tbuckley/cabot-search huggingface dataset:
Toward a more patient‐centered drug development process in clinical trials for patients with myelodysplastic syndromes/neoplasms (MDS): Practical considerations from the International Consortium for MDS (icMDS)
Authors: Fabio Efficace, Rena Buckstein, Gregory A. Abel, Johannes M. Giesinger, Pierre Fenaux, Jan Philipp Bewersdorf, Andrew M. Brunner, Rafael Bejar, Uma Borate, Amy E. DeZern, Peter Greenberg, Gail J. Roboz, Michael R. Savona, Francesco Sparano, Jacqueline Boultwood, Rami Komrokji, David A. Sallman, Zhuoer Xie, Guillermo Sanz, Hetty E. Carraway, Justin Taylor, Stephen D. Nimer, Matteo Giovanni Della Porta, Valeria Santini, Maximilian Stahl, Uwe Platzbecker, Mikkael A. Sekeres, Amer M. Zeidan
Journal: HemaSphere (2024)

Abstract Notable treatment advances have been made in recent years for patients with myelodysplastic syndromes/neoplasms (MDS), and several new drugs are under development. For example, the emerging availability of oral MDS therapies holds the promise of improving patients' health‐related quality of life (HRQoL). Within this rapidly evolving landscape, the inclusion of HRQoL and other patient‐reported outcomes (PROs) is critical to inform the benefit/risk assessment of new therapies or to assess whether patients live longer and better, for what will likely remain a largely incurable disease. We provide practical considerations to support investigators in generating high‐quality PRO data in future MDS trials. We first describe several challenges that are to be thoughtfully considered when designing an MDS‐focused clinical trial with a PRO endpoint. We then discuss aspects related to the design of the study, including PRO assessment strategies. We also discuss statistical approaches illustrating the potential value of time‐to‐event analyses and their implications within the estimand framework. Finally, based on a literature review of MDS randomized controlled trials with a PRO endpoint, we note the PRO items that deserve special attention when reporting future MDS trial results. We hope these practical considerations will facilitate the generation of rigorous PRO data that can robustly inform MDS patient care and support treatment decision‐making for this patient population.
Lenvatinib plus Pembrolizumab Following Immune Checkpoint Inhibitor Treatment in Patients with Metastatic Clear Cell Renal Cell Carcinoma: Results from Study 111/KEYNOTE-146
Authors: Chung-Han Lee, Amishi Yogesh Shah, Arpit Rao, Matthew H Taylor, Christopher Di Simone, James J Hsieh, Alvaro Pinto, Regina Gironés Sarrió, Allen Lee Cohn, Mehmet Asim Bilen, Sara Gunnestad Ribe, Øyvind Krohn Tennøe, Donald Richards, Randy F Sweis, Jay Courtright, Daniel Heinrich, Rodolfo Perini, Peter Kubiak, Daena Bock, Chinyere E Okpara, Robert J Motzer
Journal: European Urology (2024)
Tauroursodeoxycholic acid ameliorates renal injury induced by COL4A3 mutation
Authors: Shuwen Yu, Xiangchen Gu, Qimin Zheng, Yunzi Liu, Teija Suhas, Wen Du, Lin Xie, Zhengying Fang, Yafei Zhao, Mingxin Yang, Jing Xu, Yimei Wang, Meei-Hua Lin, Xiaoxia Pan, Jeffrey H. Miner, Yuanmeng Jin, Jingyuan Xie
Journal: Kidney International (2024)

COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed that the MyD88/p38 MAPK pathway plays key roles in mediating subsequent inflammation and apoptosis signaling activation. Treatment with tauroursodeoxycholic acid, a chemical chaperone drug that functions as an endoplasmic reticulum stress inhibitor, effectively suppressed endoplasmic reticulum stress, promoted secretion of the α3 chains, and inhibited the activation of the MyD88/p38 MAPK pathway. Tauroursodeoxycholic acid treatment significantly improved kidney function in vivo. These results partly clarified the pathogenesis of kidney injuries associated with Alport syndrome, especially in glomeruli, and suggested that tauroursodeoxycholic acid might be useful for the early clinical treatment of Alport syndrome.
Towards consistency in pediatric brain tumor measurements: Challenges, solutions, and the role of artificial intelligence-based segmentation
Authors: Ariana M Familiar, Anahita Fathi Kazerooni, Arastoo Vossough, Jeffrey B Ware, Sina Bagheri, Nastaran Khalili, Hannah Anderson, Debanjan Haldar, Phillip B Storm, Adam C Resnick, Benjamin H Kann, Mariam Aboian, Cassie Kline, Michael Weller, Raymond Y Huang, Susan M Chang, Jason R Fangusaro, Lindsey M Hoffman, Sabine Mueller, Michael Prados, Ali Nabavizadeh
Journal: Neuro-Oncology (2024)

Abstract MR imaging is central to the assessment of tumor burden and changes over time in neuro-oncology. Several response assessment guidelines have been set forth by the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working groups in different tumor histologies; however, the visual delineation of tumor components using MRIs is not always straightforward, and complexities not currently addressed by these criteria can introduce inter- and intra-observer variability in manual assessments. Differentiation of non-enhancing tumors from peritumoral edema, mild enhancement from absence of enhancement, and various cystic components can be challenging; particularly given a lack of sufficient and uniform imaging protocols in clinical practice. Automated tumor segmentation with artificial intelligence (AI) may be able to provide more objective delineations, but rely on accurate and consistent training data created manually (ground truth). Herein, this paper reviews existing challenges and potential solutions to identifying and defining subregions of pediatric brain tumors (PBTs) that are not explicitly addressed by current guidelines. The goal is to assert the importance of defining and adopting criteria for addressing these challenges, as it will be critical to achieving standardized tumor measurements and reproducible response assessment in PBTs, ultimately leading to more precise outcome metrics and accurate comparisons among clinical studies.
Developing a membrane-proximal CD33-targeting CAR T cell
Authors: Ruby Freeman, Sanam Shahid, Abdul G Khan, Serena C Mathew, Sydney Souness, Erin R Burns, Jasmine S Um, Kento Tanaka, Winson Cai, Sarah Yoo, Andrew Dunbar, Young Park, Devin McAvoy, Kinga K Hosszu, Ross L Levine, Jaap Jan Boelens, Ivo C Lorenz, Renier J Brentjens, Anthony F Daniyan
Journal: Journal for ImmunoTherapy of Cancer (2024)

CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking. We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice. We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both low antigen density and clinically relevant patient-derived xenograft models. Increased activation and enhanced polyfunctionality led to enhanced efficacy. Showing for the first time that a membrane-proximal CAR is superior to a membrane-distal one in the setting of CD33 targeting, our results demonstrate the rationale for targeting membrane-proximal epitopes with high-affinity binders. We also demonstrate the importance of optimizing CAR T cells for functionality in settings of both low antigen density and clinically relevant patient-derived models.
Sequence of androgen receptor-targeted vaccination with androgen deprivation therapy affects anti-prostate tumor efficacy
Authors: Anusha Muralidhar, Melissa Gamat-Huber, Sita Vakkalanka, Douglas G McNeel
Journal: Journal for ImmunoTherapy of Cancer (2024)

Androgen deprivation therapy (ADT) is the primary treatment for recurrent and metastatic prostate cancer. In addition to direct antitumor effects, ADT has immunomodulatory effects such as promoting T-cell infiltration and enhancing antigen processing/presentation. Previous studies in our laboratory have demonstrated that ADT also leads to increased expression of the androgen receptor (AR) and increased recognition of prostate tumor cells by AR-specific CD8+T cells. We have also demonstrated that ADT combined with a DNA vaccine encoding the AR significantly slowed tumor growth and improved the survival of prostate tumor-bearing mice. The current study aimed to investigate the impact of the timing and sequencing of ADT with vaccination on the tumor immune microenvironment in murine prostate cancer models to further increase the antitumor efficacy of vaccines. Male FVB mice implanted with Myc-CaP tumor cells, or male C57BL/6 mice implanted with TRAMP-C1 prostate tumor cells, were treated with a DNA vaccine encoding AR (pTVG-AR) and ADT. The sequence of administration was evaluated for its effect on tumor growth, and tumor-infiltrating immune populations were characterized. Vaccination prior to ADT (pTVG-AR → ADT) significantly enhanced antitumor responses and survival. This was associated with increased tumor infiltration by CD4+ and CD8+ T cells, including AR-specific CD8+T cells. Depletion of CD8+T cells prior to ADT significantly worsened overall survival. Following ADT treatment, however, Gr1+ myeloid-derived suppressor cells (MDSCs) increased, and this was associated with fewer infiltrating T cells and reduced tumor growth. Inhibiting Gr1+MDSCs recruitment, either by using a CXCR2 antagonist or by cycling androgen deprivation with testosterone replacement, improved antitumor responses and overall survival. Vaccination prior to ADT significantly improved antitumor responses, mediated in part by increased infiltration of CD8+T cells following ADT. Targeting MDSC recruitment following ADT further enhanced antitumor responses. These findings suggest logical directions for future clinical trials to improve the efficacy of prostate cancer vaccines.
An integrated classification of tumor suppressor <i>IKZF1</i> inactivation and oncogenic activation in Philadelphia chromosome‐like acute lymphoblastic leukemia
Authors: Zicong Huang, Ling Zhang, Xiaoyuan Gong, Jia Li, Shiyu Deng, Zihong Cai, Bingqing Tang, Kangyu Huang, Xin Li, Weihua Zhao, Yang Xu, Li Xuan, Qifa Liu, Ying Wang, Suning Chen, Hongsheng Zhou
Journal: HemaSphere (2024)

Abstract Philadelphia chromosome (Ph)‐like acute lymphoblastic leukemia (ALL) is recognized for its genetic and clinical diversity. In this study, we identified a novel high‐risk subset of Ph‐like ALL, characterized by the activation of oncogenic signaling and the inactivation of the tumor suppressor gene IKZF1 , resulting in a dismal outcome. The association between cytogenetic aberrations and clinical features was assessed on a cohort of 191 patients with Ph‐like ALL. Our findings revealed that patients with inactivation of IKZF1 combined with activation of oncogenic signaling ( CRLF2/EPOR/JAK2 rearrangements or p‐CRKL/p‐STAT5 high expression) had the worst outcome (3‐year overall survival [OS] of 28.8% vs. 80.1% for others, p &lt; 0.001; 2‐year event‐free survival [EFS] of 6.5% vs. 57.0% for others, p &lt; 0.001). Multivariable analysis demonstrated that this high‐risk feature was an independent inferior prognostic factor (adjusted hazard ratio for OS = 4.55, 95% confidence interval [CI]: 2.35–8.81, p &lt; 0.001; adjusted hazard ratio for EFS = 3.27, 95% CI: 1.99–5.39, p &lt; 0.001). Allogeneic hematopoietic stem cell transplantation was associated with improved prognoses in patients within the high‐risk subgroup. In conclusion, this study identified a clinically distinct entity that possesses effective prognostic features and provides potential guidance for refining risk stratification in Ph‐like ALL.
Treatment outcomes in patients with large B‐cell lymphoma after progression to chimeric antigen receptor T‐cell therapy
Authors: Gloria Iacoboni, Josu Iraola‐Truchuelo, Maeve O'Reilly, Víctor Navarro, Tobias Menne, Mi Kwon, Ana África Martín‐López, Sridhar Chaganti, Javier Delgado, Claire Roddie, Ariadna Pérez, Jane Norman, Manuel Guerreiro, Adam Gibb, Ana Carolina Caballero, Caroline Besley, Nuria Martínez‐Cibrián, Alberto Mussetti, Robin Sanderson, Hugo Luzardo, Sunil Iyengar, Jose Maria Sánchez, Ceri Jones, Juan‐Manuel Sancho, Pere Barba, Anne‐Louise Latif, Lucia López‐Corral, Rafael Hernani, Juan Luis Reguera, Anna Sureda, Alejandro Martin Garcia‐Sancho, Mariana Bastos, Pau Abrisqueta, Andrea Kuhnl
Journal: HemaSphere (2024)

Over 60% of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients who receive chimeric antigen receptor (CAR) T cells will experience disease progression. There is no standard next line of therapy and information in this setting is scarce and heterogeneous. We analyzed 387 R/R LBCL patients who progressed after CAR T cells from July 2018 until March 2022 in Spain and the United Kingdom. Median overall survival (OS) was 5.3 months, with significant differences according to the interval between infusion and progression (<2 months [1.9 months], 2-6 months [5.2 months], and >6 months [not reached]). After progression, 237 (61%) patients received treatment. Focusing on the first subsequent therapy, overall (complete) response rates were 67% (38%) for polatuzumab-bendamustine-rituximab (POLA), 51% (36%) for bispecific antibodies (BsAb), 45% (35%) for radiotherapy (RT), 33% (26%) for immune checkpoint inhibitors (ICIs), 25% (0%) for lenalidomide (LENA), and 25% (14%) for chemotherapy (CT). In terms of survival, 12-month progression-free survival and OS was 36.2% and 51.0% for POLA, 32.0% and 50.1% for BsAb, 30.8% and 37.5% for RT, 29.9% and 27.8% for ICI, 7.3% and 20.8% for LENA, and 6.1% and 18.3% for CT. Thirty-two (14%) patients received an allogeneic hematopoietic cell transplant with median OS not reached after a median follow-up of 15.1 months. In conclusion, patients with R/R LBCL who progress within the first 2 months after CAR T-cell therapy have dismal outcomes. Novel targeted agents, such as polatuzumab and BsAbs, can achieve prolonged survival after CAR T-cell therapy failure.
Single-cell proteomics and transcriptomics capture eosinophil development and identify the role of IL-5 in their lineage transit amplification
Authors: Joseph Jorssen, Glenn Van Hulst, Kiréna Mollers, Julien Pujol, Georgios Petrellis, Antonio P. Baptista, Sjoerd Schetters, Frédéric Baron, Jo Caers, Bart N. Lambrecht, Benjamin G. Dewals, Fabrice Bureau, Christophe J. Desmet
Journal: Immunity (2024)
Venetoclax acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against leukemia
Authors: Yan Wang, Beibei Huang, Tingting Liang, Lai Jiang, Mingming Wu, Xinru Liu, Mingming Zhu, Xian Song, Na Zhao, Haiming Wei, Changcheng Zheng, Fang Ni
Journal: Cell Reports Medicine (2024)

Natural killer (NK) cell-based immunotherapy holds promise for cancer treatment; however, its efficacy remains limited, necessitating the development of alternative strategies. Here, we report that venetoclax, an FDA-approved BCL-2 inhibitor, directly activates NK cells, enhancing their cytotoxicity against acute myeloid leukemia (AML) both in vitro and in vivo, likely independent of BCL-2 inhibition. Through comprehensive approaches, including bulk and single-cell RNA sequencing, avidity measurement, and functional assays, we demonstrate that venetoclax increases the avidity of NK cells to AML cells and promotes lytic granule polarization during immunological synapse (IS) formation. Notably, we identify a distinct CD161lowCD218b+ NK cell subpopulation that exhibits remarkable sensitivity to venetoclax treatment. Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-κB pathway, thereby facilitating IS formation in NK cells. Collectively, our findings establish venetoclax as a multifaceted immunometabolic modulator of NK cell function and provide a promising strategy for augmenting NK cell-based cancer immunotherapy.
Bridging Differences in Cohort Analyses of the Relationship between Secondhand Smoke Exposure during Pregnancy and Birth Weight: The Transportability Framework in the ECHO Program
Authors: Andreas M. Neophytou, Jenny Aalborg, Sheryl Magzamen, Brianna F. Moore, Assiamira Ferrara, Margaret R. Karagas, Leonardo Trasande, Dana Dabelea
Journal: Environmental Health Perspectives (2024)

Estimates for the effects of environmental exposures on health outcomes, including secondhand smoke (SHS) exposure, often present considerable variability across studies. Knowledge of the reasons behind these differences can aid our understanding of effects in specific populations as well as inform practices of combining data from multiple studies.
Single Cell Analysis of Human Colonoids Exposed to Uranium-Bearing Dust
Authors: Roger Atanga, Lidia L. Appell, Myranda N. Thompson, Fredine T. Lauer, Adrian Brearley, Matthew J. Campen, Eliseo F. Castillo, Julie G. In
Journal: Environmental Health Perspectives (2024)

Uranium exposure remains an important environmental legacy and physiological health concern, with hundreds of abandoned uranium mines located in the Southwestern United States largely impacting underserved indigenous communities. The negative effects of heavy metals on barrier permeability and inhibition of intestinal epithelial healing have been described; however, transcriptomic changes within the intestinal epithelial cells and impacts on lineage differentiation are largely unknown.
Myosteatosis is closely associated with sarcopenia and significantly worse outcomes in patients with cirrhosis
Authors: Simone Di Cola, Gennaro D’Amico, Paolo Caraceni, Filippo Schepis, Simone Loredana, Pietro Lampertico, Pierluigi Toniutto, Silvia Martini, Sergio Maimone, Antonio Colecchia, Gianluca Svegliati Barone, Carlo Alessandria, Alessio Aghemo, Saveria Lory Crocè, Luigi Elio Adinolfi, Maria Rendina, Lucia Lapenna, Enrico Pompili, Giacomo Zaccherini, Dario Saltini, Massimo Iavarone, Giulia Tosetti, Carolina Martelletti, Veronica Nassisi, Alberto Ferrarese, Ilaria Giovo, Chiara Masetti, Nicola Pugliese, Michele Campigotto, Riccardo Nevola, Manuela Merli, Giulia Iannone, Paola Serri, Gaetano Bertino, Clara Balsano, Nerio Iapadre, Marcello Maida, David Sacerdoti, Leonardo Antonio Natola, Carolina Ciacci, Antonella Santonicola, Raffaele Cozzolongo, Lorenzo Antonio Surace, Anna Ludovica Fracanzani, Annalisa Cespiati, Alessandro Federico, Mario Romeo, Antonio Grieco, Giuseppe Marrone, Luca Vizioli
Journal: Journal of Hepatology (2024)

Sarcopenia and myosteatosis are common in patients with cirrhosis. This study aimed to determine the prevalence of these muscle changes, their interrelations and their prognostic impact over a 12-month period.
Breaking down (and moving beyond) novelty as a trigger of curiosity
Authors: Emily G. Liquin, Tania Lombrozo
Journal: Behavioral and Brain Sciences (2024)

The Novelty Seeking Model (NSM) places "novelty" at center stage in characterizing the mechanisms behind curiosity. We argue that the NSM's conception of novelty is too broad, obscuring distinct constructs. More critically, the NSM underemphasizes triggers of curiosity that better unify these constructs and that have received stronger empirical support: those that signal the potential for useful learning.
Ignoring the role of reiterative processing and worldview transformation leads to exaggeration of the role of curiosity in creativity
Authors: Liane Gabora, Kirthana Ganesh, Iana Bashmakova
Journal: Behavioral and Brain Sciences (2024)

The Novelty-Seeking Model does not address the iterative nature of creativity, and how it restructures one's worldview, resulting in overemphasis on the role of curiosity, and underemphasis on inspiration and perseverance. It overemphasizes the product; creators often seek merely to express themselves or figure out or come to terms with something. We point to inconsistencies regarding divergent and convergent thought.
Prediction error minimization as a common computational principle for curiosity and creativity
Authors: Maxi Becker, Roberto Cabeza
Journal: Behavioral and Brain Sciences (2024)

We propose expanding the authors' shared novelty-seeking basis for creativity and curiosity by emphasizing an underlying computational principle: Minimizing prediction errors (mismatch between predictions and incoming data). Curiosity is tied to the anticipation of minimizing prediction errors through future, novel information, whereas creative AHA moments are connected to the actual minimization of prediction errors through current, novel information.
Mindfulness, curiosity, and creativity
Authors: Francesco Pagnini, Philip Maymin, Ellen Langer
Journal: Behavioral and Brain Sciences (2024)

Curiosity and creativity are manifestations of novelty-seeking mechanisms, closely intertwined and interdependent. This principle aligns seamlessly with the foundational tenets of Langerian mindfulness, which places novelty seeking as a cornerstone. Creativity, curiosity, openness, and flexibility all harmoniously converge in this framework. Spanning over four decades, research in the realm of mindfulness has diligently delved into the intricate interplay among these constructs.
Toward a causal model of curiosity and creativity
Authors: David J. Grüning, Joachim I. Krueger
Journal: Behavioral and Brain Sciences (2024)

Abstract We extend Ivancovsky et al.'s finding on the association between curiosity and creativity by proposing a sequential causal model assuming that (a) curiosity determines the motivation to seek information and that (b) creativity constitutes a capacity to act on that motivation. This framework assumes that both high levels of curiosity and creativity are necessary for information-seeking behavior.
Beyond novelty: Learnability in the interplay between creativity, curiosity and artistic endeavours
Authors: Diana Omigie, Joydeep Bhattacharya
Journal: Behavioral and Brain Sciences (2024)

Abstract Using art and aesthetics as context, we explore the notion that curiosity and creativity emanate from a single novelty-seeking mechanism and outline support for the idea. However, we also highlight the importance of learning progress tracking in exploratory action and advocate for a nuanced understanding that aligns novelty-seeking with learnability. This, we argue, offers a more comprehensive framework of how curiosity and creativity are related.
Models need mechanisms, but not labels
Authors: Seema Prasad, Bernhard Hommel
Journal: Behavioral and Brain Sciences (2024)

The target article proposes a model involving the important but not well-investigated topics of curiosity and creativity. The model, however, falls short of providing convincing explanations of the basic mechanisms underlying these phenomena. We outline the importance of mechanistic thinking in dealing with the concepts outlined in this article specifically and within psychology and cognitive neuroscience in general.
Mood regulation as a shared basis for creativity and curiosity
Authors: Daniel C. Zeitlen, Karen Gasper, Roger E. Beaty
Journal: Behavioral and Brain Sciences (2024)

We extend the work of Ivancovsky et al. by proposing that in addition to novelty seeking, mood regulation goals - including enhancing positive mood and repairing negative mood - motivate both creativity and curiosity. Additionally, we discuss how the effects of mood on state of mind are context-dependent (not fixed), and how such flexibility may impact creativity and curiosity.