Association between Case Volumes of Extracorporeal Life Support and Clinical Outcome in Out-of-Hospital Cardiac Arrest.

AIM: Extracorporeal life support (ECLS) for out-of-hospital cardiac arrest (OHCA) is increasing. There is little evidence identifying the association between hospital ECLS case volumes and outcomes in different populations receiving ECLS or conventional cardiopulmonary resuscitation (CPR). The goal of this investigation was to identify the association between ECLS case volumes and clinical outcomes of OHCA patients. METHODS: This cross-sectional observational study used the National OHCA Registry for adult OHCA cases in Seoul, Korea between January 2015 and December 2019. If the ECLS volume during the study period was >20, the institution was defined as a high-volume ECLS center. Others were defined as low-volume ECLS centers. Outcomes were good neurologic recovery (cerebral performance category 1 or 2) and survival to discharge. We performed multivariate logistic regression and interaction analyses to assess the association between case volume and clinical outcome. RESULTS: Of the 17,248 OHCA cases, 3,731 were transported to high-volume centers. Among the patients who underwent ECLS, those at high-volume centers had a higher neurologic recovery rate than those at low-volume centers (17.0% vs. 12.0%), and the adjusted OR for good neurologic recovery was 2.22 (95% confidence interval (CI): 1.15-4.28) in high-volume centers compared to low-volume centers. For patients who received conventional CPR, high-volume centers also showed higher survival-to-discharge rates (adjusted OR of 1.16, 95%CI: 1.01-1.34). CONCLUSIONS: High-volume ECLS centers showed better neurological recovery in patients who underwent ECLS. High-volume centers also had better survival-to-discharge rates than low-volume centers for patients not receiving ECLS.

Estimated health and economic impact of using high-dose influenza vaccine on respiratory and circulatory plus respiratory hospitalizations of older adults in Australia.

Background: Standard dose influenza vaccine provides moderate protection from infection, but with lower effectiveness among the elderly. High dose and adjuvanted vaccines (HD-TIV and aTIV) were developed to address this. This study aims to estimate the incremental health and economic impact of using HD-TIV (high dose trivalent vaccine) instead of aTIV (adjuvanted trivalent vaccine) on respiratory and circulatory plus respiratory hospitalizations of older people (≥65 years) in Australia. Methods: This is a modelling study comparing predicted hospitalization outcomes in people receiving HD-TIV or aTIV during an average influenza season in Australia. Hospitalization records of Australian adults ≥65 years of age from 01 April to 30 November during 15 influenza seasons (2002-2017 excluding 2009, which was a pandemic) were extracted from the Australian Institute of Health and Welfare [AIHW] and used to calculate hospitalisation rates during an average season. Relative vaccine effectiveness data for aTIV and HD-TIV were used to estimate morbidity burden related to influenza. Results: Between 2002 and 2017, the average respiratory hospitalization rate among older people during influenza season (April-November) was 3,445/100,000 population-seasons, with an average cost of AU$ 7,175 per admission. The average circulatory plus respiratory hospitalization rate among older Australian people during that time was 10,393/100,000 population-seasons, with an average cost of AU$ 7829 per admission. For older Australians, HD-TIV may avert an additional 6,315-9,410 respiratory admissions each year, with an incremental healthcare cost saving of AU$ 15.9-38.2 million per year compared to aTIV. Similar results were also noted for circulatory plus respiratory hospitalizations. Conclusions: From the modelled estimations, HD-TIV was associated with less economic burden and fewer respiratory, and circulatory plus respiratory hospitalizations than aTIV for older Australians.

Efficacy of distance training program for cardiopulmonary resuscitation utilizing smartphone application and home delivery system.

AIM OF THE STUDY: Community cardiopulmonary resuscitation (CPR) education is important for laypersons. However, during the COVID-19 pandemic, with social distancing, conventional face-to-face CPR training was unavailable. We developed a distance learning CPR training course (HEROS-Remote) using a smartphone application that monitors real-time chest compression quality and a home delivery collection system for mannikins. This study aimed to evaluate the efficacy of the HEROS-Remote course by comparing chest compression quality with that of conventional CPR training. METHODS: We applied layperson CPR education with HEROS-Remote and conventional education in Seoul during the COVID-19 pandemic. Both groups underwent a 2-min post-training chest compression test, and we tested non-inferiority. Chest compression depth, rate, complete recoil, and composite chest compression score was measured. Trainees completed a satisfaction survey on CPR education and delivery. The primary outcome was the mean chest compression depth. RESULTS: A total of 180 trainees were enrolled, with 90 assigned to each training group. Chest compression depth of HEROS-Remote training showed non-inferiority to that of conventional training (67.4 vs. 67.8, p = 0.78), as well as composite chest compression score (92.7 vs. 95.5, p = 0.16). The proportions of adequate chest compression depth, chest compression rate, and chest compressions with complete chest recoil were similar in both training sessions. In the HEROS-Remote training, 90% of the trainees were satisfied with CPR training, and 96% were satisfied with the delivery and found it convenient. CONCLUSION: HEROS-Remote training was non-inferior to conventional CPR training in terms of chest compression quality. Distance learning CPR training using a smartphone application and mannikin delivery had high user satisfaction and was logistically feasible.

Comparison of prehospital resuscitation quality during scene evacuation and early ambulance transport in out-of-hospital cardiac arrest between residential location and non-residential location.

BACKGROUND: High-quality prehospital cardiopulmonary resuscitation (CPR) is important for out-of-hospital cardiac arrest (OHCA). We aimed to evaluate prehospital CPR quality during scene evacuation and early ambulance transport in patients with OHCA according to the type of cardiac arrest location. METHODS: This retrospective observational cohort study enrolled patients with non-traumatic adult OHCA in Seoul between July 2020 and March 2022. Prehospital CPR quality data extracted from defibrillators were merged with the national OHCA database. The location of cardiac arrest was categorized into two groups (residential and non-residential). CPR quality indices including no-flow (any pause >1.5 s) fraction were compared according to the type of arrest location at each minute of EMS scene evacuation and early ambulance transport (5 min prior to 5 min after ambulance departure). RESULTS: A total of 1,222 OHCAs were enrolled in the final analysis after serial exclusion. A total of 966 OHCAs (79.1%) occurred in the residential areas. The CPR quality deteriorated during the scene evacuation in both location type. The mean no-flow fractions were significantly higher in residential places than in non-residential places. The mean proportion of adequate compression depth and rate was lower in cardiac arrests in residential places. The discrepancy in EMS CPR quality during scene evacuation was more prominent when mechanical CPR devices were not used. CONCLUSION: Deterioration of CPR quality was observed just before and during early ambulance transport, especially when the cardiac arrest location was a residential area or when only manual CPR was provided.

Design, synthesis, and biological evaluation of novel HSP27 inhibitors to sensitize lung cancer cells to clinically available anticancer agents.

Expression of heat shock protein (HSP) correlates with the oncogenic status of malignant cells and plays an important role in tumorigenesis. HSP27 is constitutively expressed at specific stages of cancer development, and several clinical trials have reported correlations between HSP27 expression and tumor progression, metastasis, and chemoresistance in various types of cancer cells. These findings indicate that HSP27 is a major drug target, particularly in chemo-resistant cancers. As part of our ongoing efforts to improve the previously identified J2, a HSP27 cross-linker, we, in this study, report the identification of NK16 as a novel inducer of abnormal HSP27 dimers that did not affect the expression of HSP90 in an NCI-H460 lung cancer cell model. When NCI-H460 cells were treated with NK16 in combination with the anticancer drug cisplatin or paclitaxel, cleavage of PARP and caspase-3 was increased compared to administration of cisplatin or paclitaxel alone. Similar results were obtained in an NCI-H460-xenografted mouse model, in which tumor growth was suppressed more by co-administration of NK16 and paclitaxel than by paclitaxel alone. We propose NK16 as a meaningful strategy to improve the anticancer efficacy of cisplatin and paclitaxel.

Quality of chest compressions during prehospital resuscitation phase from scene arrival to ambulance transport in out-of-hospital cardiac arrest.

AIM: Prehospital cardiopulmonary resuscitation is performed from scene arrival to hospital arrival. The diverse prehospital resuscitation phases can affect the quality of chest compressions. This study aimed to evaluate the dynamic changes in chest compression quality during prehospital resuscitation. METHODS: Adult out-of-hospital cardiac arrest patients treated without prehospital return of spontaneous circulation were included in Seoul between July 2020 and September 2021. The chest compressions quality was assessed using a real-time chest compression feedback device. The prehospital phase was divided by key events during the prehospital resuscitation timeline (phase 1: first 2 min after initiation of chest compression, phase 2: from the end of phase 1 to 1 min prior to ambulance departure; phase 3: from 1 min before to 1 min after ambulance departure; phase 4: from the end of phase 3 to hospital arrival). The main outcome was no-flow fraction. The no-flow fraction between prehospital phases was compared using repeated-measure analysis of variance. RESULTS: In total, 788 patients were included. Mean no-flow fraction was the highest in phase 3 (phase 1: 11.3% ± 13.8, phase 2: 19.3% ± 12.3, phase 3: 33.0% ± 34.9, phase 4: 18.7% ± 23.7, p < 0.001). The mean number of total no-flow events per minute was also the highest in phase 3. The minute-by-minute analysis showed that the no-flow fraction rapidly increased before ambulance departure and decreased during ambulance transport. CONCLUSION: Dynamic changes in chest compression quality were observed during prehospital resuscitation phase. The no-flow fraction was the highest from 1 min before to 1 min after ambulance departure.

Activation of the HSP27-AKT axis contributes to gefitinib resistance in non-small cell lung cancer cells independent of EGFR mutations.

PURPOSE: Although epidermal growth factor receptor (EGFR)-activating mutations in non-small cell lung cancer (NSCLC) usually show sensitivity to first-generation EGFR-tyrosine kinase inhibitors (TKIs), most patients relapse because of drug resistance. Heat shock protein 27 (HSP27) has been reported to be involved in the resistance of EGFR-TKIs, although the underlying mechanism is unclear. Here, we explore the mechanisms of HSP27-mediated EGFR TKI resistance and propose novel therapeutic strategies. METHODS: To determine the mechanism of HSP27 associated gefitinib resistance, differences were assessed using gefitinib-sensitive and -resistant NSCLC cell lines. In vivo xenograft experiments were conducted to elucidate the combinatorial effects of J2, a small molecule HSP27 inhibitor, and gefitinib. Analyses of human NSCLC tissues and PDX tissues were also used for comparison of HSP27 and phosphorylated AKT expression. RESULTS: Large-scale cohort analysis of NSCLC cases revealed that HSP27 expression correlated well with the incidence of EGFR mutations and affected patient survival. Increased pAKT and HSP27 was observed in gefitinib-resistant cells compared with gefitinib-sensitive cells. Moreover, increased phosphorylation of HSP27 by gefitinib augmented its protein stability and potentiated its binding activity with pAKT, which resulted in increased gefitinib resistance. However, in gefitinib-sensitive cells, stronger binding activity between EGFR and HSP27 was observed. Moreover, these phenomena occurred regardless of EGFR mutation including secondary mutations, such as T790M. AKT knockdown switched HSP27-pAKT binding to HSP27-EGFR, which promoted gefitinib sensitivity in gefitinib-resistant cells. Functional inhibition of HSP27 yielded sensitization to gefitinib in gefitinib-resistant cells by inhibiting the interaction between HSP27 and pAKT. CONCLUSIONS: Our results indicate that combination of EGFR-TKIs with HSP27 inhibitors may represent a good strategy to overcome resistance to EGFR-TKIs, especially in cancers exhibiting AKT pathway activation.

Association between the number of prehospital defibrillation attempts and neurologic outcomes in out-of-hospital cardiac arrest patients without on-scene return of spontaneous circulation.

OBJECTIVE: Delivery of prehospital defibrillation for shockable rhythms by emergency medical service providers is crucial for successful resuscitation in out-of-hospital cardiac arrest (OHCA) patients. The optimal range of prehospital defibrillation attempts for refractory shockable rhythms is unknown. This study evaluated the association between the number of prehospital defibrillation attempts and neurologic outcomes in OHCA patients. METHODS: A retrospective observational study was conducted using the nationwide OHCA registry. Adult OHCA patients who were treated by emergency medical service providers due to presumed cardiac origin with initial shockable rhythm were enrolled from 2013 to 2016. The final analysis was performed on patients without on-scene return of spontaneous circulation. The number of prehospital defibrillation attempts was categorized as follows: 2-3, 4-5, and ≥6 attempts. The primary outcome was a good neurologic recovery at hospital discharge. Multivariate logistic regression analysis was performed to evaluate the association between neurologic outcomes and the number of prehospital defibrillation attempts. RESULTS: A total of 4,513 patients were included in the final analysis. The numbers of patients for whom 2-3, 4-5, and ≥6 defibrillation attempts were made were 2,720 (60.3%), 1,090 (24.2%), and 703 (15.5%), respectively. Poorer outcomes were associated with ≥6 defibrillation attempts: survival to hospital discharge (adjusted odds ratio, 0.38; 95% confidence interval, 0.21-0.65) and good neurologic recovery (adjusted odds ratio, 0.42; 95% confidence interval, 0.21-0.84). CONCLUSION: Six or more prehospital defibrillation attempts were associated with poorer neurologic outcomes in OHCA patients with an initial shockable rhythm who were unresponsive to on-scene defibrillation and resuscitation.

Drug-Like Small Molecule HSP27 Functional Inhibitor Sensitizes Lung Cancer Cells to Gefitinib or Cisplatin by Inducing Altered Cross-Linked Hsp27 Dimers.

Relationships between heat shock protein 27 (HSP27) and cancer aggressiveness, metastasis, drug resistance, and poor patient outcomes in various cancer types including non-small cell lung cancer (NSCLC) were reported, and inhibition of HSP27 expression is suggested to be a possible strategy for cancer therapy. Unlike HSP90 or HSP70, HSP27 does not have an ATP-binding pocket, and no effective HSP27 inhibitors have been identified. Previously, NSCLC cancer cells were sensitized to radiation and chemotherapy when co-treated with small molecule HSP27 functional inhibitors such as zerumbone (ZER), SW15, and J2 that can induce abnormal cross-linked HSP27 dimer. In this study, cancer inhibition effects of NA49, a chromenone compound with better solubility, longer circulation time, and less toxicity than J2, were examined in combination with anticancer drugs such as cisplatin and gefitinib in NSCLC cell lines. When the cytotoxic drug cisplatin was treated in combination with NA49 in epidermal growth factor receptors (EGFRs) WT cell lines, sensitization was induced in an HSP27 expression-dependent manner. With gefitinib treatment, NA49 showed increased combination effects in both EGFR WT and Mut cell lines, also with HSP27 expression-dependent patterns. Moreover, NA49 induced sensitization in EGFR Mut cells with a secondary mutation of T790M when combined with gefitinib. Augmented tumor growth inhibition was shown with the combination of cisplatin or gefitinib and NA49 in nude mouse xenograft models. These results suggest the combination of HSP27 inhibitor NA49 and anticancer agents as a candidate for overcoming HSP27-mediated drug resistance in NSCLC patients.

East Asian Herbal Medicine to Reduce Primary Pain and Adverse Events in Cancer Patients : A Systematic Review and Meta-Analysis With Association Rule Mining to Identify Core Herb Combination.

Objective: Cancer pain is an important factor in cancer management that affects a patient's quality of life and survival-related outcomes. The aim of this review was to systematically evaluate the efficacy and safety of oral administration of East Asian herbal medicine (EAHM) for primary cancer pain and to explore core herb patterns based on the collected data. Methods: A comprehensive literature search was conducted in 11 electronic databases, namely, PubMed, Cochrane Library, Cumulative Index to Nursing & Allied Health Literature, EMBASE, Korean Studies Information Service System, Research Information Service System, Oriental Medicine Advanced Searching Integrated System, Korea Citation Index, Chinese National Knowledge Infrastructure Database (CNKI), Wanfang Data, and CiNii for randomized controlled trials from their inception until August 19, 2021. Statistical analysis was performed in R version 4.1.1 and R studio program using the default settings of the meta-package. When heterogeneity in studies was detected, the cause was identified through meta-regression and subgroup analysis. Methodological quality was independently assessed using the revised tool for risk of bias in randomized trials (Rob 2.0). Results: A total of 38 trials with 3,434 cancer pain patients met the selection criteria. Meta-analysis favored EAHM-combined conventional medicine on response rate (risk ratio: 1.06; 95% CI: 1.04 to 1.09, p < 0.0001), continuous pain intensity (standardized mean difference: -1.74; 95% CI: -2.17 to -1.30, p < 0.0001), duration of pain relief (standardized mean difference: 0.96, 95% CI: 0.69 to 1.22, p < 0.0001), performance status (weighted mean difference: 10.71; 95% CI: 4.89 to 16.53, p = 0.0003), and opioid usage (weighted mean difference: -20.66 mg/day; 95% CI: -30.22 to -11.10, p < 0.0001). No significant difference was observed between EAHM and conventional medicine on response rate and other outcomes. Patients treated with EAHM had significantly reduced adverse event (AE) incidence rates. In addition, based on the ingredients of herb data in this meta-analysis, four combinations of herb pairs, which were frequently used together for cancer pain, were derived. Conclusion: EAHM monotherapy can decrease adverse events associated with pain management in cancer patients. Additionally, EAHM-combined conventional medicine therapy may be beneficial for patients with cancer pain in increasing the response rate, relieving pain intensity, improving pain-related performance status, and regulating opioid usage. However, the efficacy and safety of EAHM monotherapy are difficult to conclude due to the lack of methodological quality and quantity of studies. More well-designed, multicenter, double-blind, and placebo-controlled randomized clinical trials are needed in the future. In terms of the core herb combination patterns derived from the present review, four combinations of herb pairs might be promising for cancer pain because they have been often distinctly used for cancer patients in East Asia. Thus, they are considered to be worth a follow-up study to elucidate their actions and effects. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021265804.

Characterization of IgA Deposition in the Kidney of Patients with IgA Nephropathy and Minimal Change.

Approximately 5% of patients with IgA nephropathy (IgAN) exhibit mild mesangial lesions with acute onset nephrotic syndrome and diffuse foot process effacement representative of minimal change disease (MCD). It is not clear whether these unusual cases of IgAN with MCD (IgAN-MCD) are variant types of IgAN or coincidental deposition of IgA in patients with MCD. In a retrospective multicenter cohort study of 18 hospitals in Korea, we analyzed 46 patients with IgAN-MCD. Patients with endocapillary proliferation, segmental sclerosis, and crescent were excluded, and the clinical features and prognosis of IgAN-MCD were compared with those of pure MCD. In addition, we performed galactose-deficient IgA1 (KM55) staining to characterize IgAN-MCD. Among the 21,697 patients with glomerulonephritis enrolled in the database, 46 patients (0.21%) were diagnosed with IgAN-MCD, and 1610 patients (7.4%) with pure MCD. The 46 patients with IgAN-MCD accounted for 0.6% of primary IgAN patients (n = 7584). There was no difference in prognosis between patients with IgAN-MCD and those with only MCD. IgA and KM55 showed double positivity in all patients with IgAN-MCD (n = 4) or primary IgAN (n = 5) under double immunofluorescent staining. However, in four patients with lupus nephritis, mesangial IgA was deposited, but galactose-deficient-IgA1 (Gd-IgA1) was not. These findings suggest that IgAN-MCD is a dual glomerulopathy in which MCD was superimposed on possibly indolent IgAN. We confirmed by KM55 staining that IgAN-MCD is true IgAN, enabling better characterizations of the disease. Furthermore, IgAN-MCD shows a good prognosis when treated according to the usual MCD treatment modality.

Specific Roles of HSP27 S15 Phosphorylation Augmenting the Nuclear Function of HER2 to Promote Trastuzumab Resistance.

Trastuzumab (TZMB) is widely used as first line therapy for breast cancer (BC) patients overexpressing human epidermal growth factor receptor 2 (HER2). Despite its clinical benefits, many patients suffer from primary or secondary resistance to this drug within one year. As diverse molecular mechanisms occur contemporaneously during the resistance development, we focused on elucidating the role of heat shock protein 27 (HSP27) in TZMB-resistance, as this protein simultaneously regulates the function of diverse client molecules that are involved in the resistance mechanism. By extensively utilizing TZMB-refractory breast cancer cell lines transduced with diverse phosphovariants of HSP27, our study newly revealed that specific phosphorylation of HSP27 at S15 promoted its S78 phosphorylation and served as key mediator to promote direct interactions that increase the stability of HER2 and protein kinase B (AKT). This phosphorylation promoted nuclear translocation of HER2, enhancing the distinct nuclear function of HER2 that promoted AKT activation and cyclin D1 expression. Co-administration of TZMB and a functional inhibitor of HSP27, J2, significantly reduced the S15/78 phosphorylation of HSP27, which downregulated HER2 and its downstream signals, sensitizing TZMB-refractory cell, and JIMT1-xenograft mouse models to TZMB. Collectively, p-HSP27S15 could serve as a valuable predictive marker and also a therapeutic target for TZMB-resistance.

Targeting Heat Shock Protein 27 in Cancer: A Druggable Target for Cancer Treatment?

Heat shock protein 27 (HSP27), induced by heat shock, environmental, and pathophysiological stressors, is a multi-functional protein that acts as a protein chaperone and an antioxidant. HSP27 plays a significant role in the inhibition of apoptosis and actin cytoskeletal remodeling. HSP27 is upregulated in many cancers and is associated with a poor prognosis, as well as treatment resistance, whereby cells are protected from therapeutic agents that normally induce apoptosis. This review highlights the most recent findings and role of HSP27 in cancer, as well as the strategies for using HSP27 inhibitors for therapeutic purposes.

Stigma Diminishes the Protective Effect of Social Support on Psychological Distress Among Young Black Men Who Have Sex With Men.

Addressing stigma remains a pressing HIV priority globally. Young Black men who have sex with men (YBMSM, ages 18-30; N = 474) completed an in-person baseline survey and reported their experiences of externalized stigma (i.e., racial and sexuality discrimination), internalized stigma (i.e., homonegativity), social support, and psychological distress (i.e., anxiety and depression symptoms). We used structural equation modeling to test the association between stigma and psychological distress, and examined whether social support mediated the relationship between stigma and psychological distress. Recognizing that these associations may differ by HIV status, we compared our models by self-reported HIV status (n = 275 HIV negative/unknown; n = 199 living with HIV). Our findings suggest that YBMSM who experience stigma are more vulnerable to psychological distress and may have diminished buffering through social support. These effects are accentuated among YBMSM living with HIV, highlighting the need for additional research focused on the development of tailored stigma reduction interventions for YBMSM.

Correlates of Self-Reported Viral Suppression Among HIV-Positive, Young, Black Men Who Have Sex With Men Participating in a Randomized Controlled Trial of An Internet-Based HIV Prevention Intervention.

BACKGROUND: Young, black men who have sex with men are disproportionately impacted by the US HIV epidemic, and HIV-positive, young, black men who have sex with men face stark disparities in HIV clinical outcomes. METHODS: We performed an observational analysis of the 199 HIV-positive black men aged 18 to 30 years followed up for 12 months in healthMpowerment, a randomized controlled trial of an Internet-based HIV prevention intervention, to identify time-varying correlates of self-reported viral suppression using relative risk (RR) regression. RESULTS: Retention at the 12-month visit was 84%. One hundred five (65%) of 162 participants reported being undetectable at baseline. At 3, 6, and 12 months, 83 (72%) of 115, 84 (82%) of 103, and 101 (86%) of 117 reported an undetectable viral load, respectively. In a multivariable model, participants who reported homelessness (RR, 0.85; 95% confidence interval [CI], 0.72-0.99), who had clinically significant depressive symptoms (RR, 0.88; 95% CI, 0.79-0.98), and who used methamphetamine or crack (RR, 0.61; 95% CI, 0.38-0.96) were less likely to report an undetectable viral load. Young men who engaged in condomless insertive anal intercourse were more likely to report viral suppression (RR, 1.14; 95% CI, 1.04-1.24). CONCLUSION: HIV care for young, black men who have sex with men must be multidimensional to address medical needs in the context of mental health, substance use, and housing insecurity.

Sensitization of lung cancer cells by altered dimerization of HSP27.

Heat shock protein 27 (HSP27, HSPB1) induces resistance to anticancer drugs in various cancer types, including non-small cell lung cancer (NSCLC). Therefore, pharmacological inhibition of HSP27 in NSCLC may be a good strategy for anticancer therapy. Unlike other HSPs such as HSP90 and HSP70, small molecule approaches for neutralization of HSP27 are not well established because of the absence of an ATP binding domain. Previously, small molecules with altered cross linking activity of HSP27, were identified to inhibit building a large oligomer led to sensitization in combination with radiation and chemotherapeutic drugs. In this study, a chromene compound, J2 that exhibited better cross-linking activity of HSP27 than xanthone compound, SW15 which was previously identified, was yielding sensitization to NSCLC cells with high expression of HSP27 when combined with HSP90 inhibitor and standard anticancer modalities such as taxol and cisplatin. In vivo xenograft system also showed sensitization activity of J2, as well as in vitro cell viability, cell death or apoptosis detection assay. For better druggability, several quinolone compounds, an (bio) isostere of chromone and one of well-known core in many marketed medicine, was designed and synthesized by replacement of oxygen with nitrogen in 4-pyron structure of J2. However, the cross linking activity of HSP27 disappeared by quinolone compounds and the sensitizing effects on the anticancer drugs disappeared as well, suggesting oxygene moiety of 4-pyron structure of J2 may be a pharmacophore for induction of cross linking of HSP27 and sensitization to cancer cells. In conclusion, combination of chemotherapy with small molecules that induces altered cross-linking of HSP27 may be a good strategy to overcome the resistance of anticancer drugs in HSP27-over-expressing cancer cells.

The Conjugated Double Bond of Coniferyl Aldehyde Is Essential for Heat Shock Factor 1 Mediated Cytotoprotection.

Coniferyl aldehyde (1) is previously reported as a potent inducer of heat shock factor 1 (HSF1). Here, we further examined the active pharmacophore of 1 for activation of HSF1 using the derivatives coniferyl alcohol (2), 4-hydroxy-3-methoxyphenylpropanal (3), and 4-hydroxy-3-methoxyphenylpropanol (4). Both 1 and 2 resulted in increased survival days after a lethal radiation (IR) dose. The decrease in bone marrow (BM) cellularity and Ki67-positive BM cells by IR was also significantly restored by 1 or 2 in mice. These results suggested that the vinyl moiety of 1 and 2 is necessary for inducing HSF1, which may be useful for developing small molecules for cytoprotection of normal cells against damage by cytotoxic drugs and radiation.

G protein-coupled calcium-sensing receptor is a crucial mediator of MTA-induced biological activities.

Mineral trioxide aggregate (MTA) is a calcium silicate-based bioactive material that has been extensively used in dentistry. MTA has been highlighted in its diverse biological functions and excellent clinical outcomes. However, limited insight into the intracellular signaling pathways has been provided to explain the biological activities of MTA. Here, we firstly elucidate that the extracellular calcium-sensing receptor (CaSR) is a major signaling mediator of MTA-induced biological reactions through versatile live imaging techniques of human dental pulp cells (hDPCs). We found that MTA activates diverse CaSR downstream pathways; notably, CaSR activation essentially requires dual modulation of extracellular Ca2+ and pH via MTA. Among the CaSR downstream pathways, Ca2+ mobilization from intracellular stores by the phospholipase C pathway plays an important role in osteogenic differentiation of hDPCs by regulating transcriptional activity. Our findings shed light on the signal transduction mechanism of MTA, thus providing a crucial molecular basis for the use of MTA in regenerative dental therapy.

Human salivary gland cells express bradykinin receptors that modulate the expression of proinflammatory cytokines.

Bradykinin is an important peptide modulator that affects the function of neurons and immune cells. However, there is no evidence of the bradykinin receptors and their functions in human salivary glands. Here we have identified and characterized bradykinin receptors on human submandibular gland cells. Both bradykinin B1 and B2 receptors are expressed on human submandibular gland cells, A253 cells, and HSG cells. Bradykinin increased the intracellular Ca2+ concentration ([Ca2+ ]i ) in a concentration-dependent manner. Interestingly, a specific agonist of the B1 receptor did not have any effect on [Ca2+ ]i in HSG cells, whereas specific agonists of the B2 receptor had a Ca2+ mobilizing effect. Furthermore, application of the B1 receptor antagonist, R715, did not alter the bradykinin-mediated increase in cytosolic Ca2+ , whereas the B2 receptor antagonist, HOE140, showed a strong inhibitory effect, which implies that bradykinin B2 receptors are functional in modulating the concentration of cytosolic Ca2+ . Bradykinin did not affect a carbachol-induced rise of [Ca2+ ]i and did not modulate translocation of aquaporin-5. However, bradykinin did promote the expression of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), implying the role of bradykinin in salivary gland inflammation. These data suggest that bradykinin receptors are involved in Ca2+ signaling in human submandibular gland cells and serve a unique role, which is separate from that of other salivary gland G protein-coupled receptors.

Reducing Children's Susceptibility to Alcohol Use: Effects of a Home-Based Parenting Program.

This 4-year efficacy trial tested whether a home-based, self-administered parenting program could have a long-term effect on children's cognitive susceptibility to alcohol use, and it tested hypothesized moderators and mediators of any such program effect. Using a two-group randomized controlled design, 1076 children (540 treatment; 536 control; mean age of 9.2 years at baseline) completed telephone interviews prior to randomization and follow-up interviews 12, 24, 36, and 48 months post-baseline. Mothers of children randomized to treatment received a 5-month-long parenting program during year 1, followed by two 1-month-long boosters in years 2 and 3. Exposure to the program was significantly inversely associated with susceptibility to alcohol use 48 months post-baseline (b = -0.03, p = .04), with no variation in program effects by parental alcohol use or mother's race/ethnicity or education, suggesting broad public health relevance of the parenting program. Path analyses of simple indirect effects through each hypothesized mediator showed that program exposure positively influenced parental communication to counter pro-drinking influences in the family and media domains and parental rule setting 36 months post-baseline; these variables, in turn, predicted reduced susceptibility to alcohol use 48 months post-baseline. Parallel (multiple) mediation analysis showed that the program had a significant indirect effect on susceptibility through parental rule setting. Together, the findings indicate that internalization of protective alcohol-related expectancies and intentions is possible among children whose mothers provide early exposure to alcohol-specific socialization. Additional research is needed to link alcohol-specific socialization during childhood with adolescent drinking outcomes.