tbuckley/cabot-search huggingface dataset:
Individualized Treatment Effects of Oxygen Targets in Mechanically Ventilated Critically Ill Adults
Authors: Kevin G. Buell, Alexandra B. Spicer, Jonathan D. Casey, Kevin P. Seitz, Edward T. Qian, Emma J. Graham Linck, Wesley H. Self, Todd W. Rice, Pratik Sinha, Paul J. Young, Matthew W. Semler, Matthew M. Churpek
Journal: JAMA (2024)

Importance Among critically ill adults, randomized trials have not found oxygenation targets to affect outcomes overall. Whether the effects of oxygenation targets differ based on an individual’s characteristics is unknown. Objective To determine whether an individual’s characteristics modify the effect of lower vs higher peripheral oxygenation-saturation (Sp o 2 ) targets on mortality. Design, Setting, and Participants A machine learning model to predict the effect of treatment with a lower vs higher Sp o 2 target on mortality for individual patients was derived in the Pragmatic Investigation of Optimal Oxygen Targets (PILOT) trial and externally validated in the Intensive Care Unit Randomized Trial Comparing Two Approaches to Oxygen Therapy (ICU-ROX) trial. Critically ill adults received invasive mechanical ventilation in an intensive care unit (ICU) in the United States between July 2018 and August 2021 for PILOT (n = 1682) and in 21 ICUs in Australia and New Zealand between September 2015 and May 2018 for ICU-ROX (n = 965). Exposures Randomization to a lower vs higher Sp o 2 target group. Main Outcome and Measure 28-Day mortality. Results In the ICU-ROX validation cohort, the predicted effect of treatment with a lower vs higher Sp o 2 target for individual patients ranged from a 27.2% absolute reduction to a 34.4% absolute increase in 28-day mortality. For example, patients predicted to benefit from a lower Sp o 2 target had a higher prevalence of acute brain injury, whereas patients predicted to benefit from a higher Sp o 2 target had a higher prevalence of sepsis and abnormally elevated vital signs. Patients predicted to benefit from a lower Sp o 2 target experienced lower mortality when randomized to the lower Sp o 2 group, whereas patients predicted to benefit from a higher Sp o 2 target experienced lower mortality when randomized to the higher Sp o 2 group (likelihood ratio test for effect modification P = .02). The use of a Sp o 2 target predicted to be best for each patient, instead of the randomized Sp o 2 target, would have reduced the absolute overall mortality by 6.4% (95% CI, 1.9%-10.9%). Conclusion and relevance Oxygenation targets that are individualized using machine learning analyses of randomized trials may reduce mortality for critically ill adults. A prospective trial evaluating the use of individualized oxygenation targets is needed.
Oxygen Supplementation in COVID-19—How Much Is Enough?
Authors: Richard M. Schwartzstein
Journal: JAMA (2024)

Frederik M. Nielsen, MD; Thomas L. Klitgaard, MD, PhD; Martin Siegemund, MD; Jon H. Laake, MD, PhD; Katrin M. Thormar, MD, PhD; Jade M. Cole, RN, MSc; Søren R. Aagaard, MD, PhD; Anne-Marie G. Bunzel, RN; Stine R. Vestergaard, RN; Peter K. Langhoff, MD; Caroline H. Pedersen, MD; Josefine Ø. Hejlesen, MD; Salim Abdelhamid, MD; Anna Dietz, MD; Caroline E. Gebhard, MD; Nuria Zellweger, MD; Alexa Hollinger, MD; Lone M. Poulsen, MD; Sarah Weihe, MD; Nina C. Andersen-Ranberg, MD, PhD; Ulf G. Pedersen, MD, PhD; Ole Mathiesen, MD, PhD; Anne Sofie Andreasen, MD, PhD; Helene Brix, RN; Jonas J. Thomsen, MD; Christina H. Petersen, MD; Morten H. Bestle, MD, PhD; Sine Wichmann, MD; Martin S. Lund, MD, PhD; Karoline M. Mortensen, MD; Björn A. Brand, MD; Nicolai Haase, MD, PhD; Susanne A. Iversen, MD; Klaus V. Marcussen, MD; Anne C. Brøchner, MD, PhD; Morten Borup, MD; Thorbjørn Grøfte, MD, PhD; Thomas Hildebrandt, MD; Maj-Brit N. Kjær, RN, MSc; Janus Engstrøm, BSc; Theis Lange, MSc, PhD; Anders Perner, MD, PhD; Olav L. Schjørring, MD, PhD; Bodil S. Rasmussen, MD, PhD; HOT-COVID Trial Group; Anne S. B. Eriksen; Tina Jørgensen; Sanne Lauitzen; Lone Valbjørn; Ann B. Christensen; Niels Foldager; Henrik S. Sørensen; Trine Haberlandt; Annette Vennegaard; Tayyba N. Aslam; Helen Hill; Matthew P. Wise
SOCS3 regulates pathological retinal angiogenesis through modulating SPP1 expression in microglia and macrophages
Authors: Tianxi Wang, Satoshi Kaneko, Emil Kriukov, David Alvarez, Enton Lam, Yidi Wang, Sara La Manna, Daniela Marasco, Angeles Fernandez-Gonzalez, S Alex Mitsialis, Stella Kourembanas, Andreas Stahl, Mei Chen, Heping Xu, Petr Baranov, Guoshuai Cai, Ulrich H von Andrian, Ye Sun
Journal: Molecular Therapy (2024)
Computer-aided molecular design and optimization of potent inhibitors disrupting APC‒Asef interaction
Authors: Xuefei Wang, Zeqian Du, Yuegui Guo, Jie Zhong, Kun Song, Junyuan Wang, Jianqiang Yu, Xiuyan Yang, Chen-Ying Liu, Ting Shi, Jian Zhang
Journal: Acta Pharmaceutica Sinica B (2024)

Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. At initial diagnosis, approximately 20% of patients are diagnosed with metastatic CRC (mCRC). Although the APC‒Asef interaction is a well-established target for mCRC therapy, the discovery and development of effective and safe drugs for mCRC patients remains an urgent and challenging endeavor. In this study, we identified a novel structural scaffold based on MAI inhibitors, the first-in-class APC‒Asef inhibitors we reported previously. ONIOM model-driven optimizations of the N-terminal cap and experimental evaluations of inhibitory activity were performed, and 24-fold greater potency was obtained with the best inhibitor compared to the parental compound. In addition, the cocrystal structure validated that the two-layer
Circumventing drug resistance in gastric cancer: A spatial multi-omics exploration of chemo and immuno-therapeutic response dynamics
Authors: Gang Che, Jie Yin, Wankun Wang, Yandong Luo, Yiran Chen, Xiongfei Yu, Haiyong Wang, Xiaosun Liu, Zhendong Chen, Xing Wang, Yu Chen, Xujin Wang, Kaicheng Tang, Jiao Tang, Wei Shao, Chao Wu, Jianpeng Sheng, Qing Li, Jian Liu
Journal: Drug Resistance Updates (2024)
Most recent advances and applications of extracellular vesicles in tackling neurological challenges
Authors: Mandeep Kaur, Salvatore Fusco, Bram Van den Broek, Jaya Aseervatham, Abdolmohamad Rostami, Lorraine Iacovitti, Claudio Grassi, Barbara Lukomska, Amit K. Srivastava
Journal: Medicinal Research Reviews (2024)

Over the past few decades, there has been a notable increase in the global burden of central nervous system (CNS) diseases. Despite advances in technology and therapeutic options, neurological and neurodegenerative disorders persist as significant challenges in treatment and cure. Recently, there has been a remarkable surge of interest in extracellular vesicles (EVs) as pivotal mediators of intercellular communication. As carriers of molecular cargo, EVs demonstrate the ability to traverse the blood-brain barrier, enabling bidirectional communication. As a result, they have garnered attention as potential biomarkers and therapeutic agents, whether in their natural form or after being engineered for use in the CNS. This review article aims to provide a comprehensive introduction to EVs, encompassing various aspects such as their diverse isolation methods, characterization, handling, storage, and different routes for EV administration. Additionally, it underscores the recent advances in their potential applications in neurodegenerative disorder therapeutics. By exploring their unique capabilities, this study sheds light on the promising future of EVs in clinical research. It considers the inherent challenges and limitations of these emerging applications while incorporating the most recent updates in the field.
Standing on Shoulders: Interferon Research From Viral Interference to Lupus Pathogenesis and Treatment
Authors: Mary K. Crow, Mikhail Olferiev, Kyriakos A. Kirou
Journal: Arthritis & Rheumatology (2024)

The discovery of interferon in the 1950s represents much more than the identification of the first cytokine and the key mediator of antiviral host defense. Defining the molecular nature and complexity of the type I interferon family, as well as its inducers and molecular mechanisms of action, was the work of investigators working at the highest level and producing insights of great consequence. Current knowledge of receptor-ligand interactions, cell signaling, and transcriptional regulation derives from studies of type I interferon. It is on the shoulders of the giants who produced that knowledge that others stand and have revealed critical mechanisms of the pathogenesis of systemic lupus erythematosus and other autoimmune diseases. The design of novel therapeutics is informed by the advances in investigation of type I interferon, with the potential for important impact on patient management.
MRI-guided stereotactic ablative body radiotherapy versus CT-guided percutaneous irreversible electroporation for locally advanced pancreatic cancer (CROSSFIRE): a single-centre, open-label, randomised phase 2 trial
Authors: Florentine E F Timmer, Bart Geboers, Alette H Ruarus, Laurien G P H Vroomen, Evelien A C Schouten, Susan van der Lei, Danielle J W Vos, Madelon Dijkstra, Hannah H Schulz, Joyce Bakker, Bente A T van den Bemd, Petrousjka M van den Tol, Robbert S Puijk, Birgit I Lissenberg-Witte, Tanja D de Gruijl, Jan J J de Vries, Frank J Lagerwaard, Hester J Scheffer, Anna M E Bruynzeel, Martijn R Meijerink
Journal: The Lancet. Gastroenterology & hepatology (2024)
APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease
Authors: Rosemary J. Jackson, Megan S. Keiser, Jonah C. Meltzer, Dustin P. Fykstra, Steven E. Dierksmeier, Soroush Hajizadeh, Johannes Kreuzer, Robert Morris, Alexandra Melloni, Tsuneo Nakajima, Luis Tecedor, Paul T. Ranum, Ellie Carrell, YongHong Chen, Maryam A. Nishtar, David M. Holtzman, Wilhelm Haas, Beverly L. Davidson, Bradley T. Hyman
Journal: Molecular Therapy (2024)

Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do, they have a later age of onset, milder clinical course, and less severe neuropathological findings than people without this allele. The contrast is especially stark when compared with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, a more aggressive clinical course and more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Here, we demonstrate that brain exposure to APOE ε2 via a gene therapy approach, which bathes the entire cortical mantle in the gene product after transduction of the ependyma, reduces Aβ plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE ε4. This result suggests a promising protective effect of exogenous APOE ε2 and reveals a cell nonautonomous effect of the protein on microglial activation, which we show is similar to plaque-associated microglia in the brain of Alzheimer disease patients who inherit APOE ε2. These data increase the potential that an APOE ε2 therapeutic could be effective in Alzheimer disease, even in individuals born with the risky ε4 allele.
Concurrent inhibition of ALK and SRC kinases disrupts the ALK lung tumor cell proteome
Authors: Alberto Diaz-Jimenez, Maria Ramos, Barbara Helm, Sara Chocarro, Dario Lucas Frey, Shubham Agrawal, Kalman Somogyi, Ursula Klingmüller, Junyan Lu, Rocio Sotillo
Journal: Drug Resistance Updates (2024)

Precision oncology has revolutionized the treatment of ALK-positive lung cancer with targeted therapies. However, an unmet clinical need still to address is the treatment of refractory tumors that contain drug-induced resistant mutations in the driver oncogene or exhibit resistance through the activation of diverse mechanisms. In this study, we established mouse tumor-derived cell models representing the two most prevalent EML4-ALK variants in human lung adenocarcinomas and characterized their proteomic profiles to gain insights into the underlying resistance mechanisms. We showed that Eml4-Alk variant 3 confers a worse response to ALK inhibitors, suggesting its role in promoting resistance to targeted therapy. In addition, proteomic analysis of brigatinib-treated cells revealed the upregulation of SRC kinase, a protein frequently activated in cancer. Co-targeting of ALK and SRC showed remarkable inhibitory effects in both ALK-driven murine and ALK-patient-derived lung tumor cells. This combination induced cell death through a multifaceted mechanism characterized by profound perturbation of the (phospho)proteomic landscape and a synergistic suppressive effect on the mTOR pathway. Our study demonstrates that the simultaneous inhibition of ALK and SRC can potentially overcome resistance mechanisms and enhance clinical outcomes in ALK-positive lung cancer patients. ONE SENTENCE SUMMARY: Co-targeting ALK and SRC enhances ALK inhibitor response in lung cancer by affecting the proteomic profile, offering hope for overcoming resistance and improving clinical outcomes.
High-multiplex single-cell imaging analysis reveals tumor immune contexture associated with clinical outcomes after CAR T cell therapy
Authors: Jin Jin, Li Lin, Jiao Meng, Lijun Jiang, Man Zhang, Yuekun Fang, Wanying Liu, Xiangke Xin, Xiaolu Long, Dong Kuang, Xilai Ding, Miao Zheng, Yicheng Zhang, Yi Xiao, Liting Chen
Journal: Molecular Therapy (2024)
Targeting Cell Senescence and Senolytics: Novel Interventions for Age-Related Endocrine Dysfunction
Authors: Masayoshi Suda, Karl H Paul, Utkarsh Tripathi, Tohru Minamino, Tamara Tchkonia, James L Kirkland
Journal: Endocrine Reviews (2024)

Multiple changes occur in hormonal regulation with aging and across various endocrine organs. These changes are associated with multiple age-related disorders and diseases. A better understanding of responsible underling biological mechanisms could help in the management of multiple endocrine disorders over and above hormone replacement therapy (HRT). Cellular senescence is involved in multiple biological aging processes and pathologies common in elderly individuals. Cellular senescence, which occurs in many older individuals but also across the lifespan in association with tissue damage, acute and chronic diseases, certain drugs, and genetic syndromes, may contribute to such endocrine disorders as osteoporosis, metabolic syndrome, and type 2 diabetes mellitus. Drugs that selectively induce senescent cell removal, "senolytics,", and drugs that attenuate the tissue-destructive secretory state of certain senescent cells, "senomorphics," appear to delay the onset of or alleviate multiple diseases, including but not limited to endocrine disorders such as diabetes, complications of obesity, age-related osteoporosis, and cancers as well as atherosclerosis, chronic kidney disease, neurodegenerative disorders, and many others. More than 30 clinical trials of senolytic and senomorphic agents have already been completed, are underway, or are planned for a variety of indications. Targeting senescent cells is a novel strategy that is distinct from conventional therapies such as HRT, and thus might address unmet medical needs and can potentially amplify effects of established endocrine drug regimens, perhaps allowing for dose decreases and reducing side effects.
Vaccination of Adults With Cancer: ASCO Guideline
Authors: Mini Kamboj, Kari Bohlke, Deana M. Baptiste, Kieron Dunleavy, Abbey Fueger, Lee Jones, Amar H. Kelkar, Lisa Y. Law, Kristine B. LeFebvre, Per Ljungman, Eric D. Miller, Larissa A. Meyer, Heather N. Moore, Heloisa P. Soares, Randy A. Taplitz, Edom S. Woldetsadik, Elise C. Kohn
Journal: Journal of Clinical Oncology (2024)

To guide the vaccination of adults with solid tumors or hematologic malignancies.
Longitudinal Change in Serum Neurofilament Light Chain in Type 2 Diabetes and Early Diabetic Polyneuropathy: ADDITION-Denmark
Authors: Laura L. Määttä, Signe T. Andersen, Tina Parkner, Claus V.B. Hviid, Lasse Bjerg, Mustafa A. Kural, Morten Charles, Esben Søndergaard, Jens Kuhle, Hatice Tankisi, Daniel R. Witte, Troels S. Jensen
Journal: Diabetes Care (2024)

OBJECTIVE To investigate the longitudinal development of neurofilament light chain (NfL) levels in type 2 diabetes with and without diabetic polyneuropathy (+/−DPN) and to explore the predictive potential of NfL as a biomarker for DPN. RESEARCH DESIGN AND METHODS We performed retrospective longitudinal case-control analysis of data from 178 participants of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care-Denmark (ADDITION-Denmark) cohort of people with screen-detected type 2 diabetes. Biobank samples acquired at the ADDITION-Denmark 5- and 10-year follow-ups were analyzed for serum NfL (s-NfL) using single-molecule array, and the results were compared with established reference material to obtain NfL z-scores. DPN was diagnosed according to Toronto criteria for confirmed DPN at the 10-year follow-up. RESULTS s-NfL increased over time in +DPN (N = 39) and −DPN participants (N = 139) at levels above normal age-induced s-NfL increase. Longitudinal s-NfL change was greater in +DPN than in −DPN participants (17.4% [95% CI 4.3; 32.2] or 0.31 SD [95% CI 0.03; 0.60] higher s-NfL or NfL z-score increase in +DPN compared with −DPN). s-NfL at the 5-year follow-up was positively associated with nerve conduction studies at the 10-year follow-up (P = 0.02 to &amp;lt;0.001), but not with DPN risk. Areas under the curve (AUCs) for s-NfL were not inferior to AUCs for the Michigan Neuropathy Screening Instrument questionnaire score or vibration detection thresholds. Higher yearly s-NfL increase was associated with higher DPN risk (odds ratio 1.36 [95% CI 1.08; 1.71] per 1 ng/L/year). CONCLUSIONS Our findings suggest that preceding s-NfL trajectories differ slightly between those with and without DPN and imply a possible biomarker value of s-NfL trajectories in DPN.
Withdrawal of Neurohormonal Antagonists in Breast Cancer Patients With Cardiotoxicity and Improved Left Ventricular Function
Authors: Christopher Yu, Coleen Power, Maala Sooriyakanthan, Thomas Marwick, Eitan Amir, Husam Abdel-Qadir, Chun-Po Steve Fan, Paaladinesh Thavendiranathan
Journal: JACC CardioOncology (2024)
Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors—a nationwide, prospective Swedish study
Authors: Bianca Tesi, Kristina Lagerstedt Robinson, Frida Abel, Teresita Díaz de Ståhl, Sara Orrsjö, Anna Poluha, Maria Hellberg, Sandra Wessman, Sofie Samuelsson, Tony Frisk, Hartmut Vogt, Karin Henning, Magnus Sabel, Torben Ek, Niklas Pal, Per Nyman, Geraldine Giraud, Joakim Wille, Cornelis Jan Pronk, Ulrika Norén-Nyström, Magnus Borssén, Maria Fili, Gustav Stålhammar, Nikolas Herold, Giorgio Tettamanti, Carolina Maya-Gonzalez, Linda Arvidsson, Anna Rosén, Katja Ekholm, Ekaterina Kuchinskaya, Anna-Lotta Hallbeck, Margareta Nordling, Pia Palmebäck, Per Kogner, Gunilla Kanter Smoler, Päivi Lähteenmäki, Susanne Fransson, Tommy Martinsson, Alia Shamik, Fredrik Mertens, Richard Rosenquist, Valtteri Wirta, Emma Tham, Pernilla Grillner, Johanna Sandgren, Gustaf Ljungman, David Gisselsson, Fulya Taylan, Ann Nordgren
Journal: The Lancet Regional Health - Europe (2024)

BackgroundChildhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.MethodsgWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.FindingsThe prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).InterpretationOverall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.FundingThe study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.
Interim safety and immunogenicity of COVID-19 omicron BA.1 variant-containing vaccine in children in the USA: an open-label non-randomised phase 3 trial
Authors: Avika Dixit, Richard Bennett, Kashif Ali, Carl Griffin, Robert A Clifford, Mark Turner, Rosanne Poston, Kelly Hautzinger, Anne Yeakey, Bethany Girard, Wen Zhou, Weiping Deng, Honghong Zhou, Sabine Schnyder Ghamloush, Barbara J Kuter, Karen Slobod, Jacqueline M Miller, Frances Priddy, Rituparna Das, Kashif Ali, Madhavi Ampajwala, Andrew Atz, Richard Bennett, Gary Berman, Robert Clifford, Michael Dunn, Frank Eder, George Fuchs, Carl Griffin, John M. Hernandez, Robert Jeanfreau, Kimball Johnson, William Lavery, Jay Meyer, William Muller, Richard Ohnmacht, Amruta Padhye, Khozema Palanpurwala, Carina Rodrigue, Mark Turner, Todd Vasko, John Waits, Peter Warfield
Journal: The Lancet Infectious Diseases (2024)
IgE to cyclophilins in pollen-allergic children: Epidemiologic, clinical, and diagnostic relevance of a neglected panallergen
Authors: Paolo Maria Matricardi, Ekaterina Potapova, Valentina Panetta, Jonas Lidholm, Lars Mattsson, Enrico Scala, Roberto Bernardini, Carlo Caffarelli, Antonella Casani, Rosa Cervone, Loredana Chini, Pasquale Comberiati, Giovanna De Castro, Michele Miraglia del Giudice, Iride Dello Iacono, Andrea Di Rienzo Businco, Marcella Gallucci, Arianna Giannetti, Viviana Moschese, Elena Varin, Annamaria Bianchi, Mauro Calvani, Tullio Frediani, Francesco Macrì, Nunzia Maiello, Francesco Paravati, Umberto Pelosi, Diego Peroni, Giuseppe Pingitore, Mariangela Tosca, Anna Maria Zicari, Giampaolo Ricci, Riccardo Asero, Salvatore Tripodi
Journal: Journal of Allergy and Clinical Immunology (2024)

Cyclophilins are ubiquitous panallergens whose epidemiologic, diagnostic, and clinical relevance is largely unknown and whose sensitization is rarely examined in routine allergy practice.