tbuckley/cabot-search huggingface dataset:
Engineering LNPs with polysarcosine lipids for mRNA delivery
Authors: Diana D. Kang, Xucheng Hou, Leiming Wang, Yonger Xue, Haoyuan Li, Yichen Zhong, Siyu Wang, Binbin Deng, David W. McComb, Yizhou Dong
Journal: Bioactive Materials (2024)

Since the approval of the lipid nanoparticles (LNP)-mRNA vaccines against the SARS-CoV-2 virus, there has been an increased interest in the delivery of mRNA through LNPs. However, current LNP formulations contain PEG lipids, which can stimulate the generation of anti-PEG antibodies. The presence of these antibodies can potentially cause adverse reactions and reduce therapeutic efficacy after administration. Given the widespread deployment of the COVID-19 vaccines, the increased exposure to PEG may necessitate the evaluation of alternative LNP formulations without PEG components. In this study, we investigated a series of polysarcosine (pSar) lipids as alternatives to the PEG lipids to determine whether pSar lipids could still provide the functionality of the PEG lipids in the ALC-0315 and SM-102 LNP systems. We found that complete replacement of the PEG lipid with a pSar lipid can increase or maintain mRNA delivery efficiency and exhibit similar safety profiles in vivo.
Aiming at early-stage vulnerable plaques: A nanoplatform with dual-mode imaging and lipid-inflammation integrated regulation for atherosclerotic theranostics
Authors: Yao Wang, Zhebin Chen, Qiongjun Zhu, Zhezhe Chen, Guosheng Fu, Boxuan Ma, Wenbin Zhang
Journal: Bioactive Materials (2024)

The vulnerable plaques in atherosclerosis can cause severe outcome with great danger of acute cardiovascular events. Thus, timely diagnosis and treatment of vulnerable plaques in early stage can effectively benefit the clinical management of atherosclerosis. In this work, a targeting theranostic strategy on early-stage vulnerable plaques in atherosclerosis is realized by a LAID nanoplatform with X-CT and fluorescent dual-mode imaging and lipid-inflammation integrated regulation abilities. The iodinated contrast agents (ICA), phenylboronic acid modified astaxanthin and oxidized-dextran (oxDEX) jointly construct the nanoparticles loaded with the lipid-specific probe LFP. LAID indicates an active targeting to plaques along with the dual-responsive disassembly in oxidative stress and acidic microenvironment of atherosclerosis. The X-CT signals of ICA execute the location of early-stage plaques, while the LFP combines with lipid cores and realizes the recognition of vulnerable plaques. Meanwhile, the treatment based on astaxanthin is performed for restraining the progression of plaques. Transcriptome sequencing suggests that LAID can inhibit the lipid uptake and block NF-κB pathway, which synergistically demonstrates a lipid-inflammation integrated regulation to suppression the plaques growing. The
Incidence and risk factors for cancer in people with type 1 diabetes, stratified by stages of diabetic kidney disease: a nationwide Finnish cohort study
Authors: Maija Feodoroff, Valma Harjutsalo, Sari Mäkimattila, Per-Henrik Groop
Journal: The Lancet Regional Health - Europe (2024)

BackgroundIndividuals with type 1 diabetes (T1D) have been reported to have increased overall risk of cancer. In addition, individuals with a kidney transplant/transplantation (KT) have markedly increased cancer risk due to chronic use of immunosuppressive agents. However, it has not been elucidated whether the observed excess cancer risk is related to KT or whether diabetic kidney disease (DKD) per se is a risk factor for cancer in individuals with T1D.MethodsThe study included 5035 individuals from the Finnish Diabetic Nephropathy Study (FinnDiane) and 14,061 control individuals without diabetes. We assessed the standardized incidence ratios (SIRs) for cancers in individuals with T1D compared to controls according to DKD status. Cox regression analyses were used to identify potential risk factors for cancer in individuals with type 1 diabetes.FindingsThe SIR for overall cancer for all participants was 1.14 (1.05–1.24), for participants without KT 0.92 (0.83–1.01) and for participants with KT 4.78 (4.02–5.64). Participants without KT had in fact a reduced risk of prostate cancer with a SIR of 0.54 (0.37–0.76), cancer of urinary organs 0.41 (0.21–0.73) and respiratory and intrathoracic organs, 0.62 (0.38–0.97). Participants with KT had on the contrary an increased risk of non-melanoma skin cancer, SIR 14.50 (10.99–18.86), cancer in the lymphoid and hematopoietic tissue 5.38 (2.99–8.96), mouth or pharynx 5.13 (2.08–10.66), melanoma 5.12 [2.38–9.72]) and respiratory and intrathoracic organs 2.77 (1.21–5.49). The risk of thyroid cancer was increased both in participants without KT, SIR 2.14 (1.39–3.16) and with KT 5.30 (1.68–12.78).InterpretationThe excess overall cancer risk in individuals with type 1 diabetes is only seen in KT recipients and in thyroid cancer. The individuals without KT seem to have a decreased risk of some forms of cancer.FundingFolkhälsan Research Foundation, Academy of Finland [316664], Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Novo Nordisk Foundation [NNF OC0013659], Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, Medical Society of Finland, Sigrid Jusélius Foundation, and Helsinki University Hospital Research Funds [TYH2018207 and TYH 2020305].
Effects of MgO nanoparticle addition on the mechanical properties, degradation properties, antibacterial properties and in vitro and in vivo biological properties of 3D-printed Zn scaffolds
Authors: Leiting Yu, Fengdong Sun, Yuanyuan Wang, Wei Li, Yufeng Zheng, Guangxin Shen, Yao Wang, Minfang Chen
Journal: Bioactive Materials (2024)

Bone tissue engineering is the main method for repairing large segment bone defects. In this study, a layer of bioactive MgO nanoparticles was wrapped on the surface of spherical Zn powders, which allowed the MgO nanoparticles to be incorporated into 3D-printed Zn matrix and improved the biodegradation and biocompatibility of the Zn matrix. The results showed that porous pure Zn scaffolds and Zn/MgO scaffolds with skeletal-gyroid (G) model structure were successfully prepared by selective laser melting (SLM). The average porosity of two porous scaffolds was 59.3 and 60.0%, respectively. The pores were uniformly distributed with an average pore size of 558.6–569.3 μm. MgO nanoparticles regulated the corrosion rate of scaffolds, resulting in a more uniform corrosion degradation behavior of the Zn/MgO scaffolds in simulated body fluid solution. The degradation ratio of Zn/MgO composite scaffolds in vivo was increased compared to pure Zn scaffolds, reaching 15.6% at 12 weeks. The yield strength (10.8 ± 2.4 MPa) of the Zn/MgO composite scaffold was comparable to that of cancellous bone, and the antimicrobial rate were higher than 99%. The Zn/MgO composite scaffolds could better guide bone tissue regeneration in rat cranial bone repair experiments (completely filling the scaffolds at 12 weeks). Therefore, porous Zn/MgO scaffolds with G-model structure prepared with SLM are a promising biodegradable bone tissue engineering scaffold.
An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease
Authors: Adetola A. Kassim, Josu de la Fuente, Erfan Nur, Karina L. Wilkerson, Ali D. Alahmari, Adriana Seber, Carmem Bonfim, Belinda Pinto Simões, Mohsen Alzahrani, Michael J. Eckrich, Biljana Horn, Rabi Hanna, Nathalie Dhedin, Hemalatha G. Rangarajan, Roseane Vasconcelos Gouveia, Fahad Almohareb, Mahmoud Aljurf, Mohammed Essa, Bader Alahmari, Katie Gatwood, James A. Connelly, Elisabeth Dovern, Mark Rodeghier, Michael R. DeBaun
Journal: Blood (2024)
Management of adult patients with CMML undergoing allo-HCT: recommendations from the EBMT PH&amp;G Committee
Authors: Francesco Onida, Nico Gagelmann, Yves Chalandon, Guido Kobbe, Marie Robin, Argiris Symeonidis, Theo de Witte, Raphael Itzykson, Madlen Jentzsch, Uwe Platzbecker, Valeria Santini, Guillermo Sanz, Christof Scheid, Eric Solary, Peter Valent, Raffaela Greco, Isabel Sanchez-Ortega, Ibrahim Yakoub-Agha, Lisa Pleyer
Journal: Blood (2024)

Abstract Chronic myelomonocytic leukemia (CMML) is a heterogeneous disease presenting with either myeloproliferative or myelodysplastic features. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative option, but the inherent toxicity of this procedure makes the decision to proceed to allo-HCT challenging, particularly because patients with CMML are mostly older and comorbid. Therefore, the decision between a nonintensive treatment approach and allo-HCT represents a delicate balance, especially because prospective randomized studies are lacking and retrospective data in the literature are conflicting. International consensus on the selection of patients and the ideal timing of allo-HCT, specifically in CMML, could not be reached in international recommendations published 6 years ago. Since then, new, CMML-specific data have been published. The European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&amp;G) Committee assembled a panel of experts in the field to provide the first best practice recommendations on the role of allo-HCT specifically in CMML. Recommendations were based on the results of an international survey, a comprehensive review of the literature, and expert opinions on the subject, after structured discussion and circulation of recommendations. Algorithms for patient selection, timing of allo-HCT during the course of the disease, pretransplant strategies, allo-HCT modality, as well as posttransplant management for patients with CMML were outlined. The keynote message is, that once a patient has been identified as a transplant candidate, upfront transplantation without prior disease-modifying treatment is preferred to maximize chances of reaching allo-HCT whenever possible, irrespective of bone marrow blast counts.
Integration of <i>ζ</i>-deficient CARs into the <i>CD3</i> <i>ζ</i> gene conveys potent cytotoxicity in T and NK cells
Authors: Jonas Kath, Clemens Franke, Vanessa Drosdek, Weijie Du, Viktor Glaser, Carla Fuster-Garcia, Maik Stein, Tatiana Zittel, Sarah Schulenberg, Caroline E. Porter, Lena Andersch, Annette Künkele, Joshua Alcaniz, Jens Hoffmann, Hinrich Abken, Mohamed Abou-el-Enein, Axel Pruß, Masataka Suzuki, Toni Cathomen, Renata Stripecke, Hans-Dieter Volk, Petra Reinke, Michael Schmueck-Henneresse, Dimitrios L. Wagner
Journal: Blood (2024)

Abstract Chimeric antigen receptor (CAR)-redirected immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in nonphysiological regulation of CAR-signaling and limits their accessibility due to logistical challenges, high costs and biosafety requirements. Random gene transfer modalities pose a risk of malignant transformation by insertional mutagenesis. Here, we propose a novel approach utilizing CRISPR-Cas gene editing to redirect T cells and natural killer (NK) cells with CARs. By transferring shorter, truncated CAR-transgenes lacking a main activation domain into the human CD3ζ (CD247) gene, functional CAR fusion-genes are generated that exploit the endogenous CD3ζ gene as the CAR’s activation domain. Repurposing this T/NK-cell lineage gene facilitated physiological regulation of CAR expression and redirection of various immune cell types, including conventional T cells, TCRγ/δ T cells, regulatory T cells, and NK cells. In T cells, CD3ζ in-frame fusion eliminated TCR surface expression, reducing the risk of graft-versus-host disease in allogeneic off-the-shelf settings. CD3ζ-CD19-CAR-T cells exhibited comparable leukemia control to TCRα chain constant (TRAC)-replaced and lentivirus-transduced CAR-T cells in vivo. Tuning of CD3ζ-CAR-expression levels significantly improved the in vivo efficacy. Notably, CD3ζ gene editing enabled redirection of NK cells without impairing their canonical functions. Thus, CD3ζ gene editing is a promising platform for the development of allogeneic off-the-shelf cell therapies using redirected killer lymphocytes.
Loss of <i>Dnmt3a</i> increases self-renewal and resistance to pegIFN-α in <i>JAK2</i>-V617F–positive myeloproliferative neoplasms
Authors: Marc Usart, Jan Stetka, Damien Luque Paz, Nils Hansen, Quentin Kimmerlin, Tiago Almeida Fonseca, Melissa Lock, Lucia Kubovcakova, Riikka Karjalainen, Hui Hao-Shen, Anastasiya Börsch, Athimed El Taher, Jessica Schulz, Jean-Christophe Leroux, Stefan Dirnhofer, Radek C. Skoda
Journal: Blood (2024)

Abstract Pegylated interferon alfa (pegIFN-α) can induce molecular remissions in patients with JAK2-V617F–positive myeloproliferative neoplasms (MPNs) by targeting long-term hematopoietic stem cells (LT-HSCs). Additional somatic mutations in genes regulating LT-HSC self-renewal, such as DNMT3A, have been reported to have poorer responses to pegIFN-α. We investigated whether DNMT3A loss leads to alterations in JAK2-V617F LT-HSC functions conferring resistance to pegIFN-α treatment in a mouse model of MPN and in hematopoietic progenitors from patients with MPN. Long-term treatment with pegIFN-α normalized blood parameters and reduced splenomegaly and JAK2-V617F chimerism in single-mutant JAK2-V617F (VF) mice. However, pegIFN-α in VF;Dnmt3aΔ/Δ (VF;DmΔ/Δ) mice worsened splenomegaly and failed to reduce JAK2-V617F chimerism. Furthermore, LT-HSCs from VF;DmΔ/Δ mice compared with VF were less prone to accumulate DNA damage and exit dormancy upon pegIFN-α treatment. RNA sequencing showed that IFN-α induced stronger upregulation of inflammatory pathways in LT-HSCs from VF;DmΔ/Δ than from VF mice, indicating that the resistance of VF;DmΔ/Δ LT-HSC was not due to failure in IFN-α signaling. Transplantations of bone marrow from pegIFN-α–treated VF;DmΔ/Δ mice gave rise to more aggressive disease in secondary and tertiary recipients. Liquid cultures of hematopoietic progenitors from patients with MPN with JAK2-V617F and DNMT3A mutation showed increased percentages of JAK2-V617F–positive colonies upon IFN-α exposure, whereas in patients with JAK2-V617F alone, the percentages of JAK2-V617F–positive colonies decreased or remained unchanged. PegIFN-α combined with 5-azacytidine only partially overcame resistance in VF;DmΔ/Δ mice. However, this combination strongly decreased the JAK2-mutant allele burden in mice carrying VF mutation only, showing potential to inflict substantial damage preferentially to the JAK2-mutant clone.
Worldwide cohort studies to support healthy ageing research: data availabilities and gaps
Authors: Saman Khalatbari-Soltani, Yafei Si, Marielle Dominguez, Tabitha Scott, Fiona M. Blyth
Journal: Ageing Research Reviews (2024)

Population ageing is a transforming demographic force. To support evidence-based efforts for promoting healthy ageing, a summary of data availabilities and gaps to study ageing is needed. Through a multifaceted search strategy, we identified relevant cohort studies worldwide to studying ageing and provided a summary of available pertinent measurements. Following the World Health Organization's definition of healthy ageing, we extracted information on intrinsic capacity domains and sociodemographic, social, and environmental factors. We identified 287 cohort studies. South America, the Middle East, and Africa had a limited number of cohort studies to study ageing compared to Europe, Oceania, Asia, and North America. Data availabilities of different measures varied substantially by location and study aim. Using the information collected, we developed a web-based Healthy Ageing Toolkit to facilitate healthy ageing research. The comprehensive summary of data availability enables timely evidence to contribute to the United Nations Decades of Healthy Ageing goals of promoting healthy ageing for all. Highlighted gaps guide strategies for increased data collection in regions with limited cohort studies. Comprehensive data, encompassing intrinsic capacity and various sociodemographic, social, and environmental factors, is crucial for advancing our understanding of healthy ageing and its underlying pathways.
Leveraging macrophage metabolism for anticancer therapy: opportunities and pitfalls
Authors: Piyal Saha, Paul Ettel, Thomas Weichhart
Journal: Trends in Pharmacological Sciences (2024)

Tumor-associated macrophages (TAMs) constitute an important part of the tumor microenvironment (TME) that regulates tumor progression. Tumor-derived signals, hypoxia, and competition for nutrients influence TAMs to reprogram their cellular metabolism. This altered metabolic profile creates a symbiotic communication between tumor and other immune cells to support tumor growth. In addition, the metabolic profile of TAMs regulates the expression of immune checkpoint molecules. The dynamic plasticity also allows TAMs to reshape their metabolism in response to modern therapeutic strategies. Therefore, over the years, a significant number of approaches have been implicated to reprogram cancer-promoting metabolism in TAMs. In this review, we discuss the current strategies and pitfalls, along with upcoming promising opportunities in leveraging TAM metabolism for developing better therapeutic approaches against cancer.
Metformin and feeding increase levels of the appetite-suppressing metabolite Lac-Phe in humans
Authors: Barry Scott, Emily A. Day, Katie L. O’Brien, John Scanlan, Grace Cromwell, Aine Ni Scannail, Marie E. McDonnell, David K. Finlay, Lydia Lynch
Journal: Nature Metabolism (2024)

Abstract Metformin, a widely used first-line treatment for type 2 diabetes (T2D), is known to reduce blood glucose levels and suppress appetite. Here we report a significant elevation of the appetite-suppressing metabolite N -lactoyl phenylalanine (Lac-Phe) in the blood of individuals treated with metformin across seven observational and interventional studies. Furthermore, Lac-Phe levels were found to rise in response to acute metformin administration and post-prandially in patients with T2D or in metabolically healthy volunteers.
Progression free survival of myeloma patients who become IFE-negative correlates with the detection of residual monoclonal free light chain (FLC) by mass spectrometry
Authors: H. V. Giles, M. T. Drayson, B. Kishore, C. Pawlyn, M. Kaiser, G. Cook, R. de Tute, R. G. Owen, D. Cairns, T. Menzies, F. E. Davies, G. J. Morgan, G. Pratt, G. H. Jackson
Journal: Blood Cancer Journal (2024)

Abstract Deeper responses are associated with improved survival in patients being treated for myeloma. However, the sensitivity of the current blood-based assays is limited. Historical studies suggested that normalisation of the serum free light chain (FLC) ratio in patients who were negative by immunofixation electrophoresis (IFE) was associated with improved outcomes. However, recently this has been called into question. Mass spectrometry (MS)-based FLC assessments may offer a superior methodology for the detection of monoclonal FLC due to greater sensitivity. To test this hypothesis, all available samples from patients who were IFE negative after treatment with carfilzomib and lenalidomide-based induction and autologous stem cell transplantation (ASCT) in the Myeloma XI trial underwent FLC-MS testing. FLC-MS response assessments from post-induction, day+100 post-ASCT and six months post-maintenance randomisation were compared to serum FLC assay results. Almost 40% of patients had discordant results and 28.7% of patients with a normal FLC ratio had residual monoclonal FLC detectable by FLC-MS. FLC-MS positivity was associated with reduced progression-free survival (PFS) but an abnormal FLC ratio was not. This study demonstrates that FLC-MS provides a superior methodology for the detection of residual monoclonal FLC with FLC-MS positivity identifying IFE-negative patients who are at higher risk of early progression.
Biomimetic versus arbitrary motor control strategies for bionic hand skill learning
Authors: Hunter R. Schone, Malcolm Udeozor, Mae Moninghoff, Beth Rispoli, James Vandersea, Blair Lock, Levi Hargrove, Tamar R. Makin, Chris I. Baker
Journal: Nature Human Behaviour (2024)

Abstract A long-standing engineering ambition has been to design anthropomorphic bionic limbs: devices that look like and are controlled in the same way as the biological body (biomimetic). The untested assumption is that biomimetic motor control enhances device embodiment, learning, generalization and automaticity. To test this, we compared biomimetic and non-biomimetic control strategies for non-disabled participants when learning to control a wearable myoelectric bionic hand operated by an eight-channel electromyography pattern-recognition system. We compared motor learning across days and behavioural tasks for two training groups: biomimetic (mimicking the desired bionic hand gesture with biological hand) and arbitrary control (mapping an unrelated biological hand gesture with the desired bionic gesture). For both trained groups, training improved bionic limb control, reduced cognitive reliance and increased embodiment over the bionic hand. Biomimetic users had more intuitive and faster control early in training. Arbitrary users matched biomimetic performance later in training. Furthermore, arbitrary users showed increased generalization to a new control strategy. Collectively, our findings suggest that biomimetic and arbitrary control strategies provide different benefits. The optimal strategy is probably not strictly biomimetic, but rather a flexible strategy within the biomimetic-to-arbitrary spectrum, depending on the user, available training opportunities and user requirements.
Secondary stroke prevention in people with atrial fibrillation: treatments and trials
Authors: David J Seiffge, Virginia Cancelloni, Lorenz Räber, Maurizio Paciaroni, Andreas Metzner, Paulus Kirchhof, Urs Fischer, David J Werring, Ashkan Shoamanesh, Valeria Caso
Journal: The Lancet Neurology (2024)

Atrial fibrillation is one of the most common cardiac arrhythmias and is a major cause of ischaemic stroke. Recent findings indicate the importance of atrial fibrillation burden (device-detected, subclinical, or paroxysmal and persistent or permanent) and whether atrial fibrillation was known before stroke onset or diagnosed after stroke for the risk of recurrence. Secondary prevention in patients with atrial fibrillation and stroke aims to reduce the risk of recurrent ischaemic stroke. Findings from randomised controlled trials assessing the optimal timing to introduce direct oral anticoagulant therapy after a stroke show that early start (ie, within 48 h for minor to moderate strokes and within 4–5 days for large strokes) seems safe and could reduce the risk of early recurrence. Other promising developments regarding early rhythm control, left atrial appendage occlusion, and novel factor XI inhibitor oral anticoagulants suggest that these therapies have the potential to further reduce the risk of stroke. Secondary prevention strategies in patients with atrial fibrillation who have a stroke despite oral anticoagulation therapy is an unmet medical need. Research advances suggest a heterogeneous spectrum of causes, and ongoing trials are investigating new approaches for secondary prevention in this vulnerable patient group. In patients with atrial fibrillation and a history of intracerebral haemorrhage, the latest data from randomised controlled trials on stroke prevention shows that oral anticoagulation reduces the risk of ischaemic stroke but more data are needed to define the safety profile.