tbuckley/cabot-search huggingface dataset:
Adult-Onset Type 1 Diabetes: Current Understanding and Challenges
Authors: R. David Leslie, Carmella Evans-Molina, Jacquelyn Freund-Brown, Raffaella Buzzetti, Dana Dabelea, Kathleen M. Gillespie, Robin Goland, Angus G. Jones, Mark Kacher, Lawrence S. Phillips, Olov Rolandsson, Jana L. Wardian, Jessica L. Dunne
Journal: Diabetes Care (2021)

Recent epidemiological data have shown that more than half of all new cases of type 1 diabetes occur in adults. Key genetic, immune, and metabolic differences exist between adult- and childhood-onset type 1 diabetes, many of which are not well understood. A substantial risk of misclassification of diabetes type can result. Notably, some adults with type 1 diabetes may not require insulin at diagnosis, their clinical disease can masquerade as type 2 diabetes, and the consequent misclassification may result in inappropriate treatment. In response to this important issue, JDRF convened a workshop of international experts in November 2019. Here, we summarize the current understanding and unanswered questions in the field based on those discussions, highlighting epidemiology and immunogenetic and metabolic characteristics of adult-onset type 1 diabetes as well as disease-associated comorbidities and psychosocial challenges. In adult-onset, as compared with childhood-onset, type 1 diabetes, HLA-associated risk is lower, with more protective genotypes and lower genetic risk scores; multiple diabetes-associated autoantibodies are decreased, though GADA remains dominant. Before diagnosis, those with autoantibodies progress more slowly, and at diagnosis, serum C-peptide is higher in adults than children, with ketoacidosis being less frequent. Tools to distinguish types of diabetes are discussed, including body phenotype, clinical course, family history, autoantibodies, comorbidities, and C-peptide. By providing this perspective, we aim to improve the management of adults presenting with type 1 diabetes.
MA13.07 GEMSTONE-302: A Phase 3 Study of Platinum-Based Chemotherapy with Placebo or Sugemalimab, a PD-L1 mAb, for metastatic NSCLC
Authors: C. Zhou, Z. Wang, Y. Sun, L. Cao, Z. Ma, R. Wu, Y. Yu, W. Yao, H. Wang, J. Chen, W. Zhuang, J. Cui, X. Chen, Y. Lu, H. Shen, R. Chen, X. Xu, D. Lu, J. Wang, J. Yang
Journal: Journal of Thoracic Oncology (2021)
P47.11 COMPEL: Chemotherapy With/Without Osimertinib in Patients With EGFRm Advanced NSCLC and Progression on First-Line Osimertinib
Authors: L.V. Sequist, N. Peled, A. Tufman, L. Servidio, J. Li, R. Taylor, J. Zhao
Journal: Journal of Thoracic Oncology (2021)
ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials
Authors: Roberto A. Calle, Neeta B. Amin, Santos Carvajal-Gonzalez, Trenton T. Ross, Arthur Bergman, Sudeepta Aggarwal, Collin Crowley, Anthony Rinaldi, Jessica Mancuso, Naresh Aggarwal, Veena Somayaji, Malgorzata Inglot, Theresa A. Tuthill, Kou Kou, Magalie Boucher, Greg Tesz, Robert Dullea, Kendra K. Bence, Albert M. Kim, Jeffrey A. Pfefferkorn, William P. Esler
Journal: Nature Medicine (2021)
Pharmacological Modulation of Immune Responses by Nutritional Components
Authors: Marthe T. van Daal, Gert Folkerts, Johan Garssen, Saskia Braber
Journal: Pharmacological Reviews (2021)

The incidence of noncommunicable diseases (NCDs) has increased over the last few decades, and one of the major contributors to this is lifestyle, especially diet. High intake of saturated fatty acids and low intake of dietary fiber is linked to an increase in NCDs. Conversely, a low intake of saturated fatty acids and a high intake of dietary fiber seem to have a protective effect on general health. Several mechanisms have been identified that underlie this phenomenon. In this review, we focus on pharmacological receptors, including the aryl hydrocarbon receptor, binding partners of the retinoid X receptor, G-coupled protein receptors, and toll-like receptors, which can be activated by nutritional components and their metabolites. Depending on the nutritional component and the receptors involved, both proinflammatory and anti-inflammatory effects occur, leading to an altered immune response. These insights may provide opportunities for the prevention and treatment of NCDs and their inherent (sub)chronic inflammation. <h3>Significance Statement</h3> This review summarizes the reported effects of nutritional components and their metabolites on the immune system through manipulation of specific (pharmacological) receptors, including the aryl hydrocarbon receptor, binding partners of the retinoid X receptor, G-coupled protein receptors, and toll-like receptors. Nutritional components, such as vitamins, fibers, and unsaturated fatty acids are able to resolve inflammation, whereas saturated fatty acids tend to exhibit proinflammatory effects. This may aid decision makers and scientists in developing strategies to decrease the incidence of noncommunicable diseases.
Liquid Copolymers as Biodegradable Surgical Sealant (Adv. Healthcare Mater. 19/2021)
Authors: Neta Shimony, Alona Shagan, Bat‐hen Eylon, Abraham Nyska, Adi Gross, Boaz Mizrahi
Journal: Advanced Healthcare Materials (2021)

Tissue Sealants In article number 2100803 by Boaz Mizrahi and co-workers, an elastic biodegradable sealant is designed by mixing two complementary neat (solvent-free) star shape prepolymers. This mixture, which hardens in several seconds, offers several advantages over existing tissue sealants, including excellent mechanical properties and degradation behavior, minimal cytotoxicity in vitro and biocompatibility in vivo.
FP12.07 Clinico-demographic Factors, EGFR status and their association with Stage at Diagnosis in Lung Adenocarcinoma Patients
Authors: J. Herman, S. Schmid, L. Zhan, M. Garcia, M.C. Brown, K. Khan, M. Chowdhury, A. Sabouhanian, P. Walia, E. Strom, A. Sacher, P. Bradbury, F.A. Shepherd, N. Leighl, S. Cheng, D. Patel, D. Shultz, G. Liu
Journal: Journal of Thoracic Oncology (2021)
Sphingosine 1-phosphate receptor 5 (S1PR5) regulates the peripheral retention of tissue-resident lymphocytes
Authors: Maximilien Evrard, Erica Wynne-Jones, Changwei Peng, Yu Kato, Susan N. Christo, Raissa Fonseca, Simone L. Park, Thomas N. Burn, Maleika Osman, Sapna Devi, Jerold Chun, Scott N. Mueller, George Kannourakis, Stuart P. Berzins, Daniel G. Pellicci, William R. Heath, Stephen C. Jameson, Laura K. Mackay
Journal: The Journal of Experimental Medicine (2021)

Tissue-resident memory T (TRM) cells provide long-lasting immune protection. One of the key events controlling TRM cell development is the local retention of TRM cell precursors coupled to downregulation of molecules necessary for tissue exit. Sphingosine-1-phosphate receptor 5 (S1PR5) is a migratory receptor with an uncharted function in T cells. Here, we show that S1PR5 plays a critical role in T cell infiltration and emigration from peripheral organs, as well as being specifically downregulated in TRM cells. Consequentially, TRM cell development was selectively impaired upon ectopic expression of S1pr5, whereas loss of S1pr5 enhanced skin TRM cell formation by promoting peripheral T cell sequestration. Importantly, we found that T-bet and ZEB2 were required for S1pr5 induction and that local TGF-β signaling was necessary to promote coordinated Tbx21, Zeb2, and S1pr5 downregulation. Moreover, S1PR5-mediated control of tissue residency was conserved across innate and adaptive immune compartments. Together, these results identify the T-bet–ZEB2–S1PR5 axis as a previously unappreciated mechanism modulating the generation of tissue-resident lymphocytes.
Elevated 2HG does not cause features of tumorigenesis
Authors: Julie Adam, Alina Finch, Catarina Sepulveda, Martin Ducker, Maria Blanca Torroba, Daniel Krell, Skirmantas Kriaucionis, Francis Szele, Peter Ratcliffe, Tomoyoshi Soga, Kamil Kranc, Ian Tomlinson, Chiara Bardella
Journal: Neuro-Oncology (2021)

Abstract Aims Gliomas are the most frequent brain tumours, representing 75% of all primary malignant brain tumours in adults. IDH1 (and IDH2) driver mutations occur in &amp;gt;80% of low grade gliomas and secondary GBMs, in &amp;lt;10% of primary GBMs and other cancers. How IDH1/2 mutations contribute to tumorigenesis is mostly unknown. IDH1/2 convert isocitrate to α-ketoglutarate, but when mutated possess a novel enzymatic function that reduces α-ketoglutarate to D2-hydroxyglutarate (2HG). Indeed 2HG accumulates in IDH1/2-mutant tumours, and this discovery suggested that 2HG may have a role in IDH1/2-mutant tumours onset and progression, possibly by causing dysregulations of various enzymes in the cells. Studies are undergoing to clarify the causative role of 2HG in IDH1/2-mutant tumours, but it is still not clear whether 2HG is the driver/oncometabolite. Our aim is to understand the role of 2HG in developing and adult mouse tissues and whether its accumulation might cause features of gliomagenesis. Method A constitutive D2hgdh Knock-out mouse (D2hgdh KO) was generated and the relative molecular and cellular analysis were performed. Results Brains dissected from D2hgdh KO mice appeared to be histologically normal. No differences were found in the proliferation and labelling retaining capacity of neural stem and progenitors cells (NSC/NPC) of the D2hgdh KO mice compared to controls. A comprehensive metabolites analysis showed that D2hgdh KO mouse accumulated 2HG in various organs and tissues, included total brains and in the NSC/NPC microdissected from the subventricular zone, the site of origin of many human gliomas. The DNA amount of 5mC and 5hmC extracted from brains of D2hgdh KO mice was similar to controls. A normal number of haematopoietic progenitors was also found. Conclusion Although D2hgdh KO mice accumulated 2HG in all tissues analysed, they did not develop any abnormalities and remained completely asymptomatic. This suggests that a mere increment of 2HG in developing and adult tissues may be not sufficient to cause tumorigenesis (and gliomagenesis), leading some doubts on the oncogenic roles of the 2HG in IDH1/2-mutant tumours.
3MO Oncogenic non-G12C KRAS mutations in KRAS G12C mutated lung adenocarcinomas in TRACERx and GENIE: A reservoir for intrinsic resistance to KRAS G12C inhibitors
Authors: D. Marinelli, S. Pisegna, M. Giammaruco, P. Chesi, G. Mammone, S. Ceddia, P. Gazzaniga, E. Cortesi, A.J. Gelibter
Journal: Annals of Oncology (2021)
FP09.03 Phase II Randomized Trial to Evaluate Prednisone Taper With or Without Nintedanib for the Treatment of Radiation Pneumonitis
Authors: Z. Moore, S. Lobaugh, Z. Zhang, A. Geyer, D. Gelblum, R. Abdulnour, A. Shepherd, N. Shaverdian, M. Mccune, H. Li, A. Wu, C. Simone, Ii, R. Mak, G. Weinhouse, Z. Liao, D. Gomez, P. Paik, A. Rimner
Journal: Journal of Thoracic Oncology (2021)
Association of a Sweetened Beverage Tax With Soda Consumption in High School Students
Authors: Emma K. Edmondson, Christina A. Roberto, Emily F. Gregory, Nandita Mitra, Senbagam Virudachalam
Journal: JAMA Pediatrics (2021)

<h3>Importance</h3> Sweetened beverage taxes are one policy approach to reduce intake of added sugars. Soda is the leading source of added sugars in the US diet, but few studies have examined how such taxes influence sweetened beverage intake in youth. <h3>Objective</h3> To estimate the association between the Philadelphia, Pennsylvania, beverage tax and adolescent soda intake. <h3>Design, Setting, and Participants</h3> This economic evaluation of school district–level Youth Risk Behavior Surveillance System data from September 2013 to December 2019 compared weekly soda intake in high school students in Philadelphia, a city with a sweetened beverage tax, with that in 7 comparison cities without beverage taxes. Difference-in-differences regression modeling was used to estimate change in soda intake in Philadelphia compared with control cities. Secondary analyses compared 100% juice and milk intake to explore potential substitution associations. Subgroup analyses evaluated differences by race and ethnicity and weight status (obesity and overweight or obesity). Analyses were performed between August 20 and October 20, 2020. School districts that had weighted data and a survey question on weekly soda intake from 2013 to 2019 were included. The study included high school students, grades 9 to 12, in school districts participating in the Youth Risk Behavior Surveillance System from 2013 to 2019. <h3>Exposures</h3> Implementation of a sweetened beverage tax in Philadelphia, Pennsylvania, in January 2017. <h3>Main Outcomes and Measures</h3> Reported weekly servings of soda, 100% juice, and milk. <h3>Results</h3> A total of 86 928 participants (weighted mean [SD] age, 15.8 [1.3] years; 49% female) from 8 US cities (including Philadelphia) were included. Before the tax, adolescents in the 7 comparison cities had a mean intake of 4 servings of soda per week compared with 5.4 servings per week in Philadelphia. Philadelphia’s tax was associated with a reduction of 0.81 servings of soda per week (95% CI, −1.48 to −0.14 servings;<i>P</i> = .02) 2 years after tax implementation. There was no significant difference in 100% juice or milk intake, although Philadelphia adolescents consumed more juice than those in nontaxed cities. In subgroup analyses, the tax was associated with a reduction of 1.13 servings per week in Hispanic/Latinx adolescents (95% CI, −2.04 to −0.23 servings;<i>P</i> = .01) and 1.2 servings per week in adolescents with obesity (95% CI, −2.33 to −0.13 servings;<i>P</i> = .03). <h3>Conclusions and Relevance</h3> This economic evaluation found that a sweetened beverage tax was associated with a reduction in soda intake among adolescents, providing evidence that such taxes can improve dietary behaviors.
MA07.07 Detecting Stage I Lung Cancer with High Sensitivity Using Genome-wide Multi-dimensional Fragmentomic Profiles of Cell Free DNA
Authors: W. Guo, N. Liang, Q. Ma, X. Chen, R. Liu, S. Wu, H. Bao, X. Wu, Y. Shao, B. Qiu, D. Wang, F. Tan, Y. Gao, Q. Xue, S. Gao
Journal: Journal of Thoracic Oncology (2021)
ATTR Amyloidosis: Current and Emerging Management Strategies
Authors: Jan M. Griffin, Julie L. Rosenthal, Justin L. Grodin, Mathew S. Maurer, Martha Grogan, Richard K. Cheng
Journal: JACC CardioOncology (2021)

Transthyretin cardiac amyloidosis (ATTR-CA) is increasingly diagnosed owing to the emergence of noninvasive imaging and improved awareness. Clinical penetrance of pathogenic alleles is not complete and therefore there is a large cohort of asymptomatic transthyretin variant carriers. Screening strategies, monitoring, and treatment of subclinical ATTR-CA requires further study. Perhaps the most important translational triumph has been the development of effective therapies that have emerged from a biological understanding of ATTR-CA pathophysiology. These include recently proven strategies of transthyretin protein stabilization and silencing of transthyretin production. Data on neurohormonal blockade in ATTR-CA are limited, with the primary focus of medical therapy on judicious fluid management. Atrial fibrillation is common and requires anticoagulation owing to the propensity for thrombus formation. Although conduction disease and ventricular arrhythmias frequently occur, little is known regarding optimal management. Finally, aortic stenosis and ATTR-CA frequently coexist, and transcatheter valve replacement is the preferred treatment approach.
New Approaches to Glioblastoma
Authors: Mustafa Khasraw, Yoko Fujita, Catalina Lee-Chang, Irina V. Balyasnikova, Hinda Najem, Amy B. Heimberger
Journal: Annual Review of Medicine (2021)

Faced with unique immunobiology and marked heterogeneity, treatment strategies for glioblastoma require therapeutic approaches that diverge from conventional oncological strategies. The selection and prioritization of targeted and immunotherapeutic strategies will need to carefully consider these features and companion biomarkers developed alongside treatment strategies to identify the appropriate patient populations. Novel clinical trial strategies that interrogate the tumor microenvironment for drug penetration and target engagement will inform go/no-go later-stage clinical studies. Innovative trial designs and analyses are needed to move effective agents toward regulatory approvals more rapidly.
HMG-CoA reductase inhibitors and COVID-19 mortality in Stockholm, Sweden: A registry-based cohort study
Authors: Rita Bergqvist, Viktor H. Ahlqvist, Michael Lundberg, Maria-Pia Hergens, Johan Sundström, Max Bell, Cecilia Magnusson
Journal: PLoS Medicine (2021)

Background The relationship between statin treatment and Coronavirus Disease 2019 (COVID-19) mortality has been discussed due to the pleiotropic effects of statins on coagulation and immune mechanisms. However, available observational studies are hampered by study design flaws, resulting in substantial heterogeneity and ambiguities. Here, we aim to determine the relationship between statin treatment and COVID-19 mortality. Methods and findings This cohort study included all Stockholm residents aged 45 or older ( N = 963,876), followed up from 1 March 2020 until 11 November 2020. The exposure was statin treatment initiated before the COVID-19-pandemic, defined as recorded statin dispensation in the Swedish Prescribed Drug Register between 1 March 2019 and 29 February 2020. COVID-19-specific mortality was ascertained from the Swedish Cause of Death Registry. Hazard ratios (HRs) were calculated using multivariable Cox regression models. We further performed a target trial emulation restricted to initiators of statins. In the cohort (51.6% female), 169,642 individuals (17.6%) were statin users. Statin users were older (71.0 versus 58.0 years), more likely to be male (53.3% versus 46.7%), more often diagnosed with comorbidities (for example, ischemic heart disease 23.3% versus 1.6%), more frequently on anticoagulant and antihypertensive treatments, less likely to have a university-level education (34.5% versus 45.4%), and more likely to have a low disposable income (20.6% versus 25.2%), but less likely to reside in crowded housing (6.1% versus 10.3%). A total of 2,545 individuals died from COVID-19 during follow-up, including 765 (0.5%) of the statin users and 1,780 (0.2%) of the nonusers. Statin treatment was associated with a lowered COVID-19 mortality (adjusted HR, 0.88; 95% CI, 0.79 to 0.97, P = 0.01), and this association did not vary appreciably across age groups, sexes, or COVID-19 risk groups. The confounder adjusted HR for statin treatment initiators was 0.78 (95% CI, 0.59 to 1.05, P = 0.10) in the emulated target trial. Limitations of this study include the observational design, reliance on dispensation data, and the inability to study specific drug regimens. Conclusions Statin treatment had a modest negative association with COVID-19 mortality. While this finding needs confirmation from randomized clinical trials, it supports the continued use of statin treatment for medical prevention according to current recommendations also during the COVID-19 pandemic.
Targeted core-shell nanoparticles for precise CTCF gene insert in treatment of metastatic breast cancer
Authors: Jialun Duan, Chunjie Bao, Ying Xie, Haitao Guo, Yixuan Liu, Jianwei Li, Rui Liu, Peishan Li, Jing Bai, Yan Yan, Limin Mu, Xueqi Li, Guiling Wang, Wanliang Lu
Journal: Bioactive Materials (2021)

Clustered regularly interspaced short palindromic repeats (CRISPR) technology emerges a remarkable potential for cure of refractory cancer like metastatic breast cancer. However, how to efficiently deliver the CRISPR system with non-viral carrier remains a major issue to be solved. Here, we report a kind of targeted core-shell nanoparticles (NPs) carrying dual plasmids (pHR-pCas9) for precise CCCTC-binding factor (CTCF) gene insert to circumvent metastatic breast cancer. The targeted core-shell NPs carrying pHR-pCas9 can accomplish γGTP-mediated cellular uptake and endosomal escape, facilitate the precise insert and stable expression of CTCF gene, inhibit the migration, metastasis, and colonization of metastatic breast cancer cells. Besides, the finding further reveals that the inhibitory mechanism of metastasis could be associated with up-regulating CTCF protein, followed by down-regulating stomatin (STOM) protein. The study offers a universal nanostrategy enabling the robust non-viral delivery of gene-editing system for treatment of severe illness.
Lack of Support for the Use of VMAT-2 Inhibitors for the Treatment of Tics in Tourette Syndrome
Authors: Mark S. Baron
Journal: JAMA Network Open (2021)

Barbara Coffey, MD, MS; Joseph Jankovic, MD; Daniel O. Claassen, MD; Joohi Jimenez-Shahed, MD; Barry J. Gertz, MD, PhD; Elizabeth A. Garofalo, MD; David A. Stamler, MD; Maria Wieman, MPH; Juha-Matti Savola, MD, PhD; Mark Forrest Gordon, MD; Jessica K. Alexander, PhD; Hadas Barkay, PhD; Eran Harary, MD
Abstract 18667: Lipoprotein(a) Catabolism and Apolipoprotein(a) Secretion is Regulated by Sortilin
Authors: Rocco Romagnuolo, Matthew Gemin, Marlys Koschinsky
Journal: Circulation (2015)

Elevated levels of lipoprotein(a) (Lp(a)) in plasma have been identified as an independent, causal risk factor for coronary heart disease. Lp(a) consists of a low-density lipoprotein (LDL)-like particle whose apolipoproteinB-100 (apoB-100) moiety is covalently linked to the unique glycoprotein apolipoprotein(a) (apo(a)). Recently, Lp(a) internalization by the LDL-receptor (LDLr) in hepatic cells and primary human fibroblasts has been shown to be regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9). However, Lp(a)/apo(a) internalization still occurs even with a defective LDLr or in the presence of PCSK9 (in fibroblasts and hepatic cells, respectively), indicating a role for receptors other than the LDLr in Lp(a) catabolism. Hepatic sortilin has been identified as a potential receptor mediating LDL catabolism as well as the regulation of apoB-100 secretion. Sortilin localizes to the Golgi apparatus where it mediates trafficking of specific bound ligands to the lysosome. Sortilin also localizes to clathrin-coated pits in the plasma membrane where it can act as an internalization receptor. We demonstrate in the current study that Lp(a), but not apo(a), internalization in hepatic cells is influenced by sortilin overexpression. In the presence of PCSK9, Lp(a) internalization greatly increases with sortilin overexpression compared to control. These results suggest that hepatic sortilin has the ability to act as a receptor for Lp(a) catabolism, through the LDL-like moiety, in a manner that is not dependent on the LDLr. Furthermore, Lp(a) internalization increases with sortilin overexpression in primary human fibroblasts with a defective LDLr, again emphasizing an LDLr-independent role for sortilin as a receptor for Lp(a). Interestingly, an increase in apo(a) secretion is observed with sortilin overexpression in hepatic cells. Removal of the carboxyl-terminal tail of sortilin results in an inability to promote the secretion of apo(a), indicating a direct role for the sorting motifs present in this region of sortilin for the regulation of apo(a) secretion. Taken together, these results indicate novel roles for sortilin in both Lp(a) catabolism and apo(a) secretion.
P10.03 Pembrolizumab With or Without Chemotherapy for Advanced Lung Cancer: A Real-World Analysis of Key Prognostic Factors
Authors: S. Gadgeel, M. Izano, C. Sweetnam, I. Rybkin, M. Hendawi, J. Weese, A. Patel, D. Reding, J. Treisman, A. Stafford, F. Wolf, C. Zhang, T. Brown
Journal: Journal of Thoracic Oncology (2021)