tbuckley/cabot-search huggingface dataset:
All-stage targeted therapy for the brain metastasis from triple-negative breast cancer
Authors: Zimiao Luo, Sunyi Wu, Jianfen Zhou, Weixia Xu, Qianzhu Xu, Linwei Lu, Cao Xie, Yu Liu, Weiyue Lu
Journal: Acta Pharmaceutica Sinica B (2022)

Brain metastasis is a common and serious complication of breast cancer, which is commonly associated with poor survival and prognosis. In particular, the treatment of brain metastasis from triple-negative breast cancer (BM-TNBC) has to face the distinct therapeutic challenges from tumor heterogeneity, circulating tumor cells (CTCs), blood-brain barrier (BBB) and blood-tumor barrier (BTB), which is in unmet clinical needs. Herein, combining with the advantages of synthetic and natural targeting moieties, we develop a "Y-shaped" peptide pVAP-decorated platelet-hybrid liposome drug delivery system to address the all-stage targeted drug delivery for the whole progression of BM-TNBC. Inherited from the activated platelet, the hybrid liposomes still retain the native affinity toward CTCs. Further, the peptide-mediated targeting to breast cancer cells and transport across BBB/BTB are demonstrated in vitro and in vivo. The resultant delivery platform significantly improves the drug accumulation both in orthotopic breast tumors and brain metastatic lesions, and eventually exhibits an outperformance in the inhibition of BM-TNBC compared with the free drug. Overall, this work provides a promising prospect for the comprehensive treatment of BM-TNBC, which could be generalized to other cell types or used in imaging platforms in the future.
Zero separation: infant and family-centred developmental care in times of COVID-19
Authors: Johanna Kostenzer, Luc J I Zimmermann, Silke Mader, Aurelia Abenstein, Mandy Daly, Sarah Fügenschuh, Camilla Gizzi, Julia Hoffmann, Agnes van den Hoogen, Gigi Khonyongwa-Fernandez, Mary Kinney, Johanna Kostenzer, Silke Mader, Kerstin Mondry, Corrado Moretti, Ilknur Okay, Kylie Pussell, Charles C Roehr, Charlotte von Rosenstiel-Pulver, Eleni Vavouraki, Karen Walker, Aisling Walsh, Luc J I Zimmermann
Journal: The Lancet Child & Adolescent Health (2021)
SGLT-2 inhibitors or GLP-1 receptor agonists for adults with type 2 diabetes: a clinical practice guideline
Authors: Sheyu Li, Olav Per, Lyubov Lytvyn, Gordon Guyatt, Suetonia Palmer, René Rodriguez-Gutierrez, Farid Foroutan, Thomas Agoritsas, Reed Siemieniuk, Michael Walsh, Lawrie Frere, David Tunnicliffe, Evi Nagler, Veena Manja, Bjørn Åsvold, Vivekanand Jha, Mieke Vermandere, Karim Gariani, Qian Zhao, Yan Ren, Emma Cartwright, Patrick Gee, Alan Wickes, Linda Ferns, Robin Wright, Ling Li, Qiukui Hao, Reem Mustafa
Journal: BMJ (2022)

CLINICAL QUESTIONWhat are the benefits and harms of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists when added to usual care (lifestyle interventions and/or other diabetes drugs) in adults with type 2 diabetes at different risk for cardiovascular and kidney outcomes?CURRENT PRACTICE Clinical decisions about treatment of type 2 diabetes have been led by glycaemic control for decades.SGLT-2 inhibitors and GLP-1 receptor agonists are traditionally used in people with elevated glucose level after metformin treatment.This has changed through trials demonstrating atherosclerotic cardiovascular disease (CVD) and chronic kidney disease (CKD) benefits independent of medications' glucose-lowering potential. RECOMMENDATIONSThe guideline panel issued risk-stratified recommendations concerning the use of SGLT-2 inhibitors or GLP-1 receptor agonists in adults with type 2 diabetes • Three or fewer cardiovascular risk factors without established CVD or CKD: Weak recommendation against starting SGLT-2 inhibitors or GLP-1 receptor agonists.• More than three cardiovascular risk factors without established CVD or CKD: Weak recommendation for starting SGLT-2 inhibitors and weak against starting GLP-1 receptor agonists.• Established CVD or CKD: Weak recommendation for starting SGLT-2 inhibitors and GLP-1 receptor agonists.• Established CVD and CKD: Strong recommendation for starting SGLT-2 inhibitors and weak recommendation for starting GLP-1 receptor agonists.• For those committed to further reducing their risk for CVD and CKD outcomes: Weak recommendation for starting SGLT-2 inhibitors rather than GLP-1 receptor agonists.HOW THIS GUIDELINE WAS CREATED An international panel including patients, clinicians, and methodologists created these recommendations following standards for trustworthy guidelines and This BMJ Rapid Recommendation article is one of a series that provides clinicians with trustworthy recommendations for potentially practice changing evidence.BMJ Rapid Recommendations represent a collaborative effort between the MAGIC group (https://magicevidence.org/) and The BMJ.A summary is offered here and the full version including decision aids is on the MAGICapp (https://app.magicapp.org/),for
Common variants contribute to intrinsic human brain functional networks
Authors: Bingxin Zhao, Tengfei Li, Stephen M. Smith, Di Xiong, Xifeng Wang, Yue Yang, Tianyou Luo, Ziliang Zhu, Yue Shan, Nana Matoba, Quan Sun, Yuchen Yang, Mads E. Hauberg, Jaroslav Bendl, John F. Fullard, Panagiotis Roussos, Weili Lin, Yun Li, Jason L. Stein, Hongtu Zhu
Journal: Nature Genetics (2022)
74TiP Capmatinib plus osimertinib vs platinum-pemetrexed doublet chemotherapy as second-line therapy in patients with stage IIIB/IIIC/IV EGFR-mutant, T790M-negative, MET-amplified NSCLC
Authors: Y-L. Wu, J-Y. Han, T. Kato, F. Barlesi, E.B. Garon, F. Cappuzzo, Y. Shibata, N. Smith, S. Khanna, R. Belli, A. Yovine, D. Shao-Weng Tan
Journal: Annals of Oncology (2022)
123I Scintigraphy Mirror Image of Graves Disease Induced by Radioiodine Treatment for Toxic Adenoma
Authors: Alexandre Lugat, Delphine Drui, Kalyane Bach-Ngohou, Pascale Guillot, Emmanuelle Mourrain-Langlois, Françoise Kraeber-Bodéré, Catherine Ansquer
Journal: Clinical Nuclear Medicine (2021)

A 61-year-old woman presenting with hyperthyroidism received 131I therapy for a toxic adenoma diagnosed by 123I scintigraphy. Six months later, the patient had a relapse of hyperthyroidism, and 123I scintigraphy showed a mirror image of the first scintigraphy: a high and diffuse uptake in the thyroid gland except for the previously treated nodule. Graves disease was confirmed by elevated thyrotropin receptor antibodies. The patient was cured by a second radioiodine therapy. Radioiodine-induced Graves disease may occur within 6 months of 131I treatment of toxic adenoma and can be treated with a second line of 131I.
Abstract P095: Associations Of Age At Menarche With Blood Pressures In Childhood And Adulthood
Authors: Maria P Santos, Yaling Li, Lydia A Bazzano, Jiang He, Sylvia H Ley
Journal: Circulation (2022)

Objectives: The objective is to assess the associations of the timing of menarche with the blood pressures (BP) in childhood and adulthood. Methods: Participants of the Bogalusa Heart Study were included in this analysis (n=2,295). Our main outcome variables were systolic and diastolic BP in childhood and adulthood (≥20 years old). Incident hypertension was defined as systolic BP of 140 mm Hg or higher or a diastolic BP of 90 mm Hg or higher in adulthood (Stage 2). Age of menarche was defined as the reported onset of menstruation. Findings: Incidence of hypertension in adulthood was 3.1% (59/1929). Younger age at menarche was associated with high systolic and diastolic BP at both childhood and adulthood after multiple adjustments (all p for trend &lt;0.002; Table). Compared to individuals who had the onset of menarche at 12-13 years, earlier age at menarche (OR 1.65 [95% CI 0.91-2.99]) and later age at menarche (1.17 [0.56-2.42]) had a non-significant trend of higher odds ratios for stage 2 hypertension in adulthood. Conclusion: Younger age at menarche is associated with higher systolic and diastolic BP in both childhood and adulthood.
Quantification of the Selective Advantage of Driver Mutations Is Dependent on the Underlying Model and Stage of Tumor Evolution
Authors: Ivana Bozic
Journal: Cancer Research (2022)

Abstract Measuring the selective fitness advantages provided by driver mutations has the potential to facilitate a precise quantitative understanding of cancer evolution. However, accurately measuring the selective advantage of driver mutations has remained a challenge in the field. Early studies reported small selective advantages of drivers, on the order of 1%, whereas newer studies report much larger selective advantages, as high as 1,200%. In this article, we argue that the calculated selective advantages of cancer drivers are dependent on the underlying mathematical model and stage of cancer evolution and that comparisons of numerical values of selective advantage without regard for the underlying model and stage can lead to spurious conclusions.
Abstract 12143: Differences in Outcomes Among Adults Hospitalized for Infective Endocarditis in the United States: The Impact of Congenital Heart Disease
Authors: Ryan D Byrne, Christopher R Broda, Stephen J Dolgner
Journal: Circulation (2021)

Introduction: Increased life expectancy for patients with adult congenital heart disease (ACHD) has created new and unique challenges, including management of complications such as infective endocarditis (IE). Hypothesis: Significant IE outcome differences exist between ACHD and non-ACHD patients. Methods: Hospital discharges with IE in patients &gt;=18 years from the National Inpatient Sample were identified between 2001 and 2016. Weighting was used to create national annual estimates indexed to the United States (U.S.) population. Patients were categorized into age groups: 18-44 years, 45-64 years, and 65+ years. Demographic, clinical, microbiologic, and outcome data were compared stratifying by ACHD status. Results: ACHD-related IE hospitalizations increased over time, from 1.6% in 2001 to 3.5% in 2016 (p&lt;0.001 for trend) with a 315% increase in annualized number of ACHD IE hospitalizations from 0.41/100,000 adults to 1.29/100,000 adults. ACHD patients were younger (mean age 49 vs. 65 years, p&lt;0.001). In-hospital mortality was lower in ACHD patients than non-ACHD patients (5.9% vs. 9.5%, respectively, p&lt;0.001); mortality did not change significantly over time among ACHD patients, while mortality decreased in non-ACHD patients (p&lt;0.001). Mortality was lower in ACHD patients across all age groups (all p&lt;0.01). ACHD patients were more likely to undergo valve surgery during their IE hospitalization (29.8% vs. 6.4%, p&lt;0.001). The etiology of IE varied between groups (p&lt;0.001), with increased streptococcal disease in ACHD patients (29.4% vs. 14.4%). Conclusions: A significant increase in the overall proportion of ACHD IE hospitalizations in the U.S. was identified between 2001 and 2016. ACHD patients had lower in-hospital mortality than non-ACHD patients and were more likely to undergo valve surgery. Further research is needed to better understand factors underlying the increase in ACHD IE cases as well as why ACHD patients have decreased mortality.
Abstract MP07: Are Gaps In Anticoagulation Due To Under-prescribing Or Prescriptions Not Being Filled: An Administrative Health Claims Analysis
Authors: Jingchuan Guo, Meiqi He, Nico Gabriel, Jared W Magnani, Stephen E KIMMEL, Walid Gellad, Inmaculada Hernandez
Journal: Circulation (2022)

Introduction: Previous studies evaluating factors associated with the underuse of oral anticoagulation (OAC) in patients with atrial fibrillation (AF) relied foremost on claims data, which only contains information on prescription fills but not prescriptions written. Thus it remains unclear to the extent to which OAC underuse is due to providers not prescribing OAC versus patients not filling the medication prescribed. Methods: We used Optum’s De-identified Integrated Claims-EHR data, which combined adjudicated claims data with EHR for 24 million patients across the US. We identified patients newly diagnosed with AF between January 2013 and June 2017. The electronic health records (EHR) allowed us to observe the prescriptions ordered by providers, while the claims data provided prescription fill records by patients. We evaluated patient-, provider-, and health plan-related factors associated with under-prescribing of OAC and under-filling after OAC prescribed. Multivariable logistic regression models were constructed to determine factors associated with under-prescribing and under-filling. Results: Of the 6,141 individuals in the study cohort, 51% were not prescribed OAC within six months of their AF diagnosis. Of the 2,956 patients who were prescribed, 19% did not fill it at the pharmacy. ( Figure ) In the final adjusted model, younger age, location (Northeast and South), a low CHA2DS2-VAS score, and a high HAS-BLED score were associated with a lower likelihood of being prescribed OAC. Among patients who were prescribed, Medicare enrollment (OR and 95% CI: 2.2 [1.3, 3.7]) and having a direct oral anticoagulant prescription (OR and 95% CI: 1.5 [1.2, 1.9]) were associated with lower likelihood of filling the prescription. Conclusion: The underuse of OAC among newly diagnosed patients with AF is largely driven by under-prescribing. Our findings support the development of strategies that target improving prescription orders for the underuse of OAC by millions of patients with AF.
A direct lateral entorhinal cortex to hippocampal CA2 circuit conveys social information required for social memory
Authors: Jeffrey Lopez-Rojas, Christopher A. de Solis, Felix Leroy, Eric R. Kandel, Steven A. Siegelbaum
Journal: Neuron (2022)

The hippocampus is essential for different forms of declarative memory, including social memory, the ability to recognize and remember a conspecific. Although recent studies identify the importance of the dorsal CA2 region of the hippocampus in social memory storage, little is known about its sources of social information. Because CA2, like other hippocampal regions, receives its major source of spatial and non-spatial information from the medial and lateral subdivisions of entorhinal cortex (MEC and LEC), respectively, we investigated the importance of these inputs for social memory. Whereas MEC inputs to CA2 are dispensable, the direct inputs to CA2 from LEC are both selectively activated during social exploration and required for social memory. This selective behavioral role of LEC is reflected in the stronger excitatory drive it provides to CA2 compared with MEC. Thus, a direct LEC → CA2 circuit is tuned to convey social information that is critical for social memory.
A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness
Authors: Naomi Issler, Sara Afonso, Irith Weissman, Katrin Jordan, Alberto Cebrian-Serrano, Katrin Meindl, Eileen Dahlke, Konstantin Tziridis, Guanhua Yan, José M. Robles-López, Lydia Tabernero, Vaksha Patel, Anne Kesselheim, Enriko D. Klootwijk, Horia C. Stanescu, Simona Dumitriu, Daniela Iancu, Mehmet Tekman, Monika Mozere, Graciana Jaureguiberry, Priya Outtandy, Claire Russell, Anna-Lena Forst, Christina Sterner, Elena-Sofia Heinl, Helga Othmen, Ines Tegtmeier, Markus Reichold, Ina Maria Schiessl, Katharina Limm, Peter Oefner, Ralph Witzgall, Lifei Fu, Franziska Theilig, Achim Schilling, Efrat Shuster Biton, Limor Kalfon, Ayalla Fedida, Elite Arnon-Sheleg, Ofer Ben Izhak, Daniella Magen, Yair Anikster, Holger Schulze, Christine Ziegler, Martin Lowe, Benjamin Davies, Detlef Böckenhauer, Robert Kleta, Tzipora C. Falik Zaccai, Richard Warth
Journal: Journal of the American Society of Nephrology (2022)

The endocytic reabsorption of proteins in the proximal tubule requires a complex machinery and defects can lead to tubular proteinuria. The precise mechanisms of endocytosis and processing of receptors and cargo are incompletely understood. EHD1 belongs to a family of proteins presumably involved in the scission of intracellular vesicles and in ciliogenesis. However, the relevance of EHD1 in human tissues, in particular in the kidney, was unknown.
Identification of Functional Heterogeneity of Carcinoma-Associated Fibroblasts with Distinct IL6-Mediated Therapy Resistance in Pancreatic Cancer
Authors: Kathleen M. McAndrews, Yang Chen, J. Kebbeh Darpolor, Xiaofeng Zheng, Sujuan Yang, Julienne L. Carstens, Bingrui Li, Huamin Wang, Toru Miyake, Pedro Correa de Sampaio, Michelle L. Kirtley, Mariangela Natale, Chia-Chin Wu, Hikaru Sugimoto, Valerie S. LeBleu, Raghu Kalluri
Journal: Cancer Discovery (2022)

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of fibroblasts as part of the host response to cancer. Using single-cell RNA sequencing, multiplex immunostaining, and several genetic mouse models, we identify carcinoma-associated fibroblasts (CAF) with opposing functions in PDAC progression. Depletion of fibroblast activation protein (FAP)+ CAFs results in increased survival, in contrast to depletion of alpha smooth muscle actin (αSMA)+ CAFs, which leads to decreased survival. Tumor-promoting FAP+ CAFs (TP-CAF) and tumor-restraining αSMA+ CAFs (TR-CAF) differentially regulate cancer-associated pathways and accumulation of regulatory T cells. Improved efficacy of gemcitabine is observed when IL6 is deleted from αSMA+ CAFs but not from FAP+ CAFs using dual-recombinase genetic PDAC models. Improved gemcitabine efficacy due to lack of IL6 synergizes with anti-PD-1 immunotherapy to significantly improve survival of PDAC mice. Our study identifies functional heterogeneity of CAFs in PDAC progression and their different roles in therapy response. PDAC is associated with accumulation of dense stroma consisting of fibroblasts and extracellular matrix that regulate tumor progression. Here, we identify two distinct populations of fibroblasts with opposing roles in the progression and immune landscape of PDAC. Our findings demonstrate that fibroblasts are functionally diverse with therapeutic implications. This article is highlighted in the In This Issue feature, p. 1397.
Progressive Reduction in Right Ventricular Contractile Function Attributable to Altered Actin Expression in an Aging Mouse Model of Arrhythmogenic Cardiomyopathy
Authors: Emmanuel M. Camors, Alyson H. Roth, Joseph R. Alef, Ryan D. Sullivan, Jason N. Johnson, Enkhsaikhan Purevjav, Jeffrey A. Towbin
Journal: Circulation (2022)

Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder of desmosomal dysfunction, and PKP2 (plakophilin-2) has been reported to be the most common disease-causing gene when mutation-positive. In the early concealed phase, the ACM heart is at high risk of sudden cardiac death before cardiac remodeling occurs because of mistargeted ion channels and altered Ca2+ handling. However, the results of pathogenic PKP2 variants on myocyte contraction in ACM pathogenesis remain unknown.We studied the outcomes of a human truncating variant of PKP2 on myocyte contraction using a novel knock-in mouse model with insertion of thymidine in exon 5 of Pkp2, which mimics a familial case of ACM (PKP2-L404fsX5). We used serial echocardiography, electrocardiography, blood pressure measurements, histology, cardiomyocyte contraction, intracellular calcium measurements, and gene and protein expression studies.Serial echocardiography of Pkp2 heterozygous (Pkp2-Het) mice revealed progressive failure of the right ventricle (RV) in animals older than 3 months. By contrast, left ventricular function remained normal. ECGs of 6-month-old anesthetized Pkp2-Het mice showed normal baseline heart rates and QRS complexes. Cardiac responses to β-adrenergic agonist isoproterenol (2 mg/kg) plus caffeine (120 mg/kg) were also normal. However, adrenergic stimulation enhanced the susceptibility of Pkp2-Het hearts to tachyarrhythmia and sudden cardiac death. Histological staining showed no significant fibrosis or adipocyte infiltration in the RVs and left ventricles of 6- and 12-month-old Pkp2-Het hearts. Contractility assessment of isolated myocytes demonstrated progressively reduced Pkp2-Het RV cardiomyocyte function consistent with RV failure measured by echocardiography. However, aging Pkp2-Het and control RV myocytes loaded with intracellular Ca2+ indicator Fura-2 showed comparable Ca2+ transients. Western blotting of Pkp2-RV homogenates revealed a 40% decrease in actin, whereas actin immunoprecipitation followed by a 2,4-dinitrophenylhydrazine staining showed doubled oxidation level. This correlated with a 39% increase in troponin-I phosphorylation. In contrast, Pkp2-Het left ventricular myocytes had normal contraction, actin expression and oxidation, and troponin-I phosphorylation. Last, Western blotting of cardiac biopsies revealed that actin expression was 40% decreased in RVs of patients with end-stage ACM.During the early concealed phase of ACM, reduced actin expression drives loss of RV myocyte contraction, contributing to progressive RV dysfunction.
Systemic Vasculitis Following SARS-CoV-2 mRNA Vaccination Demonstrated on FDG PET/CT
Authors: Koya Nakatani, Etsuro Sakata, Masakazu Fujihara, Kaoru Mizukawa, Takashi Koyama
Journal: Clinical Nuclear Medicine (2022)

Abstract Causality regarding adverse events following SARS-CoV-2 mRNA vaccine is undetermined for vasculitis. Herein, we report the case of an 80-year-old man who presented with a persistent high fever of 7 days' duration that began shortly after receiving a COVID-19 vaccination. There was also a complaint of persistent lower limb pain and walking difficulty on emergency transportation. FDG PET/CT demonstrated extensive linear hypermetabolic foci along the vessels of both legs, including the hips, and the arms, supraclavicular area, chest wall, and temporal regions, suggesting systemic vasculitis. Subsequent temporal artery biopsy revealed arteritis, which is not typical of giant cell arteritis.
Gallbladder Metastasis From Renal Cell Carcinoma Revealed With 18F-FDG PET/CT
Authors: Mehmet Can Baloğlu, Seyfettin Yahşi, Özge Erol Fenercioğlu, Tevfik Fikret Çermik, Nurhan Ergül
Journal: Clinical Nuclear Medicine (2022)

Abstract Gallbladder metastasis from renal cell carcinoma is a rare condition. To our knowledge, only 1 case has been reported with 18 F-FDG PET/CT findings. Herein, we report the case of a 53-year-old man with renal cell carcinoma, having gallbladder metastasis revealed with restaging 18 F-FDG PET/CT.
27P Durability of efficacy and safety with selpercatinib in patients (pts) with RET fusion+ non-small cell lung cancer (NSCLC)
Authors: A. Drilon, V. Subbiah, O. Gautschi, P. Tomasini, F.G.M. De Braud, B. Solomon, D. Shao-Weng Tan, G. Alonso, J. Wolf, K. Park, K. Goto, V. Soldatenkova, S. Szymczak, S. Barker, T. Puri, A.B. Lin, H.H.F. Loong, B. Besse
Journal: Annals of Oncology (2022)