tbuckley/cabot-search huggingface dataset:
Abstract 12751: Diallyl Trisulfide Augments Lymphangiogenesis via an Akt-Dependent Mechanism and Ameliorates Lymphedema
Authors: Junya Suzuki, Yuuki Shimizu, Zhongyue Pu, Takumi Hayashi, Yiyang Che, John W Calvert, Toyoaki Murohara
Journal: Circulation (2021)

Background: Secondary lymphedema is one of the serious clinical problems that can often occur after surgical resection of malignant tumors. However, no effective treatment options exist at present. Diallyl trisulfide (DATS) is an organic polysulfide found in garlic oil that liberates H2S under physiological conditions. We previously demonstrated that DATS augmented reparative angiogenesis and improved blood perfusion recovery in the HLI model. Here, we investigated the effects of DATS on lymphatic vessel growth and lymphedema in a mouse model and assessed its potential mechanism. Methods and Results: A mouse model of lymphedema was created by ablation of a tail surface lymphatic network, and the tail diameter was measured to estimate lymphedema at day 28 after induction of lymphedema. Lymphatic vessels were detected by immunohistochemical staining as LYVE-1 and podoplanin double-positive cells. The DATS group was intraperitoneally injected with DATS for up to 10 days following lymphedema induction. DATS treated mice (n=10) showed a smaller tail thickness compared with control wild-type (WT) mice (n=11) (p&lt;0.001) which was accompanied by a greater number of lymphatic vessels in the injured tails (p&lt;0.05). Interestingly, the distal lymphatic lumen area was dilated in the control group, whereas the DATS treatment group improve dilated lymphatic area at the distal site of the injured point (p&lt;0.001). In vitro experiments revealed that treatment with DATS promoted the differentiation of human lymphatic endothelial cells (LECs) into tube-like structures (p&lt;0.001) in a dose-dependent manner, when cultured on Matrigel matrix. DATS also stimulated the phosphorylation of Akt in LECs. Furthermore, blockade of Akt activation canceled the DATS-stimulated increase in LEC differentiation. Conclusions: Our data clearly demonstrate that DATS promotes reparative lymphatic vessel growth and ameliorates secondary lymphedema, at least in part, through activation of the Akt pathway within lymphatic endothelial cells.
DDRE-40. BIOINFORMATICS ANALYSIS OF GRADE I AND III MENINGIOMA GENE EXPRESSION SUGGESTS MMP28 AS A POSSIBLE POSITIVE PROGNOSTIC INDICATOR
Authors: Sharon Michelhaugh, Gregory Dyson, Rouba Ali-Fehmi, Aliccia Bollig-Fischer, Sandeep Mittal, Katherine Degen
Journal: Neuro-Oncology (2021)

Abstract Meningiomas are the most common primary brain tumor. Grade I meningiomas are slow growing with a good prognosis following surgical resection. High grade meningiomas (II and III) are more aggressive with greater rates of recurrence and poor prognosis despite surgical resection and radiotherapy. This study sought to identify key pathways and genes that contribute to the molecular mechanisms that separate these distinct meningioma phenotypes. FFPE specimens were evaluated and graded by a pathologist. Total RNA was extracted from tissue curls and RNA samples were measured with the Illumina DASL whole genome gene expression assay (n = 29,374 probes). A log2 transformation was applied to all of the data and quantile normalization using 21 samples. A t-test of the log2 expression of the 10 grade III samples and 11 grade I samples resulted in 1505 differentially expressed genes. The GeneCard Suite’s GeneAnalytics tool was used to perform pathway enrichment analysis. Similar to other comparable data sets, DNA Damage, Cell Cycle, EGF/EGFR Signaling, TGF-Beta Signaling, and PI3K-AKT Signaling pathways were among the 20 enriched pathways. Notably, matrix metalloprotease 28 (MMP28, also known as epilysin) was down regulated in grade III meningiomas compared to grade I (III/I expression ratio 0.315; P=0.015). MMP28 is expressed in numerous tissues including the nervous system during development and regeneration. In cancer, MMP28 is thought to enhance epithelial to mesenchymal transition by altering the TGF-B signaling pathways. MMP28 is an indicator of poor prognosis for pancreatic, lung, gastric and hepatic cancers as well as glioblastoma. However, MMP28 has also been reported as down regulated during malignant transformation in colon cancer. Our data suggest that MMP28 may have an alternative role in meningioma and serve as a positive prognostic indicator.
RADT-22. CONCURRENT TTFIELDS (200 KHZ) WITH CHEMORADIATION FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA MAY INCREASE THE RATE OF PSEUDOPROGRESSION: ANALYSIS OF A PILOT CLINICAL TRIAL
Authors: Muneeb Niazi, James Taylor, Ryan Miller, Ayesha S Ali, Voichita Bar-Ad, Nina, L Martinez, Jon Glass, Iyad Alnahhas, David Andrews, Kevin Judy, James Evans, Christopher Farrell, Haisong Liu, Wenyin Shi
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE The standard of care for the adjuvant treatment of glioblastoma is concurrent chemoradiation, maintenance temozolomide, and Tumor Treating Fields (TTFields). TTFields may reversibly impact the blood-brain barrier, most significantly at 100 kHz. We hypothesized that this may increase the rate of pseudoprogression (PsP) in patients who receive concurrent chemoradiation with TTFields (200 kHz). METHODS This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Patients with newly diagnosed glioblastoma, age ≥ 18 years, and KPS ≥ 60 were eligible. They received concurrent temozolomide (75 mg/m2), scalp-sparing radiation (60 Gy in 30 fractions), and TTFields (200 kHz). Radiation was delivered through the TTFields arrays. PsP was defined as radiographic progression of enhancing lesions without clinical decline that improved or remained stable upon subsequent imaging. The rate of PsP was determined by an evaluation of the 2nd MRI at our multidisciplinary tumor board after the completion of trimodality treatment. These findings were confirmed with official radiology reports. RESULTS 30 patients were enrolled. Of these, 29 had imaging available for evaluation. Male-to-female ratio was 20:10. Median follow-up was 11.6 months (1.6-22.4 months), median age was 58 years (19-77 years), and median KPS was 90 (70-100). 20 (66.7%) patients had unmethylated and 10 (33.3%) had methylated MGMT promotor. Median time from surgery to initiation of radiation was 34 days (26-49 days). Median time from completion of trimodality treatment to 2nd follow-up MRI was 90 days (29-109 days). 15/29 (51.7%) patients had PsP. Patients with methylated and unmethylated MGMT promotor had 50.0% (5/10) and 52.6% (10/19) rates of progression respectively. CONCLUSIONS 51.7% of the patients who received concurrent chemoradiation with TTFields demonstrated PsP. The incidence is greater than historical reports. However, these findings should be explored in larger cohorts as this study was limited by a small sample size.
RTID-03. DESIGN AND INITIATION OF PIVOTAL STUDIES FOR BERUBICIN, A NOVEL, POTENT TOPOISOMERASE II POISON FOR THE TREATMENT OF RECURRENT GLIOBLASTOMA MULTIFORME (GBM)
Authors: Sandra Silberman, Sigmund Hsu, Zena Muczyczenko, Donald Picker, Marek Sipowicz, Ewa Żak, Agnieszka Buczyńska, Mariusz Olejniczak, Waldemar Priebe
Journal: Neuro-Oncology (2021)

Abstract Berubicin (WP744) is a doxorubicin analog that crosses the blood-brain barrier (BBB), shows significant CNS uptake, and induces more DNA damage but lower lethality than doxorubicin at equivalent doses. Berubicin also prolongs the survival time of intracranial orthotopic glioma models in mice compared to temozolomide, currently the standard of care in GBM. A Phase 1 study at MD Anderson in patients with recurrent glioma treated with escalating doses of Berubicin administered qdx3 repeated q21 days showed that it was well tolerated, with myelosuppression (neutropenia and thrombocytopenia) as the dose-limiting toxicity. Of 25 patients evaluable for efficacy, there was 1 complete response (13+ years), 1 partial response, and 10 patients with stable disease for a clinical benefit rate of 48%. To assure a rapid and economically practicable development program, two companies have collaborated to conduct trials in the US and EU, leading to a potentially more rapid approval of Berubicin for treating GBM in patients with limited options. CNS Pharmaceuticals, Inc. has initiated a randomized, controlled clinical trial of Berubicin vs. lomustine in adults with recurrent GBM. WPD Pharmaceuticals has sub-licensed Berubicin to study recurrent GBM in adults in an open-label trial. This is a unique collaboration in which the same overall design, eligibility criteria, procedures, and database for patients receiving Berubicin are used by both companies, ensuring that there will be a more robust and substantial data set for evaluation of activity and safety. The primary endpoint of the CNS study, to be conducted in the US and Europe, is overall survival (OS). The WPD study conducted in the EU has a primary endpoint of overall response rate (ORR). The data from these two trials are expected to provide sufficient information to support a potential registration program in both the US and EU for the treatment of patients with glioblastoma.
Development of an MDM2 Degrader for Treatment of Acute Leukemias
Authors: Bridget Marcellino, Xiaobao Yang, He Chen, Karie Chen, Claudia Brady, Cara Clementelli, Zhijun Li, Ronald Hoffman, Jing Liu, H Ümit Kaniskan, Yue Xiong, Jian Jin, Alan H. Shih
Journal: Blood (2021)
Immunodeficiency Genes Are Associated with EBV Positive Malignancies and Hemophagocytic Lymphohistiocytosis That Can be Cured By Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Yanzhi Song, Caiyan Zhang, Zhihui Li, Erhui Yuan, Qishu Qin, Qinlong Zheng, Tong Wu
Journal: Blood (2021)
Imaging neuroinflammation with TSPO: A new perspective on the cellular sources and subcellular localization
Authors: Tomás R. Guilarte, Alexander N. Rodichkin, Jennifer L. McGlothan, Arlet Maria Acanda De La Rocha, Diana J. Azzam
Journal: Pharmacology & Therapeutics (2021)

Translocator Protein 18 kDa (TSPO), previously named Peripheral Benzodiazepine Receptor, is a well-validated and widely used biomarker of neuroinflammation to assess diverse central nervous system (CNS) pathologies in preclinical and clinical studies. Many studies have shown that in animal models of human neurological and neurodegenerative disease and in the human condition, TSPO levels increase in the brain neuropil, and this increase is driven by infiltration of peripheral inflammatory cells and activation of glial cells. Therefore, a clear understanding of the dynamics of the cellular sources of the TSPO response is critically important in the interpretation of Positron Emission Tomography (PET) studies and for understanding the pathophysiology of CNS diseases. Within the normal brain compartment, there are tissues and cells such as the choroid plexus, ependymal cells of the lining of the ventricles, and vascular endothelial cells that also express TSPO at even higher levels than in glial cells. However, there is a paucity of knowledge if these cell types respond and increase TSPO in the diseased brain. These cells do provide a background signal that needs to be accounted for in TSPO-PET imaging studies. More recently, there are reports that TSPO may be expressed in neurons of the adult brain and TSPO expression may be increased by neuronal activity. Therefore, it is essential to study this topic with a great deal of detail, methodological rigor, and rule out alternative interpretations and imaging artifacts. High levels of TSPO are present in the outer mitochondrial membrane. Recent studies have provided evidence of its localization in other cellular compartments including the plasma membrane and perinuclear regions which may define functions that are different from that in mitochondria. A greater understanding of the TSPO subcellular localization in glial cells and infiltrating peripheral immune cells and associated function(s) may provide an additional layer of information to the understanding of TSPO neurobiology. This review is an effort to outline recent advances in understanding the cellular sources and subcellular localization of TSPO in brain cells and to examine remaining questions that require rigorous investigation.
Abstract 9994: SVEAT Score Outperforms the HEART Score for Acute Chest Pain Risk Stratification in Patients Admitted to the Clinical Decision Unit
Authors: Daniel Antwi-Amoabeng, Munadel Awad, Chanwit Roongritong
Journal: Circulation (2021)

Introduction: Timely and accurate identification of subgroups at risk for major adverse cardiovascular events (MACE) among patients presenting with acute chest pain remains a challenge. The HEART score is one of the most used risk stratification tools in the United States. Recently, a new scoring system based on clinical symptoms (S), history of vascular disease (V), electrocardiography (E), age (A), and serum troponin (T), SVEAT score was shown to outperform the HEART score. Hypothesis: We predicted that the SVEAT score is superior to the HEART score in predicting a 30-day MACE in patients admitted to the clinical decision unit for chest pain evaluation. Methods: Medical records of 330 consecutive patients admitted to our clinical decision unit for acute chest pain between January 1st to April 17th, 2019, were retrospectively reviewed. The 30-day MACE was the combined endpoint of death, acute myocardial infarction, or confirmed coronary artery disease that required revascularization or medical therapy. The investigators assigned to calculate the SVEAT, and HEART scores were blinded to the results of the 30-day MACE. An area under the receiver-operator characteristic curve (AUC) for each score was then calculated. The C-statistic and a logistic model were used to compare the predictive performance of the two scores. Results: A total of 11 patients (3.33%) experienced the endpoint. The AUC of the SVEAT score (0.8876, 95% C.I. 0.82 - 0.96) was significantly higher than the HEART score (0.7960, 95% C.I. 0.71 - 0.88), p = 0.03 (Fig 1). Using logistic model, a SVEAT score with a cut-off of ≤ 4 as low-risk significantly predicts 30-day MACE (odd ratio 1.52, C.I. 1.19-1.95, p = 0.001), but the HEART score did not (odd ratio 1.29, C.I. 0.78-2.14, p = 0.32). Conclusion: The SVEAT score is a superior risk stratification tool to the HEART score in low-to-intermediate-risk acute chest pain patients without apparent acute coronary syndrome.
Abstract 14094: Characterizing Dual Combination Therapy Use In Treatment Escalation Of Hypertension: Real-world Evidence From Multinational Cohorts
Authors: Yuan Lu, Jing Li, Xialin Wang, Sreemanee Dorajoo, Mengling Feng, Min-Huei Hsu, Jason C. C Hsu, Jiyoung Hwang, Usman Iqbal, Zhengfeng J Chen, Jitendra Jonnagaddala, Yu-Chuan Y Li, Teng Liaw, Kee Yuan Ngiam, Phung-Anh Nguyen, Rae Woong Park, Nicole Pratt, Christian Reich, Sang Youl Rhee, Selva M Sathappan, Hui Xing Tan, Seng Chan You, Xin Zhang, Harlan M Krumholz, Marc Suchard, Yun Liu, Mui Van Zandt, Hua Xu
Journal: Circulation (2021)

Introduction: Over one billion adults have hypertension globally, of whom 70% cannot achieve hypertension control with monotherapy. Data are lacking on patterns of dual combination therapies prescribed to patients who escalate from monotherapy. Methods: We described dual combination therapy utilization using eleven electronic health record databases covering 118 million patients across eight countries. We identified patients who newly initiated dual combination of four most commonly used antihypertensive drug classes (angiotensin-converting enzyme inhibitor [ACEi] or angiotensin receptor blocker [ARB]; calcium channel blocker [CCB]; beta-blocker; and thiazide or thiazide-like diuretic) after being on monotherapy. Results: We identified 980,648 patients with hypertension initiating dual combination therapy with antihypertensive agents after being on monotherapy: 12,541 from Australia, 6,980 from South Korea, 2,096 from Singapore, 7,008 from China, 16,663 from Taiwan, 103,994 from France, 76,082 from Italy, and 754,137 from the United States (US). Significant variations in treatment utilization existed across countries and patient subgroups. In Australia and Singapore, starting an ACEi/ARB monotherapy followed by a CCB was most common while in South Korea, China and Taiwan, starting a CCB monotherapy followed by an ACEi/ARB was most common. In Italy, France, and the US, sequential use of an ACEi/ARB monotherapy followed by a diuretic was most common. Younger patients were more likely to be prescribed ACEi/ARB followed by either a CCB or a diuretic compared with older patients. Women were more likely to be prescribed diuretics then an ACEi/ARB or a CCB compared with men. Conclusion: A large variation in the transition between monotherapy and dual combination therapy for hypertension was observed across countries. These results highlight the need for future research to identify which dual combination therapy is most effective for which patients.
IMMU-49. DYNAMIC CHANGES AND PROGNOSTIC VALUE OF PERIPHERAL BLOOD LYMPHOCYTE SUBSETS IN INTRACRANIAL GERM CELL TUMORS
Authors: Hairong Wang, Cheng-Cheng Guo, Hongyu Chen, Yang Qun-ying, Zhong-ping Chen
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE This study was designed to retrospectively analyze the dynamic changes of peripheral blood lymphocyte subsets and prognosis among patients with intracranial germ cell tumors. METHODS A total of 150 intracranial germ cell tumors patients diagnosed between June 2011 till November 2019 were retrospectively investigated. Peripheral blood total T lymphocytes (CD3+) percentage, T helper/inducible lymphocytes(CD3+CD4+)percentage, T inhibitory/toxic lymphocytes (CD3+CD8+) percentage, B lymphocyte (CD19+) percentage, NK lymphocyte (CD3/CD16+CD56+) percentage, regulatory T cells (CD4+CD25+,CD8+CD25+), and T helper/toxic lymphocyte ratio (CD4+/CD8+ ratio) were quantified by flow cytometry analysis. Clinical information was extracted from the database in Sun Yat-sen University Cancer Center and survival data was confirmed through outpatient visits and telephone follow-up. RESULTS T lymphocytes population was increased after anti-tumor treatment, with significant difference of total T lymphocytes (CD3+), inhibitory/toxic T cells (CD3+CD8+) and regulatory T cells (CD4+CD25+ and CD8+CD25+), (p=0.008, p=0.000, p=0.008 and p=0.001 respectively), while B lymphocytes(CD19+) decreased after chemotherapy(p=0.003). The dynamic levels of T lymphocyte and B lymphocyte subpopulation after chemotherapy did not present significant differences between gender, age, and locations of tumors (p &amp;gt;0.05), except CD4+CD25+ T cells in younger children (age&amp;lt; 16 years older) increased significantly than the elder (age &amp;gt;16), p=0.04. Patients with increased CD19+ B cells presented significant suboptimal outcomes compared with the no increased (p=0.024). Similarly, increased CD3+ T cells, CD3+CD8+ T cells, CD4+CD25+ T cells reduced the risk of death (p=0.006, p=0.019, p=0.042 respectively). Multivariate Cox Regression analysis showed: increased CD19+ B cells, p=0.04, HR=1.688, 95%CI=1.025-2.779. CONCLUSION After anti-tumor treatment, cell-mediated immunity activated, enhanced, and dominated in anti-tumor response. An increased level of CD19+ subsets was an independent predictor for inferior overall survival. Systemic circulating T cells immunity played an important role and mediating antitumor responses may pave the road for new immunity strategies.
Abstract 14050: Characteristics of Extracellular Vesicle miRNAs in the Breast Milk
Authors: Young-eun Cho, Rany Vorn, Keith Crouch, Janhavi Narayanaswamy, Changgee Chang
Journal: Circulation (2021)

Introduction: An increasing number of obese mothers is a rising issue that may negatively impact the overall benefit of breastfeeding. Extracellular vesicles (EVs) in breast milk are important mediators transferring biological molecules of mothers to children, because EV-miRNAs can survive in the stomach and then might be internalized into gut epithelial cells. In this study, we examined breast milk EV-miRNAs to determine the impact of the mother’s pre-pregnancy BMI on the EV-miRNA profiles. Methods: We recruited healthy nursing mothers who delivered a singleton baby in the past 6 months. Mothers pumped breast milk after 1-hour fasting and froze them. EVs were isolated from breast milk with ultracentrifugation. EV characteristics were examined by flow cytometry using 39 different EV markers. A total of 800 miRNAs were screened using a human miRNA panel (NanoString diagnostics, WA). Differential expression analysis was performed using DESEQ2. Results: We included 27 nursing mothers; the mean age was 31.1±7.6 years old, and 92% were Caucasian. All mothers breastfed their children and 22% of mothers supplemented with formula. Mean pre-pregnancy BMI was 21.6±2.0 kg/m 2 in the lean group (BMI&lt;25kg/m 2 , n=17), and 29.1±4.5 kg/m 2 in the overweight/obese group (BMI≥25kg/m 2 , n=10). Besides BMI, all other demographics were not significantly different between groups. Breast milk EVs expressed not only general EV markers including CD9, CD63, and CD81, but also CD14, CD24, CD133/1, HLA-DRDPDQ and CD326. The most highly expressed marker is CD326 showing more than 2 times higher intensity than the general EV markers. Marker profiles were not different between groups. After normalization with housekeeping genes and spike-in controls, we obtained 10 differentially expressed miRNAs in the overweight/obese group (p&lt;0.05 cut-off). Among those, miR-490-5p, miR-139-3p, and miR-291a-3p were the top 3 deregulated miRNAs downregulated in the overweight/obese group with a fold change &gt;1.5. Conclusion: We found (1) CD326 as a breast milk EV marker, and (2) deregulated miRNAs in the overweight/obese mothers’ breast milk. Our findings will provide the opportunity to improve the quality of breast milk which ultimately promotes the children’s growth and health.
Antibody response to the BNT162b2 SARS-CoV-2 vaccine in paediatric patients with inflammatory bowel disease treated with anti-TNF therapy
Authors: Zahra Jama Shire, Frederic Reicherz, Sally Lawrence, Harjeev Sudan, Liam Golding, Abdelilah Majdoubi, Paul N Levett, Pascal M Lavoie, Kevan Jacobson
Journal: Gut (2021)