Prioritization and Meta-analysis of regulatory SNPs identified IL6, TGFB1, TLR9 and MMP7 as significantly associated with cervical cancer.

Cervical cancer is a leading women cancer globally with respect to both incidence and mortality. Its increased risk has been linked with HPV infection and genetic variations like single nucleotide polymorphisms (SNPs). Although, studies have been published which evaluates the effect of SNPs in a few candidate genes, however the role of number of regulatory SNPs (rSNPs) in cervical cancer is not available. As literature evidence has shown that non-coding rSNPs are related with increasing cervical cancer risk, we undertook this study to prioritize the important rSNPs and elucidate their role. A search was conducted in PubMed up to December 2020, which led to the identification of 263 articles and 969 SNPs in the non-coding region. These 969 SNPs were analysed through rSNPBase and RegulomeDB, leading to identification of 105 rSNPs. Afterwards, a regulatory module was constructed using protein-protein interaction data and a hub of highly interacting 23 target genes (corresponding to 34 rSNPs) was identified using MCODE. To further understand the mechanism of action of the 34 rSNPs, their transcription factor information with respect to cervical cancer was retrieved. To evaluate the pooled effect of these prioritized polymorphisms in cervical cancer patients, a meta-analysis was performed on 10,537 cases and 11,252 controls from 30 studies corresponding to 8 rSNPs. It led to identification of polymorphisms in IL6 (rs2069837), TGFB1 (rs1800469), TLR9 (rs187084) and MMP7 (rs11568818) which are significantly (p < 0.05) associated with increased cervical cancer risk at the population level. Overall, the study demonstrates that rSNPs targeting immune and inflammatory genes (IL1B, IL6, IL10, IL18, TGFB1, CCR5, CD40, TLR9, and MMP7) are associated with cervical cancer.

Enhanced Detection of Desmoplasia by Targeted Delivery of Iron Oxide Nanoparticles to the Tumour-Specific Extracellular Matrix.

Diagnostic imaging of aggressive cancer with a high stroma content may benefit from the use of imaging contrast agents targeted with peptides that have high binding affinity to the extracellular matrix (ECM). In this study, we report the use of superparamagnetic iron-oxide nanoparticles (IO-NP) conjugated to a nonapeptide, CSGRRSSKC (CSG), which specifically binds to the laminin-nidogen-1 complex in tumours. We show that CSG-IO-NP accumulate in tumours, predominantly in the tumour ECM, following intravenous injection into a murine model of pancreatic neuroendocrine tumour (PNET). In contrast, a control untargeted IO-NP consistently show poor tumour uptake, and IO-NP conjugated to a pentapeptide. CREKA that bind fibrin clots in blood vessels show restricted uptake in the angiogenic vessels of the tumours. CSG-IO-NP show three-fold higher intratumoral accumulation compared to CREKA-IO-NP. Magnetic resonance imaging (MRI) T2-weighted scans and T2 relaxation times indicate significant uptake of CSG-IO-NP irrespective of tumour size, whereas the uptake of CREKA-IO-NP is only consistent in small tumours of less than 3 mm in diameter. Larger tumours with significantly reduced tumour blood vessels show a lack of CREKA-IO-NP uptake. Our data suggest CSG-IO-NP are particularly useful for detecting stroma in early and advanced solid tumours.

Immune-mediated ECM depletion improves tumour perfusion and payload delivery.

High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin-nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα.

Biocompatibility and Targeting Efficiency of Encapsulated Quinapyramine Sulfate-Loaded Chitosan-Mannitol Nanoparticles in a Rabbit Model of Surra.

Quinapyramine sulfate (QS) produces trypanocidal effects against the parasite Trypanosoma evansi but is often poorly tolerated and causes serious reactions in animals. The encapsulation of QS in chitosan-mannitol to provide sustained release would improve both the therapeutic effect of QS and the quality of life of animals treated with this formulation. QS was encapsulated into a nanoformulation prepared from chitosan, tripolyphosphate, and mannitol nanomatrix (ChQS-NPs). ChQS-NPs were well ordered in shape, with nanoparticle size, as determined by transmission electron microscopy and atomic force microscopy. Our research revealed dose-dependent effects on biosafety and DNA damage in mammalian cells treated with ChQS-NPs. ChQS-NPs were absolutely risk-free at effective as well as many times higher doses against T. evansi ChQS-NPs were effective in rabbits, as they killed the parasites, relieving the animals from the clinical symptoms of the disease. The extent of this protection was similar to that observed with the conventional drug at higher dosages (5 mg QS/kg of body weight). ChQS-NPs are safe, nontoxic, and more effective than QS and offer a promising alternative to drug delivery against surra in animal models. ChQS-NPs may be useful for the treatment of surra due to reduced dosages and frequency of administration.