tbuckley/cabot-search huggingface dataset:
Chemical screen identifies shikonin as a broad DNA damage response inhibitor that enhances chemotherapy through inhibiting ATM and ATR
Authors: Fangfang Wang, Sora Jin, Franklin Mayca Pozo, Danmei Tian, Xiyang Tang, Yi Dai, Xinsheng Yao, Jinshan Tang, Youwei Zhang
Journal: Acta Pharmaceutica Sinica B (2021)

DNA damage response (DDR) is a highly conserved genome surveillance mechanism that preserves cell viability in the presence of chemotherapeutic drugs. Hence, small molecules that inhibit DDR are expected to enhance the anti-cancer effect of chemotherapy. Through a recent chemical library screen, we identified shikonin as an inhibitor that strongly suppressed DDR activated by various chemotherapeutic drugs in cancer cell lines derived from different origins. Mechanistically, shikonin inhibited the activation of ataxia telangiectasia mutated (ATM), and to a lesser degree ATM and RAD3-related (ATR), two master upstream regulators of the DDR signal, through inducing degradation of ATM and ATR-interacting protein (ATRIP), an obligate associating protein of ATR, respectively. As a result of DDR inhibition, shikonin enhanced the anti-cancer effect of chemotherapeutic drugs in both cell cultures and in mouse models. While degradation of ATRIP is proteasome dependent, that of ATM depends on caspase- and lysosome-, but not proteasome. Overexpression of ATM significantly mitigated DDR inhibition and cell death induced by shikonin and chemotherapeutic drugs. These novel findings reveal shikonin as a pan DDR inhibitor and identify ATM as a primary factor in determining the chemo sensitizing effect of shikonin. Our data may facilitate the development of shikonin and its derivatives as potential chemotherapy sensitizers through inducing ATM degradation.
Circular RNAs: characteristics, biogenesis, mechanisms and functions in liver cancer
Authors: Hao Shen, Boqiang Liu, Junjie Xu, Bin Zhang, Yifan Wang, Liang Shi, Xiujun Cai
Journal: Journal of Hematology & Oncology (2021)

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common malignancies globally. Despite aggressive and multimodal treatment regimens, the overall survival of HCC patients remains poor. Main Circular RNAs (circRNAs) are noncoding RNAs (ncRNAs) with covalently closed structures and tissue- or organ-specific expression patterns in eukaryotes. They are highly stable and have important biological functions, including acting as microRNA sponges, protein scaffolds, transcription regulators, translation templates and interacting with RNA-binding protein. Recent advances have indicated that circRNAs present abnormal expression in HCC tissues and that their dysregulation contributes to HCC initiation and progression. Furthermore, researchers have revealed that some circRNAs might serve as diagnostic biomarkers or drug targets in clinical settings. In this review, we systematically evaluate the characteristics, biogenesis, mechanisms and functions of circRNAs in HCC and further discuss the current shortcomings and potential directions of prospective studies on liver cancer-related circRNAs. Conclusion CircRNAs are a novel class of ncRNAs that play a significant role in HCC initiation and progression, but their internal mechanisms and clinical applications need further investigation.
Epidermolysis Bullosa Pruriginosa Treated With Baricitinib
Authors: Xingyuan Jiang, Huijun Wang, Mingyang Lee, Zhimiao Lin
Journal: JAMA Dermatology (2021)

This case report describes a 40-year-old man who had blistering and trauma-induced erosions shortly after birth and nodular prurigo-like lesions during his teenage years who presented with erythematous lichenified papules and nodules with crusts and milia over the scalp, trunk, and extremities.
19F-nanoparticles: Platform for in vivo delivery of fluorinated biomaterials for 19F-MRI
Authors: Alvja Mali, Eric L. Kaijzel, Hildo J. Lamb, Luis J. Cruz
Journal: Journal of Controlled Release (2021)

Fluorine-19 (19F) magnetic resonance imaging (MRI) features one of the most investigated and innovative techniques for quantitative and unambiguous cell tracking, providing information for both localization and number of cells. Because of the relative insensitivity of the MRI technique, a high number of magnetically equivalent fluorine atoms are required to gain detectable signals. However, an increased amount of 19F nuclei induces low solubility in aqueous solutions, making fluorine-based probes not suitable for in vivo imaging applications. In this context, nanoparticle-based platforms play a crucial role, since nanoparticles may carry a high payload of 19F-based contrast agents into the relevant cells or tissues, increase the imaging agents biocompatibility, and provide a highly versatile platform. In this review, we present an overview of the 19F-based nanoprobes for sensitive 19F-MRI, focusing on the main nanotechnologies employed to date, such as fluorine and theranostic nanovectors, including their design and applications.
Associations of the gut microbiome with hepatic adiposity in the Multiethnic Cohort Adiposity Phenotype Study
Authors: Meredith A. J. Hullar, Isaac C. Jenkins, Timothy W. Randolph, Keith R. Curtis, Kristine R. Monroe, Thomas Ernst, John A. Shepherd, Daniel O. Stram, Iona Cheng, Bruce S. Kristal, Lynne R. Wilkens, Adrian Franke, Loic Le Marchand, Unhee Lim, Johanna W. Lampe
Journal: Gut Microbes (2021)

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for liver cancer and prevalence varies by ethnicity. Along with genetic and lifestyle factors, the gut microbiome (GM) may contribute to NAFLD and its progression to advanced liver disease. Our cross-sectional analysis assessed the association of the GM with hepatic adiposity among African American, Japanese American, White, Latino, and Native Hawaiian participants in the Multiethnic Cohort. We used MRI to measure liver fat and determine nonalcoholic fatty liver disease (NAFLD) status (n = 511 cases) in 1,544 participants, aged 60–77 years, with 12–53% overall adiposity (BMI of 17.8–46.2 kg/m2). The GM was measured by 16S rRNA gene sequencing and, on a subset, by metagenomic sequencing. Alpha diversity was lower overall with NAFLD and in certain ethnicities (African Americans, Whites, and Latinos). In models regressing genus on NAFLD status, 62 of 149 genera (40%) exhibited a significant interaction between NAFLD and ethnicity stratified analysis found 69 genera significantly associated with NAFLD in at least one ethnic group. No single genus was significantly associated with NAFLD across all ethnicities. In contrast, the same bacterial metabolic pathways were over-represented in participants with NAFLD regardless of ethnicity. Imputed secondary bile acid and carbohydrate pathways were associated with NAFLD, the latter of which was corroborated by metagenomics, although different genera in different ethnicities were associated with these pathways. Overall, we found that NAFLD was associated with altered bacterial composition and metabolism, and that bacterial endotoxin, assessed by plasma lipopolysaccharide binding protein (LBP), may mediate liver fat-associated systemic inflammation in a manner that seems to vary by ethnicity.
Targeting Sirtuin1 to treat aging-related tissue fibrosis: From prevention to therapy
Authors: Xin Han, Chuan Ding, XiaNan Sang, MengYun Peng, Qiao Yang, Yan Ning, Qiang Lv, QiYuan Shan, Min Hao, KuiLong Wang, Xin Wu, Hongyan Zhang, Gang Cao
Journal: Pharmacology & Therapeutics (2021)
Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease
Authors: Gengfeng Li, Jian Lin, Cui Zhang, Han Gao, Huiying Lu, Xiang Gao, Ruixin Zhu, Zhitao Li, Mingsong Li, Zhanju Liu
Journal: Gut Microbes (2021)

Host-microbial cross-talk plays a crucial role in maintenance of gut homeostasis. However, how microbiota-derived metabolites, e.g., butyrate, regulate functions of neutrophils in the pathogenesis of inflammatory bowel disease (IBD) remains elusive. We sought to investigate the effects of butyrate on IBD neutrophils and elucidate the therapeutic potential in regulating mucosal inflammation. Peripheral neutrophils were isolated from IBD patients and healthy donors, and profiles of proinflammatory cytokines and chemokines were determined by qRT-PCR and ELISA, respectively. The migration and release of neutrophil extracellular traps (NETs) were studied by a Transwell model and immunofluorescence, respectively. The in vivo role of butyrate in regulating IBD neutrophils was evaluated in a DSS-induced colitis model in mice. We found that butyrate significantly inhibited IBD neutrophils to produce proinflammatory cytokines, chemokines, and calprotectins. Blockade of GPCR signaling with pertussis toxin (PTX) did not interfere the effects whereas pan-histone deacetylase (HDAC) inhibitor, trichostatin A (TSA) effectively mimicked the role of butyrate. Furthermore, in vitro studies confirmed that butyrate suppressed neutrophil migration and formation of NETs from both CD and UC patients. RNA sequencing analysis revealed that the immunomodulatory effects of butyrate on IBD neutrophils were involved in leukocyte activation, regulation of innate immune response and response to oxidative stress. Consistently, oral administration of butyrate markedly ameliorated mucosal inflammation in DSS-induced murine colitis through inhibition of neutrophil-associated immune responses such as proinflammatory mediators and NET formation. Our data thus reveal that butyrate constrains neutrophil functions and may serve as a novel therapeutic potential in the treatment of IBD.
An automated near-real time computational method for induction and treatment of scar-related ventricular tachycardias
Authors: Fernando O. Campos, Aurel Neic, Caroline Mendonca Costa, John Whitaker, Mark O’Neill, Reza Razavi, Christopher A. Rinaldi, None DanielScherr, Steven A. Niederer, Gernot Plank, Martin J. Bishop
Journal: Medical Image Analysis (2022)

Catheter ablation is currently the only curative treatment for scar-related ventricular tachycardias (VTs). However, not only are ablation procedures long, with relatively high risk, but success rates are punitively low, with frequent VT recurrence. Personalized in-silico approaches have the opportunity to address these limitations. However, state-of-the-art reaction diffusion (R-D) simulations of VT induction and subsequent circuits used for in-silico ablation target identification require long execution times, along with vast computational resources, which are incompatible with the clinical workflow. Here, we present the Virtual Induction and Treatment of Arrhythmias (VITA), a novel, rapid and fully automated computational approach that uses reaction-Eikonal methodology to induce VT and identify subsequent ablation targets. The rationale for VITA is based on finding isosurfaces associated with an activation wavefront that splits in the ventricles due to the presence of an isolated isthmus of conduction within the scar; once identified, each isthmus may be assessed for their vulnerability to sustain a reentrant circuit, and the corresponding exit site automatically identified for potential ablation targeting. VITA was tested on a virtual cohort of 7 post-infarcted porcine hearts and the results compared to R-D simulations. Using only a standard desktop machine, VITA could detect all scar-related VTs, simulating activation time maps and ECGs (for clinical comparison) as well as computing ablation targets in 48 minutes. The comparable VTs probed by the R-D simulations took 68.5 hours on 256 cores of high-performance computing infrastructure. The set of lesions computed by VITA was shown to render the ventricular model VT-free. VITA could be used in near real-time as a complementary modality aiding in clinical decision-making in the treatment of post-infarction VTs.
Deimplementing Continuous Pulse Oximetry in Patients With Bronchiolitis—What Are We Waiting For?
Authors: Shawn L. Ralston, Samantha A. House
Journal: JAMA Network Open (2021)

Amanda C. Schondelmeyer, MD, MSc; Amanda P. Bettencourt, PhD, APRN; Rui Xiao, PhD; Rinad S. Beidas, PhD; Courtney Benjamin Wolk, PhD; Christopher P. Landrigan, MD, MPH; Patrick W. Brady, MD, MSc; Canita R. Brent, MPH; Padmavathy Parthasarathy, MD; Andrew S. Kern-Goldberger, MD; Nathaniel Sergay, MD; Vivian Lee, MD; Christopher J. Russell, MD, MS; Julianne Prasto, MD; Sarah Zaman, MD; Kaitlyn McQuistion, MD; Kate Lucey, MD, MS; Courtney Solomon, MD; Mayra Garcia, DNP, RN, PCNS-BC; Christopher P. Bonafide, MD, MSCE; Pediatric Research in Inpatient Settings (PRIS) Network; Kyle A Lamphier; Maria Santos; Susan Wu; Phillip A Abarca; Amir Hassan; Sabrina Sedano; Jennifer R. Moore; Joshua Frankland; Kristin Van Genderen; M. Katherine Stone; Michael Spewak; Victoria Rodriguez; Waheeda Samady; Amera Al-Ali; Huong Mai; Laura El-Hage; Stan Oliveira; Jessica Hart; Laura Goldstein; Muida Menon
Early warning disease surveillance after a flood emergency - Pakistan, 2010.
Authors: G. Sabatinelli, S. R. Kakar, M. R. Khan, M. Malik, B. M. Kazi, J. K. Aurakzai, M. Gayer, F. Husain, M. Brennan, O. Bilukha, I. Shaikh, S. Cookson, C. Shahpar
Journal: MMWR Morbidity and Mortality Weekly Report (2012)
Novel potent anti-STEAP1 bispecific antibody to redirect T cells for cancer immunotherapy
Authors: Tsung-Yi Lin, Jeong A Park, Alan Long, Hong-Fen Guo, Nai-Kong V Cheung
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background The prognosis for metastatic Ewing sarcoma family of tumors (EFT) is still poor despite high-dose chemotherapy and radiation treatment. Immunotherapies hold promise, but cancer antigen-targeting immunotherapies have largely failed to induce effective T cell receptor-mediated antitumor response. However, T cell-engaging bispecific antibodies (T-BsAbs) have yet to be adequately explored. Methods Rehumanized STEAP1-IgG was used to build T-BsAb (named BC261) using the 2+2 IgG-[L]-scFv platform carrying the anti-CD3 huOKT3 scFv as the second specificity. Its binding epitope mapping, species cross-reactivity, tumor cell line staining, and in vitro cytotoxicity were investigated thoroughly. Its potency in driving tumor-infiltrating lymphocytes (TILs) was quantified using bioluminescence, correlated with in vivo antitumor response against cell line-derived or patient-derived xenografts (CDXs or PDXs) and compared with anti-STEAP1 T-BsAbs built on representative antibody platforms. Results BC261 binding epitope was mapped to its second extracellular domain of STEAP1 shared among canine and primate orthologs. BC261 induced potent cytotoxicity against panels of EFT, prostate cancer, and canine osteosarcoma cell lines despite their low antigen density. BC261 drove significantly more TILs into tumors (30-fold) and exerted superior antitumor effects compared with the other standard BsAb platforms. The antitumor efficacy of BC261 was consistent against EFT and prostate cancer CDXs and PDXs. Conclusions BC261 was highly efficient in driving T cell infiltration and tumor ablation. Either as stand-alone therapeutics or for ex vivo armed T cells, this novel anti-STEAP1 T-BsAb BC261 has therapeutic potential.
Molecular trafficking between bacteria determines the shape of gut microbial community
Authors: Seenivasan Boopathi, Danrui Liu, Ai-Qun Jia
Journal: Gut Microbes (2021)

Complex inter-bacterial interactions largely influence the structure and function of the gut microbial community. Though several host-associated phenomena have often been shown to be involved in the stability, structure, and function of the gut microbial community, the implication of contact-dependent and contact-independent inter-bacterial interactions has been overlooked. Such interactions are tightly governed at multiple layers through several extracellular organelles, including contact-dependent inhibition (CDI), nanotubes, type VI secretion system (T6SS), and membrane vesicles (MVs). Recent advancements in molecular techniques have revealed that such extracellular organelles function beyond exhibiting competitive behavior and are also involved in manifesting cooperative behaviors. Cooperation between bacteria occurs through the sharing of several beneficial molecules including nucleic acids, proteins, metabolites, and nutrients among the members of the community, while competition occurs by means of multiple toxins. Intrinsic coordination between contact-dependent and contact-independent mechanisms collectively provides a fitness advantage and increased colonization resistance to the gut microbiota, where molecular trafficking plays a key role. This review is intended to provide a comprehensive view of the salient features of the different bacterial interactions and to highlight how microbiota deploy multifaceted organelles, for exerting both cooperative and competitive behaviors. We discuss the current knowledge of bacterial molecular trafficking and its impact on shaping the gut microbial community.
PLX3397, a CSF1 receptor inhibitor, limits allotransplantation-induced vascular remodelling
Authors: Vanessa M Almonte, Unimunkh Uriyanghai, Lander Egaña-Gorroño, Dippal Parikh, Gustavo H Oliveira-Paula, Jinghang Zhang, Smitha Jayakumar, Dario F Riascos-Bernal, Nicholas E S Sibinga
Journal: Cardiovascular Research (2021)

Abstract Aims Graft vascular disease (GVD), a clinically important and highly complex vascular occlusive disease, arises from the interplay of multiple cellular and molecular pathways. While occlusive intimal lesions are composed predominantly of smooth-muscle-like cells (SMLCs), the origin of these cells and the stimuli leading to their accumulation in GVD are uncertain. Macrophages have recently been identified as both potential drivers of intimal hyperplasia and precursors that undergo transdifferentiation to become SMLCs in non-transplant settings. Colony-stimulating factor-1 (CSF1) is a well-known regulator of macrophage development and differentiation, and prior preclinical studies have shown that lack of CSF1 limits GVD. We sought to identify the origins of SMLCs and of cells expressing the CSF1 receptor (CSF1R) in GVD, and to test the hypothesis that pharmacologic inhibition of CSF1 signalling would curtail both macrophage and SMLC activities and decrease vascular occlusion. Methods and results We used genetically modified mice and a vascular transplant model with minor antigen mismatch to assess cell origins. We found that neointimal SMLCs derive from both donor and recipient, and that transdifferentiation of macrophages to SMLC phenotype is minimal in this model. Cells expressing CSF1R in grafts were identified as recipient-derived myeloid cells of Cx3cr1 lineage, and these cells rarely expressed smooth muscle marker proteins. Blockade of CSF1R activity using the tyrosine kinase inhibitor PLX3397 limited the expression of genes associated with innate immunity and decreased levels of circulating monocytes and intimal macrophages. Importantly, PLX3397 attenuated the development of GVD in arterial allografts. Conclusion These studies provide proof of concept for pharmacologic inhibition of the CSF1/CSF1R signalling pathway as a therapeutic strategy in GVD. Further preclinical testing of this pathway in GVD is warranted.
National, Regional, State, and Selected Local Area Vaccination Coverage Among Adolescents Aged 13–17 Years — United States, 2020
Authors: Cassandra Pingali, David Yankey, Laurie D. Elam-Evans, Lauri E. Markowitz, Charnetta L. Williams, Benjamin Fredua, Lucy A. McNamara, Shannon Stokley, James A. Singleton
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

The Advisory Committee on Immunization Practices (ACIP) recommends that adolescents aged 11-12 years routinely receive tetanus, diphtheria, and acellular pertussis (Tdap); meningococcal conjugate (MenACWY); and human papillomavirus (HPV) vaccines.Catch-up vaccination is recommended for hepatitis B (HepB); hepatitis A (HepA); measles, mumps, and rubella (MMR); and varicella (VAR) vaccines for adolescents whose childhood vaccinations are not current.Adolescents are also recommended to receive a booster dose of MenACWY vaccine at age 16 years, and shared clinical decision-making is recommended for the serogroup B meningococcal vaccine (MenB) for persons aged 16-23 years (1).To estimate coverage with recommended vaccines, CDC analyzed data from the 2020 National Immunization Survey-Teen (NIS-Teen) for 20,163 adolescents aged 13-17 years.*Coverage with ≥1 dose of HPV vaccine increased from 71.5% in 2019 to 75.1% in 2020.The percentage of adolescents * Eligible participants were born during January 2002-January 2008.Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine represents coverage with ≥1 Tdap dose at age ≥10 years.Meningococcal conjugate vaccine represents coverage with the quadrivalent meningococcal conjugate vaccine or meningococcal-unknown type vaccine.HPV vaccination coverage includes receipt of any HPV vaccine and does not distinguish between nine-valent (9vHPV), quadrivalent (4vHPV), or bivalent (2vHPV) vaccines.Some adolescents might have received more than the 2 or 3 recommended HPV vaccine doses.Hepatitis A, hepatitis B, varicella, and measles, mumps, and rubella vaccines are considered childhood vaccinations and are recommended for adolescents who are not up to date with these vaccinations.Estimates in this report include those who might have received vaccinations on-time or as catch-up.Except as noted, coverage estimates for ≥1 and ≥2 varicella vaccine doses were obtained among adolescents with no history of varicella disease.Influenza vaccination coverage data are not included in this report but are available at https://www.cdc.gov/flu/fluvaxview/index.htm.
Antimicrobial peptides in hidradenitis suppurativa: a systematic review*
Authors: Y. Yao, J.W. Frew, S.F. Thomsen, H.C. Ring
Journal: British Journal of Dermatology (2021)

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease of the hair follicle defined by recurrent nodules, tunnels and scarring involving the intertriginous regions. HS is associated with microbial dysbiosis and immune dysregulation. In HS, an increasing number of studies have investigated antimicrobial peptides (AMPs).To provide an overview of the literature on AMPs in HS, and to discuss the potential role of AMPs in the pathogenesis of HS.PubMed, Embase and the Cochrane Library were searched. The titles, abstracts and full texts of all articles were manually screened. Additionally, the reference lists of the included articles were screened and hand searched for relevant studies.The final literature sample comprised 18 retrospective and prospective studies (no reviews or commentaries) published between 2009 and 2020.This review demonstrates the multitude of AMPs in HS. Although the methodology of the studies varied, the included studies indicate a consistent overexpression of human β-defensin (hBD)-2, S100A7, S100A8 and S100A9 at both the mRNA and protein levels, and a decreased expression of hBD-1. Overall, the studies point to a dysregulation of AMPs in both lesional and nonlesional HS skin.
How routine NHS diabetes care can catch up after covid-19
Authors: Emma Wilkinson
Journal: BMJ (2021)

How routine NHS diabetes care can catch up after covid-19Progress may have slipped, but general practices are finding innovative ways to catch up.Emma Wilkinson reports on calls for more guidance on new drugs and more remote monitoring to support self-management Emma Wilkinson freelance journalist"There will be a need for diabetes management to catch up," as progress made before the pandemic will have slipped, says Partha Kar, NHS England's national specialty adviser for diabetes and a consultant at Portsmouth Hospitals NHS Trust."There will be a lot of people who have not had checks for two years," he tells The BMJ, adding that primary care has been under huge pressure during the pandemic and is now at the forefront of the vaccine programme.About 90% of patients with diabetes have type 2-about 3.4 million people in England-and are managed in primary care.