Cancer immunotherapy based on image-guided STING activation by nucleotide nanocomplex-decorated ultrasound microbubbles.

The cytosolic innate immune sensor cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial for priming adaptive antitumour immunity through antigen-presenting cells (APCs). Natural agonists, such as cyclic dinucleotides (CDNs), activate the cGAS-STING pathway, but their clinical translation is impeded by poor cytosolic entry and serum stability, low specificity and rapid tissue clearance. Here we developed an ultrasound (US)-guided cancer immunotherapy platform using nanocomplexes composed of 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) electrostatically bound to biocompatible branched cationic biopolymers that are conjugated onto APC-targeting microbubbles (MBs). The nanocomplex-conjugated MBs engaged with APCs and efficiently delivered cGAMP into the cytosol via sonoporation, resulting in activation of cGAS-STING and downstream proinflammatory pathways that efficiently prime antigen-specific T cells. This bridging of innate and adaptive immunity inhibited tumour growth in both localized and metastatic murine cancer models. Our findings demonstrate that targeted local activation of STING in APCs under spatiotemporal US stimulation results in systemic antitumour immunity and improves the therapeutic efficacy of checkpoint blockade, thus paving the way towards novel image-guided strategies for targeted immunotherapy of cancer.

Diabetes Mellitus and Tinnitus: an Epidemiology Study.

Objectives: Tinnitus is the perception of sound that does not arise from an external source. It is a chronic sensation that virtually all would prefer not to experience, but for most people it is not disabling and treatments for disturbing tinnitus are limited. Diabetes causes several side effects, among which its impact on the neural system is one of the most important ones. Considering that the hearing system is part of the neural system, this paper investigates the likelihood of tinnitus occurrence and its potential role of risk factor in patients with type 2 diabetes mellitus (T2DM). Methodology: This study was conducted on 250 patients from the diabetes center of Birjand, Iran. Data from all patients were collected in 2018, using a demographic questionnaire together with a standard questionnaire. Results:Sixty six of the 250 patients in the sample set had tinnitus (26% likelihood of tinnitus occurrence), with 53% of all subjects having minor disorder. A meaningful dependency between patient's age and severity of tinnitus (p <0.05) was found, with tinnitus-related problems becoming more severe among older patients. Also, a meaningful dependency was identified between the duration of diabetes and tinnitus, with the hearing disorder being more severe among patients who had diabetes for more than ten years. No meaningful dependency was found between either patient's gender and tinnitus or the level of fasting blood sugar (FBS) and glycated hemoglobin (HbA1C). The severity of tinnitus was identified. Conclusion:The present study indicates that there is an association between the age of patients with diabetes and the severity of tinnitus. Also, the duration of diabetes impacts the likelihood of having tinnitus. In patients with diabetes, tinnitus can be considered as an indicator of the development of neuropathy or a level of microangiopathy of the inner ear.

Polycarbonate-based ultra-pH sensitive nanoparticles improve therapeutic window.

Stimuli-sensitive nanomaterials with cooperative response are capable of converting subtle and gradual biological variations into robust outputs to improve the precision of diagnostic or therapeutic outcomes. In this study, we report the design, synthesis and characterization of a series of degradable ultra-pH sensitive (dUPS) polymers that amplify small acidic pH changes to efficacious therapeutic outputs. A hydrolytically active polycarbonate backbone is used to construct the polymer with pH-dependent degradation kinetics. One dUPS polymer, PSC7A, can achieve activation of the stimulator of interferon genes and antigen delivery upon endosomal pH activation, leading to T cell-mediated antitumor immunity. While a non-degradable UPS polymer induces granulomatous inflammation that persists over months at the injection site, degradable PSC7A primes a transient acute inflammatory response followed by polymer degradation and complete tissue healing. The improved therapeutic window of the dUPS polymers opens up opportunities in pH-targeted drug and protein therapy.