tbuckley/cabot-search huggingface dataset:
Exploring the impact of commonly used ionizable and pegylated lipids on mRNA-LNPs: A combined in vitro and preclinical perspective
Authors: Burcu Binici, Zahra Rattray, Assaf Zinger, Yvonne Perrie
Journal: Journal of Controlled Release (2024)

Ionizable lipids are widely recognized as the crucial component of lipid nanoparticles (LNPs). They enable mRNA encapsulation, shield it from enzymatic degradation, facilitate cellular uptake, and foster its cytosolic release for subsequent translation into proteins. In addition, PEGylated lipids are added to stabilize the particles in storage and in vivo. In this study, we investigate the potency of LNPs prepared using commonly adopted ionizable and pegylated lipids in vitro (using HEK293 cells) and in vivo (mouse studies) to consider the impact of structure on potency. LNPs were prepared using a fixed molar ratio of DSPC: Cholesterol: ionizable/cationic lipid: PEG lipid (10,38.5:50:1.5 mol%). All LNP formulations exhibited similar critical quality attributes (CQAs), including particle size <100 nm, low PDI (<0.2), near-neutral zeta potential, and high encapsulation efficiency (>90%). However, the potency of these LNPs, as measured by in vitro mRNA expression and in vivo expression following intramuscular injection in mice varied significantly. LNPs formulated with SM-102 exhibited the highest expression in vitro, whilst in vivo SM-102 and ALC-0315 LNPs showed significantly higher mRNA expression than DLin-MC3-DMA, DODAP and DOTAP LNPs. We also investigated the effect of PEG lipid choice (ALC-0159, DMG-PEG2k, and DSPE-PEG2k), which did not impact LNP CQAs, nor their clearance from the injection site. However, PEG lipid choice significantly influenced mRNA expression with the incorporation of DSPE-PEG2k reducing expression both in vitro and in vivo. This work contributes valuable insights to the evolving landscape of mRNA research, emphasizing that CQAs are a marker of the quality of the LNP production process, but not discriminatory regarding LNP potency. Similarly, standard in vitro studies do not provide insights into in vivo potency. These results further emphasize the intricacies of formulation design and the importance of bridging gaps between experimental outcomes in different settings.
Bendamustine–rituximab elicits dual tumoricidal and immunomodulatory responses via cGAS–STING activation in diffuse large B-cell lymphoma
Authors: Ruipei Xiao, Wenli Zhao, Wei Lin, Yudian Xiao, Jie Ren, Yang Zhou, Wei Meng, Enguang Bi, Ling Jiang
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Bendamustine–rituximab (BR) therapy stands out as a promising alternative for elderly patients with diffuse large B-cell lymphoma (DLBCL), demonstrating notable efficacy when conventional regimens pose challenges. Despite its clinical success, the intricate mechanisms underlying BR therapy have remained elusive. Methods DLBCL cell lines were used to investigate the mechanism of BR therapy in vitro. RNA-seq and Western blot were used to explore the target pathways of BR therapy. STING was knocked out using Crispr-cas9 and inhibited using H-151 to investigate its role in BR therapy. Bulk RNA-seq and single-cell RNA-seq data from patients were analyzed to investigate the association between STING and pyroptosis pathways, validated using STING downregulated cells. Flow cytometry, transwell experiments and co-culture experiments were performed to investigate the inflammatory phenotype of DLBCL cells after BR treatment and its effect on T-cell recruitment and activation. Results This study elucidates that BR elicits direct tumoricidal effects by promoting apoptosis and inducing cell cycle arrest. The synergistic impact with rituximab is further potentiated by complement addition, demonstrating the pivotal role of in vivo antibody-dependent cellular cytotoxicity. Moreover, our investigation reveals that, through a cGAS–STING-dependent pathway, prolonged exposure to BR induces pyroptosis in DLBCL cells. Activation of the cGAS–STING pathway by BR therapy triggers the release of inflammatory factors and upregulates major histocompatibility complex molecules, shaping an immunologically hot tumor microenvironment. Conclusions This unique dual influence not only directly targets DLBCL cells but also engages the patient’s immune system, paving the way for innovative combination therapies. The study provides comprehensive insights into the multifaceted actions of BR in DLBCL, offering a foundation for refined and personalized treatment strategies in elderly patients.
Nanotherapeutics-mediated restoration of pancreatic homeostasis and intestinal barrier for the treatment of severe acute pancreatitis
Authors: Juanhui Lin, Yuansong Wei, Xiaxian Gu, Miaoru Liu, Mengru Wang, Renxiang Zhou, Duowu Zou, Lichen Yin, Chunhua Zhou, Duanmin Hu
Journal: Journal of Controlled Release (2024)
Gut commensal bacteria Parabacteroides goldsteinii-derived outer membrane vesicles suppress skin inflammation in psoriasis
Authors: Dandan Su, Manchun Li, Yuedong Xie, Zhanxue Xu, Guowen Lv, Yaming Jiu, Jingxiong Lin, Chih-Jung Chang, Hongbo Chen, Fang Cheng
Journal: Journal of Controlled Release (2024)
Synergistic in vivo anticancer effects of 1,7-heptanediol and doxorubicin co-loadedliposomes in highly aggressive breast cancer
Authors: Muge Gu, Wei Yu, Sílvio Terra Stefanello, Jiayu Wang, Xiangqi Zhang, Yihui Zhang, Wenkai Zhang, Yuanye Guan, Victor Shahin, Yun Qian, Wei-En Yuan
Journal: Journal of Controlled Release (2024)

Breast cancer holds the highest incidence rate among women. Doxorubicin (DOX) is a potent frontline drug for the treatment of breast cancer. The anticancer mechanisms of DOX include inducing immunogenic cell death in tumor cells, causing damage to tumor DNA, and generating free radicals. However, its pharmacological efficacy and wide use are restricted by its substantial dose-dependent side effects. We have recently revealed that 1,7-Heptanediol (1,7-Hept) severely impairs the bioenergetics and metabolism of aggressive human cancer cells. In the present work, we prepared liposomes co-loaded with DOX and 1,7-Hept (DOX/1,7-Hept-lipo) and assessed their potential synergistic anti-tumor effects. In vitro studies demonstrated that 4 T1 cells (the mouse breast cancer cell) exhibited higher sensitivity to 1,7-Hept and DOX/1,7-Hept-lipo could induce ICD of 4 T1 cells. Cell viability was markedly reduced when 4 T1 cells were treated with a combination of DOX and 1,7-Hept. In a mouse breast cancer model, the DOX/1,7-Hept-lipo exhibited superior anti-tumor efficacy compared to liposomes loaded with individual drugs, resulting in almost total elimination of the tumors at lower doses of DOX with reduced systemic toxicity. Notably, the number of immune cells significantly increased in the tumor microenvironment, and macrophages were more transformed into the anti-tumor M1 phenotype. Our findings suggest strong synergistic anti-tumor effects of DOX and 1,7-Hept, enhancing the efficacy of tumor immunotherapy and mitigating the toxic side effects of DOX.
Strategic delivery of rapamycin and ranibizumab with intravitreal hydrogel depot disrupts multipathway-driven angiogenesis loop for boosted wAMD therapy
Authors: Xi Jiang, Congyan Liu, Qun Zhang, Yanli Lv, Chen Lu, Wenting Su, Jing Zhou, Huangqin Zhang, Huiling Gong, Yuping Liu, Songtao Yuan, Yan Chen, Ding Qu
Journal: Journal of Controlled Release (2024)
Intensive Blood-Pressure Control in Patients with Type 2 Diabetes
Authors: Yufang Bi, Mian Li, Yan Liu, Tingzhi Li, Jieli Lu, Peng Duan, Fengmei Xu, Qijuan Dong, Ailiang Wang, Tiange Wang, Ruizhi Zheng, Yuhong Chen, Min Xu, Xiaohu Wang, Xinhuan Zhang, Yanbo Niu, Zhiqiang Kang, Chunru Lu, Jing Wang, Xinwen Qiu, An Wang, Shujing Wu, Jingya Niu, Jingya Wang, Zhiyun Zhao, Huanfeng Pan, Xiaohua Yang, Xiaohong Niu, Shuguang Pang, Xiaoliang Zhang, Yuancheng Dai, Qin Wan, Shihong Chen, Qidong Zheng, Shaoping Dai, Juan Deng, Leshan Liu, Guixia Wang, Huiqi Zhu, Weidong Tang, Haixia Liu, Zhenfang Guo, Guang Ning, Jiang He, Yu Xu, Weiqing Wang
Journal: New England Journal of Medicine (2024)

BackgroundEffective targets for systolic blood-pressure control in patients with type 2 diabetes are unclear.MethodsWe enrolled patients 50 years of age or older with type 2 diabetes, elevated systolic blood pressure, and an increased risk of cardiovascular disease at 145 clinical sites across China. Patients were randomly assigned to receive intensive treatment that targeted a systolic blood pressure of less than 120 mm Hg or standard treatment that targeted a systolic blood pressure of less than 140 mm Hg for up to 5 years. The primary outcome was a composite of nonfatal stroke, nonfatal myocardial infarction, treatment or hospitalization for heart failure, or death from cardiovascular causes. Multiple imputation was used for missing outcome data, with an assumption that the data were missing at random.ResultsOf 12,821 patients (6414 patients in the intensive-treatment group and 6407 in the standard-treatment group) enrolled from February 2019 through December 2021, 5803 (45.3%) were women; the mean (±SD) age of the patients was 63.8±7.5 years. At 1 year of follow-up, the mean systolic blood pressure was 121.6 mm Hg (median, 118.3 mm Hg) in the intensive-treatment group and 133.2 mm Hg (median, 135.0 mm Hg) in the standard-treatment group. During a median follow-up of 4.2 years, primary-outcome events occurred in 393 patients (1.65 events per 100 person-years) in the intensive-treatment group and 492 patients (2.09 events per 100 person-years) in the standard-treatment group (hazard ratio, 0.79; 95% confidence interval, 0.69 to 0.90; P<0.001). The incidence of serious adverse events was similar in the treatment groups. However, symptomatic hypotension and hyperkalemia occurred more frequently in the intensive-treatment group than in the standard-treatment group.ConclusionsAmong patients with type 2 diabetes, the incidence of major cardiovascular events was significantly lower with intensive treatment targeting a systolic blood pressure of less than 120 mm Hg than with standard treatment targeting a systolic blood pressure of less than 140 mm Hg. (Funded by the National Key Research and Development Program of the Ministry of Science and Technology of China and others; BPROAD ClinicalTrials.gov number, NCT03808311.)
CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy
Authors: Marianna Fontana, Scott D Solomon, Jessica Kachadourian, Liron Walsh, Ricardo Rocha, David Lebwohl, Derek Smith, Jörg Täubel, Edward J Gane, Björn Pilebro, David Adams, Yousuf Razvi, Joy Olbertz, Alexandra Haagensen, Peijuan Zhu, Yuanxin Xu, Adia Leung, Alison Sonderfan, David E Gutstein, Julian D Gillmore
Journal: New England Journal of Medicine (2024)

BackgroundTransthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, often fatal disease. Nexiguran ziclumeran (nex-z) is an investigational therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) targeting the gene encoding transthyretin (TTR).MethodsIn this phase 1, open-label trial, we administered a single intravenous infusion of nex-z to patients with ATTR-CM. Primary objectives included assessment of the effect of nex-z on safety and pharmacodynamics, including the serum TTR level. Secondary end points included changes in N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, high-sensitivity cardiac troponin T levels, the 6-minute walk distance, and the New York Heart Association (NYHA) class.ResultsA total of 36 patients received nex-z and completed at least 12 months of follow-up. Of these patients, 50% were in NYHA class III and 31% had variant ATTR-CM. The mean percent change from baseline in the serum TTR level was −89% (95% confidence interval [CI], −92 to −87) at 28 days and −90% (95% CI, −93 to −87) at 12 months. Adverse events were reported in 34 patients. Five had transient infusion-related reactions, and two had transient liver-enzyme elevations that were assessed as treatment-related. Serious adverse events, most of which were consistent with ATTR-CM, were reported in 14 patients. The geometric mean factor change from baseline to month 12 was 1.02 (95% CI, 0.88 to 1.17) in the NT-proBNP level and 0.95 (95% CI, 0.89 to 1.01) in the high-sensitivity cardiac troponin T level. The median change from baseline to month 12 in the 6-minute walk distance was 5 m (interquartile range, −33 to 49). A total of 92% of the patients had either improvement or no change in their NYHA class.ConclusionsIn this phase 1 study involving patients with ATTR-CM, treatment with a single dose of nex-z was associated with transient infusion-related reactions and consistent, rapid, and durable reductions in serum TTR levels. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.)
Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity
Authors: Milton Packer, Michael R Zile, Christopher M Kramer, Seth J Baum, Sheldon E Litwin, Venu Menon, Junbo Ge, Govinda J Weerakkody, Yang Ou, Mathijs C Bunck, Karla C Hurt, Masahiro Murakami, Barry A Borlaug
Journal: New England Journal of Medicine (2024)

BackgroundObesity increases the risk of heart failure with preserved ejection fraction. Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, causes considerable weight loss, but data are lacking with respect to its effects on cardiovascular outcomes.MethodsIn this international, double-blind, randomized, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, 731 patients with heart failure, an ejection fraction of at least 50%, and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 30 to receive tirzepatide (up to 15 mg subcutaneously once per week) or placebo for at least 52 weeks. The two primary end points were a composite of adjudicated death from cardiovascular causes or a worsening heart-failure event (assessed in a time-to-first-event analysis) and the change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating better quality of life).ResultsA total of 364 patients were assigned to the tirzepatide group and 367 to the placebo group; the median duration of follow-up was 104 weeks. Adjudicated death from cardiovascular causes or a worsening heart-failure event occurred in 36 patients (9.9%) in the tirzepatide group and in 56 patients (15.3%) in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.41 to 0.95; P=0.026). Worsening heart-failure events occurred in 29 patients (8.0%) in the tirzepatide group and in 52 patients (14.2%) in the placebo group (hazard ratio, 0.54; 95% CI, 0.34 to 0.85), and adjudicated death from cardiovascular causes occurred in 8 patients (2.2%) and 5 patients (1.4%), respectively (hazard ratio, 1.58; 95% CI, 0.52 to 4.83). At 52 weeks, the mean (±SD) change in the KCCQ-CSS was 19.5±1.2 in the tirzepatide group as compared with 12.7±1.3 in the placebo group (between-group difference, 6.9; 95% CI, 3.3 to 10.6; P<0.001). Adverse events (mainly gastrointestinal) leading to discontinuation of the trial drug occurred in 23 patients (6.3%) in the tirzepatide group and in 5 patients (1.4%) in the placebo group.ConclusionsTreatment with tirzepatide led to a lower risk of a composite of death from cardiovascular causes or worsening heart failure than placebo and improved health status in patients with heart failure with preserved ejection fraction and obesity. (Funded by Eli Lilly; SUMMIT ClinicalTrials.gov number, NCT04847557.)
Retrospective Cohort Study of Novel Oral Agents Lenalidomide and Duvelisib For Relapsed or Refractory Mycosis Fungoides and Sézary Syndrome
Authors: Omar Elghawy, Austin G Yang, Jonathan H Sussman, Colin J Thomas, Jordan S Carter, Daniel J Landsburg, Jakub Svoboda, Ellen Kim, Alain H Rook, Jina Chung, Jennifer Villasenor-Park, John P Plastaras, Michael LaRiviere, Harper Hubbeling, Monica Chelius, Sunita D Nasta, Elise A Chong, Stephen J Schuster, Stefan K Barta
Journal: Journal of the American Academy of Dermatology (2024)
A Post-Pandemic Surge of Thick Melanomas in Women: A Nationwide Study on Skin Cancer Incidence During COVID-19
Authors: Areeba Ahmed, Omar Alani, Eydís Lilja Haraldsdóttir, David Hoyt, Sierra Thomas, Jonathan Ungar, Nicholas Gulati, Arni Kjalar Kristjansson, Jon Gunnlaugur Jonasson, Jonas A Adalsteinsson
Journal: Journal of the American Academy of Dermatology (2024)
Successful repurposing of empagliflozin to treat neutropenia in a severe congenital neutropenia patient with G6PC3 mutations
Authors: Grigorios Tsaknakis, Erasmia Boutakoglou, Irene Mavroudi, Christos S Mantzoros, Maria Veiga-da Cunha, Helen A Papadaki
Journal: Metabolism (2024)
Corrigendum to “Antihypertensive medication classes and risk of incident dementia in primary care patients: a longitudinal cohort study in the Netherlands” [The Lancet Regional Health—Europe, Volume 42, July 2024, 100927]
Authors: Jakob L Schroevers, Marieke P Hoevenaar-Blom, Wim B Busschers, Monika Hollander, Willem A Van Gool, Edo Richard, Jan Willem Van Dalen, Eric P Moll van Charante
Journal: The Lancet Regional Health - Europe (2024)
Lowell A. Goldsmith, MD, MPH, 1938-2024—A Personal Remembrance From 3 Friends
Authors: Ervin Epstein, Gerald S. Lazarus, Luis A. Diaz
Journal: JAMA Dermatology (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast JAMA+ AI Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Temporal Effects of Plozasiran on Lipids and Lipoproteins in Persistent Chylomicronemia
Authors: Gerald F. Watts, Robert A. Hegele, Robert S. Rosenson, Ira J. Goldberg, Antonio Gallo, Ann Mertens, Alexis Baass, Rong Zhou, Ma'an Muhsin, Jennifer Hellawell, Daniel Gaudet, Nicholas J. Leeper
Journal: Circulation (2024)
Polygenic Risk Scores for Coronary Heart Disease
Authors: Sadiya S. Khan, Michael J. Pencina
Journal: JAMA (2024)

Sarah A. Abramowitz, BA; Kristin Boulier, MD; Karl Keat, BS; Katie M. Cardone, BS; Manu Shivakumar, BS; John DePaolo, MD, PhD; Renae Judy, MS; Francisca Bermudez, BA; Nour Mimouni, BA; Christopher Neylan, MD; Dokyoon Kim, PhD; Daniel J. Rader, MD; Marylyn D. Ritchie, PhD; Benjamin F. Voight, PhD; Bogdan Pasaniuc, PhD; Michael G. Levin, MD; Scott M. Damrauer, MD; Penn Medicine BioBank; Daniel J Rader; Marylyn D Ritchie; JoEllen Weaver; Nawar Naseer; Giorgio Sirugo; Afiya Poindexter; Yi-An Ko; Kyle P. Nerz; Meghan Livingstone; Fred Vadivieso; Stephanie DerOhannessian; Teo Tran; Julia Stephanowski; Salma Santos; Ned Haubein; Joseph Dunn; Anurag Verma; Colleen M. Kripke; Marjorie Risman; Renae Judy; Colin Wollack; Shefali S. Verma; Scott M Damrauer; Yuki Bradford; Scott Dudek; Theodore Drivas
Heart Failure in Zero Gravity—External Constraint and Cardiac Hemodynamics
Authors: James P. MacNamara, Christopher M. Hearon, Giorgio Manferdelli, Aman M. Shah, Kevin G. Tayon, Ambarish Pandey, Satyam Sarma, Benjamin D. Levine
Journal: JAMA Cardiology (2024)

In this case series study, pulmonary artery systolic, diastolic, and mean pressures of 2 participants with obesity and heart failure with preserved ejection fraction were measured at zero gravity during parabolic flight to assess the effect of external constraint on left ventricular filling pressures.
The interplay between cell death and senescence in cancer
Authors: Kouhei Shimizu, Hiroyuki Inuzuka, Fuminori Tokunaga
Journal: Seminars in Cancer Biology (2024)

Cellular senescence is a state of permanent proliferative arrest that occurs in response to DNA damage-inducing endogenous and exogenous stresses, and is often accompanied by dynamic molecular changes such as a senescence-associated secretory phenotype (SASP). Accumulating evidence indicates that age-associated increases in the upstream and downstream signals of regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, are closely related to the induction of cellular senescence and its phenotype. Furthermore, elevated levels of pro-inflammatory SASP factors with aging can be both a cause and consequence of several cell death modes, suggesting the reciprocal effects of cellular senescence and cells undergoing regulated cell death. Here, we review the critical molecular pathways of the regulated cell death forms and describe the crosstalk between aging-related signals and cancer. In addition, we discuss how targeting regulated cell death could be harnessed in therapeutic interventions for cancer. ABBREVIATIONS: Abbreviations that are not standard in this field are defined at their first occurrence in the article and are used consistently throughout the article.
Polymeric immunogel prevents tumor recurrence and metastasis by dual activation of innate and adaptive immunity
Authors: Guanyu Jin, Hao Liu, Zi Mei, Qionghua Jin, Sheng Ma, Lanqing Wang, Yuanzhen Su, Letian Lv, Zijuan Wang, Huicong Zhou, Mingqiang Li, Zehuan Huang, Xuesi Chen, Shixian Lv
Journal: Bioactive Materials (2024)
Bioinspired orthogonal-shaped protein–biometal nanocrystals enable oral protein absorption
Authors: Matilde Durán-Lobato, Sulay Tovar, Juan Cuñarro, Rocío Ramos-Membrive, Iván Peñuelas, Ilaria Marigo, Federico Benetti, Miguel Chenlo, Clara V Álvarez, Vashegyi Ildikó, Rudolf Urbanics, János Szebeni, María José Alonso
Journal: Journal of Controlled Release (2024)

With the growing number of marketed biological drugs, the development of technological strategies for their oral systemic absorption, becomes increasingly important. The harsh gastrointestinal environment and low permeability of the intestinal epithelium, represent a huge challenge for their systemic delivery. Herein, bioinspired in the physiological insulin-Zn interaction, the design of orthogonal-shaped protein-biometal hybrid nanocrystals, further enveloped by a bilayer of functional biomaterials, is reported. The nanocrystals exhibited a size of 80 nm, a neutral surface charge and a high insulin loading. In vitro studies showed the capacity of the nanocomplexes to control the release of the associated insulin, while preserving its stability. In vivo evaluation showed sustained blood glucose reductions in both healthy and diabetic rats (up to 40 % and 80 %, respectively), while chronic immunotoxicity studies in mice indicated no toxicity effect. Preliminary efficacy studies in healthy awake pigs following oral capsule administration showed over 20 % absolute bioavailability.