Experiences and needs of older adults at different stages of cerebral infarction based on trajectory theory-A qualitative study
Tang, Xianping; Sun, Hong; Ge, Song; Han, Shuyu; Li, Ying; Wu, Bei
BACKGROUND:In recent years, stroke has become the second leading cause of death worldwide, and the incidence and mortality of ischemic stroke have increased significantly. This study mainly aimed to explore the experiences and needs of older adults at different stages of cerebral infarction based on the chronic illness trajectory theory. METHODS:Data were collected from 22 older adults experiencing the onset, acute, and stable stages of stroke through semi-structured interviews and were analyzed using Colaizzi's descriptive phenomenological approach. RESULTS:Multiple themes and subthemes emerged on the experiences and needs of older adults at different stages of cerebral infarction based on the three dimensions of the long-term disease trajectory theory: illness-related work, biographical work, and everyday life work. Seven themes were extracted for illness-related work, six for biographical work, and eight for everyday life work. DISCUSSIONS/CONCLUSIONS:The treatment, nursing, and rehabilitation of cerebral infarction are complex. This study indicated that patients after cerebral infarction have different experiences and needs for illness-related work. They also have distinctive and dynamically changing demands for biographical work and everyday life work. CONCLUSIONS:The experiences and needs of older patients with cerebral infarction changed dynamically at different stages of the disease. Healthcare professionals should develop effective interventions targeting these needs at various disease stages, provide patients with continuous support to shape their disease trajectories, and maintain patients' stability.
Longitudinal Impact of WTC Dust Inhalation on Rat Cardiac Tissue Transcriptomic Profiles
Park, Sung-Hyun; Lu, Yuting; Shao, Yongzhao; Prophete, Colette; Horton, Lori; Sisco, Maureen; Lee, Hyun-Wook; Kluz, Thomas; Sun, Hong; Costa, Max; Zelikoff, Judith; Chen, Lung-Chi; Gorr, Matthew W; Wold, Loren E; Cohen, Mitchell D
First responders (FR) exposed to the World Trade Center (WTC) Ground Zero air over the first week after the 9/11 disaster have an increased heart disease incidence compared to unexposed FR and the general population. To test if WTC dusts were causative agents, rats were exposed to WTC dusts (under isoflurane [ISO] anesthesia) 2 h/day on 2 consecutive days; controls received air/ISO or air only. Hearts were collected 1, 30, 240, and 360 d post-exposure, left ventricle total RNA was extracted, and transcription profiles were obtained. The data showed that differentially expressed genes (DEG) for WTC vs. ISO rats did not reach any significance with a false discovery rate (FDR) < 0.05 at days 1, 30, and 240, indicating that the dusts did not impart effects beyond any from ISO. However, at day 360, 14 DEG with a low FDR were identified, reflecting potential long-term effects from WTC dust alone, and the majority of these DEG have been implicated as having an impact on heart functions. Furthermore, the functional gene set enrichment analysis (GSEA) data at day 360 showed that WTC dust could potentially impact the myocardial energy metabolism via PPAR signaling and heart valve development. This is the first study showing that WTC dust could significantly affect some genes that are associated with the heart/CV system, in the long term. Even > 20 years after the 9/11 disaster, this has potentially important implications for those FR exposed repeatedly at Ground Zero over the first week after the buildings collapsed.
Therapeutic Targeting of Alternative Splicing: A New Frontier in Cancer Treatment
Murphy, Anthony J; Li, Alex H; Li, Peichao; Sun, Hong
The ability for cells to harness alternative splicing enables them to diversify their proteome in order to carry out complex biological functions and adapt to external and internal stimuli. The spliceosome is the multiprotein-RNA complex charged with the intricate task of alternative splicing. Aberrant splicing can arise from abnormal spliceosomes or splicing factors and drive cancer development and progression. This review will provide an overview of the alternative splicing process and aberrant splicing in cancer, with a focus on serine/arginine-rich (SR) proteins and their recently reported roles in cancer development and progression and beyond. Recent mapping of the spliceosome, its associated splicing factors, and their relationship to cancer have opened the door to novel therapeutic approaches that capitalize on the widespread influence of alternative splicing. We conclude by discussing small molecule inhibitors of the spliceosome that have been identified in an evolving era of cancer treatment.
Chapter by: Sun, Hong; Costa, Max
in: Handbook on the Toxicology of Metals by
[S.l.] : Elsevier Inc., 2021
RUNX2/miRâ€‘31/SATB2 pathway in nickelâ€‘induced BEASâ€‘2B cell transformation
Zhu, Yusha; Chen, Qiao Yi; Jordan, Ashley; Sun, Hong; Roy, Nirmal; Costa, Max
Nickel (Ni) compounds are classified as Group 1 carcinogens by the International Agency for Research on Cancer (IARC) and are known to be carcinogenic to the lungs. In our previous study, special ATâ€‘rich sequenceâ€‘binding proteinÂ 2 (SATB2) was required for Niâ€‘induced BEASâ€‘2B cell transformation. In the present study, a pathway that regulates the expression of SATB2 protein was investigated in Niâ€‘transformed BEASâ€‘2B cells using western blotting and RTâ€‘qPCR for expression, and soft agar, migration and invasion assays for cell transformation. Runtâ€‘related transcription factorÂ 2 (RUNX2), a master regulator of osteogenesis and an oncogene, was identified as an upstream regulator for SATB2. Ni induced RUNX2 expression and initiated BEASâ€‘2B transformation and metastatic potential. Previously, miRNAâ€‘31 was identified as a negative regulator of SATB2 during arsenicâ€‘induced cell transformation, and in the present study it was identified as a downstream target of RUNX2 during carcinogenesis. miRâ€‘31 expression was reduced in Niâ€‘transformed BEASâ€‘2B cells, which was required to maintain cancer hallmarks. The expression level of miRâ€‘31 was suppressed by RUNX2 in BEASâ€‘2B cells, and this increased the expression level of SATB2, initiating cell transformation. Ni caused the repression of miRâ€‘31 by placing repressive marks at its promoter, which in turn increased the expression level of SATB2, leading to cell transformation.
Identification of an 11-Autophagy-Related-Gene Signature as Promising Prognostic Biomarker for Bladder Cancer Patients
Zhou, Chaoting; Li, Alex Heng; Liu, Shan; Sun, Hong
BACKGROUND:Survival rates for highly invasive bladder cancer (BC) patients have been very low, with a 5-year survival rate of 6%. Accurate prediction of tumor progression and survival is important for diagnosis and therapeutic decisions for BC patients. Our study aims to develop an autophagy-related-gene (ARG) signature that helps to predict the survival of BC patients. METHODS:RNA-seq data of 403 BC patients were retrieved from The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) database. Univariate Cox regression analysis was performed to identify overall survival (OS)-related ARGs. The Lasso Cox regression model was applied to establish an ARG signature in the TCGA training cohort (N = 203). The performance of the 11-gene ARG signature was further evaluated in a training cohort and an independent validation cohort (N = 200) using Kaplan-Meier OS curve analysis, receiver operating characteristic (ROC) analysis, as well as univariate and multivariate Cox regression analysis. RESULTS:. The ARGs-derived high-risk bladder cancer patients exhibited significantly poor OS in both training and validation cohorts. The prognostic model showed good predictive efficacy, with the area under the ROC curve (AUCs) for 1-year, 3-year, and 5-year overall survival of 0.702 (0.695), 0.744 (0.640), and 0.794 (0.658) in the training and validation cohorts, respectively. A prognostic nomogram, which included the ARGs-derived risk factor, age and stage for eventual clinical translation, was established. CONCLUSION/CONCLUSIONS:We identified a novel ARG signature for risk-stratification and robust prediction of overall survival for BC patients.
Induction of NUPR1 and APâ€‘1 contributes to the carcinogenic potential of nickel
Murphy, Anthony; Roy, Nirmal; Sun, Hong; Jin, Chunyuan; Costa, Max
Nickel (Ni) is carcinogenic to humans, and causes cancers of the lung, nasal cavity, and paranasal sinuses. The primary mechanisms of Niâ€‘mediated carcinogenesis involve the epigenetic reprogramming of cells and the ability for Ni to mimic hypoxia. However, the exact mechanisms of carcinogenesis related to Ni are obscure. Nuclear protein 1 (NUPR1) is a stressâ€‘response gene overexpressed in cancers, and is capable of conferring chemotherapeutic resistance. Likewise, activator protein 1 (APâ€‘1) is highly responsive to environmental signals, and has been associated with cancer development. In this study, NUPR1 was found to be rapidly and highly induced in human bronchial epithelial (BEASâ€‘2B) cells exposed to Ni, and was overexpressed in Niâ€‘transformed BEASâ€‘2B cells. Similarly, APâ€‘1 subunits, JUN and FOS, were induced in BEASâ€‘2B cells following Ni exposure. Knockdown of JUN or FOS was found to significantly suppress NUPR1 induction following Ni exposure, demonstrating their importance in NUPR1 transactivation. Reactive oxygen species (ROS) are known to induce APâ€‘1, and Ni has been shown to produce ROS. Treatment of BEASâ€‘2B cells with antioxidants was unable to prevent NUPR1 induction by Ni, suggesting that NUPR1 induction by Ni relies on mechanisms other than oxidative stress. To determine how NUPR1 is transcriptionally regulated following Ni exposure, the NUPR1 promoter was cloned and inserted into a luciferase gene reporter vector. Multiple JUN binding sites reside within the NUPR1 promoter, and upon deleting a JUN binding site in the upstream most region within the NUPR1 promoter using siteâ€‘directed mutagenesis, NUPR1 promoter activity was significantly reduced. This suggests that APâ€‘1 transcriptionally regulates NUPR1. Moreover, knockdown of NUPR1 significantly reduced colony formation and anchorageâ€‘independent growth in Niâ€‘transformed BEASâ€‘2B cells. Therefore, these results collectively demonstrate a novel mechanism of NUPR1 induction following Ni exposure, and provide a molecular basis by which NUPR1 may contribute to lung carcinogenesis.
Downregulation of hedgehog-interacting protein (HHIP) contributes to hexavalent chromium-induced malignant transformation of human bronchial epithelial cells
Li, Peichao; Zhang, Xiaoru; Murphy, Anthony J; Costa, Max; Zhao, Xiaogang; Sun, Hong
Hexavalent chromium [Cr(VI)] is a potent human lung carcinogen. Multiple mechanisms have been proposed that contribute to Cr(VI)-induced lung carcinogenesis including oxidative stress, DNA damage, genomic instability and epigenetic modulation. However, the molecular mechanisms and pathways mediating Cr(VI) carcinogenicity have not been fully elucidated. Hedgehog (Hh) signaling is a key pathway that plays important roles in the formation of multiple tissues during embryogenesis and in the maintenance of stem cell populations in adults. Dysregulation of Hh signaling pathway has been reported in many human cancers. Here, we report a drastic reduction in both mRNA and protein levels of hedgehog-interacting protein (HHIP), a downstream target and a negative regulator of Hh signaling, in Cr(VI)-transformed cells. These findings point to a potential role of Hh signaling in Cr(VI)-induced malignant transformation and lung carcinogenesis. Cr(VI)-transformed cells exhibited DNA hypermethylation and silencing histone marks in the promoter region of HHIP, indicating that an epigenetic mechanism mediates Cr(VI)-induced silencing of HHIP. In addition, the major targets of Hh signaling (GLI1-3 and PTCH1) were significantly increased in Cr(VI)-transformed cells, suggesting an aberrant activation of Hh signaling in these cells. Moreover, ectopically expressing HHIP not only suppressed Hh signaling but also inhibited cell proliferation and anchorage-independent growth in Cr(VI)-transformed cells. In conclusion, these findings establish a novel regulatory mechanism underlying Cr(VI)-induced lung carcinogenesis and provide new insights for developing a better diagnostic and prognostic strategy for Cr(VI)-related human lung cancer.
Longitudinal impact on rat cardiac tissue transcriptomic profiles due to acute intratracheal inhalation exposures to isoflurane
Park, Sung-Hyun; Lu, Yuting; Shao, Yongzhao; Prophete, Colette; Horton, Lori; Sisco, Maureen; Lee, Hyun-Wook; Kluz, Thomas; Sun, Hong; Costa, Max; Zelikoff, Judith; Chen, Lung-Chi; Cohen, Mitchell D
Isoflurane (ISO) is a widely used inhalation anesthetic in experiments with rodents and humans during surgery. Though ISO has not been reported to impart long-lasting side effects, it is unknown if ISO can influence gene regulation in certain tissues, including the heart. Such changes could have important implications for use of this anesthetic in patients susceptible to heart failure/other cardiac abnormalities. To test if ISO could alter gene regulation/expression in heart tissues, and if such changes were reversible, prolonged, or late onset with time, SHR (spontaneously hypertensive) rats were exposed by intratracheal inhalation to a 97.5% air/2.5% ISO mixture on two consecutive days (2 hr/d). Control rats breathed filtered air only. On Days 1, 30, 240, and 360 post-exposure, rat hearts were collected and total RNA was extracted from the left ventricle for global gene expression analysis. The data revealed differentially-expressed genes (DEG) in response to ISO (compared to naÃ¯ve control) at all post-exposure timepoints. The data showed acute ISO exposures led to DEG associated with wounding, local immune function, inflammation, and circadian rhythm regulation at Days 1 and 30; these effects dissipated by Day 240. There were other significantly-increased DEG induced by ISO at Day 360; these included changes in expression of genes associated with cell signaling, differentiation, and migration, extracellular matrix organization, cell-substrate adhesion, heart development, and blood pressure regulation. Examination of consistent DEG at Days 240 and 360 indicated late onset DEG reflecting potential long-lasting effects from ISO; these included DEG associated with oxidative phosphorylation, ribosome, angiogenesis, mitochondrial translation elongation, and focal adhesion. Together, the data show acute repeated ISO exposures could impart variable effects on gene expression/regulation in the heart. While some alterations self-resolved, others appeared to be long-lasting or late onset. Whether such changes occur in all rat models or in humans remains to be investigated.
Polyadenylation of Histone H3.1 mRNA Promotes Cell Transformation by Displacing H3.3 from Gene Regulatory Elements
Chen, Danqi; Chen, Qiao Yi; Wang, Zhenjia; Zhu, Yusha; Kluz, Thomas; Tan, Wuwei; Li, Jinquan; Wu, Feng; Fang, Lei; Zhang, Xiaoru; He, Rongquan; Shen, Steven; Sun, Hong; Zang, Chongzhi; Jin, Chunyuan; Costa, Max
Replication-dependent canonical histone messenger RNAs (mRNAs) do not terminate with a poly(A) tail at the 3' end. We previously demonstrated that exposure to arsenic, an environmental carcinogen, induces polyadenylation of canonical histone H3.1 mRNA, causing transformation of human cells inÂ vitro. Here we report that polyadenylation of H3.1 mRNA increases H3.1 protein, resulting in displacement of histone variant H3.3 at active promoters, enhancers, and insulator regions, leading to transcriptional deregulation, G2/M cell-cycle arrest, chromosome aneuploidy, and aberrations. In support of these observations, knocking down the expression of H3.3 induced cell transformation, whereas ectopic expression of H3.3 attenuated arsenic-induced cell transformation. Notably, arsenic exposure also resulted in displacement of H3.3 from active promoters, enhancers, and insulator regions. These data suggest that H3.3 displacement might be central to carcinogenesis caused by polyadenylation of H3.1 mRNA upon arsenic exposure. Our findings illustrate the importance of proper histone stoichiometry in maintaining genome integrity.