Drug Response of Patient-Derived Lung Cancer Cells Predicts Clinical Outcomes of Targeted Therapy.

Intratumor heterogeneity leads to different responses to targeted therapies, even within patients whose tumors harbor identical driver oncogenes. This study examined clinical outcomes according to a patient-derived cell (PDC)-based drug sensitivity test in lung cancer patients treated with targeted therapies. From 487 lung cancers, 397 PDCs were established with a success rate of 82%. In 139 PDCs from advanced non-small-cell lung cancer (NSCLC) patients receiving targeted therapies, the standardized area under the curve (AUC) values for the drugs was significantly correlated with their tumor response (p = 0.002). Among 59 chemo-naive EGFR/ALK-positive NSCLC patients, the PDC non-responders showed a significantly inferior response rate (RR) and progression-free survival (PFS) for the targeted drugs than the PDC responders (RR, 25% vs. 78%, p = 0.011; median PFS, 3.4 months [95% confidence interval (CI), 2.8-4.1] vs. 11.8 months [95% CI, 6.5-17.0], p < 0.001). Of 25 EGFR-positive NSCLC patients re-challenged with EGFR inhibitors, the PDC responder showed a higher RR than the PDC non-responder (42% vs. 15%). Four patients with wild-type EGFR or uncommon EGFR-mutant NSCLC were treated with EGFR inhibitors based on their favorable PDC response to EGFR inhibitors, and two patients showed dramatic responses. Therefore, the PDC-based drug sensitivity test results were significantly associated with clinical outcomes in patients with EGFR- or ALK-positive NSCLC. It may be helpful for predicting individual heterogenous clinical outcomes beyond genomic alterations.

Evaluation of viral infection as an etiology of ME/CFS: a systematic review and meta-analysis.

BACKGROUND: Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a long-term disabling illness without a medically explained cause. Recently during COVID-19 pandemic, many studies have confirmed the symptoms similar to ME/CFS in the recovered individuals. To investigate the virus-related etiopathogenesis of ME/CFS, we conducted a systematic assessment of viral infection frequency in ME/CFS patients. METHODS: We conducted a comprehensive search of PubMed and the Cochrane Library from their inception through December 31, 2022, using selection criteria of viral infection prevalence in ME/CFS patients and controls. Subsequently, we performed a meta-analysis to assess the extent of viral infections' contribution to ME/CFS by comparing the odds ratio between ME/CFS patients and controls (healthy and/or diseased). RESULTS: Finally, 64 studies met our eligibility criteria regarding 18 species of viruses, including a total of 4971 ME/CFS patients and 9221 control subjects. The participants included healthy subjects and individuals with one of 10 diseases, such as multiple sclerosis or fibromyalgia. Two DNA viruses (human herpes virus (HHV)-7 and parvovirus B19, including their co-infection) and 3 RNA viruses (borna disease virus (BDV), enterovirus and coxsackie B virus) showed odds ratios greater than 2.0 compared with healthy and/or diseased subjects. Specifically, BDV exceeded the cutoff with an odds ratio of ≥ 3.47 (indicating a "moderate association" by Cohen's d test) compared to both healthy and diseased controls. CONCLUSION: This study comprehensively evaluated the risk of viral infections associated with ME/CFS, and identified BDV. These results provide valuable reference data for future studies investigating the role of viruses in the causation of ME/CFS.

A Randomized Phase II Study of Irinotecan Plus Cisplatin with or without Simvastatin in Ever-Smokers with Extended Disease Small Cell Lung Cancer.

PURPOSE: This study evaluated whether an addition of simvastatin to chemotherapy improves survival in ever-smokers with extensive disease (ED)-small cell lung cancer (SCLC). Materials and Methods: This is an open-label randomized phase II study conducted in National Cancer Center (Goyang, Korea). Chemonaive patients with ED-SCLC, smoking history (≥ 100 cigarettes lifetime), and Eastern Cooperative Oncology Group performance status of ≤ 2 were eligible. Patients were randomized to receive irinotecan plus cisplatin alone or with simvastatin (40 mg once daily orally) for a maximum of six cycles. Primary endpoint was the the 1-year survival rate. RESULTS: Between September 16, 2011, and September 9, 2021, 125 patients were randomly assigned to the simvastatin (n=62) or control (n=63) groups. The median smoking pack year was 40 years. There was no significant difference in the 1-year survival rate between the simvastatin and control groups (53.2% vs. 58.7%, p=0.535). The median progression-free survival and overall survival between the simvastatin arm vs. the control groups were 6.3 months vs. 6.4 months (p=0.686), and 14.4 months vs. 15.2 months, respectively (p=0.749). The incidence of grade 3-4 adverse events was 62.9% in the simvastatin group and 61.9% in the control group. In the exploratory analysis of lipid profiles, patients with hypertriglyceridemia had significantly higher 1-year survival rates than those with normal triglyceride levels (80.0% vs. 52.7%, p=0.046). CONCLUSION: Addition of simvastatin to chemotherapy provided no survival benefit in ever-smokers with ED-SCLC. Hypertriglyceridemia may be associated with better prognosis in these patient population.

Incidence Rate of Bee Venom Acupuncture Related Anaphylaxis: A Systematic Review.

BACKGROUND: Bee venom acupuncture (BVA) is an effective treatment method for various diseases. Bee venom, however, can cause adverse effects, even rarely including life-threatening anaphylaxis, so safety-related evidence is required. In this study, we systematically estimated the incidence rate of anaphylaxis in response to BVA. METHODS: We searched eight databases (MEDLINE (Pubmed), EMBASE, Cochrane Central Register of Controlled, KISS, KMBASE, Koreamed, OASIS, and NDSL) and systematically reviewed the articles that met the inclusion/exclusion criteria. RESULTS: Among 225 potentially relevant articles, 49 were selected for this study. The overall incidence rate of anaphylaxis in response to BVA was 0.045% (95% CI 0.028-0.062). Women (0.083%, 95% CI 0.010-0.157) showed a higher incidence rate than men (0.019%, 95% CI -0.018 to 0.055), while the incidence for patients who had a skin test conducted (0.041%, 95% CI 0.011-0.072) was not significantly different compared to that obtained for patients for which there was no information about a skin test (0.047%, 95% CI 0.026-0.067). The publication year affected the incidence rate: it was highest before 1999 (1.099%, 95% CI -1.043 to 3.241), lower between 2000 and 2009 (0.049%, 95% CI 0.025-0.073), and lowest between 2010 and 2021 (0.037% 95% CI 0.014-0.060). CONCLUSIONS: In this study, we provide reference data about risk size and factors of BVA-related anaphylaxis, which is essentially required for BVA application in clinics.

Comparison of assessment scores for fatigue between multidimensional fatigue inventory (MFI-K) and modified chalder fatigue scale (mKCFQ).

BACKGROUND: Because of the absence of biological parameters for fatigue, appropriate instruments for assessing the degree of fatigue are important in the diagnosis and management of people complaining of fatigue-like symptoms. This study statistically analyzed the fatigue scores from two typical questionnaire-based instruments: the Korean version of the Multidimensional Fatigue Inventory (MFI-K) and the modified Chalder Fatigue Scale (mKCFQ). METHODS: Seventy participants (males n = 40, females n = 30, median age 48 years old, range of 25-67) were grouped into three groups ('mild' = 20, 'moderate' = 42, and 'severe' = 8) according to self-reported fatigue levels using a 7-point Likert scale. The similarities and differences between two instrument-derived scores were analyzed using correlations (r) and multidimensional scaling (MDS). RESULTS: The total scores of the two assessments were significantly correlated (r = 75%, p < 0.001), as were the subscores ('Total Physical fatigue': r = 76%, p < 0.001, 'Total Mental fatigue': r = 56%, p < 0.001). Relative overestimation of the MFI-K (45.8 ± 11.3) compared to the mKCFQ (36.1 ± 16.2) was observed, which was especially prominent in the 'mild' group. The scores of the three groups were more easily distinguished by the mKCFQ than by the MFI-K. In terms of the five dimension scores, we found a higher correlation of the two assessments for 'general fatigue' (r = 79%, p < 0.001) and 'physical fatigue' (r = 66%, p < 0.001) than for the reductions in 'motivation' (r = 41%, p < 0.01) and 'activity' (r = 26%, p > 0.05). CONCLUSIONS: Our results may indicate the usefulness of the two instruments, especially for the physical symptoms of fatigue ('general' and 'physical' fatigue). Furthermore, the MFI-K may be useful for conditions of moderate-to-severe fatigue, such as chronic fatigue syndrome, but the mKCFQ may be useful for all spectra of fatigue, including in subhealthy people.

Nationwide epidemiological characteristics of chronic fatigue syndrome in South Korea.

BACKGROUND: Chronic fatigue syndrome (CFS) is a long-term disabling illness accompanied by medically unexplained fatigue. This study aimed to explore the epidemiological characteristics of CFS in South Korea. METHODS: Using the nationwide medical records provided by the Korean Health Insurance Review & Assessment Service (HIRA), we analyzed the entire dataset for CFS patients diagnosed by physicians in South Korea from January 2010 to December 2020. RESULTS: The annual mean incidence of CFS was estimated to be 44.71 ± 6.10 cases per 100,000 individuals [95% CI: 40.57, 48.76], and the prevalence rate was 57.70 ± 12.20 cases per 100,000 individuals [95% CI: 49.40, 65.79]. These two rates increased by 1.53- and 1.94-fold from 2010 to 2020, respectively, and showed an increasing trend with aging and an approximately 1.5-fold female predominance. CONCLUSIONS: This study is the first to report the nationwide epidemiological features of CFS, which reflects the clinical reality of CFS diagnosis and care in South Korea. This study will be a valuable reference for studies of CFS in the future.

Prevalence of Chronic Fatigue Syndrome (CFS) in Korea and Japan: A Meta-Analysis.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term disabling illness accompanied by fatigue unsolved by rest. However, ME/CFS is a poorly understood illness that lacks a universally accepted pathophysiology and treatment. A lack of CFS-related studies have been conducted in Asian countries. This study aimed to estimate and compare the prevalence of ME/CFS in Korea and Japan and conducted a meta-analysis. METHODS: We searched PubMed, EMBASE, Cochrane, and KMBASE for population-based prevalence studies of the two countries and synthesized the data according to the Fukuda case definition. RESULTS: Of the eight studies (five in Korea, three in Japan) included, the total prevalence rate of Korean studies was 0.77% (95% CI 0.34-1.76), and 0.76% (95% CI 0.46-1.25) for the Japanese studies. The prevalence rate in females was approximately two-fold higher than males in Korean studies (1.31% female vs. 0.60% male), while the gender difference was less obvious in Japanese studies (0.76% female vs. 0.65% male). CONCLUSIONS: Further epidemiology studies on the female ME/CFS prevalence rate between countries may be required.

The Prospects of the Two-Day Cardiopulmonary Exercise Test (CPET) in ME/CFS Patients: A Meta-Analysis.

BACKGROUND: The diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is problematic due to the lack of established objective measurements. Postexertional malaise (PEM) is a hallmark of ME/CFS, and the two-day cardiopulmonary exercise test (CPET) has been tested as a tool to assess functional impairment in ME/CFS patients. This study aimed to estimate the potential of the CPET. METHODS: We reviewed studies of the two-day CPET and meta-analyzed the differences between ME/CFS patients and controls regarding four parameters: volume of oxygen consumption and level of workload at peak (VO2peak, Workloadpeak) and at ventilatory threshold (VO2@VT, Workload@VT). RESULTS: The overall mean values of all parameters were lower on the 2nd day of the CPET than the 1st in ME/CFS patients, while it increased in the controls. From the meta-analysis, the difference between patients and controls was highly significant at Workload@VT (overall mean: -10.8 at Test 1 vs. -33.0 at Test 2, p < 0.05), which may reflect present the functional impairment associated with PEM. CONCLUSIONS: Our results show the potential of the two-day CPET to serve as an objective assessment of PEM in ME/CFS patients. Further clinical trials are required to validate this tool compared to other fatigue-inducing disorders, including depression, using well-designed large-scale studies.

Review of case definitions for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with unknown causes. From the perspectives on the etiology and pathophysiology, ME/CFS has been labeled differently, which influenced changes in case definitions and terminologies. This review sought to feature aspects of the history, developments, and differential symptoms in the case definitions. METHODS: A search was conducted through PubMed published to February 2020 using the following search keywords: case definition AND chronic fatigue syndrome [MeSH Terms]. All reference lists of the included studies were checked. Of the included studies, the number of citations and the visibility in the literatures of the definitions were considered for comparisons of the criteria. RESULTS: Since the first 'ME' case definition was developed in 1986, 25 case definitions/diagnostic criteria were created based on three conceptual factors (etiology, pathophysiology, and exclusionary disorders). These factors can be categorized into four categories (ME, ME/CFS, CFS, and SEID) and broadly characterized according to primary disorder (ME-viral, CFS-unknown, ME/CFS-inflammatory, SEID-multisystemic), compulsory symptoms (ME and ME/CFS-neuroinflammatory, CFS and SEID-fatigue and/or malaise), and required conditions (ME-infective agent, ME/CFS, CFS, SEID-symptoms associated with fatigue, e.g., duration of illness). ME and ME/CFS widely cover all symptom categories, while CFS mainly covers neurologic and neurocognitive symptoms. Fatigue, cognitive impairment, PEM, sleep disorder, and orthostatic intolerance were the overlapping symptoms of the 4 categories, which were included as SEID criteria. CONCLUSIONS: This study comprehensively described the journey of the development of case definitions and compared the symptom criteria. This review provides broader insights and explanations to understand the complexity of ME/CFS for clinicians and researchers.

Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been emerging as a significant health issue worldwide. This study aimed to systemically assess the prevalence of CFS/ME in various aspects of analyses for precise assessment. METHODS: We systematically searched prevalence of CFS/ME from public databases from 1980 to December 2018. Data were extracted according to 7 categories for analysis: study participants, gender and age of the participants, case definition, diagnostic method, publication year, and country of the study conducted. Prevalence data were collected and counted individually for studies adopted various case definitions. We analyzed and estimated prevalence rates in various angles: average prevalence, pooled prevalence and meta-analysis of all studies. RESULTS: A total of 1291 articles were initially identified, and 45 articles (46 studies, 56 prevalence data) were selected for this study. Total 1085,976 participants were enrolled from community-based survey (540,901) and primary care sites (545,075). The total average prevalence was 1.40 ± 1.57%, pooled prevalence 0.39%, and meta-analysis 0.68% [95% CI 0.48-0.97]. The prevalence rates were varied by enrolled participants (gender, study participants, and population group), case definitions and diagnostic methods. For example, in the meta-analysis; women (1.36% [95% CI 0.48-0.97]) vs. men (0.86% [95% CI 0.48-0.97]), community-based samples (0.76% [95% CI 0.53-1.10]) vs. primary care sites (0.63% [95% CI 0.37-1.10]), adults ≥ 18 years (0.65% [95% CI 0.43-0.99]) vs. children and adolescents < 18 years (0.55% [95% CI 0.22-1.35]), CDC-1994 (0.89% [95% CI 0.60-1.33]) vs. Holmes (0.17% [95% CI 0.06-0.49]), and interviews (1.14% [95% CI 0.76-1.72]) vs. physician diagnosis (0.09% [95% CI 0.05-0.13]), respectively. CONCLUSIONS: This study comprehensively estimated the prevalence of CFS/ME; 0.89% according to the most commonly used case definition CDC-1994, with women approximately 1.5 to 2 folds higher than men in all categories. However, we observed the prevalence rates are widely varied particularly by case definitions and diagnostic methods. An objective diagnostic tool is urgently required for rigorous assessment of the prevalence of CFS/ME.

Correction to: IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells.

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IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells.

BACKGROUND: Natural killer (NK) cells are an emerging new tool for cancer immunotherapy. To develop NK cell therapeutics from peripheral blood mononuclear cells (PBMCs) of healthy donors, substantial expansion of primary NK cells is necessary because of the very low number of these cells in peripheral blood. In this study, we aimed to investigate the effect of various cytokine alone or combinations, in expanded NK cells and to analyze the synergetic effect of cytokine combinations. METHODS: Human NK cells were isolated from healthy donor PBMC. Purified NK cells were stimulated with single cytokines or combinations of IL-2, IL-15, IL-18, and IL-27. The expanded NK cells were characterized by flow cytometry, cytotoxicity assay, calcein AM assay and Western blot. RESULTS: We investigated the synergistic effects of each cytokine, namely, IL-2, IL-15, IL-18, and IL-27, on human NK cells isolated from PBMCs of healthy donors and cultured for 21 days. We identified that IL-15/IL-18/IL-27-mediated activation of NK cells most potently increased NK cell proliferation, cytotoxicity, and IFN-É£ secretion compared with the activation observed with other treatments, including IL-2, IL-15, and IL-15/IL-18. Additionally, the expression of DNAM-1, NKG2D, CD69, and natural cytotoxicity receptors (NCRs; NKp30 and NKp44) increased on day 21 compared to that on day 0, demonstrating the activation of NK cells. In vitro, expanded NK cells were highly cytotoxic against cancer cells, displaying increased perforin and granzyme B accumulation. CONCLUSIONS: Taken together, these results indicated that IL-27 can synergize on NK cell expansion and activation with IL-15 and IL-18. In addition, we described an improved culture method for ex vivo expansion of human NK cells with IL-15/IL-18/IL-27 stimulation and characterized the response of NK cells to this stimulation.

Ciprofloxacin Enhances TRAIL-Induced Apoptosis in Lung Cancer Cells by Upregulating the Expression and Protein Stability of Death Receptors through CHOP Expression.

Ciprofloxacin (CIP) is a potent antimicrobial agent with multiple effects on host cells and tissues. Previous studies have highlighted their proapoptotic effect on human cancer cells. The current study showed that subtoxic doses of CIP effectively sensitized multiple cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Although TRAIL alone mediated the partial proteolytic processing of procaspase-3 in lung cancer cells, co-treatment with CIP and TRAIL efficiently restored the complete activation of caspases. We found that treatment of lung cancer with CIP significantly upregulated the expression and protein stability of death receptor (DR) 5. These effects were mediated through the regulation of transcription factor CCAT enhancer-binding protein homologous protein (CHOP) since the silencing of these signaling molecules abrogated the effect of CIP. Taken together, these results indicated that the upregulation of death receptor expression and protein stability by CIP contributed to the restoration of TRAIL-sensitivity in lung cancer cells.

A Scoping Review on Models of Integrative Medicine: What Is Known from the Existing Literature?

OBJECTIVES: Integrative medicine (IM) has been recognized and introduced into Western healthcare systems over the past two decades. Limited information on IM models is available to guide development of an optimal healthcare service. A scoping review was carried out to evaluate IM models in the extant literature, including the distinctive features of each model, to gain an understanding of the core requirements needed to develop models of IM that best meet the needs of patients. DESIGN: Directed content analysis was used to classify the IM models into systems based on coding schema developed from theoretical models and to identify the key concepts of each system. RESULTS: From 1374 articles identified, 45 studies were included. Models were categorized as theoretical and practical and were subdivided into five main models: coexistence, cooptative, cooperative, collaborative, and patient-centered care. They were then divided into three systems-independent, dependent, and integrative-on the basis of the level of involvement of general practitioners and complementary and alternative medicine (CAM) practitioners. The theoretical coexistence and cooptative models have distinct roles for different health care professionals, whereas practical models tend to be ad hoc market-driven services, dependent on patient demand. The cooperative and collaborative models were team-based, with formalized interaction between the two medical paradigms of conventional medicine and CAM, with the practical models focusing on facilitating communication, behaviors, and relationships. The patient-centered care model recognized the philosophy of CAM and required collaboration between disciplines based around patient needs. CONCLUSIONS: The focus of IM models has transferred from providers to patients with the independent and integrative systems. This may require a philosophical shift for IM. Further research is required to best understand how to practice patient-centered care in IM services.

Liver X receptor and STAT1 cooperate downstream of Gas6/Mer to induce anti-inflammatory arginase 2 expression in macrophages.

Mer signaling increases the transcriptional activity of liver X receptor (LXR) to promote the resolution of acute sterile inflammation. Here, we aimed to understand the pathway downstream of Mer signaling after growth arrest-specific protein 6 (Gas6) treatment that leads to LXR expression and transcriptional activity in mouse bone-marrow derived macrophages (BMDM). Gas6-induced increases in LXRα and LXRß and expression of their target genes were inhibited in BMDM from STAT1(-/-) mice or by the STAT1-specific inhibitor fludarabine. Gas6-induced STAT1 phosphorylation, LXR activation, and LXR target gene expression were inhibited in BMDM from Mer(-/-) mice or by inhibition of PI3K or Akt. Gas6-induced Akt phosphorylation was inhibited in BMDM from STAT1(-/-) mice or in the presence of fludarabine. Gas6-induced LXR activity was enhanced through an interaction between LXRα and STAT1 on the DNA promoter of Arg2. Additionally, we found that Gas6 inhibited lipopolysaccharide (LPS)-induced nitrite production in a STAT1 and LXR pathway-dependent manner in BMDM. Additionally, Mer-neutralizing antibody reduced LXR and Arg2 expression in lung tissue and enhanced NO production in bronchoalveolar lavage fluid in LPS-induced acute lung injury. Our data suggest the possibility that the Gas6-Mer-PI3K/Akt-STAT1-LXR-Arg2 pathway plays an essential role for resolving inflammatory response in acute lung injury.

Integrative Analyses of Uterine Transcriptome and MicroRNAome Reveal Compromised LIF-STAT3 Signaling and Progesterone Response in the Endometrium of Patients with Recurrent/Repeated Implantation Failure (RIF).

Intimate two-way interactions between the implantation-competent blastocyst and receptive uterus are prerequisite for successful embryo implantation. In humans, recurrent/repeated implantation failure (RIF) may occur due to altered uterine receptivity with aberrant gene expression in the endometrium as well as genetic defects in embryos. Several studies have been performed to understand dynamic changes of uterine transcriptome during menstrual cycles in humans. However, uterine transcriptome of the patients with RIF has not been clearly investigated yet. Here we show that several signaling pathways as well as many genes and microRNAs are dysregulated in the endometrium of patients with RIF (RIFE). Whereas unsupervised hierarchical clustering showed that overall mRNA and microRNA profiles of RIFE were similar to those of endometria of healthy women, many genes were significantly dysregulated in RIFE (cut off at 1.5 fold change). The majority (~75%) of differentially expressed genes in RIFE including S100 calcium binding protein P (S100P), Chemokine (C-X-C motif) ligand 13 (CXCL13) and SIX homeobox 1 (SIX1) were down-regulated, suggesting that reduced uterine expression of these genes is associated with RIF. Gene Set Enrichment analyses (GSEA) for mRNA microarrays revealed that various signaling pathways including Leukemia inhibitory factor (LIF) signaling and a P4 response were dysregulated in RIFE although expression levels of Estrogen receptor α (ERα) and Progesterone receptor (PR) were not significantly altered in RIFE. Furthermore, expression and phosphorylation of Signal transducer and activator of transcription 3 (STAT3) are reduced and a gene set associated with Janus kinase (JAK)-STAT signaling pathway is systemically down-regulated in these patients. Pairwise analyses of microRNA arrays with prediction of dysregulated microRNAs based on mRNA expression datasets demonstrated that 6 microRNAs are aberrantly regulated in RIFE. Collectively, we here suggest that dysregulation of several major signaling pathways and genes critical for uterine biology and embryo implantation may lead to uterine abnormalities in patients with RIF.

Tunicamycin promotes apoptosis in leukemia cells through ROS generation and downregulation of survivin expression.

Tunicamycin (TN), one of the endoplasmic reticulum stress inducers, has been reported to inhibit tumor cell growth and exhibit anticarcinogenic activity. However, the mechanism by which TN initiates apoptosis remains poorly understood. In the present study, we investigated the effect of TN on the apoptotic pathway in U937 cells. We show that TN induces apoptosis in association with caspase-3 activation, generation of reactive oxygen species (ROS), and downregulation of survivin expression. P38 MAPK (mitogen-activated protein kinase) and the generation of ROS signaling pathway play crucial roles in TN-induced apoptosis in U937 cells. We hypothesized that TN-induced activation of p38 MAPK signaling pathway is responsible for cell death. To test this hypothesis, we selectively inhibited MAPK during treatment with TN. Our data demonstrated that inhibitor of p38 (SB), but not ERK (PD) or JNK (SP), partially maintained apoptosis during treatment with TN. Pre-treatment with NAC and GSH markedly prevented cell death, suggesting a role for ROS in this process. Ectopic expression of survivin in U937 cells attenuated TN-induced apoptosis by suppression of caspase-3 cleavage, mitochondrial membrane potential, and cytochrome c release in U937 cells. Taken together, our results show that TN modulates multiple components of the apoptotic response of human leukemia cells and raise the possibility of a novel therapeutic strategy for hematological malignancies.

The expression of aminoacyl-tRNA-synthetase-interacting multifunctional protein-1 (Aimp1) is regulated by estrogen in the mouse uterus.

Aimp1 is known as a multifunctional cytokine in various cellular events. Recent study showed Aimp1 is localized in glandular epithelial, endothelial, and stromal cells in functionalis and basalis layers of the endometrium. However, the regulatory mechanism of Aimp1 in the uterus remains unknown. In the present study, we found that Aimp1 is expressed in the mouse uterus. Aimp1 transcripts were decreased at diestrus stage. However, the level of Aimp1 protein was significantly increased in the luminal epithelium in the uterine endometrium at estrus stage during the estrous cycle. We found that treatment of estrogen increased the expression of Aimp1 in the uterus in ovarectomized mice. We identified one estrogen receptor binding element (ERE) on mouse Aimp1 promoter. The activity of Aimp1 promoter was increased with estrogen treatment. Our findings indicate that Aimp1 might act as an important regulator to remodel the uterine endometrium and its expression might be regulated by estrogen during the estrous cycle. This will give us better understanding of the dynamic change of uterine remodeling during the estrous cycle.

PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death.

Deciphering the molecular basis of neuronal cell death is a central issue in the etiology of neurodegenerative diseases, such as Parkinson's and Alzheimer's. Dysregulation of p53 levels has been implicated in neuronal apoptosis. The role of histone deacetylase 3 (HDAC3) in suppressing p53-dependent apoptosis has been recently emphasized; however, the molecular basis of modulation of p53 function by HDAC3 remains unclear. Here we show that PTEN-induced putative kinase 1 (PINK1), which is linked to autosomal recessive early-onset familial Parkinson's disease, phosphorylates HDAC3 at Ser-424 to enhance its HDAC activity in a neural cell-specific manner. PINK1 prevents H2O2-induced C-terminal cleavage of HDAC3 via phosphorylation of HDAC3 at Ser-424, which is reversed by protein phosphatase 4c. PINK1-mediated phosphorylation of HDAC3 enhances its direct association with p53 and causes subsequent hypoacetylation of p53. Genetic deletion of PINK1 partly impaired the suppressive role of HDAC3 in regulating p53 acetylation and transcriptional activity. However, depletion of HDAC3 fully abolished the PINK1-mediated p53 inhibitory loop. Finally, ectopic expression of phosphomometic-HDAC3(S424E) substantially overcomes the defective action of PINK1 against oxidative stress in dopaminergic neuronal cells. Together, our results uncovered a mechanism by which PINK1-HDAC3 network mediates p53 inhibitory loop in response to oxidative stress-induced damage.