tbuckley/cabot-search huggingface dataset:
The use of master protocols for efficient trial design to evaluate radiotherapy interventions: a systematic review
Authors: Alexandra Gilbert, Robert Samuel, Daniel Cagney, David Sebag-Montefiore, Julia Brown, Sarah R Brown
Journal: JNCI Journal of the National Cancer Institute (2024)

The aim of this review was to highlight why the use of master protocols trial design is particularly useful for radiotherapy intervention trials where complex setup pathways (including quality assurance, user training, and integrating multiple modalities of treatment) may hinder clinical advances. We carried out a systematic review according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, reviewing the findings using a landscape analysis. Results were summarized descriptively, reporting on trial characteristics highlighting the benefits, limitations, and challenges of developing and implementing radiotherapy master protocols, with three case studies selected to explore these issues in more detail. Twelve studies were suitable for inclusion (4 platform trials, 3 umbrella trials, and 5 basket trials), evaluating a mix of solid tumor sites in both curative and palliative settings. The interventions were categorized into 1) novel agent and radiotherapy combinations; 2) radiotherapy dose personalization; and 3) device evaluation, with a case study provided for each intervention. Benefits of master protocol trials for radiotherapy intervention include protocol efficiency for implementation of novel radiotherapy techniques; accelerating the evaluation of novel agent drug and radiotherapy combinations; and more efficient translational research opportunities, leading to cost savings and research efficiency to improve patient outcomes. Master protocols offer an innovative platform under which multiple clinical questions can be addressed within a single trial. Due to the complexity of radiotherapy trial setup, cost and research efficiency savings may be more apparent than in systemic treatment trials. Use of this research approach may be the change needed to push forward oncological innovation within radiation oncology.
Does Maternal Diet Influence Future Infant Taste and Odor Preferences? A Critical Analysis
Authors: Catherine A. Forestell
Journal: Annual Review of Nutrition (2024)

The dietary choices a mother makes during pregnancy offer her developing fetus its earliest exposure to the family's culinary preferences. This comprehensive literature review synthesizes five decades of research, which has provided valuable insights into fetal flavor learning. Converging evidence across various species supports the functionality of fetal chemoreceptive systems by the end of gestation, enabling the detection of an extensive array of chemosensory cues derived from the maternal diet and transmitted to the amniotic fluid. The fetus effectively encodes these flavors, resulting in their enhanced acceptance after birth. While existing studies predominantly concentrate on fetal learning about odor volatiles, limited evidence suggests a capacity for learning about gustatory (i.e., taste) properties. Examining whether these prenatal odor, taste, and flavor experiences translate into enduring shifts in dietary behaviors beyond weaning remains a crucial avenue for further investigation.
Neural Control of Naturalistic Behavior Choices
Authors: Samuel K. Asinof, Gwyneth M. Card
Journal: Annual Review of Neuroscience (2024)

In the natural world, animals make decisions on an ongoing basis, continuously selecting which action to undertake next. In the lab, however, the neural bases of decision processes have mostly been studied using artificial trial structures. New experimental tools based on the genetic toolkit of model organisms now make it experimentally feasible to monitor and manipulate neural activity in small subsets of neurons during naturalistic behaviors. We thus propose a new approach to investigating decision processes, termed reverse neuroethology. In this approach, experimenters select animal models based on experimental accessibility and then utilize cutting-edge tools such as connectomes and genetically encoded reagents to analyze the flow of information through an animal's nervous system during naturalistic choice behaviors. We describe how the reverse neuroethology strategy has been applied to understand the neural underpinnings of innate, rapid decision making, with a focus on defensive behavioral choices in the vinegar fly Drosophila melanogaster.
Adverse Food Reactions: Physiological and Ecological Perspectives
Authors: Lisa L. Korn, Vassily I. Kutyavin, Nathaniel D. Bachtel, Ruslan Medzhitov
Journal: Annual Review of Nutrition (2024)

While food is essential for survival, it can also cause a variety of harmful effects, ranging from intolerance to specific nutrients to celiac disease and food allergies. In addition to nutrients, foods contain myriads of substances that can have either beneficial or detrimental effects on the animals consuming them. Consequently, all animals evolved defense mechanisms that protect them from harmful food components. These “antitoxin” defenses have some parallels with antimicrobial defenses and operate at a cost to the animal's fitness. These costs outweigh benefits when defense responses are exaggerated or mistargeted, resulting in adverse reactions to foods. Additionally, pathological effects of foods can stem from insufficient defenses, due to unabated toxicity of harmful food components. We discuss the structure of antitoxin defenses and how their failures can lead to a variety of adverse food reactions.
Motor neuron disease: improving quality of life for patients
Authors: None The Lancet
Journal: The Lancet (2024)

This week, The Lancet published the findings from COMMEND, the largest clinical trial to date of a psychological intervention for people with motor neuron disease (MND). This devastating, incurable neurodegenerative disease results from the loss of motor neurons in the motor cortex and spinal cord, causing progressive paralysis and eventual death. More than half of people with MND die within 2 years of a diagnosis. Rates of depression and anxiety in patients are high. Given the dire prognosis, interventions that can improve the quality of remaining life for patients are vital.
Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK
Authors: Rebecca L Gould, Christopher J McDermott, Benjamin J Thompson, Charlotte V Rawlinson, Matt Bursnall, Mike Bradburn, Pavithra Kumar, Emily J Turton, David A White, Marc A Serfaty, Christopher D Graham, Lance M McCracken, Laura H Goldstein, Ammar Al-Chalabi, Richard W Orrell, Tim Williams, Rupert Noad, Idris Baker, Christina Faull, Thomas Lambert, Suresh K Chhetri, John Ealing, Anthony Hanratty, Aleksandar Radunovic, Nushan Gunawardana, Gail Meadows, George H Gorrie, Tracey Young, Vanessa Lawrence, Cindy Cooper, Pamela J Shaw, Robert J Howard, Penny Andreou, Dynameni Androulaki-Korakaki, Claire Blakeley, Gary Bridges, Iain Campbell, Brittany Davenport, Annily Dee, Nicola Drewry, John Flood, Annemieke Fox, Melissa Girling, Ruth Glew, Nick Hartley, Sian Hocking, Mark Howell, Anju Keetharuth, Selina Makin, Jessica Marsh, Emily Mayberry, Alexa McDonald, Roy McPartland, Steven Meldrum, Amanda Mobley, Donnchadh Murphy, Marie Claire O'Brien, Mark Oliver, Darshna Patel, Emma Phipps, Jessica Read, Rhys Roberts, Natasha Rooney, Carla Smith, Jo Statham, Cara Thompson, Priya Varma, Anne Marie Walker, Simon Waterhouse
Journal: The Lancet (2024)
Department of Error
Journal: The Lancet (2024)

who were having surgery for their hip hemiarthroplasty with the opportunity to participate (ie, to deliberately include a sample representative of the hip fracture population as a whole). 5 We agree that patients with, for example, diabetes are at higher risk of surgical site infection.However, any such pre injury predisposition would have been balanced by the random allocation of participants to the two treatment groups.This balance is shown in the baseline characteristics table, which, for example, shows that 16•2% of participants in the single antibiotic group had diabetes and 16•7% of participants in the highdose, dual antibiotic group had diabetes.Regarding the subgroup analyses proposed by Chu and colleagues, given the much smaller numbers of participants in these subgroups, any such analyses would have been underpowered to detect differences in the rate of deep surgical site infection.Therefore, we did not include such analyses in our prespecified statistical analysis plan for the WHiTE 8 trial.We would, however, agree with the authors that further investigation of the interaction between baseline patient characteristics and deep surgical site infection is warranted and we have plans to explore these data further in future work.
Decolonising global health: why the new Pandemic Agreement should have included the principle of subsidiarity
Authors: Thana C de Campos-Rudinsky, Sarah L Bosha, Daniel Wainstock, Sharifah Sekalala, Sridhar Venkatapuram, Caesar Alimsinya Atuire
Journal: The Lancet Global Health (2024)

The negotiations for the WHO Pandemic Agreement have brought attention to issues of racism and colonialism in global health. Although the agreement aims to promote global solidarity, it fails to address these deeply embedded problems. This Viewpoint argues that not including the principle of subsidiarity into Article 4 of the agreement as a pragmatic strategy was a missed opportunity to decolonise global health governance and promote global solidarity. Subsidiarity, as a structural principle, empowers local units to make decisions and address issues at their level, fostering collaboration, coordination, and cooperation. By integrating subsidiarity, the agreement could have ensured contextually appropriate responses, empowered local communities, and achieved justice in global health. This paper discusses the elements of subsidiarity—namely, agency and non-abandonment—and highlights the need to strike a balance between them. It also maps the principle of subsidiarity within the Pandemic Agreement, emphasising the importance of creating a practical framework for its implementation. By integrating subsidiarity into the agreement, a just and decolonialised approach to pandemic prevention and response could have been closer to being realised, promoting global solidarity and addressing health inequities.
Offline: A peculiar indifference
Authors: Richard Horton
Journal: The Lancet (2024)

"Everything I thought was wrong." With those powerful yet disarming words, Linda Villarosa begins her study of America's most intractable pathology—racism. Under the Skin: Racism, Inequality, and the Health of Our Nation was published in 2022 and its messages should be central to the political debates emerging today, in advance of the US Presidential election later this year. Racism, she argues, "is the American problem in need of an American solution". But racism is, of course, more than an American problem.
Phase II Clinical Trial of Intravenous Levothyroxine to Mitigate Pharyngocutaneous Fistula in Euthyroid Patients Undergoing Salvage Laryngectomy
Authors: Molly E. Heft Neal, Catherine T. Haring, Emily Bellile, Craig C. Jaffe, Andrew G. Shuman, Steven B. Chinn, Chaz L. Stucken, Kelly M. Malloy, Keith A. Casper, Mark E.P. Prince, Douglas B. Chepeha, Andrew J. Rosko, Matthew E. Spector
Journal: Clinical Cancer Research (2024)

Patients undergoing head and neck cancer surgery after prior radiation or chemoradiation are at high risk for wound complications. Hypothyroidism is a known risk factor for wound complications, especially fistulae after salvage total laryngectomy. The purpose of this phase II clinical trial is to investigate the effect of perioperative intravenous levothyroxine supplementation on wound complications in patients undergoing salvage total laryngectomy.
MYC Inhibition Potentiates CD8+ T Cells Against Multiple Myeloma and Overcomes Immunomodulatory Drug Resistance
Authors: Lorraine N. Davis, Zachary J. Walker, Lauren T. Reiman, Sarah E. Parzych, Brett M. Stevens, Craig T. Jordan, Peter A. Forsberg, Daniel W. Sherbenou
Journal: Clinical Cancer Research (2024)

Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, are a cornerstone of multiple myeloma (MM) therapies, yet the disease inevitably becomes refractory. IMiDs exert cytotoxicity by inducing cereblon-dependent proteasomal degradation of IKZF1 and IKZF3, resulting in downregulation of the oncogenic transcription factors IRF4 and MYC. To date, clinical IMiD resistance independent of cereblon or IKZF1/3 has not been well explored. Here, we investigated the roles of IRF4 and MYC in this context.
Biomarker identification and risk prediction model development for differentiated thyroid carcinoma lung metastasis based on primary lesion proteomics
Authors: Xiaoqi Peng, Hongbo Zhao, Lijuan Ye, Fei Hou, Zihan Yi, Yanxin Ren, Lin Lu, Fukun Chen, Juan Lv, Yinghui Wang, Haolin Cai, Xihua Zheng, Qing Yang, Ting Chen
Journal: Clinical Cancer Research (2024)

The rising global high incidence of differentiated thyroid carcinoma (DTC) has led to a significant increase in patients presenting with lung metastasis of DTC (LMDTC). This population poses a significant challenge in clinical practice, necessitating the urgent development of effective risk stratification methods and predictive tools for lung metastasis.
Clinical and Genomic-Based Decision Support System to Define the Optimal Timing of Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes
Authors: Cristina Astrid Tentori, Caterina Gregorio, Marie Robin, Nico Gagelmann, Carmelo Gurnari, Somedeb Ball, Juan Carlos Caballero Berrocal, Luca Lanino, Saverio D'Amico, Marta Spreafico, Giulia Maggioni, Erica Travaglino, Elisabetta Sauta, Manja Meggendorfer, Lin-Pierre Zhao, Alessia Campagna, Victor Savevski, Armando Santoro, Najla Al Ali, David Sallman, Francesc Sole, Guillermo Garcia-Manero, Ulrich Germing, Nicolaus Kroger, Shahram Kordasti, Valeria Santini, Guillermo Sanz, Wolfgang Kern, Uwe Platzbecker, Maria Diez-Campelo, Jaroslaw P. Maciejewski, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Amer M. Zeidan, Gastone Castellani, Rami Komrokji, Francesca Ieva, Matteo Giovanni Della Porta, Massimo Bernardi, Carmen Di Grazia, Luca Vago, Giulia Rivoli, Lorenza Borin, Patrizia Chiusolo, Luisa Giaccone, Maria Teresa Voso, Jan Philipp Bewersdorf, Olivier Nibourel, Marina Díaz Beyá, Andrés Jerez, Francisca Hernández, Kyra Velázquez Kennedy, Blanca Xicoy, Marta Ubezio, Antonio Russo, Gabriele Todisco, Daniele Mannina, Stefania Bramanti, Matteo Zampini, Elena Riva, Marilena Bicchieri, Gianluca Asti, Filippo Viviani, Alessandro Buizza, Benedetta Tinterri, Anne-Sophie Kubasch, Andrea Bacigalupo, Anna Maria Raiola, Alessandro Rambaldi, Francesco Passamonti, Fabio Ciceri
Journal: Journal of Clinical Oncology (2024)

Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M).
First-Line Nivolumab and Relatlimab Plus Chemotherapy for Gastric or Gastroesophageal Junction Adenocarcinoma: The Phase II RELATIVITY-060 Study
Authors: Susanna Hegewisch-Becker, Guillermo Mendez, Joseph Chao, Radim Nemecek, Kynan Feeney, Eric Van Cutsem, Salah-Eddin Al-Batran, Wasat Mansoor, Nicholas Maisey, Roberto Pazo Cid, Matthew Burge, David Perez-Callejo, R. William Hipkin, Sourav Mukherjee, Ming Lei, Hao Tang, Satyendra Suryawanshi, Ronan J. Kelly, Niall C. Tebbutt
Journal: Journal of Clinical Oncology (2024)

Open-label phase II study (RELATIVITY-060) to investigate the efficacy and safety of first-line nivolumab, a PD-1-blocking antibody, plus relatlimab, a lymphocyte-activation gene 3 (LAG-3)-blocking antibody, plus chemotherapy in patients with previously untreated advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC).
AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML
Authors: Ece Canan Sayitoglu, Bogdan A. Luca, Allison Paige Boss, Benjamin Craig Thomas, Robert Arthur Freeborn, Molly Javier Uyeda, Pauline Ping Chen, Yusuke Nakauchi, Colin Waichler, Norman Lacayo, Rosa Bacchetta, Ravindra Majeti, Andrew J. Gentles, Alma-Martina Cepika, Maria Grazia Roncarolo
Journal: Leukemia (2024)

Abstract T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human-engineered cytotoxic CD4 + T cells. Single-cell RNA-seq of primary AML samples and CD4 + T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4 + T cell killing. Resistance-associated AML programs were enriched in AML patients with poor survival, and killing-resistant AML cells did not engage T cells in vitro. Killing-sensitive AML potently activated T cells before being killed, and upregulated ICAM1 , a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing by primary ex vivo-isolated CD8 + T cells in vitro, and engineered CD4 + T cells in vitro and in vivo. While AML heterogeneity implies that multiple factors may determine their sensitivity to T cell killing, these data show that ICAM1 acts as an immune trigger, allowing T cell killing, and could play a role in AML patient survival in vivo.
PD-1 expression contributes to functional impairment of NK cells in patients with B-CLL
Authors: Mustafa Farhat, Wayne Croft, Helen M. Parry, Kriti Verma, Francesca A. M. Kinsella, Jinsong Xu, David Bone, Tina McSkeane, Shankara Paneesha, Guy Pratt, Paul Moss, Jianmin Zuo
Journal: Leukemia (2024)

B cell chronic lymphocytic leukemia (B-CLL) is a common leukemia subtype [1] and compromised immune function is a major clinical problem leading to increased mortality among patients [2].Natural killer (NK) cells recognize and kill transformed or virally infected cells through mechanisms including granule-mediated cell lysis, cytokine release, and antibody-dependent cell-mediated cytotoxicity (ADCC) [3,4].However, NK cells are frequently dysfunctional in patients with cancer, and this profile is also seen in patients with CLL.An imbalance in the relative expression of activating and inhibitory receptors is an important mechanism of immune evasion, with decreased expression of the dominant activatory receptors NKG2D, DNAM-1 and NCRs as a common feature.This phenotype is associated with reduced degranulation and impaired lysis of target cells [5][6][7].Recent studies have shown that NK cells can express a range of inhibitory checkpoint proteins that may also negatively regulate the activity of NK cells.In particular, PD-1 expression has been demonstrated in patients with several cancer subtypes, including hematological malignancies [8,9], and is associated with functional impairment which can be reversed by PD-1 blockade [10,11].It is well established that engagement of PD-1 on T cells with its PD-L1 ligand can inhibit T cell functional responses to CLL tumor cells and mediate an exhausted T cell phenotype [12,13].Indeed, PD-1 blockade in patients with B-CLL, either as a single agent therapy or in combination with ibrutinib, has elicited clinical responses [14], although the role of PD-1 on NK cells in patients with B-CLL has not been explored.Here we investigated the expression of a range of checkpoint receptors, including PD-1, on NK cells from B-CLL patients.We characterized the phenotype and functional capacity of PD-1 pos NK cells compared to their PD-1 neg counterparts and evaluated the impact of PD-1:PD-L1 blockade on the tumor-specific activity of NK cells against both primary NK cells and NK lines.Initial studies used flow cytometry to determine the expression of checkpoint receptors on NK cells from 72 untreated stage A CLL patients and age-matched healthy controls (HDs) (Clinical demographic information in Supplementary Table ).As such, the single
Functional divergence in orthologous transcription factors: insights from AtCBF2/3/1 and OsDREB1C
Authors: Deyin Deng, Yixin Guo, Liangyu Guo, Chengyang Li, Yuqi Nie, Shuo Wang, Wenwu Wu
Journal: Molecular Biology and Evolution (2024)

Abstract Despite traditional beliefs of orthologous genes maintaining similar functions across species, growing evidence points to their potential for functional divergence. C-repeat binding factors/dehydration-responsive element binding protein 1s (CBFs/DREB1s) are critical in cold acclimation, with their overexpression enhancing stress tolerance but often constraining plant growth. In contrast, a recent study unveiled a distinctive role of rice OsDREB1C in elevating nitrogen use efficiency (NUE), photosynthesis, and grain yield, implying functional divergence within the CBF/DREB1 orthologs across species. Here, we delve into divergent molecular mechanisms of OsDREB1C and AtCBF2/3/1 by exploring their evolutionary trajectories across rice and Arabidopsis genomes, regulatomes, and transcriptomes. Evolutionary scrutiny shows discrete clades for OsDREB1C and AtCBF2/3/1, with the Poaceae-specific DREB1C clade mediated by a transposon event. Genome-wide binding profiles highlight OsDREB1C's preference for GCCGAC compared to AtCBF2/3/1's preference for A/GCCGAC, a distinction determined by R12 in the OsDREB1C AP2/ERF domain. Cross-species multiomic analyses reveal shared gene orthogroups (OGs) and underscore numerous specific OGs uniquely bound and regulated by OsDREB1C, implicated in NUE, photosynthesis, and early flowering, or by AtCBF2/3/1, engaged in hormone and stress responses. This divergence arises from gene gains/losses (∼16.7% to 25.6%) and expression reprogramming (∼62.3% to 66.2%) of OsDREB1C- and AtCBF2/3/1-regulated OGs during the extensive evolution following the rice–Arabidopsis split. Our findings illustrate the regulatory evolution of OsDREB1C and AtCBF2/3/1 at a genomic scale, providing insights on the functional divergence of orthologous transcription factors following gene duplications across species.