tbuckley/cabot-search huggingface dataset:
mRNA-LNPs induce immune activation and cytokine release in human whole blood assays across diverse health conditions.
Authors: Hong-My Nguyen, Kristin E Alexander, Mark Collinge, James C Hickey, Thomas A Lanz, Jin Li, Mark J Sheehan, Leah C Newman, Mitchell Thorn
Journal: Molecular Therapy (2024)

RNA medicines have become a promising platform for therapeutic use in recent years. Understanding the immunomodulatory effects of novel mRNA-LNPs is crucial for future therapeutic development. An in vitro whole blood assay was developed to assess the impact of mRNA-LNPs on immune cell function, cytokine release, and complement activation. mRNA-LNPs significantly increased CD69 expression on T cells and natural killer (NK) cells, and CD80/CD86 on myeloid subsets, in a dose-dependent fashion. Furthermore, mRNA-LNPs elicited a robust release of pro-inflammatory cytokines, including TNF-α, IL-1β, MCP-1, IL-6, and IP-10, indicating a potent immune response. Notably, mRNA-LNPs stimulate early cytokine production prior to triggering immune cell activation, suggesting a temporal and biological relationship. Moreover, mRNA-LNPs induce complement activation via the alternative pathway, as evidenced by increased serum sC5b-9, C3a, and Bb which can amplify the inflammatory response and potentially impact safety. In vitro effects of mRNA-LNPs in whole blood of healthy human donors were compared to those from disease cohorts including systemic lupus erythematosus (SLE), type 2 diabetes mellitus (T2DM), and cancer donors. The differences in mRNA-LNPs effects on samples from healthy and diseased populations may impact therapeutic efficacy or toxicity, indicating a need for tailoring LNPs for specific target populations.
Endoscopic treatment of an unusual post-sleeve gastrectomy complication: first use in clinical practice
Authors: Ting Wei, Dan Liu, Qingfen Zheng, Muhan Li, Jinglong Lv, Bingrong Liu
Journal: Endoscopy (2024)

Laparoscopic sleeve gastrectomy (LSG), a common form of bariatric surgery, can lead to complications, such as staple-line leaks and gastric stenosis [1] [2] [3]. Herein, we report a rare post-LSG complication and its successful endoscopic treatment ([Video 1]). A 24-year-old man was admitted with poor glycemic control for 2 months. His medical history included metabolic syndrome, and his body mass index was 33.9 kg/m2. He had undergone LSG with placement of a gastric decompression tube. On his first postoperative day, 800 mL of cloudy yellow fluid was drained, and the patient experienced abdominal pain. Several pulls on the gastric decompression tube in an attempt to remove it failed.
A cationic main-chain poly(carbonate-imidazolium) potent against Mycobacterium abscessus and other resistant bacteria in mice
Authors: Zhangyong Si, Yan Sun, Chongyun Tan, Ying Jie Ooi, Ming Li, Cheerlavancha Raju, Jamal Shubi, Yunn-Hwen Gan, Yabin Zhu, Peng Li, Mary B Chan-Park, Kevin Pethe
Journal: Biomaterials (2024)
Theoretical Framework and Emerging Challenges of Lipid Metabolism in Cancer
Authors: Qiuying Gu, Yuan Wang, Ping Yi, Chunming Cheng
Journal: Seminars in Cancer Biology (2024)

Elevated lipid metabolism is one of hallmarks of malignant tumors. Lipids not only serve as essential structural components of biological membranes but also provide energy and substrates for the proliferation of cancer cells and tumor growth. Cancer cells meet their lipid needs by coordinating the processes of lipid absorption, synthesis, transport, storage, and catabolism. As research in this area continues to deepen, numerous new discoveries have emerged, making it crucial for scientists to stay informed about the developments of cancer lipid metabolism. In this review, we first discuss relevant concepts and theories or assumptions that help us understand the lipid metabolism and -based cancer therapies. We then systematically summarize the latest advancements in lipid metabolism including new mechanisms, novel targets, and up-to-date pre-clinical and clinical investigations of anti-cancer treatment with lipid metabolism targeted drugs. Finally, we emphasize emerging research directions and therapeutic strategies, and discuss future prospective and emerging challenges. This review aims to provide the latest insights and guidance for research in the field of cancer lipid metabolism.
IL-1ra and CCL5, but not IL-10, are promising targets for treating SMA astrocyte-driven pathology
Authors: Reilly L Allison, Cecelia C Mangione, Mya Suneja, Jessica Gawrys, Brendan M Melvin, Natalya Belous, Megan LaCroix, Matthew Harmelink, Barrington G Burnett, Allison D Ebert
Journal: Molecular Therapy (2024)

Spinal muscular atrophy (SMA) is a pediatric genetic disorder characterized by the loss of spinal cord motor neurons. Although the mechanisms underlying motor neuron loss are not clear, current data suggest that glial cells contribute to disease pathology. We have previously found that SMA astrocytes drive microglial activation and motor neuron loss potentially through the upregulation of NFkB-mediated pro-inflammatory cytokines. In this study, we tested the ability of neutralizing C-C motif chemokine ligand 5 (CCL5) while increasing either interleukin 10 (IL-10) or IL-1 receptor antagonist (IL-1ra) to reduce the pro-inflammatory phenotype of SMA astrocytes. While IL-10 was ineffective, IL-1ra ameliorated SMA astrocyte-driven glial activation and motor neuron loss in iPSC-derived cultures in vitro. In vivo AAV5 delivered IL-1ra overexpression and miR-30 shRNA knockdown of CCL5 had modest but significant improvements on lifespan, weight gain, motor neuron number, and motor function of SMNΔ7 mice. Together these data identify IL-1ra and CCL5 as possible therapeutic targets for SMA and highlight the importance of glial-targeted therapeutics for neurodegenerative disease.
Targeting human plasma cells using small molecule regulated BCMA CAR T cells eliminates circulating antibodies in humanized mice
Authors: Yuchi Honaker, David Gruber, Chester Jacobs, Rene Yu-Hong Cheng, Shivani Patel, Christopher Zavala Galvan, Iram F Khan, Kevin Zhou, Karen Sommer, Alexander Astrakhan, Peter J Cook, Richard G James, David J Rawlings
Journal: Molecular Therapy (2024)
In vivo evolution of env in SHIV-AD8EO-infected rhesus macaques after AAV-vectored delivery of eCD4-Ig
Authors: Daniel O'Hagan, Siddhartha Shandilya, Lincoln J Hopkins, Patricia A Hahn, Sebastian P Fuchs, Jose M Martinez-Navio, Michael D Alpert, Mathew R Gardner, Ronald C Desrosiers, Guangping Gao, Jeffrey D Lifson, Michael Farzan, Amir Ardeshir, Mauricio A Martins
Journal: Molecular Therapy (2024)

eCD4-Ig is an entry inhibitor of the human immunodeficiency virus (HIV) that mimics the engagement of both CD4 and CCR5 with the HIV Envelope (Env) protein, a property which imbues it with remarkable potency and breadth. However, env is exceptionally genetically malleable and can evolve to escape a wide variety of entry inhibitors. Here we document the evolution of partial eCD4-Ig resistance in simian-HIV (SHIV)-AD8
Ultraslim catheter-type peroral cholangioscope-assisted endoscopic transpapillary gallbladder drainage for acute cholecystitis
Authors: Noriyuki Hirakawa, Atsushi Sofuni, Takayoshi Tsuchiya, Ryosuke Tonozuka, Shuntaro Mukai, Takao Itoi
Journal: Endoscopy (2024)

Endoscopic transpapillary gallbladder drainage (ETGBD) is clinically effective for acute cholecystitis but is technically challenging [1] [2]. In addition, the shape and bifurcation of the cystic duct represent a technical limitation and difficulty of this method [2] [3] [4]. Recently, an ultraslim catheter-type peroral cholangioscope (UC-POCS, DRES Slim Scope; Japan Lifeline Co., Ltd, Tokyo, Japan) has been developed and used clinically [5]. The UC-POCS consists of a catheter-type sheath (outer diameter 2.3 mm) with two independent lumens and a high-resolution digital camera. The device can be used as a catheter for common bile duct (CBD) cannulation ([Fig. 1]). Herein, we report a case in which UC-POCS-assisted ETGBD was performed for acute cholecystitis.
Reintervention using a through-the-mesh technique within the abdominal cavity following stent migration after endoscopic ultrasound-guided hepaticogastrostomy
Authors: Takeshi Ogura, Yuki Uba, Takafumi Kanadani, Kimi Bessho, Hiroki Nishikawa
Journal: Endoscopy (2024)

Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) is now widely performed in patients for whom endoscopic retrograde cholangiopancreatography is contraindicated, such as patients with duodenal obstruction or surgically altered anatomy [1] [2] [3]. Although EUS-HGS has a clinical effect in selected patients, the rate of adverse events is not very low. In addition, critical adverse events such as stent migration into the abdominal cavity have been reported, although various efforts to prevent stent migration have also been proposed [4] [5]. If stent migration occurs, surgical treatment is normally considered. However, EUS-HGS itself is usually performed for patients with advanced malignant tumors; therefore, surgical treatment might not be appropriate. Here we describe technical tips for successful reintervention using a through-the-mesh technique via the abdominal cavity following stent migration after EUS-HGS.
Contextual factors influencing bubble continuous positive airway pressure implementation for paediatric respiratory distress in low-income and middle-income countries: a realist review
Authors: Nadir Ijaz, Marie Nader, Matthew Ponticiello, Ashlee J Vance, Brittney J van de Water, Melissa C Funaro, Qalab Abbas, John Adabie Appiah, Mohammod Jobayer Chisti, Walter Commerell, Suiyven Elvis Dzelamunyuy, Rudimar Martinez Fernandez, Anjelica L Gonzalez, Cintia Johnston, Evance Luckson Kaiwe, Manjinder Kaur, Hans-Joerg Lang, Eric D McCollum, José Marcos González Moraga, Jayashree Muralidharan, Kelsey Renning, Herng Lee Tan, Laura Alejandra Vélez Ruiz Gaitán, Sebastián González-Dambrauskas, Patrick T Wilson, Brenda M Morrow, J Lucian Davis
Journal: The Lancet Global Health (2024)

SummaryBackgroundBubble continuous positive airway pressure (bCPAP) is a low-cost, non-invasive respiratory support therapy for children with respiratory distress, but its effectiveness is dependent on the context. We aimed to understand contextual factors influencing bCPAP implementation for children aged 1–59 months in low-income and middle-income countries (LMICs) and to develop a theory explaining how these factors influence implementation outcomes.MethodsIn this realist review, we generated an initial programme theory comprising candidate context–mechanism–outcome configurations (CMOCs) via review of key references and team discussion. On July 25, 2023, we conducted a search for peer-reviewed and grey literature, without date restrictions, describing bCPAP use for paediatric respiratory distress in LMICs. We included references describing related contexts, mechanisms, or outcomes. We coded statements from the literature supporting each CMOC, iteratively revising and adding CMOCs using inductive and deductive logic. We assembled an international, interdisciplinary panel of 22 bCPAP stakeholders to refine CMOCs using iterative surveys, focus groups, and interviews until we reached thematic saturation. This realist review is registered with PROSPERO (CRD42023403584).FindingsOf 1640 peer-reviewed references and eight grey literature references retrieved, 38 peer-reviewed articles and two grey literature documents were deemed eligible for inclusion after removal of duplicates and screening. After four rounds of expert surveys and three focus groups, we identified 18 CMOCs. CMOCs were synthesised into a final programme theory operating at five levels to influence implementation feasibility, fidelity, and sustainability: (1) the bCPAP device, (2) local partnerships and infrastructure, (3) clinical and technical teams, (4) caregivers and the community, and (5) institutional practices.InterpretationUsing realist methods with a diverse, international stakeholder panel, we generated a theory that could explain how bCPAP therapy works in different contexts. This theory could be leveraged to enhance the rigour of future bCPAP implementation trials.FundingYale National Clinician Scholars Program, US National Center for Advancing Translational Science (TL1TR001864), and National Heart, Lung, and Blood Institute (T32HL155000).
Self-amplifying mRNA vaccines protect elderly BALB/c mice against a lethal respiratory syncytial virus infection
Authors: Lulu Zuo, Qixing Liu, Ke Zhang, Lu Zhao, Siyu Lin, You Dai, Yun Sun, Yingwen Li, Pingping Zhang, Huyan Shen, Dongmei He, Shuang Ma, Xianhua Long, Yanhua Chen, Yusi Luo, Gary Wong
Journal: Molecular Therapy (2024)
Preclinical development of lentiviral vector gene therapy for Diamond-Blackfan anemia syndrome
Authors: Senthil Velan Bhoopalan, Thiyagaraj Mayuranathan, Nana Liu, Kalin Mayberry, Yu Yao, Jingjing Zhang, Jean-Yves Métais, Koon-Kiu Yan, Robert E Throm, Steven R Ellis, Yan Ju, Lei Han, Shruthi Suryaprakash, Lance E Palmer, Sheng Zhou, Jiyang Yu, Yong Cheng, Jonathan S Yen, Stephen Gottschalk, Mitchell J Weiss
Journal: Molecular Therapy (2024)

Diamond-Blackfan anemia syndrome (DBAS) is an inherited bone marrow failure disorder caused by haploinsufficiency of ribosomal protein genes, most commonly RPS19. Limited access to patient hematopoietic stem/progenitor cells (HSPCs) is a major roadblock to developing novel therapies for DBAS. We developed a novel self-inactivating third-generation RPS19-encoding lentiviral vector (LV), termed "SJEFS-S19", for DBAS gene therapy. To facilitate LV design, optimize transduction and assess potential therapeutic efficacy, we leveraged a human cellular model of DBAS based on heterozygous disruption of RPS19 in healthy donor CD34
Internal mammary node irradiation in 4541 node-positive breast cancer patients treated with newer systemic therapies and 3D-based radiotherapy (DBCG IMN2): a prospective, nationwide, population-based cohort study
Authors: Anders W. Mølby Nielsen, Lise B.J. Thorsen, Demet Özcan, Louise W. Matthiessen, Else Maae, Marie L.H. Milo, Mette H. Nielsen, Trine Tramm, Jens Overgaard, Birgitte V. Offersen
Journal: The Lancet Regional Health - Europe (2024)

<h2>Summary</h2><h3>Background</h3> Internal mammary node irradiation (IMNI) improves overall survival (OS) in node-positive breast cancer patients. However, the effect is not documented in breast cancer patients treated with newer systemic therapies and 3D-based radiotherapy (RT). Therefore, the Danish Breast Cancer Group (DBCG) IMN2 study aimed to investigate the effect of IMNI in node-positive breast cancer patients treated with newer systemic therapies and 3D-based RT. <h3>Methods</h3> DBCG IMN2 was a nationwide population-based cohort study prospectively allocating node-positive breast cancer patients with right-sided tumours to IMNI and patients with left-sided tumours to no IMNI in six RT centres. Exclusion criteria were prior malignancies, bilateral breast cancer, neoadjuvant systemic therapy, recurrence before RT, or non-standard RT. Systemic treatment included taxane-based chemotherapy, aromatase inhibitors, and trastuzumab. The primary end-point was OS. Secondary endpoints were breast cancer mortality and distant metastasis. Cox regression analyses were used for adjusted hazard ratios (HR). Clinicaltrial.gov ID: NCT06549920. <h3>Findings</h3> In the period January 2007–May 2014, a total of 4541 patients were included. Patient characteristics were distributed evenly between right- and left-sided patients. Median follow-up was 13.7 years for OS. Survival rates at 15 years were 65.0% in patients with IMNI and 60.8% without leading to an adjusted HR of 0.85 (95% CI, 0.76–0.94; p = 0.0016) for OS. Corresponding HRs were 0.84 (95% CI, 0.74–0.95; p = 0.0077) for breast cancer mortality and HR 0.87 (95% CI, 0.78–0.98; p = 0.026) for distant metastasis. No subgroups were identified for the omission of IMNI. The 15-year cumulative incidence of death from ischemic or valvular heart disease was 0.2% (95% CI, 0.0–0.5) in right-sided and 0.7% (95% CI, 0.4–1.2) in left-sided patients. <h3>Interpretation</h3> IMNI reduced distant metastasis and breast cancer mortality and improved OS in node-positive breast cancer patients, despite treatment with newer systemic therapies and 3D-based RT. <h3>Funding</h3> This work was supported by the Danish Cancer Society and Department of Clinical Medicine, Aarhus University, Denmark.
A Bioprinted and Scalable Model of Human Tubulo-Interstitial Kidney Fibrosis
Authors: Daphne Bouwens, Nazanin Kabgani, Cédric Bergerbit, Hyojin Kim, Susanne Ziegler, Sadaf Ijaz, Ali Abdallah, Tamás Haraszti, Sidrah Maryam, Abdolrahman Omidinia-Anarkoli, Laura De Laporte, Sikander Hayat, Jitske Jansen, Rafael Kramann
Journal: Biomaterials (2024)

Chronic kidney disease (CKD) affects more than 10% of the global population. As kidney function negatively correlates with the presence of interstitial fibrosis, the development of new anti-fibrotic therapies holds promise to stabilize functional decline in CKD patients. The goal of the study was to generate a scalable bioprinted 3-dimensional kidney tubulo-interstitial disease model of kidney fibrosis. We have generated novel human PDGFRβ
Underwater endoscopic submucosal dissection using conical hood and gel immersion for esophageal squamous cell carcinoma with anastomotic stricture after total pharyngolaryngectomy
Authors: Takahiro Muramatsu, Masakatsu Fukuzawa, Midori Mizumachi, Satoshi Shimai, Miki Wada, Manami Kajiwara, Takao Itoi
Journal: Endoscopy (2024)

Pharyngoesophageal defects after total pharyngolaryngectomy (TPL) are commonly reconstructed with free jejunum or anterolateral thigh flap (ALT), often resulting in anastomotic stricture [1]. Endoscopic treatment of superficial esophageal squamous cell carcinoma (ESCC) in the presence of such an anastomotic stricture is challenging and requires ingenuity of devices and scopes [2]. Endoscopic submucosal dissection (ESD) with water or gel immersion helps in difficult-to-treat situations [3] [4], and the utility of a small-caliber tapered conical hood during ESD is established [5]. Herein, we describe underwater ESD with a conical hood and gel immersion, which was performed successfully for superficial ESCC with post-TPL anastomotic stricture ([Video 1]).
Needle tip insertion technique for accurate and safe puncture in endoscopic ultrasound-guided tissue acquisition
Authors: Ryota Sagami, Yasuhisa Hiroshima, Yoshifumi Azuma, Hiroaki Tsuji, Hidefumi Nishikiori, Kazuhiro Mizukami, Kazunari Murakami
Journal: Endoscopy (2024)

Endoscopic ultrasound-guided tissue acquisition (EUS-TA) is the gold standard for diagnosing pancreatic and gastrointestinal submucosal tumors [1]. However, inaccurate puncture can occasionally lead to adverse events or insufficient tissue samples [2] [3] [4]. In standard EUS-TA procedures, puncture is performed to confirm the alignment of the external sheath with the target lesion; however, several technical challenges can arise ([Fig. 1] a). Although the needle direction and distance to the target lesion are typically controlled by focusing on the external sheath, complications such as needle deviation from the expected direction, gastrointestinal membrane mobility, and breathing-induced target movement can lead to unsuccessful or inadequate punctures ([Fig. 1] a, [Fig. 2] a, b). Misalignment of the endoscope or external sheath can also result in needle loss from the EUS view ([Fig. 2] c, d, [Video 1]). Unintended puncture routes may subsequently increase the risk of adverse events, including vascular injury.
Embedding treatment in stronger care systems
Authors: Amanda Rojek, Joshua Fieggen, Amy Paterson, Pauline Byakika-Kibwika, Modet Camara, Kim Comer, Tom E Fletcher, Stephan Günther, Sylvie Jonckheere, Gerald Mwima, Jake Dunning, Peter Horby
Journal: The Lancet Infectious Diseases (2024)
Addressing the challenges of integrating digital health technologies to measure patient-centred outcomes in clinical registries
Authors: Caroline Marra, Tim Chico, April Alexandrow, Will G Dixon, Norman Briffa, Erin Rainaldi, Max A Little, Kristin Size, Athanasios Tsanas, Joseph B Franklin, Ritu Kapur, Helen Grice, Anwar Gariban, Joy Ellery, Cathie Sudlow, Amy P Abernethy, Andrew Morris
Journal: The Lancet Digital Health (2024)

Longitudinal patient registries generate important evidence for advancing clinical care and the regulatory evaluation of health-care products. Most national registries rely on data collected as part of routine clinical encounters, an approach that does not capture real-world, patient-centred outcomes, such as physical activity, fatigue, ability to do daily tasks, and other indicators of quality of life. Digital health technologies that obtain such real-world data could greatly enhance patient registries but unresolved challenges have so far prevented their broad adoption. Based on our experience implementing digital health technologies in registries and observational studies, we propose potential solutions to three practical challenges we have repeatedly encountered: determining what to measure digitally, selecting the appropriate device, and ensuring representativeness and engagement over time. We describe the example of a hypothetical patient registry for valvular heart disease, a condition for which there is substantial variation in treatment selection and postintervention outcomes, and for which patient-centred outcome data are urgently needed to inform clinical care guidelines and health-service commissioning.
Ramifications of magnetic resonance imaging in general practice
Authors: David J Swienton
Journal: BMJ (2024)

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Evaluating the performance of the BOADICEA model in predicting 10-year breast cancer risks in UK Biobank
Authors: Carmen Petitjean, Naomi Wilcox, Lorenzo Ficorella, Joe Dennis, Jonathan Tyrer, Michael Lush, Jacques Simard, Douglas Easton, Antonis C Antoniou, Xin Yang
Journal: JNCI Journal of the National Cancer Institute (2024)

The BOADICEA model predicts breast cancer risk using cancer family history, epidemiological and genetic data. We evaluated its validity in a large prospective cohort.
Evaluation of T Cell Receptor Construction Methods from scRNA-Seq Data
Authors: Ruonan Tian, Zhejian Yu, Ziwei Xue, Jiaxin Wu, Lize Wu, Shuo Cai, Bing Gao, Bing He, Yu Zhao, Jianhua Yao, Linrong Lu, Wanlu Liu
Journal: Genomics Proteomics & Bioinformatics (2024)

T cell receptors (TCRs) serve key roles in the adaptive immune system by enabling recognition and response to pathogens and irregular cells. Various methods have been developed for TCR construction from single-cell RNA sequencing (scRNA-seq) datasets, each with its unique characteristics. Yet, a comprehensive evaluation of their relative performance under different conditions remains elusive. In this study, we conducted a benchmark analysis utilizing experimental single-cell immune profiling datasets. Additionally, we introduced a novel simulator, YASIM-scTCR (Yet Another SIMulator for single-cell TCR), capable of generating scTCR-seq reads containing diverse TCR-derived sequences with different sequencing depths and read lengths. Our results consistently showed that TRUST4 and MiXCR outperformed others across multiple datasets, while DeRR also demonstrated considerable accuracy. We also discovered that the sequencing depth inherently imposes a critical constraint on successful TCR construction from scRNA-seq data. In summary, we present a benchmark study to aid researchers in choosing the appropriate method for reconstructing TCR from scRNA-seq data.