Controlled release of paclitaxel from a self-assembling peptide hydrogel formed in situ and antitumor study in vitro

Background: A nanoscale injectable in situ-forming hydrogel drug delivery system was developed in this study. The system was based on a self-assembling peptide RADA16 solution, which can spontaneously form a hydrogel rapidly under physiological conditions. We used the RADA16 hydrogel for the controlled release of paclitaxel (PTX), a hydrophobic antitumor drug. Methods: The RADA16-PTX suspension was prepared simply by magnetic stirring, followed by atomic force microscopy, circular dichroism analysis, dynamic light scattering, rheological analysis, an in vitro release assay, and a cell viability test. Results: The results indicated that RADA16 and PTX can interact with each other and that the amphiphilic peptide was able to stabilize hydrophobic drugs in aqueous solution. The particle size of PTX was markedly decreased in the RADA16 solution compared with its size in water. The RADA16-PTX suspension could form a hydrogel in culture medium, and the elasticity of the hydrogel showed a positive correlation with peptide concentration. In vitro release measurements indicated that hydrogels with a higher peptide concentration had a longer half-release time. The RADA16-PTX hydrogel could effectively inhibit the growth of the breast cancer cell line, MDA-MB-435S, in vitro, and hydrogels with higher peptide concentrations were more effective at inhibiting tumor cell proliferation. The RADA16-PTX hydrogel was effective at controlling the release of PTX and inhibiting tumor cell growth in vitro. Conclusion: Self-assembling peptide hydrogels may work well as a system for drug delivery

Dysfunction in Serotonergic and Noradrenergic Systems and Somatic Symptoms in Psychiatric Disorders

Somatic symptoms include a range of physical experiences, such as pain, muscle tension, body shaking, difficulty in breathing, heart palpitation, blushing, fatigue, and sweating. Somatic symptoms are common in major depressive disorder (MDD), anxiety disorders, and some other psychiatric disorders. However, the etiology of somatic symptoms remains unclear. Somatic symptoms could be a response to emotional distress in patients with those psychiatric conditions. Increasing evidence supports the role of aberrant serotoninergic and noradrenergic neurotransmission in somatic symptoms. The physiological alterations underlying diminished serotonin (5-HT) and norepinephrine (NE) signaling may contribute to impaired signal transduction, reduced 5-HT, or NE release from terminals of presynaptic neurons, and result in alternations in function and/or number of receptors and changes in intracellular signal processing. Multiple resources of data support each of these mechanisms. Animal models have shown physiological responses, similar to somatic symptoms seen in psychiatric patients, after manipulations of 5-HT and NE neurotransmission. Human genetic studies have identified many single-nucleotide polymorphisms risk loci associated with somatic symptoms. Several neuroimaging findings support that somatic symptoms are possibly associated with a state of reduced receptor binding. This narrative literature review aimed to discuss the involvement of serotonergic and noradrenergic systems in the pathophysiology of somatic symptoms. Future research combining neuroimaging techniques and genetic analysis to further elucidate the biological mechanisms of somatic symptoms and to develop novel treatment strategies is needed

Dysfunction in Serotonergic and Noradrenergic Systems and Somatic Symptoms in Psychiatric Disorders

Somatic symptoms include a range of physical experiences, such as pain, muscle tension, body shaking, difficulty in breathing, heart palpitation, blushing, fatigue, and sweating. Somatic symptoms are common in major depressive disorder (MDD), anxiety disorders, and some other psychiatric disorders. However, the etiology of somatic symptoms remains unclear. Somatic symptoms could be a response to emotional distress in patients with those psychiatric conditions. Increasing evidence supports the role of aberrant serotoninergic and noradrenergic neurotransmission in somatic symptoms. The physiological alterations underlying diminished serotonin (5-HT) and norepinephrine (NE) signaling may contribute to impaired signal transduction, reduced 5-HT, or NE release from terminals of presynaptic neurons, and result in alternations in function and/or number of receptors and changes in intracellular signal processing. Multiple resources of data support each of these mechanisms. Animal models have shown physiological responses, similar to somatic symptoms seen in psychiatric patients, after manipulations of 5-HT and NE neurotransmission. Human genetic studies have identified many single-nucleotide polymorphisms risk loci associated with somatic symptoms. Several neuroimaging findings support that somatic symptoms are possibly associated with a state of reduced receptor binding. This narrative literature review aimed to discuss the involvement of serotonergic and noradrenergic systems in the pathophysiology of somatic symptoms. Future research combining neuroimaging techniques and genetic analysis to further elucidate the biological mechanisms of somatic symptoms and to develop novel treatment strategies is needed

Cytoplasmic p21 induced by p65 prevents doxorubicin-induced cell death in pancreatic carcinoma cell line

<p>Abstract</p> <p>Background</p> <p>Studies have shown the existence of p21 induction in a p53-dependent and -independent pathway. Our previous study indicates that DOX-induced p65 is able to bind the p21 promoter to activate its transactivation in the cells.</p> <p>Methods</p> <p>Over-expression and knock-down experiments were performed in Human Pancreatic Carcinoma (PANC1) cells. Cell cycle and cell death related proteins were assessed by Western Blotting. Cytotoxicity assay was checked by CCK-8 kit. Cell growth was analyzed by flow cytometers.</p> <p>Results</p> <p>Here we showed that over-expression of p65 decreased the cytotoxic effect of DOX on PANC1 cells, correlating with increased induction of cytoplasmic p21. We observed that pro-caspase-3 physically associated with cytoplasmic p21, which may be contribution to prevent p21 translocation into the nucleus. Our data also suggested that no clear elevation of nuclear p21 by p65 provides a survival advantage by progression cell cycle after treatment of DOX. Likewise, down-regulation of p65 expression enhanced the cytotoxic effect of DOX, due to a significant decrease of mRNA levels of anti-apoptotic genes, such as the cellular inhibitor of apoptosis-1 (c-IAP1), and the long isoform of B cell leukemia/lymphoma-2 (Bcl-2), leading to efficient induction of caspase-3 cleavage in the cells. More, we present evidence that over-expression of p53 or p53/p65 in the PANC1 cells were more sensitive to DOX treatment, correlated with activation of caspase-3 and clear elevation of nuclear p21 level. Our previous data suggested that expression of p21 increases Gefitinib-induced cell death by blocking the cell cycle at the G1 and G2 phases. The present findings here reinforced this idea by showing p21's ability of potentiality of DOX-induced cell death correlated with its inhibition of cell cycle progression after over-expression of p53 or p53/p65.</p> <p>Conclusion</p> <p>Our data suggested p65 could increase p53-mediated cell death in response to DOX in PANC1 cells. Thus, it is worth noting that in p53 null or defective tumors, targeting in down-regulation of p65 may well be useful, leading to the potentiality of chemotherapeutic drugs.</p

Always Strengthen Your Strengths: A Drift-Aware Incremental Learning Framework for CTR Prediction

Click-through rate (CTR) prediction is of great importance in recommendation systems and online advertising platforms. When served in industrial scenarios, the user-generated data observed by the CTR model typically arrives as a stream. Streaming data has the characteristic that the underlying distribution drifts over time and may recur. This can lead to catastrophic forgetting if the model simply adapts to new data distribution all the time. Also, it's inefficient to relearn distribution that has been occurred. Due to memory constraints and diversity of data distributions in large-scale industrial applications, conventional strategies for catastrophic forgetting such as replay, parameter isolation, and knowledge distillation are difficult to be deployed. In this work, we design a novel drift-aware incremental learning framework based on ensemble learning to address catastrophic forgetting in CTR prediction. With explicit error-based drift detection on streaming data, the framework further strengthens well-adapted ensembles and freezes ensembles that do not match the input distribution avoiding catastrophic interference. Both evaluations on offline experiments and A/B test shows that our method outperforms all baselines considered.Comment: This work has been accepted by SIGIR2