Advancing Bayesian Optimization via Learning Correlated Latent Space

Bayesian optimization is a powerful method for optimizing black-box functions with limited function evaluations. Recent works have shown that optimization in a latent space through deep generative models such as variational autoencoders leads to effective and efficient Bayesian optimization for structured or discrete data. However, as the optimization does not take place in the input space, it leads to an inherent gap that results in potentially suboptimal solutions. To alleviate the discrepancy, we propose Correlated latent space Bayesian Optimization (CoBO), which focuses on learning correlated latent spaces characterized by a strong correlation between the distances in the latent space and the distances within the objective function. Specifically, our method introduces Lipschitz regularization, loss weighting, and trust region recoordination to minimize the inherent gap around the promising areas. We demonstrate the effectiveness of our approach on several optimization tasks in discrete data, such as molecule design and arithmetic expression fitting, and achieve high performance within a small budget

Effects of a Herbal Medicine, Yukgunja-Tang, on Functional Dyspepsia Patients Classified by 3-Dimensional Facial Measurement: A Study Protocol for Placebo-Controlled, Double-Blind, Randomized Trial

Introduction. Functional dyspepsia (FD), a common upper gastrointestinal disease, is difficult to manage because of the limitations of current conventional treatments. Yukgunja-tang (YGJT) is widely used to treat FD in clinical practice in Korea, Japan, and China. However, YGJT significantly improves few symptoms of FD. In Korean medicine, FD is a well-known functional gastric disease that shows difference in the effect of herbal medicine depending on constitution or type of Korean medicine diagnosis. This study aims to investigate the efficacy of YGJT on FD patients classified by 3-dimensional facial measurement using a 3-dimensional facial shape diagnostic system (3-FSDS). Methods. A placebo-controlled, double-blind, randomized, two-center trial will be performed to evaluate the efficacy of YGJT on FD patients. Eligible subjects will be initially classified as two types by 3-dimensional facial measurement using the 3-FSDS. Ninety-six subjects (48 subjects per each type) will be enrolled. These subjects will be randomly allocated into treatment or control groups in a 2 : 1 ratio. YGJT or placebo will be administered to each group during the 8-week treatment period. The primary outcome is total dyspepsia symptom scale, and the secondary outcomes include single dyspepsia symptom scale, proportion of responders with adequate symptom relief, visual analog scale, Nepean dyspepsia index-Korean version, functional dyspepsia-related quality of life, and spleen qi deficiency questionnaire. Discussion. This is the first randomized controlled trial to assess the efficacy of the YGJT on FD patients classified by 3-dimensional facial measurement. We will compare the treatment effect of the YGJT on FD patients classified as two types using the 3-FSDS. The results of this trial will help the FD patients improve the symptoms and quality of life effectively and provide objective evidence for prescribing the YGJT to FD patients in clinical practice. Trial Registration. This trial is registered with Clinical Research Information Service Identifier: KCT0001920, 15 May, 2016

Characterization of FGFR Signaling in Prostate Cancer Stem Cells and Inhibition via TKI treatment

Cancer stem cells have been extensively studied in numerous cancers, however, there is no clear identification of this rare subpopulation and a means for an effective therapy targeting these cells although they are implicated in tumor initiation, drug resistance, reoccurrence and metastasis. The review article in Chapter 1 emphasizes how the cancer stem cells exploit a ubiquitination modification in human cancers and metastasis. Ubiquitination is a type of post-translational modification that extends the function of proteins such as stabilizing oncogenic signals and recruiting signaling proteins that favors the cancer progression beyond our current discoveries and knowledge. The studies of cancer stem cells may help us better understand the heterogeneous disease collectively termed cancer. One type of cancer in which the cancer stem cell theory may lead to alternative therapeutic options is prostate cancer. Chapter 2 presents research hypothesizing that prostate cancer stem cells (CSCs) take advantage of Fibroblast Growth Factor Receptor (FGFR) signaling for survival and proliferation among the bulk tumor and possess the ability to survive the current therapy of androgen deprivation but can be targeted by FGFR inhibitors. As tyrosine kinase inhibitors (TKIs) have shown great effectiveness for some cancers, they have shown only modest outcome in prostate cancer treatment. The research presented here focuses on studying the FGFR signaling in the rare subpopulation shown as 3-dimensional spheroids compared to a bulk tumor represented as monolayer cells. This study reveals that FGFR signaling in the prostate CSCs promote their stemness characteristics and these CSCs may possess increased metastatic potential shown by changes in their gene expression. This study provides a novel in vitro model to study FGFR signaling in prostate cancer cell lines and utilizes a novel induced pluripotent stem cell-derived cell line to improve our understanding of prostate CSCs at a cellular and molecular level. The findings from this research may assist in screening for patient subgroups who would benefit from the TKI treatment targeting FGFR as an alternative treatment option

Characterization of FGFR Signaling in Prostate Cancer Stem Cells and Inhibition via TKI treatment

Cancer stem cells have been extensively studied in numerous cancers, however, there is no clear identification of this rare subpopulation and a means for an effective therapy targeting these cells although they are implicated in tumor initiation, drug resistance, reoccurrence and metastasis. The review article in Chapter 1 emphasizes how the cancer stem cells exploit a ubiquitination modification in human cancers and metastasis. Ubiquitination is a type of post-translational modification that extends the function of proteins such as stabilizing oncogenic signals and recruiting signaling proteins that favors the cancer progression beyond our current discoveries and knowledge. The studies of cancer stem cells may help us better understand the heterogeneous disease collectively termed cancer. One type of cancer in which the cancer stem cell theory may lead to alternative therapeutic options is prostate cancer. Chapter 2 presents research hypothesizing that prostate cancer stem cells (CSCs) take advantage of Fibroblast Growth Factor Receptor (FGFR) signaling for survival and proliferation among the bulk tumor and possess the ability to survive the current therapy of androgen deprivation but can be targeted by FGFR inhibitors. As tyrosine kinase inhibitors (TKIs) have shown great effectiveness for some cancers, they have shown only modest outcome in prostate cancer treatment. The research presented here focuses on studying the FGFR signaling in the rare subpopulation shown as 3-dimensional spheroids compared to a bulk tumor represented as monolayer cells. This study reveals that FGFR signaling in the prostate CSCs promote their stemness characteristics and these CSCs may possess increased metastatic potential shown by changes in their gene expression. This study provides a novel in vitro model to study FGFR signaling in prostate cancer cell lines and utilizes a novel induced pluripotent stem cell-derived cell line to improve our understanding of prostate CSCs at a cellular and molecular level. The findings from this research may assist in screening for patient subgroups who would benefit from the TKI treatment targeting FGFR as an alternative treatment option

BioID Utilized to Identify Proteins Mediating Signaling Crosstalk between IKKbeta and STAT3

IKKβ, which is the main protein kinase in the canonical NF-κB signaling, regulates cytokine production, inflammation, cell proliferation, survival and the responses to cellular stress. In the previous research by Gallo LH. et al. [1] showed that IKKβ K171E mutant undergoes the K-63 linked ubiquitination at K147 site as well as it activates STAT3 signaling pathway. We aimed to investigate the mechanism why which the mutant IKKβ is mediating the signaling crosstalk, by investigating interacting proteins, specifically an E3 ubiquitin ligase that catalyzing the K-63linked ubiquitination of the mutant IKKβ. We utilized a new technique called BioID that enables the selective capture of proximal interacting proteins by the mutant biotin ligase fused to a protein of interest, the IKKβ K171E 4KR. Here, the results of the identified interacting proteins including E3 ubiquitin ligases which may be involved in the signaling crosstalk are shown. This project has potential to characterize the mechanism by identifying the E3 ligase, which is a promising cancer therapeutics for patients expressing activated mutants of IKKβ which were originally identified in the hematopoietic cancers patients

Jang, Korean fermented soybean product, the result of endeavors of ancients for the best taste of Korean diet

Abstract Each ethnic group has developed a food culture that enjoys delicious food by consuming natural materials or agricultural products from their respective regions. Because soybeans originated in Korea and are abundant there, a way to make delicious soybeans has been developed. Jang is a food made by fermenting soybeans, and representative types include doenjang, gochujang, kanjang, and cheongkukjang. Koreans usually season their food with jangs instead of salt. The representative seasoning of Korea traditional food is jang and yangnyom. When soybeans are fermented, soybean proteins decompose and produce fermentation by-products such as peptides, amino acids, and organic acids that provide new taste and flavor. Therefore, seasoning with jang provides a much richer taste than salt alone. Jang is an essential element of Korean food, adding taste and flavor to other dishes. Since jang is the most important and widely used food in Korean cuisine, Koreans have devoted all their efforts to making jang. These efforts include cleaning the surrounding environment, hanging meju (the blocked soybean) under the roof to dry, using charcoal and red pepper, and more. From a modern scientific perspective, their earnest devotion served functions of hygiene, moisture control, microbial inoculation, and salt control. Jang is a unique Korean food culture born from the tireless efforts of Korean mothers to feed their families with the most delicious food possible, even during times of food scarcity when they had to survive on rough grass

Characterization of FGFR signaling in prostate cancer stem cells and inhibition via TKI treatment.

Metastatic castrate-resistant prostate cancer (CRPC) remains uncurable and novel therapies are needed to better treat patients. Aberrant Fibroblast Growth Factor Receptor (FGFR) signaling has been implicated in advanced prostate cancer (PCa), and FGFR1 is suggested to be a promising therapeutic target along with current androgen deprivation therapy. We established a novel in vitro 3D culture system to study endogenous FGFR signaling in a rare subpopulation of prostate cancer stem cells (CSCs) in the cell lines PC3, DU145, LNCaP, and the induced pluripotent iPS87 cell line. 3D-propagation of PCa cells generated spheroids with increased stemness markers ALDH7A1 and OCT4, while inhibition of FGFR signaling by BGJ398 or Dovitinib decreased cell survival and proliferation of 3D spheroids. The 3D spheroids exhibited altered expression of EMT markers associated with metastasis such as E-cadherin, vimentin and Snail, compared to 2D monolayer cells. TKI treatment did not result in significant changes of EMT markers, however, specific inhibition of FGFR signaling by BGJ398 showed more favorable molecular-level changes than treatment with the multi-RTK inhibitor Dovitinib. This study provides evidence for the first time that FGFR1 plays an essential role in the proliferation of PCa CSCs at a molecular and cellular level, and suggests that TKI targeting of FGFR signaling may be a promising strategy for AR-independent CRPC