tbuckley/cabot-search huggingface dataset:
Severe Hypoglycemia and Impaired Awareness of Hypoglycemia Persist in People With Type 1 Diabetes Despite Use of Diabetes Technology: Results From a Cross-sectional Survey
Authors: Jennifer L. Sherr, Lori M. Laffel, Jingwen Liu, Wendy Wolf, Jeoffrey Bispham, Katherine S. Chapman, Daniel Finan, Lina Titievsky, Tina Liu, Kaitlin Hagan, Jason Gaglia, Keval Chandarana, Richard Bergenstal, Jeremy Pettus
Journal: Diabetes Care (2024)

To determine how diabetes technologies, including continuous glucose monitoring (CGM) and automated insulin delivery (AID) systems, impact glycemic metrics, prevalence of severe hypoglycemic events (SHEs), and impaired awareness of hypoglycemia (IAH) in people with type 1 diabetes in a real-world setting within the U.S.
Empagliflozin Reduces Liver Fat in Individuals With and Without Diabetes
Authors: Siham Abdelgani, Ahmed Khattab, John Adams, Gozde Baskoy, Marissa Brown, Geoff Clarke, Olga Larvenenko, Ralph A. DeFronzo, Muhammad Abdul-Ghani
Journal: Diabetes Care (2024)

OBJECTIVE To examine the effect of empagliflozin on liver fat content in individuals with and without type 2 diabetes (T2D) and the relationship between the decrease in liver fat and other metabolic actions of empagliflozin. RESEARCH DESIGN AND METHODS Thirty individuals with T2D and 27 without were randomly assigned to receive in double-blind fashion empagliflozin or matching placebo (2:1 ratio) for 12 weeks. Participants underwent 75-g oral glucose tolerance testing and measurement of liver fat content with MRS before therapy and at study end. Hepatic glucose production before the start of therapy was measured with 3-3H-glucose. RESULTS Empagliflozin caused an absolute reduction of 2.39% ± 0.79% in liver fat content compared with an increase of 0.91% ± 0.64% in participants receiving placebo (P &amp;lt; 0.007 with ANOVA). The decrease in liver fat was comparable in both individuals with diabetes and those without (2.75% ± 0.81% and 1.93% ± 0.78%, respectively; P = NS). The decrease in hepatic fat content caused by empagliflozin was strongly correlated with baseline liver fat content (r = −0.62; P &amp;lt; 0.001), decrease in body weight (r = 0.53; P &amp;lt; 0.001), and improvement in insulin sensitivity (r = −0.51; P &amp;lt; 0.001) but was not related to the decrease in fasting plasma glucose or HbA1c or the increase in hepatic glucose production. CONCLUSIONS Empagliflozin is effective in reducing liver fat content in individuals with and without T2D. The decrease in liver fat content is independent of the decrease in plasma glucose concentration and is strongly related to the decrease in body weight and improvement in insulin sensitivity.
Diagnosis, prognostic factors, and assessment of ALL in adults: 2024 ELN recommendations from a European expert panel
Authors: Nicola Gökbuget, Nicolas Boissel, Sabina Chiaretti, Hervé Dombret, Michael Doubek, Adele Fielding, Robin Foà, Sebastian Giebel, Dieter Hoelzer, Mathilde Hunault, David I. Marks, Giovanni Martinelli, Oliver Ottmann, Anita Rijneveld, Philippe Rousselot, Josep Ribera, Renato Bassan
Journal: Blood (2024)

Working groups of the European LeukemiaNet have published several important consensus guidelines. Acute lymphoblastic leukemia (ALL) has many different clinical and biological subgroups and the knowledge on disease biology and therapeutic options is increasing exponentially. The European Working Group for Adult ALL has therefore summarized the current state of the art and provided comprehensive consensus recommendations for diagnostic approaches, biologic and clinical characterization, prognostic factors, and risk stratification as well as definitions of endpoints and outcomes. Aspects of treatment, management of subgroups and specific situations, aftercare, and supportive care are covered in a separate publication. The present recommendation intends to provide guidance for the initial management of adult patients with ALL and to define principles as a basis for future collaborative research.
CPHIA 2023
Authors: Paul Adepoju
Journal: The Lancet Microbe (2024)

Between Nov 27 and 30, 2023, more than 5000 in-person attendees from over 90 countries attended the third International Conference on Public Health in Africa (CPHIA 2023) in Lusaka, Zambia. The policy-focused conference featured nine themes (Track 1–9) that involved plenary, parallel, and special sessions with announcements that would be relevant in 2024 and beyond.
Extracellular Matrix‐Bioinspired Anisotropic Topographical Cues of Electrospun Nanofibers: A Strategy of Wound Healing through Macrophage Polarization
Authors: Hyeonseo Park, Tejal V. Patil, Sayan Deb Dutta, Jieun Lee, Keya Ganguly, Aayushi Randhawa, Hojin Kim, Ki‐Taek Lim
Journal: Advanced Healthcare Materials (2024)

Abstract The skin serves as the body's outermost barrier and is the largest organ, providing protection not only to the body but also to various internal organs. Owing to continuous exposure to various external factors, it is susceptible to damage that can range from simple to severe, including serious types of wounds such as burns or chronic wounds. Macrophages play a crucial role in the entire wound‐healing process and contribute significantly to skin regeneration. Initially, M1 macrophages infiltrate to phagocytose bacteria, debris, and dead cells in fresh wounds. As tissue repair is activated, M2 macrophages are promoted, reducing inflammation and facilitating restoration of the dermis and epidermis to regenerate the tissue. This suggests that extracellular matrix (ECM) promotes cell adhesion, proliferation, migrationand macrophage polarization. Among the numerous strategies, electrospinning is a versatile technique for obtaining ECM‐mimicking structures with anisotropic and isotropic topologies of micro/nanofibers. Various electrospun biomaterials influence macrophage polarization based on their isotropic or anisotropic topologies. Moreover, these fibers possess a high surface‐area‐to‐volume ratio, promoting the effective exchange of vital nutrients and oxygen, which are crucial for cell viability and tissue regeneration. Micro/nanofibers with diverse physical and chemical properties can be tailored to polarize macrophages toward skin regeneration and wound healing, depending on specific requirements. This review describes the significance of micro/nanostructures for activating macrophages and promoting wound healing.
January top picks: loving medicine
Authors: Éabha Lynn
Journal: BMJ (2024)

My relationship with medicine is perhaps more like that of the old married couple than the honeymoon phase.And as with some long term marriages, I would call it turbulent.It is said, however, that the course of true love never did run smooth, and so the first episode of Sharp Scratch in 2024, "Why I still love medicine," was a fitting tribute to our stormy history.
BORIS/CTCFL epigenetically reprograms clustered CTCF binding sites into alternative transcriptional start sites
Authors: Elena M. Pugacheva, Dharmendra Nath Bhatt, Samuel Rivero-Hinojosa, Md Tajmul, Liron Fedida, Emma Price, Yon Ji, Dmitri Loukinov, Alexander V. Strunnikov, Bing Ren, Victor V. Lobanenkov
Journal: Genome biology (2024)

Abstract Background Pervasive usage of alternative promoters leads to the deregulation of gene expression in carcinogenesis and may drive the emergence of new genes in spermatogenesis. However, little is known regarding the mechanisms underpinning the activation of alternative promoters. Results Here we describe how alternative cancer-testis-specific transcription is activated. We show that intergenic and intronic CTCF binding sites, which are transcriptionally inert in normal somatic cells, could be epigenetically reprogrammed into active de novo promoters in germ and cancer cells. BORIS/CTCFL, the testis-specific paralog of the ubiquitously expressed CTCF, triggers the epigenetic reprogramming of CTCF sites into units of active transcription. BORIS binding initiates the recruitment of the chromatin remodeling factor, SRCAP, followed by the replacement of H2A histone with H2A.Z, resulting in a more relaxed chromatin state in the nucleosomes flanking the CTCF binding sites. The relaxation of chromatin around CTCF binding sites facilitates the recruitment of multiple additional transcription factors, thereby activating transcription from a given binding site. We demonstrate that the epigenetically reprogrammed CTCF binding sites can drive the expression of cancer-testis genes, long noncoding RNAs, retro-pseudogenes, and dormant transposable elements. Conclusions Thus, BORIS functions as a transcription factor that epigenetically reprograms clustered CTCF binding sites into transcriptional start sites, promoting transcription from alternative promoters in both germ cells and cancer cells.
Management of patients with muscle-invasive bladder cancer with clinical evidence of pelvic lymph node metastases
Authors: Elisabeth Grobet-Jeandin, Louis Lenfant, Ugo Pinar, Jérôme Parra, Pierre Mozer, Raphaele Renard-Penna, Constance Thibault, Morgan Rouprêt, Thomas Seisen
Journal: Nature Reviews Urology (2024)
Aftercare for patients under the Mental Health Act should be based on need, not compliance
Authors: Narut Pakunwanich, Jeremy Bjørndal, David Seedhouse
Journal: BMJ (2024)

Access to comprehensive psychiatric aftercare is necessary for patients who have been sectioned, but this is overlooked and undervalued by current mental health law, write <b>Narut Pakunwanich</b>, <b>Jeremy Bjørndal</b>, and <b>David Seedhouse</b>
Osteosarcoma Cells Secrete CXCL14 That Activates Integrin α11β1 on Fibroblasts to Form a Lung Metastatic Niche
Authors: Yanyang Xu, Chuangzhong Deng, Hongmin Chen, YiJiang Song, Huaiyuan Xu, Guohui Song, Xinliang Wang, Tianqi Luo, Weiqing Chen, Jiahui Ma, Anyu Zeng, Shujing Huang, Zhihao Chen, Jianchang Fu, Ming Gong, Yi Tai, Anfei Huang, Huixiong Feng, Jinxin Hu, Xiaojun Zhu, Qinglian Tang, Jinchang Lu, Jin Wang
Journal: Cancer Research (2024)

Abstract Cooperation between primary malignant cells and stromal cells can mediate the establishment of lung metastatic niches. Here, we characterized the landscape of cell populations in the tumor microenvironment in treatment-naïve osteosarcoma using single-cell RNA sequencing and identified a stem cell–like cluster with tumor cell–initiating properties and prometastatic traits. CXCL14 was specifically enriched in the stem cell–like cluster and was also significantly upregulated in lung metastases compared with primary tumors. CXCL14 induced stromal reprogramming and evoked a malignant phenotype in fibroblasts to form a supportive lung metastatic niche. Binding of CXCL14 to heterodimeric integrin α11β1 on fibroblasts activated actomyosin contractility and matrix remodeling properties. CXCL14-stimulated fibroblasts produced TGFβ and increased osteosarcoma invasion and migration. mAbs targeting the CXCL14-integrin α11β1 axis inhibited fibroblast TGFβ production, enhanced CD8+ T cell–mediated antitumor immunity, and suppressed osteosarcoma lung metastasis. Taken together, these findings identify cross-talk between osteosarcoma cells and fibroblasts that promotes metastasis and demonstrate that targeting the CXCL14-integrin α11β1 axis is a potential strategy to inhibit osteosarcoma lung metastasis. Significance: Cooperation between stem-like osteosarcoma cells and fibroblasts mediated by a CXCL14-integrin α11β1 axis creates a tumor-supportive lung metastatic niche and represents a therapeutic target to suppress osteosarcoma metastasis.
Myeloid and lymphoid expression of <i>C9orf72</i> regulates IL-17A signaling in mice
Authors: Francesco Limone, Alexander Couto, Jin-Yuan Wang, Yingying Zhang, Blake McCourt, Cerianne Huang, Adina Minkin, Marghi Jani, Sarah McNeer, James Keaney, Gaëlle Gillet, Rodrigo Lopez Gonzalez, Wendy A. Goodman, Irena Kadiu, Kevin Eggan, Aaron Burberry
Journal: Science Translational Medicine (2024)

A mutation in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Patients with ALS or FTD often develop autoimmunity and inflammation that precedes or coincides with the onset of neurological symptoms, but the underlying mechanisms are poorly understood. Here, we knocked out murine C9orf72 in seven hematopoietic progenitor compartments by conditional mutagenesis and found that myeloid lineage C9orf72 prevents splenomegaly, loss of tolerance, and premature mortality. Furthermore, we demonstrated that C9orf72 plays a role in lymphoid cells to prevent interleukin-17A (IL-17A) production and neutrophilia. Mass cytometry identified early and sustained elevation of the costimulatory molecule CD80 expressed on C9orf72 -deficient mouse macrophages, monocytes, and microglia. Enrichment of CD80 was similarly observed in human spinal cord microglia from patients with C9ORF72 -mediated ALS compared with non-ALS controls. Single-cell RNA sequencing of murine spinal cord, brain cortex, and spleen demonstrated coordinated induction of gene modules related to antigen processing and presentation and antiviral immunity in C9orf72 -deficient endothelial cells, microglia, and macrophages. Mechanistically, C9ORF72 repressed the trafficking of CD80 to the cell surface in response to Toll-like receptor agonists, interferon-γ, and IL-17A. Deletion of Il17a in C9orf72 -deficient mice prevented CD80 enrichment in the spinal cord, reduced neutrophilia, and reduced gut T helper type 17 cells. Last, systemic delivery of an IL-17A neutralizing antibody augmented motor performance and suppressed neuroinflammation in C9orf72 -deficient mice. Altogether, we show that C9orf72 orchestrates myeloid costimulatory potency and provide support for IL-17A as a therapeutic target for neuroinflammation associated with ALS or FTD.
Improved immunostaining of nanostructures and cells in human brain specimens through expansion-mediated protein decrowding
Authors: Pablo A. Valdes, Chih-Chieh (Jay) Yu, Jenna Aronson, Debarati Ghosh, Yongxin Zhao, Bobae An, Joshua D. Bernstock, Deepak Bhere, Michelle M. Felicella, Mariano S. Viapiano, Khalid Shah, E. Antonio Chiocca, Edward S. Boyden
Journal: Science Translational Medicine (2024)

Proteins are densely packed in cells and tissues, where they form complex nanostructures. Expansion microscopy (ExM) variants have been used to separate proteins from each other in preserved biospecimens, improving antibody access to epitopes. Here, we present an ExM variant, decrowding expansion pathology (dExPath), that can expand proteins away from each other in human brain pathology specimens, including formalin-fixed paraffin-embedded (FFPE) clinical specimens. Immunostaining of dExPath-expanded specimens reveals, with nanoscale precision, previously unobserved cellular structures, as well as more continuous patterns of staining. This enhanced molecular staining results in observation of previously invisible disease marker–positive cell populations in human glioma specimens, with potential implications for tumor aggressiveness. dExPath results in improved fluorescence signals even as it eliminates lipofuscin-associated autofluorescence. Thus, this form of expansion-mediated protein decrowding may, through improved epitope access for antibodies, render immunohistochemistry more powerful in clinical science and, perhaps, diagnosis.
RExPRT: a machine learning tool to predict pathogenicity of tandem repeat loci
Authors: Sarah Fazal, Matt C. Danzi, Isaac Xu, Shilpa Nadimpalli Kobren, Shamil Sunyaev, Chloe Reuter, Shruti Marwaha, Matthew Wheeler, Egor Dolzhenko, Francesca Lucas, Stefan Wuchty, Mustafa Tekin, Stephan Züchner, Vanessa Aguiar-Pulido
Journal: Genome biology (2024)

Abstract Expansions of tandem repeats (TRs) cause approximately 60 monogenic diseases. We expect that the discovery of additional pathogenic repeat expansions will narrow the diagnostic gap in many diseases. A growing number of TR expansions are being identified, and interpreting them is a challenge. We present RExPRT (Repeat EXpansion Pathogenicity pRediction Tool), a machine learning tool for distinguishing pathogenic from benign TR expansions. Our results demonstrate that an ensemble approach classifies TRs with an average precision of 93% and recall of 83%. RExPRT’s high precision will be valuable in large-scale discovery studies, which require prioritization of candidate loci for follow-up studies.
Rescuing lung development through embryonic inhibition of histone acetylation
Authors: Giangela Stokes, Zhuowei Li, Nicole Talaba, William Genthe, Maria B. Brix, Betty Pham, Mark D. Wienhold, Gracia Sandok, Rebecca Hernan, Julia Wynn, Haiyang Tang, Diana M. Tabima, Allison Rodgers, Timothy A. Hacker, Naomi C. Chesler, Pan Zhang, Rabi Murad, Jason X. -J. Yuan, Yufeng Shen, Wendy K. Chung, David J. McCulley
Journal: Science Translational Medicine (2024)

A major barrier to the impact of genomic diagnosis in patients with congenital malformations is the lack of understanding regarding how sequence variants contribute to disease pathogenesis and whether this information could be used to generate patient-specific therapies. Congenital diaphragmatic hernia (CDH) is among the most common and severe of all structural malformations; however, its underlying mechanisms are unclear. We identified loss-of-function sequence variants in the epigenomic regulator gene
Phase I Study of GS-3583, an FMS-like Tyrosine Kinase 3 Agonist Fc Fusion Protein, in Patients with Advanced Solid Tumors
Authors: Anthony W. Tolcher, Joshua D. Brody, Nishanthan Rajakumaraswamy, Michelle Kuhne, Torsten Trowe, Anees M. Dauki, Shantheri Pai, Ling Han, Kai-Wen Lin, Michael Petrarca, Shivaani Kummar
Journal: Clinical Cancer Research (2024)

GS-3583, an FMS-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein, expanded conventional dendritic cells (cDC) in the periphery of healthy volunteers, suggesting potential for GS-3583 to increase cDCs in the tumor microenvironment and promote T cell-mediated antitumor activity in cancer patients. This phase Ib open-label study assessed GS-3583 in adults with advanced solid tumors.
Model-Informed Clinical Pharmacology Profile of a Novel Fixed-Dose Combination of Nivolumab and Relatlimab in Adult and Adolescent Patients with Solid Tumors
Authors: Yue Zhao, Zheyi Hu, Sai Praneeth Bathena, Sarah Keidel, Karen Miller-Moslin, Paul Statkevich, Akintunde Bello, Amit Roy, Satyendra Suryawanshi
Journal: Clinical Cancer Research (2024)

Progression-free survival (PFS) was significantly improved with nivolumab 480 mg plus relatlimab 160 mg fixed-dose combination (FDC) every 4 weeks (Q4W) versus nivolumab alone in patients with previously untreated advanced melanoma in RELATIVITY-047. In addition, RELATIVITY-020 (Part D) demonstrated a manageable safety profile and potential for durable response with nivolumab plus relatlimab in previously treated patients. Here, we evaluate the clinical pharmacology profile (CPP) of nivolumab plus relatlimab to support the approved regimen for adult and adolescent patients with advanced melanoma and its continued clinical development in solid tumors.
Computational validation of clonal and subclonal copy number alterations from bulk tumor sequencing using CNAqc
Authors: Alice Antonello, Riccardo Bergamin, Nicola Calonaci, Jacob Househam, Salvatore Milite, Marc J. Williams, Fabio Anselmi, Alberto d’Onofrio, Vasavi Sundaram, Alona Sosinsky, William C. H. Cross, Giulio Caravagna
Journal: Genome biology (2024)

Abstract Copy number alterations (CNAs) are among the most important genetic events in cancer, but their detection from sequencing data is challenging because of unknown sample purity, tumor ploidy, and general intra-tumor heterogeneity. Here, we present CNAqc, an evolution-inspired method to perform the computational validation of clonal and subclonal CNAs detected from bulk DNA sequencing. CNAqc is validated using single-cell data and simulations, is applied to over 4000 TCGA and PCAWG samples, and is incorporated into the validation process for the clinically accredited bioinformatics pipeline at Genomics England. CNAqc is designed to support automated quality control procedures for tumor somatic data validation.
Phase 2 Study of the Liposomal Formulation of Eribulin (E7389-LF) in Combination with Nivolumab: Results from the Gastric Cancer Cohort
Authors: Akihito Kawazoe, Noboru Yamamoto, Naotoshi Sugimoto, Hisato Kawakami, Takashi Oshima, Kensei Yamaguchi, Kaori Hino, Motohiro Hirao, Yukinori Kurokawa, Takeshi Kawakami, Masahiro Tsuda, Hiroki Hara, Shota Kaname, Daiko Matsuoka, Yohei Otake, Keisuke Yasuda, Takao Takase, Shuya Takashima, Taro Semba, Kei Muro
Journal: Clinical Cancer Research (2024)

Abstract Purpose: E7389-LF is a liposomal formulation of the microtubule dynamics inhibitor eribulin and has shown preliminary efficacy in the treatment of gastric cancer. Study 120, a phase Ib/II open-label study, assessed efficacy and safety of E7389-LF in combination with nivolumab, a programmed cell death (PD)-1 inhibitor. This report focuses on the gastric cancer cohort within the expansion phase. Patients and Methods: Eligible patients had unresectable, measurable gastric cancer, progression following a platinum drug plus fluoropyrimidine (1L), and a taxane-containing regimen (2L). The primary objective of the expansion phase was objective response rate, secondary objectives included safety and PFS, and exploratory objectives included overall survival and biomarker evaluation. Patients received E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks, both as intravenous infusions. Tumor responses were assessed every 6 weeks by the investigators per RECIST v1.1. Plasma and tumor biomarkers were assessed. Results: In the 31 patients who received E7389-LF in combination with nivolumab, the objective response rate was 25.8% [confidence interval (CI), 11.9–44.6]. The median progression-free survival was 2.69 months (95% CI, 1.91–2.99) and median overall survival was 7.85 months (95% CI, 4.47–not estimable). The most common treatment-related TEAE of any grade were neutropenia (77.4%), leukopenia (74.2%), and decreased appetite (51.6%). E7389-LF in combination with nivolumab significantly increased CD8-positive cells at C2D1 (P = 0.039), and six of seven vascular markers and four IFNγ-related markers showed increases from C1D1. Conclusions: Promising antitumor activity was observed with E7389-LF in combination with nivolumab in patients with gastric cancer, and no new safety signals were observed, compared with either monotherapy.