Therapeutic Drug Monitoring and Individualized Medicine of Dasatinib: Focus on Clinical Pharmacokinetics and Pharmacodynamics

Dasatinib is an oral second-generation tyrosine kinase inhibitor known to be used widely in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL). Notably, although a high pharmacokinetic variability in patients and an increased risk of pleural effusion are attendant, fixed dosing remains standard practice. Retrospective studies have suggested that dasatinib exposure may be associated with treatment response (efficacy/safety). Therapeutic drug monitoring (TDM) is gradually becoming a practical tool to achieve the goal of individualized medicine for patients receiving targeted drugs. With the help of TDM, these patients who maintain response while have minimum adverse events may achieve long-term survival. This review summaries current knowledge of the clinical pharmacokinetics variation, exposure-response relationships and analytical method for individualized dosing of dasatinib, in particular with respect to therapeutic drug monitoring. In addition, it highlights the emerging insights into several controversial issues in TDM of dasatinib, with the aim of presenting up-to-date evidence for clinical decision-making and insights for future studies.

Personalized neoantigen vaccine prevents postoperative recurrence in hepatocellular carcinoma patients with vascular invasion

Background Clinically, prophylactic anti-recurrence treatments for hepatocellular carcinoma (HCC) patients after radical surgery are extremely limited. Neoantigen based vaccine can generate robust anti-tumor immune response in several solid tumors but whether it could induce anti-tumor immune response in HCC and serve as a safe and effective prophylactic strategy for preventing postoperative HCC recurrence still remain largely unclear. Methods Personalized neoantigen vaccine was designed and immunized for 10 HCC patients with high risk of postoperative recurrence in a prime-boost schedule. The safety and immune response were assessed through adverse events, tissue sequencing, ELISpot, TCR sequencing. The clinical response was evaluated by recurrence-free survival (RFS) and personalized circulating tumor DNA (ctDNA) sequencing. Results In the 10 enrolled patients, no obvious adverse events were observed during neoantigen vaccinations. Until the deadline of clinical trial, 8 of 10 patients were confirmed with clinical relapse by imaging, the other 2 patients remained relapse-free. From receiving first neoantigen vaccination, the median RFS of 10 patients were 7.4 months. Among 7 patients received all planned neoantigen vaccinations, 5 of them demonstrated neoantigen-induced T cell responses and have significantly longer RFS after radical surgery than other 5 patients without responsive neoantigens or only with prime vaccination and propensity scores matching control patients (p = 0.035). Moreover, tracking personalized neoantigen mutations in ctDNA could provide real-time evaluation of clinical response in HCC patients during neoantigen vaccination and follow up. Conclusion Personalized neoantigen vaccine is proved as a safe, feasible and effective strategy for HCC anti-recurrence, and its progression could be sensitively monitored by corresponding neoantigen mutations in ctDNA, and thus provided solid information for individualized medicine in HCC. Trial registration This study was registered at Chinese Clinical Trial Registry; Registration number: ChiCTR1900020990.

Bacteriophages for the Treatment of Graft Infections in Cardiovascular Medicine

Bacterial infections of vascular grafts represent a major burden in cardiovascular medicine, which is related to an increase in morbidity and mortality. Different factors that are associated with this medical field such as patient frailty, biofilm formation, or immunosuppression negatively influence antibiotic treatment, inhibiting therapy success. Thus, further treatment strategies are required. Bacteriophage antibacterial properties were discovered 100 years ago, but the focus on antibiotics in Western medicine since the mid-20th century slowed the further development of bacteriophage therapy. Therefore, the experience and knowledge gained until then in bacteriophage mechanisms of action, handling, clinical uses, and limitations were largely lost. However, the parallel emergence of antimicrobial resistance and individualized medicine has provoked a radical reassessment of this approach and cardiovascular surgery is one area in which phages may play an important role to cope with this new scenario. In this context, bacteriophages might be applicable for both prophylactic and therapeutic use, serving as a stand-alone therapy or in combination with antibiotics. From another perspective, standardization of phage application is also required. The ideal surgical bacteriophage application method should be less invasive, enabling highly localized concentrations, and limiting bacteriophage distribution to the infection site during a prolonged time lapse. This review describes the latest reports of phage therapy in cardiovascular surgery and discusses options for their use in implant and vascular graft infections.

Individualized VDJ recombination predisposes the available Ig sequence space

The process of recombination between variable (V), diversity (D), and joining (J) immunoglobulin (Ig) gene segments determines an individual's naive Ig repertoire and, consequently, (auto)antigen recognition. VDJ recombination follows probabilistic rules that can be modeled statistically. So far, it remains unknown whether VDJ recombination rules differ between individuals. If these rules differed, identical (auto)antigen-specific Ig sequences would be generated with individual-specific probabilities, signifying that the available Ig sequence space is individual specific. We devised a sensitivity-tested distance measure that enables inter-individual comparison of VDJ recombination models. We discovered, accounting for several sources of noise as well as allelic variation in Ig sequencing data, that not only unrelated individuals but also human monozygotic twins and even inbred mice possess statistically distinguishable immunoglobulin recombination models. This suggests that, in addition to genetic, there is also nongenetic modulation of VDJ recombination. We demonstrate that population-wide individualized VDJ recombination can result in orders of magnitude of difference in the probability to generate (auto)antigen-specific Ig sequences. Our findings have implications for immune receptor–based individualized medicine approaches relevant to vaccination, infection, and autoimmunity.

Sex and gender specific health topics in medical student learners: pulse check eight years later

Background An essential component of patient-centered, individualized medicine is considering how sex and gender affect mechanisms of health and disease. Objectives To assess medical students’ current knowledge of sex and gender specific health (SGSH) concepts compared to results from the same survey in 2012 to better inform development of curricular materials for medical education. Methods A previously designed survey tool, which assessed current knowledge of sex and gender-based medicine of medical students, was emailed to all Mayo Clinic Alix School of Medicine (MCASOM) students on Minnesota, Arizona, and Florida campuses in 2020. Descriptive and qualitative thematic results were compared to the same survey administered in 2012 to students enrolled in MCASOM. Changes in the inclusion of SGSH topics were assessed over the eight years. Results One hundred and one of 365 (27.7% response rate) surveys were returned with 2:1 female to male respondents with representation from all 4 years. The definitions of the terms “sex” and “gender” were correctly identified by most respondents (93.1%). However, only 36% (12/33) of questions related to other medical knowledge on SGSH topics had more than a 50% correct response rate. More than half of the students reported that SGSH topics were included in Gynecology, Cardiology, Pediatrics, and Immunology. SGSH topics were reported as not being routinely covered in Neurology and Nephrology, although more students said they were in 2020 then 2012. Sixty-two percent of students favored increasing SGSH in the current curriculum. Conclusions Medical students appear to understand the definition of and importance of SGSH in education. While some improvements in coverage by subject matter and topic area appear to have occurred as reported by medical students, opportunity remains to more fully integrate SGSH concepts in medical school curricula.

Non-Small Cell Lung Cancer: Challenge and Improvement of Immune Drug Resistance

Lung cancer is the leading cause of cancer deaths in the world. At present, immunotherapy has made a great breakthrough in lung cancer treatment. A variety of immune checkpoint inhibitors have been applied into clinical practice, including antibodies targeting the programmed cell death-1, programmed cell death-ligand 1, and cytotoxic T-lymphocyte antigen 4. However, in the actual clinical process, about 30%–50% of patients still do not receive long-term benefits. Abnormal antigen presentation, functional gene mutation, tumor microenvironment, and other factors can lead to primary or secondary resistance. In this paper, we reviewed the immune mechanism of immune checkpoint inhibitor resistance, various combination strategies, and prediction of biomarkers to overcome resistance in order to accurately screen out the advantageous population, expand the beneficiary population, and enable precise and individualized medicine.

Current Trends and Research Topics Regarding Intestinal Organoids: An Overview Based on Bibliometrics

Currently, research on intestinal diseases is mainly based on animal models and cell lines in monolayers. However, these models have drawbacks that limit scientific advances in this field. Three-dimensional (3D) culture systems named organoids are emerging as a reliable research tool for recapitulating the human intestinal epithelium and represent a unique platform for patient-specific drug testing. Intestinal organoids (IOs) are crypt–villus structures that can be derived from adult intestinal stem cells (ISCs), embryonic stem cells (ESCs), or induced pluripotent stem cells (iPSCs) and have the potential to serve as a platform for individualized medicine and research. However, this emerging field has not been bibliometric summarized to date. Here, we performed a bibliometric analysis of the Web of Science Core Collection (WoSCC) database to evaluate 5,379 publications concerning the use of organoids; the studies were divided into four clusters associated with the current situation and future directions for the application of IOs. Based on the results of our bibliometric analysis of IO applications, we systematically summarized the latest advances and analyzed the limitations and prospects.

The Trifecta of Single-Cell, Systems-Biology, and Machine-Learning Approaches

Together, single-cell technologies and systems biology have been used to investigate previously unanswerable questions in biomedicine with unparalleled detail. Despite these advances, gaps in analytical capacity remain. Machine learning, which has revolutionized biomedical imaging analysis, drug discovery, and systems biology, is an ideal strategy to fill these gaps in single-cell studies. Machine learning additionally has proven to be remarkably synergistic with single-cell data because it remedies unique challenges while capitalizing on the positive aspects of single-cell data. In this review, we describe how systems-biology algorithms have layered machine learning with biological components to provide systems level analyses of single-cell omics data, thus elucidating complex biological mechanisms. Accordingly, we highlight the trifecta of single-cell, systems-biology, and machine-learning approaches and illustrate how this trifecta can significantly contribute to five key areas of scientific research: cell trajectory and identity, individualized medicine, pharmacology, spatial omics, and multi-omics. Given its success to date, the systems-biology, single-cell omics, and machine-learning trifecta has proven to be a potent combination that will further advance biomedical research.