Personalized Medicine in Lung Cancer
II-Jin Kim in Cancer Genetics and Genomics for Personalized Medicine, 2017
This chemotherapeutic agent is one of the most widely used pyrimidine analogues, with a very well established role in first-line treatment of advanced NSCLC. Several studies have examined molecular determinants of sensitivity to gemcitabine. Potential candidates to predict response include genes encoding drug metabolism enzymes, transport across membranes, or target proteins. One example is human equilibrative nucleoside transporter 1 (hENT1), which transports gemcitabine into cells. hENT1 basal expression levels have been correlated with IC50 values for gemcitabine in several NSCLC cell lines.25 Also, expression of hENT1 has been analyzed by IHC, suggesting that absence of hENT1 expression may be used to predict response to gemcitabine-based chemotherapy.26 Nevertheless, prospective studies are still required to validate this and the most accurate determination method remains to be decided.
Drugs of Abuse and Addiction
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
Alcohol is the most addictive drug used. Like nicotine, alcohol is also a part of second class of mechanistic classification of drugs (Morrow, 1995; Koob et al., 1998). No single receptor is involved in effect of alcohol. Alcohol alters quite a range of receptors like GABA receptors, nAChR, NMDA receptors, GIRK channels (Morrow, 1995; Koob et al., 1998; Luscher et al., 2006). Apart from these, adenosine re-uptake is also influenced by alcohol by obstructing the equilibrative nucleoside transporter (ENT1). Alcohol also increases dopamine release like all other drugs but the exact mechanism behind this is not known in the case of alcohol (Morrow, 1995; Koob et al., 1998). This increase can be due to direct excitation of DA neurons or may be due to any other altered receptor. Involvement of all the different receptors in the action pathway of alcohol make it unclear what is the actual reason of its addiction (Koob et al., 1998; Morrow, 1995).
Cancer Biomarkers
Trevor F. Cox in Medical Statistics for Cancer Studies, 2022
We look at a study of two predictive biomarkers for pancreatic cancer, dihydropyrimidine dehydrogenase (DPD) and human equilibrative nucleoside transporter-1 (hENT1)[19]. Tumour tissue samples had been taken, prior to treatment, from patients who received chemotherapy treatment by GEM or 5FU in the ESPAC3 trial and stored in freezers at very low temperature. Cores taken from these tissue samples were placed in tissue microarrays, from which sections were cut and placed on slides, there being between four and eight sections per patient. The sections were stained so that DPD could be measured and then each was scored on a 0–3 point system by two pathologists: 0 – no staining, 1 – weak, 2 – moderate, 3 – strong staining. The more staining there is, the higher the DPD expression in the tumour. A patient's final score was taken as the mean, to the nearest integer, over all their section scores. This was converted to low and high DPD expression status; low-scores were 0,1; high-scores were 2,3. The hENT1 scores had been found for the patients in a previous translational study, using staining and determining a cutpoint to assess hENT1 expression as low and high. We will carry out some statistical analyses similar to those that appear in the DPD/hENT1 publication.
Effects of ticagrelor monotherapy vs. clopidogrel monotherapy on platelet reactivity: a randomized, crossover clinical study (SINGLE study)
Published in Platelets, 2022
Meijiao He, Wei Yan, Yun Zhang, Yihui Kong, Xuejie Han, Jie Ren, Zhongyang Zhao, Guangzhong Liu, Jing Shi, Yue Li
Clopidogrel is a prodrug requiring cytochrome P450 (CYP) enzymes for its biotransformation into active thiol metabolite[23]. Ticagrelor is an orally administered, direct-acting, reversibly-binding P2Y12 receptor antagonist. The equilibrative nucleoside transporter 1 inhibition is rapidly absorbed and activated [24,25]. The PLATO trial [26], which enrolled 18,624 patients with ACS, demonstrated that ticagrelor significantly reduced the incidence of MACE, a composite of death from vascular causes, myocardial infarction, or stroke [569 (event rate at 360 days 9.0%) vs. 668 (10.7%); hazard ratio, 0.84; 95% confidence interval, 0.75–0.94; p = .0025]. Current guidelines favored the usage of ticagrelor 90 mg twice daily over clopidogrel 75 mg once daily in patients with CAD [27,28]. In our previous study, we found that low-dose ticagrelor provided greater platelet inhibition on ADP than clopidogrel in Chinese patients with CAD [29–32]. Therefore, ticagrelor was strongly recommended for patients with CAD compared with clopidogrel. Our study showed that ticagrelor and clopidogrel monotherapies provided platelet inhibition in the ADP-induced and AA-induced platelet aggregation, and ticagrelor monotherapy provided greater platelet inhibition than clopidogrel monotherapy. The result of our study confirmed the findings of previous studies. Ticagrelor monotherapy also provided a more rapid and powerful inhibition of AA-induced platelet aggregation than clopidogrel monotherapy.
Update on optimal management for pancreatic cancer: expert perspectives from members of the Australasian Gastrointestinal Trials Group (AGITG) with invited international faculty
Published in Expert Review of Anticancer Therapy, 2022
Mike Nguyen, Eva Segelov, David Goldstein, Nick Pavlakis, Jeremy Shapiro, Timothy J Price, Adnan Nagrial, Lorraine Chantrill, Trevor Leong, John Chen, Matt Burge, Christos S Karapetis, Ian Chau, Florian Lordick, Daniel Renouf, Niall Tebbutt, Amitesh C. Roy
Further work on the clinical applicability of PDAC subtyping may yield more biomarkers to inform treatment decisions. GATA6 expression can differentiate between classical and basal like subtypes and predicts response to 5FU-based chemotherapy [106]. This is being evaluated in the prospective PASS-01 study (NCT04469556). Similarly, human equilibrative nucleoside transporter 1 (hENT1) expression has been associated with the classical tumor subtype and predicts response to GnP [107]. Dihydropyrimidine dehydrogenase (DPD) expression is a negative prognostic biomarker and predicts poorer outcomes to 5FU based therapy when associated with low hENT1 expression [108]. These biomarkers are yet to have prospective validation and enter routine clinical practice.
Phosgene: toxicology, animal models, and medical countermeasures
Published in Toxicology Mechanisms and Methods, 2021
Stephen T. Hobson, Richard A. Richieri, Missag H. Parseghian
Based on acute lung injury studies, the induction process for HSP72 requires 12 h after the initial insult to the lungs, an unacceptably long period of time in the event of phosgene exposure, although it remains at a level above baseline for up to 72 h (Villar et al. 1993). We have been developing a strategy that rapidly delivers human HSP72 into lung tissue using the scFv fragment of a proprietary cell-penetrating antibody, mAb 3E10, as an intracellular transport system for protein therapeutics (Weisbart et al. 2000; Hansen et al. 2007; Weisbart et al. 2015). The 3E10 monoclonal is a well-characterized antibody with a unique cell penetration pathway (Hansen et al. 2007) that has been found to be safe in an FDA approved Phase I clinical trial (Spertini et al. 1999). 3E10 binds DNA allowing its penetration through a specific nucleoside salvage channel found in most cells, known as the equilibrative nucleoside transporter 2 (ENT2) (Lu et al. 2004). This 100 kD fusion of a humanized 3E10 to human HSP72, formerly known as Fv-Hsp70 (Zhan et al. 2010), and now known as Fv-HSP72, targets extracellular DNA, to deliver HSP72 to damaged lung cells. Nucleoside targets are abundant, stable and quite accessible during tissue damage where there is cell necrosis (Chen et al. 1990; Parseghian and Luhrs 2006; Weisbart et al. 2015). Selectivity of this agent in vivo is based on the simple concept that tissues undergoing significant cell injury possess a high concentration of extracellular DNA. Salvaging of the DNA by surrounding cells, through the ENT2 channel, provides 3E10 the opportunity to enter those energy-deficient cells still hanging on to life in a diffusion-driven process that does not depend on ATP-fueled endocytosis.
Related Knowledge Centers
- Neurotransmission
- Nucleobase
- Nucleoside
- Parasitism
- Transmembrane Domain
- Cell Membrane
- Cancer
- Major Facilitator Superfamily
- Viral Disease
- Membrane Transport Protein