Metastasis accounts for the vast majority of cancer deaths. To minimize metastasis-associated mortality, it is crucially important to evaluate the metastatic potential (M.P.), that is, defined as a tendency of a primary tumor to colonize a distant organ. Dysregulated pH in solid tumors, especially the acidification of extracellular pH (pH e ) promotes dormant metastasis by driving protease-mediated digestion, disrupting cell-matrix interaction and increasing migration of cancer cells. Therefore, imaging intratumoral acidosis creates a unique opportunity to evaluate the M.P. In this work, a novel pH activatable probe was developed, in which two near-infrared (NIR) fluorophores were conjugated via a flexible and acid liable linkage. While the fluorescence of this probe is quenched due to intramolecular dimeric aggregate under neutral environment, the cleavage of pH liable linkage with the concomitant disruption of aggregates in acidic tumor microenvironment results in a remarkable fluorescence enhancement. This probe not only visualized the primary tumors with high target to background (T/B) signal ratio in vivo, but also revealed the correlation between the M.P. and acidosis distribution pattern in tumor. While the acidosis locate dispersedly at tumor periphery in highly metastatic tumor, it distribute more widely in lowly metastatic tumor and the acidification degree increases substantially from the margin to core areas. This pH activatable NIR fluorescent probe holds the potential to evaluate the M.P., monitor the therapeutic response and predict the prognosis by delineating acidosis in tumors.Metastasis is an extremely complex disease that requires cancer cells to escape from the primary tumor, survive in the circulation, seed at distant sites and colonize the dormant organs.1 Because of the small volume, dispersal distribution nature and genetic heterogeneity of the metastases as well as the limited sensitivity and spatial resolution of the clinical imaging technologies, it is very difficult to detect and eliminate these metastatic cells in time, which results in organ failure and causes 90% of human cancer deaths.2 Therefore, monitoring the metastatic symptom and offering timely treatment are crucially important to reduce the metastasisassociated mortality. Metastatic potential (M.P.) defined as a tendency of a primary tumor to colonize in a distant organ is determined by gene expression signature of cancer cells 3 as well as the tumor microenvironment (TME).4 Like all predictive endeavors, the accurate determination of M.P. is a daunting task. For example, while tumors such as small cell lung cancer and melanoma form secondary lesions with high frequency, glioblastoma multiforme or basal cell carcinoma remain locally invasive.5 Therefore, accurately measuring tumor M.P. provides a unique opportunity to understand the metastasis mechanism, improve the therapeutic efficacy and estimate the prognosis of metastatic cancer.As a universal characteristic of TME, solid tumors demonstrate higher intracellular pH (pH...

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Wuzhi capsule (WZC) is commonly prescribed with tacrolimus in China to ease drug-induced hepatotoxicity. Two abundant active ingredients, schisantherin A (STA) and schisandrin A (SIA) are known to inhibit CYP3A enzymes and increase tacrolimus’s exposure. Our previous study has quantitatively demonstrated the contribution of STA and SIA to tacrolimus pharmacokinetics based on physiologically-based pharmacokinetic (PBPK) modeling. In the current work, we performed reversible inhibition (RI) and time-dependent inhibition (TDI) assays with CYP3A5 genotyped human liver microsomes (HLMs), and further integrated the acquired parameters into the PBPK model to predict the drug–drug interaction (DDI) in patients with different CYP3A5 alleles. The results indicated STA was a time-dependent and reversible inhibitor of CYP3A4 while only a reversible inhibitor of CYP3A5; SIA inhibited CYP3A4 and 3A5 in a time-dependent manner but also reversibly inhibited CYP3A5. The predicted fold-increases of tacrolimus exposure were 2.70 and 2.41, respectively, after the multidose simulations of STA. SIA also increased tacrolimus’s exposure but to a smaller extent compared to STA. An optimized physiologically-based pharmacokinetic (PBPK) model integrated with CYP3A5 polymorphism was successfully established, providing more insights regarding the long-term DDI between tacrolimus and Wuzhi capsules in patients with different CYP3A5 genotypes.

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Background: The benefits of patient-focused pharmaceutical care in improving clinical outcomes and reducing health expenditure have been well documented. However, these services are not fully implemented in many developing countries like China, especially in the community setting at chain pharmacies. Methods: A cross-sectional questionnaire-based survey was conducted at nine chain pharmacies in eight provinces of China in late 2019 to assess the difference in attitude, perceived barriers, and expected facilitators of Chinese community pharmacists to deliver pharmaceutical care, as well as their willingness to develop the competencies based on age, education level, and seniority. A quantitative analysis of responses was undertaken by using nonparametric (Kruskal–Wallis) and chi-square tests (followed by Bonferroni post-hoc test). Results: A total of 1260 community pharmacists were enrolled in the survey. In total, 16.3% of participant pharmacists often felt that lack of ability had a negative impact on work especially when providing comprehensive medication guidance (39.0%); 44.4% were unsatisfied with academic degrees; 85.8% were “very willing” to improve ability of pharmaceutical care while only 46.9% and 38.4% regarded traditional practice and continuing education as of lots of help, respectively. Main barriers in capacity enhancement were linked to conflict with daily work (35.4%), conflict with family life (21.9%), and poor memories (15.3%). The most welcomed facilitators to enhance pharmaceutical care development included professional skills training (28.4%), self-study of online resources (20.3%), and adult education in universities (15.6%). Community pharmacists of different age, education level, and seniority held significantly different opinions on the above aspects (p < 0.05). Conclusion: Chinese community pharmacists showed a positive attitude towards capacity enhancement in pharmaceutical care. Specific efforts and reforms should be made to improve the professionalism and to remove barriers based on their age, different education level, and seniority.