tbuckley/cabot-search huggingface dataset:
Abstract 12950: PUMA Sequestration by IP3Rs Underlies Maladaptive Cardiac Fibrosis
Authors: Jessica Gambardella, Stanislovas Jankauskas, Xujun Wang, Gaetano Santulli
Journal: Circulation (2021)

Introduction: Following an ischemic injury, the persistence of cardiac myofibroblast (myo-FBs) contributes to fibrosis and adverse myocardial remodeling, especially if myoFBs remain active in otherwise healthy areas of the heart, away from the site of injury. The exact mechanisms underlying myo-FB activation and persistence remain unknown. Hypothesis: Since recent genome-wide association (GWA) studies have identified a significant association between gain-of-function mutations in genes encoding for inositol 1,4,5-trisphosphate receptors (IP3Rs) and ischemic heart disease, we hypothesized that IP3Rs could be involved in post-ischemic cardiac fibrosis. Methods: We applied an established model of ischemia/reperfusion (I/R) to a newly generated triple KO mouse specifically lacking all isoforms of IP3Rs in cardiac myo-FBs, in order to avoid compensatory responses. Results: After I/R, IP3Rs level is not changed in the scar area, whereas it is markedly upregulated in the remote regions. Compared to control littermates, KO mice display a reduced interstitial fibrosis and an attenuated myocardial dysfunction following I/R. Mechanistically, we show for the first time that IP3Rs modulate apoptosis in myo-FBs following ischemic injury in a calcium-independent manner, i.e. by directly sequestrating the pro-apoptotic factor PUMA (p53 upregulated modulator of apoptosis), thereby favoring the detrimental myoFBs persistence in the remote areas. Strikingly, these results were confirmed in human cardiac specimens from patients with heart failure, as well as in vitro in human FBs, in which IP3Rs are shown to regulate cell proliferation and migration. Conclusions: Our findings indicate that the IP3R-PUMA interaction selectively regulate the activation of cardiac myo-FBs located in the regions remote from the ischemic injury.
BIOM-32. ENDOPLASMIC RETICULUM PROTEIN SSR3 DETERMINES AND PREDICTS RESPONSE TO PACLITAXEL IN BREAST CANCER AND GLIOBLASTOMA
Authors: Crismita Dmello, Aarón Sonabend, Víctor Arrieta, Daniel Zhang, Deepak Kanojia, Li Chen, Andrew Gould, J Robert Kane, Jiangshan Zhang, Seong Kang, Jan Winter, Craig Horbinski, Balázs Győrffy, Alex Cordero, Catalina Chang, Brandyn Castro, Patrick Hsu, Atique Ahmed, Maciej Lesniak, Roger Stupp, Adam M Sonabend
Journal: Neuro-Oncology (2021)

Abstract Paclitaxel (PTX) is one the most potent and commonly used chemotherapies for breast and pancreatic cancer. Given the potency of this drug for glioblastomas (GBM) several ongoing clinical trials are investigating means of enhancing delivery of PTX across the blood-brain barrier for this disease. In spite of the efficacy of PTX, individual tumors exhibit variable susceptibility to this drug, with response rate in the range of 30%-60%. To identify predictive biomarkers for response to PTX, we performed a genome-wide CRISPR knock-out screen using human glioma cells. The most enriched genes in the CRISPR screen underwent further selection based on their correlation with survival in the breast cancer patient cohorts treated with PTX and not in patients treated with other chemotherapies, a finding that was validated on a second independent patient cohort. This led to the discovery of endoplasmic reticulum (ER) protein SSR3 as a putative predictive biomarker for PTX. SSR3 protein levels showed positive correlation with response to PTX in breast cancer cells, glioma cells, in multiple intracranial glioma xenografts and in GBM patient derived explant cultures. Knockout of SSR3 turned the cells resistant to PTX while its overexpression sensitized the cells to PTX. In gliomas, SSR3-mediated susceptibility to PTX relates to modulation of phosphorylation of ER stress sensor IRE1α. Thus, by using genome-wide screen combined with patient response data, we discovered a biomarker that demonstrates causal and correlative relationship with response to PTX in breast cancer and GBM. Prospective validation of this biomarker is warranted for its broad implementation for precision oncology.
A Severe Mouse Model of Alpha-Thalassemia to Study Abnormal Iron Metabolism and Erythropoiesis, Hematopoietic Stem Cell Behavior and Development of a Gene Therapy Approach for Its Treatment
Authors: Maxwell Chappell, Danuta Jadwiga Jarocha, Laura Breda, Valentina Ghiaccio, Michael Triebwasser, Megan Fedorky, Amaliris Guerra, Kandace Gollomp, Nattiya Teawtrakul, Stavros Glentis, Antonis Kattamis, Osheiza Abdulmalik, Stefano Rivella
Journal: Blood (2021)
Abstract P357: Induction Of Soluble P-selectin And CD40 Ligand And, FXIII Deficiency Promote Aberrant Coagulation And Thromboembolism In Severe COVID-19
Authors: Abaher O Al-Tamimi, Ayesha M Yusuf, Manju N Jayakumar, Abdul W Ansari, Mona Elhassan, Fatema AbdulKarim, Meganathan Kannan, Rabih Halwani, Firdos Ahmad
Journal: Circulation Research (2021)

Coagulation dysfunction and thromboembolism emerge as strong comorbidity factors in severe COVID-19. However, the underlying pathomechanisms are largely undefined. Here, we sought to identify the potential underlying molecular mechanisms of SARS-CoV-2 mediated coagulopathy and thromboembolism. In this series, 30 hospitalized COVID-19 patients presenting elevated D-dimer with (severe cases that required intensive care) or without pneumonia (moderate cases) were included in the study. Patients with anticoagulant/ antiplatelet therapy or with a history of cardiovascular diseases were excluded. Phenotypic and molecular characterizations were carried out employing basic coagulation tests, flow cytometry-based multiplex assays, and ELISA. The findings revealed slightly higher prothrombin and activated partial thromboplastin times (aPTT) with normal platelet counts. Elevated levels of plasma P-selectin and CD40 ligand (CD40L), markers of platelet activation, were observed in the moderate COVID-19 cases which were significantly abolished with the progression of COVID-19 severity. Moreover, analysis of the coagulation pathways revealed comparable FIX, prothrombin, and anti-thrombin levels, and a significantly higher level of fibrinogen was observed in both the moderate and severe patients vs. control group. Interestingly, the levels of plasma tissue factor pathway inhibitor (TFPI) and FXIII, a regulator of stable thrombus formation, were significantly lower particularly in the severe COVID-19 cases. Moreover, a dysregulated fibrinolysis was indicated by elevated tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI), and D-dimer levels in COVID-19 cases. In summary, SARS-CoV-2 infection-mediated endothelial cell lining damage potentially enhances soluble P-selectin and CD40L levels inducing platelet activation. Furthermore, in severe COVID-19, a decreased level of TFPI possibly contributes to additional thrombin generation through activation of the TF pathway and provides positive feedback to platelet activation and thrombus formation. FXIII deficiency plays a key role in thrombus instability which most likely promotes thromboembolism in the severe COVID-19.
Abstract 10993: Prognostic Value of Low T <sub>3</sub> Syndrome in Patients with Acute Decompensated Heart Failure in Osaka Prefectural Acute Heart Failure Registry (OPAR)
Authors: KUMPEI UEDA, Takahisa Yamada, Tetsuya Watanabe, Takashi Morita, Masato Kawasaki, Atsushi Kikuchi, Tsutomu Kawai, Masahiro Seo, Jun Nakamura, Kiyomi Kayama, Daisuke Sakamoto, Takehiro Kogame, Yuto Tamura, Takeshi Fujita, Keisuke Nishigaki, Yuto Fukuda, Yuki Kokubu, Masatake Fukunami
Journal: Circulation (2021)

Backgrounds: It is widely recognized that thyroid dysfunction is a potential cause of heart failure (HF). In HF, one of the alterations of thyroid functions is referred to as low T 3 syndrome marked by a reduction in serum free triiodothyronine (T 3 ) with normal levels of thyroid-stimulating hormone (TSH). However, there is little information available about the association between low T 3 syndrome and future cardiac events in patients with acute decompensated heart failure (ADHF), relating to left ventricular ejection fraction (LVEF). Methods and Results: We studied 565 patients admitted for ADHF with survival discharge in our prospective cohort study. Laboratory data including free T 3 , thyroxine and TSH were obtained at discharge. Among the patients with euthyroid (0.35 μU/mL &lt;TSH &lt;4.94 μU/mL, n=438), there was 62 patients who were diagnoses as low T 3 syndrome (free T 3 ≦1.68 pg/mL). The primary end point of this study was all-cause death (ACD). During a mean follow up period of 2.9±1.4 years, 121 patients died. Study subjects were stratified into two LVEF subgroup as follows; 239 patients had LVEF&lt;50% (HFrEF), and 199 patients had LVEF≧50% (HFpEF). While 68 HFrEF parients died, 53 HFpEF patients died. Kaplan-Meier curve analysis revealed that patients with the low free T 3 group had the greater risk of ACD than those with the normal free T 3 group in both LVEF subgroup (log-rank p=0.0233 in HFrEF and p=0.0265 in HFpEF). Multivariate Cox analysis showed that free T 3 was significantly associated with ACD after multivariable adjustment for major confounders, such as age, sex, systolic blood pressure and plasma brain natriuretic peptide level in both LVEF subgroup (p=0.0039 in HFrEF, p=0.0487 in HFpEF). Conclusion: Low T 3 syndrome was significantly associated with poor outcome in ADHF patients with both HFrEF and HFpEF.
Abstract 13835: MG53 Preserves Mitochondrial Integrity of Cardiomyocytes in Pre-Clinical Models of Ischemia Reperfusion-Induced Oxidative Stress
Authors: Hua Zhu, Kristyn Gumpper, Hanley Ma, Xinyu Zhou, Zehua Bian, Karthikeyan Krishnamurthy, Ki Ho Park, Matthew Sermersheim, Jingsong Zhou, Tao Tan, Lei Li, Jianxun Liu, PEI-HUI LIN, Jianjie Ma
Journal: Circulation (2021)

Introduction: Ischemic injury to the heart induces mitochondrial dysfunction due to an increase in oxidative stress. MG53, also known as TRIM72, is highly expressed in striated muscle and is essential for repairing damaged plasma membranes by interacting with the membrane lipid phosphatidylserine. We have previously shown that mg53-/- mice are more susceptible to ischemia-reperfusion injury, and treatment with exogenous recombinant human MG53 (rhMG53) reduces infarct damage, restores cardiac function and preserves mitochondrial membrane potential. Hypothesis: We hypothesize MG53 preserves mitochondrial integrity after an ischemic event by binding to the mitochondrial-specific lipid, cardiolipin (CL), for mitochondrial membrane repair, preventing the formation of superoxides and mitophagy. Methods: Fluorescent imaging and western blotting experiments were conducted after ischemic injury in vivo and in vitro to measure the formation of superoxides and activation of mitophagy. A lipid binding assay was used to determine MG53’s ability to bind to CL. Transfection of murine cardiomyocyte cells with the mitochondria-targeted mt-mKeima was used to measure engulfment of the mitochondria by the lysosome. Results: We found that recombinant human MG53 (rhMG53) delivered prior ischemia/reperfusion translocated to the mitochondria both in vivo and in vitro. Additionally, superoxide generation was reduced by rhMG53 treatment using ex vivo and in vitro models. A lipid binding assay revealed rhMG53 binds to CL. Treating with rhMG53 inhibited mitophagy after ischemia/reperfusion, as demonstrated by the reduction of mitochondria in the lysosome after rhMG53 treatment and a reduction in mitochondria-bound parkin, a key mediator of mitophagy. Conclusions: In this study we provide evidence that rhMG53 treatment may preserve cardiac function by preserving mitochondria in cardiomyocytes. These findings suggest MG53’s interactions with mitochondria could be an attractive avenue for the development of MG53 as a targeted protein therapy for cardioprotection.
CTIM-20. FINAL RESULTS OF CONTROLLED IL-12 MONOTHERAPY AND IN COMBINATION WITH PD-1 INHIBITOR IN ADULT SUBJECTS WITH RECURRENT GLIOBLASTOMA
Authors: Rimas Lukas, Nancy Ann Oberheim-Bush, Robert Cavaliere, Joseph Landolfi, John S Yu, Clark Chen, Christine Cordova, Christina Amidei, Jill Y Buck, Nira Hadar, Nate Demars, John Miao, John Loewy, Taylor Estupinan, Kamal Chadha, Laurence J N Cooper, E Antonio Chiocca
Journal: Neuro-Oncology (2021)

Abstract Ad-RTS-hIL-12(Ad) is a gene therapy candidate conditionally expressing IL-12 under the transcriptional control of veledimex(V) acting via the RheoSwitch Therapeutic System® gene switch. Veledimex plasma and tumor PK demonstrated a dose-response relationship and crossing the BBB. PD-1+ T-cells were increased in tumor biopsy samples after treatment with Controlled-IL-12 in a phase-l study. This finding was the rationale for conducting 2 trials of Controlled-IL-12 in combination with PD-1-inhibitor to enhance T-cell-mediated anti-tumor effects. Data from two completed phase-I studies (presented in SNO2020), and an ongoing phase-II study of Controlled-IL-12 with cemiplimab study for the treatment of recurrent glioblastoma (rGBM) will be discussed. Ziopharm has conducted 3 phase-I (NCT02026271/NCT03679754 (monotherapy), NCT03636477 (combination with nivolumab)) and one phase-ll (NCT04006119) multicenter, open-label, single-arm trial in subjects with rGBM is evaluating Ad (single intratumoral injection, 2 x 1011-viral-particles, Day0) with oral V dosing (20mg, Days 0-14) with cemiplimab infusions (350 mg IV) on Days -7, 15, then Q3W. Systemic biomarkers (serum cytokines, and immune-activation-markers), local effects (tumor cytokines, T-cell immunobiology, pathology), neoepitope, and imaging will be assessed. Subject characteristics (Controlled IL-12 monotherapy (n=75); combination (Controlled IL-12 with anti-PD-1s) (n=61) were consistent across all 3 studies. Safety profiles were comparable between monotherapy and in combination with anti-PD-1s. Adverse reactions (ARs) after nivolumab or cemiplimab were consistent with labeling of anti-PD-1s. ARs related to Controlled IL-12 were all manageable and reversible with no synergistic toxicities in combination with anti-PD-1s. Increases in serum cytokine levels and pathology findings consistent with immune-mediated anti-tumor effect were observed in subjects who received Controlled-IL-12 monotherapy and in combination with anti-PD-1s. Final survival data and results from neoepitope analysis will be presented. Further investigation is warranted to understand the impact of monotherapy vs. combination, concurrent steroids use and unifocal vs. multifocal disease on overall survival in subjects with rGBM receiving Controlled-IL-12.
BIOM-33. EV-ASSOCIATED IL13Ra2 AS A LIQUID BIOPSY BIOMARKER FOR GBM
Authors: Vladimir Khristov, Darya Nesterova, Brad Zacharia, James Connor, Achuthamangalam Madhankumar
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is both the most common and deadly malignant primary brain tumor with a 1-year survival of 37.2% and a 5-year survival of just 5.1%. Despite advances in imaging technology, distinguishing between pseudoprogression and pseudoresponse remains problematic and there is a dire need for additional diagnostic methods. Tumor-derived extracellular vesicles are found in a variety of biofluids and are good candidates for a liquid biopsy. A unique characteristic of GBM is the overexpression of the α2 variant of IL-13 receptor (IL13Rα2) in 78-96% of patients while virtually undetectable in normal brain tissue. We hypothesize that biofluids of patients with GBM contains sufficient IL13Rα2-positive extracellular vesicles (EV) to inform the clinical picture regarding disease status such as tumor recurrence and response to therapy. We have measured the levels of IL13Rα2 in the EV fraction of plasma from GBM patients and correlated these levels to patient survival, and patient clinical characteristics (n=35). We have demonstrated that the EV fraction of some patients with GBM is enriched for the IL13Rα2 receptor. The plasma level of IL13Rα2 could also predict the level of IL13Rα2 in the GBM tumor (n=9). Further, IL13Rα2 positive EVs from patient-derived GBM cell lines could be immunoprecipitated for further interrogation of genomic and proteomic molecular markers. These exciting findings lay the groundwork for a GBM liquid biopsy based on tumor-specific EVs in patient biofluids.
CTNI-41. INITIAL RESULTS OF A PHASE I WINDOW OF OPPORTUNITY TRIAL EVALUATING A FIRST-IN-CLASS CD29 INHIBITOR, OS2966, IN RECURRENT HIGH-GRADE GLIOMA
Authors: James Liu, Chibueze D Nwagwu, Amanda V Immidisetti, Gabriela Bukanowska, Anne-Marie Carbonell, Michael Vogelbaum
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND OS2966 is a first-in-class, humanized and deimmunized monoclonal antibody which antagonizes CD29/β1integrin, a mechanosignaling receptor prominently upregulated in glioblastoma. Preclinical studies in mice and non-human primates have demonstrated safety and encouraging efficacy. A two-part, ascending concentration, phase I clinical trial was therefore initiated to evaluate the safety and feasibility of delivering OS2966 directly to the site of disease via convection-enhanced delivery (CED) in recurrent high-grade glioma patients. METHODS This study has a 2-part design: In part 1, patients undergo stereotactic tumor biopsy followed by placement of a multiport CED catheter for delivery of OS2966 to the bulk contrast enhancing tumor. Subsequently, patients undergo a clinically-indicated tumor resection followed by placement of two CED catheters and delivery of OS2966 to the surrounding tumor-infiltrated brain. A unique concentration-based accelerated titration design is utilized for dose escalation. Given availability of pre and post infusion samples, pharmacodynamic data will be analyzed to explore mechanism of action of OS2966. RESULTS Two subjects have been treated at two corresponding dose levels (0.2mg/mL and 0.4 mg/mL). No dose-limiting toxicity or unexpected safety issues have been identified. To date, reported adverse events were mild (i.e., grade 1) and consistent with underlying disease and surgical procedures. No adverse events were attributed to OS2966 or CED catheter placement. Further, no clinically significant changes from baseline neurological exam have been noted for either patient through initial follow-up. Maximal tumor coverage and concomitant gross total resection were achieved for both patients. Tumor volume measured 1.63 cm3 and 16 cm3 for Patient 1 and 2 respectively with an intratumoral Vd/Vi ratio of 1.3. and 0.94. Pharmacodynamic analysis via tissue-level biomarkers is ongoing and will be presented. CONCLUSION Initial data demonstrates the safety and feasibility of direct intracranial delivery of OS2966.
Diagnosis and Management of Diffuse Large B Cell Lymphoma in Resource Constraint Settings: Society of Medical Oncology Pakistan, Pakistan Society of Haematology and Pakistan Society of Clinical Oncology Joint Clinical Practice Guideline
Authors: Raheel Iftikhar, Muhammad Ayaz Mir, Munira Moosajee, Kamran Rasheed, Syed Waqas Imam Bukhari, Ahmed Nadeem Abbasi, Tahir Sultan Shamsi, Maryam Khan, Parvez Ahmed, Hafeez ud Din, Qamar un Nisa Chaudhry, Imran N Ahmad, Natasha Ali, Muhammad Umair, Mussavir Bangash, Usman Ahmad, Wasim Sattar, Anum Zargham, Azhar Shafi, Ghassan U. Shamshad, Qurratulain Rizvi, Mohammad Usman Shaikh, Syed Muhammad Irfan, Uzma Zaidi, Naeem Naqi, Humera Mahmood, Asghar Hussain, Ahmed Ijaz Masood, Neelam Siddiqui, Misbah Masood, Mohammad Faheem, Salman Naseem Adil, Zeba Aziz
Journal: Blood (2021)
Abstract 11150: Albuminuria in Heart Failure is More Strongly Associated with Markers of Congestion Than Renal Dysfunction
Authors: Eva M Boorsma, Jozine M ter Maaten, Kevin Damman, Pierpaolo Pellicori, Marco Metra, Kenneth Dickstein, Dirk J van Veldhuisen, Gerasimos Filippatos, Leong Ng, Stefan D Anker, Faiez Zannad, John Cleland, Adriaan A Voors, Lisa Emmens
Journal: Circulation (2021)

Aims: Albuminuria is common in patients with heart failure (HF) and associated with worse outcomes. It is unknown whether albuminuria only reflects renal dysfunction or whether it is related to the pathophysiology of HF. We therefore aimed to study the clinical characteristics and biomarkers associated with albuminuria in patients with new onset or worsening HF. Methods and Results: In the current analysis, we included 2315 patients from the index cohort of BIOSTAT-CHF who had a spot urinary sample available at baseline, and validated findings in 1431 patients from the independent BIOSTAT-CHF validation cohort.Micro-albuminuria and macro-albuminuria were defined as UACR &gt;30 mg/gCr and &gt;300 mg/gCr, respectively.In the index cohort 242 patients (10%) had macro- and 819 (35.4%) had micro-albuminuria. Patients with any albuminuria were more likely to be hospitalized, had a higher NYHA-class, more clinical signs of congestion and higher concentrations of biomarkers related to congestion, such as bio-ADM, CA-125 and NT pro-BNP. Moreover, they were more likely to have a history of diabetes mellitus (56.6% vs. 27.7% for macro-albuminuria vs. no albuminuria), hypertension and atrial fibrillation (all p&lt;0.001). From multivariable linear regression the strongest predictor for log(UACR) was log NT pro-BNP (standardized B 0.41, 95% CI 0.32 - 0.50, p &lt;0.001). This correlation was similar for all estimated glomerular filtration rates (p for interaction = 0.256). A dendrogram based on hierarchical clustering (Figure) demonstrates that UACR clusters with markers of congestion and HF disease severity and not with markers of renal (dys)function. The validation cohort yielded similar findings. Conclusion: In patients with HF, the presence of albuminuria was more strongly related to markers of congestion than markers of renal dysfunction. These data may suggest a direct relationship between congestion and albuminuria or a common underlying pathophysiological mechanism.
Abstract 10676: Left Atrial Strain is Associated with Supraventricular Tachycardia in Cardiac Amyloidosis Patients
Authors: Mathijs Versteylen, Maaike Brons, Teske Arco, Marish Oerlemans
Journal: Circulation (2021)

Introduction: In cardiac amyloidosis, supraventricular tachycardia is common. Probable mechanisms are left ventricular dysfunction resulting in left atrial disease, but also direct atrial amyloid infiltration. Although measurement of left ventricular global longitudinal strain is commonly used, the value of left atrial strain remains unclear. Hypothesis: Left atrial strain should be strongly associated with the occurrence of supraventricular tachycardia in cardiac amyloidosis patients. Methods: In 69 cardiac amyloidosis patients (75% male, mean age 65 years) in our Amyloidosis Expert Center, echocardiographic strain analysis was performed using EchoPAC (version 203, General Electric Healthcare) between March 2017 and May 2020. Results: Supraventricular tachycardia occurred in 34 (43%) cardiac amyloidosis patients, which were older (70±8 vs. 60±15 years, p=0.001) but had a similar left ventricular mass index and ejection fraction. Left atrial volume index was higher (56±21 vs. 45±18 ml/m 2 , p=0.02), left ventricular global longitudinal strain (11±4 vs. 14±4, p=0.004) and left atrial reservoir strain (12±9 vs. 23±16, p=0.001) were lower. Left atrial reservoir strain was associated with supraventricular tachycardia, independent of left ventricular global longitudinal strain or left atrial volume (B-value 0.88 (confidence interval 0.80 - 0.97), p=0.01). Conclusion: Low left atrial reservoir strain was associated with the occurrence of supraventricular tachycardia independent of left atrial volume and left ventricular global longitudinal strain and therefore a promising parameter in cardiac amyloidosis patients.