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An Integrative Approach to Precision Cancer Medicine Using Patient-Derived Xenografts
Cho, Sung-Yup,Kang, Wonyoung,Han, Jee Yun,Min, Seoyeon,Kang, Jinjoo,Lee, Ahra,Kwon, Jee Young,Lee, Charles,Park, Hansoo Korean Society for Molecular and Cellular Biology 2016 Molecules and cells Vol.39 No.2
Cancer is a heterogeneous disease caused by diverse genomic alterations in oncogenes and tumor suppressor genes. Despite recent advances in high-throughput sequencing technologies and development of targeted therapies, novel cancer drug development is limited due to the high attrition rate from clinical studies. Patient-derived xenografts (PDX), which are established by the transfer of patient tumors into immunodeficient mice, serve as a platform for co-clinical trials by enabling the integration of clinical data, genomic profiles, and drug responsiveness data to determine precisely targeted therapies. PDX models retain many of the key characteristics of patients' tumors including histology, genomic signature, cellular heterogeneity, and drug responsiveness. These models can also be applied to the development of biomarkers for drug responsiveness and personalized drug selection. This review summarizes our current knowledge of this field, including methodologic aspects, applications in drug development, challenges and limitations, and utilization for precision cancer medicine.
Monoclonal Antibodies to Human Transglutaminase 4
Cho, Sung-Yup,Jeon, Ju-Hong,Kim, Chai-Wan,Shin, Dong-Myung,Jang, Gi-Yong,Jeong, Eui Man,Lee, Sang Eun,Song, Kye-Yong,Kim, In-Gyu Mary Ann Liebert 2010 Hybridoma Vol.29 No.3
<P>Transglutaminase 4 (TG4) is a member of the enzyme family that catalyzes the calcium-dependent post-translational modification of proteins via cross-linking, polyamination, or deamidation. TG4 exhibits prostate-specific expression pattern and plays a crucial role in the formation of the copulatory plug in rodents. However, the physiological function(s) of human TG4 remains speculative. Human TG4 has been postulated to participate in the maturation process of sperm by modifying its cell surface, which results in suppression of sperm antigenicity in the female genital tract. To better understand the pathophysiological role of TG4 in prostate tissue, we generated monoclonal antibodies (MAb) against human TG4 in mice by repeated injections with the recombinant human TG4. Western blot analysis demonstrated that the selected MAbs react specifically with TG4, but not with other isoenzymes of the TG family. Immunocytochemical and immunohistochemical analyses showed that specific staining is observed with the cells overexpressing TG4 and with the paraffin-embedded prostate tissue specimens obtained from the benign prostate hyperplasia and prostate cancer patients, respectively. Our results indicate that these MAbs are suitable for detecting TG4 in the cultured cells or prostate tissues for investigating the biological functions of human TG4.</P>
Cho, Sung-Yup,Chae, Jeesoo,Na, Deukchae,Kang, Wonyoung,Lee, Ahra,Min, Seoyeon,Kang, Jinjoo,Choi, Boram,Lee, Jieun,Sung, Chang Ohk,Chuang, Jeffrey H.,Lee, Charles,Lee, Won-Suk,Park, Hansoo,Kim, Jong-Il American Association for Cancer Research 2019 Clinical Cancer Research Vol.25 No.9
<P><B>Purpose:</B></P><P>Genomic and transcriptomic alterations during metastasis are considered to affect clinical outcome of colorectal cancers, but detailed clinical implications of metastatic alterations are not fully uncovered. We aimed to investigate the effect of metastatic evolution on <I>in vivo</I> treatment outcome, and identify genomic and transcriptomic alterations associated with drug responsiveness.</P><P><B>Experimental Design:</B></P><P>We developed and analyzed patient-derived xenograft (PDX) models from 35 patients with colorectal cancer including 5 patients with multiple organ metastases (MOMs). We performed whole-exome, DNA methylation, and RNA sequencing for patient and PDX tumors. With samples from patients with MOMs, we conducted phylogenetic and subclonal analysis and <I>in vivo</I> drug efficacy test on the corresponding PDX models.</P><P><B>Results:</B></P><P>Phylogenetic analysis using mutation, expression, and DNA methylation data in patients with MOMs showed that mutational alterations were closely connected with transcriptomic and epigenomic changes during the tumor evolution. Subclonal analysis revealed that initial primary tumors with larger number of subclones exhibited more dynamic changes in subclonal architecture according to metastasis, and loco-regional and distant metastases occurred in a parallel or independent fashion. The PDX models from MOMs demonstrated therapeutic heterogeneity for targeted treatment, due to subclonal acquisition of additional mutations or transcriptomic activation of bypass signaling pathway during tumor evolution.</P><P><B>Conclusions:</B></P><P>This study demonstrated <I>in vivo</I> therapeutic heterogeneity of colorectal cancers using PDX models, and suggests that acquired subclonal alterations in mutations or gene expression profiles during tumor metastatic processes can be associated with the development of drug resistance and therapeutic heterogeneity of colorectal cancers.</P>
Trends in Patient Satisfaction from 1989-2003: Adjusted for Patient Characteristics
Cho, Sung-Hyun,Kim, Chang-Yup Korean Society of Nursing Science 2007 Journal of Korean Academy of Nursing Vol.37 No.2
Purpose. To identify trends in patient satisfaction adjusted for sociodemographic factors and health status from 1989-2003. Methods. Five repeated cross-sectional surveys were used. The study sample included 290,534 household members 20 years of age and over from the five survey periods of 1989, 1992, 1995, 1999, and 2003. Satisfaction was measured using a five-point scale, ranging from "very satisfied" to "very dissatisfied." Crude satisfaction rates, representing the proportion of patients satisfied (very satisfied or satisfied), were calculated for each survey period. Satisfaction rates adjusted for age, sex, marital status, education, and self-rated health status were calculated for each of the five years. Results. Crude satisfaction rates increased from 15.4% in 1989 to 40.5% in 2003. The proportions of satisfaction and dissatisfaction were reversed after 15 years had passed. However, the satisfaction trend was not linear throughout the different years, with 1992 being the year with the lowest satisfaction rate (9.7%). These trends in crude rates did not change even after adjusting for patient characteristics. The odds of satisfaction in 1992 were 38% lower (odds ratio 0.62, 95% CI 0.60 to 0.64) than the odds in 1989. In 2003, the odds of satisfaction were 4.01 times (95% CI 3.89 to 4.13) the odds for 1989. Older, female, married, and less-educated people were more likely to be satisfied. Patients who rated their health as 'very good' had the highest satisfaction rate, and those with "neutral" health ratings had the lowest. General hospitals achieved substantial improvement whereas pharmacies became the lowest-rated of all institutions. Conclusions. The Korean health system has achieved better patient satisfaction rates over the past 15 years. Increased health expenditure, resources, and quality improvement efforts may have contributed to this progress.
Transglutaminase 2 inhibits apoptosis induced by calcium-overload through down-regulation of Bax
Cho, Sung-Yup,Lee, Jin-Haeng,Bae, Han-Dong,Jeong, Eui-Man,Jang, Gi-Yong,Kim, Chai-Wan,Shin, Dong-Myung,Jeon, Ju-Hong,Kim, In-Gyu Korean Society for Biochemistry and Molecular Bion 2010 Experimental and molecular medicine Vol.42 No.9
An abrupt increase of intracellular $Ca^{2+}$ is observed in cells under hypoxic or oxidatively stressed conditions. The dysregulated increase of cytosolic $Ca^{2+}$ triggers apoptotic cell death through mitochondrial swelling and activation of $Ca^{2+}$-dependent enzymes. Transglutaminase 2 (TG2) is a $Ca^{2+}$-dependent enzyme that catalyzes transamidation reaction producing cross-linked and polyaminated proteins. TG2 activity is known to be involved in the apoptotic process. owever, the pro-apoptotic role of TG2 is still controversial. In this study, we investigate the role of TG2 in apoptosis induced by $Ca^{2+}$-overload. verexpression of TG2 inhibited the A23187-induced apoptosis through suppression of caspase-3 and -9 activities, cytochrome c release into cytosol, and mitochondria membrane depolarization. Conversely, down-regulation of TG2 caused the increases of cell death, caspase-3 activity and cytochrome c in cytosol in response to $Ca^{2+}$-overload. Western blot analysis of Bcl-2 family proteins showed that TG2 reduced the expression level of Bax protein. Moreover, overexpression of Bax abrogated the anti-apoptotic effect of TG2, indicating that TG2-mediated suppression of Bax is responsible for inhibiting cell death under $Ca^{2+}$-overloaded con conditions. Our findings revealed a novel anti-apoptotic pathway involving TG2, and suggested the induction of TG2 as a novel strategy for promoting cell survival in diseases such as ischemia and neurodegeneration.