tbuckley/cabot-search huggingface dataset:
NIMG-27. REGORAFENIB RESPONSE ASSESSMENT USING FET PET IN PATIENTS WITH PROGRESSIVE GLIOMA
Authors: Jan-Michael Werner, Elena Bauer, Philipp Lohmann, Caroline Tscherpel, Anna Brunn, Martina Deckert, Christoph Kabbasch, Gabriele Stoffels, Gereon Fink, Karl-Josef Langen, Norbert Galldiks
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The REGOMA phase 2 trial showed an encouraging overall survival benefit of the multikinase inhibitor regorafenib in glioblastoma patients at first progression. We used O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the early assessment of response to regorafenib in patients with progressive glioma in an advanced disease stage. METHODS Thirty patients with progressive glioma were treated according to the REGOMA trial and prospectively followed. FET PET and MRI were performed at baseline and after the second cycle of regorafenib. Static PET parameters such as maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) and metabolic tumor volumes (MTV) were calculated. Threshold values of FET PET parameters to predict a response were established by ROC analyses using an overall survival of ≥ 6 months as reference. The predictive value of FET PET parameters and their changes concerning overall survival was subsequently evaluated using the Kaplan-Meier test. MRI changes were evaluated according to the RANO criteria. RESULTS Up to now, 18 of 30 patients (glioblastoma, 83%; age range, 24-71 years) were eligible for data evaluation. The median number of tumor relapses before regorafenib was 2 (range, 1-4). During regorafenib (median cycles, 4; range, 2-9 cycles), CTCAE grade 3 or 4 side effects occurred in 56% and 11%, respectively. The median overall survival was 6 months (range, 3-18 months). After two cycles of regorafenib, a TBRmean reduction of 13% predicted a significantly longer overall survival (12 vs. 6 months; P=0.034). In contrast, MRI changes evaluated according to RANO criteria (i.e., Stable Disease or Partial Response vs. Progressive Disease) were not predictive (11 vs. 8 months; P=0.644). CONCLUSION Data suggest that amino acid PET using the tracer FET may be clinically valuable for identifying responders to regorafenib early after treatment initiation.
Abstract 9906: Not All Heart Failure Patients Are Men, Not All Caregivers Are Women: Comparing Differences by Gender
Authors: Michael A Stawnychy, Ercole Vellone, Valentina Zeffiro, Barbara Riegel
Journal: Circulation (2021)

Background: Male patients with female caregivers are well represented in dyadic HF research. However, patient-caregiver dyads that are all male, all female, or female patients with male caregivers are not well described. Aim: Compare self-care, clinical, and psychosocial characteristics of patient-caregiver dyads based on the genders of dyad members. Methods: Secondary analysis of a cross-sectional study of patient-caregiver dyads (n=277) using the Caregiver Contribution to Self-Care of HF Index (CC-SCHFI) v2. Dyads were grouped by Patient-Caregiver gender: Male patient-Female caregiver, Female patient-Male caregiver, Female-Female, and Male-Male. Self-care was assessed using the Self-Care of Heart Failure Index and the matching CC-SCHFI. Standardized scores for both indexes range from 0-100 points; higher scores equal better self-care. Characteristics of dyad gender groups (comorbidities, HF duration, NYHA functional class, quality of life (QOL), age, marriage, habitation status, and length and type of caregiving relationship) were compared using chi-square, ANOVA and Kruskal-Wallis equality-of-populations rank tests. Results: Female caregivers of male patients were typically spouses (48%), whereas the majority of caregivers in other dyads were adult children/children-in-law (63-73%). Female patients cared for by female caregivers were older, not married and had worse physical QOL. Male and female caregivers of similar gender patients were younger (47.3±14.0 and 47.7±12.1), less likely to live with the patient and spent the fewest number of hours/day caregiving. Patients in these dyads were more likely to live alone and male patients had the lowest self-care monitoring (48.2±20.1 vs 59.2±18.3 for male patients with female caregivers, p =.06). Males caring for female patients had the lowest contribution to self-care maintenance (63.3±20.3, p =.04) and lower contributions to self-care monitoring, management, and self-efficacy. Conclusion: Patient-caregiver dyads of similar and mixed genders differ across a number of self-care, clinical, and psychosocial characteristics. Results suggest that dyad members’ genders may need to be considered in clinical and research practice.
CTIM-12. A PHASE 1 TRIAL OF IMMUNORADIOTHERAPY WITH THE IDO ENZYME INHIBITOR (BMS-986205) AND NIVOLUMAB IN PATIENTS WITH NEWLY DIAGNOSED MGMT PROMOTER UNMETHYLATED IDHwt GLIOBLASTOMA
Authors: Rimas Lukas, Sean Sachdev, Priya Kumthekar, Karan Dixit, Sean Grimm, Vinai Gondi, Laura Sharp, Ray Lezon, David James, Maciej Lesniak, Roger Stupp, Derek Wainwright
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND IDHwt glioblastoma with unmethylated MGMT gene promoter carries a poor prognosis. Preclinical studies have shown that combination of radiotherapy and dual immunotherapy with nivolumab and IDO inhibition significantly prolongs survival of mice with an orthotopic glioblastoma [Ladomersky, et al. CCR 2018;24(11):2559-2573]. In a clinical trial in patients with newly diagnosed glioblastoma with unmethylated MGMT we substituted temozolomide for dual immunotherapy combination. METHODS Phase 1 trial [NCT04047706] using a 3 + 3 dose-escalation design. All received standard radiotherapy (30 x 2 Gy) with addition of once daily oral BMS-986205 and intravenous nivolumab (240mg every 2 weeks) begining on day 1 of radiotherapy and continuing until disease progression or intolerance. BMS-986205 dosing was increased from 50 mg to 100 mg. DLT period encompasses 6 weeks of radiotherapy and the 4 subsequent weeks. Immunocorrelatives being conducted before and after treatment include mass spectrometry for tryptophan and kynurenine levels, immunohistochemistry of resected tumor, and RNA-sequencing and flow cytometric analysis of PBMCs. RESULTS Twelve patients were treated on 2 dose levels of BMS-986205 (50, 100 mg). Treatment-emergent toxicity was as expected for this population. Three (25%) treatment-related SAEs were reported. Dose limiting toxicity of grade 3 transaminase elevation was observed in 2 patients at the 100 mg dose level, while at lower doses of BMS-986205 no substantial alterations of liver enzymes was observed. No other relevant treatment related toxicity occured. Ongoing immunocorrelative profiling and preliminary outcome data (all patients minimal follow-up &amp;gt;12 months) will be available at the time of the meeting. CONCLUSIONS Dose limiting toxicity of BMS-986205 in combination with nivolumab and radiotherapy is hepatic (reversible) transaminitis. The recommended dose for further investigation is 50 mg. Accrual is ongoing for the MGMT promoter methylated cohort using the same regimen without withholding temozolomide. A randomized phase 2/3 trial is approved within the NRG network.
Abstract 10477: Targeting the Methyltransferase Setd7 Prevents Myocardial Ischemic Injury: A Translational Study
Authors: Samuele Ambrosini, Fabrizio Montecucco, Detmar Kolijn, Alexander Akhmedov, Daniela Pedicino, Shafeeq Ahmed Mohammed, Attila Kiss, Antonio Paolo P Beltrami, Filippo crea, Thomas F Luescher, Nazha Hamdani, Sarah Costantino, Francesco Paneni
Journal: Circulation (2021)

Introduction: Despite appropriate revascularization strategies, a significant number of patients with myocardial infarction (MI) develop ischemic heart failure suggesting that breakthrough therapies are yet to be approved in this setting. Methylation of non-histone proteins is emerging as a central regulatory mechanism in health and disease. The methyltransferase SETD7 has shown to methylate and alter the function of a variety of proteins in vitro, however its function in the heart is poorly understood. Hypothesis: In the present study we sought to determine the role of SETD7 in myocardial ischemic injury. Methods: Experiments were performed in neonatal rat ventricular myocytes (NRVM), SETD7 knockout mice (SETD7-/-) undergoing myocardial ischemia/reperfusion (I/R) injury, rats undergoing permanent left anterior descending (LAD) artery ligation, myocardial samples from patients with and without ischemic cardiomyopathy (ICM) as well as peripheral blood mononuclear cells from patients with ST elevation MI (STEMI) and age-matched healthy controls. Results: We show that SETD7 is activated upon energy deprivation in cultured NRVMs and methylates the Hippo pathway effector YAP, leading to its cytosolic retention and impaired transcription of antioxidant genes. Pharmacological inhibition of SETD7 by (R)-PFI-2 restored YAP nuclear localization thus preventing mitochondrial reactive oxygen species (mtROS) and apoptosis. SETD7 deletion in mice attenuated I/R injury, mtROS and LV dysfunction by restoring YAP-dependent transcriptional programs. SETD7/YAP dysregulation was also observed in rats with permanent LAD ligation and LV specimens from ICM patients. Of note, (R)-PFI-2 treatment prevented titin oxidation and myofilament stiffness in cardiomyocytes isolated from I/R mice and patients with ICM. Finally, SETD7 was upregulated in STEMI patients and its expression negatively correlated with antioxidant genes. Conclusions: In the present study we show that SETD7-dependent methylation of YAP is required for its inactivation, thus leading to myocyte oxidative stress and apoptosis. Therefore, we identified SETD7 as a valid and druggable therapeutic target to protect the heart during ischemia.
Temporal trend and attributable risk factors of stroke burden in China, 1990–2019: an analysis for the Global Burden of Disease Study 2019
Authors: Qingfeng Ma, Rui Li, Lijun Wang, Peng Yin, Yuan Wang, Chuming Yan, Yi Ren, Zhengmin Qian, Michael G Vaughn, Stephen Edward McMillin, Simon I Hay, Mohsen Naghavi, Miao Cai, Chongjian Wang, Zilong Zhang, Maigeng Zhou, Hualiang Lin, Yin Yang
Journal: The Lancet Public Health (2021)

Understanding the temporal trend of the disease burden of stroke and its attributable risk factors in China, especially at provincial levels, is important for effective prevention strategies and improvement. The aim of this analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) is to investigate the disease burden of stroke and its risk factors at national and provincial levels in China from 1990 to 2019.Following the methodology in the GBD 2019, the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) of stroke cases in the Chinese population were estimated by sex, age, year, stroke subtypes (ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage), and across 33 provincial administrative units in China from 1990 to 2019. Attributable mortality and DALYs of underlying risk factors were calculated by a comparative risk assessment.In 2019, there were 3·94 million (95% uncertainty interval 3·43-4·58) new stroke cases in China. The incidence rate of stroke increased by 86·0% (73·2-99·0) from 1990, reaching 276·7 (241·3-322·0) per 100 000 population in 2019. The age-standardised incidence rate declined by 9·3% (3·3-15·5) from 1990 to 2019. Among 28·76 million (25·60-32·21) prevalent cases of stroke in 2019, 24·18 million (20·80-27·87) were ischaemic stroke, 4·36 million (3·69-5·05) were intracerebral haemorrhage, and 1·58 million (1·32-1·91) were subarachnoid haemorrhage. The prevalence rate increased by 106·0% (93·7-118·8) and age-standardised prevalence rate increased by 13·2% (7·7-19·1) from 1990 to 2019. In 2019, there were 2·19 million (1·89-2·51) deaths and 45·9 million (39·8-52·3) DALYs due to stroke. The mortality rate increased by 32·3% (8·6-59·0) from 1990 to 2019. Over the same period, the age-standardised mortality rate decreased by 39·8% (28·6-50·7) and the DALY rate decreased by 41·6% (30·7-50·9). High systolic blood pressure, ambient particulate matter pollution exposure, smoking, and diet high in sodium were four major risk factors for stroke burden in 2019. Moreover, we found marked differences of stroke burden and attributable risk factors across provinces in China from 1990 to 2019.The disease burden of stroke is still severe in China, although the age-standardised incidence and mortality rates have decreased since 1990. The stroke burden in China might be reduced through blood pressure management, lifestyle interventions, and air pollution control. Moreover, because substantial heterogeneity of stroke burden existed in different provinces, improved health care is needed in provinces with heavy stroke burden.National Key Research and Development Program of China and Taikang Yicai Public Health and Epidemic Control Fund.
Abstract 13455: Endothelium-Derived Hydrogen Sulfide Modulates Endothelial-Mesenchymal Transition in Heart Failure
Authors: Zhen Li, Huijing Xia, Thomas E Sharp, Kyle Lapenna, John W Elrod, Josef Pfeilschifter, Karl-Friedrich Beck, Traci T Goodchild, David J Lefer
Journal: Circulation (2021)

Introduction: Hydrogen sulfide (H 2 S) is a critical endogenous signaling molecule that exerts protective effects in the setting of heart failure (HF). Cystathionine γ-lyase (CSE), one of three H 2 S producing enzyme, is predominantly localized in the vascular endothelium. The interaction between endothelial cell derived H 2 S and endothelial-mesenchymal transition (EndoMT), an important pathological process contributing to the formation of fibrosis, has yet to be investigated. Methods: Endothelial cell specific CSE knockout (EC-CSE KO) and overexpressing (EC-CSE Tg) mice were subjected to transverse aortic constriction (TAC) to induce HF with reduced ejection fraction (HFrEF). Cardiac function, vascular reactivity, and treadmill exercise capacity following TAC were measured to determine the severity of HF. Histological analysis was performed to investigate changes in cardiac fibrosis. Vimentin and Von Willebrand factor co-immunostaining were utilized to investigate EndoMT activation. Results: EC-CSE KO mice exhibited reduced circulating H 2 S level, which was accompanied by increased EndoMT in the myocardium, resulting in increased perivascular fibrosis in the heart, impaired cardiac and vascular function, and worsened exercise performance. In contrast, genetic overexpression of CSE in endothelial cells elevated circulating and myocardial H 2 S, led to decreased EndoMT and subsequent fibrosis, preserved cardiac and endothelial function, and improved exercise capacity. Conclusions: Our data demonstrate that endothelial CSE modulates endothelial-mesenchymal transition to ameliorate the severity of pressure overload - induced heart failure. These data further suggest that endothelium-derived H 2 S is a potential therapeutic for the treatment of heart failure with reduced ejection fraction.
CSIG-16. PATHWAY-BASED APPROACH REVEALS DIFFERENTIAL SENSITIVITY OF GLIOBLASTOMA TO E2F1 INHIBITION
Authors: Alvaro Alvarado, Kaleab Tessema, Sree Muthukrishnan, Riki Kawaguchi, Vivek Swarup, Steven Goldman, Harley Kornblum
Journal: Neuro-Oncology (2021)

Abstract The great phenotypic heterogeneity of glioblastoma (GBM) – both inter and intratumorally – has hindered therapeutic efforts. While genome-based molecular subtyping has revealed that GBMs may be parsed into several molecularly distinct categories, this insight has not translated to a significant extension of patient survival. We hypothesize that, rather than gene expression as a whole, analysis of targetable pathways could yield important insights into the development of novel classification schemes and, most importantly, to targeted therapeutics. Here, we interrogated tumor samples using a pathway-based approach to resolve tumoral heterogeneity. The Cancer Genome Atlas samples were clustered using gene set enrichment analysis and the resulting 3 clusters were informative of patient survival and only modestly overlapped with prior molecular classification. We validated our approach by generating gene lists from common elements found in the top contributing genesets for a particular cluster and testing the top targets in appropriate gliomasphere patient-derived lines. Samples enriched for cell cycle related genesets showed a decrease in sphere formation capacity, proliferation and in vivo tumor growth when E2F1, our top target, was silenced. Consistent with our theory, E2F1 knockdown had little or no effect on the growth of the non-enriched lines, despite their ability to proliferate in vitro and in vivo. We similarly analyzed single cell RNAseq datasets and correlated cell cycle and stemness signatures with the gene lists we generated as well as with molecular states and cell specific signatures. Finally, we confirmed a connection between E2F1 and cellular inhibitor of PP2A (CIP2A) in a cluster of samples. Loss of function studies reveals a diminished capacity for DNA damage regulation in E2F1 activated samples. Our studies relate inter- and intratumoral heterogeneity to critical cellular pathways dysregulated in GBM, with the ultimate goal of establishing a pipeline for patient- and tumor-specific precision medicine.
A Glutathione Activatable Photosensitizer for Combined Photodynamic and Gas Therapy under Red Light Irradiation
Authors: Ran Wang, Xiang Xia, Yanjun Yang, Xiang Rong, Ting Liu, Zehou Su, Xiaolong Zeng, Jianjun Du, Jiangli Fan, Wen Sun, Xiaojun Peng
Journal: Advanced Healthcare Materials (2021)

Although photodynamic therapy (PDT) is a promising approach for cancer therapy, most existing photosensitizers lack selectivity for tumor cells and the overexpressed glutathione (GSH) in tumor cells reduces the PDT efficiency. Therefore, designing photosensitizers that can be selectively activated within tumor cells and combine PDT with other therapeutic modalities represents a route for precise and efficient anticancer treatment. Herein, an organic activatable photosensitizer, CyI-DNBS, bearing 2,4-dinitrobenzenesulfonate (DNBS) as the cage group is reported. CyI-DNBS can be uptaken by cancer cells after which the cage group is selectively removed by the intracellular GSH, resulting in the generation of SO2 for gas therapy. The reaction also releases the activated photosensitizer, CyI-OH, that can produce singlet oxygen (1 O2 ) under red light irradiation. Therefore, CyI-DNBS targets cancer cells for both photodynamic and SO2 gas therapy treatments. The activatable photosensitizer provides a new approach for PDT and SO2 gas synergistic therapy and demonstrates excellent anticancer effect in vivo.
Abstract 10439: Deacetylation of Histone H2AX by Sirt1 Regulates DNA Damage Response and Protects Cardiomyocytes Against Doxorubicin-Induced Injury
Authors: Atsushi Kuno, Ryusuke Hosoda
Journal: Circulation (2021)

Introduction: Accumulated DNA damage has been implicated in doxorubicin (DOX)-induced cardiotoxicity. We recently found that deletion of SIRT1, a histone deacetylase, in the cardiomyocyte worsens DOX-induced cardiac injury in mice. However, its molecular mechanism remains unclear. Ser139 phosphorylation of histone H2AX catalyzed by ATM (mutated in ataxia-telangiectasia) at the sites of DNA damage mediates DNA repair. Hypothesis: Deacetylation of H2AX by SIRT1 mediates DNA damage response and protects cardiomyocytes from DOX-induced injury. Methods and Results: Wild-type (WT) and tamoxifen-inducible cardiomyocyte-specific SIRT1 knockout (SIRT1 cKO) mice received DOX (4 IP injections of 5 mg/kg/week) or a vehicle. Immunoblotting showed that myocardial phospho-Ser139 H2AX level was increased by 1.6-fold in WT at 1 week after final DOX, but such a response was absent in SIRT1 cKO. Ser1981 phosphorylation of ATM by DOX were comparable in WT and SIRT1 cKO. The increase in TUNEL-positive nuclei by DOX was greater in SIRT1 cKO (0.13 to 0.38%) than WT (0.07 to 0.19%), suggesting higher DNA damage in SIRT1 cKO. In H9c2 cardiomyocytes, SIRT1 knockdown (KD) also abolished Ser139 phosphorylation of H2AX by DOX without changing phospho-ATM levels. Increases in DNA damage evaluated by the comet assay and cleavage of caspase-3 by DOX were also enhanced by SIRT1 KD. Immunostaining for acetyl-Lys5 H2AX in the heart sections revealed that acetyl-Lys5 H2AX levels were increased in SIRT1 cKO by 58% compared with WT. In H9c2 cells, acetyl-Lys5 H2AX level was also increased by SIRT1 KD and reduced by expression of wild-type SIRT1. In COS7 cells, a mutant in which Lys5 was substituted to glutamine (K5Q H2AX), a mimic of acetylated Lys5, showed attenuated Ser139 phosphorylation of H2AX by DOX. DOX-induced cleavage of caspase-3 was enhanced in H9c2 cells expressing K5Q H2AX as well as S139A H2AX, that cannot be phosphorylated at Ser139, compared with cells expressing WT H2AX. Conclusions: Aberrant Lys5 acetylation of H2AX via SIRT1 suppression interferes Ser139 phosphorylation, leading to accumulation of damaged DNA and promotion of the apoptotic response. Such regulation of the DNA damage response underlies protection by SIRT1 against DOX-induced cardiotoxicity.
Abstract 12394: Development of a Heparin Dosing Algorithm to Maintain Therapeutic Anticoagulation During Atrial Fibrillation Ablation
Authors: Matthew Martini, Marcus Mahnke, Daniel S Modaff, Blake Fleeman, Ryan T Kipp, Jennifer Wright, Joshua Meadow, Matthew Kalscheur
Journal: Circulation (2021)

Introduction: Therapeutic anticoagulation during atrial fibrillation (AF) ablation reduces the risk of cerebral thromboembolism during ablation. Heparin dosing strategies vary and can result in sub-therapeutic anticoagulation. Hypothesis: We hypothesize that a heparin dosing algorithm will improve maintenance of guideline-based therapeutic activated clotting times (ACT) during AF ablation. Methods: Starting from published guidance on heparin dosing during AF ablation, an artificial intelligence algorithm based on a decision tree and other mathematical considerations was developed. The algorithm launches directly from the electronic medical record and captures deidentified data for future improvements. The rules were modified over several months to establish the tested algorithm. The strategy utilized heparin boluses and an infusion. Dosing was adapted based on an individual patient’s response to the first heparin bolus. Goal ACT was 300-350 s. Outcomes from a month prior to algorithm introduction were compared to those from one month using the developed algorithm. The measured outcomes included time from first bolus to therapeutic ACT (&gt;300 s), number of heparin boluses to achieve goal ACT, time in left atrium below therapeutic ACT, and ACT value when below goal in left atrium. Results: Data from seventeen pre-algorithm procedures were compared to fourteen procedures completed using the dosing algorithm. Compared to procedures using typical dosing, procedures using the dosing algorithm reached goal ACT faster (16.1 ± 5.3 min compared to 26.2 ± 14.5 min, p = 0.02) with fewer heparin boluses (1.1 ± 0.3 boluses compared to 1.6 ± 0.9 boluses, p = 0.04). The ACT did drift below goal in some cases (n = 4 using algorithm and n = 5 using typical dosing). The time below goal was not different between dosing strategies (16.5 ± 8.7 min for algorithm compared to 22.4 ± 7.9 min for typical dosing). However, when the ACT drifted below goal with the dosing algorithm, it was significantly closer to goal than with typical dosing (295 ± 3 s compared to 268 ± 21 s, p = 0.02). Conclusion: An artificial intelligence algorithm based on a decision tree and adaptation to individual patient kinetics may improve maintenance of guideline based therapeutic ACT during AF ablation.