Browsing by Author "Qin, Li"

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    14-3-3σ regulation of and interaction with YAP1 in acquired gemcitabine resistance via promoting ribonucleotide reductase expression
    (Impact Journals, LLC, 2016-04-05) Qin, Li; Dong, Zizheng; Zhang, Jian-Ting; Department of Pharmacology and Toxicology, IU School of Medicine
    Gemcitabine is an important anticancer therapeutics approved for treatment of several human cancers including locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Its clinical effectiveness, however, is hindered by existence of intrinsic and development of acquired resistances. Previously, it was found that 14-3-3σ expression associates with poor clinical outcome of PDAC patients. It was also found that 14-3-3σ expression is up-regulated in gemcitabine resistant PDAC cells and contributes to the acquired gemcitabine resistance. In this study, we investigated the molecular mechanism of 14-3-3σ function in gemcitabine resistance and found that 14-3-3σ up-regulates YAP1 expression and then binds to YAP1 to inhibit gemcitabine-induced caspase 8 activation and apoptosis. 14-3-3σ association with YAP1 up-regulates the expression of ribonucleotide reductase M1 and M2, which may mediate 14-3-3σ/YAP1 function in the acquired gemcitabine resistance. These findings suggest a possible role of YAP1 signaling in gemcitabine resistance.
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    The Association between Nocturnal Cardiac Arrhythmias and Sleep-Disordered Breathing: The DREAM Study
    (American Academy of Sleep Medicine, 2016-06-15) Selim, Bernardo J.; Koo, Brian B.; Qin, Li; Jeon, Sangchoon; Won, Christine; Redeker, Nancy S.; Lampert, Rachel J.; Concato, John P.; Bravata, Dawn M.; Ferguson, Jared; Strohl, Kingman; Bennett, Adam; Zinchuk, Andrey; Yaggi, Henry K.; Department of Medicine, IU School of Medicine
    STUDY OBJECTIVES: To determine whether sleep-disordered breathing (SDB) is associated with cardiac arrhythmia in a clinic-based population with multiple cardiovascular comorbidities and severe SDB. METHODS: This was a cross-sectional analysis of 697 veterans who underwent polysomnography for suspected SDB. SDB was categorized according to the apnea-hypopnea index (AHI): none (AHI < 5), mild (5 ≥ AHI < 15), and moderate-severe (AHI ≥ 15). Nocturnal cardiac arrhythmias consisted of: (1) complex ventricular ectopy, (CVE: non-sustained ventricular tachycardia, bigeminy, trigeminy, or quadrigeminy), (2) combined supraventricular tachycardia, (CST: atrial fibrillation or supraventricular tachycardia), (3) intraventricular conduction delay (ICD), (4) tachyarrhythmias (ventricular and supraventricular), and (5) any cardiac arrhythmia. Unadjusted, adjusted logistic regression, and Cochran-Armitage testing examined the association between SDB and cardiac arrhythmias. Linear regression models explored the association between hypoxia, arousals, and cardiac arrhythmias. RESULTS: Compared to those without SDB, patients with moderate-severe SDB had almost three-fold unadjusted odds of any cardiac arrhythmia (2.94; CI 95%, 2.01-4.30; p < 0.0001), two-fold odds of tachyarrhythmias (2.16; CI 95%,1.47-3.18; p = 0.0011), two-fold odds of CVE (2.01; 1.36-2.96; p = 0.003), and two-fold odds of ICD (2.50; 1.58-3.95; p = 0.001). A linear trend was identified between SDB severity and all cardiac arrhythmia subtypes (p value linear trend < 0.0001). After adjusting for age, BMI, gender, and cardiovascular diseases, moderate-severe SDB patients had twice the odds of having nocturnal cardiac arrhythmias (2.24; 1.48-3.39; p = 0.004). Frequency of obstructive respiratory events and hypoxia were strong predictors of arrhythmia risk. CONCLUSIONS: SDB is independently associated with nocturnal cardiac arrhythmias. Increasing severity of SDB was associated with an increasing risk for any cardiac arrhythmia.
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    Determinants of 14-3-3σ dimerization and function in drug and radiation resistance
    (2013-11) Li, Zhaomin; Peng, Hui; Qin, Li; Qi, Jing; Zuo, Xiaobing; Liu, Jing-Yuan; Zhang, Jian-Ting; Department of Pharmacology and Toxicology, IU School of Medicine
    Many proteins exist and function as homodimers. Understanding the detailed mechanism driving the homodimerization is important and will impact future studies targeting the “undruggable” oncogenic protein dimers. In this study, we used 14-3-3σ as a model homodimeric protein and performed a systematic investigation of the potential roles of amino acid residues in the interface for homodimerization. Unlike other members of the conserved 14-3-3 protein family, 14-3-3σ prefers to form a homodimer with two subareas in the dimeric interface that has 180° symmetry. We found that both subareas of the dimeric interface are required to maintain full dimerization activity. Although the interfacial hydrophobic core residues Leu12 and Tyr84 play important roles in 14-3-3σ dimerization, the non-core residue Phe25 appears to be more important in controlling 14-3-3σ dimerization activity. Interestingly, a similar non-core residue (Val81) is less important than Phe25 in contributing to 14-3-3σ dimerization. Furthermore, dissociating dimeric 14-3-3σ into monomers by mutating the Leu12, Phe25, or Tyr84 dimerization residue individually diminished the function of 14-3-3σ in resisting drug-induced apoptosis and in arresting cells at G2/M phase in response to DNA-damaging treatment. Thus, dimerization appears to be required for the function of 14-3-3σ.
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    The Determining Risk of Vascular Events by Apnea Monitoring (DREAM) Study: Design, Rationale and Methods
    (Springer, 2016-05) Koo, Brian B.; Won, Christine; Selim, Bernardo J.; Qin, Li; Jeon, Sangchoon; Redeker, Nancy S.; Bravata, Dawn M.; Strohl, Kingman P.; Concato, John; Yaggi, Henry K.; Department of Neurology, IU School of Medicine
    Purpose The goal of the Determining Risk of Vascular Events by Apnea Monitoring (DREAM) study is to develop a prognostic model for cardiovascular outcomes, based on physiologic variables—related to breathing, sleep architecture, and oxygenation—measured during polysomnography in US veterans. Methods The DREAM study is a multi-site, retrospective observational cohort study conducted at three Veterans Affairs (VA) centers (West Haven, CT; Indianapolis, IN; Cleveland, OH). Veterans undergoing polysomnography between January 1, 2000 and December 31, 2004 were included based on referral for evaluation of sleep-disordered breathing, documented history and physical prior to sleep testing, and ≥2-h sleep monitoring. Demographic, anthropomorphic, medical, medication, and social history factors were recorded. Measures to determine sleep apnea, sleep architecture, and oxygenation were recorded from polysomnography. VA Patient Treatment File, VA–Medicare Data, Vista Computerized Patient Record System, and VA Vital Status File were reviewed on dates subsequent to polysomnography, ranging from 0.06 to 8.8 years (5.5 ± 1.3 years; mean ± SD). Results The study population includes 1840 predominantly male, middle-aged veterans. As designed, the main primary outcome is the composite endpoint of acute coronary syndrome, stroke, transient ischemic attack, or death. Secondary outcomes include incidents of neoplasm, congestive heart failure, cardiac arrhythmia, diabetes, depression, and post-traumatic stress disorder. Laboratory outcomes include measures of glycemic control, cholesterol, and kidney function. (Actual results are pending.) Conclusions This manuscript provides the rationale for the inclusion of veterans in a study to determine the association between physiologic sleep measures and cardiovascular outcomes and specifically the development of a corresponding outcome-based prognostic model.
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    Development, Validation, and Assessment of an Ischemic Stroke or Transient Ischemic Attack-Specific Prediction Tool for Obstructive Sleep Apnea
    (Elsevier, 2017-08) Sico, Jason J.; Yaggi, H. Klar; Ofner, Susan; Concato, John; Austin, Charles; Ferguson, Jared; Qin, Li; Tobias, Lauren; Taylor, Stanley; Vaz Fragoso, Carlos A.; McLain, Vincent; Williams, Linda S.; Bravata, Dawn M.; Biostatistics, School of Public Health
    BACKGROUND: Screening instruments for obstructive sleep apnea (OSA), as used routinely to guide clinicians regarding patient referral for polysomnography (PSG), rely heavily on symptomatology. We sought to develop and validate a cerebrovascular disease-specific OSA prediction model less reliant on symptomatology, and to compare its performance with commonly used screening instruments within a population with ischemic stroke or transient ischemic attack (TIA). METHODS: Using data on demographic factors, anthropometric measurements, medical history, stroke severity, sleep questionnaires, and PSG from 2 independently derived, multisite, randomized trials that enrolled patients with stroke or TIA, we developed and validated a model to predict the presence of OSA (i.e., Apnea-Hypopnea Index ≥5 events per hour). Model performance was compared with that of the Berlin Questionnaire, Epworth Sleepiness Scale (ESS), the Snoring, Tiredness, Observed apnea, high blood Pressure, Body mass index, Age, Neck circumference, and Gender instrument, and the Sleep Apnea Clinical Score. RESULTS: The new SLEEP Inventory (Sex, Left heart failure, ESS, Enlarged neck, weight [in Pounds], Insulin resistance/diabetes, and National Institutes of Health Stroke Scale) performed modestly better than other instruments in identifying patients with OSA, showing reasonable discrimination in the development (c-statistic .732) and validation (c-statistic .731) study populations, and having the highest negative predictive value of all in struments. CONCLUSIONS: Clinicians should be aware of these limitations in OSA screening instruments when making decisions about referral for PSG. The high negative predictive value of the SLEEP INventory may be useful in determining and prioritizing patients with stroke or TIA least in need of overnight PSG.
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    Diagnosing and Treating Sleep Apnea in Patients With Acute Cerebrovascular Disease
    (American Heart Association, 2018-08-21) Bravata, Dawn M.; Sico, Jason; Vaz Fragoso, Carlos A.; Miech, Edward J.; Matthias, Marianne S.; Lampert, Rachel; Williams, Linda S.; Concato, John; Ivan, Cristina S.; Fleck, J.D.; Tobias, Lauren; Austin, Charles; Ferguson, Jared; Radulescu, Radu; Iannone, Lynne; Ofner, Susan; Taylor, Stanley; Qin, Li; Won, Christine; Yaggi, H. Klar; Medicine, School of Medicine
    Background Obstructive sleep apnea ( OSA ) is common among patients with acute ischemic stroke and transient ischemic attack. We evaluated whether continuous positive airway pressure for OSA among patients with recent ischemic stroke or transient ischemic attack improved clinical outcomes. Methods and Results This randomized controlled trial among patients with ischemic stroke/transient ischemic attack compared 2 strategies (standard or enhanced) for the diagnosis and treatment of OSA versus usual care over 1 year. Primary outcomes were National Institutes of Health Stroke Scale and modified Rankin Scale scores. Among 252 patients (84, control; 86, standard; 82, enhanced), OSA prevalence was as follows: control, 69%; standard, 74%; and enhanced, 80%. Continuous positive airway pressure use occurred on average 50% of nights and was similar among standard (3.9±2.1 mean hours/nights used) and enhanced (4.3±2.4 hours/nights used; P=0.46) patients. In intention-to-treat analyses, changes in National Institutes of Health Stroke Scale and modified Rankin Scale scores were similar across groups. In as-treated analyses among patients with OSA, increasing continuous positive airway pressure use was associated with improved National Institutes of Health Stroke Scale score (no/poor, -0.6±2.9; some, -0.9±1.4; good, -0.3±1.0; P=0.0064) and improved modified Rankin Scale score (no/poor, -0.3±1.5; some, -0.4±1.0; good, -0.9±1.2; P=0.0237). In shift analyses among patients with OSA, 59% of intervention patients had best neurological symptom severity (National Institutes of Health Stroke Scale score, 0-1) versus 38% of controls ( P=0.038); absolute risk reduction was 21% (number needed to treat, 4.8). Conclusions Although changes in neurological functioning and functional status were similar across the groups in the intention-to-treat analyses, continuous positive airway pressure use was associated with improved neurological functioning among patients with acute ischemic stroke/transient ischemic attack with OSA
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    Infarct Location and Sleep Apnea: Evaluating the Potential Association in Acute Ischemic Stroke.
    (Elsevier, 2015-10) Stahl, Stephanie M.; Yaggi, H. Klar; Taylor, Stanley; Qin, Li; Ivan, Cristina S.; Austin, Charles; Ferguson, Jared; Radulescu, Radu; Tobias, Lauren; Sico, Jason; Vaz Fragoso, Carlos A.; Williams, Linda S.; Lampert, Rachel; Miech, Edward J.; Matthias, Marianne S.; Kapoor, John; Bravata, Dawn M.; Department of Neurology, IU School of Medicine
    Background: The literature about the relationship between obstructive sleep apnea (OSA) and stroke location is conflicting with some studies finding an association and others demonstrating no relationship. Among acute ischemic stroke patients, we sought to examine the relationship between stroke location and the prevalence of OSA; OSA severity based on apnea-hypopnea index (AHI), arousal frequency, and measure of hypoxia; and number of central and obstructive respiratory events. Methods: Data were obtained from patients who participated in a randomized controlled trial (NCT01446913) that evaluated the effectiveness of a strategy of diagnosing and treating OSA among patients with acute ischemic stroke and transient ischemic attack. Stroke location was classified by brain imaging reports into subdivisions of lobes, subcortical areas, brainstem, cerebellum, and vascular territory. The association between acute stroke location and polysomnographic findings was evaluated using logistic regression for OSA presence and negative binomial regression for AHI. Results: Among 73 patients with complete polysomnography and stroke location data, 58 (79%) had OSA. In unadjusted models, no stroke location variable was associated with the prevalence or severity of OSA. Similarly, in multivariable modeling, groupings of stroke location were also not associated with OSA presence. Conclusions: These results indicate that OSA is present in the majority of stroke patients and imply that stroke location cannot be used to identify a group with higher risk of OSA. The results also suggest that OSA likely predated the stroke. Given this high overall prevalence, strong consideration should be given to obtaining polysomnography for all ischemic stroke patients.
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    Molecular mechanisms of acquired gemcitabine resistance in pancreatic cancer
    (2014-11) Qin, Li; Zhang, Jian-Ting
    Most pancreatic cancer patients receiving gemcitabine chemotherapy eventually develop resistance to gemcitabine. To improve survival and prognosis of pancreatic cancer patients, better understanding the mechanisms of gemcitabine resistance and discovery of new therapeutic targets are required. In this study, I investigated the molecular mechanisms of acquired gemcitabine resistance using a stepwise gemcitabine-selected pancreatic cancer cell line in comparison to the parental cell line. I found that 14-3-3σ is up-regulated in the drug resistant cell line due to demethylation in its first exon, and the up-regulation of 14-3-3σ gene expression, in turn, contributes to gemcitabine resistance. Intriguingly, I found that demethylation of the 14-3-3σ gene in gemcitabine resistant cells is reversibly regulated by DNMT1 and UHRF1. Furthermore, I found that 14-3-3σ over-expression causes gemcitabine resistance by inhibiting gemcitabine-induced apoptosis and caspase-8 activation possibly via binding to YAP1. The finding of demethylation of the 14-3-3σ gene in gemcitabine resistant cells led to a hypothesis that other genes may also be changed epigenetically following gemcitabine selection. By RRBS (Reduced Representation Bisulfite Sequencing) analysis, 845 genes were found to have altered methylation. One of these genes, PDGFD, was further investigated and found to have reversible demethylation at its promoter region in the drug resistant cells and contribute to gemcitabine resistance possibly via autocrine activation of the STAT3 signaling pathway. Together, these findings not only provide evidence that 14-3-3σ and PDGFD over-expression contribute to acquired gemcitabine resistance and that reversible epigenetic changes may play an important role in acquired gemcitabine resistance, but also demonstrate that the molecular mechanisms of acquired gemcitabine resistance in pancreatic cancer cells are complex and multifaceted.
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    Polysomnographic Phenotypes of Obstructive Sleep Apnea and Incident Type 2 Diabetes: Results from the DREAM Study
    (American Thoracic Society, 2021) Ding, Qinglan; Qin, Li; Wojeck, Brian; Inzucchi, Silvio E.; Ibrahim, Ahmad; Bravata, Dawn M.; Strohl, Kingman P.; Yaggi, Henry K.; Zinchuk, Andrey V.; Medicine, School of Medicine
    Rationale: Obstructive sleep apnea (OSA) is associated with cardiovascular disease and incident type 2 diabetes (T2DM). Seven OSA phenotypes, labeled on the basis of their most distinguishing polysomnographic features, have been shown to be differentially associated with incident cardiovascular disease. However, little is known about the relevance of polysomnographic phenotypes for the risk of T2DM. Objectives: To assess whether polysomnographic phenotypes are associated with incident T2DM and to compare the predictive value of baseline polysomnographic phenotypes with the Apnea-Hypopnea Index (AHI) for T2DM. Methods: The study included 840 individuals without baseline diabetes from a multisite observational U.S. veteran cohort who underwent OSA evaluation between 2000 and 2004, with follow-up through 2012. The primary outcome was incident T2DM, defined as no diagnosis at baseline and a new physician diagnosis confirmed by fasting blood glucose >126 mg/dL during follow-up. Relationships between the seven polysomnographic phenotypes (1. mild, 2. periodic limb movements of sleep [PLMS], 3. non-rapid eye movement and poor sleep, 4. rapid eye movement and hypoxia, 5. hypopnea and hypoxia, 6. arousal and poor sleep, and 7. combined severe) and incident T2DM were investigated using Cox proportional hazards regression and competing risk regression models with and without adjustment for baseline covariates. Likelihood ratio tests were conducted to compare the predictive value of the phenotypes with the AHI. Results: During a median follow-up period of 61 months, 122 (14.5%) patients developed incident T2DM. After adjustment for baseline sociodemographics, fasting blood glucose, body mass index, comorbidities, and behavioral risk factors, hazard ratios among persons with "hypopnea and hypoxia" and "PLMS" phenotypes as compared with persons with "mild" phenotype were 3.18 (95% confidence interval [CI], 1.53-6.61] and 2.26 (95% CI, 1.06-4.83) for incident T2DM, respectively. Mild OSA (5 ⩽ AHI < 15) (vs. no OSA) was directly associated with incident T2DM in both unadjusted and multivariable-adjusted regression models. The addition of polysomnographic phenotypes, but not AHI, to known T2DM risk factors greatly improved the predictive value of the computed prediction model. Conclusions: Polysomnographic phenotypes "hypopnea and hypoxia" and "PLMS" independently predict risk of T2DM among a predominantly male veteran population. Polysomnographic phenotypes improved T2DM risk prediction comared with the use of AHI.
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    Reversible epigenetic regulation of 14-3-3σ expression in acquired gemcitabine resistance by uhrf1 and DNA methyltransferase 1
    (American Society for Pharmacology & Experimental Therapeutics (ASPET), 2014-11) Qin, Li; Dong, Zizheng; Zhang, Jian-Ting; Department of Pharmacology and Toxicology, IU School of Medicine
    Although gemcitabine is the most commonly used drug for treating pancreatic cancers, acquired gemcitabine resistance in a substantial number of patients appears to hinder its effectiveness in successful treatment of this dreadful disease. To understand acquired gemcitabine resistance, we generated a gemcitabine-resistant pancreatic cancer cell line using stepwise selection and found that, in addition to the known mechanisms of upregulated expression of ribonucleotide reductase, 14-3-3σ expression is dramatically upregulated, and that 14-3-3σ overexpression contributes to the acquired resistance to gemcitabine and cross-resistance to cytarabine. We also found that the increased 14-3-3σ expression in the gemcitabine-resistant cells is due to demethylation of the 14-3-3σ gene during gemcitabine selection, which could be partially reversed with removal of the gemcitabine selection pressure. Most importantly, the reversible methylation/demethylation of the 14-3-3σ gene appears to be carried out by DNA methyltransferase 1 under regulation by Uhrf1. These findings suggest that the epigenetic regulation of gene expression may play an important role in gemcitabine resistance, and that epigenetic modification is reversible in response to gemcitabine treatment.