Structure-Activity Relationship Study of Tris-Benzamides as Estrogen Receptor Coregulator Binding Modulators.

Estrogen receptor coregulator binding modulators (ERXs) are a novel class of molecules targeting the interaction between estrogen receptor α (ERα) and its coregulator proteins, which has proven to be an attractive strategy for overcoming endocrine resistance in breast cancer. We previously reported ERX-11, an orally bioavailable tris-benzamide, that demonstrated promising antitumor activity against ERα-positive breast cancer cells. To comprehend the significance of the substituents in ERX-11, we carried out structure-activity relationship studies. In addition, we introduced additional alkyl substituents at either the N- or C-terminus to improve binding affinity and biological activity. Further optimization guided by conformational restriction led to the identification of a trans-4-phenylcyclcohexyl group at the C-terminus (18h), resulting in a greater than 10-fold increase in binding affinity and cell growth inhibition potency compared to ERX-11. Tris-benzamide 18h disrupted the ERα-coregulator interaction and inhibited the ERα-mediated transcriptional activity. It demonstrated strong antiproliferative activity on ERα-positive breast cancer cells both in vitro and in vivo, offering a promising potential as a therapeutic candidate for treating ERα-positive breast cancer.

Novel LIPA-Targeted Therapy for Treating Ovarian Cancer.

Ovarian cancer (OCa) is the most lethal form of gynecologic cancer, and the tumor heterogeneities at the molecular, cellular, and tissue levels fuel tumor resistance to standard therapies and pose a substantial clinical challenge. Here, we tested the hypothesis that the heightened basal endoplasmic reticulum stress (ERS) observed in OCa represents an exploitable vulnerability and may overcome tumor heterogeneity. Our recent studies identified LIPA as a novel target to induce ERS in cancer cells using the small molecule ERX-41. However, the role of LIPA and theutility of ERX-41 to treat OCa remain unknown. Expression analysis using the TNMplot web tool, TCGA data sets, and immunohistochemistry analysis using a tumor tissue array showed that LIPA is highly expressed in OCa tissues, compared to normal tissues. ERX-41 treatment significantly reduced the cell viability and colony formation ability and promoted the apoptosis of OCa cells. Mechanistic studies revealed a robust and consistent induction of ERS markers, including CHOP, elF2α, PERK, and ATF4, upon ERX-41 treatment. In xenograft and PDX studies, ERX-41 treatment resulted in a significant reduction in tumor growth. Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of ERS induction, which could be exploited to treat heterogeneity in OCa.

Fabrication and validation of flexible neural electrodes based on polyimide tape and gold sheet.

This research was conducted to apply polyimide tape, which has the advantages of low price ans strong adhesive strength, to the neural electrode process. In addition, to maximize the low-cost characteristics, a fabrication process based on UV laser patterning rather than a photolithography process was introduced. The fabrication process started by attaching the gold sheet on the conductive double-sided tape without being torn or crushed. Then, the gold sheet and the double-sided tape were patterned together using UV laser. The patterned layer was transferred to the single-side polyimide tape. For insulation layer, electrode site opened single-sided polyimide tape was prepared. Polydimethylsiloxane was used as an adhesion layer, and alignment between electrode sites and opening sites was processed manually. The minimum line width achieved through the proposed fabrication process was approximately 100 µm, and the sheet resistance of the conductive layer was 0.635 Ω/sq. Measured cathodal charge storage capacity was 0.72 mC/cm2 and impedance at 1 kHz was 4.07 kΩ/cm2. Validation of fabricated electrode was confirmed by conducting 30 days accelerated soak test, flexibility test, adhesion test and ex vivo stimulation test. The novel flexible neural electrodes based on single-sided polyimide tape and UV laser patterned gold sheet was fabricated successfully. Conventional neural electrode fabrication processes based on polyimide substrate has a disadvantages such as long fabrication time, expensive costs, and probability of delamination between layers. However, the novel fabrication process which we introduced can overcome many shortcomings of existing processes, and offers great advantages such as simplicity of fabrication, inexpensiveness, flexibility and long-term reliability.

Fabrication of Implantable Microelectrode Array using Cyclic Olefin Copolymer and SU-8 via Photocrosslinking Lamination.

In this work, a fabrication process for implantable electrodes using a Cyclic Olefin Copolymer (COC) substrate and a SU-8 passivation layer was presented. COC and SU-8 were shown to be suitable for implantable neural electrodes due to their biocompatibility, chemical resistance, and thermal stability. The electrodes were successfully patterned on the COC film, and the SU-8 passivation layer was coated while maintaining site-opened via photolithography. The photocrosslinking lamination of the substrate and passivation layer was used to produce electrodes with fine line widths of 20um without applying heat.

Low dead space encapsulation and integration of circuits for retinal prosthesis based on cyclic olefin copolymer.

A retinal prosthesis is a device that can provide artificial vision to people who have lost their sight from certain retinal disorder. Because the device needs to be inserted into the body, high flexibility and reliability is required. Recently, devices using thermoplastic polymers such as LCP and COC as substrates have been studied. Being a highly functional integrated device, retinal prosthesis poses many design challenges. Among them, the stimulation chip embedding can be a particularly important task. Although it is common to use a wire bonding method for chip embedding, there are several limitations that are difficult to apply to implantable device. In this investigation, a novel approach is developed for high spaceefficient electrical connections and perform reliable encapsulation of integrated circuits to replace wire bonding. Since designing and manufacturing the stimulator chip used in retinal prosthesis requires non-negligible cost, a silicon die with the identical shape was selected as a substitute for testing purposes.

Clinical Relevance of Red Blood Cell Distribution Width (RDW) in Endometrial Cancer: A Retrospective Single-Center Experience from Korea.

BACKGROUND: Red blood cell distribution width (RDW) is a standard parameter of complete blood count and indicates the variability in red blood cell size. This study aimed to determine whether preoperative RDW can be used to predict the recurrence and prognosis of endometrial carcinoma. METHODS: The medical records of 431 patients diagnosed with endometrial carcinoma were retrospectively reviewed between May 2006 and June 2018. In addition to RDW, the clinicopathological factors, survival curves, and prognoses of the patients with endometrial carcinoma were compared between the high (n = 213) and low (n = 218) groups according to the median RDW value (12.8%). RESULTS: The patients with high RDW had significantly advanced-stage (p = 0.00) pelvic lymph node metastasis (p = 0.01) and recurrence (p = 0.01) compared to those in the low-RDW group. In univariate analysis with DFS as the endpoint, surgical stage, type II histology, grade, RDW, and lymph node metastasis were independently associated with survival. Patients with high RDW values had significantly shorter disease-free survival and overall survival than those with low RDW values (log-rank p = 0.03, log-rank p = 0.04, respectively). CONCLUSION: Our results demonstrate that RDW is a simple and convenient indicator of endometrial carcinoma recurrence. Prospective studies are needed to validate the findings of the current study.

The effects of workers' job stress on organizational commitment and leaving intention in commercial sports centers.

The purpose of this study is to identify the factors affecting the job stress of commercial sports center workers on organizational commitment and turnover intention. The causal relationship between their demographic characteristics and job stress was investigated for 261 out of 300 workers working at commercial sports centers in Seoul, Incheon, and Gyeonggi province. There was a difference by work type, and it was found that there was a difference between regular and contract workers. Role-related and interpersonal relationships had a negative influence relationship in terms of tenure commitment, normative commitment, and affective commitment. Job characteristics, role-related, interpersonal relationship, and compensation system had an influence on turnover intention. In other words, it was found that role-related and interpersonal relationships had a positive effect on turnover intention, and job characteristics and compensation system had a negative effect on turnover intention. It was found that job stress affects both organizational commitment and turnover intention. The results of this study indicate that job stress, organizational commitment, and turnover intention should be dealt with mainly in order to reduce turnover intention of commercial sports center workers. In other words, clearer guidelines on the role of commercial sports center workers and various welfare programs for improving human relationships should be provided. Therefore, commercial sports centers should continuously research and develop ways to maximize job satisfaction from the perspective of workers in order to reduce job stress and induce positive organizational commitment.

Enhanced processing map of Ti-6Al-2Sn-2Zr-2Mo-2Cr-0.15Si aided by extreme gradient boosting.

A processing map is required for Ti alloys to find processing parameters securing a high formability. This study adopted the extreme gradient boosting (XGB) approach of machine learning to predict a flow curve and plot a processing map with less experiments for the first time. The optimum XGB model predicted flow curves of Ti-6Al-2Sn-2Zr-2Mo-2Cr-0.15Si at 1073-1273 K and 10 s-1. The predicted data were used to plot a processing map, which showed a higher accuracy in the instability map as compared with the map without XGB. The XGB model also anticipated the power dissipation map at low strain rates. The low accuracy at high strain rates would be improved by alleviating the bias towards a flow hardening. This work has successfully proven the potential usefulness of XGB for plotting an enhanced processing map in light of a higher accuracy with less experiments.

Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress.

Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.

Excitatory synapses and gap junctions cooperate to improve Pv neuronal burst firing and cortical social cognition in Shank2-mutant mice.

NMDA receptor (NMDAR) and GABA neuronal dysfunctions are observed in animal models of autism spectrum disorders, but how these dysfunctions impair social cognition and behavior remains unclear. We report here that NMDARs in cortical parvalbumin (Pv)-positive interneurons cooperate with gap junctions to promote high-frequency (>80 Hz) Pv neuronal burst firing and social cognition. Shank2-/- mice, displaying improved sociability upon NMDAR activation, show impaired cortical social representation and inhibitory neuronal burst firing. Cortical Shank2-/- Pv neurons show decreased NMDAR activity, which suppresses the cooperation between NMDARs and gap junctions (GJs) for normal burst firing. Shank2-/- Pv neurons show compensatory increases in GJ activity that are not sufficient for social rescue. However, optogenetic boosting of Pv neuronal bursts, requiring GJs, rescues cortical social cognition in Shank2-/- mice, similar to the NMDAR-dependent social rescue. Therefore, NMDARs and gap junctions cooperate to promote cortical Pv neuronal bursts and social cognition.

Psychophysiological Response According to the Greenness Index of Subway Station Space.

This study proposed a plan for implementing a pleasant and healthy indoor landscape in subway station space. To this end, it established a 3D landscape model of the subway interior by reviewing previous studies on indoor landscape and the greenness index of indoor spaces. Moreover, it investigated and analyzed psychophysiological responses of users to environmental indoor landscape design in subway station space. Subway stations were classified as underground subway stations and ground subway stations according to the presence of natural light inflow. The greenness index of indoor spaces was also divided into four types of 0%, 10%, 15%, and 20%. Through this process, eight 3D landscape models of the subway interior were implemented. In addition, this study investigated psychophysiological responses of 60 male and female adults in their 20 s and 30 s using the models implemented. The investigation result was analyzed based on a frequency analysis, the χ2 test, T-test, one-way analysis of variance, and multidimensional scaling, which were performed in SPSS Statistics 25. The results of this study can be summarized as follows. First, physiological responses of research subjects were analyzed based on their prefrontal α wave asymmetric values. The analytic result showed that the environment where interior landscape was adopted produced more positive effects than the environment where interior landscape was not adopted. Second, psychological responses of research subjects were examined based on their greenness index preference, awareness of interior landscape area, attention restoration effect, and space images. The analytic result indicated that, among eight 3D landscape models of the subway interior, they preferred the model with the greenness index of 15% for underground subway stations. In addition, they preferred the model with the greenness index of 10% the most for ground subway stations.

Effect of the Lapping Platen Groove Density on the Characteristics of Microabrasive-Based Lapping.

Microabrasive-based lapping is widely used in the manufacturing of single-crystal substrates such as sapphire, SiC, and GaN. Although many studies have been conducted to improve the lapping process characteristics, most of them focused on process conditions or consumables. In this study, the effect of the lapping platen groove density on the lapping characteristics was studied using a sapphire substrate. Groove density was defined as the ratio of groove width to groove pitch, and the displacement of the lapping head was measured to calculate the oil film thickness. It was confirmed that, for groove densities below 0.30, hydroplaning occurs when the oil film thickness increases. When the oil film thickness is larger than the abrasive particle size, the material removal rate is low because the abrasive does not participate in the lapping process. When the oil film was developed, the experimental results showed a high surface roughness and poor flatness of the substrate, as only large abrasive particles participated in the lapping process. Therefore, to improve the lapping characteristics, it is important to reduce the groove density by reducing the groove pitch, which prevents the development of the oil film.

Effect of undissolved Nb carbides on mechanical properties of hydrogen-precharged tempered martensitic steel.

Nb carbides have attracted significant attention to enhance the resistance of tempered martensitic (TM) steel to hydrogen embrittlement (HE). However, previous studies have elucidated the role of Nb carbides in HE resistance without categorizing their types (i.e., undissolved and newly precipitated). This study focuses on the effect of "undissolved" Nb carbides on the tensile and fatigue properties of hydrogen-precharged TM steels. It validated the following two factors for the HE resistance of the TM steels containing undissolved Nb carbides: hydrogen-trapping by the carbides and refinement of prior austenite grain. The former factor rarely affected the HE resistance owing to the interfacial incoherency between the undissolved carbides and ferritic matrix. Such results are distinguished from previous studies focusing on the newly precipitated carbides. In contrast, the latter factor contributed significantly to the HE resistance via the decrease in hydrogen contents per unit surface of prior austenite grain boundaries.

Age­dependent alterations in the immunoreactivity of macrophage inflammatory protein­3α and its receptor CCR6 in the gerbil hippocampus.

Neuroinflammation is a primary characteristic of the aging brain. During normal aging, macrophage inflammatory protein­3α (MIP­3α) and its receptor C­C chemokine receptor type 6 (CCR6) serve pivotal roles in the neuroinflammatory process in the brain. The aim of the present study was to investigate age­dependent alterations in the immunoreactivity of MIP­3α and CCR6 in the gerbil hippocampus at postnatal month (PM) 1, 6, 12 and 24 via immunohistochemistry. In the PM 1 group, both MIP­3α and CCR6 immunoreactivity were observed primarily in the stratum pyramidale in the hippocampus proper and in the granule cell layer in the dentate gyrus. In the PM 6 and PM 12 groups, MIP­3α in the stratum pyramidale and granule cell layer was decreased compared with the PM 1 group, and CCR6 immunoreactivity in both layers was faint. In the PM 24 group, MIP­3α expression in the stratum pyramidale and granule cell layer was higher than that in the PM 1 group, and CCR6 immunoreactivity in both layers was increased compared with the PM 12 group; however, it was decreased compared with the PM 1 group. In conclusion, MIP­3α and CCR6 immunoreactivity were altered in the hippocampus during normal aging. The results of the current study suggested that age­dependent alterations of MIP­3α and CCR6 may be associated with age­related neuroinflammation in the hippocampus.

Peptide Ligation via the Suzuki-Miyaura Cross-Coupling Reaction.

Chemoselective ligation of two 28-mer peptides has been accomplished using the Suzuki-Miyaura cross-coupling reaction at or near physiological temperature in an aqueous solution containing sodium dodecyl sulfate in 83% yield. The effects of Pd source, solvent, base, and temperature were investigated, and the optimized reaction conditions were studied for compatibility with naturally present and artificially introduced functional groups in peptides including S-protected thiol and azide. The peptide conjugations were carried out in high yield (90%) with their functional groups intact. This method also allowed for facile introduction of an affinity tag or fluorescent probe into 20-mer peptides in >80% yield. These results suggest that the Suzuki-Miyaura cross-coupling is useful for multiple conjugations of peptides in conjunction with conventional conjugation reactions performed in sequence.

Estrogen receptor coregulator binding modulator (ERX-11) enhances the activity of CDK4/6 inhibitors against estrogen receptor-positive breast cancers.

BACKGROUND: CDK4/6 inhibitors in combination with endocrine therapy (AE/AI/SERDs) are approved for the treatment of ER+ advanced breast cancer (BCa). However, not all patients benefit from CDK4/6 inhibitors therapy. We previously reported a novel therapeutic agent, ERX-11, that binds to the estrogen receptor (ER) and modulates ER-coregulator interactions. Here, we tested if the combination of ERX-11 with agents approved for ER+ BCa would be more potent. METHODS: We tested the effect of combination therapy using BCa cell line models, including those that have acquired resistance to tamoxifen, letrozole, or CDK4/6 inhibitors or have been engineered to express mutant forms of the ER. In vitro activity was tested using Cell Titer-Glo, MTT, and apoptosis assays. Mechanistic studies were conducted using western blot, reporter gene assays, RT-qPCR, and mass spectrometry approaches. Xenograft, patient-derived explants (PDEs), and xenograft-derived explants (XDE) were used for preclinical evaluation and toxicity. RESULTS: ERX-11 inhibited the proliferation of therapy-resistant BCa cells in a dose-dependent manner, including ribociclib resistance. The combination of ERX-11 and CDK4/6 inhibitor was synergistic in decreasing the proliferation of both endocrine therapy-sensitive and endocrine therapy-resistant BCa cells, in vitro, in xenograft models in vivo, xenograft-derived explants ex vivo, and in primary patient-derived explants ex vivo. Importantly, the combination caused xenograft tumor regression in vivo. Unbiased global mass spectrometry studies demonstrated profound decreases in proliferation markers with combination therapy and indicated global proteomic changes in E2F1, ER, and ER coregulators. Mechanistically, the combination of ERX-11 and CDK4/6 inhibitor decreased the interaction between ER and its coregulators, as evidenced by immunoprecipitation followed by mass spectrometry studies. Biochemical studies confirmed that the combination therapy significantly altered the expression of proteins involved in E2F1 and ER signaling, and this is primarily driven by a transcriptional shift, as noted in gene expression studies. CONCLUSIONS: Our results suggest that ERX-11 inhibited the proliferation of BCa cells resistant to both endocrine therapy and CDK4/6 inhibitors in a dose-dependent manner and that the combination of ERX-11 with a CDK4/6 inhibitor may represent a viable therapeutic approach.

A Structure-Activity Relationship Study of Bis-Benzamides as Inhibitors of Androgen Receptor-Coactivator Interaction.

The interaction between androgen receptor (AR) and coactivator proteins plays a critical role in AR-mediated prostate cancer (PCa) cell growth, thus its inhibition is emerging as a promising strategy for PCa treatment. To develop potent inhibitors of the AR-coactivator interaction, we have designed and synthesized a series of bis-benzamides by modifying functional groups at the N/C-terminus and side chains. A structure-activity relationship study showed that the nitro group at the N-terminus of the bis-benzamide is essential for its biological activity while the C-terminus can have either a methyl ester or a primary carboxamide. Surveying the side chains with various alkyl groups led to the identification of a potent compound 14d that exhibited antiproliferative activity (IC50 value of 16 nM) on PCa cells. In addition, biochemical studies showed that 14d exerts its anticancer activity by inhibiting the AR-PELP1 interaction and AR transactivation.

Comparative study on the effects of Cr, V, and Mo carbides for hydrogen-embrittlement resistance of tempered martensitic steel.

In this study, the ideal alloying element (among Cr, V, and Mo carbides) to enhance the resistance to hydrogen embrittlement (HE) in a tempered martensitic steel was investigated. Four types of steels were designed to contain cementites, Cr-rich M7C3 carbides, V carbides, and Mo carbides, respectively. These steels were tailored to possess a comparable tensile strength (~1.6 GPa). The HE resistances of these steels were evaluated through the slow strain rate test and cyclic corrosion test. The results showed an enhanced HE resistance, characterized by a high notch fracture strength after hydrogen charging, in the samples containing V carbides and Mo carbides. In particular, Mo carbide was regarded as the most ideal alloying element for HE resistance because of the high resistivity parameter, inhibited hydrogen penetration, and suppressed strength loss by internal hydrogen.

Composition and biochemical properties of l-carnitine fortified Makgeolli brewed by using fermented buckwheat.

Makgeolli is a traditional Korean alcoholic rice beverage. It is brewed of ingredients containing starch, Nuruk, and water. In order to improve the quality and functionality of Makgeolli, the Rhizopus oligosporus fermented buckwheat containing 18.7 mg/kg of l-carnitine were utilized to brew l-carnitine fortified Makgeolli with rice. Makgeolli was prepared in two-stage fermentation method and total rutin and quercetin in each fermented buckwheat Makgeolli were increased 1.8-fold greater than buckwheat Makgeolli. DPPH antioxidant activity was enhanced in fermented buckwheat Makgeolli than buckwheat Makgeolli (21.9%-65.7%). The amounts of l-carnitine in rice Makgeolli, buckwheat Makgeolli, and fermented buckwheat Makgeolli were 0.9, 0.8-1.0, and 1.0-1.9 mg/L, respectively. The fermented buckwheat Makgeolli not only promoted health benefit by increasing l-carnitine and flavonols, but also made effective alcohol production (2.8%-8.4%) compared to common buckwheat Makgeolli, indicating the potential industrial application with health benefits.