tbuckley/cabot-search huggingface dataset:
CTNI-49. PHASE 1 STUDY OF ST101, A FIRST-IN-CLASS PEPTIDE ANTAGONIST OF CCAAT/ENHANCER-BINDING PROTEIN ß, IN PATIENTS WITH ADVANCED SOLID TUMORS, WITH A PHASE 2 EXPANSION IN RECURRENT GLIOBLASTOMA MULTIFORME
Authors: Stefan Symeonides, Jeff Evans, Hendrik-Tobias Arkenau, Meredith McKean, Nehal Lakhani, Emerson Lim, Gerald Falchook, Jim Rotolo, Gina Capiaux, Rob Michel, Stephen Kaesshaefer, Alice Bexon
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND C/EBPβ is a transcription factor that is active during embryofetal development but held in an inactive state in most mature cells (Zahnow 2009). C/EBPβ is upregulated or overactivated in multiple cancers, where it inversely correlates with disease prognosis and survival due to activation of a gene signature that promotes tumor cell proliferation and survival. ST101 is a cell-penetrating peptide antagonist of C/EBPβ. ST101 exposure leads to selective tumor cell death in multiple human cancer cell lines, including GBM, without impacting normal cell viability. In vivo, ST101 displays rapid uptake into multiple organs, the ability to cross the blood-brain barrier, and a long plasma half-life due to its resistance to degradations. It has potent anti-tumor activity in multiple GBM models, as a single agent or in combination, which supported moving into clinical development. TRIAL DESIGN This phase 1-2 study is enrolling patients ≥ 18 years of age with advanced, unresectable metastatic solid tumors refractory to or intolerant of other therapeutic options. We began recruitment in August 2020. The primary objective of phase 1 is to evaluate safety and tolerability of ST101. Secondary objectives include the recommendation of a dose and regimen of ST101 for further evaluation, pharmacokinetics, several pharmacodynamic measures, and preliminary efficacy. Patients receive intravenous ST101 once weekly in a standard 3 + 3 design. Enrollment is ongoing, and by 21 May 2021, 15 patients have been recruited in four dose-escalation cohorts up to 4 mg/kg; a 5th cohort (6 mg/kg) is ongoing. The recommended phase 2 dose will be used in a 15-30 patient GBM expansion cohort, with a Simon 2-stage design, which requires one response or two patients with PFS6 in the first cohort to continue the study. Up to 120 patients are planned in a total of four expansion cohorts, which should be enrolling by Q3 2021.
NCOG-48. LONGITUDINAL ASSESSMENT OF SUBJECTIVE COGNITIVE FUNCTION IN A BRAIN TUMOR SAMPLE: IMPROVED CORRESPONDENCE WITH NEUROPSYCHOLOGICAL PERFORMANCE OVER TIME
Authors: Melissa Gardner, Giuliana Zarrella, Jorg Dietrich, Michael Parsons
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Estimates of subjective cognitive function (SCF) generally show minimal correlation with objective measures of neurocognitive function (NCF). Our group recently validated a new metric of SCF in neuro-oncology patients, creating the Cognitive Index of the Functional Assessment of Cancer Therapy-Brain (FACT-Br-CI). This study examines whether brain tumor (BT) patients evaluated on more than one occasion show improved relationship between SCF and NCF. We hypothesized that change scores in SCF and NCF across evaluation would be more highly correlated than SCF and NCF at either timepoint. METHODS A retrospective study of BT patients who completed two neuropsychological evaluations (baseline, follow-up) was conducted. NCF was measured by the clinical trial battery composite (CTBC), a mean of 6 commonly used neuropsychological test scores. SCF was measured by the FACT-Br-CI. Mood/Anxiety were measured by the Beck scales (BAI/BDI-II). Change over time on each metric was evaluated with paired t-test. Correlational analyses evaluated relationships between NCF, SCF, and mood within and between time points. RESULTS Twenty-nine patients (16 female; mean age=54.6y; mean education=15.5y) completed all CTBC measures and FACT-Br-CI, 28 of whom completed and BDI and/or BAI. On group analyses, there were no significant differences between baseline and follow-up on CTBC (t=-.53;p=ns) or FACT-Br-CI (t=-.98;p=ns). Correlations between CTBC and FACT-Br-CI were nonsignificant at baseline (r=.24;p=ns), but significant at follow-up (r=.56;p=0.002). Change scores over time were unrelated (r=-.104;p=ns). Similar to previous studies, the FACT-BR-CI correlated with the BDI-II at baseline (r=-.38;p=0.04) and follow-up (r=-.59;p&amp;lt; 0.001) and with the BAI at follow-up (r=-.44;p=0.02). CONCLUSION In this small group of brain tumor patients seen for repeated neuropsychological evaluations, we found that agreement between SCF and NCF was much higher on their second than initial evaluation. These findings suggest that patients may develop enhanced awareness of their cognitive function from an initial evaluation that persists over time.
Abstract 14053: Sumoylation of the Cardiac Sodium Channel Na <sub>V</sub> 1.5 Does Not Increase Late Sodium Current
Authors: Jin-young Yoon, Alexander Greiner, Julia Jacobs, William J Kutschke, Young-Rae Kim, Daniel S Matasic, Haider Mehdi, Kaikobad J Irani, Barry London
Journal: Circulation (2021)

Introduction: The sodium current (I Na ) controlling cardiac cell excitability is conducted via the Na + channel Na V 1.5 (encoded by SCN5A ). Dysregulation of Na V 1.5 has been implicated in arrhythmia, with increased late Na V 1.5 current (I Na,L ) causing long QT type 3. Many Na V 1.5 post-translational modifications have been reported by us and others, including SUMOylation, the addition of a Small Ubiquitin-like MOdifier (SUMO) at K442-Na V 1.5. Plant et al. (2020) recently reported that hypoxia increases I Na,L by increased Na V 1.5 SUMOylation. Hypothesis: SUMOylation modifies peak but not late Na V 1.5 currents through membrane localization. Methods: SUMOylation of Na V 1.5 by SUMO1 was detected by immunoprecipitation and immunoblot. The effects of SUMOylation on peak I Na and I Na,L were measured using patch clamp in HEK293 cells transfected with wild type (WT) or mutant K442R-Na V 1.5 with/without the β1 subunit and in neonatal rat cardiac myocytes (NRCMs). Tetrodotoxin (TTX) was used to quantitate I Na,L in NRCMs. Na V 1.5 trafficking was detected by immunofluorescence. Results: Na V 1.5 was SUMOylated by SUMO1 in HEK cells, NRCMs, and human heart samples. Overexpressing or directly applying SUMO1 induced hyperSUMOylation of Na V 1.5 at K442 and increased the amplitude of peak I Na in NRCMs and in HEK cells overexpressing WT but not K442R-Na v 1.5. SUMOylation did not affect I Na,L in HEK293 cells expressing Na V 1.5 with/without the β1 subunit or in NRCMs (Fig. 1A, B). SUMO1 enhanced membrane localization of Na V 1.5 in HEK293 cells (Fig. 1C) with minimal changes to steady state activation, inactivation or channel kinetics. Conclusion: SUMOylation of Na v 1.5 at K442 increases peak I Na without changing I Na,L , at least in part by altering membrane abundance. Our findings do not support SUMOylation as a mechanism for changes in I Na,L .
Poly(ADP-ribose)polymerase-1 regulates activation of AP-1 by DNA damage
Authors: Irina A. Lonskaya, Viatcheslav Soldatenkov
Journal: Cancer Research (2006)

808  PARP-1 catalytic activity is stimulated by variety of genotoxic agents and ionizing radiation. Accordingly, PARP-1 has been regarded as a component of cellular responses to genotoxic stress, albeit its function was attributed exclusively to DNA damage repair. Recent studies, including data from our laboratory (1-3), have also implicated PARP-1 in the regulation of physiological gene expression and in transcriptional response to various pathophysiological stimuli (reviewed in Soldatenkov and Potaman, Current Drug Targets, 2004). Here we investigated the PARP-1 function in the activation of nuclear transcription factors, such as activator protein-1 (AP-1), which participates in adaptive responses of genome to various oxidant and toxic stimuli. In PARP-1 expressing cells radiation-induced DNA damage resulted in strong stimulation of the PARP-1 catalytic activity which was abrogated by pre-treatment of cells with the EB-47 or DPQ, specific and potent inhibitors of the reaction of poly(ADP-ribosyl)ation. We found that although PARP-1 (+/+) cells were capable of responding to genotoxic insult by activating the AP-1 pathway, PARP-1 deficient cells evidently lose their ability to activate AP-1 in response to DNA damage. Genetic inhibition of PARP-1 resulted in delayed activation of Jun B, Jun D and c-Jun, and dramatically diminished DNA-binding activity of Fos family proteins. Furthermore, using a real-time PCR we show that PARP-1 proficient cells exposed to DNA-damaging treatment exhibit early and marked induction of the AP-1 components, and that stimulation of AP-1 expression by DNA damage was dramatically attenuated in cells with PARP-1 null genetic background. Reduced activation of AP-1 transcription factors as part of faulty induction of stress-inducible cytoprotective genes may provide an explanation for enhanced susceptibility of PARP-1 deficient cells to genotoxic stimuli. This work was supported in part by grant CA74175 from the National Cancer Institute. (1) J. Biol. Chem. 2002, 277: 665; (2) J. Biol. Chem. 2005, 280: 17076; (3) J. Mol. Biol. 2005, 348: 609.
Abstract 13470: Update on Lipid Profiles and Lipid Modifying Therapies in Heart Transplant Recipients, a Single Center Experience
Authors: Lin Cao, Kelly Schlendorf, Sandip Zalawadiya, Shi Huang, Frank Harrell, Joann Lindenfeld, Wen-Liang Song
Journal: Circulation (2021)

Introduction: Statin use after heart transplant (HT) has been shown to reduce rates of CAV and improve morbidity and mortality regardless of lipid profile. However, drug-drug interactions (DDIs) between statins and immunosuppressive therapies limit their use, particularly at higher doses. Recently, non-statin lipid modifying therapies have also been used in the HT population, despite a lack of outcome trials. Objective: We sought to examine current trends in lipid profiles and lipid-lowering therapy use in the HT population. Methods: We performed a retrospective chart review of 198 HT recipients (average age 53.6 years, 139 males, 59 females) transplanted between 4/8/2016 and 3/24/2020 at a single center. Of those patients, 82 underwent HT for ischemic cardiomyopathy (ICM), and 116 underwent HT for nonischemic cardiomyopathy (NICM). Lipid panels and medications were collected pre-transplant, immediately post-transplant, and 1-year post-transplant. Most recent values were also collected. At each point the 2018 lipid guidelines were used to determine the recommended intensity of statin each patient should ideally be on if they were not transplant patients. Results: Median cholesterol, triglyceride, HDL, and LDL values were reasonably well-controlled post HT. Despite high overall rates of statin use, our data suggest that most HT recipients are on lower than guideline-recommended statin doses due to DDI, particularly in the ICM group. The proportion of patients on non-statin lipid modifying therapies increased over time. Conclusions: There is emerging evidence that non-statin therapies added to statins can further reduce atherothrombotic events in non-transplant patients. These therapies may offer options for additional lipid control in transplant recipients whose statin use is limited by DDIs. However, the pathophysiology of CAV and atherosclerosis are different, and outcome trials of non-statin lipid therapies in HT patients are urgently needed.
Abstract 10737: The Impact of Diabetes on Percutaneous Coronary Intervention Outcomes in STEMI Patients: The Asia-Pacific Evaluation of Cardiovascular Therapies (ASPECT) Collaboration
Authors: Mark Y Wong, Jonathan J Yap, Hui Jun Chih, Angela L Brennan, Bryan P Yan, Alan Fong, John F Beltrame, Ika P Wijaya, Hoai Nguyen, Christopher Reid, Khung Keong K Yeo
Journal: Circulation (2021)

Introduction: Diabetes is associated with poorer outcomes and increased complication rates in STEMI patients undergoing percutaneous coronary intervention (PCI). Regional variations have been described but data are notably lacking in the Asia-Pacific region. Aims: We report the associations of diabetes with clinical characteristics and outcomes in STEMI patients undergoing PCI across the Asia-Pacific. Methods: The Asia Pacific Evaluation of Cardiovascular Therapies (ASPECT) collaboration consists of data from the registries of contributing PCI centres across Australia, Hong Kong, Singapore, Malaysia, Indonesia and Vietnam. Clinical characteristics, lesion characteristics, and outcomes were provided for STEMI patients. Key outcomes included overall mortality at 30 days, and major adverse cardiovascular events (MACE; defined as peri-procedural myocardial infarctions, emergency CABG, stent thrombosis, target vessel revascularisation, cerebrovascular events, or death) at 30 days. Results: A total of 12,144 STEMI patients (mean(SD) age 59.3(12.3)) were included, of which 3912 (32.2%) had diabetes. Patients with diabetes were likely to be older, have a history of cardiovascular disease and previous acute coronary events (all p&lt;0.05). They were also more likely to present with out-of-hospital cardiac arrest, require mechanical ventricular support and have lower estimated ejection fractions (all p&lt;0.05). With regards to lesion characteristics, diabetic patients had a higher rate of multi-vessel disease, type C ACC-AHA lesions and diffuse lesions &gt;20mm (all p&lt;0.05). After adjustment for demographics, clinical presentation, lesion characteristics and procedural factors, diabetes was significantly associated with increased 30 day mortality (9.6%vs 5.5%, OR 1.70 (95% CI 1.33-2.18)) and 30-day MACE rates (13.3% vs 8.6%, OR 1.68 (95% CI 1.4-2.02)). Further analyses investigated inter-regional variations in this association. Conclusions: Diabetes portends poorer clinical outcomes in STEMI patients undergoing PCI in the Asia-Pacific. The development of effective preventative measures and interventional strategies targeted at this high-risk group is crucial.
Increasing Incidence of Pediatric <i>Clostridioides difficile </i>Colonization—More Exploration Is Needed
Authors: Minjing Luo, Yutong Fei
Journal: JAMA Pediatrics (2021)

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Abstract 13840: Trends in Incidence and Long-Term Prognosis of Acute Kidney Disease Following Coronary Angiography in Chinese Cohort With 9,665 Patients From 2008 to 2017: An Observational Study
Authors: Qiang Li, Jin Liu, Haozhang Huang, Weihua Chen, Shanshan Shi, Yong Liu
Journal: Circulation (2021)

Introduction: Acute Kidney Disease (AKD) is a disease that recently received close attention and was found prone to a poor prognosis. However, few studies have explored the trends of the incidence and prognosis of AKD over the last decade. Methods: This retrospective cohort study collected data from 9,665 patients who underwent CAG. Their preoperative and postoperative serum creatinine (Scr) values within 7-90 day were analyzed for the period of January 2008 to December 2017. Univariate and multivariate logistic regression analyses were used to estimate the odds ratio of AKD between 2008 and 2017. Survival data were evaluated using univariate and multivariate Cox regression analyses. Results: The research team analyzed a total of 9,665 patients in Guangdong Provincial People’s hospital, with an average age of 61.6±9.6 years and 40.1% (3,876) females. The overall incidence of AKD in that decade was 18.8%, and the overall mortality rate was 323.0 per 1,000 person-years. Compared with 2008, the incidence of AKD in 2017 decreased from 25.1% to 12.8% (Adjusted odds ratios [a OR], 0.40, 95%CI, 0.31-0.51, P-value &lt;0.01, P for trend &lt;0.01). On the contrary, 323.0‰ AKD patients died in total, significantly increased from 138.2 to 544.1 per 1,000 person-years in 2008 (Adjusted hazard ratio [a HR], 2.85; 95%CI, 1.20-6.73; P-value =0.02, P for trend=0.02). These findings were consistent across different gender and age groups. Conclusions: From 2008 to 2017, the incidence of AKD decreased significantly, while AKD associated mortality showed a notably increased trend. Our findings support more active measures to prevent AKD and improve the prognosis of AKD patients
Abstract 11152: Peripheral Artery Disease and 30-Year Risk of Kidney Outcomes in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Amy Paskiewicz, Frances M Wang, Junichi Ishigami, Yuanjie Pang, Yingying Sang, Shoshana Ballew, Morgan Grams, Gerardo M HEISS, Josef Coresh, Kuni Matsushita
Journal: Circulation (2021)

Introduction: Peripheral artery disease (PAD) increases the risk of various adverse outcomes such as other cardiovascular diseases, lower-extremity amputation, and infection. However, its impact on kidney outcomes is yet to be characterized. Hypothesis: Both symptomatic and asymptomatic PAD will be associated with kidney outcomes. Methods: Using data from the ARIC study (1987-1989), we categorized 13,864 participants with estimated glomerular filtration rate (eGFR) &gt;15 mL/min (mean age 54 [SD 6 years]) into symptomatic PAD (clinical history or intermittent claudication); asymptomatic PAD (ankle-brachial index [ABI] ≤0.90 but not symptomatic PAD); and ABI categories of 0.91-1.00, 1.01-1.10, 1.11-1.20 (reference), 1.21-1.30, and &gt;1.30. Incident end-stage kidney disease (ESKD) was defined by the need for renal replacement therapy or death due to chronic kidney disease (CKD), and incident CKD was defined by ≥25% decline in eGFR to &lt;60 mL/min or hospitalizations with CKD diagnosis among those with ≥eGFR 60 at baseline. We ran multivariable Cox models. Results: There were 580 ESKD cases and 4,602 CKD cases over ~30 years of follow-up. Both symptomatic PAD and asymptomatic PAD were significantly associated with incident ESKD with hazard ratios (HR) of 2.21 (95%CI 1.16-4.22) and 1.59 (1.07-2.36), respectively, after adjusting for potential confounders such as other cardiovascular diseases and diabetes (Table). The corresponding HRs for incident CKD were 1.43 (1.05-1.95) and 1.60 (1.35-1.90). Borderline low ABI 0.91-1.00 showed an elevated risk of kidney outcomes in demographically- adjusted Model 1. Conclusions: Symptomatic PAD and asymptomatic PAD were independently associated with a higher long-term risk of ESKD and CKD. These results further support the close link between atherosclerosis and kidney prognosis and highlight the need for kidney monitoring in persons with PAD regardless of leg symptoms.
Abstract 10664: Quantitative T2 Mapping to Diagnose Cardiac Sarcoidosis and Predict Incident Heart Failure
Authors: Gilberto Aquino, Jordan Chamberlin, Andrew Wortham, William Rieter, Ennis James, Brian A Houston, Akos Varga-Szemes, Natalie Stringer, Madison Kocher, Jeffrey Waltz, Megan Mercer, Jeremy R Burt
Journal: Circulation (2021)

Introduction/Hypothesis: Myocardial native T2 quantification using cardiac magnetic resonance (CMR) may be helpful to diagnose active cardiac sarcoidosis and predict prognosis without the need for IV gadolinium. Methods: At a large academic institution, 66 consecutive patients with biopsy-proven pulmonary sarcoidosis underwent CMR for evaluation of active cardiac sarcoidosis (CS) from January 2017 to January 2020. Of these, 56 patients were identified who fit inclusion criteria. Active clinical CS was defined according to the Japanese Ministry of Health and Welfare criteria for diagnosis of CS. Quantitative T2 mapping of all AHA myocardial segments was evaluated and incident heart failure (HF) was recorded. A power calculation was performed beforehand which suggested n &gt; 50 was adequate. Results: The best fit model to identify active clinical CS was the mean T2 value of the basal segments (AUC 0.902, 95% CI 0.821-0.983; see Figure 1). Mean basal T2 &gt;51 ms was the optimal cutoff with accuracy of 91.1%, sensitivity of 71.4%, and specificity of 97.6%. T2 &gt;49 ms was the most sensitive cutoff (92.9%) with a negative predictive value of 96.2%. The best fit model to predict incident HF was the average T2 value of the basal segments (AUC 0.830, 95% 0.702-0.959). For every 1 ms increase in T2 value, there was a 41% increased risk for incident HF (odds ratio 1.41 95% CI 1.12-1.92, p=0.013). Conclusion: Measurement of mean basal myocardial T2 values efficiently identified patients with active clinical cardiac sarcoidosis and predicted incident heart failure. Quantitative T2 mapping is highly sensitive and specific for the diagnosis.
Abstract 14368: Valproic Acid Activates Irg1-Itaconate and Improve Donor Heart Function After Extended Storage Time
Authors: Ienglam Lei, Wei Huang, Richard Mortensen, Zhong Wang, Eugene Chen, Paul C Tang
Journal: Circulation (2021)

Background: Cold ischemic storage and subsequent reperfusion injury contributes to the primary graft dysfunction after heart transplantation. Valproic acid (VPA) has been shown to reduce myocardial infarction injury. However, the role of VPA in donor heart preservation is unknown. Methods: We investigate the role of VPA on donor heart preservation using both ex-vivo perfusion and heterotopic transplantation in murine models. Results: Our results demonstrate the administration of VPA to histidine-tryptophan-ketoglutarate (HTK) cardioplegia can significantly improve donor heart function after perfusion with extend storage time (16 hours, n=8). Specifically, VPA reduced the accumulation of succinate, a metabolite that involved in reperfusion injury, during cold storage. We further show that VPA increases the Irg1 expression. Irg1 is known to produce itaconate and suppress the succinate accumulation during ischemia. We found that the effect of VPA in donor heart function is significantly reduced in Irg1 knockout mice compared to wild type mice after 16 hours of cold storage. Furthermore, VPA reduced oxidative stress of donor heart via Nrf2 antioxidant pathway activation. However, Irg1 deletion decreased the induction of antioxidant genes expression by VPA. Administration of 4-octyl-itaconate rescued donor heart function after extended storage. Conclusion: Our results demonstrate that VPA could improve donor heart function and ischemic tolerance. This is in part through Irg1/itaconate mediated anti-oxidative activities. Importantly, VPA preserved cardiac function after perfusion with extended storage times. This strategy can extend the tolerable ischemic time for donor heart for heart transplant and may reduce the incidence of primary graft dysfunction.