tbuckley/cabot-search huggingface dataset:
Biofluid specific protein coronas affect lipid nanoparticle behavior in vitro
Authors: Demian van Straten, Helena Sork, Luuk van de Schepop, Rowan Frunt, Kariem Ezzat, Raymond M Schiffelers
Journal: Journal of Controlled Release (2024)

Lipid nanoparticles (LNPs) have successfully entered the clinic for the delivery of mRNA- and siRNA-based therapeutics, most recently as vaccines for COVID-19. Nevertheless, there is a lack of understanding regarding their in vivo behavior, in particular cell targeting. Part of this LNP tropism is based on the adherence of endogenous protein to the particle surface. This protein forms a so-called corona that can change, amongst other things, the circulation time, biodistribution and cellular uptake of these particles. The formation of this protein corona, in turn, is dependent on the nanoparticle properties (e.g., size, charge, surface chemistry and hydrophobicity) as well as the biological environment from which it is derived. With the potential of gene therapy to target virtually any disease, administration sites other than intravenous route are considered, resulting in tissue specific protein coronas. For neurological diseases, intracranial administration of LNPs results in a cerebral spinal fluid derived protein corona, possibly changing the properties of the lipid nanoparticle compared to intravenous administration. Here, the differences between plasma and CSF derived protein coronas on a clinically relevant LNP formulation were studied in vitro. Protein analysis showed that LNPs incubated in human CSF (C-LNPs) developed a protein corona composition that differed from that of LNPs incubated in plasma (P-LNPs). Lipoproteins as a whole, but in particular apolipoprotein E, represented a higher percentage of the total protein corona on C-LNPs than on P-LNPs. This resulted in improved cellular uptake of C-LNPs compared to P-LNPs, regardless of cell origin. Importantly, the higher LNP uptake did not directly translate into more efficient cargo delivery, underlining that further assessment of such mechanisms is necessary. These findings show that biofluid specific protein coronas alter LNP functionality, suggesting that the site of administration could affect LNP efficacy in vivo and needs to be considered during the development of the formulation.
The potential of developing high hepatic clearance drugs via controlled release: Lessons from Kirchhoff's Laws
Authors: Leslie Z. Benet, Markus Ville Tiitto, Jasleen K. Sodhi
Journal: Journal of Controlled Release (2024)

When a new molecular entity is predicted to exhibit high clearance in humans, pharmaceutical sponsors almost universally search for similar acting back-up compounds that will demonstrate low clearance. Here we show that, except for oral dosing, there can be marked advantages to developing and commercializing controlled release formulations of high clearance drugs, the expertise of readers of this journal. Our recent publications demonstrate that the universally held pharmacokinetic principle that drug delivery rate has no effect on measured drug clearance is not correct. Rather, we show that if clearance from the drug delivery site is markedly less than the iv bolus clearance of a drug, the in vivo drug clearance can be the drug delivery clearance controlled by the designed dosage form. This approach will be especially advantageous for high hepatic clearance drugs. These advantages include not being concerned with: a) saturable nonlinear kinetics, b) significant pharmacogenomic differences, c) drug-drug induction mechanisms, and d) in many cases drug-drug inhibition interactions. This is due to the ability of a drug sponsor to design clearance, independent of the pharmacokinetic characteristics for high clearance compounds, where clearance from the dosage form becomes the drug clearance from the patient. Recognition of this principle, as described here, results from our development of the use of Kirchhoff's Laws from physics to derive rate-defining clearance and rate constant elimination processes independent of differential equation derivations. The key message for readers of this journal is that high clearance drugs are potentially drugable through formulation design and should not be outright disregarded, since for such drugs the dose-corrected area under the curve can be increased if the release rate from the injection site is controlled and slow resulting in drug clearance from the body controlled by clearance from the dosage form. The concepts presented here describe previously unrecognized advantages of controlled release formulations.
Suppression of RCAN1 alleviated lipid accumulation and mitochondrial fission in diabetic cardiomyopathy
Authors: Songren Shu, Hao Cui, Zirui Liu, Hang Zhang, Yicheng Yang, Xiao Chen, Zhiwei Zeng, Leilei Du, Mengxia Fu, Ziang Yang, Peizhi Wang, Chuangshi Wang, Huimin Gao, Qiaoxi Yang, Xiaojun Lin, Tianshuo Yang, Zhice Chen, Sijin Wu, Xiaohu Wang, Ruojin Zhao, Shengshou Hu, Jiangping Song
Journal: Metabolism (2024)

Although metabolic disturbance is a characteristic of diabetic cardiomyopathy (DbCM), the detailed pathogenesis of DbCM remains unknown.
Vibration-controlled transient elastography for significant fibrosis in treatment-naïve chronic hepatitis B patients: A systematic review and meta-analysis
Authors: Mi Na Kim, Jihyun An, Eun Hwa Kim, Hee Yeon Kim, Han Ah Lee, Jung Hwan Yu, Young-Joo Jin, Young Eun Chon, Seung Up Kim, Dae Won Jun, Ji Won Han, Miyoung Choi
Journal: Clinical and Molecular Hepatology (2024)

Backgrounds/Aims: Accurate diagnosis of significant liver fibrosis in patients with chronic hepatitis B (CHB) is crucial when determining whether to initiate antiviral treatment (AVT). We conduct a meta-analysis to assess the diagnostic performance of vibration-controlled transient elastography (VCTE) for significant liver fibrosis in AVT-naïve CHB patients with serum alanine transaminase (ALT) levels within 5-fold the upper limit of normal (ULN).Methods: The Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases were searched to identify studies that compared the performance of VCTE and liver biopsy (reference standard) when diagnosing significant liver fibrosis (≥F2) in AVT-naïve CHB patients with ALT within 5-fold the ULN. A hierarchical summary receiver operating characteristic curve (HSROC) and bivariate model were performed to evaluate the diagnostic performance of VCTE in the meta-analysis.Results: Eight studies (2,003 patients) were included. The summary sensitivity and specificity for diagnosis of significant liver fibrosis were 0.78 (95% confidence interval [CI], 0.66–0.86) and 0.72 (95% CI, 0.60–0.82), respectively. The HSROC for the diagnosis of significant liver fibrosis was 0.81 (95% CI, 0.72–0.86). The optimal cutoff value of VCTE for diagnosis of significant liver fibrosis was 7.7 kPa with a sensitivity of 0.64 (95% CI, 0.50–0.76) and specificity of 0.83 (95% CI, 0.72–0.90).Conclusions: Our study demonstrated that VCTE has an acceptable diagnostic performance for significant liver fibrosis in AVT-naïve CHB patients with ALT within 5-fold the ULN.
Polyp size measurement during colonoscopy using a virtual scale: variability and systematic differences
Authors: Querijn N.E. van Bokhorst, Britt B.S.L. Houwen, Yark Hazewinkel, Manon van der Vlugt, Hanneke Beaumont, Joep Grootjans, Arjan van Tilburg, Marlou P.M. Adriaanse, Barbara A.J. Bastiaansen, Yvette H. van Beurden, Maxime E.S. Bronzwaer, Brecht W.E. Hens, Lowiek M. Hubers, Gem M. Kramer, Selma J. Lekkerkerker, Berrie Meijer, Fraukje A. Ponds, Dewkoemar Ramsoekh, Paul Fockens, Patrick M.M. Bossuyt, Evelien Dekker
Journal: Endoscopy (2024)

BACKGROUND : Accurate polyp size measurement is important for polyp risk stratification and decision-making regarding polypectomy and surveillance. Recently, a virtual scale (VS) function has been developed that allows polyp size measurement through projection of an adaptive VS onto colorectal polyps during real-time endoscopy. We aimed to evaluate the VS in terms of variability and systematic differences. METHODS : We conducted a video-based study with 120 colorectal polyps, measured by eight dedicated colorectal gastroenterologists (experts) and nine gastroenterology residents following endoscopy training (trainees). Three endoscopic measurement methods were compared: (1) visual, (2) snare and (3) VS measurement. We evaluated the method-specific variance (as measure of variability) in polyp size measurements and systematic differences between these methods. RESULTS : Variance in polyp size measurements was significantly lower for VS measurements compared to visual and snare measurements for both experts (0.52 vs. 1.59 and 1.96, p < 0.001) and trainees (0.59 vs. 2.21 and 2.53, p < 0.001). VS measurement resulted in a higher percentage of polyps assigned to the same size category by all endoscopists compared to visual and snare measurements (experts: 69 % vs. 55 % and 59 %; trainees: 67 % vs. 51 % and 47 %) and reduced the maximum difference between individual endoscopists regarding the percentage of polyps assigned to the ≥ 10 mm size category (experts: 1.7 % vs. 10.0 % and 5.0 %; trainees: 2.5 % vs. 6.7 % and 11.7 %). Systematic differences between methods were < 0.5 mm. CONCLUSIONS : Use of the VS leads to lower polyp size measurement variability and more uniform polyp sizing by individual endoscopists compared to visual and snare measurements.
Artificial intelligence for diabetes care: current and future prospects
Authors: Bin Sheng, Krithi Pushpanathan, Zhouyu Guan, Quan Hziung Lim, Zhi Wei Lim, Samantha Min Er Yew, Jocelyn Hui Lin Goh, Yong Mong Bee, Charumathi Sabanayagam, Nick Sevdalis, Cynthia Ciwei Lim, Chwee Teck Lim, Jonathan Shaw, Weiping Jia, Elif Ilhan Ekinci, Rafael Simó, Lee-Ling Lim, Huating Li, Yih-Chung Tham
Journal: The Lancet Diabetes & Endocrinology (2024)
Foritinib in advanced ROS1-rearranged non-small-cell lung cancer in China: a multicentre, open-label, single-arm, phase 2 study
Authors: Jin-Ji Yang, Jianying Zhou, Si-Yang Maggie Liu, Mingjun Li, Zhiye Zhang, Ying Cheng, Yun Fan, Hongming Pan, Baoqing Wang, Gongyan Chen, Ke Wang, Liyan Jiang, Yanping Hu, Jianhua Shi, Xiaorong Dong, Cuimin Ding, Yunpeng Liu, Zhe Liu, Wangjun Liao, Wei Li, Jun Wang, Shanyong Yi, Qiong Zhao, Aimin Zang, Yuan Chen, Jiuwei Cui, Pengfei Luo, Xionghu Shen, Meili Sun, Changli Wang, Yi-Long Wu
Journal: The Lancet Respiratory Medicine (2024)
Analytical treatment interruption in children living with HIV: position statement from the EPIICAL consortium
Authors: Louise Kuhn, Shaun Barnabas, Nicola Cotugno, Holly Peay, Philip Goulder, Mark Cotton, Avy Violari, Savita Pahwa, Kavidha Reddy, Alfredo Tagarro, Kennedy Otwombe, Samantha Fry, Paula Vaz, Maria Grazia Lain, Tacilta Nhampossa, Moherndran Archary, Almoustapha Issiaka Maiga, Thanyawee Puthanakit, Cissy M Kityo, Caroline Foster, Pablo Rojo, Nigel Klein, Eleni Nastouli, Caroline T Tiemessen, Anita de Rossi, Thumbi Ndung'u, Deborah Persaud, Mathias Lichterfeld, Carlo Giaquinto, Paolo Palma, Paolo Rossi
Journal: The Lancet HIV (2024)
Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study
Authors: Leonard H van den Berg, Jeffrey D Rothstein, Pamela J Shaw, Suma Babu, Michael Benatar, Robert C Bucelli, Angela Genge, Jonathan D Glass, Orla Hardiman, Vincenzo Libri, Theodore Mobach, Björn Oskarsson, Gary L Pattee, John Ravits, Christopher E Shaw, Markus Weber, Lorne Zinman, Paymaan Jafar-Nejad, Frank Rigo, Luan Lin, Toby A Ferguson, Anthony L Gotter, Danielle Graham, Michael Monine, Jennifer Inra, Susie Sinks, Satish Eraly, Steve Garafalo, Stephanie Fradette
Journal: The Lancet Neurology (2024)
Anti-BCMA/GPRC5D bispecific CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, single-centre, phase 1 trial
Authors: Dian Zhou, Qian Sun, Jieyun Xia, Weiying Gu, Jun Qian, Wanchuan Zhuang, Zhiling Yan, Hai Cheng, Wei Chen, Feng Zhu, Kunming Qi, Depeng Li, Wei Sang, Lili Zhu, Sha Ma, Hujun Li, Huanxin Zhang, Tingting Qiu, Dongmei Yan, Yanlei Zhang, Shuixiu Peng, Alex H Chang, Kailin Xu, Zhenyu Li
Journal: The Lancet Haematology (2024)
Synergistic rheumatoid arthritis therapy by interrupting the detrimental feedback loop to orchestrate hypoxia M1 macrophage polarization using an enzyme-catalyzed nanoplatform
Authors: Dong Guo, Hui Liu, Sheng Zhao, Xinya Lu, Haoyu Wan, Yitao Zhao, Xinzhi Liang, Anbiao Zhang, Mengyuan Wu, Zhisheng Xiao, Ning Hu, Zhong Li, Denghui Xie
Journal: Bioactive Materials (2024)
Mechanisms of intestinal dysbiosis: new insights into tuft cell functions
Authors: Nathalie Coutry, Imène Gasmi, Fabien Herbert, Philippe Jay
Journal: Gut Microbes (2024)

Symbiosis between the host and intestinal microbial communities is essential for human health. Disruption in this symbiosis is linked to gastrointestinal diseases, including inflammatory bowel diseases, as well as extra-gastrointestinal diseases. Unbalanced gut microbiome or gut dysbiosis contributes in multiple ways to disease frequency, severity and progression. Microbiome taxonomic profiling and metabolomics approaches greatly improved our understanding of gut dysbiosis features; however, the precise mechanisms involved in gut dysbiosis establishment still need to be clarified. The aim of this review is to present new actors and mechanisms underlying gut dysbiosis formation following parasitic infection or in a context of altered Paneth cells, revealing the existence of a critical crosstalk between Paneth and tuft cells to control microbiome composition.
Gelatin and lipidoid integrate to create gelasomes to enhance siRNA delivery with low toxicity
Authors: Abilash Gangula, Dhananjay Suresh, Agasthya Suresh Babu, Zhaohui Li, Anandhi Upendran, Raghuraman Kannan
Journal: Bioactive Materials (2024)

RNAi therapeutics possess the potential to cure many uncurable human diseases. For instance, RNAi therapeutics using liposomes showed remarkable survival benefits in patients with liver diseases. However, the extension of liposomes to deliver RNA to cure other ailments has largely been unsuccessful. Therefore, researchers are focusing on designing and testing different combinations of materials for versatile RNA delivery applications. Yet, an efficient and safe RNA delivery platform has not been identified. In this work, we have developed a new class of RNA-delivery vehicle called "Gelasomes," using an incongruous combination of gelatin and lipidoid to exploit each material's unique properties while overcoming their inherent limitations. The low
Neonatal intestinal colonization of <i>Streptococcus agalactiae</i> and the multiple modes of protection limiting translocation
Authors: Kara G. Greenfield, Olivia S. Harlow, Lila T. Witt, Evelyn M. Dziekan, Christian R. Tamar, Josephine Meier, Jane E. Brumbaugh, Emily R. Levy, Kathryn A. Knoop
Journal: Gut Microbes (2024)

Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is a predominant pathogen of neonatal sepsis, commonly associated with early-onset neonatal sepsis. GBS has also been associated with cases of late-onset sepsis potentially originating from the intestine. Previous findings have shown GBS can colonize the infant intestinal tract as part of the neonatal microbiota. To better understand GBS colonization dynamics in the neonatal intestine, we collected stool and milk samples from prematurely born neonates for identification of potential pathogens in the neonatal intestinal microbiota. GBS was present in approximately 10% of the cohort, and this colonization was not associated with maternal GBS status, delivery route, or gestational weight. Interestingly, we observed the relative abundance of GBS in the infant stool negatively correlated with maternal IgA concentration in matched maternal milk samples. Using a preclinical murine model of GBS infection, we report that both vertical transmission and direct oral introduction resulted in intestinal colonization of GBS; however, translocation beyond the intestine was limited. Finally, vaccination of dams prior to breeding induced strong immunoglobulin responses, including IgA responses, which were associated with reduced mortality and GBS intestinal colonization. Taken together, we show that maternal IgA may contribute to infant immunity by limiting the colonization of GBS in the intestine.
Selective Serotonin Reuptake Inhibitor and Serotonin-Noradrenaline Reuptake Inhibitor Withdrawal Changes DSM Presentation of Mental Disorders: Results from the Diagnostic Clinical Interview for Drug Withdrawal
Authors: Fiammetta Cosci, Virginie-Anne Chouinard, Guy Chouinard
Journal: Psychotherapy and Psychosomatics (2024)

Introduction: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause withdrawal at dose decrease, discontinuation, or switch. Current diagnostic methods (e.g., DSM) do not take such phenomenon into account. Using a new nosographic classification of withdrawal syndromes due to SSRI/SNRI decrease or discontinuation [by Psychother Psychosom. 2015;84(2):63–71], we explored whether DSM is adequate to identify DSM disorders when withdrawal occurs. Methods: Seventy-five self-referred patients with a diagnosis of withdrawal syndrome due to discontinuation of SSRI/SNRI, diagnosed via the Diagnostic Clinical Interview for Drug Withdrawal 1 – New Symptoms of Selective Serotonin Reuptake Inhibitors or Serotonin-Norepinephrine Reuptake Inhibitors (DID-W1), and at least one DSM-5 diagnosis were analyzed. Results: In 58 cases (77.3%), the DSM-5 diagnosis of current mental disorder was not confirmed when the DID-W1 diagnosis of current withdrawal syndrome was established. In 13 cases (17.3%), the DSM-5 diagnosis of past mental disorder was not confirmed when criteria for DID-W1 diagnosis of lifetime withdrawal syndrome were met. In 3 patients (4%), the DSM-5 diagnoses of current and past mental disorders were not confirmed when the DID-W1 diagnoses of current and lifetime withdrawal syndromes were taken into account. The DSM-5 diagnoses most frequently mis-formulated were current panic disorder (50.7%, n = 38) and past major depressive episode (18.7%, n = 14). Conclusion: DSM needs to be complemented by clinimetric tools, such as the DID-W1, to detect withdrawal syndromes induced by SSRI/SNRI discontinuation, decrease, or switch, following long-term use.
In vivo CRISPR/Cas9-mediated screen reveals a critical function of TFDP1 and E2F4 transcription factors in hematopoiesis
Authors: Ngoc Tung Tran, Robin Graf, Ernesto Acevedo-Ochoa, Janine Trombke, Timm Weber, Thomas Sommermann, Claudia Salomon, Ralf Kühn, Klaus Rajewsky, Van Trung Chu
Journal: Leukemia (2024)

Abstract Hematopoiesis is a continuous process of blood cell production driven by hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. Proliferation and differentiation of HSPCs are regulated by complex transcriptional networks. In order to identify transcription factors with key roles in HSPC-mediated hematopoietic reconstitution, we developed an efficient and robust CRISPR/Cas9-based in vivo genetic screen. Using this experimental system, we identified the TFDP1 transcription factor to be essential for HSPC proliferation and post-transplant hematopoiesis. We further discovered that E2F4, an E2F transcription factor, serves as a binding partner of TFDP1 and is required for HSPC proliferation. Deletion of TFDP1 caused downregulation of genes associated with the cell cycle, with around 50% of these genes being identified as direct targets of TFDP1 and E2F4. Thus, our study expands the transcriptional network governing hematopoietic development through an in vivo CRISPR/Cas9-based genetic screen and identifies TFDP1/E2F4 as positive regulators of cell cycle genes in HSPCs.
Clinical features associated with poor response and early relapse following BCMA-directed therapies in multiple myeloma
Authors: Matthew J. Rees, Aytaj Mammadzadeh, Abiola Bolarinwa, Mohammed E. Elhaj, Arwa Bohra, Radhika Bansal, Sikander Ailawadhi, Ricardo Parrondo, Saurabh Chhabra, Amit Khot, Suzanne Hayman, Angela Dispenzieri, Francis Buadi, David Dingli, Rahma Warsame, Prashant Kapoor, Morie A. Gertz, Eli Muchtar, Taxiarchis Kourelis, Wilson Gonsalves, S. Vincent Rajkumar, Yi Lin, Shaji Kumar
Journal: Blood Cancer Journal (2024)

Abstract Three classes of BCMA-directed therapy (BDT) exist: antibody drug-conjugates (ADCs), CAR-T, and T-cell engagers (TCEs), each with distinct strengths and weaknesses. To aid clinicians in selecting between BDTs, we reviewed myeloma patients treated at Mayo Clinic with commercial or investigational BDT between 2018-2023. We identified 339 individuals (1-exposure = 297, 2-exposures = 38, 3-exposures = 4) who received 385 BDTs (ADC = 59, TCE = 134, CAR-T = 192), with median follow-up of 21-months. ADC recipients were older, with more lines of therapy (LOT), and penta-refractory disease. Compared to ADCs, CAR-T (aHR = 0.29, 95%CI = 0.20–0.43) and TCEs (aHR = 0.62, 95%CI = 0.43–0.91) had better progression-free survival (PFS) on analysis adjusted for age, the presence of extramedullary (EMD), penta-refractory disease, multi-hit high-risk cytogenetics, prior BDT, and the number of LOT in the preceding 1-year. Likewise, compared to ADCs, CAR-T (aHR = 0.28, 95%CI = 0.18–0.44) and TCEs (aHR = 0.60, 95%CI = 0.39–0.93) had superior overall survival. Prior BDT exposure negatively impacted all classes but was most striking in CAR-T, ORR 86% vs. 50% and median PFS 13-months vs. 3-months. Of relapses, 54% were extramedullary in nature, and a quarter of these cases had no history of EMD. CAR-T demonstrates superior efficacy and where feasible, should be the initial BDT. However, for patients with prior BDT or rapidly progressive disease, an alternative approach may be preferable.
Hypnotics on Obstructive Sleep Apnea Severity and Endotypes: A Systematic Review and Meta-Analysis
Authors: Ludovico Messineo, Scott A Sands, Gonzalo Labarca
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Low arousal threshold and poor muscle responsiveness are common determinants of obstructive sleep apnea (OSA). Hypnotics were hypothesized as an alternative OSA treatment via raising the arousal threshold and possibly genioglossus responsiveness.
Management of Stage III Non–Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update
Authors: Megan E. Daly, Navneet Singh, Nofisat Ismaila, Megan E. Daly, Navneet Singh, Nofisat Ismaila, Mara B. Antonoff, Douglas A. Arenberg, Jeffrey Bradley, Elizabeth David, Frank Detterbeck, Martin Früh, Matthew A. Gubens, Amy C. Moore, Sukhmani K. Padda, Jyoti D. Patel, Tanyanika Phillips, Angel Qin, Clifford Robinson, Charles B. Simone
Journal: Journal of Clinical Oncology (2024)

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Endothelial RUNX3 controls LSEC dysfunction and angiocrine LRG1 signaling to prevent liver fibrosis
Authors: Uttam Ojha, Somi Kim, Chang Yun Rhee, Jihye You, Yoon Ha Choi, Soo-Hyun Yoon, Soo Young Park, Yu Rim Lee, Jong Kyoung Kim, Suk-Chul Bae, You Mie Lee
Journal: Hepatology (2024)

Liver fibrosis represents a global health burden, given the paucity of approved antifibrotic therapies. Liver sinusoidal endothelial cells (LSECs) play a major gatekeeping role in hepatic homeostasis and liver disease pathophysiology. In early tumorigenesis, runt-related transcription factor 3 (RUNX3) functions as a sentinel; however, its function in liver fibrosis in LSECs remains unclear. This study aimed to investigate the role of RUNX3 as an important regulator of the gatekeeping functions of LSECs and explore novel angiocrine regulators of liver fibrosis.