tbuckley/cabot-search huggingface dataset:
We want healthy athletes and fair competition
Authors: Yannis P Pitsiladis, Fabio Pigozzi, Michael Geistlinger, José Kawazoe Lazzoli, Maher Zahar, Norbert Bachl, Pedro Manonelles Marqueta, William O Roberts, Klaus-Michael Braumann, Eduardo H De Rose, Demitri Constantinou, Anca Ionescu, Christian Schneider, Patrick Shu-Hang Yung, Xavier Bigard
Journal: British Journal of Sports Medicine (2024)
Hexamerization: explaining the original sin of IgG-mediated complement activation in acute lung injury
Authors: Hrishikesh S. Kulkarni
Journal: Journal of Clinical Investigation (2024)

Although antibody-mediated lung damage is a major factor in transfusion-related acute lung injury (ALI), autoimmune lung disease (for example, coatomer subunit α [COPA] syndrome), and primary graft dysfunction following lung transplantation, the mechanism by which antigen-antibody complexes activate complement to induce lung damage remains unclear. In this issue of the JCI, Cleary and colleagues utilized several approaches to demonstrate that IgG forms hexamers with MHC class I alloantibodies. This hexamerization served as a key pathophysiological mechanism in alloimmune lung injury models and was mediated through the classical pathway of complement activation. Additionally, the authors provided avenues for exploring therapeutics for this currently hard-to-treat clinical entity that has several etiologies but a potentially focused mechanism.
Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia
Authors: Kyriakie Sarafoglou, Mimi S Kim, Maya Lodish, Eric I Felner, Laetitia Martinerie, Natalie J Nokoff, María Clemente, Patricia Y Fechner, Maria G Vogiatzi, Phyllis W Speiser, Richard J Auchus, Gelliza B G Rosales, Eiry Roberts, George S Jeha, Robert H Farber, Jean L Chan
Journal: New England Journal of Medicine (2024)

Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels.
Adjunctive Statistical Standardization of Adjuvant Estrogen Receptor and Progesterone Receptor in Canadian Cancer Trials Group MA.27 Postmenopausal Breast Cancer Trial of Exemestane Versus Anastrozole
Authors: Judith-Anne W. Chapman, Jane Bayani, Sandip SenGupta, John M.S. Bartlett, Tammy Piper, Mary Anne Quintayo, Shakeel Virk, Paul E. Goss, James N. Ingle, Matthew J. Ellis, George W. Sledge, G. Thomas Budd, Manuela Rabaglio, Rafat H. Ansari, Richard Tozer, David P. D'Souza, Haji Chalchal, Silvana Spadafora, Vered Stearns, Edith A. Perez, Karen A. Gelmon, Timothy J. Whelan, Catherine Elliott, Lois E. Shepherd, Bingshu E. Chen, Karen J. Taylor
Journal: Journal of Clinical Oncology (2024)

ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes.
Multifaceted Hydrogel Scaffolds: Bridging the Gap between Biomedical Needs and Environmental Sustainability
Authors: Narsimha Mamidi, Fátima Franco De Silva, Alejandro Bedón Vacas, Javier Adonay Gutiérrez Gómez, Naomi Yael Montes Goo, Daniela Ruiz Mendoza, Rui L. Reis, Subhas C. Kundu
Journal: Advanced Healthcare Materials (2024)

Abstract Hydrogels are dynamically evolving 3D networks composed of hydrophilic polymer scaffolds with significant applications in the healthcare and environmental sectors. Notably, protein‐based hydrogels mimic the extracellular matrix, promoting cell adhesion. Further enhancing cell proliferation within these scaffolds are matrix‐metalloproteinase‐triggered amino acid motifs. Integration of cell‐friendly modules like peptides and proteins expands hydrogel functionality. These exceptional properties position hydrogels for diverse applications, including biomedicine, biosensors, environmental remediation, and the food industry. Despite significant progress, there is ongoing research to optimize hydrogels for biomedical and environmental applications further. Engineering novel hydrogels with favorable characteristics is crucial for regulating tissue architecture and facilitating ecological remediation. This review explores the synthesis, physicochemical properties, and biological implications of various hydrogel types and their extensive applications in biomedicine and environmental sectors. It elaborates on their potential applications, bridging the gap between advancements in the healthcare sector and solutions for environmental issues.
Dynamic Covalent Hydrogel as a Single‐dose Vaccine Adjuvant for Sustained Antigen Release and Significantly Elevated Humoral Immunity
Authors: Zhiyuan Shi, Zihan Gao, Xinyu Zhuang, Xinghui Si, Zichao Huang, Yaxin Di, Sheng Ma, Zhaopei Guo, Chang Li, Ningyi Jin, Leaf Huang, Mingyao Tian, Wantong Song, Xuesi Chen
Journal: Advanced Healthcare Materials (2024)

Vaccine is the most important way for fighting against infection diseases. However, multiple injections and unsatisfied immune responses are the main obstacles for current vaccine application. Herein, a dynamic covalent hydrogel (DCH) is used as a single-dose vaccine adjuvant for eliciting robust and sustained humoral immunity. By adjusting the mass ratio of the DCH gel, 10-30 d constant release of the loaded recombinant protein antigens is successfully realized, and it is proved that sustained release of antigens can significantly improve the vaccine efficacy. When loading SARS-CoV-2 RBD (Wuhan and Omicron BA.1 strains) antigens into this DCH gel, an over 32 000 times and 8000 times improvement is observed in antigen-specific antibody titers compared to conventional Aluminum adjuvanted vaccines. The universality of this DCH gel adjuvant is confirmed in a Nipah G antigen test as well as a H1N1 influenza virus antigen test, with much improved protection of C57BL/6 mice against H1N1 virus infection than conventional Aluminum adjuvanted vaccines. This sustainably released, single-dose DCH gel adjuvant provides a new promising option for designing next-generation infection vaccines.
Osimertinib after Chemoradiotherapy in Stage III <i>EGFR</i> -Mutated NSCLC
Authors: Shun Lu, Terufumi Kato, Xiaorong Dong, Myung-Ju Ahn, Le-Van Quang, Nopadol Soparattanapaisarn, Takako Inoue, Chih-Liang Wang, Meijuan Huang, James Chih-Hsin Yang, Manuel Cobo, Mustafa Özgüroğlu, Ignacio Casarini, Dang-Van Khiem, Virote Sriuranpong, Eduardo Cronemberger, Toshiaki Takahashi, Yotsawaj Runglodvatana, Ming Chen, Xiangning Huang, Ellie Grainger, Dana Ghiorghiu, Toon van der Gronde, Suresh S Ramalingam
Journal: New England Journal of Medicine (2024)

Osimertinib is a recommended treatment for advanced non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (
Hold the salt for kidney regeneration
Authors: Yun Xia, Thomas M Coffman
Journal: Journal of Clinical Investigation (2024)

The macula densa (MD) is a distinct cluster of approximately 20 specialized kidney epithelial cells that constitute a key component of the juxtaglomerular apparatus. Unlike other renal tubular epithelial cell populations with functions relating to reclamation or secretion of electrolytes and solutes, the MD acts as a cell sensor, exerting homeostatic actions in response to sodium and chloride changes within the tubular fluid. Electrolyte flux through apical sodium transporters in MD cells triggers release of paracrine mediators, affecting blood pressure and glomerular hemodynamics. In this issue of the JCI, Gyarmati and authors explored a program of MD that resulted in activation of regeneration pathways. Notably, regeneration was triggered by feeding mice a low-salt diet. Furthermore, the MD cells showed neuron-like properties that may contribute to their regulation of glomerular structure and function. These findings suggest that dietary sodium restriction and/or targeting MD signaling might attenuate glomerular injury.
CHIPing away at immunity: the role of clonal hematopoiesis of indeterminate potential in bacterial pneumonia
Authors: Elsa N. Bou Ghanem
Journal: Journal of Clinical Investigation (2024)

The occurrence of clonal hematopoiesis of indeterminate potential (CHIP), in which advantageous somatic mutations result in the clonal expansion of blood cells, increases with age, as do an increased risk of mortality and detrimental outcomes associated with CHIP. However, the role of CHIP in susceptibility to pulmonary infections, which also increase with age, is unclear. In this issue of the JCI, Quin and colleagues explored the role of CHIP in bacterial pneumonia. Using characterization of immune cells from human donors and mice lacking tet methylcytosine dioxygenase 2 (Tet2), the authors mechanistically link myeloid immune cell dysfunction to CHIP-mediated risk of bacterial pneumonia. The findings suggest that CHIP drives inflammaging and immune senescence, and provide Tet2 status in older adults as a potential prognostic tool for informing treatment options related to immune modulation.
Novel medications for problematic alcohol use
Authors: Markus Heilig, Katie Witkiewitz, Lara A Ray, Lorenzo Leggio
Journal: Journal of Clinical Investigation (2024)

Alcohol-related harm, a major cause of disease burden globally, affects people along a spectrum of use. When a harmful pattern of drinking is present in the absence of significant behavioral pathology, low-intensity brief interventions that provide information about health consequences of continued use provide large health benefits. At the other end of the spectrum, profound behavioral pathology, including continued use despite knowledge of potentially fatal consequences, warrants a medical diagnosis, and treatment is strongly indicated. Available behavioral and pharmacological treatments are supported by scientific evidence but are vastly underutilized. Discovery of additional medications, with a favorable balance of efficacy versus safety and tolerability can improve clinical uptake of treatment, allow personalized treatment, and improve outcomes. Here, we delineate the clinical conditions when pharmacotherapy should be considered in relation to the main diagnostic systems in use and discuss clinical endpoints that represent meaningful clinical benefits. We then review specific developments in three categories of targets that show promise for expanding the treatment toolkit. GPCRs remain the largest category of successful drug targets across contemporary medicine, and several GPCR targets are currently pursued for alcohol-related indications. Endocrine systems are another established category, and several promising targets have emerged for alcohol indications. Finally, immune modulators have revolutionized treatment of multiple medical conditions, and they may also hold potential to produce benefits in patients with alcohol problems.
A non-stationary bivariate extreme value model to estimate real-time pedestrian crash risk by severity at signalized intersections using artificial intelligence-based video analytics
Authors: Hassan Bin Tahir, Md Mazharul Haque
Journal: Analytic Methods in Accident Research (2024)

Vehicle-pedestrian crashes are generally severe due to the vulnerability of pedestrians compared to the occupants of vehicles. However, the estimation of pedestrian crash risk by severity has not been given adequate attention in the field of proactive safety assessments applying traffic conflict techniques. This study proposes a novel analytical framework to estimate real-time pedestrian crash risk by severity at the signal cycle level while incorporating the effect of time-varying exogenous variables. Specifically, the study applies a non-stationary bivariate extreme value model to jointly model the post encroachment time and Delta-V for estimating real-time pedestrian crash risk by severity at individual signal cycles. The proposed framework is tested on 144 h of video data collected from three signalized intersections in Queensland, Australia. The developed bivariate extreme value model has been found to reliably predict severe and non-severe pedestrian crash frequencies compared to the historical crash records of severe and non-severe pedestrian crashes at those signalized intersections. Results suggest that the frequency of pedestrian conflicts per signal cycle and average pedestrian speed in a signal cycle are associated with real-time pedestrian crash risks. In addition, pedestrian conflicts per signal cycle and average vehicle speed per cycle were associated with the interaction severity component of the non-stationary bivariate extreme value model. The proposed proactive estimation of pedestrian crash risk by severity levels can help design time-sensitive countermeasures for vulnerable road users.
Galacturonic acid-capsaicin prodrug for prolonged nociceptive-selective nerve blockade
Authors: Qi Li, Xiaosi Li, Yanqi Zhang, Qiuyun Yang, Sarah F Hathcock, Yuhao Cai, Prabhakar Busa, Stephany Pang, Libo Tan, Brandon J Kim, Chao Zhao
Journal: Journal of Controlled Release (2024)
Leptomeningeal metastases in isocitrate dehydrogenase-wildtype glioblastomas revisited: Comprehensive analysis of incidence, risk factors, and prognosis based on post-contrast fluid-attenuated inversion recovery
Authors: Yae Won Park, Geon Jang, Si Been Kim, Kaeum Choi, Kyunghwa Han, Na-Young Shin, Sung Soo Ahn, Jong Hee Chang, Se Hoon Kim, Seung-Koo Lee, Rajan Jain
Journal: Neuro-Oncology (2024)

Abstract Background The incidence of leptomeningeal metastases (LM) has been reported diversely. This study aimed to investigate the incidence, risk factors, and prognosis of LM in patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma. Methods A total of 828 patients with IDH-wildtype glioblastoma were enrolled between 2005 and 2022. Baseline preoperative MRI including post-contrast fluid-attenuated inversion recovery (FLAIR) was used for LM diagnosis. Qualitative and quantitative features, including distance between tumor and subventricular zone (SVZ) and tumor volume by automatic segmentation of the lateral ventricles and tumor, were assessed. Logistic analysis of LM development was performed using clinical, molecular, and imaging data. Survival analysis was performed. Results The incidence of LM was 11.4%. MGMTp unmethylation (odds ratio [OR] = 1.92, P = .014), shorter distance between tumor and SVZ (OR = 0.94, P = .010), and larger contrast-enhancing tumor volume (OR = 1.02, P &amp;lt; .001) were significantly associated with LM. The overall survival (OS) was significantly shorter in patients with LM than in those without (log-rank test; P &amp;lt; .001), with median OS of 12.2 and 18.5 months, respectively. The presence of LM remained an independent prognostic factor for OS in IDH-wildtype glioblastoma (hazard ratio = 1.42, P = .011), along with other clinical, molecular, imaging, and surgical prognostic factors. Conclusions The incidence of LM is high in patients with IDH-wildtype glioblastoma, and aggressive molecular and imaging factors are correlated with LM development. The prognostic significance of LM based on post-contrast FLAIR imaging suggests the acknowledgment of post-contrast FLAIR as a reliable diagnostic tool for clinicians.
Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD
Authors: Yewei Wang, Md Ashik Ullah, Olivia G Waltner, Shruti S Bhise, Kathleen S Ensbey, Christine R Schmidt, Samuel Rw Legg, Tomoko Sekiguchi, Ethan L Nelson, Rachel D Kuns, Nicole S Nemychenkov, Erden Atilla, Albert C Yeh, Shuichiro Takahashi, Julie R Boiko, Antiopi Varelias, Bruce R Blazar, Motoko Koyama, Simone A Minnie, Andrew D Clouston, Scott N Furlan, Ping Zhang, Geoffrey R Hill
Journal: Journal of Clinical Investigation (2024)

Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.
Sulfoxide-containing polymers conjugated prodrug micelles with enhanced anticancer activity and reduced intestinal toxicity
Authors: Yechun Wang, Jiafeng Wang, JunJun Li, Yongli Mu, Jiajia Ying, Zimeng Liu, Mengjie Wu, Yu Geng, Xuefei Zhou, Tianhua Zhou, Youqing Shen, Leimin Sun, Xiangrui Liu, Quan Zhou
Journal: Journal of Controlled Release (2024)
Personalized ctDNA for Monitoring Disease Status in Head and Neck Squamous Cell Carcinoma
Authors: Glenn J. Hanna, Michael J. Dennis, Nicole Scarfo, Michelle S. Mullin, Rosh K.V. Sethi, Kartik Sehgal, Donald J. Annino, Laura A. Goguen, Robert I. Haddad, Roy B. Tishler, Danielle N. Margalit, Ravindra Uppaluri, Jonathan D. Schoenfeld, Eleni M. Rettig
Journal: Clinical Cancer Research (2024)

Many patients with locoregionally advanced human papillomavirus-negative head and neck squamous cell carcinoma (HNSCC) relapse. ctDNA has the potential to identify minimal residual disease, but its clinical utility for virus-negative HNSCC is not well understood.
Generalized genetic liability to substance use disorders
Authors: Alex P Miller, Ryan Bogdan, Arpana Agrawal, Alexander S Hatoum
Journal: Journal of Clinical Investigation (2024)

Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common and compared with individual SUDs is characterized by greater severity, additional psychiatric comorbidities, and worse outcomes. Here, we review evidence for the role of generalized genetic liability to various SUDs. Coaggregation of SUDs has familial contributions, with twin studies suggesting a strong contribution of additive genetic influences undergirding use disorders for a variety of substances (including alcohol, nicotine, cannabis, and others). GWAS have documented similarly large genetic correlations between alcohol, cannabis, and opioid use disorders. Extending these findings, recent studies have identified multiple genomic loci that contribute to common risk for these SUDs and problematic tobacco use, implicating dopaminergic regulatory and neuronal development mechanisms in the pathophysiology of generalized SUD genetic liability, with certain signals demonstrating cross-species and translational validity. Overlap with genetic signals for other externalizing behaviors, while substantial, does not explain the entirety of the generalized genetic signal for SUD. Polygenic scores (PGS) derived from the generalized genetic liability to SUDs outperform PGS for individual SUDs in prediction of serious mental health and medical comorbidities. Going forward, it will be important to further elucidate the etiology of generalized SUD genetic liability by incorporating additional SUDs, evaluating clinical presentation across the lifespan, and increasing the granularity of investigation (e.g., specific transdiagnostic criteria) to ultimately improve the nosology, prevention, and treatment of SUDs.
Increased endothelial sclerostin caused by elevated DSCAM mediates multiple trisomy 21 phenotypes
Authors: David M McKean, Qi Zhang, Priyanka Narayan, Sarah U Morton, Viktoria Strohmenger, Vi T Tang, Sophie McAllister, Ananya Sharma, Daniel Quiat, Daniel Reichart, Daniel M DeLaughter, Hiroko Wakimoto, Joshua M Gorham, Kemar Brown, Barbara McDonough, Jon A Willcox, Min Young Jang, Steven R DePalma, Tarsha Ward, Richard Kim, John D Cleveland, J G Seidman, Christine E Seidman
Journal: Journal of Clinical Investigation (2024)

Trisomy 21 (T21), a recurrent aneuploidy occurring in 1:800 births, predisposes to congenital heart disease (CHD) and multiple extracardiac phenotypes. Despite a definitive genetic etiology, the mechanisms by which T21 perturbs development and homeostasis remain poorly understood. We compared the transcriptome of CHD tissues from 49 patients with T21 and 226 with euploid CHD (eCHD). We resolved cell lineages that misexpressed T21 transcripts by cardiac single-nucleus RNA sequencing and RNA in situ hybridization. Compared with eCHD samples, T21 samples had increased chr21 gene expression; 11-fold-greater levels (P = 1.2 × 10-8) of SOST (chr17), encoding the Wnt inhibitor sclerostin; and 1.4-fold-higher levels (P = 8.7 × 10-8) of the SOST transcriptional activator ZNF467 (chr7). Euploid and T21 cardiac endothelial cells coexpressed SOST and ZNF467; however, T21 endothelial cells expressed 6.9-fold more SOST than euploid endothelial cells (P = 2.7 × 10-27). Wnt pathway genes were downregulated in T21 endothelial cells. Expression of DSCAM, residing within the chr21 CHD critical region, correlated with SOST (P = 1.9 × 10-5) and ZNF467 (P = 2.9 × 10-4). Deletion of DSCAM from T21 endothelial cells derived from human induced pluripotent stem cells diminished sclerostin secretion. As Wnt signaling is critical for atrioventricular canal formation, bone health, and pulmonary vascular homeostasis, we concluded that T21-mediated increased sclerostin levels would inappropriately inhibit Wnt activities and promote Down syndrome phenotypes. These findings imply therapeutic potential for anti-sclerostin antibodies in T21.
Belantamab Mafodotin, Pomalidomide, and Dexamethasone in Multiple Myeloma
Authors: Meletios Athanasios Dimopoulos, Meral Beksac, Ludek Pour, Sosana Delimpasi, Vladimir Vorobyev, Hang Quach, Ivan Spicka, Jakub Radocha, Pawel Robak, Kihyun Kim, Michele Cavo, Kazuhito Suzuki, Kristin Morris, Farrah Pompilus, Amy Phillips-Jones, Xiaoou L Zhou, Giulia Fulci, Neal Sule, Brandon E Kremer, Joanna Opalinska, María-Victoria Mateos, Suzanne Trudel
Journal: New England Journal of Medicine (2024)

Triplet or quadruplet therapies incorporating proteasome inhibitors, immunomodulators, and anti-CD38 antibodies have led to prolonged survival among patients with newly diagnosed multiple myeloma; however, most patients have a relapse. Frontline lenalidomide therapy has increased the number of patients with lenalidomide-refractory disease at the time of the first relapse.