tbuckley/cabot-search huggingface dataset:
Abstract MP263: CD8+ T-cells Regulate Macrophage Recruitment And Retention After Myocardial Infarction
Authors: Gualberto Munoz, Hallie Roerden, Penny Huebsch, Kristine Y DeLeon-Pennell
Journal: Circulation Research (2021)

Heart failure is the number one reason for admission, with myocardial infarctions (MI) as the underlying etiology in of 70% cases. Macrophages facilitate cardiac healing after the MI. Resident macrophages die due to the initial ischemic event and are replaced by monocyte-derived macrophages. The adaptive immune system, including cytotoxic CD8+ T-cells, are known regulators of inflammation and are upregulated in the circulation and in the infarct after an MI. Previously we showed mice deficient in CD8+ T-cells were protected from adverse remodeling. We hypothesized that after an MI, CD8+ T-cells regulate the recruitment and retention of monocytes. To test our hypothesis, C57Bl6J (WT; n≥3/day post-MI) and mice deficient in CD8+ T-cells (CD8-/-; n≥3/day post-MI) underwent permanent occlusion and tissue was collected at post-MI days 0 (no MI), 1, 3, 7, and 14. Mac3 staining of the infarct was performed to determine the macrophage time course. Infarct tissue was analyzed by bulk RNAseq (n=3/day/genotype) to determine possible genetic regulators at post-MI days 1, 7, and 14. Data was clustered based on the genetic markers of macrophage subtypes identified in previous single cell genomic studies. Mac3 staining of WT mice showed macrophages begin to infiltrate as early as post-MI day 1, peaking at day 7, and beginning to reach baseline levels by day 14. Interestingly, CD8-/- mice had a delay in macrophage recruitment at day 1; however, by day 3 there was almost double the amount of macrophages compared to the WT group. While no differences were observed at day 7 post-MI, CD8-/- mice had elevated macrophages at post-MI day 14 compared to the WT mice. Based on the gene clusters, the infarct tissue of CD8-/- mice had increased markers of resident-like macrophages at post-MI days 7 and 14 compared to WT mice. Resident macrophages have been shown to be cardioprotective post-MI, suggesting a possible protective mechanism in CD8-/- mice. In conclusion, our data indicates that CD8+ T-cells influence cardiac remodeling over the post-MI time course by facilitating in macrophage recruitment and retention. Furthermore, in the absence of CD8+ T-cells, there was an increase in resident-like macrophages that could prove to point to a more favorable repopulation of cells post-MI.
Acute myeloid leukemia cell membrane-coated nanoparticles for cancer vaccination immunotherapy
Authors: Daniel T. Johnson, Jiarong Zhou, Ashley V. Kroll, Ronnie H. Fang, Ming Yan, Crystal Xiao, Xiufen Chen, Justin Kline, Liangfang Zhang, Dong-Er Zhang
Journal: Leukemia (2021)

Abstract Cancer vaccines are promising treatments to prevent relapse after chemotherapy in acute myeloid leukemia (AML) patients, particularly for those who cannot tolerate intensive consolidation therapies. Here, we report the development of an AML cell membrane-coated nanoparticle (AMCNP) vaccine platform, in which immune-stimulatory adjuvant-loaded nanoparticles are coated with leukemic cell membrane material. This AMCNP vaccination strategy stimulates leukemia-specific immune responses by co-delivering membrane-associated antigens along with adjuvants to antigen-presenting cells. To demonstrate that this AMCNP vaccine enhances leukemia-specific antigen presentation and T cell responses, we modified a murine AML cell line to express membrane-bound chicken ovalbumin as a model antigen. AMCNPs were efficiently acquired by antigen-presenting cells in vitro and in vivo and stimulated antigen cross-presentation. Vaccination with AMCNPs significantly enhanced antigen-specific T cell expansion and effector function compared with control vaccines. Prophylactic vaccination with AMCNPs enhanced cellular immunity and protected against AML challenge. Moreover, in an AML post-remission vaccination model, AMCNP vaccination significantly enhanced survival in comparison to vaccination with whole leukemia cell lysates. Collectively, AMCNPs retained AML-specific antigens, elicited enhanced antigen-specific immune responses, and provided therapeutic benefit against AML challenge.
TAMI-47. MIR-542-3P CONTRIBUTES TO THE HK2-MEDIATED HIGH GLYCOLYTIC PHENOTYPE IN HUMAN GLIOMA CELLS
Authors: Junhyung Kim, Min Woo Park, Ju Won Ahn, Jeong Min Sim, Suwan Kim, Young Joon Park, Jinhyung Heo, Ji Hun Jeong, Mihye Lee, Jaejoon Lim, Jong-Seok Moon
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The elevation of glucose metabolism is linked to high-grade gliomas such as glioblastoma multiforme (GBM). The high glycolytic phenotype is associated with cellular proliferation and resistance to treatment with chemotherapeutic agents in GBM. MicroRNA-542-3p (miR-542-3p) has been implicated in several tumors including gliomas. However, the role of miR-542-3p in glucose metabolism in human gliomas remains unclear. METHODS We measured the levels of cellular proliferation in human glioma cells. We measured the glycolytic activity in miR-542-3p knockdown and over-expressed human glioma cells. We measured the levels of miR-542-3p and HK2 in glioma tissues from patients with low- and high-grade gliomas using imaging analysis. RESULTS We show that knockdown of miR-542-3p significantly suppressed cellular proliferation in human glioma cells. Knockdown of miR-542-3p suppressed HK2-induced glycolytic activity in human glioma cells. Consistently, over-expression of miR-542-3p increased HK2-induced glycolytic activity in human glioma cells. The levels of miR-542-3p and HK2 were significantly elevated in glioma tissues of patients with high-grade gliomas relative to that in low-grade gliomas. The elevation of HK2 levels in patients with high-grade gliomas were positively correlated with the high levels of miR-542-3p in GBM and low-grade gliomas (LGG) based on the datasets from the Cancer Genome Atlas (TCGA) database. Moreover, the high levels of miR-542-3p were associated with poor survival rate in the TCGA database. CONCLUSIONS miR-542-3p contributes to the HK2-mediated high glycolytic phenotype in human glioma cells.
TMOD-05. GENETIC AND MOLECULAR PROPERTIES OF LONG-TERM PROLIFERATING TUMORSPHERE -FORMING GLIOMA DERIVED CELLS
Authors: Noriyuki Kijima, Daisuke kanematsu, Tomoko Shofuda, Ema Yoshioka, Atsuyo Yamamoto, Yukako Handa, Hayato Fukusumi, Asako Katsuma, Shusuke Moriuchi, Masahiro Nonaka, Yoshiko Okita, Naohiro Tsuyuguchi, Takehiro Uda, Toshiyuki Kawashima, Junya Fukai, Yoshinori Kodama, Masayuki Mano, Yuichiro Higuchi, Hiroshi Suemizu, Yonehiro Kanemura
Journal: Neuro-Oncology (2021)

Abstract Long-term proliferating tumorsphere (LTP-TS)-forming glioma derived cells (GDCs) and patient derived xenografts (PDXs) are essential tools for translational research for glioma. However, only small subsets of glioma samples are established as LTP-TS and/or PDXs and little is known about the genetics and molecular properties of LTP-TS -forming GDCs and PDX. In this study, we aim to analyze the characteristics of LTP-TS -forming GDCs and PDXs. We tried primary sphere cultures from 56 glioma patient-derived samples and established 14 LTP-TS -forming GDCs out of 48 glioblastoma samples and no long-term sphere culture was isolated from grade3 and grade 2 gliomas. LTP-TS -forming GDCs had self-renewal ability and possessed certain multipotency. However, they significantly less expressed SOX1 FOXG1 and TUBB3, whereas they expressed LGALS1 significantly higher than normal neural stem/progenitor cells. In addition, we found that LTP-TS -forming GDCs shared the same genetic profiles with original patients’ tumors. Furthermore, we investigated the genetic differences between the glioma tissues which were successfully established as LTP-TS -forming GDCs and those which were not. We found that glioma tissues with TERT promotor mutations and triple CNA (EGFR, CDKN2A, and PTEN loci) are significantly established as LTP-TS -forming GDCs. Lastly, we next investigated in vivo characteristics of glioma PDXs. We have injected glioma PDXs lines into immunodeficient mice and histopathologically analyzed the characteristics of xenografts. Each xenograft well recapitulated histological features of original patients’ tumors and tumor cells remarkably invade through subventricular zone. In conclusion, each LTP-TS -forming GDCs and PDXs had various gene expression profiles, reflecting intratumoral and interpatient heterogeneities of glioma. In addition, TERT promotor mutations and triple CNA significantly correlated with success rate of LTP-TS -forming GDCs. These findings will be of use and advance the preclinical and translational researches of glioma.
Evaluation of safety and activity of everolimus plus exemestane in metastatic breast cancer: A single institution experience.
Authors: Ilaria Ferrarini, Atefeh Raoufi, Ilaria Bertolini, Sara Fancelli, Carmine De Angelis, Francesca Diodati, Andrea Fontana, Barbara Salvadori, Elisabetta Landucci, Andrea Michelotti, Andrea Antonuzzo, Silvio Roncella, Alfredo Falcone
Journal: Journal of Clinical Oncology (2016)

e14554 Background: Everolimus (EV) is an oral inhibitor of mammalian target of rapamicin (mTOR), recently approved in combination with exemestane (EX) for the treatment of hormonal positive metastatic breast cancer (MBC) progressed to a non steroideal aromatase inhibitor Methods: 63 consecutive patients (pts) were retrospectively evaluated and treated with EV plus EX from July 2012 to April 2015. At the beginning of EV’s therapy median age was 63 years (range 45-80); pts older than 70 were 15. Visceral metastases were present in 35 pts (56%) and 18 pts (28.6%) had more than two sites of metastasis. 19 pts (30%) and 18 (28.5%) had liver and lung involvement respectively. Pts received previous hormonal therapy for metastatic disease for a median number lines of 1 (range 0-4) and chemotherapy for a median line of 1 (range 0-5) respectively. EV plus EX was administered as first line in 10 pts (15.8%). Results: Oral mucositis, observed in 45 pts (71%), was the most common toxicity: it presented with a grade 3 appearance in 10 pts (16%). Then in order of frequency: skin toxicity in 22 pts (35%), fatigue in 19 pts (30%) and transaminase increase in 18 pts (28.5%). Non-infectious pneumonitis was reported in 11 pts (17%) with only 1 case of grade 3; diarrhea in 12 pts (19%), in all cases of grade 1 or 2; hyperglycemia and hypercholesterolemia respectively in 15 (23.8%) and 10 pts (16%) respectively with a case of grade 3 in both. Other relevant observed toxicity were, anemia in 10 pts (16%) and piastrinopenia in 5 pts (7.9%). Overall, 27 pts (43%) reduced EV dosage to 5 mg per day. 15 pts (23.8%) were 70 years or older and among them 6 (43%) stopped treatment for toxicity and 8 (53%) decreased EV dosage. Furthermore, we admitted 2 pts for enteritis. The incidence of toxicity was similar in elderly patients, except for fatigue observed in 7 pts (46.6%). Conclusions: In our real life experience the activity and toxicity of EV plus EX treatment was comparable to BOLERO-2 study except for oral mucositis and metabolic disorder. A careful patient’s proactive monitoring is strictly necessary in order to minimize the toxicity and obtained the best results of combination.
Abstract 10173: Risk Factors of Cardiovascular Disease in Breast Cancer Patients
Authors: Aniket Kawatkar, Aileen Baecker, Mingsum Lee, Chun Chao, Joan Ryoo, chengyi zheng, Rita F Redberg
Journal: Circulation (2021)

Introduction: Cardiovascular disease (CVD) events during cancer treatment can interfere with the delivery of curative therapy. In adult cancer survivors, CVD mortality is second only to cancer recurrence related mortality. We evaluated the demographic and clinical risk factors of CVD in breast cancer patients. Methods: A retrospective cohort study was conducted at Kaiser Permanente Southern California (KPSC) health system. We identified adult members (18+) diagnosed with primary breast cancer from 01/2000-12/2019 using the KPSC cancer registry. We only included patient who had at least one year of continuous health plan enrollment prior to their cancer diagnosis to determine risk factors status and to ensure they did not have any history of CVD (defined as cardiac arrest, cardiomyopathy, congestive heart failure, coronary atherosclerosis, heart valve disorders, myocardial infarction, ventricular fibrillation, dysrhythmias or stroke) prior to their cancer diagnosis. We evaluated the association of age at cancer diagnosis; race; ethnicity; obesity; cancer stage; and history of depression, drug abuse, renal failure, liver disease, lipid disorder, diabetes and hypertension using a proportional hazard model. All patients were followed from their cancer diagnosis to the earliest date of CVD (failure event) diagnosis or death or health plan disenrollment or end of study (12/2020). Results: In the cohort of 36,840 patients (Table 1), 11,993 (33%) had a CVD diagnosis during follow-up (average follow-up 5.3 years). The hazard rate of CVD increased significantly with age. Distant metastatic disease was associated with 7-fold higher CVD hazard as compared to in-situ cancer. Most other clinical factors significantly increased the hazard rate (Table 1). Conclusions: In breast cancer patients naïve to CVD disease prior to cancer diagnosis, the hazard rate of CVD post cancer diagnosis is significantly higher in older individuals and those with metastatic disease.
BIOM-13. DEVELOPMENT AND VALIDATION OF AN LC-MS/MS ASSAY TO MEASURE GLUTATHIONE, GLUTATHIONE DISULFIDE, CYSTEINE, AND CYSTINE IN HUMAN BRAIN AND HUMAN GLIOBLASTOMA
Authors: Miao Liu, Tigran Margaryan, Nader Sanai, Artak Tovmasyan
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Oxidative stress is implicated in many pathological conditions. Herein, we report on our development and validation of a sensitive and rapid LC-MS/MS method for the determination of oxidative stress biomarkers glutathione (GSH), glutathione disulfide (GSSG), cysteine (Cys) and cystine (CySS) in human brain and glioblastoma tissue. METHODS Freshly-acquired human glioblastoma tissue was homogenized with N-ethylmaleimide solution to prevent thiol oxidation. Analytes were then extracted from homogenate samples by protein precipitation with 2% sulfosalicylic acid (SSA). Stable isotope-labeled analytes were used as internal standards. Independent calibration curves for thiols and disulfides were prepared in analytical solutions. Three levels of quality controls were prepared in human brain homogenate. The detection was performed on Sciex QTRAP 6500+ mass spectrometer in positive electrospray ionization mode. RESULTS Linear regression model was used to cover a concentration ranging 0.4-100 µmol/L for GSSG/CySS and 1-400 µmol/L for GSH/Cys. Chromatographic separation was optimized on Intrada Amino Acid column with total run time of 5 min using gradient elution. For all analytes the maximum coefficient of variation for intra- and inter-day precision was 11.4% and the accuracy was within 80.9-113.7% in analytical solution and matrix. The analytes were stable in brain homogenate for 1 hour and 3 hours at room temperature (RT) and 4 °C, respectively. Stability at -80°C was demonstrated for at least 35 days in human brain homogenate. Stability of stock and working solutions was demonstrated for at least 4 hours (RT) and 25 days (-20°C). CONCLUSIONS A bioanalytical method to quantify GSH, GSSG, Cys, and CySS is successfully developed and validated. The method is currently applied to measure thiols and related disulfides in human glioblastoma tissue undergoing 5-aminolevulinic acid sonodynamic therapy (NCT04559685).
The High Mobility Group A1 Chromatin Regulator Drives Immune Evasion during MPN Progression By Repressing Genes Involved in Antigen Presentation and Immune Attack
Authors: Joseph Kim, Jung-Hyun Kim, Leslie Cope, Liping Li, Raajit Rampal, Richard Koche, Donna M Williams, Jerry L. Spivak, Alison R. Moliterno, Linda Resar
Journal: Blood (2021)
Abstract 13169: Serum Calcium is Positively Associated With Right Ventricular Function as Assessed by Hemodynamics and Echocardiography
Authors: Carlos Lynes, Timothy E Thayer, Andrew P Defilippis, Evan Brittain
Journal: Circulation (2021)

Introduction: The physiologic role of calcium for cardiomyocyte contractility is well established. Post cardiac surgery, maintaining normocalcemia is associated with improved right ventricular (RV) function as compared to hypocalcemia. Hypothesis: We hypothesize that lower serum ionized calcium (iCa) is associated with RV dysfunction in non-surgical subjects. Methods: From a de-identified electronic health record, we extracted demographic, laboratory, echocardiographic, and first right heart catheterization (RHC) data to perform a cross-sectional analysis. iCa, obtained within 2 days of RHC, was tested for association with hemodynamics and pulmonary artery pulsatility index (PAPI; pulmonary artery pulse pressure / right atrial pressure) as a measure of RV function. We tested the association of iCa with reader-assessed RV dysfunction by echocardiography. RV dysfunction was coded as 0=none, 1=mild, 2=moderate, and 3=severe. All analyses were performed using ordinal regression adjusted for age, sex, and self-declared race. Results: From the 1,658 participants identified: median age 61 years, 42% female, 76% white, 18% black, 82% with mean pulmonary artery pressure ≥20mmHg, and 28% with pulmonary vascular resistance ≥3 Wood units. We observed a positive association between iCa and PAPI (Figure 1A, P&lt;0.0001, n=1,658). Higher iCa was positively associated with systemic pressures and negatively associated with pulmonary pressures (P&lt;0.01). By echocardiography, lower iCa was associated with higher prevalence of RV dysfunction (Figure 1B, P&lt;0.0001, n=1,355). Conclusion: In a clinical population referred for RHC, we concluded that higher iCa was associated with better RV function assessed by invasive hemodynamics and echocardiography. Further studies are needed to assess whether there is an etiologic relationship between iCa and RV function.
Abstract 10307: Predictors of Growth Trajectory in Infants with Congenital Heart Disease
Authors: Amy J Lisanti, Jungwon Min, Nadya Golfenshtein, Chitra Ravishankar, John M Costello, Desiree Fleck, Liming Huang, Barbara Medoff-Cooper
Journal: Circulation (2021)

Introduction: Infants born with critical congenital heart disease (cCHD) are known to experience growth failure in infancy, particularly those with single ventricle physiology. Differences in early weight-for-age Z-score growth trajectory (WAZ-GT) within this population have not been defined. We aimed to describe the WAZ-GT of infants with cCHD after cardiac surgery in the first 4 months of life and assess potential risk factors. Methods: This is a secondary analysis of a previously reported RCT, REACH telehealth program (2012-2017, Trial NCT01941667). Sample included both intervention and control infants (n=178). Weights over the first 4 months of life were converted to WAZ using the World Health Organization standards. WAZ-GT classes were identified using latent class growth modeling. Multinomial logistic regression models were used to examine the associations between socio-demographic and clinical characteristics and WAZ-GT classes. Results: Four distinct classes of WAZ-GT were identified (maintaining WAZ &gt;0, 14%; stable around WAZ=0, 35%; partially recovered, 28%; never recovered, 23%; see Figure). No differences existed in WAZ-GT when stratified by single and two ventricle physiology or by telehealth intervention and control groups. The stable around WAZ=0 class was assigned as the reference group. Compared with these infants, those in the never recovered class were 3-6 times more likely to have length of stay (LOS) ≥ 14 days, tube feeding at discharge, and low appetite. Partially recovered infants were 3 times more likely to have LOS ≥ 14 days and be an only child. Infants maintaining WAZ &gt;0 were 3 times more likely to have two ventricle physiology and parents with at least a college education and who did not report infant borderline appetite. Conclusions: This study is the first to describe distinct classes of WAZ-GT for infants with cCHD early in infancy. We identified associated predictors that can be used to target interventions in this vulnerable population.
Elapsed time since BNT162b2 vaccine and risk of SARS-CoV-2 infection: test negative design study
Authors: Ariel Israel, Eugene Merzon, Alejandro A Schäffer, Yotam Shenhar, Ilan Green, Avivit Golan-Cohen, Eytan Ruppin, Eli Magen, Shlomo Vinker
Journal: BMJ (2021)

To determine whether time elapsed since the second injection of the Pfizer-BioNTech BNT162b2 mRNA vaccine was significantly associated with the risk of covid-19 infection after vaccination in people who received two vaccine injections.Test negative design study.Electronic health records of a large state mandated healthcare organisation, Israel.Adults aged ≥18 years who had received a reverse transcription polymerase chain reaction (RT-PCR) test between 15 May 2021 and 17 September 2021, at least three weeks after their second vaccine injection, had not received a third vaccine injection, and had no history of covid-19 infection.Positive result for the RT-PCR test. Individuals who tested positive for SARS-CoV-2 and controls were matched for week of testing, age category, and demographic group (ultra-orthodox Jews, individuals of Arab ancestry, and the general population). Conditional logistic regression was adjusted for age, sex, socioeconomic status, and comorbid conditions.83 057 adults received an RT-PCR test for SARS-CoV-2 during the study period and 9.6% had a positive result. Time elapsed since the vaccine injection was significantly longer in individuals who tested positive (P<0.001). Adjusted odds ratio for infection at time intervals >90 days since vaccination were significantly increased compared with the reference of <90 days: 2.37 (95% confidence interval 1.67 to 3.36) for 90-119 days, 2.66 (1.94 to 3.66) for 120-149 days, 2.82 (2.07 to 3.84) for 150-179 days, and 2.82 (2.07 to 3.85) for ≥180 days (P<0.001 for each 30 day interval).In this large population of adults tested for SARS-CoV-2 by RT-PCR after two doses of mRNA BNT162b2 vaccine, a gradual increase in the risk of infection was seen for individuals who received their second vaccine dose after at least 90 days.
A practical strategy to develop isoform-selective near-infrared fluorescent probes for human cytochrome P450 enzymes
Authors: Lei Feng, Xiangge Tian, Dahong Yao, Zhenlong Yu, Xiaokui Huo, Zhenhao Tian, Jing Ning, Jingnan Cui, Tony D. James, Xiaochi Ma
Journal: Acta Pharmaceutica Sinica B (2021)

Currently, the development of selective fluorescent probes toward targeted enzymes is still a great challenge, due to the existence of numerous isoenzymes that share similar catalytic capacity. Herein, a double-filtering strategy was established to effectively develop isoenzyme-specific fluorescent probe(s) for cytochrome P450 (CYP) which are key enzymes involving in metabolism of endogenous substances and drugs. In the first-stage of our filtering approach, near-infrared (NIR) fluorophores with alkoxyl group were prepared for the screening of CYP-activated fluorescent substrates using a CYPs-dependent incubation system. In the second stage of our filtering approach, these candidates were further screened using reverse protein-ligand docking to effectively determine CYP isoenzyme-specific probe(s). Using our double-filtering approach, probes
Somatic <i>STAT3</i> Mutations in CD8+ T Cells of HTLV-2 Positive Blood Donors
Authors: Daehong Kim, Mikko Myllymäki, Matti Kankainen, Timo Jarvinen, Giljun Park, Roberta Bruhn, Edward L Murphy, Satu Mustjoki
Journal: Blood (2021)