Plasmacytoid Precursor Dendritic Cells From NOD Mice Exhibit Impaired Function : Are They a Component of Diabetes Pathogenesis?

OBJECTIVE—Plasmacytoid precursor dendritic cell facilitating cells (p-preDC FCs) play a critical role in facilitation of syngeneic and allogeneic hematopoietic stem cell (HSC) engraftment. Here, we evaluated the phenotype and function of CD8+/TCR− FCs from NOD mice

HyBryte™ use in early-stage cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is a rare type of non-Hodgkin lymphoma of the skin, where at later stages skin-homing malignant T-cells affect lymph nodes, blood, and visceral organs. Even though early CTCL does not affect survival, it can progress to more advanced stages of disease and have a significant effect on the quality of life of patients. Although expectant management is a treatment consideration in early disease stages, most patients cycle through different skin-directed therapies throughout their lifetime. It can become a challenge to manage the serious and accumulating risk of side effects of these therapies, including various skin cancers and skin damage. Adverse effects from topical therapies limit their long-term utility. Thus, there is an unmet need for well-characterized therapies that have a rapid onset of action and minimal long-term/cumulative side effect profile. Most recently, the results of a Phase 3 study of topical HyBryte™ as a potential treatment for CTCL demonstrated its efficacy and safety profile. This article summarizes what is known about HyBryte™, focuses on its mechanism of action, and highlights its effectiveness, safety, and tolerability in the context of other current FDA-approved topical therapies for CTCL

Insight in modulation of inflammation in response to diclofenac intervention: a human intervention study

Background. Chronic systemic low-grade inflammation in obese subjects is associated with health complications including cardiovascular diseases, insulin resistance and diabetes. Reducing inflammatory responses may reduce these risks. However, available markers of inflammatory status inadequately describe the complexity of metabolic responses to mild anti-inflammatory therapy. Methods. To address this limitation, we used an integrative omics approach to characterize modulation of inflammation in overweight men during an intervention with the non-steroidal anti-inflammatory drug diclofenac. Measured parameters included 80 plasma proteins, >300 plasma metabolites (lipids, free fatty acids, oxylipids and polar compounds) and an array of peripheral blood mononuclear cells (PBMC) gene expression products. These measures were submitted to multivariate and correlation analysis and were used for construction of biological response networks. Results. A panel of genes, proteins and metabolites, including PGE2 and TNF-alpha, were identified that describe a diclofenac-response network (68 genes in PBMC, 1 plasma protein and 4 plasma metabolites). Novel candidate markers of inflammatory modulation included PBMC expression of annexin A1 and caspase 8, and the arachidonic acid metabolite 5,6-DHET. Conclusion. In this study the integrated analysis of a wide range of parameters allowed the development of a network of markers responding to inflammatory modulation, thereby providing insight into the complex process of inflammation and ways to assess changes in inflammatory status associated with obesity. Trial registration. The study is registered as NCT00221052 in clinicaltrials.gov database. © 2010 van Erk et al; licensee BioMed Central Ltd

In Vivo Islet Protection by a Nuclear Import Inhibitor in a Mouse Model of Type 1 Diabetes

Insulin-dependent Type 1 diabetes (T1D) is a devastating autoimmune disease that destroys beta cells within the pancreatic islets and afflicts over 10 million people worldwide. These patients face life-long risks for blindness, cardiovascular and renal diseases, and complications of insulin treatment. New therapies that protect islets from autoimmune destruction and allow continuing insulin production are needed. Increasing evidence regarding the pathomechanism of T1D indicates that islets are destroyed by the relentless attack by autoreactive immune cells evolving from an aberrant action of the innate, in addition to adaptive, immune system that produces islet-toxic cytokines, chemokines, and other effectors of islet inflammation. We tested the hypothesis that targeting nuclear import of stress-responsive transcription factors evoked by agonist-stimulated innate and adaptive immunity receptors would protect islets from autoimmune destruction.Here we show that a first-in-class inhibitor of nuclear import, cSN50 peptide, affords in vivo islet protection following a 2-day course of intense treatment in NOD mice, which resulted in a diabetes-free state for one year without apparent toxicity. This nuclear import inhibitor precipitously reduces the accumulation of islet-destructive autoreactive lymphocytes while enhancing activation-induced cell death of T and B lymphocytes derived from autoimmune diabetes-prone, non-obese diabetic (NOD) mice that develop T1D. Moreover, in this widely used model of human T1D we noted attenuation of pro-inflammatory cytokine and chemokine production in immune cells.These results indicate that a novel form of immunotherapy that targets nuclear import can arrest inflammation-driven destruction of insulin-producing beta cells at the site of autoimmune attack within pancreatic islets during the progression of T1D

Modeling of non-steroidal anti-inflammatory drug effect within signaling pathways and miRNA-regulation pathways

To date, it is widely recognized that Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) can exert considerable anti-tumor effects regarding many types of cancers. The prolonged use of NSAIDs is highly associated with diverse side effects. Therefore, tailoring down the NSAID application onto individual patients has become a necessary and relevant step towards personalized medicine. This study conducts the systemsbiological approach to construct a molecular model (NSAID model) containing a cyclooxygenase (COX)-pathway and its related signaling pathways. Four cancer hallmarks are integrated into the model to reflect different developmental aspects of tumorigenesis. In addition, a Flux-Comparative-Analysis (FCA) based on Petri net is developed to transfer the dynamic properties (including drug responsiveness) of individual cellular system into the model. The gene expression profiles of different tumor-types with available drug-response information are applied to validate the predictive ability of the NSAID model. Moreover, two therapeutic developmental strategies, synthetic lethality and microRNA (miRNA) biomarker discovery, are investigated based on the COX-pathway. In conclusion, the result of this study demonstrates that the NSAID model involving gene expression, gene regulation, signal transduction, protein interaction and other cellular processes, is able to predict the individual cellular responses for different therapeutic interventions (such as NS-398 and COX-2 specific siRNA inhibition). This strongly indicates that this type of model is able to reflect the physiological, developmental and pathological processes of an individual. The approach of miRNA biomarker discovery is demonstrated for identifying miRNAs with oncogenic and tumor suppressive functions for individual cell lines of breast-, colon- and lung-tumor. The achieved results are in line with different independent studies that investigated miRNA biomarker related to diagnostics of cancer treatments, therefore it might shed light on the development of biomarker discovery at individual level. Particular results of this study might contribute to step further towards personalized medicine with the systemsbiological approach

Image1_HyBryte™ use in early-stage cutaneous T-cell lymphoma.TIFF

Cutaneous T-cell lymphoma (CTCL) is a rare type of non-Hodgkin lymphoma of the skin, where at later stages skin-homing malignant T-cells affect lymph nodes, blood, and visceral organs. Even though early CTCL does not affect survival, it can progress to more advanced stages of disease and have a significant effect on the quality of life of patients. Although expectant management is a treatment consideration in early disease stages, most patients cycle through different skin-directed therapies throughout their lifetime. It can become a challenge to manage the serious and accumulating risk of side effects of these therapies, including various skin cancers and skin damage. Adverse effects from topical therapies limit their long-term utility. Thus, there is an unmet need for well-characterized therapies that have a rapid onset of action and minimal long-term/cumulative side effect profile. Most recently, the results of a Phase 3 study of topical HyBryte™ as a potential treatment for CTCL demonstrated its efficacy and safety profile. This article summarizes what is known about HyBryte™, focuses on its mechanism of action, and highlights its effectiveness, safety, and tolerability in the context of other current FDA-approved topical therapies for CTCL.</p

Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial

Dermatology-oncolog