Association between combination COVID-19-influenza vaccination and long COVID in middle-aged and older Europeans: A cross-sectional study.

The potential impact of combined COVID-19 and influenza vaccination on long COVID remains uncertain. In the present cross-sectional study, we aimed to investigate the plausible association between them in middle-aged and older Europeans based on the Survey of Health, Ageing, and Retirement in Europe (SHARE). A total of 1910 participants were recruited in the analyses. The study outcome was long COVID. Participants were divided into 4 groups through the self-reported status of COVID-19 and influenza vaccination. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. 1397 participants experienced long COVID. After multivariable adjustment, those vaccinated with neither COVID-19 nor influenza vaccine had higher risk of long COVID (OR, 1.72; 95% CI, 1.26-2.35) compared to those vaccinated with both vaccines. Furthermore, adding the 4 statuses of COVID-19 vaccination/influenza vaccination to conventional risk model improved risk reclassification for long COVID (continuous net reclassification improvement was 16.26% [p = .003], and integrated discrimination improvement was 0.51% [p = .005]). No heterogeneity was found in the subgroup analyses (all p-interaction ≥0.05). Our study might provide a strategy for people aged 50 and over to reduce the occurrence of long COVID, that is, to combine the use of the COVID-19 vaccine and influenza vaccines.

Grip strength affects the association between platelet count and disability-free survival: Evidence from the China Health and Retirement Longitudinal Study.

BACKGROUND AND AIMS: Previous studies found elevated platelet count (PLT), especially long-term persist high or increased PLT was associated with less likelihood disability-free survival (DFS). However, whether grip strength affects the relationship between them is still not elucidated. METHODS: A total of 6252 participants were recruited in the analysis based on the China Health and Retirement Longitudinal Study. The primary outcome was DFS, evaluated by a composite endpoint based on the first occurrence of either disability (having difficulty in at least one of the 6 activities of daily living: namely, dressing, bathing, continence, eating, getting into or out of bed, and toileting) or all-cause mortality. RESULTS: The association of PLT with primary outcome was significantly modified by grip strength (pinteraction = 0.022). The rates of primary outcome were significantly lower among participants with lower baseline PLT in participants with normal grip strength (multivariable odds ratio [OR], 0.67; 95% confidence interval [CI], 0.54-0.84; ptrend < 0.001), but not in those with low grip strength (multivariable OR, 1.70; 95% CI, 0.88-3.15; ptrend = 0.135), for the lowest quartile vs the highest quartile. Adding baseline PLT (quartiles or continuous) to a model containing conventional risk factors significantly improved risk reclassification for primary outcome among those with normal grip strength (most of p < 0.05). CONCLUSION: An inverse dose-response association of PLT with DFS was found among participants with normal grip strength, but not among those with low grip strength. Low grip strength might weaken the benefit of low PLT on DFS among middle-aged and older Chinese.

Biomimetic Lipopolysaccharide-Free Bacterial Outer Membrane-Functionalized Nanoparticles for Brain-Targeted Drug Delivery.

The blood-brain barrier (BBB) severely blocks the intracranial accumulation of most systemic drugs. Inspired by the contribution of the bacterial outer membrane to Escherichia coli K1 (EC-K1) binding to and invasion of BBB endothelial cells in bacterial meningitis, utilization of the BBB invasion ability of the EC-K1 outer membrane for brain-targeted drug delivery and construction of a biomimetic self-assembled nanoparticle with a surface featuring a lipopolysaccharide-free EC-K1 outer membrane are proposed. BBB penetration of biomimetic nanoparticles is demonstrated to occur through the transcellular vesicle transport pathway, which is at least partially dependent on internalization, endosomal escape, and transcytosis mediated by the interactions between outer membrane protein A and gp96 on BBB endothelial cells. This biomimetic nanoengineering strategy endows the loaded drugs with prolonged circulation, intracranial interstitial distribution, and extremely high biocompatibility. Based on the critical roles of gp96 in cancer biology, this strategy reveals enormous potential for delivering therapeutics to treat gp96-overexpressing intracranial malignancies.

Prodrug Delivery Using Dual-Targeting Nanoparticles To Treat Breast Cancer Brain Metastases.

Brain metastases from breast cancer are the most frequent brain metastasis in women, which are often difficult to be surgically removed due to the multifocal and infiltrative intracranial growth patterns. Cytotoxic drugs have potent anti-breast cancer properties. However, owing to the toxic side effects and the blood-brain barrier (BBB), these drugs cannot be fully and aggressively exploited with systemic administration and hence have very limited application for brain metastases. In this study, hyaluronidase-activated prodrug hyaluronic-doxorubicin (hDOX) was assembled by the BBB and metastatic breast cancer dual-targeting nanoparticles (NPs), which were constructed based on transcytosis-targeting peptide and hyaluronic acid co-modified poly(lactic-co-glycolic acid)-poly(ε-carbobenzoxy-l-lysine). hDOX showed enzyme-recovered DNA insertion, selective cytotoxicity to metastatic breast cancer cells rather than astrocytes, and efficient loading into dual-targeting NPs. hDOX@NPs displayed the ability of dually targeting the BBB and metastatic breast cancer and significantly extended the median survival time of mice with intracranial metastatic breast cancer. Based on these improvements, this prodrug delivery tactic may serve as an important direction for drug therapy against brain metastases.

Escape from abluminal LRP1-mediated clearance for boosted nanoparticle brain delivery and brain metastasis treatment.

Breast cancer brain metastases (BCBMs) are one of the most difficult malignancies to treat due to the intracranial location and multifocal growth. Chemotherapy and molecular targeted therapy are extremely ineffective for BCBMs due to the inept brain accumulation because of the formidable blood‒brain barrier (BBB). Accumulation studies prove that low density lipoprotein receptor-related protein 1 (LRP1) is promising target for BBB transcytosis. However, as the primary clearance receptor for amyloid beta and tissue plasminogen activator, LRP1 at abluminal side of BBB can clear LRP1-targeting therapeutics. Matrix metalloproteinase-1 (MMP1) is highly enriched in metastatic niche to promote growth of BCBMs. Herein, it is reported that nanoparticles (NPs-K-s-A) tethered with MMP1-sensitive fusion peptide containing HER2-targeting K and LRP1-targeting angiopep-2 (A), can surmount the BBB and escape LRP1-mediated clearance in metastatic niche. NPs-K-s-A revealed infinitely superior brain accumulation to angiopep-2-decorated NPs-A in BCBMs bearing mice, while comparable brain accumulation in normal mice. The delivered doxorubicin and lapatinib synergistically inhibit BCBMs growth and prolongs survival of mice bearing BCBMs. Due to the efficient BBB penetration, special and remarkable clearance escape, and facilitated therapeutic outcome, the fusion peptide-based drug delivery strategy may serve as a potential approach for clinical management of BCBMs.

Overcoming Mfsd2a-Mediated Low Transcytosis to Boost Nanoparticle Delivery to Brain for Chemotherapy of Brain Metastases.

Microvessels of the blood-brain barrier (BBB) exclusively express the major facilitator superfamily domain-containing protein 2a (Mfsd2a), which is the key transporter for docosahexaenoic acid uptake into the brain. Mfsd2a suppresses caveolae-mediated transcytosis to regulate BBB transcellular permeability via controlling lipid composition of BBB endothelial cells. It is speculated that Mfsd2a can restrain BBB crossing efficiency and brain accumulation efficiency of brain-targeting drug delivery systems, which penetrate the BBB often through the receptor-mediated transcytosis pathway. Transcytosis across the BBB is a crucial bottleneck for targeted chemotherapy of brain metastases. To overcome this issue, a pair of priming nanoparticles (NPs) and following drug-loaded NPs are designed. Tunicamycin-(TM)-loaded transcytosis-targeting-peptide-(TTP)-decorated NPs (TM@TTP) are used to boost BBB transcytosis via inhibiting Mfsd2a. Doxorubicin (DOX)-loaded TTP and CD44-specific hyaluronic acid (HA)-comodified NPs (DOX@TTP-HA) are designed as following drug-loaded NPs. The brain accumulation efficacy of following DOX@TTP-HA with priming is 4.30-fold higher than that without priming through the enhanced transcytosis pathway rather than the tight junction opening. Effective BBB crossing and brain accumulation, selective tumor uptake, excellent antitumor efficacy, and low hepatotoxicity are achieved by TM@TTP and DOX@TTP-HA, suggesting this tactic as a significant therapeutic strategy against breast cancer brain metastases.

PSMA-targeted nanoparticles for specific penetration of blood-brain tumor barrier and combined therapy of brain metastases.

Breast cancer brain metastases (BCBM) represent a major cause of morbidity and mortality among patients with breast cancer. Systemic drug therapy, which is usually effective against peripheral breast cancers, is often ineffective on BCBM due to its poor penetration through the blood-brain tumor barrier (BTB). In this study, prostate-specific membrane antigen (PSMA) with internalization function was found to be specifically up-regulated on BCBM-associated BTB while barely detectable in normal blood-brain barrier (BBB). Here, a nanotechnology approach is reported that can overcome the BTB through ACUPA (A) and cyclic TT1 (cT) co-functionalized nanoparticles (A-NPs-cT). A-NPs-cT selectively target PSMA on BTB for specific BTB crossing and specially bind with p32 for BCBM targeting. We disclosed the effectual synergism of doxorubicin (DOX) and lapatinib (LAP) for BCBM combined therapy. A-NPs-cT exhibited boosted uptake than integrin-targeting RGD-modified NPs in BTB endothelial cells and displayed about 4.57-fold stronger penetration through the BCBM-associated BTB as compared to the normal BBB. In vivo studies showed specific BTB crossing, and remission of BCBM and prolonged survival with DOX and LAP combinatorial regimen. A-NPs-cT based DOX and LAP innovative combined therapy envisioned improved therapeutic intervention for clinical management of BCBM, for which surgery is generally inapplicable and insufficient.

LRP1-upregulated nanoparticles for efficiently conquering the blood-brain barrier and targetedly suppressing multifocal and infiltrative brain metastases.

Brain metastases present mostly multifocal, infiltrative and co-opting growth with the blood-brain barrier (BBB) remaining intact. The BBB, as the barrier of drug delivery to such lesions, is the major cause of the failure of systemic drug therapy and needs to be conquered. Angiopep-2 ligates the low density lipoprotein receptor related protein 1 (LRP1) on brain microvascular endothelial cells (BMECs) to drive transcytosis for BBB crossing. However, besides tight junction, low transcytosis is increasingly deemed to be a crucial factor in restricting BBB permeability. Herein, it is reported that statins-loaded Angiopep-2-anchored nanoparticles (S@A-NPs) can raise LRP1 expression to surmount the low transcytosis of BBB. We demonstrate that S@A-NPs can selectively heighten LRP1 expression on both BMECs and brain metastatic tumor cells, efficiently and self-promotingly penetrate through the BBB and target brain metastases through Angiopep-2 mediated endocytosis and statins induced LRP1 up-regulation. The systemic administration of S@A-NPs loaded with doxorubicin (S@A-NPs/DOX) observably lengthens median survival of mice bearing brain metastases. Due to the efficient BBB passing and brain metastasis targeting, S@A-NPs/DOX may serve as a potential approach for clinical management of brain metastases.

Nanosizing Noncrystalline and Porous Silica Material-Naturally Occurring Opal Shale for Systemic Tumor Targeting Drug Delivery.

Opal shale, as a naturally occurring and noncrystalline silica material with porous structure, has the potential to be a drug delivery carrier. In this study, we obtained opal shale nanoparticles (OS NPs) through the techniques of ultrasonic emulsion and differential centrifugation. The OS NPs exhibited markedly lower cytotoxicity than crystalline mesoporous silica nanoparticles. The highly porous structure and the strong adsorbability endowed OS NPs with the ability of loading and sustained release of doxorubicin (DOX). DOX-loaded OS NPs improved tumor cellular uptake and antiproliferation compared with free drug. Interestingly, OS NPs possessed strong binding with the nuclear envelope, which can be beneficial to the nucleus localization and apoptosis inducing of loaded DOX. We further demonstrated the tumor passive targeting ability, prolonged blood circulation, and enhanced antitumor effect with limited in vivo toxicity. Our results suggest that OS NPs can be applied for tumor targeting drug delivery, which may have a significant influence on the development of silica-based drug delivery system.