The use of nanoparticles for targeted drug delivery in non-small cell lung cancer

Lung cancer is a global health problem affecting millions of people each year. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer with various conventional treatment available in the clinic. Application of these treatments alone often results in high rates of cancer reoccurrence and metastasis. In addition, they can cause damage to healthy tissues, resulting in many adverse effects. Nanotechnology has emerged as a modality for the treatment of cancer. When used in combination with nanoparticles, it is possible to improve the pharmacokinetic and pharmacodynamic profiles of pre-existing drugs used in cancer treatment. Nanoparticles have physiochemical properties such as small size which allowing passage through challenging areas of the body, and large surface area allows for higher doses of drugs to be brought to the tumor site. Nanoparticles can be functionalized which involves modifying the surface chemistry of the particles and allows for the conjugation of ligands (small molecules, antibodies, and peptides). Ligands can be chosen for their ability to target components that are specific to or are upregulated in cancer cells, such as targeting receptors on the tumor surface that are highly expressed in the cancer. This ability to precisely target the tumor can improve the efficacy of drugs and decrease toxic side effects. This review will discuss approaches used for targeting drugs to tumors using nanoparticles, provide examples of how this has been applied in the clinic and highlight future prospects for this technology

The use of nanoparticles for targeted drug delivery in non-small cell lung cancer

PM003/2016). CL and EO acknowledge the funding provided by the Associate Laboratory for Green Chemistry LAQV which is financed by national funds from FCT/MCTES, Fundação para a Ciência e a Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior, through the projects UIDB/50006/2020 and UIDP/50006/2020. E.O. thanks the CEEC contract CEECIND/00648/2017to the FCT/MCTES. Publisher Copyright: Copyright © 2023 Holder, Ferguson, Oliveira, Lodeiro, Trim, Byrne, Bertolo and Wilson.Lung cancer is a global health problem affecting millions of people each year. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer with various conventional treatment available in the clinic. Application of these treatments alone often results in high rates of cancer reoccurrence and metastasis. In addition, they can cause damage to healthy tissues, resulting in many adverse effects. Nanotechnology has emerged as a modality for the treatment of cancer. When used in combination with nanoparticles, it is possible to improve the pharmacokinetic and pharmacodynamic profiles of pre-existing drugs used in cancer treatment. Nanoparticles have physiochemical properties such as small size which allowing passage through challenging areas of the body, and large surface area allows for higher doses of drugs to be brought to the tumor site. Nanoparticles can be functionalized which involves modifying the surface chemistry of the particles and allows for the conjugation of ligands (small molecules, antibodies, and peptides). Ligands can be chosen for their ability to target components that are specific to or are upregulated in cancer cells, such as targeting receptors on the tumor surface that are highly expressed in the cancer. This ability to precisely target the tumor can improve the efficacy of drugs and decrease toxic side effects. This review will discuss approaches used for targeting drugs to tumors using nanoparticles, provide examples of how this has been applied in the clinic and highlight future prospects for this technology.publishersversionpublishe

A new role under sortilin's belt in cancer.

The neurotensin receptor-3 also known as sortilin was the first member of the small family of vacuolar protein sorting 10 protein domain (Vps10p) discovered two decades ago in the human brain. The expression of sortilin is not confined to the nervous system but sortilin is ubiquitously expressed in many tissues. Sortilin has multiple roles in the cell as a receptor or a co-receptor, in protein transport of many interacting partners to the plasma membrane, to the endocytic pathway and to the lysosomes for protein degradation. Sortilin could be considered as the cells own shuttle system. In many human diseases including neurological diseases and cancer, sortilin expression has been shown to be deregulated. In addition, some studies have highlighted that the extracellular domain of sortilin is shedded into the culture media by an unknown mechanism. Sortilin can be released in exosomes and appears to control some mechanisms of exosome biogenesis. In lung cancer cells, sortilin can associate with two receptor tyrosine kinase receptors called the TES complex found in exosomes. Exosomes carrying the TES complex can convey a microenvironment control through the activation of ErbB signaling pathways and the release of angiogenic factors. Deregulation of sortilin function is now emerging to be implicated in four major human diseases- cardiovascular disease, Type 2 diabetes mellitus, Alzheimer’s disease and cancer

Natural Killer T Cell Ligand α-Galactosylceramide Enhances Protective Immunity Induced by Malaria Vaccines

The important role played by CD8+ T lymphocytes in the control of parasitic and viral infections, as well as tumor development, has raised the need for the development of adjuvants capable of enhancing cell-mediated immunity. It is well established that protective immunity against liver stages of malaria parasites is primarily mediated by CD8+ T cells in mice. Activation of natural killer T (NKT) cells by the glycolipid ligand, α-galactosylceramide (α-GalCer), causes bystander activation of NK, B, CD4+, and CD8+ T cells. Our study shows that coadministration of α-GalCer with suboptimal doses of irradiated sporozoites or recombinant viruses expressing a malaria antigen greatly enhances the level of protective anti-malaria immunity in mice. We also show that coadministration of α-GalCer with various different immunogens strongly enhances antigen-specific CD8+ T cell responses, and to a lesser degree, Th1-type responses. The adjuvant effects of α-GalCer require CD1d molecules, Vα14 NKT cells, and interferon γ. As α-GalCer stimulates both human and murine NKT cells, these findings should contribute to the design of more effective vaccines against malaria and other intracellular pathogens, as well as tumors

Non-small cell lung carcinoma (NSCLC): Implications on molecular pathology and advances in early diagnostics and therapeutics.

Continuous revision of the histologic and stage-wise classification of lung cancer by the World Health Organization (WHO) provides the foundation for therapeutic advances by promoting molecular targeted and immunotherapies and ensuring accurate diagnosis. Cancer epidemiologic data provide helpful information for cancer prevention, diagnosis, and management, supporting health-care interventions. Global cancer mortality projections from 2016 to 2060 show that cancer will overtake ischemic heart diseases (IHD) as the leading cause of death (18.9 million) immediately after 2030, surpassing non-small cell lung cancer (NSCLC), which accounts for 85 percent of lung cancers. The clinical stage at the diagnosis is the main prognostic factor in NSCLC therapies. Advanced early diagnostic methods are essential as the initial stages of cancer show reduced mortality compared to the advanced stages. Sophisticated approaches to proper histological classification and NSCLC management have improved clinical efficiency. Although immune checkpoint inhibitors (ICIs) and targeted molecular therapies have refined the therapeutic management of late-stage NSCLC, the specificity and sensitivity of cancer biomarkers should be improved by focusing on prospective studies, followed by their use as therapeutic tools. The liquid biopsy candidates such as circulating tumor cells (CTCs), circulating cell-free tumor DNA (cfDNA), tumor educated platelets (TEP), and extracellular vesicles (EVs) possess cancer-derived biomolecules and aid in tracing: driver mutations leading to cancer, acquired resistance caused by various generations of therapeutic agents, refractory disease, prognosis, and surveillance. [Abstract copyright: © 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

Alternative Splicing and Protein Diversity: Plants Versus Animals

Plants, unlike animals, exhibit a very high degree of plasticity in their growth and development and employ diverse strategies to cope with the variations during diurnal cycles and stressful conditions. Plants and animals, despite their remarkable morphological and physiological differences, share many basic cellular processes and regulatory mechanisms. Alternative splicing (AS) is one such gene regulatory mechanism that modulates gene expression in multiple ways. It is now well established that AS is prevalent in all multicellular eukaryotes including plants and humans. Emerging evidence indicates that in plants, as in animals, transcription and splicing are coupled. Here, we reviewed recent evidence in support of co-transcriptional splicing in plants and highlighted similarities and differences between plants and humans. An unsettled question in the field of AS is the extent to which splice isoforms contribute to protein diversity. To take a critical look at this question, we presented a comprehensive summary of the current status of research in this area in both plants and humans, discussed limitations with the currently used approaches and suggested improvements to current methods and alternative approaches. We end with a discussion on the potential role of epigenetic modifications and chromatin state in splicing memory in plants primed with stresses

Novel Transcriptional and DNA Methylation Abnormalities of SORT1 Gene in Non-Small Cell Lung Cancer.

Sortilin is an important regulator with potential tumour-suppressor function by limiting EGFR signalling. In this study, we undertook a comprehensive expression analysis of sortilin transcript variants and the DNA methylation status of their corresponding promoters in human non-small cell carcinomas (NSCLCs). RNA/DNA was extracted from 81 NSCLC samples and paired normal tissue. mRNA expression was measured by qPCR and DNA methylation determined by pyrosequencing. BigDye-terminator sequencing was used to confirm exon-8 alternative splicing. Results demonstrated that both SORT1A and SORT1B variants were downregulated in lung tumours. The SORT1A/SORT1B expression ratio was higher in tumours compared to normal tissue. SORT1B promoter hypermethylation was detected in lung tumours compared to normal lung (median difference 14%, Mann-Whitney test p = 10-6). Interestingly, SORT1B is hypermethylated in white blood cells, but a small and very consistent drop in methylation (6%, p = 10-15) was observed in the lung cancer cases compared to control subjects. We demonstrate that the SORT1B exon-8 splice variation, reported in sequence databases, is also a feature of SORT1A. The significantly altered quantitative and qualitative characteristics of sortilin mRNA in NSCLC indicate a significant involvement in tumour pathogenesis and may have significant impact for its utility as a predictive marker in lung cancer management

A multi-omics study of circulating phospholipid markers of blood pressure.

High-throughput techniques allow us to measure a wide-range of phospholipids which can provide insight into the mechanisms of hypertension. We aimed to conduct an in-depth multi-omics study of various phospholipids with systolic blood pressure (SBP) and diastolic blood pressure (DBP). The associations of blood pressure and 151 plasma phospholipids measured by electrospray ionization tandem mass spectrometry were performed by linear regression in five European cohorts (n = 2786 in discovery and n = 1185 in replication). We further explored the blood pressure-related phospholipids in Erasmus Rucphen Family (ERF) study by associating them with multiple cardiometabolic traits (linear regression) and predicting incident hypertension (Cox regression). Mendelian Randomization (MR) and phenome-wide association study (Phewas) were also explored to further investigate these association results. We identified six phosphatidylethanolamines (PE 38:3, PE 38:4, PE 38:6, PE 40:4, PE 40:5 and PE 40:6) and two phosphatidylcholines (PC 32:1 and PC 40:5) which together predicted incident hypertension with an area under the ROC curve (AUC) of 0.61. The identified eight phospholipids are strongly associated with triglycerides, obesity related traits (e.g. waist, waist-hip ratio, total fat percentage, body mass index, lipid-lowering medication, and leptin), diabetes related traits (e.g. glucose, insulin resistance and insulin) and prevalent type 2 diabetes. The genetic determinants of these phospholipids also associated with many lipoproteins, heart rate, pulse rate and blood cell counts. No significant association was identified by bi-directional MR approach. We identified eight blood pressure-related circulating phospholipids that have a predictive value for incident hypertension. Our cross-omics analyses show that phospholipid metabolites in the circulation may yield insight into blood pressure regulation and raise a number of testable hypothesis for future research

Genetic association and characterization of FSTL5 in isolated clubfoot

ACKNOWLEDGEMENTS: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The authors thank the staff and participants of the ARIC study for their important contributions. Funding for GENEVA was provided by National Human Genome Research Institute grant U01HG004402 (E.Boerwinkle). We thank H. Hobbs and J. Cohen for contributing control samples for replication genotyping, Nadav Ahituv for sharing RNA-seq data for both bat and mouse embryonic limb buds, Tommy Hyatt for designing the custom genotyping assay, and members of the UT Southwestern Transgenic Core facility, including John Ritter, Mylinh Nguyen, and Robert Hammer. Publicly available mouse embryonic expression analysis results were provided online at https://oncoscape.v3.sttrcancer.org/atlas.gs.washington.edu.mouse.rna/landing (24). The authors acknowledge the contributions and support of the Center for Excellence in Clubfoot Research at Scottish Rite for Children, including Shawne Faulks and Kristhen Atala. Fstl5 mutant rats were produced by the NIH Mutant Rat Resource at UT Southwestern Medical Center (R24RR03232601, R24OD011108, R01HD036022, and (5R01HD053889). This study was supported by funding from the Scottish Rite for Children Research Fund (J.J.R.), Shriners Hospital for Children (J.T.H), and the National Institutes of Health award R01HD043342 (J.T.H.).Peer reviewedPostprin