HSCT at Hospital Israelita Albert Einstein, São Paulo. Body composition was assessed by chest computed tomography and treatment related mortality, graft versus host disease, neutrophil grafting, and overall survival were analyzed.Results: 148 HSCT patients were evaluated, 50 patients were eligible: 60% with autologous and 40% with allogeneic transplantation. Body mass index in patients was (female: 26.9 ± 4.7 kg/m2; 30.1± 4.9 kg/m2) - autologous and (female: 24.3 ± 5.15 kg/m2; male: 26.4 ± 2.0 kg/m2) - allogeneic. In autologous transplant group, we found a positive association between age and death risk with an increase of 63.5% in this risk (p=0.006) and also Karnofsky performance scale with decrease of 11.9% in death risk (p<0.001). A negative association between muscle radiodensity and death risk was observed in allogeneic transplantation patients with risk decrease of 20.1% (p = 0.032). We found a positive association between T4 muscle area and radiodensity with risk of acute graft versus host disease (p= 0.028). Conclusion: In population studied, body composition assessed by chest tomography showed the importance of radiodensity for better prognosis.

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