The Role of Organic Cation Transporters in the Pharmacokinetics, Pharmacodynamics and Drug-Drug Interactions of Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors (TKIs) decisively contributed in revolutionizing the therapeutic approach to cancer, offering non-invasive, tolerable therapies for a better quality of life. Nonetheless, degree and duration of the response to TKI therapy vary depending on cancer molecular features, the ability of developing resistance to the drug, on pharmacokinetic alterations caused by germline variants and unwanted drug-drug interactions at the level of membrane transporters and metabolizing enzymes. A great deal of approved TKIs are inhibitors of the organic cation transporters (OCTs). A handful are also substrates of them. These transporters are polyspecific and highly expressed in normal epithelia, particularly the intestine, liver and kidney, and are, hence, arguably relevant sites of TKI interactions with other OCT substrates. Moreover, OCTs are often repressed in cancer cells and might contribute to the resistance of cancer cells to TKIs. This article reviews the OCT interactions with approved and in-development TKIs reported in vitro and in vivo and critically discusses the potential clinical ramifications thereof

Gender bias in team formation: The case of the European Science Foundation's grants

This paper investigates gender bias (if any) when teams are formed. We use data from the European Science Foundation to estimate if female scientists have the same opportunities as their male colleagues to join a team when applying for funds. To assess gender bias, we construct a control group of scientists with the competencies for being invited to join the team but do not join. By comparing the proportion of female scientists in the control group with the one in the observed teams, we find a gender bias against female scientists only when a project leader is a male scientist. At the same time, we do not observe gender bias when the project leader is a female scientist

Impact of family characteristics on the gender publication gap: evidence for physicists in France

The publication gender gap in science has been extensively studied. Although women have been found to be less productive than men, little is known about the reasons behind gender differences. Unique longitudinal data collected by surveying a large sample of French physicists gave us the opportunity to investigate the role of family characteristics over time. Using panel data econometrics, we confirm the existence of an average gender gap of about two-thirds of a journal article per year, and about one-third when taking into account several important control variables such as age and career characteristics. We find that female scientists suffer an average productivity loss of about one article when they have a young child, while male scientists suffer an insignificant loss. We also find that female scientists benefit from having large families, with a productivity gain of 0.63 articles per year per child

It’s not the winning but the taking part that counts: how the process of applying for competitive grants is of benefit to researchers

“The most important thing in the Olympic Games is not winning but taking part.” So goes the famous saying by Pierre de Coubertin, the father of modern Olympic Games. But does the same apply for competitive research grants? Charles Ayoubi, Michele Pezzoni and Fabiana Visentin report on their study which finds that simply taking part in an application process has a positive effect on researchers’ publication rates and on the average impact factor of the journals in which they publish. Participating in a competitive grant also allows applicants to enhance their learning, explore new trends of research, and extend their collaboration networks

Transcriptomic and Functional Evidence for Differential Effects of MCF-7 Breast Cancer Cell-Secretome on Vascular and Lymphatic Endothelial Cell Growth

Vascular and lymphatic vessels drive breast cancer (BC) growth and metastasis. We assessed the cell growth (proliferation, migration, and capillary formation), gene-, and protein-expression profiles of Vascular Endothelial Cells (VECs) and Lymphatic Endothelial Cells (LECs) exposed to a conditioned medium (CM) from estrogen receptor-positive BC cells (MCF-7) in the presence or absence of Estradiol. We demonstrated that MCF-7-CM stimulated growth and capillary formation in VECs but inhibited LEC growth. Consistently, MCF-7-CM induced ERK1/2 and Akt phosphorylation in VECs and inhibited them in LECs. Gene expression analysis revealed that the LECs were overall (≈10-fold) more sensitive to MCF-7-CM exposure than VECs. Growth/angiogenesis and cell cycle pathways were upregulated in VECs but downregulated in LECs. An angiogenesis proteome array confirmed the upregulation of 23 pro-angiogenesis proteins in VECs. In LECs, the expression of genes related to ATP synthesis and the ATP content were reduced by MCF-7-CM, whereas MTHFD2 gene, involved in folate metabolism and immune evasion, was upregulated. The contrasting effect of MCF-7-CM on the growth of VECs and LECs was reversed by inhibiting the TGF-β signaling pathway. The effect of MCF-7-CM on VEC growth was also reversed by inhibiting the VEGF signaling pathway. In conclusion, BC secretome may facilitate cancer cell survival and tumor growth by simultaneously promoting vascular angiogenesis and inhibiting lymphatic growth. The differential effects of BC secretome on LECs and VECs may be of pathophysiological relevance in BC

The Farnesoid X Receptor as a Master Regulator of Hepatotoxicity

The nuclear receptor farnesoid X receptor (FXR, NR1H4) is a bile acid (BA) sensor that links the enterohepatic circuit that regulates BA metabolism and elimination to systemic lipid homeostasis. Furthermore, FXR represents a real guardian of the hepatic function, preserving, in a multifactorial fashion, the integrity and function of hepatocytes from chronic and acute insults. This review summarizes how FXR modulates the expression of pathway-specific as well as polyspecific transporters and enzymes, thereby acting at the interface of BA, lipid and drug metabolism, and influencing the onset and progression of hepatotoxicity of varying etiopathogeneses. Furthermore, this review article provides an overview of the advances and the clinical development of FXR agonists in the treatment of liver diseases

How fast is this novel technology going to be a hit?

Despite the high interest of scholars in identifying successful inventions, little attention has been devoted to investigate how (fast) the novel ideas embodied in original inventions are re-used in follow-on inventions. We overcome this limitation by empirically mapping and characterizing the trajectory of novel technologies' re-use in follow-on inventions. Specifically, we consider the factors affecting the time needed for a novel technology to be legitimated as well as to reach its full technological impact. We analyze how these diffusion dynamics are affected by the antecedent characteristics of the novel technology. We characterize novel technologies as those that make new combinations with existing technological components and trace these new combinations in follow-on inventions. We find that novel technologies combining for the first time technological components which are similar and which are familiar to the inventors' community require a short time to be legitimated but show a low technological impact. In contrast, combining for the first time technological components with a science-based nature generates technologies with a long legitimation time but also high technological impact

Characterization of ligand-induced thermal stability of the human organic cation transporter 2 (OCT2)

Introduction: The human organic cation transporter 2 (OCT2) is involved in the transport of endogenous quaternary amines and positively charged drugs across the basolateral membrane of proximal tubular cells. In the absence of a structure, the progress in unraveling the molecular basis of OCT2 substrate specificity is hampered by the unique complexity of OCT2 binding pocket, which seemingly contains multiple allosteric binding sites for different substrates. Here, we used the thermal shift assay (TSA) to better understand the thermodynamics governing OCT2 binding to different ligands.Methods: Molecular modelling and in silico docking of different ligands revealed two distinct binding sites at OCT2 outer part of the cleft. The predicted interactions were assessed by cis-inhibition assay using [$^{3}$H]1-methyl-4-phenylpyridinium ([$^{3}$H]MPP$^{+}$) as a model substrate, or by measuring the uptake of radiolabeled ligands in intact cells. Crude membranes from HEK293 cells harboring human OCT2 (OCT2-HEK293) were solubilized in n-Dodecyl-β-D-Maltopyranoside (DDM), incubated with the ligand, heated over a temperature gradient, and then pelleted to remove heat-induced aggregates. The OCT2 in the supernatant was detected by western blot.Results: Among the compounds tested, cis-inhibition and TSA assays showed partly overlapping results. Gentamicin and methotrexate (MTX) did not inhibit [$^{3}$H]MPP$^{+}$ uptake but significantly increased the thermal stabilization of OCT2. Conversely, amiloride completely inhibited [$^{3}$H]MPP$^{+}$ uptake but did not affect OCT2 thermal stabilization. [$^{3}$H]MTX intracellular level was significantly higher in OCT2-HEK293 cells than in wild type cells. The magnitude of the thermal shift (ΔT$_{m}$) did not provide information on the binding. Ligands with similar affinity showed markedly different ΔT$_{m}$, indicating different enthalpic and entropic contributions for similar binding affinities. The ΔT$_{m}$ positively correlated with ligand molecular weight/chemical complexity, which typically has high entropic costs, suggesting that large ΔT$_{m}$ reflect a larger displacement of bound water molecules.Discussion: In conclusion, TSA might represent a viable approach to expand our knowledge on OCT2 binding descriptors

Renal Glycosuria as a Novel Early Sign of Colistin-Induced Kidney Damage in Mice

The polymyxin colistin represents a last-resort antibiotic for multidrug-resistant infections, but its use is limited by the frequent onset of acute drug-induced kidney injury (DIKI). It is essential to closely monitor kidney function prior to and during colistin treatment in order to pinpoint early signs of injury and minimize long-term renal dysfunction. To facilitate this, a mouse model of colistin-induced nephrotoxicity was used to uncover novel early markers of colistin-induced DIKI. Increased urinary levels of kidney injury molecule-1 (Kim-1) as well as glycosuria were observed in colistin-treated mice, where alterations of established clinical markers of acute kidney injury (serum creatinine and albuminuria) and emerging markers such as cystatin C were inaccurate in flagging renal damage as confirmed by histology. A direct interaction of colistin with renal glucose reabsorption was ruled out by a cis-inhibition assay in mouse brush border membrane vesicles (BBMV). Immunohistochemical examination and protein quantification by Western blotting showed a marked reduction in the protein amount of sodium-glucose transporter 2 (Sglt2), the main kidney glucose transporter, in renal tissue from colistin-treated mice in comparison to that in control animals. Consistently, BBMV isolated from treated mouse kidneys also showed a reduction in ex vivo glucose uptake compared to that in BBMV isolated from control kidneys. These findings support pathology observations of colistin-induced proximal tubule damage at the site of the brush border membrane, where Sglt2 is expressed, and open avenues for the study of glycosuria as a sensitive, specific, and accessible marker of DIKI during colistin therapy