tbuckley/cabot-search huggingface dataset:
PDE1 Inhibition Modulates Ca <sub>v</sub> 1.2 Channel to Stimulate Cardiomyocyte Contraction
Authors: Grace K. Muller, Joy Song, Vivek Jani, Yuejin Wu, Ting Liu, William P.D. Jeffreys, Brian O’Rourke, Mark E. Anderson, David A. Kass
Journal: Circulation Research (2021)

Rationale: cAMP activation of PKA (protein kinase A) stimulates excitation-contraction (EC) coupling, increasing cardiac contractility. This is clinically achieved by β-ARs (β-adrenergic receptor) stimulation or PDE3i (inhibition of phosphodiesterase type-3), although both approaches are limited by arrhythmia and chronic myocardial toxicity. PDE1i (Phosphodiesterase type-1 inhibition) also augments cAMP and enhances contractility in intact dogs and rabbits. Unlike β-ARs or PDE3i, PDE1i-stimulated inotropy is unaltered by β-AR blockade and induces little whole-cell Ca 2+ (intracellular Ca 2+ concentration; [Ca 2+ ] i ) increase. Positive inotropy from PDE1i was recently reported in human heart failure. However, mechanisms for this effect remain unknown. Objective: Define the mechanism(s) whereby PDE1i increases myocyte contractility. Methods and Results: We studied primary guinea pig myocytes that express the PDE1C isoform found in larger mammals and humans. In quiescent cells, the potent, selective PDE1i (ITI-214) did not alter cell shortening or [Ca 2+ ] i , whereas β-ARs or PDE3i increased both. When combined with low-dose adenylate cyclase stimulation, PDE1i enhanced shortening in a PKA-dependent manner but unlike PDE3i, induced little [Ca 2+ ] i rise nor augmented β-ARs. β-ARs or PDE3i reduced myofilament Ca 2+ sensitivity and increased sarcoplasmic reticulum Ca 2+ content and phosphorylation of PKA-targeted serines on TnI (troponin I), MYBP-C (myosin binding protein C), and PLN (phospholamban). PDE1i did not significantly alter any of these. However, PDE1i increased Ca v 1.2 channel conductance similarly as PDE3i (both PKA dependent), without altering Na + -Ca 2+ exchanger current density. Cell shortening and [Ca 2+ ] i augmented by PDE1i were more sensitive to Ca v 1.2 blockade and to premature or irregular cell contractions and [Ca 2+ ] i transients compared to PDE3i. Conclusions: PDE1i enhances contractility by a PKA-dependent increase in Ca v 1.2 conductance with less total [Ca 2+ ] i increase, and no significant changes in sarcoplasmic reticulum [Ca 2+ ], myofilament Ca 2+ -sensitivity, or phosphorylation of critical EC-coupling proteins as observed with β-ARs and PDE3i. PDE1i could provide a novel positive inotropic therapy for heart failure without the toxicities of β-ARs and PDE3i.
Abstract 286: Targeting Formyl Peptide Receptors as a Novel Approach to Treat Hypertension
Authors: Chengxue X Qin, Kristy L Jackson, Thomas Giddy, Minh Deo, Kiriazis Helen, Owen L Woodman, Rebecca H Ritchie, Geoffrey Head
Journal: Circulation Research (2020)

Introduction: It is estimated that 15-30% of hypertensive patients are resistant to available drugs; and thus identifying novel therapeutic strategies is imperative. We have previously demonstrated that the formyl peptide receptor-1/2 (FPR) small-molecule agonist, Cmpd17b, exhibits anti-inflammatory and vasodilator actions. We investigated the efficacy of Cmpd17b to reduce hypertension and its associated end-organ damage. Methods: Hypertensive (BPH/2J) and normotensive (BPN/3J) mice underwent 24h conscious blood pressure recordings via telemetry from baseline until 4 weeks post Cmpd17b treatment (50 mg/kg/day, i.p.) or vehicle (8% tween80 in saline with 10% dimethyl sulfoxide, i.p.). The abdominal aorta dimension was assessed via ultrasound imaging at baseline and study end. Results: Hypertensive mice exhibited elevated mean arterial pressure compared to normotensive mice at baseline (Table). Cmpd17b reduced mean arterial pressure, left ventricle fibrosis, angiotensinogen expression and improved vascular distensibility. Conclusion: This study is the first to demonstrate that chronic FPR agonist administration reduces blood pressure in hypertensive mice, and further supports development of FPR-based therapies against hypertension-related organ damage.
Enasidenib (ENA) Monotherapy with Addition of Azacitidine in Non-Responders Is Effective in Older Patients with Newly Diagnosed IDH2 Mutated Acute Myeloid Leukemia (AML): A Completed Phase 2/1b Sub-Study of the Beat AML Master Trial
Authors: Eytan M. Stein, Ying Huang, Uma Borate, Maria R. Baer, Wendy Stock, Tibor Kovacsovics, William Blum, Gary J. Schiller, Rebecca L. Olin, James M. Foran, Mark Litzow, Tara Lin, Prapti A. Patel, Matthew C Foster, Michael Boyiadzis, Robert H. Collins, Jo-Anne Vergilio, Nyla A Heerema, Leonard Rosenberg, Ashley Owen Yocum, Timothy Chen, Franchesca Druggan, Sonja Marcus, Mona Stefanos, Jordan Chervin, Abigail Shoben, Brian J. Druker, Amy Burd, John C. Byrd, Ross L. Levine, Alice S. Mims
Journal: Blood (2020)
Abstract PO-069: Characterizing cell-to-cell heterogeneity and chromosome instability induced by <i>USP22</i> deficiency in colorectal cancer
Authors: Lucile M. Jeusset, Zelda D. Lichtensztejn, Kirk J. McManus
Journal: Cancer Research (2020)

Abstract Chromosome instability (CIN) is an aberrant phenotype characterized by an increased rate of gains and losses of chromosomes. CIN is observed in most cancer types, including 85% of colorectal cancer (CRC) cases. Although CIN is a driver of tumor heterogeneity and associated with drug resistance and poor patient prognosis, the genetic defects underlying CIN remain poorly understood. Ubiquitin Specific Peptidase 22 (USP22) is a deubiquitinating enzyme that targets mono-ubiquitin on lysine 120 of histone H2B (H2Bub1). H2Bub1 is a dynamic post-translational modification that modulates chromatin compaction. Importantly, homozygous or heterozygous USP22 deletion is observed in 45% of CRC cases, suggesting this may be a pathogenic event promoting CRC progression. Accordingly, we sought to characterize the impact reduced USP22 expression has on CIN. To reduce USP22 expression in karyotypically stable CRC (HCT116) and immortalized fibroblast (hTERT) cell lines, we employed transient siRNA silencing and stable CRISPR-Cas9 knockout (KO) models. Single-cell quantitative image-based analyses were utilized to monitor CIN-associated phenotypes, including changes in nuclear areas, micronucleus formation and chromosome numbers. In HCT116, USP22 silencing induced CIN phenotypes and an increase in H2Bub1 abundance in mitotic chromosomes. Subsequent mechanistic studies determined that this is accompanied by an increase in the recruitment of the spindle assembly checkpoint kinase BUB1 at metaphase centromeres and an increased frequency of lagging chromosomes in anaphase. Collectively, these data suggest that reduced USP22 expression alters H2Bub1 regulation in mitosis, which impairs mitotic fidelity, thereby inducing CIN. In addition, to assess the relevance of reduced USP22 expression in a distinct cellular context, the impact of USP22 silencing was assessed in hTERT, revealing similar CIN phenotypes, including changes in nuclear area and chromosome numbers. To assess the long-term impact USP22 deletions have on CIN, novel homozygous and heterozygous USP22-KO HCT116 clones were generated and monitored for three months, which revealed dynamic CIN phenotypes and ongoing changes in chromosome complements relative to controls. Collectively, these data identify USP22 as a novel CIN gene and indicate that USP22 deletions in cancer may drive intra-tumor genetic heterogeneity and thereby promote oncogenesis. Citation Format: Lucile M. Jeusset, Zelda D. Lichtensztejn, Kirk J. McManus. Characterizing cell-to-cell heterogeneity and chromosome instability induced by USP22 deficiency in colorectal cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-069.
A multifunctional cross-validation high-throughput screening protocol enabling the discovery of new SHP2 inhibitors
Authors: Yihui Song, Min Zhao, Yahong Wu, Bin Yu, Hong-Min Liu
Journal: Acta Pharmaceutica Sinica B (2020)

The protein tyrosine phosphatase Src homology phosphotyrosyl phosphatase 2 (SHP2) is implicated in various cancers, and targeting SHP2 has become a promising therapeutic approach. We herein described a robust cross-validation high-throughput screening protocol that combined the fluorescence-based enzyme assay and the conformation-dependent thermal shift assay for the discovery of SHP2 inhibitors. The established method can effectively exclude the false positive SHP2 inhibitors with fluorescence interference and was also successfully employed to identify new protein tyrosine phosphatase domain of SHP2 (SHP2-PTP) and allosteric inhibitors. Of note, this protocol showed potential for identifying SHP2 inhibitors against cancer-associated SHP2 mutation SHP2-E76A. After initial screening of our in-house compound library (∼2300 compounds), we identified 4 new SHP2-PTP inhibitors (0.17% hit rate) and 28 novel allosteric SHP2 inhibitors (1.22% hit rate), of which SYK-85 and WS-635 effectively inhibited SHP2-PTP (SYK-85: IC50 = 0.32 μmol/L; WS-635: IC50 = 4.13 μmol/L) and thus represent novel scaffolds for designing new SHP2-PTP inhibitors. TK-147, an allosteric inhibitor, inhibited SHP2 potently (IC50 = 0.25 μmol/L). In structure, TK-147 could be regarded as a bioisostere of the well characterized SHP2 inhibitor SHP-099, highlighting the essential structural elements for allosteric inhibition of SHP2. The principle underlying the cross-validation protocol is potentially feasible to identify allosteric inhibitors or those inactivating mutants of other proteins.
“Old Drugs, New Tricks” – Local controlled drug release systems for treatment of degenerative joint disease
Authors: Marianna A. Tryfonidou, Geert de Vries, Wim E. Hennink, Laura B. Creemers
Journal: Advanced Drug Delivery Reviews (2020)

Osteoarthritis (OA) and chronic low back pain (CLBP) caused by intervertebral disc (IVD) degeneration are joint diseases that have become major causes for loss of quality of life worldwide. Despite the unmet need, effective treatments other than invasive, and often ineffective, surgery are lacking. Systemic administration of drugs entails suboptimal local drug exposure in the articular joint and IVD. This review provides an overview of the potency of biomaterial-based drug delivery systems as novel treatment modality, with a focus on the biological effects of drug release systems that have reached translation at the level of in vivo models and relevant ex vivo models. These studies have shown encouraging results of biomaterial-based local delivery of several types of drugs, mostly inhibitors of inflammatory cytokines or other degenerative factors. Prevention of inflammation and degeneration and pain relief was achieved, although mainly in small animal models, with interventions applied at an early disease stage. Less convincing data were obtained with the delivery of regenerative factors. Multidisciplinary efforts towards tackling the discord between in vitro and in vivo release, combined with adaptations in the regulatory landscape may be needed to enhance safe and expeditious introduction of more and more effective controlled release-based treatments with the OA and CLBP patients.
Updated Follow-up of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Treated with Lisocabtagene Maraleucel in the Phase 1 Monotherapy Cohort of Transcend CLL 004, Including High-Risk and Ibrutinib-Treated Patients
Authors: Tanya Siddiqi, Jacob D. Soumerai, Kathleen A. Dorritie, Deborah M. Stephens, Peter A. Riedell, Jon E. Arnason, Thomas J. Kipps, Heidi H. Gillenwater, Lucy Gong, Lin Yang, Ken Ogasawara, William G. Wierda
Journal: Blood (2020)
A Systematic Review of Evidence Supporting the Use of Autologous Cell Vaccines in the Treatment of Hematological Malignancies
Authors: Donald Bastin, Sarwat Khan, Joshua Montroy, Michael A. Kennedy, Nicole Forbes, Andre B Martel, Laura Baker, Louise Gresham, Dominique Boucher, Boaz Wong, Jean-Simon Diallo, Dean Fergusson, Manoj Lalu, Rebecca C Auer, Natasha Kekre
Journal: Blood (2020)
Expression of a foreign antigen by intratumoral DNA electroporation to enhance anti-tumor immune response
Authors: Olga Radkevich-Brown, Jayanth Panyam, Wei-Zen Wei
Journal: Cancer Research (2007)

1885  Most tumor-associated antigens (TAA) are normal self-proteins that induce weak immune responses because of immunological tolerance. A major challenge in cancer immunotherapy is how to enhance such immune responses. We hypothesize that a strong immune reactivity to a foreign recall antigen expressed intratumorally will cause tumor cell destruction and lead to enhanced immune priming to TAA. To test the feasibility of expressing a foreign antigen in a solid tumor, we monitored the activity of firefly luciferase introduced into BALB/c mammary tumors D2F2 by DNA electroporation. Mice were inoculated subcutaneously with 1x105 D2F2 cells. When tumors reached 3x3 mm in size, mice received 100-200 μg of luciferase DNA in 50-100 μl of PBS intratumorally (i.t.) twice, 3 days apart. Each DNA injection was followed immediately by electroporation at the injection site using a tweezer electrode to deliver 8 pulses, each at 100 V for 25 msec. Luciferase activity was measured twice a wk starting on d.7 after the 1st DNA electroporation. Mice received i.v. injection of 1.6 mg D-luciferin, the luciferase substrate, and were imaged with the Kodak IS4000MM small animal imager. The intratumoral luciferase activity was maximal between d.7 and d.10 after the 1st DNA electroporation and declined progressively until no activity was detected on d.21. Intratumoral expression of luciferase was verified by in vitro luciferase assay of the tumor lysate. To test whether i.t. DNA electroporation induced immune reactivity to the expressed foreign protein, pE2TM DNA was electroporated into D2F2 tumor. pE2TM encodes the extracellular and transmembrane domains of human ErbB-2 (Her-2), a TAA overexpressed in several types of human cancers. Her-2 is the human homolog of mouse ErbB-2 and a foreign, heterologous Ag in mice. After two i.t. DNA electroporations, Her-2-specific antibodies and T cells were detected by flow cytometry and IFN-γ ELISPOT, respectively. These results demonstrate the feasibility of expressing a foreign antigen by i.t. DNA electroporation and its recognition by the immune system, suggesting the possibility of converting a solid tumor into a cancer vaccine reservoir. The effect of intratumoral delivery of a foreign recall antigen on tumor cell destruction and immune priming to TAA is under investigation. This work is supported by CA76340, CA125680, and Wayne State University.
Phase II Study of Blinatumomab and Concurrent Oral Tyrosine Kinase Inhibitor Therapy As Consolidation and Maintenance Therapy for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Following Chemotherapy-Sparing Induction
Authors: Mark B. Geyer, Amber C. King, Justin C. O'Brien, Jae H. Park
Journal: Blood (2020)
THU0492 MAGNETIC RESONANCE IMAGING OF THE SACROILIAC JOINTS IN PATIENTS WITH HYPERMOBILITY: A RETROSPECTIVE COHORT STUDY
Authors: A. Jones, C. Ciurtin, H. Kazkaz, M. Hall-Craggs
Journal: Annals of the Rheumatic Diseases (2020)

Background: The incidence of inflammatory and structural lesions on magnetic resonance imaging of sacroiliac joints (MRI SIJs) in patients with hypermobility related disorders has not been fully investigated. Hypermobile patients are more susceptible to pelvic instability and biomechanical stress of the SIJs, leading to MRI SIJ changes similar to those occurring in spondyloarthritis (SpA). Patients with hypermobility and suspected SpA pose a unique challenge owing to the high prevalence of back pain in the hypermobility cohort and the absence of spinal restriction on clinical examination. Objectives: In this study, we aim to investigate the incidence of MRI SIJ lesions in patients with hypermobility. Methods: We performed a retrospective study of all patients with a confirmed diagnosis of hypermobility related disorders (including hypermobility syndrome, hypermobility spectrum disorders and Ehlers-Danlos Syndromes) referred for an MRI lumbar spine and SIJ between 2011 and 2019 to investigate long-standing back pain. MRIs were examined by a musculoskeletal (MSK) radiologist with more than 25 years of experience, who was blinded to the clinical outcome of the patients. MRI SIJs were assessed for the presence of bone marrow oedema, subchondral sclerosis, erosion, fatty change, enthesitis, ankylosis, joint fluid and capsulitis. Results: 51 patients with confirmed hypermobility related disorders were referred for MRI SIJ and lumbar spine between 2011 and 2019. 3 patients demonstrated clinical features in keeping with a diagnosis of SpA and were excluded from the study. 15/48 (31.3%) of patients with hypermobility and back pain (but no clinical picture of SpA) were found to have inflammatory and/or structural lesions on MRI SIJ. The most frequent lesions were small foci of bone marrow oedema (16.6%) followed by subchondral sclerosis (12.5%) and fatty change (10.4%). The incidence of erosions was 4.2%. Conclusion: There is a relatively high incidence of inflammatory and structural lesions on MRI SIJ of patients with hypermobility. The presence of hypermobility should be taken into consideration when interpreting MRI changes in patients with suspected SpA. Further research into long-term outcomes of MRI SIJs in patients with hypermobility and back pain is required to establish the clinical significance of these findings. Disclosure of Interests: : Alexis Jones: None declared, Coziana Ciurtin Grant/research support from: Pfizer, Consultant of: Roche, Modern Biosciences, Hanadi Kazkaz: None declared, Margaret Hall-Craggs: None declared
THU0086 Serum il-15 levels and peripheral blood lymphocyte (pbl) cd69 expression in rheumatoid arthritis (ra) patients
Authors: AM Ortiz, R Garcia-Vicuña, E Tomero, A Laffon, I González-Alvaro
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> We have recently described that IL-15 induces higher CD69 expression on lymphocytes compared to several cytokines described in rheumatoid synovium. A growing body of evidence supports that these two molecules can play an important role in the perpetuation of synovitis in RA. <h3>Objectives</h3> To determine IL-15 serum levels and the expression of CD69 on PBL from RA patients and to assess their possible correlation with several clinical and biological parameters. <h3>Methods</h3> IL-15 and TNF-a serum levels were measured by ELISA (R&amp;D Systems) and CD69 expression on PBL was assessed by flow cytometry, both in RA patients (n = 25) and healthy donors (n = 15). Each RA patient was evaluated at the time of sample collection for the following variables: morning stiffness (MS), pain visual analogic scale (0–100 mm), number of tender (TJC) and swollen (SJC) joints (Fuchs 28 joints count), patient and physician global disease activity assessment (GDA) in a Likert scale (0–4), ESR and CRP. Those patients that fulfilled 5 or more of the next criteria were considered to have an active disease: pain score &gt; 25 mm; TJC &gt; 5; SJC &gt; 3; patient GDA &gt; 1; physician GDA &gt; 1; ESR &gt; 25 mm and RCP &gt; 0.8 mg/dl. DAS28 score was also calculated. Student t test and Pearson correlation test were applied for statistical analysis. <h3>Results</h3> IL-15 and TNF-a serum levels from RA patients were significantly higher than that from healthy donors (314.6 ± 72.3 vs. 12.9 ± 3.1 pg/ml, p = 0.0001; and 233.1 ± 97.9 vs 74.2 ± 30 pg/ml, p = 0.06, respectively). The percentage of CD69 positive PBL in RA patients was also higher that in controls (12.6 ± 1.2 vs. 9.7 ± 0.8; p = 0.03). The percentage of CD69<sup>+</sup> PBL correlated with DAS score (r = 0.382; p &lt; 0.05). In addition, MS and TNF-a levels also correlated (r = 0.49; p = 0.015). Mean serum concentrations of IL15 and TNF-a in patients with active disease were higher than these cytokine levels in patients considered inactive (274 vs. 112.4 pg/ml and 337.6 vs. 211 pg/ml, respectively), although this difference did not reached statistical significance likely due to the low number of patients with inactive disease (n = 6). <h3>Conclusion</h3> Our data showed a correlation between CD69 expression on PBL and clinical parameters, suggesting a pathogenic role for this molecule in RA. Further studies are needed to evaluate the clinical significance of elevated levels of IL15 in RA patients.
The Effect of Crizanlizumab on the Number of Days Requiring Opioid Use for Management of Pain Associated with Vaso-Occlusive Crises in Patients with Sickle Cell Disease: Results from the Sustain Trial
Authors: Wally R Smith, Kenneth I. Ataga, Santosh L. Saraf, Olufolake A. Adisa, Miranda Bailey, Nicholas Ramscar, Ashley Bonner, Stephen Brown, Laura Pastor
Journal: Blood (2020)
Learning from a pandemic: how the post-covid NHS can reach its full potential
Authors: Jeremy Marlow, James O’Shaughnessy, Bruce Keogh, Nitin Chaturvedi
Journal: BMJ (2020)

Out of the tragedy of the pandemic, there is a unique opportunity to accelerate reform in the NHS and prepare for a world living with and after covid-19, write <b>Jeremy Marlow and colleagues</b>
高コレステロール血症の日本人患者における低用量シンバスタチン治療による血清コレステロール濃度と冠動脈疾患の間の関係に関する大規模コホート研究 日本脂質介入試験(J-LIT)の一次予防コホート研究
Authors: Matsuzaki M, Kita T, Mabuchi H, Matsuzawa Y, Nakaya N, Oikawa S, Saito Y, Sasaki J, Itakura H
Journal: Circulation (2002)
Venetoclax Exposure-Efficacy and Exposure-Safety Relationships in Subjects with Treatment-Naïve Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy
Authors: Doerthe Eckert, Deanna Brackman, Rajeev Menon, Ahmed Hamed Salem, Jalaja Potluri, B. Douglas Smith, Andrew H. Wei, John Hayslip, Dale Miles, Sven Mensing, Sathej Gopalakrishnan, Jiuhong Zha
Journal: Blood (2020)
Effective Erythropoiesis from Human iPSC-Derived RBC in Immunodeficient Mice
Authors: Jiusheng Deng, Moira M. Lancelot, Ryan Jajosky, Kristin Deeb, Natia Saakadze, Yongixng Gao, Senquan Liu, Sean R. Stowell, Linzhao Cheng, John D Roback
Journal: Blood (2020)
COMMODORE Cohort: A Novel, Real-World, Noninterventional Cohort Study Using a Patient-Centered Approach to Evaluate the Safety and Effectiveness of C5 Inhibitors in Patients with Paroxysmal Nocturnal Hemoglobinuria
Authors: Aijing Shang, Imi Faghmous, Dan Drozd, Pablo Katz
Journal: Blood (2020)