tbuckley/cabot-search huggingface dataset:
Patient-derived colorectal cancer spheroids for single cell characterization of intratumor heterogenity in response to EGFR inhibition.
Authors: Jeremy D. Kratz, Carley M. Sprackling, Peter F. Favreau, Mohammad R. Karim, Cheri Pasch, Linda Clipson, Melissa C Skala, Dustin A. Deming
Journal: Journal of Clinical Oncology (2019)

569 Background: Epidermal growth factor receptor inhibitors (EGFRi) have improved clinical outcomes in patients (pts) with metastatic colorectal cancer (mCRC). Molecular profiling and primary tumor sidedness are used to predict population benefit. Our group has recently demonstrated that patient-derived organotypic cancer spheroids (PDOCS) and optical metabolic imaging (OMI) can predict in vivo chemotherapy response. Translational tools are needed to characterize targeted therapeutic response to predict clinical outcomes. Methods: PDOCS were generated from patients with mCRC at time of molecular profiling. Following culture maturation, PDOCS were treated with physiologic doses of EGFRi panitumumab. Response was evaluated by change in sphere diameter and OMI to exploit intrinsic autofluorescence of NAD(P)H and FAD at spheroid and single-cell level. Effect size was calculated using Glass’s delta (GΔ) defined as differences in means between treatment groups normalized to control standard deviation with comparison to predetermined sensitivity thresholds. Results: PDOCS from pts with mCRC were generated from tissue biopsies, surgical specimens, and malignant effusions (n = 38). Mutational profiles were stratified by RAS status from next-generation sequencing. Six PDOCS were evaluable for experimental and clinical response. KRAS mutation predicted primary resistance to EGFRi with no difference in diameter (GΔ = -0.01) or single cell response by OMI (GΔ = 0.02). RAS wild-type PDOCS had significant response with decreased diameter with EGFRi (P &lt; 0.001). Gaussian fit of single-cell analyses revealed heterogeneity in EGFRi sensitivity. Differential sensitivity to EGFRi in RAS wild-type population correlated with clinical response. Conclusions: PDOCS predict response to panitumumab in these preliminary investigations. Diameter and OMI analyses provide complementary information of line-specific sensitivity. Further studies are warranted to characterize the molecular profiles underlying intratumor heterogenity. Prospective investigations are needed to understand the predictive role of this technique in targeted therapeutic response.
A Phase 1 Trial of Ruxolitinib, Lenalidomide and Methylprednisolone for Relapsed/Refractory Multiple Myeloma Patients
Authors: James R Berenson, To Jennifer, Tanya M. Spektor, Carley Turner, Regina Swift, Benjamin Eades, Gary Schwartz, Shahrooz Eshaghian, Laura V. Stampleman, Robert A. Moss, Alberto Bessudo, Ravindranath Patel, Stephen Lim, Robert Vescio
Journal: Blood (2018)
Abstract 20477: Impact of Same-Hospital Readmissions in Heart Failure Patient Population
Authors: Shilpkumar Arora, Varun Kumar, Urvi Shah, Sopan Lahewala, Byomesh Tripathi, Bhaskar Bhardwaj, Subir Bhatia, Mihir Dave, Neil Patel, Abhishek Mishra, Vishwa Kundoor, Priti Malik, Smit Patel, Radha Gopalan, Umesh Gidwani
Journal: Circulation (2017)

Background: Heart Failure (HF) is one of the most common reasons for hospital readmissions, causing substantial healthcare burden. But studies to compare outcome for same-hospital readmissions vs different-hospital readmissions are lacking. Methods: HCUP’s Nationwide Readmissions Database (NRD) from 2013-14 was used for HF related hospitalizations using appropriate ICD-9-CM diagnostic codes. 30-day readmissions were identified and classified into two groups: same-hospital readmissions and different-hospital readmissions. A comparative analysis was conducted focused on three metrics - mortality, length of stay (LOS) and cost of hospitalization. Cost was calculated after adjusting for inflation and merging with cost to charge ratio provided by HCUP. We used hierarchical two level modeling and propensity score matching to adjust for confounders. Results: A total of 277,476 HF readmissions were identified in 2013-14, of which 78% were same-hospital readmissions (49.12% female, 72.98% age >= 65). Univariate an...
Abstract 20906: Prognosis in Heart Failure: A TNM-Like Classification for Risk Stratification
Authors: Maria Alfarano, Paolo Severino, Mariateresa Pucci, Ilaria Mancini, Ilaria Ferrari, Stefano Peroni, Simone Calcagno, Antonio Fusto, Danilo Alunni Fegatelli, Annarita Vestri, Susanna Sciomer, Massimo Mancone, Francesco Fedele
Journal: Circulation (2017)

Introduction: NYHA is the most used classification for heart failure (HF), but it does not include patient’s clinical features. We proposed a new staging system for HF, named HLM (JACC 2014;20;63(19):1959-60), analogous to the TNM classification used in Oncology. HLM refers to heart damage (H), lung involvement (L), and malfunction (M) of peripheral organs (i.e. kidney, liver, hematopoiesis and central nervous system). Hypothesis: The aim was a preliminary comparison between HLM and NYHA at 6 and 12 months to assess the most accurate prognosis of HF patients in terms of rehospitalization for major adverse cardiovascular and cerebrovascular events (MACCE) and mortality. Methods: We enrolled 1064 consecutive patients with the diagnosis of or at risk for HF. According to HLM classification, all parameters for heart, lungs and peripheral organs function were collected and each patient was classified according to NYHA and HLM. At 6 and 12 months patients were followed up for rehospitalization for MACCE and cardiac death rates were calculated. Results: At 6 and 12 months follow-up, comparing to NYHA, HLM showed a greater area under the ROC curve (AUC) for rehospitalization as well as for cardiac death (Fig. 1). MACCE and cardiac death rates have been assessed separately for each parameter (H, L and M): L and M showed the most accurate prognostic power; at 1 year follow-up, L2 was significantly correlated (p=0.004) with rehospitalization as well as L3 (p=0.000), M1 (p=0.004), M2 (p=0.008) and M3 (p=0.003). M2 was significantly correlated (p=0.02) with cardiovascular mortality as well as M3 (p=0.004 ). Conclusions: Our preliminary data suggest that, compared to NYHA, HLM better stratifies risk of rehospitalization for MACCE and of cardiac death in HF patients. Regarding HLM, lung involvement (L2-3) and two or more organs dysfunction (M2-3) presented the most accurate prognostic power. Those preliminary results need to be confirmed in a greater population with a longer follow up.
Novel prognostic biomarkers and their association with survival in pancreatic cancers.
Authors: Anup Kasi, Suhaib Bajwa, Stephen K. Williamson, Weijing Sun, Joaquina Celebre Baranda, Obdulia Covarrubias Zambrano, Madumali Kalubowilage, Stefan H Bossmann
Journal: Journal of Clinical Oncology (2019)

296 Background: Early detection of pancreatic cancer would allow for improved survival outcomes. Methods: We retrospectively evaluated serum protease levels and the survival of 15 pancreatic cancer patient samples (6 localized and 9 metastatic) at the KU Cancer Center. Available serum protease assays measured matrix metalloproteinases (MMPs), urokinase plasminogen activator (uPA), arginase, neutrophil elastase (NE), cathepsin B (CTSB) and cathepsin E (CTSE). The assays utilize fluorescent nanoparticle-based nanobiosensors which increase fluorescence upon posttranslational modification or enzymatic cleavage of targeted compounds and were read by a Spectral scan plate reader. Survival analysis was performed using Kaplan-Meier methods. Results: Baseline characteristics for all 15 patients are in (Table). Median OS was 18.8m in patients with high CTSB expression (mean &gt;51968.9) vs 9.7m in low CTSB expression (p=0.04). Similarly, median OS was 20.4m in high CTSE expression (&gt;123264.8) vs 10m in low CTSE expression (p=0.05). Whereas, median OS was 16.3m in low NE expression (mean &lt;30293.5) vs 9.6m in high NE expression (p=0.06). MMPs, uPA, and Arginase were not associated with survival. Conclusions: Higher CTSB expression is associated with statistically significant improvement in survival. CTSB is a lysosomal protease involved in processing antigens and overexpression could aid in immunologic cancer suppression. CTSB is also involved in the development of desmoplasia which is hypothesized to be a physical barrier to metastasis. CTSE and NE expression did not meet statistically significant association with survival, likely due to sample size. Hence, we identify CTSB as a potential prognostic biomarker in pancreatic cancer. However, these findings need to be validated in a larger study. [Table: see text]
Abstract MP23: Completeness in the Abstraction of Cardiac Biomarkers and Cardiac Pain Data From Electronic Health Records (EHR). Findings From the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Anna Kucharska-Newton, Manuela Bullo, Matthew Loop, Carlton Moore, Stephanie W Haas, Wayne Rosamond, Wendell Futrell, Kehan Luo, Harish Yadav, Brittany Bogle
Journal: Circulation (2018)

Background: Calibration of case-finding algorithms from electronic health records (EHR) against established disease surveillance protocols is key to avoiding misclassification bias when using EHR data in epidemiological research. We examined the agreement in the classification of troponin I levels and identification of cardiac pain in hospital EHR data against manually abstracted charts for hospitalizations observed by the ARIC community surveillance of cardiovascular events. Methods: A structured data request for laboratory data and provider notes was submitted to hospitals in the ARIC community surveillance program. Computer programs were developed to extract dates of service, type of laboratory assays performed, and individual assay values for days 1-4 of each hospitalization. Presence of cardiac pain was extracted from provider notes using natural language processing protocols. We calculated percent agreement for troponin I values, kappa statistics for their classification as abnormal (values ≥ twice upper limit normal (ULN)), equivocal (values ≥ULN, but &lt; twice ULN) normal (&lt;ULN), and incomplete, and validity statistics for cardiac pain. Abstraction of information from the medical records by trained abstractors was considered the “gold standard” for comparisons. The analysis sample consisted of all events eligible for full abstraction discharged from one hospital in 2014. Analytical code was created using a “training” dataset randomly-selected from the analysis sample, with the final results computed using a validation sample. Results: Of the 126 EHRs, 104 were eligible for abstraction of cardiac biomarkers and pain information. Agreement in the troponin I values was 75.5% (95%CI: 65.8%, 83.6%) for day 1 of the hospitalization, decreasing thereafter to 62.5% (95%CI: 24.5%, 91.5%) for Day 4. The kappa coefficient for the classification of troponin I values was 0.96 (95% CI: 0.90, 1.00), We observed a high sensitivity in the abstraction of information on cardiac pain (0.99 (95%CI: 0.94, 1.0)). The specificity of cardiac pain information was 0.24 (95% CI: 0.16, 0.35) when extracted from all note types, increasing to 0.90 (95%CI: 0.75, 0.97) if extracted from discharge notes. Conclusion: Troponin I values and manifestation of ischemia such as cardiac pain are critical to the classification of acute coronary events. Therefore, the observed excellent agreement with the gold standard ARIC abstraction shows promise for the use of EHRs in the surveillance of acute cardiovascular disease.
Expression patterns of PD-L1 and other immune checkpoint molecules in gastric cancer.
Authors: Kenichi Nakamura, Keiichi Hatakeyama, Tetsuro Toriumi, Yusuke Koseki, Yuhei Waki, Keiichi Fujiya, Satoshi Kamiya, Rie Makuuchi, Yutaka Tanizawa, Etsuro Bando, Taiichi Kawamura, Ken Yamaguchi, Masanori Terashima
Journal: Journal of Clinical Oncology (2019)

49 Background: Immune checkpoint inhibitors (ICPIs) have provided clinical benefit for various malignancies. A new attempt was recently made to combine PD-1/PD-L1 inhibitors and other ICPIs. In order to establish a new strategy for ICPI combination therapy, we must first understand the expression patterns of PD-L1 and other ICP molecules. To identify possible candidate agents for application in combination therapy with PD-1/PD-L1, we analyzed the expression patterns of ICP molecules in gastric cancer. Methods: Tumor samples were obtained from 278 patients who underwent gastrectomy for gastric cancer from 2014 to 2016, and a comprehensive gene expression analysis using a DNA microarray. We analyzed the TCGA dataset to identify the candidate ICP molecules in relation to PD-L1. The immune landscape was evaluated according to the expression patterns of known immune cell markers reported by Bindea et al. Results: Seven ICP molecules ( PD-L2, IDO1, CD80, ICOS, CTLA4, LAG3 and TIM3) were coexpressed with PD-L1 in the TCGA dataset. In our cohort, all of these molecules were also coexpressed (R &gt; 0.5, P &lt; 0.0001). Using a cluster analysis based on these gene expression profiles, patients were divided into Group A, characterized by the co-overexpression of PD-L1 and other ICP molecules, and Group B, characterized by the underexpression of PD-L1. In Group A, PD-L2 (R = 0.67) and IDO1 (R = 0.61) were particularly strongly associated with the PD-L1 expression. In Group B, elevated expressions of CTLA4 and ICOS were predominantly observed, and these expressions were strongly correlated with each other (R = 0.90). The tumor stage was significantly more advanced in Group B than in Group A (P = 0.02). Accordingly, Group A exhibited a better survival outcome than Group B. The immune landscape of Group A was particularly enriched for Th1, NK CD56dim and activated dendritic cells. Conclusions: PD-L1 and several immune checkpoint molecules tend to be coexpressed in gastric cancer. The combination of PD-L1/-L2 and IDO1 target agents may be a new strategy for treating gastric cancer with PD-L1 overexpression. In contrast, the underexpression of PD-L1 might be an indication for the use of CTLA4- and/or ICOS-directed therapies.
Oxygen and Carbon Dioxide Rhythms Are Circadian Clock Controlled and Differentially Directed by Behavioral Signals
Authors: Yaarit Adamovich, Benjamin Ladeuix, Jonathan Sobel, Gal Manella, Adi Neufeld-Cohen, Mohammad H. Assadi, Marina Golik, Yael Kuperman, Ariel Tarasiuk, Maarten P. Koeners, Gad Asher
Journal: Cell Metabolism (2019)
Comparative Effectiveness of Combination Glasdegib+ Low-Dose Cytarabine (GLAS+LDAC) Vs Combination Venetoclax + Low-Dose Cytarabine (VEN+LDAC) Among Older Acute Myeloid Leukemia (AML) Patients Ineligible for Intensive Chemotherapy (NIC): Indirect Treatment Comparison (ITC) Methods
Authors: Tracy Westley, Anna Forsythe, Timothy J Bell, Joseph C Cappelleri, Geoffrey Chan, Gabriel Tremblay
Journal: Blood (2018)
Nanopackaging of cytolytic peptides (melittin) for cancer therapeutics
Authors: Neelesh Soman, Gregory Lanza, Paul Schlesinger, Samuel Wickline
Journal: Cancer Research (2008)

5722  Cytolytic peptides (or host-defense peptides) are cationic amphipathic 5-30 amino acid long peptides that have an evolutionary conserved membrane-permeabilizing molecular design that various plants and animals utilize to kill invading microorganisms. Their effectiveness in controlling antibiotic-resistant infections and cancer therapeutics has stimulated renewed interest in this class of biologics for potential translational application. However, their clinical utility is hampered due to their non-specificity of action, systemic toxicity, and serum protease degradation. We now demonstrate the safe in vivo application of a “first-generation” cytolytic peptide (melittin, a 26 amino-acid peptide found in honey bee venom) for cancer therapeutics by incorporating it onto a lipid monolayer of a perfluorocarbon (PFC) nanoparticle (NP, size ~200 nm) that serves as a unique and stable drug-delivery vehicle for the peptide. As contrasted with liposomal delivery vehicles that are destroyed upon melittin binding, the hydrophobic brominated PFC core of the NP allows it to maintain its structural integrity as revealed by transmission electron microscopy. Furthermore, melittin in these NPs is firmly incorporated in the lipid monolayer (dissociation constant ~1.5 nM by surface plasmon resonance). Circular dichroism and tryptophan fluorescence studies confirm an alpha-helical conformation of melittin in the lipid monolayer that interacts directly with and is stabilized by the perfluoro-octylbromide core of the NP. In stark contrast to the toxic systemic effects of free melittin peptide, NPs loaded with melittin avoid any significant red blood cell lysis up to lipid:melittin ratio 120. Cancer cell (C32 melanoma) proliferation assays in vitro reveal that IC50 for melittin-NPs is 32.3 (±5.7) µM versus 0.97 (±0.49) µM for free melittin, further confirming the systemic safety profile when complexed to this NP carrier. Cancer cell death was induced by delivery of NP-associated melittin to the cell, which was confirmed by confocal microscopy with the use of fluorescein-melittin loaded NPs. Flow cytometric analysis and lactate dehydrogenase/ cytochrome c release assay indicates that the mechanism of cell death upon melittin internalization is apoptosis rather than necrosis. When free melittin is delivered in vivo to tumor bearing mice, toxic levels are observed at an LD50 ~ 4 mg/kg. In contrast four doses of melittin-loaded NPs (equivalent melittin dose 8 mg/kg) are effective in causing a 6.7-fold reduction in the weight of B16 melanoma tumors in C57BL/6 mice (n=5, p = 0.002) without causing any untoward systemic toxicity. Thus, PFC nanoparticles represent the first class of unique lipid-based nanocarriers that provide an effective in vivo delivery vehicle for melittin and other cytolytic peptides by preventing their degradation, eliminating systemic toxicity, and simultaneously maintaining efficacy as an anticancer therapeutic.
Reduction in Spontaneous Reporting Rates of Hemolysis with IVIG After Implementation of an Immunoaffinity Chromatography Step for Isoagglutinin Reduction
Authors: Amgad Shebl, Susie Gabriel, Kristy Van Dinther, Alphonse Hubsch, Liane Hoefferer, Susan Welsh
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract A45: Tumor suppressor miR-584-5p regulates MYC and sensitizes MYC-amplified medulloblastoma to vincristine and ionizing radiation
Authors: Nourhan Abdelfattah, Subapriya Rajamanickam, Santosh Timilsina, Panneerdoss Subbarayalu, Benjamin Onyeagucha, Manjeet Rao
Journal: Cancer Research (2018)

Abstract Despite recent improvements in the overall survival of medulloblastoma (MB), only a modest percentage of patients survive high-risk disease. Furthermore, the toxicity associated with current therapies inflicts debilitating lifelong side effects on surviving MB patients. Using an unbiased microRNA screen, we identified miR-584-5p as a potent tumor suppressor that uniquely sensitizes MB to both ionizing radiation (IR) and vincristine (VCR), which are commonly used in combination to treat MB. Our studies revealed that miR-584-5p inhibited MB stem cell proliferation and consequently growth in vivo. Notably, we discovered that miR-584-5p imparts its tumor-suppressor and therapy-sensitizing effects by inhibiting histone deacetylase 1 (HDAC1), eukaryotic translation initiation factor 4e family member 3 (eIF4E3), and C-MYC. We demonstrated that miR-584-5p overexpression or the knockdown of its target genes including eIF4E3 and HDAC1 resulted in G2-M arrest, DNA damage, spindle defects, and apoptosis in MB cells. Meta-analysis of normal brain and MB tumor samples showed that while miR-584-5p is highly expressed in normal brain and cerebellum, it is highly downregulated across all MB subtypes. miR-584-5p targets, on the other hand, are highly overexpressed in MB tumors compared to normal cerebellum. Taken together, this study highlights a previously unidentified role for miR-584-5p, eIF4E3, and HDAC1 in regulating microtubule dynamics and DNA repair pathways. In addition, our study identifies novel targets that can affect the therapeutic efficacy of VCR and IR in MB and sets the stage for a new paradigm of treating medulloblastoma using microRNA-based therapeutics. Citation Format: Nourhan Abdelfattah, Subapriya Rajamanickam, Santosh Timilsina, Panneerdoss Subbarayalu, Benjamin Onyeagucha, Manjeet Rao. Tumor suppressor miR-584-5p regulates MYC and sensitizes MYC-amplified medulloblastoma to vincristine and ionizing radiation [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A45.
Coagulation and Fibrinolysis Imbalance Demonstrated By Novel Simultaneous Thrombin and Plasmin Generation Assay during L-Asparaginase Treatment Phase of Induction Therapy in Pediatric Acute Lymphoblastic Leukemia
Authors: Takashi Ishihara, Keiji Nogami, Satoshi Ochi, Toshiaki Ishida, Yoshiyuki Kosaka, Akihisa Sawada, Masami Inoue, Shinya Osone, Toshihiko Imamura, Hajime Hosoi, Midori Shima
Journal: Blood (2018)
A&amp;E doctors urge NHS not to abandon four hour target
Authors: Gareth Iacobucci
Journal: BMJ (2019)

Emergency medicine doctors have urged the NHS and the government not to abandon the four hour target for 95% of A&E patients to be admitted, transferred, or discharged, warning that such a move would harm patients.

The warning came after NHS England’s chief executive, Simon Stevens, told the House of Commons Health Committee that existing standards would be likely to be altered to reflect changes in clinical practice since the target was introduced by the Labour government in 2004.

NHS England is currently reviewing its clinical standards and is due to set out changes in March in line with recommendations in the NHS’s long term plan.1

Stevens told the MPs that he did not want to “prejudge the outcome” of the review, which is being led by NHS England’s medical director, Stephen …
Abstract 16071: Higher Non-High Density Lipoprotein Cholesterol Thresholds Are More Predictive of Need for Lipid-Lowering Pharmacotherapy in Children
Authors: Amy Zawacki, Ann Dodge, Jens Eickhoff, Wenzhu Sun, Erin Marriott, Amy Peterson
Journal: Circulation (2017)

Introduction: Guidelines recommend screening all children ages 9-11 and 17-21 with a non-fasting lipid panel; if non-HDL-C > 145mg/dL, a fasting lipid panel should be obtained. Most pediatric dysli...
Abstract 14494: Cardiomentopexy Slows Progression to Heart Failure After Pressure Overload-induced Left Ventricular Hypertrophy in Rats
Authors: Jian Wang, Qing-Jun Zhang, Timothy Pirolli, Zhi-Ping Liu, Joseph Forbess
Journal: Circulation (2017)

Introduction: The application of the pedicled greater omentum to the heart has been shown to benefit in ischemic heart disease model. The impact of cardio-omentopexy in a pressure overload-induced ...
Two-Year Safety and Efficacy Outcomes with Fostamatinib in Adult Patients with Immune Thrombocytopenia (ITP): Open-Label Extension to Phase 3 Trial Program
Authors: Anne-Marie Duliege, Donald M. Arnold, Ralph Boccia, Michael Boxer, Nichola Cooper, Quentin A Hill, Darla K Liles, Michelle Sholzberg, Hany Zayed, Sandra Tong, James B. Bussel
Journal: Blood (2018)
Commentary: We never again want to say, “I’m sorry, your child has died”
Authors: Adam Brooks, John-Joe Reilly, Carla Hope
Journal: BMJ (2019)

Although much of the media focus on knife crime has been on London,1 the epidemic of violence is occurring across the UK, as Emma Wilkinson’s article makes clear.2 Queen’s Medical Centre in Nottingham provides care to a population of four million across the East Midlands and has the UK’s largest major trauma centre. On average the centre now sees one patient a week with severe life threatening knife injuries, a fourfold increase over the past five years. Of most concern is that in 2018 we resuscitated 28 children with serious knife wounds, 50% more than in the previous year. Our data show that these young victims of violent crime are more likely than their peers to present to …