tbuckley/cabot-search huggingface dataset:
Adenosine kinase inhibition protects mice from abdominal aortic aneurysm via epigenetic modulation of VSMC inflammation
Authors: Jiean Xu, Zhiping Liu, Qiuhua Yang, Qian Ma, Yaqi Zhou, Yongfeng Cai, Dingwei Zhao, Guizhen Zhao, Tammy Lu, Kunfu Ouyang, Mei Hong, Ha Won Kim, Huidong Shi, Jifeng Zhang, David Fulton, Clint Miller, Rajeev Malhotra, Neal L Weintraub, Yuqing Huo
Journal: Cardiovascular Research (2024)

Abstract Aims Abdominal aortic aneurysm (AAA) is a common, serious vascular disease with no effective pharmacological treatment. The nucleoside adenosine plays an important role in modulating vascular homeostasis, which prompted us to determine whether adenosine kinase (ADK), an adenosine metabolizing enzyme, modulates AAA formation via control of the intracellular adenosine level, and to investigate the underlying mechanisms. Methods and results We used a combination of genetic and pharmacological approaches in murine models of AAA induced by calcium chloride (CaCl2) application or angiotensin II (Ang II) infusion to study the role of ADK in the development of AAA. In vitro functional assays were performed by knocking down ADK with adenovirus-short hairpin RNA in human vascular smooth muscle cells (VSMCs), and the molecular mechanisms underlying ADK function were investigated using RNA-sequencing, isotope tracing, and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The heterozygous deficiency of ADK protected mice from CaCl2- and Ang II-induced AAA formation. Moreover, specific knockout of ADK in VSMCs prevented Ang II-induced AAA formation, as evidenced by reduced aortic extracellular elastin fragmentation, neovascularization, and aortic inflammation. Mechanistically, ADK knockdown in VSMCs markedly suppressed the expression of inflammatory genes associated with AAA formation, and these effects were independent of adenosine receptors. The metabolic flux and ChIP-qPCR results showed that ADK knockdown in VSMCs decreased S-adenosylmethionine (SAM)-dependent transmethylation, thereby reducing H3K4me3 binding to the promoter regions of the genes that are associated with inflammation, angiogenesis, and extracellular elastin fragmentation. Furthermore, the ADK inhibitor ABT702 protected mice from CaCl2-induced aortic inflammation, extracellular elastin fragmentation, and AAA formation. Conclusion Our findings reveal a novel role for ADK inhibition in attenuating AAA via epigenetic modulation of key inflammatory genes linked to AAA pathogenesis.
Novel IL-4/HB-EGF-dependent crosstalk between eosinophils and macrophages controls liver regeneration after ischaemia and reperfusion injury
Authors: Yang Yang, Long Xu, Constance Atkins, Lily Kuhlman, Jie Zhao, Jong-Min Jeong, Yankai Wen, Nicolas Moreno, Kang Ho Kim, Yu A An, Fenfen Wang, Steve Bynon, Vincenzo Villani, Bin Gao, Frank Brombacher, Raymond Harris, Holger K Eltzschig, Elizabeth Jacobsen, Cynthia Ju
Journal: Gut (2024)

Objective Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair. Design Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf). Result We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury. Conclusion Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis.
Pacemaker Channels and the Chronotropic Response in Health and Disease
Authors: Konstantin Hennis, Chiara Piantoni, Martin Biel, Stefanie Fenske, Christian Wahl-Schott
Journal: Circulation Research (2024)

Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of cardiovascular disease-including ischemic heart disease, heart failure, and arrhythmias. While the clinical significance of regulating changes in heart rate, known as the chronotropic effect, is undeniable, the mechanisms controlling these changes remain not fully understood. Heart rate acceleration and deceleration are mediated by increasing or decreasing the spontaneous firing rate of pacemaker cells in the sinoatrial node. During the transition from rest to activity, sympathetic neurons stimulate these cells by activating β-adrenergic receptors and increasing intracellular cyclic adenosine monophosphate. The same signal transduction pathway is targeted by positive chronotropic drugs such as norepinephrine and dobutamine, which are used in the treatment of cardiogenic shock and severe heart failure. The cyclic adenosine monophosphate-sensitive hyperpolarization-activated current (I
Distribution shift detection for the postmarket surveillance of medical AI algorithms: a retrospective simulation study
Authors: Lisa M. Koch, Christian F. Baumgartner, Philipp Berens
Journal: npj Digital Medicine (2024)

Distribution shifts remain a problem for the safe application of regulated medical AI systems, and may impact their real-world performance if undetected. Postmarket shifts can occur for example if algorithms developed on data from various acquisition settings and a heterogeneous population are predominantly applied in hospitals with lower quality data acquisition or other centre-specific acquisition factors, or where some ethnicities are over-represented. Therefore, distribution shift detection could be important for monitoring AI-based medical products during postmarket surveillance. We implemented and evaluated three deep-learning based shift detection techniques (classifier-based, deep kernel, and multiple univariate kolmogorov-smirnov tests) on simulated shifts in a dataset of 130'486 retinal images. We trained a deep learning classifier for diabetic retinopathy grading. We then simulated population shifts by changing the prevalence of patients' sex, ethnicity, and co-morbidities, and example acquisition shifts by changes in image quality. We observed classification subgroup performance disparities w.r.t. image quality, patient sex, ethnicity and co-morbidity presence. The sensitivity at detecting referable diabetic retinopathy ranged from 0.50 to 0.79 for different ethnicities. This motivates the need for detecting shifts after deployment. Classifier-based tests performed best overall, with perfect detection rates for quality and co-morbidity subgroup shifts at a sample size of 1000. It was the only method to detect shifts in patient sex, but required large sample sizes (
The application of machine learning techniques in posttraumatic stress disorder: a systematic review and meta-analysis
Authors: Jing Wang, Hui Ouyang, Runda Jiao, Suhui Cheng, Haiyan Zhang, Zhilei Shang, Yanpu Jia, Wenjie Yan, Lili Wu, Weizhi Liu
Journal: npj Digital Medicine (2024)

Abstract Posttraumatic stress disorder (PTSD) recently becomes one of the most important mental health concerns. However, no previous study has comprehensively reviewed the application of big data and machine learning (ML) techniques in PTSD. We found 873 studies meet the inclusion criteria and a total of 31 of those in a sample of 210,001 were included in quantitative analysis. ML algorithms were able to discriminate PTSD with an overall accuracy of 0.89. Pooled estimates of classification accuracy from multi-dimensional data (0.96) are higher than single data types (0.86 to 0.90). ML techniques can effectively classify PTSD and models using multi-dimensional data perform better than those using single data types. While selecting optimal combinations of data types and ML algorithms to be clinically applied at the individual level still remains a big challenge, these findings provide insights into the classification, identification, diagnosis and treatment of PTSD.
Helminth Infections and Diabetes: Mechanisms Accounting for Risk Amelioration
Authors: Anuradha Rajamanickam, Subash Babu
Journal: Annual Review of Nutrition (2024)

The global prevalence of type 2 diabetes mellitus (T2D) is increasing rapidly, with an anticipated 600 million cases by 2035. While infectious diseases such as helminth infections have decreased due to improved sanitation and health care, recent research suggests a link between helminth infections and T2D, with helminths such as Schistosoma , Nippostrongylus , Strongyloides , and Heligmosomoides potentially mitigating or slowing down T2D progression in human and animal models. Helminth infections enhance host immunity by promoting interactions between innate and adaptive immune systems. In T2D, type 1 immune responses are suppressed and type 2 responses are augmented, expanding regulatory T cells and innate immune cells, particularly type 2 immune cells and macrophages. This article reviews recent research shedding light on the favorable effects of helminth infections on T2D. The potential defense mechanisms identified include heightened insulin sensitivity and reduced inflammation. The synthesis of findings from studies investigating parasitic helminths and their derivatives underscores promising avenues for defense against T2D.
Role of endothelial Raptor in abnormal arteriogenesis after lower limb ischaemia in type 2 diabetes
Authors: Ting Liu, Jiachen Zhang, Fangyuan Chang, Mengyu Sun, Jinlong He, Ding Ai
Journal: Cardiovascular Research (2024)

Abstract Aims Proper arteriogenesis after tissue ischaemia is necessary to rebuild stable blood circulation; nevertheless, this process is impaired in type 2 diabetes mellitus (T2DM). Raptor is a scaffold protein and a component of mammalian target of rapamycin complex 1 (mTORC1). However, the role of the endothelial Raptor in arteriogenesis under the conditions of T2DM remains unknown. This study investigated the role of endothelial Raptor in ischaemia-induced arteriogenesis during T2DM. Methods and results Although endothelial mTORC1 is hyperactive in T2DM, we observed a marked reduction in the expression of endothelial Raptor in two mouse models and in human vessels. Inducible endothelial-specific Raptor knockout severely exacerbated impaired hindlimb perfusion and arteriogenesis after hindlimb ischaemic injury in 12-week high-fat diet fed mice. Additionally, we found that Raptor deficiency dampened vascular endothelial growth factor receptor 2 (VEGFR2) signalling in endothelial cells (ECs) and inhibited VEGF-induced cell migration and tube formation in a PTP1B-dependent manner. Furthermore, mass spectrometry analysis indicated that Raptor interacts with neuropilin 1 (NRP1), the co-receptor of VEGFR2, and mediates VEGFR2 trafficking by facilitating the interaction between NRP1 and Synectin. Finally, we found that EC-specific overexpression of the Raptor mutant (loss of mTOR binding) reversed impaired hindlimb perfusion and arteriogenesis induced by endothelial Raptor knockout in high-fat diet fed mice. Conclusion Collectively, our study demonstrated the crucial role of endothelial Raptor in promoting ischaemia-induced arteriogenesis in T2DM by mediating VEGFR2 signalling. Thus, endothelial Raptor is a novel therapeutic target for promoting arteriogenesis and ameliorating perfusion in T2DM.
Measuring protective efficacy and quantifying the impact of drug resistance: A novel malaria chemoprevention trial design and methodology
Authors: Andria Mousa, Gina Cuomo-Dannenburg, Hayley A. Thompson, R. Matthew Chico, Khalid B. Beshir, Colin J. Sutherland, David Schellenberg, Roly Gosling, Michael Alifrangis, Emma Filtenborg Hocke, Helle Hansson, Ana Chopo-Pizarro, Wilfred F. Mbacham, Innocent M. Ali, Mike Chaponda, Cally Roper, Lucy C. Okell
Journal: PLoS Medicine (2024)

Recently revised WHO guidelines on malaria chemoprevention have opened the door to more tailored implementation. Countries face choices on whether to replace old drugs, target additional age groups, and adapt delivery schedules according to local drug resistance levels and malaria transmission patterns. Regular routine assessment of protective efficacy of chemoprevention is key. Here, we apply a novel modelling approach to aid the design and analysis of chemoprevention trials and generate measures of protection that can be applied across a range of transmission settings.
Stimuli‐Responsive Hydrogels for Antibacterial Applications
Authors: Zhe Hao, Xiyan Li, Ruizhong Zhang, Libing Zhang
Journal: Advanced Healthcare Materials (2024)

Hydrogels have emerged as promising candidates for biomedical applications, especially in the field of antibacterial therapeutics, due to their unique structural properties, highly tunable physicochemical properties, and excellent biocompatibility. The integration of stimuli-responsive functions into antibacterial hydrogels holds the potential to enhance their antibacterial properties and therapeutic efficacy, dynamically responding to different external or internal stimuli, such as pH, temperature, enzymes, and light. Therefore, this review describes the applications of hydrogel dressings responsive to different stimuli in antibacterial therapy. The collaborative interaction between stimuli-responsive hydrogels and antibacterial materials is discussed. This synergistic approach, in contrast to conventional antibacterial materials, not only amplifies the antibacterial effect but also alleviates adverse side effects and diminishes the incidence of multiple infections and drug resistance. The review provides a comprehensive overview of the current challenges and outlines future research directions for stimuli-responsive antibacterial hydrogels. It underscores the imperative for ongoing interdisciplinary research aimed at unraveling the mechanisms of wound healing. This understanding is crucial for optimizing the design and implementation of stimuli-responsive antibacterial hydrogels. Ultimately, this review aims to offer scientific guidance for the development and practical clinical application of stimuli-responsive antibacterial hydrogel dressings.
Safety and Efficacy of the Combination Lurbinectedin plus Doxorubicin from a Phase 1b Trial in Patients with Advanced/Metastatic Soft-Tissue Sarcoma
Authors: Gregory M. Cote, Candace L. Haddox, Edwin Choy, Priscilla A. Merriam, Emanuele Mazzola, Vinayak Venkataraman, Thierry Alcindor, Andrew J. Wagner, George D. Demetri, Suzanne George
Journal: Clinical Cancer Research (2024)

Purpose: While cytotoxic chemotherapy is the standard first-line treatment for patients with metastatic soft-tissue sarcoma (STS), clinical outcomes remain suboptimal. Our prior study showed lurbinectedin plus doxorubicin is well tolerated with promising clinical activity in STS. We designed this phase 1b trial to optimize dosing as the basis for a randomized trial in leiomyosarcoma and to further explore the safety profile and efficacy signal. Patients and Methods: Patients had advanced/metastatic STS and no prior anthracycline/lurbinectedin/trabectedin. Escalation followed a 3 + 3 design with 3-week cycles: lurbinectedin (3.2 mg/m2 day 1) and two doxorubicin levels (DL1, 25 mg/m2 day 1; DL2, 25 mg/m2 days 1 and 8). The primary objectives were to identify the maximum tolerated dose and recommended dose for subsequent randomized trials. Results: Ten patients were enrolled in a 6-month period. The most common treatment-emergent adverse events were grade (G) 2 fatigue and nausea, and G2 cytopenias with no febrile neutropenia events. There were two dose-limiting toxicities (DLTs) at DL2 [day 8 (G2 alanine aminotransferase [ALT]/aspartate aminotransferase increase, G3 neutropenia)], and one DLT in DL1 (G3 ALT increase). These were reversible and all patients continued the study. DL1 was chosen for further study. At the time of data cutoff, the estimated median progression-free survival is 16.5 months [95% confidence interval (CI), 6.0–ND]. The objective response rate was 60% (6/10 confirmed partial responses). Conclusions: In this phase 1b study, the recommended dose is lurbinectedin 3.2 mg/m2 in combination with doxorubicin 25 mg/m2 every 3 weeks. The study combination was well tolerated and demonstrated intriguing clinical activity.
Dosimetric Considerations for 177Lu-DOTATATE Therapy in a Patient With Chronic Renal Failure Under Hemodialysis
Authors: Sarah Chaib, Perrine Tylski, Choaib Lachachi, Tassadit Keniza, Elise Levigoureux
Journal: Clinical Nuclear Medicine (2024)

This case report explores the use of 177 Lu-DOTATATE in a hemodialysis patient. For the first time, this study assesses the average dose received by the bone marrow, the primary organ at risk, using an original double estimation method through independently acquired imaging and biological samples counting data. Despite elevated doses, the absorbed doses to the bone marrow (0.662-0.740 Gy) were within safe limits. Radiation protection measurements for staff were also compliant. This work supports that effective early dialysis and systematic personalized dosimetry are crucial for hemodialysis patients undergoing 177 Lu-PRRT due to their variability (residual excretion, treatment history, etc).
Tailored Phototherapy Agent by Infection Site In Situ Activated Against Methicillin‐Resistant <i>S. aureus</i>
Authors: Lixia Guo, Yafei Tian, Liang Zhou, Shiyue Kang, Chengwu Zhang, Wen Liu, Haipeng Diao, Liheng Feng
Journal: Advanced Healthcare Materials (2024)

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a promising treatment approach for multidrug resistant infections. PDT/PTT combination therapy can more efficiently eliminate pathogens without drug resistance. The key to improve the efficacy of photochemotherapy is the utilization efficiency of non-radiation energy of phototherapy agents. Herein, a facile phototherapy molecule (SCy-Le) with the enhancement of non-radiative energy transfer is designed by an acid stimulation under a single laser. Introduction of the protonated receptor into SCy-Le results in a distorted intramolecular charge in the infected acidic microenvironment, pH ≈ 5.5, which in turn, enhances light capture, reduces the singlet-triplet transition energies (ΔE
The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma
Authors: Anthony M. Cirrincione, Alexandra M. Poos, Bachisio Ziccheddu, Marcella Kaddoura, Marc-Andrea Bärtsch, Kylee Maclachlan, Monika Chojnacka, Benjamin Diamond, Lukas John, Philipp Reichert, Stefanie Huhn, Patrick Blaney, Dylan Gagler, Karsten Rippe, Yanming Zhang, Ahmet Dogan, Alexander M. Lesokhin, Faith Davies, Hartmut Goldschmidt, Roland Fenk, Katja C. Weisel, Elias K. Mai, Neha Korde, Gareth J. Morgan, Saad Usmani, Ola Landgren, Marc S. Raab, Niels Weinhold, Francesco Maura
Journal: Blood (2024)
Antigen escape as a shared mechanism of resistance to BCMA-directed therapies in multiple myeloma
Authors: Ross S. Firestone, Nicholas D. Socci, Tala Shekarkhand, Menglei Zhu, Wei Ge Qin, Malin Hultcrantz, Sham Mailankody, Carlyn Rose Tan, Neha Korde, Alexander M. Lesokhin, Hani Hassoun, Urvi Shah, Kylee H. Maclachlan, Sridevi Rajeeve, Heather J. Landau, Michael Scordo, Gunjan L. Shah, Oscar B. Lahoud, Sergio Giralt, Kazunori Murata, Saad Z. Usmani, David J. Chung
Journal: Blood (2024)

Abstract B-cell maturation antigen (BCMA)–targeting therapeutics have dramatically improved outcomes in relapsed/refractory multiple myeloma (RRMM). However, whether the mechanisms of resistance between these therapies are shared and how the identification of such mechanisms before therapy initiation could refine clinical decision-making remains undefined. We analyzed outcomes for 72 RRMM patients treated with teclistamab, a CD3 × BCMA bispecific antibody, 42% (30/72) of whom had prior BCMA-directed therapy exposure. Malignant plasma cell BCMA expression was present in all BCMA therapy–naïve patients. Prior therapy–mediated loss of plasma cell BCMA expression before teclistamab treatment, measured by immunohistochemistry, was observed in 3 patients, none of whom responded to teclistamab, and 1 of whom also did not respond to ciltacabtagene autoleucel. Whole exome sequencing of tumor DNA from 1 patient revealed biallelic loss of TNFRSF17 following treatment with belantamab mafodotin. Low-to-undetectable peripheral blood soluble BCMA levels correlated with the absence of BCMA expression by bone marrow plasma cells. Thus, although rare, loss of BCMA expression following TNFRSF17 gene deletions can occur following any BCMA-directed therapy and prevents response to subsequent anti-BCMA–directed treatments, underscoring the importance of verifying the presence of a target antigen.
Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity
Authors: Chuan Qin, Min Zhang, Da-Peng Mou, Luo-Qi Zhou, Ming-Hao Dong, Liang Huang, Wen Wang, Song-Bai Cai, Yun-Fan You, Ke Shang, Jun Xiao, Di Wang, Chun-Rui Li, Yi Hao, Michael Heming, Long-Jun Wu, Gerd Meyer Zu Hörste, Chen Dong, Bi-Tao Bu, Dai-Shi Tian, Wei Wang
Journal: Science Immunology (2024)

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti-B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8