Combination Chemical and Mechanical Tumor Immunomodulation Using Cavitating Mesoporous Silica Nanoparticles.

Combinatorial methods to repolarize tumor-associated macrophages from anti-inflammatory to pro-inflammatory phenotypes offers a promising route for cancer immunotherapy. However, most studies examine biochemical combinations alone. Therefore, we studied simultaneous chemical and mechanical stimuli as orthogonal cues for enhanced immunomodulation.

Magnetic Cellular Backpacks for Spatial Targeting, Imaging, and Immunotherapy.

Adoptive cell transfer (ACT) therapies are growing in popularity due to their ability to interact with diseased tissues in a specific manner. Disc-shaped particles, or "backpacks", that bind to cellular surfaces show promise for augmenting the therapeutic potential of adoptively transferred cells by resisting phagocytosis and locally releasing drugs to maintain cellular activity over time. However, many ACTs suffer from limited tumor infiltration and retention and lack a method for real-time spatial analysis.

Microrobots for Biomedicine: Unsolved Challenges and Opportunities for Translation.

Microrobots are being explored for biomedical applications, such as drug delivery, biological cargo transport, and minimally invasive surgery. However, current efforts largely focus on proof-of-concept studies with nontranslatable materials through a "" approach, limiting the potential for clinical adaptation. While these proof-of-concept studies have been key to advancing microrobot technologies, we believe that the distinguishing capabilities of microrobots will be most readily brought to patient bedsides through a "" approach, which involves focusing on unsolved problems to inform the design of microrobots with practical capabilities.

Bubble-Based Microrobots with Rapid Circular Motions for Epithelial Pinning and Drug Delivery.

Remotely powered microrobots are proposed as next-generation vehicles for drug delivery. However, most microrobots swim with linear trajectories and lack the capacity to robustly adhere to soft tissues. This limits their ability to navigate complex biological environments and sustainably release drugs at target sites.

Tissue-adhesive hydrogel for multimodal drug release to immune cells in skin.

Both innate and adaptive immune systems play a crucial role in the pathology of skin diseases. To control these cells, there is a need for transdermal drug delivery systems that can target multiple cell populations at independently tunable rates. Herein, we describe a tissue-adhesive hydrogel system that contains particles capable of regulating the release of small molecule drugs at defined rates.

Magnetic systems for cancer immunotherapy.

Immunotherapy is a rapidly developing area of cancer treatment due to its higher specificity and potential for greater efficacy than traditional therapies. Immune cell modulation through the administration of drugs, proteins, and cells can enhance antitumoral responses through pathways that may be otherwise inhibited in the presence of immunosuppressive tumors. Magnetic systems offer several advantages for improving the performance of immunotherapies, including increased spatiotemporal control over transport, release, and dosing of immunomodulatory drugs within the body, resulting in reduced off-target effects and improved efficacy.

Coffee Consumption and C-Reactive Protein Levels: A Systematic Review and Meta-Analysis.

Coffee contains bioactive compounds with anti-inflammatory properties, and its consumption may reduce c-reactive protein (CRP) levels, a biomarker of chronic inflammation. A previous meta-analysis reported no overall association between blood CRP level and coffee consumption by modeling the coffee consumption in categories, with substantial heterogeneity. However, the coffee cup volume was not considered.

Nurse-Driven mHealth Implementation Using the Technology Inpatient Program for Smokers (TIPS): Mixed Methods Study.

Background: Smoking is the leading cause of preventable death and disease, yet implementation of smoking cessation in inpatient settings is inconsistent. The Technology Inpatient Program for Smokers (TIPS) is an implementation program designed to reach smokers with a mobile health (mHealth) intervention using stakeholder-supported strategies.

Objective: The purpose of this study was to determine the impact of the TIPS implementation strategies on smoker-level engagement of the mHealth intervention during care transition.

Estradiol induces BDNF/TrkB signaling in triple-negative breast cancer to promote brain metastases.

Breast cancer brain metastases (BM) affect younger women disproportionally, including those lacking estrogen receptor (ER), progesterone receptor, and HER2 (known as triple-negative breast cancer; TNBC). Previous studies in preclinical models showed that pre-menopausal levels of estradiol (E2) promote TNBC-BM through incompletely understood mechanisms involving reactive astrocytes. Herein, a novel mechanism involving E2-dependent upregulation of brain-derived neurotrophic factor (BDNF) in astrocytes, and subsequent activation of tumor cell tropomyosin kinase receptor B (TrkB), is identified.

Development of Novel Patient-Derived Xenografts from Breast Cancer Brain Metastases.

Brain metastases are an increasing burden among breast cancer patients, particularly for those with HER2 and triple negative (TN) subtypes. Mechanistic insight into the pathophysiology of brain metastases and preclinical validation of therapies has relied almost exclusively on intracardiac injection of brain-homing cells derived from highly aggressive TN MDA-MB-231 and HER2 BT474 breast cancer cell lines. Yet, these well characterized models are far from representing the tumor heterogeneity observed clinically and, due to their fast progression , their suitability to validate therapies for established brain metastasis remains limited.

Post-injury administration of a combination of memantine and 17β-estradiol is protective in a rat model of traumatic brain injury.

Traumatic brain injury (TBI) often leads to substantial adverse cognitive and health outcomes, including permanent disability and death. Preventing these outcomes requires attenuation of the secondary biochemical damage that follows the initial biomechanical insult, but a clinically proven pharmacotherapeutic capable of such has not been identified. In fact, the heterogeneous nature of TBI and the complexity of secondary injury cascades suggest a polytherapeutic approach that targets multiple pathways might be necessary.

17β-estradiol confers protection after traumatic brain injury in the rat and involves activation of G protein-coupled estrogen receptor 1.

Abstract Traumatic brain injury (TBI) is a significant public health problem in the United States. Despite preclinical success of various drugs, to date all clinical trials investigating potential therapeutics have failed. Recently, sex steroid hormones have sparked interest as possible neuroprotective agents after traumatic injury.

Collaborative project to co-ordinate care for patients with dementia.

Health leaders from across Suffolk joined together in a collaborative action-learning project to identify ways of offering more productive and personalised care for patients with dementia and their carers. The project revealed a range of factors necessary for success, notably professional collaboration and effective facilitation. The outcome was a range of evidenced-based recommendations to improve care and efficiency, as well as ensuring that the quality, innovation, productivity and prevention (QIPP) agenda was met.

TLR3 activation stimulates cytokine secretion without altering agonist-induced human small airway contraction or relaxation.

Respiratory infections exacerbate chronic lung diseases promoting airway inflammation and hyperreactivity. Toll-like receptor 3 (TLR3) recognizes viral double-stranded (ds) RNA such as polyinosinic-polycytidylic acid [poly(I:C)] and stimulates innate immune responses. The objective of this study was to test the hypothesis that dsRNA promotes lung inflammation and alters airway responsiveness to cholinergic and beta-adrenergic receptor agonists in human lung slices.

Characterization of the epitope for anti-human respiratory syncytial virus F protein monoclonal antibody 101F using synthetic peptides and genetic approaches.

Chimeric 101F (ch101F) is a mouse-human chimeric anti-human respiratory syncytial virus (HRSV) neutralizing antibody that recognizes residues within antigenic site IV, V, VI of the fusion (F) glycoprotein. The binding of ch101F to a series of peptides overlapping aa 422-438 spanning antigenic site IV, V, VI was analysed. Residues 423-436 comprise the minimal peptide sequence for ch101F binding.

Relationship between the loss of neutralizing antibody binding and fusion activity of the F protein of human respiratory syncytial virus.

To elucidate the relationship between resistance to HRSV neutralizing antibodies directed against the F protein and the fusion activity of the F protein, a recombinant approach was used to generate a panel of mutations in the major antigenic sites of the F protein. These mutant proteins were assayed for neutralizing mAb binding (ch101F, palivizumab, and MAb19), level of expression, post-translational processing, cell surface expression, and fusion activity. Functional analysis of the fusion activity of the panel of mutations revealed that the fusion activity of the F protein is tolerant to multiple changes in the site II and IV/V/VI region in contrast with the somewhat limited spectrum of changes in the F protein identified from the isolation of HRSV neutralizing antibody virus escape mutants.

Contribution of cysteine residues in the extracellular domain of the F protein of human respiratory syncytial virus to its function.

The mature F protein of all known isolates of human respiratory syncytial virus (HRSV) contains fifteen absolutely conserved cysteine (C) residues that are highly conserved among the F proteins of other pneumoviruses as well as the paramyxoviruses. To explore the contribution of the cysteines in the extracellular domain to the fusion activity of HRSV F protein, each cysteine was changed to serine. Mutation of cysteines 37, 313, 322, 333, 343, 358, 367, 393, 416, and 439 abolished or greatly reduced cell surface expression suggesting these residues are critical for proper protein folding and transport to the cell surface.

The cytoplasmic domain of the F protein of Human respiratory syncytial virus is not required for cell fusion.

The cytoplasmic domains of the fusion proteins encoded by several viruses play a role in cell fusion and contain sites for palmitoylation associated with viral protein trafficking and virus assembly. The fusion (F) protein of Human respiratory syncytial virus (HRSV) has a predicted cytoplasmic domain of 26 residues containing a single palmitoylated cysteine residue that is conserved in bovine RSV F protein, but not in the F proteins of other pneumoviruses such as pneumonia virus of mice, human metapneumovirus and avian pneumovirus. The cytoplasmic domains in other paramyxovirus fusion proteins such as Newcastle disease virus F protein play a role in fusion.

Use of a novel cell-based fusion reporter assay to explore the host range of human respiratory syncytial virus F protein.

Human respiratory syncytial virus (HRSV) is an important respiratory pathogen primarily affecting infants, young children, transplant recipients and the elderly. The F protein is the only virion envelope protein necessary and sufficient for virus replication and fusion of the viral envelope membrane with the target host cell. During natural infection, HRSV replication is limited to respiratory epithelial cells with disseminated infection rarely, if ever, occurring even in immunocompromised patients.