tbuckley/cabot-search huggingface dataset:
Aspirin therapy is associated with a lower risk of pregnancy loss in both <scp><i>JAK2‐</i></scp> and <scp><i>CALR‐</i></scp>mutated essential thrombocythemia—A Mayo Clinic study of 200 pregnancies
Authors: Naseema Gangat, Amritpal Singh, Rimal Ilyas, Giuseppe Gaetano Loscocco, Michelle Elliott, Kebede Begna, Animesh Pardanani, Ayalew Tefferi
Journal: American Journal of Hematology (2024)

Abstract Two‐hundred pregnancies involving 100 women with essential thrombocythemia (ET) were accessed from Mayo Clinic databases (1990–2023). Median platelet count displayed a decline during pregnancy, nadiring at 48% of baseline, in the third trimester: 704–369 × 10 9 /L. Live birth rate was 72%. Of 53 (27%) unintentional pregnancy losses, 48 (24%) occurred in the first trimester. Other fetal complications included preterm birth 3%, intrauterine growth retardation 3%, and stillbirth 1%. Maternal complications included major hemorrhage (7%), preeclampsia (6%), thrombosis (1%), and placental abruption (0.5%). Antepartum management included no specific therapy in 52 (26%), aspirin alone in 112 (56%), aspirin combined with cytoreductive drugs or systemic anticoagulants in 23 (12%), and other permutations in the remaining. Postpartum systemic anticoagulation was documented in 29 (15%) pregnancies. Unintentional first‐trimester loss was predicted by prior fetal loss (43% vs. 18%; p &lt; .01), diabetes mellitus (DM; 67% vs. 23%; p = .02), and absence of aspirin therapy (45% vs. 14%; p &lt; .01); the salutary effect of aspirin therapy was independent of the other two risk factors and apparent in both high (presence of ≥1 risk factor; 33% vs. 61%; p = .07) and low (absence of both risk factors; 10% vs. 34%; p &lt; .01) risk scenarios. The benefit of aspirin therapy, in preventing first‐trimester loss, was significant in both JAK2 ‐mutated (18% vs. 50%; p &lt; .01) and CALR ‐mutated (8% vs. 43%; p &lt; .01) cases. Aspirin use was also associated with a lower risk of venous thrombosis (0% vs. 3%; p = .03). By contrast, the use of systemic anticoagulation, antepartum or postpartum, did not influence fetal or maternal complication rates. CALR mutation and DM predicted maternal hemorrhage (13% vs. 4%; p = .05) and preeclampsia (33% vs. 5%; p = .03), respectively. The current study demonstrates the protective role of aspirin in preventing first‐trimester loss in ET, independent of driver mutation status or other risk factors.
The BMJ Commission on the Future of Academic Medicine
Authors: Kamran Abbasi
Journal: BMJ (2024)

deteriorating career pathways, restricted funding, and health service pressures are breaking it further.The complex challenges are global, with regional and national subtleties.Scan the landscape of commercialised life sciences, wasteful research and development, and exploitative scientific publishing-taking in a colossal waste of public money-and you quickly realise that this one system failure sits at the centre of the Venn diagram.Academic medicine is not an irrelevant silo.
Adoption of high-sensitivity cardiac troponin for risk stratification of patients with suspected myocardial infarction: a multicentre cohort study
Authors: Michael McDermott, Dorien M Kimenai, Atul Anand, Zen Huang, Andrew Houston, Sophie Williams, Felicity Evison, Suzy Gallier, Catalina Carenzo, Ben Glampson, Madina Hasan, Alexander Robertson, Thomas Phillips, Cai Davis, Elizabeth Sapey, Erik Mayer, Suzanne Mason, Matthew Stammers, Nicholas L Mills
Journal: The Lancet Regional Health - Europe (2024)

Guidelines recommend high-sensitivity cardiac troponin to risk stratify patients with possible myocardial infarction and identify those eligible for discharge. Our aim was to evaluate adoption of this approach in practice and to determine whether effectiveness and safety varies by age, sex, ethnicity, or socioeconomic deprivation status.
A phase I study to evaluate the safety and tolerability of JCXH-211 (a self-replicating mRNA encoding IL-12) intratumoral injection in patients with malignant solid tumors: Results from the phase Ia dose escalation.
Authors: Ngocdiep T. Le
Journal: Journal of Clinical Oncology (2024)

2539 Background: Although interleukin (IL)-12 demonstrated strong preclinical antitumor activity and potent immune-stimulating potentials clinically, systemic administration of IL-12 protein was associated with poor clinical safety profiles. IL-12 functions locally through paracrine and autocrine mechanisms, thus maximizing local concentration of IL-12 in the tumors is important. JCXH-211 is a self-replicating ribonucleic acid (srRNA) encoding human IL-12 encapsulated in lipid nanoparticles. Intratumoral (IT) administration of JCXH-211 is expected to produce the desired spatiotemporal distribution of IL-12 in the cancer lesions. srRNA features enhanced translatability in immunosuppressed tumor microenvironment (TME) than in normal tissues further limiting off-target toxicity. Additionally, the self-replicating nature of JCXH-211 engages multiple immune effector mechanisms and helps inflame TME. We present interim results of the dose escalation part of JCXH-211 IT injection as monotherapy in patients (pts) with malignant solid tumors. Enrollment for the 100 μg cohort is ongoing and updated data will be presented at the meeting. Methods: Pts with advanced solid tumors suitable for IT injection are enrolled. JCXH-211 at 5, 25, 50, and 100 μg are given every 4 weeks (Q4W). Dose Limiting Toxicities (DLT) are monitored for 28 days after 1 st dose. Dose escalation follows “3+3” principle. Tumor assessment is performed Q6W using RECIST v1.1. Results: Ten pts with advanced cancers have been enrolled in 5 μg, 25 μg, and 50 μg cohorts: 3 melanoma (MEL), 3 breast cancer (BC), 2 head and neck cancer (HNSC), 1 nasopharyngeal cancer and 1 sarcoma. Nine pts completed DLT observation without DLT; 1 pt withdrew early. No drug-related SAE was reported. Most drug-related AEs were Grade 1/2 and recovered quickly. Only 1 pt in the 25 μg cohort reported 3 Grade 3 AEs possibly related to drug: lymphocytopenia (2 events) and anemia. Seven pts completed at least one post-dose tumor assessment. Three pts experienced shrinkages of the treated lesions by 13.0%, 33.3% and 43.0%, corresponding to BC, HNSC and MEL in the 5 μg, 25 μg, and 50 μg cohorts, respectively. Tumor shrinkage of 31% was also observed in a non-injected lesion of an HNSC pt receiving 25μg JCXH-211 suggesting abscopal effects. Histopathological analysis of the treated lesions demonstrated increased T and NK cell infiltration (as high as 138 folds) post study drug administration. Conclusions: JCXH-211 IT administration with doses of 5μg, 25μg, 50μg Q4W demonstrated good safety profile. Antitumor activities were observed in the heavily pretreated late-stage pts. Significant increases of T and NK cell infiltration were observed. These data support continued evaluation of JCXH-211 IT. Clinical trial information: NCT05727839 .
IK-175, an oral AHR inhibitor, as monotherapy and in combination with nivolumab in patients with urothelial carcinoma resistant/refractory to PD-1/L1 inhibitors.
Authors: David H Aggen, Meredith McKean, Jean H. Hoffman-Censits, Nehal J. Lakhani, Omar Alhalabi, Elizabeth A. Guancial, Babar Bashir, I. Alex Bowman, Alan Tan, Trupti Lingaraj, Katherine Kim, Marissa Timothy, Nerymar Ortiz-Otero, Wilmin Bartolini, Katherine Kacena, Sergio Santillana, Jason J. Luke
Journal: Journal of Clinical Oncology (2024)

2599 Background: IK-175 is an oral, selective, small molecule Aryl Hydrocarbon Receptor (AHR) inhibitor. AHR is a ligand-activated transcription factor that binds kynurenine causing gene expression that promotes an immunosuppressive tumor microenvironment, possibly driving resistance to PD-1/L1 inhibitors (CPIs). Urothelial carcinoma (UC) demonstrates increased AHR signaling and nuclear protein localization as shown by gene expression analysis and tissue-based immunohistochemistry. Methods: This is a first-in-human, open-label, multicenter, study of IK-175 monotherapy and with nivolumab initially in solid tumors and for expansion in UC. Dose expansion patients received 1200mg QD of IK-175. Nivolumab was given at 480mg q4w in the combination cohorts. Both monotherapy and combination expansion arms utilized Simon 2-stage designs, and enrolled heavily pretreated UC patients who progressed ≤ 12 weeks of last dose of PD-1/L1 inhibitors (CPIs) and were enriched for nuclear AHR+ tumors by IHC. Study objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, MTD, RP2D and antitumor activity (RECIST 1.1) of IK-175 as a monotherapy and in combination with nivolumab. Results: Fifty-seven UC expansion patients were evaluated for safety. Median age was 69 years (range 26-81), 52/57 (91%) patients received ≥2 lines of prior therapy including CPIs. 5/14 monotherapy and 14/43 combo had nuclear AHR+ tumors. The most common treatment-related AEs were nausea, fatigue, and diarrhea. Infrequent immune-related AEs occurred in &lt;9% of patients and included adrenal insufficiency, proteinuria, rash, pneumonitis, and immune-related arthritis. Significant reduction in tumor target lesions (-30% to -100%) was observed in 6/46 (13%) response-evaluable UC patients (both arms). DCR was 46% and 49% for monotherapy and combination. Confirmed partial responses were observed in 1/13 (7.7%) monotherapy (DoR 22.6 months) and 2/33 (6%) in combo (DoR 4.4 and 7.3 months). Two patients in combo were treated beyond progression (for 4 and 10 months) due to investigator-assessed clinical benefit, including tumor shrinkage of target lesions. Conclusions: IK-175 showed a predictable, consistent safety profile as a monotherapy and in combination with nivolumab. Meaningful clinical benefit and objective, durable, prolonged responses were demonstrated in both monotherapy and combination arms in heavily pretreated UC patients with tumors refractory to CPI and supports further development of this asset in solid tumors. Clinical trial information: NCT04200963 .
Neurological disorders caused by novel non-coding repeat expansions: clinical features and differential diagnosis
Authors: Elisa Vegezzi, Hiroyuki Ishiura, D Cristopher Bragg, David Pellerin, Francesca Magrinelli, Riccardo Currò, Stefano Facchini, Arianna Tucci, John Hardy, Nutan Sharma, Matt C Danzi, Stephan Zuchner, Bernard Brais, Mary M Reilly, Shoji Tsuji, Henry Houlden, Andrea Cortese
Journal: The Lancet Neurology (2024)
A phase I/II study to evaluate the safety, pharmacokinetics, and efficacy of PRJ1-3024 in patients with advanced solid tumors.
Authors: Panpan Zhang, Yanru Qin, Jifang Gong, Yongsheng Wang, Kunyu Yang, Yongsheng Li, Guanghai Dai, Ji Zhu, Sha Sha, Ming Tong, Xuebin Liao, Lin Shen
Journal: Journal of Clinical Oncology (2024)

2590 Background: PRJ1-3024 is a small molecule hematopoietic progenitor kinase 1 (HPK1) inhibitor designed to potentiate T-cell function. It was demonstrated that HPK1 activity suppresses immune functions of a wide range of cells including cluster of differentiation CD4 + , CD8 + T cells and dendritic cells (DCs), mediates T-cell dysfunction and is a potential therapeutic target for T-cell-based immunotherapies. These results strongly support inhibitor of HPK1 functioning as a potential cancer immunotherapy agent. Methods: This is a multicenter, open-label study. Primary objective of phase I study is to determine the maximum tolerated dose and recommended Phase 2 dose. Secondary objectives are to evaluate safety, PK, and efficacy of PRJ1-3024. It is dosed orally once daily. Dose-limiting toxicity (DLT) assessment to be completed after 24 days (from the first dose to the end of Cycle 1 continuous 21 medication days). Exploratory analysis of pharmacodynamic targets including multiple cytokines, SLP-76 phosphorylation, cfDNA and IgG typing. Results: As of Dec. 22, 2023, 30 patients were enrolled in 6 dose cohorts: 80, 160, 300, 320, 500, and 700mg. Median age was 59 years (range 36-69). Diagnoses were NSCLC (9), Melanoma (3), TNBC (3), Gastric Cancer (3), HNSCC (3), Esophagus Carcinoma (2), Colon Cancer (2), and other types (5). The most common TEAEs (in ≥2 pts) were diarrhea (12), vomiting (12), nausea (9), proteinuria (8), loss of appetite (6), etc. No DLT events, irAEs or treatment-related deaths occurred in all dose cohorts. 9 subjects reported SAEs, only 2 cases were evaluated to be probably related (6.7%), namely ‘myocardial ischemic’ and ‘acute kidney injury’. 1 melanoma subject achieved sustained PR, had been on treatment for more than 7 months up to now. 4 subjects achieved SD (1 NSCLC, 1 HNSCC, 2 TNBCs). PK and PD assessments will be released in due course. Conclusions: PRJ1-3024 is shown to be well tolerated in Chinese advanced solid tumor patients. Further safety and efficacy results would be presented at the conference. Clinical trial information: NCT05315167 .
High‐Performance NIR‐II Fluorescent Type I/II Photosensitizer Enabling Augmented Mild Photothermal Therapy of Tumors by Disrupting Heat Shock Proteins
Authors: Quanheng Jiang, Jingyu Li, Zhong Du, Mengyuan Li, Liying Chen, Xunwen Zhang, Xialian Tang, Yaowei Shen, Dalong Ma, Wen Li, Lin Li, Nuernisha Alifu, Qinglian Hu, Jie Liu
Journal: Advanced Healthcare Materials (2024)

NIR-II fluorescent photosensitizers as phototheranostic agents hold considerable promise in the application of mild photothermal therapy (MPTT) for tumors, as the reactive oxygen species generated during photodynamic therapy can effectively disrupt heat shock proteins. Nevertheless, the exclusive utilization of these photosensitizers to significantly augment the MPTT efficacy has rarely been substantiated, primarily due to their insufficient photodynamic performance. Herein, the utilization of high-performance NIR-II fluorescent type I/II photosensitizer (AS2
Efficacy of the Allosteric MEK Inhibitor Trametinib in Relapsed and Refractory Juvenile Myelomonocytic Leukemia: a Report from the Children’s Oncology Group
Authors: Elliot Stieglitz, Alex G. Lee, Steven P. Angus, Christopher Davis, Donald A. Barkauskas, David Hall, Scott C. Kogan, Julia Meyer, Steven D. Rhodes, Sarah K. Tasian, Xiaoling Xuei, Kevin Shannon, Mignon L. Loh, Elizabeth Fox, Brenda J. Weigel
Journal: Cancer Discovery (2024)

Abstract Juvenile myelomonocytic leukemia (JMML) is a hematologic malignancy of young children caused by mutations that increase Ras signaling output. Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment, but patients with relapsed or refractory (advanced) disease have dismal outcomes. This phase II trial evaluated the safety and efficacy of trametinib, an oral MEK1/2 inhibitor, in patients with advanced JMML. Ten infants and children were enrolled, and the objective response rate was 50%. Four patients with refractory disease proceeded to HSCT after receiving trametinib. Three additional patients completed all 12 cycles permitted on study and continue to receive off-protocol trametinib without HSCT. The remaining three patients had progressive disease with two demonstrating molecular evolution by the end of cycle 2. Transcriptomic and proteomic analyses provided novel insights into the mechanisms of response and resistance to trametinib in JMML. ClinicalTrials.gov Identifier: NCT03190915. Significance: Trametinib was safe and effective in young children with relapsed or refractory JMML, a lethal disease with poor survival rates. Seven of 10 patients completed the maximum 12 cycles of therapy or used trametinib as a bridge to HSCT and are alive with a median follow-up of 24 months. See related commentary by Ben-Crentsil and Padron, p. 1574
Global burden of type 1 diabetes in adults aged 65 years and older, 1990-2019: population based study
Authors: Kaijie Yang, Xue Yang, Chenye Jin, Shuangning Ding, Tingting Liu, Bing Ma, Hao Sun, Jing Zhang, Yongze Li
Journal: BMJ (2024)

Abstract Objectives To estimate the burden, trends, and inequalities of type 1 diabetes mellitus (T1DM) among older adults at global, regional, and national level from 1990 to 2019. Design Population based study. Population Adults aged ≥65 years from 21 regions and 204 countries and territories (Global Burden of Disease and Risk Factors Study 2019) from 1990 to 2019. Main outcome measures Primary outcomes were T1DM related age standardised prevalence, mortality, disability adjusted life years (DALYs), and average annual percentage change. Results The global age standardised prevalence of T1DM among adults aged ≥65 years increased from 400 (95% uncertainty interval (UI) 332 to 476) per 100 000 population in 1990 to 514 (417 to 624) per 100 000 population in 2019, with an average annual trend of 0.86% (95% confidence interval (CI) 0.79% to 0.93%); while mortality decreased from 4.74 (95% UI 3.44 to 5.9) per 100 000 population to 3.54 (2.91 to 4.59) per 100 000 population, with an average annual trend of −1.00% (95% CI −1.09% to −0.91%), and age standardised DALYs decreased from 113 (95% UI 89 to 137) per 100 000 population to 103 (85 to 127) per 100 000 population, with an average annual trend of −0.33% (95% CI −0.41% to −0.25%). The most significant decrease in DALYs was observed among those aged &lt;79 years: 65-69 (−0.44% per year (95% CI −0.53% to −0.34%)), 70-74 (−0.34% per year (−0.41% to −0.27%)), and 75-79 years (−0.42% per year (−0.58% to −0.26%)). Mortality fell 13 times faster in countries with a high sociodemographic index versus countries with a low-middle sociodemographic index (−2.17% per year (95% CI −2.31% to −2.02%) v −0.16% per year (−0.45% to 0.12%)). While the highest prevalence remained in high income North America, Australasia, and western Europe, the highest DALY rates were found in southern sub-Saharan Africa, Oceania, and the Caribbean. A high fasting plasma glucose level remained the highest risk factor for DALYs among older adults during 1990-2019. Conclusions The life expectancy of older people with T1DM has increased since the 1990s along with a considerable decrease in associated mortality and DALYs. T1DM related mortality and DALYs were lower in women aged ≥65 years, those living in regions with a high sociodemographic index, and those aged &lt;79 years. Management of high fasting plasma glucose remains a major challenge for older people with T1DM, and targeted clinical guidelines are needed.
An Octopus‐Inspired Stimulus‐Responsive Structural Color Hydrogel for Uterus Cervical Canal Stent
Authors: Lihao Zhang, Lehao Ren, Yufei Chen, Yue Cao, Sunlong Li, Weipeng Lu, Yaoyuan Jia, Yachun Li, Cihui Liu, Chen Li, Qian Dong
Journal: Advanced Healthcare Materials (2024)

Abstract Soft‐bodied aquatic organisms have exhibited remarkable capabilities in navigating and moving within liquid environments serving as a profound inspiration for the development of bionic robots with intricate movements. Traditional rigid components are being replaced by stimulus‐responsive soft materials such as hydrogels and shape memory polymers, leading to the creation of dynamically responsive soft robots. In this study, the development of a bionic robot inspired by the shape of an octopus and the adsorptive properties of its tentacles, specifically tailored for targeted stimulation and pH sensing in the cervix, are presented. This approach involves the design of a soft, water‐based Janus adhesive hydrogel patch that adheres to specific parts of the cervix and responds to pH changes through external stimuli. The hydrogel patch incorporates inverse opal microstructures mimicking the legs of an octopus, to facilitate efficient and stable locomotion, unidirectional transport of biofluids, and pH‐responsive behavior. This miniature bionic robot showcases controlled adhesion and precise unidirectional fluid transport highlighting its potential for targeted stimulus response and pH sensing in the uterine cervical tract. This breakthrough opens new avenues for medical applications within the expanding field of soft‐bodied robotics.
Primary cilia as a targetable node between biliary injury, senescence and regeneration in liver transplantation.
Authors: Hannah Esser, Alastair Morris Kilpatrick, Tak Yung Man, Rhona Aird, Daniel Rodrigo-Torres, Madita Lina Buch, Luke Boulter, Sarah Walmsley, Gabriel Corneliu Oniscu, Stefan Schneeberger, Sofia Ferreira-Gonzalez, Stuart John Forbes
Journal: Journal of Hepatology (2024)

Biliary complications are a major cause of morbidity and mortality in liver transplantation. Up to 25% of patients that develop biliary complications require additional surgical procedures, re-transplantation or die in the absence of a suitable regraft. Here, we investigate the role of the primary cilium, a highly-specialised sensory organelle, in biliary injury leading to post-transplant biliary complications. Human biopsies were used to study the structure and function of primary cilia in liver transplant recipients that develop biliary complications (N=7) in comparison with recipients without biliary complications (N=12). To study the biological effects of the primary cilia during transplantation, we generated murine models that recapitulate liver procurement and cold storage, and assessed the elimination of the primary cilia in biliary epithelial cells in the K19CreERT Kif3aflox/flox mouse model. To explore the molecular mechanisms responsible for the observed phenotypes we used in vitro models of ischemia, cellular senescence and primary cilia ablation. Finally, we used pharmacological and genetic approaches to target cellular senescence and the primary cilia, both in mouse models and discarded human donor livers. Prolonged ischemic periods before transplantation result in ciliary shortening and cellular senescence, an irreversible cell cycle arrest that blocks regeneration. Our results indicate that primary cilia damage results in biliary injury and a loss of regenerative potential. Senescence negatively impacts primary cilia structure and triggers a negative feedback loop that further impairs regeneration. Finally, we explore how targeted interventions for cellular senescence and/or the stabilisation of the primary cilia improve biliary regeneration following ischemic injury. Primary cilia play an essential role in biliary regeneration and we demonstrate that senolytics and cilia-stabilising treatments provide a potential therapeutic opportunity to reduce the rate of biliary complications and improve clinical outcomes in liver transplantation. Up to 25% of liver transplants result in biliary complications, leading to additional surgery, retransplants, or death. We found that the incidence of biliary complications is increased by damage to the primary cilium, an antenna that protrudes from the cell and is key to regeneration. Here, we show that treatments that preserve the primary cilia during the transplant process provide a potential solution to reduce the rates of biliary complications.
Poly(p-coumaric acid) nanoparticles alleviate temporomandibular joint osteoarthritis by inhibiting chondrocyte ferroptosis
Authors: Jiaxin Guo, Kai Su, Liying Wang, Bingyu Feng, Xinru You, Miao Deng, Wei Seong Toh, Jun Wu, Bin Cheng, Juan Xia
Journal: Bioactive Materials (2024)