Predicting drug pharmacokinetics and effect in vascularized tumors using computer simulation

In this paper, we investigate the pharmacokinetics and effect of doxorubicin and cisplatin in vascularized tumors through two-dimensional simulations. We take into account especially vascular and morphological heterogeneity as well as cellular and lesion-level pharmacokinetic determinants like P-glycoprotein (Pgp) efflux and cell density. To do this we construct a multi-compartment PKPD model calibrated from published experimental data and simulate 2-h bolus administrations followed by 18-h drug washout. Our results show that lesion-scale drug and nutrient distribution may significantly impact therapeutic efficacy and should be considered as carefully as genetic determinants modulating, for example, the production of multidrug-resistance protein or topoisomerase II. We visualize and rigorously quantify distributions of nutrient, drug, and resulting cell inhibition. A main result is the existence of significant heterogeneity in all three, yielding poor inhibition in a large fraction of the lesion, and commensurately increased serum drug concentration necessary for an average 50% inhibition throughout the lesion (the IC50 concentration). For doxorubicin the effect of hypoxia and hypoglycemia (“nutrient effect”) is isolated and shown to further increase cell inhibition heterogeneity and double the IC50, both undesirable. We also show how the therapeutic effectiveness of doxorubicin penetration therapy depends upon other determinants affecting drug distribution, such as cellular efflux and density, offering some insight into the conditions under which otherwise promising therapies may fail and, more importantly, when they will succeed. Cisplatin is used as a contrast to doxorubicin since both published experimental data and our simulations indicate its lesion distribution is more uniform than that of doxorubicin. Because of this some of the complexity in predicting its therapeutic efficacy is mitigated. Using this advantage, we show results suggesting that in vitro monolayer assays using this drug may more accurately predict in vivo performance than for drugs like doxorubicin. The nonlinear interaction among various determinants representing cell and lesion phenotype as well as therapeutic strategies is a unifying theme of our results. Throughout it can be appreciated that macroscopic environmental conditions, notably drug and nutrient distributions, give rise to considerable variation in lesion response, hence clinical resistance. Moreover, the synergy or antagonism of combined therapeutic strategies depends heavily upon this environment

Leaders eat last : cara pemimpin sejati menginspirasi loyalitas kerja sama, dan keberhasilan tim

Para pemimpin adalah mereka yang maju lebih dulu mengadang bahaya. Mereka mengesampingkan kepentingan diri sendiri demi melindungi kita atau demi membawa kita ke masa depan.Para pemimpin sigap mengorbankan milik mereka demi menyelamatkan milik kita. Dan mereka tidak akan pernah mengorbankan milik kita untuk menyelamatkan milik mereka.Itulah arti menjadi pemimpin.Dalam organisasi yang sukses, para pemimpin hebat menciptakan lingkungan yang memungkinkan orang-orang secara alami bekerja sama untuk melakukan hal-hal luar biasa.Ketika kita merasa yakin bahwa mereka akan membuat kita aman, kita akan bekerja bahu-membahu di belakang mereka, berkarya tanpa lelah untuk mewujudkan visi mereka, dan dengan bangga mengikuti arah langkah mereka.Apakah Anda seorang pemimpin?xiii, 370 hl

Leaders eat last : why some teams pull together and others don't

350 p. ; 24 cm

The infinite game

In this revelatory new book, Simon Sinek offers a framework for leading with an infinite mindset. On one hand, none of us can resist the fleeting thrills of a promotion earned or a tournament won, yet these rewards fade quickly. In pursuit of a Just Cause, we will commit to a vision of a future world so appealing that we will build it week after week, month after month, year after year. Although we do not know the exact form this world will take, working toward it gives our work and our life meaning

The infinite game

xiv, 251 p. ; 24 cm