Diabetes is a global eye health issue. Given the rising in diabetes prevalence and ageing population, this poses significant challenge to perform diabetic retinopathy (DR) screening for these ...patients. Artificial intelligence (AI) using machine learning and deep learning have been adopted by various groups to develop automated DR detection algorithms. This article aims to describe the state-of-art AI DR screening technologies that have been described in the literature, some of which are already commercially available. All these technologies were designed using different training datasets and technical methodologies. Although many groups have published robust diagnostic performance of the AI algorithms for DR screening, future research is required to address several challenges, for examples medicolegal implications, ethics, and clinical deployment model in order to expedite the translation of these novel technologies into the healthcare setting.
Background Asthma is related to airway inflammation and oxidative stress. High levels of reactive oxygen and nitrogen species can induce cytotoxic DNA damage. Nevertheless, little is known about the ...possible role of allergen-induced DNA damage and DNA repair as modulators of asthma-associated pathology. Objective We sought to study DNA damage and DNA damage responses induced by house dust mite (HDM) in vivo and in vitro. Methods We measured DNA double-strand breaks (DSBs), DNA repair proteins, and apoptosis in an HDM-induced allergic asthma model and in lung samples from asthmatic patients. To study DNA repair, we treated mice with the DSB repair inhibitor NU7441. To study the direct DNA-damaging effect of HDM on human bronchial epithelial cells, we exposed BEAS-2B cells to HDM and measured DNA damage and reactive oxygen species levels. Results HDM challenge increased lung levels of oxidative damage to proteins (3-nitrotyrosine), lipids (8-isoprostane), and nucleic acid (8-oxoguanine). Immunohistochemical evidence for HDM-induced DNA DSBs was revealed by increased levels of the DSB marker γ Histone 2AX (H2AX) foci in bronchial epithelium. BEAS-2B cells exposed to HDM showed enhanced DNA damage, as measured by using the comet assay and γH2AX staining. In lung tissue from human patients with asthma, we observed increased levels of DNA repair proteins and apoptosis, as shown by caspase-3 cleavage, caspase-activated DNase levels, and terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling staining. Notably, NU7441 augmented DNA damage and cytokine production in the bronchial epithelium and apoptosis in the allergic airway, implicating DSBs as an underlying driver of asthma pathophysiology. Conclusion This work calls attention to reactive oxygen and nitrogen species and HDM-induced cytotoxicity and to a potential role for DNA repair as a modulator of asthma-associated pathophysiology.
The discovery of vitamin E (α-tocopherol) began in 1922 as a vital component required in reproduction. Today, there are eight naturally occurring vitamin E isoforms, namely α-, β-, γ- and ...δ-tocopherol and α-, β-, γ- and δ-tocotrienol. Vitamin E is potent antioxidants, capable of neutralizing free radicals directly by donating hydrogen from its chromanol ring. α-Tocopherol is regarded the dominant form in vitamin E as the α-tocopherol transfer protein in the liver binds mainly α-tocopherol, thus preventing its degradation. That contributed to the oversight of tocotrienols and resulted in less than 3% of all vitamin E publications studying tocotrienols. Nevertheless, tocotrienols have been shown to possess superior antioxidant and anti-inflammatory properties over α-tocopherol. In particular, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase to lower cholesterol, attenuating inflammation via downregulation of transcription factor NF-κB activation, and potent radioprotectant against radiation damage are some properties unique to tocotrienols, not tocopherols. Aside from cancer, vitamin E has also been shown protective in bone, cardiovascular, eye, nephrological and neurological diseases. In light of the different pharmacological properties of tocopherols and tocotrienols, it becomes critical to specify which vitamin E isoform(s) are being studied in any future vitamin E publications. This review provides an update on vitamin E therapeutic potentials, protective effects and modes of action beyond cancer, with comparison of tocopherols against tocotrienols. With the concerted efforts in synthesizing novel vitamin E analogs and clinical pharmacology of vitamin E, it is likely that certain vitamin E isoform(s) will be therapeutic agents against human diseases besides cancer.
Summary Lung cancer is a leading cause of cancer-related mortality worldwide, and is classically divided into two major histological subtypes: non-small-cell lung cancer (NSCLC) and small-cell lung ...cancer (SCLC). Although NSCLC and SCLC are considered distinct entities with different genomic landscapes, emerging evidence highlights a convergence in therapeutically relevant targets for both histologies. In adenocarcinomas with defined alterations such as EGFR mutations and ALK translocations, targeted therapies are now first-line standard of care. By contrast, many experimental and targeted agents remain largely unsuccessful for SCLC. Intense preclinical research and clinical trials are underway to exploit unique traits of lung cancer, such as oncogene dependency, DNA damage response, angiogenesis, and cellular plasticity arising from presence of cancer stem cell lineages. In addition, the promising clinical activity observed in NSCLC in response to immune checkpoint blockade has spurred great interest in the field of immunooncology, with the scope to develop a diverse repertoire of synergistic and personalised immunotherapeutics. In this Review, we discuss novel therapeutic agents for lung cancer that are in early-stage development, and how prospective clinical trials and drug development may be shaped by a deeper understanding of this heterogeneous disease.
Lung cancer has traditionally been classified by histology. However, a greater understanding of disease biology and the identification of oncogenic driver alterations has dramatically altered the ...therapeutic landscape. Consequently, the new classification paradigm of non-small-cell lung cancer is further characterized by molecularly defined subsets actionable with targeted therapies and the treatment landscape is becoming increasingly complex. This review encompasses the current standards of care for targeted therapies in lung cancer with driver molecular alterations. Targeted therapies for
exon 19 deletion and L858R mutations, and
and
rearrangements are well established. However, there is an expanding list of approved targeted therapies including for
V600E,
exon 20 insertion, and
G12C mutations,
exon 14 alterations, and
and
rearrangements. In addition, there are numerous other oncogenic drivers, such as
exon 20 insertion mutations, for which there are emerging efficacy data for targeted therapies. The importance of diagnostic molecular testing, intracranial efficacy of novel therapies, the optimal sequencing of therapies, role for targeted therapies in early-stage disease, and future directions for precision oncology approaches to understand tumor evolution and therapeutic resistance are also discussed.
The gene encoding the receptor-tyrosine kinase RET was first discovered more than three decades ago, and activating RET rearrangements and mutations have since been identified as actionable drivers ...of oncogenesis. Several multikinase inhibitors with activity against RET have been explored in the clinic, and confirmed responses to targeted therapy with these agents have been observed in patients with RET-rearranged lung cancers or RET-mutant thyroid cancers. Nevertheless, response rates to RET-directed therapy are modest compared with those achieved using targeted therapies matched to other oncogenic drivers of solid tumours, such as sensitizing EGFR or BRAF
mutations, or ALK or ROS1 rearrangements. To date, no RET-directed targeted therapeutic has received regulatory approval for the treatment of molecularly defined populations of patients with RET-mutant or RET-rearranged solid tumours. In this Review, we discuss how emerging data have informed the debate over whether the limited success of multikinase inhibitors with activity against RET can be attributed to the tractability of RET as a drug target or to the lack, until 2017, of highly specific inhibitors of this oncoprotein in the clinic. We emphasize that novel approaches to targeting RET-dependent tumours are necessary to improve the clinical efficacy of single-agent multikinase inhibition and, thus, hasten approvals of RET-directed targeted therapies.
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Andrographis paniculata has long been part of the traditional herbal medicine system in Asia and in Scandinavia. Andrographolide was isolated as a major bioactive constituent of A. ...paniculata in 1951, and since 1984, andrographolide and its analogs have been scrutinized with modern drug discovery approach for anti-inflammatory properties. With this accumulated wealth of pre-clinical data, it is imperative to review and consolidate different sources of information, to decipher the major anti-inflammatory mechanisms of action in inflammatory diseases, and to provide direction for future studies. Andrographolide and its analogs have been shown to provide anti-inflammatory benefits in a variety of inflammatory disease models. Among the diverse signaling pathways investigated, inhibition of NF-κB activity is the prevailing anti-inflammatory mechanism elicited by andrographolide. There is also increasing evidence supporting endogenous antioxidant defense enhancement by andrographolide through Nrf2 activation. However, the exact pathway leading to NF-κB and Nrf2 activation by andrographolide has yet to be elucidated. Validation and consensus on the major mechanistic actions of andrographolide in different inflammatory conditions are required before translating current findings into clinical settings. There are a few clinical trials conducted using andrographolide in fixed combination formulation which have shown anti-inflammatory benefits and good safety profile. A concerted effort is definitely needed to identify potent andrographolide lead compounds with improved pharmacokinetics and toxicological properties. Taken together, andrographolide and its analogs have great potential to be the next new class of anti-inflammatory agents, and more andrographolide molecules are likely moving towards clinical study stage in the near future.
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Molecular targets modulated by artemisinins in respiratory diseases.
Artemisinins are sesquiterpene lactones with a peroxide moiety that are isolated from the herb Artemisia annua. It ...has been used for centuries for the treatment of fever and chills, and has been recently approved for the treatment of malaria due to its endoperoxidase properties. Progressively, research has found that artemisinins displayed multiple pharmacological actions against inflammation, viral infections, and cell and tumour proliferation, making it effective against diseases. Moreover, it has displayed a relatively safe toxicity profile. The use of artemisinins against different respiratory diseases has been investigated in lung cancer models and inflammatory-driven respiratory disorders. These studies revealed the ability of artemisinins in attenuating proliferation, inflammation, invasion, and metastasis, and in inducing apoptosis. Artemisinins can regulate the expression of pro-inflammatory cytokines, nuclear factor-kappa B (NF-κB), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), promote cell cycle arrest, drive reactive oxygen species (ROS) production and induce Bak or Bax-dependent or independent apoptosis. In this review, we aim to provide a comprehensive update of the current knowledge of the effects of artemisinins in relation to respiratory diseases to identify gaps that need to be filled in the course of repurposing artemisinins for the treatment of respiratory diseases. In addition, we postulate whether artemisinins can also be repurposed for the treatment of COVID-19 given its anti-viral and anti-inflammatory properties.
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