tbuckley/cabot-search huggingface dataset:
AZD3152 neutralizes SARS-CoV-2 historical and contemporary variants and is protective in hamsters and well tolerated in adults
Authors: Yingyun Cai, Seme Diallo, Kim Rosenthal, Kuishu Ren, Daniel J. Flores, Andrew Dippel, Vaheh Oganesyan, Nydia van Dyk, Xiaoru Chen, Erin Cantu, Rakesh Choudhary, Michal Sulikowski, Hibret Adissu, Bhavna Chawla, Swagata Kar, Chang Liu, Aiste Dijokaite-Guraliuc, Juthathip Mongkolsapaya, Saravanan Rajan, Yueh-Ming Loo, Rohini Beavon, Chris Webber, Lee-Jah Chang, Steven Thomas, Lindsay Clegg, Huixia Zhang, Gavin R. Screaton, Nora Philbin, Mark Harre, Abdulhafez Selim, Nuria Martinez-Alier, Alison Uriel, Taylor S. Cohen, John L. Perez, Mark T. Esser, Wade Blair, Joseph R. Francica
Journal: Science Translational Medicine (2024)

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in variants that can escape neutralization by therapeutic antibodies. Here, we describe AZD3152, a SARS-CoV-2–neutralizing monoclonal antibody designed to provide improved potency and coverage against emerging variants. AZD3152 binds to the back left shoulder of the SARS-CoV-2 spike protein receptor binding domain and prevents interaction with the human angiotensin-converting enzyme 2 receptor. AZD3152 potently neutralized a broad panel of pseudovirus variants, including the currently dominant Omicron variant JN.1 but has reduced potency against XBB subvariants containing F456L. In vitro studies confirmed F456L resistance and additionally identified T415I and K458E as escape mutations. In a Syrian hamster challenge model, prophylactic administration of AZD3152 protected hamsters from weight loss and inflammation-related lung pathologies and reduced lung viral load. In the phase 1 sentinel safety cohort of the ongoing SUPERNOVA study ( ClinicalTrials.gov : NCT05648110), a single 600-mg intramuscular injection of AZD5156 (containing 300 mg each of AZD3152 and cilgavimab) was well tolerated in adults through day 91. Observed serum concentrations of AZD3152 through day 91 were similar to those observed with cilgavimab and consistent with predictions for AZD7442, a SARS-CoV-2–neutralizing antibody combination of cilgavimab and tixagevimab, in a population pharmacokinetic model. On the basis of its pharmacokinetic characteristics, AZD3152 is predicted to provide durable protection against symptomatic coronavirus disease 2019 caused by susceptible SARS-CoV-2 variants, such as JN.1, in humans.
Proteomic analysis of Alzheimer’s disease cerebrospinal fluid reveals alterations associated with <i>APOE</i> ε4 and atomoxetine treatment
Authors: Eric B. Dammer, Anantharaman Shantaraman, Lingyan Ping, Duc M. Duong, Ekaterina S. Gerasimov, Suda Parimala Ravindran, Valborg Gudmundsdottir, Elisabet A. Frick, Gabriela T. Gomez, Keenan A. Walker, Valur Emilsson, Lori L. Jennings, Vilmundur Gudnason, Daniel Western, Carlos Cruchaga, James J. Lah, Thomas S. Wingo, Aliza P. Wingo, Nicholas T. Seyfried, Allan I. Levey, Erik C. B. Johnson
Journal: Science Translational Medicine (2024)

Alzheimer’s disease (AD) is currently defined by the aggregation of amyloid-β (Aβ) and tau proteins in the brain. Although biofluid biomarkers are available to measure Aβ and tau pathology, few markers are available to measure the complex pathophysiology that is associated with these two cardinal neuropathologies. Here, we characterized the proteomic landscape of cerebrospinal fluid (CSF) changes associated with Aβ and tau pathology in 300 individuals using two different proteomic technologies—tandem mass tag mass spectrometry and SomaScan. Integration of both data types allowed for generation of a robust protein coexpression network consisting of 34 modules derived from 5242 protein measurements, including disease-relevant modules associated with autophagy, ubiquitination, endocytosis, and glycolysis. Three modules strongly associated with the apolipoprotein E ε4 ( APOE ε4) AD risk genotype mapped to oxidant detoxification, mitogen-associated protein kinase signaling, neddylation, and mitochondrial biology and overlapped with a previously described lipoprotein module in serum. Alterations of all three modules in blood were associated with dementia more than 20 years before diagnosis. Analysis of CSF samples from an AD phase 2 clinical trial of atomoxetine (ATX) demonstrated that abnormal elevations in the glycolysis CSF module—the network module most strongly correlated to cognitive function—were reduced by ATX treatment. Clustering of individuals based on their CSF proteomic profiles revealed heterogeneity of pathological changes not fully reflected by Aβ and tau.
TRPML1 triggers ferroptosis defense and is a potential therapeutic target in AKT-hyperactivated cancer
Authors: Hai-Liang Zhang, Bing-Xin Hu, Zhi-Peng Ye, Zhi-Ling Li, Shan Liu, Wen-Qing Zhong, Tian Du, Dong Yang, Jia Mai, Li-Chao Li, Yu-Hong Chen, Xian-Ying Zhu, Xuan Li, Gong-Kan Feng, Xiao-Feng Zhu, Rong Deng
Journal: Science Translational Medicine (2024)

Targeting ferroptosis for cancer therapy has slowed because of an incomplete understanding of ferroptosis mechanisms under specific pathological contexts such as tumorigenesis and cancer treatment. Here, we identify TRPML1-mediated lysosomal exocytosis as a potential anti-ferroptotic process through genome-wide CRISPR-Cas9 activation and kinase inhibitor library screening. AKT directly phosphorylated TRPML1 at Ser 343 and inhibited K552 ubiquitination and proteasome degradation of TRPML1, thereby promoting TRPML1 binding to ARL8B to trigger lysosomal exocytosis. This boosted ferroptosis defense of AKT-hyperactivated cancer cells by reducing intracellular ferrous iron and enhancing membrane repair. Correlation analysis and functional analysis revealed that TRPML1-mediated ferroptosis resistance is a previously unrecognized feature of AKT-hyperactivated cancers and is necessary for AKT-driven tumorigenesis and cancer therapeutic resistance. TRPML1 inactivation or blockade of the interaction between TRPML1 and ARL8B inhibited AKT-driven tumorigenesis and cancer therapeutic resistance in vitro and in vivo by promoting ferroptosis. A synthetic peptide targeting TRPML1 inhibited AKT-driven tumorigenesis and enhanced the sensitivity of AKT-hyperactivated tumors to ferroptosis inducers, radiotherapy, and immunotherapy by boosting ferroptosis in vivo. Together, our findings identified TRPML1 as a therapeutic target in AKT-hyperactivated cancer.
New government drug repurposing programs: Opportunities and uncertainties
Authors: Johnathon Liddicoat, Ashleigh Hamidzadeh, Kathleen Liddell, Marco Schito, David Simon, Mateo Aboy, Timo Minssen
Journal: Science Translational Medicine (2024)

Drug repurposing can be cheaper and faster than developing new compounds. Yet, it remains underused, partially because of regulatory and intellectual property challenges. Policy-makers in the United States and Europe have created seven drug development programs that aim to overcome these challenges using a variety of different strategies.
Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency
Authors: John V. Pluvinage, Thomas Ngo, Camille Fouassier, Maura McDonagh, Brandon B. Holmes, Christopher M. Bartley, Sravani Kondapavulur, Charlotte Hurabielle, Aaron Bodansky, Vincent Pai, Sam Hinman, Ava Aslanpour, Bonny D. Alvarenga, Kelsey C. Zorn, Colin Zamecnik, Adrian McCann, Andoni I. Asencor, Trung Huynh, Weston Browne, Asritha Tubati, Michael S. Haney, Vanja C. Douglas, Martineau Louine, Bruce A.C. Cree, Stephen L. Hauser, William Seeley, Sergio E. Baranzini, James A. Wells, Serena Spudich, Shelli Farhadian, Prashanth S. Ramachandran, Leslie Gillum, Chadwick M. Hales, Julie Zikherman, Mark S. Anderson, Jinoos Yazdany, Bryan Smith, Avindra Nath, Gina Suh, Eoin P. Flanagan, Ari J. Green, Ralph Green, Jeffrey M. Gelfand, Joseph L. DeRisi, Samuel J. Pleasure, Michael R. Wilson
Journal: Science Translational Medicine (2024)

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.
Gut microbiota signatures of vulnerability to food addiction in mice and humans
Authors: Solveiga Samulėnaitė, Alejandra García-Blanco, Jordi Mayneris-Perxachs, Laura Domingo-Rodríguez, Judit Cabana-Domínguez, Noèlia Fernàndez-Castillo, Edurne Gago-García, Laura Pineda-Cirera, Aurelijus Burokas, Jose Espinosa-Carrasco, Silvia Arboleya, Jessica Latorre, Catherine Stanton, Koji Hosomi, Jun Kunisawa, Bru Cormand, Jose Manuel Fernández-Real, Rafael Maldonado, Elena Martín-García
Journal: Gut (2024)

Food addiction is a multifactorial disorder characterised by a loss of control over food intake that may promote obesity and alter gut microbiota composition. We have investigated the potential involvement of the gut microbiota in the mechanisms underlying food addiction.
<i>MUC5B</i> Idiopathic Pulmonary Fibrosis Risk Variant Promotes a Mucosecretory Phenotype and Loss of Small Airway Secretory Cells
Authors: Jonathan S Kurche, Carlyne D Cool, Rachel Z Blumhagen, Evgenia Dobrinskikh, David Heinz, Jeremy A Herrera, Ivana V Yang, David A. Schwartz
Journal: American Journal of Respiratory and Critical Care Medicine (2024)
International medical graduates (IMG) representation at international oncology conference meetings.
Authors: Arya Mariam Roy, Ziad Bakouny, Nazli Dizman, Zeynep Irem Ozay, Bhavesh Mohan Lal, Rashad Nawfal, Marc Eid, Razane El Hajj Chehade, Marc Machaalani, Ayesha Butt, Charu Aggarwal, Tanios S. Bekaii-Saab, Mariana Chavez-MacGregor, Gilberto Lopes, Ariela Lucy Marshall, Martina Cathryn Murphy, Taofeek K. Owonikoko, Alfred Ian Lee, Toni K. CHOUEIRI
Journal: Journal of Clinical Oncology (2024)

9000 Background: Despite IMGs accounting for up to one-third of all practicing oncologists in the United States, little is known about their contributions to presentations at international oncology meetings, such as the American Society of Clinical Oncology (ASCO). Therefore, we investigated the representation of IMGs in invited faculty roles at ASCO Annual Meetings. Methods: Speaker presentation details at ASCO 2022 and 2023 Annual Meetings were collected using publicly available program guides. We collected presentation-level variables of invited faculty roles (discussant, moderator, chairmanship, session topic presenter) and original research type (oral abstract, poster discussion, plenary session). Speaker-level variables comprised presumed gender, academic rank, and institution. Speakers were categorized into the following groups - American Medical Graduate (AMG): currently affiliated with a US institution, completed medical school in the US; IMG: affiliated with a US institution, completed medical school outside the US; non-US based speakers: affiliated with an institution outside the US; non-MD speakers. Univariable and multivariable analyses were employed to assess factors associated with the selection of presenters for invited faculty roles. Results: A total of 3337 presentations (1649 from 2022, 1688 from 2023) were included. 71.6% of the speakers were US-based, 56.6% were male and 40.5% were full professors. The highest proportion of podium presentations was by AMGs (48.5%), followed by non-US based (28.3%), IMGs (14.1%), and non-MD (9.1%) speakers. 57% of IMG presentations consisted of original research compared to 48.7% for AMGs (Table). Notably, compared to AMGs, IMGs were significantly less likely to be included in invited faculty roles (odds ratio [OR] 0.72 [95% CI 0.58 – 0.88], p &lt;0.01), a finding that remained significant after accounting for gender and academic rank (adjusted OR 0.75 [0.61 – 0.94], p= 0.01). Conclusions: Relative to IMGs’ original research output, IMGs appear to receive less invitations for ASCO Annual Meeting invited faculty roles compared to AMGs. Our findings suggest potential under-representation and under-recognition of IMGs in these roles, despite their contributions to the oncology workforce in the US. [Table: see text]
Utilizing data to drive solutions for healthcare worker wellbeing.
Authors: Amy Gallagher, Julia Faller, Kristin Cianchetti, Steven J. Nurkin, Gary Mann, Amy Allen Case
Journal: Journal of Clinical Oncology (2024)

9012 Background: Oncology Healthcare Workers (HCWs) provide extraordinary treatment to patients coping with distinct challenges. While experiences of burnout, compassion fatigue, and moral distress are not new, the COVID-19 pandemic further emphasized that intentional effort is needed to mitigate these negative work-related consequences. While Roswell Park Comprehensive Cancer Center (Roswell) initiated pre-pandemic grassroots efforts to examine burnout and build organizational resilience, deliberate resources were deemed necessary to support HCW resilience and well-being. Roswell committed to building a division solely focused on employee resiliency and burnout prevention. Methods: Qualitative and quantitative data were collected to identify organizational needs and pain points. Qualitative data was collected by the Resiliency Director who held over 100 conversations in 100 days with diverse personnel across the institute. Discussions focused on two questions (e.g., What’s working well? and What are the pebbles in employees’ shoes?) to assess organizational strengths are growth areas. Quantitative data was obtained through the Mini-Z, a validated burnout screener. All employees were emailed an invitation to take the survey over an 8-week period starting in December 2022. Concerned employees could self-refer to the Employee Assistance Program at the screener’s conclusion. Results: Qualitative data was categorized into Maslach's burnout drivers (workload, relationships, recognition, fairness, autonomy, and values conflict). Highlights included staff shortages, eroding of relationships during the pandemic, siloed communication, inconsistent recognition, micromanagement, and use of antiquated systems. Mini-Z results are displayed in the table. An interactive dashboard helped further examine demographics, role, and departmental data. Press Ganey employee engagement data also supported improvements for staff well-being, transparent communication, collaboration, recognition, and enhanced technology. Conclusions: Quantitative and qualitative data can drive individual, departmental, and organizational interventions to support HCW well-being. The newly established MedStaff Satisfaction and Wellness group is using the data to focus on recognizing the needs of the medical staff on an organizational level and is preparing to offer solutions to key stakeholders. HCWs are now incorporating activities aiming to build psychological safety, enhance communication, and advance well-being into their work routines through training, wellness activities, and emotional support. The Mini-Z screener has been made available in the Employee Health Portal permitting ease of personal reassessment. [Table: see text]
Keeping health care professionals healthy: Systematic strategies for mitigation, wellness, and burnout prevention.
Authors: Juee Kotwal, Natalie Schnaitmann, Stefanie Mooney, Lucia Lemus Mejia, Joanna Luna, Daniela Mejia, Karen L. Clark, Matthew J. Loscalzo, William Dale
Journal: Journal of Clinical Oncology (2024)

9013 Background: Health care professionals are deeply committed to the compassionate care of their patients. However, the same level of caring and compassion is not typically extended to colleagues, much less toward themselves. Escalating issues include: burnout, demoralization, personal conflicts, early retirement, and high turnover. Literature and training offer few suggestions to proactively address these complexities. There is a lack of attention to creating truly healthy work environments, with strategic infrastructure to enhance leadership, communication, and relationship among team members that directly impact wellness, engagement, and productivity. We will present the Staff Leadership Model (SLM) that integrates courageous and compassionate communication to foster healthier work environments, including how to implement and sustain the necessary infrastructure. Methods: In 4 large academic cancer settings, evolving iterations of the SLM were developed since 1995, focusing on maximizing inherent human capacities. In 2007, the Department of Supportive Care Medicine (DSCM), an interdisciplinary department at City of Hope (COH), systematically integrated the SLM. Specific processes, such as onboarding and skills training, regularly scheduled, open and honest communication, ways of working agreements, and performance evaluations that actively support value-driven behaviors, were implemented. Tailored interpersonal strategies were implemented, such as small group democratic meeting structure that equalizes all members, and problem-solving skills to deal with conflict. Clinicians received annual Press Ganey-administered surveys that measured clinician engagementas well as clinician resilience, measuring the ability to disconnect from work and ability to find meaning in their work, providing early warning indicators of burnout. Results: Sustained success has been demonstrated: 1) 5 years top tier clinician/staff engagement scores, with increase from 4.24 in 2022 to 4.32 in 2023 (+0.14 vs. overall COH) ; 2) 3.96 resilience index score vs. 3.80 overall COH in 2023 (3.23 decompression score vs. COH 2.94 and 4.69 activation score vs. COH 4.65); 3) Growth of the department from 25 professionals in 2007 to 170+ in 2024; 4) A clearly-defined clinical triage created through the expertise of the professionals; and 5) Staff creativity and leadership resulting in the creation and consistent growth of innovative, market-differentiating programs. Conclusions: Results support the relationship between the SLM and healthier work environments that increase engagement and decrease burnout, as reflected by the consistently high scores. The resilience index is a new survey measure with one year data. Cause-effect relation will continue to be evaluated. Overall, SLM creates a culture of health, wellness, support, and optimized individuals and teams.
Hematology/oncology clinical investigator training: Is current model of education adequate?
Authors: Ardaman Shergill, Kirk Cahill, Ajay Major, Anand Ashwin Patel, Kenneth Stuart Cohen, Peter H. O'Donnell
Journal: Journal of Clinical Oncology (2024)

9005 Background: Clinical investigator training (CIT) is commonly performed in an apprenticeship manner rather than following a prospective education model. This may lead to disparities in educational prospects. There is greater accesiblity for training opportunites prevailing in larger academic institutions – an advantage not always within reach for majority of oncology patients and professionals. Lack of predefined standard competencies during fellowship training may lead to significant heterogeneity, weaken the current pipeline, and decrease the number of principal investigators (PIs) for clinical trials. We performed a national needs assessment to understand oncology trainee and faculty perceptions of CIT. Methods: Program directors and leaders at 102 U.S. hematology/oncology (hem/onc) fellowship programs were contacted via email to invite their respective trainees and faculty to answer a 32-question cross-sectional survey. The study was IRB excempt. The survey was developed with the University of Chicago Survey Lab. Four thematic areas were interrogated: current level of experience in CI, knowledge of PI roles and responsibilities (R/R), areas of perceived weakness/lack of confidence related to CI, and interest in a course that teaches CI. Response frequencies and descriptive statistics were analyzed, with the goal of informing future targeted educational initiatives. Results: 207 respondents from 47/102 (46%) institutions completed the survey between 5/2023 – 11/2023. Respondents included 92 (40%) trainees and 137 (60%) attendings, 47% were men, 47% women and 57% had more than 9 years of experience as an attending post-speciality training. Among attendings, only 4.4% reported never participating in CIT, compared to 55.4% of trainees. Informal or “on the job” teaching was the most common method of learning PI R/R with response rate of 58% in attendings and 62% in trainees. Trainees reported lack of confidence and need for education in all aspects of CIT, and 85% indicated high level of interest in enrolling in a CIT course. Most attendings reported lack of confidence in areas of budget development (57%), quality of life (70%) and translational correlatives (51%). Others reported feeling weaknesses in designing primary and secondary end points (32%), letter of intent writing (33%) and creating protocols (31%). 53% of the attendings were interested in enrolling in a CIT course. Conclusions: To our knowledge, this is the first reported survey formally assessing current perceptions of preparedness in CIT within hem/onc in the U.S. Our findings strongly indicate that CIT educational gaps exist, even for attendings with prior CIT experience, and that training deficits are marked for trainees. A structured, practical, and widely-accessible CIT program is urgently needed to prepare the future hem/onc workforce. Acknowledgement: MERITS program and Section of Hem/Onc at University of Chicago.