tbuckley/cabot-search huggingface dataset:
An Engineered Tumor-on-a-Chip Device with Breast Cancer–Immune Cell Interactions for Assessing T-cell Recruitment
Authors: Aereas Aung, Vardhman Kumar, Jomkuan Theprungsirikul, Shruti K. Davey, Shyni Varghese
Journal: Cancer Research (2019)

Recruitment of immune cells to a tumor is determined by the complex interplay between cellular and noncellular components of the tumor microenvironment. Ex vivo platforms that enable identification of key components that promote immune cell recruitment to the tumor could advance the field significantly. Herein, we describe the development of a perfusable multicellular tumor-on-a-chip platform involving different cell populations. Cancer cells, monocytes, and endothelial cells were spatially confined within a gelatin hydrogel in a controlled manner by using 3D photopatterning. The migration of the encapsulated endothelial cells against a chemokine gradient created an endothelial layer around the constructs. Using this platform, we examined the effect of cancer cell-monocyte interaction on T-cell recruitment, where T cells were dispersed within the perfused media and allowed to infiltrate. The hypoxic environment in the spheroid cultures recruited more T cells compared with dispersed cancer cells. Moreover, the addition of monocytes to the cancer cells improved T-cell recruitment. The differences in T-cell recruitment were associated with differences in chemokine secretion including chemokines influencing the permeability of the endothelial barrier. This proof-of-concept study shows how integration of microfabrication, microfluidics, and 3D cell culture systems could be used for the development of tumor-on-a-chip platforms involving heterotypic cells and their application in studying recruitment of cells by the tumor-associated microenvironment. SIGNIFICANCE: This study describes how tumor-on-chip platforms could be designed to create a heterogeneous mix of cells and noncellular components to study the effect of the tumor microenvironment on immune cell recruitment.
Abstract 12949: Increase in Left Ventricular Fibrosis With LVAD Therapy and in Model of Mechanical Unloading and Potential Anti-Fibrotic Therapy of the Novel Designer Natriuretic Peptide CD-NP in vitro
Authors: Tomoko Ichiki, John A Schirger, Frank C Brozovich, Brenda K Huntley, Ondrej Lisy, S. Jeson Sangaralingham, Paul M McKie, Soon J Park, John C Burnett
Journal: Circulation (2011)

Introduction: Reports of LVAD unloading on myocardial fibrosis has reported both decreases and increases, the latter supporting a need for co-therapies targeting fibrosis. The natriuretic peptides ...
Treatment Patterns and Outcomes of 1205 Patients on Novel Agents in the US Veterans Health Administration (VHA) System: Results from the Largest Retrospective EMR and Chart Review Study in the Real-World Setting
Authors: Christopher R Frei, Hannah Le, Daniel McHugh, Cynthia Elesinmogun, Samantha Galley, Kathleen Franklin, Juan Tavera, Michelle Janania Martinez, David J Gregorio, Snegha Ananth, Ricardo Uribe, Prathibha Surapaneni, Manuel Ricardo Espinoza-Gutarra, Michael Song, Xavier Jones, Chengwen Teng, Obiageri O Obodozie-Ofoegbu, Zohra Nooruddin
Journal: Blood (2019)
An overview on recent in vivo biological application of cerium oxide nanoparticles
Authors: Baskaran Stephen Inbaraj, Bing-Huei Chen
Journal: Asian Journal of Pharmaceutical Sciences (2019)

Cerium oxide nanoparticles (CNPs) possess a great potential as therapeutic agents due to their ability to self-regenerate by reversibly switching between two valences +3 and +4. This article reviews recent articles dealing with in vivo studies of CNPs towards Alzheimer's disease, obesity, liver inflammation, cancer, sepsis, amyotrophic lateral sclerosis, acute kidney injury, radiation-induced tissue damage, hepatic ischemia reperfusion injury, retinal diseases and constipation. In vivo anti-cancer studies revealed the effectiveness of CNPs to reduce tumor growth and angiogenesis in melanoma, ovarian, breast and retinoblastoma cancer cell-induced mice, with their conjugation with folic acid, doxorubicin, CPM, or CXC receptor-4 antagonist ligand eliciting higher efficiency. After conjugation with triphenylphosphonium or magnetite nanoparticles, CNPs were shown to combat Alzheimer's disease by reducing amyloid-β, glial fibrillary acidic protein, inflammatory and oxidative stress markers in mice. By improving muscle function and longevity, the citrate/EDTA-stabilized CNPs could ameliorate amyotrophic lateral sclerosis. Also, they could effectively reduce obesity in mice by scavenging ROS and reducing adipogenesis, triglyceride synthesis, GAPDH enzyme activity, leptin and insulin levels. In CCl4-induced rats, stress signaling pathways due to inflammatory cytokines, liver enzymes, oxidative and endoplasmic reticulum messengers could be attenuated by CNPs. Commercial CNPs showed protective effects on rats with hepatic ischemia reperfusion and peritonitis-induced hepatic/cardiac injuries by decreasing oxidative stress and hepatic/cardiac inflammation. The same CNPs could improve kidney function by diminishing renal superoxide, hyperglycemia and tubular damage in peritonitis-induced acute kidney injury in rats. Radiation-induced lung and testicular tissue damage could be alleviated in mice, with the former showing improvement in pulmonary distress and bronchoconstriction and the latter exhibiting restoration in spermatogenesis rate and spermatid/spermatocyte number. Through enhancement of gastrointestinal motility, the CNPs could alleviate constipation in both young and old rats. They could also protect rat from light-induced retinal damage by slowing down neurodegenerative process and microglial activation.
Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: A retrospective study.
Authors: Kosuke Hamada, Taro Iguchi, Satoshi Tamada, Minoru Kato, Takeshi Yamasaki, Yuji Takeyama, Yasuomi Shimizu, Sayaka Yasuda, Tatsuya Nakatani
Journal: Journal of Clinical Oncology (2019)

293 Background: In Asia, including Japan, combined androgen blockade (CAB) therapy with bicalutamide is widely used for metastatic prostate cancer. Alternative anti-androgen therapy (AAT) with flutamide (FLU) after CAB therapy with bicalutamide was common before the androgen receptor-targeted therapy era. The AAT response rate was 20–30%, and there is no evidence of prolonged overall survival (OS), but we have encountered effective clinical cases. Currently, two prospective clinical studies are ongoing, but this is the first retrospective study comparing FLU and enzalutamide (ENZ) for castration-resistant prostate cancer (CRPC). Methods: In our hospital, 55 patients were diagnosed with CRPC after CAB therapy and administered FLU or ENZ between May 2014 and December 2017. Patients with FLU failure then received ENZ. The study evaluation included 1) prostate-specific antigen (PSA) best response with initial therapy, 2) PSA progression-free survival with initial therapy (PSA-PFS), 3) PSA best response with ENZ therapy, 4) PSA-PFS of ENZ therapy (PSA-PFS-ENZ), and 5) OS. Results: As first-line CRPC therapy, patients received ENZ (n=29) or FLU (n=26). In the FLU group, 18 patients showed disease progression and then received ENZ. The PSA best response was statistically higher in the ENZ group. PSA-PFS was significantly statistically longer in the ENZ group (hazard ratio (HR) 1.85, 95% confidence interval (CI) 0.53–0.64, p=0.02). However, there was no significant difference in PSA best response with ENZ therapy and PSA-PFS-ENZ between the ENZ and post-FLU ENZ groups (HR 0.80, 95% CI 0.33–1.94, p=0.62) or in OS between the ENZ and post-FLU ENZ groups (HR 1.85, 95% CI 0.53–6.42, p=0.33). Conclusions: AAT with subsequent FLU after CAB therapy with bicalutamide may be suitable for some CRPC patients. (NCT02346578 and NCT02918968).
REPLY:
Authors: Yanling Ma, Philip M. Brown, Yaron Rotman
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. We appreciate Dr. Galmozzi's interest in our study and insightful comments. Briefly, we recently discovered single‐nucleotide polymorphisms (SNPs), in or near the 17‐beta hydroxysteroid dehydrogenase 13 (HSD17B13) gene, that associate with histological features of nonalcoholic fatty liver disease. Mechanistically, we found an association of rs72613567 with the presence of two splicing variants (G‐insertion and Delta‐6), which cause loss of function.1 Dr. Galmozzi is concerned that a G‐nucleotide insertion as a consequence of a 5′‐splice site SNP is yet to be reported, highlighting the appeal of our report. He raises technical concerns regarding the validity of this finding, which we are happy to address. First, Dr. Galmozzi questions the design of HSD17B13‐G‐insertion primers. This, unfortunately, is due to a misunderstanding as the primers he cites are those designed to generate an HSD17B13‐G‐insertion plasmid from HSD17B13‐Flag using two‐step Q5 site‐directed mutagenesis. For splice variant detection, we used the primers listed as "splice variant detection and sequence forward/reverse," mapped to exons 4 and 7 (Supporting Fig. S1A), which were used to amplify a section of HSD17B13 complementary DNA. We subsequently purified the PCR products (Supporting Fig. S1B) and sequenced them to identify the new variants (Supporting Fig. S1C). Notably, Abul‐Husn et al. independently identified the same variants using a different approach (RNA sequencing),2 strengthening our findings and supporting the presence of this splice variant. We apologize if primer naming in our article was unclear and led to such misunderstanding. Dr. Galmozzi is also concerned about primer specificity for isoform detection. We designed reverse primers located within exon 6 or across the boundary of exons 5 and 7, to detect exon 6–containing variants (non‐delta 6) and exon 6–skipping variants (delta 6), respectively. The specificity of primers was tested using a competition assay.3 Briefly, high–copy number HSD17B13‐delta 6 DNA was added to serially diluted HSD17B13 variant A DNA to test the specificity of non‐delta 6 primers, and vice versa for delta 6 primers. We selected the primers with the best efficiency and specificity for our quantification assay and found them to be specific to one variant (Supporting Fig. S2). In conclusion, we believe our findings and those of Abul‐Husn et al. convincingly show that rs72613567 is indeed associated with a pattern of alternative splicing. Although the underlying mechanism is outside the focus of our initial article, we believe it merits further study.
Negative Regulation of Osteoclast Commitment by Intracellular Protein Phosphatase Magnesium‐Dependent 1A
Authors: Oh Chan Kwon, Bongkun Choi, Eun‐Jin Lee, Ji‐Eun Park, Eun‐Ju Lee, Eun‐Young Kim, Sang‐Min Kim, Min‐Kyung Shin, Tae‐Hwan Kim, Seokchan Hong, Chang‐Keun Lee, Bin Yoo, William H. Robinson, Yong‐Gil Kim, Eun‐Ju Chang
Journal: Arthritis & Rheumatology (2019)

Objective Increased protein phosphatase magnesium‐dependent 1A ( PPM 1A) levels in patients with ankylosing spondylitis regulate osteoblast differentiation in bony ankylosis; however, the potential mechanisms that regulate osteoclast differentiation in relation to abnormal bone formation remain unclear. This study was undertaken to investigate the relationship of PPM 1A to osteoclast differentiation by generating conditional gene‐knockout ( PPM 1A fl/fl ;LysM‐Cre) mice and evaluating their bone phenotype. Methods The bone phenotypes of LysM‐Cre mice (n = 6) and PPM 1A fl/fl ;LysM‐Cre mice (n = 6) were assessed by micro–computed tomography. Osteoclast differentiation was induced by culturing bone marrow–derived macrophages in the presence of RANKL and macrophage colony‐stimulating factor (M‐ CSF ), and was evaluated by counting tartrate‐resistant acid phosphatase–positive multinucleated cells. Levels of messenger RNA for PPM 1A , RANK , and osteoclast‐specific genes were examined by real‐time quantitative polymerase chain reaction, and protein levels were determined by Western blotting. Surface RANK expression was analyzed by fluorescence flow cytometry. Results The PPM 1A fl/fl ;LysM‐Cre mice displayed reduced bone mass ( P &lt; 0.001) and increased osteoclast differentiation ( P &lt; 0.001) and osteoclast‐specific gene expression ( P &lt; 0.05) compared with their LysM‐Cre littermates. Mechanistically, reduced PPM 1A function in osteoclast precursors in PPM 1A fl/fl ;LysM‐Cre mice induced osteoclast lineage commitment by up‐regulating RANK expression ( P &lt; 0.01) via p38 MAPK activation in response to M‐ CSF . PPM 1A expression in macrophages was decreased by Toll‐like receptor 4 activation ( P &lt; 0.05). The Ankylosing Spondylitis Disease Activity Score was negatively correlated with the expression of PPM 1A in peripheral blood mononuclear cells from patients with axial spondyloarthritis (SpA) (γ = −0.7072, P &lt; 0.0001). Conclusion The loss of PPM 1A function in osteoclast precursors driven by inflammatory signals contributes to osteoclast lineage commitment and differentiation by elevating RANK expression, reflecting a potential role of PPM 1A in dynamic bone metabolism in axial SpA.
Preliminary Translational Results from an Ongoing Phase 1 Study of Flotetuzumab, a CD123 x CD3 Dart®, in AML/MDS: Rationale for Combining Flotetuzumab and Anti-PD-1/PD-L1 Immunotherapies
Authors: Michael P Rettig, John Godwin, Norbert Vey, Bernard Fox, Carmen Ballesteros-Merino, Carlo B Bifulco, Daner Li, Daniel Primo, Joan Ballesteros, Jichao Sun, Helene Lelièvre, Jan Baughman, Ross La Motte-Mohs, John Muth, Paul Moore, Ezio Bonvini, Jon Wigginton, John F DiPersio, Jan Davidson-Moncada
Journal: Blood (2017)
Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening
Authors: Grant L. Lin, Kelli M. Wilson, Michele Ceribelli, Benjamin Z. Stanton, Pamelyn J. Woo, Sara Kreimer, Elizabeth Y. Qin, Xiaohu Zhang, James Lennon, Surya Nagaraja, Patrick J. Morris, Michael Quezada, Shawn M. Gillespie, Damien Y. Duveau, Aleksandra M. Michalowski, Paul Shinn, Rajarshi Guha, Marc Ferrer, Carleen Klumpp-Thomas, Sam Michael, Crystal McKnight, Paras Minhas, Zina Itkin, Eric H. Raabe, Lu Chen, Reem Ghanem, Anna C. Geraghty, Lijun Ni, Katrin I. Andreasson, Nicholas A. Vitanza, Katherine E. Warren, Craig J. Thomas, Michelle Monje
Journal: Science Translational Medicine (2019)

Diffuse midline gliomas (DMGs) are universally lethal malignancies occurring chiefly during childhood and involving midline structures of the central nervous system, including thalamus, pons, and spinal cord. These molecularly related cancers are characterized by high prevalence of the histone H3K27M mutation. In search of effective therapeutic options, we examined multiple DMG cultures in sequential quantitative high-throughput screens (HTS) of 2706 approved and investigational drugs. This effort generated 19,936 single-agent dose responses that inspired a series of HTS-enabled drug combination assessments encompassing 9195 drug-drug examinations. Top combinations were validated across patient-derived cell cultures representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-histone deacetylase (HDAC) inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to key metabolic processes and the cellular unfolded protein response after treatment with panobinostat and marizomib. Mitigation of drug-induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking nicotinamide adenine dinucleotide (NAD+) production via nicotinamide phosphoribosyltransferase (NAMPT) inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study provides a comprehensive single-agent and combinatorial drug screen for DMG and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores underrecognized metabolic vulnerabilities in DMG.
Abstract 109: Automated External Defibrillators Are Rarely Used for In-Hospital Cardiac Arrest in Denmark
Authors: Mathilde Staerk, Kasper G Lauridsen, Kristian Krogh, Hans Kirkegaard, Bo Løfgren
Journal: Circulation (2019)

Introduction: Automated External Defibrillators (AEDs) are widely distributed in the pre-hospital setting and reported to reduce time to defibrillation and increase survival from out-of-hospital cardiac arrest. During in-hospital cardiac arrest (IHCA), AEDs may allow for early defibrillation before the cardiac arrest team arrives with a manual defibrillator. However, the effect of AEDs for IHCA remains unclear. This study aimed to investigate AED usage and contribution to defibrillation before cardiac arrest team arrival during IHCA. Methods: We obtained data on IHCAs in 2016 and 2017 from the Danish nationwide registry on IHCA (DANARREST). Data included information on initial rhythm, type of defibrillator, time to first rhythm analysis, time to arrival of the cardiac arrest team, time to first defibrillation, and return of spontaneous circulation (ROSC). Results: Of 4,496 IHCAs, AEDs were used in 421 resuscitation attempts (9%). Time registrations were excluded for 6 non-shockable IHCAs due to errors in registration. Of the 421 IHCAs, 82% (n=347) were non-shockable and 16% (n=68) were shockable (data missing for 6 IHCAs). ROSC was achieved in 46% (n=158) of patients with non-shockable rhythms and 59% (n=40) of patients with shockable rhythms. For IHCAs with a shockable rhythm and usage of an AED, rhythm analysis was performed before arrival of the cardiac arrest team in 50% (n=34) of cases and defibrillation with an AED were performed in 46% (n=27) of the cases. Patients with shockable rhythms defibrillated before arrival of the cardiac team, more often achieved ROSC compared to patients defibrillated after cardiac arrest team arrival (p=0.0024). Data regarding time registration are shown in the table. Conclusion: AEDs are used in approximately 1 of 10 resuscitation attempts in Danish hospitals and contribute to defibrillation before arrival of the cardiac arrest team in 1 of 14 cardiac arrest patients.
Ixazomib or Lenalidomide Maintenance Following Autologous Stem Cell Transplantation and Ixazomib, Lenalidomide, and Dexamethasone (IRD) Consolidation in Patients with Newly Diagnosed Multiple Myeloma: Results from a Large Multi-Center Randomized Phase II Trial
Authors: Ravi Vij, Thomas G. Martin, Nitya Nathwani, Mark A. Fiala, Feng Gao, Abhinav Deol, Francis K. Buadi, Jonathan L. Kaufman, Craig C Hofmeister, Tara K. Gregory, Jesus G. Berdeja, Ajai Chari, Ashley E. Rosko
Journal: Blood (2019)
Abstract 356: Dynamic Susceptibility Contrast Magnetic Resonance Imaging to Quantify Perfusion Changes in Early Ischemic Brain Insult Following Cardiac Arrest in a Swine Model
Authors: Miriam Peckham, Adam DeHavenon, Matthew D Alexander, Jeffrey Anderson, Scott McNally, Stephen H McKellar, Joseph Tonna, Ka-ho Wong, Jacob Steenblik, Scott T Youngquist
Journal: Circulation (2019)

Introduction: Derangement of the cerebrovascular unit (CVU) following ischemia-reperfusion from cardiac arrest contributes to overall brain injury. MRI can detect perfusion changes, but imaging timing and severity of injury vary in the clinical population. Hypothesis: We hypothesized that a large-animal model with fixed periods of global ischemia followed by standardized reperfusion and time to image acquisition would demonstrate a reliable gradient of perfusion changes. Such a model would allow neuroprotective strategies to be tested using early imaging biomarkers to quantify effects on cerebral perfusion. Methods: 10 healthy swine were placed under isoflurane anesthesia and underwent control MRI with dynamic susceptibility contrast (DSC) perfusion. Following imaging, animals were randomized to sham, 10, 15, 20, and 30-minute arrest groups, after which extracorporeal membrane oxygenation (ECMO) catheters were placed in the distal aorta and right atrium. Ventricular fibrillation was then induced by a bipolar pacing catheter for the fixed period of ischemia, after which animals were reperfused at 2.8-3.5 L/min with unblended oxygenated blood. After 4 minutes they were defibrillated. Over the next 2 hours they were weaned from pump and decannulated with epinephrine and fluid boluses given for hemodynamic support. Animals were then re-imaged within 2 hours post-resuscitation using the same pre-arrest protocol. DSC post-processing was performed and regions of interest were drawn in the bilateral frontal lobes to quantify perfusion parameters. Results: Baseline hemodynamic parameters, including BP, Heart Rate, ETCO2, and SpO2 were similar between animals. When comparing pre- to post-arrest MRI, there was a linear correlation of increasing Cerebral Blood Volume (CBV) with ischemic duration (r=0.69, p=0.028), and downward trend of Cerebral Blood Flow (CBF) with duration (r=-0.48, p=0.164). Conclusion: MRI DSC perfusion abnormalities were observed early in the post arrest period following fixed periods of ischemia with CBV correlated with ischemia duration consistent with dysfunctional vasodilation and uncoupling of the CVU. CBF showed a downward trend with injury severity. The effect of vasopressors and fluids on these findings is unclear.
The Aquilegia genome reveals a hybrid origin of core eudicots
Authors: Gökçe Aköz, Magnus Nordborg
Journal: Genome biology (2019)

Abstract Background Whole-genome duplications (WGDs) have dominated the evolutionary history of plants. One consequence of WGD is a dramatic restructuring of the genome as it undergoes diploidization, a process under which deletions and rearrangements of various sizes scramble the genetic material, leading to a repacking of the genome and eventual return to diploidy. Here, we investigate the history of WGD in the columbine genus Aquilegia , a basal eudicot, and use it to illuminate the origins of the core eudicots. Results Within-genome synteny confirms that columbines are ancient tetraploids, and comparison with the grape genome reveals that this tetraploidy appears to be shared with the core eudicots. Thus, the ancient gamma hexaploidy found in all core eudicots must have involved a two-step process: first, tetraploidy in the ancestry of all eudicots, then hexaploidy in the ancestry of core eudicots. Furthermore, the precise pattern of synteny sharing suggests that the latter involved allopolyploidization and that core eudicots thus have a hybrid origin. Conclusions Novel analyses of synteny sharing together with the well-preserved structure of the columbine genome reveal that the gamma hexaploidy at the root of core eudicots is likely a result of hybridization between a tetraploid and a diploid species.
Factors Predictive of Remission of Chronic Anterior Uveitis
Authors: Lucia Sobrin, Maxwell Pistilli, Kurt Dreger, Srishti Kothari, Naira Khachatryan, Pichaporn Artornsombudh, Siddharth S. Pujari, C. Stephen Foster, Douglas A. Jabs, Robert B. Nussenblatt, James T. Rosenbaum, Grace A. Levy-Clarke, H. Nida Sen, Eric B. Suhler, Jennifer E. Thorne, Nirali P. Bhatt, John H. Kempen
Journal: Ophthalmology (2019)
Enasidenib Plus Azacitidine Significantly Improves Complete Remission and Overall Response Compared with Azacitidine Alone in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) with Isocitrate Dehydrogenase 2 (IDH2) Mutations: Interim Phase II Results from an Ongoing, Randomized Study
Authors: Courtney D. DiNardo, Andre C. Schuh, Eytan M. Stein, Pau Montesinos Fernandez, Andrew Wei, Stephane De Botton, Amer M. Zeidan, Amir T. Fathi, Lynn Quek, Hagop M. Kantarjian, Mark G. Frattini, Frederik Lersch, Jing Gong, Aleksandra Franovic, Kyle MacBeth, Paresh Vyas, Hartmut Döhner
Journal: Blood (2019)
Additional Cytotoxic Chemotherapy Is Unlikely to Eliminate Measurable Residual Acute Myeloid Leukemia (AML)
Authors: Jacob Appelbaum, Anisha Loeb, Kelda Gardner, Carole M. Shaw, Paul C. Hendrie, Colin D. Godwin, Mary-Elizabeth M. Percival, Anna B. Halpern, Bart L. Scott, Vivian G. Oehler, Roland B. Walter, Pamela S. Becker, Michael C. Jensen, Elihu H. Estey
Journal: Blood (2019)