tbuckley/cabot-search huggingface dataset:
The use of nondirected donor organs in living donor liver transplantation: Perspectives and guidance
Authors: Alyson N. Fox, AnnMarie Liapakis, Ramesh Batra, Therese Bittermann, Juliet Emamaullee, Sukru Emre, Yuri Genyk, Hyosun Han, Whitney Jackson, Elizabeth Pomfret, Muhammad Raza, Manuel Rodriguez‐Davalos, Susan Rubman Gold, Benjamin Samstein, Akhil Shenoy, Timucin Taner, John P. Roberts
Journal: Hepatology (2021)

Abstract Interest in anonymous nondirected living organ donation is increasing in the United States and a small number of transplantation centers are accumulating an experience regarding nondirected donation in living donor liver transplantation. Herein, we review current transplant policy, discuss emerging data, draw parallels from nondirected kidney donation, and examine relevant considerations in nondirected living liver donation. We aim to provide a consensus guidance to ensure safe evaluation and selection of nondirected living liver donors and a schema for just allocation of nondirected grafts.
Abstract MP248: Sequestrosome1/p62 Regulates Redox Homeostasis Via The Nrf2-keap1 Pathway In The Murine Heart
Authors: Amir N Fatahian, Rajeshwary Ghosh, Karla M Pires, TARIQ MOSLEH, Vishaka Vinod, Sidney Vowles, Kenneth S Campbell, J David D Symons, Sihem Boudina
Journal: Circulation Research (2021)

Sequestosome1 (p62) is a multifunctional signaling molecule and an autophagy adaptor protein. Previous work demonstrated that mice with whole-body p62 knockout recapitulated many detrimental features of aging. Of note, these mice developed late onset obesity and systemic abnormalities that could have contributed to their aging phenotype. Multiple studies have also shown that cardiac dysfunction can be linked to an increase in oxidative stress. The Nrf2-Keap1 pathway is critical for protection against oxidative stress and p62 has been shown to interact with Keap1, thus allowing Nrf2 activation to induce anti-oxidant responses. However, the role of p62 in the heart is not well known. We tested the hypothesis that p62 plays an important homeostatic role in the heart through the regulation of redox homeostasis via the Nrf2-Keap1 pathway. Wild-type and cardiomyocytes-specific p62 knockout (cp62 KO) mice at 8 weeks and 60 weeks of age were used. At 8 weeks, cp62KO mice exhibited mild but significant contractile dysfunction compared to the wild-type controls. By 60 weeks, the KO mice developed cardiac hypertrophy, fibrosis and increased oxidative stress. cp62 KO hearts had decreased Nrf2 nuclear translocation and activation as evidenced by a 50% (p&lt;0.005) reduction in the expression of the Nrf2 target glutathione S-transferase A4 ( Gsta2 ) gene. These findings were further validated by transcriptomic analysis followed by KEGG pathway analysis, which indicated that redox pathways were altered in the 60-week p62 null hearts. To examine the mechanisms involved in p62 regulation of Nrf2-Keap signaling, we utilized rat cardiac H9c2 myoblasts. Loss of p62 using p62 siRNA in H9c2 cells resulted in decreased Nrf2 levels and increased oxidative stress. These pathological consequences of suppressing p62 could be attributed to increased Nrf2 degradation via the proteasome. Together, these results reveal a previously uncharacterized role for p62 in the maintenance of cardiac redox signaling in the mouse heart.
CSIG-06. ELUCIDATING THE ROLE OF CO-OCCURRING MUTATIONS IN FGFR1-DRIVEN PEDIATRIC LOW-GRADE GLIOMA
Authors: Eric Morin, Jeromy DiGiacomo, Seth Malinowski, Sanda Alexandrescu, David Jones, Keith Ligon, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2021)

Abstract Pediatric low-grade gliomas (pLGGs) have excellent survival, however, with current standard of care, most patients suffer lifelong severe sequalae. pLGGs are almost exclusively driven by single activating mutations in the mitogen-activated protein kinase (MAPK) pathway. As targeted molecular therapy clinical trials focusing on BRAF-altered pLGGs are showing promising results in early clinical trials, similar efforts are underway for FGFR1-altered tumors. In our cohort of FGFR1-4 altered gliomas, we observe frequent occurrence of a second alteration associated with activation of the MAPK or mammalian target of rapamycin (mTOR) pathways in pLGGs. Most commonly in the phosphatase NF1, PIK3CA, PIK3R1 PTPN11 or within the FGFR1 gene itself. However, the impact of second co-occurring mutations on therapeutic response and resistance has not been explored. To address this, we established mouse neural stem cell models over-expressing hot-spot mutated FGFR1 alone or in combination with a second alteration. Immunoblotting revealed that the addition of a second alteration attenuated phosphorylation of ERK, AKT and S6 and influenced cell proliferation both in normal growth conditions and in absence of growth factor. Treatment with an FGFR inhibitor (Infigratinib) showed reduced drug response in double mutant cells compared to hot-spot mutated FGFR1 alone. This was associated with less reduction of phosphorylation of ERK and S6 in the double mutant cells upon treatment. In conclusion, the presence of a second alteration influences proliferation and drug response in models of FGFR1-mutated pLGG, potentially by modulating MAPK and mTOR signaling.
Plans to reform adult social care fall short of promises, say critics
Authors: Jacqui Wise
Journal: BMJ (2021)

The government's long awaited proposals on adult social care have been criticised for failing to tackle the current high levels of unmet need and workforce shortages. The white paper for social care reform, People at the Heart of Care ,1 sets out how £1bn (€1.18bn; $1.33bn) for system reform will be spent over the next three years:
TMOD-12. COMPARING TUMOR CELL INVASION AND MYELOID CELL COMPOSITION IN GENETICALLY IDENTICAL PRIMARY AND RELAPSING GLIOBLASTOMA
Authors: Roland Kälin, Dongxu Zhao, Huabin Zhang, Ramazan Uyar, Jörg-Christian Tonn, Rainer Glass
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) recurrence after treatment is almost inevitable, but addressing this issue with adequate preclinical models has remained challenging. Here, we introduce a GBM mouse model allowing non-invasive and scalable de-bulking of a tumor mass located deeply in the brain, which can be combined with conventional therapeutic approaches. Towards this aim we genetically engineered mouse GBM cells to stably express the herpes simplex virus thymidine kinase. Strong reduction of the GBM volume is achieved after pharmacologically inducing a tumor-specific cell death mechanism by the prodrug ganciclovir. This is followed by GBM re-growth over a predictable timeframe. Pharmacological de-bulking followed by tumor relapse was accomplished with an orthotopic mouse glioma model. Relapsing experimental tumors recapitulated pathological features often observed in recurrent human GBM, like increased invasiveness or altered immune cell composition. Orthotopic implantation of GBM cells originating from biopsies of one patient at initial or follow-up treatment reproduced these findings. Interestingly, relapsing GBM of both models contained a much higher ratio of monocyte-derived macrophages (MDMs) versus microglia than primary GBM. This was not altered when combining pharmacological de-bulking with invasive surgery. We interpret that factors released from viable primary GBM cells preferentially attract microglia whereas relapsing tumors preponderantly release chemoattractants for MDMs. All in all, this relapse model has the capacity to provide novel insights into clinically highly relevant aspects of GBM treatment.
Quality of Death Certificate Occupation Information
Authors: Samuel Milham, Jr., M.D.
Journal: JNCI Journal of the National Cancer Institute (1985)

Quality of Death Certificate Occupation Information Get access Samuel Milham, Jr., M.D. Samuel Milham, Jr., M.D. Epidemiology Section, ET-13, Division of Health, Washington State Department of Social and Health Services, Olympia, Washington 98504 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 74, Issue 2, February 1985, Page 539, https://doi.org/10.1093/jnci/74.2.539 Published: 01 February 1985
Abstract 10426: Worse Clinical Outcomes in Patients with Acute Coronary Syndrome and Prior or New Onset Heart Failure: Insights from 47,474 Patients in a Pooled Analysis of Randomized Clinical Trials
Authors: Nathan Goodwin, Robert M Clare, Daniel Wojdyla, Josephine Harrington, Anish Badjatiya, Jacob A Udell, Javed Butler, James L Januzzi, Puja Parikh, Stefan K James, John H Alexander, Renato D Lopes, Lars C Wallentin, E Magnus M Ohman, Adrian F Hernandez, William S Jones
Journal: Circulation (2021)

Introduction: Heart failure (HF) frequently complicates acute coronary syndrome (ACS). Despite known associated high rates of mortality, there are only limited data regarding recurrent ischemic events and re-hospitalization for HF (HHF) in those with HF and ACS. Methods: We used a pooled dataset of four randomized clinical ACS trials (Platelet Inhibition and Patient Outcomes [PLATO], Apixaban for Prevention of Acute Ischemic Events 2 [APPRAISE-2], Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome [TRA-CER], and Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndrome [TRILOGY ACS]). We assessed the association between HF status (history of HF, de novo HF, no HF) at presentation for ACS on death, future ischemic events, and HHF at one year following hospital discharge using Cox proportional hazards analysis and estimated cumulative event rates using cumulative incidence function. Results: Of 47,474 patients presenting with ACS, 11.1% showed evidence of acute HF, 55.0% of whom had no previous history of HF. Patients with prior/chronic HF were more likely to present with acute HF than those with no previous HF (40.3% vs 6.9%). Compared to those without HF, patients with prior and de novo HF were at a significantly increased risk at one year of all-cause mortality (adjusted HR (aHR) 2.10, 95% Confidence Interval [CI] 1.80-2.45, and aHR 1.51, CI 1.18-1.93, respectively), MACE (aHR 1.50, CI 1.34-1.69, and aHR 1.40, CI 1.14-1.72), recurrent MI (aHR 1.58, CI 1.41-1.78, and aHR 1.40, CI 1.15-1.70), stroke (aHR 1.93, CI 1.67-2.32, and aHR 1.38, CI 1.09-1.75), and HHF (aHR 2.38, CI 2.09-2.71, and aHR 1.53, CI 1.24-1.88). Conclusion: Following an ACS event, both prior and de novo HF were found to be major predictors of death, recurrent ischemic events, and HHF by one year. These findings highlight the need for improved strategies to prevent and manage adverse outcomes in this high-risk population.
TMOD-01. AN IN VIVO FUNCTIONAL GENOMICS SCREEN TO IDENTIFY NOVEL DRIVERS OF LUNG-TO-BRAIN METASTASIS
Authors: Nikoo Aghaei, Fred C Lam, Ekkhard Kasper, Chitra Venugopal, Sheila K Singh
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Brain metastases, the most common tumors of the central nervous system, occur in approximately 20% of primary adult cancers. In particular, 40% of patients with non-small cell lung cancer develop brain metastasis. As systemic therapies for the treatment of non-small cell lung cancer become increasingly effective at controlling primary disease, patients are ironically succumbing to their brain metastases. This highlights a large unmet need to develop novel targeted therapies for the treatment of lung-to-brain metastases (LBM). We hypothesize that an in vivo functional genomic screen can identify novel genes that drive LBM. METHODS To do this, we developed a patient-derived xenograft (PDX) mouse model of LBM using patient lung cancer cell lines. This PDX model of LBM enables the use of fluorescent and bioluminescent in vivo imaging to track the progression of lung tumor and brain metastases. RESULTS We have performed an in vivo genome-wide CRISPR activation screening to identify novel drivers of LBM. We will derive candidate genes through mouse brain and lung tissue sequencing after mice reach endpoint. EXPECTED AREA OF FINDINGS This platform will lead to potential therapeutic targets to prevent the formation of LBM and prolong the survival of patients with non-small cell lung cancer. LIMITATIONS There may be limitations in getting candidate hits that overlap in all mice in our first replicate. This can be remedied by conducting the in vivo screen in at least three biological replicates. CONCLUSION To the best of our knowledge, this is the first genome-wide in vivo CRISPR activation screen searching for drivers of LBM using a PDX animal model. This study can provide a framework to gain a deeper understanding of the regulators of BM formation which will hopefully lead to targeted drug discovery.
Parathyroidectomy in Elderly Individuals With Primary Hyperparathyroidism
Authors: Anand R. Habib, Mitchell H. Katz
Journal: JAMA Internal Medicine (2021)

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Opto-vTrap, an optogenetic trap for reversible inhibition of vesicular release, synaptic transmission, and behavior
Authors: Joungha Won, Yuriy Pankratov, Minwoo Wendy Jang, Sunpil Kim, Yeon Ha Ju, Sangkyu Lee, Seung Eun Lee, Arie Kim, Soowon Park, C. Justin Lee, Won Do Heo
Journal: Neuron (2021)
Meeting the Moment: Bioethics in the Time of Black Lives Matter
Authors: Camisha Russell
Journal: The American Journal of Bioethics (2021)

In this article, I begin by describing what I call this Black Lives Matter moment in the US. I then offer three reasons for considering racism as a bioethical issue, the least discussed of which is the way in which racism acts as a barrier to the creation of better healthcare systems. Next, I argue that the concept of race itself constitutes a bioethical issue in a way that is not fully reducible to racism. Finally, I discuss how we, both bioethicists and health care professionals, might meet this moment by identifying individual points of responsibility (beyond liability) for structural injustice.
Abstract 11607: Protein Citrullination Landscape of Human Coronary Atherosclerosis
Authors: Aneta Stachowicz, Chunhong Mao, James Hixson, Fannie R Jackson, Richard Vander Heide, Jennifer E Van Eyk, David M Herrington, Justyna P Fert-Bober
Journal: Circulation (2021)

Introduction: Recently, an irreversible enzymatic post-translational modification, citrullination, has been shown to be present in the cardiovascular system (e.g. aorta). Citrullination, in which arginine is converted to citrulline, can alter protein structure and function, and produce autoantigens Hypothesis: Emerging evidence suggest a potential role for autoimmunity in the pathogenesis of atherosclerosis. However, it remains unknown whether of post-translational citrullination of arterial proteins contributes to local inflammatory processes that initiate or accelerate the atherosclerotic process. The aim of this study was to investigate changes in protein citrullination in human left anterior descending (LAD) coronary artery specimens with and without early atherosclerosis obtained from autopsied young adults with no clinical manifestations of coronary disease. Methods: Segments of the mid-LAD from 74 autopsied individuals (age range:15-55 yrs., 75% male, 67% White) were graded by a pathologist for percent of surface area involved with fatty streaks (FS) or fibrous plaque (FP). The frozen samples were homogenized and digested with Lys-C for subsequent proteomic mass-spectrometry using a data-independent acquisition (DIA) proteomic strategy with a hyper-citrullinated spectral library approach and our published CitFinder software. Results: We found 133 differentially expressed proteins (FDR&lt;0.05) between control, FS and FP groups. Among them, 19 citrullinated proteins with 26 modified amino acid residues were identified. Citrullinated peptides from fibrinogen alpha chain (R84) and transgelin (R146) were upregulated in FP samples in comparison to FS and normal samples. Similarly, the citrullination site (R269) on alpha-enolase was significantly increased in the FP samples compared to normal. Interestingly, citrullination (R110) on myosin light polypeptide 6 was downregulated in FP samples. Conclusions: These data represent the most comprehensive interrogation of citrullinated proteins in human arterial samples to-date and suggest a possible association between this modification of several key proteins involved in tight junction, vascular smooth muscle contraction and inflammation and early atherosclerosis.
TMOD-20. CASE REPORT: THE ODYSSEY TO THE RIGHT DIAGNOSIS. SURPRISING GLIOBLASTOMA MIMICS
Authors: Patrick Dorin, Wolfgang Jochum, Arno Lauber, Marian Christoph Neidert, Thomas Hundsberger
Journal: Neuro-Oncology (2021)

Abstract A 57-year-old female presented at the emergency room with acute onset aphasia but unremarkable cCT (incl. angiography and perfusion). Suspecting an ischemic stroke, she received thrombolysis with quick recovery of aphasia. Afterwards, myoclonic jerks of the face and right arm occurred leading to anticonvulsant therapy. Follow-up cMRI surprisingly demonstrated swollen T2w-hyperintense and Gd-enhancing left limbic, temporal and frontal lobes. Suspected herpes-simplex-encephalitis was treated with aciclovir despite unremarkable CSF results (no pleocytosis, no BBB disruption, negative HSV-PCR) on day 2 and follow-up (day 5). Due to persisting cognitive deficits, autoimmune limbic encephalitis was suspected, and intravenous immunoglobulin therapy was added. Three weeks later, she experienced new neurological symptoms (weakness, blurred vision, vomiting, headache). Follow-up brain MRI demonstrated a massive increase of multifocal Gd-enhancing lesions. Partial resection revealed the diagnosis of an IDH-wildtype glioblastoma (GB). Next generation oncogene panel testing demonstrated a GOPC-ROS1 fusion which is rarely found in GB. Due to the gliomatosis-like infiltration of both hemispheres, radiotherapy was deemed to be too toxic. Instead, she received two cycles of lomustine in absence of a MGMT-promotor methylation. Two months later cMRI showed a symptomatic second multilocular progression. 2nd-line therapy with a ROS-inhibitor was rejected, whereupon she died five weeks later. Our case is in several aspects peculiar: It demonstrates that rare GB-mimics (i.e. HSV- and autoimmune limbic encephalitis) can only be ruled out in a fast manner by brain biopsy. Watchful waiting may neglect fast progression of GB leading to the inability to provide optimal treatment (i.e. radiotherapy). Thrombolysis is strictly contraindicated in primary brain tumors, but was unharmful in our case most probably to the early tumor stage without relevant neoangiogenesis. Rare genetic abnormalities like ROS1-fusions which are reported mostly in childhood glioblastoma may be present and serve as a therapeutic target also in adult GB.
Abstract 10387: Utility of Esophageal Image Segmentation for Guidance of Posterior Wall Lesions During Atrial Fibrillation Ablation
Authors: MirMilad Pourmousavi Khoshknab, Tarek Zghaib, Lingyu Xu, Jeffrey Arkles, Pasquale Santangeli, Francis Marchlinski, Yuchi Han, Benoit Desjardins, Saman Nazarian
Journal: Circulation (2021)

Introduction: Despite luminal esophageal temperature (LET) monitoring, esophageal injury remains a risk which impacts decision making during atrial fibrillation (AF) ablation. We sought to compare procedural characteristics including radiofrequency (RF) power, duration, and LET, among ablation procedures with and without visualization of esophageal segmentations relative to the left atrial dome. Hypothesis: We sought to test the hypothesis that esophageal image registration and visualization during AF ablation would improve operator efficiency and reduce esophageal temperature changes during the procedure. Methods: The retrospective cohort included 63 patients (mean age 65.5 ± 8.8 years, 33% female, 54% paroxysmal AF) that underwent pre-procedural cardiac magnetic resonance (CMR) and LET monitoring. Of all patients, 35 underwent standard AF ablation without esophageal image segmentation, and 28 underwent AF ablation with registration of esophageal image segmentation. Results: Total RF time was shorter with esophageal visualization (28.6 ± 11.8 min versus 39.1 ± 22.5 min, P&lt;0.05). The distribution of ablation power delivery was skewed toward higher power with esophageal visualization (P&lt;0.001), while the mean LET was identical among patient groups and the standard deviation of LET was lower in those with esophageal visualization (35.9 ± 0.5 °C versus 35.9 ± 0.7 °C, P=NS). The within patient standard deviation for LET change during posterior wall ablation was 0.3 ± 0.1 °C and 0.4 ± 0.2 °C for patients with and without esophageal visualization respectively (P=0.017). Conclusions: Esophageal visualization was associated with improved efficiency of AF ablation using higher power and resulting in shorter RF time, while reducing the variation in esophageal temperature.