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Background: Cerebrospinal fluid (CSF) flow is crucial for brain homeostasis and its dysfunction is highly associated with neurodegenerative diseases. Restoring CSF circulation is proposed as a key strategy for the treatment of the diseases. Among the methods to improve CSF circulation, focused ultrasound (FUS) stimulation has emerged as a promising non-invasive brain stimulation technique, with effectiveness evidenced by ex vivo studies. However, due to technical disturbances in in vivo imaging combined with FUS, direct evidence of real-time in vivo CSF flow enhancement by FUS remains elusive., Objective: To investigate whether FUS administered through the skull base can enhance CSF influx in living animals with various real-time imaging techniques., Methods: We demonstrate a novel method of applying FUS through the skull base, facilitating cortical CSF influx, evidenced by diverse in vivo imaging techniques. Acoustic simulation confirmed effective sonication of our approach through the skull base. After injecting fluorescent CSF tracers into cisterna magna, FUS was administered at the midline of the jaw through the skull base for 30 min, during which imaging was performed concurrently., Results: Enhanced CSF influx was observed in macroscopic imaging, demonstrated by the influx area and intensity of the fluorescent dyes after FUS. In two-photon imaging, increased fluorescence was observed in the perivascular space (PVS) after stimulation. Moreover, particle tracking of microspheres showed more microspheres entering the imaging field, with increased mean speed after FUS., Conclusion: Our findings provide direct real-time in vivo imaging evidence that FUS promotes CSF influx and flow in the PVS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: South Korea operates a complete enumeration surveillance of coronavirus disease 2019 (COVID-19). Online mental health survey links were distributed to all COVID-19 confirmed patients within three days of confirmation of infection. This study evaluates the trend of depressive symptoms, anxiety symptoms, post-traumatic stress symptoms, somatic symptoms, and suicidal ideation of COVID-19 confirmed cases across the pandemic from January 2020 to July 2022., Methods: A total of 99,055 responses were analyzed. Validated questionnaires were used to assess depressive symptoms (Patient Health Questionnaire-9), anxiety symptoms (Generalized Anxiety Disorder-7), post-traumatic stress symptoms (Primary Care Post Traumatic Stress Disorder screen), somatic symptoms (Patient Health Questionnaire-15), and suicidal ideation (P4 suicidality screener). Log-binomial regression was used to estimate prevalence ratio across 11 quarters (Q) of the year (2020Q1 to 2022Q3). Stratified analysis was conducted by sex to compare risk between males and females when adjusted prevalence was high., Results: Compared to 2022Q1 (January-March), all symptoms had their highest prevalence ratio during 2020Q1 to 2020Q3 (January-September). The difference in adjusted symptom prevalence between males and females was nonsignificant during high-risk periods., Conclusions: Adverse mental health symptoms were most prevalent during the early pandemic, with a nonsignificant difference in prevalence observed between males and females. Greater attention should be given to individuals who experienced COVID-19 infection during the early stages of the pandemic., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest with the materials presented., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Contact urticaria (CU) is an inflammatory skin disorder triggered by specific substances upon skin contact, leading to immediate acute or chronic manifestations characterized by swelling and redness. While mesenchymal stem cells (MSCs) are increasingly recognized for their therapeutic potential in immune diseases, research on the efficacy and mechanisms of stem cell therapy for urticaria remains scarce. This study investigates the regulatory role of embryonic-stem-cell-derived multipotent MSCs (M-MSCs) administered in a CU mouse model. Therapeutic effects of M-MSC administration were assessed in a Trimellitic anhydride-induced contact urticaria model, revealing significant inhibition of urticarial reactions, including ear swelling, itchiness, and skin lesion. Moreover, M-MSC administration exerted control over effector T cell activities in major lymphoid and peripheral tissues, while also suppressing mast cell degranulation in peripheral tissues. Notably, the inhibitory effects mediated by M-MSCs were found to be TGF-β-dependent. Our study demonstrates the capacity of M-MSCs to regulate contact urticaria in a murine model, harmonizing the activation of inflammatory T cells and mast cells. Additionally, we suggest that TGF-β derived from M-MSCs could play a pivotal role as an inhibitory mechanism in contact urticaria., (© 2023. The Author(s).)

Introduction: This prospective study aimed to investigate the efficacy and safety of preemptive antiviral therapy with tenofovir disoproxil fumarate (TDF) for HBsAg-positive patients with newly diagnosed diffuse large B-cell lymphoma receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy., Methods: We enrolled 73 patients from 20 institutions. The primary end point was the absolute risk of hepatitis B virus (HBV)-related hepatitis during preemptive TDF therapy and for 24 weeks after withdrawal from TDF. Hepatitis was defined as a more than 3-fold increase in serum alanine aminotransferase from baseline or an alanine aminotransferase level of ≥100 U/L. HBV-related hepatitis was defined as hepatitis with an increase in serum HBV-DNA to >10 times that of the pre-exacerbation baseline or an absolute increase of ≥20,000 IU/mL compared with the baseline., Results: No patient developed HBV reactivation or HBV-related hepatitis during preemptive antiviral therapy (until 48 weeks after completion of R-CHOP chemotherapy) with TDF. All adverse events were grade 1 or 2. HBV reactivation was reported in 17 (23.3%) patients. All HBV reactivation was developed at a median of 90 days after withdrawal from TDF (range, 37-214 days). Six (8.2%) patients developed HBV-related hepatitis at a median of 88 days after withdrawal from TDF (range, 37-183 days)., Discussion: Preemptive TDF therapy in HBsAg-positive patients with diffuse large B-cell lymphoma receiving R-CHOP chemotherapy was safe and effective for preventing HBV-related hepatitis. However, a long-term maintenance strategy of preemptive TDF therapy should be recommended because of the relatively high rate of HBV-related hepatitis after withdrawal from TDF ( ClinicalTrials.gov ID: NCT02354846)., (Copyright © 2023 by The American College of Gastroenterology.)

Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest.

Purpose: Febrile neutropenia (FN) can cause suboptimal treatment and treatment-related mortality (TRM) in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP)., Materials and Methods: We conducted a prospective cohort study to evaluate the effectiveness of pegfilgrastim prophylaxis in DLBCL patients receiving R-CHOP, and we compared them with the PROCESS cohort (n=485)., Results: Since January 2015, 986 patients with DLBCL were enrolled. Pegfilgrastim was administered at least once in 930 patients (94.3%), covering 90.3% of all cycles. FN developed in 137 patients (13.9%) in this cohort (23.7% in the PROCESS cohort, p<0.001), and 4.2% of all cycles (10.2% in the PROCESS cohort, p<0.001). Dose delay was less common (≥3 days: 18.1% vs. 23.7%, p=0.015; ≥5 days: 12.0% vs. 18.3%, p=0.023) in this cohort than in the PROCESS cohort. The incidence of TRM (3.2% vs. 5.6%, p=0.047) and infection-related death (1.8% vs. 4.5%, p=0.004) was lower in this cohort than in the PROCESS cohort. The 4-year overall survival (OS) and progression-free survival (PFS) rates of the two cohorts were not different (OS: 73.0% vs. 71.9%, p=0.545; PFS: 69.5% vs. 68.8%, p=0.616). However, in patients aged ≥75 years, the 4-year OS and PFS rates were higher in this cohort than in the PROCESS cohort (OS: 49.6% vs. 33.7%, p=0.032; PFS: 44.2% vs. 30.3% p=0.047)., Conclusion: Pegfilgrastim prophylaxis is effective in the prevention of FN and infection-related death in DLBCL patients receiving R-CHOP, and it also improves OS in patients aged ≥75 years.

Introduction: Emergency nurses serve a vital role in disaster situations. Understanding their disaster preparedness and willingness to respond to a disaster is important in maintaining appropriate disaster management. The purpose of this study was to explore emergency nurses' disaster preparedness and willingness to respond based on demographic and disaster-related characteristics, and their willingness to respond based on specific disaster situations., Methods: In this descriptive, cross-sectional study, the Disaster Preparedness Questionnaire for Nurses and willingness to report to duty by type of event were used to collect data from 158 nurses working in four regional emergency medical centers from 1 December 2019 to 30 April 2020 in the early stages of the COVID-19 pandemic., Results: Emergency nurses with personal disaster experience as a victim or witness ( t = 3.65, p < 0.001), professional disaster experience (i.e., working as a nurse) ( t = 3.58, p < 0.001), who were current members of Korean Disaster Medical Assistance Teams ( t = 6.26, p < 0.001), and who received disaster-related training within a year ( t = 5.84, p < 0.001) showed a high level of perceived disaster preparedness. Emergency nurses who have professional disaster experience (i.e., working as a nurse) ( t = 2.42, p = 0.017), are on a current disaster team ( t = 2.39, p = 0.018), and have received disaster training ( t = 2.73, p = 0.007) showed a high level of willingness to respond. Our study showed a high willingness to respond to natural disasters and low willingness to respond to technological disasters., Discussion: To promote the engagement of emergency nurses in disaster response, disaster education programs should be expanded. Enhancing the safety of disaster response environments through supplementing medical personnel, distributing available resources, and providing sufficient compensation for emergency nurses is also essential.

Autophagy, an intracellular recycling system, is essential for the meiotic maturation of porcine oocytes. Trehalose has been reported as a novel mammalian target of rapamycin (mTOR)-independent autophagy inducer in many cells. Furthermore, we previously have demonstrated that trehalose supplementation during in vitro maturation of porcine oocytes improves the developmental competence of parthenogenetic embryos, possibly via autophagic activation, whereas the underlying mechanisms remain unclear. Therefore, the aim of this study was to address this issue. We found that trehalose plays a role as an autophagy activator by autophagic flux assay and determined that it promotes phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) inhibition and vacuolar protein sorting 34 (VPS34)/mTOR activation by immunoblotting, both in cumulus cells (CCs) and oocytes. However, interestingly, the effects and the mechanisms regulated by trehalose were different in them, respectively. In CCs, the autophagy was activated through the improvement of lysosomal function/autophagic clearance viability by upregulation of coordinated lysosomal expression and regulation genes via PI3K/Akt inhibition. Whereas in oocytes, autophagy was activated via induction of VPS34, which directly influences autophagosome formation, and the precise meiotic process was ensured via Akt inhibition and mTOR activation. Taken together, this study furtherly elucidates the novel detailed mechanism of trehalose during porcine oocyte maturation, thus laying the biological foundations for pharmacological application., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The April 2019 wildfires in Gangwon Province, South Korea forced the evacuation of 1500 individuals and cost more than $100 million in damages, making it the worst wildfire disaster in Korean history. The purpose of this paper was to investigate the mental health effects on survivors following the wildfires., Methods: Between April and May 2019, outreach psychological support services were delivered to people impacted by the wildfires. Post-disaster psychological responses using a checklist and the Clinical Global Impression Scale-Severity (CGI-S) were evaluated for 206 wildfires survivors. The CGI-S was administered consequently at 1, 3, and 6 months after baseline measurement., Results: Among four response categories, somatic responses (76.2%) were most frequently observed among the wildfire survivors. Specifically, insomnia (59.2%), anxiety (50%), chest tightness (34%), grief (33%), flashbacks (33%), and depression (32.5%) were reported by over 30% of the participants. The mean CGI-S scores were significantly decreased at 1 month (mean score = 1.94; SE = 0.09) compared to baseline (mean score = 2.94; SE = 0.08) and remained at the decreased level until 6 months (mean score = 1.66; SE = 0.11). However, participants with flashbacks showed significantly higher CGI-S scores compared to those without flashback at 6 months., Conclusions: Wildfire survivors have various post-disaster responses, especially somatic responses. While most participants' mental health improved over time, a few of them may have experienced prolonged psychological distress after 6 months. Flashbacks were particularly associated with continuing distress. These results suggest that the characteristics of responses should be considered in early phase intervention and in follow-up plans for disaster survivors., (© 2022. The Author(s).)

Background: Cancer stem-like cells (CSCs) play a pivotal role in lung tumor formation and progression. Nerve injury-induced protein 1 (Ninjurin1, Ninj1) has been implicated in lung cancer; however, the pathological role of Ninj1 in the context of lung tumorigenesis remains largely unknown., Methods: The role of Ninj1 in the survival of non-small cell lung cancer (NSCLC) CSCs within microenvironments exhibiting hazardous conditions was assessed by utilizing patient tissues and transgenic mouse models where Ninj1 repression and oncogenic Kras G12D/+ or carcinogen-induced genetic changes were induced in putative pulmonary stem cells (SCs). Additionally, NSCLC cell lines and primary cultures of patient-derived tumors, particularly Ninj1 high and Ninj1 low subpopulations and those with gain- or loss-of-Ninj1 expression, and also publicly available data were all used to assess the role of Ninj1 in lung tumorigenesis., Results: Ninj1 expression is elevated in various human NSCLC cell lines and tumors, and elevated expression of this protein can serve as a biomarker for poor prognosis in patients with NSCLC. Elevated Ninj1 expression in pulmonary SCs with oncogenic changes promotes lung tumor growth in mice. Ninj1 high subpopulations within NSCLC cell lines, patient-derived tumors, and NSCLC cells with gain-of-Ninj1 expression exhibited CSC-associated phenotypes and significantly enhanced survival capacities in vitro and in vivo in the presence of various cell death inducers. Mechanistically, Ninj1 forms an assembly with lipoprotein receptor-related protein 6 (LRP6) through its extracellular N-terminal domain and recruits Frizzled2 (FZD2) and various downstream signaling mediators, ultimately resulting in transcriptional upregulation of target genes of the LRP6/β-catenin signaling pathway., Conclusions: Ninj1 may act as a driver of lung tumor formation and progression by protecting NSCLC CSCs from hostile microenvironments through ligand-independent activation of LRP6/β-catenin signaling., (© 2022. The Author(s).)

Background: COVID-19 patients experience various stressors during the quarantine period and after release from quarantine. However, stressors experienced during each period remain unclear., Methods: A total of 15 mental health experts from the integrated psychological support group for COVID-19participated in this study. Psychological support was provided for the total 932 confirmed COVID-19 patients and their families. Qualitative data were collected using Focus Group Interview (FGI). The participants were divided into two groups and semi-structured questions were used to allow participants to speak their minds., Results: During the quarantine period, difficulties of being diagnosed with COVID-19, concerns about recovery from COVID-19, stress related to quarantine, issues related to the treatment environment, and limited information about COVID-19 and communication were frequently reported. After release from quarantine, the reported main stressors include reinfection or reactivation, concerns about complications, and financial difficulties. Confusion as vectors and victims, stigma and discrimination, and conflicts within a family were observed during both periods., Conclusions: COVID-19 patients suffered various stressors during the quarantine period and after release from quarantine. Moreover, returning to their daily life required timely psychosocial support, intervention, and treatment for COVID-19 infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Park, Lee, Lee, Lee, Kim, Kim, Oh, Ha, Hyun, Lee, Kim, Jeon, Kim and Sim.)

Objective: A disaster in the hospital is particularly serious and quite different from other ordinary disasters. This study aimed at analyzing the activity outcomes of a disaster medical assistance team (DMAT) for a fire disaster at the hospital., Methods: The data which was documented by a DMAT and emergent medical technicians of a fire department contained information about the patient's characteristics, medical records, triage results, and the hospital which the patient was transferred from. Patients were categorized into four groups according to results of field triage using the simple triage and rapid treatment method., Results: DMAT arrived on the scene in 37 minutes. One hundred and thirty eight (138) patients were evacuated from the disaster scene. There were 25 patients (18.1%) in the Red group, 96 patients (69.6%) in the Yellow group, and 1 patient (0.7%) in the Green group. One patient died. There were 16 (11.6%) medical staff and hospital employees. The injury of the caregiver or the medical staff was more severe compared to the family protector., Conclusions: For an effective disaster-response system in hospital disasters, it is important to secure the safety of medical staff, to utilize available medical resources, to secure patients' medical records, and to reorganize the DMAT dispatch system.

In general, optical properties of a top-emitting organic light-emitting diode (OLED) are dependent on the cavity effect of the OLED structure. Therefore, the optical path length of the many thin solid films in the OLED, which is strongly affected by the refractive index and thickness of each material, controls the cavity effect of the cell. In previous research, a parameter space method for optimizing the inorganic layer thickness of a red OLED structure was introduced to achieve the required bandwidth and peak wavelength. This is a simple method with high accuracy and can also be applied to red, green, and blue OLED structures. To design an OLED cell with a practical approach, however, the RGB OLED device requires the thickness of each inorganic layer and organic layer in all three R, G, and B OLED structures to be same. In this study, we applied the parameter space method to an RGB OLED device to find out and optimize the thickness of three inorganic parameters: Indium Tin Oxide (ITO), cathode, and capping layer (CPL) using the finite-difference time-domain (FDTD) method. The parameters ITO, cathode, and CPL were scanned from 18 to 21 nm, 5 to 100 nm, and 10 to 200 nm, respectively. The peak wavelength and bandwidth lines of the three spectral colors were placed on a map of the three inorganic layer thickness parameters to find the optimized points that can provide the desired optical characteristics with the same film thickness in the cell.

Effector and regulatory functions of various leukocytes in allergic diseases have been well reported. Although the role of conventional natural killer (NK) cells has been established, information on its regulatory phenotype and function are very limited. Therefore, the objective of this study was to investigate the phenotype and inhibitory functions of transforming growth factor (TGF)-β-producing regulatory NK (NKreg) subset in mice with MC903-induced atopic dermatitis (AD). Interestingly, the population of TGF-β-producing NK cells in peripheral blood monocytes (PBMCs) was decreased in AD patients than in healthy subjects. The number of TGF-β + NK subsets was decreased in the spleen or cervical lymph node (cLN), but increased in ear tissues of mice with AD induced by MC903 than those of normal mice. We further observed that TGF-β + NK subsets were largely included in CD1d hi PD-L1 hi CD27 + NK cell subset. We also found that numbers of ILC2s and T H 2 cells were significantly decreased by adoptive transfer of CD1d hi PD-L1 hi CD27 + NK subsets. Notably, the ratio of splenic Treg per T H 2 was increased by the adoptive transfer of CD1d hi PD-L1 hi CD27 + NK cells in mice. Taken together, our findings demonstrate that the TGF-β-producing CD1d hi PD-L1 hi CD27 + NK subset has a previously unrecognized role in suppressing T H 2 immunity and ILC2 activation in AD mice, suggesting that the function of TGF-β-producing NK subset is closely associated with the severity of AD in humans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Min, Koo, Noh, Lee, Jo, Lee, Kang, Hyun, Choi and Kim.)

Rationale: The heat shock protein (Hsp) system plays important roles in cancer stem cell (CSC) and non-CSC populations. However, limited efficacy due to drug resistance and toxicity are obstacles to clinical use of Hsp90 inhibitors, suggesting the necessity to develop novel Hsp90 inhibitors overcoming these limitations. Methods: The underlying mechanism of resistance to Hsp90 inhibitors was investigated by colony formation assay, sphere formation assay, western blot analysis, and real-time PCR. To develop anticancer Hsp90 inhibitors that overcome the signal transducer and activator of transcription 3 (STAT3)-mediated resistance, we synthesized and screened a series of synthetic deguelin-based compounds in terms of inhibition of colony formation, migration, and viability of non-small cell lung cancer (NSCLC) cells and toxicity to normal cells. Regulation of Hsp90 by the selected compound NCT-80 [5-methoxy-N-(3-methoxy-4-(2-(pyridin-3-yl)ethoxy)phenyl)-2,2-dimethyl-2H-chromene-6-carboxamide] was investigated by immunoprecipitation, drug affinity responsive target stability assay, binding experiments using ATP-agarose beads and biotinylated drug, and docking analysis. The antitumor, antimetastatic, and anti-CSC effects of NCT-80 were examined in vitro and in vivo using various assays such as MTT, colony formation, and migration assays and flow cytometric analysis and tumor xenograft models. Results: We demonstrated a distinct mechanism in which Hsp90 inhibitors that block N-terminal ATP-binding pocket causes transcriptional upregulation of Wnt ligands through Akt- and ERK-mediated activation of STAT3, resulting in NSCLC cell survival in an autocrine or paracrine manner. In addition, NCT-80 effectively reduced viability, colony formation, migration, and CSC-like phenotypes of NSCLC cells and their sublines with acquired resistance to anticancer drugs by inducing apoptosis and inhibiting epithelial-mesenchymal transition and the growth of NSCLC patient-derived xenograft tumors without overt toxicity. With regards to mechanism, NCT-80 directly bound to the C-terminal ATP-binding pocket of Hsp90, disrupting the interaction between Hsp90 and STAT3 and degrading STAT3 protein. Moreover, NCT-80 inhibited chemotherapy- and EGFR TKI-induced programmed cell death ligand 1 expression and potentiated the antitumor effect of chemotherapy in the LLC-Luc allograft model. Conclusions: These data indicate the potential of STAT3/Wnt signaling pathway as a target to overcome resistance to Hsp90 inhibitors and NCT-80 as a novel Hsp90 inhibitor that targets both CSCs and non-CSCs in NSCLC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Introduction: Acquired haemophilia A (AHA) treatment involves the haemostatic treatment for acute haemorrhage and immunosuppressive therapy (IST) to eradicate FVIII inhibitory antibodies., Aim: We assessed the clinical features of AHA and analysed treatment outcomes in Korea. We further identified prognostic factors affecting treatment outcomes., Methods: Medical records of 55 patients with AHA from 18 institutions were reviewed retrospectively. Logistic and Cox regression analyses were performed to elucidate clinical factors affecting the achievement of complete remission (CR). The primary endpoint was time to CR after IST, and secondary endpoints were time to haemostasis, the achievement of CR, and overall survival (OS)., Results: Among the 55 patients, 50 (91%) had bleeding symptoms. Bleeding was severe in 74% of patients. Thirty-six (72%) patients received haemostatic therapy. Of the 42 patients who received IST, 23 (52%) received steroid alone, with a 52% response rate, and 10 (25%) received a combination of steroid and cyclophosphamide, with an 83% response rate. Five (16%) patients relapsed after a median duration of 220 days. There were eight deaths. In the Cox regression analysis, the FVIII inhibitor titre ≥ 20 BU/mL was the only significant prognostic factor affecting time to CR and haemostasis. No significant difference was observed in OS based on the inhibitor titre., Conclusion: The present study demonstrated the demographic data of AHA in Korea and showed that FVIII inhibitory antibody titre was a predictor of time to achieve CR after IST., (© 2021 John Wiley & Sons Ltd.)

Objective: To compare pressure injury (PI) incidence based on repositioning intervals and support surfaces in acute care settings., Methods: This pragmatic, quasi-experimental trial recruited a total of 251 critically ill patients who were at low or moderate risk for PI development. Participants were assigned to three interventions: a 2-hour repositioning interval using an air mattress, a 2-hour repositioning interval using a foam mattress, or a 3-hour repositioning interval using a foam mattress. Data were collected by nurses every shift over the course of 14 days. Pressure injury incidence was analyzed using a χ2 test., Results: There were no statistically significant differences in PI incidence between the groups with a 2-hour repositioning interval. However, the PI incidence in the group using a foam mattress with a 3-hour repositioning interval was significantly lower than in the group using an air mattress with a 2-hour repositioning interval (odds ratio, 0.481; 95% confidence interval, 0.410-0.565)., Conclusions: The findings showed that PIs decreased when the repositioning interval was extended from every 2 hours to every 3 hours while using foam mattresses. This study suggests that a 3-hour repositioning interval using a foam mattress could be applied to reduce the risk of PI development for patients at low or moderate risk., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To estimate real-world outcomes in East Asian populations, we conducted a nationwide retrospective analysis of the efficacy and safety of lenalidomide for del(5q) myelodysplastic syndrome (MDS) patients with transfusion-dependent anemia in Korea., Methods: Patients aged ≥19 years who had received lenalidomide for the treatment of lower-risk, red blood cell (RBC) transfusion-dependent del(5q) MDS were selected. A filled case report form (CRF) with information from electronic medical records was requested from members of the acute myeloid leukemia (AML)/MDS Working Party of the Korean Society of Hematology. All the CRFs were gathered and analyzed., Results: A total of 31 patients were included in this study. Of 28 evaluable patients, 19 (67.9%) achieved RBC transfusion independence (RBC-TI). Female sex and the development of thrombocytopenia during treatment were associated with achieving RBC-TI. The most common non-hematologic toxicities were pruritus, fatigue, and rashes. All non-hematologic toxicities of grades ≥3 were limited to rash (12.9%) and pruritus (6.5%). Dose reduction was required in 15 of the 19 responders (78.9%). The most common final stable dosing schedule for the responders was 5 mg once every other day (31.6%)., Conclusion: Lenalidomide efficacy and tolerability were similar in the Asian del(5q) MDS patients and western patients. Dose reduction during treatment was common, but it was not associated with inferior outcomes.

Objective: To examine the features of powered mobility device-related injuries and identify the predictors of injury severity in such settings., Methods: Emergency Department-based Injury In-depth Surveillance data from 2011 to 2018 were used in this retrospective study. Participants were assigned to the mild/moderate and severe groups based on their excess mortality ratio-adjusted injury severity score and their general injury-related factors and injury outcome-related factors were compared., Results: Of 407 patients, 298 (79.2%) were assigned to the mild/moderate group and 109 (26.8%) to the severe group. The severe group included a higher percentage of patients aged 70 years or older (43.0% vs. 59.6%, P=0.003), injuries incurred in the daytime (72.6% vs. 82.4%, P=0.044), injuries from traffic accidents and falls (P=0.042), head injuries (38.6% vs. 80.7%, P<0.001), torso injuries (16.8% vs. 32.1%, P=0.001), overall hospital admission (28.5% vs. 82.6%, P<0.001), intensive care unit admission (1.7% vs. 37.6%, P<0.001), death after admission (1.4% vs. 10.3%, P=0.034), and total mortality (0.7% vs. 9.2%, P<0.001). The odds ratios (ORs) for injury severity were as follows: age 70 years or older (OR, 2.124; 95% confidence interval [CI], 1.239-3.642), head injury (OR, 10.441; 95% CI, 5.465-19.950), and torso injury (OR, 4.858; 95% CI, 2.495-9.458)., Conclusion: The proportions of patients aged 70 years or older, head and torso injuries, injuries from traffic accidents and falls, and injuries in the daytime were higher in the severe group. Our results highlight the need for measures to address these factors to lower the incidence of severe injuries.

Slow-cycling/dormant cancer cells (SCCs) have pivotal roles in driving cancer relapse and drug resistance. A mechanistic explanation for cancer cell dormancy and therapeutic strategies targeting SCCs are necessary to improve patient prognosis, but are limited because of technical challenges to obtaining SCCs. Here, by applying proliferation-sensitive dyes and chemotherapeutics to non-small cell lung cancer (NSCLC) cell lines and patient-derived xenografts, we identified a distinct SCC subpopulation that resembled SCCs in patient tumors. These SCCs displayed major dormancy-like phenotypes and high survival capacity under hostile microenvironments through transcriptional upregulation of regulator of G protein signaling 2 (RGS2). Database analysis revealed RGS2 as a biomarker of retarded proliferation and poor prognosis in NSCLC. We showed that RGS2 caused prolonged translational arrest in SCCs through persistent eukaryotic initiation factor 2 (eIF2α) phosphorylation via proteasome-mediated degradation of activating transcription factor 4 (ATF4). Translational activation through RGS2 antagonism or the use of phosphodiesterase 5 inhibitors, including sildenafil (Viagra), promoted ER stress-induced apoptosis in SCCs in vitro and in vivo under stressed conditions, such as those induced by chemotherapy. Our results suggest that a low-dose chemotherapy and translation-instigating pharmacological intervention in combination is an effective strategy to prevent tumor progression in NSCLC patients after rigorous chemotherapy.

Rationale: Cancer stem cells (CSCs) are known to cause tumor recurrence and drug resistance. The heat shock protein (HSP) system plays a major role in preserving expression and function of numerous oncoproteins, including those involved in the CSC activities. We explored novel anticancer drugs, especially those targeting HSP components required for the functional role of CSCs. Methods: Investigation of the role of the HSP system in CSCs and screening of a natural product chemical library were performed by utilizing cancer cell lines, primary cultures of patient-derived xenografts (PDXs), and their putative CSC subpopulations (i.e., those grown under sphere-forming conditions, stably transfected with reporter vectors carrying NANOG or POUSF1 promoters, or carrying high ALDH activity) in vitro and PDX and Kras G12D/+ -driven tumor models in vivo. Regulation of the HSP system was investigated by immunoprecipitation, drug affinity responsive target stability assay, binding experiments using ATP-agarose beads and biotinylated drug, and docking analysis. Results: The HSP system was activated in CSCs via transcriptional upregulation of the HSP system components, especially HSP70. Evodiamine (Evo) was identified to induce apoptosis in both CSC and bulk non-CSC populations in human lung, colon, and breast cancer cells and their sublines with chemoresistance. Evo administration decreased the multiplicity, volume, and load of lung tumors in Kras G12D/+ transgenic mice and the growth of cancer cell line- and PDX-derived tumors without detectable toxicity. Mechanistically, Evo disrupted the HSP system by binding the N-terminal ATP-binding pocket of HSP70 and causing its ubiquitin-mediated degradation. Conclusions: Our findings illustrate HSP70 as a potential target for eliminating CSCs and Evo as an effective HSP70-targeting anticancer drug eradicating both CSCs and non-CSCs with a minimal toxicity., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Rationale: The type I insulin-like growth factor receptor (IGF-1R) signaling pathway plays key roles in the development and progression of numerous types of human cancers, and Src and AXL have been found to confer resistance to anti-IGF-1R therapies. Hence, co-targeting Src and AXL may be an effective strategy to overcome resistance to anti-IGF-1R therapies. However, pharmacologic targeting of these three kinases may result in enhanced toxicity. Therefore, the development of novel multitarget anticancer drugs that block IGF-1R, Src, and AXL is urgently needed. Methods: We synthesized a series of phenylpyrazolo[3,4- d ]pyrimidine (PP)-based compounds, wherein the PP module was conjugated with 2,4-bis-arylamino-1,3-pyrimidines (I2) via a copper(I)-catalyzed alkyne-azide cycloaddition reaction. To develop IGF-1R/Src/AXL-targeting small molecule kinase inhibitors, we selected LL6 as an active compound and evaluated its antitumor and antimetastatic effects in vitro and in vivo using the MTT assay, colony formation assays, migration assay, flow cytometric analysis, a tumor xenograft model, the Kras G12D/+ -driven spontaneous lung tumorigenesis model, and a spontaneous metastasis model using Lewis lung carcinoma (LLC) allografts. We also determined the toxicity of LL6 in vitro and in vivo . Results: LL6 induced apoptosis and suppressed viability and colony-forming capacities of various non-small cell lung cancer (NSCLC) cell lines and their sublines with drug resistance. LL6 also suppressed the migration of NSCLC cells at nontoxic doses. Administration of LL6 in mice significantly suppressed the growth of NSCLC xenograft tumors and metastasis of LLC allograft tumors with outstanding toxicity profiles. Furthermore, the multiplicity, volume, and load of lung tumors in Kras G12D/+ transgenic mice were substantially reduced by the LL6 treatment. Conclusions: Our results show the potential of LL6 as a novel IGF-1R/Src/AXL-targeting small molecule kinase inhibitor, providing a new avenue for anticancer therapies., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: Myeloid-derived suppressor cells (MDSCs) facilitate tumor growth and development by suppressing T cell function; however, their role in acute myeloid leukemia (AML) remains unclear. Here, we investigated the immunosuppressive role and prognostic value of blasts with an MDSC-like phenotype., Methods: CD11b + CD33 + HLA-DR - MDSC-like blasts from bone marrow mononuclear cells of patients with AML were analyzed. To investigate their T cell-suppressing function, MDSC-like blasts were isolated using flow cytometry and co-cultured with CD8 + cytotoxic T cells and NB4 leukemic cells. Treatment outcomes were then compared between the MDSC-like blasts low (≤9.76%) and high (>9.76%) groups to identify clinical significance., Results: MDSC-like blasts showed higher expression of arginase-1 and inducible nitric oxide synthase. Isolated MDSC-like blasts significantly suppressed CD8 + T cell proliferation induced by phytohemagglutinin A. NB4 cell proliferation was significantly suppressed upon co-culture with CD8 + cytotoxic T cells and partially restored upon co-culture with MDSC-like blasts. Patients with high MDSC-like blasts at diagnosis showed substantially shorter overall survival and leukemia-free survival relative to low MDSC-like blasts patients, with subgroup analysis showing statistically significant differences in patients not receiving allogeneic hematopoietic stem cell transplantation., Conclusion: We demonstrated that MDSC-like blasts drive AML-specific immune-escape mechanisms by suppressing T cell proliferation and restoring T cell-suppressed NB4 cell proliferation, with clinically higher fractions of MDSC-like blasts at diagnosis resulting in poor prognosis., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT-lymphoma) is an extranodal lymphoma that occurs at various sites in the body. There is a limited understanding of the incidence and survival rates of MALT-lymphoma. To investigate the nation-wide incidence and survival rates of MALT-lymphoma in Korea during 1999-2017, the data on MALT-lymphoma were retrieved from the Korea Central Cancer Registry., Methods: During the time period of 1999-2017, 11,128 patients were diagnosed with MALT-lymphoma. The age and sex of the patients and the Surveillance, Epidemiology, and End Results (SEER) summary stage of the tumor were analyzed, and the relative survival rates (RSRs) were calculated., Results: The age-standardized incidence rates of MALT-lymphoma in 2017 among males and females were 1.53 and 1.61 per 100,000 individuals, respectively, whereas those in 1999 among males and females were 0.21 and 0.20, respectively in Korea. The RSRs were more than 97% at 10 years post-diagnosis between 1993 and 2017. The 5-year RSRs were 87.4%, 94.8%, 97.8%, and 98.6% during 1996-2000, 2001-2005, 2006-2010, and 2013-2017, respectively. Based on SEER summary staging, the 5-year RSRs during 2013-2017 were 100.3%, 90.8%, 91.3%, and 97.9% for patients with localized, regional, distant, and unknown stages of MALT-lymphoma, respectively., Conclusion: Although the incidence of MALT-lymphoma is low in Korea, it has been increasing in recent years. The prognosis of MALT-lymphoma is good even at advanced stages. These findings provide useful insights to clinicians about MALT-lymphoma and inform patients about the survival rate., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2020 The Korean Academy of Medical Sciences.)

Quiescent cancer cells are believed to cause cancer progression after chemotherapy through unknown mechanisms. We show here that human non-small cell lung cancer (NSCLC) cell line-derived, quiescent-like, slow-cycling cancer cells (SCC) and residual patient-derived xenograft (PDX) tumors after chemotherapy experience activating transcription factor 6 (ATF6)-mediated upregulation of various cytokines, which acts in a paracrine manner to recruit fibroblasts. Cancer-associated fibroblasts (CAF) underwent transcriptional upregulation of COX2 and type I collagen (Col-I), which subsequently triggered a slow-to-active cycling switch in SCC through prostaglandin E 2 (PGE 2 )- and integrin/Src-mediated signaling pathways, leading to cancer progression. Both antagonism of ATF6 and cotargeting of Src/COX2 effectively suppressed cytokine production and slow-to-active cell cycling transition in SCC, withholding cancer progression. Expression of COX2 and Col-I and activation of Src were observed in patients with NSCLC who progressed while receiving chemotherapy. Public data analysis revealed significant association between COL1A1 and SRC expression and NSCLC relapse. Overall, these findings indicate that a proinflammatory niche created by the interplay between SCC and CAF triggers tumor progression. SIGNIFICANCE: Cotargeting COX2 and Src may be an effective strategy to prevent cancer progression after chemotherapy., (©2020 American Association for Cancer Research.)

Objectives: The aim of this study was to investigate the accuracy of bedside ultrasound (US) performed by emergency physicians for diagnosing skull fractures in children 0 to 4 years old compared with the accuracy of head computed tomography (CT). We also sought to investigate characteristics and precautions associated with US., Methods: This single-center prospective study involved children 0 to 4 years old who had a history of head trauma. Bedside US was performed by emergency medicine physicians, and the results were compared with CT scan interpretations provided by attending radiologists. The accuracy of US for the diagnosis of skull fractures was calculated, and the errors were reviewed., Results: A total of 87 patients were enrolled. Skull fracture was present in 13 patients (14.9%), according to CT. Bedside US had a sensitivity and specificity of 76.9% (95% confidence interval [CI], 46.0%-93.8%) and 100% (95% CI, 93.9%-100%), respectively. Overall positive predictive value was 100% (95% CI, 65.5%-100%), and negative predictive value was 96.1% (95% CI, 88.3%-99.0%). Three false-negative cases were observed., Conclusions: Bedside US performed by emergency medicine physicians with short focused US training is a useful tool for diagnosing skull fractures in children 0 to 4 years of age. However, there were 3 false-negative cases. A meticulous examination is needed in the area adjacent to the orbital wall and skull base.

Metabolic rewiring to utilize aerobic glycolysis is a hallmark of cancer. However, recent findings suggest the role of mitochondria in energy generation in cancer cells and the metabolic switch to oxidative phosphorylation (OXPHOS) in response to the blockade of glycolysis. We previously demonstrated that the antitumor effect of gracillin occurs through the inhibition of mitochondrial complex II-mediated energy production. Here, we investigated the potential of gracillin as an anticancer agent targeting both glycolysis and OXPHOS in breast and lung cancer cells. Along with the reduction in adenosine triphosphate (ATP) production, gracillin markedly suppresses the production of several glycolysis-associated metabolites. A docking analysis and enzyme assay suggested phosphoglycerate kinase 1 (PGK1) is a potential target for the antiglycolytic effect of gracillin. Gracillin reduced the viability and colony formation ability of breast cancer cells by inducing apoptosis. Gracillin displayed efficacious antitumor effects in mice bearing breast cancer cell line or breast cancer patient-derived tumor xenografts with no overt changes in body weight. An analysis of publicly available datasets further suggested that PGK1 expression is associated with metastasis status and poor prognosis in patients with breast cancer. These results suggest that gracillin is a natural anticancer agent that inhibits both glycolysis and mitochondria-mediated bioenergetics.

This trial was designed to investigate the efficacy and toxicity of bendamustine, carboplatin, and dexamethasone (BCD) for relapsed or refractory peripheral T-cell lymphomas (PTCLs), which would be expected to exhibit more promising clinical outcomes compared with bendamustine therapy alone. After treatments with BCD, eight patients exhibited a complete response (CR; 29%) and seven exhibited a partial response (PR; 25%). The overall response rate (ORR) was 54%. Five patients proceeded to ASCT and three patients finally achieved CR. The median progression-free survival (PFS) was 4.4 months (2.8-6.0, 95% CI). For a total of 85 cycles of BCD, grade 3 or 4 neutropenia, thrombocytopenia, and anemia occurred in 17.6, 38.8, and 16.5% of cycles, respectively. Only one patient experienced febrile neutropenia. BCD was a considerable salvage regimen for relapsed or refractory PTCLs with acceptable toxicity; AITL or ASCT eligible patients were more effective to BCD. ClinicalTrials.gov Identifier: NCT02424045.

We investigated the effect of the modulation of Na/H exchanger 1 (NHE1) on apoptosis, differentiation, and chemoresistance in acute myeloid leukemia (AML) cells to evaluate the possibility of NHE1 modulation as a novel therapeutic strategy for AML. The pHi of leukemia cell lines except KG1a was higher than that of normal bone marrow mononuclear cells (BM MNCs). Notably, in K562, cytarabine (AraC)-resistant OCI-AML2, and primary leukemia cells, pHi was significantly higher than that of normal BM MNCs. Western blotting and real-time quantitative PCR confirmed that the increased NHE1 expression was responsible for the higher pHi. Specifically, compared to CD34 + CD38 + leukemia cells, the mean fluorescence intensity of NHE1 was significantly higher in CD34 + CD38 - leukemic stem cells. The out of range in pHi by treatment with an NHE inhibitor, the amiloride analogue 5-(N,N-hexamethylene) amiloride (HMA), or an NHE activator, phorbol 12-myristate 13-acetate (PMA), resulted in dose- and time-dependent inhibition of leukemia cell proliferation. PMA induced CD14 + differentiation of leukemia cells, whereas HMA induced cell cycle arrest at the G1 phase. HMA could induce apoptosis of leukemia cells even in AraC-resistant cells and showed an additive effect on apoptosis in AraC-sensitive cells. Our result revealed that AML cells prefer more alkalic intracellular moiety than normal BM MNCs following increased NHE1 expression and that NHE1 modulation can induce apoptosis and differentiation of AML cells. These findings imply that NHE1 is a potential target in cytotoxic or differentiation-induction treatment for AML., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Tyrosine kinase inhibitors (TKIs) improve the survival rate of patients with chronic myeloid leukemia (CML). However, elderly patients often experience adverse events and require dose adjustments, leading to dose interruptions or treatment discontinuation. We therefore investigated TKI dosing patterns and subsequent outcomes in elderly CML patients., Patients and Methods: Using the National Health Information Database, we identified patients with CML aged ≥ 70 years who were prescribed TKIs (imatinib, dasatinib, nilotinib, or radotinib) during 2007-2013. Data on age, sex, prescribed medication, and date of death were extracted., Results: Among the 378 patients, the median age was 75 (range, 70-92) years; the median follow-up period was 53 (range, 1-133) months. Imatinib, dasatinib, nilotinib, and radotinib were prescribed to 324 (85.7%), 110 (29.1%), 93 (24.6%), and 15 (4.0%) patients, respectively. In 42 patients (12.2%), the initial dose was lower than the recommended dose for chronic-phase CML. At last follow-up, 249 patients (65.9%) were receiving a reduced dose. The mean ± standard deviation dose densities of imatinib, dasatinib, nilotinib, and radotinib were 207 ± 121.6, 29 ± 26.7, 235 ± 197, and 123 ± 95.4 mg/day, respectively. The estimated 5-year overall survival probability was 61.0%. Initial TKI dose or dose reduction within first year did not affect the overall survival (P = .0571 and .1826, respectively)., Conclusion: Dose reduction was observed in 65.9% of the patients at their last visit; except for imatinib, TKI dose densities were < 50% of the recommended dose for the chronic phase. Therefore, the recommended TKI doses might be too high for elderly patients with CML., (Copyright © 2019. Published by Elsevier Inc.)

Mitochondria play a pivotal role in cancer bioenergetics and are considered a potential target for anticancer therapy. Considering the limited efficacy and toxicity of currently available mitochondria-targeting agents, it is necessary to develop effective mitochondria-targeting anticancer drugs. By screening a large chemical library consisting of natural products with diverse chemical entities, we identified gracillin, a steroidal saponin, as a mitochondria-targeting antitumor drug. Gracillin displayed broad-spectrum inhibitory effects on the viability of a large panel of human cancer cell lines, including those carrying acquired resistance to chemotherapy or EGFR-targeting drugs, by inducing apoptosis. We show that gracillin attenuates mitochondria-mediated cellular bioenergetics by suppressing ATP synthesis and by producing reactive oxygen species (ROS). Mechanistically, gracillin disrupts complex II (CII) function by abrogating succinate dehydrogenase (SDH) activity without affecting the succinate:ubiquinone reductase. The gracillin-induced cell death was potentiated by 3-nitropropionic acid (3-NPA) or thenoyltrifluoroacetone (TTFA), which inhibit CII by binding to the active site of SDHA or to the ubiquinone-binding site, respectively. Finally, we show that gracillin effectively suppressed the mutant-Kras-driven lung tumorigenesis and the growth of xenograft tumors derived from cell lines or patient tissues. Gracillin displayed no obvious pathophysiological features in mice. Collectively, gracillin has potential as a CII-targeting antitumor drug.

Competing Interests: Authors' Disclosures of Potential Conflicts of Interest: No potential conflicts of interest relevant to this article were reported.

Objective: This study aimed to examine whether injury severity differs with respect to age among elderly pedestrians involved in traffic accidents and identify factors affecting injury severity., Methods: Using emergency department-based injury in-depth surveillance data, we analyzed the data of patients aged ≥60 years who were victims of pedestrian traffic accidents during 2011 to 2016. The pedestrians' ages were divided into 5-year age strata beginning at 60 years. In a multivariate analysis, injury severity was classified as severe to critical or mild to moderate., Results: The analysis included 10,449 patients. All age groups had a female predominance, and accidents most frequently occurred during the early morning. Multivariate analyses revealed that compared to the 60 to 64 years group, the odds ratios for incurring a severe injury were 1.18 (95% confidence interval [CI], 1.02 to 1.37) for the 65 to 69 years group, 1.42 (95% CI, 1.23 to 1.64) for the 70 to 74 years group, 1.70 (95% CI, 1.45 to 1.98) for the 75 to 79 years group, and 1.83 (95% CI, 1.56 to 2.15) for the ≥80 years group., Conclusion: In this study of emergency department-based data, we found that injury severity increased with age among elderly victims of traffic accidents. Furthermore, injury severity varied with respect to sex, time and location of the accident, and type of vehicle involved. Therefore, measures intended to reduce and prevent traffic accidents involving elderly pedestrians should consider these findings.

Objective: This study aimed to investigate associations among spirituality, coping strategies, quality of life (QOL), and the effects of depression and anxiety thereon in cancer patients., Method: In total, 237 cancer patients referred to a psycho-oncology clinic at a university hospital in Korea were enrolled. After identifying predictors of patient QOL in a stepwise regression model, we developed a hypothetical path model wherein interpersonal coping was considered as a mediating variable between spirituality (meaning/peace) and QOL and wherein depression and anxiety affected each of these three variables., Result: The direct effect of spirituality (meaning/peace) on QOL was 36.7%. In an indirect model, interpersonal coping significantly mediated the relationship between spirituality (meaning/peace) and QOL. Depression exerted the largest negative effect on spirituality (meaning/peace), interpersonal coping, and QOL. Anxiety had negative effects on spirituality (meaning/peace) and QOL, but a positive effect on interpersonal coping., Significance of Results: Interpersonal coping strategies work as a partial mediator of the relationship between meaning/peace subscales of spirituality and QOL. Effective management of depression may help in achieving better outcomes associated therewith. Greater attention and efforts to improve social connectedness and meaning of life in spiritual well-being may improve the QOL of cancer patients.

Recovery from DNA damage is critical for cell survival. However, serious damage cannot be repaired, leading to cell death for prevention of abnormal cell growth. Previously, we demonstrated that 4N-DNA accumulates via the initiation of an abnormal interphase without cytokinesis and that re-replication occurs during a prolonged recovery period in the presence of severe DNA damage in mitotic cells. Mitotic phosphorylated Plk1 is typically degraded during mitotic exit. However, Plk1 has unusually found to be dephosphorylated in mitotic slippage without cytokinesis during recovery from mitotic DNA damage. Here, we investigated how Plk1 dephosphorylation is established during recovery from mitotic DNA damage. Mitotic DNA damage activated ATM and Chk1/2 and repressed Cdk1 and Greatwall protein kinase, followed by PP2A activation through the dissociation of ENSA and PP2A-B55. Interaction between Plk1 and PP2A-B55α or PP2A-B55δ was strongly induced during recovery from mitotic DNA damage. Moreover, the depletion of PP2A-B55α and/or PP2A-B55δ by siRNA transfection led to the recovery of Plk1 phosphorylation and progression of the cell cycle into the G 1 phase. Therefore, to adapt to severe DNA damage, the activated Greatwall/ENSA signaling pathway was repressed by ATM/Chk1/2, even in mitotic cells. Activation of the PP2A-B55 holoenzyme complex induced the dephosphorylation of Plk1 and Cdk1, and finally, mitotic slippage occurred without normal chromosome segregation and cytokinesis.

Dental enamel is the highly mineralized tissue covering the tooth surface and is formed by ameloblasts. Ameloblasts have been known to be impossible to detect in adult tooth because they are shed by apoptosis during enamel maturation and tooth eruption. Owing to these, little was known about appropriate cell surface markers to isolate ameloblast-like cells in tissues. To overcome these problems, epithelial cells were selectively cultivated from the gingival tissues and used as a stem cell source for ameloblastic differentiation. When gingival epithelial cells were treated with a specified concentration of BMP2, BMP4, and TGFβ-1, the expression of ameloblast-specific markers was increased, and both the MAPK and Smad signaling pathways were activated. Gingival epithelial cells differentiated into ameloblast-like cells through epithelial-mesenchymal transition. By RNA-Seq analysis, we reported 20 ameloblast-specific genes associated with cell surface, cell adhesion, and extracellular matrix function. These cell surface markers might be useful for the detection and isolation of ameloblast-like cells from dental tissues.

This study aimed to determine whether the combination of procalcitonin (PCT) and S100B improves prognostic performance compared to either alone in cardiac arrest (CA) patients treated with targeted temperature management (TTM).We performed a prospective cohort study of CA patients treated with TTM. PCT and S100B levels were obtained at 0, 24, 48, and 72 hours after return of spontaneous circulation. The prognostic performance was analyzed using each marker and the combination of the 2 markers for predicting poor neurological outcome at 3 months and mortality at 14 days and 3 months.A total of 97 patients were enrolled, of which 67 (69.1%) had poor neurological outcome. S100B showed a better prognostic performance (area under the curve [AUC], 0.934; sensitivity, 77.6%; and specificity, 100%) than PCT (AUC, 0.861; sensitivity, 70.2%; and specificity, 83.3%) with the highest prognostic value at 24 hours. The combination of 24-hour PCT and S100B values (S100B ≥0.2 μg/L or PCT ≥6.6 ng/mL) improved sensitivity (85.07%) compared with S100B alone. In multivariate analysis, PCT was associated with mortality at 14 days (odds ratio [OR]: 1.064, 95% confidence interval [CI]: 1.014-1.118), whereas S100B was associated with neurological outcomes at 3 months (OR: 9.849, 95% CI: 2.089-46.431).The combination of PCT and S100B improved prognostic performance compared to the use of either biomarker alone in CA patient treated with TTM. Further studies that will identify the optimal cutoff values for these biomarkers must be conducted.

Background: Posttraumatic stress symptoms (PTSS) in patients with psychological trauma lead to poor health-related quality of life. Understanding of the relationships among PTSS, anxiety, depression, and illness intrusiveness will guide the development of efficient approaches to enhance subjective well-being in patients with psychological trauma. This study investigated whether anxiety and depression mediate the relationship between PTSS and illness intrusiveness in the hope of providing more comprehensive and effective trauma treatment., Methods: Psychiatric outpatients who visited the trauma clinic of a university hospital (n = 260) participated in this study. Assessments were conducted for PTSS, anxiety, depression, and illness intrusiveness. Structural equation modeling and path analysis were performed to analyze the mediating effects of anxiety and depression on the relationship between PTSS and illness intrusiveness., Results: PTSS had both direct and indirect exacerbating effects on illness intrusiveness. Anxiety exhibited the largest direct exacerbating effect on illness intrusiveness. The indirect effects of PTSS on illness intrusiveness through anxiety alone and through a depression-to-anxiety pathway were significant, but the indirect effect through depression alone was not., Conclusion: The findings demonstrate that anxiety, both independently and as part of an interrelated pathway with depression, partially mediates the relationship between PTSS and illness intrusiveness. Appropriate interventions and a comprehensive approach to alleviate anxiety and depression could mitigate the negative effects of PTSS on illness intrusiveness in patients with psychological trauma., Competing Interests: Disclosure: The authors have no potential conflicts of interest to disclose.