tbuckley/cabot-search huggingface dataset:
CD40- and 41BB-specific antibody fusion proteins with PDL1 blockade-restricted agonism
Authors: Juliane Medler, Kirstin Kucka, Vinicio Melo, Tengyu Zhang, Stefan von Rotenhan, Jakob Ulrich, Edwin Bremer, Michael Hudecek, Andreas Beilhack, Harald Wajant
Journal: Theranostics (2022)

Background: A strategy to broaden the applicability of checkpoint inhibitors is the combined use with antibodies targeting the immune stimulatory receptors CD40 and 41BB. However, the use of anti-CD40 and anti-41BB antibodies as agonists is problematic in two ways. First, anti-CD40 and anti-41BB antibodies need plasma membrane-associated presentation by FcγR binding to exert robust agonism but this obviously limits their immune stimulatory efficacy by triggering ADCC, CDC or anti-inflammatory FcγRIIb activities. Second, off tumor activation of CD40 and 41BB may cause dose limiting systemic inflammation. Methods: To overcome the FcγR-dependency of anti-41BB and anti-CD40 antibodies, we genetically fused such antibodies with a PDL1-specific blocking scFv as anchoring domain to enable FcγR-independent plasma membrane-associated presentation of anti-CD40- and anti-41BB antibodies. By help of GpL-tagged variants of the resulting bispecific antibodies, binding to their molecular targets was evaluated by help of cellular binding studies. Membrane PDL1-restricted engagement of CD40 and 41BB but also inhibition of PDL1-induced PD1 activation were evaluated in coculture assays with PDL1-expressing tumor cell lines and 41BB, CD40 and PD1 responsible cell lines or T-cells. Results: The binding properties of the bispecific antibody fusion proteins remained largely unchanged compared to their parental molecules. Upon anchoring to membrane PDL1, the bispecific antibody fusion proteins activated CD40/41BB signaling as efficient as the parental anti-CD40/anti-41BB antibodies when bound to FcγRs or cells expressing membrane-bound CD40L/41BBL. PD1 inhibition remained intact and the anti-41BB fusion protein thus showed PDL1-restricted costimulation of T-cells activated in vitro with anti-CD3 or a BiTe. Conclusions: Targeting of anti-CD40 and anti-41BB fusion proteins to membrane PDL1 with a blocking PDL1 scFv links PD1-PDL1 checkpoint blockade intrinsically with engagement of CD40 or 41BB.
Knowledge Gaps, Challenges, and Opportunities in Health and Prevention Research for Asian Americans, Native Hawaiians, and Pacific Islanders: A Report From the 2021 National Institutes of Health Workshop
Authors: Alka M. Kanaya, Ann W. Hsing, Sela V. Panapasa, Namratha R. Kandula, Maria Rosario G. Araneta, Daichi Shimbo, Paul Wang, Scarlett L. Gomez, Jinkook Lee, K.M. Venkat Narayan, Marjorie K.L. Mala Mau, Sonali Bose, Martha L. Daviglus, Frank B. Hu, Nadia Islam, Chandra L. Jackson, Merle Kataoka-Yahiro, John S.K. Kauwe, Simin Liu, Grace X. Ma, Tung Nguyen, Latha Palaniappan, V. Wendy Setiawan, Chau Trinh-Shevrin, Janice Y. Tsoh, Dhananjay Vaidya, Barbara Vickrey, Thomas J. Wang, Nathan D. Wong, Sean Coady, Yuling Hong
Journal: Annals of Internal Medicine (2022)

Asian Americans (AsA), Native Hawaiians, and Pacific Islanders (NHPI) comprise 7.7% of the U.S. population, and AsA have had the fastest growth rate since 2010. Yet the National Institutes of Health (NIH) has invested only 0.17% of its budget on AsA and NHPI research between 1992 and 2018. More than 40 ethnic subgroups are included within AsA and NHPI (with no majority subpopulation), which are highly diverse culturally, demographically, linguistically, and socioeconomically. However, data for these groups are often aggregated, masking critical health disparities and their drivers. To address these issues, in March 2021, the National Heart, Lung, and Blood Institute, in partnership with 8 other NIH institutes, convened a multidisciplinary workshop to review current research, knowledge gaps, opportunities, barriers, and approaches for prevention research for AsA and NHPI populations. The workshop covered 5 domains: 1) sociocultural, environmental, psychological health, and lifestyle dimensions; 2) metabolic disorders; 3) cardiovascular and lung diseases; 4) cancer; and 5) cognitive function and healthy aging. Two recurring themes emerged: Very limited data on the epidemiology, risk factors, and outcomes for most conditions are available, and most existing data are not disaggregated by subgroup, masking variation in risk factors, disease occurrence, and trajectories. Leveraging the vast phenotypic differences among AsA and NHPI groups was identified as a key opportunity to yield novel clues into etiologic and prognostic factors to inform prevention efforts and intervention strategies. Promising approaches for future research include developing collaborations with community partners, investing in infrastructure support for cohort studies, enhancing existing data sources to enable data disaggregation, and incorporating novel technology for objective measurement. Research on AsA and NHPI subgroups is urgently needed to eliminate disparities and promote health equity in these populations.
Integrative analysis of 3604 GWAS reveals multiple novel cell type-specific regulatory associations
Authors: Charles E. Breeze, Eric Haugen, Alex Reynolds, Andrew Teschendorff, Jenny van Dongen, Qing Lan, Nathaniel Rothman, Guillaume Bourque, Ian Dunham, Stephan Beck, John Stamatoyannopoulos, Nora Franceschini, Sonja I. Berndt
Journal: Genome biology (2022)

Genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) are known to preferentially co-locate to active regulatory elements in tissues and cell types relevant to disease aetiology. Further characterisation of associated cell type-specific regulation can broaden our understanding of how GWAS signals may contribute to disease risk.To gain insight into potential functional mechanisms underlying GWAS associations, we developed FORGE2 ( https://forge2.altiusinstitute.org/ ), which is an updated version of the FORGE web tool. FORGE2 uses an expanded atlas of cell type-specific regulatory element annotations, including DNase I hotspots, five histone mark categories and 15 hidden Markov model (HMM) chromatin states, to identify tissue- and cell type-specific signals. An analysis of 3,604 GWAS from the NHGRI-EBI GWAS catalogue yielded at least one significant disease/trait-tissue association for 2,057 GWAS, including > 400 associations specific to epigenomic marks in immune tissues and cell types, > 30 associations specific to heart tissue, and > 60 associations specific to brain tissue, highlighting the key potential of tissue- and cell type-specific regulatory elements. Importantly, we demonstrate that FORGE2 analysis can separate previously observed accessible chromatin enrichments into different chromatin states, such as enhancers or active transcription start sites, providing a greater understanding of underlying regulatory mechanisms. Interestingly, tissue-specific enrichments for repressive chromatin states and histone marks were also detected, suggesting a role for tissue-specific repressed regions in GWAS-mediated disease aetiology.In summary, we demonstrate that FORGE2 has the potential to uncover previously unreported disease-tissue associations and identify new candidate mechanisms. FORGE2 is a transparent, user-friendly web tool for the integrative analysis of loci discovered from GWAS.
68Ga–Prostate-Specific Membrane Antigen–Avid Malignant Pleural Effusion in a Patient With Metastatic Adenoid Cystic Carcinoma and Concordance With 18F-FDG PET/CT
Authors: Maike José Maria Uijen, Jetty Anne Mina Weijers, Chantal Maria Leonarda Driessen, Carla Marie Louise van Herpen, James Nagarajah
Journal: Clinical Nuclear Medicine (2022)

Adenoid cystic carcinoma (ACC) is a rare cancer that arises from salivary glands and other secretory glands. Pulmonary metastases are frequently observed in ACC patients with metastatic disease. Previous research showed that ACC often shows high PSMA uptake on 68Ga-PSMA-11 PET/CT. Here, we present PET images from an ACC patient with pulmonal, pleural metastases, and malignant pleural effusion, with comparable tracer uptake on 68Ga-PSMA-11 PET and 18F-FDG PET.
Abstract 136: Understanding Multi-allelic Heterozygous Variant Contributions to Dilated Cardiomyopathy
Authors: Cassandra Happe, Dekker Deacon, Rossin Erbe, Kevin Tenerelli, Vivien Tran, Eric Alder, Neil Chi, Adam Engler
Journal: Circulation Research (2017)

Dilated cardiomyopathy (DCM) is a multivariate disease with poorly understood mechanisms, but recently 30+ different mutations have been suggested to contribute to disease pathology. We have identified the first incidence where a family with high DCM prevalance is caused by the co-segregation of two heterozygous mutations in dissimilar cytoskeletal proteins, i.e. α-tropomyosin (TPM1; +/c.G97A) and vinculin (VCL; +/c.659dupA). To better understand the disease mechanism, we generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from the family cohort carrying the variants and modeled these variants in human embryonic stem cell-derived CMs (hESC-CMs) via CRISPR to discern the functional consequences that could induce DCM. Affected CMs contracted with decreased energy compared to non-carrier control CMs. Decreased sodium and potassium channel expression accompanied slowed action potential kinetics in affected vs. non-carrier-derived CMs, which together suggests that VCL and/or TPM1 mutations may cause unique downstream transcriptome regulation that leads to the dysfunction we observed in vitro . To assess the combinatorial regulation by mutations in these dissimilar genes, hESC-CMs were engineered to mirror altered protein expression; these cells exhibited prolonged calcium transients and contractions with decreased energy and irregular timing, suggesting that reduced VCL creates CMs with dysfunctional mechanical properties, resulting in part from prolonged Ca 2+ handling, which would likely adversely affect TPM1 mutant phenotypes leading to DCM when the variants co-segregated. Given the lack of disease in single variant carriers, these data provide a unique set of analyses that result in identification of how dissimilar but co-segregating variants can result in disease.
Drugs, hippies, and doctors
Authors: H. A. Wilmer
Journal: JAMA (1968)

The doctor-patient relationship is rapidly becoming pharmaceuticalized. Every physician has his own particular pharmacologic armamentarium. Armamentarium indeed! A formidable array of chemical weapons and chemical solace. The more drugs that have become available, the more physicians have felt relieved of the burden of taking a careful history, of listening to patients. Time is running short in the consultation room. Physicians are increasingly dependent upon the prescription of drugs. It is a rare experience for a patient to leave a doctor's office without a prescription in his hand. Now, there are more specific drugs, more potent drugs in widespread use than there are patients, diseases, disorders, or symptoms. Every physician knows that his own attitudes and beliefs about drugs alter their effectiveness. Prescribing drugs has always been good medicine for doctors, often assuring them a good night's sleep. Tranquilized patients are "more amenable" to psychotherapy even though some appear as zombies,
Abstract 131: Anti-inflammatory and Mitochondrial Effects of Butyrate in Shr Astrocytes <i>in vitro</i>
Authors: Tao Yang, Ty Redler, Carla G Bueno Silva, Rebeca Arocha, Jordan Schmidt, Christopher Martyniuk, Jasenka Zubcevic
Journal: Circulation Research (2017)

Emerging evidence demonstrates a significant link between gut dysbiosis and hypertension (HTN). Butyrate is one of the major fermented end-products of gut microbiota that reportedly produces beneficial effects on the immune system and metabolism. A contraction in butyrate-producing bacteria in the gut of spontaneously hypertensive rats (SHR) suggests that reduced butyrate may be associated with HTN. Considering its role in mitochondrial metabolism, we proposed that the positive anti-inflammatory effects of butyrate may be mediated via improvement in mitochondrial function in astrocytes. Methods: Sprague Dawley (SD) and SHR primary astrocytes from two-day old pups were cultured in DMEM, supplemented with 10% FBS and 1% pen/strep, for 14 days, prior to treatment with butyrate (0-1mM) for 4 hours. Cells were then subjected to the Seahorse XFe24 Extracellular Flux Analyzer to evaluate mitochondrial function following butyrate treatment. Additional samples were collected for total RNA isolation for real time PCR analysis of inflammatory factors and transcripts related to mitochondrial function and stress. Results: Butyrate significantly increased both basal and maximal mitochondrial respiration (by 3-4 fold, P&lt;0.001) and elevated proton leak (by 4 fold, P&lt;0.01) in astrocytes from SD rats but not SHR. Furthermore, we observed a trend for an increase in both ATP-linked and non-mitochondrial respiration in SD astrocytes compared to SHR (by 2-3 fold, P=0.07). This was associated with a significant reduction in relative expression levels in catalase (by 50%, P&lt;0.05) and a trend in reduction in Sod1 and Sod2 (by 25%-50%, P=0.1) in astrocytes harvested from SD rats but not the SHR. Conversely, butyrate significantly lowered expression of pro-inflammatory Ccl2 (by 33%, P&lt;0.05) and Tlr4 (by 48%, P &lt;0.05) in astrocytes of SHR, but not SD rats. Conclusion: Butyrate modulated mitochondrial bioenergetics in SD but not the SHR, suggesting that the mitochondria of astrocytes may be less sensitive to the effects of butyrate in HTN. In addition, butyrate reduced inflammatory mediators in the SHR, but had no effect in the SD rat astrocytes. Thus, central anti-inflammatory effects of butyrate may be mediated via a mitochondria-independent mechanism.
TCT-90 Clinical Outcomes Three Year After Revascularization With a Biodegradable Polymer Ultra-thin Strut Sirolimus-eluting Stent and a Biodegradable Polymer Biolimus-eluting Stent. From the SORT OUT VII trial.
Authors: Julia Ellert, Lisette Okkels Jensen, Michael Maeng, Bent Raungaard, Christian Terkelsen, Knud Hansen, Johnny Kahlert, Svend Eggert Jensen, Hans Erik Bøtker, Henrik Hansen, Jens Aaroe, Steen Dalby Kristensen, Jens Lassen, Karsten Veien, Evald Christiansen
Journal: Journal of the American College of Cardiology (2018)
Comment on Hamblin et al. Capillary Ketone Concentrations at the Time of Colonoscopy: A Cross-Sectional Study With Implications for SGLT2 Inhibitor–Treated Type 2 Diabetes. Diabetes Care 2021;44:e124–e126
Authors: Venkatesan Thiruvenkatarajan, Emily J. Meyer, David Jesudason
Journal: Diabetes Care (2021)
Diet, lipids, and antitumor immunity
Authors: Hannah Prendeville, Lydia Lynch
Journal: Cellular and Molecular Immunology (2022)

Tumour growth and dissemination is largely dependent on nutrient availability. It has recently emerged that the tumour microenvironment is rich in a diverse array of lipids that increase in abundance with tumour progression and play a role in promoting tumour growth and metastasis. Here, we describe the pro-tumorigenic roles of lipid uptake, metabolism and synthesis and detail the therapeutic potential of targeting lipid metabolism in cancer. Additionally, we highlight new insights into the distinct immunosuppressive effects of lipids in the tumour microenvironment. Lipids threaten an anti-tumour environment whereby metabolic adaptation to lipid metabolism is linked to immune dysfunction. Finally, we describe the differential effects of commondietary lipids on cancer growth which may uncover a role for specific dietary regimens in association with traditional cancer therapies. Understanding the relationship between dietary lipids, tumour, and immune cells is important in the context of obesity which may reveal a possibility to harness the diet in the treatment of cancers.
Clinical implication of KRAS mutation variants in patients with resected colon cancer.
Authors: Jin Ho Baek, Byung Woog Kang, Gyu Seog Choi, Jong Gwang Kim
Journal: Journal of Clinical Oncology (2022)

179 Background: This study evaluated the clinical implication of KRAS mutation variants in patients with resected colon cancer (CC). Methods: We retrospectively reviewed 482 patients diagnosed with CC and underwent curative surgical resection at Kyungpook National University Chilgok Hospital. The inclusion criteria were: pathologically diagnosed with primary CC; stage I–III CC according to the 7 th edition of American Joint Committee on Cancer staging system; and with available test results for KRAS mutation status. In total, 345 patients met these criteria and were included in this study. Results: Among the 345 patients, 140 (40.6%) exhibited KRAS mutations, with their incidences as follows: 90/140 (64.3%) in Exon 2 Codon 12, 37/140 (26.4%) in Exon 2 Codon 13, 1/140 (0.1%) in Exon 3 Codon 59, 7/140 (5.0%) in Exon 3 Codon 61, and 5/140 (3.6%) in Exon 4 Codon 146. KRAS mutation status was not a significant prognostic factor for disease-free survival (DFS) or overall survival (OS). Although, there were no significant differences in survival between patients with Exon 2 Codon 12 and Exon 2 Codon 13 mutations, poorer DFS ( p = 0.085) and OS ( p = 0.005) were seen in those with Exon 3 Codon 61 mutation than in others. Conclusions: KRAS mutation status was not correlated with survival, but Exon 3 Codon 61 mutation might be a poor prognostic factor in resected CC patients.
Patient Centricity Driving Formulation Innovation: Improvements in Patient Care Facilitated by Novel Therapeutics and Drug Delivery Technologies
Authors: Susanne Page, Tarik Khan, Peter Kühl, Gregoire Schwach, Kirsten Storch, Hitesh Chokshi
Journal: The Annual Review of Pharmacology and Toxicology (2022)

Innovative formulation technologies can play a crucial role in transforming a novel molecule to a medicine that significantly enhances patients’ lives. Improved mechanistic understanding of diseases has inspired researchers to expand the druggable space using new therapeutic modalities such as interfering RNA, protein degraders, and novel formats of monoclonal antibodies. Sophisticated formulation strategies are needed to deliver the drugs to their sites of action and to achieve patient centricity, exemplified by messenger RNA vaccines and oral peptides. Moreover, access to medical information via digital platforms has resulted in better-informed patient groups that are requesting consideration of their needs during drug development. This request is consistent with health authority efforts to upgrade their regulations to advance age-appropriate product development for patients. This review describes formulation innovations contributingto improvements in patient care: convenience of administration, preferred route of administration, reducing dosing burden, and achieving targeted delivery of new modalities.
An Explainable Machine Learning Approach Reveals Prognostic Significance of Right Ventricular Dysfunction in Nonischemic Cardiomyopathy
Authors: Ahmed S. Fahmy, Ibolya Csecs, Arghavan Arafati, Salah Assana, Tuyen T. Yankama, Talal Al-Otaibi, Jennifer Rodriguez, Yi-Yun Chen, Long H. Ngo, Warren J. Manning, Raymond Y. Kwong, Reza Nezafat
Journal: JACC. Cardiovascular imaging (2022)
TCT-550 Safety and Efficacy of Ultra-thin Biodegradable Polymer-coated Everolimus-eluting Stent in Real-world Patients with Coronary Artery Disease – One-year Outcomes of Indian Multi-centric Study
Authors: Manjinder Sandhu, Harish Sanadhya, Tarun Dave, Shailendra Trivedi, P. Mangalanandan, Rashmit Pandya, Asif Raheem, Vineet Malik, Bharat Bhushan Chanana
Journal: Journal of the American College of Cardiology (2018)
TCT-764 ECCENTRICITY OF THE AORTIC ANNULUS IS NOT ASSOCIATED WITH FUNCTIONAL IMPAIRMENT OF THE TRANSAPICAL JENAVALVE IN AN IN VITRO HYDRODYNAMIC TEST MODEL
Authors: Stephan Ensminger, Stephan Achenbach, Jochen Boergermann, Jan Gummert, Smita R. Jategaonkar, Maximilian Kuetting, Annika Schuhbaeck, Ulrich Steinseifer, Marc Utzenrath
Journal: Journal of the American College of Cardiology (2013)
Bacterial extracellular vesicles as bioactive nanocarriers for drug delivery: Advances and perspectives
Authors: Han Liu, Qin Zhang, Sicheng Wang, Weizong Weng, Yingying Jing, Jiacan Su
Journal: Bioactive Materials (2021)

Nanosized extracellular vesicles derived from bacteria contain diverse cargo and transfer intercellular bioactive molecules to cells. Due to their favorable intercellular interactions, cell membrane-derived bacterial extracellular vesicles (BEVs) have great potential to become novel drug delivery platforms. In this review, we summarize the biogenesis mechanism and compositions of various BEVs. In addition, an overview of effective isolation and purification techniques of BEVs is provided. In particular, we focus on the application of BEVs as bioactive nanocarriers for drug delivery. Finally, we summarize the advances and challenges of BEVs after providing a comprehensive discussion in each section. We believe that a deeper understanding of BEVs will open new avenues for their exploitation in drug delivery applications.
Michael
Authors: G. Nicholas Rogentine
Journal: Annals of Internal Medicine (1993)

Ad Libitum1 May 1993MichaelG. Nicholas Rogentine, MDG. Nicholas Rogentine, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-118-9-199305010-00017 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Barely fifteen,Played center for your team,Small town Georgia.Marrow transplantation,Matched sister, older than you,A gift of life, possibly.Nine hundred rads, whole body,Death certainWithout your sister's gift.A race with deathThose twenty-five days;Lost. Author, Article, and Disclosure InformationAffiliations: Previousarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1993Volume 118, Issue 9Page: 745KeywordsBone marrowRacial and ethnic issuesTransplantation ePublished: 15 August 2000 Issue Published: 1 May 1993 Copyright & PermissionsCopyright © 1993 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Reprogramming the spleen into a functioning ‘liver’ in vivo
Authors: Chunyan Liu, Lintao Wang, Mengzhen Xu, Yajie Sun, Zhen Xing, Junfeng Zhang, Chunming Wang, Lei Dong
Journal: Gut (2022)

Objective Liver regeneration remains one of the biggest clinical challenges. Here, we aim to transform the spleen into a liver-like organ via directly reprogramming the splenic fibroblasts into hepatocytes in vivo. Design In the mouse spleen, the number of fibroblasts was through silica particles (SiO 2 ) stimulation, the expanded fibroblasts were converted to hepatocytes (iHeps) by lentiviral transfection of three key transcriptional factors (Foxa3, Gata4 and Hnf1a), and the iHeps were further expanded with tumour necrosis factor-α (TNF-α) and lentivirus-mediated expression of epidermal growth factor (EGF) and hepatocyte growth factor (HGF). Results SiO 2 stimulation tripled the number of activated fibroblasts. Foxa3, Gata4 and Hnf1a converted SiO 2 -remodelled spleen fibroblasts into 2×10 6 functional iHeps in one spleen. TNF-α protein and lentivirus-mediated expression of EGF and HGF further enabled the total hepatocytes to expand to 8×10 6 per spleen. iHeps possessed hepatic functions—such as glycogen storage, lipid accumulation and drug metabolism—and performed fundamental liver functions to improve the survival rate of mice with 90% hepatectomy. Conclusion Direct conversion of the spleen into a liver-like organ, without cell or tissue transplantation, establishes fundamental hepatic functions in mice, suggesting its potential value for the treatment of end-stage liver diseases.