tbuckley/cabot-search huggingface dataset:
Electroencephalography-Guided Anesthesia and Delirium in Older Adults After Cardiac Surgery
Authors: Alain Deschamps, Arbi Ben Abdallah, Eric Jacobsohn, Tarit Saha, George Djaiani, Renée El-Gabalawy, Charles Overbeek, Jennifer Palermo, Athanase Courbe, Isabelle Cloutier, Rob Tanzola, Alex Kronzer, Bradley A. Fritz, Eva M. Schmitt, Sharon K. Inouye, Michael S. Avidan, André Denault, David Mazer, Alexis Turgeon, François Martin Carrier, Deschamps Alain, Scott Beattie, Hilary Grocott, Richard Hall, Gregory Hare, Manoj Lalu, Philip Jones, Greg Bryson, Jessica Spence, Summer Syed, Diem Tran, Renée El-Gabalawy, Tarit Saha, Eric Jacobsohn, George Djaiani, Yoan Lamarche
Journal: JAMA (2024)

Intraoperative electroencephalogram (EEG) waveform suppression, suggesting excessive general anesthesia, has been associated with postoperative delirium.
Reflections and Roadmaps: Career Development Beyond the FDA-AACR Oncology Educational Fellowship
Authors: Timil Patel, Chris Chen, Samer Al Hadidi, Yasmin Kadry, Rajeshwari Sridhara, Erin Purcell, Laura Wisch, Jon Retzlaff, Margaret Foti, Richard Pazdur, Paul Kluetz, Jennifer Gao
Journal: Clinical Cancer Research (2024)

In 2020, the U.S. Food and Drug Administration's Oncology Center of Excellence, in collaboration with the American Association for Cancer Research, launched a novel educational partnership known as the FDA-AACR Oncology Educational Fellowship. This year-long program is aimed for hematology/oncology fellows, scientists, and early-career investigators, offering an in-depth exploration of the regulatory review process by blending didactic learning with practical cases discussing oncology drug approvals. The fellowship has been met with enthusiastic feedback, with participants lauding its role in demystifying the regulatory landscape and enhancing their professional careers. This paper reflects on the experiences of four alumni, showcasing the program's transformative impact across diverse oncology career paths in government, academia, and industry.
An adipoincretin effect links adipostasis with insulin secretion
Authors: Giovanni Solinas, Barbara Becattini
Journal: Trends in Endocrinology and Metabolism (2024)

The current paradigm for the insulin system focuses on the phenomenon of glucose-stimulated insulin secretion and insulin action on blood glucose control. This historical glucose-centric perspective may have introduced a conceptual bias in our understanding of insulin regulation. A body of evidence demonstrating that in vivo variations in blood glucose and insulin secretion can be largely dissociated motivated us to reconsider the fundamental design of the insulin system as a control system for metabolic homeostasis. Here, we propose that a minimal glucose-centric model does not accurately describe the physiological behavior of the insulin system and propose a new paradigm focusing on the effects of incretins, arguing that under fasting conditions, insulin is regulated by an adipoincretin effect.
Pigmented skin lesions
Authors: Richard Barlow, Ali Shah, Padma Mohandas
Journal: BMJ (2024)

This is part of a series of occasional articles on common problems in primary care. The BMJ welcomes contributions from GPs. ### What you need to know A 74 year old white man with fair skin that burns and tans easily has a pigmented lesion on the upper back that his partner noticed three months ago. It is slowly enlarging. The man is retired from office work. He grew up in Africa, and historically enjoyed a lot of outdoor activities. He has no family history of melanoma. Examining the entirety of the back, the lesion stands out compared with his other lesions, most of which appear as stuck on, and have macroscopic crumbly keratotic cerebriform surfaces. The lesion in question has no associated tenderness or induration. It is raised with an irregular border and asymmetry of colour. Dermatological presentations account for about a quarter of primary care consultations in the UK,1 with concerns about pigmented lesions and skin cancer comprising a large proportion. As a result, specialist dermatology services in the UK receive more than one million new referrals each year, about 50% of which relate to pigmented skin lesions2 (box 1). About 6% of patients with a pigmented skin lesion are diagnosed subsequently with melanoma or squamous cell carcinoma via urgent skin cancer referral pathways.6 Box 1 ### Global epidemiology of skin cancer In the UK, dermatology specialist services receive more referrals via specialised urgent skin cancer target pathways than any other specialty. This is partly explained by skin cancer being the commonest cancer in the UK.3 … RETURN TO TEXT
Mis-splicing of Mitotic Regulators Sensitizes SF3B1-Mutated Human HSCs to CHK1 Inhibition
Authors: Martina Sarchi, Courtnee A. Clough, Edie I. Crosse, Jason Kim, Laura D. Baquero Galvis, Nelli Aydinyan, Rachel Wellington, Feini Yang, Anna Gallì, J. Philip Creamer, Sintra Stewart, Robert K. Bradley, Luca Malcovati, Sergei Doulatov
Journal: Blood Cancer Discovery (2024)

Abstract Splicing factor SF3B1 mutations are frequent somatic lesions in myeloid neoplasms that transform hematopoietic stem cells (HSCs) by inducing mis-splicing of target genes. However, the molecular and functional consequences of SF3B1 mutations in human HSCs and progenitors (HSPCs) remain unclear. Here, we identify the mis-splicing program in human HSPCs as a targetable vulnerability by precise gene editing of SF3B1 K700E mutations in primary CD34+ cells. Mutant SF3B1 induced pervasive mis-splicing and reduced expression of genes regulating mitosis and genome maintenance leading to altered differentiation, delayed G2/M progression, and profound sensitivity to CHK1 inhibition (CHK1i). Mis-splicing or reduced expression of mitotic regulators BUBR1 and CDC27 delayed G2/M transit and promoted CHK1i sensitivity. Clinical CHK1i prexasertib selectively targeted SF3B1-mutant immunophenotypic HSCs and abrogated engraftment in vivo. These findings identify mis-splicing of mitotic regulators in SF3B1-mutant HSPCs as a targetable vulnerability engaged by pharmacological CHK1 inhibition. Significance: In this study, we engineer precise SF3B1 mutations in human HSPCs and identify CHK1 inhibition as a selective vulnerability promoted by mis-splicing of mitotic regulators. These findings uncover the mis-splicing program induced by mutant SF3B1 in human HSPCs and show that it can be therapeutically targeted by clinical CHK1 inhibitors.
Advances in viscosupplementation and tribosupplementation for early-stage osteoarthritis therapy
Authors: Christian D. DeMoya, Anisha Joenathan, Taylor B. Lawson, David T. Felson, Thomas P. Schaer, Manish Bais, Michael B. Albro, Janne Mäkelä, Brian D. Snyder, Mark W. Grinstaff
Journal: Nature Reviews Rheumatology (2024)
Tumor growth in recurrent glioblastoma—RANO: when to plan the baseline scan?
Authors: Lisa Dobber, Marjolein Geurts, Martin J van den Bent
Journal: Neuro-Oncology (2024)

Journal Article Corrected proof Tumor growth in recurrent glioblastoma—RANO: when to plan the baseline scan? Get access Lisa Dobber, Lisa Dobber Department of Neurology, Erasmus MC Cancer Center, Rotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar Marjolein Geurts, Marjolein Geurts Department of Medical Oncology, Erasmus MC Cancer Center, Rotterdam, The NetherlandsDepartment of Neurology, Erasmus MC Cancer Center, Rotterdam, The Netherlands https://orcid.org/0000-0003-2369-0035 Search for other works by this author on: Oxford Academic PubMed Google Scholar Martin J van den Bent Martin J van den Bent Department of Neurology, Erasmus MC Cancer Center, Rotterdam, The Netherlands Corresponding Author: Martin van den Bent, Department of Neurology, Erasmus MC Cancer Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam 010-7041415, The Netherlands (mjvandenbent@neuro-oncology.nl). https://orcid.org/0000-0001-5710-5127 Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, noae095, https://doi.org/10.1093/neuonc/noae095 Published: 10 June 2024 Article history Corrected and typeset: 10 June 2024 Published: 10 June 2024
FDA Approval Summary: Durvalumab and Pembrolizumab, Immune Checkpoint inhibitors for the Treatment of Biliary Tract Cancer
Authors: Sandra J. Casak, Vaibhav Kumar, Chi Song, Mengdie Yuan, Anup K. Amatya, Joyce Cheng, Pallavi S. Mishra-Kalyani, Shenghui Tang, Steven J. Lemery, Doris Auth, Gina Davis, Paul G. Kluetz, Richard Pazdur, Lola A. Fashoyin-Aje
Journal: Clinical Cancer Research (2024)

On September 2, 2022, the Food and Drug Administration (FDA) approved durvalumab in combination with cisplatin and gemcitabine, for the treatment of patients with unresectable or metastatic biliary tract cancers (BTC). On October 31, 2023, the FDA approved pembrolizumab in combination with cisplatin and gemcitabine for the same indication. Approvals were based on two randomized, multiregional, placebo-controlled trials, which randomly allocated patients to receive durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966) in combination with chemotherapy or placebo in combination with chemotherapy. Overall survival (OS) was the primary endpoint in both studies. In both studies, a statistically significant and clinically meaningful improvement in OS was demonstrated. In the TOPAZ-1 trial the median OS of patients receiving durvalumab was 12.8 months (95% confidence interval [CI] 11.1, 14.0) and 11.5 months (95% CI 10.1, 12.5) in patients receiving placebo (HR 0.80 [95% CI 0.66, 0.97]). In the KEYNOTE-966 trial, the median OS of patients receiving pembrolizumab was 12.7 months (95% CI 11.5, 13.6) and 10.9 months (95% CI 9.9, 11.6) in patients receiving placebo (HR 0.83 [95% CI 0.72, 0.95]). The addition of checkpoint inhibitors to standard of care chemotherapy for this indication did not reveal any new adverse event signals and the safety profile was generally consistent with the known clinical experience with durvalumab, pembrolizumab, and the backbone chemotherapy regimen. The approvals of durvalumab and pembrolizumab in combination with standard of care cisplatin and gemcitabine for the treatment of unresectable or metastatic BTC add two new therapeutic option for these patients.
Effect of Polymer and Cell Membrane Coatings on Theranostic Applications of Nanoparticles: A Review
Authors: Bahareh Rezaei, Asma Harun, Xian Wu, Poornima Ramesh Iyer, Shahriar Mostufa, Stefano Ciannella, Ioannis H. Karampelas, Jeffrey Chalmers, Indrajit Srivastava, Jenifer Gómez‐Pastora, Kai Wu
Journal: Advanced Healthcare Materials (2024)

The recent decade has witnessed a remarkable surge in the field of nanoparticles, from their synthesis, characterization, and functionalization to diverse applications. At the nanoscale, these particles exhibit distinct physicochemical properties compared to their bulk counterparts, enabling a multitude of applications spanning energy, catalysis, environmental remediation, biomedicine, and beyond. This review focuses on specific nanoparticle categories, including magnetic, gold, silver, and quantum dots (QDs), as well as hybrid variants, specifically tailored for biomedical applications. A comprehensive review and comparison of prevalent chemical, physical, and biological synthesis methods are presented. To enhance biocompatibility and colloidal stability, and facilitate surface modification and cargo/agent loading, nanoparticle surfaces are coated with different synthetic polymers and very recently, cell membrane coatings. The utilization of polymer- or cell membrane-coated nanoparticles opens a wide variety of biomedical applications such as magnetic resonance imaging (MRI), hyperthermia, photothermia, sample enrichment, bioassays, drug delivery, etc. With this review, the goal is to provide a comprehensive toolbox of insights into polymer or cell membrane-coated nanoparticles and their biomedical applications, while also addressing the challenges involved in translating such nanoparticles from laboratory benchtops to in vitro and in vivo applications. Furthermore, perspectives on future trends and developments in this rapidly evolving domain are provided.
Comparable relapse incidence after unrelated allogeneic stem cell transplantation with post‐transplant cyclophosphamide versus conventional anti‐graft versus host disease prophylaxis in patients with acute myeloid leukemia: A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Authors: Arnon Nagler, Maud Ngoya, Jacques‐Emmanuel Galimard, Myriam Labopin, Igor Wolfgang Blau, Nicolaus Kröger, Tobias Gedde‐Dahl, Thomas Schroeder, David Burns, Urpu Salmenniemi, Alessandro Rambaldi, Goda Choi, Régis Peffault de Latour, Jan Vydra, Henrik Sengeloev, Matthias Eder, Stephan Mielke, Edouard Forcade, Alexander Kulagin, Fabio Ciceri, Mohamad Mohty
Journal: American Journal of Hematology (2024)

Abstract We compared relapse incidence (RI) post‐unrelated transplantation with post‐transplant cyclophosphamide (PTCy) versus no PTCy graft‐versus‐host disease (GVHD) prophylaxis, in 7049 acute myeloid leukemia (AML) patients in remission, 707 with PTCy, and 6342 without (No PTCy). The patients in the PTCy group were younger, 52.7 versus 56.6 years ( p &lt; .001). There were more 9/10 donors in the PTCy group, 33.8% versus 16.4% ( p &lt; .001), and more received myeloablative conditioning, 61.7% versus 50.2% ( p &lt; .001). In the No PTCy group, 87.7% of patients received in vivo T‐cell depletion. Neutrophil and platelet engraftment were lower in the PTCy versus No PTCy group, 93.8% and 80.9% versus 97.6% and 92.6% ( p &lt; .001). RI was not significantly different in the PTCy versus the No PTCy group, hazard ratio (HR) of 1.11 (95% confidence interval [CI] 0.9–1.37) ( p = .31). Acute GVHD grades II–IV and III–IV, were significantly lower in the PTCy versus the No PTCy group, HR of 0.74 (95% CI 0.59–0.92, p = .007) and HR = 0.56 (95% CI 0.38–0.83, p = .004), as were total and extensive chronic GVHD, HRs of 0.5 (95% CI 0.41–0.62, p &lt; .001) and HR = 0.31 (95% CI 0.22–0.42, p &lt; .001). Non‐relapse mortality (NRM) was significantly lower with PTCy versus the No PTCy group, HR of 0.67 (95% CI 0.5–0.91, p = .007). GVHD‐free, relapse‐free survival (GRFS) was higher in the PTCy versus the No PTCy group, HR of 0.69 (95% CI 0.59–0.81, p = .001). Leukemia‐free survival (LFS) and overall survival (OS) did not differ between the groups. In summary, we observed comparable RI, OS, and LFS, significantly lower incidences of GVHD and NRM, and significantly higher GRFS in AML patients undergoing unrelated donor‐hematopoietic stem cell transplantation with PTCy versus No PTCy GVHD prophylaxis.
Ixazomib plus daratumumab and dexamethasone: Final analysis of a phase 2 study among patients with relapsed/refractory multiple myeloma
Authors: Sosana Delimpasi, Meletios A. Dimopoulos, Jan Straub, Argiris Symeonidis, Luděk Pour, Roman Hájek, Cyrille Touzeau, Viralkumar K. Bhanderi, Jesus G. Berdeja, Petr Pavlíček, Jeffrey V. Matous, Pawel J. Robak, Kaveri Suryanarayan, Alison Miller, Miguel Villarreal, Dasha Cherepanov, Jaydeep K. Srimani, Huilan Yao, Richard Labotka, Robert Z. Orlowski
Journal: American Journal of Hematology (2024)

Novel therapies have improved outcomes for multiple myeloma (MM) patients, but most ultimately relapse, making treatment decisions for relapsed/refractory MM (RRMM) patients increasingly challenging. We report the final analysis of a single-arm, phase 2 study evaluating the oral proteasome inhibitor (PI) ixazomib combined with daratumumab and dexamethasone (IDd; NCT03439293). Sixty-one RRMM patients (ixazomib/daratumumab-naïve; 1-3 prior therapies) were enrolled to receive IDd (28-day cycles) until disease progression/unacceptable toxicity. Median age was 69 years; 14.8% of patients had International Staging System stage III disease; 14.8% had received three prior therapies. Patients received a median of 16 cycles of IDd. In 59 response-evaluable patients, the overall response rate was 64.4%; the confirmed ≥very good partial response (VGPR) rate (primary endpoint) was 30.5%. Rates of ≥VGPR in patient subgroups were: high-risk cytogenetics (n = 15, 26.7%), expanded high-risk cytogenetics (n = 24, 29.2%), aged ≥75 years (n = 12, 16.7%), lenalidomide-refractory (n = 21, 28.6%), and prior PI/IMiD therapy (n = 58, 31.0%). With a median follow-up of 31.6 months, median progression-free survival was 16.8 months (95% confidence interval: 10.1-23.7). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 54.1% of patients; 44.3% had serious TEAEs; TEAEs led to dose modifications/reductions/discontinuations in 62.3%/36.1%/16.4%. There were five on-study deaths. Any-grade and grade ≥3 peripheral neuropathy occurred in 18.0% and 1.6% of patients. Quality of life was generally maintained throughout treatment. IDd showed a positive risk-benefit profile in RRMM patients and was active in clinically relevant subgroups with no new safety signals.
Publisher Correction: Correlates of protection against symptomatic SARS-CoV-2 in vaccinated children
Authors: Youjia Zhong, Alicia Y. H. Kang, Carina J. X. Tay, Hui’ En Li, Nurul Elyana, Chee Wah Tan, Wee Chee Yap, Joey M. E. Lim, Nina Le Bert, Kuan Rong Chan, Eugenia Z. Ong, Jenny G. Low, Lynette P. Shek, Elizabeth Huiwen Tham, Eng Eong Ooi
Journal: Nature Medicine (2024)
Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson’s disease
Authors: Paul J. Hop, Dongbing Lai, Pamela J. Keagle, Desiree M. Baron, Brendan J. Kenna, Maarten Kooyman, None Shankaracharya, Cheryl Halter, Letizia Straniero, Rosanna Asselta, Salvatore Bonvegna, Alexandra I. Soto-Beasley, Zbigniew K. Wszolek, Ryan J. Uitti, Ioannis Ugo Isaias, Gianni Pezzoli, Nicola Ticozzi, Owen A. Ross, Jan H. Veldink, Tatiana M. Foroud, Kevin P. Kenna, John E. Landers
Journal: Nature Genetics (2024)

Abstract Despite substantial progress, causal variants are identified only for a minority of familial Parkinson’s disease (PD) cases, leaving high-risk pathogenic variants unidentified 1,2 . To identify such variants, we uniformly processed exome sequencing data of 2,184 index familial PD cases and 69,775 controls. Exome-wide analyses converged on RAB32 as a novel PD gene identifying c.213C &gt; G/p.S71R as a high-risk variant presenting in ~0.7% of familial PD cases while observed in only 0.004% of controls (odds ratio of 65.5). This variant was confirmed in all cases via Sanger sequencing and segregated with PD in three families. RAB32 encodes a small GTPase known to interact with LRRK2 (refs. 3,4 ). Functional analyses showed that RAB32 S71R increases LRRK2 kinase activity, as indicated by increased autophosphorylation of LRRK2 S1292. Here our results implicate mutant RAB32 in a key pathological mechanism in PD—LRRK2 kinase activity 5–7 —and thus provide novel insights into the mechanistic connections between RAB family biology, LRRK2 and PD risk.
Prominent misinformation interventions reduce misperceptions but increase scepticism
Authors: Emma Hoes, Brian Aitken, Jingwen Zhang, Tomasz Gackowski, Magdalena Wojcieszak
Journal: Nature Human Behaviour (2024)

Current interventions to combat misinformation, including fact-checking, media literacy tips and media coverage of misinformation, may have unintended consequences for democracy. We propose that these interventions may increase scepticism towards all information, including accurate information. Across three online survey experiments in three diverse countries (the United States, Poland and Hong Kong; total n = 6,127), we tested the negative spillover effects of existing strategies and compared them with three alternative interventions against misinformation. We examined how exposure to fact-checking, media literacy tips and media coverage of misinformation affects individuals' perception of both factual and false information, as well as their trust in key democratic institutions. Our results show that while all interventions successfully reduce belief in false information, they also negatively impact the credibility of factual information. This highlights the need for further improved strategies that minimize the harms and maximize the benefits of interventions against misinformation.
Estrogen counteracts age-related decline in beige adipogenesis through the NAMPT-regulated ER stress response
Authors: Jooman Park, Ruoci Hu, Yanyu Qian, Shaolei Xiong, Asma Sana El-Sabbagh, Meram Ibrahim, Jaden Wang, Ziqiao Xu, Zhengjia Chen, Qing Song, Zhenyuan Song, Gege Yan, Abeer M. Mahmoud, Yanlin He, Brian T. Layden, Jiwang Chen, Sang-Ging Ong, Pingwen Xu, Yuwei Jiang
Journal: Nature Aging (2024)
ASS1 metabolically contributes to the nuclear and cytosolic p53-mediated DNA damage response
Authors: Lisha Qiu Jin Lim, Lital Adler, Emma Hajaj, Leandro R. Soria, Rotem Ben-Tov Perry, Naama Darzi, Ruchama Brody, Noa Furth, Michal Lichtenstein, Elizabeta Bab-Dinitz, Ziv Porat, Tevie Melman, Alexander Brandis, Sergey Malitsky, Maxim Itkin, Yael Aylon, Shifra Ben-Dor, Irit Orr, Amir Pri-Or, Rony Seger, Yoav Shaul, Eytan Ruppin, Moshe Oren, Minervo Perez, Jordan Meier, Nicola Brunetti-Pierri, Efrat Shema, Igor Ulitsky, Ayelet Erez
Journal: Nature Metabolism (2024)
Efficient site-specific integration of large genes in mammalian cells via continuously evolved recombinases and prime editing
Authors: Smriti Pandey, Xin D. Gao, Nicholas A. Krasnow, Amber McElroy, Y. Allen Tao, Jordyn E. Duby, Benjamin J. Steinbeck, Julia McCreary, Sarah E. Pierce, Jakub Tolar, Torsten B. Meissner, Elliot L. Chaikof, Mark J. Osborn, David R. Liu
Journal: Nature Biomedical Engineering (2024)

Abstract Methods for the targeted integration of genes in mammalian genomes suffer from low programmability, low efficiencies or low specificities. Here we show that phage-assisted continuous evolution enhances prime-editing-assisted site-specific integrase gene editing (PASSIGE), which couples the programmability of prime editing with the ability of recombinases to precisely integrate large DNA cargoes exceeding 10 kilobases. Evolved and engineered Bxb1 recombinase variants (evoBxb1 and eeBxb1) mediated up to 60% donor integration (3.2-fold that of wild-type Bxb1) in human cell lines with pre-installed recombinase landing sites. In single-transfection experiments at safe-harbour and therapeutically relevant sites, PASSIGE with eeBxb1 led to an average targeted-gene-integration efficiencies of 23% (4.2-fold that of wild-type Bxb1). Notably, integration efficiencies exceeded 30% at multiple sites in primary human fibroblasts. PASSIGE with evoBxb1 or eeBxb1 outperformed PASTE (for ‘programmable addition via site-specific targeting elements’, a method that uses prime editors fused to recombinases) on average by 9.1-fold and 16-fold, respectively. PASSIGE with continuously evolved recombinases is an unusually efficient method for the targeted integration of genes in mammalian cells.
A shifting role of thalamocortical connectivity in the emergence of cortical functional organization
Authors: Shinwon Park, Koen V. Haak, Stuart Oldham, Hanbyul Cho, Kyoungseob Byeon, Bo-yong Park, Phoebe Thomson, Haitao Chen, Wei Gao, Ting Xu, Sofie Valk, Michael P. Milham, Boris Bernhardt, Adriana Di Martino, Seok-Jun Hong
Journal: Nature Neuroscience (2024)