Biology subjects

Hafeez, N.

Publications and source records attributed to Hafeez, N..

3 recordsLinked to original sources

bioRxiv2026

Systemic Nanobubbles Enable Ultrasound-Guided STING Immunotherapy in Breast Cancer

Activation of the STING pathway can induce potent antitumor immunity, but effective delivery of STING agonists to the tumor while limiting systemic exposure remains challenging. We previously developed MUSIC, an ultrasound-guided platform that uses microbubbles (MBs) to deliver the STING agonist 2'3'-cGAMP and locally activate antitumor immunity. However, the vascular confinement of MBs and the need for intratumoral administration limit the potential for systemic tumor targeting. To overcome these limitations, we developed SONATA (Systemic Oncotherapy using Nanobubbles for Acoustically-guided Tumor Activation), which employs nanobubbles (NBs) that are approximately 10-fold smaller than conventional MBs, enabling systemic administration and tumor extravasation. Following NB accumulation within tumors, ultrasound exposure triggers localized cGAMP release, facilitating delivery to targeted CD11b+ antigen-presenting cells (APCs) and STING activation with spatial and temporal control. NBs are composed of the same components as MBs, including phospholipid shells and a perfluorobutane core and are functionalized with anti-CD11b antibodies to target CD11b+ APCs and spermine-modified dextran to stably load cGAMP through nanocomplex formation. Upon ultrasound activation, SONATA induced phosphorylation of STING, TBK1, and IRF3 and increased IFN-{beta} production in bone marrow-derived macrophages. In an orthotopic breast cancer model, intravenously administered SONATA combined with tumor-localized ultrasound significantly inhibited tumor growth compared with controls. Furthermore, SONATA synergized with immune checkpoint blockade prolonged the median survival of tumor-bearing mice. Collectively, these findings establish SONATA as a systemically administered immunotherapy platform that enables ultrasound-guided, spatially controlled STING activation.

bioengineering↗

bioRxiv2024

Decoupling of GABA and Glutamine-Glutamate Dynamics and their role in tactile perception: An fMRS Study

Tactile processing is fundamental for our daily lives. In particular, adaptation, the mechanism by which neural (and behavioural) responses change due to repeated stimulation, is key in adjusting our responses to the environment and is often affected in neurodevelopmental conditions such as autism and ADHD. While GABA and glutamate--the main inhibitory and excitatory neurotransmitters-- are known to be fundamental for encoding sensory input, we know little regarding the dynamic responses of the GABA and glutamatergic systems during tactile processing. Here, we examine how GABA and glutamine+glutamate (Glx) in vivo dynamics change during repetitive tactile stimulation and how these changes relate to tactile perception in a healthy population, using functional magnetic resonance spectroscopy (fMRS). Our study showed that repetitive tactile stimulation induced a decoupling between GABA and Glx during the first stimulation blocks as suggested by a negative correlation between GABA and Glx, which changed from a positive correlation at baseline. Subsequently, a multivariate time series analysis showed a predictive temporal relationship between Glx and GABA, showing that changes in these metabolites are temporally linked with an estimated lag of 6 seconds informing on a complex metabolite response function. The absence of gross metabolite change suggests that Glx and GABA adjust in relation to each other in response to repeated tactile stimulation. Furthermore, individual differences in the changed GABA and Glx levels correlated with perceptual measures of touch. Together, our study highlights the complex relationship between GABA and glutamate in tactile processing and demonstrates that experience-dependence plasticity induces a decoupling between these key metabolites. Further study into their dynamic interplay may be key to understanding adaptation as meso-levels in the brain and how these mechanisms differ in neurodevelopmental and neurological conditions.

neuroscience↗

bioRxiv2024

Post-transcriptional regulation of IFI16 promotes inflammatory endothelial pathophenotypes observed in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease driven by endothelial cell inflammation and dysfunction, resulting in the pathological remodeling of the pulmonary vasculature. Innate immune activation has been linked to PAH development; however, the regulation, propagation, and reversibility of the induction of inflammation in PAH is poorly understood. Here, we demonstrate a role for interferon inducible protein 16 (IFI16), an innate immune sensor, as a modulator of endothelial inflammation in pulmonary hypertension, utilizing human pulmonary artery endothelial cells (PAECs). Inflammatory stimulus of PAECs with IL-1{beta} up-regulates IFI16 expression, inducing proinflammatory cytokine up-regulation and cellular apoptosis. IFI16 mRNA stability is regulated by post-transcriptional m6A modification, mediated by Wilms tumor 1-associated protein (WTAP), a structural stabilizer of the methyltransferase complex, via regulation of m6A methylation of IFI16. Additionally, m6A levels are increased in the peripheral blood mononuclear cells of PAH patients compared to control, indicating that quantifying this epigenetic change in patients may hold potential as a biomarker for disease identification. In summary, our study demonstrates IFI16 mediates inflammatory endothelial pathophenotypes seen in pulmonary arterial hypertension.

cell biology↗