The LKB1-TSSK1B axis controls YAP phosphorylation to regulate the Hippo-YAP pathway.

The Hippo pathway's main effector, Yes-associated protein (YAP), plays a crucial role in tumorigenesis as a transcriptional coactivator. YAP's phosphorylation by core upstream components of the Hippo pathway, such as mammalian Ste20 kinase 1/2 (MST1/2), mitogen-activated protein kinase kinase kinase kinases (MAP4Ks), and their substrate, large tumor suppressor 1/2 (LATS1/2), influences YAP's subcellular localization, stability, and transcriptional activity. However, recent research suggests the existence of alternative pathways that phosphorylate YAP, independent of these core upstream Hippo pathway components, raising questions about additional means to inactivate YAP. In this study, we present evidence demonstrating that TSSK1B, a calcium/calmodulin-dependent protein kinase (CAMK) superfamily member, is a negative regulator of YAP, suppressing cellular proliferation and oncogenic transformation. Mechanistically, TSSK1B inhibits YAP through two distinct pathways. Firstly, the LKB1-TSSK1B axis directly phosphorylates YAP at Ser94, inhibiting the YAP-TEAD complex's formation and suppressing its target genes' expression. Secondly, the TSSK1B-LATS1/2 axis inhibits YAP via phosphorylation at Ser127. Our findings reveal the involvement of TSSK1B-mediated molecular mechanisms in the Hippo-YAP pathway, emphasizing the importance of multilevel regulation in critical cellular decision-making processes.

Radiation shielding effects of lead equivalent thickness of a radiation protective apron and distance during C-arm fluoroscopy-guided pain interventions: A randomized trial.

BACKGROUND: The present study aimed to evaluate the degree of radiation shielding effects according to lead equivalent thickness and distance during C-arm fluoroscopy-guided lumbar interventions. METHODS: The exposure time and air kerma were recorded using a fluoroscope. The effective dose (ED) was measured with and without the shielding material of the lead apron using 2 dosimeters at 2 positions. According to the lead equivalent thickness of the shielding material and distance from the side of the table, the groups were divided into 4 groups: group 1 (lead equivalent thickness 0.6 mm, distance 0 cm), group 2 (lead equivalent thickness 0.6 mm, distance 5 cm), group 3 (lead equivalent thickness 0.3 mm, distance 0 cm), and group 4 (lead equivalent thickness 0.3 mm, distance 5 cm). Mean differences such as air kerma, exposure time, ED, and ratio of EDs (ED with protector/ED without protector) were analyzed. RESULTS: A total of 400 cases (100 cases in each group) were collected. The ratio of ED was significantly lower in groups 1 and 2 (9.18 ±â€…2.78% and 9.56 ±â€…3.29%, respectively) when compared to that of groups 3 and 4 (21.93 ±â€…4.19% and 21.53 ±â€…4.30%, respectively). The reductive effect of a 5-cm distance was 33.3% to 36.1% when comparing the ED between groups 1 and 2 and groups 3 and 4. CONCLUSIONS: The 0.3- and 0.6-mm lead equivalent thickness protectors have a radiation attenuation effect of 78.1% to 78.5% and 90.4% to 90.8%, respectively. The 5-cm distance from the side of the table reduces radiation exposure by 33.3% to 36.1%.

Gastric insufflation and surgical view according to mask ventilation method for laparoscopic cholecystectomy: a randomized controlled study.

BACKGROUND: Proper mask ventilation is important to prevent air inflow into the stomach during induction of general anesthesia, and it is difficult to send airflow only through the trachea without gastric inflation. Changes in gastric insufflation according to mask ventilation during anesthesia induction were compared. METHODS: In this prospective, randomized, single-blind study, 230 patients were analyzed to a facemask-ventilated group (Ventilation group) or no-ventilation group (Apnea group) during anesthesia induction. After loss of consciousness, pressure-controlled ventilation at an inspiratory pressure of 15 cmH2O was performed for two minutes with a two-handed mask-hold technique for Ventilation group. For Apnea group, only the facemask was fitted to the face for one minute with no ventilation. Next, endotracheal intubation was performed. The gastric cross-sectional area (CSA, cm2) was measured using ultrasound before and after induction. After pneumoperitoneum with carbon dioxide, gastric insufflation of the surgical view was graded by the surgeon for each group. RESULTS: Increase of postinduction antral CSA on ultrasound were not significantly different between Ventilation group and Apnea group (0.04 ± 0.3 and 0.02 ± 0.28, p-value = 0.225). Additionally, there were no significant differences between the two groups in surgical grade according to surgeon's judgement. CONCLUSIONS: Pressure-controlled ventilation at an inspiratory pressure of 15 cmH2O for two minutes did not increase gastric antral CSA and insufflation of stomach by laparoscopic view. TRIAL REGISTRATION: http://cris.nih.go.kr (KCT0003620) on 13/3/2019.

Effects of Compression of the Ulnar Artery on the Radial Artery Catheterization.

Background: The study was designed to evaluate the effects of compression of the ulnar artery on blood flow (BF) and internal cross-sectional area (CSAi) of the radial artery. We also evaluated the success rate and time of successful ultrasound-guided radial artery catheterization at the first attempt with or without compression of the ulnar artery. Methods: Patients were randomly allocated to the Compression group or Standard group to be treated with or without the application of ulnar artery compression, respectively. Hemodynamic stability was confirmed, and ultrasound-guided radial artery catheterization was performed. In the Compression group, an assistant compressed the ulnar artery at 5 cm above the wrist crease and the catheterization was performed after the loss of the distal ulnar artery BF. In the Standard group, the catheterization was performed without compression of the ulnar artery. Before and after the catheterization, BF and CSAi of the radial artery were evaluated. Success rate and time to successful catheterization at the first attempt were recorded. Results: BF and CSAi of the radial artery were similar in the two groups (37.5 [19.3−66] vs. 37.0 [20.6−53.7] mL/min, respectively, p = 0.63; 4.0 [4.0−6.0] vs. 4.0 [3.0−5.0] mm2, respectively, p = 0.095). In the Compression group, BF and CSAi were changed to 80.9 [35.9−128.5] mL/min (p < 0.001) and 5.0 [4.0−7.0] mm2 (p < 0.001), respectively, after compression of the ulnar artery. There was a trend that the success rate of ultrasound-guided radial artery catheterization at the first attempt was higher in the Compression group than in the Standard group (58/59 vs. 53/59, respectively, p = 0.05), although the difference was not statistically significant. However, the time to successful ultrasound-guided radial artery catheterization at the first attempt was significantly shorter in the Compression group than in the Standard group (34 [27−41] s vs. 46 [36−60] s, p < 0.001). Conclusion: Compression of the ulnar artery augmented BF and CSAi of the radial artery. It resulted in a significantly shorter success time for ultrasound-guided radial artery catheterization at the first attempt.

Phosphorylation analysis of the Hippo-YAP pathway using Phos-tag.

Phosphorylation is an essential regulatory mechanism in cells that modifies diverse substrates, such as proteins, carbohydrates, lipids, and nucleotides. Protein phosphorylation regulates function, subcellular localization, and protein-protein interactions. Protein kinases and phosphatases catalyze this reversible mechanism, subsequently influencing signal transduction. The dysregulation of protein phosphorylation leads to many diseases, such as cancer, neurodegenerative diseases, and metabolic diseases. Therefore, analyzing the phosphorylation status and identifying protein phosphorylation sites are critical for elucidating the biological functions of specific phosphorylation events. Unraveling the critical phosphorylation events associated with diseases and specific signaling pathways is promising for drug discovery. To date, highly accurate and sensitive approaches have been developed to detect the phosphorylation status of proteins. In this review, we discuss the application of Phos-tag to elucidate the biological functions of Hippo pathway components, with emphasis on the identification and quantitation of protein phosphorylation under physiological and pathological conditions. SIGNIFICANCE: We here provide a comprehensive overview of Phos-tag technique-based strategies to identify phosphorylated proteins at the cellular level in the Hippo-YAP pathway that comprises a major driving force for cellular homeostasis. We clarify the links of applying Phos-tag in elucidating the biological functions of the Hippo pathway components with particular attention to the identification and quantitation of protein phosphorylation under physiological and pathological conditions. We believe that our paper will make a significant contribution to the literature because these detailed phosphorylation modifications and functional diversity of the Hippo pathway components in physiological and pathological processes are only beginning to come to the fore, highlighting the potential for discovering new therapeutic targets. Moreover, this line of research can provide further insight into the inextricable link between phos-tag applications as a molecular tool and cellular signaling modality, offering new directions for an integrated research program toward understanding cellular regulation at the molecular level. Given the broad research and practical applications, we believe that this paper will be of interest to the readership of your journal.

The Association between Two-Stage Tourniquet Application during Total Knee Replacement and Blood Loss: A Retrospective Cohort Study.

Tourniquet use during total knee arthroplasty improves the surgical field, but is associated with several complications. The medical records of 506 patients who underwent elective total knee arthroplasty or total knee replacement from January 2017 to December 2020 were reviewed. A total of 331 patients who had undergone total knee arthroplasty were included. In the first half course group, the tourniquet was inflated with a pressure of 300 mmHg after manual banding before the incision and deflated after cement insertion. In the two-stage group, the tourniquet was inflated and deflated at the same stages of the procedure as in the first half course group. However, in this second group, the tourniquet was deflated for 15 min and then inflated again, and, finally, it was deflated after skin closure. The estimated blood loss, the number of patients who needed medications to control their blood pressure, and opioid usage at the post-anesthesia care unit were similar in both groups. The two-stage tourniquet technique was not related to reduced total blood loss in total knee arthroplasty.

Clinical impact of medication adherence on 10-year cardio-cerebrovascular mortality in newly diagnosed hypertensive patients.

The purpose of this study is to evaluate the impact of medication adherence on cardio-cerebrovascular (CCV) mortality in newly diagnosed hypertensive patients. The authors retrospectively reviewed data from 20,836 patients who newly diagnosed hypertension from January 1, 2003 to December 31, 2005. Medication adherence was calculated from the compliance ratio (CR) during the first year after the diagnosis of hypertension. CCV mortality for 10 years was assessed according to the presence or absence of complications of hypertension. The risk of CCV death was significantly reduced in the CR ≥ 70% group than in the CR < 70% group (hazard ratio, 0.70; p = .004) for 10 years. In the patients without complications, the risk of CCV death was significantly lower in the CR ≥ 70% group than in the CR < 70% group (hazard ratio, 0.56; p = .014). However, in patients with complications, there was no significant difference in risk of CCV death between the CR ≥ 70% group and the CR < 70% group (hazard ratio, 0.79; p = .100). Only the CR ≥ 90% group had a significantly lower risk of CCV death (hazard ratio, 0.56; p < .001) for those with complications. Medication adherence is significantly associated with CCV mortality during 10 years in newly diagnosed hypertensives patients. Patients with complications of hypertension have to continue a high adherence rate (CR ≥ 90) for better long-term clinical outcomes.

Extracts of Perilla frutescens var. Acuta (Odash.) Kudo Leaves Have Antitumor Effects on Breast Cancer Cells by Suppressing YAP Activity.

Yes-associated protein (YAP)/WW domain-containing transcription factor (TAZ) is critical for cell proliferation, survival, and self-renewal. It has been shown to play a crucial oncogenic role in many different types of tumors. In this study, we investigated the antitumor effect of the extracts of Perilla frutescens var. acuta (Odash.) Kudo leaves (PLE) on Hippo-YAP/TAZ signaling. PLE induced the phosphorylation of YAP/TAZ, thereby inhibiting their activity. In addition, the treatment suppresses YAP/TAZ transcriptional activity via the dissociation of the YAP/TAZ-TEAD complex. To elucidate the molecular mechanism of PLE in the regulation of YAP activity, we treated WT and cell lines with gene knockout (KO) for Hippo pathway components with PLE. The inhibitory effects of PLE on YAP-TEAD target genes were significantly attenuated in LATS1/2 KO cells. Moreover, we found the antitumor effect of PLE on MDA-MB-231 and BT549, both of which are triple-negative breast cancer (TNBC) cell lines. PLE reduced the viability of TNBC cells in a dose-dependent manner and induced cell apoptosis. Further, PLE inhibited the migration ability in MDA-MB-231 cells. This ability was weakened in YAP and TEAD-activated clones suggesting that the inhibition of migration by PLE is mainly achieved by regulating YAP activity. Taken together, the results of this study indicate that PLE suppressed cell growth and increased the apoptosis of breast cancer (BC) cells via inactivation of YAP activity in a LATS1/2-dependent manner.

Patients' perception about opioids and addiction in South Korea.

BACKGROUND: Chronic pain affects approximately 22% of the world's population. Opioids can be useful in chronic pain management. However, some patients have negative perception of opioids. The purpose of this research was to evaluate patients' perception about opioids and investigate problems associated with prescribing and taking opioids in South Korea. METHODS: Patients who visited a pain clinic in 14 university hospitals of South Korea from September through October 2018 were asked to complete anonymous questionnaires about taking opioids. RESULTS: Of the 368 patients that were surveyed (female 53.3%, male 46.7%), 56.8% were prescribed opioids. In the opioid group, 92.8% patients had heard of opioids from their doctor and 72.6% of them had a positive perception about opioids. The side effects associated with opioid use were constipation (35.4%), dizziness (24.6%), nausea and vomiting (17.4%), dysuria (6.2%), and addiction (2.0%). In the no opioid group, the primary sources of information about opioids were doctors (49.2%), mass media (30.8%), and the internet (16.2%). The main reasons why 39.0% patients did not take opioids were fear of addiction (57.7%) and side effects (38.5%). There were 71.5% and 60.9% patients in the opioid and no opioid group, respectively, who wished to take opioids when their numeric rating scale pain score was ≥ 7. CONCLUSIONS: Perception of opioids among patients who take them was either neutral or positive. However, 39.0% patients who have not been prescribed opioids did not want an opioid prescription, citing fear of addiction and side effects as the primary reasons.

Dual Mode Radiative Transition from a Phenoselenazine Derivative and Electrical Switching of the Emission Mechanism.

Dual emission featuring both thermally activated delayed fluorescence (TADF) and phosphorescence was engineered into a single metal-free molecule, phenyl(10-phenyl-10H-phenoselenazin-3-yl)methanone. Selenium incorporated into the molecule increases the spin-orbit coupling to facilitate both TADF and phosphorescence, whereas donor-acceptor units promote TADF emission. The relative contribution of the green TADF and yellow phosphorescence can be controlled by the driving voltage of the devices. At low voltage, phosphorescence emission dominates the electroluminescence, whereas TADF is the major component at high voltages. The mechanism of dual emission was explored using experimental and theoretical methods.

Hesperetin inhibit EMT in TGF-ß treated podocyte by regulation of mTOR pathway.

Renal fibrosis is one of the characteristic features of chronic kidney disease (CKD). Fibrotic change not only impairs the filtration function of the kidney but is also recognized as a marker of end-stage renal disease (ESRD). The epithelial to mesenchymal transition (EMT) is known to play a role in embryonic development and organ formation, but it is getting much attention for its pathological role in the invasion and metastasis of carcinoma. Recently, it has also been reported that EMT plays a role in the formation of fibrosis during chronic inflammation. EMT contribute to the development of the fibrosis in CKD. Moreover, glomerular podocytes and tubular epithelial cells can also undergo mesenchymal transition in CKD. Hesperetin is a flavonoid present in citrus and is well known for its antioxidant and anti-inflammatory properties. In this study, we investigated the effects of hesperetin on the EMT-elicited podocytes. First, we generated an EMT model by treating transforming growth factor (TGF)-ß1, a potent inducer of EMT to the podocytes. TGF-ß1 decreased the expression of epithelial markers such as nephrin, zonula occludens-1 (ZO-1), while it increased the mesenchymal markers, including fibronectin (FN), vimentin, and α-smooth muscle actin (α-SMA) in the podocytes. Hesperetin suppressed EMT-like changes elicited by TGF-ß1. Interestingly, hesperetin did not interfere with the Smad signaling-the classical TGF-ß signaling-pathway, which was confirmed by the experiment with smad 2/3 -/- podocytes. Instead, hesperetin suppressed EMT-like changes by inhibiting the mTOR pathway-one of the alternative TGF-ß signaling pathways. In conclusion, hesperetin has a protective effect on the TGF-ß1 elicited EMT-like changes of podocytes through regulation of mTOR pathway. It could be a good candidate for the suppression of kidney fibrosis in various CKD.

Role of the Hippo Pathway in Fibrosis and Cancer.

The Hippo pathway is the key player in various signaling processes, including organ development and maintenance of tissue homeostasis. This pathway comprises a core kinases module and transcriptional activation module, representing a highly conserved mechanism from Drosophila to vertebrates. The central MST1/2-LATS1/2 kinase cascade in this pathway negatively regulates YAP/TAZ transcription co-activators in a phosphorylation-dependent manner. Nuclear YAP/TAZ bind to transcription factors to stimulate gene expression, contributing to the regenerative potential and regulation of cell growth and death. Recent studies have also highlighted the potential role of Hippo pathway dysfunctions in the pathology of several diseases. Here, we review the functional characteristics of the Hippo pathway in organ fibrosis and tumorigenesis, and discuss its potential as new therapeutic targets.

Self-Forgiveness Moderates the Effects of Depression on Suicidality.

OBJECTIVE: Not all depressive individuals are suicidal. An increasing body of studies has examined forgiveness, especially self-forgiveness, as a protective factor of suicide based on that suicide is often accompanied by negative self-perceptions. However, less has been studied on how different subtypes of forgiveness (i.e., forgiveness-of-self, forgiveness-of-others and forgiveness-of-situations) could alleviate the effects of depression on suicide. Hence, this study examined forgiveness as a moderator of depression and suicidality. METHODS: 305 participants, consisted of 87 males and 218 females, were included in the study. The mean age was 41.05 (SD: 14.48; range: 19-80). Depression, anxiety, and forgiveness were measured through self-report questionnaires, and suicidal risk was measured through a structuralized interview. Moderations were examined through hierarchical regression analyses. RESULTS: Depression positively correlated with suicidality. RESULTS: of the hierarchical regression analysis indicated forgiveness as a moderator of depression on suicidality. Further analysis indicated only forgiveness-of-self as a significant moderator; the effects of forgiveness-of-others and forgiveness-of-situation were not significant. CONCLUSION: These findings suggest that forgiveness-of-self is essential in reducing of the effects of depression on suicidality. It is suggested that self-acceptance and the promotion of self-forgiveness should be considered as an important factor when developing suicide prevention strategies.

Screening Tool for Anxiety Disorders: Development and Validation of the Korean Anxiety Screening Assessment.

OBJECTIVE: This study evaluated the psychometric properties of the Korean Anxiety Screening Assessment (K-ANX) developed for screening anxiety disorders. METHODS: Data from 613 participants were analyzed. The K-ANX was evaluated for reliability using Cronbach's alpha, item-total correlation, and test information curve, and for validity using focus group interviews, factor analysis, correlational analysis, and item characteristics based on item response theory (IRT). The diagnostic sensitivity and specificity of the K-ANX were compared with those of the Beck Anxiety Inventory (BAI) and Generalized Anxiety Disorder 7-item scale (GAD-7). RESULTS: The K-ANX showed excellent internal consistency (α=0.97) and item-total coefficients (0.92-0.97), and a one-factor structure was suggested. All items were highly correlated with the total scores of the BAI, GAD-7, and Penn State Worry Questionnaire. IRT analysis indicated the K-ANX was most informative as a screening tool for anxiety disorders at the range between 0.8 and 1.6 (i.e., top 21.2 to 5.5 percentiles). Higher sensitivity (0.795) and specificity (0.937) for identifying anxiety disorders were observed in the K-ANX compared to the BAI and GAD-7. CONCLUSION: The K-ANX is a reliable and valid measure to screen anxiety disorders in a Korean sample, with greater sensitivity and specificity than current measures of anxiety symptoms.

Radiation safety: a focus on lead aprons and thyroid shields in interventional pain management.

C-arm fluoroscopy is useful equipment in interventional pain management because it helps to guide correct needle targeting for the accurate injection and drug delivery. However, due to increased use of C-arm fluoroscopy in various pain procedures, the risk of radiation exposure is a significant concern for pain physicians. The harmful biological effects of ionizing radiation on the human body are well known. It is therefore necessary to strive to reduce radiation exposure. Lead aprons with thyroid shields are the most fundamental radiation protective devices for interventional procedures, and are very effective. However, the operator's radiation safety cannot be guaranteed because pain physicians seem to lack sufficient interest, knowledge, and awareness about radiation safety. Also, inappropriate care and use of radiation protective devices may result in a higher risk of radiation exposure. The purpose of this article was to review the literature on radiation safety with a focus on lead aprons and thyroid shields and present recommendations related to those devices during C-arm fluoroscopic-guided interventions by pain physicians.

The effects of crystalloid versus synthetic colloid in vitro on immune cells, co-cultured with mouse splenocytes.

This study assessed the effects of crystalloid versus synthetic colloid in vitro on immune cells co-cultured with mouse splenocytes. Mouse splenocytes were co-cultured with three different types of fluid: Plasma solution-A® (CJ HealthCare, Seoul, Korea; the crystalloid group); Tetraspan 6%® (B. Braun Medical, Melsungen, Germany; the Colloid-T group); and Volulyte 6%® (Fresenius Kabi, Bad Homburg vor dér-Höhe, Germany; Colloid-V group). To evaluate the acquired immune response, cluster of differentiation (CD) 4+ T cells and CD8+ T cells were measured. To evaluate the innate immune response, neutrophils were measured. The frequencies of CD4+ and CD8+ T cells did not differ significantly among the three groups on day 1 or 3. However, the frequencies of CD4+ and CD8+ T cells in the two synthetic colloid groups were significantly higher than those in the crystalloid group on day 7. On day 1, the frequency of neutrophils was significantly lower in the two synthetic colloid groups, compared with the crystalloid group. However, the values on the other days were similar among all three groups. In conclusion, crystalloid had a limited effect on the immune response; on the other hand, synthetic colloid increased the acquired immune response, although it temporarily inhibited the innate immune response.

Epidural Blood Patch for the Treatment of Spontaneous and Iatrogenic Orthostatic Headache.

BACKGROUND: The cerebrospinal fluid (CSF) leakage could be happened spontaneously or related to the procedures such as spinal anesthesia, epidural anesthesia, CSF tapping, intrathecal chemotherapy or other spinal procedures. The leakage of CSF leads to intracranial hypotension of which distinguishing clinical feature is orthostatic headache. The epidural blood patch is a gold-standard treatment for intracranial hypotension-related orthostatic headaches. OBJECTIVE: We conducted this study to compare the efficacy and number of epidural blood patches for spontaneous and iatrogenic orthostatic headaches. STUDY DESIGN: Retrospective study. SETTING: University hospital inpatient and outpatient referred to our pain clinic. METHODS: Sex, weight, height, cause of orthostatic headache, leakage site evaluation test, epidural blood patch injection level, number of administered epidural blood patches, and pain intensity data were collected. We classified patients into two groups according to the cause of orthostatic headache: spontaneous (Group S) and iatrogenic (Group I). Patients with myelograms were also divided into 2 groups: multiple cerebrospinal fluid (CSF) leakages and no multiple leakages. RESULTS: Overall, 133 patients (162 procedures) were managed using epidural blood patches. Groups S and I included 34 and 99 patients, respectively. In Group I, 90.9% of the patients achieved complete recovery following a single procedure, whereas 44.1% of Group S patients required repeated procedures. The average number of administered epidural blood patches was significantly higher in Group S (1.48 ± 0.64) than in Group I (1.11 ± 0.35; P = 0.007). Among 23 patients evaluated via myelography, 12 had multiple CSF leakages. Patients with multiple leakages required a significantly higher number of epidural blood patches, compared to patients without multiple leakages (P = 0.023). LIMITATIONS: This retrospective study reveals several limitations including insufficient evaluation of CSF leakage site by myelogram and the retrospective nature of the study itself. CONCLUSIONS: Most patients with iatrogenic orthostatic headache required a single epidural blood patch, although most did not undergo a myelogram or similar test. Patients with spontaneous orthostatic headache or multiple CSF leakages were more likely to require a repeated epidural blood patch.Key words: CSF leakage, dural puncture, epidural blood patch, intracranial hypotension, orthostatic headache, spinal headache.