tbuckley/cabot-search huggingface dataset:
Development and validation of a clinical risk model for postoperative outcome in newly diagnosed glioblastoma: a report of the RANO <i>resect</i> group
Authors: Philipp Karschnia, Jacob S Young, Gilbert C Youssef, Antonio Dono, Levin Häni, Tommaso Sciortino, Francesco Bruno, Stephanie T Juenger, Nico Teske, Jorg Dietrich, Michael Weller, Michael A Vogelbaum, Martin van den Bent, Juergen Beck, Niklas Thon, Jasper K W Gerritsen, Shawn Hervey-Jumper, Daniel P Cahill, Susan M Chang, Roberta Rudà, Lorenzo Bello, Oliver Schnell, Yoshua Esquenazi, Maximilian I Ruge, Stefan J Grau, Raymond Y Huang, Patrick Y Wen, Mitchel S Berger, Annette M Molinaro, Joerg-Christian Tonn
Journal: Neuro-Oncology (2024)

Abstract Background Following surgery, patients with newly diagnosed glioblastoma frequently enter clinical trials. Nuanced risk assessment is warranted to reduce imbalances between study arms. Here, we aimed (I) to analyze the interactive effects of residual tumor with clinical and molecular factors on outcome and (II) to define a postoperative risk assessment tool. Methods The response assessment in neuro-oncology (RANO) resect group retrospectively compiled an international, seven-center training cohort of patients with newly diagnosed glioblastoma. The combined associations of residual tumor with molecular or clinical factors and survival were analyzed, and recursive partitioning analysis was performed for risk modeling. The resulting model was prognostically verified in a separate external validation cohort. Results Our training cohort compromised 1003 patients with newly diagnosed isocitrate dehydrogenase-wildtype glioblastoma. Residual tumor, O6-methylguanine DNA methyltransferase (MGMT) promotor methylation status, age, and postoperative Karnofsky Performance Score were prognostic for survival and incorporated into regression tree analysis. By individually weighting the prognostic factors, an additive score (range, 0–9 points) integrating these four variables distinguished patients with low (0–2 points), intermediate (3–5 points), and high risk (6–9 points) for inferior survival. The prognostic value of our risk model was retained in treatment-based subgroups and confirmed in an external validation cohort of 258 patients with glioblastoma. Compared to previously postulated models, goodness-of-fit measurements were superior for our model. Conclusions The novel RANO risk model serves as an easy-to-use, yet highly prognostic tool for postoperative patient stratification prior to further therapy. The model may serve to guide patient management and reduce imbalances between study arms in prospective trials.
Characterization of genetic landscape and novel inflammatory biomarkers in patients with adult‐onset Still's disease
Authors: Joanne Topping, Leon Chang, Fatima Nadat, James A Poulter, Alice Ibbotson, Samuel Lara‐Reyna, Christopher M Watson, Clive Carter, Linda P Pournara, Jan Zernicke, Rebecca L. Ross, Catherine Cargo, Paul A. Lyons, Kenneth G.C. Smith, Francesco Del Galdo, Jürgen Rech, Bruno Fautrel, Eugen Feist, Michael F. McDermott, Sinisa Savic
Journal: Arthritis & Rheumatology (2024)

Objective Adult‐onset Still disease (AOSD) is a systemic autoinflammatory disorder (AID) of unknown etiology. Genetic studies have been limited. Here, we conducted detailed genetic and inflammatory biomarker analysis of a large cohort with AOSD to investigate the underlying pathology and identify novel targets for potential treatment. Methods We investigated AOSD cases (n = 60) for rare germline and somatic variants using whole exome sequencing with virtual gene panels. Transcriptome profiles were investigated by bulk RNA sequencing whole blood. Cytokine profiling was performed on an extended patient cohort (n = 106) alongside measurements of NLRP3 inflammasome activation using a custom assay and type I interferon (IFN) score using a novel method. Results We observed higher than expected frequencies of rare germline variants associated with monogenic AIDs in AOSD cases (AOSD 38.4% vs healthy controls [HCs] 20.4%) and earlier onset of putative somatic variants associated with clonal hematopoiesis of indeterminate potential. Transcriptome profiling revealed a positive correlation between Still Activity Score and gene expression associated with the innate immune system. ASC/ NLRP3 specks levels and type I IFN scores were significantly elevated in AOSD cases compared with HCs ( P = 0.0001 and 0.0015, respectively), in addition to several cytokines: interleukin (IL)‐6 ( P &lt; 0.0001), IL‐10 ( P &lt; 0.0075), IL‐12p70 ( P = 0.0005), IL‐18 ( P &lt; 0.0001), IL‐23 ( P &lt; 0.0001), IFN‐α2 ( P = 0.0009), and IFNγ ( P = 0.0002). Conclusion Our study shows considerable genetic complexity within AOSD and demonstrates the potential utility of the ASC/ NLRP3 specks assay for disease stratification and targeted treatment. The enriched genetic variants identified may not by themselves be sufficient to cause disease, but may contribute to a polygenic model for AOSD.
Editor’s Note: Multiple Injections of Electroporated Autologous T Cells Expressing a Chimeric Antigen Receptor Mediate Regression of Human Disseminated Tumor
Authors: Yangbing Zhao, Edmund Moon, Carmine Carpenito, Chrystal M. Paulos, Xiaojun Liu, Andrea L. Brennan, Anne Chew, Richard G. Carroll, John Scholler, Bruce L. Levine, Steven M. Albelda, Carl H. June
Journal: Cancer Research (2024)
Characterisation of incident interstitial lung disease in late systemic sclerosis
Authors: Sabrina Hoa, Claudie Berger, Nouha Lahmek, Maggie Larche, Mohammed Osman, May Choi, Janet Pope, Carter Thorne, Marie Hudson
Journal: Arthritis & Rheumatology (2024)

Objective Interstitial lung disease (ILD) is a common and potentially lethal complication of systemic sclerosis (SSc). Screening by HRCT is recommended in all patients with risk factors, including early disease. Little is known on late presentations of ILD. This study aimed to characterize the incidence, risk factors and outcomes of late‐onset SSc‐ILD. Methods Subjects enrolled in the Canadian Scleroderma Research Group (CSRG) cohort from 2004 to 2020 without prevalent ILD were included. Incidence and risk factors for ILD (on HRCT) were compared according to disease duration above (late) and below (earlier) 7 years from first non‐Raynaud manifestation. Risk of ILD progression was compared using Kaplan‐Meier and multivariable Cox models. Results Overall, 199/969 (21%) patients developed incident ILD over a median of 2.4 [1.2, 4.3] years. The incidence rate in late SSc (3.7/100 person‐years) was lower than in earlier SSc (relative risk 0.68, 95%CI:0.51‐0.92). Risk factors for incident ILD included male sex, diffuse subtype, myositis, anti‐topoisomerase I autoantibodies and higher C‐reactive protein levels. Patients with late‐onset ILD were also less frequently White and more frequently had arthritis and anti‐RNA‐polymerase III autoantibodies. Lung disease severity was similar between late‐ and earlier‐onset SSc‐ILD (FVC 88% and 87%, DLCO 64% and 62%, respectively). Progression rates were also similar between late‐ and earlier‐onset SSc‐ILD (log‐rank p=0.8, hazard ratio 1.11, 95% CI: 0.58‐2.10). Conclusion ILD can present in late SSc. Risk factors and progression rates overlapped with earlier‐onset SSc‐ILD. Surveillance for ILD should continue in longstanding SSc. Frequency and modality of monitoring remain to be defined.
Phase II randomized study of maintenance atezolizumab (A) versus atezolizumab + talazoparib (AT) in patients with SLFN11 positive extensive stage small cell lung cancer. S1929
Authors: Nagla Abdel Karim, Jieling Miao, Karen L Reckamp, Carl M Gay, Lauren A Byers, Ying-Qi Zhao, Mary W Redman, Daniel R Carrizosa, Wei-Lien Wang, William J Petty, Kathan Mehta, Bryan A Faller, Edem S Agamah, Samer S Kasbari, Rajini K Malisetti, Atul Kumar, John Schallenkamp, Krishna C Alluri, Jhanelle E Gray, Karen Kelly
Journal: Journal of Thoracic Oncology (2024)
Real-world effectiveness of nirmatrelvir-ritonavir and molnupiravir in non-hospitalised adults with Covid-19: a population-based, retrospective cohort study cohort study
Authors: Anselm Jorda, Dominik Ensle, Hubert Eser, Florentin Glötzl, Benjamin Riedl, Marton Szell, Arschang Valipour, Alexander Zoufaly, Christoph Wenisch, Doris Haider, Heinz Burgmann, Florian Thalhammer, Florian Götzinger, Bernd Jilma, Robin Ristl, Ursula Karnthaler, Markus Zeitlinger
Journal: Clinical Microbiology and Infection (2024)

ObjectivesThe real-world effectiveness of the oral antivirals nirmatrelvir-ritonavir and molnupiravir against the SARS-CoV-2 Omicron variant remains uncertain. We aimed to estimate their effectiveness in non-hospitalised adults with Covid-19.MethodsThis retrospective cohort study used data from the Municipal Department for Public Health Services of Vienna, Austria, to identify non-hospitalised adults with confirmed SARS-CoV-2 infection between Jan-2022–May-2023. Nirmatrelvir-ritonavir users were compared with untreated controls and molnupiravir users with untreated controls by calculating adjusted risk differences (aRDs) using a covariate-adjusted logistic regression model with inverse probability weighting. Outcomes were hospitalisation and all-cause death within 28 days.ResultsWe identified 113,399 eligible cases (90,481 untreated controls, 12,166 nirmatrelvir-ritonavir users, and 10,752 molnupiravir users). Over 96% of the patients were immunised by previous infection or vaccination. In the nirmatrelvir-ritonavir analysis, the estimated risk of hospitalisation was 0.57% (95%CI, 0.35–0.78) in nirmatrelvir-ritonavir users and 1.09% (95%CI, 0.86–1.32) in untreated controls (aRD -0.53%; 95%CI, -0.77–-0.28). The estimated risk of death was 0.0% (95%CI, 0.0–0.0) in nirmatrelvir-ritonavir users and 0.13% (95%CI, 0.08–0.18) in untreated controls (aRD -0.13%, 95%CI, -0.18–-0.08). The number needed to treat to prevent hospitalisation and death was 190 (95%CI, 130–356) and 792 (95%CI, 571–1289), respectively. These statistically significant aRDs were restricted to the subgroup of patients ≥60 years. In the molnupiravir analysis, the estimated risk of hospitalisation was 1.36% (95%CI, 0.95–1.77) in molnupiravir users and 1.16% (95%CI, 0.93–1.39) in untreated controls (aRD 0.2%; 95%CI, -0.08–0.49). The estimated risk of death was 0.12% (95%CI, 0.01–0.23) in molnupiravir users and 0.14% (95%CI, 0.06–0.21) in untreated controls (aRD, -0.01%; 95%CI, -0.08–-0.06).ConclusionsAmong outpatients aged ≥60 years with Covid-19 in an Omicron-dominated era, treatment with nirmatrelvir-ritonavir was associated with a lower risk of hospitalisation and all-cause death within 28 days, albeit with wide confidence intervals and high numbers needed to treat. This finding was not observed in molnupiravir users and younger nirmatrelvir-ritonavir users.
Clinical Profile of Herpes Zoster-related Hospitalizations and Complications: A French Population-Based Database Study
Authors: Paul Loubet, Laetitia Roustand, Aurélie Schmidt, Pandora Jacquemet, Benoît de Wazières, Clémentine Vabre, Marie Nishimwe, Emmanuel Faure
Journal: Journal of Infection (2024)

Highlights•Retrospective, medico-economic analysis using the French hospital database•Between 2013-2020, 62 077 adults were hospitalized with herpes zoster or PHN•22% of hospitalized people were immunocompromised (IC) and have prolonged stay•Risk of in-hospital death was higher in the IC vs non-IC population (8% vs 4%)•Mean annual cost per patient was higher in IC vs non-IC population (€8018 vs €5603)AbstractObjectiveTo estimate the incidence of hospitalization with a diagnosis of herpes zoster (HZ) and post-herpetic neuralgia (PHN) in France between 2013 and 2020, overall and stratified by age-group and immune status.MethodsRetrospective observational, database study, using the French hospital discharge database, which includes private and public data for all day-care and inpatient stays. Adults aged ≥18 years, hospitalized between January 1, 2013, and December 31, 2020, with a diagnosis of HZ or PHN were included.ResultsOverall, 62 077 adults had a first hospitalization with a diagnosis of HZ or PHN during the observation period. HZ and/or PHN incidence ranged between 14.6 and 16.3 hospitalizations/100 000 persons and was highest in people aged ≥80 years (97.6 hospitalizations/100 000 persons).The immunocompromised (IC) population accounted for 22% of the overall study population. IC patients had longer lengths of stay for HZ per episode compared with non-IC patients (15.5 ± 19.4 days vs 12.2 ± 13.5 days) and higher in-patient mortality (8% vs 4%).Average annual hospitalization costs per patient were higher in the IC vs non-IC population (€8018 vs €5603).ConclusionsOlder age increases hospitalization rates up to 6-fold and IC status increases in-patient mortality up to two-fold.
Genomic analysis confirmed the importation of first mPox Clade Ib case in Kerala, India from Dubai, UAE
Authors: Anita M Shete, Shubin Chenayil, Rima R Sahay, C B Sindhu, Savita Yadav, Pranita Gawande, Deepak Y Patil, Abhinendra Kumar, Sreelekshmy Mohandas, Pragya D Yadav
Journal: Journal of Infection (2024)
Association of CD19+-Targeted Chimeric Antigen Receptor (CAR) T-cell Therapy with Hypogammaglobulinemia, Infection and Mortality
Authors: Natalia M. Sutherland, Baijun Zhou, Lingxiao Zhang, Mei-Sing Ong, Joseph S. Hong, Andrew Pak, Katherine J. Liu, Matthew J. Frigault, Marcela V. Maus, Joshua A. Hill, Kerry Reynolds, Jolan E. Walter, Carlos A. Camargo, Sara Barmettler
Journal: Journal of Allergy and Clinical Immunology (2024)
Fabrication of MnO<sub>2</sub>‐Modified Decellularized Tendon Membrane for Enhancing Tendon Repair
Authors: Wanqing Lun, Huajun Wang, Mengyuan Li, Jiuzhi Ma, Yilin Ding, Xiaofei Zheng, Xiaodong Cao, Qingtao Li
Journal: Advanced Healthcare Materials (2024)

Abstract Repairing tendon/ligament injuries is a major challenge in sports medicine. It has been reported that tendon injury healing is hindered by massive production of reactive oxygen species (ROS). Manganese oxides nanoparticles are generally non‐toxic, can scavenge ROS, promote tissue regeneration, and hold promise for sustainable nanotechnologies. However, the effective and safe integration of MnO 2 nanoparticles on decellularized scaffold mediating tissue repair is still a great challenge. To address these issues, an in situ MnO 2 ‐modified decellularized scaffold is developed to enhance tendon regeneration through improving microenvironment. The decellularized fibrous membrane is designed and prepared using the central tendon of the porcine diaphragm. Then MnO 2 nanozymes are in situ grown on the collagen fibers using tannic acid (TA) as cross‐linking agent and reducing agent. The results showed that MnO 2 ‐modified scaffold eliminates excessive accumulation of ROS in cells, protects mitochondrial, and maintains the phenotype of tendon cells in an oxidative stress environment. Notably, it is found that the MnO 2 ‐modified scaffold exhibits good biocompatibility and is able to promote the tendon healing in the rat patellar tendon defect model. Altogether, this study confirmed that this nanozyme‐functionalized decellularized extracellular matrix effectively enhanced tendon repair by scavenging ROS, which provides new strategies for enhancing tendon regeneration.
Macrophage activation syndrome
Authors: Peter A. Nigrovic
Journal: Arthritis & Rheumatology (2024)

Macrophage activation syndrome (MAS) is a state of immune hyperactivation that can result in life‐threatening multisystem end‐organ dysfunction. Often termed a “cytokine storm”, MAS occurs among the rheumatic diseases most typically in Still's disease but also in systemic lupus erythematosus and Kawasaki disease. MAS can also accompany infection, malignancy, and inborn errors of immunity. This review provides a practical, evidence‐based guide to the understanding, recognition, and management of MAS in children and adults, with a primary focus on MAS complicating Still's disease.
Leveraging Organ‐on‐Chip Models to Investigate Host–Microbiota Dynamics and Targeted Therapies for Inflammatory Bowel Disease
Authors: Tim Kaden, Raquel Alonso‐Román, Johannes Stallhofer, Mark S. Gresnigt, Bernhard Hube, Alexander S. Mosig
Journal: Advanced Healthcare Materials (2024)

Abstract Inflammatory bowel disease (IBD) is an idiopathic gastrointestinal disease with drastically increasing incidence rates. Due to its multifactorial etiology, a precise investigation of the pathogenesis is extremely difficult. Although reductionist cell culture models and more complex disease models in animals have clarified the understanding of individual disease mechanisms and contributing factors of IBD in the past, it remains challenging to bridge research and clinical practice. Conventional 2D cell culture models cannot replicate complex host–microbiota interactions and stable long‐term microbial culture. Further, extrapolating data from animal models to patients remains challenging due to genetic and environmental diversity leading to differences in immune responses. Human intestine organ‐on‐chip (OoC) models have emerged as an alternative in vitro model approach to investigate IBD. OoC models not only recapitulate the human intestinal microenvironment more accurately than 2D cultures yet may also be advantageous for the identification of important disease‐driving factors and pharmacological interventions targets due to the possibility of emulating different complexities. The predispositions and biological hallmarks of IBD focusing on host–microbiota interactions at the intestinal mucosal barrier are elucidated here. Additionally, the potential of OoCs to explore microbiota‐related therapies and personalized medicine for IBD treatment is discussed.
Intervening to Preserve Function in Ischemic Cardiomyopathy with a Porous Hydrogel and Extracellular Matrix Composite in a Rat Myocardial Infarction Model
Authors: Yasunari Hayashi, Taro Fujii, Seungil Kim, Takahiro Ozeki, Stephen F. Badylak, Antonio D'Amore, Masato Mutsuga, William R. Wagner
Journal: Advanced Healthcare Materials (2024)

Abstract Multiple hydrogels are developed for injection therapy after myocardial infarction, with some incorporating substances promoting tissue regeneration and others emphasizing mechanical effects. In this study, porosity and extracellular matrix‐derived digest (ECM) are incorporated, into a mechanically optimized, thermoresponsive, degradable hydrogel (poly(N‐isopropylacrylamide‐co‐N‐vinylpyrrolidone‐co‐MAPLA)) and evaluate whether this biomaterial injectate can abrogate adverse remodeling in rat ischemic cardiomyopathy. After myocardial infarction, rats are divided into four groups: NP (non‐porous hydrogel) without either ECM or porosity, PM (porous hydrogel) from the same synthetic copolymer with mannitol beads as porogens, and PME with porosity and ECM digest added to the synthetic copolymer. PBS injection alone is a control group. Intramyocardial injections occurred 3 days after myocardial infarction followed by serial echocardiography and histological assessments 8 weeks after infarction. Echocardiographic function and neovascularization improved in the PME group compared to the other hydrogels and PBS injection. The PME group also demonstrated improved LV geometry and macrophage polarization (toward M2) compared to PBS, whereas differences are not observed in the NP or PM groups versus control. These results demonstrate further functional improvement may be achieved in hydrogel injection therapy for ischemic cardiomyopathy by incorporating porosity and ECM digest, representing combined mechanical and biological effects.
Incorporating Hydrogel (with Low Polymeric Content) into 3D‐Printed PLGA Scaffolds for Local and Sustained Release of BMP2 in Repairing Large Segmental Bone Defects
Authors: Rongpeng Dong, Mingyang Kang, Yang Qu, Tingting Hou, Jianwu Zhao, Xueliang Cheng
Journal: Advanced Healthcare Materials (2024)

Abstract Treating large bone defects remains a considerable challenge for clinicians: bone repair requires scaffolds with mechanical properties and bioactivities. Herein, based on crosslinking o‐phthalaldehyde (OPA) with amine groups, 4‐arm polyethylene glycol (4armPEG)‐OPA/Gelatin hydrogel loaded with bone morphogenetic protein 2 (BMP2) is prepared and a three dimensional (3D)‐printed poly (lactic‐co‐glycolic acid) (PLGA) porous scaffold is filled with the hydrogel solution. The composite scaffold, with a compression modulus of 0.68 ± 0.097 GPa similar to the cancellous bone, has a porosity of 56.67 ± 4.72% and a pore size of about 380 µm, promoting bone growth. The hydrogel forms a porous network at low concentrations, aiding protein release and cell migration. The hydrogel degrades in approximately three weeks, and the scaffold takes five months, matching bone repair timelines. BMP2 release experiment shows a sustained BMP2 release with a 72.4 ± 0.53% release ratio. The ALP activity test and alizarin red staining shows effective osteogenic promotion, while RT‐PCR confirms BMP2@Gel enhanced COL‐1 and OPN expression. Animal experiments further validate the composite scaffold's bone repair efficacy. This study demonstrates the effectiveness of the hydrogel in releasing BMP2 and the mechanical support of the 3D‐printed PLGA porous scaffold, providing a new treatment for bone defects.
Mitochondrial Proteome Defined Molecular Pathological Characteristics of Oncocytic Thyroid Tumors
Authors: Lu Li, Likun Zhang, Wenhao Jiang, Zhiqiang Gui, Zhihong Wang, Hao Zhang, Yi He, Yi Zhu, Tiannan Guo, Haixia Guan, Zhiyan Liu, Yaoting Sun, Jianqing Gao
Journal: Endocrine Pathology (2024)
ASCL1 Drives the Development of Neuroendocrine Prostate Cancer
Authors: Caden N. McQuillen, Nicholas J. Brady
Journal: Cancer Research (2024)

Therapeutic resistance to androgen receptor (AR)–targeting agents remains a significant clinical problem during the treatment of prostate cancer, with the incidence rate of resistant disease increasing as more men are treated with next-generation AR-targeted therapies. Lineage plasticity and progression to neuroendocrine prostate cancer (NEPC) are mechanisms by which prostate tumors lose dependence on androgen signaling and escape treatment. Although many known genetic alterations can predispose tumors to acquiring the NEPC phenotype, it remains unclear what, if any, drivers are essential to this progression. In this issue of Cancer Research, Rodarte and colleagues identified ASCL1 as one such essential regulator. Through the use of genetically engineered mouse models, the authors demonstrated that whereas ASCL1 was dispensable for tumor formation and growth, ASCL1 loss nearly completely abrogated the development of NEPC and instead redirected lineage trajectories toward a basal-like phenotype. This study provides an important new model for the study of NEPC, reveals the ability of ASCL1+ NEPC cells to also assume a NEUROD1+ state, and demonstrates the changes to tumor cell phenotypes following ASCL1 loss. See related article by Rodarte et al., p. 3522