ELK3 destabilization by speckle-type POZ protein suppresses prostate cancer progression and docetaxel resistance.

Accumulating evidence demonstrates that the activity regulation of ELK3, a member of the E26 transformation-specific oncogene family, is critical to regulating cell proliferation, migration, and survival in human cancers. However, the molecular mechanisms of how ELK3 induces chemoresistance in prostate cancer (PCa) have not been elucidated. In this study, we found that SPOP and ELK3 are an interacting partner. The interaction between SPOP and ELK3 resulted in increased ELK3 ubiquitination and destruction, assisted by checkpoint kinase-mediated ELK3 phosphorylation. Notably, the modulation of SPOP-mediated ELK3 protein stability affected the c-Fos-induced cell proliferation and invasion of PCa cells. The clinical involvement of the SPOP-ELK3 axis in PCa development was confirmed by an immunohistochemical assay on 123 PCa tissues, with an inverse correlation between increased ELK3 and decreased SPOP being present in ~80% of the specimens. This observation was supported by immunohistochemistry analysis using a SPOP-mutant PCa specimen. Finally, docetaxel treatment induced cell death by activating checkpoint kinase- and SPOP-mediated ELK3 degradation, while SPOP-depleted or SPOP-mutated PCa cells showed cell death resistance. Notably, this observation was correlated with the protein levels of ELK3. Taken together, our study reveals the precise mechanism of SPOP-mediated degradation of ELK3 and provides evidence that SPOP mutations contribute to docetaxel resistance in PCa.

Dysregulated CREB3 cleavage at the nuclear membrane induces karyoptosis-mediated cell death.

Cancer cells often exhibit resistance to apoptotic cell death, but they may be vulnerable to other types of cell death. Elucidating additional mechanisms that govern cancer cell death is crucial for developing new therapies. Our research identified cyclic AMP-responsive element-binding protein 3 (CREB3) as a crucial regulator and initiator of a unique cell death mechanism known as karyoptosis. This process is characterized by nuclear shrinkage, deformation, and the loss of nuclear components following nuclear membrane rupture. We found that the N-terminal domain (aa 1-230) of full-length CREB3 (CREB3-FL), which is anchored to the nuclear inner membrane (INM), interacts with lamins and chromatin DNA. This interaction maintains a balance between the outward force exerted by tightly packed DNA and the inward constraining force, thereby preserving INM integrity. Under endoplasmic reticulum (ER) stress, aberrant cleavage of CREB3-FL at the INM leads to abnormal accumulation of the cleaved form of CREB3 (CREB3-CF). This accumulation disrupts the attachment of CREB3-FL to the INM, resulting in sudden rupture of the nuclear membrane and the onset of karyoptosis. Proteomic studies revealed that CREB3-CF overexpression induces a DNA damage response akin to that caused by UVB irradiation, which is associated with cellular senescence in cancer cells. These findings demonstrated that the dysregulation of CREB3-FL cleavage is a key factor in karyoptotic cell death. Consequently, these findings suggest new therapeutic strategies in cancer treatment that exploit the process of karyoptosis.

Empathy With Patients and Post-Traumatic Stress Response in Verbally Abused Healthcare Workers.

OBJECTIVE: The current study examined the differential empathic capacity, post-traumatic symptoms, and coping strategies in healthcare workers (HCWs) according to the exposure of verbal or physical workplace violence (WPV). METHODS: Using online survey, a total of 422 HCWs employed at a training general hospital of South Korea participated and completed self-reporting questionnaires including the WPV questionnaire with coping strategy, the Jefferson Scale of Physician Empathy. RESULTS: Those who experienced either only verbal violence or both physical and verbal violence had lower Jefferson Scale of Physician Empathy scores (p<0.05). Posttraumatic stress symptom severity was higher among people who experienced verbal violence than physical violence. HCWs' exposure to verbal violence was associated with severe posttraumatic symptoms and a low level of empathy with patients (p<0.05). More than half of the victims of verbal violence responded that they did not take any action, receive organizational protection, or peer support, while most physically-abused HCWs received institutional intervention or help from others. CONCLUSION: Our findings highlight the critical importance of reducing verbal violence, which may represent a larger psychological burden compared to physical violence, by actively implementing effective strategies and policies at the institutional level.

Fargesin Inhibits EGF-Induced Cell Transformation and Colon Cancer Cell Growth by Suppression of CDK2/Cyclin E Signaling Pathway.

Although the lignan compound fargesin is a major ingredient in Shin-Yi, the roles of fargesin in carcinogenesis and cancer cell growth have not been elucidated. In this study, we observed that fargesin inhibited cell proliferation and transformation by suppression of epidermal growth factor (EGF)-stimulated G1/S-phase cell cycle transition in premalignant JB6 Cl41 and HaCaT cells. Unexpectedly, we found that signaling pathway analyses showed different regulation patterns in which fargesin inhibited phosphatidylinositol 3-kinase/AKT signaling without an alteration of or increase in mitogen activated protein kinase (MAPK) in JB6 Cl41 and HaCaT cells, while both signaling pathways were abrogated by fargesin treatment in colon cancer cells. We further found that fargesin-induced colony growth inhibition of colon cancer cells was mediated by suppression of the cyclin dependent kinase 2 (CDK2)/cyclin E signaling axis by upregulation of p21WAF1/Cip1, resulting in G1-phase cell cycle accumulation in a dose-dependent manner. Simultaneously, the suppression of CDK2/cyclin E and induction of p21WAF1/Cip1 were correlated with Rb phosphorylation and c-Myc suppression. Taken together, we conclude that fargesin-mediated c-Myc suppression inhibits EGF-induced cell transformation and colon cancer cell colony growth by the suppression of retinoblastoma (Rb)-E2F and CDK/cyclin signaling pathways, which are mainly regulated by MAPK and PKB signaling pathways.

Burnout as a Mediator in the Relationship between Work-Life Balance and Empathy in Healthcare Professionals.

OBJECTIVE: This cross-sectional study aimed to 1) explore the relationships among work-life balance (WLB), burnout, and empathy and 2) investigate the roles of the subtypes of burnout relating to WLB and empathy. METHODS: A total of 105 health care professionals from a general hospital in Seoul were assessed using the Maslach Burnout Inventory, Jefferson Scale of Physician Empathy, and a one-sentence-question on subjective WLB. Multiple questions on psychiatric problems, including sleep problems, anxiety, depressive symptom, and alcohol problems, were also included. RESULTS: In the mediation analyses, personal achievement was considered as a potential mediating variable between WLB and empathy. The direct effect (ß=3.93, 95% CI: 1.21-6.64) and the indirect effect (ß=1.95, 95% CI: 0.52-3.76) of WLB on empathy were also significant. CONCLUSION: Interventions encouraging personal achievement may help mitigate burnout of health professionals.

FBXW7-mediated stability regulation of signal transducer and activator of transcription 2 in melanoma formation.

In this study, we provide critical evidence that STAT2 stability regulation plays an essential role in melanoma cell proliferation and colony growth. We found that the interaction of FBXW7 and STAT2 induced STAT2 destabilization via a ubiquitination-mediated proteasomal degradation pathway. Notably, GSK3ß-mediated STAT2 phosphorylation facilitated STAT2-FBXW7 interactions via the DNA binding domain of STAT2 and domains 1, 2, 6, and 7 of FBXW7 WD40. Importantly, the inverse correlation between protein levels of STAT2 and FBXW7 were observed not only in human melanoma cells but also in a human skin cancer tissue array. The relationship between protein levels of STAT2 and FBXW7, cell proliferation, and colony growth were similarly observed in the melanoma cell lines SK-MEL-2, -5, and -28. Moreover, STAT2 knockdown in melanoma cells suppressed melanoma cell proliferation and colony formation. These data demonstrated that FBXW7-mediated STAT2 stability regulation plays an essential role in melanoma cell proliferation and cancer growth.

RSK2-Mediated ELK3 Activation Enhances Cell Transformation and Breast Cancer Cell Growth by Regulation of c-fos Promoter Activity.

Ribosomal S6 kinase 2 (RSK2), regulated by Ras/Raf/MEKs/ERKs, transmits upstream activation signals to downstream substrates including kinases and transcription and epigenetic factors. We observed that ELK members, including ELK1, 3, and 4, highly interacted with RSK2. We further observed that the RSK2-ELK3 interaction was mediated by N-terminal kinase and linker domains of RSK2, and the D and C domains of ELK3, resulting in the phosphorylation of ELK3. Importantly, RSK2-mediated ELK3 enhanced c-fos promoter activity. Notably, chemical inhibition of RSK2 signaling using kaempferol (a RSK2 inhibitor) or U0126 (a selective MEK inhibitor) suppressed EGF-induced c-fos promoter activity. Moreover, functional deletion of RSK2 by knockdown or knockout showed that RSK2 deficiency suppressed EGF-induced c-fos promoter activity, resulting in inhibition of AP-1 transactivation activity and Ras-mediated foci formation in NIH3T3 cells. Immunocytofluorescence assay demonstrated that RSK2 deficiency reduced ELK3 localization in the nucleus. In MDA-MB-231 breast cancer cells, knockdown of RSK2 or ELK3 suppressed cell proliferation with accumulation at the G1 cell cycle phase, resulting in inhibition of foci formation and anchorage-independent cancer colony growth in soft agar. Taken together, these results indicate that a novel RSK2/ELK3 signaling axis, by enhancing c-Fos-mediated AP-1 transactivation activity, has an essential role in cancer cell proliferation and colony growth.

Surface conversion of ZnO nanorods to ZIF-8 to suppress surface defects for a visible-blind UV photodetector.

ZnO nanomaterials are promising building blocks for an efficient UV photodetector; however, their slow sensing behavior and undesired response to visible light, which are attributed to surface defects, such as oxygen or zinc vacancies, are challenges that remain to be addressed. Here, we transformed the ZnO nanorod surface into a zeolitic imidazolate framework-8 (ZIF-8) to eliminate ZnO surface defects. Vertical-type photodetectors were fabricated incorporating a Schottky junction at the ZIF-8/gold (Au) top electrode and could respond to UV light with a rapid response and recovery (1-2 s) and demonstrated a UV-to-visible rejection ratio in the order of 103, qualifying them as efficient visible-blind UV photodetectors. It is noteworthy that the ZIF-8 layer effectively separated the photogenerated electron-hole pairs, and thus reduced their recombination probability. The enhanced photodetector displayed excellent figures-of-merit: a responsivity of 291 A W-1 and a detectivity of 5.9 × 1013 cm Hz1/2 W-1 under illumination at 295 nm.

Effects of Extracorporeal Shockwave Therapy in Chronic Stroke Patients With Knee Osteoarthritis: A Pilot Study.

OBJECTIVE: To evaluate the effects of extracorporeal shockwave therapy (ESWT) on pain, function, and ultrasonographic features of chronic stroke patients with knee osteoarthritis (OA). METHODS: A total of 18 chronic stroke patients (33 knee joints) with unilateral or bilateral knee OA (Kellgren-Lawrence grade ≥1) were enrolled in this study. The patients were randomly allocated to an experimental group receiving ESWT (n=9) or a control group receiving sham ESWT (n=9). For the ESWT group, patients received 1,000 pulses weekly for 3 weeks, totaling to an energy dose of 0.05 mJ/mm2 on the proximal medial tibia of the affected knee. The assessments were performed before the treatment, immediately after the first treatment, and 1 week after the last treatment using the following: the visual analog scale (VAS) for pain; patient perception of the clinical severity of OA; the Korean version of Modified Barthel Index (ambulation and chair/bed transfer); the Functional Independence Measure scale (FIM; bed/chair/wheelchair transfer, toilet transfer, walking, and stairs); and ultrasonographic features (articular cartilage thickness, Doppler activity, and joint effusion height). RESULTS: The experimental group showed a significant improvement in VAS score (4.50±1.87 to 2.71±1.38) and patient perception of the clinical severity of OA (1.87±0.83 to 2.75±0.46). The bed/chair/wheelchair transfer components of the FIM score also improved significantly (4.12±1.55 to 4.62±1.30). In terms of the ultrasonographic features, increased Doppler activity was observed in the medial knee in the experimental group immediately following ESWT. CONCLUSION: It is suggested that ESWT may reduce pain and improve function in chronic stroke patients with OA, and may increase vascular activity at the target site.

Locally placed nanoscale gold islands film within a TiO2 photoanode for enhanced plasmon light absorption in dye sensitized solar cells.

As metal nanostructures demonstrated extraordinary plasmon resonance, their optical characteristics have widely been investigated in photo-electronic applications. However, there has been no clear demonstration on the location effect of plasmonic metal layer within the photoanode on both optical characteristics and photovoltaic performances. In this research, the gold (Au) nano-islands (NIs) film was embedded at different positions within the TiO2 nanoparticulate photoanode in dye-sensitized solar cells (DSSC) to check the effect of plasmon resonance location on the device performance; at the top, in the middle, at the bottom of the TiO2 photoanode, and also at all the three positions. The Au NIs were fabricated by annealing a Au thin film at 550 °C. The DSSC having the Au NIs-embedded TiO2 photoanode exhibited an increase in short circuit currents (Jsc) and power conversion efficiency (PCE) owing to the plasmon resonance absorption. Thus, the PCE was increased from 5.92% (reference: only TiO2 photoanode) to 6.52% when the Au NIs film was solely positioned at the bottom, in the middle or at the top of TiO2 film. When the Au NIs films were placed at all the three positions, the Jsc was increased by 16% compared to the reference cell, and consequently the PCE was further increased to 7.01%.

Molecular Targeting of ERKs/RSK2 Signaling Axis in Cancer Prevention.

RSK2 is a downstream signaling protein of ERK1 and ERK2 and plays a key role in physiological homeostasis. For this reason, RSK2 is a highly conserved protein among the p90RSK family members. In its location in the signaling pathway, RSK2 is a kinase just upstream of transcription and epigenetic factors, and a few kinases involved in cell cycle regulation and protein synthesis. Moreover, activation of RSK2 by growth factors is directly involved in cell proliferation, anchorage-independent cell transformation and cancer development. Direct evidences regarding the etiological roles of RSK2 in cancer development in humans have been published by our research group illustrating that elevated total- and phospho-RSK2 protein levels mediated by ERK1 and ERK2 are higher in skin cancer tissues compared to normal skin tissues. Notably, it has been shown that RSK2 ectopic expression in JB6 Cl41 cells induces cell proliferation and anchorage- independent cell transformation. Importantly, knockdown of RSK2 suppresses Ras-mediated foci formation and anchorage-independent colony growth of cancer cells. Kaempferol is a one of the natural compounds showing selectivity in inhibiting RSK2 activity in epidermal growth factor-induced G1/S cell cycle transition and cell transformation. Thus, ERKs/RSK2 signaling axis is an important target signaling molecule in chemoprevention.

Paenibacillus insulae sp. nov., isolated from soil.

A Gram-stain-positive, motile, endospore-forming, and strictly aerobic rod-shaped bacterium designated DS80(T) was isolated from an island soil. The strain DS80(T) grew at temperatures between 15 and 40°C (optimum = 30°C) and at pH values ranging from 5.0 to 9.0 (optimum = 7.0). The phylogenetic analysis based on the comparisons of the 16S rRNA gene sequences showed that the isolate was affiliated to the genus Paenibacillus and was mostly related to Paenibacillus assamensis GPTSA11(T) (with the sequence similarity of 96.33%) and Paenibacillus urinalis 5402403(T)(95.48%). The G+C content of the genomic DNA was 44.0 mol% and the major fatty acids were anteiso-C15:0, iso-C15:0, iso-C16:0, and C16:1 ω11c. Strain DS80(T) contained MK-7 as the major menaquinone, and phosphatidylglycerol, phosphatidylethanolamine, and diphosphatidylglycerol as the major polar lipids. The peptidoglycan contained a major amount of meso-diaminopimelic acid. The chemotaxonomic profile of strain DS80(T) was consistent with that of Paenibacillus. However, the phenotypic properties clearly separated the strain from other species of the genus. Accordingly, a new species, Paenibacillus insulae sp. nov., is proposed (type strain =DS80(T) =JCM 17278(T) =KCTC 13833(T)).

In vitro and in vivo evaluation of the effect of puerarin on hepatic cytochrome p450-mediated drug metabolism.

Puerarin (8-ß-D-glucopyranosyl-7-hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a major pharmacological component of Puerariae Radix, the root of Pueraria lobata. We investigated the effect of puerarin on hepatic cytochrome P450-mediated drug metabolism in rats and humans. The in vitro cytochrome P450 inhibitory effect of puerarin in human and rat liver microsomes was evaluated using the following model cytochrome P450 substrates: phenacetin for CYP1A, diclofenac for CYP2C, dextromethorphan for CYP2D, and testosterone for CYP3A. The in vivo pharmacokinetics of intravenous and oral buspirone, a probe substrate for CYP3A, was studied with single simultaneous intravenous coadministration of puerarin in rats. In the in vitro cytochrome P450 inhibition study, the rate of disappearance of testosterone was significantly reduced in the presence of 10 µM PU, while that of other cytochrome P450 substrates was not significantly affected in both human and rat liver microsomes, suggesting that puerarin inhibits the in vitro hepatic CYP3A-mediated metabolism in the human and rat systems (IC50 = 15.5 ± 3.9 µM). After intravenous administration of buspirone with single simultaneous coadministration of intravenous puerarin at a dose of 10 mg/kg in rats, the total area under the plasma concentration-time curve from time zero to time infinity was increased while time-averaged total body clearance decreased. When buspirone was orally administered in rats with the 10 mg/kg intravenous puerarin coadministration, both total area under the plasma concentration-time curve from time zero to time infinity and the extent of absolute oral bioavailability were significantly increased. Therefore, results of the in vitro microsomal and in vivo pharmacokinetic studies suggest the possible inhibition of hepatic CYP3A-mediated drug metabolism by puerarin administration, potentially leading to metabolism-mediated herb-drug interactions with clinical significance.

Temperature dependence of bis(triisopropylsilylethynyl)-pentacene nanofilm deposited on octadecyltrichlorosilane self assembled monolayer surface as a transistor channel.

Highly pure 6,13-bis(triisopropylsilylethynyl)pentacene (TIPS-PEN) nanofilms were deposited on a hydrophobic OTS-SAM surface at two different substrate temperatures (70 degrees C and 90 degrees C) via the vacuum thermal evaporation (VTE) method. X-ray reflectivity measurements over a wide temperature range (30 degrees C-284 degrees C) revealed that out-of-plane crystallinity of the film (approximately 10 nm) remains intact but in-plane crystallinity starts to become poor from approximately 100 degrees C, and to become much more worse from 260 degrees C. Atomic force microscope images showed that TIPS-PEN films (approximately 55 nm) prepared at the substrate temperature of 90 degrees C or above commonly have a number of huge cracks between enormous crystal domains (up to 3 microm) whereas the films didn't form such morphology below T(s) = 90 degrees C. These results clearly suggest that an optimum substrate temperature of TIPS-PEN nanofilms on OTS-SAM surface must be somewhere between 70 degrees C and 90 degrees C, and the process temperature must be kept below 90 degrees C in order to form and maintain a highly crystalline film for an organic thin film transistor device since in-plane crystallinity of a semiconductor channel deeply affects the performance of a transistor.