tbuckley/cabot-search huggingface dataset:
Lenalidomide Exposure at Time of CAR T-Cells Expansion Enhances Response of Refractory/Relapsed Aggressive Large B-Cell Lymphomas
Authors: Jean Lemoine, Florence Morin, Roberta Di Blasi, Laetitia Vercellino, Alexis Cuffel, Naoufal Benlachgar, Jerome Larghero, Isabelle Madelaine, Julien Calvani, Veronique Meignin, Sophie Caillat-Zucman, Sylvie Chevret, Catherine Thieblemont
Journal: Blood (2021)
A Phase II Study of Lenalidomide, Ixazomib, Dexamethasone, and Daratumumab in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma (AFT-41)
Authors: Elizabeth K. O'Donnell, Vera Jean Suman, Susan M. Geyer, Omar Nadeem, Shira Dinner, Andrew J. Yee, Jacob P. Laubach, Clifton C. Mo, Sascha A. Tuchman, Kristen Donadio, Sarah Sinclair, Noopur S. Raje, Paul G. Richardson
Journal: Blood (2021)
CBIO-07. ST-401: A BRAIN-PENETRANT MICROTUBULE-TARGETING AGENT THAT KILLS CANCER CELLS IN INTERPHASE
Authors: Juan Jesus Vicente Ruiz, Linda G Wordeman, Nephi Stella
Journal: Neuro-Oncology (2021)

Abstract Microtubule targeting agents (MTAs) are indispensable medicines to treat a wide range of cancers, and evidence suggests that glioblastoma is sensitive to disruptions in microtubule (MT) functions; but most MTAs do not cross the blood brain barrier. To address this limitation, we developed a brain-penetrant MTA, ST-401, that inhibited the growth of human glioblastoma in culture at nanomolar concentrations (Horne et al. (2020) Neuro-Onc Adv. 3(1): vdaa165). Of note, ST-401 binds to the colchicine site, inhibits tubulin assembly and reversibly reduces MT dynamics in cells with a milder activity compared to the reference MTA, nocodazole. Pharmacokinetic analysis of ST-401 in mice shows brain penetration reaching antitumor concentrations, and in vivo testing of ST-401 demonstrated significant antitumor and radiosensitizing activities. Testing of ST-401 on the NCI 60 cancer cell panel indicated that its anti-tumor activity 1) did not correlate with any of the compounds tested thus far and 2) only weakly correlated with MTAs that act through alternate mechanisms [Taxol and Vinblastine]. Thus, ST-401 may kill cancer cells through a novel mechanism related to disruption of MT function that is different from MTAs tested thus far on the NCI 60 cancer cell panel. As initial step to discover this novel mechanism of action, we studied the anti-tumor activity of ST-401 and nocodazole in HCT116 cells in culture. As expected, low concentrations (30 and 100 nM) of nocodazole killed HCT116 cells in mitosis and increased p-P53; by contrast these low concentrations of ST-401 killed HCT116 cells in interphase and did not increase p-P53. Our study shows that the brain-penetrant MTA, ST-401, kills cancers in interphase, a response that contrasts with the activity of the reference MTA nocodazole. ST-401 represents a promising chemical scaffold to develop brain-penetrant therapeutics for the treatment of patients diagnosed with glioblastoma.
Regulation of epigenetic homeostasis in uveal melanoma and retinoblastoma
Authors: Peiwei Chai, Ruobing Jia, Yongyun Li, Chuandi Zhou, Xiang Gu, Ludi Yang, Hanhan Shi, Hao Tian, Huimin Lin, Jie Yu, Ai Zhuang, Shengfang Ge, Renbing Jia, Xianqun Fan
Journal: Progress in Retinal and Eye Research (2021)
Abstract 6948: Barriers to Obtaining a Home Aed for Pediatric Patients With Primary Arrhythmia Syndromes
Authors: Brynn E Dechert-Crooks, Martin J LaPage
Journal: Circulation (2021)

Introduction: Guidelines for primary arrhythmia syndromes (PAS) recommend the presence of automatic external defibrillator (AED) at least during athletic participation. Studies have shown a cost-effective and life-saving benefit to these patients having a home ED. Objective: To evaluate the challenges in obtaining a home AED. Methods: A single center retrospective chart review identified pediatric patients with a PAS in which the obtention of an AED was discussed during a clinical evaluation. These families were then surveyed by telephone regarding the method, ease, and challenges of securing a home AED. Results: Home AED discussion was documented for 28 patients of which 27 (96%) participated in the survey. Nearly all (25 of 27) attempted to obtain an AED; though only 15 (55%) were ultimately successful. Most, 17/25 (68%) initially attempted via insurance; while 4 purchased independently, 2 received a donated AED, and 2 abandoned due to cost. For patients utilizing insurance, only 7 (41%) were successful, with 5/7 utilizing a 3 rd party facilitator of insurance approval (LifeSure). LifeSure successfully gained coverage in 5 of 6 (83%) attempted cases. Of the 10 failing to obtain insurance coverage, 6 do not have an AED, 3 self-purchased one, and 1 received a donated AED. On a difficulty scale of 1-5 (1=easy; 5=very challenging), families perceived the mean difficulty score to obtaining an AED through insurance at 3.5 vs. 1.16 for those not attempting insurance. Insurance was viewed as a major barrier (scale score &gt;3) for 9 of the 17 (53%) families attempting to use it. Mean difficulty score when using LifeSure vs. not, was 1.8 vs 4.5. Families able to afford a self-purchased AED perceived minimal challenges, mean scale score 1.5. Conclusions: When clinically appropriate, families of pediatric patients with a primary arrhythmia syndrome successfully obtained an AED in about half of cases. Insurance was perceived as a major barrier. Use of a 3 rd party service to facilitate insurance coverage was highly successful and relatively simple. Though shown to be life-saving and cost-effective, access to home AED is inequitable and disadvantaged by financial and insurance barriers.
Abstract 14349: Transcatheter Edge-to-Edge Mitral Repair versus Surgery in Medicare Patients
Authors: Joanna Chikwe, Amy Roach, Natalia Egorova
Journal: Circulation (2021)

Background: The optimal therapy for patients with primary mitral regurgitation eligible for transcatheter mitral edge-to-edge repair (TEER) and surgery is not known. This study compared mid-term outcomes of TEER and mitral surgery for primary mitral regurgitation. Methods: Centers for Medicare and Medicaid data was used to identify 158,931 adults who underwent mitral repair (42.9%, n=68,166) or TEER (14.5%, n=23,008) between July 2012 and June 2019. Patients undergoing mitral replacement (42.6%, n=67,757), previous mitral intervention (3.1%, n=4877), secondary, rheumatic or infectious etiology (26.3%, n=41,821), coronary or valve surgery (22.2%, n=35,438), and urgent procedures (15.6%, n=24,768) were excluded, and 4550 propensity matched patient pairs created. The primary outcome was 3-year survival. Stroke and mitral re-intervention were compared using competing risk analysis, with a landmark analysis of new atrial fibrillation (AF) after 30-days. Results: In the overall cohort patients undergoing TEER were older, with worse comorbidity and frailty than patients undergoing surgery. In propensity matched patients mean age was 77.3 vs. 76.4 years (P=NS) and frailty score was 0.2 vs. 0.19 (P=NS). Three-year mortality after surgery was 14% (standard error (SE) 0.02) versus 34% (standard error (SE) 0.03) after TEER (p&lt;0.0001) (Figure). In competing risk analysis at three years stroke rates were similar (hazard ratio (HR) 1.07, 95% confidence interval (CI) 0.80-1.45), mitral reintervention was less common (HR 0.26, 95% CI 0.20-0.34); new AF was significantly less common (HR 0.82, 95% CI 0.7-0.96) after surgical repair compared to TEER. Conclusion: In propensity matched patients with primary mitral regurgitation surgical mitral repair was associated with superior survival, freedom from new AF and mitral re-intervention. This treatment difference, which may be due to selection bias, should be evaluated in randomized trials.
Abstract 12682: Markers of Microbial Translocation Biomarkers in People Living With HIV Infection and Their Relationship With Myocardial Function and Fibrosis: Myocardial and Coronary Abnormalities in HIV Infection (MACHIN) Study
Authors: Farhaad Khan, April Banayan, Pavan Reddy, Arazin Minasian, Ahsan Javed, Samuel Valencerina, Hossein Bahrami
Journal: Circulation (2021)

Background: Microbial translocation (MT) is suggested to play a role in increases risk of myocardial fibrosis (MF) and LV dysfunction in people living with HIV infection (PLWH). We investigated the association of biomarkers of MT with myocardial disease in MACHIN study. Methods: Biomarkers of MT (soluble CD14 (sCD14), FABP, SGP130, and BDG) were measured in serum samples of 92 participants (54 PLWH and 38 HIV- controls, mean age 47±14 years, 28% female). Myocardial structure and function were assessed using CMR. In addition, our protocol included detection of overt MF using delayed-enhancement images as well as diffuse MF using extracellular volume (ECV)-measured by T1 mapping. Results: FABP levels were significantly higher in PLWH compared to controls (percentage of people in higher tertile 17% vs 47%, respectively, OR: 4.4, 95% CI: 1.4-13.5, p: 0.01) and this association was significant after adjustment for age and race. Higher values of FABP were significantly correlated with presence and extent of MF. Participants with higher tertile of FABP had a significantly higher odds of presence of MF (ECV above median) compared to controls (OR: 5.9, 95% CI: 1.3, 27.0, p: 0.02) after adjustment for HIV status, age, gender, and race. Furthermore, participants with high FABP also had higher extent of MF (calculated ECV values) compared to controls (adjusted regression coefficient 6.7%, p&lt;0.01). Importantly, while HIV infection was significantly associated with presence and extent of MF, these associations were not significant when FABP was added to the models, suggesting that FABP may explain the relationship between HIV infection and MF. PLWH had significantly higher levels of sCD14 compared to controls (p &lt;0.05), even after adjustment for age, gender, and race (p-value: 0.04). However, serum levels of sCD14 was not associated with LV and RV systolic function, LV mass, MF, or delayed-enhancement on cardiac MRI. SGP130 and BDG were not significantly associated with MF. Conclusion: Increased levels of biomarkers of microbial translocation is observed in virologically-suppressed PLWH and may explain the increased risk of MF in these patients.
IMMU-19. EVALUATING EFFECTS OF REVERSING DISTINCT FACETS OF IMMUNOSUPPRESSION IN EXPERIMENTAL GBM
Authors: Katayoun Ayasoufi, Zachariah Tritz, Cori Fain, Roman Khadka, Fang Jin, Michael Hansen, Aaron Johnson
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma is associated with severe and multifaceted immunosuppression affecting all immune organs. Immunosuppression in GBM is a critical barrier to the success of immunotherapies and patient survival. We demonstrated that immunosuppression in the GL261-model of experimental GBM presents with significant thymic and spleen atrophy, MHCII downregulation, presence of potent immunosuppressive factors in serum, and sequestration of T-cells in the bone marrow. Parabiosis studies determined that soluble factors mediate immunosuppression by inhibiting T-cell proliferation, thymic involution, and loss of peripheral T-cells. In contrast, bone marrow T-cell sequestration was not mediated through soluble factors. While the immunosuppression in GBM is severe, a causative link between each facet of immunosuppression and overall survival is lacking. We used two strategies to block T-cell sequestration into the bone marrow and evaluated the extent survival was impacted in experimental GBM. First, we evaluated the extent a novel and off-the-shelf combination immunotherapy that uses extended 1/2-life IL-2 and anti-PD-1 reverses bone marrow T-cell sequestration. Sham treatment or anti-PD1 monotherapy did not alter T-cell sequestration in the bone marrow and animals had no enhanced survival. Extended 1/2-life IL-2 monotherapy and combination strategy both prevented T-cell sequestration into the bone marrow. However, only combined therapy, which also prevented MHC class II downregulation, improved survival. Second, we determined that glioma-bearing adrenalectomized mice do not present with bone marrow T-cell sequestration. However, sera of glioma-bearing adrenalectomized mice is as immunosuppressive as glioma-bearing controls. Blocking bone marrow T-cell sequestration in the presences of serum immunosuppression led to no survival benefit in glioma-bearing adrenalectomized mice compared to controls. In short, bone marrow T-cell sequestration alone does not correspond with overall survival in experimental glioma. Importantly, a concerted effort to reverse MHC class II downregulation and define inhibitory circulating factors may have the highest impact in immunotherapeutic efficacy and improving patient survival.
DDRE-09. MULTI-INSTITUTION RETROSPECTIVE EXPERIENCE WITH LENVATINIB FOR PROGRESSIVE MALIGNANT GLIOMA
Authors: Jose Carrillo, Naveed Wagle, Jose Carrillo, Joanna Juntila, Minhdan Nguyen, Judy Truong, Eve Landa, Erin Curry, Tiffany Juarez, Santosh Kesari
Journal: Neuro-Oncology (2021)

Abstract Despite treatment with radiation and temozolomide chemotherapy, malignant gliomas inevitably recur after treatment and have poor prognosis. Clinical trials should be offered when available, but effective treatment options for multiply recurrent tumors is sparse. In our multi-institutional retrospective cohort, we looked at recurrent malignant gliomas treated with Lenvatinib multi-kinase inhibitor. Patients consented to an IRB-approved study protocol that allows for longitudinal history review and analysis at our institution. Lenvatinib is a targeted therapy that is FDA approved for Differentiated Thyroid Cancer, Renal Cell Carcinoma, Hepatocellular Carcinoma, and Endometrial Carcinoma. Lenvatinib binds to tyrosine kinase receptors inhibiting kinase activity by VEGFR1-3, FGFR1-4, PDGFRa, FGF, KIT, and RET. In this cohort, patients received radiation and temozolomide chemotherapy, N=15, median age was 45.5, and 47% were male. At time of surgery 40% underwent biopsy, 40% had STR, and 20% had GTR. Glioblastoma was the most common tumor type at 87%, 6.7% were recurrent anaplastic astrocytoma, and 6.7% were recurrent glioma NOS. IDH mutation was seen in 13% of our cohort, and MGMT methylation was seen in 27%, all patients had available IDH and MGMT data. Patients were heavily treated, median number of recurrences was 3. Patient mean PFS was 2.7 months, and median OS was 24.0 months. Clincal Benefit Rate (PR+SD) to Lenvatinib in recurrent disease was 57%, with 29% Partial Responses and 29% Stable Disease as best radiographic response. This retrospective cohort supports further evaluation of the efficacy of Lenvatinib in recurrent malignant glioma in a clinical trial.
Management of cardiovascular disease using an mHealth tool: a randomized clinical trial
Authors: Si-Hyuck Kang, Hyunyoung Baek, Jihoon Cho, Seok Kim, Hee Hwang, Wonjae Lee, Jin Joo Park, Yeonyee E. Yoon, Chang-Hwan Yoon, Young-Seok Cho, Tae-Jin Youn, Goo-Yeong Cho, In-Ho Chae, Dong-Ju Choi, Sooyoung Yoo, Jung-Won Suh
Journal: npj Digital Medicine (2021)

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death and morbidity worldwide. This randomized controlled, single-center, open-label trial tested the impact of a mobile health (mHealth) service tool optimized for ASCVD patient care. Patients with clinical ASCVD were enrolled and randomly assigned to the intervention or control group. Participants in the intervention group were provided with a smartphone application named HEART4U, while a dedicated interface integrated into the electronic healthcare record system was provided to the treating physicians. A total of 666 patients with ASCVD were enrolled, with 333 patients in each group. The estimated baseline 10-year risk of cardiovascular disease was 9.5% and 10.8% in the intervention and control groups, respectively, as assessed by the pooled cohort risk equations. The primary study endpoint was the change in the estimated risk at six months. The estimated risk increased by 1.3% and 1.1%, respectively, which did not differ significantly (P = 0.821). None of the secondary study endpoints showed significant differences between the groups. A post-hoc subgroup analysis showed the benefit was greater if a participant in the intervention group accessed the application more frequently. The present study demonstrated no significant benefits associated with the use of the mHealth tool in terms of the predefined study endpoints in stable patients with ASCVD. However, it also suggested that motivating patients to use the mHealth tool more frequently may lead to greater clinical benefit. Better design with a positive user experience needs to be considered for developing future mHealth tools for ASCVD patient care.Trial Registration: ClinicalTrials.gov NCT03392259.
Abstract 10602: Baseline Clinical and Genetic Data Based Machine Learning Predictions of 1-Year Ischemic Outcomes Following Percutaneous Coronary Intervention
Authors: Caroline Grant, Anvi Raina, Ryan Lennon, Shaun G Goodman, Rajiv Gulati, Amir Lerman, Yves Rosenberg, Derek So, Michael E Farkouh, Arjun Athreya, Naveen L Pereira
Journal: Circulation (2021)

Background: Ischemic event rates are low after percutaneous coronary intervention (PCI), conversely second generation P2Y12 inhibitors increase bleeding therefore identifying patients at risk to enable precision in prescribing dual anti-platelet therapy (DAPT) is of clinical interest. Prior machine-learning predictive analyses have been limited by use of older generation stents and lack of genetic data. We utilized clinical and genetic data of patients with new generation stents enrolled in TAILOR-PCI, a 40-center international trial to predict ischemic events after PCI. Methods: There were 4398 eligible post PCI patients with acute coronary syndromes or stable coronary artery disease who were randomly split into training (n=3299) and validation (n=1099) cohorts. The primary endpoint comprising of cardiovascular death, myocardial infarction, stroke, or stent thrombosis within 12 months of PCI was predicted with patient characteristics prior to hospital discharge. First, random forests were used for feature selection with 1,000 bootstraps comprising equal numbers of those with and without ischemic events to minimize the bias of sample imbalance. Features were selected by a consensus on variable-importance over bootstraps. Second, using these features in the training cohort, support vector machines (SVM) with a polynomial kernel was trained with repeated 5-fold cross validation to choose a model with highest area under the receiver operating characteristic curve (AUC) which was then used to predict ischemic events in the validation cohort. Results: The primary endpoint occurred in 2.4% of patients. Using 89 clinical and genetic variables in the random-forest feature selection step, variable importance-based consensus identified 50 top predictors. These 50 predictors achieved AUC=0.703 in the SVM training cohort and AUC=0.744 (specificity=0.84; sensitivity =0.43) in the SVM validation cohort. Conclusions: Machine learning methods using baseline clinical and genetic data enables prediction of infrequent ischemic events in post PCI patients receiving new generation stents. The role of such artificial intelligence algorithms in individualization of DAPT by identifying high or low risk patients needs to be explored.
Hematopoiesis and innate immunity: an inseparable couple for good and bad times, bound together by an hormetic relationship
Authors: Mariusz Z. Ratajczak, Magdalena Kucia
Journal: Leukemia (2021)

Abstract Hematopoietic and immune cells originate from a common hematopoietic/lymphopoietic stem cell what explains that these different cell types often share the same receptors and respond to similar factors. Moreover, the common goal of both lineages is to ensure tissue homeostasis under steady-state conditions, fight invading pathogens, and promote tissue repair. We will highlight accumulating evidence that innate and adaptive immunity modulate several aspects of hematopoiesis within the hormetic zone in which the biological response to low exposure to potential stressors generally is favorable and benefits hematopoietic stem/progenitor cells (HSPCs). Innate immunity impact on hematopoiesis is pleiotropic and involves both the cellular arm, comprised of innate immunity cells, and the soluble arm, whose major component is the complement cascade (ComC). In addition, several mediators released by innate immunity cells, including inflammatory cytokines and small antimicrobial cationic peptides, affect hematopoiesis. There are intriguing observations that HSPCs and immune cells share several cell-surface pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs) and cytosol-expressed NOD, NOD-like, and RIG-I-like receptors and thus can be considered “pathogen sensors”. In addition, not only lymphocytes but also HSPCs express functional intracellular complement proteins, defined as complosome which poses challenging questions for further investigation of the intracellular ComC-mediated intracrine regulation of hematopoiesis.
Abstract 11655: Echocardiographic Assessment of Strain and Associations With Markers of Clinical Severity in Multi-System Inflammatory Syndrome in Children (MIS-C) Associated With COVID-19
Authors: Daniel McAree, Jennifer Arzu, Amanda Hauck, Jen Acevedo, Michael R Carr, Ami B Patel, Nazia Husain
Journal: Circulation (2021)

Introduction: Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 can cause cardiovascular dysfunction. We aimed to determine if strain abnormalities persist in MIS-C patients 3-10 weeks post-discharge, and whether acute markers of clinical severity are associated with lower strain at subacute follow-up. Methods: We performed a retrospective cohort study of MIS-C patients admitted at a single center from 3/2020-3/2021. Demographic and clinical variables during hospitalization were obtained. Global longitudinal strain (GLS), 4-chamber longitudinal strain (4C-LS), mid-papillary circumferential strain (CS), and left atrial strain (LAS) at 3-10 week follow-up were compared to age matched controls (n=10). Bivariate analyses were performed using Spearman rank correlation and two-sample t-test or Wilcoxon rank sum test. Results: Sixty MIS-C patients were identified (age 8.9 +/- 4 years, 35/60 male, 39% Hispanic, 29% African American). Hypotension (65%), ICU admission (57%), and inotropic support (45%) were common; 7% received mechanical ventilation. No deaths or need for ECMO were reported. Median length of stay (LOS) was 7 days. LVEF was &lt;55% in 28% during hospitalization (median 57% [52-61]) and 6% at follow-up (median 65% [61-67]). Peak NT-proBNP (median 5321 pg/ml [IQR 1712, 17400]) and peak CRP (median 17 mg/dl [12, 22]) were significantly associated with hypotension, ICU admission, and total ICU days. Forty-five patients had available follow-up imaging for strain. CS (mean -26.0 vs -28.6; p=0.009) and LAS (mean -34.5 vs -51.2; p=0.001) were lower in MIS-C vs controls, but not GLS or 4C-LS. Lower CS (-24.2 +/- 3.1 vs -26.7 +/- 2.7; p=0.04) and lower 4C-LS (-19.1 +/- 1.9 vs -21.2 +/- 3.3; p=0.04) were associated with abnormal EF (&lt;55%) during acute illness. CS was lower in those admitted to ICU (-25.1 +/- 2.6 vs -27.5 +/- 2.9; p=0.03). Peak CRP correlated with lower CS (r= -0.41, p=0.03) and GLS (r= -0.55, p=0.01) at follow-up. Conclusions: MIS-C patients show abnormal strain during subacute follow-up despite improvement in EF. Lower CS, GLS, and 4C-LS were associated with in-hospital markers of clinical severity. This data may allow for identification of at-risk MIS-C patients and help guide outpatient cardiology follow-up.