tbuckley/cabot-search huggingface dataset:
Peptidomimetic-based antibody surrogate for HER2
Authors: Mengmeng Zheng, Chunpu Li, Mi Zhou, Ru Jia, Fengyu She, Lulu Wei, Feng Cheng, Qi Li, Jianfeng Cai, Yan Wang
Journal: Acta Pharmaceutica Sinica B (2021)

Inhibition of human epidermal growth factor receptor 2 mediated cell signaling pathway is an important therapeutic strategy for HER2-positive cancers. Although monoclonal antibodies are currently used as marketed drugs, their large molecular weight, high cost of production and susceptibility to proteolysis could be a hurdle for long-term application. In this study, we reported a strategy for the development of artificial antibody based on γ-AApeptides to target HER2 extracellular domain (ECD). To achieve this, we synthesized a one-bead-two-compound (OBTC) library containing 320,000 cyclic γ-AApeptides, from which we identified a γ-AApeptide, M-3-6, that tightly binds to HER2 selectively. Subsequently, we designed an antibody-like dimer of M-3-6, named M-3-6-D, which showed excellent binding affinity toward HER2 comparable to monoclonal antibodies. Intriguingly, M-3-6-D was completely resistant toward enzymatic degradation. In addition, it could effectively inhibit the phosphorylation of HER2, as well as the downstream signaling pathways of AKT and ERK. Furthermore, M-3-6-D also efficiently inhibited cell proliferation in vitro, and suppressed tumor growth in SKBR3 xenograft model in vivo, implying its therapeutic potential for the treatment of cancers. Its small molecular weight, antibody-like property, resistance to proteolysis, may enable it a new generation of artificial antibody surrogate. Furthermore, our strategy of artificial antibody surrogate based on dimers of cyclic γ-AApeptides could be applied to a myriad of disease-related receptor targets in future.
CHANGE IN QRS 3D VOLTAGE TIME INTEGRAL (3D QRS AREA) WITH CARDIAC RESYNCHRONIZATION THERAPY PREDICTS SUBSEQUENT LEFT VENTRICULAR REVERSE REMODELING AND HEART FAILURE HOSPITALIZATIONS
Authors: Tucker Morey, Christopher J. Harvey, Uzair Mahmood, Nikhil Parimi, Sean Lacy, Ashley DeBauge, Seth Sheldon, Madhu Reddy, Amit Noheria
Journal: Journal of the American College of Cardiology (2021)
Covid-19: Wider use of FFP3 masks may be needed because of airborne transmission, say scientific advisers
Authors: Elisabeth Mahase
Journal: BMJ (2021)

<h3>OBJECTIVE</h3> Blood oxygenation level dependent (BOLD) contrast functional MRI images show activated cortical areas by detecting a reduced concentration of deoxyhaemoglobin (deoxy-Hb) during neuronal activity; however, near infrared spectroscopy (NIRS) has shown various patterns of cerebral blood oxygenation (CBO) changes in the frontal lobe during cognitive tasks. To determine if various patterns of CBO changes occur in the frontal lobe when the brain is directly stimulated, changes in CBO in the frontal lobe induced by deep brain stimulation in patients with implanted electrodes were evaluated. <h3>METHODS</h3> Six patients were studied, including five with Parkinson9s disease and one with essential tremor. To reduce tremor or rigidity, the electrodes were implanted at the thalamic nucleus ventralis intermedius (VIM: three Parkinson9s disease and one essential tremor) or the globus pallidus internus (GPi: two Parkinson9s disease). Using NIRS, changes of deoxy-Hb, oxyhaemoglobin (oxy-Hb) and total haemoglobin (total Hb) were measured in the bilateral frontal lobes during various stimulus conditions. <h3>RESULTS</h3> High frequency (120 Hz) GPi stimulation consistently increased oxy-Hb and total Hb with a decrease of deoxy-Hb in an intensity and time dependent manner. Oxy-Hb and total Hb increased immediately after the onset of stimulation and then gradually decreased when stimulation was continued. By contrast, high frequency (120 Hz) VIM stimulation decreased oxy-Hb, deoxy Hb and total Hb in an intensity dependent manner. In the severe tremor patient with VIM stimulation, frequency response was examined by decreasing stimulus frequencies; deoxy-Hb increased at high frequencies (70–40 Hz), and then decreased below the control level at low frequencies (30–0 Hz), whereas oxy-Hb and total Hb increased consistently at high and low frequencies. <h3>CONCLUSION</h3> The electrical stimulation of GPi and VIM caused various CBO changes in the frontal lobe, which were similar to those found during cognitive tasks. Such a multiplicity of CBO changes in the frontal lobe may be caused by complex neuronal circuits in the frontal lobe which has many neuronal connections to other cortical areas or the basal ganglia.
ONE-YEAR OUTCOMES WITH OPTICAL COHERENCE TOMOGRAPHY GUIDANCE IN PERCUTANEOUS CORONARY INTERVENTION
Authors: Rahul Jaswaney, Shilpkumar Arora, Ryan Zuzek, Chinmay Jani, Irfan Helmy, Kirten Patel, Mohammed N. Osman, Guilherme Attizzani
Journal: Journal of the American College of Cardiology (2021)
Gsx1 promotes locomotor functional recovery after spinal cord injury
Authors: Misaal Patel, Ying Li, Jeremy Anderson, Sofia Castro-Pedrido, Ryan Skinner, Shunyao Lei, Zachary Finkel, Brianna Rodriguez, Fatima Esteban, Ki-Bum Lee, Yi Lisa Lyu, Li Cai
Journal: Molecular Therapy (2021)

Promoting residential cells, particularly endogenous neural stem and progenitor cells (NSPCs), for tissue regeneration represents a potential strategy for the treatment of spinal cord injury (SCI). However, adult NSPCs differentiate mainly into glial cells and contribute to glial scar formation at the site of injury. Gsx1 is known to regulate the generation of excitatory and inhibitory interneurons during embryonic development of the spinal cord. In this study, we show that lentivirus-mediated expression of Gsx1 increases the number of NSPCs in a mouse model of lateral hemisection SCI during the acute stage. Subsequently, Gsx1 expression increases the generation of glutamatergic and cholinergic interneurons and decreases the generation of GABAergic interneurons in the chronic stage of SCI. Importantly, Gsx1 reduces reactive astrogliosis and glial scar formation, promotes serotonin (5-HT) neuronal activity, and improves the locomotor function of the injured mice. Moreover, RNA sequencing (RNA-seq) analysis reveals that Gsx1-induced transcriptome regulation correlates with NSPC signaling, NSPC activation, neuronal differentiation, and inhibition of astrogliosis and scar formation. Collectively, our study provides molecular insights for Gsx1-mediated functional recovery and identifies the potential of Gsx1 gene therapy for injuries in the spinal cord and possibly other parts of the central nervous system. Promoting residential cells, particularly endogenous neural stem and progenitor cells (NSPCs), for tissue regeneration represents a potential strategy for the treatment of spinal cord injury (SCI). However, adult NSPCs differentiate mainly into glial cells and contribute to glial scar formation at the site of injury. Gsx1 is known to regulate the generation of excitatory and inhibitory interneurons during embryonic development of the spinal cord. In this study, we show that lentivirus-mediated expression of Gsx1 increases the number of NSPCs in a mouse model of lateral hemisection SCI during the acute stage. Subsequently, Gsx1 expression increases the generation of glutamatergic and cholinergic interneurons and decreases the generation of GABAergic interneurons in the chronic stage of SCI. Importantly, Gsx1 reduces reactive astrogliosis and glial scar formation, promotes serotonin (5-HT) neuronal activity, and improves the locomotor function of the injured mice. Moreover, RNA sequencing (RNA-seq) analysis reveals that Gsx1-induced transcriptome regulation correlates with NSPC signaling, NSPC activation, neuronal differentiation, and inhibition of astrogliosis and scar formation. Collectively, our study provides molecular insights for Gsx1-mediated functional recovery and identifies the potential of Gsx1 gene therapy for injuries in the spinal cord and possibly other parts of the central nervous system.
A RARE CASE OF LEFT ATRIAL MYXOMA WITH CORONARY FISTULA IN A PATIENT WITH DYSPNEA ON EXERTION
Authors: Phillip Tran, Hanh D. Le, Trung M. Tran, Duy K. Doan, Huong Nguyen, Hanh T.T. Le, Vien X. Phan, Huong Tran, Binh N. Trinh, Hoai V. Nguyen
Journal: Journal of the American College of Cardiology (2021)
Frequency of Interruptions to Sitting Time: Benefits for Postprandial Metabolism in Type 2 Diabetes
Authors: Ashleigh R. Homer, Frances C. Taylor, Paddy C. Dempsey, Michael J. Wheeler, Parneet Sethi, Melanie K. Townsend, Megan S. Grace, Daniel J. Green, Neale D. Cohen, Robyn N. Larsen, Bronwyn A. Kingwell, Neville Owen, David W. Dunstan
Journal: Diabetes Care (2021)

OBJECTIVE To determine whether interrupting sitting with brief bouts of simple resistance activities (SRAs) at different frequencies improves postprandial glucose, insulin, and triglycerides in adults with medication-controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Participants (n = 23, 10 of whom were female, with mean ± SD age 62 ± 8 years and BMI 32.7 ± 3.5 kg · m−2) completed a three-armed randomized crossover trial (6- to 14-day washout): sitting uninterrupted for 7 h (SIT), sitting with 3-min SRAs (half squats, calf raises, gluteal contractions, and knee raises) every 30 min (SRA3), and sitting with 6-min SRAs every 60 min (SRA6). Net incremental areas under the curve (iAUCnet) for glucose, insulin, and triglycerides were compared between conditions. RESULTS Glucose and insulin 7-h iAUCnet were attenuated significantly during SRA6 (glucose 17.0 mmol · h · L−1, 95% CI 12.5, 21.4; insulin 1,229 pmol · h · L−1, 95% CI 982, 1,538) in comparison with SIT (glucose 21.4 mmol · h · L−1, 95% CI 16.9, 25.8; insulin 1,411 pmol · h · L−1, 95% CI 1,128, 1,767; P &amp;lt; 0.05) and in comparison with SRA3 (for glucose only) (22.1 mmol · h · L−1, 95% CI 17.7, 26.6; P = 0.01) No significant differences in glucose or insulin iAUCnet were observed in comparison of SRA3 and SIT. There was no statistically significant effect of condition on triglyceride iAUCnet. CONCLUSIONS In adults with medication-controlled T2D, interrupting prolonged sitting with 6-min SRAs every 60 min reduced postprandial glucose and insulin responses. Other frequencies of interruptions and potential longer-term benefits require examination to clarify clinical relevance.
FOCUSED ECHOCARDIOGRAPHY FOR REDEFINING THE PROGNOSIS OF PATIENTS HOSPITALIZED WITH COVID-19 BEYOND CLINICAL DATA - DATA FROM THE PROVAR-COVID STUDY
Authors: Bruno Ramos Nascimento, Sander Luis G. Pimentel, Kaciane K.B. Oliveira, Juliane Franco, Clara L. Fraga, Frederico V.B. Macedo, Rodrigo T.L. Rocha, Renata Eliane Ávila, Marcia Barbosa, Craig Sable, Luiza P.A. Santos, Renan M. Oliveira, Antonio Ribeiro, Andrea Beaton, Maria Carmo Nunes
Journal: Journal of the American College of Cardiology (2021)
Salvage Autologous Stem Cell Transplantation in Patients with Relapsed or Refractory Primary Central Nervous System Lymphoma
Authors: Jaewon Hyung, Jung Yong Hong, Dok Hyun Yoon, Kyoungmin Lee, Shin Kim, Chan-Sik Park, Jooryung Huh, Jin-Sook Ryu, Cheolwon Suh
Journal: Blood (2017)
SUCTION THROMBECTOMY OF CHRONIC, MASSIVE AND HYPERMOBILE RIGHT ATRIAL THROMBUS IN A YOUNG MAN
Authors: Pavan Reddy, Syed Haider, Arsalan Rehmani, Alaa Omar, Preeti Jadhav, Joseph Daibes, Joseph Bracker, Tak Kwan, Omar Latouff, Apurva Patel
Journal: Journal of the American College of Cardiology (2021)
THE SAFETY AND EFFICACY OF SINGLE AND MULTIPLE ASCENDING DOSES OF MEDI6570 IN PARTICIPANTS WITH TYPE 2 DIABETES MELLITUS
Authors: Andrea L. Vavere, Marvin Sinsakul, Emily Ongstad, Ye Yang, Vijayalakshmi Varma, Vincent Dubois, Angelica Quartino, Sotirios Karathanasis, Ruchi Gupta, Liron Abuhatzira, Anna Collén, Michael Koren, Richard George
Journal: Journal of the American College of Cardiology (2021)
Discovery of K<sub>V</sub>1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges
Authors: Špela Gubič, Louise A. Hendrickx, Žan Toplak, Maša Sterle, Steve Peigneur, Tihomir Tomašič, Luis A. Pardo, Jan Tytgat, Anamarija Zega, Lucija P. Mašič
Journal: Medicinal Research Reviews (2021)

Abstract The K V 1.3 voltage‐gated potassium ion channel is involved in many physiological processes both at the plasma membrane and in the mitochondria, chiefly in the immune and nervous systems. Therapeutic targeting K V 1.3 with specific peptides and small molecule inhibitors shows great potential for treating cancers and autoimmune diseases, such as multiple sclerosis, type I diabetes mellitus, psoriasis, contact dermatitis, rheumatoid arthritis, and myasthenia gravis. However, no K V 1.3‐targeted compounds have been approved for therapeutic use to date. This review focuses on the presentation of approaches for discovering new K V 1.3 peptide and small‐molecule inhibitors, and strategies to improve the selectivity of active compounds toward K V 1.3. Selectivity of dalatazide (ShK‐186), a synthetic derivate of the sea anemone toxin ShK, was achieved by chemical modification and has successfully reached clinical trials as a potential therapeutic for treating autoimmune diseases. Other peptides and small‐molecule inhibitors are critically evaluated for their lead‐like characteristics and potential for progression into clinical development. Some small‐molecule inhibitors with well‐defined structure–activity relationships have been optimized for selective delivery to mitochondria, and these offer therapeutic potential for the treatment of cancers. This overview of K V 1.3 inhibitors and methodologies is designed to provide a good starting point for drug discovery to identify novel effective K V 1.3 modulators against this target in the future.
SERIAL ASSESSMENT OF HEMODYNAMIC RESPONSE TO TREATMENT WITH SYSTEMIC ANTICOAGULATION WITH AND WITHOUT ULTRASOUND ASSISTED CATHETER-DIRECTED THROMBOLYSIS IN SUBMASSIVE PULMONARY EMBOLISM
Authors: Isha Samreen, Gouthami Chennu, Michael Divita, Hisham Hakeem, Nicholas Lariccia, Gautam Visveswaran, Marc Cohen
Journal: Journal of the American College of Cardiology (2021)
A Data-Driven Simulation of the Exposure Notification Cascade for Digital Contact Tracing of SARS-CoV-2 in Zurich, Switzerland
Authors: Dominik Menges, Hélène E. Aschmann, André Moser, Christian L. Althaus, Viktor von Wyl
Journal: JAMA Network Open (2021)

Digital contact tracing (DCT) apps have been released in several countries to help interrupt SARS-CoV-2 transmission chains. However, the effect of DCT on pandemic mitigation remains to be demonstrated.
Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies
Authors: Zheng Tian, Ming Liu, Ya Zhang, Xin Wang
Journal: Journal of Hematology & Oncology (2021)

Abstract Harnessing the power of immune cells, especially T cells, to enhance anti-tumor activities has become a promising strategy in clinical management of hematologic malignancies. The emerging bispecific antibodies (BsAbs), which recruit T cells to tumor cells, exemplified by bispecific T cell engagers (BiTEs), have facilitated the development of tumor immunotherapy. Here we discussed the advances and challenges in BiTE therapy developed for the treatment of hematologic malignancies. Blinatumomab, the first BiTE approved for the treatment of acute lymphocytic leukemia (ALL), is appreciated for its high efficacy and safety. Recent studies have focused on improving the efficacy of BiTEs by optimizing treatment regimens and refining the molecular structures of BiTEs. A considerable number of bispecific T cell-recruiting antibodies which are potentially effective in hematologic malignancies have been derived from BiTEs. The elucidation of mechanisms of BiTE action and neonatal techniques used for the construction of BsAbs can improve the treatment of hematological malignancies. This review summarized the features of bispecific T cell-recruiting antibodies for the treatment of hematologic malignancies with special focus on preclinical experiments and clinical studies.
HEMATOMA AND CARDIAC IMPLANTABLE ELECTRONIC DEVICE INFECTION. INSIGHTS FROM THE WRAP-IT TRIAL
Authors: Khaldoun G. Tarakji, Panagiotis Korantzopoulos, Francois Philippon, Mauro Biffi, Suneet Mittal, Jeanne Poole, Charles Kennergren, Daniel Lexcen, Jeff Lande, Bruce Wilkoff
Journal: Journal of the American College of Cardiology (2021)
CLINICAL AND ECONOMIC BURDEN OF OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY IN THE UNITED STATES
Authors: Sneha S. Jain, Sophia S. Li, Jipan Xie, Megan B. Sutton, Jennifer T. Fine, Jay M. Edelberg, Wei Gao, John A. Spertus, David J. Cohen
Journal: Journal of the American College of Cardiology (2021)
Functional Characterization of Organoids Derived From Irreversibly Damaged Liver of Patients With NASH
Authors: Sarah McCarron, Brooke Bathon, Donna M. Conlon, Deepti Abbey, Daniel J. Rader, Katerina Gawronski, Christopher D. Brown, Kim M. Olthoff, Abraham Shaked, Tobias D. Raabe
Journal: Hepatology (2021)

NASH will soon become the leading cause of liver transplantation in the United States and is also associated with increased COVID-19 mortality. Currently, there are no Food and Drug Administration-approved drugs available that slow NASH progression or address NASH liver involvement in COVID-19. Because animal models cannot fully recapitulate human NASH, we hypothesized that stem cells isolated directly from end-stage liver from patients with NASH may address current knowledge gaps in human NASH pathology.We devised methods that allow the derivation, proliferation, hepatic differentiation, and extensive characterization of bipotent ductal organoids from irreversibly damaged liver from patients with NASH. The transcriptomes of organoids derived from NASH liver, but not healthy liver, show significant up-regulation of proinflammatory and cytochrome p450-related pathways, as well as of known liver fibrosis and tumor markers, with the degree of up-regulation being patient-specific. Functionally, NASH liver organoids exhibit reduced passaging/growth capacity and hallmarks of NASH liver, including decreased albumin production, increased free fatty acid-induced lipid accumulation, increased sensitivity to apoptotic stimuli, and increased cytochrome P450 metabolism. After hepatic differentiation, NASH liver organoids exhibit reduced ability to dedifferentiate back to the biliary state, consistent with the known reduced regenerative ability of NASH livers. Intriguingly, NASH liver organoids also show strongly increased permissiveness to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vesicular stomatitis pseudovirus as well as up-regulation of ubiquitin D, a known inhibitor of the antiviral interferon host response.Expansion of primary liver stem cells/organoids derived directly from irreversibly damaged liver from patients with NASH opens up experimental avenues for personalized disease modeling and drug development that has the potential to slow human NASH progression and to counteract NASH-related SARS-CoV-2 effects.
De Novo Mutation Rate Variation and Its Determinants in <i>Chlamydomonas</i>
Authors: Eugenio López-Cortegano, Rory J Craig, Jobran Chebib, Toby Samuels, Andrew D Morgan, Susanne A Kraemer, Katharina B Böndel, Rob W Ness, Nick Colegrave, Peter D Keightley
Journal: Molecular Biology and Evolution (2021)

De novo mutations are central for evolution, since they provide the raw material for natural selection by regenerating genetic variation. However, studying de novo mutations is challenging and is generally restricted to model species, so we have a limited understanding of the evolution of the mutation rate and spectrum between closely related species. Here, we present a mutation accumulation (MA) experiment to study de novo mutation in the unicellular green alga Chlamydomonas incerta and perform comparative analyses with its closest known relative, Chlamydomonas reinhardtii. Using whole-genome sequencing data, we estimate that the median single nucleotide mutation (SNM) rate in C. incerta is μ = 7.6 × 10-10, and is highly variable between MA lines, ranging from μ = 0.35 × 10-10 to μ = 131.7 × 10-10. The SNM rate is strongly positively correlated with the mutation rate for insertions and deletions between lines (r > 0.97). We infer that the genomic factors associated with variation in the mutation rate are similar to those in C. reinhardtii, allowing for cross-prediction between species. Among these genomic factors, sequence context and complexity are more important than GC content. With the exception of a remarkably high C→T bias, the SNM spectrum differs markedly between the two Chlamydomonas species. Our results suggest that similar genomic and biological characteristics may result in a similar mutation rate in the two species, whereas the SNM spectrum has more freedom to diverge.
Linking chondrocyte and synovial transcriptional profile to clinical phenotype in osteoarthritis
Authors: Julia Steinberg, Lorraine Southam, Andreas Fontalis, Matthew J Clark, Raveen L Jayasuriya, Diane Swift, Karan M Shah, Roger A Brooks, Andrew W McCaskie, Jeremy Mark Wilkinson, Eleftheria Zeggini
Journal: Annals of the Rheumatic Diseases (2021)

To determine how gene expression profiles in osteoarthritis joint tissues relate to patient phenotypes and whether molecular subtypes can be reproducibly captured by a molecular classification algorithm.We analysed RNA sequencing data from cartilage and synovium in 113 osteoarthritis patients, applying unsupervised clustering and Multi-Omics Factor Analysis to characterise transcriptional profiles. We tested the association of the molecularly defined patient subgroups with clinical characteristics from electronic health records.We detected two patient subgroups in low-grade cartilage (showing no/minimal degeneration, cartilage normal/softening only), with differences associated with inflammation, extracellular matrix-related and cell adhesion pathways. The high-inflammation subgroup was associated with female sex (OR 4.12, p=0.0024) and prescription of proton pump inhibitors (OR 4.21, p=0.0040). We identified two independent patient subgroupings in osteoarthritis synovium: one related to inflammation and the other to extracellular matrix and cell adhesion processes. A seven-gene classifier including MMP13, APOD, MMP2, MMP1, CYTL1, IL6 and C15orf48 recapitulated the main axis of molecular heterogeneity in low-grade knee osteoarthritis cartilage (correlation ρ=-0.88, p<10-10) and was reproducible in an independent patient cohort (ρ=-0.85, p<10-10).These data support the reproducible stratification of osteoarthritis patients by molecular subtype and the exploration of new avenues for tailored treatments.
Abstract 19273: Short and Long Term Outcomes in Children With Trisomy 21 Following Interventions for Congenital Heart Disease (CHD): A Study From the Pediatric Cardiac Care Consortium (PCCC).
Authors: Jennifer K Peterson, Kirsti G Catton, Lazaros Kochilas, Shaun P Setty
Journal: Circulation (2016)

Methods: Retrospective review of the PCCC for 7809 patients (4081 females) with Trisomy 21 who underwent transcatheter or surgical intervention for CHD from 1982 to 2007. Short term outcomes includ...
IMPACT OF SURGICAL AND TRANSCATHETER AORTIC VALVE REPLACEMENT IN PATIENTS WITH LOW-GRADIENT AORTIC STENOSIS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Hiroki Ueyama, Toshiki Kuno, Matthew Harrington, Hisato Takagi, Parasuram Melarcode Krishnamoorthy, Samin Sharma, Annapoorna Kini, Stamatios Lerakis
Journal: Journal of the American College of Cardiology (2021)
SUCCESSIVE DISTAL TRANSRADIAL APPROACH FOR CORONARY ANGIOGRAPHY AND INTERVENTION IN THE SAME ARM
Authors: Takeshi Yamada, Yuki Matsubara, Soichiro Washimi, Norimasa Taniguchi, Shunsuke Nakajima, Tetsuya Hata, Akihiko Takahashi
Journal: Journal of the American College of Cardiology (2021)
A MACHINE LEARNING MODEL FOR CHARACTERIZATION OF MIXED AORTIC VALVE DISEASE PATIENTS
Authors: Rashmi Nedadur, Zeinab Navidi Ghaziani, Maala Sooriyakanthan, Natalie Ho, Geraldine Ong, Howard Leong-Poi, Bo Wang, Wendy Tsang
Journal: Journal of the American College of Cardiology (2021)