tbuckley/cabot-search huggingface dataset:
Brazil’s G20 leadership offers glimmers of hope for global health equity
Authors: Deisy Ventura, Anne-Emanuelle Birn, Ruth Iguiñiz Romero, Michael Knipper
Journal: BMJ (2024)

The Rio de Janeiro declarations chart possibilities in an era of inequity, war, climate change, and pandemics, but their shortfalls must be acknowledged, write <b>Deisy Ventura and colleagues</b>
A multilineage screen identifies actionable synthetic lethal interactions in human cancers
Authors: Samson H. Fong, Brent M. Kuenzi, Nicole M. Mattson, John Lee, Kyle Sanchez, Ana Bojorquez-Gomez, Kyle Ford, Brenton P. Munson, Katherine Licon, Sarah Bergendahl, John Paul Shen, Jason F. Kreisberg, Prashant Mali, Jeffrey H. Hager, Michael A. White, Trey Ideker
Journal: Nature Genetics (2024)
DNA tetrahedral nanoparticles: Co-delivery of siOTUD6B/DOX against triple-negative breast cancer
Authors: Wenxiang Zhang, Xue Yang, Zheng Qu, Peikai Ding, Xiangyi Kong, Xiangyu Wang, Qiang Liu, Xingsong Zhang, Ye Lu, Jing Wang, Zhengju Chen, Yi Fang
Journal: Journal of Controlled Release (2024)
Dual-responsive nanoparticles for enhanced drug delivery in breast Cancer chemotherapy
Authors: Yuxin Ren, Peishan Li, Ying Xie, Jiarui Xu, Qian Luo, Ming Chen, Rui Liu, Hexuan Feng, Yuling Chen, Yixuan Liu, Chunjie Bao, Jialun Duan, Jianwei Li, Wanliang Lu
Journal: Journal of Controlled Release (2024)
Glucose uptake capacity of leukaemia cells in vitro correlates with response to induction therapy in acute myeloid leukaemia
Authors: Suqi Deng, Juan Du, Kexiu Huang, Robert Peter Gale, Danqi Pan, Lu Wang, Junjie Wei, Xue Zheng, Ying Xu, Shengqian Xie, Wei Zhou, Weihao Xiao, Bo Liu, Zhiyang Chen, Zhenyu Ju, Hui Zeng
Journal: Leukemia (2024)
Mini‐consolidations or intermediate‐dose cytarabine for the post‐remission therapy of AML patients over 60. A retrospective study from the DATAML and SAL registries
Authors: Christian Récher, Pierre‐Yves Dumas, Emilie Bérard, Suzanne Tavitian, Thibaut Leguay, Jean Galtier, Camille Alric, Audrey Bidet, Eric Delabesse, Jean Baptiste Rieu, Jean‐Philippe Vial, François Vergez, Isabelle Luquet, Emilie Klein, Anne‐Charlotte de Grande, Audrey Sarry, Sven Zukunft, Uwe Platzbecker, Carsten Müller‐Tidow, Claudia D. Baldus, Martin Bornhäuser, Hubert Serve, Sarah Bertoli, Arnaud Pigneux, Christoph Röllig
Journal: American Journal of Hematology (2024)

Abstract According to current recommendations, older AML patients in first complete remission (CR) after induction chemotherapy should receive consolidation with intermediate‐dose cytarabine (IDAC). However, no study has demonstrated the superiority of IDAC over other regimen. In this retrospective study, we compared the efficacy of mini‐consolidations (idarubicin 8 mg/m 2 day 1, cytarabine 50 mg/m 2 /12 h, day 1–5) and IDAC. Inclusion criteria were newly diagnosed AML, age &gt; 60 years, first CR after induction and at least 1 cycle of consolidation. Of the 796 included patients, 322 patients received mini‐consolidations and 474 patients received IDAC. Mini‐consolidation patients were older, and more often, they had de novo AML and unfavorable risk. The rate of allogeneic transplantation was higher in the IDAC group. The median number of cycles was higher in the mini‐consolidation group (4 vs. 2; p &lt; .0001). Median relapse‐free survival was 18 months with mini‐consolidations and 12 months with IDAC ( p = .0064). In multivariate analysis, the risk of relapse or death was significantly higher in the IDAC group ( p = .004). Median OS was 36 versus 31 months with mini‐consolidations or IDAC, respectively ( p = .46). In multivariate analysis, the consolidation regimen had no significant influence on OS ( p = .43). In older AML patients, post‐remission therapy with mini‐consolidations represents an alternative to IDAC.
Reinforcement learning model for optimizing dexmedetomidine dosing to prevent delirium in critically ill patients
Authors: Hong Yeul Lee, Soomin Chung, Dongwoo Hyeon, Hyun-Lim Yang, Hyung-Chul Lee, Ho Geol Ryu, Hyeonhoon Lee
Journal: npj Digital Medicine (2024)

Abstract Delirium can result in undesirable outcomes including increased length of stays and mortality in patients admitted to the intensive care unit (ICU). Dexmedetomidine has emerged for delirium prevention in these patients; however, optimal dosing is challenging. A reinforcement learning-based Artificial Intelligence model for Delirium prevention (AID) is proposed to optimize dexmedetomidine dosing. The model was developed and internally validated using 2416 patients (2531 ICU admissions) and externally validated on 270 patients (274 ICU admissions). The estimated performance return of the AID policy was higher than that of the clinicians’ policy in both derivation (0.390 95% confidence interval [CI] 0.361 to 0.420 vs. −0.051 95% CI −0.077 to −0.025) and external validation (0.186 95% CI 0.139 to 0.236 vs. −0.436 95% CI −0.474 to −0.402) cohorts. Our finding indicates that AID might support clinicians’ decision-making regarding dexmedetomidine dosing to prevent delirium in ICU patients, but further off-policy evaluation is required.
Accurately predicting mood episodes in mood disorder patients using wearable sleep and circadian rhythm features
Authors: Dongju Lim, Jaegwon Jeong, Yun Min Song, Chul-Hyun Cho, Ji Won Yeom, Taek Lee, Jung-Been Lee, Heon-Jeong Lee, Jae Kyoung Kim
Journal: npj Digital Medicine (2024)

Wearable devices enable passive collection of sleep, heart rate, and step-count data, offering potential for mood episode prediction in mood disorder patients. However, current models often require various data types, limiting real-world application. Here, we develop models that predict future episodes using only sleep-wake data, easily gathered through smartphones and wearables when trained on an individual's sleep-wake history and past mood episodes. Using mathematical modeling to longitudinal data from 168 patients (587 days average clinical follow-up, 267 days wearable data), we derived 36 sleep and circadian rhythm features. These features enabled accurate next-day predictions for depressive, manic, and hypomanic episodes (AUCs: 0.80, 0.98, 0.95). Notably, daily circadian phase shifts were the most significant predictors: delays linked to depressive episodes, advances to manic episodes. This prospective observational cohort study (ClinicalTrials.gov: NCT03088657, 2017-3-23) shows sleep-wake data, combined with prior mood episode history, can effectively predict mood episodes, enhancing mood disorder management.
Cutaneous T cell lymphoma atlas reveals malignant TH2 cells supported by a B cell-rich tumor microenvironment
Authors: Ruoyan Li, Johanna Strobl, Elizabeth F. M. Poyner, Aya Balbaa, Fereshteh Torabi, Pavel V. Mazin, Nana-Jane Chipampe, Emily Stephenson, Ciro Ramírez-Suástegi, Vijaya Baskar Mahalingam Shanmugiah, Louis Gardner, Bayanne Olabi, Rowen Coulthard, Rachel A. Botting, Nina Zila, Elena Prigmore, Nusayhah H. Gopee, Marta A. Chroscik, Efpraxia Kritikaki, Justin Engelbert, Issac Goh, Hon Man Chan, Harriet F. Johnson, Jasmine Ellis, Victoria Rowe, Win Tun, Gary Reynolds, Dexin Yang, April Rose Foster, Laure Gambardella, Elena Winheim, Chloe Admane, Benjamin Rumney, Lloyd Steele, Laura Jardine, Julia Nenonen, Keir Pickard, Jennifer Lumley, Philip Hampton, Simeng Hu, Fengjie Liu, Xiangjun Liu, David Horsfall, Daniela Basurto-Lozada, Louise Grimble, Chris M. Bacon, Sophie C. Weatherhead, Hanna Brauner, Yang Wang, Fan Bai, Nick J. Reynolds, Judith E. Allen, Constanze Jonak, Patrick M. Brunner, Sarah A. Teichmann, Muzlifah Haniffa
Journal: Nature Immunology (2024)

Cutaneous T cell lymphoma (CTCL) is a potentially fatal clonal malignancy of T cells primarily affecting the skin. The most common form of CTCL, mycosis fungoides, can be difficult to diagnose, resulting in treatment delay. We performed single-cell and spatial transcriptomics analysis of skin from patients with mycosis fungoides-type CTCL and an integrated comparative analysis with human skin cell atlas datasets from healthy and inflamed skin. We revealed the co-optation of T helper 2 (T
Transcription of a centromere-enriched retroelement and local retention of its RNA are significant features of the CENP-A chromatin landscape
Authors: B. J. Chabot, R. Sun, A. Amjad, S. J. Hoyt, L. Ouyang, C. Courret, R. Drennan, L. Leo, A. M. Larracuente, L. J. Core, R. J. O’Neill, B. G. Mellone
Journal: Genome biology (2024)

Centromeres depend on chromatin containing the conserved histone H3 variant CENP-A for function and inheritance, while the role of centromeric DNA repeats remains unclear. Retroelements are prevalent at centromeres across taxa and represent a potential mechanism for promoting transcription to aid in CENP-A incorporation or for generating RNA transcripts to maintain centromere integrity. In this study, we probe into the transcription and RNA localization of the centromere-enriched retroelement G2/Jockey-3 (hereafter referred to as Jockey-3) in Drosophila melanogaster, currently the only in vivo model with assembled centromeres. We find that Jockey-3 is a major component of the centromeric transcriptome and produces RNAs that localize to centromeres in metaphase. Leveraging the polymorphism of Jockey-3 and a de novo centromere system, we show that these RNAs remain associated with their cognate DNA sequences in cis, suggesting they are unlikely to perform a sequence-specific function at all centromeres. We show that Jockey-3 transcription is positively correlated with the presence of CENP-A and that recent Jockey-3 transposition events have occurred preferentially at CENP-A-containing chromatin. We propose that Jockey-3 preferentially inserts at the centromere to ensure its own selfish propagation, while contributing to transcription across these regions. Given the conservation of retroelements as centromere components through evolution, our findings may offer a basis for understanding similar associations in other species.
Alternative lengthening of telomere-based immortalization renders H3G34R -mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens
Authors: Anna Laemmerer, Christian Lehmann, Lisa Mayr, Katharina Bruckner, Lisa Gabler, Daniel Senfter, Philipp Meyer, Theresa Balber, Christine Pirker, Carola N Jaunecker, Dominik Kirchhofer, Petra Vician, Michelle Griesser, Sabine Spiegl-Kreinecker, Maria T Schmook, Tatjana Traub-Weidinger, Peter Kuess, Franziska Eckert, Aniello Federico, Sibylle Madlener, Natalia Stepien, Bernhard Robl, Alicia Baumgartner, Johannes A Hainfellner, Karin Dieckmann, Christian Dorfer, Karl Roessler, Nina S Corsini, Klaus Holzmann, Wolfgang M Schmidt, Andreas Peyrl, Amedeo A Azizi, Christine Haberler, Alexander Beck, Stefan M Pfister, Julia Schueler, Daniela Lötsch-Gojo, Jürgen A Knoblich, Walter Berger, Johannes Gojo
Journal: Neuro-Oncology (2024)

Abstract Background Diffuse hemispheric glioma, H3 G34R/V-mutant (DHG-H3G34) is characterized by poor prognosis and lack of effective treatment options. DHG-H3G34R further harbor deactivation of alpha-thalassemia/mental retardation syndrome X-linked protein (ATRX; DHG-H3G34R_ATRX) suggesting a unique interaction of these 2 oncogenic alterations. In this study, we dissect their cell biological interplay, investigate the impact on telomere stabilization, and consequently validate a targeted therapy approach. Methods We characterized patient-derived primary pediatric high-grade glioma (pHGG) models for telomere-maintenance mechanisms, DNA damage stress (including protein expression, pH2AX/Rad51 foci, cell-cycle arrest) and their sensitivity towards poly-ADP ribose polymerase inhibitor (PARPi) combinations. Human induced pluripotent stem cells (iPSCs) were used for modeling the disease. The anticancer activity of PARPi combinations in vivo was studied in Chorioallantoic Membrane (CAM) and orthotopic in vivo experiments. Finally, we treated a DHG-H3G34R_ATRX patient with PARPi combination therapy. Results We elaborate that alternative lengthening of telomeres (ALT) is a key characteristic of DHG-H3G34R_ATRX. A dominant cooperative effect between H3G34R and ATRX loss in ALT activation also became apparent in iPSCs, which endogenously exert telomerase activity. In both, patient-derived DHG-H3G34R_ATRX models and H3G34R+/ATRX- iPSCs, the ALT-phenotype was associated with increased basal DNA damage stress, mediating synergistic susceptibility towards PARPi (talazoparib, niraparib) combinations with topoisomerase-I inhibitors (topotecan, irinotecan). In a first-of-its-kind case, treatment of a DHG-H3G34R_ATRX patient with the brain-penetrant PARP inhibitor niraparib and topotecan resulted in significant tumor reduction. Conclusions Our preclinical and clinical data strongly support the further development of PARPi together with DNA damage stress-inducing treatment regimens for DHG-H3G34R_ATRX.
Sodium Zirconium Cyclosilicate for Management of Hyperkalemia During Spironolactone Optimization in Patients with Heart Failure
Authors: Mikhail N Kosiborod, David Z I Cherney, Akshay S Desai, Jeffrey M Testani, Subodh Verma, Khaja Chinnakondepalli, David Dolling, Shachi Patel, Magnus Dahl, James M Eudicone, Lovisa Friberg, Mario Ouwens, Murillo O Antunes, Kim A Connelly, Vagner Madrini, Luca Kuthi, Anuradha Lala, Miguel Lorenzo, Patrícia O Guimarães, Marta Cobo Marcos, Béla Merkely, Julio Nuñez, Iain Squire, Jan Václavík, Jerzy Wranicz, Mark C Petrie
Journal: Journal of the American College of Cardiology (2024)

Mineralocorticoid receptor antagonists (MRA) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF) but are underused in clinical practice. Observational data suggest that hyperkalemia is the leading obstacle for the suboptimal use of MRA.
Rivaroxaban for 18 Months Versus 6 Months in Patients With Cancer and Acute Low-Risk Pulmonary Embolism: An Open-Label, Multicenter, Randomized Clinical Trial (ONCO PE Trial)
Authors: Yugo Yamashita, Takeshi Morimoto, Nao Muraoka, Wataru Shioyama, Ryuki Chatani, Tatsuhiro Shibata, Yuji Nishimoto, Yoshito Ogihara, Kosuke Doi, Maki Oi, Taro Shiga, Daisuke Sueta, Kitae Kim, Yasuhiro Tanabe, Norimichi Koitabashi, Takuma Takada, Satoshi Ikeda, Hitoshi Nakagawa, Kengo Tsukahara, Masaaki Shoji, Jiro Sakamoto, Shinji Hisatake, Yutaka Ogino, Masashi Fujita, Naohiko Nakanishi, Tomohiro Dohke, Seiichi Hiramori, Ryuzo Nawada, Kazuhisa Kaneda, Koh Ono, Takeshi Kimura
Journal: Circulation (2024)

Background: The optimal duration of anticoagulation therapy for patients with cancer and acute low-risk pulmonary embolism (PE) is clinically relevant, but evidence is lacking. Prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding. Methods: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 32 institutions in Japan, we randomly assigned patients with cancer and acute low-risk PE of the simplified version of the Pulmonary Embolism Severity Index score of 1, in a 1:1 ratio, to receive either an 18-month or a 6-month rivaroxaban treatment. The primary end point was recurrent venous thromboembolism (VTE) at 18 months. The major secondary end point was major bleeding at 18 months according to the criteria of the International Society on Thrombosis and Hemostasis. The primary hypothesis was that an 18-month treatment was superior to a 6-month treatment in terms of the primary end point. Results: From February 2021 to March 2023, 179 patients were randomized, and after the exclusion of one patient who withdrew consent, 178 were included in the intention-to-treat population: 89 patients in the 18-month rivaroxaban group and 89 in the 6-month rivaroxaban group. The mean age was 65.7 years; 47% of the patients were men, and 12% had symptoms of PE at baseline. The primary end point of recurrent VTE occurred in 5 of the 89 patients (5.6%) in the 18-month rivaroxaban group and in 17 of the 89 (19.1%) in the 6-month rivaroxaban group (odds ratio, 0.25 [95% CI, 0.09–0.72]; P =0.01). Among 22 recurrent VTE, 5 patients presented with a symptomatic recurrent VTE; recurrent PE occurred in 11 patients, including 2 with main and 4 with lobar PEs; and recurrent deep vein thrombosis was seen in 11 patients, including 3 with proximal deep vein thromboses. The major secondary end point of major bleeding occurred in 7 of the 89 patients (7.8 %) in the 18-month rivaroxaban group and in 5 of the 89 patients (5.6%) in the 6-month rivaroxaban group (odds ratio, 1.43 [95% CI, 0.44–4.70]; P =0.55). Conclusions: In patients with cancer and acute low-risk PE of the simplified version of the Pulmonary Embolism Severity Index score of 1, the 18-month rivaroxaban treatment was superior to the 6-month rivaroxaban treatment with respect to recurrent VTE events.
Afatinib boosts CAR-T cell antitumor therapeutic efficacy via metabolism and fate reprogramming
Authors: Yueyu Dai, Yue Liu, Lingna An, Fangyuan Zhong, Xi Zhang, Shifeng Lou
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Chimeric antigen receptor T (CAR-T) cell therapy has been shown remarkable efficacy in the treatment of hematological malignancies in recent years. However, a considerable proportion of patients would experience tumor recurrence and deterioration. Insufficient CAR-T cell persistence is the major reason for relapse. Multiple strategies to enhance the long-term antitumor effects of CAR-T cells have been explored and developed. In this study, we focused on tyrosine kinase inhibitors (TKIs), which have emerged immunomodulatory potential besides direct tumoricidal effects. Methods Here, we screened 50 approved TKIs drugs and identified that afatinib (AFA) markedly enhanced the expressing of CD62L and inhibited reactive oxygen species level in T cells. And the underlying mechanisms of AFA medicating T cells were explored by detecting signal transduction, and metabolism pattern. Furthermore, we co-cultured AFA with CAR-T cells during the preparation stage and multianalyses of differentiation characteristics, metabolic profiling, and RNA sequencing revealed that AFA induce comprehensive metabolism remodeling and fate reprogramming. Based on it, we finally identified the antitumor efficacy of AFA-pretreatment CAR-T compared with negative-control CAR-T. Results We identified that AFA blocked the T-cell receptor (TCR) and phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin signaling pathways, induced metabolic reprogramming and modulated T-cell differentiation. When combined with CAR-T cells, AFA inhibited the exhaustion and enhanced the persistence and cytotoxicity. Our results revealed that the pretreatment of AFA enables to boost CAR-T cells with strong antitumor cytotoxicity in leukemia mouse model. Conclusions Our study systematically demonstrated that AFA pretreatment effectively enhanced CAR-T cells antitumor performance, which presents a novel optimization strategy for potent and durable CAR-T cell therapy.
Phase I study of a recombinant attenuated oncolytic virus, MEDI5395 (NDV–GM-CSF), administered systemically in combination with durvalumab in patients with advanced solid tumors
Authors: Diwakar Davar, Benedito A Carneiro, Grace K Dy, Siddharth Sheth, Mitesh J Borad, Kevin J Harrington, Sandip P Patel, Evanthia Galanis, Adel Samson, Sonia Agrawal, Zhongying Chen, Chunling Fan, Maozhen Gong, Jenny Burton, Eric Tu, Nicholas Durham, Kevin Laubscher, Fernanda Arnaldez, Dmitriy Zamarin
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background MEDI5395 is a recombinant attenuated Newcastle disease virus engineered to express a human granulocyte-macrophage colony-stimulating factor transgene. Preclinically, MEDI5395 demonstrated broad oncolytic activity, augmented by concomitant programmed cell death-1/programmed cell death ligand-1 (PD-L1) axis blockade. Durvalumab is an anti-PD-L1 immune checkpoint inhibitor approved for the treatment of various solid tumors. We describe the results of the first-in-human study combining intravenous MEDI5395 with durvalumab in patients with advanced solid tumors. Methods This phase I, open-label, multicenter, dose-escalation, dose-expansion study recruited adult patients with advanced solid tumors, who had relapsed or were refractory or intolerant to ≥1 prior line of standard treatment. MEDI5395 was administered intravenously as six doses over 15–18 days. The dose-escalation phase assessed four-dose levels (10 8 , 10 9 , 10 10 , 10 11 focus forming units (FFU)) of MEDI5395, with sequential or delayed durvalumab. Durvalumab 1500 mg was administered intravenously every 4 weeks up to 2 years. The dose-expansion phase was not initiated. The primary objectives were to evaluate safety and tolerability, dose-limiting toxicities (DLTs) and the dose and schedule of MEDI5395 plus durvalumab administration. Secondary objectives included the assessment of the efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI5395. Results 39 patients were treated with MEDI5395; 36 patients also received durvalumab. All 39 patients experienced ≥1 treatment-emergent adverse event (TEAE), most commonly fatigue (61.5%), nausea (53.8%) and chills (51.3%). Grade 3–4 TEAEs occurred in 27 (69.2%) patients; these were deemed MEDI5395-related in 12 (30.8%) patients. Two patients experienced a DLT, and the maximum tolerated dose of MEDI5395 with sequential and delayed durvalumab at study termination was 10 11 and 10 10 FFU, respectively. Four patients (10.3%) achieved a partial response (PR). Patients with PR or stable disease tended to have higher baseline PD-L1 and CD8+ levels in their tumor tissue. A tendency to dose-dependent pharmacokinetics of the viral genome was observed in whole blood and a tendency to dose-dependent viral shedding was observed in saliva and urine. Neutralizing antibodies were observed in all patients but did not appear to impact efficacy negatively. Conclusion This study demonstrates the feasibility, safety and preliminary efficacy of MEDI5395 with durvalumab in patients with advanced solid tumors. Trial registration number NCT03889275
Tumor and Blood B Cell Abundance Outperforms Established Immune Checkpoint Blockade Response Prediction Signatures in Head and Neck Cancer
Authors: T-G Chang, A Spathis, A A Schäffer, N Gavrielatou, F Kuo, D Jia, S Mukherjee, C Sievers, P Economopoulou, M Anastasiou, M Moutafi, L R Pal, J Vos, A S Lee, S Lam, K Zhao, P Jiang, C T Allen, P Foukas, G Gomatou, G Altan-Bonnet, L G T Morris, A Psyrri, E Ruppin
Journal: Annals of Oncology (2024)
Clinical benefit with tebentafusp in a patient with GNAQ mutant metastatic blue nevus-associated melanoma
Authors: Matthew R Kudelka, Allison L Richards, Philip Friedlander, Jedd D Wolchok, Andrea P Moy, Alexander N Shoushtari
Journal: Journal for ImmunoTherapy of Cancer (2024)

Melanoma arising in association with a blue nevus (BN) is rare but has molecular similarities to uveal melanoma (UM), including GNAQ/11 mutations. Tebentafusp was recently approved for UM based on improved overall survival in a phase 3 study. We hypothesized that tebentafusp may be active in BN-associated melanoma. Here, we present a case of metastatic BN-associated melanoma with rapid response and ~1 year of disease control on tebentafusp. We also explore molecular and histological features of secondary resistance. Our case highlights that PD-1-resistant melanomas should be screened for GNAQ/11 mutations, as tebentafusp may be a treatment option in this extremely rare disease.