tbuckley/cabot-search huggingface dataset:
A proteolysis-targeting chimera molecule selectively degrades ENL and inhibits malignant gene expression and tumor growth
Authors: Xin Li, Yuan Yao, Fangrui Wu, Yongcheng Song
Journal: Journal of Hematology & Oncology (2022)

Abstract Background Chromosome translocations involving mixed lineage leukemia 1 (MLL1) cause acute leukemia in most infants and 5–10% children/adults with dismal clinical outcomes. Most frequent MLL1-fusion partners AF4/AFF4, AF9/ENL and ELL, together with CDK9/cyclin-T1, constitute super elongation complexes (SEC), which promote aberrant gene transcription, oncogenesis and maintenance of MLL1-rearranged (MLL1-r) leukemia. Notably, ENL, but not its paralog AF9, is essential for MLL1-r leukemia (and several other cancers) and therefore a drug target. Moreover, recurrent ENL mutations are found in Wilms tumor, the most common pediatric kidney cancer, and play critical roles in oncogenesis. Methods Proteolysis-Targeting Chimera (PROTAC) molecules were designed and synthesized to degrade ENL. Biological activities of these compounds were characterized in cell and mouse models of MLL1-r leukemia and other cancers. Results Compound 1 efficiently degraded ENL with DC 50 of 37 nM and almost depleted it at ~ 500 nM in blood and solid tumor cells. AF9 (as well as other proteins in SEC) was not significantly decreased. Compound 1 -mediated ENL reduction significantly suppressed malignant gene signatures, selectively inhibited cell proliferation of MLL1-r leukemia and Myc-driven cancer cells with EC50s as low as 320 nM, and induced cell differentiation and apoptosis. It exhibited significant antitumor activity in a mouse model of MLL1-r leukemia. Compound 1 can also degrade a mutant ENL in Wilms tumor and suppress its mediated gene transcription. Conclusion Compound 1 is a novel chemical probe for cellular and in vivo studies of ENL (including its oncogenic mutants) and a lead compound for further anticancer drug development.
Reducing neuroinflammation via therapeutic compounds and lifestyle to prevent or delay progression of Parkinson’s disease
Authors: Elodie Kip, Louise C. Parr-Brownlie
Journal: Ageing Research Reviews (2022)

Parkinson's disease (PD) is the second most common age-associated neurodegenerative disorder and is characterised by progressive loss of dopamine neurons in the substantia nigra. Peripheral immune cell infiltration and activation of microglia and astrocytes are observed in PD, a process called neuroinflammation. Neuroinflammation is a fundamental response to protect the brain but, when chronic, it triggers neuronal damage. In the last decade, central and peripheral inflammation were suggested to occur at the prodromal stage of PD, sustained throughout disease progression, and may play a significant role in the pathology. Understanding the pathological mechanisms of PD has been a high priority in research, primarily to find effective treatments once symptoms are present. Evidence indicates that early life exposure to neuroinflammation as a consequence of life events, environmental or behaviour factors such as exposure to infections, pollution or a high fat diet increase the risk of developing PD. Many studies show healthy habits and products that decrease neuroinflammation also reduce the risk of PD. Here, we aim to stimulate discussion about the role of neuroinflammation in PD onset and progression. We highlight that reducing neuroinflammation throughout the lifespan is critical for preventing idiopathic PD, and present epidemiological studies that detail risk and protective factors. It is possible that introducing lifestyle changes that reduce neuroinflammation at the time of PD diagnosis may slow symptom progression. Finally, we discuss compounds and therapeutics to treat the neuroinflammation associated with PD.
Highly sensitive H2O2-scavenging nano-bionic system for precise treatment of atherosclerosis
Authors: Xiaoyu Liang, Huiyang Li, Xuanling Li, Xinxin Tian, Aiai Zhang, Qingzhi Luo, Jianwei Duan, Youlu Chen, Liyun Pang, Chen Li, Xing-Jie Liang, Yong Zeng, Jing Yang
Journal: Acta Pharmaceutica Sinica B (2022)

In atherosclerosis, chronic inflammatory processes in local diseased areas may lead to the accumulation of reactive oxygen species (ROS). In this study, we devised a highly sensitive H2O2-scavenging nano-bionic system loaded with probucol (RPP-PU), to treat atherosclerosis more effectively. The RPP material had high sensitivity to H2O2, and the response sensitivity could be reduced from 40 to 10 μmol/L which was close to the lowest concentration of H2O2 levels of the pathological environment. RPP-PU delayed the release and prolonged the duration of PU in vivo. In Apolipoprotein E deficient (ApoE‒/‒) mice, RPP-PU effectively eliminated pathological ROS, reduced the level of lipids and related metabolic enzymes, and significantly decreased the area of vascular plaques and fibers. Our study demonstrated that the H2O2-scavenging nano-bionic system could scavenge the abundant ROS in the atherosclerosis lesion, thereby reducing the oxidative stress for treating atherosclerosis and thus achieve the therapeutic goals with atherosclerosis more desirably.
Urgent cytoreduction for newly diagnosed acute myeloid leukemia patients allows acquisition of pretreatment genomic data and enrollment on investigational clinical trials
Authors: Kunhwa Kim, Marina Konopleva, Courtney D. DiNardo, Gautam Borthakur, Sanam Loghavi, Guilin Tang, Naval Daver, Naveen Pemmaraju, Elias Jabbour, Caitlin R. Rausch, Musa Yilmaz, Koji Sasaki, Nicholas J. Short, Nitin Jain, Mark Brandt, Sherry Pierce, Guillermo Garcia‐Manero, Farhad Ravandi, Hagop Kantarjian, Tapan M. Kadia
Journal: American Journal of Hematology (2022)

Newly diagnosed acute myeloid leukemia is often deemed a medical emergency, requiring urgent treatment. This is in contradiction with the need for accurate cytogenetic and molecular data, which is not immediately available, to select optimal therapy. We hypothesized that cytoreduction with hydroxyurea or cytarabine would enable urgent disease control and provide a bridge to clinical trial enrollment. We analyzed three prospective frontline clinical trials that allowed the use of cytoreduction before treatment initiation. Among 274 patients with a median age of 62 (range, 18-89), there was no significant difference in short- and long-term outcome and safety among patients who did (CytoRed) or did not receive (NoCytoRed) cytoreduction. The overall response rate in CytoRed group was 91%, compared with 86% in NoCytoRed group (p = .264). The 30- and 60-day mortality rates were 2% and 7% in CytoRed group, compared with 2% (p = .978) and 6% (p = .652) in NoCytoRed group, respectively. There was no significant difference in overall survival (OS) between in CytoRed group compared with NoCytoRed group (Hazard ratio 0.97, 95% CI 0.70-1.37, p = .879). Results were unchanged after stratification by age (< or ≥65 years) or after multivariate analyses for OS. Our data suggests that urgent cytoreduction using hydroxyurea or cytarabine is a feasible and safe approach to facilitate acquisition of complete diagnostic information prior to treatment initiation on a clinical trial.
TCTAP A-005 AVR ST Elevation Myocardial Infarction: A Not So Urgent Cardiac Emergency. A Single Tertiary Center Experience in Malaysia
Authors: Jian-Chen Lim, Ramachandran Sathappan, Yew Fung Kwan, Tze Ming Chan, Hazleena Mohamed Hasnan, Nor Hanim Mohd Amin
Journal: Journal of the American College of Cardiology (2022)
TCTAP A-072 Immediate Effect of Percutaneous Coronary Intervention by Bioresorbable Scaffold or Drug-Eluting Stent on Superficial Wall Strain of Stenotic Coronary Arteries
Authors: Xinlei Wu, Mick P.L. Renkens, Laura Kerkmeijer, Neil O’Leary, Mattia Lunardi, Jiayue Huang, Daixin Ding, Robbert De Winter, Yoshinobu Onuma, Patrick W. Serruys, William Wijns, Joanna Wykrzykowska, Shengxian Tu
Journal: Journal of the American College of Cardiology (2022)
Annals Graphic Medicine - The Things We Share
Authors: Christine Lynn Chen
Journal: Annals of Internal Medicine (2022)

Web ExclusivesApril 2022Annals Graphic Medicine - The Things We ShareFREEChristine Lynn Chen, BAChristine Lynn Chen, BAUniversity of Texas Southwestern Medical Center, Dallas, Texas (C.L.C.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G21-0054 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: University of Texas Southwestern Medical Center, Dallas, Texas (C.L.C.)Disclosures: The author has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G21-0054.Author/Illustrator Information: Christine Lynn Chen, BA, is a current medical student at UT Southwestern Medical Center who is passionate about creating illustrations and animations that explore complex human stories in medicine and beyond (e-mail, christinel.[email protected]edu). You can explore more of her work on her website (www.christinelynnchen.com) or on Instagram (www.instagram.com/pristinethinpen).This article was published at Annals.org on 12 April 2022. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics April 2022Volume 175, Issue 4Page: W51-W52 ePublished: 12 April 2022 Issue Published: April 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Sequential double stent placement using the stent-pushing-stent technique over a single wire during double-balloon ERCP
Authors: Álvaro Martínez-Alcalá, Katarzyna M. Pawlak, Ivan Jovanovic, Klaus Mönkemüller
Journal: Endoscopy (2022)

Double-balloon enteroscopy (DBE)-assisted endoscopic retrograde cholangiopancreatography (ERCP) is now an established technique to perform various types of diagnostic and therapeutic interventions in patients with surgically altered upper gastrointestinal anatomy [1]. Herein, we present a novel and simple technique of dual stenting using the stent-pushing-stent technique.
An interventional nationwide surveillance program lowers postoperative infection rates in elective colorectal surgery. A cohort study (2008–2019)
Authors: Nares Arroyo-Garcia, Josep M. Badia, Ana Vázquez, Miguel Pera, David Parés, Enric Limón, Alexander Almendral, Marta Piriz, Cecilia Díez, Domenico Fraccalvieri, Joaquín López-Contreras, Miquel Pujol
Journal: International Journal of Surgery (2022)

Colorectal surgery is associated with the highest rate of surgical site infection (SSI). This study analyses the effectiveness of an interventional surveillance program on SSI rates after elective colorectal surgery.Cohort study showing temporal trends of SSI rates and Standardized Infection Ratio (SIR) in elective colorectal surgery over a 12-year period. Prospectively collected data of a national SSI surveillance program was analysed and the effect of specific interventions was evaluated. Patient and procedure characteristics, as well as SIR and SSI rates were stratified by risk categories and type of SSI analysed using stepwise multivariate logistic regression models.In a cohort of 42,330 operations, overall cumulative SSI incidence was 16.31%, and organ-space SSI (O/S-SSI) was 8.59%. There was a 61.63% relative decrease in SSI rates (rho = -0.95804). The intervention which achieved the greatest SSI reduction was a bundle of 6 measures. SSI in pre-bundle period was 19.73% vs. 11.10% in post-bundle period (OR 1.969; IC 95% 1.860-2.085; p < 0.0001). O/S-SSI were 9.08% vs. 6.06%, respectively (OR 1.547; IC 95% 1.433-1.670; p < 0.0001). Median length of stay was 7 days, with a significant decrease over the studied period (rho = -0.98414). Mortality of the series was 1.08%, ranging from 0.35% to 2.0%, but a highly significant decrease was observed (rho = -0.67133).Detailed analysis of risk factors and postoperative infection in colorectal surgery allows strategies for reducing SSI incidence to be designed. An interventional surveillance program has been effective in decreasing SIR and SSI rates.
Eosinophil-mediated suppression and anti–IL-5 enhancement of plasmacytoid dendritic cell interferon responses in asthma
Authors: Kimberly A. Dill-McFarland, Justin T. Schwartz, Hongfang Zhao, Baomei Shao, Patricia C. Fulkerson, Matthew C. Altman, Michelle A. Gill
Journal: Journal of Allergy and Clinical Immunology (2022)
Correction: Tracking daratumumab clearance using mass spectrometry: implications on M protein monitoring and reusing daratumumab
Authors: Nadine Abdallah, David Murray, Angela Dispenzieri, Prashant Kapoor, Morie A. Gertz, Martha Q. Lacy, Suzanne R. Hayman, Francis K. Buadi, Wilson Gonsalves, Eli Muchtar, Nelson Leung, David Dingli, Taxiarchis Kourelis, Rahma Warsame, Moritz Binder, Robert A. Kyle, S. Vincent Rajkumar, Shaji Kumar
Journal: Leukemia (2022)

We noted a mistake in the Introduction section in the following sentence: "and ability to differentiate therapeutic monoclonal antibodies from endogenous M proteins based on unique retention time and mass".The use of mass and retention time is actually not true for the MALDI method.We would like to correct this sentence and replace it with: "with ability to aid in differentiating therapeutic monoclonal antibodies from endogenous M proteins on the basis of mass to charge".
Prelimbic cortex drives discrimination of non-aversion via amygdala somatostatin interneurons
Authors: Joseph M. Stujenske, Pia-Kelsey O'Neill, Carolina Fernandes-Henriques, Itzick Nahmoud, Samantha R. Goldburg, Ashna Singh, Laritza Diaz, Margarita Labkovich, William Hardin, Scott S. Bolkan, Thomas R. Reardon, Timothy J. Spellman, C. Daniel Salzman, Joshua A. Gordon, Conor Liston, Ekaterina Likhtik
Journal: Neuron (2022)
TCTAP C-118 A Case of Small Vessel Chronic Total Occlusion Treated With Drug-Coated Balloon
Authors: Heng Shee Kim, Vicknesan Kulasingham, Azrina Abdul Kadir, Adelyn Nisha Henry, Choon Keong Tee, Kumutha Gobal, Chu Zhen Quek, Mahadevan Gurudevan, Hou Tee Lu
Journal: Journal of the American College of Cardiology (2022)
Protease inhibitor Camostat Mesyalte blocks wild type SARS-CoV-2 and D614G viral entry in human engineered miniature lungs
Authors: Tong Wu, Seyed A. Rabi, William A. Michaud, David Becerra, Sarah E. Gilpin, Mari Mino-Kenudson, Harald C. Ott
Journal: Biomaterials (2022)
Defining Recovery From Alcohol Use Disorder: Development of an NIAAA Research Definition
Authors: Brett T. Hagman, Daniel Falk, Raye Litten, George F. Koob
Journal: American Journal of Psychiatry (2022)

The objective of this article is to provide an operational definition of recovery from alcohol use disorder (AUD) to facilitate the consistency of research on recovery and stimulate further research. The construct of recovery has been difficult to operationalize in the alcohol treatment and recovery literature. Several formal definitions of recovery have been developed but have limitations because 1) they require abstinence from both alcohol and substance use, 2) they do not include the DSM-5 diagnostic criteria for AUD as part of the recovery process (i.e., no focus on remission from AUD), 3) they do not link remission and cessation from heavy drinking to improvements in biopsychosocial functioning and quality-of-life constructs, and 4) they do not distinguish between alcohol and other drug use. The authors present a newly developed National Institute on Alcohol Abuse and Alcoholism (NIAAA) definition of recovery from DSM-5 AUD based on qualitative feedback from key recovery stakeholders (e.g., researchers, clinicians, and recovery specialists). The definition views recovery as both a process of behavioral change and an outcome and incorporates two key components of recovery, namely, remission from DSM-5 AUD and cessation from heavy drinking, a nonabstinent recovery outcome. The NIAAA definition of recovery also emphasizes the importance of biopsychosocial functioning and quality of life in enhancing recovery outcomes. This new NIAAA definition of recovery is an operational definition that can be used by diverse stakeholders to increase consistency in recovery measurement, stimulate research to better understand recovery, and facilitate the process of recovery.
TCTAP A-030 Ten Years Survival Benefit and Appropriateness of Surgical or Percutaneous Revascularization Based on Individual Predicted All-Cause Mortality in Patients With Complex Coronary Artery Disease
Authors: Patrick W. Serruys, Chao Gao, Scot Garg, Yoshinobu Onuma, David R. Holmes, Marie-Claude Morice, Friedrich Wilhelm Mohr, Michael J. Mack
Journal: Journal of the American College of Cardiology (2022)
TCTAP C-079 Left Main In-Stent Restenosis; A Successful Story of Using Shockwave Technology
Authors: Khairul Shafiq Ibrahim, Mohd Firdaus Hadi, Rizmy Najme Khir, Zubin Ibrahim, Raja Ezman Raja Shariff, Sazzli Kasim
Journal: Journal of the American College of Cardiology (2022)
TCTAP A-084 Short-Term Efficacy and Safety Outcome of Standalone Balloon Aortic Valvuloplasty: Registry From Thammasat Heart Center, Thailand
Authors: Nattaporn Sangrutaikan, Kid Bhumimuang, Pisit Hutayanon, Muenpetch Muenkaew
Journal: Journal of the American College of Cardiology (2022)
α-Synuclein arginylation in the human brain
Authors: Jun Zhao, Buyan Pan, Marie Fina, Yun Huang, Marie Shimogawa, Kelvin C. Luk, Elizabeth Rhoades, E. James Petersson, Dawei W. Dong, Anna Kashina
Journal: Translational Neurodegeneration (2022)

Abstract Background Alpha-synuclein (α-syn) exhibits pathological misfolding in many human neurodegenerative disorders. We previously showed that α-syn is arginylated in the mouse brain and that lack of arginylation leads to neurodegeneration in mice. Methods Here, we tested α-syn arginylation in human brain pathology using newly derived antibodies in combination with Western blotting, biochemical assays, and experiments in live neurons. Results We found that α-syn was arginylated in the human brain on E46 and E83, two sites previously implicated in α-syn pathology and familial cases of Parkinson’s disease. The levels of arginylation in different brain samples ranged between ~ 3% and ~ 50% of the total α-syn pool, and this arginylation nearly exclusively concentrated in the subcellular α-syn fraction that sedimented at low centrifugation speeds and appeared to be simultaneously targeted by multiple posttranslational modifications. Arginylated α-syn was less susceptible to S129 phosphorylation and pathological aggregation in neurons. The arginylation level inversely correlated with the overall α-syn levels and with patient age, suggesting a possible causal relationship between arginylation decline and α-syn-dependent neuropathology. Conclusion We propose that α-syn arginylation constitutes a potential neuroprotective mechanism that prevents its abnormal accumulation during neurodegeneration and aging in the human brain.
Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non–Small Cell Lung Cancer
Authors: Joshua K. Sabari, Vamsidhar Velcheti, Kazuhide Shimizu, Matthew R. Strickland, Rebecca S. Heist, Mohini Singh, Naema Nayyar, Anita Giobbie-Hurder, Subba R. Digumarthy, Justin F. Gainor, Anant P. Rajan, Edwin Nieblas-Bedolla, Aaron C. Burns, Jill Hallin, Peter Olson, James G. Christensen, Sylvia C. Kurz, Priscilla K. Brastianos, Hiroaki Wakimoto
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Patients with KRAS-mutant non–small cell lung cancer (NSCLC) with brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), a potent oral small-molecule KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib has been optimized for favorable pharmacokinetic properties, including long half-life (∼24 hours), extensive tissue distribution, dose-dependent pharmacokinetics, and central nervous system penetration; however, BM-specific antitumor activity of KRASG12C inhibitors remains to be fully characterized. Experimental Design: A retrospective database query identified patients with KRAS-mutant NSCLC to understand their propensity to develop BM. Preclinical studies assessed physiochemical and pharmacokinetic properties of adagrasib. Mice bearing intracranial KRASG12C-mutant NSCLC xenografts (LU99-Luc/H23-Luc/LU65-Luc) were treated with clinically relevant adagrasib doses, and levels of adagrasib in plasma, cerebrospinal fluid (CSF), and brain were determined along with antitumor activity. Preliminary clinical data were collected from 2 patients with NSCLC with untreated BM who had received adagrasib 600 mg twice daily in the phase Ib cohort of the KRYSTAL-1 trial; CSF was collected, adagrasib concentrations measured, and antitumor activity in BM evaluated. Results: Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM (≥40%). Adagrasib penetrated into CSF and demonstrated tumor regression and extended survival in multiple preclinical BM models. In 2 patients with NSCLC and untreated BM, CSF concentrations of adagrasib measured above the target cellular IC50. Both patients demonstrated corresponding BM regression, supporting potential clinical activity of adagrasib in the brain. Conclusions: These data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM. See related commentary by Kommalapati and Mansfield, p. 3179
Predictors of immune-related adverse events and outcomes in patients with NSCLC treated with immune-checkpoint inhibitors
Authors: M Serino, C Freitas, M Martins, P Ferreira, C Cardoso, F Veiga, V Santos, D Araújo, H Novais-Bastos, A Magalhães, H Queiroga, G Fernandes, V Hespanhol
Journal: Pulmonology (2022)

To identify predictors of immune-related adverse events (IRAEs) in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). Assess associations between outcomes and the development of IRAEs. Retrospective analysis of patients with NSCLC treated with ICIs between 2016 and 2020 in the Pulmonology Department of our hospital. Patients with and without IRAEs were compared. A logistic regression analysis was performed to determine predictors of IRAEs. Progression-free survival (PFS) and overall survival (OS) curves were calculated using the Kaplan-Meier method, and the long-rank test was used to assess survival differences between groups. Univariate and multivariate Cox proportional-hazards regression models were used to identify factors associated with PFS and OS. The value considered statistically significant was p≤0.05. A total of 184 patients (77.7% men, mean age 66.9±9.5 years) treated with ICIs were analyzed. During follow-up, 49 (26.6%) patients developed IRAEs and 149 (81.0%) died. According to the multivariate logistic regression analysis, treatment with statins (OR:3.15; p = 0.007), previous systemic corticosteroid therapy (OR:3.99; p = 0.001), disease controlled as response to ICI (OR:5.93; p < 0.001) and higher hemoglobin values (OR:1.28; p = 0.040) were independent predictors for the development of IRAEs. Patients who developed IRAEs had significantly longer medians of PFS (41.0 vs 9.0 weeks, p < 0.001) and OS (89.0 vs 28.0 weeks; p < 0.001). Patients treated with statins, pre-ICI systemic corticosteroids, higher baseline hemoglobin value and controlled disease as initial response to ICI had a higher risk of developing IRAEs. The development of IRAEs was associated with better outcomes.