tbuckley/cabot-search huggingface dataset:
Multiplex DNA fluorescence in situ hybridization to analyze maternal vs. paternal C. elegans chromosomes
Authors: Silvia Gutnik, Jia Emil You, Ahilya N. Sawh, Aude Andriollo, Susan E. Mango
Journal: Genome biology (2024)

Abstract Recent advances in microscopy have enabled studying chromosome organization at the single-molecule level, yet little is known about inherited chromosome organization. Here we adapt single-molecule chromosome tracing to distinguish two C. elegans strains (N2 and HI) and find that while their organization is similar, the N2 chromosome influences the folding parameters of the HI chromosome, in particular the step size, across generations. Furthermore, homologous chromosomes overlap frequently, but alignment between homologous regions is rare, suggesting that transvection is unlikely. We present a powerful tool to investigate chromosome architecture and to track the parent of origin.
<i>Notes from the Field</i>: Surveillance for Multisystem Inflammatory Syndrome in Children — United States, 2023
Authors: Anna R. Yousaf, Katherine N. Lindsey, Michael J. Wu, Ami B. Shah, Rebecca J. Free, Regina M. Simeone, Laura D. Zambrano, Angela P. Campbell, Steven Crook, Amy Clark, Tiffanie Fulton-Kennedy, Ashley Gent, Walaa Elbedewy, Gabrielle Williams, Amanda Hartley, Kaleb Kitchens, Gillian Richardson, Marion Deming, Cole Burkholder, Jacob Reece, Tom Haupt, Amanda Mandi, Paige D’Heilly, Ayotola Falodun, C.J. Gil, Chelsea Campbell, Kimberly Carlson, Heather D. Reid, Deepam Thomas, Haytham Safi, Jacqueline Denning, Stacy Davidson, Maya Scullin, Allison Longenberger, Kelly Blythe, Xandy Peterson Pompa, Augustina Manuzak, Spencer Cunningham, Kate Cleavinger, Jannifer Anderson, Carmen Rodriguez, Lesley Roush
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious condition typically occurring 2-6 weeks after SARS-CoV-2 infection and characterized by fever and multiorgan involvement (1,2).In May 2020, CDC created an MIS-C case definition and established a passive national surveillance system for voluntary case reporting by state and local health departments.*In 2022, CDC and the Council of State and Territorial Epidemiologists (CSTE) created a new surveillance case definition that went into effect on January 1, 2023 † (3).Approximately 87% of cases reported using the 2020 case definition also meet the 2023 case definition.This report describes 2023 MIS-C cases and compares them with cases reported earlier in the COVID-19 pandemic.
Evolution of nasal and olfactory infection characteristics of SARS-CoV-2 variants
Authors: Mengfei Chen, Andrew Pekosz, Jason S. Villano, Wenjuan Shen, Ruifeng Zhou, Heather Kulaga, Zhexuan Li, Amy Smith, Asiana Gurung, Sarah E. Beck, Kenneth W. Witwer, Joseph L. Mankowski, Murugappan Ramanathan, Nicholas R. Rowan, Andrew P. Lane
Journal: Journal of Clinical Investigation (2024)

SARS-CoV-2 infection of the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. By studying infection of human biopsies in vitro and in a hamster model in vivo, we demonstrated a transition in nasal tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variant revealed that SARS-CoV-2 WA1 or Delta infect a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possessed broader cellular invasion capacity into the submucosa, while Omicron displayed enhanced nasal respiratory infection and longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon were more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa were accompanied by a decline of phagocytosis related genes. Furthermore, robust basal stem cell activation contributed to neuroepithelial regeneration and restores ACE2 expression post-infection. Together, our study characterized the nasal tropism of SARS-CoV-2 strains, immune clearance, and regeneration post infection. The shifting characteristics of viral infection at the airway portal provides insight into the variability of COVID-19 clinical features, particularly long COVID, and may suggest differing strategies for early local intervention.
Adult and neonatal models of chemogenetic heart failure caused by oxidative stress
Authors: Fotios Spyropoulos, Apabrita Ayan Das, Markus Waldeck-Weiermair, Shambhu Yadav, Arvind K. Pandey, Ruby Guo, Taylor A. Covington, Venkata Thulabandu, Kosmas Kosmas, Benjamin Steinhorn, Xiaoli Liu, Helen Christou, Thomas Michel
Journal: Journal of Clinical Investigation (2024)
Targeted therapies prime oncogene-driven lung cancers for macrophage-mediated destruction
Authors: Kyle Vaccaro, Juliet Allen, Troy W. Whitfield, Asaf Maoz, Sarah Reeves, José Velarde, Dian Yang, Anna Meglan, Juliano Ribeiro, Jasmine Blandin, Nicole Phan, George W. Bell, Aaron N. Hata, Kipp Weiskopf
Journal: Journal of Clinical Investigation (2024)

Macrophage immune checkpoint inhibitors, such as anti-CD47 antibodies, show promise in clinical trials for solid and hematologic malignancies. However, the best strategies to use these therapies remain unknown, and ongoing studies suggest they may be most effective when used in combination with other anticancer agents. Here, we developed a novel screening platform to identify drugs that render lung cancer cells more vulnerable to macrophage attack, and we identified therapeutic synergy exists between genotype-directed therapies and anti-CD47 antibodies. In validation studies, we found the combination of genotype-directed therapies and CD47 blockade elicited robust phagocytosis and eliminated persister cells in vitro and maximized anti-tumor responses in vivo. Importantly, these findings broadly applied to lung cancers with various RTK/MAPK pathway alterations—including EGFR mutations, ALK fusions, or KRASG12C mutations. We observed downregulation of β2-microglobulin and CD73 as molecular mechanisms contributing to enhanced sensitivity to macrophage attack. Our findings demonstrate that dual inhibition of the RTK/MAPK pathway and the CD47/SIRPa axis is a promising immunotherapeutic strategy. Our study provides strong rationale for testing this therapeutic combination in patients with lung cancers bearing driver mutations.
Repolarization of Immunosuppressive Macrophages by Targeting SLAMF7-Regulated CCL2 Signaling Sensitizes Hepatocellular Carcinoma to Immunotherapy
Authors: Jialei Weng, Zheng Wang, Zhiqiu Hu, Wenxin Xu, Jia-Lei Sun, Fu Wang, Qiang Zhou, Shaoqing Liu, Min Xu, Minghao Xu, Dongmei Gao, Ying-Hao Shen, Yong Yi, Yi Shi, Qiongzhu Dong, Chenhao Zhou, Ning Ren
Journal: Cancer Research (2024)

Immune checkpoint inhibitors have limited efficacy in hepatocellular carcinoma (HCC). Macrophages are the most abundant immune cells in HCC, suggesting that a better understanding of the intrinsic processes by which tumor cells regulate macrophages could help identify strategies to improve response to immunotherapy. As signaling lymphocytic activation molecule (SLAM) family members regulate various immune functions, we investigated the role of specific SLAM receptors in the immunobiology of HCC. Comparison of the transcriptomic landscapes of immunotherapy-responsive and nonresponsive patients with advanced HCC identified SLAMF7 upregulation in immunotherapy-responsive HCC, and patients with HCC who responded to immunotherapy also displayed higher serum levels of SLAMF7. Loss of Slamf7 in liver-specific knockout mice led to increased hepatocarcinogenesis and metastasis, elevated immunosuppressive macrophage infiltration, and upregulated PD-1 expression in CD8+ T cells. HCC cell-intrinsic SLAMF7 suppressed MAPK/ATF2-mediated CCL2 expression to regulate macrophage migration and polarization in vitro. Mechanistically, SLAMF7 associated with SH2 domain-containing adaptor protein B (SHB) through its cytoplasmic 304 tyrosine site to facilitate the recruitment of SHIP1 to SLAMF7 and inhibit the ubiquitination of TRAF6, thereby attenuating MAPK pathway activation and CCL2 transcription. Pharmacological antagonism of the CCL2/CCR2 axis potentiated the therapeutic effect of anti-PD-1 antibody in orthotopic HCC mouse models with low SLAMF7 expression. In conclusion, this study highlights SLAMF7 as a regulator of macrophage function and a potential predictive biomarker of immunotherapy response in HCC. Strategies targeting CCL2 signaling to induce macrophage repolarization in HCC with low SLAMF7 might enhance the efficacy of immunotherapy.
Future direction of total neoadjuvant therapy for locally advanced rectal cancer
Authors: Yoshinori Kagawa, J. Joshua Smith, Emmanouil Fokas, Jun Watanabe, Andrea Cercek, Florian R. Greten, Hideaki Bando, Qian Shi, Julio Garcia-Aguilar, Paul B. Romesser, Natally Horvat, Hanna Sanoff, William Hall, Takeshi Kato, Claus Rödel, Arvind Dasari, Takayuki Yoshino
Journal: Nature Reviews Gastroenterology & Hepatology (2024)
Single-cell sequencing shows mosaic aneuploidy in most human embryos
Authors: Sarah A Robertson, Robert I Richards
Journal: Journal of Clinical Investigation (2024)

Mammalian preimplantation embryos often contain chromosomal defects that arose in the first divisions after fertilization and affect a subpopulation of cells - an event known as mosaic aneuploidy. In this issue of the JCI, Chavli et al. report single-cell genomic sequencing data for rigorous evaluation of the incidence and degree of mosaic aneuploidy in healthy human in vitro fertilization (IVF) embryos. Remarkably, mosaic aneuploidy occurred in at least 80% of human blastocyst-stage embryos, with often less than 20% of cells showing defects. These findings confirm that mosaic aneuploidy is prevalent in human embryos, indicating that the process is a widespread event that rarely has clinical consequences. There are major implications for preimplantation genetic testing of aneuploidy (PGT-A), a test commonly used to screen and select IVF embryos for transfer. The application and benefit of this technology is controversial, and the findings provide more cause for caution on its use.
Cytoplasmic retention of the DNA/RNA-binding protein FUS ameliorates organ fibrosis in mice
Authors: Manuel Chiusa, Youngmin A Lee, Ming-Zhi Zhang, Raymond C Harris, Taylor Sherrill, Volkhard Lindner, Craig R Brooks, Gang Yu, Agnes B Fogo, Charles R Flynn, Jozef Zienkiewicz, Jacek Hawiger, Roy Zent, Ambra Pozzi
Journal: Journal of Clinical Investigation (2024)

Uncontrolled accumulation of extracellular matrix leads to tissue fibrosis and loss of organ function. We previously demonstrated in vitro that the DNA/RNA-binding protein fused in sarcoma (FUS) promotes fibrotic responses by translocating to the nucleus, where it initiates collagen gene transcription. However, it is still not known whether FUS is profibrotic in vivo and whether preventing its nuclear translocation might inhibit development of fibrosis following injury. We now demonstrate that levels of nuclear FUS are significantly increased in mouse models of kidney and liver fibrosis. To evaluate the direct role of FUS nuclear translocation in fibrosis, we used mice that carry a mutation in the FUS nuclear localization sequence (FUSR521G) and the cell-penetrating peptide CP-FUS-NLS that we previously showed inhibits FUS nuclear translocation in vitro. We provide evidence that FUSR521G mice or CP-FUS-NLS-treated mice showed reduced nuclear FUS and fibrosis following injury. Finally, differential gene expression analysis and immunohistochemistry of tissues from individuals with focal segmental glomerulosclerosis or nonalcoholic steatohepatitis revealed significant upregulation of FUS and/or collagen genes and FUS protein nuclear localization in diseased organs. These results demonstrate that injury-induced nuclear translocation of FUS contributes to fibrosis and highlight CP-FUS-NLS as a promising therapeutic option for organ fibrosis.
25 year trends in cancer incidence and mortality among adults aged 35-69 years in the UK, 1993-2018: retrospective secondary analysis
Authors: Jon Shelton, Ewa Zotow, Lesley Smith, Shane A Johnson, Catherine S Thomson, Amar Ahmad, Lars Murdock, Diana Nagarwalla, David Forman
Journal: BMJ (2024)

Abstract Objective To examine and interpret trends in UK cancer incidence and mortality for all cancers combined and for the most common cancer sites in adults aged 35-69 years. Design Retrospective secondary data analysis. Data sources Cancer registration data, cancer mortality and national population data from the Office for National Statistics, Public Health Wales, Public Health Scotland, Northern Ireland Cancer Registry, NHS England, and the General Register Office for Northern Ireland. Setting 23 cancer sites were included in the analysis in the UK. Participants Men and women aged 35-69 years diagnosed with or who died from cancer between 1993 to 2018. Main outcome measures Change in cancer incidence and mortality age standardised rates over time. Results The number of cancer cases in this age range rose by 57% for men (from 55 014 cases registered in 1993 to 86 297 in 2018) and by 48% for women (60 187 to 88 970) with age standardised rates showing average annual increases of 0.8% in both sexes. The increase in incidence was predominantly driven by increases in prostate (male) and breast (female) cancers. Without these two sites, all cancer trends in age standardised incidence rates were relatively stable. Trends for a small number of less common cancers showed concerning increases in incidence rates, for example, in melanoma skin, liver, oral, and kidney cancers. The number of cancer deaths decreased over the 25 year period, by 20% in men (from 32 878 to 26 322) and 17% in women (28 516 to 23 719); age standardised mortality rates reduced for all cancers combined by 37% in men (−2.0% per year) and 33% in women (−1.6% per year). The largest decreases in mortality were noted for stomach, mesothelioma, and bladder cancers in men and stomach and cervical cancers and non-Hodgkin lymphoma in women. Most incidence and mortality changes were statistically significant even when the size of change was relatively small. Conclusions Cancer mortality had a substantial reduction during the past 25 years in both men and women aged 35-69 years. This decline is likely a reflection of the successes in cancer prevention (eg, smoking prevention policies and cessation programmes), earlier detection (eg, screening programmes) and improved diagnostic tests, and more effective treatment. By contrast, increased prevalence of non-smoking risk factors are the likely cause of the observed increased incidence for a small number of specific cancers. This analysis also provides a benchmark for the following decade, which will include the impact of covid-19 on cancer incidence and outcomes.
Toward the Improvement of the Mechanical and Tribological Properties of Braided Ligament for ACL Reconstruction: A “Carrot and Stick” Strategy
Authors: Shenglin Li, Shuhan Wang, Jiasheng Shao, Jiali Wang, Wenliang Liu, Linxin Chen, Zeng Li, Chao Zhang, Jian Song
Journal: Advanced Healthcare Materials (2024)

Abstract Bone tunnel enlargement has been troubling the clinical adoption of braided artificial ligaments for decades, to which mechanical and tribological performance promotion shall be an effective and promising approach. Herein, a “carrot and stick” strategy has been introduced with two types of polyethylene terephthalate (PET) fibers to fabricate hybrid textures, which is expected to advance fatigue and tribological performance without yielding essential mechanical strength and biocompatibility. Owing to advancements in such a “carrot and stick” strategy, the obtained grafts present three promising properties: i) enhancement of mechanical strength; ii) coefficient of friction (COF) reduction of 25% at the greatest extent, thus lowering the risk of bone tunnel enlargement; iii) final displacement shrinkage of graft length after cyclic loadings, favored in the clinic for isometric reconstruction. The results obtained in this study show that the “carrot and stick” strategy can be a creative and convenient method to optimize the service life, saving the complication rate of artificial ligaments for clinical applications.
Cost-effectiveness of intervention combinations towards the elimination of vertical transmission of HIV in limited-resource settings: a mathematical modelling study
Authors: Joshua M Chevalier, Megan A Hansen, Elif Coskun, Karla Therese L Sy, Janeen Drakes, Stephanie Dowling, Amanda Williams, Sarah Jenkins, Carolyn Amole, Prudence Haimbe, Felton Mpasela, Hilda Shakwelele, Brooke E Nichols
Journal: The Lancet Global Health (2024)

Since 2000, there has been a substantial global reduction in the vertical transmission of HIV. Despite effective interventions, gaps still remain in progress towards elimination in many low-income and middle-income countries. We developed a mathematical model to determine the most cost-effective combinations of interventions to prevent vertical transmission.
Eating disorders and obesity: bridging clinical, neurobiological, and therapeutic perspectives
Authors: Lucia Camacho-Barcia, Katrin Elisabeth Giel, Susana Jiménez-Murcia, Julio Álvarez Pitti, Nadia Micali, Ignacio Lucas, Romina Miranda-Olivos, Lucero Munguia, Manuel Tena-Sempere, Stephan Zipfel, Fernando Fernández-Aranda
Journal: Trends in Molecular Medicine (2024)

Eating disorders (EDs) and obesity are complex health conditions sharing various risk and maintenance factors, intensified in cases of comorbidity. This review explores the similarities and connections between these conditions, examining different facets from a multidisciplinary perspective, among them comorbidities, metabolic and psychological factors, neurobiological aspects, and management and therapy implications. We aim to investigate the common characteristics and complexities of weight and EDs and explore their interrelationships in individuals who experience both. The rising prevalence of EDs in people with obesity necessitates integrated approaches to study this comorbidity and to identify and analyze both common and distinct features of these conditions. This review may offer new opportunities for simultaneous prevention and management approaches, as well as future lines of research.
Efficacy, safety, and biomarker analyses of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with advanced non-small cell lung cancer
Authors: Arun Rajan, Houssein Abdul Sater, Osama Rahma, Richy Agajanian, Wiem Lassoued, Jennifer L Marté, Yo-Ting Tsai, Renee N Donahue, Elizabeth Lamping, Shania Bailey, Andrew Weisman, Beatriz Walter-Rodriguez, Rena Ito, Yulia Vugmeyster, Masashi Sato, Andreas Machl, Jeffrey Schlom, James L Gulley
Journal: Journal for ImmunoTherapy of Cancer (2024)

Bintrafusp alfa, a first-in-class bifunctional fusion protein targeting transforming growth factor-β (TGF-β) and programmed cell death ligand 1, has demonstrated encouraging efficacy as second-line treatment in patients with non-small cell lung cancer (NSCLC) in a dose expansion cohort of the phase 1, open-label clinical trial (NCT02517398). Here, we report the safety, efficacy, and biomarker analysis of bintrafusp alfa in a second expansion cohort of the same trial (biomarker cohort). Patients with stage IIIb/IV NSCLC who were either immune checkpoint inhibitor (ICI)-naïve (n=18) or ICI-experienced (n=23) were enrolled. The primary endpoint was the best overall response. Paired biopsies (n=9/41) and peripheral blood (n=14/41) pretreatment and on-treatment were studied to determine the immunological effects of treatment and for associations with clinical activity. Per independent review committee assessment, objective responses were observed in the ICI-naïve group (overall response rate, 27.8%). No new or unexpected safety signals were identified. Circulating TGF-β levels were reduced (>97%; p<0.001) 2 weeks after initiation of treatment with bintrafusp alfa and remained reduced up to 12 weeks. Increases in lymphocytes and tumor-associated macrophages (TAMs) were observed in on-treatment biospies, with an increase in the M2 (tumor trophic TAMs)/M1 (inflammatory TAMs) ratio associated with poor outcomes. Specific peripheral immune analytes at baseline and early changes after treatment were associated with clinical response. Bintrafusp alfa was observed to have modest clinical activity and manageable safety, and was associated with notable immunologic changes involving modulation of the tumor immune microenvironment in patients with advanced NSCLC.
Biomarkers for response to TIL therapy: a comprehensive review
Authors: Víctor Albarrán Fernández, Pablo Ballestín Martínez, Joachim Stoltenborg Granhøj, Troels Holz Borch, Marco Donia, Inge Marie Svane
Journal: Journal for ImmunoTherapy of Cancer (2024)

Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) has demonstrated durable clinical responses in patients with metastatic melanoma, substantiated by recent positive results of the first phase III trial on TIL therapy. Being a demanding and logistically complex treatment, extensive preclinical and clinical effort is required to optimize patient selection by identifying predictive biomarkers of response. This review aims to comprehensively summarize the current evidence regarding the potential impact of tumor-related factors (such as mutational burden, neoantigen load, immune infiltration, status of oncogenic driver genes, and epigenetic modifications), patient characteristics (including disease burden and location, baseline cytokines and lactate dehydrogenase serum levels, human leucocyte antigen haplotype, or prior exposure to immune checkpoint inhibitors and other anticancer therapies), phenotypic features of the transferred T cells (mainly the total cell count, CD8:CD4 ratio, ex vivo culture time, expression of exhaustion markers, costimulatory signals, antitumor reactivity, and scope of target tumor-associated antigens), and other treatment-related factors (such as lymphodepleting chemotherapy and postinfusion administration of interleukin-2).