tbuckley/cabot-search huggingface dataset:
RADT-08. A VOLUMETRIC ANALYSIS OF STEREOTACTIC RADIOSURGERY LOW DOSE VOLUMES IN PREVENTING FUTURE BRAIN METASTASES
Authors: John Shumway, Won Sup Yoon, Xianming Tan, Eric Schreiber, Ted Yanagihara, Sivakumar Jaikumar, Deanna Sasaki-Adams, Carolyn Quinsey, Matthew Ewend, Shiva Das, Lawrence Marks, Colette Shen
Journal: Neuro-Oncology (2021)

Abstract PURPOSE/OBJECTIVE(S) Stereotactic radiosurgery (SRS), compared to whole brain radiotherapy is limited in its ability to prevent development of brain metastases in untreated areas. The purpose of this study is to assess whether low-dose volumes delivered to uninvolved regions of the brain during SRS can reduce the risk of developing brain metastases in those regions. MATERIALS AND METHODS Data were collected for 69 patients with brain metastases who were treated with SRS at least two occasions. The regions of uninvolved brain receiving a high, intermediate, and low dose of incidental radiotherapy were defined as the volume receiving at least 10, 5, and 2.5 Gy if the prescribed dose was &amp;lt; 25 Gy (1-3 fraction plans) or the volume receiving at least 15, 7.5, and 5 Gy if the prescribed dose was ≥ 25 Gy (5 fraction plans). A second round metastasis was considered to occur within a given dose level if 20% or more of the tumor was found within that dose level. Probabilities were calculated based on the volume of each dose level as a percentage of total brain volume and were used to estimate the expected number of cases with at least one metastasis occurring in each dose level. RESULTS The average number of metastases treated in both rounds of SRS was two. The expected and observed number of cases with at least one second round metastasis were 0 and 2 for the high dose level (p=0.151), 7 and 3 for the intermediate dose level (p=0.018), and 17 and 11 for the low dose level (p=0.094). CONCLUSION We observed fewer than expected new metastases within prior SRS low dose levels based on volumetric probabilities, though this difference was only significant for the intermediate dose level. This suggests that low dose volumes from SRS may provide benefit in preventing future regional metastases.
Outcomes of Single Versus Tandem Hematopoietic Stem Cell Autologous Transplant in High-Risk Myeloma Patients: A Single-Center Experience
Authors: Shona Philip, Mina Dehghani, Lenicio Siqueira, Anthony Quint, Selay Lam, Chai Wye Phua, Anargyros Xenocostas, Uday Deotare, Martha L Louzada
Journal: Blood (2021)
Giving and taking: ethical treatment assignment in controlled trials
Authors: Stephen Senn, Iain Chalmers
Journal: Journal of the Royal Society of Medicine (2021)

The current version of the Declaration of Helsinki states that ‘the benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention(s) … ’. This wording implies that it is acceptable for patients to be assigned to receive an unproven new intervention and to be denied a best current proven intervention. We assert that patients being invited to participate in controlled trials cannot, ethically, be expected to forego proven beneficial forms of care. Patients being treated in controlled trials should not knowingly be disadvantaged compared with similar patients being treated in usual clinical care, where they have access to beneficial care. In this article, we have tried to separate for discussion ‘the withholding of effective care from trial participants’, ‘informed consent to treatment’, ‘blinding’ and ‘use of placebos’.
Genetic predisposition of the severity of joint destruction in rheumatoid arthritis; a population based study
Authors: Rachel Knevel, Gerður Gröndal, Tom W J Huizinga, A Willemien Visser, Helgi Jónsson, Arnór Víkingsson, Árni Jón Geirsson, Kristján Steinsson, Annette H M van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> The susceptibility to rheumatoid arthritis (RA) is partly heritable, whether the severity of RA is also influenced by genetics is not determined. Evaluation on the heritability of the severity of RA is basic to further studies on genetic factors. The authors aimed to determine whether joint destruction is heritable. <h3>Methods</h3> Iceland has an unique comprehensive genealogy database covering today9s population and stretching back to ≥1000 years ago, as well as genome wide SNP data of a large part of the population. Hand and feet radiographs of 325 RA patients of Iceland were scored according to the Sharp–van der Heijde method. The degree of relatedness between patients was estimated in two ways. First kinship coefficients (KC) on the genealogic data were expressed; second the identical-by-descent (IBD) was estimated applying long-range phasing on the genetic profile of the patients. The degree of relatedness was tested against the similarity in joint destruction rates by linear regression analysis and the heritability of joint destruction was calculated. <h3>Results</h3> Significant associations between degree of relatedness and similarity in joint destruction rates were observed for both methods of determining relatedness (P<sub>KC</sub>=0.018, P<sub>IBD</sub>=0.003). The estimated heritability was 45% using KC and 58% using the estimated IBD data. <h3>Conclusions</h3> The severity of joint destruction in RA is influenced by genetic factors.
Results of the Compassionate Program of Inotuzumab Ozogamicin for Adult Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia in Spain
Authors: Josep-Maria Ribera, Olga Garcia, Pau Montesinos, Rebeca Rodríguez-Veiga, María García-Fortes, Abelardo Barez Garcia, Itziar Oiartzabal, Jose A Gonzalez-Campos, Jose Angel Mendez Sanchez, Maite Zudaire, Lucia Villalon, Oriana López-Godino, Cristina Gil, Ana Vicent, Raquel Saldaña, Marta Valero, Anna Torrent, Jesus Maria Hernández-Rivas
Journal: Blood (2021)
Radiomic signatures of posterior fossa ependymoma: Molecular subgroups and risk profiles
Authors: Michael Zhang, Edward Wang, Derek Yecies, Lydia T Tam, Michelle Han, Sebastian Toescu, Jason N Wright, Emre Altinmakas, Eric Chen, Alireza Radmanesh, Jordan Nemelka, Ozgur Oztekin, Matthias W Wagner, Robert M Lober, Birgit Ertl-Wagner, Chang Y Ho, Kshitij Mankad, Nicholas A Vitanza, Samuel H Cheshier, Tom S Jacques, Paul G Fisher, Kristian Aquilina, Mourad Said, Alok Jaju, Stefan Pfister, Michael D Taylor, Gerald A Grant, Sarah Mattonen, Vijay Ramaswamy, Kristen W Yeom
Journal: Neuro-Oncology (2021)

Abstract Background The risk profile for posterior fossa ependymoma (EP) depends on surgical and molecular status [Group A (PFA) versus Group B (PFB)]. While subtotal tumor resection is known to confer worse prognosis, MRI-based EP risk-profiling is unexplored. We aimed to apply machine learning strategies to link MRI-based biomarkers of high-risk EP and also to distinguish PFA from PFB. Methods We extracted 1800 quantitative features from presurgical T2-weighted (T2-MRI) and gadolinium-enhanced T1-weighted (T1-MRI) imaging of 157 EP patients. We implemented nested cross-validation to identify features for risk score calculations and apply a Cox model for survival analysis. We conducted additional feature selection for PFA versus PFB and examined performance across three candidate classifiers. Results For all EP patients with GTR, we identified four T2-MRI-based features and stratified patients into high- and low-risk groups, with 5-year overall survival rates of 62% and 100%, respectively (P &amp;lt; .0001). Among presumed PFA patients with GTR, four T1-MRI and five T2-MRI features predicted divergence of high- and low-risk groups, with 5-year overall survival rates of 62.7% and 96.7%, respectively (P = .002). T1-MRI-based features showed the best performance distinguishing PFA from PFB with an AUC of 0.86. Conclusions We present machine learning strategies to identify MRI phenotypes that distinguish PFA from PFB, as well as high- and low-risk PFA. We also describe quantitative image predictors of aggressive EP tumors that might assist risk-profiling after surgery. Future studies could examine translating radiomics as an adjunct to EP risk assessment when considering therapy strategies or trial candidacy.
Understanding and tracking the impact of long COVID in the United Kingdom
Authors: Ash Routen, Lauren O’Mahoney, Daniel Ayoubkhani, Amitava Banerjee, Chris Brightling, Melanie Calvert, Nishi Chaturvedi, Ian Diamond, Rosalind Eggo, Paul Elliott, Rachael A. Evans, Shamil Haroon, Emily Herret, Margaret E. O’Hara, Roz Shafran, Julie Stanborough, Terence Stephenson, Jonathan Sterne, Helen Ward, Kamlesh Khunti
Journal: Nature Medicine (2021)
A Phase 1, Open-Label, Multicenter Study of HMPL-306 in Advanced Hematological Malignancies with Isocitrate Dehydrogenase (IDH) Mutations
Authors: Anu Doraiswamy, Vijayvel Jayaprakash, Marek Kania, Marjo Hahka-Kemppinen, Zhao Yang, Mark Rudinski, Farhad Ravandi
Journal: Blood (2021)
Abstract 10221: Premature Ventricular Contractions in Chronic Thromboembolic Pulmonary Hypertension Undergoing Pulmonary Thromboendarterectomy Surgery
Authors: Sai Vanam, Muhammad Munir, Douglas Darden, Masihullah Barat, Lucas Keyt, Tanner Long, Gregory K Feld, Jonathan C Hsu, Ulrika Birgersdotter-green, Gordon Ho, David Krummen, Farshad Raissi, Timothy Fernandes, David Poch, Nick Kim, Demosthenes G Papamatheakis, Kim Kerr, Victor Pretorius, Michael M Madani, Frederick Han, Kurt S Hoffmayer
Journal: Circulation (2021)

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and progressive subtype of severe pulmonary hypertension. Premature ventricular contractions (PVC) are common and can be a marker of cardiomyopathy. We aimed to describe the incidence, location and predictors of PVCs in CTEPH patients undergoing Pulmonary Thromboendarterectomy surgery (PTE). Hypothesis: PVCs are common in CTEPH patients and the right ventricle would be the most common location of PVCs. Methods: We reviewed the charts of 883 consecutive patients who were referred for PTE. 12-lead ECGs were reviewed for presence of PVC. Demographics, baseline lab and imaging were extracted from chart review. Predictors of PVCs were analyzed using multivariate backward logistic regression. PVC location was identified using standard location algorithms based on the 12-lead ECG. Results: Overall, 6.5% (n=57) of patients had PVCs. Surprisingly, the majority of PVCs originated from the left ventricle (75.4%, N=43). The most common location was non-outflow tracts with LV non-outflow tract (59.3%, N=34), followed by RV non-out tract (19.3%, N=11). Within the non-outflow tract region, the majority of the PVC location appeared to be septal related (moderator band, posterior fascicle or posterior medial papillary muscle). The mitral annulus was also a common location (15.8%, N=9). In a multivariate model, heart failure (OR 2.8, p=&lt;0.01), coronary artery disease (CAD) (OR 2.8, p=&lt;0.01), sleep apnea (OR 2.2, p=0.02) and obesity (OR 1.6, p=&lt;0.01) increased the odds of having PVCs. Conclusions: PVCs are not uncommon in CTEPH patients undergoing PTE surgery. Overall, 6.5% of patients had PVCs with the majority originating in the left ventricle (75.4%). Using standard ECG criteria, the most common location was the LV non-outflow tract. Heart failure, CAD, sleep apnea and obesity increased the odds of having a PVC.
Abstract 12937: Sex Differences on Clinical Outcomes After Thoracic Endovascular Aortic Repair
Authors: Sarah Yousef, James Brown, Edgar Aranda-Michel, Derek Serna-Gallegos, Yisi Wang, Courtenay Dunn-Lewis, Ibrahim Sultan
Journal: Circulation (2021)

Introduction: Thoracic endovascular aortic repair (TEVAR) has been increasingly utilized for the treatment of descending thoracic aortic aneurysms and dissections. Further research is warranted to understand outcomes of TEVAR in various populations. Hypothesis: Sex will not influence outcomes after nonelective TEVAR. Methods: This was an observational study from the Nationwide Readmissions Database analyzing men (n=3903) and women (n=2691) with aortic aneurysm or Type B aortic dissection who underwent nonelective TEVAR from 2010-2017. Appropriate trend weighting was used to generate national estimates. International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes were used to identify patients with thoracic aortic aneurysms or dissections who underwent TEVAR. 30-day and 90-day readmissions, in-hospital mortality, postoperative complications, and cost were compared between the two groups. Mixed model logistic regression was used to determine predictors of readmission, treating each participating hospital as a random effect. Results: The study population consisted of 6594 patients (3903 men, 2691 women) who underwent nonelective TEVAR. In-hospital mortality was 9.3% (n=613) and was not significantly different between groups (9.85% in men vs 8.50% in women, p=0.06). Of the remaining 5981 patients, women were more likely than men to be older, to have chronic pulmonary disease, and to have aneurysm rather than dissection as their indication for TEVAR. Women were less likely to have chronic kidney disease. Postoperatively, women were less likely to develop respiratory failure (9.41% vs 11.75%), acute kidney injury (17.93% vs 33.87%), and mesenteric ischemia (2.63% vs 4.36%). On multivariable regression, female sex was not associated with an increased risk of readmission at 30 days (OR 1.04, 95% CI 0.87-1.25, p=0.67) or 90 days (OR 1.06, 95% CI 0.90-1.25, p=0.48) as compared to male sex. Conclusions: Sex was not an independent predictor of 30-day and 90-day readmissions after nonelective TEVAR. While males had higher rates of complications such as acute kidney injury and mesenteric ischemia, mortality did not differ significantly between the two groups.
Abstract 13592: QRS 3D Voltage Time Integral (3D QRS Area) is a Predictor for Pacing Induced Cardiomyopathy
Authors: Sean Lacy, Nikhil Parimi, Tucker Morey, Uzair Mahmood, Chris Harvey, Seth Sheldon, Madhu Reddy, Amit Noheria
Journal: Circulation (2021)

Introduction: The instantaneous absolute 3D ECG voltage integrated over the duration of QRS (VTI QRS-3D ), also measured as 3D QRS area, is a marker for left ventricular electrical dyssynchrony in patients with left bundle branch block. Hypothesis: We sought to investigate if VTI QRS-3D predicts pacing induced cardiomyopathy in patients with chronic (&gt;3 months) right ventricular pacing (RVp). Methods: We retrospectively evaluated RVp ECGs from consecutive patients with pacing induced cardiomyopathy (left ventricular ejection fraction ≤50%) and compared to patients with normal ejection fraction (&gt;50%). Patients were excluded if they did not have ECG and/or echocardiogram. 12-lead ECGs were converted to orthogonal X, Y, Z leads using Kors matrix. VTI QRS-3D was obtained by voltage-time-integral from root-mean-squared 3D ECG. Results: We analyzed 320 RVp patients (age 73 ± 14 years, 40% female), 206 with preserved ejection fraction (LVEF 60.4 ± 4.1%) and 114 with pacing induced cardiomyopathy (LVEF 29.2 ± 8.1%). Pacing induced cardiomyopathy was associated with a longer QRS duration, larger QRS voltage and larger VTI QRS-3D (Table). VTI QRS-3D ≥90 μVs had 81% sensitivity to identify pacing induced cardiomyopathy (specificity 47%). Conclusions: In the setting of chronic right ventricle pacing, QRS 3D voltage time integral ≥90 μVs on ECG can be used as a screening tool to identify patients needing further evaluation for cardiomyopathy.
Abstract 13223: Split-Intein Mediated Adeno Associated Virus Delivery of CRISPR/dHFCas9-TET3CD as Antifibrotic Therapy
Authors: Xingbo Xu, Melanie S Hulshoff, Xiaoying Tan, Sabine Maamari, Guido Krenning, Gerd Hasenfuss, Michael Zeisberg, Oliver J Müller, Elisabeth Zeisberg
Journal: Circulation (2021)

Introduction: Cardiac fibrosis is characterized by excessive deposition of extracellular matrix for which no specific therapy is available as of yet. Gene methylation plays an important role in the progression of cardiac fibrosis. We previously demonstrated that high-fidelity CRISPR/Cas9-based gene-specific hydroxymethylation rescues gene expression of fibrosis suppressor genes and attenuates renal fibrosis. Its efficacy in treating cardiac fibrosis, however, has not been examined. Hypothesis: While AAV-mediated delivery of CRISPR/Cas9 holds great therapeutic potential to treat cardiac fibrosis, several challenges still need to be overcome. We here aimed to circumvent the limiting viral packaging capacity of AAVs, and to identify the best AAV serotype to target mouse cardiac fibroblasts. Methods: We utilized split-intein mediated protein-splicing to divide dHFCas9-TET3CD (dHFCas9 fused to the catalytic domain of TET3) into two parts in order to perform AAV-mediated gene-specific demethylation of a fibrosis suppressor gene. Moreover, we explored the efficacy of 9 different serotypes in targeting mouse cardiac fibroblasts. To explore the antifibrotic efficacy of the fused dHFCas9-TET3CD in vivo, the Angiotensin-II induced cardiac fibrosis mouse model was used. Results: We identified that AAV9-SLRSPPS has a tropism for mouse cardiac fibroblasts with an efficiency of 72% in vitro and 51% and 32% in vivo after 7 days and 4 weeks, respectively. We showed that upon AAV transduction, the fused dHFCas9-TET3CD protein leads to gene-specific demethylation and attenuates cardiac fibrosis in the Angiotensin-II induced cardiac fibrosis mouse model . Conclusions: We demonstrate the use of a Cas9 derivative (dHFCas9-TET3CD) in combination with the split-intein technology and the AAV9-SLRPPS serotype to perform targeted demethylation both in vitro and in vivo which results in amelioration of cardiac fibrosis in vivo. This new technology holds promise not only for cardiac disease but for any disease associated with hypermethylation as well as for other applications where CRISPR/Cas9 in combination with AAV is useful.
Abstract MP213: Activation Of Biosynthetic Pathways Regulates Cardiomyocyte Cell Cycle Induction In Human Cardiomyocyte
Authors: Riham Abouleisa, Lindsey Mcnally, Abou B Salama, Sally Hammad, Qinghui Ou, Collin Wells, Pawel Lorkiewicz, Roberto bolli, Tamer Mohamed, Bradford G Hill
Journal: Circulation Research (2021)

Induction of cardiomyocyte proliferation is a promising therapeutic approach to treat heart failure. Several studies have identified metabolism as an important regulator of myocyte proliferation; however, the changes in metabolism during cardiomyocyte division remain unclear. Here, we use ectopic expression of cyclin B1, Cyclin D1, CDK1, and CDK4 (termed 4F) as a tool for understanding how metabolism influences cardiomyocyte proliferation. Mature hiPS-CMs stimulated to proliferate by 4F expression showed significant downregulation of oxidative phosphorylation genes, decreased glucose oxidation, and upregulation of genes that regulate biosynthetic pathways of glucose metabolism such as those involved in NAD(P) + synthesis ( NAMPT, NADK1, NNT ), the hexosamine biosynthetic pathway (HBP) and protein O-GlcNAcylation ( GFPT1 , OGT, OGA ), and the serine biosynthesis pathway (SBP; PHGDH , PSAT1 , SHMT2 ). In 4F-expressing hiPSC-CMs, stable isotope tracing indicated higher enrichment of glucose-derived 13 C in pentose phosphate intermediates, UDP-hexose, phospholipid precursors, NAD + , pyrimidines, UDP-HexNAc, and products of the serine biosynthesis pathway and one-carbon metabolism, suggesting that cell cycle induction activates biosynthetic pathways in cardiomyocytes. Knocking down nicotinamide phosphoribosyltransferase (NAMPT), a critical enzyme in the NAD + salvage pathway, 2 days before 4F overexpression significantly inhibited cell cycle progression in 4F-transduced hiPS-CMs. OGA overexpression, which catalyzes the hydrolytic cleavage of O-GlcNAc from post-transitionally modified proteins, completely abolished 4F-mediated cell cycle induction. Furthermore, NCT503, an inhibitor of the rate-limiting step in the serine biosynthesis pathway, abolished 4F-mediated increases in cell cycle markers. In a gain-of-function approach, we overexpressed phosphoenolpyruvate carboxykinase 2 (PCK2), which can drive carbon from the Krebs cycle to the glycolytic intermediate pool. PCK2 overexpression significantly augmented 4F-mediated cell cycle entry. These findings suggest that a metabolic shift from catabolic to anabolic activity is a critical step for cardiomyocyte cell cycle entry and is required to facilitate proliferation.
STEM-02. THERAPEUTIC INTERVENTION OF LUNG-, BREAST-, AND MELANOMA-BRAIN METASTASIS
Authors: Agata Kieliszek, Blessing Bassey-Archibong, Chitra Venugopal, Sheila K Singh
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The incidence of brain metastases (BM) is tenfold higher than that of primary brain tumours. BM predominantly originate from primary lung, breast, and melanoma tumours with a 90% mortality rate within one year of diagnosis, posing a large unmet clinical need to identify novel therapies against BM.This unmet clinical need is largely attributed to a small population of cancer stem cells (CSCs), termed BM-initiating cells (BMICs), that are able to escape a primary tumour, drive metastasis and facilitate the formation of a secondary tumour in the brain. METHODS Using a large in-house biobank of patient-derived BMIC lines, the Singh Lab has generated murine orthotopic patient-derived xenograft models of BM and captured a “premetastatic” population of BMICs that have just seeded the brains of mice before forming clinically detectable tumours: a cell population that is impossible to detect in human patients but represents a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable tumours. RESULTS RNA sequencing of pre-metastatic BMICs from all three primary tumour models with subsequent Connectivity Map analysis identified a lead compound that exhibits selective anti-BM activity in vitro. Preliminary in vivo work has shown that this lead compound reduces the tumor burden of treated mice compared to vehicle control while providing a significant survival advantage. Ongoing mechanistic investigations aim to delineate the protein target of this compound in the context of the observed selective anti-BMIC phenotype. CONCLUSION Identification of novel small molecules that target premetastatic BM cells could prevent the formation of BM and dramatically improve the prognosis of at-risk cancer patients.