Reducing State Conflicts between Network Motifs Synergistically Enhances Cancer Drug Effects and Overcomes Adaptive Resistance.

Inducing apoptosis in cancer cells is a primary goal in anti-cancer therapy, but curing cancer with a single drug is unattainable due to drug resistance. The complex molecular network in cancer cells causes heterogeneous responses to single-target drugs, thereby inducing an adaptive drug response. Here, we showed that targeted drug perturbations can trigger state conflicts between multi-stable motifs within a molecular regulatory network, resulting in heterogeneous drug responses. However, we revealed that properly regulating an interconnecting molecule between these motifs can synergistically minimize the heterogeneous responses and overcome drug resistance. We extracted the essential cellular response dynamics of the Boolean network driven by the target node perturbation and developed an algorithm to identify a synergistic combinatorial target that can reduce heterogeneous drug responses. We validated the proposed approach using exemplary network models and a gastric cancer model from a previous study by showing that the targets identified with our algorithm can better drive the networks to desired states than those with other control theories. Of note, our approach suggests a new synergistic pair of control targets that can increase cancer drug efficacy to overcome adaptive drug resistance.

The simplified Edinburgh Postnatal Depression Scale (EPDS) for antenatal depression: is it a valid measure for pre-screening?

The identification of antenatal depression is critical but poorly conducted. The aim of this study was to construct a simplified depression survey scale and to verify its efficacy as a pre-screening for antenatal depression. A total of 494 pregnant women in the third trimester of gestation who had received antenatal care at Seoul St. Mary's Hospital from July 2009 to June 2010 were included. The Edinburgh Postnatal Depression Scale (EPDS) questionnaire was completed by them. The subjects were randomly divided into two groups: 250 of training set and 244 of validation set. We designed a simplified questionnaire comprising two items of EPDS using the training set. We then validated its efficacy with the training set and reaffirmed the results with the validation set. The sum of item 5 (scare or panic) and item 8 (sadness or misery) explained 75.5% of the total score of the EPDS (AUC = 0.947). Using a score of 3 as a cut-off value of the simplified scale, sensitivity was 92.4% and specificity was 86.3%. The positive and negative predictive values were 56.2% and 98.4%, retrospectively. This study suggests that the simplified EPDS can be an efficient instrument to rule out depression during pregnancy.

Network Dynamics Caused by Genomic Alteration Determine the Therapeutic Response to FGFR Inhibitors for Lung Cancer.

Recently, FGFR inhibitors have been highlighted as promising targeted drugs due to the high prevalence of FGFR1 amplification in cancer patients. Although various potential biomarkers for FGFR inhibitors have been suggested, their functional effects have been shown to be limited due to the complexity of the cancer signaling network and the heterogenous genomic conditions of patients. To overcome such limitations, we have reconstructed a lung cancer network model by integrating a cell line genomic database and analyzing the model in order to understand the underlying mechanism of heterogeneous drug responses. Here, we identify novel genomic context-specific candidates that can increase the efficacy of FGFR inhibitors. Furthermore, we suggest optimal targets that can induce more effective therapeutic responses than that of FGFR inhibitors in each of the FGFR-resistant lung cancer cells through computational simulations at a system level. Our findings provide new insights into the regulatory mechanism of differential responses to FGFR inhibitors for optimal therapeutic strategies in lung cancer.

Network Analysis Identifies Regulators of Basal-Like Breast Cancer Reprogramming and Endocrine Therapy Vulnerability.

Basal-like breast cancer is the most aggressive breast cancer subtype with the worst prognosis. Despite its high recurrence rate, chemotherapy is the only treatment for basal-like breast cancer, which lacks expression of hormone receptors. In contrast, luminal A tumors express ERα and can undergo endocrine therapy for treatment. Previous studies have tried to develop effective treatments for basal-like patients using various therapeutics but failed due to the complex and dynamic nature of the disease. In this study, we performed a transcriptomic analysis of patients with breast cancer to construct a simplified but essential molecular regulatory network model. Network control analysis identified potential targets and elucidated the underlying mechanisms of reprogramming basal-like cancer cells into luminal A cells. Inhibition of BCL11A and HDAC1/2 effectively drove basal-like cells to transition to luminal A cells and increased ERα expression, leading to increased tamoxifen sensitivity. High expression of BCL11A and HDAC1/2 correlated with poor prognosis in patients with breast cancer. These findings identify mechanisms regulating breast cancer phenotypes and suggest the potential to reprogram basal-like breast cancer cells to enhance their targetability. SIGNIFICANCE: A network model enables investigation of mechanisms regulating the basal-to-luminal transition in breast cancer, identifying BCL11A and HDAC1/2 as optimal targets that can induce basal-like breast cancer reprogramming and endocrine therapy sensitivity.

Determining Public Opinion of the COVID-19 Pandemic in South Korea and Japan: Social Network Mining on Twitter.

OBJECTIVES: This study analyzed the perceptions and emotions of Korean and Japanese citizens regarding coronavirus disease 2019 (COVID-19). It examined the frequency of words used in Korean and Japanese tweets regarding COVID-19 and the corresponding changes in their interests. METHODS: This cross-sectional study analyzed Twitter posts (Tweets) from February 1, 2020 to April 30, 2020 to determine public opinion of the COVID-19 pandemic in Korea and Japan. We collected data from Twitter (https://twitter.com/), a major social media platform in Korea and Japan. Python 3.7 Library was used for data collection. Data analysis included KR-WordRank and frequency analyses in Korea and Japan, respectively. Heat diagrams, word clouds, and rank flowcharts were also used. RESULTS: Overall, 1,470,673 and 4,195,457 tweets were collected from Korea and Japan, respectively. The word trend in Korea and Japan was analyzed every 5 days. The word cloud analysis revealed "COVID-19", "Shinchonji", "Mask", "Daegu", and "Travel" as frequently used words in Korea. While in Japan, "COVID-19", "Mask", "Test", "Impact", and "China" were identified as high-frequency words. They were divided into four categories: social distancing, prevention, issue, and emotion for the rank flowcharts. Concerning emotion, "Overcome" and "Support" increased from February in Korea, while "Worry" and "Anxiety" decreased in Japan from April 1. CONCLUSIONS: As a result of the trend, people's interests in the economy were high in both countries, indicating their reservations on the economic downturn. Therefore, focusing policies toward economic stability is essential. Although the interest in prevention increased since April in both countries, the general public's relaxation regarding COVID-19 was also observed.

Realizing Cancer Precision Medicine by Integrating Systems Biology and Nanomaterial Engineering.

Many clinical trials for cancer precision medicine have yielded unsatisfactory results due to challenges such as drug resistance and low efficacy. Drug resistance is often caused by the complex compensatory regulation within the biomolecular network in a cancer cell. Recently, systems biological studies have modeled and simulated such complex networks to unravel the hidden mechanisms of drug resistance and identify promising new drug targets or combinatorial or sequential treatments for overcoming resistance to anticancer drugs. However, many of the identified targets or treatments present major difficulties for drug development and clinical application. Nanocarriers represent a path forward for developing therapies with these "undruggable" targets or those that require precise combinatorial or sequential application, for which conventional drug delivery mechanisms are unsuitable. Conversely, a challenge in nanomedicine has been low efficacy due to heterogeneity of cancers in patients. This problem can also be resolved through systems biological approaches by identifying personalized targets for individual patients or promoting the drug responses. Therefore, integration of systems biology and nanomaterial engineering will enable the clinical application of cancer precision medicine to overcome both drug resistance of conventional treatments and low efficacy of nanomedicine due to patient heterogeneity.

The highly enantioselective phase-transfer catalytic mono-alkylation of malonamic esters.

The phase-transfer catalytic alkylation of N,N-dialkylmalonamic tert-butyl esters in the presence of 1 mol% of (S,S)-3,4,5-trifluorophenyl-NAS bromide afforded highly enantioselective (S)-mono-alpha-alkylated products (up to 96% ee), which could be readily converted into versatile chiral building blocks without loss of chirality.

Quantitative evaluation and reversion analysis of the attractor landscapes of an intracellular regulatory network for colorectal cancer.

BACKGROUND: Cancer reversion, converting the phenotypes of a cancer cell into those of a normal cell, has been sporadically observed throughout history. However, no systematic analysis has been attempted so far. RESULTS: To investigate this from a systems biological perspective, we have constructed a logical network model of colorectal tumorigenesis by integrating key regulatory molecules and their interactions from previous experimental data. We identified molecular targets that can reverse cancerous cellular states to a normal state by systematically perturbing each molecular activity in the network and evaluating the resulting changes of the attractor landscape with respect to uncontrolled proliferation, EMT, and stemness. Intriguingly, many of the identified targets were well in accord with previous studies. We further revealed that the identified targets constitute stable network motifs that contribute to enhancing the robustness of attractors in cancerous cellular states against diverse regulatory signals. CONCLUSIONS: The proposed framework for systems analysis is applicable to the study of tumorigenesis and reversion of other types of cancer.

The effect of inflatable obstetric belts in nulliparous pregnant women receiving patient-controlled epidural analgesia during the second stage of labor.

OBJECTIVE: The aim of this study was to evaluate the effect of inflatable obstetric belts on uterine fundal pressure in the management of the second stage of labor. METHOD: Between July 2009 and December 2010, 188 nulliparous women with a singleton pregnancy at term were enrolled and only one dropped. The participants were randomized to receive either standard care (control group, n = 91) or uterine fundal pressure by the Labor Assister (Baidy M-520/Curexo, Inc., Seoul, Korea; active group, n = 97) during the second stage of labor in addition to standard care. The Labor Assister is an inflatable obstetric belt that is synchronized to apply constant fundal pressure during a uterine contraction. The primary endpoint was duration of the second stage of labor in women who delivered vaginally (control, n = 80 versus active, n = 93). It was not analyzed in women who delivered by cesarean section (n = 14) and delivered precipitously (n = 1). The secondary outcomes are perinatal outcomes and perineal laceration. Participants received patient-controlled epidural analgesia. RESULTS: The 93 women in the active group spent less time in the second stage of labor when compared to the 80 women in the control group (46.51 ± 28.01 min versus 75.02 ± 37.48 min, p < 0.001). There was no significant difference in perinatal outcomes and perineal laceration between the two groups. CONCLUSION: The uterine fundal pressure exerted by the inflatable obstetric belt reduces the duration of the second stage of labor without complications in nulliparous women who receive patient-controlled epidural analgesia.

Extraanatomic reconstruction for isolated thoracic aorta coarctation in an adult patient.

A 42-year-old male patient with no medical history except hypertension presented with intermittent chest pain radiating to the left shoulder. From coronary computed tomography, a coarctation of proximal descending thoracic aorta was found demonstrating near aortic occlusion. From various available surgical options for this condition, we chose extraanatomic bypass from the left subclavian artery to the descending aorta.

Highly enantioselective phase-transfer catalytic alkylation in the preparation of non-natural alpha-amino acids via solid phase synthesis using aldimine linker.

A new Merrifield-resin-derived glycinimine tert-butyl ester (9) was prepared and applied to the enantioselective synthesis of non-natural alpha-amino acids. High enantioselectivities (86 to >99% ee) were accomplished by employing the aldimine linker under phase-transfer alkylation conditions, using 50% aqueous CsOH in toluene/chloroform (7:3) at 0 degrees C in the presence of N-(9-anthracenylmethyl)-O(9)-allylcinchonidium bromide (10 mol %).

Biarylcarboxybenzamide derivatives as potent vanilloid receptor (VR1) antagonistic ligands.

Seventeen biarylcarboxybenzamide derivatives were prepared for the study of their agonistic/antagonistic activities to the vanilloid receptor (VR1) in rat DRG neurons. The replacement of the piperazine moiety of the lead compound 1 with phenyl ring showed quite enhanced antagonistic activity. Among the prepared derivatives, N-(4-tert-butylphenyl)-4-pyridine-2-yl-benzamide (2, IC(50)=31 nM) and N-(4-tert-butylphenyl)-4-(3-methylpyridine-2-yl)benzamide (3g, IC(50)=31 nM), showed 5-fold higher antagonistic activity than 1 in (45)Ca(2+)-influx assay.

Synthesis of 2-substituted-pyrrolidinethiourea derivatives and their antagonist effect on vanilloid receptor.

Four pyrrolidine derivatives were prepared by the formation of a 5-membered ring based on capsazepine. Among them, the two carbon extended derivatives, 4a (IC(50)=55 microM) and 4b (IC(50)=3 microM), both showed different levels of antagonist activity against the vanilloid receptor in a (45)Ca(2+)-influx assay.

N-4-Substituted-benzyl-N'-tert-butylbenzyl thioureas as vanilloid receptor ligands: investigation on the role of methanesulfonamido group in antagonistic activity.

A series of N-4-substituted-benzyl-N'-tert-butylbenzyl thioureas were prepared for the study of their agonistic/antagonistic activities to the vanilloid receptor in rat DRG neurons. Their structure-activity relationship reveals that not only the two oxygens and amide hydrogen of sulfonamido group, but also the optimal size of methyl in methanesulfonamido group play an integral role for the antagonistic activity on vanilloid receptor.

Synthesis of N,N',N"-trisubstituted thiourea derivatives and their antagonist effect on the vanilloid receptor.

Twenty-seven N,N',N"-trisubstituted thiourea derivatives were prepared. Among them, 1-[3-(4'-hydroxy-3'-methoxy-phenyl)-propyl]-1,3-diphenethyl-thiourea (8l, IC(50)=0.32 microM), showed 2-fold higher antagonistic activity than that of capsazepine (3, IC(50)=0.65 microM) against the vanilloid receptor in a (45)Ca(2+)-influx assay.

N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thioureas as potent vanilloid receptor antagonistic ligands.

A series of N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butylbenzyl thioureas were prepared for the study of their agonistic/antagonistic activities to the vanilloid receptor in rat DRG neurons. Their structure-activity relationship reveals that there is a space for another hydrophobic binding interaction around 2-position in 4-tert-butylbenzyl region. Among the prepared derivatives, 6n show the highest antagonistic activity against the vanilloid receptor (IC(50)=15 nM).